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back to  Polyunsaturated Fatty Acids (PUFAs)

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PUFAs Review References
(405 References: 2000-2004)

O'Keefe, J. H., Jr. and L. Cordain (2004). "Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer." Mayo Clin Proc 79(1): 101-8.

            Our genetic make-up, shaped through millions of years of evolution, determines our nutritional and activity needs. Although the human genome has remained primarily unchanged since the agricultural revolution 10,000 years ago, our diet and lifestyle have become progressively more divergent from those of our ancient ancestors. Accumulating evidence suggests that this mismatch between our modern diet and lifestyle and our Paleolithic genome is playing a substantial role in the ongoing epidemics of obesity, hypertension, diabetes, and atherosclerotic cardiovascular disease. Until 500 generations ago, all humans consumed only wild and unprocessed food foraged and hunted from their environment. These circumstances provided a diet high in lean protein, polyunsaturated fats (especially omega-3 [omega-3] fatty acids), monounsaturated fats, fiber, vitamins, minerals, antioxidants, and other beneficial phytochemicals. Historical and anthropological studies show hunter-gatherers generally to be healthy, fit, and largely free of the degenerative cardiovascular diseases common in modern societies. This review outlines the essence of our hunter-gatherer genetic legacy and suggests practical steps to re-align our modern milieu with our ancient genome in an effort to improve cardiovascular health.


Zolfaghari, R. and A. C. Ross (2003). "Recent advances in molecular cloning of fatty acid desaturase genes and the regulation of their expression by dietary vitamin A and retinoic acid." Prostaglandins Leukot Essent Fatty Acids 68(2): 171-9.

            Vitamin A, as an essential micronutrient, is involved in higher animals in embryonic development and postnatal growth, reproduction and maintenance of normal skin, immunity and vision. Recently, studies in vivo and in cell lines have shown that vitamin A and its active metabolite, retinoic acid, regulate the expression of fatty acid desaturases including stearoyl-CoA desaturase and delta-5 desaturase. Whereas the former desaturase catalyzes the formation of monounsaturated from saturated fatty acids, the latter enzyme is involved in the desaturation pathway of dietary essential fatty acids for production of polyunsaturated fatty acids. The reaction products of these desaturases serve as critical regulators in a wide range of physiological processes which include fetal growth and development, reproduction, cell differentiation, immune and inflammatory responses.


Wood, L. G., D. A. Fitzgerald, et al. (2003). "Hypothesis: vitamin E complements polyunsaturated fatty acids in essential fatty acid deficiency in cystic fibrosis." J Am Coll Nutr 22(4): 253-7.

            While several studies have demonstrated essential fatty acid (EFA) deficiency in plasma and tissue lipids of cystic fibrosis (CF) patients, the reasons for this deficiency are not well established. It is believed that reduced EFA intake, malabsorption of fat, altered desaturase/lipase activity and defective cystic fibrosis transmembrane conductance regulator (CFTR) altering utilisation of EFA in epithelial cells contribute to the development of EFA deficiency in CF. It is likely that increased metabolism of arachidonic acid to eicosanoids such as leukotrienes, thromboxane and prostaglandins may also be a contributing factor. Evidence is presented that elevated oxidative damage to EFA and impaired antioxidant defences, in particular vitamin E, may contribute to the development of EFA deficiency in CF. Furthermore, antioxidant supplementation in CF may improve EFA status.


Wen, Z. Y. and F. Chen (2003). "Heterotrophic production of eicosapentaenoic acid by microalgae." Biotechnol Adv 21(4): 273-94.

            Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid that plays an important role in the regulation of biological functions and prevention and treatment of a number of human diseases such as heart and inflammatory diseases. As fish oil fails to meet the increasing demand for purified EPA, alternative sources are being sought. Microalgae contain large quantities of high-quality EPA and they are considered a potential source of this important fatty acid. Some microalgae can be grown heterotrophically on cheap organic substrate without light. This mode of cultivation can be well controlled and provides the possibility to maximize EPA production on a large scale. Numerous strategies have been investigated for commercial production of EPA by microalgae. These include screening of high EPA-yielding microalgal strains, improvement of strains by genetic manipulation, optimization of culture conditions, and development of efficient cultivation systems. This paper reviews recent advances in heterotrophic production of EPA by microalgae with an emphasis on the use of diatoms as producing organisms.


Weber, L. W., M. Boll, et al. (2003). "Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model." Crit Rev Toxicol 33(2): 105-36.

            The use of many halogenated alkanes such as carbon tetrachloride (CCl4), chloroform (CHCl3) or iodoform (CHI3), has been banned or severely restricted because of their distinct toxicity. Yet CCl4 continues to provide an important service today as a model substance to elucidate the mechanisms of action of hepatotoxic effects such as fatty degeneration, fibrosis, hepatocellular death, and carcinogenicity. In a matter of dose,exposure time, presence of potentiating agents, or age of the affected organism, regeneration can take place and lead to full recovery from liver damage. CCl4 is activated by cytochrome (CYP)2E1, CYP2B1 or CYP2B2, and possibly CYP3A, to form the trichloromethyl radical, CCl3*. This radical can bind to cellular molecules (nucleic acid, protein, lipid), impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis). Adduct formation between CCl3* and DNA is thought to function as initiator of hepatic cancer. This radical can also react with oxygen to form the trichloromethylperoxy radical CCl3OO*, a highly reactive species. CCl3OO* initiates the chain reaction of lipid peroxidation, which attacks and destroys polyunsaturated fatty acids, in particular those associated with phospholipids. This affects the permeabilities of mitochondrial, endoplasmic reticulum, and plasma membranes, resulting in the loss of cellular calcium sequestration and homeostasis, which can contribute heavily to subsequent cell damage. Among the degradation products of fatty acids are reactive aldehydes, especially 4-hydroxynonenal, which bind easily to functional groups of proteins and inhibit important enzyme activities. CCl4 intoxication also leads to hypomethylation of cellular components; in the case of RNA the outcome is thought to be inhibition of protein synthesis, in the case of phospholipids it plays a role in the inhibition of lipoprotein secretion. None of these processes per se is considered the ultimate cause of CCl4-induced cell death; it is by cooperation that they achieve a fatal outcome, provided the toxicant acts in a high single dose, or over longer periods of time at low doses. At the molecular level CCl4 activates tumor necrosis factor (TNF)alpha, nitric oxide (NO), and transforming growth factors (TGF)-alpha and -beta in the cell, processes that appear to direct the cell primarily toward (self-)destruction or fibrosis. TNFalpha pushes toward apoptosis, whereas the TGFs appear to direct toward fibrosis. Interleukin (IL)-6, although induced by TNFalpha, has a clearly antiapoptotic effect, and IL-10 also counteracts TNFalpha action. Thus, both interleukins have the potential to initiate recovery of the CCl4-damaged hepatocyte. Several of the above-mentioned toxication processes can be specifically interrupted with the use of antioxidants and mitogens, respectively, by restoring cellular methylation, or by preserving calcium sequestration. Chemicals that induce cytochromes that metabolize CCl4, or delay tissue regeneration when co-administered with CCl4 will potentiate its toxicity thoroughly, while appropriate CYP450 inhibitors will alleviate much of the toxicity. Oxygen partial pressure can also direct the course of CCl4 hepatotoxicity. Pressures between 5 and 35 mmHg favor lipid peroxidation, whereas absence of oxygen, as well as a partial pressure above 100 mmHg, both prevent lipid peroxidation entirely. Consequently, the location of CCl4-induced damage mirrors the oxygen gradient across the liver lobule. Mixed halogenated methanes and ethanes, found as so-called disinfection byproducts at low concentration in drinking water, elicit symptoms of toxicity very similar to carbon tetrachloride, including carcinogenicity.


von Schacky, C. (2003). "The role of omega-3 fatty acids in cardiovascular disease." Curr Atheroscler Rep 5(2): 139-45.

            Plant-derived alpha-linolenic acid has been studied in a limited number of investigations. So far, some epidemiologic and a few mechanistic studies suggest a potential of protection from cardiovascular disease, but this potential remains to be proven in intervention studies. In contrast, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are prevalent in fish and fish oils, have been studied in thousands of investigations. A consistent body of evidence has been elaborated in various types of investigations, ultimately demonstrating reduction in total mortality, cardiovascular mortality, and morbidity by ingestion of roughly 1 g/d of EPA plus DHA. Current guidelines, however, do not discern between the omega-3 fatty acids mentioned; in fact, most even do not differentiate polyunsaturated fatty acids at all. Unfortunately, this complicates efficient implementation of an effective means of prophylaxis of atherosclerosis.


Vanschoonbeek, K., M. P. de Maat, et al. (2003). "Fish oil consumption and reduction of arterial disease." J Nutr 133(3): 657-60.

            Fish oil consumption may help to normalize the prethrombotic state and reduce arterial disease. This antithrombotic potential of fish oil, rich in (n-3) polyunsaturated fatty acids (PUFA), has been attributed to a reduction in platelet activation, a lowering of plasma triglycerides and (vitamin K-dependent) coagulation factors and/or a decrease in vascular tone. Most intervention studies have shown only moderate effects of (n-3) PUFA on these hemostatic variables. On the other hand, the usually small prolongation in bleeding time with fish oil does not appear to lead to bruising or hemorrhage, at least in healthy subjects. This contrasts with the increased bleeding risk accompanying the more prominent antihemostatic effects of antiplatelet and anticoagulant drugs. Here we propose that the beneficial effect of (n-3) PUFA diet is related to down-regulation of the mutually positive interactions of platelet activation and coagulation. In addition, we consider the possibility that the dietary effect on hemostatic and lipid factors involves transcription regulation of multiple genes, perhaps in a subject-dependent manner.


Uauy, R., D. R. Hoffman, et al. (2003). "Term infant studies of DHA and ARA supplementation on neurodevelopment: results of randomized controlled trials." J Pediatr 143(4 Suppl): S17-25.

            Healthy term infants who are not breast-fed may need long-chain polyunsaturated fatty acids (LCPUFA) in their feeding, based on the changes in plasma and tissue fatty composition. However, consistent functional effects across different studies conducted over the past two decades has been more difficult to document. The interpretation of these data has scientific and public interest with the introduction of LCPUFA supplemented formula. There are 14 controlled trials in term infants that have included formula feeding with or without LCPUFA and functional assessment of visual and other measures of neural development; in addition, 7 have evaluated specific measures related to cognitive development. We chose to examine the effect of DHA dose provided daily on the development of visual acuity to explain the differences in visual acuity responses across randomized studies. A "meta-regression" was performed with the use of a DHA effective dose as the independent variable and visual acuity at 4 months as the dependent variable. Since the two main dietary determinants of DHA status are the LNA provided and the preformed DHA consumed, we defined DHA equivalent dose across studies by assuming a 1%, 5%, and 10% conversion of LNA to DHA. Results indicate a strong and significant effect of DHA equivalent dose on magnitude of the visual acuity response at all conversions tested; greatest significance was found when using a 10% bioequivalency (r(2)=0.68, and P=.001). We conclude that there is a significant relation between the total DHA equivalents provided and effectiveness as defined by visual acuity measurements at 4 months of age.


Trushina, E. N., O. K. Mustafina, et al. (2003). "[The mechanism of action of polyunsaturated fatty acids on the immune system]." Vopr Pitan 72(3): 35-40.

            This article presents the literature materials about polyunsaturated fatty acids as nutritional immunomodulators.


Stein, J. (2003). "Visual motion sensitivity and reading." Neuropsychologia 41(13): 1785-93.

            Reading is more difficult than speaking because an arbitrary set of visual symbols must be rapidly identified, ordered and translated into the sounds they represent. Many poor readers have particular problems with the rapid visual processing required for these tasks because they have a mild impairment of the visual magnocellular system. This deficit has been demonstrated using neuropathological, evoked potential, functional magnetic resonance imaging and psychophysical techniques. The sensitivity of the M-system in both good and bad readers correlates with their orthographic abilities, suggesting that the M-system plays an important part in their development. This role is probably to mediate steady direction of visual attention and eye fixations on words. Thus many children with reading difficulties have unsteady eye control and this causes the letters they are trying to read to appear to move around, so that they cannot tell what order they are meant to be in. Therefore, boosting M-performance using yellow filters, or training eye fixation, can improve reading performance very significantly. Several genetic linkage studies have associated reading difficulties with the MHC control region on the short arm of chromosome 6. This system has recently been shown to help regulate the differentiation of M-cells. This association could also explain the high incidence of autoimmune conditions in poor readers. Other chromosomal sites are associated with the metabolism of polyunsaturated fatty acids (PUFAs) as found in fish oils, and this could explain why PUFA supplements can improve reading.


Spiteller, G. (2003). "Are lipid peroxidation processes induced by changes in the cell wall structure and how are these processes connected with diseases?" Med Hypotheses 60(1): 69-83.

            Apparently nature uses the unique sensitivity of polyunsaturated fatty acids (PUFAs) versus oxygen to generate chemical signals if the surface of a cell is influenced by an outside or inside event; for instance the attack of microorganisms, proliferation, aging or by treatment of isolated cells with surfactants. It seems that mammalian and plant cells respond equally to such changes in their structures by transformation of polyunsaturated fatty acids localized in the phospholipid layer of the cell wall to lipidhydroperoxides (LOOHs). These lipid peroxidation (LPO) processes involve all PUFAs, not only arachidonic acid.Slight physiological changes of the cell wall for instance by proliferation seem to activate enzymes, e.g., phospholipases and lipoxygenases (LOX). When an outside impact (for instance by attack of microorganisms) exceeds a certain level LOX commit suicide and liberate iron ions. These start a nonenzymatic LPO. Enzymatic and nonenzymatic LPO distinguish fundamentally which has not been recognized in the past. In the enzymatic LPO processes peroxyl radicals generated as intermediates cannot leave the enzyme complex. In contrast in a nonenzymatic LPO process peroxyl radicals are not trapped. They attack nearly any kind of biological molecules, for instance proteins. Thus only the amount of an outside impact decides if proliferation, apoptosis, or necrosis is started.Some evidence indicates that cancer might be the consequence of a low response of cells to induce apoptotic LPO processes. In contrast to high level of LPO processes induces diseases combined with inflammation, for instance rheumatic arthritis. After consumption of food rich in linoleic acid its LPO products become increased in low density lipoprotein (LDL). This LDL is able to enter endothelial cells and damage cells from inside, long before an inflammatory response is detectable.


Skerrett, P. J. and C. H. Hennekens (2003). "Consumption of fish and fish oils and decreased risk of stroke." Prev Cardiol 6(1): 38-41.

            Consumption of fish and fish oils was first associated with decreased risk of cardiovascular disease almost 50 years ago. Since then, a number of epidemiologic studies have evaluated whether their consumption is specifically associated with stroke. Ecologic/cross-sectional and case-control studies have generally shown an inverse association between consumption of fish and fish oils and stroke risk. Results from five prospective studies have been less consistent, with one showing no association, one showing a possible inverse association, and three demonstrating a significant inverse association. In the latest and largest of these, the Nurses Health Study, the relative risk of total stroke was lower, although not significantly so, among women who regularly ate fish than among those who did not. A significant decrease in the risk of thrombotic stroke (relative risk, 0.49; 95% confidence interval, 0.26-0.93) was observed among women who ate fish at least two times per week compared with women who ate fish less than once per month, after adjustment for age, smoking, and other cardiovascular risk factors; a nonsignificant decrease was observed among women in the highest quintile of long-chain omega-3 polyunsaturated fatty acid intake. No association was observed between consumption of fish or fish oil and hemorrhagic stroke. These data support the hypothesis that consumption of fish several times per week reduces the risk of thrombotic stroke but does not increase the risk of hemorrhagic stroke.


Silveira Rodriguez, M. B., S. Monereo Megias, et al. (2003). "[Functional nutrition and optimal nutrition. Near or far?]." Rev Esp Salud Publica 77(3): 317-31.

            The concept of functional food, about which scientific agreement is still lacking, springs from the field of Optimum Nutrition, aimed at modifying genetic and physiological aspects of human life and at the prevention and treatment of a growing number of diseases, far beyond merely covering nutritional requirements. From the European Union perspective, functional foods can be natural as well as industrially processed foods. The leading functional foods regarding which the soundest scientific evidence exists are probiotics, live microbial food ingredients represented mainly by fermented dairy products. Prebiotics, such as inulin-type fructans, are the trophic substrate of probiotics and potential intestinal microflora selectors. The combination of prebiotics and probiotics is termed synbiotic. Innumerable substances are known to have functional effects: soluble and insoluble fiber, phytosterols, phytoestrogens, monounsaturated and polyunsaturated fatty acids, phenol derivatives, vitamins and other phytochemicals. Functional foods exert their actions on different systems, especially the gastrointestinal, cardiovascular and immunological ones, acting too as enhancers of development and differentiation and positively modulating nutrient metabolism, gene expression, oxidative stress and the psychic sphere. The establishment of Health Claims must be firmly based upon scientific knowledge and legal regulation. Efficient biomarkers related to biological response must be found. Furthermore, it is essential to analyze possible diet or drug interactions as well as it is indispensable to conduct valid studies on humans. The prime objective must be the diet as a whole. Thus, the future challenge of a functional diet emerges.


Shapiro, H. (2003). "Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system?" Prostaglandins Leukot Essent Fatty Acids 68(3): 219-24.

            The intake of n-3 polyunsaturated fatty acids (PUFAs) in many industrialized countries is relatively low and its increased consumption has protective and modifying effects on such diverse conditions as atherosclerosis, ventricular arrhythmias, multiple sclerosis, major depression and inflammatory and autoimmune diseases. In addition, n-3 PUFAs have been shown to alleviate pain in patients with rheumatoid arthritis, inflammatory bowel disease and in a number of other painful conditions. This has been attributed to the inhibition of pro-inflammatory eicosanoid and cytokine production by peripheral tissues. n-3 PUFAs have also been shown to inhibit eicosanoid production in glial cells, block voltage-gated sodium channels (VGSCs), inhibit neuronal protein kinases and modulate gene expression. They also appear to have mood-stabilizing and sympatholytic effects. The present article explores the possibility that, based on what is known about their neural and non-neural effects, n-3 PUFAs directly attenuate the neuronal and glial processes that underlie neuropathic and inflammatory pain.


Rouzer, C. A. and L. J. Marnett (2003). "Mechanism of free radical oxygenation of polyunsaturated fatty acids by cyclooxygenases." Chem Rev 103(6): 2239-304.


Rouvinen-Watt, K. (2003). "Nursing sickness in the mink--a metabolic mystery or a familiar foe?" Can J Vet Res 67(3): 161-8.

            Nursing sickness, the largest single cause of mortality in adult female mink (Mustela vison), is an example of a metabolic disorder, which develops when the demands for lactation require extensive mobilization of body energy reserves. The condition is characterized by progressive weight loss, emaciation, and dehydration with high concentrations of glucose and insulin in the blood. Morbidity due to nursing sickness can be as high as 15% with mortality around 8%, but the incidence is known to vary from year to year. Stress has been shown to trigger the onset of the disease and old females and females with large litters are most often affected. Increasing demand for gluconeogenesis from amino acids due to heavy milk production may be a predisposing factor. Glucose metabolism is inextricably linked to that of protein and fats. In obesity (or lipodystrophy), the ability of adipose tissue to buffer the daily influx of nutrients is overwhelmed (or absent), interfering with insulin-mediated glucose disposal and leading to insulin resistance. Polyunsaturated fatty acids of the n-3 family play an important role in modulating insulin signalling and glucose uptake by peripheral tissue. The increasing demand on these fatty acids for milk fat synthesis towards late lactation may result in deficiency in the lactating female, thus impairing glucose disposal. It is suggested that the underlying cause of mink nursing sickness is the development of acquired insulin resistance with 3 contributing key elements: obesity (or lipodystrophy), n-3 fatty acid deficiency, and high protein oxidation rate. It is recommended that mink breeder females be kept in moderate body condition during fall and winter to avoid fattening or emaciation. A dietary n-3 fatty acid supplement during the lactation period may be beneficial for improved glycemic control. Lowering of dietary protein reduces (oxidative) stress and improves water balance in the nursing females and may, therefore, prevent the development and help in the management of nursing sickness. It is also surmised that other, thus far unexplained, metabolic disorders seen in male and female mink may be related to acquired insulin resistance.


Rivellese, A. A. and S. Lilli (2003). "Quality of dietary fatty acids, insulin sensitivity and type 2 diabetes." Biomed Pharmacother 57(2): 84-7.

            Epidemiological evidence and intervention studies clearly indicate that the quality of dietary fat influences insulin sensitivity in humans, in particular, saturated fat worsens it, while monounsaturated and omega-6 polyunsaturated fats improve it. Long chain omega-3 fatty acids do not seem to have any effect on insulin sensitivity, at least in humans. Moreover, there is also good epidemiological evidence that the quality of dietary fat may influence the risk of type 2 diabetes, again with saturated fat increasing and unsaturated fat decreasing this risk. No intervention study is available at the moment on this specific point, even if in the Finnish Diabetes Prevention Study the incidence of type 2 diabetes was reduced by a multifactorial intervention, which also included a reduction of saturated fat intake.


Ristic, V. and G. Ristic (2003). "[Role and importance of dietary polyunsaturated fatty acids in the prevention and therapy of atherosclerosis]." Med Pregl 56(1-2): 50-3.

            INTRODUCTION: Hyperlipoproteinemia is a key factor in development of atherosclerosis, whereas regression of atherosclerosis mostly depends on decreasing the plasma level of total and LDL-cholesterol. Many studies have reported the hypocholesterolemic effect of linolenic acid. TYPES OF POLYUNSATURATED FATTY ACIDS (PUFA): Linoleic and alpha-linolenic acids are essential fatty acids. The main sources of linoleic acid are vegetable seeds and of alpha-linolenic acid-green parts of plants. alpha-linolenic acid is converted to eicosapentaenoic and docosahexaenoic acid. Linoleic acid is converted into arachidonic acid competing with eicosapentaenoic acid in the starting point for synthesis of eicosanoids, which are strong regulators of cell functions and as such, very important in physiology and pathophysiology of cardiovascular system. Eicosanoids derived from eicosapentaneoic acid have different biological properties in regard to those derived from arachidonic acid, i.e. their global effects result in decreased vasoconstriction, platelet aggregation and leukocyte toxicity. ROLE AND SIGNIFICANT OF PUFA: The n-6 to n-3 ratio of polyunsaturated fatty acids in the food is very important, and an optimal ratio 4 to 1 in diet is a major issue. Traditional western diets present absolute or relative deficiency of n-3 polyunsaturated fatty acids, and a ratio 15-20 to 1. In our diet fish and fish oil are sources of eicosapentaenoic and docosahexaenoic acid. Refined and processed vegetable oils change the nature of polyunsaturated fatty acids and obtained derivates have atherogenic properties.


Rennie, K. L., J. Hughes, et al. (2003). "Nutritional management of rheumatoid arthritis: a review of the evidence." J Hum Nutr Diet 16(2): 97-109.

            Rheumatoid arthritis (RA) is a debilitating disease and is associated with increased risk of cardiovascular disease and osteoporosis. Poor nutrient status in RA patients has been reported and some drug therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs), prescribed to alleviate RA symptoms, may increase the requirement for some nutrients and reduce their absorption. This paper reviews the scientific evidence for the role of diet and nutrient supplementation in the management of RA, by alleviating symptoms, decreasing progression of the disease or by reducing the reliance on, or combating the side-effects of, NSAIDs. Supplementation with long-chain n-3 polyunsaturated fatty acids (PUFA) consistently demonstrates an improvement in symptoms and a reduction in NSAID usage. Evidence relating to other fatty acids, antioxidants, zinc, iron, folate, other B vitamins, calcium, vitamin D and fluoride are also considered. The present evidence suggests that RA patients should consume a balanced diet rich in long-chain n-3 PUFA and antioxidants. More randomized long-term studies are needed to provide evidence for the benefits of specific nutritional supplementation and to determine optimum intake, particularly for n-3 PUFA and antioxidants.


Rapoport, S. I. (2003). "In vivo approaches to quantifying and imaging brain arachidonic and docosahexaenoic acid metabolism." J Pediatr 143(4 Suppl): S26-34.

            A novel in vivo fatty acid method has been developed to quantify and image brain metabolism of nutritionally essential polyunsaturated fatty acids (PUFAs). In unanesthetized rodents, a radiolabeled PUFA is injected intravenously, and its rate of incorporation into brain phospholipids is determined by chemical analysis or quantitative autoradiography. Results indicate that about 5% of brain arachidonic acid (20:4 n-6) and of docosahexaenoic acid (22:6 n-3) acid are lost daily by metabolism and are replaced from dietary sources through the plasma. Calculated turnover rates of PUFAs in brain phospholipids, due to deesterification by phospholipase A(2) (PLA(2)) followed by reesterification, are very rapid, consistent with active roles of PUFAs in signal transduction and other processes. Turnover rates of arachidonate and docosahexaenoate are independent of each other and probably are regulated by independent sets of enzymes. Brain incorporation of radiolabeled arachidonate can be imaged in response to drugs that bind to receptors coupled to PLA(2) through G proteins, thus measuring PLA(2)-initiated signal transduction. The in vivo fatty method is being extended for human studies using positron emission tomography.


Pereira, S. L., A. E. Leonard, et al. (2003). "Recent advances in the study of fatty acid desaturases from animals and lower eukaryotes." Prostaglandins Leukot Essent Fatty Acids 68(2): 97-106.

            The biosynthesis of polyunsaturated fatty acids (PUFAs) in different organisms can involve a variety of pathways, catalyzed by a complex series of desaturation and elongation steps. A range of different desaturases have been identified to date, capable of introducing double bonds at various locations on the fatty acyl chain. Some recently identified novel desaturases include a delta4 desaturase from marine fungi, and a bi-functional delta5/delta6 desaturase from zebrafish. Using molecular genetics approaches, these desaturase genes have been isolated, identified, and expressed in variety of heterologous hosts. Results from these studies will help increase our understanding of the biochemistry of desaturases and the regulation of PUFA biosynthesis. This is of significance because PUFAs play critical roles in multiple aspects of membrane physiology and signaling mechanisms which impact human health and development.


Nkondjock, A., B. Shatenstein, et al. (2003). "Specific fatty acids and human colorectal cancer: an overview." Cancer Detect Prev 27(1): 55-66.

            BACKGROUND: Evidence suggests that dietary fats are associated with risk of colorectal cancer. The effect of fats depends not only on the quantity, but also on their composition in specific fatty acids. Moreover, fats are peroxidizable, and peroxidation products as well as antioxidants play a role in the pathogenic process of colorectal cancer. METHODS: The published literature was reviewed for the relationship between dietary intake or concentration of specific fatty acids in adipose tissue, erythrocytes, plasma or feces in relation to colorectal cancer. RESULTS: Increased concentrations of short-chain fatty acids (SCFAs) and eicosanopentaenoic acid (EPA) seem to protect against colorectal cancer. Increased concentrations of medium-chain fatty acids (MCFAs) and arachidonic acid (AA) might be associated with increased risk. Long-chain saturated fatty acids (LCSFAs) seem unrelated to colorectal cancer, while the associations between monounsaturated fatty acids (MUFAs), trans fatty acids, polyunsaturated fatty acids (PUFAs) such as linoleic acid (LA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), omega-3/omega-6 ratio and colorectal cancer are unconvincing. CONCLUSIONS: It is suggested that the substitution of food with high MCFAs and AA content by a SCFAs- and EPA-rich diet may contribute to reduced risk of colorectal cancer.


Nichols, D. S. (2003). "Prokaryotes and the input of polyunsaturated fatty acids to the marine food web." FEMS Microbiol Lett 219(1): 1-7.

            The investigation of prokaryotes in aquatic ecology is often limited to their role in nutrient cycling and the degradation of organic matter. While this aspect of the microbial loop is undoubtedly important, further aspects of bacterial roles in marine food webs exist which have not been fully considered in light of recent research in related fields. The concept of bacteria providing essential nutrients may derive importance from two aspects of their role in the marine environment; firstly as a primary food source for omnivorous, sestonivorous and filtering benthic animals and secondly as components of the commensal microbial communities of marine animals. Many marine organisms lack the de novo ability to produce n-3 polyunsaturated fatty acids (PUFA) and hence rely on a dietary supply of PUFA. The issue of PUFA origin in the marine food web is particularly salient in light of recent research demonstrating the influence of PUFA levels on the efficiency of energy transfer between trophic levels. The assumption that microalgae provide the bulk of de novo PUFA production for all marine food webs must be actively reviewed with respect to particular microbial niches such as sea ice, marine animals and abyssal communities.


Napier, J. A., L. V. Michaelson, et al. (2003). "The role of cytochrome b5 fusion desaturases in the synthesis of polyunsaturated fatty acids." Prostaglandins Leukot Essent Fatty Acids 68(2): 135-43.

            The biosynthetic pathway of polyunsaturated fatty acids (PUFAs) has been the subject of much interest over the last few years. Significant progress has been made in the identification of the enzymes required for PUFA synthesis; in particular, the fatty acid desaturases which are central to this pathway have now all been identified. These "front-end" desaturases are all members of the cytochrome b(5) fusion desaturase superfamily, since they contain an N-terminal domain that is orthologous to the microsomal cytochrome b(5). Examination of the primary sequence relationships between the various PUFA-specific cytochrome b(5) fusion desaturases and related fusion enzymes allows inferences regarding the evolution of this important enzyme class. More importantly, this knowledge helps underpin our understanding of polyunsaturated fatty acid biosynthesis.


Mozzi, R., S. Buratta, et al. (2003). "Metabolism and functions of phosphatidylserine in mammalian brain." Neurochem Res 28(2): 195-214.

            Phosphatidylserine (PtdSer) is involved in cell signaling and apoptosis. The mechanisms regulating its synthesis and degradation are still not defined. Thus, its role in these processes cannot be clearly established at molecular level. In higher eukaryotes, PtdSer is synthesized from phosphatidylethanolamine or phosphatidylcholine through the exchange of the nitrogen base with free serine. PtdSer concentration in the nervous tissue membranes varies with age, brain areas, cells, and subcellular components. At least two serine base exchange enzymes isoforms are present in brain, and their biochemical properties and regulation are still largely unknown because their activities vary with cell type and/or subcellular fraction, developmental stage, and differentiation. These peculiarities may explain the apparent contrasting reports. PtdSer cellular levels also depend on its decarboxylation to phosphatidylethanolamine and conversion to lysoPtdSer by phospholipases. Several aspects of brain PtdSer metabolism and functions seem related to the high polyunsaturated fatty acids content, particularly docosahexaenoic acid (DHA).


Moreno, J. J. and M. T. Mitjavila (2003). "The degree of unsaturation of dietary fatty acids and the development of atherosclerosis (review)." J Nutr Biochem 14(4): 182-95.

            Atherosclerosis is the principal contributor to the pathogenesis of myocardial and cerebral infarction, gangrene and loss of function in the extremities. It results from an excessive inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. Atherosclerotic lesions develop fundamentally in three stages: dysfunction of the vascular endothelium, fatty streak formation and fibrous cap formation. Each stage is regulated by the action of vasoactive molecules, growth factors and cytokines. This multifactorial etiology can be modulated through the diet. The degree of unsaturation of dietary fatty acids affects lipoprotein composition as well as the expression of adhesion molecules and other pro-inflammatory factors, and the thrombogenicity associated with atherosclerosis development. Thus, the preventive effects of a monounsaturated-fatty acid-rich diet on atherosclerosis may be explained by the enhancement of high-density lipoprotein-cholesterol levels and the impairment of low-density lipoprotein-cholesterol levels, the low-density lipoprotein susceptibility to oxidation, cellular oxidative stress, thrombogenicity and atheroma plaque formation. On the other hand, the increase of high-density lipoprotein cholesterol levels and the reduction of thrombogenicity, atheroma plaque formation and vascular smooth muscle cell proliferation may account for the beneficial effects of polyunsaturated fatty acid on the prevention of atherosclerosis. Thus, the advantages of the Mediterranean diet rich in olive oil and fish on atherosclerosis may be due to the modulation of the cellular oxidative stress/antioxidant status, the modification of lipoproteins and the down-regulation of inflammatory mediators.


Meydani, M. (2003). "Soluble adhesion molecules: surrogate markers of cardiovascular disease?" Nutr Rev 61(2): 63-8.

            Expression of adhesion molecules on the surface of endothelial and immune cells is important for the interaction between immune and endothelial cells during the inflammatory process. Several of these adhesion molecules have been identified and are believed to be important in the pathogenesis of atherosclerosis. The soluble forms of adhesion molecules are shed from cell surfaces and released into blood circulation; their measurement may have use as markers in predicting cardiovascular disease. Experimental and some clinical data have indicated that reducing expression of some adhesion molecules is another mechanism by which dietary fats such as n-3 polyunsaturated fatty acids and oleic acid, as well as vitamin E and other antioxidants found in fruits and vegetables, may lower the risk of cardiovascular disease.


Merzouk, H. and N. A. Khan (2003). "Implication of lipids in macrosomia of diabetic pregnancy: can n-3 polyunsaturated fatty acids exert beneficial effects?" Clin Sci (Lond) 105(5): 519-29.

            Macrosomia or fetal obesity is a frequent complication of pregnancy in diabetes mellitus. Several alterations observed in carbohydrate and lipid metabolism in macrosomic infants of diabetic mothers are thought to be a consequence of maternal hyperglycaemia leading to fetal hyperinsulinaemia. Macrosomic infants of diabetic mothers are prone to the development of glucose intolerance, obesity and diabetes during childhood and adulthood. Furthermore, increasing evidence is accumulating regarding the importance of n -3 polyunsaturated fatty acids (PUFAs) in the reduction of plasma lipids and hyperglycaemia. In this review article, we shed light on the abnormalities in lipid metabolism in macrosomia. We also raise the question of the possible beneficial effects of n -3 PUFAs in diabetic pregnancy and in the prevention and treatment of long-term metabolic abnormalities associated with macrosomia.


Lichtenstein, A. H. (2003). "Dietary fat and cardiovascular disease risk: quantity or quality?" J Womens Health (Larchmt) 12(2): 109-14.

            When considering dietary fat quantity, there are two main factors to consider, impact on body weight and plasma lipoprotein profiles. Data supporting a major role of dietary fat quantity in determining body weight are weak and may be confounded by differences in energy density, dietary fiber, and dietary protein. With respect to plasma lipoprotein profiles, relatively consistent evidence indicates that under isoweight conditions, decreasing the total fat content of the diet causes an increase in triglyceride and decrease in high-density lipoprotein (HDL) cholesterol levels. When considering dietary fat quality, current evidence suggests that saturated fatty acids tend to increase low-density lipoprotein (LDL) cholesterol levels, whereas monounsaturated and polyunsaturated fatty acids tend to decrease LDL cholesterol levels. Long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) (20:5n-3) and docosahexaenoic acid (DHA) (22:6n-3), are associated with decreased triglyceride levels in hypertriglyceridemic patients and decreased risk of developing coronary heart disease (CHD). Dietary trans-fatty acids are associated with increased LDL cholesterol levels. Hence, a diet low in saturated and trans-fatty acids, with adequate amounts of monounsaturated and polyunsaturated fatty acids, especially long-chain omega-3 fatty acids, would be recommended to reduce the risk of developing CHD. Additionally, the current data suggest it is necessary to go beyond dietary fat, regardless of whether the emphasis is on quantity or quality, and consider lifestyle. This would include encouraging abstinence from smoking, habitual physical activity, avoidance of weight gain with age, and responsible limited alcohol intake (one drink for females and two drinks for males per day).


Li, D. (2003). "Omega-3 fatty acids and non-communicable diseases." Chin Med J (Engl) 116(3): 453-8.

            OBJECTIVE: To review the relation between dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA) and non-communicable diseases. METHOD: Data were collected from scientific journals and conference publications, MEDLINE (1979 - 2002) and current content which included 68 prospective, cross-sectional, case control and dietary-intervention studies. Scientific paper selections were based on the association between omega-3 PUFA and non-communicable diseases. RESULTS: omega-3 PUFA has beneficial effects on increasing heart rate variability, decreasing the risk of stroke, reducing both systolic and diastolic blood pressure, insulin resistance and glucose metabolism. Long chain omega-3 PUFA has anti-cancer and anti-inflammatory activities. omega-3 PUFA has also been reported to have a beneficial effect on attention-deficit/hyperactivity disorder and schizophrenia, and may be effective in managing depression in adults. CONCLUSIONS: Results from epidemiological and dietary intervention studies have shown that omega-3 PUFA represent powerfully a class of bioactive compounds and that dietary intake of omega-3 PUFA plays a critical role in human health in relation to non-communicable diseases.


Lebeau, T. and J. M. Robert (2003). "Diatom cultivation and biotechnologically relevant products. Part II: current and putative products." Appl Microbiol Biotechnol 60(6): 624-32.

            While diatoms are widely present in terms of diversity and abundance in nature, few species are currently used for biotechnologically applications. Most studies have focussed on intracellularly synthesised eicosapentaenoic acid (EPA), a polyunsaturated fatty acid (PUFA) used for pharmaceutical applications. Applications for other intracellular molecules, such as total lipids for biodiesel, amino acids for cosmetic, antibiotics and antiproliferative agents, are at the early stage of development. In addition, the active principle component must be identified amongst the many compounds of biotechnological interest. Biomass from diatom culture may be applied to: (1). aquaculture diets, due to the lipid- and amino-acid-rich cell contents of these microorganisms, and (2). the treatment of water contaminated by phosphorus and nitrogen in aquaculture effluent, or heavy metal (bioremediation). The most original application of microalgal biomass, and specifically diatoms, is the use of silicon derived from frustules in nanotechnology. The competitiveness of biotechnologically relevant products from diatoms will depend on their cost of production. Apart from EPA, which is less expensive when obtained from Phaeodactylum tricornutum than from cod liver, comparative economic studies of other diatom-derived products as well as optimisation of culture conditions are needed. Extraction of intracellular metabolites should be also optimised to reduce production costs, as has already been shown for EPA. Using cell immobilisation techniques, benthic diatoms can be cultivated more efficiently allowing new, biotechnologically relevant products to be investigated.


Leaf, A., Y. F. Xiao, et al. (2003). "Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids." Pharmacol Ther 98(3): 355-77.

            This is a review of our present understanding of the mechanism by which the n-3 polyunsaturated fatty acids (PUFA) in fish oils prevent fatal ventricular arrhythmias in animals and cultured heart cells. A brief review of three clinical trials that suggest that these PUFAs prevent sudden cardiac death is also included in order to emphasize the potential importance of these fatty acids in human nutrition. The PUFAs act by stabilizing electrically every cardiac myocyte by modulating conductance of ion channels in the sarcolemma, particularly the fast, voltage-dependent sodium current and the L-type calcium currents, though other ion currents are also affected. Work in progress suggests that the primary site of action of the PUFAs may be on the phospholipid bilayer of the heart cells in the microdomains through which the ion channels penetrate the membrane bilayer in juxtaposition with the ion channels rather than directly on the channel protein itself. These PUFAs then allosterically alter the conformation and conductance of the channels. Both potential benefits and possible adverse effects of the PUFAs in man will be discussed. Knowing that the ion channels have been structurally conserved among all excitable tissues, we tested their effects on the electrophysiology of rat hippocampal CA1 neurons and found that the sodium and calcium ion channels in these neurons were also affected by PUFAs. An attempt to show the place of the PUFAs in human nutrition during the 2-4 million years of our evolution will conclude the review.


Leaf, A., J. X. Kang, et al. (2003). "Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils." Circulation 107(21): 2646-52.


Lapillonne, A., S. D. Clarke, et al. (2003). "Plausible mechanisms for effects of long-chain polyunsaturated fatty acids on growth." J Pediatr 143(4 Suppl): S9-16.

            A few studies conducted over the past decade suggest that formulas supplemented with long-chain polyunsaturated n-3 fatty acids may adversely affect growth of preterm infants. Others suggest that a high intake of alpha-linolenic acid (ALA; 18:3 n-3), the precursor of the long-chain polyunsaturated n-3 fatty acids, also may limit growth. The majority of studies, however, have not shown an effect of either long-chain polyunsaturated n-3 fatty acids or their precursor on growth. Nonetheless, the importance of growth during infancy and the possibility that these fatty acids may inhibit growth under some circumstances makes the issue worthy of further consideration. At the very least, plausible mechanisms for such an effect of n-3 PUFA on growth should be considered. These include (1) altered nutrient intake, absorption, and/or utilization; (2) low plasma and tissue contents of arachidonic acid (ARA;20:4 n-6); (3) an imbalance between n-6 and n-3 LCPUFA eicosanoid precursors and, hence, the eicosanoids produced from each; (4) altered membrane characteristics; and (5) effects on gene expression. Each of these is discussed. It is concluded that any or all are feasible but that none can be specifically implicated. Moreover, since few studies were designed specifically to assess growth, the reported effects of n-3 PUFA on growth could represent chance findings secondary to the suboptimal design. Furthermore, although additional data are needed for a definitive conclusion, the observed effects on growth, regardless of mechanism, does not appear to be biologically significant.


Lada, A. T. and L. L. Rudel (2003). "Dietary monounsaturated versus polyunsaturated fatty acids: which is really better for protection from coronary heart disease?" Curr Opin Lipidol 14(1): 41-6.

            PURPOSE OF REVIEW: The purpose is to evaluate recent findings concerning dietary fats and the risk of coronary heart disease. Monounsaturated fatty acids are often regarded as healthy, and many have recommended their consumption instead of saturated fatty acids and polyunsaturated fatty acids. Support for the benefits of monounsaturated fatty acids comes largely from epidemiological data, but they have not been an isolated, single variable in such studies. Beneficial effects on the plasma lipid profile and LDL oxidation rates have also been identified. More recent findings have questioned the impact of suspected beneficial effects on coronary heart disease, indicating that studies with more conclusive endpoints are needed. RECENT FINDINGS: Human dietary studies often produce conflicting results regarding the effects of monounsaturated and polyunsaturated fatty acids on the plasma lipid profile. Monounsaturated and polyunsaturated fatty acids both appear to reduce total and LDL-cholesterol compared with saturated fatty acids; however, the effect on HDL is less clear. Lowered HDL levels in response to low-fat or polyunsaturated fatty acid diets and the decreased protection from oxidation of polyunsaturated fatty acid-enriched LDL may not indicate increased coronary heart disease risk. Several lines of evidence also suggest that polyunsaturated fatty acids may protect against atherosclerosis. SUMMARY: Recommendations to substitute monounsaturated fatty acids for polyunsaturated fatty acids or a low-fat carbohydrate diet seem premature without more research into the effects on the development of atherosclerosis. Current opinions favoring monounsaturated fatty acids are based on epidemiological data and risk factor analysis, but are questioned by the demonstrated detrimental effects on atherosclerosis in animal models.


Kroes, R., E. J. Schaefer, et al. (2003). "A review of the safety of DHA45-oil." Food Chem Toxicol 41(11): 1433-46.

            Polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), are natural constituents of the human diet; however, dietary intakes of these fatty acids are below recommended values. The main dietary source of DHA is fatty fish, with lesser amounts provided by shellfish, marine mammals, and organ meats. The addition to traditional food products of refined oils produced by marine microalgae represents potential sources of supplemental dietary DHA. DHA45-oil is manufactured through a multi-step fermentation and refining process using a non-toxigenic and non-pathogenic marine protist. Comprising approximately 45% DHA, and lesser concentrations of palmitic acid and docosapentaenoic acid, DHA45-oil is intended for use in foods as a dietary source of DHA. The safety of DHA45-oil was evaluated in various genotoxicity and acute, subchronic, and reproductive toxicity studies. DHA45-oil produced negative results in genotoxicity assays and demonstrated a low acute oral toxicity in mice and rats. Dietary administration of DHA45-oil to rats in subchronic and one-generation reproductive studies produced results consistent with those observed in oral studies using high concentrations of omega-3 PUFAs from fish or other microalgal-derived oils. The results of these studies, as well as those of various published metabolic, toxicological, and clinical studies with DHA-containing oils, support the safety of DHA45-oil as a potential dietary source of DHA.


Koo, W. W. (2003). "Efficacy and safety of docosahexaenoic acid and arachidonic acid addition to infant formulas: can one buy better vision and intelligence?" J Am Coll Nutr 22(2): 101-7.

            Long chain polyunsaturated fatty acids (LCPUFA) namely arachidonic acid (ARA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3) are highly concentrated in the phospholipid bilayer of biologically active brain and retinal neural membranes and are important in phototransduction and neuronal function. The rationale for adding these LCPUFA to infant formula (IF) was primarily because of their presence in large quantities in the retina and brain and in human milk. In addition, infants fed IF containing LCPUFA and breastfed infants have comparable ARA and DHA levels in red cell and plasma, in contrast to the lower ARA and DHA levels in those fed IF containing only the essential fatty acids: linoleic (LA, 18:2n-6) and linolenic (LNA, 18:3n-3), the precursors to ARA and DHA, respectively. However, functional benefits in particular visual or neural development from IF containing LCPUFA remains controversial. Potential for excessive and/or imbalanced intake of n-6 and n-3 fatty acids exists with increasing fortification of LCPUFA to infant foods other than IF.


Julius, U. (2003). "Fat modification in the diabetes diet." Exp Clin Endocrinol Diabetes 111(2): 60-5.

            The modification of dietary fat in the diet of diabetic patients is of interest with respect to metabolic and other consequences of this modification. To begin with the data are reviewed for the use of monounsaturated fatty acids (MUFA) in the diabetes diet. Compared to a carbohydrate-rich diet, glucose concentrations are lower. Blood pressure was also found to be lower. There were no major differences with respect to lipid concentrations. HDL-cholesterol levels tended to be higher after a MUFA-rich diet. In type-1 diabetic patients, the number of circulating big VLDL particles was greater after a MUFA diet than after a carbohydrate-rich diet. Comparisons were also made between diets enriched with MUFA and with polyunsaturated fatty acids (PUFA). With respect to lipid concentrations, different groups observed different effects. While one group saw no differences in fasting lipids, they measured a higher remnant-like particle cholesterol after a diet enriched with MUFA. Another group found higher total and LDL-cholesterol levels after a PUFA-rich diet than after a MUFA-diet. In their study, fasting glucose, insulin and fasting chylomicrons and postprandial chylomicrons and VLDL were higher following the PUFA diet. A MUFA-rich diet increased endothelium-dependent flow-mediated dilatation in the superficial femoral artery. Alpha-linolenic acid appears to be a precursor of eicospentaenoic and docosahexaenoic fatty acids. As a diet rich in n-6 PUFA reduces this conversion, a n-6/n-3 PUFA ratio not exceeding 4 - 6 should be observed. No prospective data are available for alpha-linolenic acid in diabetic patients. The review summarizes the results of the Lyon Diet Heart Study and the Nurses' Health Study. Both studies saw a reduced cardiovascular risk associated with a higher intake of alpha-linolenic acid. Finally, data on the effects of fish oil are given. The latter has a clearly expressed triglyceride-lowering effect. Data with respect to glucose control are heterogeneous. Major studies did not find any influence in glucose concentrations. Hepatic glucose production and peripheral insulin sensitivity remained constant. Evidently, nerve function can be improved by fish oil. Data have been compiled comparing the effects of fish oil with those of olive oil, linseed oil and sunflower oil.


Joy, C. B., R. Mumby-Croft, et al. (2003). "Polyunsaturated fatty acid supplementation for schizophrenia." Cochrane Database Syst Rev(2): CD001257.

            BACKGROUND: Limited evidence supports a hypothesis suggesting that schizophrenic symptoms may be the result of altered neuronal membrane structure and metabolism. This structure and metabolism is dependent on blood plasma levels of certain essential fatty acids and their metabolites. OBJECTIVES: To review the effects polyunsaturated fatty acids for people with schizophrenia. SEARCH STRATEGY: The initial search of 1998 was updated. We searched the Cochrane Schizophrenia Group's Register (July 2002), and authors of included studies and relevant pharmaceutical companies were contacted. SELECTION CRITERIA: All randomised clinical trials of polyunsaturated fatty acid treatment for schizophrenia. DATA COLLECTION AND ANALYSIS: Reviewers, working independently, selected, quality assessed, and extracted relevant data. Analysis was on an intention-to-treat basis. Where possible and appropriate Relative Risk (RR) and their 95% confidence intervals (CI) were calculated and the number needed to treat (NNT) estimated. For continuous data, weighted mean differences (WMD) and their 95% confidence intervals were calculated. Data were inspected for heterogeneity. MAIN RESULTS: Five short small studies (n=313) were included. One small study (n=30) suggested that an omega-3 EFA (ecisapentenoic acid (EPA) enriched oil) may have some antipsychotic properties when compared with placebo, even if not given as a supplement to standard drugs (RR not needing antipsychotic drugs 0.73 CI 0.54 to 1.00; RR less than 25% improvement in PANSS 0.54 CI 0.3 to 0.96, NNT 3 CI 2 to 29). Other studies comparing omega-3 EFA's with placebo as a supplement to antipsychotics were too small to be conclusive. There was a suggestion that people already on antipsychotics when given omega-3 EFA supplementation had greater improvement of mental state compared to those receiving a placebo supplementation but the result were not significant (n=29, 1 RCT, RR <25% improvement in PANSS 0.62 CI 0.37 to 1.05). However, the mental state of both medicated and un-medicated patients was significantly better for those receiving omega-3 EFA supplementation (n=59, 2 RCTs, RR <25% improved on PANSS 0.58 CI 0.39 to 0.85, NNT 3 CI 2-8). Medium term data, however, did not favour either group (n=87, 1 RCT, MD PANSS endpoint -1.0 CI -8.15 to 6.15). All studies had low attrition (<10% total, n=271, 4 RCTs, RR leaving the study early 0.91 CI 0.36 to 2.33). Another study (n=31) comparing two types of omega-3 EFA's, ecisapentenoic acid enriched oil and docosahexanoic acid oil, also found no differences between these two EFA's in measures of mental state. One small (n=16) study investigated the effects of an omega-6 EFA compared with placebo for tardive dyskinesia and found no clear effects. There is not a clear dose response to omega-3 supplementation. Adverse effects seem rare but diarrhoea may be a problem in the medium term. REVIEWER'S CONCLUSIONS: The use of omega-3 polyunsaturated fatty acids for schizophrenia remains experimental and large well designed, conducted and reported studies are indicated and needed.


Iusupova, G. I., T. V. Fedichkina, et al. (2003). "[Sources of lipids in parenteral and enteral nutrition]." Vopr Pitan 72(3): 32-5.

            The review is devoted to sources of lipids in enteral and parenteral nutrition. The role of omega-3 and omega polyunsaturated fatty acids in metabolism of some lipid mediators is examined.


Innis, S. M. (2003). "Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids." J Pediatr 143(4 Suppl): S1-8.

            Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are important structural components of the central nervous system. These fatty acids are transferred across the placenta, are present in human milk, and are accumulated in the brain and retina during fetal and infant development. The high concentrations of DHA in the retina and of DHA and ARA in brain gray matter suggests that these fatty acids have important roles in retinal and neural function. Animal studies have shown that depletion of DHA from the retina and brain results in reduced visual function and learning deficits. The latter effects may be explained by changes in the membrane bilayer that alter membrane-associated receptors and signal transduction systems, ion channel activity, or direct effects on gene expression. DHA can be formed in the liver from alpha linolenic acid, but it is unclear if the rate of DHA synthesis in humans is sufficient to support optimal brain and retinal development. Although there is no evidence that the ability to form ARA from linoleic acid is limiting, supplementation with DHA reduces tissue ARA, possibly creating a conditional need for ARA in infants with a dietary intake of DHA. The amount of DHA in human milk varies widely and is positively correlated with visual and language development in breast-fed infants. Advances in understanding essential fatty acid requirements will benefit from intervention studies that use functionally relevant tests to probe the deficiency or adequacy of physiologically important pools of DHA and ARA in developing infants.


Hu, F. B. (2003). "Plant-based foods and prevention of cardiovascular disease: an overview." Am J Clin Nutr 78(3 Suppl): 544S-551S.

            Evidence from prospective cohort studies indicates that a high consumption of plant-based foods such as fruit and vegetables, nuts, and whole grains is associated with a significantly lower risk of coronary artery disease and stroke. The protective effects of these foods are probably mediated through multiple beneficial nutrients contained in these foods, including mono- and polyunsaturated fatty acids, n-3 fatty acids, antioxidant vitamins, minerals, phytochemicals, fiber, and plant protein. In dietary practice, healthy plant-based diets do not necessarily have to be low in fat. Instead, these diets should include unsaturated fats as the predominant form of dietary fat (eg, fats from natural liquid vegetable oils and nuts), whole grains as the main form of carbohydrate, an abundance of fruit and vegetables, and adequate n-3 fatty acids. Such diets, which also have many other health benefits, deserve more emphasis in dietary recommendations to prevent chronic diseases.


Higuchi, Y. (2003). "Chromosomal DNA fragmentation in apoptosis and necrosis induced by oxidative stress." Biochem Pharmacol 66(8): 1527-35.

            Chromosomal DNA dysfunction plays a role in mammalian cell death. Oxidative stress producing reactive oxygen species (ROS) induces chromatin dysfunction such as single- and double-strand DNA fragmentation leading to cell death through apoptosis or necrosis. More than 1 Mbp giant DNA, 200-800 or 50-300 kbp high molecular weight (HMW) DNA and internucleosomal DNA fragments are produced by oxidative stress and by some agents producing ROS during apoptosis or necrosis in several types of mammalian cells. Some nucleases involved in the chromosomal DNA fragmentation in apoptosis or necrosis are classified. ROS-mediated DNA fragmentation is caused and enhanced by polyunsaturated fatty acids (PUFAs) or their hydroperoxides through lipid peroxidation. A reduction of intracellular GSH levels induced by the inhibition of cystein transport or GSH biosynthesis leads to cell death through over production and accumulation of ROS in some types of mammalian cells. The ROS accumulation system has been used as a model of oxidative stress to discuss whether ROS-mediated DNA fragmentation associated with cell death is based on apoptosis or necrosis.


Havaux, M. (2003). "Spontaneous and thermoinduced photon emission: new methods to detect and quantify oxidative stress in plants." Trends Plant Sci 8(9): 409-13.

            Peroxidation of polyunsaturated fatty acids is one of the main events triggered by oxidative stress in cells. Some lipid peroxidation products are light-emitting species, and their luminescence can be used as an internal marker of oxidative stress. However, this spontaneous chemiluminescence is weak and difficult to measure. Recent studies have shown that an alternative approach that involves measuring thermoluminescence bands at high temperature (in the range 80-150 degrees C) is a simple way of detecting and quantifying lipid peroxidative damage and oxidative stress in plants.


Hardie, R. C. (2003). "Regulation of TRP channels via lipid second messengers." Annu Rev Physiol 65: 735-59.

            In Drosophila photoreceptors, the light-sensitive current is mediated downstream of phospholipase C by TRP (transient receptor potential) channels. Recent evidence suggests that Drosophila TRP channels are activated by diacylglycerol (DAG) or its metabolites (polyunsaturated fatty acids), possibly in combination with the reduction in phosphatidyl inositol 4,5 bisphosphate (PIP2). Consistent with this view, diacylglycerol kinase is identified as a key enzyme required for response termination. Signaling is critically dependent upon efficient PIP2 synthesis; mutants of this pathway in combination with genetically targeted PIP2 reporters provide unique insights into the kinetics and regulation of PIP2 turnover. Recent evidence indicates that a growing number of mammalian TRP homologues are also regulated by lipid messengers, including DAG, arachidonic acid, and PIP2.


Haag, M. (2003). "Essential fatty acids and the brain." Can J Psychiatry 48(3): 195-203.

            OBJECTIVE: To review the role of essential fatty acids in brain membrane function and in the genesis of psychiatric disease. METHOD: Medline databases were searched for published articles with links among the following key words: essential fatty acids, omega-3 fatty acids, docosahexanoic acid, eicosapentanoic acid, arachidonic acid, neurotransmission, phospholipase A2, depression, schizophrenia, mental performance, attention-deficit hyperactivity disorder, and Alzheimer's disease. Biochemistry textbooks were consulted on the role of fatty acids in membrane function, neurotransmission, and eicosanoid formation. The 3-dimensional structures of fatty acids were obtained from the Web site of the Biochemistry Department, University of Arizona (2001). RESULTS: The fatty acid composition of neuronal cell membrane phospholipids reflects their intake in the diet. The degree of a fatty acid's desaturation determines its 3-dimensional structure and, thus, membrane fluidity and function. The ratio between omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), in particular, influences various aspects of serotoninergic and catecholaminergic neurotransmission, as shown by studies in animal models. Phospholipase A2 (PLA2) hydrolyzes fatty acids from membrane phospholipids: liberated omega-6 PUFAs are metabolized to prostaglandins with a higher inflammatory potential, compared with those generated from the omega-3 family. Thus the activity of PLA2 coupled with membrane fatty acid composition may play a central role in the development of neuronal dysfunction. Intervention trials in human subjects show that omega-3 fatty acids have possible positive effects in the treatment of various psychiatric disorders, but more data are needed to make conclusive directives in this regard. CONCLUSION: The ratio of membrane omega-3 to omega-6 PUFAs can be modulated by dietary intake. This ratio influences neurotransmission and prostaglandin formation, processes that are vital in the maintenance of normal brain function.


Gil, A., M. Ramirez, et al. (2003). "Role of long-chain polyunsaturated fatty acids in infant nutrition." Eur J Clin Nutr 57 Suppl 1: S31-4.

            OBJECTIVE: To review briefly the influence of dietary long-chain polyunsaturated fatty acids (LC-PUFA) on tissue composition and functionality in early infancy. Moreover, the influences of LC-PUFA sources on plasma composition as well as the effects of these fatty acids on intestinal repair after malnutrition are discussed. RESULTS: Human milk not only supplies essential fatty acids but also contains up to 2% of the total fatty acids as LC-PUFA, of which arachidonic acid (AA) and docosahexaenoic acid (DHA) are considered the most important. Plasma and erythrocyte levels of both AA and DHA are decreased in infants fed artificial standard milk formulae. However, the supplementation of formulae with these fatty acids in amounts close to that of human milk leads to tissue LC-PUFA patterns similar to those of breast-fed infants. However, the bioavailability of LC-PUFA depends on the typical LC-PUFA source; egg phospholipids increases both AA and DHA in plasma phospholipids and HDL more than a mixture of tuna and fungal triglycerides. CONCLUSIONS: Dietary LC-PUFA affects positively the growth and development of the infant and ameliorates the visual and cognitive functions, particularly in preterm infants. Likewise, LC-PUFA improves intestinal repair in severe protein-energy malnutrition; therefore, its qualitative and quantitative dietary supply should be considered.


Formigoni, A. and E. Trevisi (2003). "Transition cow: interaction with fertility." Vet Res Commun 27 Suppl 1: 143-52.

            In recent years a progressive worsening of fertility indices in dairy cow herds has been observed. Several factors (genetic, dietary and management) seem to be more related to poor fertility than milk yield level. The degree and the length of the energy deficit during the transition period are inversely related to reproductive indices (e.g. conception rate is <30% for BCS decreases over one unit). A serious energy deficit reduces (or suppresses) pulsatile secretion of gonadotrophins (ovarian dysfunction and/or smaller follicles): IGF-I and insulin plasma levels (slower follicle growth and higher embryonic mortality); and progesterone production from the corpus luteum (higher rate of embryonic abortions). The diet influences fertility in several ways. Excess of rumen degradable proteins, apart from negative energy balance, negatively affects reproductive activity. Conversely, some nutrients (i.e. some polyunsaturated fatty acids or some amino acids) seem to show positive effects on fertility. Finally, the relationship between health status, often compromised during the transition period, and fertility efficiency is discussed. The release of cytokines seems to be related directly and indirectly (mainly by the change in usual hepatic metabolism to the malfunction of reproductive apparatus. Quick recovery of reproductive activity requires the adoption of strategies around calving to cover the higher environmental and nutritive requirements and to prevent disorders of any kind.


De Caterina, R., R. Madonna, et al. (2003). "Antiarrhythmic effects of omega-3 fatty acids: from epidemiology to bedside." Am Heart J 146(3): 420-30.

            Omega-3 polyunsaturated fatty acids are emerging as a safe and effective means to reduce sudden death after acute myocardial infarction. This review summarizes the epidemiological background for the use of omega-3 fatty acids with this indication, clinical trials performed so far, and experimental data supporting their antiarrhythmic efficacy.


Davydov, V. V. and A. I. Bozhkov (2003). "[Metabolism of endogenous aldehydes: participation in oxidative stress-induced lesions and its age aspects]." Biomed Khim 49(4): 374-87.

            This review summarizes the data regarding the synthesis and utilization of endogenous aldehydes and mechanisms of their cytotoxic effect. Peroxidation of polyunsaturated fatty acids is the main source of endogenous aldehydes. There are many different aldehydes generated in the cell. The most abundant is 4-hydroxy-2,3-nonenal synthesized from linoleic acid. Aldehydes may react with proteins and nucleic acids and change their functional properties. Aldehyde utilization mainly occurs in reactions catalysed by aldehyde dehydrogenase, aldehyde reductase and glutathione-S-transferase. The major pathway of their catabolism is accompanied with their conjugation with glutathione. Endogenous aldehyde utilization has its tissue- and age-dependent specificity. The status of aldehyde catabolism can modulate free radical alteration effect on the cell. An adequate stimulation of endogenous aldehyde utilization in the situation of enhancement of free radical generation may promote increasing the cell resistance to oxidative stress injury. Senescence is accompanied by a decrease in endogenous aldehyde utilization intensity in tissues. This could be important in the pathogenesis of age-dependent pathology.


Das, U. N. and Fams (2003). "Long-chain polyunsaturated fatty acids in the growth and development of the brain and memory." Nutrition 19(1): 62-5.


Das, U. N. (2003). "Can perinatal supplementation of long-chain polyunsaturated fatty acids prevent diabetes mellitus?" Eur J Clin Nutr 57(2): 218-26.

            It is suggested that the negative correlation between breast-feeding and insulin resistance and diabetes mellitus can be related to the presence of significant amounts of long-chain polyunsaturated fatty acids in the human breast milk. Based on this, it is proposed that provision of adequate amounts of long chain polyunsaturated fatty acids during the critical periods of brain growth and development can prevent or postpone the development diabetes mellitus.


Das, U. N. (2003). "Can memory be improved? A discussion on the role of ras, GABA, acetylcholine, NO, insulin, TNF-alpha, and long-chain polyunsaturated fatty acids in memory formation and consolidation." Brain Dev 25(4): 251-61.

            It is proposed that long-chain polyunsaturated fatty acids when given from the perinatal period will ensure proper development and growth of the brain and maintain the activity and/or concentrations of ras, nitric oxide, insulin, and various neurotransmitters and cytokines at physiological level and thus, improve memory and prevent learning deficits.


Das, U. N., E. J. Ramos, et al. (2003). "Metabolic alterations during inflammation and its modulation by central actions of omega-3 fatty acids." Curr Opin Clin Nutr Metab Care 6(4): 413-9.

            PURPOSE OF REVIEW: To discuss the possible relationship between long-chain polyunsaturated fatty acids, cytokines, anandamides, nitric oxide, leptin, various neurotransmitters in the brain, and their role in anorexia of acute and chronic inflammatory conditions and cancer. RECENT FINDINGS: Recent studies have shown that long-chain polyunsaturated fatty acids, especially the omega-3 series, have antiinflammatory actions, increase the concentrations of anandamides, enhance the levels of acetylcholine and nitric oxide and modulate the concentrations and actions of various neurotransmitters, including leptin, in the brain. Patients suffering from acute and chronic inflammatory conditions have low tissue concentrations of various long-chain polyunsaturated fatty acids, and high levels of proinflammatory cytokines that can cause anorexia and decrease food intake. SUMMARY: It is suggested that supplementation of long-chain polyunsaturated fatty acids may have a role in the prevention and treatment of acute and chronic inflammatory conditions, improving anorexia associated with these conditions.


Das, U. N. (2003). "Folic acid says NO to vascular diseases." Nutrition 19(7-8): 686-92.

            OBJECTIVES: The possible link between folic acid or folate and tetrahydrobiopterin (H(4)B), vitamin C, polyunsaturated fatty acids (PUFAs), and nitric oxide (NO), which may explain the beneficial actions of these nutrients in various vascular conditions, was investigated. METHODS: The literature pertaining to the actions of folic acid/folate, H(4)B, vitamin C, PUFAs, and NO was reviewed. RESULTS: Impaired endothelial NO (eNO) activity is an early marker for cardiovascular disease. Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folate not only reduces plasma homocysteine levels but also enhances eNO synthesis and shows anti-inflammatory actions. It stimulates endogenous H(4)B regeneration, a cofactor necessary for eNO synthesis, inhibits intracellular superoxide generation, and thus enhances the half-life of NO. H(4)B in turn enhances NO generation and augments arginine transport into the cells. Folic acid increases the concentration of omega-3 PUFAs, which also enhance eNO synthesis. Vitamin C augments eNO synthesis by increasing intracellular H(4)B and stabilization of H(4)B. Insulin stimulates H(4)B synthesis and PUFA metabolism, suppresses the production of proinflammatory cytokine tumor necrosis factor-alpha and superoxide anion, and enhances NO generation. The ability of folate to augment eNO generation is independent of its capacity to lower plasma homocysteine levels. CONCLUSIONS: The common mechanism by which folic acid, H(4)B, vitamin C, omega-3 fatty acids, and L-arginine bring about their beneficial actions in various vascular diseases is by enhancing eNO production. Hence, it remains to be determined whether a judicious combination of folic acid, vitamins B12, B6, and C, H(4)B, L-arginine, and omega-3 fatty acids in appropriate amounts may form a novel approach in the prevention and management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, peripheral vascular disease, and some neurodegenerative conditions.


Das, U. N. (2003). "Metabolic syndrome X is common in Indians: but, why and how?" J Assoc Physicians India 51: 987-98.

            Metabolic syndrome X is common in Indians. But the exact cause for this is not clear. Earlier, I proposed that this could be due to low activities of delta6 and delta5 desaturases and consequent decreased plasma and tissue concentrations of long-chain polyunsaturated fatty acids of omega-6 and omega-3 series since perinatal period. This implies that perinatal to adult life supplementation of long-chain polyunsaturated fatty acids could prevent, arrest or postpone the development of metabolic syndrome X and its complications.


Danbara, N., T. Yuri, et al. (2003). "[Inhibitory effect of n-3 polyunsaturated fatty acids on colorectal cancers]." Nippon Rinsho 61 Suppl 7: 519-21.


Colin, A., J. Reggers, et al. (2003). "[Lipids, depression and suicide]." Encephale 29(1): 49-58.

            Polyunsatured fatty acids are made out of a hydrocarbonated chain of variable length with several double bonds. The position of the first double bond (omega) differentiates polyunsatured omega 3 fatty acids (for example: alpha-linolenic acid or alpha-LNA) and polyunsatured omega 6 fatty acids (for example: linoleic acid or LA). These two classes of fatty acids are said to be essential because they cannot be synthetised by the organism and have to be taken from alimentation. The omega 3 are present in linseed oil, nuts, soya beans, wheat and cold water fish whereas omega 6 are present in maize, sunflower and sesame oil. Fatty acids are part of phospholipids and, consequently, of all biological membranes. The membrane fluidity, of crucial importance for its functioning, depends on its lipidic components. Phospholipids composed of chains of polyunsatured fatty acids increase the membrane fluidity because, by bending some chains, double bonds prevent them from compacting themselves perfectly. Membrane fluidity is also determined by the phospholipids/free cholesterol ratio, as cholesterol increases membrane viscosity. A diet based on a high proportion of essential polyunsatured fatty acids (fluid) would allow a higher incorporation of cholesterol (rigid) in the membranes to balance their fluidity, which would contribute to lower blood cholesterol levels. Brain membranes have a very high content in essential polyunsatured fatty acids for which they depend on alimentation. Any dietary lack of essential polyunsatured fatty acids has consequences on cerebral development, modifying the activity of enzymes of the cerebral membranes and decreasing efficiency in learning tasks. EPIDEMIOLOGICAL DATA: The prevalence of depression seems to increase continuously since the beginning of the century. Though different factors most probably contribute to this evolution, it has been suggested that it could be related to an evolution of alimentary patterns in the Western world, in which polyunsatured omega 3 fatty acids contained in fish, game and vegetables have been largely replaced by polyunsatured omega 6 fatty acids of cereal oils. Some epidemiological data support the hypothesis of a relation between lower depression and/or suicide rates and a higher consumption of fish. These data do not however prove a relation of causality. CHOLESTEROL AND DEPRESSION: Several cohort studies (on nondepressed subjects) have assessed the relationship between plasma cholesterol and depressive symptoms with contradictory results. Though some results found a significant relationship between a decrease of total cholesterol and high scores of depression, some other did not. Studies among patients suffering from major depression signalled more constantly an association between low cholesterol and major depression. Besides, some trials showed that clinical recovery may be associated with a significant increase of total cholesterol. CHOLESTEROL AND SUICIDAL BEHAVIOR: The hypothesis that a low cholesterol level may represent a suicidal risk factor was discovered accidentally following a series of epidemiological studies which revealed an increase of the suicidal risk among subjects with a low cholesterol level. Though some contradictory studies do exist, this relationship has been confirmed by several subsequent cohort studies. These findings have challenged the vast public health programs aimed at promoting the decrease of cholesterol, and even suggested to suspend the administration of lipid lowering drugs. Recent clinical studies on populations treated with lipid lowering drugs showed nevertheless a lack of significant increase of mortality, either by suicide or accident. In addition, several controlled studies among psychiatric patients revealed a decrease of the concentrations of plasma cholesterol among patients who had attempted suicide in comparison with other patients. POLYUNSATURATED FATTY ACID AND DEPRESSION: In major depression, all studies revealed a significant decrease of the polyunsaturated omega 3 fatty acids and/or an increase of the omega 6/omega 3 ratio in plasma and/or in the membranes of the red cells. In addition, two studies found a higher severity of depression when the level of polyunsaturated omega 3 fatty acids or the ratio omega 3/omega 6 was low. Parallel to these modifications, other biochemical perturbations have been reported in major depression, particularly an activation of the inflammatory response system, resulting in an increase of the pro-inflammatory cytokines (interleukins: IL-1b, IL-6 and interferon g) and eicosanoids (among others, prostaglandin E2) in the blood and the CSF of depressed patients. These substances cause a peroxidation and, consequently a catabolism of membrane phospholipids, among others those containing polyunsaturated fatty acids. The cytokines and eicosanoids derive from polyunsaturated fatty acids and have opposite physiological functions according to their omega 3 or omega 6 precursor. Arachidonic acid (omega 6) is, among others, precursor of pro-inflammatory prostaglandin E2 (PGE2), whereas polyunsaturated omega 3 fatty acids inhibit the formation of PGE2. It has been shown that a dietary increase of polyunsaturated omega 3 fatty acids reduced strongly the production of IL-1 beta, IL-2, IL-6 and TNF-alpha (tumor necrosis factor-alpha). In contrast, diets with a higher supply of linoleic acid (omega 6) increased significantly the production of pro-inflammatory cytokines, like TNF-alpha. Therefore, polyunsaturated omega 3 fatty acids could be associated at different levels in the pathophysiology of major depression, on the one hand through their role in the membrane fluidity which influences diverse steps of neurotransmission and, on the other hand, through their function as precursor of pro-inflammatory cytokines and eicosanoids disturbing neurotransmission. In addition, antidepressants could exhibit an immunoregulating effect by reducing the release of pro-inflammatory cytokines, by increasing the release of endogenous antagonists of pro-inflammatory cytokines like IL-10 and, finally, by acting like inhibitors of cyclo-oxygenase. THERAPEUTIC USE OF FATTY ACIDS: Data available concerning the administration of supplements of DHA (docosahexanoic acid) or other polyunsaturated fatty acids omega 3 are limited. In a double blind placebo-controlled study on 30 patients with bipolar disorder, the addition of polyunsaturated omega 3 fatty acids was associated with a longer period of remission. Moreover, nearly all the other prognosis measures were better in the omega 3 group. Very recently, a controlled trial showed the benefits of adding an omega 3 fatty acid, eicosopentanoic acid, among depressed patients. After 4 weeks, six of the 10 patients receiving the fatty acid were considered as responders in comparison with only one of the ten patients receiving placebo. CONCLUSIONS: Some epidemiological, experimental and clinical data favour the hypothesis that polyunsaturated fatty acids could play a role in the pathogenesis and/or the treatment of depression. More studies however are needed in order to better precise the actual implication of those biochemical factors among the various aspects of depressive illness.


Cockburn, F. (2003). "Role of infant dietary long-chain polyunsaturated fatty acids, liposoluble vitamins, cholesterol and lecithin on psychomotor development." Acta Paediatr Suppl 92(442): 19-33.


Cleland, L. G., M. J. James, et al. (2003). "The role of fish oils in the treatment of rheumatoid arthritis." Drugs 63(9): 845-53.

            Fish oils are a rich source of omega-3 long chain polyunsaturated fatty acids (n-3 LC PUFA). The specific fatty acids, eicosapentaenoic acid and docosahexaenoic acid, are homologues of the n-6 fatty acid, arachidonic acid (AA). This chemistry provides for antagonism by n-3 LC PUFA of AA metabolism to pro-inflammatory and pro-thrombotic n-6 eicosanoids, as well as production of less active n-3 eicosanoids. In addition, n-3 LC PUFA can suppress production of pro-inflammatory cytokines and cartilage degradative enzymes.In accordance with the biochemical effects, beneficial anti-inflammatory effects of dietary fish oils have been demonstrated in randomised, double-blind, placebo-controlled trials in rheumatoid arthritis (RA). Also, fish oils have protective clinical effects in occlusive cardiovascular disease, for which patients with RA are at increased risk.Implementation of the clinical use of anti-inflammatory fish oil doses has been poor. Since fish oils do not provide industry with the opportunities for substantial profit associated with patented prescription items, they have not received the marketing inputs that underpin the adoption of usual pharmacotherapies. Accordingly, many prescribers remain ignorant of their biochemistry, therapeutic effects, formulations, principles of application and complementary dietary modifications. Evidence is presented that increased uptake of this approach can be achieved using bulk fish oils. This approach has been used with good compliance in RA patients. In addition, an index of n-3 nutrition can be used to provide helpful feedback messages to patients and to monitor the attainment of target levels.Collectively, these issues highlight the challenges in advancing the use of fish oil amid the complexities of modern management of RA, with its emphasis on combination chemotherapy applied early.


Chung, F. L., J. Pan, et al. (2003). "Formation of trans-4-hydroxy-2-nonenal- and other enal-derived cyclic DNA adducts from omega-3 and omega-6 polyunsaturated fatty acids and their roles in DNA repair and human p53 gene mutation." Mutat Res 531(1-2): 25-36.

            The cyclic 1,N(2)-propanodeoxyguanosine adducts, derived from alpha,beta-unsaturated aldehydes or enals, including acrolein (Acr), crotonaldehyde (Cro), and trans-4-hydroxy-2-nonenal (HNE), have been detected as endogenous DNA lesions in rodent and human tissues. Collective evidence has indicated that the oxidative metabolism of polyunsaturated fatty acids (PUFAs) is an important pathway for endogenous formation of these adducts. In a recent study, we examined the specific role of different types of fatty acids, omega-3 and omega-6 PUFAs, in the formation of cyclic adducts of Acr, Cro, and HNE. Our studies showed that the incubation of deoxyguanosine 5'-monophosphate with omega-3 or omega-6 fatty acids under oxidative conditions in the presence of ferrous sulfate yielded different amounts of Acr, Cro, and HNE adducts, depending on the types of fatty acids. We observed that Acr- and Cro-dG adducts are primarily formed from omega-3, and the adducts derived from longer chain enals, such as HNE, were detected exclusively from omega-6 fatty acids. Acr adducts are also formed from omega-6 fatty acids, but to a lesser extent; the yields of Acr adducts are proportional to the number of double bonds present in the PUFAs. Two previously unknown cyclic adducts, one from pentenal and the other from heptenal, were detected as products from omega-3 and omega-6 fatty acids, respectively. Because omega-6 PUFAs are known to be involved in the promotion of tumorigenesis, we investigated the role of HNE adducts in p53 gene mutation by mapping the HNE binding to the human p53 gene with UvrABC nuclease and determined the formation of HNE-dG adducts in the gene. The results showed that HNE-dG adducts are preferentially formed in a sequence-specific manner at the third base of codon 249 in the p53 gene, a mutational hotspot in human cancers. The DNA repair study using plasmid DNA containing HNE-dG adducts as a substrate in HeLa cell extracts showed that HNE adducts are readily repaired, and that nucleotide excision repair appears to be a major pathway involved. Together, results of these studies provide a better understanding of the involvement of different PUFAs in DNA damage and their possible roles in tumorigenesis.


Christon, R. A. (2003). "Mechanisms of action of dietary fatty acids in regulating the activation of vascular endothelial cells during atherogenesis." Nutr Rev 61(8): 272-9.

            Dietary long chain omega-3 polyunsaturated fatty acids from fish oil appear to be clearly efficient in regulating endothelial dysfunction (or activation), which is the first stage of atherogenesis. Studies on endothelial cells in vitro have shown that the main dietary PUFA and oleic acid may prevent endothelium activation either by inhibiting the expression of adhesion molecules or by improving the nitric oxide production. Saturated fatty acids and also linoleic acid do not inhibit endothelium activation. The mechanisms involved in this inhibition could be related to endothelial cell membrane characteristics or redox status. However, these findings need to be confirmed in vivo.


Chiarla, C., I. Giovannini, et al. (2003). "[Use of unconventional lipid substrates in parental nutrition]." Clin Ter 154(2): 135-40.

            In addition to the classic soybean oil fat emulsion, developed more than 40 years ago and still widely used, emulsions with other lipid substrates are available today for parenteral nutrition; these substrates implement the benefits offered by soybean oil when mixed with it in given proportions. Soybean oil triglycerides are rich in linoleic acid, a long chain omega-6 polyunsaturated fatty acid, which is essential and is an indispensable component of parenteral nutrition. However, very high doses of omega-6 polyunsaturated fatty acids should be avoided, particularly in some critical illnesses. Medium chain triglycerides, long well known to nutritionists and dietitians for their easy intestinal absorption, have become available in parenteral nutrition emulsions in a mixture with soybean oil. Medium chain triglycerides are completely and readily used for energy production and do not interfere significantly in the production of inflammatory mediators, in the composition of cell membranes and in body organ and system functions. Omega-3 polyunsaturated fatty acids, essential fatty acids derived from fish oil, permeate cell structure and affect cell activity with different mechanisms, playing also an important role in the modulation of inflammatory processes. Omega-3 emulsions in parenteral nutrition are currently added as a supplement to other fat emulsions. Knowledge of these "non-conventional" fat emulsions is being continuously improved by investigative work and clinical experience.


Chanussot, F. and L. Benkoel (2003). "Prevention by dietary (n-6) polyunsaturated phosphatidylcholines of intrahepatic cholestasis induced by cyclosporine A in animals." Life Sci 73(4): 381-92.

            Previous findings showed that dietary (n-6) polyunsaturated phosphatidylcholines (vegetable lecithin) could efficiently prevent intrahepatic cholestasis induced by cyclosporine A in rats. Mechanistic studies showed that expressions in rat liver of Na(+), K(+)-ATPase, Ca(2+), Mg(2+)-ATPase and F-actin were both decreased by drug administration and both enhanced by (n-6) lecithin enriched diet. There is a possible direct effect of phosphatidylcholines, vectors of polyunsaturated fatty acids provided by the metabolism of the dietary lecithin, on the aforesaid hepatic parameters. Such modulations by drug and diet result in reversed modifications of membrane composition and fluidity. Final outcome is decreased and enhanced bile lipid secretion by cyclosporine and vegetable lecithin enriched diet respectively. Moreover, we advance the hypothesis of a bypass process including a separate and functional actin-independent way for the non micellar and phospholipid-dependent secretion of bile lipids. The relationships between the ATPases, the microfilament components such as F-actin and the different transporters still remain to be clarified. Furthermore, one can speculate on beneficial effects in humans of diets enriched in vegetable lecithins that might prevent cholestasis induced by cyclosporine A.


Chajes, V. and P. Bougnoux (2003). "Omega-6/omega-3 polyunsaturated fatty acid ratio and cancer." World Rev Nutr Diet 92: 133-51.


Carver, J. D. (2003). "Advances in nutritional modifications of infant formulas." Am J Clin Nutr 77(6): 1550S-1554S.

            Modifications to infant formulas are continually being made as the components of human milk are characterized and as the nutrient needs of diverse groups of infants are identified. Formulas with long-chain polyunsaturated fatty acids added in amounts similar to those in human milk have recently become available in the United States; infants fed these formulas or human milk have higher tissue concentrations of long-chain polyunsaturated fatty acids and reportedly have better visual acuity than do infants fed nonsupplemented formulas. Selenium, an important antioxidant, is present in higher concentrations in human milk than in non-fortified cow milk-based formula, and the selenium intakes of infants fed nonfortified formulas are reported to be at or below recommended levels. Blood selenium concentrations and plasma glutathione peroxidase activity are higher in infants fed selenium-supplemented formulas or human milk than in infants fed non-fortified formulas. Nucleotides and their related products play key roles in many biological processes. Although nucleotides can be synthesized endogenously, they are considered "conditionally essential." Nucleotide concentrations in human milk are higher than in unsupplemented cow milk-based formulas, and studies in animals and human infants suggest that dietary nucleotides play a role in the development of the gastrointestinal and immune systems. Formulas for preterm infants after hospital discharge are designed to meet the needs of a population in whom growth failure is common. Several studies have shown that preterm infants fed nutrient-enriched formulas after hospital discharge have higher rates of catch-up growth than do infants fed standard term-infant formulas.


Brenner, R. R. (2003). "Hormonal modulation of delta6 and delta5 desaturases: case of diabetes." Prostaglandins Leukot Essent Fatty Acids 68(2): 151-62.

            Animal biosynthesis of high polyunsaturated fatty acids from linoleic, alpha-linolenic and oleic acids is mainly modulated by the delta6 and delta5 desaturases through dietary and hormonal stimulated mechanisms. From hormones, only insulin activates both enzymes. In experimental diabetes mellitus type-1, the depressed delta6 desaturase is restored by insulin stimulation of the gene expression of its mRNA. However, cAMP or cycloheximide injection prevents this effect. The depression of delta6 and delta5 desaturases in diabetes is rapidly correlated by lower contents of arachidonic acid and higher contents of linoleic in almost all the tissues except brain. However, docosahexaenoic n-3 acid enhancement, mainly in liver phospholipids, is not explained yet. In experimental non-insulin dependent diabetes, the effect upon the delta6 and delta5 desaturases is not clear. From all other hormones glucagon, adrenaline, glucocorticoids, mineralocorticoids, oestriol, oestradiol, testosterone and ACTH depress both desaturases, and a few hormones: progesterone, cortexolone and pregnanediol are inactive.


Bistrian, B. R. (2003). "Clinical aspects of essential fatty acid metabolism: Jonathan Rhoads Lecture." JPEN J Parenter Enteral Nutr 27(3): 168-75.

            The clinical implications of the metabolism of the 2 essential fatty acids, linoleic and alpha-linolenic acid, are most clearly related to the membrane phospholipid concentrations of their elongation and desaturation products, arachidonic, eicosapentaenoic, and docosahexaenoic acid. Levels of these very long chain polyunsaturated fatty acids can be altered by diet, prematurity, and disease which can affect growth (nutritional repletion) and the intensity and character of systemic inflammation as well as cognitive and visual function in infants.


Bhatnagar, D. and P. N. Durrington (2003). "Omega-3 fatty acids: their role in the prevention and treatment of atherosclerosis related risk factors and complications." Int J Clin Pract 57(4): 305-14.

            Fatty acids are an important source of energy which can have an influence on serum lipids. Omega-3 and omega-6 fatty acids, both polyunsaturated fatty acids, have been advocated as replacement for saturated fat. Omega-3 fatty acids, derived from fish and certain green plants, lower serum triglycerides, but they have also been shown to have a direct effect on myocardial contractility, blood pressure, platelet function, coagulation factors, cell-mediated immunity and markers of inflammation. Recently available clinical trial data, including those using the concentrated omega-3 fatty acid preparation Omacor, indicate that omega-3 fatty acids are valuable in preventing sudden death following myocardial infarction. Studies indicate that omega-3 fatty acids are just as effective as, or have a benefit superior to, statins in secondary prevention. Omacor is also useful in the treatment of hypertriglyceridaemia, both as monotherapy and in combination with statins.


Beltowski, J., G. Wojcicka, et al. (2003). "[Peroxisome proliferator-activated receptors (PPAR) in pathophysiology of the circulatory system and prospective use of agonists of these receptors in therapy]." Postepy Hig Med Dosw 57(2): 199-217.

            Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate the expression of target genes. Three types of PPAR have been identified: PPAR alpha, PPAR beta/delta and PPAR gamma. The known endogenous PPAR ligands are polyunsaturated fatty acids and eicosanoids, such as 15-deoxy-delta 12,14-prostaglandin J2 and leukotriene B4. Two classes of drugs, fibrates and thiazolidinediones, bind to PPAR alpha and PPAR gamma, respectively. PPARs are involved in the regulation of the lipid metabolism and adipogenesis but are also expressed in the vasculature. PPARs activators inhibit inflammatory reactions within the vascular wall, inhibit vascular smooth muscle cells migration and proliferation and affect foam cells formation by changing the expression of scavenger receptors. PPAR agonists lower blood pressure and improve endothelial function in different animal models of hypertension as well as in humans. PPAR gamma ligands inhibit the development of atherosclerosis in LDL receptor deficient and apolipoprotein E deficient mice and in diabetic humans. PPAR gamma agonists have also been shown to attenuate myocardial hypertrophy and protect against ischemia-reperfuion injury.


Bauman, D. E. and J. M. Griinari (2003). "Nutritional regulation of milk fat synthesis." Annu Rev Nutr 23: 203-27.

            Certain diets cause a marked reduction in milk fat production in ruminants. Commonly referred to as milk fat depression (MFD), the mechanism involves an interrelationship between rumen microbial processes and tissue metabolism. Numerous theories to explain this interrelationship have been proposed and investigations offer little support for theories that are based on a limitation in the supply of lipogenic precursors. Rather, the basis involves alterations in rumen biohydrogenation of dietary polyunsaturated fatty acids and a specific inhibition of mammary synthesis of milk fat. The biohydrogenation theory proposes that under certain dietary conditions, typical pathways of rumen biohydrogenation are altered to produce unique fatty acid intermediates that inhibit milk fat synthesis. Trans-10, cis-12 conjugated linoleic acid (CLA) has been identified as one example that is correlated with the reduction in milk fat. Investigations with pure isomers have shown that trans-10, cis-12 CLA is a potent inhibitor of milk fat synthesis, and similar to diet-induced MFD, the mechanism involves a coordinated reduction in mRNA abundance for key enzymes involved in the biochemical pathways of fat synthesis. A more complete identification of these naturally produced inhibitors of fat synthesis and delineation of cellular mechanisms may offer broader opportunities for application and understanding of the regulation of lipid metabolism.


Bassett, C. N. and T. J. Montine (2003). "Lipoproteins and lipid peroxidation in Alzheimer's disease." J Nutr Health Aging 7(1): 24-9.

            Alzheimer's Disease (AD) is a clinical-pathological entity that probably derives from different causes. Mounting evidence strongly implicates regionally increased oxidative damage to brain beyond what occurs with aging as one of the processes that may contribute to AD progression. While several different classes of molecules may be affected, lipid peroxidation is thought to be a prominent and especially deleterious form of oxidative damage in brain due to this organ's relative enrichment in polyunsaturated fatty acids. Our laboratory recently has demonstrated that lipoproteins in AD brain extracellular fluid are more vulnerable to oxidation than lipoproteins in control brain extracellular fluid. Apolipoprotein E (apoE) is the principal apolipoprotein in the central nervous system (CNS), and it serves as the major apolipoprotein that is capable of lipid transport and regulation of lipid metabolism through known receptor-mediated processes. Moreover, inheritance of the APOE4 allele represents the strongest genetic risk factor for sporadic AD. Evidence suggests that apoE isoforms may specifically influence the cellular distribution of lipid peroxidation products in brain and may therefore contribute to the stratification of risk for AD associated with APOE. Here, we review possible mechanisms whereby lipoprotein trafficking and lipid peroxidation converge to contribute to neurodegeneration in AD brain.


Aruoma, O. I. (2003). "Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods." Mutat Res 523-524: 9-20.

            The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Downs syndrome) and aging challenges continue to emerge from difficulties associated with methods used in evaluating antioxidant actions in vivo. Our interest presently is focused on development of neurodegeneration models based on the integrity of neuronal cells in the central nervous system and how they are protected by antioxidants when challenged by neurotoxins as well as Fenton chemistry models based on the profile of polyunsaturated fatty acids (PUFAs) for the assessment of antioxidant actions in vivo. Use continues to be made of several in vitro analytical tools to characterise the antioxidant propensity of bioactive compounds in plant foods and supplements. For example, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), total oxidant scavenging capacity (TOSC), the deoxyribose assay, assays involving oxidative DNA damage, assays involving reactive nitrogen intermediates (e.g. ONOO(-)), Trolox equivalent antioxidant capacity (TEAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. There is need to agree governance on in vitro antioxidant methods based on an understanding of the mechanisms involved. Because some of the assays are done in non-physiological pH values, it is impossible to extrapolate the results to physiological environment. The consensus of opinion is that a mix of these tools should be used in assessing the antioxidant activities in vitro. The proof of bio-efficacy must emanate from application of reliable in vivo models where markers of baseline oxidative damage are examined from the standpoint of how they are affected by changes in diet or by antioxidant supplements.


Agostoni, C. and F. Haschke (2003). "Infant formulas. Recent developments and new issues." Minerva Pediatr 55(3): 181-94.

            Infant formulas on the market today should be aimed at providing the best alternative to breast milk for infants of those women who are unable to continue breastfeeding until 6 months of age and substituting ideally for human milk after 6 months of age approaching the structural and functional effects observed in breastfed infants. The aim is to mimic the functional outcome of the breastfed infant (e.g. growth and development), and not to copy the composition of human milk. For this purpose, the following compounds have been added to formulas and are reviewed: long-chain polyunsaturated fatty acids (LCPUFA) for brain composition and neurodevelopment, probiotics and prebiotics for the fecal flora and the local intestinal defense, and nucleotides for promoting the immune response. Changes in protein quantity and quality allow to balance the blood amino acid pattern (possibly relevant to the early stages of brain development for the neurotransmitter function) and reducing the protein intake could be important for the prevention of later overweight. Hydrolysed proteins are important in the prevention of atopic disorders. Many trials have been published so far with short-term assessments, most of them with positive findings. However, we need more data on the long-term follow-up of infants who were fed the new formulas. Such data will allow to look at neural performance, prevention of overweight and obesity, and effects on the immune-allergic pattern.


Ziboh, V. A., Y. Cho, et al. (2002). "Biological significance of essential fatty acids/prostanoids/lipoxygenase-derived monohydroxy fatty acids in the skin." Arch Pharm Res 25(6): 747-58.

            The skin displays a highly active metabolism of polyunsaturated fatty acids (PUFA). Dietary deficiency of linoleic acid (LA), an 18-carbon (n-6) PUFA, results in characteristic scaly skin disorder and excessive epidermal water loss. Although arachidonic acid (AA), a 20-carbon (n-6) PUFA, is metabolized via cyclooxygenase pathway into predominantly prostaglandin E2 (PGE2) and PGF2alpha, the metabolism of AA via the 15-lipoxygenase (15-LOX) pathway, which is very active in skin epidermis and catalyzes the transformation of AA into predominantly 15S-hydroxyeicosatetraenoic acid (15S-HETE). Additionally, the 15-LOX also metabolizes the 18-carbon LA into 13S-hydroxyoctadecadienoic acid (13S-HODE), respectively. Interestingly, 15-LOX catalyzes the transformation of dihomo-gamma-linolenic acid (DGLA), derived from dietary gamma-linolenic acid, to 15S-hydroxyeicosatrienoic acid (15S-HETrE). These monohydroxy fatty acids are incorporated into the membrane inositol phospholipids which undergo hydrolytic cleavage to yield substituted-diacylglycerols such as 13S-HODE-DAG from 13S-HODE and 15S-HETrE-DAG from 15S-HETrE. These substituted-monohydroxy fatty acids seemingly exert anti-inflammatory/antiproliferative effects via the modulation of selective protein kinase C as well as on the upstream/down-stream nuclear MAP-kinase/AP-1/apoptotic signaling events.


Yu, F. L. (2002). "17Beta-estradiol epoxidation as the molecular basis for breast cancer initiation and prevention." Asia Pac J Clin Nutr 11 Suppl 7: S460-6.

            Epidemiological and animal studies have indicated that 17beta-estradiol (E2) is involved in breast cancer; however, the mechanism is unclear. We found that E2 could be activated by epoxidation, resulting in its ability to inhibit nuclear DNA-dependent RNA synthesis, and to bind DNA, forming DNA adducts both in vitro and in vivo. Because epoxidation is required for the activation of many chemical carcinogens, including benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene and aflatoxins, we proposed previously that E2 epoxidation is the underlying mechanism for the initiation of breast cancer. The first part of this review is to present the experimental evidence obtained from this laboratory in support of this hypothesis. Based on these newly discovered insights on E2 epoxidation and its initiation role in breast cancer carcinogenesis, a method to screen chemopreventive agents against breast cancer has been developed. This constitutes the second part of the review. Two examples will be used to illustrate the utility of this screening technique. The effect of fat on breast cancer has been a longstanding but unresolved issue. Epidemiological studies provide conflicting results regarding the association of dietary fat and breast cancer. Because vegetable oils contain various amount of mono- and polyunsaturated fatty acids, they are potential antioxidants. Data are presented to show that commercial vegetable oils, independent of their mono- or polyunsaturated fatty acid content, are all able to prevent the formation of E2 epoxide, as measured by the loss of the ability of E2 to inhibit nuclear RNA synthesis in vitro. Tamoxifen (TAM), an anti-estrogen used for breast cancer treatment, has recently been found to have a strong breast cancer preventive effect. The mechanism for this is unknown. Using the same screening technique, we found that when incubated together with E2 for epoxidation, TAM was able to prevent the formation of E2 epoxide, as evidenced by both the loss of the ability of E2 to inhibit nuclear RNA synthesis and the reduced binding of [3H]-labelled E2 to nuclear DNA in a dose-dependent manner. These experimental results suggest that the breast cancer preventive effect of TAM is to prevent the formation of E2 epoxide through a competitive epoxidation mechanism with E2.


Yehuda, S., S. Rabinovitz, et al. (2002). "The role of polyunsaturated fatty acids in restoring the aging neuronal membrane." Neurobiol Aging 23(5): 843-53.

            In addition to a gradual loss of neurons in various brain regions, major biochemical changes in the brain affect the neuronal membrane that is the "site of action" for many essential functions including long-term potentiation (LTP), learning and memory, sleep, pain threshold, and thermoregulation. Normal physiological functioning includes the transmission of axonal information, regulation of membrane-bound enzymes, control of ionic channels and various receptors. All are highly dependent on membrane fluidity, where rigidity is increased during aging. The significantly higher level of cholesterol in aging neuronal membrane, the slow rate of cholesterol turnover, and the decreased level of total polyunsaturated fatty acids (PUFA) may result from poor passage rate via the blood-brain barrier, or from a decreased rate of incorporation into the membrane, or a decrease in the activities of delta-6 and delta-9 desaturase enzymes. The added oxidative stress, which leads to an increase of free radicals leading to a decrease in membrane fluidity, may respond to a restricted diet, and thereby overcome the damaging effects of the free radicals. A central focus of this review is that a specific ratio of n-3/n-6 PUFA can restore many of these age-related effects.


Yavin, E., A. Brand, et al. (2002). "Docosahexaenoic acid abundance in the brain: a biodevice to combat oxidative stress." Nutr Neurosci 5(3): 149-57.

            Docosahexaenoic acid (DHA) (22:6) is a polyunsaturated fatty acid of the n - 3 series which is believed to be a molecular target for lipid peroxides (LPO) formation. Its ubiquitous nature in the nervous tissue renders it particularly vulnerable to oxidative stress, which is high in brain during normal activity because of high oxygen consumption and generation of reactive oxygen species (ROS). Under steady state conditions potentially harmful ROS and LPO are maintained at low levels due to a strong antioxidant defense mechanism, which involves several enzymes and low molecular weight reducing compounds. The present review emphasizes a paradox: a discrepancy between the expected high oxidability of the DHA molecule due to its high degree of unsaturation and certain experimental results which would indicate no change or even decreased lipid peroxidation when brain tissue is supplied or enriched with DHA. The following is a critical review of the experimental data relating DHA levels in the brain to lipid peroxidation and oxidative damage there. A neuroprotective role for DHA, possibly in association with the vinyl ether (VE) linkage of plasmalogens (pPLs) in combating free radicals is proposed.


Wallis, J. G., J. L. Watts, et al. (2002). "Polyunsaturated fatty acid synthesis: what will they think of next?" Trends Biochem Sci 27(9): 467.

            Polyunsaturated fatty acids have crucial roles in membrane biology and signaling processes in most living organisms. However, it is only recently that molecular genetic approaches have allowed detailed studies of the enzymes involved in their synthesis. New evidence has revealed a range of pathways in different organisms. These include a complex sequence for synthesis of docosahexaenoic acid (22:6) in mammals and a polyketide synthase pathway in marine microbes.


Waitzberg, D. L., P. H. Lotierzo, et al. (2002). "Parenteral lipid emulsions and phagocytic systems." Br J Nutr 87 Suppl 1: S49-57.

            Lipid emulsions (LE) for parenteral use are complex emulsions containing fatty acids, glycerol, phospholipids and tocopherol in variable amounts and concentrations. In clinical practice, LE have been employed for more than 30 years. Fatty acids may have different impacts on phagocytic cells according to their structure. Experimental and clinical studies have consistently shown that LE modify monocyte/macrophage and polymorphonuclear phagocytosis. The inhibitory effect of LE on the functional activity of the phagocytic system, although still clinically controversial, may have a harmful impact because total parenteral nutrition with lipids may be recommended in hypercatabolic conditions where inflammation and infection are present. LE based on triglycerides containing long chain fatty acids (termed long chain triglycerides or LCT) are the main parenteral fat source and are typically rich in n-6 polyunsaturated fatty acids. They may have adverse effects on the immune system, especially when given in high doses over a short period of time. However when administered properly they can be used safely. LE containing medium chain triglycerides (MCT) may have some advantages because of their positive effects on polymorphonuclear cells, macrophages, and cytokine production, particularly in critically ill or immunocompromised patients. New parenteral LE containing n-3 polyunsaturated fatty acids or monounsaturated olive oil are already available in Europe. Judicious use of these new LE is mandatory especially relating on their potential impact on the immune system. New experimental and clinical studies are required to further establish the role of LE in clinical nutrition.


Wainwright, P. E. (2002). "Dietary essential fatty acids and brain function: a developmental perspective on mechanisms." Proc Nutr Soc 61(1): 61-9.

            Brain development is a complex interactive process in which early disruptive events can have long-lasting effects on later functional adaptation. It is a process that is dependent on the timely orchestration of external and internal inputs through sophisticated intra- and intercellular signalling pathways. Long-chain polyunsaturated fatty acids (LCPUFA), specifically arachidonic acid and docosahexaenoic acid (DHA), accrue rapidly in the grey matter of the brain during development, and brain fatty acid (FA) composition reflects dietary availability. Membrane lipid components can influence signal transduction cascades in various ways, which in the case of LCPUFA include the important regulatory functions mediated by the eicosanoids, and extend to long-term regulation through effects on gene transcription. Our work indicates that FA imbalance as well as specific FA deficiencies can affect development adversely, including the ability to respond to environmental stimulation. For example, although the impaired water-maze performance of mice fed a saturated-fat diet improved in response to early environmental enrichment, the brains of these animals showed less complex patterns of dendritic branching. Dietary n-3 FA deficiency influences specific neurotransmitter systems, particularly the dopamine systems of the frontal cortex. We showed that dietary deficiency of n-3 FA impaired the performance of rats on delayed matching-to-place in the water maze, a task of the type associated with prefrontal dopamine function. We did not, however, find an association over a wider range of brain DHA levels and performance on this task. Some, but not all, studies of human infants suggest that dietary DHA may play a role in cognitive development as well as in some neurodevelopmental disorders; this possibility has important implications for population health.


Turner, N. D., L. A. Braby, et al. (2002). "Opportunities for nutritional amelioration of radiation-induced cellular damage." Nutrition 18(10): 904-12.

            The closed environment and limited evasive capabilities inherent in space flight cause astronauts to be exposed to many potential harmful agents (chemical contaminants in the environment and cosmic radiation exposure). Current power systems used to achieve space flight are prohibitively expensive for supporting the weight requirements to fully shield astronauts from cosmic radiation. Therefore, radiation poses a major, currently unresolvable risk for astronauts, especially for long-duration space flights. The major detrimental radiation effects that are of primary concern for long-duration space flights are damage to the lens of the eye, damage to the immune system, damage to the central nervous system, and cancer. In addition to the direct damage to biological molecules in cells, radiation exposure induces oxidative damage. Many natural antioxidants, whether consumed before or after radiation exposure, are able to confer some level of radioprotection. In addition to achieving beneficial effects from long-known antioxidants such as vitamins E and C and folic acid, some protection is conferred by several recently discovered antioxidant molecules, such as flavonoids, epigallocatechin, and other polyphenols. Somewhat counterintuitive is the protection provided by diets containing elevated levels of omega-3 polyunsaturated fatty acids, considering they are thought to be prone to peroxidation. Even with the information we have at our disposal, it will be difficult to predict the types of dietary modifications that can best reduce the risk of radiation exposure to astronauts, those living on Earth, or those enduring diagnostic or therapeutic radiation exposure. Much more work must be done in humans, whether on Earth or, preferably, in space, before we are able to make concrete recommendations.


Tijet, N. and A. R. Brash (2002). "Allene oxide synthases and allene oxides." Prostaglandins Other Lipid Mediat 68-69: 423-31.

            Allene oxides are unstable epoxides formed by the enzymatic dehydration of the lipoxygenase products of polyunsaturated fatty acids. The allene oxide synthases are of two structurally-unrelated types. In plants, a subfamily of cytochromes P450, designated as CYP74A, use the hydroperoxides of linoleic and linolenic acids as substrate. Both the 9- and 13-hydroperoxides may be converted to allene oxides and subsequently give rise to plant signaling molecules. In corals, a catalase-related hemoprotein functions as the allene oxide synthase. These marine invertebrates, as well as starfish, form allene oxides from the 8R-hydroperoxide of arachidonic acid. The coral allene oxide synthase from Plexaura homomalla occurs as the N-terminal domain of a natural fusion protein with the 8R-lipoxygenase that forms its substrate. This enzyme may be involved in biosynthesis of the cyclopentenone eicosanoids such as the clavulones.


Thompson, M. B. and B. K. Speake (2002). "Energy and nutrient utilisation by embryonic reptiles." Comp Biochem Physiol A Mol Integr Physiol 133(3): 529-38.

            Most reptiles are oviparous, with the developing embryos relying on the contents of the yolk to sustain development until hatching (lecithotrophy). The yolk is composed primarily of lipid and protein, which act as an energy source and the essential components to build embryonic tissue. Nevertheless, yolk and the resulting embryos contain many other nutrients, including inorganic ions, vitamins, carotenoids, water and hormones. Apart from water and oxygen, which may be taken up by eggs, and some inorganic ions that can come from the eggshell or even from outside the egg, everything required by the embryo must be in the egg when it is laid. Approximately 20% of squamate reptiles are viviparous, exhibiting a variety of placental complexities. Species with complex placentae have reduced yolk volumes, with the mother augmenting embryonic nutrition by provision across the placenta (placentotrophy). Despite assumed advantages of placentotrophy, only 5 out of approximately 100 lineages of viviparous squamates exhibit substantial placentotrophy. This paper reviews available and recent information on the yolk contents of a variety of squamate reptiles to ask the question, how are nutrients transported from the yolk to the embryo or across the placenta? Although, current available data suggest that, in broad terms, yolk is taken up by embryos without discrimination of the nutrients, there are some apparent exceptions, including the very long chain polyunsaturated fatty acids. In addition, fundamental differences in the patterns of energy utilisation in lizards and snakes suggest fundamental differences in lipid profiles in these taxa, which appear to reflect the differences between placentotrophic and lecithotrophic viviparous lizards.


Tapiero, H., G. N. Ba, et al. (2002). "Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies." Biomed Pharmacother 56(5): 215-22.

            Linoleic and alpha-linolenic acids, obtained from plant material in the diet are the precursors in tissues of two families with opposing effects which are referred to as "essential fatty acids" (EFA): arachidonic acid (AA) and pentaene (eicosapentaenoic acid: EPA) and hexaene (docosahexaenoic acid: DHA) acids. The role of EFA is crucial, without a source of AA or compounds which can be converted into AA, synthesis of prostaglandins (PGs) by a cyclooxygenase (COX) enzyme would be compromised, and this would seriously affect many normal metabolic processes. COX, also known as prostaglandin endoperoxide synthase (Pghs) or as prostaglandin G/H synthase, is a key membrane bound enzyme responsible for the oxidation of AA to PGs. Two COX isoforms have been identified, COX-1 and COX-2 that form PGH2, a common precursor for the biosynthesis of thromboxane A2 (TxA2), prostacyclin (PGI2) and PGs (PGD2, PGE2, PGF2alpha. COX-1 enzyme is expressed constitutively in most cells and tissues. Its expression remains constant under either physiological or pathological conditions controlling synthesis of those PGs primarily involved in the regulation of homeostatic functions. In contrast, COX-2 is an intermediate response gene that encodes a 71-kDa protein. COX-2 is normally absent from most cells but highly inducible in certain cells in response to inflammatory stimuli resulting in enhanced PG release. PGs formed by COX-2 primarily mediate pain and inflammation but have multiple effects that can favour tumorigenesis. They are more abundant in cancers than in normal tissues from which the cancers arise. COX-2 is a participant in the pathway of colon carcinogenesis, especially when mutation of the APC (Adenomatous Polyposis Coli) tumour suppressor gene is the initiating event. In addition, COX-2 up-regulation and elevated PGE2 levels are involved in breast carcinogenesis. It seems that there is a correlation between COX-2 level of expression and the size of the tumours and their propensity to invade underlying tissue. Inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) of COX enzymes which significantly suppress PGE2 levels, reduced breast cancer incidence and protected against colorectal cancer. Therefore it is suggested that consumption of a diet enriched in n-3 PUFA (specifically EPA and DHA) and inhibition of COX-2 by NSAIDs may confer cardioprotective effects and provide a significant mechanism for the prevention and treatment of human cancers.


Tang, D. G., E. La, et al. (2002). "Fatty acid oxidation and signaling in apoptosis." Biol Chem 383(3-4): 425-42.

            It is well established that fatty acid metabolites of cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 are implicated in essential aspects of cellular signaling including the induction of programmed cell death. Here we review the roles of enzymatic and non-enzymatic products of polyunsaturated fatty acids in controlling cell growth and apoptosis. Also, the spontaneous oxidation of polyunsaturated fatty acids yields reactive aldehydes and other products of lipid peroxidation that are potentially toxic to cells and may also signal apoptosis. Significant conflicting data in terms of the role of LOX enzymes are highlighted, prompting a re-evaluation of the relationship between LOX and prostate cancer cell survival. We include new data showing that LNCaP, PC3, and Du145 cells express much lower levels of 5-LOX mRNA and protein compared with normal prostate epithelial cells (NHP2) and primary prostate carcinoma cells (TP1). Although the 5-LOX activating protein inhibitor MK886 killed these cells, another 5-LOX inhibitor AA861 hardly showed any effect. These observations suggest that 5-LOX is unlikely to be a prostate cancer cell survival factor, implying that the mechanisms by which LOX inhibitors induce apoptosis are more complex than expected. This review also suggests several mechanisms involving peroxisome proliferator activated receptor activation, BCL proteins, thiol regulation, and mitochondrial and kinase signaling by which cell death may be produced in response to changes in non-esterified and non-protein bound fatty acid levels. Overall, this review provides a context within which the effects of fatty acids and fatty acid oxidation products on signal transduction pathways, particularly those involved in apoptosis, can be considered in terms of their overall importance relative to the much better studied protein or peptide signaling factors.


Stoll, B. A. (2002). "Upper abdominal obesity, insulin resistance and breast cancer risk." Int J Obes Relat Metab Disord 26(6): 747-53.

            PURPOSE: A majority of prospective studies show breast cancer risk to be higher in obese postmenopausal women with upper abdominal adiposity than in those with overall adiposity. The evidence is more limited and inconsistent in the case of premenopausal women. The review examines evidence that aberrant insulin signalling may be involved in the promotion of mammary carcinogenesis. The aetiology and concomitants of abdominal visceral obesity are examined. MECHANISMS: Clinical and experimental evidence suggests that the higher breast cancer risk associated with greater abdominal visceral obesity may be related to aberrant insulin signalling through the insulin receptor substrate 1 pathway, leading to insulin resistance, hyperinsulinaemia and increased concentrations of endogenous oestrogen and androgen. The putative role of aberrant insulin signalling in the promotion of mammary carcinogenesis may help to explain clinical relationships between breast cancer risk and age at menarche, pregnancies and onset of obesity. CONCLUSION: Overall adiposity in women adversely affects breast cancer risk mainly by greater exposure of mammary epithelial tissue to endogenous oestrogen. Upper abdominal adiposity appears to involve an additional effect related to the presence of insulin resistance. Aetiological factors in the development of hyperinsulinaemic insulin resistance are still uncertain but may involve aberrant susceptibility genes in adipocyte insulin receptors or in the insulin receptor substrate 1 pathway. Epigenetic factors are also likely to contribute, including high free fatty acid levels and obesity. Dietary fatty acids, particularly polyunsaturated fatty acids, are known to regulate adipocyte differentiation through the nuclear peroxisome proliferator-activated receptor gamma, and may also have a role in insulin resistance. These aetiological factors are likely to be relevant to the high risk of postmenopausal breast cancer in industrialised Western populations.


Stoll, B. A. (2002). "Linkage between retinoid and fatty acid receptors: implications for breast cancer prevention." Eur J Cancer Prev 11(4): 319-25.

            Certain dietary retinoids and polyunsaturated fatty acids (PUFAs) consistently inhibit progression of mammary carcinogenesis both in animal studies and cell culture, but clinically, their effect is inconsistent. New evidence of synergistic interaction between the nuclear receptors for the two groups of nutritional agents suggests that appropriate selective ligands from each group might be combined in breast cancer chemoprevention studies. Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor that is activated by PUFAs, eicosanoids and antidiabetic agents such as troglitazone. Such activation can cause growth inhibition in human mammary cancer cells in culture and the effect is enhanced by ligands of retinoic acid receptor (RAR) and retinoid X receptor (RXR). In mouse mammary tissue in organ culture, an RXR-selective ligand has been shown to enhance the effect of troglitazone in suppressing carcinogen-induced pre-neoplastic changes. A PPAR/RXR heterodimer is involved in tumour growth inhibition and has been shown to bind directly to nuclear oestrogen response elements (ERE) independently of oestrogen receptor (ER) activity. A combination of an RXR-selective retinoid with either troglitazone or else a long-chain n-3 PUFA, is proposed for a short-term study in postmenopausal women after primary surgery for intraductal breast cancer. The resulting activation of PPAR/RXR expression may increase response to retinoid administration, especially in the presence of obesity and insulin resistance, because of the ability of PPAR gamma ligands to reduce insulin-like growth factor I (IGF-I) concentrations. Serial core biopsies of breast tissue over a short term are proposed to identify changes in phenotype, which may influence progression to invasiveness. In addition to cytomorphological criteria, expression of ER alpha and beta, RAR alpha and beta, and IGF-I receptor in the nucleus should be examined.


Srinivasan, V. (2002). "Melatonin oxidative stress and neurodegenerative diseases." Indian J Exp Biol 40(6): 668-79.

            Oxidative Stress is implicated as one of the primary factors that contribute to the development of neurodegenerative diseases like Alzheimer's Disease, Parkinsonism and neurological conditions like epileptic seizures, stroke, brain damage, neurotrauma etc. The increased formation and release of oxygen free radicals coupled with the rather low antioxidative potential of the central nervous system are the major reasons that account for the enhanced oxidative stress seen in neuronal cells. In addition to this, brain is also enriched with polyunsaturated fatty acids that render neuronal cells easily vulnerable to oxidative attack. The fact that there is increased incidence of neurodegenerative disorders in aged individuals, has prompted many investigators to search for a common factor whose progressive decline with increase in age could account for increased oxidative stress resulting in senescence and age associated degenerative diseases. Since melatonin, the hormone secreted from the pineal gland has a remarkable anti-oxidant property and whose rate of production declines with increase in age, has prompted many to suggest that this hormone plays a crucial role in the genesis of neurodegenerative diseases. Melatonin cannot only scavenges oxygen free radicals like super oxide radical (O2-), hydroxyl radical (*OH), peroxyl radical (LOO*) and peroxynitrite anion (ONOO-), but can also enhance the antioxidative potential of the cell by stimulating the synthesis of antioxidative enzymes like super oxide dismutase (SOD), glutathione peroxidase (GPX), and also the enzymes that are involved in the synthesis of glutathione. In many instances, melatonin increases the expression of m RNA's of the antioxidative enzymes. Melatonin administration has been shown to be effective in counteracting the neurodegenerative conditions both in experimental models of neurodegenerative diseases and in patients suffering from such diseases. A disturbance of melatonin rhythm and secretion also has been noted in patients suffering from certain neurodegenerative diseases. From all these, it is evident that melatonin has a neuroprotective role.


Sprecher, H. (2002). "The roles of anabolic and catabolic reactions in the synthesis and recycling of polyunsaturated fatty acids." Prostaglandins Leukot Essent Fatty Acids 67(2-3): 79-83.

            Generally the biosynthesis and degradation of compounds take place in separate subcellular compartments. The synthesis of 22 carbon acids, with their first double bond at position 4, requires anabolic enzymes in the endoplasmic reticulum as well as peroxisomal beta-oxidation enzymes. Partial degradation-resynthesis cycles, using enzymes in these two subcellular compartments, may play an important role in determining what PUFA are available for membrane lipid biosynthesis.


Spiteller, G. (2002). "Are changes of the cell membrane structure causally involved in the aging process?" Ann N Y Acad Sci 959: 30-44.

            Lipid peroxidation is recognized by proliferation, wounding, and aging. The connecting link between these different events is a change in cell wall structure, which activates membrane bound phospholipases. These cleave phospholipids. Thus liberated polyunsaturated fatty acids (PUFAs) are substrates for lipoxygenases, which accept equally well linoleic acid and arachidonic acid and generate lipid hydroperoxides (LOOHs). If the amount of free PUFAs exceeds a certain amount, lipoxygenases commit suicide. The consequence is liberation of free iron ions that react with LOOHs by formation of radicals. These start a chain reaction. LOO* radicals produced in the course of this process attack proteins, nucleic acids, and also double bonds of all unsaturated compounds by epoxidation. Morever LOOHs are decomposed to toxic epoxy acids and alphabetagammadelta-unsaturated aldehydes. Both species react with glutathione. The resulting products seem to induce apoptosis. Since the products generated by wounding or aging are formed by decomposition of LOOHs the investigation of the aging processes can be simplified by studying the physiological action of artificially generated lipid peroxidation products derived from pure PUFAs. Degradation products of LOOHs are generated by thermal decomposition of fat-containing PUFAs. These products are induced into the body by adsorption in the intestine. They are at least partly incorporated in low density lipoproteins (LDLs). Primarily investigations seem to indicate that an overload of a diet rich in PUFAs induces only after two days an increase in oxidized LDL/PUFAs for a factor up to two in young people and for a factor of more than two in old individuals.


Simopoulos, A. P. (2002). "The importance of the ratio of omega-6/omega-3 essential fatty acids." Biomed Pharmacother 56(8): 365-79.

            Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries, that are being exported to the rest of the world.


Simopoulos, A. P. (2002). "Omega-3 fatty acids in inflammation and autoimmune diseases." J Am Coll Nutr 21(6): 495-505.

            Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)--are more biologically potent than alpha-linolenic acid (ALA). Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn's disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB(4) produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.


Siems, W., S. Quast, et al. (2002). "Oxidative stress in chronic renal failure as a cardiovascular risk factor." Clin Nephrol 58 Suppl 1: S12-9.

            Myocardial injury has been shown to be the most critical factor influencing quality of life and mortality in patients with chronic renal failure. Oxidative stress has been postulated to be an important risk factor for cardiovascular disorders. One reason for oxidative stress in patients with renal failure is the underlying disease itself. Renal toxicity, ischemia/reperfusion and immunological disorders of the kidney result in an elevated formation of reactive oxygen species active in the pathogenesis of kidney disease. However, treatment procedures were also shown to induce oxidative stress. Increased formation of free radicals leads to an accelerated lipid peroxidation (LPO). Furthermore, secondary aldehydic LPO products, e.g. malondialdehyde (MDA) and 4-hydroxynonenal (HNE), are formed which were shown to deplete antioxidants, inhibit protein syntheses, mitochondrial respiration, and enzyme functions. F2-isoprostanes, also metabolites of polyunsaturated fatty acids, represent an additional in vivo marker of oxidative stress. Both isoprostanes and aldehydic LPO products can be removed by hemodialysis, however, this suggests only in part their binding to other molecules which cause tissue damage. Protein carbonyls are end-products of such interventions. Oxysterols, another form of free-radical initiated oxidation products, were shown to initiate atherosclerosis and plaque formation increasing dramatically the risk of coronary heart disease. Today there is no doubt that the correction of the oxidant/antioxidant imbalance in patients with chronic renal failure is an important approach for the reduction of the risk of those patients to develop cardiovascular disorders. The complete correction of renal anemia represents an effective means of strengthening antioxidant capacity and, therefore, of reducting cardiovascular risk potential.


Sethi, S. (2002). "Inhibition of leukocyte-endothelial interactions by oxidized omega-3 fatty acids: a novel mechanism for the anti-inflammatory effects of omega-3 fatty acids in fish oil." Redox Rep 7(6): 369-78.

            Omega-3 fatty acids which are abundant in fish oil improve the prognosis of several chronic inflammatory diseases that are characterized by leukocyte-mediated tissue injury. The omega-3 fatty acids, such as eicosapentaenoic acid (EPA), are highly polyunsaturated and readily undergo oxidation. Our data suggest that the beneficial effects of fish oil may be due to the oxidative modification of omega-3 fatty acids. The oxidized products inhibit leukocyte adhesion receptor expression and leukocyte-endothelial interactions. Oxidized EPA is a potent inhibitor of leukocyte interactions with the endothelium compared to native EPA, both in vitro and in an in vivo context of inflammation. The effects of oxidized EPA are mediated through activation of PPARalpha and subsequent inhibition of NF-kappaB, leading to the down-regulation of leukocyte adhesion receptor expression required for leukocyte-endothelial interactions. We propose that oxidation of EPA and its activation of PPARalpha and subsequent inhibition of NF-kappaB is the underlying mechanism for the beneficial effects of fish oil.


Saugstad, L. F. (2002). "Third World adversity: African infant precocity and the role of environment." Nutr Health 16(3): 147-60.

            The war against illiteracy has not been won. The number of illiterates approaches a billion. Most reside in Third World countries--former colonies--where they are caught in a poverty trap of disease, low agricultural production and environmental adversity requiring technology beyond their means. I argue against the commonly held view that this is mainly attributable to the four hundred years of traffic in men. According to the late K.O. Dike, middle men along the African coast barred foreign merchants from the hinterland, and because of this the social, political structure and sovereignty of the African states remained fundamentally unchanged during the period 1400-1807, whereas a few decades after colonisation the socio-political system collapsed and was replaced by a small rich elite and many poor, while resources were taken out of Africa. Present poverty and underdevelopment represent as great a challenge as the trade in slaves. As did the African Middle-Men of that time, African leaders now must unite in an ambitious and confident Pan-African Union demonstrating strength. Western countries should focus on reducing poverty and improving nutrition. This also makes terrorism and legal and illegal migration less likely. Education is important, but the West should not limit its effort to fighting illiteracy but should also support the establishment of institutions for higher education. Africa possessed optimal conditions and an enriched environment for human evolution. African Infant Precocity is a persistent example. The human brain, like other brains, consists 60% of poly-unsaturated fatty acids (Marine-Fat), the rest being water. A sufficient amount is required to secure optimal brain growth. It normalizes brain function, and prevents sudden cardiac and infant death, which have been increasing in Western societies. Humans are unique in having a mismatch between the need for brain food--marine fat--and our common high protein diet. Nowhere is the neglect of the brain greater than in pregnancy when protein is the only major nutrient considered. Declining levels of polyunsaturated fatty acids have been observed in human milk. Deficient intake could, if not corrected, gradually impair brain function as has been seen in animal experiments.


Sanderson, P., Y. E. Finnegan, et al. (2002). "UK Food Standards Agency alpha-linolenic acid workshop report." Br J Nutr 88(5): 573-9.

            The UK Food Standards Agency convened a group of expert scientists to review current research investigating whether n-3 polyunsaturated fatty acids (PUFA) from plant oils (alpha-linolenic acid; ALA) were as beneficial to cardiovascular health as the n-3 PUFA from the marine oils, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The workshop also aimed to establish priorities for future research. Dietary intake of ALA has been associated with a beneficial effect on CHD; however, the results from studies investigating the effects of ALA supplementation on CHD risk factors have proved equivocal. The studies presented as part of the present workshop suggested little, if any, benefit of ALA, relative to linoleic acid, on risk factors for cardiovascular disease; the effects observed with fish-oil supplementation were not replicated by ALA supplementation. There is a need, therefore, to first prove the efficacy of ALA supplementation on cardiovascular disease, before further investigating effects on cardiovascular risk factors. The workshop considered that a beneficial effect of ALA on the secondary prevention of CHD still needed to be established, and there was no reason to look further at existing CHD risk factors in relation to ALA supplementation. The workshop also highlighted the possibility of feeding livestock ALA-rich oils to provide a means of increasing the dietary intake in human consumers of EPA and DHA.


Sacks, F. M. and M. Katan (2002). "Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease." Am J Med 113 Suppl 9B: 13S-24S.

            Several dietary approaches have reduced cardiovascular events in randomized clinical trials. Replacing saturated fat with polyunsaturated fat prevented coronary events in men, and a Mediterranean diet and fatty fish improved survival. None of these trials had much impact on total fat intake but rather increased vegetable oils, n-3 fatty acids, or many other plant foods or nutrients that are linked to coronary prevention. The reductions in cardiovascular disease (CVD) caused by these dietary therapies compare favorably with drug treatments for hyperlipidemia and hypertension. Improvement in blood lipid risk factors is an important mechanism to explain the results of trials of unsaturated fats. When saturated or trans unsaturated fats are replaced with monounsaturated or n-6 polyunsaturated fats from vegetable oils, primarily low-density lipoprotein (LDL) cholesterol decreases. The LDL to high-density lipoprotein (HDL) cholesterol ratio decreases. When carbohydrates are used to replace saturated fats, in a low-fat diet, LDL and HDL decrease similarly, and the ratio is not improved; triglycerides increase as well when carbohydrate increases, except when low glycemic index foods are used. The n-3 polyunsaturated fats in fish oils suppress cardiac arrhythmias and reduce triglycerides, but they have little effect on LDL or HDL cholesterol levels. The theme should be that diet has benefits that come directly from foods, as well as from the reduction in saturated fats, cholesterol, meats, and fatty dairy foods. It is likely that many diets could be designed that could prevent CVD. This potential diversity is crucial for engaging the diverse cultures and tastes of people worldwide in cardiovascular disease prevention.


Ryzhenkov, V. E. (2002). "[Features of the effect of saturated and unsaturated fatty acids on lipid metabolism, lipoproteins, and development of ischemic heart disease]." Vopr Pitan 71(3): 40-5.

            The effect of saturated, mono- and polyunsaturated fatty acid on lipid, lipoprotein metabolism and ischaemic heart disease is reviewed. Optimal effect on lipid and lipoprotein metabolism and prevention of ischemic heart disease exert only physiologically correlated amount of saturated and unsaturated fatty acid. Especially negative metabolic action is noted by use of heated oils contained polyunsaturated fatty acids.


Rodrigo, R. and G. Rivera (2002). "Renal damage mediated by oxidative stress: a hypothesis of protective effects of red wine." Free Radic Biol Med 33(3): 409-22.

            Over the last decade, oxidative stress has been implicated in the pathogenesis of a wide variety of seemingly unrelated renal diseases. Epidemiological studies have documented an association of moderate wine consumption with a decreased risk of cardiovascular and neurological diseases; however, similar studies in the kidney are still lacking. The kidney is an organ highly vulnerable to damage caused by reactive oxygen species (ROS), likely due to the abundance of polyunsaturated fatty acids in the composition of renal lipids. ROS are involved in the pathogenic mechanism of conditions such as glomerulosclerosis and tubulointerstitial fibrosis. The health benefits of moderate consumption of red wine can be partly attributed to its antioxidant properties. Indeed, the kidney antioxidant defense system is enhanced after chronic exposure to moderate amounts of wine, a response arising from the combined effects of ethanol and the nonalcoholic components, mainly polyphenols. Polyphenols behave as potent ROS scavengers and metal chelators; ethanol, in turn, modulates the activity of antioxidant enzymes. Therefore, a hypothesis that red wine causes a decreased vulnerability of the kidney to the oxidative challenges could be proposed. This view is partly supported by direct evidences indicating that wine and antioxidants isolated from red wine, as well as other antioxidants, significantly attenuate or prevent the oxidative damage to the kidney. The present hypothesis paper provides a collective body of evidence suggesting a protective role of moderate wine consumption against the production and progression of renal diseases, based on the existing concepts on the pathophysiology of kidney injury mediated by oxidative stress.


Rivellese, A. A., C. De Natale, et al. (2002). "Type of dietary fat and insulin resistance." Ann N Y Acad Sci 967: 329-35.

            Animal studies have already shown the possibility to modulate insulin action by changing not only the amount of total fat, but also the type of fat. In these studies, saturated fat significantly increased insulin resistance, long- and short-chain omega(3) fatty acids significantly improved it, whereas the effects of monounsaturated and omega(6) polyunsaturated fatty acids ranged somewhere in between the two. A recent multicenter study (the Kanwu study) on humans has shown that shifting from a diet rich in saturated fatty acids to one rich in monounsaturated fat improved insulin sensitivity in healthy people, while a moderate omega(3) supplementation did not affect it; this second finding confirms previous results in type 2 diabetic patients with hypertriglyceridemia. There are also other aspects of the metabolic syndrome that can be influenced by the different type of dietary fat, particularly blood pressure and lipid metabolism. With respect to blood pressure, the majority of studies show that omega(3) fatty acids are able to reduce blood pressure in hypertensive patients, but not in normotensive individuals; this result has been confirmed also by the Kanwu study, where no changes in blood pressure were seen after omega(3) supplementation in healthy people. On the other hand, in this study, the change from saturated to monounsaturated fatty acids was able to significantly reduce diastolic blood pressure. As to the lipid abnormalities more frequently present in the metabolic syndrome (i.e., hypertriglyceridemia and low HDL cholesterol), the main effects are related to omega(3) fatty acids, which surely reduce triglyceride levels, but at the same time increase LDL cholesterol. In conclusion, there is so far sound evidence in humans that the quality of dietary fat is able to influence insulin resistance and some of the related metabolic abnormalities.


Ratledge, C. (2002). "Regulation of lipid accumulation in oleaginous micro-organisms." Biochem Soc Trans 30(Pt 6): 1047-50.

            A small number of eukaryotic micro-organisms, the oleaginous species, can accumulate triacylglycerols as cellular storage lipids, sometimes up to 70% of the biomass. Some of these lipids, particularly those containing high proportions of polyunsaturated fatty acids of nutritional and dietary importance, are now in commercial production; these are known as single-cell oils. The biochemistry of lipid accumulation has been investigated in yeasts and filamentous fungi and can now be described in some detail: lipid accumulation is triggered by cells exhausting nitrogen from the culture medium, but glucose continues to be assimilated. Activity of isocitrate dehydrogenase within the mitochondrion, however, now slows or even stops due to the diminution of AMP within the cells. This leads to the accumulation of citrate, which is transported into the cytosol and cleaved to acetyl-CoA by ATP:citrate lyase, an enzyme that does not occur in non-oleaginous species. This enzyme is therefore essential for lipid accumulation. The presence of this enzyme does not, however, explain why different species of oleaginous micro-organisms have different capacities for lipid accumulation. The extent of lipid accumulation is considered to be controlled by the activity of malic enzyme (ME), which acts as the sole source of NADPH for fatty acid synthase (FAS). If ME is inhibited, or genetically disabled, then lipid accumulation is very low. There is no general pool of NADPH which can otherwise be used by FAS. The stability of ME is therefore crucial and it is proposed that ME is physically attached to FAS as part of the lipogenic metabolon. ME activity correlates closely with lipid accumulation in two filamentous fungi, Mucor circinelloides and Mortierella alpina. When ME ceases to be active, lipid accumulation also stops. No other enzyme activity shows such a correlation.


Qi, K., M. Hall, et al. (2002). "Long-chain polyunsaturated fatty acid accretion in brain." Curr Opin Clin Nutr Metab Care 5(2): 133-8.

            Brain is highly enriched in long-chain polyunsaturated fatty acids (PUFAs), particularly arachidonic acid and docosahexaenoic acid, which play important roles in brain structural and biologic functions. Plasma transport, in the form of free fatty acids or esterified FAs in lysophosphatidylcholine and lipoproteins, and de-novo synthesis contribute to brain accretion of long-chain PUFAs. Transport of long-chain PUFAs from plasma may play important roles because of the limited ability of brain to synthesize long-chain PUFAs, in the face of high demand for them. Although several proteins involved in facilitated fatty acid transport (e.g. fatty acid transport protein, fatty acid binding protein and very-long-chain acyl-coenzyme A synthetase) have been found in brain, their roles in fatty acid accumulation in brain are poorly defined. The primary pathways that are involved in long-chain PUFA accumulation in brain may vary according to brain region and developmental stage.


Pond, C. M. (2002). "Adipose tissue, the immune system and exercise fatigue: how activated lymphocytes compete for lipids." Biochem Soc Trans 30(2): 270-5.

            Adipose depots that contain lymph nodes, and probably intermuscular fat in skeletal and cardiac muscle, are specialized to provision adjacent tissue in a paracrine mode. Perinodal adipocytes respond selectively to various cytokines and incorporate proportionately more polyunsaturated fatty acids. Lipolysis in the adipocytes of node-containing depots can be stimulated via inflammation of the enclosed lymph nodes. Repeated immune stimulation elicits properties characteristic of perinodal adipocytes in those elsewhere in the same depot, and hours later in other node-containing depots, but not in nodeless depots. Such site-specific properties of adipose tissue enable partitioning of dietary and metabolic supplies of fatty acids between competing tissues. Local interactions emancipate the peripheral immune system from competing with other tissues for lipids during immune responses, and may be especially important during periods of high demand, such as strenuous exercise. Biopsies of subcutaneous adipose tissue from sites remote from lymph nodes do not adequately represent the composition of fatty acids available to the immune system in situ, and perhaps that supplied to other tissues. Intermuscular fat in skeletal and cardiac muscle may also indicate paracrine relationships between adipocytes and "end-user" tissues. The concept of paracrine interactions between certain adipocytes and "user" tissue may account for the widespread contiguity between these tissues in vivo.


Pilacik, B., T. W. Nofer, et al. (2002). "F2-isoprostanes biomarkers of lipid peroxidation: their utility in evaluation of oxidative stress induced by toxic agents." Int J Occup Med Environ Health 15(1): 19-27.

            Isoprostanes are prostaglandin-like compounds that are produced by free radical mediated peroxidation of polyunsaturated fatty acids. There is a direct evidence showing that F2-isoprostanes can be utilized as a marker of lipid peroxidation due to the mechanism of their formation (nonenzymatic oxidation of arachidonic acid), chemical stability, sensitive and non-invasive methods of their estimation. An altered generation of F2-isoprostanes has been found in a variety of pathological syndromes associated with oxidative stress. Their quantification allows to elucidate the role of free radicals in oxidative injury. This paper reviews briefly the recent data on isoprostanes: biochemical mechanisms of their formation, methods of their measurement, and the possibilities of their utilization as a quantitative/qualitative marker of oxidative stress in vivo.


Picklo, M. J., T. J. Montine, et al. (2002). "Carbonyl toxicology and Alzheimer's disease." Toxicol Appl Pharmacol 184(3): 187-97.

            A large amount of data has implicated reactive carbonyls as neurotoxic mediators of oxidative damage in the progression of Alzheimer's disease (AD) and other neurodegenerative diseases. The oxidation of polyunsaturated fatty acids, reducing sugars, and amino acids leads to the formation of carbonyls and carbonyl adduction products such as 4-hydroxy-2-nonenal (HNE), advanced glycation end products (AGEs), and protein-bound carbonyls. Levels of these products are elevated in AD. In this review, we examine the role that carbonyls may play in the development of this disease. We focus upon the chemistry of these molecules and the evidence for their involvement in AD. The biological effects of these carbonyl species in model systems and their relationship to AD are discussed. Lastly, we examine the potential mechanisms that the brain utilizes to detoxify carbonyl species and possible therapeutic interventions based on carbonyl detoxification.


Petibois, C., G. Cazorla, et al. (2002). "Biochemical aspects of overtraining in endurance sports: a review." Sports Med 32(13): 867-78.

            Top-level performances in endurance sports require several years of hard training loads. A major objective of this endurance training is to reach the most elevated metabolic adaptations the athlete will be able to support. As a consequence, overtraining is a recurrent problem that highly-trained athletes may experience during their career. Many studies have revealed that overtraining could be highlighted by various biochemical markers but a principal discrepancy in the diagnosis of overtraining stems from the fact that none of these markers may be considered as universal. In endurance sports, the metabolic aspects of training fatigue appear to be the most relevant parameters that may characterise overtraining when recovery is not sufficient, or when dietary habits do not allow an optimal replenishment of substrate stores. From the skeletal muscle functions to the overall energetic substrate availability during exercise, six metabolic schemes have been studied in relation to overtraining, each one related to a central parameter, i.e. carbohydrates, branched-chain amino acids, glutamine, polyunsaturated fatty acids, leptin, and proteins. We summarise the current knowledge on these metabolic hypotheses regarding the occurrence of overtraining in endurance sports.


Perry, I. J. (2002). "Healthy diet and lifestyle clustering and glucose intolerance." Proc Nutr Soc 61(4): 543-51.

            Glucose intolerance represents a spectrum of abnormalities, including impaired fasting glucose, impaired glucose tolerance and type 2 diabetes. It is a major public health challenge worldwide, with rapidly increasing prevalence rates in both developed and developing countries. This global epidemic of diabetes is largely driven by the globalisation of Western culture and lifestyles. Specifically, there is now evidence from large-scale observational studies, and from intervention studies, of powerful synergistic interactions between diet, obesity, exercise, smoking and alcohol in the development of glucose intolerance. It is estimated that >90% of cases of type 2 diabetes in the population could be prevented with the adoption of a prudent diet (high in cereal fibre and polyunsaturated fatty acids and low in trans-fatty acids and glycaemic load), avoidance of overweight and obesity (BMI<25 kg/m2), engagement in moderate to vigorous physical activity for at least 0.5 h/d, non-smoking and moderate alcohol consumption. These findings are biologically plausible and have major public health implications. They form the basis for a clear, simple and coherent message for health promotion and public policy. However, to make progress on these issues health will need to be placed at the centre of public policy and relevant vested interests tackled, notably in the food, entertainment, tobacco and automobile industries.


Orzechowski, A., P. Ostaszewski, et al. (2002). "Bioactive substances of plant origin in food--impact on genomics." Reprod Nutr Dev 42(5): 461-77.

            In the past decade, substantial progress has been made concerning our knowledge of bioactive components in plant foods and their links to health. Human diets of plant origin contain many hundreds of compounds which cannot be considered as nutrients, but appear to play a role in the maintenance of health. These substances are called nutraceuticals. In some cases where the disease process is at least partially understood, elements of protection can be related to a single compound or structurally related group of compounds in the diet. Bioactive components of food which are of special interest include the following groups: polyphenols, phytoestrogens, phytosterols, phytates and polyunsaturated fatty acids. Most of them are featured by antioxidant properties. In the first part of this review, we indicate the main groups of bioactive compounds giving a description of their localisation, chemical properties and biological actions. Recently, it was shown, however, that the bioavailability of potential antioxidants from plant foods is generally too low to have any substantial direct effect on reactive oxygen species. As a result of that it is postulated that dietary compounds, even in very low concentrations, may have a far greater impact than previously appreciated on the regulation of gene expression. The second part of this paper concerns the action of the literally most important bioactive substances on the molecular mechanisms of the control of genes which in turn affect cellular metabolism. A few current studies on the action of selected nutraceuticals on the activity of transcription factors such as AP-1, NF-kappaB, SREBPs, PPARs as final targets in the signal transduction cascade and gene regulation are included. A detailed analysis of numerous factors of dietary origin with their targets is far beyond the scope of this paper. However, continuing research on the effects of nutraceuticals on gene expression should provide insight into the mechanisms of prevention of diseases such as obesity, diabetes, atherosclerosis, hypertension and cancer by dietary manipulations.


Ordovas, J. M. (2002). "Gene-diet interaction and plasma lipid responses to dietary intervention." Biochem Soc Trans 30(2): 68-73.

            Strategies for disease prevention can have a major impact on people's health. However, major gaps exist in our knowledge with regard to nutritional adequacy, nutrient-disease interactions, nutrient-gene interactions, and effective strategies for implementation of dietary recommendations which have the potential to decrease the disease burden and to contribute to successful aging of the population. Coronary heart disease is one of the major causes of mortality in the world. We have sound evidence that high levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk of coronary heart disease. Lipoprotein concentrations are associated with environmental variables such as diet and lifestyle, but genetics also play a significant role. We have examined polymorphisms at candidate loci to determine their usefulness as markers for dietary responses. A G/A polymorphism 75 bp upstream from the gene encoding apolipoprotein AI (APOA1) has been described in approximately 30% of the population. Our studies show that this polymorphism is associated with variability in the HDL-C response to dietary fat, specifically to polyunsaturated fatty acids (PUFA) in the diet. Carriers of the A allele respond to increases in dietary PUFA with elevations in HDL-C levels, probably due to altered interactions of transcription factors with the mutated promoter. Therefore carriers of the A allele can potentially decrease their atherogenic risk by consuming high-PUFA diets. Likewise, we have examined the interaction between other dietary habits, such as alcohol drinking, and variability at the APOE locus, and have demonstrated that the classical associations between APOE polymorphism and LDL-C levels are observed primarily in those subjects who consume alcohol. Moreover, we have found a subgroup of the population, APOE4 carriers, for whom drinking alcohol may exert detrimental effects on lipid metabolism. This knowledge will contribute towards the development of more effective personalized dietary recommendations.


Ong, A. S. and S. H. Goh (2002). "Palm oil: a healthful and cost-effective dietary component." Food Nutr Bull 23(1): 11-22.

            Palm oil is an excellent choice for food manufacturers because of its nutritional benefits and versatility. The oil is highly structured to contain predominantly oleic acid at the sn2-position in the major triacylglycerols to account for the beneficial effects described in numerous nutritional studies. Oil quality and nutritional benefits have been assured for the variety of foods that can be manufactured from the oil directly or from blends with other oils while remaining trans-free. The oxidative stability coupled with the cost-effectiveness is unparalleled among cholesterol-free oils, and these values can be extended to blends of polyunsaturated oils to provide long shelf-life. Presently the supply of genetic-modification-free palm oil is assured at economic prices, since the oil palm is a perennial crop with unparalleled productivity. Numerous studies have confirmed the nutritional value of palm oil as a result of the high monounsaturation at the crucial 2-position of the oil's triacylglycerols, making the oil as healthful as olive oil. It is now recognized that the contribution of dietary fats to blood lipids and cholesterol modulation is a consequence of the digestion, absorption, and metabolism of the fats. Lipolytic hydrolysis of palm oil glycerides containing predominantly oleic acid at the 2 position and palmitic and stearic acids at the 1 and 3 positions allows for the ready absorption of the 2-monoacrylglycerols while the saturated free fatty acids remain poorly absorbed. Dietary palm oil in balanced diets generally reduced blood cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides while raising the high-density lipoprotein (HDL) cholesterol. Improved lipoprotein(a) and apo-A1 levels were also demonstrated from palm oil diets; an important benefits also comes from the lowering of blood triglycerides (or reduced fat storage) as compared with those from polyunsaturated fat diets. Virgin palm oil also provides carotenes apart from tocotrienols and tocopherols that have been shown to be powerful antioxidants and potential mediators of cellular functions. These compounds can be antithrombotic, cause an increase of the prostacyclin/thromboxane ratio, reduce restenosis, and inhibit HMG-CoA-reductase (thus reducing) cholesterol biosynthesis). Red palm oil is a rich source of beta-carotene as well as of alpha-tocopherol and tocotrienols.


O'Neill, S. (2002). "Cardiac Ca(2+) regulation and the tuna fish sandwich." News Physiol Sci 17: 162-5.

            Following myocardial ischemia and reperfusion, there is a risk of fatal arrhythmias that result from damage to cellular Ca(2+) homeostasis mechanisms. n-3 Polyunsaturated fatty acids seem to protect against these arrhythmias by mechanisms involving the sarcoplasmic reticulum and the sarcolemma.


Ntambi, J. M., Y. Choi, et al. (2002). "Effects of conjugated linoleic acid (CLA) on immune responses, body composition and stearoyl-CoA desaturase." Can J Appl Physiol 27(6): 617-28.

            Conjugated linoleic acid (CLA) has shown a wide range of biologically beneficial effects; reduction of incidence and severity of animal carcinogenesis, reduction of the adverse effects of immune stimulation, reduction of severity of atherosclerosis, growth promotion in young rats, and modulation of stearoyl-CoA desaturase (SCD). One of the most interesting aspects of CLA is its ability to reduce body fat while enhancing lean body mass which is associated with the trans-10,cis-12 isomer of CLA. The effects of CLA are unique characteristics that have not been observed with other polyunsaturated fatty acids. In this review, we will focus on the effects of CLA on immune responses, body compositional changes and stearoyl-CoA desaturase.


Minda, H., E. Larque, et al. (2002). "Systematic review of fatty acid composition of plasma phospholipids of venous cord blood in full-term infants." Eur J Nutr 41(3): 125-31.

            The purpose of this review was to systematically evaluate the variability of the fatty acid composition of venous cord blood phospholipids in different populations. In an attempt to review published evidence systematically, we found 19 data sets describing fatty acid composition of venous cord blood phospholipids in 11 European and 2 American countries. The amount of saturated-, monounsaturated- and parent essential polyunsaturated fatty acids exhibited relatively moderate variability among the data sets reviewed. Values of arachidonic acid and docosahexaenoic acid showed two-fold variability among the data sets. The highest values of docosahexaenoic acid were observed in countries with apparently higher consumption of dietary fat from sea fish. Considering the differences in blood sampling, laboratory methods and data presentation, we conclude that fatty acid composition of venous cord blood phospholipids in healthy, full-term infants shows relatively modest variability; hence, it is suitable for the estimation of in utero fatty acid supply.


McEntee, M. F. and J. Whelan (2002). "Dietary polyunsaturated fatty acids and colorectal neoplasia." Biomed Pharmacother 56(8): 380-7.

            Epidemiology has implicated dietary fat in mortality associated with some of the most common forms of cancer, including those affecting the intestinal tract, breast and prostate. Polyunsaturated fatty acids, and arachidonate in particular, have been unequivocally linked to experimental colorectal carcinogenesis. Dietary, pharmacologic and genetic manipulation of tissue arachidonic acid and its conversion to bioactive lipids has provided insights into pathogenic mechanisms as well as compelling evidence to support rational preventative and therapeutic methods of disease intervention. While it is clear that conversion of arachidonate to prostaglandins and other bioactive lipids contributes significantly to tumorigenesis in the intestinal tract and other organs, it is also clear that no single metabolic pathway or lipid in this complex biochemical network is solely responsible for dietary or pharmacologic benefits evident in epidemiologic studies. We will review some of these data and provide a summary of our own work showing that conversion of arachidonate to prostaglandin E2 contributes significantly to tumor growth through the modulation of apoptosis and cellular proliferation.


Mayser, P., H. Grimm, et al. (2002). "n-3 fatty acids in psoriasis." Br J Nutr 87 Suppl 1: S77-82.

            Increased concentrations of free arachidonic acid (AA) and its proinflammatory metabolites have been observed in psoriatic lesions. Replacement of arachidonic acid by alternative precursor polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA), which can be metabolized via the same enzymatic pathways as AA, might be a therapeutic option in psoriasis. However the results of studies evaluating the therapeutic benefit of dietary fish oil have been conflicting and not clearly dose-dependent. To overcome the slow kinetics and limited availability of oral supplementation, we have performed three studies to assess the efficacy and safety of an intravenously administered fish oil derived lipid emulsion on different forms of psoriasis. Patients received daily infusions of either an n-3 fatty acid-based lipid emulsion (Omegaven) or a conventional n-6 lipid emulsion (Lipoven) in different time and dose regimens. In addition to an overall assessment of the clinical course of psoriasis, EPA- and AA-derived neutrophil 5-lipoxygenase (LO)--products, thromboxane (TX) B2/B3, PAF and plasma free fatty acids were investigated. Treatment with n-3 fatty acids resulted in a considerably higher response rate than infusion of n-6 lipids. A more than 10-fold increase in neutrophil EPA-derived 5-LO product formation was noted in the n-3 group, accompanied by a rapid increase in plasma-free EPA within the first days. In conclusion, intravenous n-3-fatty acid administration causes reduction of psoriasis, which may be related to changes in inflammatory eicosanoid generation. The rapidity of the response to intravenous n-3 lipids exceeds by orders of magnitude the hitherto reported kinetics of improvement of psoriatic lesions upon use of oral supplementation.


Martin, C. E., C. S. Oh, et al. (2002). "Yeast desaturases." Biochem Soc Trans 30(Pt 6): 1080-2.

            The Saccharomyces OLE1 gene encodes the intrinsic membrane-bound Delta-9 fatty acid desaturase. OLE1 expression is regulated at the levels of transcription and mRNA stability by nutrient fatty acids and molecular oxygen. Its transcription is controlled through two distinct promoter elements, the fatty acid response element (FAR) region, and a downstream low-oxygen response element (LORE) that dramatically amplifies FAR-activated expression under hypoxic or cobalt-stimulated growth conditions. Transcription activation through both elements is repressed by unsaturated fatty acids. The half-life of the OLE1 mRNA is also dramatically reduced upon exposure to unsaturated fatty acids. OLE1 expression is governed by two homologous membrane-bound proteins, Spt23p and Mga2p, which activate OLE1 expression through N-terminal polypeptides that are released from the membrane through a ubiquitin-mediated mechanism that involves processing by the 23 S proteosome. Although proteolytic processing of Spt23p can be repressed by polyunsaturated fatty acids, Mga2p processing in normoxic cells appears to be regulated by a different mechanism. Mga2p is essential, however, for the induction of the high levels of expression that are triggered by hypoxia through the LORE promoter element. Surprisingly, Mga2p also plays a critical role in controlling OLE1 mRNA stability, suggesting that there may be a functional linkage between OLE1 transcription and the regulation of OLE1 mRNA stability.


Marquez, M., C. E. Yepez, et al. (2002). "[Basic aspects and measurement of the antioxidant vitamins A and E]." Invest Clin 43(3): 191-204.

            Vitamin E usually works as a biological antioxidant, preventing the oxidation of polyunsaturated fatty acids and proteins, for which it is considered an important protective factor in the development of diseases related to oxidative processes. Beyond its antioxidant properties, it has been involved also in genetic expression, mitochondrial metabolism, cell differentiation and immune system regulation. From the point of view of its antioxidant protection properties, values > or = 1200-1300 micrograms/dL are considered optimum levels (standardized according to plasmatic lipid levels). In relation to the beneficial advantage effects of vitamin E on primary or secondary atherosclerotic disease, data are not conclusive. Vitamin A is part of the organism's defense barrier against free radicals. Its antioxidant mechanism of action includes scavenging of single oxygen and thiol free radicals, and it also could be related to processes that involve genetic expression and cell differentiation. As an antioxidant, vitamin A plasmatic levels > or = 80 micrograms/dL are considered optimal. The highest risk of using this vitamin is related to its acute or chronic toxicity. Quantification of serum vitamin E (alpha tocopherol) and vitamin A (retinol) are made by high performance liquid chromatography (HPLC), method of high precision, sensitivity and reproducibility.


Maccarrone, M. and A. Finazzi-Agro (2002). "Endocannabinoids and their actions." Vitam Horm 65: 225-55.

            Endocannabinoids are a new class of lipid mediators, which includes amides and esters of long-chain polyunsaturated fatty acids. Anandamide (I) and 2-arachidonoylglycerol (II) are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of delta 9-tetrahydrocannabinol (III), the active principle of Cannabis sativa preparations such as hashish and marijuana. The pathways leading to the synthesis and release of anandamide and 2-arachidonoylglycerol from neuronal and nonneuronal cells are rather uncertain. Instead, evidence has accumulated showing that the activity of these compounds at their specific receptors is limited by cellular uptake through a specific membrane transporter, followed by intracellular degradation by a fatty acid amide hydrolase. Here, the endocannabinoids and the endocannabinoid-like compounds most relevant for human physiology will be discussed, along with the synthetic and degradative pathways of anandamide and 2-arachidonoylglycerol and their molecular targets on the cell surface. The main actions of the endocannabinoids in human cells and tissues will also be reviewed, focusing on the activities most recently discovered in the central nervous system and in the periphery.


Maccarrone, M., M. Bari, et al. (2002). "Endocannabinoid degradation, endotoxic shock and inflammation." Curr Drug Targets Inflamm Allergy 1(1): 53-63.

            Endocannabinoids are an emerging class of lipid mediators, which include amides and esters of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors. Endotoxic shock is a potentially lethal failure of multiple organs that can be initiated by the inflammatory agent lipopolysaccharide (LPS), present in the outer membrane of gram-negative bacteria. LPS has been recently shown to stimulate the production of AEA in rat macrophages, and of 2-AG in rat platelets. The mechanism responsible for this effect has not been elucidated. On the other hand, mast cells are multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system, where they play an essential role in inflammation. As yet, little is known about endogenous modulators and mechanisms of mast cell activation. Here, we review recent literature on the role of endocannabinoids in endotoxic shock and inflammation, and report our recent research on the effects of LPS on the production of AEA and 2-AG in human lymphocytes, and on AEA degradation by a specific AEA membrane transporter (AMT) and an AEA-degrading enzyme (fatty acid amide hydrolase, FAAH). We also report the ability of the HMC-1 human mast cells to degrade AEA through a nitric oxide-sensitive AMT and a FAAH. The role of endocannabinoids in HMC-1 degranulation is discussed as well. Taken together, it can be suggested that human lymphocytes and mast cells take part in regulating the peripheral endocannabinoid system, which can affect some activities of these cells.


Lovejoy, J. C. (2002). "The influence of dietary fat on insulin resistance." Curr Diab Rep 2(5): 435-40.

            Dietary fat has been implicated in the development of insulin resistance in both animals and humans. Most, although not all, studies suggest that higher levels of total fat in the diet result in greater whole-body insulin resistance. Although, in practice, obesity may complicate the relationship between fat intake and insulin resistance, clinical trials demonstrate that high levels of dietary fat can impair insulin sensitivity independent of body weight changes. In addition, it appears that different types of fat have different effects on insulin action. Saturated and certain monounsaturated fats have been implicated in causing insulin resistance, whereas polyunsaturated and omega-3 fatty acids largely do not appear to have adverse effects on insulin action. Given the importance of insulin resistance in the development of diabetes and heart disease, establishing appropriate levels of fat in the diet is an important clinical goal.


Lord, R. S., B. Bongiovanni, et al. (2002). "Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites." Altern Med Rev 7(2): 112-29.

            Estrogens are known for their proliferative effects on estrogen-sensitive tissues resulting in tumorigenesis. Results of experiments in multiple laboratories over the last 20 years have shown that a large part of the cancer-inducing effect of estrogen involves the formation of agonistic metabolites of estrogen, especially 16-alpha-hydroxyestrone. Other metabolites, such as 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone. An ELISA method for measuring 2- and 16-alpha-hydroxylated estrogen (OHE) metabolites in urine is available and the ratio of urinary 2-OHE/16-alpha-OHE (2/16-alpha ratio) is a useful biomarker for estrogen-related cancer risk. The CYP1A1 enzyme that catalyzes 2-hydroxyestrone (2-OHE1) formation is inducible by dietary modification and supplementation with the active components of cruciferous vegetables, indole-3-carbinol (I-3-C), or diindolylmethane (DIM). Other dietary components, especially omega-3 polyunsaturated fatty acids and lignans in foods like flax seed, also exert favorable effects on estrogen metabolism. Thus, there appear to be effective dietary means for reducing cancer risk by improving estrogen metabolism. This review presents the accumulated evidence to help clinicians evaluate the merit of using tests that measure estrogen metabolites and using interventions to modify estrogen metabolism.


Lingjaerde, O. (2002). "[Neurobiological findings in schizophrenia]." Tidsskr Nor Laegeforen 122(21): 2123-7.

            BACKGROUND: Schizophrenia is a syndrome with important neurobiological abnormalities which have not yet been fully clarified and whose aetiology is poorly understood. MATERIAL AND METHODS: The paper gives a survey of the most important neurobiological abnormalities found in schizophrenia, based on relevant research publications, mainly from the most recent decades. RESULTS AND INTERPRETATIONS: Pathomorphological findings in schizophrenia include ventricular and cortical sulcal enlargement, reduction of cortical thickness, cellular changes with reduction of dendrites and synapses, presumably resulting in reduced cortico-cortical and cortico-subcortical connections. These abnormalities are thought to be mainly developmental in origin, mostly on a genetic basis, but also with varying contributions from prenatal or perinatal damage. In a subgroup of schizophrenics there is a poorly understood neurodegenerative process going on also after the debut of the psychosis. Neurochemically, interest has focused mostly on dopaminergic dysfunction, but other transmitters like serotonin, glutamate and GABA are also involved, as is probably the neurotensin peptide. There is also increasing evidence of disturbed cell membrane composition and function in schizophrenia, especially with regard to polyunsaturated fatty acids.


Lenzi, A., L. Gandini, et al. (2002). "Polyunsaturated fatty acids of germ cell membranes, glutathione and blutathione-dependent enzyme-PHGPx: from basic to clinic." Contraception 65(4): 301-4.

            The lipid metabolism in sperm cells is important both for energy production and for cell structure. A special composition of membrane phospholipids, rich in polyunsaturated fatty acids (PUFA), and the different composition of sperm and immature germ cell membrane are described and discussed. Testis germ cells as well as epididymal maturing spermatozoa are endowed with enzymatic and non-enzymatic scavenger systems to prevent lipoperoxidative damage. Catalase, superoxide dismutase, and glutathione-dependent oxidoreductases are present in variable amounts in the different developmental stages. Phospholipid hydroperoxide glutathione peroxidase (PHGPx) activity and roles in caput and cauda epididymal sperm cells are discussed. Also seminal plasma has a highly specialized scavenger system that defends the sperm membrane against lipoperoxidation and the degree of PUFA insaturation acts to achieve the same goal. Systemic predisposition and a number of pathologies can lead to an anti-oxidant/pro-oxidant disequilibrium. Scavengers, such as glutathione can be used to treat these cases as they can restore the physiological constitution of PUFA in the cell membrane.


Laybourn-Parry, J. (2002). "Survival mechanisms in Antarctic lakes." Philos Trans R Soc Lond B Biol Sci 357(1423): 863-9.

            In Antarctic lakes, organisms are confronted by continuous low temperatures as well as a poor light climate and nutrient limitation. Such extreme environments support truncated food webs with no fish, few metazoans and a dominance of microbial plankton. The key to success lies in entering the short Antarctic summer with actively growing populations. In many cases, the most successful organisms continue to function throughout the year. The few crustacean zooplankton remain active in the winter months, surviving on endogenous energy reserves and, in some cases, continuing development. Among the Protozoa, mixotrophy is an important nutritional strategy. In the extreme lakes of the McMurdo Dry Valleys, planktonic cryptophytes are forced to sustain a mixotrophic strategy and cannot survive by photosynthesis alone. The dependence on ingesting bacteria varies seasonally and with depth in the water column. In the Vestfold Hills, Pyramimonas, which dominates the plankton of some of the saline lakes, also resorts to mixotrophy, but does become entirely photosynthetic at mid-summer. Mixotrophic ciliates are also common and the entirely photosynthetic ciliate Mesodinium rubrum has a widespread distribution in the saline lakes of the Vestfold Hills, where it attains high concentrations. Bacteria continue to grow all year, showing cycles that appear to be related to the availability of dissolved organic carbon. In saline lakes, bacteria experience sub-zero temperatures for long periods of the year and have developed biochemical adaptations that include anti-freeze proteins, changes in the concentrations of polyunsaturated fatty acids in their membranes and suites of low-temperature enzymes.


Larque, E., H. Demmelmair, et al. (2002). "Perinatal supply and metabolism of long-chain polyunsaturated fatty acids: importance for the early development of the nervous system." Ann N Y Acad Sci 967: 299-310.

            The long-chain polyunsaturated fatty acids, arachidonic (AA) and docosahexaenoic acid (DHA), are essential structural lipid components of biomembranes. During pregnancy, long-chain polyunsaturated fatty acids (LC-PUFA) are preferentially transferred from mother to fetus across the placenta. This placental transfer is mediated by specific fatty acid binding and transfer proteins. After birth, preterm and full-term babies are capable of converting linoleic and alpha-linolenic acids into AA and DHA, respectively, as demonstrated by studies using stable isotopes, but the activity of this endogenous LC-PUFA synthesis is very low. Breast milk provides preformed LC-PUFA, and breast-fed infants have higher LC-PUFA levels in plasma and tissue phospholipids than infants fed conventional formulas. Supplementation of formulas with different sources of LC-PUFA can normalize LC-PUFA status in the recipient infants relative to reference groups fed human milk. Some, but not all, randomized, double-masked placebo-controlled clinical trials in preterm and healthy full-term infants demonstrated benefits of formula supplementation with DHA and AA for development of visual acuity up to 1 year of age and of complex neural and cognitive functions. From the available data, we conclude that LC-PUFA are conditionally essential substrates during early life that are related to the quality of growth and development. Therefore, a dietary supply during pregnancy, lactation, and early childhood that avoids the occurrence of LC-PUFA depletion is desirable, as was recently recommended by an expert consensus workshop of the Child Health Foundation.


Kuhn, H., M. Walther, et al. (2002). "Mammalian arachidonate 15-lipoxygenases structure, function, and biological implications." Prostaglandins Other Lipid Mediat 68-69: 263-90.

            Lipoxygenases (LOXs) constitute a heterogeneous family of lipid peroxidizing enzymes capable of oxygenating polyunsaturated fatty acids to their corresponding hydroperoxy derivatives. In mammals, LOXs are classified with respect to their positional specificity of arachidonic acid oxygenation into 5-, 8-, 12-, and 15-LOXs. Arachidonate 15-LOXs may be sub-classified into a reticulocyte-type (type-1) and an epidermis-type (type-2) enzyme. Since the leukocyte-type 12-LOXs are very similar to the reticulocyte-type 15-LOXs, these enzymes are designated 12/15-LOXs. Several LOX isoforms, in particular the reticulocyte-type 15-LOX and the human 5-LOX, are well characterized with respect to their structural and functional properties On the other hand, the biological role of most LOX-isozymes including the reticulocyte-type 15-LOC is far from clear. This review is intended to summarize the recent developments in 15-LOX research with particular emphasis to molecular enzymology and regulation of gene expression. In addition, the major hypotheses on the physiological and patho-physiological roles of 15-LOXs will be discussed briefly.


Kelavkar, U., W. Glasgow, et al. (2002). "The effect of 15-lipoxygenase-1 expression on cancer cells." Curr Urol Rep 3(3): 207-14.

            Lipoxygenases oxidatively metabolize polyunsaturated fatty acids to a rich spectrum of biologically active products. One enzyme of the lipoxygenase family, Arachidonate 15-lipoxygenase-1 (arachidonate:oxygen 15-oxidoreductase, EC, is implicated in several forms of epithelial cell cancers, and provides a rationale for exploring its role in the progression and metastasis of cancers. Thus, 15-LO-1 could be a marker of the growth and spread of cancers. The importance of 15-LO-1 expression is imparted by its metabolic product of linoleic acid, yielding 13-(S)-hydroxyoctadecadienoic acid (13-(S)-HODE). In order to maximize our understanding of the roles of lipoxygenases and cyclooxygenases in cancer, it is necessary to correlate their metabolic pathways to the respective expression levels, and not exaggerate the presence or absence of an enzyme or its function when it clearly is not there. It is also important to acknowledge that some forms of these enzymes may not even be relevant to human disease. Although it is unlikely that any single gene is sufficient to account for the complex etiology of cancer, 15-LO-1 overexpression is clearly a key component in the cell proliferation process. This article is divided into three sections emphasizing the key role of 15-LO-1 in prostate, colorectal, and breast cancers.


Jump, D. B. (2002). "The biochemistry of n-3 polyunsaturated fatty acids." J Biol Chem 277(11): 8755-8.


Jump, D. B. (2002). "Dietary polyunsaturated fatty acids and regulation of gene transcription." Curr Opin Lipidol 13(2): 155-64.

            Dietary polyunsaturated fatty acids (PUFAs) are a source of energy and structural components for cells. PUFAs also have dramatic effects on gene expression by regulating the activity or abundance of four families of transcription factor, including peroxisome proliferator activated receptor (PPAR) (alpha, beta and gamma), liver X receptors (LXRs) (alpha and beta), hepatic nuclear factor-4 (HNF-4)alpha and sterol regulatory element binding proteins (SREBPs) 1 and 2. These transcription factors play a major role in hepatic carbohydrate, fatty acid, triglyceride, cholesterol and bile acid metabolism. Non-esterified fatty acids or fatty acid metabolites bind to and regulate the activity of PPARs, LXRs and HNF-4. In contrast, PUFAs regulate the nuclear abundance of SREBPs by controlling the proteolytic processing of SREBP precursors, or regulating transcription of the SREBP-1c gene or turnover of mRNA(SREBP-1c). The n3 and n6 PUFAs are feed-forward activators of PPARs, while these same fatty acids are feedback inhibitors of LXRs and SREBPs. Saturated fatty acyl coenzyme A thioesters activate HNF-4 alpha, while coenzyme A thioesters of PUFAs antagonize HNF-4 alpha action. Understanding how fatty acids regulate the activity and abundance of these and other transcription factors will likely provide insight into the development of novel therapeutic strategies for better management of whole body lipid and cholesterol metabolism.


Jones, P. J. and V. W. Lau (2002). "Effect of n-3 polyunsaturated fatty acids on risk reduction of sudden death." Nutr Rev 60(12): 407-9.

            Two recent reports confirm the role of n-3 polyunsaturated fatty acid (PUFA) consumption in risk reduction for sudden death. The mechanism likely involves an antiarrhythmic effect, further supporting the role of dietary n-3 PUFA in maintenance of human health.


Johnson, I. T. (2002). "Anticarcinogenic effects of diet-related apoptosis in the colorectal mucosa." Food Chem Toxicol 40(8): 1171-8.

            The crypt is the fundamental unit of epithelial proliferation in the intestinal mucosa. The progeny of the pluripotent stem cells located near the base of the crypt migrate towards the crypt orifice, divide once or twice more, and then undergo differentiation, senescence and exfoliation. Programmed cell death (apoptosis) also occurs deep in the proliferative zone. Various lines of evidence suggest that apoptosis provides a protective mechanism against neoplasia by removing genetically damaged stem cells from the epithelium before they can undergo clonal expansion. Several different classes of food constituents, including certain polyunsaturated fatty acids, the short-chain fatty acid butyrate, and some phytochemicals including flavonoids and glucosinolates breakdown products, can modulate both cellular proliferation and programmed death. Each of these food components has also been shown to suppress the emergence of aberrant crypt foci in animal models of carcinogenesis. Further mechanistic and clinical studies are required to establish whether such dietary effects can be exploited to achieve preventive or therapeutic effects in humans.


Jensen, C. L. and W. C. Heird (2002). "Lipids with an emphasis on long-chain polyunsaturated fatty acids." Clin Perinatol 29(2): 261-81, vi.

            In addition to their role as a source of energy, several fatty acids are important components of cell membranes and/or precursors of biologically important eicosanoids. The long-chain polyunsaturated fatty acids, docosahexaenoic acid (DHA) and arachidonic acid (AA), are important for optimal visual function and neurodevelopment. These fatty acids are present in human milk but, until recently, have not been included in formulas marketed in the United States. Although the results of clinical trials assessing the effect of DHA and AA intakes on visual and cognitive development have been inconsistent, some studies suggest benefits. Adequate intake of these fatty acids may be especially important for the preterm infant.


Jackson, M. J., F. McArdle, et al. (2002). "Effects of micronutrient supplements on u.v.-induced skin damage." Proc Nutr Soc 61(2): 187-9.

            Development of an orally-administered systemic agent that could reduce the effects of u.v. exposure on skin could potentially have a major effect on the incidence of skin cancers and photo-ageing. A number of micronutrients have been suggested to have metabolic properties that could induce this protection, and our data indicate that n-3 polyunsaturated fatty acids are particularly effective in this role. The mechanisms of action of n-3 polyunsaturated fatty acids appear to depend on their anti-inflammatory properties, acting to reduce the u.v.-induced release of cytokines and other mediators from a variety of skin cell types.


Invitti, C. (2002). "[Obesity and low-grade systemic inflammation]." Minerva Endocrinol 27(3): 209-14.

            The aim of this review is to deal with the significance of obesity as a promotor of a chronic low-grade inflammatory reaction favouring the development of atherosclerosis and cardiovascular diseases. Adipose tissue synthetizes and releases inflammatory cytokines involved in various atherothrombotic mechanisms and in glucose and lipid metabolism. A local renin-angiotensin system may partially support the obesity related hypertension. Most obese subjects had elevated plasma levels of inflammatory markers which correlate with the degree of obesity and insulin resistance and decrease after weight reduction and exercise. Some evidences suggest that long-chain polyunsaturated fatty acids and thiazolidinediones may be useful in preventing atherosclerosis. Obesity, by itself, has been considered an independent risk factor for cardiovascular diseases. The hypothesis that it is linked to the associated low-grade chronic inflammation is supported by the existence of altered indexes of chronic inflammation also in obese children who are free of other pathological conditions. Further research will be required to determine the pathophysiological meaning of the chronic inflammation associated to obesity.


Hu, F. B. and W. C. Willett (2002). "Optimal diets for prevention of coronary heart disease." Jama 288(20): 2569-78.

            CONTEXT: Coronary heart disease (CHD) remains the leading cause of mortality in industrialized countries and is rapidly becoming a primary cause of death worldwide. Thus, identification of the dietary changes that most effectively prevent CHD is critical. OBJECTIVE: To review metabolic, epidemiologic, and clinical trial evidence regarding diet and CHD prevention. DATA SOURCES AND STUDY SELECTION: We searched MEDLINE through May 2002 for epidemiologic and clinical investigations of major dietary factors (fat, cholesterol, omega-3 fatty acids, trans-fatty acids, carbohydrates, glycemic index, fiber, folate, specific foods, and dietary patterns) and CHD. We selected 147 original investigations and reviews of metabolic studies, epidemiologic studies, and dietary intervention trials of diet and CHD. DATA EXTRACTION: Data were examined for relevance and quality and extracted by 1 of the authors. DATA SYNTHESIS: Compelling evidence from metabolic studies, prospective cohort studies, and clinical trials in the past several decades indicates that at least 3 dietary strategies are effective in preventing CHD: substitute nonhydrogenated unsaturated fats for saturated and trans-fats; increase consumption of omega-3 fatty acids from fish, fish oil supplements, or plant sources; and consume a diet high in fruits, vegetables, nuts, and whole grains and low in refined grain products. However, simply lowering the percentage of energy from total fat in the diet is unlikely to improve lipid profile or reduce CHD incidence. Many issues remain unsettled, including the optimal amounts of monounsaturated and polyunsaturated fats, the optimal balance between omega-3 and omega-6 polyunsaturated fats, the amount and sources of protein, and the effects of individual phytochemicals, antioxidant vitamins, and minerals. CONCLUSIONS: Substantial evidence indicates that diets using nonhydrogenated unsaturated fats as the predominant form of dietary fat, whole grains as the main form of carbohydrates, an abundance of fruits and vegetables, and adequate omega-3 fatty acids can offer significant protection against CHD. Such diets, together with regular physical activity, avoidance of smoking, and maintenance of a healthy body weight, may prevent the majority of cardiovascular disease in Western populations.


Herrera, E. (2002). "Implications of dietary fatty acids during pregnancy on placental, fetal and postnatal development--a review." Placenta 23 Suppl A: S9-19.

            During pregnancy, the mother adapts her metabolism to support the continuous draining of substrates by the fetus. Her increase in net body weight (free of the conceptus) corresponds to the accumulation of fat depots during the first two-thirds of gestation, switching to an accelerated breakdown of these during the last trimester. Under fasting conditions, adipose tissue lipolytic activity is highly enhanced, and its products, free fatty acids (FFA) and glycerol, are mainly driven to maternal liver, where FFA are converted to ketone bodies and glycerol to glucose, which easily cross the placenta and sustain fetal metabolism. Lipolytic products reaching maternal liver are also used for triglyceride synthesis that are released in turn to the circulation, where together with an enhanced transfer of triglycerides among the different lipoprotein fractions, and a decrease in extrahepatic lipoprotein lipase activity, increase the content of triglycerides in all the lipoprotein fractions. Long chain polyunsaturated fatty acids (LCPUFA) circulate in maternal plasma associated to lipoprotein triglycerides, and in a minor proportion in the form of FFA. Despite the lack of a direct placental transfer of triglycerides, diffusion of their fatty acids to the fetus is ensured by means of lipoprotein receptors, lipoprotein lipase activity and intracellular lipase activities in the placenta. Maternal plasma FFA are also an important source of LCPUFA to the fetus, and their placental uptake occurs via a selective process of facilitated membrane translocation involving a plasma membrane fatty acid-binding protein. This mechanism together with a selective cellular metabolism determine the actual rate of placental transfer and its selectivity, resulting even in an enrichment of certain LCPUFA in fetal circulation as compared to maternal. The degree to which the fetus is capable of fatty acid desaturation and elongation is not clear, although both term and preterm infants can synthesize LCPUFA from parental essential fatty acids. Nutritional status of the mother during gestation is related to fetal growth, and excessive dietary intake of certain LCPUFA has inhibitory effects on Delta-5- and Delta-6-desaturases. This inhibition causes major declines in arachidonic acid levels, as directly found in pregnant and lactating rats fed a fish oil-rich diet as compared to olive oil. An excess in dietary PUFA may also enhance peroxidation and reduce antioxidant capacity. Thus, since benefit to risks of modifying maternal fat intake in pregnancy and lactation are not yet completely established, additional studies are needed before recommendations to increase LCPUFA intake in pregnancy are made.


Herrera, E. (2002). "Lipid metabolism in pregnancy and its consequences in the fetus and newborn." Endocrine 19(1): 43-55.

            During early pregnancy there is an increase in body fat accumulation, associated with both hyperphagia and increased lipogenesis. During late pregnancy there is an accelerated breakdown of fat depots, which plays a key role in fetal development. Besides using placental transferred fatty acids, the fetus benefits from two other products: glycerol and ketone bodies. Although glycerol crosses the placenta in small proportions, it is a preferential substrate for maternal gluconeogenesis, and maternal glucose is quantitatively the main substrate crossing the placenta. Enhanced ketogenesis under fasting conditions and the easy transfer of ketones to the fetus allow maternal ketone bodies to reach the fetus, where they can be used as fuels for oxidative metabolism as well as lipogenic substrates. Although maternal cholesterol is an important source of cholesterol for the fetus during early gestation, its importance becomes minimal during late pregnancy, owing to the high capacity of fetal tissues to synthesize cholesterol. Maternal hypertriglyceridemia is a characteristic feature during pregnancy and corresponds to an accumulation of triglycerides not only in very low-density lipoprotein but also in low- and high-density lipoprotein. Although triglycerides do not cross the placental barrier, the presence of lipoprotein receptors in the placenta, together with lipoprotein lipase, phospholipase A2, and intracellular lipase activities, allows the release to the fetus of polyunsaturated fatty acids transported as triglycerides in maternal plasma lipoproteins. Normal fetal development needs the availability of both essential fatty acids and long chain polyunsaturated fatty acids, and the nutritional status of the mother during gestation has been related to fetal growth. However, excessive intake of certain long chain fatty acids may cause both declines in arachidonic acid and enhanced lipid peroxidation, reducing antioxidant capacity.


Haggarty, P. (2002). "Placental regulation of fatty acid delivery and its effect on fetal growth--a review." Placenta 23 Suppl A: S28-38.

            More than 90 per cent of the fat deposition in the fetus occurs in the last 10 weeks of pregnancy during which it increases exponentially to reach a rate of accretion of around 7 g/day close to term. All of the n -3 and n -6 fatty acid structure acquired by the fetus has to cross the placenta and fetal blood is enriched in long chain polyunsaturated fatty acids (LCPUFA) relative to the maternal supply. The placenta may regulate its own fatty acid substrate supply via the action of placental leptin on maternal adipose tissue. Fatty acids cross the microvillous and basal membranes by simple diffusion and via the action of membrane bound and cytosolic fatty acid binding proteins (FABPs). The direction and magnitude of fatty acid flux is mainly dictated by the relative abundance of available binding sites. The fatty acid mix delivered to the fetus is largely determined by the fatty acid composition of the maternal blood although the placenta is able to preferentially transfer the important PUFA to the fetus as a result of selective uptake by the syncytiotrophoblast, intracellular metabolic channelling of individual fatty acids, and selective export to the fetal circulation. Placental FABP polymorphisms may affect these processes. There is little evidence to suggest that placental delivery of fatty acids limits normal fetal growth although the importance of the in utero supply may be to support post-natal development as most of the LCPUFA accumulated by the fetus is stored in the adipose tissue for use in early post-natal life.


Grimm, H., K. Mayer, et al. (2002). "Regulatory potential of n-3 fatty acids in immunological and inflammatory processes." Br J Nutr 87 Suppl 1: S59-67.

            Over the last few years immunonutrition has gained increasing importance. Among other compounds lipids, especially n-3 polyunsaturated fatty acids, were shown to influence the immune response. The anti-inflammatory effects they exert can be induced by free fatty acids, triglyceride fatty acids, after incorporation into the membrane phopspholipid bilayer or following metabolism to eicosanoids. n-3 Fatty acids influence inflammatory cell activation processes from signal transduction to protein expression even involving effects at the genomic level. n-3 Fatty acid-mediated mechanisms decreased cytokine-induced adhesion molecule expression, thereby reducing inflammatory leucocyte-endothelium interactions and modified lipid mediator synthesis, thus influencing the transendothelial migration of leucocytes and leucocyte trafficking in general. Even the metabolic repertoire of specific immunocompetent cells such as cytokine release or proliferation is modified by n-3 fatty acids. Beyond this they regulate lipid homeostasis shifting the metabolic pathways towards energy supply thus optimizing the function of immune cells. Due to the regulatory impact on different processes of inflammatory and immune cell activation n-3 fatty acids provide positive effects on various states of immune deficiencies and diseases with a hyperinflammatory character, among which selected examples are presented.


Giusto, N. M., G. A. Salvador, et al. (2002). "Age-associated changes in central nervous system glycerolipid composition and metabolism." Neurochem Res 27(11): 1513-23.

            In this review, changes in brain lipid composition and metabolism due to aging are outlined. The most striking changes in cerebral cortex and cerebellum lipid composition involve an increase in acidic phospholipid synthesis. The most important changes with respect to fatty acyl composition involve a decreased content in polyunsaturated fatty acids (20:4n-6, 22:4n-6, 22:6n-3) and an increased content in monounsaturated fatty acids (18:1n-9 and 20:1n-9), mainly in ethanolamine and serineglycerophospholipids. Changes in the activity of the enzymes modifying the phospholipid headgroup occur during aging. Serine incorporation into phosphatidylserine through base-exchange reactions and phosphatidylcholine synthesis through phosphatidylethanolamine methylation increases in the aged brain. Phosphatidate phosphohydrolase and phospholipase D activities are also altered in the aged brain thus producing changes in the lipid second messengers diacylglycerol and phosphatidic acid.


Gil, A. (2002). "Polyunsaturated fatty acids and inflammatory diseases." Biomed Pharmacother 56(8): 388-96.

            Inflammation is overall a protective response, whose main goal is to liberate the human being of cellular lesions caused by micro-organisms, toxins, allergens, etc., as well as its consequences, and of death cells and necrotic tissues. Chronic inflammation, which is detrimental to tissues, is the basic pathogenic mechanism of hypersensitivity reactions against xenobiotics. Other frequent pathologies, for instance atherosclerosis, chronic hepatitis, inflammatory bowel disease (IBD), liver cirrhosis, lung fibrosis, psoriasis, and rheumatoid arthritis are also chronic inflammatory diseases. Chemical mediators of inflammation are derived from blood plasma or different cell-type activity. Biogenic amines, eicosanoids and cytokines are within the most important mediators of inflammatory processes. The different activities of eicosanoids derived from arachidonic acid (20:4 n-6) versus those derived from eicosapentaenoic acid (20:5 n-3) are one of the most important mechanisms to explain why n-3, or omega-3, polyunsaturated fatty acids (PUFA) exhibit anti-inflammatory properties in many inflammatory diseases. Dietary supplements ranging 1-8 g per day of n-3 PUFA have been reportedly beneficial in the treatment of IBD, eczema, psoriasis and rheumatoid arthritis. In addition, recent experimental studies in rats with experimental ulcerative colitis, induced by intrarectal injection of trinitrobenzene sulphonic acid, have documented that treatment with n-3 long-chain PUFA reduces mucosal damage as assessed by biochemical and histological markers of inflammation. Moreover, the defence antioxidant system in this model is enhanced in treated animals, provided that the n-3 PUFA supply is adequately preserved from oxidation.


Field, C. J., I. R. Johnson, et al. (2002). "Nutrients and their role in host resistance to infection." J Leukoc Biol 71(1): 16-32.

            Almost all nutrients in the diet play a crucial role in maintaining an "optimal" immune response, such that deficient and excessive intakes can have negative consequences on immune status and susceptibility to a variety of pathogens. Iron and vitamin A deficiencies and protein-energy malnutrition are highly prevalent worldwide and are important to the public health in terms of immunocompetence. There are also nutrients (i.e., glutamine, arginine, fatty acids, vitamin E) that provide additional benefits to immunocompromised persons or patients who suffer from various infections. The remarkable advances in immunology of recent decades have provided insights into the mechanisms responsible for the effects of various nutrients in the diet on specific functions in immune cells. In this review, we will present evidence and proposed mechanisms for the importance of a small group of nutrients that have been demonstrated to affect host resistance to infection will be presented. An inadequate status of some of these nutrients occurs in many populations in the world (i.e., vitamin A, iron, and zinc) where infectious disease is a major health concern. We will also review nutrients that may specifically modulate host defense to infectious pathogens (long-chain polyunsaturated n-3 fatty acids, vitamin E, vitamin C, selenium, and nucleotides). A detailed review of the effect of long-chain polyunsaturated n-3 fatty acids on host defense is provided as an example of how the disciplines of nutrition and immunology have been combined to identify key mechanisms and propose nutrient-directed management of immune-related syndromes.


Feussner, I. and C. Wasternack (2002). "The lipoxygenase pathway." Annu Rev Plant Biol 53: 275-97.

            Lipid peroxidation is common to all biological systems, both appearing in developmentally and environmentally regulated processes of plants. The hydroperoxy polyunsaturated fatty acids, synthesized by the action of various highly specialized forms of lipoxygenases, are substrates of at least seven different enzyme families. Signaling compounds such as jasmonates, antimicrobial and antifungal compounds such as leaf aldehydes or divinyl ethers, and a plant-specific blend of volatiles including leaf alcohols are among the numerous products. Cloning of many lipoxygenases and other key enzymes within the lipoxygenase pathway, as well as analyses by reverse genetic and metabolic profiling, revealed new reactions and the first hints of enzyme mechanisms, multiple functions, and regulation. These aspects are reviewed with respect to activation of this pathway as an initial step in the interaction of plants with pathogens, insects, or abiotic stress and at distinct stages of development.


Feldman, E. B. (2002). "The scientific evidence for a beneficial health relationship between walnuts and coronary heart disease." J Nutr 132(5): 1062S-1101S.

            The author and four independent experts evaluated the intent and quality of scientific evidence for a potential beneficial health relationship between the intake of walnuts and the reduction and prevention of coronary heart disease. The report also addresses the supporting evidence for the health benefit of other tree nuts and selected legumes. Compared to most other nuts, which contain monounsaturated fatty acids, walnuts are unique because they are rich in n-6 (linoleate) and n-3 (linolenate) polyunsaturated fatty acids. Walnuts contain multiple health-beneficial components, such as having a low lysine:arginine ratio and high levels of arginine, folate, fiber, tannins, and polyphenols. Though walnuts are energy rich, clinical dietary intervention studies show that walnut consumption does not cause a net gain in body weight when eaten as a replacement food. Five controlled, peer-reviewed, human clinical walnut intervention trials, involving approximately 200 subjects representative of the 51% of the adult population in the United States at risk of coronary heart disease were reviewed. The intervention trials consistently demonstrated walnuts as part of a heart-healthy diet, lower blood cholesterol concentrations. None of these studies were of extended duration that would be essential for evaluation of the sustainability of the observed outcomes. These results were supported by several large prospective observational studies in humans, all demonstrating a dose response-related inverse association of the relative risk of coronary heart disease with the frequent daily consumption of small amounts of nuts, including walnuts.


Farrell, A. P. (2002). "Coronary arteriosclerosis in salmon: growing old or growing fast?" Comp Biochem Physiol A Mol Integr Physiol 132(4): 723-35.

            A review is presented of what we know and what we suspect regarding the formation of coronary arteriosclerotic lesions in salmonids. Coronary lesions are a fact of life for both Atlantic and Pacific species of migrating salmon. Severe forms of lesions, usually restricted to the main coronary artery, are typically found in the majority of a salmon population when they are spawning. Vascular injury to the coronary artery, as a result of the bulbus arteriosus being excessively distended, is proposed as an initiating mechanism for coronary lesion formation, possibly explaining why severe lesions are restricted primarily to the main coronary artery. Evidence is presented that coronary arteriosclerosis in salmonids develops in immature fish, well before maturation, and progresses with age. Growth and growth rate are implicated in lesion progression. A faster growth rate could produce a more stressful life style, which in turn initiates more coronary vascular injury. Dietary factors, especially polyunsaturated fatty acids (and their metabolites), can significantly stimulate vascular smooth muscle proliferation in the salmon coronary artery, but a possible linkage to the progression of coronary lesions has yet to be studied. Whether coronary lesions negatively impact blood flow to the salmon heart has not been properly studied. Nevertheless, the coronary blood supply to the heart has functional importance when salmon exercise and the coronary flow reserve may be reached when fish swim under mild hypoxic conditions. If coronary arterial lesions do adversely affect blood flow to the heart, the selective effects would be most prominent in years when upstream migration conditions are particularly severe.


Farkas, E., M. C. de Wilde, et al. (2002). "Chronic cerebral hypoperfusion-related neuropathologic changes and compromised cognitive status: window of treatment." Drugs Today (Barc) 38(5): 365-76.

            Neurodegenerative disorders, and dementia in particular, have been shown to have a cerebrovascular pathogenic component often in the form of reduced cerebral blood flow. The debate whether such a reduced brain perfusion is a primary trigger or a secondary symptom in the neuropathological progression of dementia has not been conclusively decided yet. However, compelling experimental evidence has been collected to demonstrate an initiating role of reduced cerebral blood flow in neurodegenerative processes. Along these lines, experimental cerebral hypoperfusion in rodents was shown to impair spatial learning and to generate neuronal damage and associated gliosis in sensitive brain regions like the hippocampus and frontoparietal cortex. Since suboptimal cerebral blood supply was thus identified as a potential trigger of cognitive decline, the improvement of cerebral blood flow in cognitive disorders has emerged as an alternative treatment to moderate the symptoms and to delay the onset of advanced dementia. Various drugs, such as cholinergic compounds, hemorheologic agents and vascular smooth muscle relaxants, have already been tested in some instances for their efficacy to increase brain perfusion. In this respect, both clinical and preclinical trials delivered positive data. Furthermore, not only the treatment but also the prevention of the development of cognitive deficiency can target the cerebrovascular system. For this purpose, long-chain polyunsaturated fatty acids derived from fish oil (also known as n-3 PUFAs) have been considered as dietary supplements. These fatty acids appeared particularly effective in the prevention of hypertension-associated vascular pathology. The present review provides an overview of the actions of these compounds focusing on cerebral blood flow, neurodegeneration and cognitive decline.


Duplus, E. and C. Forest (2002). "Is there a single mechanism for fatty acid regulation of gene transcription?" Biochem Pharmacol 64(5-6): 893-901.

            Besides their role as energetic molecules, fatty acids (FAs) also act as signals involved in regulating gene expression. This review focuses on a few examples of FA regulation. The hepatic lipogenic enzyme, fatty acid synthase (FAS) is negatively regulated by polyunsaturated FAs (PUFAs) which suppress sterol regulatory element-binding protein 1 (SREBP 1) gene expression and nuclear content in hepatocytes, thereby reducing FAS gene transcription. It was proposed recently that this reduction in SREBP 1 was the result of a PUFA-induced antagonism of ligand-dependent activation of the liver X nuclear receptor (LXR), known to be an inducer of the SREBP 1 gene. In contrast, several genes are turned on by long-chain (LCFAs) and nonmetabolized FAs in a physiologically relevant manner. These include the acyl-CoA oxidase (AOX), the liver carnitine palmitoyltransferase 1 (L-CPT 1) and the liver fatty acid binding protein (L-FABP). While induction of AOX gene transcription appears to be PPARalpha-dependent, that of the L-CPT 1 gene seems disconnected from PPAR activation. Results obtained in preadipocytes and in intestine cells are in support of a key role played by the beta/delta isoform of PPAR in LCFA induction of the FABP gene. Transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene is stimulated by unsaturated and nonmetabolized LCFAs specifically in adipocytes. Our results reported here support the notion that the mechanisms by which PPARgamma activators and FAs induce transcription of the PEPCK gene are distinct. Altogether these data argue that several FA effects are PPAR-independent. Evidences suggesting that other transcription factors might be involved are debated. It seems now clear that depending upon the cell-specific context and the target gene, FAs can take very different routes to alter transcription.


Dunbar, B. L. and J. E. Bauer (2002). "Metabolism of dietary essential fatty acids and their conversion to long-chain polyunsaturated metabolites." J Am Vet Med Assoc 220(11): 1621-6.


Drsata, J. (2002). "[Enzyme inhibition in the drug therapy of benign prostatic hyperplasia]." Cas Lek Cesk 141(20): 630-5.

            Enzyme inhibition belongs to common mechanisms of drug action and enzymes of hormone metabolism belong to targets in the treatment of benign prostatic hyperplasia. Transformation of testosterone to 5 alpha-dihydrotestosterone is catalyzed by cholestenone-5 alpha-reductase (EC, 5 alpha-reductase). Different effects of dihydrotestosterone and testosterone represent a rational basis for pharmacotherapy by 5 alpha-reductase inhibition. The enzyme is active in the prostate and other organs and tissues, with different distribution of at least two 5 alpha-reductase isoenzymes. Beside this, progesterone-5 alpha-reductase (EC as another enzyme with 5 alpha-reductase activity is present in human tissues including the prostate. The existence of several 5 alpha-reductase activities gives bright possibilities of 5 alpha-reductase inhibition. Basic 5 alpha-reductase inhibitors are synthetic steroid (e.g. finasteride--Proscar). Various mechanisms of their effect (classical reversible competitive inhibition, mechanism-based "suicide" inhibitors, tightly bound irreversible inhibitors...) represent different pharmacokinetic patterns, too. Non-steroidal 5 alpha-reductase inhibitors (e.g. polyunsaturated fatty acids) are effective components of several phytopharmaceuticals. They receive attention due to their complexity and low hazards. Extracts of Serenoa repens seeds (Permixon, Capistan in the Czech Republic), of Pygeum africanum, of Urtica radicis roots (Urtica, Urtiron) or catequine structures from the green tea belong to this group. Beside androgens, participation of estrogens in the origin and development of benign prostatic hyperplasia is probable. Inhibition of the "aromatase" complex, which catalyzes transformation of androgens to estrogens, may contribute to the complexity of phytotherapeutic effects.


Diggle, C. P. (2002). "In vitro studies on the relationship between polyunsaturated fatty acids and cancer: tumour or tissue specific effects?" Prog Lipid Res 41(3): 240-53.

            In vitro cell culture experiments have lead to the consensus in the literature that certain PUFAs have a selective cytotoxic or anti-proliferative effect on tumour cells and a minimal, or no effect on normal cells. Re-examination of key publications showed that when normal cells were used for comparison, they were generally not from the same cell, tissue, or species type as the tumour cells. Recently, investigations have included more appropriate normal control cells, and though tumour specific cytotoxic/anti-proliferative PUFA effects are found in some cell types, in others the normal cells are more sensitive. Cell type differences were found in the relative ability of individual PUFAs to act. However, within a cell type differences in susceptibility were influenced by grade and stage of tumour, immortalisation and tumourigenic status, cell culture media and cell plating density. Together these results suggest that the consensus is not valid, and that susceptibility to PUFA is cell type specific, and alters during neoplastic progression. Furthermore, the cytotoxic/anti-proliferative effect induced by both n-3 and n-6 PUFAs on a wide variety of cell types, associated with an increase in lipid peroxidation in vitro, cannot account for the in vivo data on the relationship between dietary fat and certain cancers. However, the effects of PUFAs and their metabolites on cell signalling pathways may explain the in vivo data.


Di Minno, G., A. Tufano, et al. (2002). "Polyunsaturated fatty acids, thrombosis and vascular disease." Pathophysiol Haemost Thromb 32(5-6): 361-4.

            In the 80's, retrospective studies showed an inverse relation between fish consumption and ischemic heart disease (IHD) mortality. In parallel, fish fats containing the polyunsaturated fatty acid (PUFA) eicosapentaenoic (EPA) were shown to impair platelet aggregation and thromboxane formation. The results of the large prospective trials, the Diet and Reinfarction Trial (DART) and the Lyon Heart Study in the secondary prevention of myocardial infarction, have further supported the interrelationships between diet and dietary prevention of IHD. In the DART Study, the cardioprotection by EPA was paralleled by an increase plasma content of EPA. In the Lyon, in addition to changes in the content of EPA, changes in other well known variables (i.e. leukocytes and vitamin E), often abnormal in subjects prone to arterial thrombosis, have been found. The GISSI Prevenzione Trial was a prospective, multicentric, open labeled trial with a factorial design, in which 11,324 recent (<3 mo) survivors of a first myocardial infarction were assigned to receive, in addition to the usual strategy, a supplementation of n-3 PUFA, vitamin E, or the combination of the two. Cardiovascular death (-30%), coronary heart disease death (-35%), total death (-20%) and sudden death (-45%) were all significantly reduced by the n-3 PUFA supplementation. The reduced tendency to sudden death of survivors of myocardial infarction on treatment with n-3 PUFA are in keeping with a series of scanty but reliable clinical data as well as of experimental studies. However, we believe that large-scale prospective multicentric randomized trials aimed at preventing sudden death in high-risk patients as well as at testing the effects of n-3 PUFA in patients with intracoronary devices and sustained ventricular arrhythmias, are a major direction to be followed to better understand the n-3 PUFA and sudden death issue.


Demaison, L. and D. Moreau (2002). "Dietary n-3 polyunsaturated fatty acids and coronary heart disease-related mortality: a possible mechanism of action." Cell Mol Life Sci 59(3): 463-77.

            Epidemiological and interventional studies indicate that dietary n-3 PUFA reduces mortality due to coronary heart disease (CHD). They act at a low dose, since one or two meals with fatty fish per week is sufficient to provide protection when compared with no fish intake. These fatty acids are effective in providing primary prevention in low- and high-risk subjects and secondary prevention. At high doses, dietary n-3 PUFAs have several beneficial properties. First, they act favourably on blood characteristics: they are hypocholesterolemic and hypotriglyceridemic; they reduce platelet aggregation; they exhibit antithrombotic and fibrinolytic activities; they reduce blood viscosity and they exhibit antiinflammatory action. Second, they reduce ischemia/reperfusion-induced cellular damage. This effect is apparently due to the incorporation of eicosapentaenoic acid in membrane phospholipids. Third, they reduce ischemia and reperfusion arrhythmias. All the effects exerted by n-3 PUFAs at high doses are incompatible with the beneficial action on CHD mortality in humans observed at low doses, where their main properties are related to circulation in the form of free fatty acids. Numerous experimental studies have indicated that low concentrations of exogenous n-3 PUFAs reduce the severity of cardiac arrhythmias. This effect is probably responsible for the protective action of n-3 PUFA on CHD mortality. Further studies are necessary to confirm this assumption in animals. Such studies should take account of the fact that only a low dose of n-3 PUFA (20 mg/kg/day) is necessary to afford protection. Furthermore, since the beneficial effect of n-3 PUFAs on CHD mortality is observed in fish eaters versus no-fish eaters, and since populations in industrialised countries consume excess n-6 PUFAs, control animals in long-term dietary experiments should be fed a diet with only n-6 fatty acids as a source of PUFAs.


De Caterina, R. and R. Madonna (2002). "[Antiarrhythmia effects of omega-3 fatty acids. A review]." Ital Heart J 3(3 Suppl): 297-308.

            Omega-3 polyunsaturated fatty acids have been effective in reducing cardiovascular mortality in the recent GISSI-Prevenzione study. In a post-hoc analysis of this study an important observation has been the reduction of sudden cardiac death. The hypothesis that a protection from sudden death occurs because of antiarrhythmic effects of omega-3 fatty acids is supported by studies on cellular and animal models. A few intervention studies before the GISSI-Prevenzione and several retrospective analyses of epidemiological studies, in which nutritional variables connected with the intake of omega-3 fatty acids had been recorded, also support such a hypothesis. This review critically summarizes this type of evidence and indicates current research directions for its further validation.


Das, U. N. (2002). "Estrogen, statins, and polyunsaturated fatty acids: similarities in their actions and benefits-is there a common link?" Nutrition 18(2): 178-88.

            OBJECTIVES: To investigate whether there is any common link between estrogen, statins, and polyunsaturated fatty acids (PUFAs), which have similar actions and benefits. METHODS: To critically review the literature pertaining to the actions of estrogen, statins, and various PUFAs. RESULTS: Estrogen, statins, and PUFAs enhance nitric oxide synthesis, suppress the production of proinflammatory cytokines such as tumor necrosis factor(alpha), interleukin-1, interleukin-2, and interleukin-6, show antioxidant-like and antiatherosclerotic properties, have neuroprotective actions, and by themselves or their products inhibit tumor cell proliferation and improve osteoporosis. Estrogen, statins, and PUFAs not only have similar actions but also appear to interact with each other. For instance, the binding of estrogen to its receptor on the cell membrane may be determined by its lipid content, statins and PUFAs inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, statins influence the metabolism of PUFAs, and PUFA deficiency enhances 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Statins and PUFAs inhibit tumor cell proliferation, suppress ras activity, and may prevent neurodegeneration and improve cognitive functions such as learning and memory. This suggests that PUFAs might be mediators of the actions of statins. Estrogen boosts cognitive performance in women after menopause and may protect against Alzheimer's disease. CONCLUSIONS: The common link between estrogen, statins, and PUFAs may be nitric oxide. Hence, a combination(s) of estrogen or its derivatives, statins, and various PUFAs may form a novel approach in the management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, osteoporosis, cancer, neurodegenerative conditions, and to improve memory.


Das, U. (2002). "A radical approach to cancer." Med Sci Monit 8(4): RA79-92.

            Reactive oxygen species are known to be potentially dangerous, but are also needed for signal-transduction pathways. Tumor cells have relatively low amounts of superoxide dismutase (SOD), which quenches superoxide anion (O2(-*)), and as a result of a higher level of aerobic metabolism, higher concentrations of O2(-*) , compared to normal cells. But this may not be true of all tumor cells. Some tumor cells have relatively higher amounts of vitamin E, a potent anti-oxidant, and a higher level of anaerobic metabolism, resulting in a balance that is tilted more towards higher anti-oxidant capacity. In both instances of higher aerobic and anaerobic metabolism methods designed to augment free radical generation in tumor cells can cause their death. It is suggested that free radicals and lipid peroxides suppress the expression of Bcl-2, activate caspases and shorten telomere, and thus inducing apoptosis of tumor cells. Ionizing radiation, anthracyclines, bleomycin and cytokines produce free radicals and thus are useful as anti-cancer agents. But they also produce many side-effects. 2-methoxyoestradiol and polyunsaturated fatty acids (PUFAs) inhibit SODs and cause an increase of O2(-*) in tumor cells leading to their death. In addition, PUFAs (especially gamma-linolenic acid), 2-methoxyoestradiol and thalidomide may possess anti-angiogenic activity. This suggests that free radicals can suppress angiogenesis. Limited clinical studies done with gamma-linolenic acid showed that it can regress human brain gliomas without any significant side-effects. Thus, PUFAs, thalidomide and 2-methoxyoestradiol or their derivatives may offer a new radical approach to the treatment of cancer.


Das, U. N. (2002). "Is type 2 diabetes mellitus a disorder of the brain?" Nutrition 18(7-8): 667-72.

            I propose that type 2 diabetes mellitus is due to damage to neurons in the ventromedial hypothalamus or to a defect in the action or properties of insulin or insulin receptors in the brain. These neuronal abnormalities are probably secondary to a marginal deficiency of long-chain polyunsaturated fatty acids during the critical periods of brain growth and development. Hence, supplementation of adequate amounts of long-chain polyunsaturated fatty acids during the third trimester of pregnancy to 2 y postterm can prevent or postpone the development of diabetes mellitus.


Das, U. N. (2002). "The lipids that matter from infant nutrition to insulin resistance." Prostaglandins Leukot Essent Fatty Acids 67(1): 1-12.

            Breast-fed infants showed decreased incidence of obesity, hypertension, diabetes mellitus, and coronary heart disease in later life and higher cognitive function. Breast milk is rich in long-chain polyunsaturated fatty acids (LCPUFAs) and brain preferentially accumulates LCPUFAs during the last trimester of pregnancy and the first few months of life. Breast-fed infants showed significantly lower plasma glucose levels and higher percentage of docosahexaenoic acid and total percentages of LCPUFAs in their skeletal muscle biopsies compared with formula fed. LCPUFAs suppress the production of pro-inflammatory cytokines, regulate the function of several neurotransmitters, enhance the number of insulin receptors in the brain and other tissues, and decrease insulin resistance. LCPUFAs may enhance the production of bone morphogenetic proteins (BMPs), which participate in neurogenesis. It is proposed that the beneficial effects of breast feeding in later life can be attributed to its rich LCPUFA content. It is likely that inadequate breast feeding results in marginal deficiency of LCPUFAs during the critical stages of development, which can lead to insulin resistance. Hence, promoting prolonged breast feeding and/or supplementing LCPUFAs during the critical stages of development may be beneficial in preventing insulin resistance.


Das, U. N. (2002). "Essential fatty acids as possible enhancers of the beneficial actions of probiotics." Nutrition 18(9): 786.

            I investigated whether there is a common link between essential fatty acids and probiotics, which have similar actions and benefits in atopy.I made a critical review of the literature pertaining to the actions of essential fatty acids and probiotics on immune response and the interaction between them with particular reference to atopy.Colonization of the human gastrointestinal tract occurs in the first months and years of life. Probiotics are cultures of beneficial bacteria of healthy gut microflora, which reduce dietary antigen load and thus protect against atopy. A significant reduction in the risk of childhood asthma and other atopic conditions was reported in children who were exclusively breast-fed for at least 4 mo after birth. This beneficial action can be attributed to the immunomodulatory, nutritional, or other components of human milk Human breast milk is rich in long-chain polyunsaturated fatty acids (LCPUFAs), which have immunomodulatory actions. Probiotics and LCPUFAs modulate T-helper 1 and 2 responses, show antibioticlike actions, and alleviate changes related to allergic inflammation. LCPUFAs promote the adhesion of probiotics to mucosal surfaces, which augments the health-promoting effects of probiotics.In view of the similarity in their actions and because LCPUFAs promote the actions of probiotics, I believe that a combination of LCPUFAs and probiotics offer significant protection against atopy. It is likely that breast-feeding and probiotics are two naturally occurring, appropriate events in early human life that have significant health benefits.


Culig, Z., H. Klocker, et al. (2002). "Androgen receptors in prostate cancer." Endocr Relat Cancer 9(3): 155-70.

            The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.


Cordain, L., B. A. Watkins, et al. (2002). "Fatty acid analysis of wild ruminant tissues: evolutionary implications for reducing diet-related chronic disease." Eur J Clin Nutr 56(3): 181-91.

            HYPOTHESES: Consumption of wild ruminant fat represented the primary lipid source for pre-agricultural humans. Hence, the lipid composition of these animals' tissues may provide insight into dietary requirements that offer protection from chronic disease in modern humans. METHOD: We examined the lipid composition of muscle, brain, marrow and subcutaneous adipose tissue (AT) from 17 elk (Cervus elaphus), 15 mule deer (Odocoileus hemionus), and 17 antelope (Antilicapra americana) and contrasted them to wild African ruminants and pasture and grain-fed cattle. RESULTS: Muscle fatty acid (FA) was similar among North American species with polyunsaturated fatty acids/saturated fatty acids (P/S) values from 0.80 to 1.09 and n-6/n-3 FA from 2.32 to 2.60. Marrow FA was similar among North American species with high levels (59.3-67.0%) of monounsaturated FA; a low P/S (0.24-0.33), and an n-6/n-3 of 2.24-2.88. Brain had the lowest n-6/n-3 (1.20-1.29), the highest concentration of 22:6 n-3 (elk, 8.90%; deer, 9.62%; antelope, 9.25%) and a P/S of 0.69. AT had the lowest P/S (0.05-0.09) and n-6/n-3 (2.25-2.96). Conjugated linoleic acid (CLA) isomers were found in marrow of antelope (1.5%), elk (1.0%) and deer (1.0%), in AT (deer, 0.3%; antelope, 0.3%) in muscle (antelope, 0.4%; elk, trace), but not in brain. CONCLUSIONS: Literature comparisons showed tissue lipids of North American and African ruminants were similar to pasture-fed cattle, but dissimilar to grain-fed cattle. The lipid composition of wild ruminant tissues may serve as a model for dietary lipid recommendations in treating and preventing chronic disease.


Contreras, M. A. and S. I. Rapoport (2002). "Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues." Curr Opin Lipidol 13(3): 267-72.

            Recent literature provides a basis for understanding the behavioral, functional, and structural consequences of nutritional deprivation or disease-related abnormalities of n-3 polyunsaturated fatty acids. The literature suggests that these effects are mediated through competition between n-3 and n-6 polyunsaturated fatty acids at certain enzymatic steps, particularly those involving polyunsaturated fatty acid elongation and desaturation. One critical enzymatic site is a delta6-desaturase. On the other hand, an in-vivo method in rats, applied following chronic n-3 nutritional deprivation or chronic administration of lithium, indicates that the cycles of de-esterification/re-esterification of docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6) within brain phospholipids operate independently of each other, and thus that the enzymes regulating each of these cycles are not likely sites of n-3/n-6 competition.


Conklin, K. A. (2002). "Dietary polyunsaturated fatty acids: impact on cancer chemotherapy and radiation." Altern Med Rev 7(1): 4-21.

            Preclinical studies have shown that certain polyunsaturated fatty acids may actually enhance the cytotoxicity of several antineoplastic agents and the anticancer effects of radiotherapy. These effects are possibly mediated by incorporation of the polyunsaturated fatty acids into cancer cell membranes, thus altering the physical and functional properties. In addition, certain polyunsaturated fatty acids may also reduce or prevent some of the side effects of these therapies, and administering antioxidants to prevent polyunsaturated fatty acid-induced oxidative stress may further enhance the impact of chemotherapy and radiation.


Casimiro, C. (2002). "[Etiopathogenic factors in colorectal cancer. Nutritional and life-style aspects. 2.]." Nutr Hosp 17(3): 128-38.

            INTRODUCTION: Colorectal Cancer (CRC) is more prevalent in the countries that have an occidental type diet (rich in meat, animal fat, and refined carbohydrates and poor in fibre). Genetic differences among the various populations do not seem to be very important regarding this issue. Several geographic areas are suffering a growing rise in incidence that seems to be related to a greater local prosperity and a concomitant occidentalization of their diet. NUTRITIONAL FACTORS: High fibre content in food has traditionally been considered as a protector factor against CRC because of multiple epidemiological studies; clinical trials have not been able to confirm it maybe due to methodological problems. Vegetables in general more than fruit, seem to have a certain protective effect, among the former, cruciferous vegetables and garlic should be highlighted. Red or processed meat seems to enhance risk, meanwhile it is not clear for white meat and fish seems to be protective. Ingestion of a high-calorie diet, overweight and the total contents of fat in diet seem to be related to a rise in the incidence of CRC; nowadays the possible protective effect of mono and polyunsaturated fatty acids (particularly the n-3) is starting to be considered. Among micronutrients calcium, vitamin D, folates, flavonoids, antioxidant vitamins (A, C and E) and selenium can be protective meanwhile iron may enhance risk. STYLE OF LIFE FACTORS: Tobacco seems to be an important risk factor for CCRC even for those who use it moderately. Alcohol (specially liquors and beer) seems to be a direct risk factor also, in addition to its co-carcinogenic effect with tobacco. Physical exercise is increasingly been considered as a protective factor. Industrial workers who are in contact for many years with inorganic dust coming from plastic substances and fuel oil could have a greater risk of developing CRC. CONCLUSIONS: A vegetable rich, red meat and fat poor diet seems to be ideal to avoid CRC. It is convenient to do exercise on a regular basis and to avoid overweight and the use of tobacco and alcohol. Protection against industrial waste substances is also important.


Caramia, G. (2002). "[Polyunsaturated fatty acids: omega-3 in child development]." Pediatr Med Chir 24(5): 337-45.

            The understanding of the role of lipids has made major advances following the identification, by George and Mildred Burr, of so-called "essential fatty acids", i.e. linoleic acid (LA) and alpha-linolenic acid (ALA). LA is supplied by animal and vegetal fats, while ALA reaches higher levels in breastmilk, fish, and olive oil. For both LA and ALA, the human body depends exclusively on the dietary supply. These lipids play a major role as structural components of cell membranes, in particular of neurons, nerves, myelinated sheath, retina, vessels, heart, and blood cells; moreover, they act as precursors of several short-life compounds with hormone-like action: prostaglandins, prostacylins, thromboxanes, leukotriens, all with a regulatory effect on several cell functions, and on cholesterol pathway. It has been suggested a "health programming" role for food, due to the impact of the type of feeding on the subsequent neuromotor development, learning abilities, behavior, metabolism, blood pressure, bone mineralization, and degenrative diseases. This is the consequence of changes of the genomic expression, with a guided clone selection. This is in line with the "imprinting hypothesis" proposed by K. Lorenz (1973 Nobel Prize for Physiology and Medicine), who suggested that stimulations at a particular age may drive animal behavior for the rest of their life.


Calder, P. C. and R. F. Grimble (2002). "Polyunsaturated fatty acids, inflammation and immunity." Eur J Clin Nutr 56 Suppl 3: S14-9.

            Consumption of n-6 polyunsaturated fatty acids greatly exceeds that of n-3 polyunsaturated fatty acids. The n-6 polyunsaturated fatty acid arachidonic gives rise to the eicosanoid family of inflammatory mediators (prostaglandins, leukotrienes and related metabolites) and through these regulates the activities of inflammatory cells, the production of cytokines and the various balances within the immune system. Fish oil and oily fish are good sources of long chain n-3 polyunsaturated fatty acids. Consumption of these fatty acids decreases the amount of arachidonic acid in cell membranes and so available for eicosanoid production. Thus, n-3 polyunsaturated fatty acids act as arachidonic acid antagonists. Components of both natural and acquired immunity, including the production of key inflammatory cytokines, can be affected by n-3 polyunsaturated fatty acids. Although some of the effects of n-3 fatty acids may be brought about by modulation of the amount and types of eicosanoids made, it is possible that these fatty acids might elicit some of their effects by eicosanoid-independent mechanisms. Such n-3 fatty acid-induced effects may be of use as a therapy for acute and chronic inflammation, and for disorders which involve an inappropriately activated immune response.


Calder, P. C. (2002). "Dietary modification of inflammation with lipids." Proc Nutr Soc 61(3): 345-58.

            The n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in high proportions in oily fish and fish oils. The n-3 PUFA are structurally and functionally distinct from the n-6 PUFA. Typically, human inflammatory cells contain high proportions of the n-6 PUFA arachidonic acid and low proportions of n-3 PUFA. The significance of this difference is that arachidonic acid is the precursor of 2-series prostaglandins and 4-series leukotrienes, which are highly-active mediators of inflammation. Feeding fish oil results in partial replacement of arachidonic acid in inflammatory cell membranes by EPA. This change leads to decreased production of arachidonic acid-derived mediators. This response alone is a potentially beneficial anti-inflammatory effect of n-3 PUFA. However, n-3 PUFA have a number of other effects which might occur downstream of altered eicosanoid production or might be independent of this activity. For example, animal and human studies have shown that dietary fish oil results in suppressed production of pro-inflammatory cytokines and can decrease adhesion molecule expression. These effects occur at the level of altered gene expression. This action might come about through antagonism of the effects of arachidonic acid-derived mediators or through more direct actions on the intracellular signalling pathways which lead to activation of transcription factors such as nuclear factor kappa B (NFB). Recent studies have shown that n-3 PUFA can down regulate the activity of the nuclear transcription factor NFB. Fish oil feeding has been shown to ameliorate the symptoms in some animal models of chronic inflammatory disease and to protect against the effects of endotoxin and similar inflammatory challenges. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some patients with asthma, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory. There are indications that inclusion of n-3 PUFA in enteral and parenteral formulas might be beneficial to patients in intensive care or post-surgery.


Brunner, J., K. G. Parhofer, et al. (2002). "Cholesterol, essential fatty acids, and suicide." Pharmacopsychiatry 35(1): 1-5.

            Epidemiological and clinical studies have described an association between lower serum cholesterol concentrations and increased suicide risk that is not entirely attributable to depression-related malnutrition and weight loss. Recent epidemiological studies with greater samples and longer follow-up periods, however, have even shown a positive correlation between cholesterol concentrations and suicide risk after controlling for potential confounding variables. A meta-analysis of earlier intervention trials suggested that cholesterol lowering could cause or worsen depressive symptoms and increase the risk of suicide. Large trials of statins (simvastatin, lovastatin, and pravastatin) did not show an increase of suicide mortality. The aim of this selective review is to critically discuss the current evidence for a potential link between cholesterol, essential fatty acids, depression, suicide, impulsivity, and aggression. Preclinical data support the hypothesis that cholesterol reduction may contribute to the serotonergic abnormalities that have been postulated in suicidal subjects. Recently, it was hypothesised that a decreased consumption of polyunsaturated fatty acids, especially omega-3 fatty acids, may be a risk factor for depression and suicide. Currently, we do not have sufficient evidence that cholesterol-lowering therapies increase the risk of depression and suicide. Increasing the dietary intake of omega-3 fatty acids may increase central serotonergic activity and reduce impulsive and aggressive behaviours.


Broadhurst, C. L., Y. Wang, et al. (2002). "Brain-specific lipids from marine, lacustrine, or terrestrial food resources: potential impact on early African Homo sapiens." Comp Biochem Physiol B Biochem Mol Biol 131(4): 653-73.

            The polyunsaturated fatty acid (PUFA) composition of the mammalian central nervous system is almost wholly composed of two long-chain polyunsaturated fatty acids (LC-PUFA), docosahexaenoic acid (DHA) and arachidonic acid (AA). PUFA are dietarily essential, thus normal infant/neonatal brain, intellectual growth and development cannot be accomplished if they are deficient during pregnancy and lactation. Uniquely in the human species, the fetal brain consumes 70% of the energy delivered to it by mother. DHA and AA are needed to construct placental and fetal tissues for cell membrane growth, structure and function. Contemporary evidence shows that the maternal circulation is depleted of AA and DHA during fetal growth. Sustaining normal adult human brain function also requires LC-PUFA.Homo sapiens is unlikely to have evolved a large, complex, metabolically expensive brain in an environment which did not provide abundant dietary LC-PUFA. Conversion of 18-carbon PUFA from vegetation to AA and DHA is considered quantitatively insufficient due to a combination of high rates of PUFA oxidation for energy, inefficient and rate limited enzymatic conversion and substrate recycling. The littoral marine and lacustrine food chains provide consistently greater amounts of pre-formed LC-PUFA than the terrestrial food chain. Dietary levels of DHA are 2.5-100 fold higher for equivalent weights of marine fish or shellfish vs. lean or fat terrestrial meats. Mammalian brain tissue and bird egg yolks, especially from marine birds, are the richest terrestrial sources of LC-PUFA. However, land animal adipose fats have been linked to vascular disease and mental ill-health, whereas marine lipids have been demonstrated to be protective. At South African Capesites, large shell middens and fish remains are associated with evidence for some of the earliest modern humans. Cape sites dating from 100 to 18 kya cluster within 200 km of the present coast. Evidence of early H. sapiens is also found around the Rift Valley lakes and up the Nile Corridor into the Middle East; in some cases there is an association with the use of littoral resources. Exploitation of river, estuarine, stranded and spawning fish, shellfish and sea bird nestlings and eggs by Homo could have provided essential dietary LC-PUFA for men, women, and children without requiring organized hunting/fishing, or sophisticated social behavior. It is however, predictable from the present evidence that exploitation of this food resource would have provided the advantage in multi-generational brain development which would have made possible the advent of H. sapiens. Restriction to land based foods as postulated by the savannah and other hypotheses would have led to degeneration of the brain and vascular system as happened without exception in all other land based apes and mammals as they evolved larger bodies.


Brenna, J. T. (2002). "Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man." Curr Opin Clin Nutr Metab Care 5(2): 127-32.

            Alpha-linolenic acid (18:3n-3) is the major n-3 (omega 3) fatty acid in the human diet. It is derived mainly from terrestrial plant consumption and it has long been thought that its major biochemical role is as the principal precursor for long chain polyunsaturated fatty acids, of which eicosapentaenoic (20:5n-3) and docosahexaenoic acid (22:6n-3) are the most prevalent. For infants, n-3 long chain polyunsaturated fatty acids are required for rapid growth of neural tissue in the perinatal period and a nutritional supply is particularly important for development of premature infants. For adults, n-3 long chain polyunsaturated fatty acid supplementation is implicated in improving a wide range of clinical pathologies involving cardiac, kidney, and neural tissues. Studies generally agree that whole body conversion of 18:3n-3 to 22:6n-3 is below 5% in humans, and depends on the concentration of n-6 fatty acids and long chain polyunsaturated fatty acids in the diet. Complete oxidation of dietary 18:3n-3 to CO2 accounts for about 25% of 18:3n-3 in the first 24 h, reaching 60% by 7 days. Much of the remaining 18:3n-3 serves as a source of acetate for synthesis of saturates and monounsaturates, with very little stored as 18:3n-3. In term and preterm infants, studies show wide variability in the plasma kinetics of 13C n-3 long chain polyunsaturated fatty acids after 13C-18:3n-3 dosing, suggesting wide variability among human infants in the development of biosynthetic capability to convert 18:3n-3 to 22:6n3. Tracer studies show that humans of all ages can perform the conversion of 18:3n-3 to 22:6n3. Further studies are required to establish quantitatively the partitioning of dietary 18:3n-3 among metabolic pathways and the influence of other dietary components and of physiological states on these processes.


Bomba, A., R. Nemcova, et al. (2002). "Improvement of the probiotic effect of micro-organisms by their combination with maltodextrins, fructo-oligosaccharides and polyunsaturated fatty acids." Br J Nutr 88 Suppl 1: S95-9.

            Probiotics could represent an effective alternative to the use of synthetic substances in nutrition and medicine. The data concerning the efficacy of probiotics are often contradictory. This paper focuses on the enhancement of the efficacy of probiotics by their combination with synergistically acting components of natural origin. Maltodextrins can be obtained by enzymatic hydrolysis of starch and are suitable for consumption. Administration of Lactobacillus paracasei together with maltodextrin decreased the number of Escherichia coli colonising the jejunal mucosa of gnotobiotic piglets by 1 logarithm compared to the control group. Fructo-oligosaccharides (FOS) are naturally occurring oligosaccharides, mainly of plant origin. L. paracasei administered in combination with FOS significantly increased counts of Lactobacillus spp., Bifidobacterium spp., total anaerobes and total aerobes compared to the control group as well as the L. paracasei group. It also significantly decreased Clostridium and Enterobacterium counts in the faeces of the weanling piglets compared with the control group. Dietary lipids influence the gastrointestinal microbiota and specifically the population of lactic acid bacteria. In gnotobiotic piglets the oral administration of an oil containing polyunsaturated fatty acids (PUFA) significantly increased the number of L. paracasei adhering to jejunal mucosa compared to the control group. Our results showed that maltodextrin KMS X-70 and PUFA can be used to enhance the effect of probiotic micro-organisms in the small intestine, and similarly FOS enhance the effect of probiotic micro-organisms in the large intestine.


Bolle, P., M. G. Evandri, et al. (2002). "The controversial efficacy of vitamin E for human male infertility." Contraception 65(4): 313-5.

            Vitamin E (VE) is major lipophilic chain-breaking antioxidant which protects tissue polyunsaturated fatty acids (PUFA) against peroxidation, a property that could be beneficial in the male reproductive physiology because the membranes of germ cells and spermatozoa are very sensitive to oxidation because of their high content of PUFA. Some of the available data on the efficacy of VE as an oral drug for male infertility or as an additive during in vitro manipulations of spermatozoa were reviewed here, observing that they are often contradictory, possibly because: (1) antioxidant therapy could be ineffective in certain studies not concentrated on men in whom oxidative stress is implicated as an infertility factor, and (2) the VE antioxidant therapy is a double-edged sword strictly depending on the dosage or the in vitro concentration of the vitamin. Thus, further laboratory and clinical studies with better-defined experimental conditions should be performed to establish the in vitro and in vivo efficacy of VE for human male infertility.


Bocher, V., I. Pineda-Torra, et al. (2002). "PPARs: transcription factors controlling lipid and lipoprotein metabolism." Ann N Y Acad Sci 967: 7-18.

            Nuclear receptors are transcription factors that are activated by ligands and subsequently bind to regulatory regions in target genes, thereby modulating their expression. Nuclear receptors thus allow the organism to integrate signals coming from the environment and to adapt by modifying the expression levels of relevant genes. The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma constitute a subfamily of nuclear receptors. PPARalpha has been shown to bind and to be activated by leukotriene B4 and the hypolipidemic drugs of the fibrate class; PPARbeta/delta ligands are polyunsaturated fatty acids and prostaglandins; while prostaglandin J2 derivatives and the antidiabetic glitazones are, respectively, natural and synthetic ligands for PPARgamma. Upon binding and activation by their ligands, they regulate the transcription of numerous genes involved in intracellular lipid metabolism, lipoprotein metabolism, and reverse cholesterol transport in a subtype- and tissue-specific manner. PPARs therefore constitute interesting targets for the development of therapeutic compounds useful in the treatment of disorders of lipid and lipoprotein metabolism.


Blee, E. (2002). "Impact of phyto-oxylipins in plant defense." Trends Plant Sci 7(7): 315-22.

            Phyto-oxylipins are metabolites produced in plants by the oxidative transformation of unsaturated fatty acids via a series of diverging metabolic pathways. Biochemical dissection and genetic approaches have provided compelling evidence that these oxygenated derivatives actively participate in plant defense mechanisms. During the past decade, interest in this field was focused on the biosynthesis of jasmonic acid (one branch of C18 polyunsaturated fatty acid metabolism) and on its relationship to the other plant defense-signaling pathways. However, recently, antisense strategies have revealed that oxylipins other than jasmonates are probably also essential for the resistance of plants to pathogens.


Black, H. S. (2002). "Pro-oxidant and anti-oxidant mechanism(s) of BHT and beta-carotene in photocarcinogenesis." Front Biosci 7: d1044-55.

            An hypothesis for the role of free radicals in cancer was elaborated by D. Harman in 1962 who suggested that it might be possible to reduce the extent of damage caused by free radicals through three dietary changes: (i) caloric reduction, i.e., lowering the level of free radical reactions arising in the course of normal metabolism; (ii) minimize dietary components that tend to increase the level of free radical reactions (e.g., polyunsaturated fats); and (iii) supplement the diet with one or more free radical reaction inhibitors (anti-oxidants). With respect to (ii) and (iii), lipid peroxidation exemplifies the type of chain reaction initiated by free radicals, with unsaturated fatty acids being the primary center of free radical attack. Anti-oxidants act as free radical scavengers and are able to terminate these reactions. Indeed, the phenolic anti-oxidant butylated hydroxytoluene (BHT), and the carotenoid beta-carotene, have both been shown to influence photocarcinogenesis, although the lack of correlation between physicochemical parameters and pathophysiological responses is apparent in both instances. The bimolecular rate constant for reaction of BHT with model peroxyl radicals is low while beta-carotene is highly reactive. However, both are able to efficiently inhibit lipid peroxidation reactions in biological membranes. Indeed, the influence of photocarcinogenesis by both BHT and beta-carotene is diminished as the level of dietary fat decreases, pointing to the involvement of lipid peroxidative reactions. Nevertheless, the mode of action of BHT in inhibiting photocarcinogenesis appears to be related to dose-diminution resulting from an increased spectral absorbance of the stratum corneum. On the other hand, beta-carotene has no such effect and may actually exacerbate photocarcinogenesis under certain dietary conditions. This paradox points to the complex relationship between chemical mechanisms and biological mode of action of anti-oxidants in photocarcinogenesis. Recent clinical and experimental data also suggest that supplementation of the complex and intricately balanced natural antioxidant defense system with one or more anti-oxidants as a cancer prevention strategy will demand extreme caution.


Belury, M. A. (2002). "Dietary conjugated linoleic acid in health: physiological effects and mechanisms of action." Annu Rev Nutr 22: 505-31.

            Conjugated linoleic acid (CLA) is a group of polyunsaturated fatty acids found in beef, lamb, and dairy products that exist as positional and stereo-isomers of octadecadienoate (18:2). Over the past two decades numerous health benefits have been attributed to CLA in experimental animal models including actions to reduce carcinogenesis, atherosclerosis, onset of diabetes, and body fat mass. The accumulation of CLA isomers and several elongated/desaturated and beta-oxidation metabolites have been found in tissues of animals fed diets with CLA. Molecular mechanisms of action appear to include modulation of eicosanoid formation as well as regulation of the expression of genes coding for enzymes known to modulate macronutrient metabolism. This review focuses on health benefits, metabolism, and potential mechanisms of action of CLA and postulates the implications regarding dietary CLA for human health.


Belluzzi, A. (2002). "N-3 fatty acids for the treatment of inflammatory bowel diseases." Proc Nutr Soc 61(3): 391-5.

            The aim of the present paper is to briefly review the literature relating to clinical studies of the use of polyunsaturated long-chain fatty acids in the treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. The reasons for the discrepancies in the findings could be related to the different study designs, different treatments, overlapping of treatment effects, as well as the variety of treatment formulations and doses used, which have led to results that are, in certain instances, very difficult to explain. Emphasis on a treatment formulation which reduces the incidence of side effects, together with careful selection of patients and experimental design, seems to be associated with benefits, and these studies point to the therapeutic potential for these lipids in the therapy of IBD. It is possible that these fatty acids act by reducing low-grade active inflammation rather than by preventing reinitiation of the inflammatory process from a truly quiescent state. Whether this treatment is applicable to all IBD patients has not been fully elucidated. Nevertheless, taken together, all these studies suggest the effectiveness of these new therapeutic approaches, not only when conventional treatment fails or when it is not possible to treat chronically, but also, in some instances, as first choice.


Beckles Willson, N., T. M. Elliott, et al. (2002). "Omega-3 fatty acids (from fish oils) for cystic fibrosis." Cochrane Database Syst Rev(3): CD002201.

            BACKGROUND: Epidemiological (population studies) and other studies suggest that a diet rich in omega-3 essential fatty acids (derived from fish oil) may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis. OBJECTIVES: To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality. To identify any adverse events associated with omega-3 polyunsaturated fatty acid supplementation. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialised trials register, which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Authors and persons interested in the question were contacted. Date of the most recent search of the Group's specialised register: May 2002. SELECTION CRITERIA: Randomised controlled trials in patients with cystic fibrosis in which omega-3 fatty acid supplements were compared with a placebo oil. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected the trials to be included in the review and assessed the methodological quality of the trials using two approaches: Cochrane assessment of allocation concealment and Jadad quality assessment score. Using data acquisition forms, two reviewers independently extracted data. Missing data has been requested. MAIN RESULTS: The initial literature search identified six trials. Two trials, involving 31 participants satisfied our inclusion criteria and were included in the review. Both compared omega-3 fatty acids to olive oil controls for a six week treatment period. One study (19 participants) showed an improvement in FEV1, FVC, Shwachman score and reduction in sputum volume in the fish oil group at the end of this short treatment period. REVIEWER'S CONCLUSIONS: The review of trials found that regular omega-3 supplements may provide some benefits for people with cystic fibrosis with relatively few adverse effects, although the evidence is insufficient to draw firm conclusions. There is insufficient evidence to recommend routine use of supplements of omega-3 fatty acids in people with cystic fibrosis. The most notable feature highlighted by this review was the lack of data for many of the outcomes likely to be meaningful to people with or making treatment decisions about CF. A large, long-term, multi-centre, randomised controlled study is needed in order to determine if there is a significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.


Bastian, L. and A. Weimann (2002). "Immunonutrition in patients after multiple trauma." Br J Nutr 87 Suppl 1: S133-4.

            Severe trauma threatens the life of the victim, both directly and indirectly via immunological dysregulation during the subsequent clinical course. Inflammatory or infectious episodes may complicate the clinical course and ultimately result in sepsis and multiple organ failure, which have mortality rates of up to 80%. Immunomodulatory intervention aims to ameliorate the early hyperinflammatory phase (systemic inflammatory response syndrome, SIRS) to avoid the development of sepsis. One of the immunomodulation strategies is enteral feeding supplemented with specific nutrients, such as glutamine, n-3-polyunsaturated fatty acids, and nucleotides ('immunonutrition'), because changes in the GALT (gut-associated lymphoid tissue) immune response may contribute to intestinal dysfunction and increase susceptibility to post injury gut-derived sepsis. In a prospective, randomized, double-blind, controlled study in twenty-nine patients suffering severe trauma we were able to show that immunonutrition (arginine, n-3-fatty acids, and nucleotides) significantly reduces the number of SIRS days per patient, and also lowers the multiple organ failure (MOF) score on day 3 and days 8-11 (P<0.05). Other studies have reported a reduction in septic complications and MOF rates, shortened hospital stay, and reduction in the use of antibiotics in patients randomized to the immune-enhancing diet. This improved clinical outcome was reflected in a reduction in hospital costs. In the recovery period after trauma (1-72 h after injury) a limitation of the inflammatory response of immunocompetent cells must be achieved as quickly as possible (<72 h). The only strategy available to clinicians caring for trauma patients is immunonutrition, and this should be strongly considered as a rational approach improving immune function and reducing septic complications in critically ill or injured patients.


Baggio, B. (2002). "Fatty acids, calcium and bone metabolism." J Nephrol 15(6): 601-4.

            Epidemiological, clinical and experimental evidence suggests that fatty acids may have an effect (due to their chemical structure) on calcium metabolism in animals and man. Fatty acid deficiency in animals can lead to a loss of bone calcium and matrix, resulting in marked bone demineralization, and treatment with a mixture of omega-3 and omega-6 polyunsaturated fatty acids can induce significant reduction in some biochemical markers of bone reabsorption. A relationship, between phospholipid fatty acid content, calcium-regulating hormones and intestinal, renal, and bone calcium metabolism alterations, has been reported in patients with renal stones and hypercalciuria. Recent studies have shown specific effects of fatty acids on the gene expression of some bone cytokines. Fatty acids might be involved in calcium metabolism influencing cellular calcium ion transport directly, as second messengers, or generating, through the cyclooxygenase pathway, potential biological mediators which have complex effects on bone remodeling. Experimental and clinical documentation of the specific and indirect effects of fatty acids on calcium and bone metabolism could open up new and interesting clinical prospects.


Astrup, A., B. Buemann, et al. (2002). "Low-fat diets and energy balance: how does the evidence stand in 2002?" Proc Nutr Soc 61(2): 299-309.

            The role of high-fat diets in weight gain and obesity is assessed by evidence-based principles. Four meta-analyses of weight change occurring on ad libitum low-fat diets in intervention trials consistently demonstrate a highly significant weight loss of 3-4 kg in normal-weight and overweight subjects (P < 0.001). The analyses also find a dose-response relationship, i.e. the reduction in percentage energy as fat is positively associated with weight loss. Weight loss is also positively related to initial weight; a 10 % reduction in dietary fat is predicted to produce a 4-5 kg weight loss in an individual with a BMI of 30 kg/m2. The non-fat macronutrient composition of the diet is also important. Whereas the glycaemic index of the carbohydrate may play a role for cardiovascular risk factors, there is so far no evidence that low-glycaemic index foods facilitate weight control. In contrast, intervention studies show that sugar in drinks is more likely to produce weight gain than solid sugar in foods. Although the evidence is weak, alcoholic beverages promote a positive energy balance, and wine may be more obesity-promoting than beer. Protein is more satiating and thermogenic than carbohydrates, and one intervention study has shown that an ad libitum low-fat diet where carbohydrate was replaced by protein produced more weight loss after 6 months (8.1 v. 5.9 kg). The evidence linking particular fatty acids to body fatness is weak. If anything, monounsaturated fat may be more fattening than polyunsaturated and saturated fats, and no ad libitum dietary intervention study has shown that a normal-fat high-monounsaturated fatty acid diet is equivalent or superior to a low-fat diet in the prevention of weight gain and obesity. The evidence strongly supports the low-fat diet as the optimal choice for the prevention of weight gain and obesity, while the use of a normal-fat high-monounsaturated fatty acid diet is unsubstantiated.


Anderson, M. and K. L. Fritsche (2002). "(n-3) Fatty acids and infectious disease resistance." J Nutr 132(12): 3566-76.

            The current view of the manner in which (n-3) polyunsaturated fatty acids (PUFA) affect the immune system is centered on their ability to alter cytokine production and secondarily to diminish eicosanoid biosynthesis. The purpose of this article is to review the evidence that (n-3) PUFA affect host infectious disease resistance. Although there have been a few human clinical trials involving (n-3) PUFA and human infectious disease, the data are equivocal and the study designs confounded by the simultaneous inclusion of other immunonutrients (i.e., arginine and nucleotides) with the (n-3) PUFA. Thus, this review focuses on animal feeding trials that include an in vivo challenge of the host with a live infectious agent. Host survival and pathogen clearance are the most common end points measured in these studies. The data suggest that (n-3) PUFA can both improve and impair host resistance to a number of pathogens. However, the data are still quite limited in breadth and depth. For those pathogens for which data exist, the number of published studies in general does not exceed two or three. Emphasis is placed on defining important microbiological and immunological differences in various host-pathogen interactions that might help explain the incongruity in the findings published to date. The authors believe that direct examination of (n-3) PUFA on human infectious disease resistance is warranted.


Anantharaju, A., A. Feller, et al. (2002). "Aging Liver. A review." Gerontology 48(6): 343-53.

            Aging is characterized by a progressive decline of cellular functions. The aging liver appears to preserve its function relatively well. Aging is associated in human liver with morphological changes such as decrease in size attributable to decreased hepatic blood flow. Ultrastructural analysis of the human liver has revealed that the integrity of mitochondria and enzymatic activity remain mostly unchanged with aging. Reactive oxygen species (ROS) are involved in the aging process and result mainly from nonenzymatic processes in the liver. Endogenous free radicals are generated within mitochondria and suspected to cause severe injury to mitochondrial DNA. This damaged DNA accumulates with aging. In addition, polyunsaturated fatty acids, highly sensitive to ROS, decrease in liver mitochondria from human centenarians, a feature acquired during evolution as a protective mechanism to favor longevity. Diet is considered the main environmental factor having effect on lifespan. It has a major impact on aging liver, the central metabolic organ of the body. The ubiquitin proteolytic pathway in the liver serves to destroy many proteins, among them p21 which is encoded by abundant mRNA in senescent cells, can inhibit cell proliferation and favors DNA repair. Drug therapy in the elderly may be complicated by several factors such as decline in body weight, renal function, liver mass and hepatic blood flow, making adverse drug reactions more frequent. Hepatic drug metabolism is mainly mediated by the cytochrome P(450 )system and drug interactions in the elderly are likely related to the progressive decline of this system after the fifth decade of life and another decrease in individuals aged >70. Antihypertensive therapy in the elderly depends upon either hepatic or renal function and should be adjusted accordingly. Finally, telomerases are the biological clocks of replicative lifespan. Shortening of telomeric ends of chromosomes correlates with aging and decline in the replicative potential of the cell: replicative senescence. Telomere DNA of human somatic cells shortens during each cell division thus leading to a finite proliferation. Transfection of the telomerase reverse transcriptase gene results in elongation of telomeres and extension of lifespan. This also applies to humans. Replicative senescence in human cells evolved as a mechanism to protect them from continuous divisions leading to multiple mutations. Longer-lived species such as humans had to develop replicative senescence to ensure that they would have the increased protection that their longevity necessitates.


Albertini, R., R. Moratti, et al. (2002). "Oxidation of low-density lipoprotein in atherosclerosis from basic biochemistry to clinical studies." Curr Mol Med 2(6): 579-92.

            Although it has been known for long time that atherosclerosis is associated with lipid deposition, only recently it has been accepted that the plasmatic concentration of cholesterol, especially LDL cholesterol, is a risk factor for atherosclerosis. However, chemically modified LDL, but not native LDL, is able to induce the formation of foam cells, the hallmark of atherosclerosis. LDL oxidation is likely to be the most important form of LDL modification in humans. In biochemical terms, LDL oxidation is a free radical driven chain reaction where polyunsaturated fatty acids are converted to lipid peroxides, which easily decompose to many products, including biologically active aldehydes. The assay of LDL oxidation in biological fluids is problematic; direct assays detect a product of LDL oxidation whereas indirect assays give an indicator of LDL oxidation susceptibility. In general, epidemiological studies support the concept that the level of plasmatic lipophilic antioxidants, tocopherols and carotenoids, is low in populations at increased risk for atherosclerosis. However, clinical trials based on vitamin E as antioxidant showed inconclusive results, suggesting that supplementation with vitamin E is not generically recommended for atherosclerotic patients. These results, however, do not contradict that oxidation of lipoprotein is involved in atherosclerosis; rather, this negative outcome raises a number of considerations such as the need for a reliable marker of lipoprotein oxidation in plasma and a more complete information about the physiological triggers of lipoprotein oxidation.


Albertazzi, P. and K. Coupland (2002). "Polyunsaturated fatty acids. Is there a role in postmenopausal osteoporosis prevention?" Maturitas 42(1): 13-22.

            OBJECTIVE: To review the effect of a diet supplemented with polyunsaturated fatty acids (PUFA) on prevention or treatment of osteoporosis. METHODS: MEDLINE (1966-April 2001), Allied Complementary Medicine (1985-2001), Cochrane Library and Database of Systematic Reviews (1st Quarter 2001) was searched. Five reviews and no systematic reviews were found on this topic in the Cochrane Library. Eleven relevant in-vivo studies were identified on the effect of these compounds on bone. Eight were animal studies and three were randomised control trials (RCT) in human. RESULTS: There are two classes of PUFA designated as n-3 and n-6 with alpha-linolenic acid (ALA). These two different types of PUFA differently influence prostaglandin formation and hence modulate bone metabolism differently. These are several in vitro and animal data suggesting that diet with a low n-6/n-3 ratio may have beneficial effects on bone mineral density. Only three, short-term, small studies have been performed in human so far. Two studies, one performed with bone markers and one with bone density showed a positive effect of PUFA on bone. While a third study showed no effect. CONCLUSIONS: Preliminary, data have suggested that a diet with a low n-6/n-3 ratio may have beneficial effects on bone mineral density. Further studies are, however, required to fully assess the dose and type of PUFA to be used for optimum bone effects. This may be useful particularly for the prevention of disease in the elderly, since a diet rich in n-3 PUFA has been shown to have additional benefit on the cardiovascular, central nervous system and joints.


Ziegler, O., D. Quilliot, et al. (2001). "[Macronutrients, fat mass, fatty acid flux and insulin sensitivity]." Diabetes Metab 27(2 Pt 2): 261-70.

            Obesity and visceral or upper body fat distribution, have a major impact on insulin sensitivity. There is strong evidence to suggest that free fatty acids (FFA) contribute to the pathogenesis of insulin resistance and the metabolic syndrome. Increased FFA release from adipose tissue or failure of FFA using tissues to remove them normally, lead to increased triglycerides (TG) and FFA fluxes. Increased delivery of FFA to muscle reduces muscle glucose uptake and utilisation by substrate competition or direct inhibition of glucose transport. Insulin resistance has been correlated with the size of intramuscular TG store. Intracellular TG have been involved in beta cell failure the so called lipotoxicity phenomena. The rate of FFA to the liver is a major determinant of hepatic TG secretion. So the regulation of FFA distribution between FFA using tissues and the partition of FFA between storage and oxidation could be involved in the developpment of insulin resistance. The dietary macronutrients could play a role in nutrient partitioning but their role in the etiology of insulin resistance is poorly understood due to a paucity of credible intervention studies in humans. However deleterious effects of saturated fatty acids on insulin action and the beneficial effects of polyunsaturated fatty acids (PUFAs) could be suspected from animal studies, and from epidemiological or clinical studies in humans. A very high intake of sucrose or fructose could be deleterious but low glycemic index foods, and fibers could have protective effects. Weight loss can induce marked improvement in insulin resistance, but weight maintenance is also required to keep long term good metabolic results.


Zakar, T. and F. Hertelendy (2001). "Regulation of prostaglandin synthesis in the human uterus." J Matern Fetal Med 10(4): 223-35.

            Prostaglandins are important regulators of many aspects of reproductive processes from ovulation, fertilization and pregnancy recognition to labor and parturition. These biologically potent compounds are members of the large family of eicosanoids, derived from polyunsaturated fatty acids, principally arachidonic acid, found in the membrane phospholipids of virtually every cell of the human body, accounting for the ubiquity of prostaglandins, which act in a paracrine or autocrine fashion via discrete receptors. The availability of specific prostaglandins in various cells and tissues depends on the presence and activity of specific enzymes that convert a common precursor to the end product, as well as on the rate of enzymatic or spontaneous inactivation of the bioactive compounds. Here we offer a brief review of the regulation of prostaglandin generation in human uterine tissues, focusing on their role in labor and parturition at term and preterm.


Yavin, E., S. Glozman, et al. (2001). "Docosahexaenoic acid accumulation in the prenatal brain: prooxidant and antioxidant features." J Mol Neurosci 16(2-3): 229-35; discussion 279-84.

            Docosahexaenoic acid (DHA; 22:6n-3) is the major polyunsaturated fatty acid (FA) in the adult rat brain and it accumulates significantly more than any other FA prior to birth. Under normal nutritional conditions, fetal-brain DHA accumulation is substantial, with a "DHA accretion spurt" being demonstrated in the last period of gestation. Under stress conditions, this spurt may be harmful owing to an increase in multiple double-bond targets for lipid peroxidation. The "DHA accretion spurt" is supported by the maternal supply of DHA or its precursor. Under maternal dietary n-3 FA deficiency, DHA content in the fetal brain can be restored by direct intraamniotic injection of mM concentrations of ethyl-DHA (Et-DHA). This approach may hold a potential advantage in the event of maternal-fetal insufficiency, a stress that may cause intrauterine growth retardation. It also revealed a potential beneficial effect after in utero ischemic stress; brain slices from Et-DHA-treated fetuses formed less oxidation products, as detected by thiobarbituric acid (TBA), compared to controls. Furthermore, brain-lipid extracts from Et-DHA but not ethyl-oleate treated fetuses, exhibited hydroxyl radical scavenging activity, as demonstrated by electron spin-resonance technique. Part of the beneficial effect of Et-DHA administration on the fetal brain may be attributed to enhanced free-radical scavenging capability, a phenomenon not directly related to vitamin E or lipid-soluble antioxidant levels.


Yamamori, H., K. Takagi, et al. (2001). "[omega-3 Polyunsaturated fatty acid fat emulsion]." Nippon Rinsho 59 Suppl 5: 914-8.


Willson, T. M., M. H. Lambert, et al. (2001). "Peroxisome proliferator-activated receptor gamma and metabolic disease." Annu Rev Biochem 70: 341-67.

            The nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) is a transcription factor that is activated by polyunsaturated fatty acids and their metabolites and is essential for fat cell formation. Although obesity is a strong risk factor for type 2 diabetes mellitus and other metabolic diseases, potent PPAR gamma activators such as the glitazone drugs lower glucose and lipid levels in patients with type 2 diabetes and also have antiatherosclerotic and antihypertensive effects. We review recent studies providing insight into the paradoxical relationship between PPAR gamma and metabolic disease. We also review recent advances in understanding the structural basis for PPAR gamma activation by ligands. The unusual ligand-binding properties of PPAR gamma suggest that it will be possible to discover new chemical classes of receptor "modulators" with distinct pharmacological activities for the treatment of type 2 diabetes and other metabolic diseases.


Watkins, B. A., H. E. Lippman, et al. (2001). "Bioactive fatty acids: role in bone biology and bone cell function." Prog Lipid Res 40(1-2): 125-48.

            Bone is a unique tissue providing support, movement, and mineral balance for the body. Bone growth is achieved in the young by a process called modeling, and maintained during adulthood by a process termed remodeling. Three types of cells are responsible for the formation of cartilage and bone; the chondrocyte, osteoblast, and osteoclast. These cells are under the influence of a plethora of regulatory molecules, which govern their action to provide an individual optimal bone mass. Interruption of this homeostatic machinery, especially in the elderly, often results in a loss of bone mass (osteoporosis) or cartilage damage (rheumatoid arthritis). Many pharmacological agents have been made available in an effort to prevent or alleviate these pathologies, however, one vector often overlooked is the diet. This review focuses on the relationship between dietary polyunsaturated fatty acids and bone biology, both in vivo and in vitro.


Watkins, B. A., Y. Li, et al. (2001). "Lipids as modulators of bone remodelling." Curr Opin Clin Nutr Metab Care 4(2): 105-10.

            Bone remodelling processes are regulated by systemic hormones and a multitude of local and systemic factors, including prostaglandins, cytokines, and growth factors. Dietary fatty acids and their derivatives (eicosanoids) have been a recent focus of investigation on bone and cartilage metabolism. Specific fatty acids are recognized modulators of eicosanoid biosynthesis, signal transduction, and gene expression. The actions of polyunsaturated fatty acids have not been extensively examined in the skeletal system. Promising research on fatty acids and bone remodelling should evaluate the potential effects on pathways for osteoclastogenesis and osteoblastogenesis.


Watkins, B. A., Y. Li, et al. (2001). "Omega-3 polyunsaturated fatty acids and skeletal health." Exp Biol Med (Maywood) 226(6): 485-97.

            This minireview on skeletal biology describes the actions of prostaglandins and cytokines involved in the local regulation of bone metabolism, it documents the role of lipids in bone biology, and it presents relationships between fatty acids and other factors that impact skeletal metabolism. The data presented herein show consistent and reproducible beneficial effects of omega-3 (n-3) fatty acids on bone metabolism and bone/joint diseases. Polyunsaturated fatty acids modulate eicosanoid biosynthesis in numerous tissues and cell types, alter signal transduction, and influence gene expression. These effects have not been explored in the skeletal system. Future research on n-3 fatty acids in bone biology should focus on the following two aspects. First, the further elucidation of how n-3 fatty acids alter biochemical and molecular processes involved in bone modeling and bone cell differentiation, and second, the evaluation of the potential pharmaceutical applications of these nutraceutical fatty acids in maintaining bone mineral status and controlling inflammatory bone/joint diseases.


Watkins, B. A., Y. Li, et al. (2001). "Nutraceutical fatty acids as biochemical and molecular modulators of skeletal biology." J Am Coll Nutr 20(5 Suppl): 410S-416S; discussion 417S-420S.

            Several systemic hormones and localized growth factors coordinate events of bone formation and resorption to support bone growth in the young and maintain bone mineral content in the adult. Some of the more important factors produced in the bone microenvironment that impact skeletal biology include prostaglandins, cytokines, and insulin-like growth factors. Dietary fat sources that exert potent biological effects on the skeletal tissues belong to the omega-6 and omega-3 families of essential fatty acids. Specific long-chain polyunsaturated fatty acids (PUFA) belonging to these families are substrates for prostanoids that influence the differentiation and activity of cells in bone and cartilage tissues. These PUFA appear to alter prostanoid formation, cell-to-cell signaling processes, and impact transcription factors in vivo. Hence, these biologically active PUFA can be called nutraceutical fatty acids. This review highlights the role of nutraceutical fatty acids on bone metabolism and joint disease. The recent discovery of transcription factors controlling osteoblast function, and soluble proteins directing osteoclastogenesis and osteoblastogenesis offer new research opportunities for studying nutraceutical fatty acids in skeletal biology.


Veerkamp, J. H. and A. W. Zimmerman (2001). "Fatty acid-binding proteins of nervous tissue." J Mol Neurosci 16(2-3): 133-42; discussion 151-7.

            Fatty acid-binding proteins (FABPs) are cytosolic 14-15 kDa proteins, which are supposed to be involved in fatty acid (FA) uptake, transport, and targeting. They may modulate FA concentration and in this way influence function of enzymes, membranes, ion channels and receptors, and gene expression and cellular growth and differentiation. Nine FABP types can be discerned with a specific tissue distribution. In spite of 30-70% amino acid sequence identity, they have a similar tertiary, beta-clam structure in which the FA is bound. Nervous tissue contains four FABP types with a distinct spatio-temporal distribution. Myelin (M)-FABP is only present in the peripheral nerves, brain (B)-FABP and epidermal (E)-FABP mainly in glial cells and neurons, respectively of pre- and perinatal brain, and heart (H)-FABP in adult brain. Possible functions of FABPs in the nervous system are discussed. Binding studies with a range of physiological FA showed no large differences between recombinant proteins of the four human FABP types in binding specificity and affinity, also not for polyunsaturated FA (PUFA). The transfer of FA from fixed liposomes to mitochondria was similarly promoted by the four types. A marked difference in conformational stability was observed with H-FABP > B-FABP > M-FABP > E-FABP. Surface epitopes of H-FABP showed reaction with anti-B-FABP antibodies, but no other cross-reactivity of FABP type and heterologous antibodies was observed. The functional significance of the distinct spatio-temporal pattern of the four FABP types remains to be elucidated.


Uauy, R., D. R. Hoffman, et al. (2001). "Essential fatty acids in visual and brain development." Lipids 36(9): 885-95.

            Essential fatty acids are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LC-PUFA). These fatty acids serve as specific precursors for eicosanoids, which regulate numerous cell and organ functions. Recent human studies support the essential nature of n-3 fatty acids in addition to the well-established role of n-6 essential fatty acids in humans, particularly in early life. The main findings are that light sensitivity of retinal rod photoreceptors is significantly reduced in newborns with n-3 fatty acid deficiency, and that docosahexaenoic acid (DHA) significantly enhances visual acuity maturation and cognitive functions. DHA is a conditionally essential nutrient for adequate neurodevelopment in humans. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oil sources of LC-PUFA results in increased blood levels of DHA and arachidonic acid, as well as an associated improvement in visual function in formula-fed infants matching that of human breast-fed infants. The effect is mediated not only by the known effects on membrane biophysical properties, neurotransmitter content, and the corresponding electrophysiological correlates but also by a modulating gene expression of the developing retina and brain. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation and retinal and nervous system development. Regulation of gene expression by LC-PUFA occurs at the transcriptional level and may be mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the family of steroid hormone receptors. DHA also has significant effects on photoreceptor membranes and neurotransmitters involved in the signal transduction process; rhodopsin activation, rod and cone development, neuronal dendritic connectivity, and functional maturation of the central nervous system.


Tisdale, M. J. (2001). "Cancer anorexia and cachexia." Nutrition 17(5): 438-42.

            Patients with cancer cachexia experience a profound wasting of adipose tissue and lean body mass. Anorexia, although often present, is insufficient to account for tissue wasting because 1) cachexia involves massive depletion of skeletal muscle that does not occur during anorexia, 2) nutritional supplementation cannot replenish the loss of lean body mass, 3) cachexia can occur without anorexia, and 4) food intake might be normal for the lower weight of the cancer patient. Anorexia can arise from 1) decreased taste and smell of food, 2) early satiety, 3) dysfunctional hypothalamic membrane adenylate cyclase, 4) increased brain tryptophan, and 5) cytokine production. Appetite stimulants such as cyproheptadine, medroxyprogesterone acetate, and megestrol acetate do not significantly improve lean body mass. Tumor products might be more important in the development of cachexia. Cachectic patients excrete in their urine a lipid-mobilizing factor that directly stimulates lipolysis in a cyclic AMP-dependent manner and increases energy expenditure. Loss of skeletal muscle in cachexia is caused by upregulation of the ubiquitin-proteasome catabolic pathway. Cachexia-inducing tumors elaborate a sulfated glycoprotein, which directly initiates protein catabolism in skeletal muscle. The action of this proteolysis-inducing factor is attenuated by the polyunsaturated fatty acid eicosapentaenoic acid, which is also effective in preventing loss of skeletal muscle in cancer patients. Antagonists of tumor catabolic factors will provide important new agents in the treatment of cancer cachexia.


Thatcher, W. W., A. Guzeloglu, et al. (2001). "Uterine-conceptus interactions and reproductive failure in cattle." Theriogenology 56(9): 1435-50.

            The dialogue between trophectoderm cells of the conceptus and epithelial cells of the endometrium is critical to CL maintenance and embryo survival. The signal transduction mechanisms by which bovine interferon (IFN)-tau regulates cyclooxygenase (COX)-2 expression and secretion of prostaglandin F2alpha (PGF2alpha) in bovine endometrial (BEND) cells is examined. Stimulation of Protein Kinase C with a phorbol ester (phorbol 12, 13 dibutyrate [PDBu]) activates COX-2 gene expression and PGF2alpha secretion via the mitogen-activated protein kinase (MAPK) pathway. Interferon-tau attenuates PDBu activation of PGF2alpha secretion, but this inhibitory effect appears to be independent of the MAPK pathway. Embryonic IFN-tau, acting through a Type I IFN receptor, activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway resulting in activation or repression of interferon-stimulated genes. Experimental evidence is provided that IFN-tau regulation of STATs regulates gene expression of COX-2 in a manner that decreases secretion of PGF2alpha. Maternal regulation of the antiluteolytic pathway is discussed relative to the ability of the polyunsaturated fatty acid, eicosapentaenoic (EPA), to decrease endometrial secretion of PGF2alpha and progesterone to increase both conceptus development and IFN-tau secretion.


Terano, T. (2001). "Effect of omega 3 polyunsaturated fatty acid ingestion on bone metabolism and osteoporosis." World Rev Nutr Diet 88: 141-7.


Stein, J. (2001). "The magnocellular theory of developmental dyslexia." Dyslexia 7(1): 12-36.

            Low literacy is termed 'developmental dyslexia' when reading is significantly behind that expected from the intelligence quotient (IQ) in the presence of other symptoms--incoordination, left-right confusions, poor sequencing--that characterize it as a neurological syndrome. 5-10% of children, particularly boys, are found to be dyslexic. Reading requires the acquisition of good orthographic skills for recognising the visual form of words which allows one to access their meaning directly. It also requires the development of good phonological skills for sounding out unfamiliar words using knowledge of letter sound conversion rules. In the dyslexic brain, temporoparietal language areas on the two sides are symmetrical without the normal left-sided advantage. Also brain 'warts' (ectopias) are found, particularly clustered round the left temporoparietal language areas. The visual magnocellular system is responsible for timing visual events when reading. It therefore signals any visual motion that occurs if unintended movements lead to images moving off the fovea ('retinal slip'). These signals are then used to bring the eyes back on target. Thus, sensitivity to visual motion seems to help determine how well orthographic skill can develop in both good and bad readers. In dyslexics, the development of the visual magnocellular system is impaired: development of the magnocellular layers of the dyslexic lateral geniculate nucleus (LGN) is abnormal; their motion sensitivity is reduced; many dyslexics show unsteady binocular fixation; hence poor visual localization, particularly on the left side (left neglect). Dyslexics' binocular instability and visual perceptual instability, therefore, can cause the letters they are trying to read to appear to move around and cross over each other. Hence, blanking one eye (monocular occlusion) can improve reading. Thus, good magnocellular function is essential for high motion sensitivity and stable binocular fixation, hence proper development of orthographic skills. Many dyslexics also have auditory/phonological problems. Distinguishing letter sounds depends on picking up the changes in sound frequency and amplitude that characterize them. Thus, high frequency (FM) and amplitude modulation (AM) sensitivity helps the development of good phonological skill, and low sensitivity impedes the acquisition of these skills. Thus dyslexics' sensitivity to FM and AM is significantly lower than that of good readers and this explains their problems with phonology. The cerebellum is the head ganglion of magnocellular systems; it contributes to binocular fixation and to inner speech for sounding out words, and it is clearly defective in dyslexics. Thus, there is evidence that most reading problems have a fundamental sensorimotor cause. But why do magnocellular systems fail to develop properly? There is a clear genetic basis for impaired development of magnocells throughout the brain. The best understood linkage is to the region of the Major Histocompatibility Complex (MHC) Class 1 on the short arm of chromosome 6 which helps to control the production of antibodies. The development of magnocells may be impaired by autoantibodies affecting the developing brain. Magnocells also need high amounts of polyunsaturated fatty acids to preserve the membrane flexibility that permits the rapid conformational changes of channel proteins which underlie their transient sensitivity. But the genes that underlie magnocellular weakness would not be so common unless there were compensating advantages to dyslexia. In developmental dyslexics there may be heightened development of parvocellular systems that underlie their holistic, artistic, 'seeing the whole picture' and entrepreneurial talents.


Sprecher, H. (2001). "Differences in the regulation of the biosynthesis and esterification of 20- versus 22-carbon polyunsaturated fatty acids." World Rev Nutr Diet 88: 190-5.


Spiteller, G. (2001). "Peroxidation of linoleic acid and its relation to aging and age dependent diseases." Mech Ageing Dev 122(7): 617-57.

            Cell proliferation, cell injury and aging are connected with changes in the cell membrane structure. Apparently these changes activate, in mammalian as well as in plant cells, lipases which liberate polyunsaturated fatty acids (PUFAs). PUFAs are the substrates for lipoxygenases which convert them to corresponding hydroperoxides (LOOHs). Lipoxygenases commit suicide by releasing iron ions. LOOHs react with iron ions to generate radicals. Thus, a nonenzymic lipid peroxidation process (LPO) is induced. It is speculated that the change from enzymic to nonenzymic LPO is connected with the switch from apoptosis to necrosis and that LOOHs produced in enzymic reactions are degraded specifically to signal compounds which induce physiological responses, while nonenzymic reactions seem to induce generation of reactive oxygen species, cell death and age related diseases. Enzymic and nonenzymic LPO processes concern all PUFAs not only arachidonic acid. The main PUFA in mammals is linoleic acid. Since these products serve signalling functions, different degradation paths of linoleic-hydroperoxides are described in detail and the physiological properties of LPO products are discussed in relation to aging and age related diseases.


Spiteller, G. (2001). "Lipid peroxidation in aging and age-dependent diseases." Exp Gerontol 36(9): 1425-57.

            Aging is related with an increase in oxidation products derived from nucleic acids, sugars, sterols and lipids. Evidence will be presented that these different oxidation products are generated by processes induced by changes in the cell membrane structure (CMS), and not by superoxide, as commonly assumed. CMS activate apparently membrane bound phospholipases A2 in mammals and plants. Such changes occur by proliferation, aging and especially by wounding. After activation of phospholipases, influx of Ca2+ ions and activation of lipoxygenases (LOX) is induced. The LOX transform polyunsaturated fatty acids (PUFAs) into lipid hydroperoxides (LOOHs), which seem to be decomposed by action of enzymes to signalling compounds.Following severe cell injury, LOX commit suicide. Their suicide liberates iron ions that induce nonenzymic lipid peroxidation (LPO) processes by generation of radicals. Radicals attack all compounds with the structural element -CH=CH-CH(2)-CH=CH-. Thus, they act on all PUFAs independently either in free or conjugated form. The most abundant LPO products are derived from linoleic acid. Radicals induce generation of peroxyl radicals, which oxidise a great variety of biological compounds including proteins and nucleic acids.Nonenzymic LPO processes are induced artificially by the treatment of pure PUFAs with bivalent metal ions. The products are separable after appropriate derivatisation by gas chromatography (GC). They are identified by electron impact mass spectrometry (EI/MS).The complete spectrum of LPO products obtained by artificial LPO of linoleic acid is detectable after wounding of tissue, in aged individuals and in patients suffering from age-dependent diseases. Genesis of different LPO products derived from linoleic acid will be discussed in detail. Some of the LPO products are of high chemical reactivity and therefore escape detection in biological surrounding. For instance, epoxides and highly unsaturated aldehydic compounds that apparently induce apoptosis.


Spector, A. A. (2001). "Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain." J Mol Neurosci 16(2-3): 159-65; discussion 215-21.

            Polyunsaturated fatty acids (PUFA), which comprise 25-30% of the fatty acids in the human brain, are necessary for normal brain development and function. PUFA cannot be synthesized de novo and must be supplied to the brain by the plasma. It is necessary to know the PUFA content and composition of the various plasma lipids and lipoproteins in order to understand how these fatty acids are taken up and metabolized by the brain. Human plasma free fatty acid (FFA) ordinarily contains about 15% linoleic acid (18:2n-6) and 1% arachidonic acid (AA) (20:4n-6). Plasma triglycerides, phospholipids, and cholesterol esters also are rich in linoleic acid, and the phospholipids and cholesterol esters contain about 10% AA. These findings suggest that the brain probably can obtain an adequate supply of n-6 PUFA from either the plasma FFA or lipoproteins. By contrast, the plasma ordinarily contains only one-tenth as much n-3 PUFA, and the amounts range from 1% alpha-linolenic acid (18:3n-3) in the plasma FFA to 2% docosahexaenoic acid (22:6n-3, DHA) in the plasma phospholipids. The main n-3 PUFA in the brain is DHA. Therefore, if the plasma FFA is the primary source of fatty acid for the brain, much of the DHA must be synthesized in the brain from n-3 PUFA precursors. Alternatively, if the brain requires large amounts of preformed DHA, the phospholipids contained in plasma lipoproteins are the most likely source.


Simmer, K. (2001). "Longchain polyunsaturated fatty acid supplementation in infants born at term." Cochrane Database Syst Rev(4): CD000376.

            BACKGROUND: The n-3 and n-6 fatty acids linolenic acid and linoleic acid are precursors of the n-3 and n-6 longchain fatty acids (LCPUFA). Infant formula has historically only contained the precursor fatty acids. Controversy exists over whether LCPUFA are also essential nutrients in infancy. Over the last few years some manufacturers have added LCPUFA to formulae and marketed them as providing an advantage for the development of term infants. OBJECTIVES: The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to term infants. SEARCH STRATEGY: Trials were identified by MEDLINE, checking reference lists of articles and conference proceedings, and by personal communication. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Ten randomised studies were identified. One of these studies was excluded due to supplementation commencing after three weeks of age. Eight of the nine included trials were assessed to be of good quality. There was insufficient information available to assess the quality of the other included trial. MAIN RESULTS: Visual acuity was assessed by visual evoked potentials (VEP) at 4 and 7-8 months in the studies of Makrides et al (1995 & 1996). The supplemented infants had an improved rate of visual maturation at both time points in the first study, but no difference was found between the groups at the same time points in the second study. VEP acuity was also assessed in the study of Austed et al (1997) and no effect of supplementation was found at any time point over the first year. This contrasts with the study of Birch et al (1998) where VEP acuity was better in the supplemented group compared with the control group at 6 weeks, 4 and 12 months but not at 6 months. Visual acuity was assessed by Teller acuity cards in the study of Carlson et al (1996), Clausen et al (1996), Austed et al (1997) and Birch et al (1998). Supplementation had no effect on visual acuity over the first year of life except at one of five time points in the study of Carlson et al (1996). Intellectual development was measured in seven studies. The two largest studies showed no effect of supplementation on development, either at 18 months (Lucas et al 1999) or at one and three years (Janowsky et al 1995, Scott et al 1997). The next largest study reported better developmental scores at 18 months in the supplemented group (Birch et al 2000) but when combined with data of Lucas et al, no significant benefit is shown. Makrides et al (1995 & 1996) also showed no benefit to development with supplementation over the first two years of life. Agostini et al 1995 reported a benefit in development at 4 months of age with supplementation but when the infants were followed up with the same test at 1 and 2 years, no difference between groups was found (Agostini et al 1997). The Portland study showed no effect of supplementation on language development at one and three years (Janowsky et al 1995, Scott et al 1997). Clausen et al (1996) reported better novelty preference measured by Fagan Infant test at nine months in supplemented infants compared with controls. Willatts et al (1998) reported better problem solving at 10 months with supplementation. Growth was measured in the studies of Makrides et al (1995 & 1996), Austed et al (1997), Willatts et al 1998, Lucas et al 1999 and Birch et al 2000. LCPUFA supplementation did not influence growth in any of these studies. REVIEWER'S CONCLUSIONS: At present there is little evidence from randomised trials of LCPUFA supplementation to support the hypothesis that LCPUFA supplementation confers a benefit for visual or general development of term infants. Minor effects on VEP acuity have been suggested but appear unlikely when all studies are reviewed. A beneficial effect on information processing is possible but larger studies over longer periods are required to conclude that LCPUFA supplementation provides a benefit when compared with standard formula. Data from randomised trials do not suggest that LCPUFA supplements influence the growth of term infants.


Sikka, S. C. (2001). "Relative impact of oxidative stress on male reproductive function." Curr Med Chem 8(7): 851-62.

            Impairment of normal spermatogenesis and sperm function are the most common causes of male factor infertility. Abnormal sperm function is difficult to evaluate and treat. There is a lack of understanding of the factors contributing to normal and abnormal sperm function leading to infertility. Many recent studies indicate that oxygen-derived free radicals induce damage to spermatozoa. The excessive generation of these reactive oxygen species (superoxide, hydroxyl, nitric oxide, peroxide, peroxynitrile) by immature and abnormal spermatozoa and by contaminating leukocytes associated with genitourinary tract inflammation have been identified with idiopathic male infertility. Mammalian spermatozoa membranes are rich in polyunsaturated fatty acids. This makes them very susceptible to oxygen-induced damage, which is mediated by lipid peroxidation. In a normal situation, the antioxidant mechanisms present in the reproductive tissues and their secretions are likely to quench these reactive oxygen species (ROS) and protect against oxidative damage to gonadal cells and mature spermatozoa. During chronic disease states, aging, toxin exposure, or genitourinary infection/inflammation, these cellular antioxidant mechanisms downplay and create a situation called oxidative stress. Thus, a balance between ROS generation and antioxidant capacity plays a critical role in the pathophysiology of disease state. Recent efforts towards the development of new reliable assays to evaluate this oxidative stress status have resulted in the establishment of ROS-TAC score. Such assessment of oxidative stress status (OSS) may help in designing newer modes of male factor infertility treatment by suitable antioxidants.


Shureiqi, I. and S. M. Lippman (2001). "Lipoxygenase modulation to reverse carcinogenesis." Cancer Res 61(17): 6307-12.

            New studies of the relationship between polyunsaturated fatty acid metabolismand carcinogenesis have led to novel molecular targets for cancer chemoprevention research. These targets include procarcinogenic lipoxygenases (LOXs), including 5-, 8-, and 12-LOX, and anticarcinogenic LOXs, including 15-LOX-1 and possibly 15-LOX-2. Recent studies indicate that 15-LOX-1 is down-regulated in colorectal cancer cells and that the ability of nonsteroidal anti-inflammatory drugs, a class of clinically active cancer chemopreventive agents, to induce apoptosis and growth inhibition in these cells was dependent on the induction of 15-LOX-1 and its metabolic product 13-S-hydroxyoctadecadienoic acid. Consistent with the colorectal studies, 15-LOX very recently has shown anticarcinogenic activity in esophageal and prostatic carcinogenesis. Inhibitors of other LOXs (e.g., 5-LOX) have preclinical anticarcinogenic activity and are being developed for clinical chemoprevention study. These and other LOX data led us to propose that the various LOX pathways exist in a dynamic balance that shifts during carcinogenesis toward 5-, 8-, and 12-LOX (and cyclooxygenase-2) and away from 15-LOX. A novel approach for cancer chemoprevention would involve LOX modulators, i.e., agents that can induce the anticarcinogenic and/or inhibit the procarcinogenic LOXs, thereby shifting the balance of LOX activities from procarcinogenic to anticarcinogenic metabolism of polyunsaturated fatty acids.


Shimakata, T. (2001). "[Polyunsaturated fatty acid]." Nippon Rinsho 59 Suppl 2: 45-9.


Shahidi, F. (2001). "Headspace volatile aldehydes as indicators of lipid oxidation in foods." Adv Exp Med Biol 488: 113-23.

            Aldehydes are secondary breakdown products of unsaturated lipids. In particular, polyunsaturated lipid fatty acids of the omega-6 and omega-3 families are highly susceptible to oxidation. Using static headspace analysis, the specific aldehyde markers were studied. While linoleic, gamma-linolenic and arachidonic acids found in different foods were precursors of hexanal, propanal was the dominant aldehyde formed from the breakdown of alpha-linolenic, eicosapentaenoic and docosahexaenoic acids. Thus, use of selected aldehydes for monitoring oxidation of food lipids is recommended.


Segal-Isaacson, C. J., E. Carello, et al. (2001). "Dietary fats and diabetes mellitus: is there a good fat?" Curr Diab Rep 1(2): 161-9.

            As knowledge of the fatty acid functions has increased, so has the complexity of making dietary fat recommendations to people with type 2 diabetes. Oleic acid seems to offer a slight advantage over linoleic acid in reducing plasma glucose, insulin levels, total cholesterol, low-density lipoproteins (LDLs), and triglycerides, but may also have atherogenic properties through another mechanism. A diet containing a higher proportion of polyunsaturated fatty acids (PUFAs) may require a concomitant increase in antioxidant intake because PUFAs oxidize easily and are then converted to oxidized LDL, which is more atherogenic. In addition to raising total and LDL cholesterol, long chain saturated free fatty acids may interact with plasma glucose to increase insulin secretion. Omega-3 fatty acids decrease triglycerides and reduce the risk of fatal cardiac arrhythmias. Glycemic control does not appear to be adversely affected by omega-3 fatty acids at amounts of up to 3 g/d.


Schrooyen, P. M., R. van der Meer, et al. (2001). "Microencapsulation: its application in nutrition." Proc Nutr Soc 60(4): 475-9.

            The development of new functional foods requires technologies for incorporating health-promoting ingredients into food without reducing their bioavailability or functionality. In many cases, microencapsulation can provide the necessary protection for these compounds, but in all cases bioavailability should be carefully studied. The present paper gives an overview of the application of various microencapsulation technologies to nutritionally-important compounds, i.e. vitamins, n-3 polyunsaturated fatty acids, Ca, Fe and antioxidants. It also gives a view on future technologies and trends in microencapsulation technology for nutritional applications.


Schmidt, E. B., J. H. Christensen, et al. (2001). "Marine n-3 fatty acids: basic features and background." Lipids 36 Suppl: S65-8.

            There is some evidence from epidemiology that intake of n-3 polyunsaturated fatty acids (PUFA) from seafood may protect against coronary artery disease (CAD). This hypothesis is further supported from animal data showing a beneficial effect of n-3 PUFA on thrombosis and atherosclerosis in animals fed fish oils in most, but not all, studies. There are several mechanisms by which an increased intake of marine n-3 PUFA may protect against CAD; the most universal finding is a reduction of plasma triglycerides. It is puzzling, however, that a very low amount of n-3 PUFA, with no known beneficial biochemical effects, seems to be cardioprotective. It has therefore been of paramount interest to perform clinical trials. Such evidence and trials are discussed in later chapters, and the results have been very encouraging.


Sauerwald, T. U., H. Demmelmair, et al. (2001). "Polyunsaturated fatty acid supply with human milk." Lipids 36(9): 991-6.

            Polyunsaturated fatty acids in human milk may derive from diet, liberation from maternal body stores, or endogenous synthesis from precursor fatty acids. The contribution of each of these sources has not been studied in detail. Although maternal diet is a key factor affecting human milk composition, other factors such as gestational age, stage of lactation, nutritional status, and genetic background are known to influence the fat content and fatty acid composition in human milk. Both linoleic and alpha-linolenic acids, the essential fatty acids, are present in human milk, as are several other n-6 and n-3 longer chain polyunsaturated fatty acids that are required for optimal growth and development of infants. The fatty acid profile of human milk from lactating women of different countries is remarkably stable, but there is variability in some of the components, such as docosahexaenoic acid, which is mainly due to differences in dietary habits. Tracer techniques with stable isotopes have been valuable in assessing the kinetics of fatty acid metabolism during lactation and in determining the origin of fatty acids in human milk. Based on these studies, the major part of polyunsaturated fatty acids in human milk seems not to be provided directly from the diet but from maternal tissue stores.


Sauer, L. A., R. T. Dauchy, et al. (2001). "Polyunsaturated fatty acids, melatonin, and cancer prevention." Biochem Pharmacol 61(12): 1455-62.

            Many nutritional, hormonal, and environmental factors affect carcinogenesis and growth of established tumors in rodents. In some cases, these factors may either enhance or attenuate the neoplastic process. Recent experiments performed in our laboratory using tissue-isolated rat hepatoma 7288CTC in vivo or during perfusion in situ have demonstrated new interactions among four of these factors. Two agents, dietary linoleic acid (C18:2n6) and "light at night," enhanced tumor growth, and two others, melatonin and n3 fatty acids, attenuated growth. Linoleic acid stimulated tumor growth because it is converted by hepatoma 7288CTC to the mitogen, 13-hydroxyoctadecadienoic acid (13-HODE). Melatonin, the neurohormone synthesized and secreted at night by the pineal gland, and dietary n3 fatty acids are potent antitumor agents. Both inhibited tumor linoleic acid uptake and 13-HODE formation. Artificial light, specifically "light at night," increased tumor growth because it suppressed melatonin synthesis and enhanced 13-HODE formation. Melatonin and n3 fatty acids acted via similar or identical G(i) protein-coupled signal transduction pathways, except that melatonin receptors and putative n3 fatty acid receptors were used. The results link the four factors in a common mechanism and provide new insights into the roles of dietary n6 and n3 polyunsaturated fatty acid intake, "light at night," and melatonin in cancer prevention in humans.


Russell, L. (2001). "The importance of patients' nutritional status in wound healing." Br J Nurs 10(6 Suppl): S42, S44-9.

            Good nutritional status is essential for wound healing to take place. Ignoring nutritional status may compromise the patient's ability to heal and subsequently prolong the stages of wound healing. Glucose provides the body with its power source for wound healing and this give energy for angiogenesis and the deposition of new tissue. Therefore, it is vital that the body receives adequate amounts of glucose to provide additional energy for wound healing. Fatty acids are essential for cell structure and have an important role in the inflammatory process. Wound healing is dependent on good nutrition and the presence of suitable polyunsaturated fatty acids in the diet. Protein deficiency has been demonstrated to contribute to poor healing rates with reduced collagen formation and wound dehiscence. High exudate loss can result in a deficit of as much as 100g of protein in one day. This subsequently needs to be replaced with a high protein diet. Vitamins are also important in wound healing. Vitamin C deficiency contributes to fragile granulation tissue. There is a correlation between low serum albumin and body mass index (BMI) and the development of pressure ulcers. Also, low serum albumin and high Waterlow score have a positive association. The body automatically renews tissue while we are asleep but this does not mean that protein synthesis does not take place during our wakeful hours. Holistic assessment of nutrition and early detection of malnutrition are essential to promote effective wound healing.


Rogers, P. J. (2001). "A healthy body, a healthy mind: long-term impact of diet on mood and cognitive function." Proc Nutr Soc 60(1): 135-43.

            Certain dietary risk factors for physical ill health are also risk factors for depression and cognitive impairment. Although cholesterol lowering has been suggested to increase vulnerability to depression, there is better support for an alternative hypothesis that intake of n-3 long-chain polyunsaturated fatty acids can affect mood (and aggression). Possible mechanisms for such effects include modification of neuronal cell membrane fluidity and consequent impact on neurotransmitter function. Stronger evidence exists concerning a role for diet in influencing cognitive impairment and cognitive decline in older age, in particular through its impact on vascular disease. For example, cognitive impairment is associated with atherosclerosis, type 2 diabetes and hypertension, and findings from a broad range of studies show significant relationships between cognitive function and intakes of various nutrients, including long-chain polyunsaturated fatty acids, antioxidant vitamins, and folate and vitamin B12. Further support is provided by data on nutrient status and cognitive function. Almost all this evidence, however, comes from epidemiological and correlational studies. Given the problem of separating cause and effect from such evidence, and the fact that cognitive impairment and cognitive decline (and depression) are very likely to be significant factors contributing to the consumption of a poor diet, greater emphasis should now be placed on conducting intervention studies. An efficient approach to this problem could be to include assessments of mood and cognitive function as outcome measures in studies designed primarily to investigate the impact of dietary interventions on markers of physical health.


Renaud, S. and D. Lanzmann-Petithory (2001). "Coronary heart disease: dietary links and pathogenesis." Public Health Nutr 4(2B): 459-74.

            For decades it has been postulated that the main environmental factor for coronary heart disease (CHD) was the intake of saturated fatty acids (SFA). Nevertheless, confirmation of the role of SFA in CHD through intervention trials has been disappointing. It was only when the diet was enriched in n-3 fatty acids that CHD was significantly prevented, especially cardiac death. In addition to n-3 fatty acids, many other foodstuffs or nutrients such as fibers, antioxidants, folic acid, calcium and even alcohol contribute to prevent CHD. Thus the relationship between diet and CHD morbidity and mortality appears to be much more complex than formerly suspected considering as key factors only SFA, linoleic acid, cholesterol and atherosclerosis. Some of the mechanisms are briefly described, but many additional nutrients (or non nutrients) may also play an important role in the pathogenesis of CHD. Finally, as a result of the most recent epidemiologic studies the ideal diet may comprise: 8% energy from SFA, 5% from polyunsaturated fatty acids with a ratio 5/1 of linoleic/alpha-linolenic acid+longer chains n-3, oleic acid as desired, large intake of cereals, vegetables, legumes and fruits, fish twice a week, cheese and yogurt as dairy products, rapeseed and olive oils as edible fat. Without side effects, such a diet can be highly palatable, easily enjoyed by many populations and may prevent effectively and rapidly (within a few weeks or months) CHD.


Rapoport, S. I. (2001). "In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling." J Mol Neurosci 16(2-3): 243-61; discussion 279-84.

            A method, model, and "operational equations" are described to quantify in vivo turnover rates and half-lives of fatty acids within brain phospholipids, as well as rates of incorporation of these fatty acids into brain from plasma. In awake rats, recycling of fatty acids within brain phospholipids, due to deesterification and reesterification, is very rapid, with half-lives in some cases of minutes to hours. Plasma fatty acids make only a small contribution (2-4%) to the net quantity of fatty acids that are reesterified. This explains why many weeks are necessary to recover normal brain n-3 polyunsaturated fatty acid concentrations following their prolonged dietary deprivation. Changes in recycling of specific fatty acids in response to centrally acting drugs can help to identify enzyme targets for drug action. For example, recycling of arachidonate is specifically reduced by 80% in rats treated chronically with lithium, a drug effective against bipolar disorder; the effect reflects downregulation of gene expression of an arachidonate-specific phospholipase A2. When combined with neuroimaging (quantitative autoradiography in rodents or positron-emission tomography [PET] in macaques or humans), intravenously injected radiolabeled fatty acids can be used to localize and quantify brain PLA2-mediated signal transduction, and to examine neuroplastic remodeling of brain lipid membranes.


Ramirez, M., L. Amate, et al. (2001). "Absorption and distribution of dietary fatty acids from different sources." Early Hum Dev 65 Suppl: S95-S101.

            Lipids have physical, chemical, and physiological properties that make them important factors in human nutrition. They form a group of compounds of varied chemical nature that have the common property of being soluble in organic solvents but insoluble in water. This basic property affects their digestion, absorption, and transport in the blood and metabolism at cellular level. Firstly, fatty-acid chain length and number of double bonds influence fat absorption. Thus, medium-chain fatty acids (MCFA) are better absorbed than long-chain fatty acids. Secondly, the positional distribution of fatty acids (FA) in dietary triglycerides (TG) determine whether FA are absorbed as 2-monoglycerides (2-MG) or free fatty acids (FFA), and hence, influences the composition of chylomicroms (CM) because triglycerides (TG) are resyntethysed in the intestinal mucosa using 2-MG from dietary lipids. Generally, the absorption of FA in the sn-2 position of TG is favored, whereas no specificity has been found for the fatty acids in the sn-1 and sn-3 positions. Finally, some FA of nutritional interest, namely, long-chain polyunsaturated fatty acids (LCP), are present in dietary lipid sources as both TG or phospholipids (PL). Fatty acids esterified as PL or TG may show different availability. In fact, some authors have suggested a better absorption of LCP-PL. Moreover, dietary LCP in form of TG or PL differently affects the composition of HDL and LDL PL.


Przybyszewski, W. M. (2001). "[Participation of final products of lipid peroxidation in the anticancer mechanism of ionizing radiation and radiomimetic cytostatics]." Postepy Hig Med Dosw 55(6): 803-13.

            This review reports the evidence for the participation of final products of lipid peroxidation in the anticancer mechanism of ionising radiation and radiomimetic cytostatics. Processes of lipid peroxidation occur endogenously in response to oxidative stress and great diversity of reactive metabolites is formed. However, direct observation of radical reaction in pathophysiology of cells, tissues and organs is limited technically. Most investigations focused on the indirect assessment of their final products, aldehydes. The peroxidative breakdown of polyunsaturated fatty acids is believed to be involved in the regulation of cell division, and antitumor effect through biochemical and genetic processes.


Pratico, D., J. A. Lawson, et al. (2001). "The isoprostanes in biology and medicine." Trends Endocrinol Metab 12(6): 243-7.

            Isoprostanes are a new class of lipids, isomers of the conventional enzymatically derived prostaglandins, which are produced in vivo primarily by a free radical-catalyzed peroxidation of polyunsaturated fatty acids. F2-isoprostanes, isomers of the enzyme-derived prostaglandin F2alpha, are the most studied species, but analogous isomers of other prostaglandins and leukotrienes have been described. Because of their mechanism of formation, specific structural features that distinguish them from other free radical-generated products and chemical stability, they can provide a reliable index for the oxidant component of several diseases in vivo. Consistent data suggest that formation of F2-isoprostanes is altered in a variety of clinical settings putatively associated with oxidant stress. Moreover, measurement of F2-isoprostanes might provide a sensitive biochemical basis for dose-selection in studies of natural and synthetic antioxidants. Finally, some F2-isoprostanes possess potent biological activities in vitro and in vivo, suggesting that they may also act as mediators of the cellular effects of oxidative stress.


Pond, C. M. (2001). "Long-term changes in adipose tissue in human disease." Proc Nutr Soc 60(3): 365-74.

            Redistribution of white adipose tissue is a long-term symptom of several chronic diseases. Although the roles of adipocytes in acute illness have been thoroughly studied, how or why short-term responses of adipose tissue to disease sometimes produce long-term redistribution, and the causal relationship between the anatomical changes and the associated metabolic syndromes are poorly understood. The present paper reviews explanations for the redistribution of adipose tissue after infection with HIV, and in Crohn's disease; both conditions that share the peculiarity of selective expansion of certain adipose depots while others are depleted. HIV adipose tissue redistribution syndrome (HARS) develops gradually after several months of infection with the HIV both in untreated patients and in those taking protease inhibitors and nucleoside reverse transcriptase inhibitors. Some current theories about the causes of HARS are critically assessed, and reasons presented for implicating local interactions between the immune system and perinodal adipocytes. Some evolutionary aspects of conspicuous long-term changes in the distribution of human adipose tissue are discussed. Adipose tissue acts as a social signal, indicating dietary history and previous exposure to pathogens. A distinctive symptom of Crohn's disease is selective enlargement of the mesenteric adipose tissue near the diseased lymph nodes and intestine. Perinodal adipocytes have site-specific properties not found in adipocytes from nodeless depots, such as perirenal and epididymal, that may equip them to interact locally with lymph-node lymphoid cells, making polyunsaturated fatty acids selectively and rapidly available to activated immune cells. Studies of the time course of activation of perinodal adipocytes via the lymph nodes they enclose indicate that prolonged or frequent stimulation recruits more adipocytes to control by immune cells, which may lead to selective enlargement of node-containing depots. These concepts suggest hypotheses about HARS and the anomalous development of mesenteric adipose tissue in Crohn's disease that could form the basis for further investigations.


Patel, A. J., M. Lazdunski, et al. (2001). "Lipid and mechano-gated 2P domain K(+) channels." Curr Opin Cell Biol 13(4): 422-8.

            The two pore domain K(+) channels TREK and TRAAK are opened by membrane stretch. The activating mechanical force comes from the bilayer membrane and is independent of the cytoskeleton. Emerging work shows that mechano-gated TREK and TRAAK are opened by various lipids, including long chain polyunsaturated anionic fatty acids and neutral cone-shaped lysophospholipids. TREK-1 shares the properties of the Aplysia neuronal S channel, a presynaptic background K(+) channel involved in behavioral sensitization, a simple form of learning.


Parthasarathy, S., N. Khan-Merchant, et al. (2001). "Oxidative stress in cardiovascular disease." J Nucl Cardiol 8(3): 379-89.

            The oxidative hypothesis of cardiovascular disease (CVD) has undergone tremendous changes during the past few years. Innumerable new proatherogenic effects have been added to the existing list that could be attributed to oxidative stress. However, both animal and human trials with a variety of antioxidants have failed to establish unambiguously a protective role for antioxidants in the prevention of CVD. This could be because of poor choice and dosage of antioxidants, incompatible experimental models, oxidative metabolism of the antioxidant, unrealistic expectations, and other reasons. More importantly, recent studies suggest that oxidative stress also could induce antioxidant enzymes in both cell culture and in vivo systems. In lieu of the potential of known deterrents of CVD such as exercise, estrogens, and the consumption of polyunsaturated fatty acids to induce an oxidative stress, the possibility that natural enhancement of antioxidant defense in the artery could better serve to deter CVD cannot be ignored. Thus, if oxidative stress does play a role in CVD, it may be better, in the absence of suitable animal models that respond to antioxidants, to adhere to behavioral and dietary changes that have been shown to benefit CVD.


Paduraru, I., J. Hurjui, et al. (2001). "[Recent data about the LDL-atherogenesis relationship]." Rev Med Chir Soc Med Nat Iasi 105(1): 31-6.

            The steps in pathophysiology of ATS make easier the understanding of waves of processes that lead to the disfunction of the endothelial cells, hypertrophy of the arterial wall and in the end to the complication which drawn from this process. Atherogenic process which is characterised by proaterofenethic and atherogenetic mechanism imbalance suppose three phases: early, transition and terminal phase. The initial phase involve the focal influx and LDL-cholesterol accumulation in the arterial intima, the ROS (reactive oxygen species) and azot generation by smooth muscular cells, macrophages and endothelial cells and oxidative modification of LDL. Scientific data revealed that LDL oxidation is mediated by peroxinitrite (ONOO) anion which could act directly over the thiol groups or indirectly through OH and NO radicals from peroxinitrous acid breakdown and who initiate the polyunsaturated fatty acids peroxidation and the oxidation of apolipoprotein B-100. LDL completely oxidated are recognised by scavenger receptors which are not regulated by up and down regulation. The last event of the early atherogenic process is the formation of foam cells from macrophages through LDL modified captation by scavenger receptors.


Ntambi, J. M. and H. Bene (2001). "Polyunsaturated fatty acid regulation of gene expression." J Mol Neurosci 16(2-3): 273-8; discussion 279-84.

            Polyunsaturated fatty acids (PUFAs), specifically the n-3 and n-6 series, play a key role in the progression or prevention of human diseases such as obesity, diabetes, cancer, neurological and heart disease, mainly by affecting cellular membrane lipid composition, metabolism, signal-transduction pathways, and by direct control of gene expression. PUFAs show regulation of gene expression in several tissues, including brain, liver, heart, and adipose. Most recently, research has focused on identifying the mechanisms by which PUFAs regulate lipogenic gene expression. Research to date indicates that PUFA-mediated regulation of the genetic expression and proteolytic maturation of a group of transcription factors termed sterol regulatory element binding proteins (SREBPs) accounts for the suppression of hepatic lipogenic gene expression. However, our recent studies on the transcriptional regulation of the stearoyl-coenzyme A (CoA) desaturase gene, encoding a key enzyme in the cellular synthesis of monounsaturated fatty acids from saturated fatty acids indicates that PUFA can suppress gene transcription by a mechanism independent of SREBP maturation.


Nordoy, A., R. Marchioli, et al. (2001). "n-3 polyunsaturated fatty acids and cardiovascular diseases." Lipids 36 Suppl: S127-9.

            An expert round table discussion on the relationship between intake of n-3 polyunsaturated fatty acids (PUFA) mainly of marine sources and coronary heart disease at the 34th Annual Scientific Meeting of European Society for Clinical Investigation came to the following conclusions: 1. Consumption of 1-2 fish meals/wk is associated with reduced coronary heart disease (CHD) mortality. 2. Patients who have experienced myocardial infarction have decreased risk of total, cardiovascular, coronary, and sudden death by drug treatment with 1 g/d of ethylesters of n-3 PUFA, mainly as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The effect is present irrespective of high or low traditional fish intake or simultaneous intake of other drugs for secondary CHD prevention. n-3 PUFA may also be given as fatty fish or triglyceride concentrates. 3. Patients who have experienced coronary artery bypass surgery with venous grafts may reduce graft occlusion rates by administration of 4 g/d of n-3 PUFA. 4. Patients with moderate hypertension may reduce blood pressure by administration of 4 g/d of n-3 PUFA. 5. After heart transplantation, 4 g/d of n-3 PUFA may protect against development of hypertension. 6. Patients with dyslipidemia and or postprandial hyperlipemia may reduce their coronary risk profile by administration of 1-4 g/d of marine n-3 PUFA. The combination with statins seems to be a potent alternative in these patients. 7. There is growing evidence that daily intake of up to 1 energy% of nutrients from plant n-3 PUFA (alpha-linolenic acid) may decrease the risk for myocardial infarction and death in patients with CHD. This paper summarizes the conclusions of an expert panel on the relationship between n-3 PUFA and CHD. The objectives for the experts were to formulate scientifically sound conclusions on the effects of fish in the diet and the administration of marine n-3 PUFA, mainly eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), and eventually of plant n-3 PUFA, alpha-linolenic acid (ALA, 18:3n-3), on primary and secondary prevention of CHD. Fish in the diet should be considered as part of a healthy diet low in saturated fats for everybody, whereas additional administration of n-3 PUFA concentrates could be given to specific groups of patients. This workshop was organized on the basis of questions sent to the participants beforehand, on brief introductions by the participants, and finally on discussion and analysis by a group of approximately 40 international scientists in the fields of nutrition, cardiology, epidemiology, lipidology, and thrombosis.


Napier, J. A. and L. V. Michaelson (2001). "Genomic and functional characterization of polyunsaturated fatty acid biosynthesis in Caenorhabditis elegans." Lipids 36(8): 761-6.

            The biosynthetic pathway for polyunsaturated fatty acids in the model animal Caenorhabditis elegans was examined in the context of the completed genome sequence. The genomic organization and location of seven desaturase genes and one elongase activity, all previously identified by functional characterization, were elucidated. A pathway for the biosynthesis of polyunsaturated fatty acids in C. elegans was proposed based on these genes. The role of gene duplication in enzyme evolution and proliferation is discussed.


Nakamura, M. T., H. P. Cho, et al. (2001). "Metabolism and functions of highly unsaturated fatty acids: an update." Lipids 36(9): 961-4.

            This review briefly examines the recent progress in knowledge about the synthesis and degradation of highly unsaturated fatty acids (HUFA) and their functions. Following the cloning of mammalian Delta6-desaturase (D6D), the D6D mRNA was found in many tissues, including adult brain, maternal organs, and fetal tissue, suggesting an active synthesis of HUFA in these tissues. The cloning also confirmed the long-postulated hypothesis that the same pathway is followed in n-6 and n-3 HUFA synthesis. Dietary n-6 and n-3 HUFA both induce fatty acid oxidation enzymes in peroxisomes when compared to their respective precursor polyunsaturated fatty acids. This suggests that peroxisomes may be the primary site of HUFA degradation when HUFA are supplied in excess from the diet. Peroxisome proliferators strongly induce the enzymes for the HUFA synthesis. The mechanism of this induction is currently unknown. Recent studies revealed new HUFA functions that are not mediated by eicosanoids. These functions include endocytosis/exocytosis, ion-channel modulation, DNA polymerase inhibition, and regulation of gene expression. These new discoveries will enable us to re-examine the underlying mechanisms for the classical symptoms of essential fatty acid deficiency as well as vitamin E deficiency. Progress has also been made in understanding the mechanism by which dietary HUFA reduce body fat deposition. One mechanism is induction of genes for fatty acid oxidation, which is mediated by peroxisome proliferator-activated receptor-alpha. Another likely mechanism is that HUFA suppress genes for fatty acid synthesis by reducing both mRNA and protein maturation of sterol regulatory element binding protein-1.


Musarella, M. A. (2001). "Molecular genetics of macular degeneration." Doc Ophthalmol 102(3): 165-77.

            Macular degeneration is a leading cause of blindness that affects the aged population. The complexity of the molecular basis of macular disease is now beginning to be elucidated with the identification of disease-causing genes. For example, mutations in the ABCR gene, (recently identified in cones as well) which codes for retinal rod-specific ABCR protein is responsible for Stargardt macular dystrophy/fundus flavimaculatus, an autosomal recessive macular dystrophy with juvenile onset, which accounts for 7% of human retinal degenerative diseases. The gene mutant in X-linked juvenile retinoschisis, XLRS1, is the first macular dystrophy gene to be isolated by positional cloning. Mutations in the peripherin/RDS gene have been shown to be associated with a variety of distinct forms of macular degenerations. The tissue inhibitor of metalloproteinase 3 (TIMP3) is implicated in autosomal dominant Sorsby fundus dystrophy. Best vitelliform macular dystrophy was mapped to 11q12-q13. The cloned gene product is the protein bestrophin, which is a retinal specific gene expressed in the RPE and possibly involved in the metabolism and transport of polyunsaturated fatty acids. The cloning of genes for rare heritable forms of macular degeneration will increase our understanding of the basic pathogenesis of the disease process. In the future this should also allow us to test the hypothesis that the coincidence of subclinical mutations in a number of genes involved in the formation and function of the macula can be responsible for cases of age-related macula-degeneration which is by far the most common form of these macular disorders.


Mostofsky, D. I. (2001). "Models and methods for studying behavior in polyunsaturated fatty acid research." Lipids 36(9): 913-7.

            This report examines a range of models and procedures applicable to polyunsaturated fatty acid (PUFA) research and considers their relative merits. Considerations pertaining to cost, efficiency, and scientific rigor are of particular interest. Parallel activities in other areas of behavioral neuroscience, such as behavioral pharmacology and toxicology, that have profitably exploited various behavior designs for the study of human and animal cognition are noted. Special attention is given to the utility of operant conditioning models and schedules of reinforcement, which are currently underrepresented in PUFA research. Investigations of analogs of complex human behavior as well as implications for generalizing laboratory results to clinical phenomena are addressed.


Moore, S. A. (2001). "Polyunsaturated fatty acid synthesis and release by brain-derived cells in vitro." J Mol Neurosci 16(2-3): 195-200; discussion 215-21.

            The brain is more highly enriched than most other tissues in long-chain polyunsaturated fatty acids (PUFA), particularly docosahexaenoic acid (DHA). In vitro studies of PUFA synthesis and release utilizing cell cultures of astrocytes, neurons, and cerebral microvascular endothelium have contributed significantly to our understanding of mechanisms potentially involved in the accretion of PUFA in brain. Both cerebral endothelium and astrocytes avidly elongate and desaturate precursors of the long-chain PUFAs when grown individually or in various co-culture combinations. The products, such as arachidonic acid (AA) and DHA, are released from the cells. In contrast, neurons appear unable to carry out fatty acid desaturation and thus are dependent upon preformed long-chain PUFA. Indeed, neurons co-cultured with astrocytes accumlate docosahexaenoate synthesized by the glial cells. Cerebral endothelial cultures are additionally capable of enriching the basolateral compartment (analogous to the brain extracellular space) with n-3 PUFA when grown in a membrane/chamber apparatus. The enrichment of this compartment with DHA is increased when cerebral endothelium is co-cultured with astrocytes. These data suggest that endothelial cells and astrocytes cooperate in the local synthesis and release of PUFA, collectively maintaining a brain environment enriched in long-chain PUFA.


Martinez, M. (2001). "Restoring the DHA levels in the brains of Zellweger patients." J Mol Neurosci 16(2-3): 309-16; discussion 317-21.

            Patients with the Zellweger syndrome and its variants have very low levels of docosahexaenoic acid (DHA) in the brain, retina, and other tissues. Such a marked DHA deficiency could be related to the pathogenesis of peroxisomal disorders. Therefore, restoring the DHA levels in these patients can probably improve the clinical course of the disease. With this rationale, 20 patients with generalized peroxisomal disorders have been treated to date with DHA ethyl ester, at daily doses of 100-500 mg, for variable periods of time. Treatment has been always accompanied by a nutritious diet, normal for the age, in order to provide all the necessary nutrients and avoid a polyunsaturated fatty acid (PUFA) imbalance. The most constant improvement has been normalization of the DHA levels and liver function. Vision has improved in about half the patients and muscle tone has generally increased. Magnetic resonance imaging (MRI) examination revealed improvement of myelination in 9 patients. Significantly, the clinical improvement has been most marked in those patients who started the treatment before 6 mo of age. Biochemically, the plasma very long-chain fatty acids (VLCFA) 26:0 and 26:1n-9 decreased markedly despite the complete diet provided. In erythrocytes, the plasmalogen ratio 18: ODMA/18:0 increased in most cases, and sometimes even normalized. All these beneficial effects suggest that DHA deficiency plays a fundamental role in the pathogenesis of peroxisomal disease. Because DHA accretion is maximal during early brain development, it is essential to initiate the treatment as soon as possible. Otherwise, restoration of brain DHA levels and prevention of further damage will not be possible.


Marathe, G. K., S. M. Prescott, et al. (2001). "Oxidized LDL contains inflammatory PAF-like phospholipids." Trends Cardiovasc Med 11(3-4): 139-42.

            Atherosclerosis has an underlying inflammatory component. Oxidation of low-density lipoprotein (LDL) particles to modified forms promotes atherogenesis by supplying cholesterol and through the oxidative generation of agents that activate macrophages, smooth muscle and endothelial cells. A primary target of oxidizing compounds, derived from cigarette smoke, dietary sources, exuberant inflammatory cell responses and normal cellular metabolism among other sources, are the esterified polyunsaturated fatty acids in the phospholipid shell that surrounds the insoluble lipids of the lipoprotein core. One type of phospholipid oxidation product mimics the structure of the potent inflammatory mediator platelet-activating factor (PAF), and these oxidation products activate the PAF receptor found on platelets, monocytes and leukocytes. Production of such PAF mimetics is, in contrast to the physiologic generation of PAF, uncontrolled. PAF mimetics and other phospholipid oxidation products are found in atherosclerotic lesions or even in blood after exposure to cigarette smoke. Here we summarize our data describing the structure, activity and metabolism of the PAF-like lipids found in atherogenic LDL particles.


Mahadik, S. P., D. Evans, et al. (2001). "Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia." Prog Neuropsychopharmacol Biol Psychiatry 25(3): 463-93.

            1. Schizophrenia is a major mental disorder that has a lifetime risk of 1% and affects at young age (average age at the onset 24 +/- 4.6 years) in many cultures around the world. The etiology is unknown, the pathophysiology is complex, and most of the patients need treatment and care for the rest of their lives. 2. Cellular oxidative stress is inferred from higher tissue levels of reactive oxygen species (ROS, e.g., O2*-, OH*, OH-, NO* and ONOO--) than its antioxidant defense that cause peroxidative cell injury, i.e., peroxidation of membrane phospholipids, particularly esterified essential polyunsaturated fatty acids (EPUFAS), proteins and DNA. 3. Oxidative stress can lead to global cellular with predominantly neuronal peroxidation, since neurons are enriched in highly susceptible EPUFAs and proteins, and damages DNA is not repaired effectively. 4. Such neuronal peroxidation may affect its function (i.e., membrane transport, loss of mitochondrial energy production, gene expression and therefore receptor-mediated phospholipid-dependent signal transduction) that may explain the altered information processing in schizophrenia. 5. It is possible that the oxidative neuronal injury can be prevented by dietary supplementation of antioxidants (e.g., vitamins E, C and A; beta-carotene, Q-enzyme, flavons, etc.) and that membrane phospholipids can be corrected by dietary supplementation of EPUFAs. 6. It may be that the oxidative stress is lower in populations consuming a low caloric diet rich in antioxidants and EPUFAs, and minimizing smoking and drinking. 7. Oxidative stress exists in schizophrenia based on altered antioxidant enzyme defense, increased lipid peroxidation and reduced levels of EPUFAs. The life style of schizophrenic patients is also prooxidative stress, i.e., heavy smoking, drinking, high caloric intake with no physical activity and treatment with pro-oxidant drugs. 8. The patients in developed countries show higher levels of lipid peroxidation and lower levels of membrane phospholipids as compared to patients in the developing countries. 9. Initial observations on the improved outcome of schizophrenia in patients supplemented with EPUFAs and antioxidants suggest the possible beneficial effects of dietary supplementation. 10. Since the oxidative stress exists at or before the onset of psychosis the use of antioxidants from the very onset of psychosis may reduce the oxidative injury and dramatically improve the outcome of illness.


Lobaccaro, J. M., J. J. Repa, et al. (2001). "[Regulation of lipid metabolism by the orphan nuclear receptors]." Ann Endocrinol (Paris) 62(3): 239-47.

            Lipids (cholesterol and fatty acids) are essential nutriments and have a major impact on gene expression. Hence cholesterol intracellular concentration is precisely controlled by some complex mechanisms involving transcriptional regulations. The excess of cholesterol in cells is converted into oxysterols. These cholesterol metabolites are important signalisation molecules that modulate several transcription factors involved in cholesterol homeostasis. Schematically, regulation of cholesterol homeostasis is achieved by three different but complementary pathways: 1) endogeneous biosynthesis, which corresponds to the de novo synthesis of cholesterol and is controlled by sterol response element binding proteins (SREBPs); 2) the transport, intracellular absorption and esterification of the cholesterol; 3) the metabolic conversion into bile acids and steroid hormones. These three pathways are closely linked, however we will schematically detail the role of the orphan nuclear receptors on the modulation of these three levels of regulation. Phenotype analyses of knock-out or transgenic mice pointed out the respective role of the "enterohepatic" orphan nuclear receptors LXRalpha, LXRB, FXR, LRH-1, the nuclear receptor PPARalpha, and their heterodimeric partner RXR, as well as the peculiar receptor SHP. Complex feed-backs have thus been demonstrated. These transciptional regulations have several targets: the P450 cytochromes involved in the bile acid synthesis Cyp7a1 and Cyp8b1; the intestinal bile acid binding protein IBABP; the cholesteryl ester transfert protein CETP and phospholipid transfert protein PLTP, both involved in the HDL catabolism; the ABC cholesterol transporters ABCG1/ABC8 and ABCAI/ABCI. At last it seems that polyunsaturated fatty acids could activate LXRalpha transcription through its activation by PPARalpha. In the near future, the identification and study of new target genes by transcriptomic or proteomic analyses will allow a better understanding of lipid homeostasis in physiological as well as pathophysiological conditions.


Leiba, A., H. Amital, et al. (2001). "Diet and lupus." Lupus 10(3): 246-8.

            The effect of dietary modifications has been extensively studied in lupus animal models. Calorie, protein, and especially fat restriction, caused a significant reduction in immune-complex deposition in the kidney, reduced proteinuria and prolongation of the mice's life span. The addition of polyunsaturated fatty acids (PUFAs), such as fish oil or linseed oil, was also related to decreased mice morbidity and mortality in animal models of lupus and of antiphospholipid syndrome. PUFAs such as eicosapetaenoic acid (EPA) and docosahexaenoic acid (DHA) competitively inhibit arachidonic acid with a resultant decrease in inflammatory eicosanoids and cytokines. Human studies support the effect of a PUFAs-enriched diet, both scrologically and clinically. Large scale clinical studies are needed to confirm the primary results.


Lee, S. H. and I. A. Blair (2001). "Oxidative DNA damage and cardiovascular disease." Trends Cardiovasc Med 11(3-4): 148-55.

            Reactive oxygen species can directly cause covalent modifications to DNA. Alternatively, they can initiate the formation of lipid hydroperoxides, which undergo homolytic decomposition to the alpha,beta-unsaturated aldehyde genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal through two quite separate pathways. One pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide. The other pathway involves the intermediate formation of 4-hydroperoxy-2-nonenal. Lipid hydroperoxides can also be derived from the action of lipoxygenases and cyclooxygenases on polyunsaturated fatty acids. 4,5-Epoxy-2(E)-decenal forms etheno-2'-deoxyadenosine adduct with DNA, a mutagenic lesion observed in human tissue DNA samples. Several new ethano- and etheno-DNA adducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. Malondialdehyde, another genotoxic bifunctional electrophile, forms a propano adduct with 2'-deoxyguanosine (M1G-dR) rather than an etheno adduct. Very little is known about the consequences of lipid hydroperoxide-mediated DNA damage in cardiovascular diseases. This should prove to be an important area for future research.


Leaf, A. (2001). "Diet and sudden cardiac death." J Nutr Health Aging 5(3): 173-8.

            The purpose of this paper is to review the evidence that dietary factors, namely the ingestion of the n-3 (or w-3) polyunsaturated fatty acids of fish oils can prevent fatal cardiac arrhythmias (so-called sudden cardiac death) in experimental animals, and probably in humans as well. The mechanism for this striking effect results from the ability of these fatty acids to directly stabilize electrically every contractile myocyte in the heart. This is accomplished by modulation by the free n-3 fatty acids of the ionic currents in heart cells; particularly the voltage-dependent sodium currents which initiate action potentials and the L-type calcium currents, which initiate release of sarcoplasmic reticulum stores of calcium into the cytosol of heart cells. The resultant rise in cytosolic calcium concentration initiates contraction of the heart cells and the beating rate of the heart. The gradually accumulating clinical evidence that these fish oil fatty acids are potent preventors of cardiac sudden death in humans will be reviewed. With some 250,000 deaths occurring within one hour of the onset of acute myocardial infarctions annually in the USA alone and millions more in the whole world, the potential large public health benefit from this understanding is evident.


Leaf, A. (2001). "The electrophysiologic basis for the antiarrhythmic and anticonvulsant effects of n-3 polyunsaturated fatty acids: heart and brain." Lipids 36 Suppl: S107-10.

            The n-3 polyunsaturated fatty acids (PUFA) have been shown to be antiarrhythmic in animals and probably in humans. PUFA stabilize the electrical activity of isolated cardiac myocytes by modulating sarcolemmal ion channels, so that a stronger electrical stimulus is required to elicit an action potential and the refractory period is markedly prolonged. Inhibition of voltage-dependent sodium currents, which initiate action potentials in excitable tissues, and of the L-type calcium currents, which initiate release of sarcoplasmic calcium stores, thus increasing cytosolic free calcium concentrations and activating the contractile proteins in myocytes, appears at present to be the probable major antiarrhythmic mechanisms of PUFA. Because the ion channels in neurons have channel proteins essentially homologous to those in the heart, the n-3 fatty acids would appear to be likely to affect the electrical activity in the brain in a manner similar to their effects in the heart, and accumulating evidence supports this notion. Evidence of important beneficial neurological effects of dietary n-3 PUFA are emerging with more likely to be discovered.


Leaf, A. and Y. F. Xiao (2001). "The modulation of ionic currents in excitable tissues by n-3 polyunsaturated fatty acids." J Membr Biol 184(3): 263-71.


Leaf, A. (2001). "Electrophysiologic basis for the antiarrhythmic and anticonvulsant effects of omega 3 polyunsaturated fatty acids." World Rev Nutr Diet 88: 72-8.


Larque, E., S. Zamora, et al. (2001). "Dietary trans fatty acids in early life: a review." Early Hum Dev 65 Suppl: S31-41.

            Trans fatty acids are unsaturated fatty acids with at least a double trans configuration, resulting in a more rigid molecule close to a saturated fatty acid. These appear in dairy fat because of ruminal activity, and in hydrogenated oils; margarines, shortenings and baked goods contain relatively high levels of trans fatty acids. These fatty acids can be incorporated into both fetal and adult tissues, although the transfer rate through the placenta continues to be a contradictory subject. In preterm infants and healthy term babies, trans isomers have been inversely correlated to infantile birth weight. However, in multigenerational studies using animals, there is no correlation between birth weight, growth, and dietary trans fatty acids. Maternal milk reflects precisely the daily dietary intake of trans fatty acids, from 2% to 5% of the total fatty acids in human milk. The level of linoleic acid in human milk is increased by a high trans diet, but long-chain polyunsaturated fatty acids remain mostly unaffected. Likewise, infant tissues incorporate trans fatty acids from maternal milk, raising the level of linoleic acid and relatively decreasing arachidonic and docosahexaenoic acids. This suggests an inhibitory effect of trans fatty acid on liver Delta-6 fatty-acid desaturase activity. As opposed to blood and liver, the brain appears to be protected from the trans fatty-acid accumulation in experimental animals, but no data have yet been reported for human newborns. Further investigations in humans are needed to definitively establish the potential physiological consequences of trans fatty-acid intake during the neonatal period.


Lapillonne, A. and S. E. Carlson (2001). "Polyunsaturated fatty acids and infant growth." Lipids 36(9): 901-11.

            Because of the rapid rate of growth during infancy, and the potentially deleterious effect of differences in the availability of dietary essential nutrients, growth is an important outcome variable in any study assessing a diet designed for infants. Nearly 10 yr after the first demonstration of reduced growth in preterm infants fed a fish oil-enriched formula, there is very little additional information to confirm or refute the finding that long-chain n-3 polyunsaturated fatty acid (LC-PUFA) intake can modulate growth in infants. To evaluate the issue of a possible relationship between PUFA intake and growth of infants, we reviewed a total of 32 randomized studies, 13 in preterm infants and 19 in term infants. From the data published to date, it seems clear that long-chain n-3 fatty acids can reduce growth achievement in preterm and term infants under some experimental conditions. However, the effect of n-3 PUFA supplementation on the growth of preterm and term infants appears to be minimal and of questionable clinical and/or physiologic relevance. Nonetheless, n-3 fatty acids have an effect on gene transcription, at least in some species, and this finding may provide important clues to the mechanism by which n-3 and n-6 fatty acids regulate growth.


Lakatta, E. G., S. J. Sollott, et al. (2001). "The old heart: operating on the edge." Novartis Found Symp 235: 172-96; discussion 196-201, 217-20.

            Excitation of cardiac cells is accompanied by Ca2+ influx which triggers a transient increase in cytosolic [Ca2+], (Cai), and contraction. While the amplitudes of the Cai transient and contraction increase with the extent of cell Ca2+ loading, excess Ca2+ loading leads to dysregulation of Ca2+ homeostasis, impaired contraction, arrhythmia and cell death. The cell Ca2+ load is determined by membrane structure and permeability characteristics, the intensity of stimuli that modulate Ca2+ influx or efflux via regulatory function of proteins within membranes, and reactive oxygen species (ROS), which affect both membrane structure and function. Cardiocytes of senescent hearts exhibit a reduced threshold for pathologic manifestations of excess Ca2+ loading during stimulation (physiologic or pharmacologic) that increases Ca2+ influx, e.g. in response to neurotransmitters, post-ischaemic reperfusion, or oxidative stress. Cell 'remodelling' is one cause of the relative Ca2+ intolerance of cardiocytes in the senescent heart; cells increase in size and changes occur in the amounts of proteins that regulate Ca2+ handling due, in part, to altered gene expression; another cause is a change in the composition of membranes in which Ca2+ regulatory proteins reside, e.g. an increase in membrane omega 6:omega 3 polyunsaturated fatty acids (PUFA); a third cause is an enhanced likelihood for intracellular generation of ROS. Each class of these determinants changes with ageing and reduces the threshold for Ca2+ overload to occur with the older heart. The risk of excess Ca2+ loading within the senescent heart can potentially be reduced by gene therapy to restore Ca2+ regulatory proteins, by diet to reverse the membrane omega 6:omega 3 PUFA imbalance, or by antioxidants.


Kulkarni, A. P. (2001). "Lipoxygenase--a versatile biocatalyst for biotransformation of endobiotics and xenobiotics." Cell Mol Life Sci 58(12-13): 1805-25.

            Lipoxygenase, a member of the arachidonate cascade enzymes, dioxygenates polyenoic fatty acids to finally yield products with profound and distinct biological activity. This review summarizes the available evidence for another role played by lipoxygenases in the metabolism of endobiotics and xenobiotics. Although other mechanisms exist, a direct hydrogen abstraction by the enzyme and the peroxyl radical-dependent chemical oxidation appear to be central to the co-oxidase activity of lipoxygenases. Besides polyunsaturated fatty acids, H2O2, fatty acid hydroperoxides, and synthetic organic hydroperoxides support the lipoxygenase-catalyzed xenobiotic oxidation. The major reactions documented thus far include oxidation, epoxidation, hydroxylation, sulfoxidation, desulfuration, dearylation, and N-dealkylation. It is noteworthy that lipoxygenases are also capable of glutathione conjugation of certain xenobiotics. The enzyme system appears to be inducible following exposure to chemicals. Lipoxygenases are inhibited by a large number of chemicals, some of which also serve as co-substrates. Available data suggest that lipoxygenases contribute to in vivo metabolism of xenobiotics in mammals.


Kromhout, D. (2001). "Diet and cardiovascular diseases." J Nutr Health Aging 5(3): 144-9.

            In spite of the decreasing trend in age-adjusted cardiovascular disease mortality in Western European countries, an increase in the cardiovascular morbidity is expected because of the ageing of the population. Consequently the health care cost for these diseases will increase. This article focuses on the role of diet in the occurrence of cardiovascular diseases.Total and HDL cholesterol are major determinants of coronary heart disease. Saturated and trans fatty acids have a total and LDL cholesterol elevating effect and unsaturated fatty acids a lowering effect. N-3 polyunsaturated fatty acids seem to have a protective effect on coronary heart disease occurrence independent of cholesterol. Dietary antioxidants could be of importance because they may prevent oxidation of the atherogenic cholesterol rich LDL lipoproteins. There is however no convincing evidence that either vitamin E, carotenoids or vitamin C protect against coronary heart disease. Observational research has shown that flavonols, polyphenols with strong antioxidant properties present in plant foods, may protect against coronary heart disease. Blood pressure is a major determinant of coronary heart disease and stroke. Historically salt is viewed as the most important dietary determinant of blood pressure. Recent research shows that also a low-fat diet rich in potassium, calcium and magnesium lowers blood pressure substantially. This suggests a multifactorial influence of different nutrients on blood pressure. It can be concluded that a diet low in saturated and trans fatty acids and rich in plant foods in combination with regular fish consumption is associated with a low risk of cardiovascular mortality.


Kromhout, D. (2001). "Epidemiology of cardiovascular diseases in Europe." Public Health Nutr 4(2B): 441-57.

            Within Europe large differences exist in mortality from coronary heart disease and stroke. These diseases show a clear West-East gradient with high rates in Eastern Europe. In spite the decreasing trend in age-adjusted cardiovascular disease mortality in Western European countries an increase in the number of cardiovascular patients is expected because of the ageing of the population. Consequently the health care cost for these diseases will increase. Total and HDL cholesterol are major determinants of coronary heart disease. Saturated and trans fatty acids have a total and LDL cholesterol elevating effect and unsaturated fatty acids a lowering effect. N-3 polyunsaturated fatty acids seem to have a protective effect on coronary heart disease occurrence independent of their effect on cholesterol. Dietary antioxidants could be of importance because they may prevent oxidation of the atherogenic cholesterol rich LDL lipoproteins. There is however no convincing evidence that either vitamin E, carotenoids or vitamin C protect against coronary heart disease. Observational research has shown that flavonols, polyphenols with strong antioxidant properties present in plant foods, may protect against coronary heart disease. Blood pressure is a major determinant of coronary heart disease and stroke. Historically salt is viewed as the most important dietary determinant of blood pressure. Recent research shows that also a low-fat diet rich in potassium, calcium and magnesium lowers blood pressure substantially. This suggests a multifactorial influence of different nutrients on blood pressure. It can be concluded that a diet low in saturated and trans fatty acids and rich in plant foods in combination with regular fish consumption is associated with a low risk of cardiovascular mortality.


Kristensen, S. D., A. M. Iversen, et al. (2001). "n-3 polyunsaturated fatty acids and coronary thrombosis." Lipids 36 Suppl: S79-82.

            Studies of Greenland Eskimos showed that a very high intake of marine n-3 fatty acids markedly inhibited platelet reactivity and suggested that intake of these fatty acids might prevent coronary thrombosis. Later studies with lower, more practical doses of n-3 fatty acids also have shown a platelet inhibitory effect of n-3 fatty acids, albeit fairly marginal. Furthermore, n-3 fatty acids have little effect on measures of blood coagulability and may slightly decrease fibrinolysis. In animal models, n-3 fatty acids often have been shown to inhibit thrombosis, but again the doses have tended to be very high. Finally, there has been little effect of (low-dose) n-3 fatty acids in clinical trials in humans on the incidence of myocardial infarction. Overall, there is little evidence for a major antithrombotic effect of practical doses of n-3 fatty acids on coronary thrombosis. This does not exclude a beneficial effect of n-3 fatty acids on coronary heart disease as suggested from clinical trials, but the major effect may be antiarrhythmic rather than antithrombotic.


Krempf, M. (2001). "[Dietary recommendations for dyslipidemic individuals]." Ann Med Interne (Paris) 152(3): 198-200.

            Diet prescription is a fundamental first-line element in the management of patients with dyslipidemia. Weight loss should be a primary goal for all overweight patients. A 5 to 10% weight loss is often sufficient to obtain a significant improvement in lipid levels. Dietary fat should not provide more than 30% of total calorie intake. Saturated fatty acids should not exceed 7% and polyunsaturated fatty acids should also be limited to 7 to 10%. For monounsaturated fatty acids the dietary allowance can be a bit wider, up to 15% of total calorie intake. Carbohydrates, particularly complex carbohydrates, should replace the fat calories. Dietary fiber (more than 20g/d) as well as soy protein or phyto-sterols can be helpful in reducing LDL-cholesterol by about 10%. Consumption of fruits and vegetables should also be encouraged because they provide antioxidants that have effects on other cardiovascular risk factors. Long-term education is needed to encourage the patient to comply with this type of diet. Psycho-behavioral strategies can be useful here.


Koletzko, B., C. Agostoni, et al. (2001). "Long chain polyunsaturated fatty acids (LC-PUFA) and perinatal development." Acta Paediatr 90(4): 460-4.

            This paper reports on the conclusions of a workshop on the role of long chain polyunsaturated fatty acids (LC-PUFA) in maternal and child health. The attending investigators involved in the majority of randomized trials examining LC-PUFA status and functional outcomes summarize the current knowledge in the field and make recommendations for dietary practice. Only studies published in full or in abstract form were used as our working knowledge base. Conclusions: For healthy infants we recommend and strongly support breastfeeding as the preferred method of feeding, which supplies preformed LC-PUFA. Infant formulas for term infants should contain at least 0.2% of total fatty acids as docosahexaenoic acid (DHA) and 0.35% as arachidonic acid (AA). Since preterm infants are born with much less total body DHA and AA, we suggest that preterm infant formulas should include at least 0.35% DHA and 0.4% AA. Higher levels might confer additional benefits and should be further investigated because optimal dietary intakes for term and preterm infants remain to be defined. For pregnant and lactating women we consider it premature to recommend specific LC-PUFA intakes. However, it seems prudent for pregnant and lactating women to include some food sources of DHA in their diet in view of their assumed increase in LC-PUFA demand and the relationship between maternal and foetal DHA status.


Koletzko, B., M. Rodriguez-Palmero, et al. (2001). "Physiological aspects of human milk lipids." Early Hum Dev 65 Suppl: S3-S18.

            Human milk from healthy and well-nourished mothers is the preferred form of feeding for all healthy newborn infants. The nutrient supply with human milk supports normal growth and development of the infant. Here the general characteristics of human milk lipids and recent knowledge on lactational physiology, composition and functional aspects of human milk lipids are discussed. Lipids in human milk represent the main source of energy for the breastfed baby and supply essential nutrients such as fat-soluble vitamins and polyunsaturated fatty acids (PUFA). The essential fatty acids linoleic and alpha-linolenic acids (LA and ALA) are precursors of long-chain polyunsaturated fatty acids (LC-PUFA), including arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acids (AA and DHA). LC-PUFA serve as indispensable structural components of cellular membranes and are deposited to a considerable extent in the growing brain and the retina during perinatal development. The supply of preformed LC-PUFA with human milk lipids has been related to functional outcomes of the recipient infants such as visual acuity and development of cognitive functions during the first year of life. Recent stable isotope studies indicate that the major portion of milk PUFA is not derived directly from the maternal diet, but stems from endogenous body stores. Thus, not only the woman's current but also her long-term dietary intake is of marked relevance for milk fat composition.


Kim, H. Y., M. Akbar, et al. (2001). "Inhibition of neuronal apoptosis by polyunsaturated fatty acids." J Mol Neurosci 16(2-3): 223-7; discussion 279-84.

            The effect of polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (22:6n-3; DHA) and arachidonic acid (20:4n-6; AA), on apoptotic cell death was evaluated based on DNA fragmentation and caspase-3 activity induced by serum starvation using Neuro-2A and PC-12 cells. The presence of 20:4n-6 in the medium during serum starvation decreased DNA fragmentation and this initial protective effect was diminished with prolonged serum starvation. The observed protective effect of 20:4n-6 was not affected by the inhibitors of cyclooxygenase (COX) and lipoxygenase. Conversely, 22:6n-3 became protective only after the enrichment of cells with this fatty acid at least for 24 h prior to the serum deprivation. DNA fragmentation as well as caspase-3 activity was reduced in 22:6n-3 enriched cells with a concomitant decrease in protein and mRNA levels. During the enrichment period, 22:6n-3 steadily increased its incorporation into PS leading to a significant increase in the total PS content; the protective effect of 22:6n-3 paralleled the PS accumulation. Neither direct exposure of cells to nor enrichment with 18:1n-9 had any protective effect. In conclusion, it is proposed that 20:4n-6 prevents neuronal apoptosis primarily due to the action of nonesterified 20:4n-6 but 22:6n-3, at least in part, through PS accumulation.


Kersten, S. (2001). "Mechanisms of nutritional and hormonal regulation of lipogenesis." EMBO Rep 2(4): 282-6.

            Fat build-up is determined by the balance between lipogenesis and lipolysis/fatty acid oxidation. In the past few years, our understanding of the nutritional, hormonal and particularly transcriptional regulation of lipogenesis has expanded greatly. Lipogenesis is stimulated by a high carbohydrate diet, whereas it is inhibited by polyunsaturated fatty acids and by fasting. These effects are partly mediated by hormones, which inhibit (growth hormone, leptin) or stimulate (insulin) lipogenesis. Recent research has established that sterol regulatory element binding protein-1 is a critical intermediate in the pro- or anti-lipogenic action of several hormones and nutrients. Another transcription factor implicated in lipogenesis is the peroxisome proliferator activated receptor gamma. Both transcription factors are attractive targets for pharmaceutical intervention of disorders such as hypertriglyceridemia and obesity.


Jagla, A. and J. Schrezenmeir (2001). "Postprandial triglycerides and endothelial function." Exp Clin Endocrinol Diabetes 109(4): S533-47.

            Several studies support the association between postprandially elevated triglyceride levels and atherosclerosis. Histological and cell culture investigations revealed, that triglyceride rich postprandial lipoproteins are taken up by macrophages and smooth muscle cells and are detectable as part of foam cells in vascular lesions. Remnant particles, generated by lipolysis of postprandial lipoproteins in vitro and fatty acids increase the permeability of the endothelium and are cytotoxic for endothelial cells. Besides these morphological changes of cells, lipoproteins have been shown to exert effects on cellular functions like the expression of membrane proteins and the production or release of several bioactive substances regulating communication with blood cells and other cell systems of the vascular wall, blood pressure and hemostasis. This review concentrates on the influence of postprandial lipoproteins on factors involved in the interaction of endothelial cells with blood leukocytes and factors mediating blood pressure regulation. Increased expression of adhesion molecules has been detected immunehistochemically in atherosclerotic plaques in animals and humans. It was demonstrated that patients with elevated triglyceride levels have increased levels of soluble adhesion molecules. Furthermore, postprandial lipoproteins were shown to induce membrane expression of adhesion molecules. This effect seems to be at least in part mediated by the oxidative modification of the particles. Accordingly chylomicrons separated after ingestion of safflower oil, rich in polyunsaturated linoleic acid, induced higher adhesion molecule expression at higher oxidant concentration compared with chylomicrons separated after ingestion of olive oil, rich in monounsaturated oleic acid. Several authors described effects of fatty acids on the expression of adhesion molecules. On the one hand, they may exert stimulatory effects as such, on the other hand cytokine induced adhesion molecule expression may be enhanced by certain fatty acids and inhibited by others, implying an interference with signal transduction processes. Effects of lipoproteins on vasoactive substances seem to be implicated in endothelial dysfunction, too. The endothelium-derived relaxing factor nitric oxide (NO) has gained increasingly attention in the last two decades and is regarded as protective against hypertension and atherosclerosis. It was demonstrated that chylomicrons and their remnants inhibited endothelium-dependent relaxations in isolated aortas. Vasodilatatory responses and nitric oxide metabolism were shown to be affected by the amount and composition of dietary fat. Cell culture experiments revealed modulation of NO release by certain fatty acids. Plasma levels of endothelin-1, a strong vasoconstrictor, have been shown to be increased in patients with type 2 diabetes and metabolic syndrome, respectively. Postprandially elevated triglycerides increased endothelin-levels in addition to insulin in patients with metabolic syndrome. In summary, there is evidence that the association between postprandial triglycerides and the metabolic syndrome is driven by direct influences on endothelial functions because plasma triglyceride levels are associated with levels of humoral risk markers of endothelial origin, and postprandial lipoproteins stimulate the release and/or expression of endothelial mediators in vitro, which induce atherogenesis and hypertension.


Iuliano, L., F. Micheletta, et al. (2001). "Low-density lipoprotein oxidation." Ital Heart J 2(12): 867-72.

            Free radical mediated oxidation of low-density lipoproteins (LDL), which has been extensively studied in the last two decades, plays a central role in the development of the atherosclerotic plaque. Oxidation involves the lipid moiety of LDL in a chain reaction mechanism. In the initial phase, free radicals preferentially attack highly oxidizable polyunsaturated fatty acids. Subsequent recruitment of other molecules includes cholesterol and phospholipids. The process of oxidation is counteracted by antioxidants present in LDL. By-products formed during oxidation of LDL lipids, which may have biological activity, react with amino acid residues of the LDL protein backbone with the consequent modification of chemical and immunological properties responsible for cellular receptor shift. Oxidation-altered apolipoprotein B of oxidized LDL is, in fact, recognized by the macrophage scavenger receptor responsible for foam cell formation. The mechanism of LDL oxidation and the impact on atherogenesis are discussed.


Infante, J. P. and V. A. Huszagh (2001). "Impaired arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acid synthesis by phenylalanine metabolites as etiological factors in the neuropathology of phenylketonuria." Mol Genet Metab 72(3): 185-98.

            The recent literature on polyunsaturated fatty acid metabolism in phenylketonuria (PKU) is critically analyzed. The data suggest that developmental impairment of the accretion of brain arachidonic (20:4n-6) and docosahexaenoic (22:6n-3, DHA) acids is a major etiological factor in the microcephaly and mental retardation of uncontrolled PKU and maternal PKU. These fatty acids appear to be synthesized by the recently elucidated carnitine-dependent, channeled, mitochondrial fatty acid desaturases for which alpha-tocopherolquinone (alpha-TQ) is an essential enzyme cofactor. alpha-TQ can be synthesized either de novo or from alpha-tocopherol. The fetus and newborn would primarily rely on de novo alpha-TQ synthesis for these mitochondrial desaturases because of low maternal transfer of alpha-tocopherol. Homogentisate, a pivotal intermediate in the de novo pathway of alpha-TQ synthesis, is synthesized by 4-hydroxyphenylpyruvate dioxygenase. The major catabolic products of excess phenylalanine, viz. phenylpyruvate and phenyllactate, are proposed to inhibit alpha-TQ synthesis at the level of the dioxygenase reaction by competing with its 4-hydroxyphenylpyruvate substrate, thus leading to a developmental impairment of 20:4n-6 and 22:6n-3 synthesis in uncontrolled PKU and fetuses of PKU mothers. The data suggest that dietary supplementation with carnitine, 20:4n-6, and 22:6n-3 may have therapeutic value for PKU mothers and for PKU patients who have been shown to have a low plasma status of these essential metabolites.


Hynes, G. R. and P. J. Jones (2001). "Leptin and its role in lipid metabolism." Curr Opin Lipidol 12(3): 321-7.

            Since the discovery of leptin in 1994, a considerable amount of research has focused on leptin as a central regulator of body weight. In the animal model, research has demonstrated leptin action through hypothalamic centres altering both satiety and energy expenditure. In contrast to animal studies, it is unlikely that leptin functioning in the human system exerts such a profound role in body weight regulation. Human studies suggest that leptin levels are strongly correlated with both percentage fat mass and body mass index, in accordance with the proposed 'lipostatic theory'. Current research suggests the existence of a unique inter-relationship between dietary fat, leptin expression and leptin action within the peripheral system. More specifically, it has been demonstrated that polyunsaturated fatty acid (PUFA) intake influences adipose tissue expression of leptin, and of several lipogenic enzymes and transcription factors. In addition, leptin stimulates triglyceride depletion in white adipose tissue without increasing free fatty acid release, thus favouring fatty acids versus glucose as a fuel source. Recent studies suggest that the reduction in adipose hypertrophy observed with n-3 PUFA-containing fish oil feeding might involve a leptin-specific process. A large amount of evidence supports direct functioning of leptin in peripheral lipid metabolism in vivo and in vitro. It is possible that PUFAs will maintain an efficient level of circulating leptin, thus preventing leptin insensitivity and weight gain. There has been much recent progress in clinical leptin research, from energy expenditure to leptin analogue efficacy; the purpose of the present review is to summarize our current understanding of leptin functioning.


Huang, Y. S., P. Mukerji, et al. (2001). "Transgenic production of long-chain polyunsaturated fatty acids." World Rev Nutr Diet 88: 243-8.


Hu, F. B., R. M. van Dam, et al. (2001). "Diet and risk of Type II diabetes: the role of types of fat and carbohydrate." Diabetologia 44(7): 805-17.

            Although diet and nutrition are widely believed to play an important part in the development of Type II (non-insulin-dependent) diabetes mellitus, specific dietary factors have not been clearly defined. Much controversy exists about the relations between the amount and types of dietary fat and carbohydrate and the risk of diabetes. In this article, we review in detail the current evidence regarding the associations between different types of fats and carbohydrates and insulin resistance and Type II diabetes. Our findings indicate that a higher intake of polyunsaturated fat and possibly long-chain n-3 fatty acids could be beneficial, whereas a higher intake of saturated fat and trans-fat could adversely affect glucose metabolism and insulin resistance. In dietary practice, exchanging nonhydrogenated polyunsaturated fat for saturated and trans-fatty acids could appreciably reduce risk of Type II diabetes. In addition, a low-glycaemic index diet with a higher amount of fiber and minimally processed whole grain products reduces glycaemic and insulinaemic responses and lowers the risk of Type II diabetes. Dietary recommendations to prevent Type II diabetes should focus more on the quality of fat and carbohydrate in the diet than quantity alone, in addition to balancing total energy intake with expenditure to avoid overweight and obesity.


Heird, W. C. (2001). "The role of polyunsaturated fatty acids in term and preterm infants and breastfeeding mothers." Pediatr Clin North Am 48(1): 173-88.

            DHA and AA, which are components of breast milk but not infant formulas marketed in the United States and some other countries, are important components of the brain, and DHA is a major component of the retina. Also, many studies have demonstrated advantages of breastfeeding versus formula-feeding on subsequent cognitive and visual function; however, available data are insufficient to justify the conclusion that the presence of DHA and AA in breast milk is partially or soley responsible for the apparent advantages of breastfeeding. On the other hand, many studies of DHA (and AA)-supplemented versus unsupplemented formulas have shown clear advantages of the supplemented formulas on visual acuity at 2 and 4 months of age or neurodevelopmental status at 12 to 18 months of age. Although one logically may assume that these early effects may have long-term effects, this assumption is not warranted by the available data. One of the major problems is the difficulty of assessing visual and cognitive function of infants. Scores on standard neurodevelopmental tests at 1 year of age, for example, are only weakly correlated with performance at school age (when more definitive assessments are possible), and little is known about the predictability of later visual function from behavioral or electrophysiologic assessments of visual function early in life. Even prematurely born infants can synthesize DHA and AA and other omega-3 and omega-6 LC-PUFAs from the dietary EFAs, LA and ALA. Nonetheless, plasma, erythrocyte and brain lipid levels of DHA are lower in infants whose diets do not contain DHA. Whether more optimal intakes of ALA result in higher plasma and tissue levels of this FA is unclear. The breast-milk content of LC-PUFAs is not regulated by the mammary gland but, rather, reflects the concentrations of LC-PUFAs in maternal plasma lipids that, in turn, are dependent on maternal diet and, probably, maternal activities of the desaturases and elongases involved in converting dietary LA and ALA to LC-PUFAs. This occurrence suggests that some infants receive sufficient LC-PUFA to support normal rates of deposition, whereas others may not. Also, some infants probably can synthesize additional LC-PUFAs from the LA and ALA contents of human milk. Thus, depending on maternal diet and maternal and infant desaturase and elongase activities, some breastfed infants may receive less than adequate LC-PUFAs to support normal rates of deposition. Clearly, the role of LC-PUFAs in infant development is not a simple issue. Also, no foolproof method exists to ensure an adequate but not excessive intake. Thus, because some evidence shows that dietary LC-PUFA (DHA, AA, or both) as components of breast milk or formula confers at least transient developmental benefits, supplementation of infant formulas with LC-PUFAs is supportable provided that the supplements used are safe. The safety of all available supplements is unknown; however, some trials reveal few reasons for major concerns about the safety of single-cell oils, low-EPA fish oil, or egg-yolk phospholipid or triglyceride fractions.


Hamosh, M. (2001). "Overview: conditionally essential nutrients: can long-chain polyunsaturated fatty acids and nucleotides qualify?" Adv Exp Med Biol 501: 357-63.


Hamosh, M., T. R. Henderson, et al. (2001). "Long-chain polyunsaturated fatty acids (LC-PUFA) during early development: contribution of milk LC-PUFA to accretion rates varies among organs." Adv Exp Med Biol 501: 397-401.

            Long-chain polyunsaturated fatty acids (LC-PUFA) accretion (essential for growth and neural development) was studied from late fetal throughout weaning age in the ferret, a species with maternal LC-PUFA sufficiency during pregnancy and lactation. The data show that a) accretion rate of LC-PUFA is rapid during early postnatal development, b) milk LC-PUFA decrease during lactation, c) adipose tissue LC-PUFA level is directly related to milk LC-PUFA level, while accretion in brain and liver exceeds dietary intake, d) accretion of arachidonic acid occurs earlier than docosahexaenoic acid, suggesting earlier development of n6-fatty acid endogenous synthesis.


Grimm, H. and A. Kraus (2001). "Immunonutrition--supplementary amino acids and fatty acids ameliorate immune deficiency in critically ill patients." Langenbecks Arch Surg 386(5): 369-76.

            BACKGROUND: Immunonutrition with omega-3 fatty acids and the "conditionally essential" amino acids arginine, glutamine, cysteine, and taurine can enhance the immune response in critically ill patients. This is due to the immunomodulating properties of these nutrients. Immunonutrition is especially important when a patient's immune response is compromised, as is the case post-operatively or after trauma. Immune deficiency is severely aggravated in sepsis and the systemic inflammatory response syndrome (SIRS). The resulting metabolic stress is characterized by glycolysis, lipolysis, and proteolysis, which may escalate to an hypercatabolic response or "autocannabilism." Catabolic metabolism results in insufficiency of both specific and unspecific immunocompetent cells. CONCLUSIONS: Immunonutrition should be started early in such patients for an optimal beneficial effect, preferably via the enteral route. It should include medium chain and long chain triglycerides, polyunsaturated omega-3 and omega-6 fatty acids (in the ratio 1:2), olive oil, and conventional amino acid preparations supplemented with the conditionally essential amino acids arginine, glutamine, cysteine, and taurine.


Grimble, R. F. (2001). "Nutritional modulation of immune function." Proc Nutr Soc 60(3): 389-97.

            The inflammatory response to injury and infection, although an essential part of immune function, carries the risk of severe tissue depletion and immunosuppression. These outcomes increase morbidity and delay recovery. Evidence is accumulating that single-nucleotide polymorphisms in the genes controlling pro-inflammatory cytokine production adversely influence the response. Immunonutrition provides a means of modulating the inflammatory response to injury and infection, and thereby improves clinical outcome. n-3 Polyunsaturated fatty acids (n-3 PUFA), glutamine, arginine, S amino acids and nucleotides are important components of immunonutrient mixes. While animal model studies suggest that all these components may exert a beneficial effect in patients, the number of large randomized placebo-controlled trials utilizing immunonutrition is fairly limited and the observed effects are relatively small. Meta-analyses suggest that while immunonutrition may not reduce mortality rates, a reduction in hospital length of stay, decreased requirements for ventilation and lower infection rates are achieved by this mode of nutrition. The present paper discusses some underlying reasons for the difficulty in demonstrating the clinical efficacy of immunonutrition. Paramount among these reasons is the antioxidant status and genetic background of the patient. A number of studies suggest that there is an inverse relationship between inflammation and T-cell function. Immuno-enhancive effects have been shown in a number of studies in which n-3 PUFA, glutamine and N-acetyl cysteine have been employed. All these nutrients may exert their effects by suppressing inflammation; n-3 PUFA by direct suppression of the process and glutamine and N-acetyl cysteine by acting indirectly on antioxidant status. Glutamine and nucleotides exert a direct effect on lymphocyte proliferation. Preliminary data suggests that not all genotypes are equally sensitive to the effects of immunonutrition. When further studies have been conducted to discern the precise interaction between each individual's genotype of relevance to the response to injury and infection, and immunonutrients, the level of precision in the application of immunonutrition will undoubtedly improve.


Grimaldi, P. A. (2001). "Fatty acid regulation of gene expression." Curr Opin Clin Nutr Metab Care 4(5): 433-7.

            Over the past 10 years it has become evident that fatty acids regulate cellular functions by modulating gene expression. Fatty acids and fatty acid metabolites exert some of their effects on gene expression by affecting the activity of nuclear transcription factors, peroxisome proliferator-activated receptors and sterol regulatory element binding protein type 1. The present review describes the latest developments in the field, with particular emphasis on the physiological roles of the various peroxisome proliferator-activated receptor isotypes, including their implication in the control of proliferation and differentiation of normal and malignant cells, and on the mechanisms implicated in the regulation of sterol regulatory element binding protein type 1 activity by polyunsaturated fatty acids.


Griffin, B. A. (2001). "The effect of n-3 fatty acids on low density lipoprotein subfractions." Lipids 36 Suppl: S91-7.

            A predominance of small, dense low density lipoprotein (LDL) represents a significant source of increased risk for the development of coronary heart disease in Westernized countries. Dietary long-chain n-3 polyunsaturated fatty acids exert a potent triglyceride-lowering effect that redistributes LDL subfractions toward larger and lighter particles. These dietary fatty acids thus have a key role to play in providing protection against this particularly atherogenic type of LDL.


Giovannini, M. (2001). "Overview: conditionally essential nutrients: long-chain polyunsaturated fatty acids." Adv Exp Med Biol 501: 351-5.


Gibson, R. A. and M. Makrides (2001). "Long-chain polyunsaturated fatty acids in breast milk: are they essential?" Adv Exp Med Biol 501: 375-83.

            The need for long-chain polyunsaturated fatty acids (LC-PUFA), such as docosahexaenoic acid (DHA, C22:6n3) and arachidonic acid (AA, C20:4n6), in the diet of infants in order to achieve full developmental potential is a matter of intense investigation by several research groups worldwide. It has been widely reported that breast-fed infants perform better on tests that assess neurodevelopmental outcomes than do formula-fed infants. Although human milk contains LC-PUFA that are absent from formula, it is necessary to demonstrate that any beneficial effects of human milk on infant development are purely attributed to the presence of LC-PUFA in human milk and their absence from formula to establish causality. The hypothesis that dietary DHA is associated with developmental outcome needs to be plausible; the effect must be consistent, specific, and independent of confounding factors. The hypothesis is certainly plausible. DHA is avidly incorporated and retained in brain cerebral phospholipids, and a most consistent finding has been the lower level of cerebral DHA in the brains of formula-fed infants (receiving no DHA) relative to those fed human milk (receiving DHA). The formula-fed infants in these studies were generally fed formulas with adequate alpha-linolenic acid levels, and this may indicate a nutritional requirement for preformed DHA. Several studies have compared the effects of breast- and formula-feeding on functional outcomes in preterm and term infants. While many of the outcomes have involved visual testing, others have attempted more global assessments. The results have shown differences in favor of breast-feeding but have been colored by the strong socioeconomic differences between mothers who choose to breast feed and those who choose formula-feeding. Randomized clinical trials involving preterm infants have shown a clear requirement for DHA for full visual and neural development. These results are consistent with primate studies. However, intervention studies with term infants that have attempted to improve the DHA supply of infant formula and hence infant development have not yielded consistent results. Some randomized studies have demonstrated improved visual and developmental indices in supplemented over unsupplemented infants, others have failed to demonstrate an effect. This disparity could be due to methodological and environmental differences. It is also notable that supplemental regimens have not specifically added DHA and have included other LC-PUFA, raising the question as to the specificity of the effect. However, only tissue DHA levels have consistently correlated with outcomes.


Geay, Y., D. Bauchart, et al. (2001). "Effect of nutritional factors on biochemical, structural and metabolic characteristics of muscles in ruminants, consequences on dietetic value and sensorial qualities of meat." Reprod Nutr Dev 41(1): 1-26.

            Ruminant meat is an important source of nutrients and is also of high sensory value. However, the importance and nature of these characteristics depend on ruminant nutrition. The first part of this review is focused on biochemical and dietetic value of this meat. It offers a panel of quantitative and qualitative contributions, especially through its fatty acids characteristics. Since saturated and trans-monounsaturated fatty acids are considered as harmful to human health, their amount in muscles can be reduced by increasing the proportions of dietary polyunsaturated fatty acids (PUFA) absorbed by the animals. On the contrary, some fatty acids (n-6 and n-3 PUFA, conjugated linoleic acid) specifically incorporated in muscle tissues would play a favourable role in the prevention or reduction of major diseases in human (cancers, atherosclerosis, obesity) and therefore be recommended. The second part of this review treats different aspects of the sensorial qualities of meat. Skeletal muscle structure and its biochemical components influence muscle transformation to meat and sensorial qualities including tenderness, colour, flavour and juiciness. This paper shows how nutrition can influence, in ruminants, metabolic activity as well as muscle structure and composition, and thereby affect meat quality.


Funk, C. D. and T. Cyrus (2001). "12/15-lipoxygenase, oxidative modification of LDL and atherogenesis." Trends Cardiovasc Med 11(3-4): 116-24.

            Lipoxygenases comprise a family of non-heme iron-containing dioxygenases that stereospecifically insert molecular oxygen into free or esterified polyunsaturated fatty acids. The dual specificity 12/15-lipoxygenases have been implicated in the oxidative modification of low-density lipoproteins and foam cell formation primarily based on in vitro studies. Recent in vivo data obtained with 12/15-lipoxygenase-deficient mice crossbred to apolipoprotein E-deficient mice have established a proatherogenic role for this pathway. In contrast, previous experiments with macrophage expressing 15-lipoxygenase transgenic rabbits have suggested an anti-atherogenic role. Possible explanations are presented that may elucidate these differences.


Forsyth, J. S. and S. E. Carlson (2001). "Long-chain polyunsaturated fatty acids in infant nutrition: effects on infant development." Curr Opin Clin Nutr Metab Care 4(2): 123-6.

            In the past year, two groups of investigators reported the effects of feeding n-3 and n-6 long chain polyunsaturated fatty acids on term-infant development. In general, these small randomised studies, along with two recent large randomised clinical trials, one with preterm and one with term infants, confirm and extend data on efficacy from smaller clinical studies reported in the past ten years. In addition, two independent systematic reviews published this year evaluated all but the most recent studies. Both systematic reviews concluded that there were benefits of feeding long chain polyunsaturated fatty acids to preterm infants in the short-term and acknowledged the absence of studies to address their effects on long-term visual development in infants. The continuing controversy as to the need for long chain polyunsaturated fatty acids by term infants is highlighted by the different conclusions reached in the systematic reviews. A middle view can also be supported by the data; that is, that fewer term infants than preterm infants can benefit from these fatty acids because of greater long chain polyunsaturated fatty acid accumulation in utero. Differences in intrauterine accumulation of these fatty acids may also play a role in inconsistent results among term studies.


Field, C. J., M. T. Clandinin, et al. (2001). "Polyunsaturated fatty acids and T-cell function: implications for the neonate." Lipids 36(9): 1025-32.

            Infant survival depends on the ability to respond effectively and appropriately to environmental challenges. Infants are born with a degree of immunological immaturity that renders them susceptible to infection and abnormal dietary responses (allergies). T-lymphocyte function is poorly developed at birth. The reduced ability of infants to respond to mitogens may be the result of the low number of CD45RO+ (memory/antigen-primed) T cells in the infant or the limited ability to produce cytokines [particularly interferon-y, interleukin (IL)-4, and IL-10. There have been many important changes in optimizing breast milk substitutes for infants; however, few have been directed at replacing factors in breast milk that convey immune benefits. Recent research has been directed at the neurological, retinal, and membrane benefits of adding 20:4n-6 (arachidonic acid; AA) and 22:6n-3 (docosahexaenoic acid; DHA) to infant formula. In adults and animals, feeding DHA affects T-cell function. However, the effect of these lipids on the development and function of the infant's immune system is not known. We recently reported the effect of adding DHA + AA to a standard infant formula on several functional indices of immune development. Compared with standard formula, feeding a formula containing DHA + AA increased the proportion of antigen mature (CD45RO+) CD4+ cells, improved IL-10 production, and reduced IL-2 production to levels not different from those of human milk-fed infants. This review will briefly describe T-cell development and the potential immune effect of feeding long-chain polyunsaturated fatty acids to the neonate.


Emken, E. A. (2001). "Stable isotope approaches, applications, and issues related to polyunsaturated fatty acid metabolism studies." Lipids 36(9): 965-73.

            The use of stable isotope tracers for investigating fatty acid metabolism in human subjects has increased substantially over the last decade. Advances in analytical instrumentation, commercial availability of labeled substrates, and safety considerations are major reasons for this increased use of stable isotope tracers. Several experimental design options are available for using either deuterium or carbon-13 as tracers for fatty acid and lipid studies. Options include feeding a pulse dose of labeled fat or a mixture containing two or more labeled fats. Multiple doses of the labeled fat can be fed at timed intervals to increase enrichments. Administration by injection or continuous intravenous infusion is an alternative. Another option is to use diets containing foods from plants that have slightly higher natural carbon-13 enrichment. Each basic experimental design has its specific strengths, and the best choice of experimental design depends on the study objectives. Stable isotope studies have been used to address a variety of questions related to unsaturated fatty acid metabolism in humans. Examples are provided that illustrate the use of stable isotopes to investigate oxidation of docosahexaenoic acid, desaturation of linoleic and linolenic acids in infants and adults, incorporation of long-chain n-6 and n-3 fatty acids, bioequivalency of linolenic acid in primates, 13C nuclear magnetic resonance spectra of arachidonic acid in living rat brain, and effect of triacylglycerol structure on absorption. Radioisotope and stable isotope tracer studies in animals and humans are responsible for much of our understanding of fatty acid and lipid metabolism. However, tracer studies have limitations, and there are some unresolved issues associated with isotope studies. Examples of unresolved issues are quantification of isotope data, validity of in vivo fatty acid metabolite results, kinetic modeling, subject variability, and use of blood lipid data as a reflection of tissue lipid metabolism. Resolving these issues, developing novel methodology, and applying stable isotope tracer methods to questions related to PUFA metabolism are broad areas of interesting and challenging research opportunities.


Edmond, J. (2001). "Essential polyunsaturated fatty acids and the barrier to the brain: the components of a model for transport." J Mol Neurosci 16(2-3): 181-93; discussion 215-21.

            Several areas of research have contributed to the establishment of a paradigm that meets the requirements for the selective uptake of essential polyunsaturated fatty acids (EPUFA) into brain. First, discrete studies have demonstrated that cholesterol and the nonessential fatty acids, (palmitic, oleic, stearic) do not enter the brain parenchyma. These studies demonstrated that the 18 carbon-monocarboxylic fatty acids, linoleic acid with two cis-double bonds entered brain, whereas oleic acid, with one cis-double bond, did not enter brain. It was concluded the entry of essential fatty acids into brain is accomplished in a highly selective and discrete manner. Further, the typical blood-borne lipoproteins do not traverse the endothelial cells of the capillary network and enter into the brain, otherwise cholesterol, palmitic, oleic, and stearic acids from blood would be located within brain. Second, several investigators have shown that the endothelial cells of the capillary network contain lipoprotein receptors, yet one conclusion is that the brain does not utilize low-density lipoprotein (LDL)-cholesterol. Third, recently, the existence and function of a significant number of distinctive trans-membrane monocarboxylic acid transporters, (MCTs) and fatty acid transport proteins (FATPs) have been described. No transporters have been described to date with the specificity necessary to transfer only EPUFA into brain. A blueprint with the minimal elements for delivery and selectivity is proposed. Lipoproteins enter the endothelial cells because the lipoprotein receptors are positioned on their luminal membrane. Essential fatty acid transporter(s) are positioned on the abluminal membrane of these endothelial cells to allow for the entry of EPUFA into brain. Within the endothelial cell there is opportunity for lipid management and transformation such that EPUFAs are selectively culled for delivery to the essential fatty acid transporter(s), which facilitates their transfer into brain.


Duchen, K. and B. Bjorksten (2001). "Polyunsaturated n-3 fatty acids and the development of atopic disease." Lipids 36(9): 1033-42.

            The relationship between polyunsaturated longchain fatty acids and atopy has been discussed for decades. Higher levels of the essential fatty acids linoleic acid and alpha-linolenic acid and lower levels of their longer metabolites in plasma phospholipids of atopic as compared to nonatopic individuals have been reported by several, but not all, studies. Largely similar findings have been reported in studies of cell membranes from immunological cells from atopics and non-atopics despite differences in methodology, study groups, and definitions of atopy. An imbalance in the metabolism of the n-6 fatty acids, particularly arachidonic acid and dihomo-gamma-linolenic acid, leading to an inappropriate synthesis of prostaglandin (PG) E2 and PGE1 was hypothesized early on but has not been corroborated. The fatty acid composition of human milk is dependent on the time of lactation not only during a breast meal but also the time of the day and the period of lactation. This explains the discrepancies in reported findings regarding the relationship between milk fatty acids and atopic disease in the mother. Prospective studies show disturbances in both the n-6 and n-3 fatty acid composition between milk from atopic and nonatopic mothers. Only the composition of long-chain polyunsaturated n-3 fatty acids was related to atopic development in the children, however. A relationship between lower levels of n-3 fatty acids, particularly eicosapentaenoic acid (20:5 n-3), and early development of atopic disease is hypothesized.


Donnet-Hughes, A., E. J. Schiffrin, et al. (2001). "The intestinal mucosa as a target for dietary polyunsaturated fatty acids." Lipids 36(9): 1043-52.

            Several studies have reported beneficial effects of dietary polyunsaturated fatty acids (PUFA) on various aspects of both human and animal health, and particular reference has been made to their effects on systemic immune responses. Both immune stimulation and immune suppression have been reported, with the outcome dependent on the type of PUFA, the target cell, as well as the immune competence of the cells before exposure. The systemic and the mucosal immune systems are discrete entities, which have evolved specific approaches in the defense of the host. The latter comprises several interconnected tissues, which communicate with one another through the action of soluble mediators and the trafficking of cellular components. After the oral mucosa, the intestinal epithelium and its associated gut-associated lymphoid tissue are the primary targets of dietary components. Absorption of dietary PUFA and its incorporation into intestinal tissues has been well studied, but the consequences of these events in relation to local immune responses have received little attention. This article describes some of the immune mechanisms operating at this barrier and, where possible, pinpoints areas for which a modulatory role for PUFA has already been demonstrated. Although not an exhaustive treatise of the subject, it is hoped that this review will foster research into the specific interaction between dietary PUFA and cell populations comprising the intestinal barrier.


Donadio, J. V. (2001). "The emerging role of omega-3 polyunsaturated fatty acids in the management of patients with IgA nephropathy." J Ren Nutr 11(3): 122-8.

            Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis in the world, affects mostly young adults, and shows a widely variable clinical course with many patients developing progressive renal disease, culminating in terminal renal failure in 20% to 40% of those afflicted. Until recently, no treatment options have been available for IgAN. Although a cure for the disease remains elusive, drugs that slow disease progression are becoming available, including omega-3 (n-3) fatty acids. The largest long-term clinical trial evaluating n-3 fatty acids in high-risk patients with IgAN showed that early and prolonged treatment with n-3 fatty acids retards renal progression. The rationale for using these fats involves potential mechanisms that reduce renal inflammation and glomerulosclerosis, hallmarks of progressive disease.


Donadio, J. V. (2001). "n-3 Fatty acids and their role in nephrologic practice." Curr Opin Nephrol Hypertens 10(5): 639-42.

            During the past year, a newly reported clinical trial has strengthened the argument for recommending daily treatment with n-3 polyunsaturated fatty acids in patients with immunoglobulin A nephropathy (the most common form of primary glomerulonephritis in the world) who are at high risk for progression of renal disease. Studies are underway that involve a combination of cyclosporine A, a commonly prescribed immunosuppressive agent in solid-organ transplantation, with a high-potency n-3 polyunsaturated fatty acid to reduce cyclosporine toxicity. Two studies reported during the past year show promise that dietary supplementation with n-3 polyunsaturated fatty acids will substantially decrease vascular access graft thrombosis in patients receiving maintenance hemodialysis, and may reduce hypercalciuria in patients who suffer from kidney stones.


Demmelmair, H., T. Sauerwald, et al. (2001). "Polyunsaturated fatty acid metabolism during lactation." World Rev Nutr Diet 88: 184-9.


Das, U. N. (2001). "Essential fatty acids as possible mediators of the actions of statins." Prostaglandins Leukot Essent Fatty Acids 65(1): 37-40.

            Statins and polyunsaturated fatty acids have similar actions: both enhance endothelial nitric oxide synthesis, inhibit the production of pro-inflammatory cytokines, lower cholesterol levels, prevent atherosclerosis and are of benefit in coronary heart disease, stroke and osteoporosis. Statins enhance the conversion of linoleic acid and eicosapentaenoic acid to their long chain derivatives. Animals with essential fatty acid deficiency show an increase in HMG-CoA reductase activity, which reverts to normalcy following topical application of linoleic acid. Similarly to statins, polyunsaturated fatty acids also inhibit HMG-CoA reductase activity. In view of the similarity in their actions and as statins influence essential fatty acid metabolism, it is suggested that essential fatty acids and their metabolites may serve as second messengers of the actions of statins.


Das, U. N. (2001). "Is obesity an inflammatory condition?" Nutrition 17(11-12): 953-66.

            Obesity may be a low-grade systemic inflammatory disease. Overweight and obese children and adults have elevated serum levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers of inflammation and closely associated with cardiovascular risk factors and cardiovascular and non-cardiovascular causes of death. This may explain the increased risk of diabetes, heart disease, and many other chronic diseases in the obese. The complex interaction between several neurotransmitters such as dopamine, serotonin, neuropeptide Y, leptin, acetylcholine, melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin and insulin receptors in the brain ultimately determines and regulates food intake. Breast-feeding of more than 12 mo is associated with decreased incidence of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs inhibit the production of proinflammatory cytokines and enhance the number of insulin receptors in various tissues and the actions of insulin and several neurotransmitters. LCPUFAs may enhance the production of bone morphogenetic proteins, which participate in neurogenesis, so these fatty acids might play an important role in brain development and function. It is proposed that obesity is a result of inadequate breast feeding, which results in marginal deficiency of LCPUFAs during the critical stages of brain development. This results in an imbalance in the structure, function, and feedback loops among various neurotransmitters and their receptors, which ultimately leads to a decrease in the number of dopamine and insulin receptors in the brain. Hence, promoting prolonged breast feeding may decrease the prevalence of obesity. Exercise enhances parasympathetic tone, promotes antiinflammation, and augments brain acetylcholine and dopamine levels, events that suppress appetite. Acetylcholine and insulin inhibit the production of proinflammatory cytokines and provide a negative feedback loop for postprandial inhibition of food intake, in part, by regulating leptin action. Statins, peroxisome proliferator-activated receptor-gamma binding agents, non-steroidal antiinflammatory drugs, and infant formulas supplemented with LCPUFAs, and LCPUFAs themselves, which suppress inflammation, may be beneficial in obesity.


Darlington, L. G. and T. W. Stone (2001). "Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders." Br J Nutr 85(3): 251-69.

            The generation of reactive oxygen species (free radicals) is an important factor in the development and maintenance of rheumatoid arthritis in humans and animal models. One source of free radicals is nitric oxide produced within the synoviocytes and chondrocytes and giving rise to the highly toxic radical peroxynitrite. Several cytokines, including tumour necrosis factor-alpha (TNFalpha) are involved in the formation of free radicals, partly by increasing the activity of nitric oxide synthase. Indeed, nitric oxide may mediate some of the deleterious effects of cytokines on bone resorption. Aspirin, tetracyclines, steroids and methotrexate can suppress nitric oxide synthase. Dietary antioxidants include ascorbate and the tocopherols and beneficial effects of high doses have been reported especially in osteoarthritis. There is also evidence for beneficial effects of beta-carotene and selenium, the latter being a component of the antioxidant enzyme glutathione peroxidase. The polyunsaturated fatty acids (PUFA) include the n-3 compounds, some of which are precursors of eicosanoid synthesis, and the n-6 group which can increase formation of the pro-inflammatory cytokines TNFalpha and interleukin-6, and of reactive oxygen species. Some prostaglandins, however, suppress cytokine formation, so that n-3 PUFA often oppose the inflammatory effects of some n-6-PUFA. gamma-linolenic acid (GLA) is a precursor of prostaglandin E1, a fact which may account for its reported ability to ameliorate arthritic symptoms. Fish oil supplements, rich in n-3 PUFA such as eicosapentaenoic acid have been claimed as beneficial in rheumatoid arthritis, possibly by suppression of the immune system and its cytokine repertoire. Some other oils of marine origin (e.g. from the green-lipped mussel) and a range of vegetable oils (e.g. olive oil and evening primrose oil) have indirect anti-inflammatory actions, probably mediated via prostaglandin E1. Overall, there is a growing scientific rationale for the use of dietary supplements as adjuncts in the treatment of inflammatory disorders such as rheumatoid arthritis and osteoarthritis.


Cunnane, S. C., C. R. Nadeau, et al. (2001). "NMR and isotope ratio mass spectrometry studies of in vivo uptake and metabolism of polyunsaturates by the developing rat brain." J Mol Neurosci 16(2-3): 173-80; discussion 215-21.

            This article describes the application of in vivo 13C-nuclear magnetic resonance (NMR) spectroscopy and gas chromatography (GC)-combustion-isotope ratio mass spectrometry to the study of brain uptake and metabolism of polyunsaturated fatty acids in the suckling rat model. NMR spectroscopy is uniquely suited to the non-invasive detection of nonradioactive metabolites in living animals. We applied this approach to the noninvasive detection of 13C-arachidonate in brain and liver of living suckling rats but found that technical limitations in our model, mainly poor signal-to-noise, largely prevent useful results at this time. However, in a tracer study using simultaneous doses of 13C-gamma-linolenate and 13C-arachidonate, 13C-NMR of tissue lipid extracts quantitatively demonstrated a 10-fold greater (liver) or 17-fold greater (brain) accumulation of pre-formed vs newly synthesized arachidonate. GC-combustion-isotope ratio mass spectrometry was used to trace the utilization of [U-13C]-alpha-linolenate into three products in the brain: docosahexaenoate, cholesterol, and palmitate. The rationale was that although alpha-linolenate is used in de novo lipogenesis, the quantitative importance of this pathway is unknown. Our results in the suckling rat show that 2-13% of carbon from [U-13C]-alpha-linolenate appearing in brain lipids is in docosahexaenoate while the rest is in brain lipids synthesized de novo. Overall, these results indicate that the suckling rat brain prefers pre-formed to newly synthesized arachidonate and that alpha-linolenate is readily utilized in brain lipid synthesis. These methods are suited to comparative studies of the metabolism of polyunsaturates and they support previous observations that the metabolism of some polyunsaturates such as alpha-linolenate extends well beyond the traditional desaturation-chain elongation pathway.


Cunnane, S. C. (2001). "Application of new methods and analytical approaches to research on polyunsaturated fatty acid homeostasis." Lipids 36(9): 975-9.

            New methods and analytical approaches are important to challenge and/or validate established beliefs in any field including the metabolism of polyunsaturated fatty acids (PUFA; polyunsaturates). Four methods that have recently been applied toward obtaining a better understanding of the homeostasis of PUFA include the following: whole-body fatty acid balance analysis, magnetic resonance imaging (MRI), 13C nuclear magnetic resonance (NMR) spectroscopy, and gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Whole-body balance studies permit the measurement of both the percentage of oxidation of linoleate and alpha-linolenate and their conversion to long-chain PUFA. This method has shown that beta-oxidation to CO2 is normally the predominant metabolic fate of linoleate and alpha-linolenate. Furthermore, models of experimental undernutrition in both humans and animals show that beta-oxidation of linoleate and alpha-linolenate markedly exceeds their intake, despite theoretically sufficient intake of linoleate or alpha-linolenate. Preliminary results suggest that by using MRI to measure body fat content, indirect whole-body linoleate balance can be done in living humans. 13C NMR spectroscopy provided unexpected evidence that linoleate and alpha-linolenate were metabolized into lipids synthesized de novo, an observation later quantified by tracer mass balance done using GC-C-IRMS. This latter method showed that within 48 h of dosing with 13C-alpha-linolenate, >80% underwent beta-oxidation to CO2 by suckling rats, whereas 8-9% was converted to newly synthesized lipids and <1 % to docosahexaenoate. Further application of these recently developed methods in different models should clarify the emerging importance of beta-oxidation and carbon recycling in PUFA homeostasis in mammals including humans.


Craig-Schmidt, M. C. (2001). "Isomeric fatty acids: evaluating status and implications for maternal and child health." Lipids 36(9): 997-1006.

            "Isomeric fatty acids" is a term that refers to the trans- and positional isomers formed during hydrogenation of naturally occurring oils. The purposes of this paper are as follows: (i) to summarize potential exposure of infants to isomeric fatty acids by reviewing estimates of isomeric fatty acids in the maternal diet, in human milk, and in infant formula/infant foods, and (ii) to evaluate the evidence for adverse effects of isomeric fatty acids on infant development with respect to growth and essential fatty acid status. Estimates of the intake of trans-fatty acids vary widely both within and across populations. Current estimates of trans-fatty acids in the North American population are 4-11% of total fatty acids or 3-13 g/(person x d), whereas in Mediterranean countries in which olive oil is the primary fat and in Far Eastern countries in which little commercially hydrogenated fat is consumed, per capita consumption of trans-fatty acids is <1-2 g/d. The trans-fatty acid content of human milk reflects the cross-cultural variation in the maternal diet, with trans-fatty acids in human milk samples ranging from 6 to 7% in North America to <0.5% in Hong Kong. Trans-fatty acids are transferred from the maternal diet through the placenta to the developing fetus or through milk to the breast-fed infant. In some studies, plasma trans-fatty acids are inversely related to birth weight and head circumference. The hypothesis that dietary trans-fatty acids could inhibit biosynthesis of long-chain polyunsaturated fatty acids with 20 and 22 carbon atoms and thus affect infant development is supported by studies demonstrating an inverse correlation of plasma trans-fatty acids with n-3 and n-6 longchain polyunsaturated fatty acids in infants. However, no such relationship has been observed in human milk. A definitive answer concerning a potentially adverse effect of dietary trans-fatty acids on infant development awaits future studies.


Cracowski, J. L., P. Devillier, et al. (2001). "Vascular biology of the isoprostanes." J Vasc Res 38(2): 93-103.

            Isoprostanes are a family of compounds produced from polyunsaturated fatty acids via a free-radical-catalysed mechanism. F(2)-isoprostanes are prostaglandin F(2alpha) isomers derived from arachidonic acid. These compounds induce potent vasoconstriction, mediated primarily by TP receptor stimulation, and in some vessels by the release of cyclooxygenase products. This vasoconstriction may be modulated by the endothelium through the release of NO. Potent vasoconstriction is also observed with E(2)-isoprostanes. Experimental and clinical data suggest a role for F(2)-isoprostanes in atherogenesis. These compounds can be detected in free forms in biological fluids as well as esterified in low-density lipoproteins or cell membranes. Their quantification represents a reliable marker of lipid peroxidation. Elevated levels of F(2)-isoprostanes in biological fluids in pathological conditions including atherosclerosis, ischaemia-reperfusion injury, and inflammatory vascular diseases, suggest a relationship between lipid peroxidation and such diseases. F(2)-isoprostanes are currently being investigated as non-invasive quantitative markers to monitor the response to anti-oxidant treatment.


Cowing, B. E. and K. E. Saker (2001). "Polyunsaturated fatty acids and epidermal growth factor receptor/mitogen-activated protein kinase signaling in mammary cancer." J Nutr 131(4): 1125-8.

            Mammary cancer is the second leading cause of cancer death in women, the second most common neoplasm in dogs and the third leading neoplasm in cats. Mammary tumors are similar in morphology and progression in these species, so cats and dogs are good models for determining treatment or prevention modalities for the human population. Epidemiological, in vitro and rodent studies have demonstrated that polyunsaturated fatty acids (PUFA) can influence the growth, progression and metastasis of mammary cancer. Although a role of PUFA in modulating mammary cancer growth has been shown, the mechanisms by which this occurs remain unclear. Recent studies have demonstrated that PUFA may influence the activity of the epidermal growth factor receptor/mitogen-activated protein kinase pathway, which is involved in regulating several oncogenes (c-myc, c-fos, neu/c-erb-b2) involved in the progression of cancer. We review the potential mechanism by which PUFA may modulate the growth of mammary cancer through regulation of the epidermal growth factor receptor/mitogen-activated protein kinase signal transduction cascade.


Colombo, J. (2001). "Recent advances in infant cognition: implications for long-chain polyunsaturated fatty acid supplementation studies." Lipids 36(9): 919-26.

            The assessment of cognitive function in early life has recently become an issue for consideration in long-chain polyunsaturated fatty acid (LC-PUFA) supplementation studies. This article reviews the various means by which such assessment has been done in past LC-PUFA supplementation studies and provides some background on recent advances in the measurement of infant cognition that may need to be considered when planning or designing future supplementation studies. These include (i) consideration of the specificity of LC-PUFA effects on cognition, (ii) inclusion of multiple tasks or levels of measurement as outcome measures, and (iii) a stronger emphasis on developmental processes in the design of such studies.


Clarke, S. D. (2001). "Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome." J Nutr 131(4): 1129-32.

            This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the (n-3) family, play pivotal roles as "fuel partitioners" in that they direct fatty acids away from triglyceride storage and toward oxidation, and that they enhance glucose flux to glycogen. In doing this, PUFA may protect against the adverse symptoms of the metabolic syndrome and reduce the risk of heart disease. PUFA exert their beneficial effects by up-regulating the expression of genes encoding proteins involved in fatty acid oxidation while simultaneously down-regulating genes encoding proteins of lipid synthesis. PUFA govern oxidative gene expression by activating the transcription factor peroxisome proliferator-activated receptor alpha. PUFA suppress lipogenic gene expression by reducing the nuclear abundance and DNA-binding affinity of transcription factors responsible for imparting insulin and carbohydrate control to lipogenic and glycolytic genes. In particular, PUFA suppress the nuclear abundance and expression of sterol regulatory element binding protein-1 and reduce the DNA-binding activities of nuclear factor Y, Sp1 and possibly hepatic nuclear factor-4. Collectively, the studies discussed suggest that the fuel "repartitioning" and gene expression actions of PUFA should be considered among criteria used in defining the dietary needs of (n-6) and (n-3) and in establishing the dietary ratio of (n-6) to (n-3) needed for optimum health benefit.


Clarke, S. D. (2001). "Nonalcoholic steatosis and steatohepatitis. I. Molecular mechanism for polyunsaturated fatty acid regulation of gene transcription." Am J Physiol Gastrointest Liver Physiol 281(4): G865-9.

            This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the n-3 family, play pivotal roles as "fuel partitioners" in that they direct fatty acids away from triglyceride storage and toward oxidation and they enhance glucose flux to glycogen. In doing this, PUFA may reduce the risk of enhanced cellular apoptosis associated with excessive cellular lipid accumulation. PUFA exert their beneficial effects by upregulating the expression of genes encoding proteins involved in fatty acid oxidation while simultaneously downregulating genes encoding proteins of lipid synthesis. PUFA govern oxidative gene expression by activating the transcription factor peroxisome proliferator-activated receptor-alpha. PUFA suppress lipogenic gene expression by reducing the nuclear abundance and DNA binding affinity of transcription factors responsible for imparting insulin and carbohydrate control to lipogenic and glycolytic genes. In particular, PUFA suppress the nuclear abundance and expression of sterol regulatory element binding protein-1 and reduce the DNA binding activities of nuclear factor Y, stimulatory protein 1, and possibly hepatic nuclear factor-4. Collectively, the studies discussed suggest that the fuel "repartitioning" and gene expression actions of PUFA should be considered among the criteria used in defining the dietary needs of n-6 and n-3 fatty acids and in establishing the dietary ratio of n-6 to n-3 fatty acids needed for optimum health benefit.


Chalon, S., S. Vancassel, et al. (2001). "Polyunsaturated fatty acids and cerebral function: focus on monoaminergic neurotransmission." Lipids 36(9): 937-44.

            More and more reports in recent years have shown that the intake of polyunsaturated fatty acids (PUFA) constitutes an environmental factor able to act on the central nervous system (CNS) function. We recently demonstrated that the effects of PUFA on behavior can be mediated through effects on the monoaminergic neurotransmission processes. Supporting this proposal, we showed that chronic dietary deficiency in alpha-linolenic acid in rats induces abnormalities in several parameters of the mesocortical and mesolimbic dopaminergic systems. In both systems, the pool of dopamine stored in presynaptic vesicles is strongly decreased. This may be due to a decrease in the number of vesicles. In addition, several other factors of dopaminergic neurotransmission are modified according to the system affected. The mesocortical system seems to be hypofunctional overall [e.g., decreased basal release of dopamine (DA) and reduced levels of dopamine D2 (DAD2) receptors]. In contrast, the mesolimbic system seems to be hyperfunctional overall (e.g., increased basal release of DA and increased levels of DAD2 receptors). These neurochemical changes are in agreement with modifications of behavior already described with this deficiency. The precise mechanisms explaining the effects of PUFA on neurotransmission remain to be clarified. For example, modifications of physical properties of the neuronal membrane, effects on proteins (receptors, transporters) enclosed in the membrane, and effects on gene expression and/or transcription might occur. Whatever the mechanism, it is therefore assumed that interactions exist among PUFA, neurotransmission, and behavior. This might be related to clinical findings. Indeed, deficits in the peripheral amounts of PUFA have been described in subjects suffering from neurological and psychiatric disorders. Involvement of the monoaminergic neurotransmission function has been demonstrated or hypothesized in several of these diseases. It can therefore be proposed that functional links exist among PUFA status, neurotransmission processes, and behavioral disorders in humans. Animal models are tools of choice for the understanding of such links. Improved prevention and complementary treatment of neurological and psychiatric diseases can be expected from these studies.


Caplan, M. S. and T. Jilling (2001). "The role of polyunsaturated fatty acid supplementation in intestinal inflammation and neonatal necrotizing enterocolitis." Lipids 36(9): 1053-7.

            Dietary polyunsaturated fatty acid (PUFA) supplementation has been shown to reduce the incidence of necrotizing enterocolitis (NEC) in a recent randomized, controlled trial. These compounds are known to modulate the inflammatory cascade and to influence intestinal health in a variety of ways. Although the pathophysiology of NEC is not well understood, recent evidence suggests that platelet-activating factor (PAF) is a key endogenous mediator of intestinal necrosis in animals. Using a neonatal rat model of NEC that includes the key risk factors of asphyxia and formula feeding, we investigated the role of dietary PUFA supplementation on the incidence and pathophysiology of NEC. Our findings suggest that PUFA reduce the incidence of NEC by modulating PAF metabolism and endotoxin translocation.


Calder, P. C. and R. B. Zurier (2001). "Polyunsaturated fatty acids and rheumatoid arthritis." Curr Opin Clin Nutr Metab Care 4(2): 115-21.

            Rheumatoid arthritis is characterized by infiltration of T lymphocytes, macrophages and plasma cells into the synovium, and the initiation of a chronic inflammatory state that involves overproduction of proinflammatory cytokines and a dysregulated T-helper-1-type response. Eicosanoids synthesized from arachidonic acid and cytokines cause progressive destruction of cartilage and bone. The n-6 polyunsaturated fatty acid gamma-linolenic acid is the precursor of di-homo-gamma-linolenic acid. The latter and the n-3 polyunsaturated fatty acid eicosapentaenoic acid, which is found in fish oil, are able to decrease the production of arachidonic acid-derived eicosanoids and to decrease the production of proinflammatory cytokines and reactive oxygen species, and the reactivity of lymphocytes. A number of double-blind, placebo-controlled trials of gamma-linolenic acid and fish oil in rheumatoid arthritis have shown significant improvements in a variety of clinical outcomes. These fatty acids should be included as part of the normal therapeutic approach to rheumatoid arthritis. However, it is unclear what the optimal dosage of the fatty acids is, or whether there would be extra benefit from using them in combination.


Calder, P. C. (2001). "Polyunsaturated fatty acids, inflammation, and immunity." Lipids 36(9): 1007-24.

            The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. In particular, the proportion of different types of polyunsaturated fatty acids (PUFA) in these cells is readily changed, and this provides a link between dietary PUFA intake, inflammation, and immunity. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds, which have important roles in inflammation and in the regulation of immunity. Fish oil contains the n-3 PUFA eicosapentaenoic acid (EPA). Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators. In addition, EPA is a substrate for cyclooxygenase and lipoxygenase and gives rise to mediators that often have different biological actions or potencies than those formed from AA. Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages. Supplementation of the diet of healthy human volunteers with fish oil-derived n-3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of proinflammatory cytokines. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease. Clinical studies have reported that fish oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory and immunomodulatory.


Calder, P. C. (2001). "omega 3 polyunsaturated fatty acids, inflammation and immunity." World Rev Nutr Diet 88: 109-16.


Buonocore, G., S. Perrone, et al. (2001). "Free radicals and brain damage in the newborn." Biol Neonate 79(3-4): 180-6.

            Newborns and particularly preterm infants are at high risk of oxidative stress and they are very susceptible to free radical oxidative damage. Indeed, there is evidence of an imbalance between antioxidant- and oxidant-generating systems which causes oxidative damage. The brain may be especially at risk of free radical-mediated injury because neuronal membranes are rich in polyunsaturated fatty acids and because the human newborn has a relative deficiency of brain superoxide dismutase and glutathione peroxidase. The brain of the term fetus is at higher risk of oxidative stress than that of the preterm fetus, as a consequence of its higher concentration of polyunsaturated fatty acids and the maturity of the N-methyl-D-aspartate receptor system at term. There seems to be a maturation-dependent window of vulnerability to free radical attack during oligodendrocyte development. Early in its differentiation, the oligodendrocyte may be vulnerable because of active acquisition of iron for differentiation at a time of relative delay in the development of certain key antioxidant defenses in the brain. Excess free iron and deficient iron-binding and -metabolizing capacity are additional features favoring oxidant stress in premature infants. Free radicals may be generated by different mechanisms, such as ischemia-reperfusion, neutrophil and macrophage activation, Fenton chemistry, endothelial cell xanthine oxidase, free fatty acid and prostaglandin metabolism and hypoxia. Reactive oxidant production by these different mechanisms contributes in a piecewise manner to the pathogenesis of perinatal brain injury.


Brunner, J., K. G. Parhofer, et al. (2001). "[Cholesterol, omega-3 fatty acids, and suicide risk: empirical evidence and pathophysiological hypotheses]." Fortschr Neurol Psychiatr 69(10): 460-7.

            Studies in psychiatric patients described an association between lower serum cholesterol concentrations, suicidality, depression, impulsivity, and aggression which is not entirely attributable to depression-related malnutrition and weight-loss. Several lines of evidence suggest that a serotonergic deficit in the prefrontal cortex may predispose vulnerable subjects to impulsive, autoaggressive, and suicidal behaviour in stressful life-events. In-vitro studies, animal experiments, and human in-vivo studies support the hypothesis that cholesterol reduction may contribute to the serotonergic abnormalities which have been postulated in suicidal subjects. Recently it was hypothesized that decreased consumption of polyunsaturated fatty acids, especially omega-3 fatty acids, may be a risk factor for depression and suicide. Data from human studies in healthy volunteers suggest that increasing the dietary intake of omega-3 fatty acids may increase central serotonergic activity and reduce impulsive and aggressive behaviours. Earlier epidemiological studies showed an association between low cholesterol concentrations and increased suicide risk. Recent epidemiological studies with greater samples and longer follow-up periods, however, even showed a positive correlation between cholesterol concentrations and suicide risk after controlling for potential confounding variables. Large trials of statins (simvastatin, lovastatin, pravastatin) did not show an increase of suicide mortality.


Boelsma, E., H. F. Hendriks, et al. (2001). "Nutritional skin care: health effects of micronutrients and fatty acids." Am J Clin Nutr 73(5): 853-64.

            Human skin is continuously exposed to internal and external influences that may alter its condition and functioning. As a consequence, the skin may undergo alterations leading to photoaging, inflammation, immune dysfunction, imbalanced epidermal homeostasis, or other skin disorders. Modern nutritional science is developing new insights into the relation between food intake and health, and effects of food ingredients may prove to be biologically relevant for optimal skin condition. The objective of this review was to evaluate the present knowledge about the interrelation of nutrients and skin, particularly the photoprotective effects of nutrients, the influences of nutrients on cutaneous immune responses, and therapeutic actions of nutrients in skin disorders. The nutrients of focus were vitamins, carotenoids, and polyunsaturated fatty acids. Supplementation with these nutrients was shown to provide protection against ultraviolet light, although the sun-protection factor was relatively small compared with that of topical sunscreens. An increase in delayed-type hypersensitivity skin responses after supplementation with nutrients has proven beneficial, especially in elderly people, and may boost cell-mediated immunity. Dietary consumption of certain plants or fish oil is known to modulate the balance of lipid inflammatory mediators and, therefore, is valuable in the treatment of inflammatory skin disorders. It was concluded that nutritional factors exert promising actions on the skin, but information on the effects of low-to-moderate doses of nutrients consumed long term by healthy individuals is obviously lacking, as are data on direct effects on basal skin properties, including hydration, sebum production, and elasticity.


Blair, I. A. (2001). "Lipid hydroperoxide-mediated DNA damage." Exp Gerontol 36(9): 1473-81.

            Lipid hydroperoxides are formed in vivo through free radical pathways from the action of reactive oxygen species on polyunsaturated fatty acids. They are also formed as specific products of lipoxygenases and cyclooxygenases. Homolytic decomposition of lipid hydroperoxides to the alpha,beta-unsaturated aldehyde genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal occurs through two quite distinct pathways. One pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide and the other pathway involves the intermediate formation of another potential genotoxin, 4-hydroperoxy-2-nonenal. 4,5-Epoxy-2(E)-decenal forms the unsubstituted etheno-2-deoxyadenosine adduct with DNA, a mutagenic lesion which has been observed in human tissue DNA samples. Several new ethano- and etheno-DNA-adducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. 4-Hydroxy-2-nonenal forms propano adducts with 2'-deoxyguanosine. It can also up-regulate cyclooxygenase-2 expression. As cyclooxygenase-2 converts linoleic acid into lipid hydroperoxides, this provides a potential mechanism for increased production of genotoxic bifunctional electrophiles. Malondialdehyde (beta-hydroxy-acrolein), another genotoxic bifunctional electrophile, is formed during homolytic decomposition of lipid hydroperoxides that contain more than two double bonds. Other sources of malondialdehyde include, hydroxyl radical-mediated decomposition of the 2'-deoxyribose DNA backbone and formation as a side-product during the biosynthesis of thromboxane A(2). Malondialdehyde reacts with DNA to form primarily a propano adduct with 2'-deoxyguanosine (M(1)G-dR). Significant advances in the characterization and analysis of lipid hydroperoxide-derived endogenous DNA-adducts have been made over the last decade so that dosimetry studies of human populations are now possible. Such studies will help elucidate the role of lipid hydroperoxide-derived endogenous DNA as mediators of cancer


Berry, E. M. (2001). "Who's afraid of n-6 polyunsaturated fatty acids? Methodological considerations for assessing whether they are harmful." Nutr Metab Cardiovasc Dis 11(3): 181-8.

            N-6 fatty acids are essential for normal growth, development and health, and so extreme care is necessary before deciding that they are harmful. Theoretical and epidemiological evidence suggests the involvement of n-6 polyunsaturated fatty acids (PUFAs) in disease progression or prevention; however, n-6 function cannot be considered in isolation but needs to be seen as part of the complex of nutrient interactions with n-3 fatty acids (which compete for the same enzymatic pathways) and antioxidants. Insulin sensitivity might be the common factor relating disease to fatty acid metabolism both within and between the fatty acid pathways. High linoleate to arachidonate concentrations have been observed in insulin resistance, diabetic complications and some tumours, but these are multifactorial processes that include many lifestyle determinants and it is therefore wrong to condemn only n-6 fatty acids in their etiology. The results based on the criteria for assessing diet and disease are still insufficient to declare n-6 fatty acids a serious health risk; at most, the verdict should be "not proven". The question may never be conclusively answered not only because prospective dietary intervention trials (unlike those with n-3 fish oil capsules) are fraught with dosage and compliance problems, but also because of high background linoleate consumption. Tissue fatty acid composition may be a suitable biomarker for PUFA intake but there are many theoretical and methodological problems concerning other suitable markers because of the multiplicity of their biological effects. Before making evidence-based dietary recommendations, future research should consider: 1) how n-3 and n-6 dietary PUFAs affect the physiological balance (dose-response) of their derivatives such as eicosanoids and the newly-discovered fatty acid amides; 2) the metabolic interactions between n-6 and n-3 fatty acid pathways (including gene-nutrient effects); 3) the need for antioxidant cover (quantity and quality); 4) prospective intervention trials.


Berry, J. K. and C. L. Baum (2001). "Malnutrition in chronic obstructive pulmonary disease: adding insult to injury." AACN Clin Issues 12(2): 210-9.

            Weight loss in patients with chronic obstructive pulmonary disease has a negative effect on the clinical course of the patient. Causes of weight loss in this population are known to include the effects of an energy imbalance, increased cytokines, hypoxia, and glucocorticoid use. This article delineates mechanisms included in these processes and highlights specific deleterious aspects of each. In addition, the effects of the following therapies are discussed in light of recent research findings: nutrition support, anabolic steroids, recombinant human growth hormone, and polyunsaturated fatty acids. This review summarizes the current state of knowledge in this area.


Bar-Tana, J. (2001). "Peroxisome proliferator-activated receptor gamma (PPARgamma) activation and its consequences in humans." Toxicol Lett 120(1-3): 9-19.

            Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the superfamily of nuclear receptors. It binds and is activated by natural polyunsaturated fatty acids, eicosanoids, synthetic thiazolidinediones and related analogues. Biological effects exerted by PPARgamma ligands are mostly concerned with differentiation processes, sensitization to insulin and atherogenesis, and are paradigmatically ascribed to PPARgamma transactivation of PPARgamma-responsive genes. The PPARgamma paradigm and its consequences in humans are analyzed here in terms of the tissue specificity of PPARgamma, loss and gain of function mutants of PPARgamma, PPARgamma-responsive genes and clinical effects of PPARgamma ligands. Differentiation, as well as some of the atherogenic effects induced by PPARgamma ligands, does conform to the PPARgamma paradigm. However, sensitization to insulin as well as some of the antiatherogenic effects of PPARgamma ligands is not accounted for by PPARgamma activation, thus calling for an alternative target for insulin sensitizers.


Arnesen, H. (2001). "n-3 fatty acids and revascularization procedures." Lipids 36 Suppl: S103-6.

            Largely initiated by studies among Greenland Eskimos in the early 1970s, great attention has been given to the possible effects of the very long chain n-3 polyunsaturated fatty acids (PUFA) in a variety of cardiovascular disease states. A series of possibly positive effects on pathogenetic mechanisms in cardiovascular disease has evolved from laboratory studies in cell cultures and animals as well as in humans, focusing mainly on eicosanoid metabolism with reduced activities of platelets and leucocytes, reduced plasma triglycerides and, antiarrhythmic effects in the myocardium. A rationale for a positive effect of very long chain n-3 PUFA in the secondary prophylaxis after revascularization procedures obviously also exists. The positive clinical effects based on prospectively randomized trials are summarized as follows. After coronary artery bypass grafting (CABG), the SHOT study showed statistically significant reduction in angiographic vein graft occlusion in 610 patients after 1 yr with supplementation of 3.4 g/d of highly concentrated very long chain n-3 PUFA. The reduction in occlusion rates was significantly related to the change in the n-3 PUFA concentration in serum phospholipids during the study period with the occlusion rate in the upper quartile of such changes at only approximately 50% of that in the lower quartile. These results were also clearly related to the presence of angina pectoris and occurrence of myocardial infarction after 1 yr. Several studies were conducted in patients after percutaneous transluminal coronary angioplasty (PTCA). By 1993, two meta-analyses indicated a positive effect on the restenosis rate, a significant problem after otherwise successful PTCA. During the late 1990s, three large prospective randomized placebo-controlled angiographic studies were conducted with very long n-3 PUFA 5.1-8.0 g/d, all with completely negative results. Today, therefore, very long chain n-3 PUFA supplementation cannot be recommended to reduce the incidence of restenosis after PTCA. All studies were performed without stenting of the coronary lesion. In the very special revascularization procedure of heart transplantation, evolving hypertension and accelerated atherosclerosis have been major clinical problems. In other studies, positive effects by supplementation with very long chain n-3 PUFA (3.4-5.7 g/d) were obtained on the surrogate end points coronary vasoreactivity to acetylcholine and hypertension, respectively. On the basis of the presently available literature from clinical studies, recommendations for supplementation with very long chain n-3 PUFA can be given to patients after venous CABG (up to 3.4 g/d), and after heart transplantation (3.4-5.7 g/d) but not to patients after traditional PTCA. In fact, data from substudies suggested the possibility that large doses (5.1 g/d) of very long chain n-3 PUFA might be contraindicated because they induce a proinflammatory state in patients under oxidative stress.


Alarcon de la Lastra, C., M. D. Barranco, et al. (2001). "Mediterranean diet and health: biological importance of olive oil." Curr Pharm Des 7(10): 933-50.

            Olive oil, the main fatty component of the Mediterranean diet, is characterized by consisting of monounsaturated fatty acids as well as by its elevated content in antioxidant agents. This oil exhibits numerous biological functions which are beneficial for the state of health. A diet rich in monounsaturated fatty acids provides an adequate fluidity to the biological membranes, diminishing the hazard of lipid peroxidation which affects polyunsaturated fatty acids. Moreover, the antioxidants present in olive oil are able to scavenge free radicals and afford an adequate protection against peroxidation. Regarding the heart, olive oil decreases the plasmatic levels of LDL-cholesterol and increases those of HDL-cholesterol, hence diminishing the risk of suffering from heart complaints. In this context, it has been suggested that increased consumption of monounsaturated fatty acids in place of polyunsaturated fatty acids will render circulating lipoproteins less sensitive to peroxidation and thereby diminish the development of atherosclerosis. Olive oil has also been proven to contribute to a better control of the hypertriglyceridemia accompanying diabetes and may reduce the risk of breast cancer and colorectum. On the other hand, several investigations have suggested that olive oil can be beneficial in inflammatory and autoimmune diseases, such as rheumatoid arthritis. In this sense, some reports have indicated that olive oil modifies inflammatory cytokines production. As for the digestive system, olive oil enhances gallbladder emptying consequently reducing cholelithiasis risk, decreases the pancreatic exocrine secretion and gastric secretory function in response to food. Finally, it has been demonstrated that a diet rich in olive oil is associated with a high percentage of gastric ulcer healing and affords a higher resistance against non steroidal antiinflammatory drugs-induced gastric ulcerogenesis.


Aguilera, C. M., M. C. Ramirez-Tortosa, et al. (2001). "[Protective effect of monounsaturated and polyunsaturated fatty acids on the development of cardiovascular disease]." Nutr Hosp 16(3): 78-91.

            Cardiovascular disease has a multifactorial aetiology, as is illustrated by the existence of numerous risk indicators, many of which can be influenced by dietary means. In this article, the effects of unsaturated fatty acids on cardiovascular disease are reviewed, with special emphasis on the modifications of the lipoprotein profile and the mechanism by which fatty acids may affect the immune response on the development of the atherosclerotic lesion. Atherosclerosis occurs fundamentally in three stages: dysfunction of the vascular endothelium, fatty streak and fibrous cap formation. Each of the three stages is regulated by the action of vasoactive molecules, growth factors and cytokines, mediators of the immune response. Dietary lipid quality can affect the lipoprotein metabolism, altering their concentrations in the blood, permitting a greater or lesser recruitment of them in the artery wall. The replacement of dietary saturated fat by mono- or polyunsaturated fats significantly lowers the plasma-cholesterol and LDL-cholesterol levels. Likewise, an enriched monounsaturated fatty acid diet prevents LDL oxidative modifications more than an enriched polyunsaturated diet, and the oxidation of LDL in patients with peripheral vascular disease mediated by n-3 fatty acids can be reduced by the simultaneous consumption of olive oil. However, strong controversy surrounds the effect of the different unsaturated fatty acids. The type of dietary fat can directly or indirectly influence some of the mediating factors of the immune response; n-3 fatty acids have powerful antiinflammatory properties. Dietary fatty acids strongly determine the susceptibility of lipoproteins to oxidation, which also has an impact on the activation of molecules of adhesion and other inflammatory factors. Moreover, several works have demonstrated a direct effect of fatty acids on the genetic expression of many of those factors. Finally, certain aspects of blood platelet function, blood coagulability, and fibrinolytic activity associated with cardiovascular risk, are modulated by dietary fatty acids; n-3 fatty acids strongly inhibits platelet aggregation and activate thrombolytic processes.


Agostoni, C. and M. Giovannini (2001). "Cognitive and visual development: influence of differences in breast and formula fed infants." Nutr Health 15(3-4): 183-8.

            Several recent studies document a beneficial effect of breast-feeding on later neurodevelopmental outcomes. The mechanisms involved are still in need of elucidation, but evidence is accruing that the fatty acid (FA) composition of human milk plays a role. The composition of body fats, from circulating erythrocyte lipids to brain phospholipids, is linked in infants to the early feeding mode and which FA predominates among circulating lipids influences visual and neurodevelopmental performance test scores. In these studies, greater differences were found between breast-fed and standard formula-fed infants, the latter showing low tissue long-chain polyunsaturated fatty acids (LCPUFA: arachidonic acid, AA, 20:4n-6; eicosapentaenoic acid, EPA, 20:5n-3; docosahexaenoic acid, DHA, 22:6n-3) accretion and lower visual and neurodevelopmental test scores. Human milk contains LCPUFA, while most available formulas, especially those intended for full-term infants, do not. With the progressive introduction of solid foods, the question arises whether a specific or "ideal" dietary lipid mixture can be found to meet growth requirements and ensure a lipid balance adequate for the early and effective preventive purposes. These complementary aspects are challenges for the paediatric nutrition researcher today.


Abeywardena, M. Y. and R. J. Head (2001). "Longchain n-3 polyunsaturated fatty acids and blood vessel function." Cardiovasc Res 52(3): 361-71.

            The cardiovascular health benefits of longchain n-3 polyunsaturated fatty acids (PUFAs) have been reported to exert at several different cellular control mechanisms. These include, effects on lipoprotein metabolism, haemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms. The majority of such cardiovascular benefits of n-3 PUFAs are likely to be mediated in the vascular wall and at the vascular endothelium level, since this monolayer of cells plays a central role in the regulation and maintenance of cardiovascular homeostasis and function. While these processes include endothelium-derived vasorelaxant and vasoconstrictor compounds, the vascular endothelium also plays host to many receptors, binding proteins, transporters and signalling mechanisms. Accordingly, endothelial dysfunction, which underlies many cardiovascular disease conditions, can trigger acute vascular events including vasospasm, thrombosis or restenosis leading to ischaemia. The longchain n-3 PUFAs have been reported to possess several properties that may positively influence vascular function. These include favourable mediator profiles (nitric oxide, eicosanoids) that influence vascular reactivity, change in vascular tone via actions on selective ion channels, and maintenance of vascular integrity. In addition to direct effects on contractility, n-3 PUFAs may affect vascular function, and the process of atherogenesis, via inhibition of vascular smooth muscle cell proliferation at the gene expression level, and by modifying expression of inflammatory cytokinesis and adhesion molecules. Collectively, these properties are consistent with pleiotropic actions of longchain n-3 PUFAs, and may explain the beneficial cardiovascular protection of this family of fatty acids that have been clearly evident through epidemiological data as well from more recent large-scale clinical trials.


Ziegler, O., D. Quilliot, et al. (2000). "[Physiopathology of obesity. Dietary factors, and regulation of the energy balance]." Ann Endocrinol (Paris) 61 Suppl 6: 12-23.

            Energy balance and macronutrient balance are the cornerstones upon which any theories of obesity must be built. Obesity can only occur when energy intake remains higher than energy expenditure for an extended period of time. However the macronutrient composition of the diet can also affect energy balance. Fat is a key nutrient because it is poorly regulated at both the level of consumption and oxidation. Psychological and behavioural profiles of obese subjects are clearly important because they can affect food choice and eating patterns. The role of eating frequency and circadian distribution of food is still debated. Eating disorders could be implicated in the development of obesity, but it is uncertain whether obesity is a direct result or a cause of the eating disorder. There are strong evidence to suggest that dietary restraint is associated with loss of dietary control and excessive eating. Early stages of fat storage involve expansion of existing adipocytes (hypertrophy) and later stages involve the recruitment of new adipocytes (hyperplasia). The mechanisms controlling the transformation of preadipocyte could also involve specific dietary components such as polyunsaturated fatty acids or proteins. The age of adiposity rebound, that is a risk factor for later obesity has been found significantly younger in children consuming a high protein diet. These factors could be involved during early infancy or even in utero, according to the hypothesis of fetal programming of adult diseases. There is a need for more longitudinal studies on the role of macronutrient composition, food choice or eating disorders, especially among children, teenagers and young adults.


Ziboh, V. A., C. C. Miller, et al. (2000). "Metabolism of polyunsaturated fatty acids by skin epidermal enzymes: generation of antiinflammatory and antiproliferative metabolites." Am J Clin Nutr 71(1 Suppl): 361S-6S.

            In the skin epidermis, the metabolism of polyunsaturated fatty acids (PUFAs) is highly active. Dietary deficiency of linoleic acid (LA), the major 18-carbon n-6 PUFA in normal epidermis, results in a characteristic scaly skin disorder and excessive epidermal water loss. Because of the inability of normal skin epidermis to desaturate LA to gamma-linolenic acid, it is transformed by epidermal 15-lipoxygenase to mainly 13-hydroxyoctadecadienoic acid, which functionally exerts antiproliferative properties in the tissue. In contrast, compared with LA, arachidonic acid (AA) is a relatively minor 20-carbon n-6 PUFA in the skin and is metabolized via the cyclooxygenase pathway, predominantly to the prostaglandins E(2), F(2)(alpha), and D(2). AA is also metabolized via the 15-lipoxygenase pathway, predominantly to 15-hydroxyeicosatetraenoic acid. At low concentrations, the prostaglandins function to modulate normal skin physiologic processes, whereas at high concentrations they induce inflammatory processes. PUFAs derived from other dietary oils are also transformed mainly into monohydroxy fatty acids. For instance, epidermal 15-lipoxygenase transforms dihomo-gamma-linolenic acid (20:3n-6) to 15-hydroxyeicosatrienoic acid, eicosapentaenoic acid (20:5n-3) to 15-hydroxyeicosapentaenoic acid, and docosahexaenoic acid (22:6n-3) to 17-hydroxydocosahexaenoic acid, respectively. These monohydroxy acids exhibit antiinflammatory properties in vitro. Thus, supplementation of diets with appropriate purified vegetable oils, fish oil, or both may generate local cutaneous antiinflammatory and antiproliferative metabolites which could serve as less toxic in vivo monotherapies or as adjuncts to standard therapeutic regimens for the management of inflammatory skin disorders.


Ziboh, V. A., C. C. Miller, et al. (2000). "Significance of lipoxygenase-derived monohydroxy fatty acids in cutaneous biology." Prostaglandins Other Lipid Mediat 63(1-2): 3-13.

            The skin displays a highly active metabolism of polyunsaturated fatty acids (PUFA). Dietary deficiency of linoleic acid (LA), an 18-carbon (n-6) PUFA, results in characteristic scaly skin disorder and excessive epidermal water loss. Although arachidonic acid (AA), a 20-carbon (n-6) PUFA, is metabolized via cyclooxygenase pathway into predominantly prostaglandin E2 (PGE2) and PGF2alpha. The 15-lipoygenase is very active in this tissue and catalyzes the transformation of 20-carbon AA into predominantly 15-hydroxyeicosatetraenoic acid (15-HETE). Similarly, the epidermal 15-lipoxygenase also catalyzes the transformation of 18-carbon LA and 20-carbon dihomo-gamma-linolenic acid (DGLA) to 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatrienoic acid (15-HETrE), respectively. The monohydroxy fatty acids are incorporated in phospholipids which undergo catalysis to yield substituted-diacylglycerols (13-HODE-DAG) and 15-HETrE-DAG) which exert anti-inflammatory/antiproliferative effects on the skin.


Youdim, K. A., A. Martin, et al. (2000). "Essential fatty acids and the brain: possible health implications." Int J Dev Neurosci 18(4-5): 383-99.

            Linoleic and alpha-linolenic acid are essential for normal cellular function, and act as precursors for the synthesis of longer chained polyunsaturated fatty acids (PUFAs) such as arachidonic (AA), eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), which have been shown to partake in numerous cellular functions affecting membrane fluidity, membrane enzyme activities and eicosanoid synthesis. The brain is particularly rich in PUFAs such as DHA, and changes in tissue membrane composition of these PUFAs reflect that of the dietary source. The decline in structural and functional integrity of this tissue appears to correlate with loss in membrane DHA concentrations. Arachidonic acid, also predominant in this tissue, is a major precursor for the synthesis of eicosanoids, that serve as intracellular or extracellular signals. With aging comes a likely increase in reactive oxygen species and hence a concomitant decline in membrane PUFA concentrations, and with it, cognitive impairment. Neurodegenerative disorders such as Parkinson's and Alzheimer's disease also appear to exhibit membrane loss of PUFAs. Thus it may be that an optimal diet with a balance of n-6 and n-3 fatty acids may help to delay their onset or reduce the insult to brain functions which these diseases elicit.


Yamada, K. and H. Tachibana (2000). "Recent topics in anti-oxidative factors." Biofactors 13(1-4): 167-72.

            Lipids and anti-oxidative factors regulate immune functions such as immunoglobulin production and chemical mediator release. For example, polyunsaturated fatty acids (PUFA) enhance IgE production of isolated rat lymphocytes, but not in the presence of alpha-tocopherol. In addition, anti-oxidative factors such as tea polyphenols and flavonoids exert inhibitory effect on chemical mediator release from rat peritoneal exudate cells (PEC). Some of these immunoregulatory activities of food components could be expressed in vivo. Oral administrations of perilla and fish oils or tea polyphenols led to a significant decrease of LTB4 releasing activity of rat PEC, but IgE production enhancing activity of PUFA was not expressed in vivo. On the other hand, alpha-tocopherol feeding enhanced serum IgA level as well as IgA productivity of mesenteric lymph node lymphocytes. These results suggest that dietary fats and antioxidants are effective for the alleviation of allergic symptom and activation of immune functions.


Woodcock, E. A., J. F. Arthur, et al. (2000). "Inositol 1,4,5-trisphosphate and reperfusion arrhythmias." Clin Exp Pharmacol Physiol 27(9): 734-7.

            1. The present review focuses on the role of the Ca2+-releasing second messenger inositol 1,4,5-trisphosphate (IP3) in initiating arrhythmias during early reperfusion following a period of myocardial ischaemia. 2. Evidence for an arrhythmogenic action of IP3 was provided by studies showing a correlation between the extent of the increase in IP3 and the incidence of arrhythmias in early reperfusion. In addition, phospholipase C inhibitors selective for thrombin receptor stimulation were anti-arrhythmic only when arrhythmias were thrombin initiated. 3. Mechanisms by which IP3 could initiate arrhythmias are discussed, with particular emphasis on the role of slow and unscheduled Ca2+ release. 4. The reperfusion-induced IP3 and arrhythmogenic responses can be initiated through either alpha1-adrenoceptors or thrombin receptors, but endothelin receptor stimulation was ineffective. Further studies have provided evidence that the noradrenaline-mediated response was mediated by alpha1A-receptors, while the alpha1B-adrenoceptor subtype appeared to be protective. 5. Reperfusion-induced IP3 responses could be inhibited by procedures known to reduce the incidence of arrhythmias under these conditions, including preconditioning, inhibiting Na+/H+ exchange or by dietary supplementation with n-3 polyunsaturated fatty acids. 6. Inositol 1,4,5-trisphosphate generation in cardiomyocytes can be facilitated by raising intracellular Ca2+ and it seems likely that the rise in Ca2+ in ischaemia and reperfusion is responsible for the generation of IP3, which will, in turn, further exacerbate Ca2+ overload.


Willatts, P. and J. S. Forsyth (2000). "The role of long-chain polyunsaturated fatty acids in infant cognitive development." Prostaglandins Leukot Essent Fatty Acids 63(1-2): 95-100.

            Dietary long-chain polyunsaturated fatty acids (LCPUFA) in infancy are necessary for normal brain growth and development, and may play an important role in the development of infant cognition. Several randomized, controlled studies have evaluated the effects of feeding both term and preterm infants formula containing LCPUFA or no LCPUFA on a variety of measures of cognitive behaviour. Studies of the relation of LCPUFA to performance on tests of psychomotor development have produced inconsistent results, with supplemented infants demonstrating either higher scores or no differences in comparison to controls. This pattern suggests that global tests of development may be insufficiently sensitive for detecting the effects of LCPUFA on infant cognitive function. In contrast, studies assessing the influence of LCPUFA on development of specific cognitive behaviours have shown a significant advantage for supplemented infants on measures of visual attention and problem solving. These results suggest that LCPUFA may enhance more efficient information processing or attention regulation in infants. Whether there are any long-term effects of dietary LCPUFA in infancy on childhood cognition is not known.


Weber, P. and D. Raederstorff (2000). "Triglyceride-lowering effect of omega-3 LC-polyunsaturated fatty acids--a review." Nutr Metab Cardiovasc Dis 10(1): 28-37.

            There is increasing evidence that serum triglycerides are a significant and independent risk factor for CVD. The aim of this report is to review recent literature pertinent to the triglyceride-lowering effect of omega-3 long chain polyunsaturated fatty acids (LC-PUFA). Animal data are not considered because they are difficult to extrapolate to the human situation. A large body of evidence derived from epidemiological studies and clinical trials has consistently demonstrated that this effect is dose-dependent and can be achieved by diet. The smallest amount of omega-3 LC-PUFA needed to significantly lower serum triglycerides appears to be approximately 1 g/day as provided by a fish diet. Use of fish oil administering as little as 0.21 g EPA and 0.12 g DHA per day significantly lowered serum triglycerides in hyperlipidemics. In normolipidemics, a daily intake of 0.17 g EPA and 0.11 g DHA, given as a fish oil supplement, induced a non-significant reduction of 22%. These findings must be considered as preliminary and warrant further research. Intake of omega-3 LC-PUFA is frequently reported to modestly increase LDL cholesterol. However, in normo- or slightly hyperlipidemic individuals who received omega-3 LC-PUFA for 4 months or longer, changes of LDL cholesterol were not significantly different from a placebo group. Both EPA and DHA lower serum triglycerides, but they may have a differential effect on lipoproteins. Intake of omega-3 LC-PUFA in the amount mentioned above is safe.


Wang, X. and P. J. Quinn (2000). "The location and function of vitamin E in membranes (review)." Mol Membr Biol 17(3): 143-56.

            Vitamin E is a fat-soluble vitamin that consists of a group of tocols and tocotrienols with hydrophobic character, but possessing a hydroxyl substituent that confers an amphipathic character on them. The isomers of biological importance are the tocopherols, of which alpha-tocopherol is the most potent vitamin. Vitamin E partitions into lipoproteins and cell membranes, where it represents a minor constituent of most membranes. It has a major function in its action as a lipid antioxidant to protect the polyunsaturated membrane lipids against free radical attack. Other functions are believed to be to act as membrane stabilizers by forming complexes with the products of membrane lipid hydrolysis, such as lysophospholipids and free fatty acids. The main experimental approach to explain the functions of vitamin E in membranes has been to study its effects on the structure and stability of model phospholipid membranes. This review describes the function of vitamin E in membranes and reviews the current state of knowledge of the effect of vitamin E on the structure and phase behaviour of phospholipid model membranes.


Valk, E. E. and G. Hornstra (2000). "Relationship between vitamin E requirement and polyunsaturated fatty acid intake in man: a review." Int J Vitam Nutr Res 70(2): 31-42.

            Vitamin E is the general term for all tocopherols and tocotrienols, of which alpha-tocopherol is the natural and biologically most active form. Although gamma-tocopherol makes a significant contribution to the vitamin E CONTENT in foods, it is less effective in animal and human tissues, where alpha-tocopherol is the most effective chain-breaking lipid-soluble antioxidant. The antioxidant function of vitamin E is critical for the prevention of oxidation of tissue PUFA. Animal experiments have shown that increasing the degree of dietary fatty acid unsaturation increases the peroxidizability of the lipids and reduces the time required to develop symptoms of vitamin E deficiency. From these experiments, relative amounts of vitamin E required to protect the various fatty acids from being peroxidized, could be estimated. Since systematic studies on the vitamin E requirement in relation to PUFA consumption have not been performed in man, recommendations for vitamin E intake are based on animal experiments and human food intake data. An intake of 0.6 mg alpha-tocopherol equivalents per gram linoleic acid is generally seen as adequate for human adults. The minimum vitamin E requirement at consumption of fatty acids with a higher degree of unsaturation can be calculated by a formula, which takes into account the peroxidizability of unsaturated fatty acids and is based on the results of animal experiments. There are, however, no clear data on the vitamin E requirement of humans consuming the more unsaturated fatty acids as for instance EPA (20:5, n-3) and DHA (22:6, n-3). Studies investigating the effects of EPA and DHA supplementation have shown an increase in lipid peroxidation, although amounts of vitamin E were present that are considered adequate in relation to the calculated oxidative potential of these fatty acids. Furthermore, a calculation of the vitamin E requirement, using recent nutritional intake data, shows that a reduction in total fat intake with a concomitant increase in PUFA consumption, including EPA and DHA, will result in an increased amount of vitamin E required. In addition, the methods used in previous studies investigating vitamin E requirement and PUFA consumption (for instance erythrocyte hemolysis), and the techniques used to assess lipid peroxidation (e.g. MDA analysis), may be unsuitable to establish a quantitative relation between vitamin E intake and consumption of highly unsaturated fatty acids. Therefore, further studies are required to establish the vitamin E requirement when the intake of longer-chain, more-unsaturated fatty acids is increased. For this purpose it is necessary to use functional techniques based on the measurement of lipid peroxidation in vivo. Until these data are available, the widely used ratio of at least 0.6 mg alpha-TE/g PUFA is suggested. Higher levels may be necessary, however, for fats that are rich in fatty acids containing more than two double bonds.


Uauy, R. and D. R. Hoffman (2000). "Essential fat requirements of preterm infants." Am J Clin Nutr 71(1 Suppl): 245S-50S.

            The interest in factors that modify early infant development has led investigators to focus on n-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFAs) in the past 2 decades. The presence of docosahexaenoic acid (DHA) and arachidonic acid (AA) in breast milk, compared with their absence from infant formulas available in the United States, has prompted clinical trials designed to examine whether LCPUFA enrichment of infant formula has beneficial effects on maturational events of the visual system. These trials have shown significant functional advantages of LCPUFA supplementation for preterm infants, whereas benefits for full-term infants remain controversial. The growth and safety of preterm infants was not compromised by LCPUFA enrichment, although these issues remain to be resolved in clinical trials with full-term infants.


Uauy, R., P. Mena, et al. (2000). "Essential fatty acids in early life: structural and functional role." Proc Nutr Soc 59(1): 3-15.

            Essential fatty acids (EFA) are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LCPUFA). These fatty acids serve as specific precursors for eicosanoids that regulate numerous cell and organ functions. Results from animal and recent human studies support the essential nature of n-3 EFA in addition to the well-established role of n-6 EFA for human subjects, particularly in early life. The most significant effects relate to neural development and maturation of sensory systems. Recent studies using stable-isotope-labelled tracers demonstrate that even preterm infants are able to form arachidonic acid (AA) and docosahexaenoic acid (DHA), but that synthesis is extremely low. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation, and retinal and nervous system development. Regulation of gene expression by LCPUFA occurs at the transcriptional level and is mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the steroid hormone receptor family. Two types of polyunsaturated fatty acid responsive transcription factors have been characterized, the peroxisome proliferator-activated receptor (PPAR) and the hepatic nuclear factor 4alpha. DHA also has significant effects on photoreceptor membranes involved in the signal transduction process, rhodopsin activation, and rod and cone development. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oils, sources of LCPUFA, results in increased blood levels of DHA and AA, as well as an associated improvement in visual function in formula-fed premature infants to match that of human milk-fed infant. Recent clinical trials convincingly support LCPUFA supplementation of preterm infant formulations and possibly term formula to mimic human milk composition.


Tisdale, M. J. (2000). "Metabolic abnormalities in cachexia and anorexia." Nutrition 16(10): 1013-4.

            An increased glucose requirement by many solid tumors produces an increased metabolic demand on the liver, resulting in an increased energy expenditure. In addition, several cytokines and tumor catabolic products have been suggested as being responsible for the depletion of adipose tissue and skeletal-muscle mass in cachexia. A sulphated glycoprotein of molecular mass 24 kDa, produced by cachexia-inducing tumors and present in the urine of cancer patients actively losing weight, has been shown to be capable of inducing direct muscle catabolism in vitro and a state of cachexia in vivo, with specific loss of the non-fat carcass mass. In vitro studies have shown the bioactivity of this proteolysis-inducing factor to be attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid. Preliminary clinical studies have shown that eicosapentaenoic acid stabilizes body weight and protein and fat reserves in patients with pancreatic carcinoma. Further trials are required to confirm the efficacy of eicosapentaenoic acid and to determine the anticachectic activity in other types of cancer.


Sugano, M. and F. Hirahara (2000). "Polyunsaturated fatty acids in the food chain in Japan." Am J Clin Nutr 71(1 Suppl): 189S-96S.

            The amount of polyunsaturated fatty acids (PUFAs) in the food chain in Japan is reviewed on the basis of the newest nutrition survey data. The Japanese are currently consuming, on average, approximately 26% of energy as fats with ratios of polyunsaturated to saturated fats and n-6 to n-3 fatty acids of approximately 1.2:1 and 4:1, respectively. The significant contributors to this relatively high n-3 PUFA intake are not only fish and shellfish but also edible vegetable oils, almost exclusively rapeseed and soybean oils. Thus, the dietary habits of the Japanese have made possible a high n-3 PUFA intake within a low-fat regimen. In this context, the gradual decline, particularly in younger persons, in fish consumption habits weighs on our minds. Analyses of health indexes, including the increased average life span, support the superiority of the current Japanese eating pattern that harmonizes with the Western regimens. However, at present it cannot be disregarded that food intake varies considerably in all age groups, and only a limited number of people are consuming the recommended allowance for dietary fats.


Subbanagounder, G., A. D. Watson, et al. (2000). "Bioactive products of phospholipid oxidation: isolation, identification, measurement and activities." Free Radic Biol Med 28(12): 1751-61.

            There is considerable evidence to suggest that oxidation of LDL plays an important role in atherogenesis. Polyunsaturated fatty acids, a major oxidative target, are present as phospholipids in the outer core of the lipoprotein particle. Studies from several laboratories have shown an increase in the levels of phospholipid oxidation products in atherosclerotic lesions and of antibodies to oxidized phospholipids in mice and humans with lesions. Significantly, phospholipid oxidation products have been demonstrated (in vitro) to selectively activate processes in vascular wall cells that may contribute to atherogenesis. This review discusses activities, methods for isolation, identification and measurement of bioactive phospholipids. Past studies suggest that defined and relatively simple current technologies allow identification of bioactive phospholipid oxidation products and measurement of their levels in tissue.


Stone, N. J. (2000). "The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardio (GISSI)-Prevenzione Trial on fish oil and vitamin E supplementation in myocardial infarction survivors." Curr Cardiol Rep 2(5): 445-51.

            A recent large-scale, open-label, randomized, controlled trial in 11, 324 myocardial infarction (MI) survivors has shown low-dose fish oil, but not vitamin E, to reduce significantly the cumulative rate of all-cause death, nonfatal MI, and nonfatal stroke. Neither intervention significantly reduced the other primary endpoint, the cumulate rate of cardiovascular death, nonfatal MI, and nonfatal stroke. Analysis of secondary endpoints indicated that the benefits of the 875 mg fish oil capsules containing 850 to 882 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters was in reducing mortality and not in a reduction of nonfatal MI. It was a safe intervention. The internal validity and external validity of the data was examined and the findings placed in clinical perspective. Important questions remain about the benefits of increased plant sources of n-3 polyunsaturated fatty acids (PUFA) for those who cannot obtain or consume fish. Also the benefits of diet versus fish oil supplementation haven't been determined precisely. Although it seems reasonable to increase sources of n-3 PUFA in the diet for those at high risk of coronary heart disease, current data do not support a policy of promoting fish oil capsules for secondary prevention of coronary heart disease.


Spickett, C. M., A. Jerlich, et al. (2000). "The reactions of hypochlorous acid, the reactive oxygen species produced by myeloperoxidase, with lipids." Acta Biochim Pol 47(4): 889-99.

            Myeloperoxidase (MPO), an abundant enzyme in phagocytes, has been implicated in the pathogenesis of various inflammatory diseases including atherosclerosis. The major oxidant produced by MPO, hypochlorous acid (HOCl), is able to modify a great variety of biomolecules by chlorination and/or oxidation. In this paper the reactions of lipids (preferentially unsaturated fatty acids and cholesterol) with either reagent HOCl or HOCl generated by the MPO-hydrogen peroxide-chloride system are reviewed. One of the major issues has been whether the reaction of HOCl with lipids of low density lipoprotein (LDL) yields predominantly chlorohydrins or lipid hydroperoxides. Electrospray mass spectrometry provided direct evidence that chlorohydrins rather than peroxides are the major products of HOCl- or MPO-treated LDL phosphatidylcholines. Nevertheless lipid peroxidation is a possible alternative reaction of HOCl with polyunsaturated fatty acids if an additional radical source such as pre-formed lipid hydroperoxides is available. In phospholipids carrying a primary amino group such as phosphatidylethanolamine chloramines are the preferred products compared to chlorohydrins. Cholesterol can be converted by HOCl to great variety of oxysterols besides three isomers of chlorohydrins. For the situation in vivo it appears that the type of reaction occurring between HOCl and lipids would very much depend on the circumstances, e.g. the pH and the presence of radical initiators. The biological effects of lipid chlorohydrins are not yet well understood. It has been shown that chlorohydrins of both unsaturated fatty acids as well as of cholesterol may cause lysis of target cells, possibly by disruption of membrane structures.


Singleton, C. B., B. D. Walker, et al. (2000). "N-3 polyunsaturated fatty acids and cardiac mortality." Aust N Z J Med 30(2): 246-51.


Sinclair, A. J., K. J. Murphy, et al. (2000). "Marine lipids: overview "news insights and lipid composition of Lyprinol"." Allerg Immunol (Paris) 32(7): 261-71.

            The omega 3 polyunsaturated fatty acids have had a major impact on thinking in medicine in the last twenty years. The parent fatty acid in the omega 3 fatty acid family is alpha-linolenic acid (ALA) which is an essential fatty acid found in high concentrations in certain plant oils, such as flaxseed oil, walnut oil and canola oil. Several longer chain or derived omega 3 fatty acids are formed from alpha-linolenic acid and these are mainly found in fish, fish oils and from other marine organisms. The main marine omega 3 fatty acids are eicosapentaenoic acid (EPA), docosapentaenoic acid and docosahexaenoic acid (DHA). It is of interest that DHA is specifically localised in the retina and the brain in humans and other mammals. The longer chain omega 3 fatty acids are rapidly incorporated into cell membrane phospholipids where it is regarded they influence the metabolism/metabolic events within the cells. The mechanisms by which these changes occur include alteration in the fluidity of membranes such that there are subtle changes in receptor function, alteration in cell signalling mechanisms, membrane-bound enzymes, regulation of the synthesis of eicosanoids, and regulation of gene expression. In this chapter, we report a comparison between the composition of the oil derived from the New Zealand Green Lipped Mussel (Lyprinol') and two other oils rich in omega 3 fatty acids, namely flaxseed oil and tuna oil. The main lipid classes in Lyprinol' were sterol esters, triglycerides, free fatty acids, sterols and phospholipids while triglycerides were the main lipids in the other two oils. The main omega 3 fatty acids in Lyprinol' were EPA and DHA, while in flaxseed oil and tuna oil the main omega 3 fatty acids were ALA and DHA, respectively. The main sterols in Lyprinol' were cholesterol and desmosterol/brassicasterol, while in flaxseed oil and tuna oil the main sterols were beta-sitosterol and cholesterol, respectively. Epidemiological observations, populations' studies and basic research indicate the possibility of influencing the outcome of cardiovascular disease, inflammatory disorders and neural function by ingestion of the omega 3 polyunsaturated fatty acids.


Simopoulos, A. P. (2000). "Human requirement for N-3 polyunsaturated fatty acids." Poult Sci 79(7): 961-70.

            The diet of our ancestors was less dense in calories, being higher in fiber, rich in fruits, vegetables, lean meat, and fish. As a result, the diet was lower in total fat and saturated fat, but contained equal amounts of n-6 and n-3 essential fatty acids. Linoleic acid (LA) is the major n-6 fatty acid, and alpha-linolenic acid (ALA) is the major n-3 fatty acid. In the body, LA is metabolized to arachidonic acid (AA), and ALA is metabolized to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The ratio of n-6 to n-3 essential fatty acids was 1 to 2:1 with higher levels of the longer-chain polyunsaturated fatty acids (PUFA), such as EPA, DHA, and AA, than today's diet. Today this ratio is about 10 to 1:20 to 25 to 1, indicating that Western diets are deficient in n-3 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. The n-3 and n-6 EPA are not interconvertible in the human body and are important components of practically all cell membranes. The N-6 and n-3 fatty acids influence eicosanoid metabolism, gene expression, and intercellular cell-to-cell communication. The PUFA composition of cell membranes is, to a great extent, dependent on dietary intake. Therefore, appropriate amounts of dietary n-6 and n-3 fatty acids need to be considered in making dietary recommendations. These two classes of PUFA should be distinguished because they are metabolically and functionally distinct and have opposing physiological functions; their balance is important for homeostasis and normal development. Studies with nonhuman primates and human newborns indicate that DHA is essential for the normal functional development of the retina and brain, particularly in premature infants. A balanced n-6/n-3 ratio in the diet is essential for normal growth and development and should lead to decreases in cardiovascular disease and other chronic diseases and improve mental health. Although a recommended dietary allowance for essential fatty acids does not exist, an adequate intake (AI) has been estimated for n-6 and n-3 essential fatty acids by an international scientific working group. For Western societies, it will be necessary to decrease the intake of n-6 fatty acids and increase the intake of n-3 fatty acids. The food industry is already taking steps to return n-3 essential fatty acids to the food supply by enriching various foods with n-3 fatty acids. To obtain the recommended AI, it will be necessary to consider the issues involved in enriching the food supply with n-3 PUFA in terms of dosage, safety, and sources of n-3 fatty acids.


Simmer, K. (2000). "Longchain polyunsaturated fatty acid supplementation in preterm infants." Cochrane Database Syst Rev(2): CD000375.

            BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: The n-3 and n-6 essential fatty acids alpha linolenic acid and linoleic acid are the precursors of the n-3 and n-6 longchain polyunsaturated fatty acids (LCPUFA). Controversy exists over whether LCPUFA are essential nutrients for preterm infants who may not be able to synthesise sufficient amounts of LCPUFA to satisfy the needs of the developing brain and retina. The aim of this review is to assess whether supplementation of infant formula with LCPUFA is safe and of benefit to preterm infants. SEARCH STRATEGY: Trials were identified by MEDLINE and by checking reference lists of relevant articles and conference proceedings. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Eight randomised trials were identified. Five were assessed as being of high quality and one is awaiting assessment. Problems with the remaining two included a change in assessment methodology mid-study (Memphis 1996) and assessment methodology that deviated from generally accepted international standards (Bologna 1996). MAIN RESULTS: Studies from Dallas (Uauy et al 1990, Birch et al 1992, Hoffman & Uauy 1992, Uauy et al 1994) and Memphis (Carlson et al 1991, Carlson et al 1992, Carlson et al 1993, Werkman & Carlson 1996) suggest that early visual development is better in formula-fed infants who receive a LCPUFA supplement compared with those fed standard formula. However, the effects were not long-term, with no differences detected between groups after 4 months of age. The Bologna group (Fadelli et al 1996) reported some differences in the visual evoked potential at 3 months post-term but their methodology was questionable making interpretation of the data difficult. In the largest study (the Mead Johnson study, Hansen et al 1997), no difference in visual acuity was demonstrated between LCPUFA supplemented and control infants at 2 and 4 months post-term. The Memphis studies used the Fagan Infantest (Fagan 1970) to measure infant development and demonstrated lower novelty preferences (possibly predictive of lower intelligence) in preterm infants supplemented with LCPUFA. However, the supplemented infants had more looks at the novel stimulus and each look was of shorter duration which may represent more rapid visual information processing. Normalised weight (expressed as SD from the mean for age) was lower in preterm infants who were fed supplemented formula in the Memphis studies. No difference in growth between supplemented and control infants was documented in the Dallas, Bologna, Alberta (Clandinin et al 1997) and Wyeth (Vanderhoof et al 1997) studies while the Mead Johnson study documented higher weights in supplemented infants compared with controls at two months post-term. The Dallas study documented little effect of LCPUFA supplements on bleeding time and membrane fragility. REVIEWER'S CONCLUSIONS: No long-term benefit has been demonstrated for preterm infants receiving formula supplemented with LCPUFA. There is some evidence that n-3 LCPUFA supplementation of formula increases the early rate of visual maturation in preterm infants. Supplementation of formula with n-3 and n-6 LCPUFA does not impair the growth of preterm infants.


Simmer, K. (2000). "Longchain polyunsaturated fatty acid supplementation in infants born at term." Cochrane Database Syst Rev(2): CD000376.

            BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: The n-3 and n-6 essential fatty acids alpha linolenic acid and linoleic acid are the precursors of the n-3 and n-6 longchain polyunsaturated fatty acids (LCPUFA). Controversy exists over whether LCPUFA are essential nutrients during infancy. The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to term infants. SEARCH STRATEGY: Trials were identified by MEDLINE, checking reference lists of articles and conference proceedings, and by personal communication. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: Eight randomised studies were identified. One of these studies was excluded due to supplementation commencing after three weeks of age, and one is awaiting assessment. The remaining six trials were assessed to be of good quality. MAIN RESULTS: Visual acuity was assessed by visual evoked potentials at 4 and 7-8 months in the studies of Makrides et al (1995 & 1996). The supplemented infants had an improved rate of visual maturation at both time points in the first study, but no difference was found between the groups at 4 months in the second study. Visual acuity was assessed by Teller acuity cards in the study of Carlson et al (1996), Clausen et al (1996) and Austed et al (1997). Supplementation had no consistent effect on visual acuity over the first year of life. General development was measured in five studies, all with small numbers. Two suggested a benefit of supplementation. One reported a benefit with supplementation at 4 months ( developmental quotient, DQ measured with the Brunet Lezine test, Agostini et al 1995), but when the groups were reassessed with the same test at 1 and 2 years, no differences were found in DQ (Agostini et al 1997). The other study reported a benefit with supplementation at 9 months (novelty preference measured by Fagan Infantest, Clausen et al 1996). The Adelaide studies showed no effect of supplementation on DQ at one year (Bayley Scales of Infant Development (BSID), Makrides et al 1995 &1996). The Portland study showed no effect of supplementation on development at one year (BSID) or at three years (Stanford Binet IQ test). The Portland study showed no effect of supplementation on language development at one year (McArthur Communicative Development Inventory, Janowsky et al 1995) or at three years (Peabody Picture Vocabulary Test, Scott et al 1997). Growth was measured in a small number of infants in the studies of Makrides et al (1995 & 1996) and Austed et al (1997). There was no suggestion that LCPUFA supplementation reduced the growth of term infants. REVIEWER'S CONCLUSIONS: At present there is little evidence from randomised trials of LCPUFA supplementation to support the hypothesis that LCPUFA supplementation confers any benefit on visual or cognitive development. There are no data from the randomised trials presently available to indicate that LCPUFA supplements influence the growth of term infants.


Shimano, H. (2000). "Sterol regulatory element-binding protein-1 as a dominant transcription factor for gene regulation of lipogenic enzymes in the liver." Trends Cardiovasc Med 10(7): 275-8.

            Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix (bHLH) type transcription factors that control expression of genes involved in biosynthesis of cholesterol and fatty acids. Dietary studies with normal, transgenic, and knockout mice have established SREBP-1 as a dominant transcription factor regulating gene expression of lipogenic enzyme in the liver. Polyunsaturated fatty acids inhibit hepatic lipogenic enzymes through suppressing SREBP-1. Whereas SREBP-2 exerts sterol regulation through cleavage of the membrane-bound precursor protein to liberate the active nuclear form into the nucleus, SREBP-1 controls lipogenic enzymes by self-regulating its own transcription level. Promoter analysis of the SREBP-1 gene will be important to clarify the mechanism of nutritional regulation of lipogenic genes.


Shenkin, A. (2000). "Micronutrients in the severely-injured patient." Proc Nutr Soc 59(3): 451-6.

            The trace element and vitamin requirements of severely-ill injured patients depend on a complex interaction of the status of the patient at the time of admission, ongoing losses and the potential benefit of supplying large amounts of individual micronutrients. Characteristic clinical deficiency states are now uncommon, but subclinical deficiency is of growing concern. The main effects of subclinical deficiency are: (1) an altered balance of reactive oxygen species and antioxidants, leading to oxidative damage of polyunsaturated fatty acids and nucleic acids, and possibly to increased activation of the transcription factor nuclear factor-kappaB, with increased production of pro-inflammatory cytokines: (2) impaired immune function with increased likelihood of infectious complications. Laboratory tests to optimize intake in such critically-ill patients lack sensitivity and specificity, this situation being made worse as a result of the acute-phase response. Recent studies have indicated the clinical benefit of providing large amounts of certain micronutrients in burned and head-injured patients. Further clinical studies are now required to define optimal levels of provision in different disease states, with a particular emphasis on markers of tissue function and clinical outcome.


Severus, W. E. and B. Ahrens (2000). "[Omega-3 fatty acids in psychiatry]." Nervenarzt 71(1): 58-62.

            Omega-3 fatty acids (ALA, EPA, DHA) are essential polyunsaturated fatty acids. Due to their pivotal involvement in signal transduction processes in the CNS, a role for these fatty acids in psychiatric disorders has been postulated. This review summarizes the latest findings on the physiological function of these compounds in the CNS and gives a comprehensive overview on the emerging therapeutic role of these psychoactive drugs in psychiatric disorders, with special emphasis being put on affective disorders and schizophrenia.


Schwartz, J. (2000). "Role of polyunsaturated fatty acids in lung disease." Am J Clin Nutr 71(1 Suppl): 393S-6S.

            DF Horrobin hypothesized that the low prevalence of lung disease among Eskimos is the result of their diet, which is high in n-3 fatty acids. The n-3 and n-6 fatty acids shunt eicosanoid production away from the arachidonic acid pathway, and hence decrease the production of bronchoconstrictive leukotrienes. Animal studies showed that eicosapentaenoic acid or gamma-linolenic acid supplementation of animals exposed to endotoxins results in decreased effects on thromboxane B(2) and pulmonary vascular resistance. Small human trials confirmed that supplementation with eicosapentaenoic acid results in increased eicosapentaenoic acid in phospholipids and decreased generation of leukotrienes by neutrophils. Hence, a protective effect of such fatty acids in lung disease is biologically plausible. The results of human intervention studies looking at respiratory outcomes have been mixed, but they do suggest a possible difference between long-term and short-term effects. Epidemiologic studies showed possible protective effects against asthma in children, but weak to no evidence of such effects in adults. Results for bronchitis are more positive, although intervention trials are lacking. Recently, a cross-sectional analysis of data from the first National Health and Nutrition Examination Survey reported an approximately 80-mL difference in forced expiratory volume at 1 s between adults with high compared with low fish consumption. This response was not limited to asthmatic subjects. Others found that both fish consumption and n-3 fatty acid consumption (as estimated from food-frequency questionnaires) were protective against physician-diagnosed emphysema and chronic bronchitis and low spirometry values. Only smokers were included in this analysis. These results suggest that dietary fatty acids may play a role in lung disease; further work is needed to elucidate that role.


Schmidt, E. B., H. A. Skou, et al. (2000). "N-3 fatty acids from fish and coronary artery disease: implications for public health." Public Health Nutr 3(1): 91-8.

            OBJECTIVE: To review and discuss the effect of n-3 polyunsaturated fatty acids (PUFA) from fish in the prevention and, primarily, in the treatment of coronary artery disease (CAD). DESIGN: Overview of the literature. SETTING: Denmark. RESULTS: There is good evidence that fish consumption may reduce the risk of CAD. CONCLUSIONS: Fish can be recommended to reduce the risk of CAD both in healthy subjects and in patients with a high risk of CAD or with documented CAD. The use of fish oil concentrates can not be recommended in general, but may be considered in patients after a myocardial infarction or in patients with hypertriglyceridaemia. An increased intake of n-3 polyunsaturated fatty acids from fish may have substantial implications for public health and health economy by decreasing the risk of coronary events and sudden cardiac death.


Schlimme, E., D. Martin, et al. (2000). "Nucleosides and nucleotides: natural bioactive substances in milk and colostrum." Br J Nutr 84 Suppl 1: S59-68.

            Nucleotides, nucleosides and nucleobases belong to the non-protein-nitrogen (NPN) fraction of milk. The largest amounts of ribonucleosides and ribonucleotides--ribose forms only were considered in this review--were measured directly after parturition in bovine milk and other ruminants as well as in the milk of humans. Generally, concentrations of most of the nucleos(t)ides tend to decrease gradually with advancing lactation period or nursing time. The species-specific pattern of these minor constituents in milk from different mammals is a remarkable property and confirms, at least, the specific physiological impact of these minor compounds in early life. The physiological capacity of these compounds in milk is given by the total potentially available nucleosides. The main dietary sources of nucleos(t)ides are nucleoproteins and nucleic acids which are converted in the course of intestinal digestion into nucleosides and nucleobases the preferred forms for absorption in the intestine. Thus, nucleosides and nucleobases are suggested to be the acting components of dietary and/or supplemented nucleic acid-related compounds in the gut. They are used by the body as exogenous trophochemical sources and can be important for optimal metabolic functions. Up to 15 % of the total daily need for a breast-fed infant was calculated to come from this dietary source. Concerning their biological role they not only act as metabolites but are also involved as bioactive substances in the regulation of body functions. Dietary nucleotides affect immune modulation, e.g. they enhance antibody responses of infants as shown by a study with more than 300 full-term healthy infants. Dietary nucleos(t)ides are found to contribute to iron absorption in the gut and to influence desaturation and elongation rates in fatty acid synthesis, in particular long-chain polyunsaturated fatty acids in early stages of life. The in vitro modulation of cell proliferation and apoptosis has been described by ribonucleosides, in particular by modified components using human cell culture models. Due to the bio- and trophochemical properties of dietary nucleos(t)ides, the European Commission has allowed the use of supplementation with specific ribonucleotides in the manufacture of infant and follow-on formula. From the technochemical point of view, the ribonucleoside pattern is influenced by thermal treatment of milk. In addition ribonucleosides are useful indicators for quantifying adulterations of milk and milk products.


Sauerwald, T. U., H. Demmelmair, et al. (2000). "Polyunsaturated fatty acid supply with human milk. Physiological aspects and in vivo studies of metabolism." Adv Exp Med Biol 478: 261-70.

            The origin of polyunsaturated fatty acids (PUFA) in human milk has not been studied in detail. Diet, liberation from maternal stores and endogenous synthesis from precursors may contribute to PUFA present in human milk. Other factors influencing lipid content and fatty acid composition such as gestational age, stage of lactation, nutritional status and genetical background are known. In a series of in vivo studies using stable isotope methodologies we investigated the metabolism of PUFA during lactation. With this techniques the transfer of single dietary fatty acids into human milk, the oxidation and the deposition in tissues were estimated. Our studies demonstrate that the major part of PUFA in human milk seems not to be derived directly from the maternal diet but from body stores. Nevertheless diet is important, because long term intakes affect composition of body stores.


SanGiovanni, J. P., C. S. Berkey, et al. (2000). "Dietary essential fatty acids, long-chain polyunsaturated fatty acids, and visual resolution acuity in healthy fullterm infants: a systematic review." Early Hum Dev 57(3): 165-88.

            BACKGROUND: Biologically active neural tissue is rich in docosahexaenoic acid (DHA), an omega-3 long-chain polyunsaturated fatty acid (LCPUFA). We conducted a systematic review to examine the nature of discordant results from studies designed to test the hypothesis that dietary DHA leads to better performance on visually-based tasks in healthy, fullterm infants. We also conducted a meta-analysis to derive combined estimates of behavioral- and electrophysiologic-based visual resolution acuity differences and sample sizes that would be useful in planning future research. STUDY DESIGN AND METHODS: Twelve empirical studies on LCPUFA intake during infancy and visual resolution acuity were identified through bibliographic searches, examination of monograph and review article reference lists, and written requests to researchers in the field. Works were reviewed for quality and completeness of information. Study design and conduct information was extracted with a standardized protocol. Acuity differences between groups consuming a source of DHA and groups consuming DHA-free diets were calculated as a common outcome from individual studies; this difference score was evaluated against a null value of zero and then used, with the method of DerSimonian and Laird (Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-188), to derive combined estimates of visual resolution acuity differences within seven age categories. RESULTS OF RANDOMIZED COMPARISONS: The combined visual resolution acuity difference measured with behaviorally based methods between DHA-supplemented formula fed groups and DHA-free formula fed groups is 0.32+/-0.09 octaves (combined difference+/-S.E.M., P=0.0003) at 2 months of age. The direction of this value indicates higher acuity in DHA-fed groups. RESULTS OF NON-RANDOMIZED STUDY DESIGNS: The combined visual resolution acuity difference measured with behaviorally based methods between human milk fed groups and DHA-free formula fed groups is 0.49+/-0.09 octaves (P< or =0.000001) at 2 months of age and 0.18+/-0.08 octaves (P=0.04) at 4 months of age. Acuity differences for electrophysiologic-based measures are also greater than zero at 4 months (0.37+/-0.16 octaves, P=0.02). CONCLUSION: Some aspect of dietary n-3 intake is associated with performance on visual resolution acuity tasks at 2, and possibly, 4 months of age in healthy fullterm infants. Whether n-3 intake confers lasting advantage in the development of visually based processes is still in question.


Sanders, T. A. (2000). "Polyunsaturated fatty acids in the food chain in Europe." Am J Clin Nutr 71(1 Suppl): 176S-8S.

            Intakes of partially hydrogenated fish oil and animal fats have declined and those of palm, soybean, sunflower, and rapeseed oils have increased in northern Europe in the past 30 y. Soybean and rapeseed oils are currently the most plentiful liquid vegetable oils and both have desirable ratios of n-6 to n-3 fatty acids. However, soybean and rapeseed oils are commonly partially hydrogenated for use in commercial frying to decrease susceptibility to oxidative degradation. This process leads to selective losses of alpha-linolenic acid (18:3n-3). Intake of linoleic acid (18:2n-6) has risen in many northern European countries. In the United Kingdom, intakes have increased from approximately 10 g/d in the late 1970s to approximately 15 g/d in the 1990s. The intake of alpha-linolenic acid is estimated to be approximately 1-2 g/d but varies with the type of culinary oil used. There are few reliable estimates of the intake of long-chain n-3 fatty acids, but those are generally approximately 0.1-0.5 g/d. The increased use of intensive, cereal-based livestock production systems has resulted in a lower proportion of n-3 fatty acids in meat compared with traditional extensive production systems. Overall, there has been a shift in the balance between n-6 and n-3 fatty acids over the past 30 y. This shift is reflected in the declining concentrations of docosahexaenoic acid and rising concentrations of linoleic acid in breast milk.


Sakac, V. and M. Sakac (2000). "[Free oxygen radiacals and kidney diseases--part I]." Med Pregl 53(9-10): 463-74.

            ADVERSE EFFECTS OF OXYGEN: Adverse effect of oxygen on anaerobes implies oxidation of the basic cell constituents NAD(P)H, thiols, iron-sulphur proteins, pteridines and others) and inactivation of the essential components of the active site of enzymes. Oxygen can also adversely affect the aerobes, especially if long-term influence is taken into consideration, while exposition to high-pressure oxygen causes considerable damages. Direct influence of oxygen on aerobes due to slow and limited enzyme inactivation (for example glutamate decarboxylase) and small number of affected "targets" is not responsible for total adverse effects of oxygen. Even in 1954 it was supposed that oxygen free radicals are the most responsible for the adverse effects of oxygen. ATMOSPHERIC (TRIPLET) OXYGEN: Electron configuration of triplet oxygen explains its reactivity since it is a biradical. The reactions of oxygen with non-radicals are possible with participation of transition metals (except zinc), while its reactivity is much more expressed in case of reactions with other radical species. ACTIVE OXYGEN: More reactive forms of oxygen, known as singlet oxygen, can be generated by an input of energy to triplet oxygen. Singlet-oxygen is obtained mainly by photoexcitation in the presence of initiators (methylene blue, chlorophyll etc.) and as a product of reactions of ozone with certain biomolecules. REDUCED FORMS OF OXYGEN: If a single electron is added to the triplet oxygen, it must enter one of the antibonding molecular orbitals and produce the superoxide radical--(O2.-). Addition of one more electron produces peroxide ion--O2(2-), which forms hydro peroxide in presence of H+, the most common two-electron reduction product of oxygen in biological systems. The four-reduction product of oxygen in biological systems is water. SUPEROXIDE RADICAL: The in vivo production of superoxide radical is possible in many different ways mentioned in this paper. This radical species is unstable in water solutions because of dismutation reaction leading to non-enzymic generation of hydroperoxide. The most reactive radical species--hydroxyl radical is produced from hydro peroxide by Fenton or Haber-Weiss reactions in the presence of catalytic transition metals (iron or copper). HYDROXYL RADICAL: Hydroxyl radicals are the most reactive radical species. The way of their generation has been shown in detail in this paper with special emphasis given to Fenton and Haber-Weiss reactions, that is, transition metals (iron and copper) as catalizators for these reactions. The reactivity of hydroxyl radical can be recognized by monitoring the second-order rate constants for reactions of the hydroxyl radical with some organic compounds in aqueous solution presented in this paper. Although the number of compounds that can be affected and damaged by hydroxyl radicals is great, until now, attention has been paid mostly to investigation of attacks of these radical species on lipids, proteins and DNA. LIPID PEROXIDATION: Radicals react with lipids and cause oxidative destruction of unsaturated, that is, polyunsaturated fatty acids, known as lipid peroxidation. Both lipids in biological systems and lipids as food constituents are submitted to this process. Lipid peroxidation is a chain reaction and its mechanism has been shown in detail in this paper. Lipid peroxidation in cells leads to direct damage of cell membranes with indirect damages of other cell constituents, caused by reactivity of secondary products of this reaction, aldehydes. This complex reaction is responsible for damages of many tissues and progress of some diseases (atherosclerosis). OXIDATIVE STRESS: Protection of an organism from oxygen free radicals implies activity of enzymatic (catalase, SOD, glutathione peroxidase, glutathione reductase etc.) and nonenzymatic (vitamin E. vitamin C. glutathione, uric acid etc.) systems of protection. Disturbance of the balance between production of oxygen free radicals (or some other radical species) and activity of antioxidative system of protection causes the so called oxidative stress. An organism can tolerate a mild oxidative stress but a higher disturbance between the production of free radicals and the activity of the antioxidative protection results in lipid protein and DNA as well as numerous diseases.


Ross, M. A. (2000). "Could oxidative stress be a factor in neurodevelopmental disorders?" Prostaglandins Leukot Essent Fatty Acids 63(1-2): 61-3.

            There is evidence of co-morbidity in the neurodevelopmental disorders and they display depletion of polyunsaturated fatty acids (PUFAs) in their plasma and red cell membranes. This suggests an abnormal fatty acid metabolism, which may affect cell signalling and synthesis of eicosanoids. This common feature in the neurodevelopmental disorders may be genetic in origin: however, oxidative stress may also contribute to decreased PUFAs found in these disorders.


Roche, H. M. and M. J. Gibney (2000). "Effect of long-chain n-3 polyunsaturated fatty acids on fasting and postprandial triacylglycerol metabolism." Am J Clin Nutr 71(1 Suppl): 232S-7S.

            Elevated plasma triacylglycerol concentrations have been associated with increased risk of coronary heart disease (CHD). In the past, the epidemiologic evidence about the causal role of triacylglycerols in CHD has not been well regarded, but recent prospective evidence shows that nonfasting plasma triacylglycerol concentration is a strong and independent predictor of future myocardial infarction. Elevated plasma triacylglycerol concentrations are associated with other CHD risk factors, namely reduced HDL-cholesterol concentrations and a preponderance of highly atherogenic, small, dense LDL particles. Plasma triacylglycerol concentrations increase after the ingestion of a fat-containing meal, and elevated postprandial triacylglycerolemia leads to a series of metabolic reactions that reduce HDL-cholesterol concentrations and promote the formation of small, dense LDL particles. The magnitude of the postprandial response is largely determined by fasting plasma triacylglycerol concentrations. Metabolism of plasma triacylglycerols also influences postprandial factor VII activation and the postprandial lipemic responsiveness to dietary cholesterol. Therefore, dietary factors that improve fasting plasma triacylglycerol concentrations must have a role in a healthy diet. Eicosapentaenoic and docosahexaenoic acids are n-3 polyunsaturated fatty acids (PUFAs) in fish oil that effectively reduce plasma triacylglycerol concentrations. Because n-3 PUFAs are effective at low doses (1 g n-3 PUFA/d), they provide a realistic option for the optimization of plasma triacylglycerol metabolism.


Richardson, A. J. and B. K. Puri (2000). "The potential role of fatty acids in attention-deficit/hyperactivity disorder." Prostaglandins Leukot Essent Fatty Acids 63(1-2): 79-87.

            As currently defined, attention-deficit/hyperactivity disorder (ADHD) encompasses a broad constellation of behavioural and learning problems and its definition and diagnosis remain controversial. The aetiology of ADHD is acknowledged to be both complex and multifactorial. The proposal considered here is that at least some features of ADHD may reflect an underlying abnormality of fatty acid metabolism. Clinical and biochemical evidence is discussed which suggests that a functional deficiency of certain long-chain polyunsaturated fatty acids could contribute to many of the features associated with this condition. The implications in terms of fatty acid treatment proposals are also discussed; such a form of treatment is relatively safe compared to existing pharmacological interventions, although further studies are still needed in order to evaluate its potential efficacy in the management of ADHD symptoms.


Reaven, G. M. (2000). "Diet and Syndrome X." Curr Atheroscler Rep 2(6): 503-7.

            Syndrome X is a cluster of abnormalities, associated with resistance to insulin-mediated glucose uptake, that increases risk of coronary heart disease. Increased carbohydrate intake (with reciprocal decreased fat intake) within the boundaries of menus that can be followed in the free-living state have not been shown to decrease insulin resistance directly, by enhancing insulin sensitivity, or indirectly, by producing and maintaining weight loss. Moreover, such diets accentuate the metabolic abnormalities that constitute Syndrome X. Substitution of monounsaturated fat, polyunsaturated fat, or both for saturated fat results in the same reduction in low-density lipoprotein-cholesterol concentration as seen in diets low in fat and high in carbohydrates but without any untoward effects on the various manifestations of Syndrome X. Consequently, substituting unsaturated fat for saturated fat, without increasing intake of dietary protein or carbohydrate, may be useful for patients with hypercholesterolemia, Syndrome X, or both.


Price, P. T., C. M. Nelson, et al. (2000). "Omega-3 polyunsaturated fatty acid regulation of gene expression." Curr Opin Lipidol 11(1): 3-7.

            This review describes the mechanisms by which polyunsaturated fatty acids regulate the activity of the nuclear transcription factors, peroxisome proliferator-activated receptor and sterol regulatory element binding protein-1, and it describes the role that the peroxisome proliferator-activated receptor and sterol regulatory element binding protein-1 play in coordinating the regulation of lipid synthesis, lipid oxidation, and thermogenesis. Finally, the requirement for dietary polyunsaturated fatty acids, particularly n-3 fatty acids, is defined in terms of the effects polyunsaturated fatty acids exert on gene expression and the role that these effects play in overall energy balance.


Pompeia, C., L. R. Lopes, et al. (2000). "Effect of fatty acids on leukocyte function." Braz J Med Biol Res 33(11): 1255-68.

            Fatty acids have various effects on immune and inflammatory responses, acting as intracellular and intercellular mediators. Polyunsaturated fatty acids (PUFAs) of the omega-3 family have overall suppressive effects, inhibiting lymphocyte proliferation, antibody and cytokine production, adhesion molecule expression, natural killer cell activity and triggering cell death. The omega-6 PUFAs have both inhibitory and stimulatory effects. The most studied of these is arachidonic acid that can be oxidized to eicosanoids, such as prostaglandins, leukotrienes and thromboxanes, all of which are potent mediators of inflammation. Nevertheless, it has been found that many of the effects of PUFA on immune and inflammatory responses are not dependent on eicosanoid generation. Fatty acids have also been found to modulate phagocytosis, reactive oxygen species production, cytokine production and leukocyte migration, also interfering with antigen presentation by macrophages. The importance of fatty acids in immune function has been corroborated by many clinical trials in which patients show improvement when submitted to fatty acid supplementation. Several mechanisms have been proposed to explain fatty acid modulation of immune response, such as changes in membrane fluidity and signal transduction pathways, regulation of gene transcription, protein acylation, and calcium release. In this review, evidence is presented to support the proposition that changes in cell metabolism also play an important role in the effect of fatty acids on leukocyte functioning, as fatty acids regulate glucose and glutamine metabolism and mitochondrial depolarization.


Poli, G. and R. J. Schaur (2000). "4-Hydroxynonenal in the pathomechanisms of oxidative stress." IUBMB Life 50(4-5): 315-21.

            Here we review the current knowledge on the biochemistry and molecular pathology of oxidative stress with specific regard to a major aldehydic end-product stemming from peroxidation of biomembranes, that is 4-hydroxynonenal (HNE). This multifunctional molecule, which derives from the most represented class of polyunsaturated fatty acids in the membranes, is potentially able to undergo a number of reactions with proteins, phospholipids, and nucleic acids. Despite an active metabolism in most of the cell types, HNE can be detected in several biological tissues by means of sufficiently precise methods, although with different sensitivity. In particular, relatively high steady-state levels of HNE are often detectable in a large variety of human disease processes, pointing to some involvement of the aldehyde in their pathogenesis. Among the prominent pathobiochemical effects of HNE is its remarkable stimulation of fibrogenesis and inflammation, which indicates a potential contribution of the aldehyde to the pathogenesis of several chronic diseases, whose progression is indeed supported by inflammatory reactions and characterized by fibrosis. Further, of interest appears to be the ability of HNE to modulate cell proliferation through interference with the activity of cyclins and protein kinases and with the apoptotic machinery. Finally, on the basis of the already achieved evidence, pursuing investigation of the role of HNE in signal transduction and gene expression seems very promising.


Pietta, P. G. (2000). "Flavonoids as antioxidants." J Nat Prod 63(7): 1035-42.

            Flavonoids are phenolic substances isolated from a wide range of vascular plants, with over 8000 individual compounds known. They act in plants as antioxidants, antimicrobials, photoreceptors, visual attractors, feeding repellants, and for light screening. Many studies have suggested that flavonoids exhibit biological activities, including antiallergenic, antiviral, antiinflammatory, and vasodilating actions. However, most interest has been devoted to the antioxidant activity of flavonoids, which is due to their ability to reduce free radical formation and to scavenge free radicals. The capacity of flavonoids to act as antioxidants in vitro has been the subject of several studies in the past years, and important structure-activity relationships of the antioxidant activity have been established. The antioxidant efficacy of flavonoids in vivo is less documented, presumably because of the limited knowledge on their uptake in humans. Most ingested flavonoids are extensively degraded to various phenolic acids, some of which still possess a radical-scavenging ability. Both the absorbed flavonoids and their metabolites may display an in vivo antioxidant activity, which is evidenced experimentally by the increase of the plasma antioxidant status, the sparing effect on vitamin E of erythrocyte membranes and low-density lipoproteins, and the preservation of erythrocyte membrane polyunsaturated fatty acids. This review presents the current knowledge on structural aspects and in vitro antioxidant capacity of most common flavonoids as well as in vivo antioxidant activity and effects on endogenous antioxidants.


Pepe, S. (2000). "Mitochondrial function in ischaemia and reperfusion of the ageing heart." Clin Exp Pharmacol Physiol 27(9): 745-50.

            1. In addition to Ca2+-dependent mediation of excitation-contraction coupling during cardiac work and ATP hydrolysis, Ca2+ also stimulates the Krebs' cycle and mitochondrial matrix dehydrogenases to maintain the nicotinamide adenine dinucleotide redox potential and ATP synthesis. Thus, the balance between energy demand and supply is maintained during increases in cardiac work by elevated cytosolic Ca2+ that is transmitted to the mitochondrial matrix via regulation of uniporter and antiporter pathways across the inner mitochondrial membrane. 2. Brief ischaemia perturbs Ca2+ homeostasis but mitochondrial buffering of Ca2+ permits maintained mitochondrial function. However, prolonged ischaemia and reperfusion causes Ca2+ 'overload' at supramicromolar levels. The onset of vicious cycles that abrogate contractile function and, ultimately, may cause irreversible cell injury involves: (i) loss of ionic homeostasis, energy production and anti-oxidant enzyme activity; (ii) activation of phospholipases; and (iii) accumulation of free radicals, membrane lipid peroxidation products and protein adducts. 3. Increased permeability of the inner mitochondrial membrane to solutes occurs causing mitochondrial swelling, 'proton leak', reduced efficiency of the respiratory chain and uncoupling of oxidative phosphorylation. The opening of the mitochondrial permeability transition pore is potentiated by high mitochondrial Ca2+ and inducers, such as Pi, long-chain acyl coenzyme (Co)A and oxygen free radicals. Opening of this channel depolarizes the mitochondrion and dissipates the H+ electrochemical gradient (delta muH), preventing oxidative phosphorylation. Together with the release of cytochrome c and subsequent activation of caspase pathways, these events precede cell death. 4. Compared with younger counterparts, the senescent myocardium has a reduced capacity to recover from ischaemia and reperfusion. The consequent events described above are augmented in ageing. Elevated mitochondrial Ca2+ and increased dehydrogenase activation are linked to inefficient mitochondrial function and limited postischaemic recovery of contractile function. 5. Notably, a distinct decrease in the ratio of mitochondrial membrane omega-3 to omega-6 polyunsaturated fatty acids (PUFA) and a decrease in the mitochondrial phospholipid cardiolipin occurs in aged rat hearts. A diet rich in omega-3 PUFA directly increases membrane omega-3:omega-6 PUFA and cardiolipin content and also facilitates improved tolerance of ischaemia and reperfusion. A major consequence of dietary omega-3 PUFA may be the effect of altered mitochondrial Ca2+ flux and Ca2+-dependent processes.


Parang, K., L. I. Wiebe, et al. (2000). "Novel approaches for designing 5'-O-ester prodrugs of 3'-azido-2', 3'-dideoxythymidine (AZT)." Curr Med Chem 7(10): 995-1039.

            3'-Azido-2',3'-dideoxythymidine (AZT, 1, zidovudine, RetrovirTM) is used to treat patients with human immunodeficiency virus (HIV) infection. AZT, after conversion to AZT-5'-triphosphate (AZT-TP) by cellular enzymes, inhibits HIV-reverse transcriptase (HIV-RT). The major clinical limitations of AZT are due to clinical toxicities that include bone marrow suppression, hepatic abnormalities and myopathy, absolute dependence on host cell kinase-mediated activation which leads to low activity, limited brain uptake, a short half-life of about one hour in plasma that dictates frequent administration to maintain therapeutic drug levels, low potential for metabolic activation and/or high susceptibility to catabolism, and the rapid development of resistance by HIV-1. These limitations have prompted the development of strategies for designing prodrugs of AZT. A variety of 5'-O-substituted prodrugs of AZT constitute the subject of this review. The drug-design rationale on which these approaches are based is that the ester conjugate will be converted by hydrolysis and/or enzymatic cleavage to AZT or its 5&prime;-monophosphate (AZT-MP). Most prodrug derivatives of AZT have been prepared by derivatization of AZT at its 5'-O position to provide two prominent classes of compounds that encompass: A) 5'-O-carboxylic esters derived from 1) cyclic 5'-O-carboxylic acids such as steroidal 17b-carboxylic acids, 1-adamantanecarboxylic acid, bicyclam carboxylic acid derivatives, O-acetylsalicylic acid, and carbohydrate derivatives, 2) amino acids, 3) 1, 4-dihydro-1-methyl-3-pyridinylcarboxylic acid, 4) aliphatic fatty acid analogs such as myristic acid containing a heteroatom, or without a heteroatom such as stearic acid, and 5) long chain polyunsaturated fatty acid analogs such as retinoic acid, and B) masked phosphates such as 1) phosphodiesters that include monoalkyl or monoaryl phosphate, carbohydrate, ether lipid, ester lipid, and foscarnet derivatives, 2) a variety of phosphotriesters that include dialkylphosphotriesters, diarylphosphotriesters, glycolate and lactate phosphotriesters, phosphotriester approaches using simultaneous enzymatic and chemical hydrolysis of bis(4-acyloxybenzyl) esters, bis(S-acyl-2-thioethyl) (SATE) esters, cyclosaligenyl prodrugs, glycosyl phosphotriesters, and steroidal phosphotriesters, 3) phosphoramidate derivatives, 4) dinucleoside phosphate derivatives that possess a second anti-HIV moiety such as AZT-P-ddA, AZT-P-ddI, AZTP2AZT, AZTP2ACV), and 5) 5'-hydrogen phosphonate and 5'-methylene phosphonate derivatives of AZT. In these prodrugs, the conjugating moiety is linked to AZT via a 5'-O-ester or 5'-O-phosphate group. 5'-O-Substituted AZT prodrugs have been designed with the objectives of improving anti-HIV activity, enhancing blood-brain barrier penetration, modifying pharmacokinetic properties to increase plasma half-life and improving drug delivery with respect to site-specific targeting or drug localization. Bypassing the first phosphorylation step, regulating transport and conferring sustained release of AZT prolong its duration of action, decrease toxicity and improve patient acceptability. The properties of these prodrugs and their anti-HIV activities are now reviewed.


Osmundsen, H. and P. Clouet (2000). "Metabolic effects of omega-3 fatty acids." Biofactors 13(1-4): 5-8.

            Some metabolic effects of dietary marine oils, or of dietary eicosapentaenoic or docosahexaenoic acid are reviewed. It is pointed out that docosahexaenoic acid appears more effective as regards induction of peroxisomal beta-oxidation. Similarly, docosahexaenoic appears more powerful in terms of suppression of hepatic delta9-desaturase activity and mRNA-levels. The potential inhibitory effect of polyunsaturated fatty acids, particularly docosahexaenoic acid, on mitochondrial beta-oxidation is discussed. Experiments with rats suggesting that the hypolipidaemic response of eicosapentaenoic acid is more marked when the fatty acid was given to fed rats, as compared to fasted rats, are discussed.


Neuringer, M. (2000). "Infant vision and retinal function in studies of dietary long-chain polyunsaturated fatty acids: methods, results, and implications." Am J Clin Nutr 71(1 Suppl): 256S-67S.

            Animal and human studies have documented several effects of different dietary and tissue concentrations of long-chain polyunsaturated fatty acids (LCPUFAs) on retinal function and vision. The enhanced visual development associated with increased intakes of LCPUFAs, particularly docosahexaenoic acid (DHA), provides the strongest evidence for the importance of these fatty acids in infant nutrition. The 2 primary visual measures used to assess the efficacy of infant formula LCPUFA supplementation are the electroretinogram and visual acuity. This review briefly describes the methodology, neural basis, and interpretation of these measures, as well as other measures of visual development that may be used to extend the functional evaluation of infants fed formulas with different fatty acid compositions.


Motil, K. J. (2000). "Infant feeding: a critical look at infant formulas." Curr Opin Pediatr 12(5): 469-76.

            Commercially available infant formulas serve as the best alternative to human milk when breastfeeding is not possible. Infant formulas are designed specifically to mimic the composition of human milk or the functional aspects of human milk feeding. This review highlights the issues related to the composition of infant formulas. The most hotly debated issue currently is whether to add long-chain polyunsaturated fatty acids to infant formulas. Other controversial topics include the safety and efficacy of soy-based protein formulas, protein quantity and quality as they relate to the infant's nutritional needs and feeding tolerance, and the replacement of lactose with other carbohydrate sources for specialized infant formulas. Recent modifications in the fat blend of infant formulas have led to improved fat digestibility. However, the full spectrum of benefits associated with the addition of nucleotides awaits further study. Modifications to infant formulas are made when the preponderance of scientific evidence suggests that the compositional change will better meet the nutritional needs of the infant.


Mizugaki, M. (2000). "[Microdetermination of eicosanoids using mass spectrometry]." Nippon Yakurigaku Zasshi 115(4): 244-50.

            Prostaglandins (PGs), thromboxanes (TXs) and leukotrienes (LTs), named eicosanoids, are derived from polyunsaturated fatty acids such as arachidonic and eicosapentaenoic acids. Eicosanoids have various physiological actions, and they are closely associated with various pathological conditions. Quantitative analysis of eicosanoids production, therefore, may be useful as an index of pathological states and medical therapeutic effects. Quantitative methods require high sensitivity and selectivity because of the low concentration, short half-life time of their active compounds and coexistence of structurally similar interfering compounds. From this view point, gas chromatography/mass spectrometry (GC/MS) is one of the useful techniques for determination of eicosanoids. Using GC/MS, we have developed determination methods for various eicosanoids and applied them to clinical studies. Although GC/MS is highly sensitive and selective, it often requires tedious and time-consuming derivatization and purification procedures. Liquid chromatography/mass spectrometry (LC/MS), on the other hand, is a simple and rapid determination method. LC/MS is sufficiently applicable to determination of prostanoids, and we previously established a new determination method for LTE4. In the present paper, I describe an advanced determination method for 11-dehydro TXB2, a stable urinary metabolite of TXA2, using liquid chromatography/tandem mass spectrometry (LC/MS-MS).


Mattos, R., C. R. Staples, et al. (2000). "Effects of dietary fatty acids on reproduction in ruminants." Rev Reprod 5(1): 38-45.

            Fats in the diet can influence reproduction positively by altering both ovarian follicle and corpus luteum function via improved energy status and by increasing precursors for the synthesis of reproductive hormones such as steroids and prostaglandins. Dietary fatty acids of the n-3 family reduce ovarian and endometrial synthesis of prostaglandin F2alpha, decrease ovulation rate in rats and delay parturition in sheep and humans. Polyunsaturated fatty acids such as linoleic, linolenic, eicosapentaenoic and docosahexaenoic acids may inhibit prostaglandin F2alpha synthesis through mechanisms such as decreased availability of its precursor arachidonic acid, an increased competition by these fatty acids with arachidonic acid for binding to prostaglandin H synthase, and inhibition of prostaglandin H synthase synthesis and activity. It is not known whether polyunsaturated fatty acids regulate expression of candidate genes such as phospholipase A2 and prostaglandin H synthase via activation of nuclear transcription factors such as peroxisome proliferator-activated receptors. Manipulation of the fatty acid profile of the diet can be used potentially to amplify suppression of uterine synthesis of prostaglandin F2alpha during early pregnancy in cattle, which may contribute to a reduction in embryonic mortality. Feeding fats and targeting of fatty acids to reproductive tissues may be a potential strategy to integrate nutrition and reproductive management to improve animal productivity.


Masson, M., T. Loftsson, et al. (2000). "Marine lipids for prodrugs, soft compounds and other pharmaceutical applications." Pharmazie 55(3): 172-7.

            In the present review we discuss different approaches to pharmaceutical applications of marine lipids. Investigation of the use of marine lipids as dermal permeation enhancers, the synthesis of triacylglycerols highly enriched in polyunsaturated fatty acids, dermal pro-drugs derivatives of unsaturated fatty acids and diacyl glyceryl derivatives, and the possible synthesis of soft disinfectants from marine fatty acids.


Mann, N. (2000). "Dietary lean red meat and human evolution." Eur J Nutr 39(2): 71-9.

            Scientific evidence is accumulating that meat itself is not a risk factor for Western lifestyle diseases such as cardiovascular disease, but rather the risk stems from the excessive fat and particularly saturated fat associated with the meat of modern domesticated animals. In our own studies, we have shown evidence that diets high in lean red meat can actually lower plasma cholesterol, contribute significantly to tissue omega-3 fatty acid and provide a good source of iron, zinc and vitamin B12. A study of human and pre-human diet history shows that for a period of at least 2 million years the human ancestral line had been consuming increasing quantities of meat. During that time, evolutionary selection was in action, adapting our genetic make up and hence our physiological features to a diet high in lean meat. This meat was wild game meat, low in total and saturated fat and relatively rich in polyunsaturated fatty acids (PUFA). The evidence presented in this review looks at various lines of study which indicate the reliance on meat intake as a major energy source by pre-agricultural humans. The distinct fields briefly reviewed include: fossil isotope studies, human gut morphology, human encephalisation and energy requirements, optimal foraging theory, insulin resistance and studies on hunter-gatherer societies. In conclusion, lean meat is a healthy and beneficial component of any well-balanced diet as long as it is fat trimmed and consumed as part of a varied diet.


Makrides, M. and R. A. Gibson (2000). "Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation." Am J Clin Nutr 71(1 Suppl): 307S-11S.

            Much interest has been expressed about the long-chain polyunsaturated fatty acid (LCPUFA) requirements of both preterm and term infants, whereas relatively little attention has been given to the LCPUFA needs of mothers, who may provide the primary source of LCPUFAs for their fetuses and breast-fed infants. Although maternal requirements for LCPUFAs are difficult to estimate because of large body stores and the capacity to synthesize LCPUFAs from precursors, biochemical and clinical intervention studies have provided some clues. From a biochemical viewpoint, there appears to be no detectable reduction in plasma n-3 LCPUFA concentrations during pregnancy, whereas there is a clear decline during the early postpartum period. The postpartum decrease in maternal plasma docosahexaenoic acid (DHA) concentration is not instantaneous, may be long-term, is independent of lactation, and is reversible with dietary DHA supplementation (200-400 mg/d). From a functional standpoint, the results of randomized clinical studies suggest that n-3 LCPUFA supplementation during pregnancy does not affect the incidences of pregnancy-induced hypertension and preeclampsia without edema. However, n-3 LCPUFA supplementation may cause modest increases in the duration of gestation, birth weight, or both. To date, there is little evidence of harm as a result of n-3 LCPUFA supplementation during either pregnancy or lactation. However, researchers need to further elucidate any potential benefits of supplementation for mothers and infants. Careful attention should be paid to study design, measurement of appropriate health outcomes, and defining minimum and maximum plasma n-3 LCPUFA concentrations that are optimal for both mothers and infants.


Lewis, N. M., S. Seburg, et al. (2000). "Enriched eggs as a source of N-3 polyunsaturated fatty acids for humans." Poult Sci 79(7): 971-4.

            Dietary intake of omega-3 fatty acids (n-3 PUFA) decreases the risk of heart disease, inhibits the growth of prostate and breast cancer, delays the loss of immunological functions, and is required for normal fetal brain and visual development. The US has not established a recommended daily intake for n-3 PUFA. However, Canada has established the Canadian Recommended Nutrient Intake (CRNI) at 0.5% of energy. Dietary sources of n-3 PUFA include fish, chicken, eggs, canola oil, and soybean oil. Food consumption studies in the US indicate that the majority of Americans do not meet the CRNI for n-3 PUFA. Mean n-3 PUFA consumption was 78% of the CRNI for Midwestern women during pregnancy. In Midwestern women at risk for breast cancer, the mean n-3 PUFA consumption is approximately 50% of the CRNI. Increased consumption of n-3 PUFA requires identification of a food source that the public would eat in sufficient amounts to meet recommended intake. N-3 PUFA-enriched eggs can be produced by modifying hens diets. When 70 g/kg of cod liver oil, canola oil, or linseed oil are added to a commercial control diet, the n-3 PUFA are increased from 1.2% of egg yolk fatty acids to 6.3, 4.6, and 7.8%, respectively. Feeding flaxseed increases linolenic acid in the egg yolk about 30-fold, and docosahexaenoic acid (DHA) increases nearly fourfold. When individuals are fed four n-3 PUFA-enriched eggs a day for 4 wk, plasma total cholesterol levels and low-density lipoprotein cholesterol (LDL-C) do not increase significantly. Plasma triglycerides (TG) are decreased by addition of n-3 PUFA-enriched eggs to the diet. N-3 PUFA may influence LDL particle size, causing a shift toward a less atherogenic particle. Blood platelet aggregation is significantly decreased in participants consuming n-3 PUFA-enriched eggs. Overall results of studies to date demonstrate positive effects and no negative effects from consumption of n-3-enriched eggs. Three n-3 PUFA-enriched eggs provide approximately the same amount of n-3 PUFA as one meal with fish. It is recommended that n-3 PUFA-enriched eggs be used as one source of n-3 PUFA to increase individual consumption to meet the current Canadian recommendations.


Lesage, F. and M. Lazdunski (2000). "Molecular and functional properties of two-pore-domain potassium channels." Am J Physiol Renal Physiol 279(5): F793-801.

            The two-pore-domain K(+) channels, or K(2P) channels, constitute a novel class of K(+) channel subunits. They have four transmembrane segments and are active as dimers. The tissue distribution of these channels is widespread, and they are found in both excitable and nonexcitable cells. K(2P) channels produce currents with unusual characteristics. They are quasi-instantaneous and noninactivating, and they are active at all membrane potentials and insensitive to the classic K(+) channel blockers. These properties designate them as background K(+) channels. They are expected to play a major role in setting the resting membrane potential in many cell types. Another salient feature of K(2P) channels is the diversity of their regulatory mechanisms. The weak inward rectifiers TWIK-1 and TWIK-2 are stimulated by activators of protein kinase C and decreased by internal acidification, the baseline TWIK-related acid-sensitive K(+) (TASK)-1 and TASK-2 channels are sensitive to external pH changes in a narrow range near physiological pH, and the TWIK-related (TREK)-1 and TWIK-related arachidonic acid-stimulated K(+) (TRAAK) channels are the first cloned polyunsaturated fatty acids-activated and mechanogated K(+) channels. The recent demonstration that TASK-1 and TREK-1 channels are activated by inhalational general anesthetics, and that TRAAK is activated by the neuroprotective agent riluzole, indicates that this novel class of K(+) channels is an interesting target for new therapeutic developments.


Latruffe, N., M. C. Malki, et al. (2000). "Regulation of the peroxisomal beta-oxidation-dependent pathway by peroxisome proliferator-activated receptor alpha and kinases." Biochem Pharmacol 60(8): 1027-32.

            The first PPAR (peroxisome proliferator-activated receptor) was cloned in 1990 by Issemann and Green (Nature 347:645-650). This nuclear receptor was so named since it is activated by peroxisome proliferators including several drugs of the fibrate family, plasticizers, and herbicides. This receptor belongs to the steroid receptor superfamily. After activation by a specific ligand, it binds to a DNA response element, PPRE (peroxisome proliferator response element), which is a DR-1 direct repeat of the consensus sequence TGACCT x TGACCT. This mechanism leads to the transcriptional activation of target genes (Motojima et al., J Biol Chem 273:16710-16714, 1998). After the first discovery, several isoforms were characterized in most of the vertebrates investigated. PPAR alpha, activated by hypolipidemic agents of the fibrate family or by leukotrienes; regulates lipid metabolism as well as the detoxifying enzyme-encoding genes. PPAR beta/delta, which is not very well known yet, appears to be more specifically activated by fatty acids. PPAR gamma (subisoforms 1, 2, 3) is activated by the prostaglandin PGJ2 or by antidiabetic thiazolidinediones (Vamecq and Latruffe, Lancet 354:411-418, 1999). This latter isoform is involved in adipogenesis. The level of PPAR expression is largely dependent on the tissue type. PPAR alpha is mainly expressed in liver and kidney, while PPAR beta/delta is almost constitutively expressed. In contrast, PPAR gamma is largely expressed in white adipose tissue. PPAR is a transcriptional factor that requires other nuclear proteins in order to function, i.e. RXRalpha (9-cis-retinoic acid receptor alpha) in all cases in addition to other regulatory proteins. Peroxisomes are specific organelles for very long-chain and polyunsaturated fatty acid catabolism. From our results and those of others, the inventory of the role of PPAR alpha in the regulation of peroxisomal fatty acid beta-oxidation is presented. In relation to this, we showed that PPAR alpha activates peroxisomal beta-oxidation-encoding genes such as acyl-CoA oxidase, multifunctional protein, and thiolase (Bardot et al., FEBS Lett 360:183-186, 1995). Moreover, rat liver PPAR alpha regulatory activity is dependent on its phosphorylated state (Passilly et al., Biochem Pharmacol 58:1001-1008, 1999). On the other hand, some signal transduction pathways such as protein kinase C are modified by peroxisome proliferators that increase the phosphorylation level of some specific proteins (Passilly et al. Eur J Biochem 230:316-321, 1995). From all these findings, PPAR alpha and kinases appear to play an important role in lipid homeostasis.


Kris-Etherton, P. M., D. S. Taylor, et al. (2000). "Polyunsaturated fatty acids in the food chain in the United States." Am J Clin Nutr 71(1 Suppl): 179S-88S.

            In the United States, intake of n-3 fatty acids is approximately 1.6 g/d ( approximately 0.7% of energy), of which 1.4 g is alpha-linolenic acid (ALA; 18:3) and 0.1-0.2 g is eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6). The primary sources of ALA are vegetable oils, principally soybean and canola. The predominant sources of EPA and DHA are fish and fish oils. Intake data indicate that the ratio of n-6 to n-3 fatty acids is approximately 9.8:1. Food disappearance data between 1985 and 1994 indicate that the ratio of n-6 to n-3 fatty acids has decreased from 12.4:1 to 10.6:1. This reflects a change in the profile of vegetable oils consumed and, in particular, an approximate 5.5-fold increase in canola oil use. The ratio of n-6 to n-3 fatty acids is still much higher than that recommended (ie, 2.3:1). Lower ratios increase endogenous conversion of ALA to EPA and DHA. Attaining the proposed recommended combined EPA and DHA intake of 0.65 g/d will require an approximately 4-fold increase in fish consumption in the United States. Alternative strategies, such as food enrichment and the use of biotechnology to manipulate the EPA and DHA as well as ALA contents of the food supply, will become increasingly important in increasing n-3 fatty acid intake in the US population.


Kidd, P. M. (2000). "Parkinson's disease as multifactorial oxidative neurodegeneration: implications for integrative management." Altern Med Rev 5(6): 502-29.

            Parkinson's disease (PD) is the most common movement pathology, severely afflicting dopaminergic neurons within the substantia nigra (SN) along with non-dopaminergic, extra-nigral projection bundles that control circuits for sensory, associative, premotor, and motor pathways. Clinical, experimental, microanatomic, and biochemical evidence suggests PD involves multifactorial, oxidative neurodegeneration, and that levodopa therapy adds to the oxidative burden. The SN is uniquely vulnerable to oxidative damage, having high content of oxidizable dopamine, neuromelanin, polyunsaturated fatty acids, and iron, and relatively low antioxidant complement with high metabolic rate. Oxidative phosphorylation abnormalities impair energetics in the SN mitochondria, also intensifying oxygen free radical generation. These pro-oxidative factors combine within the SN dopaminergic neurons to create extreme vulnerability to oxidative challenge. Epidemiologic studies and long-term tracking of victims of MPTP (1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine) poisoning, suggest oxidative stress compounded by exogenous toxins may trigger the neurodegenerative progression of PD. Rational, integrative management of PD requires: (1) dietary revision, especially to lower calories; (2) rebalancing of essential fatty acid intake away from pro-inflammatory and toward anti-inflammatory prostaglandins; (3) aggressive repletion of glutathione and other nutrient antioxidants and cofactors; (4) energy nutrients acetyl L-carnitine, coenzyme Q10, NADH, and the membrane phospholipid phosphatidylserine (PS), (5) chelation as necessary for heavy metals; and (6) liver P450 detoxification support.


Kang, J. X. and A. Leaf (2000). "Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids." Am J Clin Nutr 71(1 Suppl): 202S-7S.

            In animal feeding studies, and probably in humans, n-3 polyunsaturated fatty acids (PUFAs) prevent fatal ischemia-induced cardiac arrhythmias. We showed that n-3 PUFAs also prevented such arrhythmias in surgically prepared, conscious, exercising dogs. The mechanism of the antiarrhythmic action of n-3 PUFAs has been studied in spontaneously contracting cultured cardiac myocytes of neonatal rats. Adding arrhythmogenic toxins (eg, ouabain, high Ca(2+), lysophosphatidylcholine, beta-adrenergic agonist, acylcarnitine, and the Ca(2+) ionophore) to the myocyte perfusate caused tachycardia, contracture, and fibrillation of the cultured myocytes. Adding eicosapentaenoic acid (EPA: 5-15 micromol/L) to the superfusate before adding the toxins prevented the expected tachyarrhythmias. If the arrhythmias were first induced, adding the EPA to the superfusate terminated the arrhythmias. This antiarrhythmic action occurred with dietary n-3 and n-6 PUFAs; saturated fatty acids and the monounsaturated oleic acid induced no such action. Arachidonic acid (AA; 20:4n-6) is anomalous because in one-third of the tests it provoked severe arrhythmias, which were found to result from cyclooxygenase metabolites of AA. When cyclooxygenase inhibitors were added with the AA, the antiarrhythmic effect was like those of EPA and DHA. The action of the n-3 and n-6 PUFAs is to stabilize electrically every myocyte in the heart by increasing the electrical stimulus required to elicit an action potential by approximately 50% and prolonging the relative refractory time by approximately 150%. These electrophysiologic effects result from an action of the free PUFAs to modulate sodium and calcium currents in the myocytes. The PUFAs also modulate sodium and calcium channels and have anticonvulsant activity in brain cells.


Joy, C. B., R. Mumby-Croft, et al. (2000). "Polyunsaturated fatty acid (fish or evening primrose oil) for schizophrenia." Cochrane Database Syst Rev(2): CD001257.

            BACKGROUND: Limited evidence gives support to an hypothesis suggesting that the symptoms of schizophrenia may result from altered neuronal membrane structure and metabolism. The latter are dependent on blood plasma levels of certain essential fatty acids (EFAs) and their metabolites. Several studies have shown those with schizophrenia often have low levels of the particular EFAs necessary for normal nerve cell membrane metabolism. OBJECTIVES: To review the effects of supplementing standard antipsychotic treatment with polyunsaturated fatty acids, whether essential (EFAs) or non-essential, for those with schizophrenia and, in recent updates to also evaluate the effects of EFA's as a sole antipsychotic treatment. To evaluate the relative efficacy of different types of fatty acid supplementation. SEARCH STRATEGY: Relevant randomised trials were identified by searching the following electronic databases: Biological Abstracts (1985-1998), CINAHL (1982-1998), Cochrane Library (Issue 4, 1999), Cochrane Schizophrenia Group's Register (February 2000), EMBASE (1980-1998), MEDLINE (1966-1998) and PsycLIT (1974-1998). In addition, reviewers searched references of included and excluded studies and contacted authors to identify further studies. SELECTION CRITERIA: All randomised clinical trials of polyunsaturated fatty acid supplementation to standard treatment or as primary intervention for schizophrenia (however defined) versus standard care. DATA COLLECTION AND ANALYSIS: Reviewers evaluated data independently and analysed on an intention-to-treat basis. They assumed that people who left the study early or were lost to follow-up had no improvement. Where possible and appropriate relative risk (RR) and their 95% confidence intervals (CI) were calculated. The number needed to treat (NNT) was estimated. For continuous data weighted mean differences (WMD) and their 95% confidence intervals were calculated. Data were inspected for heterogeneity and publication biases. MAIN RESULTS: Four relatively small trials (total n=204) showed low levels of loss to follow up and adverse effects for those taking essential fatty acids. Early results from a few trials suggest a positive effect of eicosapentaenoic acid (EPA) over placebo for scale-derived mental state outcomes. The data, however, is limited making these results difficult to analyse and interpret with confidence. A single small study (n=30) investigated the value of using EPA as sole treatment for people hospitalised for relapse. Results suggest that EPA may help one third of people avoid instigation of standard antipsychotic drugs for 12 weeks (RR 0.6, CI 0.4-0.91). There were no clear effects of primrose oil (omega-6) EFA supplementation. REVIEWER'S CONCLUSIONS: All data are preliminary, but results look encouraging for fish oil. EPA does not seem harmful, may be acceptable to people with schizophrenia and have moderately positive effect. A further trial is soon to be reported from the USA and more are underway or planned in the South Africa and Norway. Considering that EPA may be an acceptable intervention, large, long simple studies reporting clincially meaningful data should be anticipated.


James, M. J., R. A. Gibson, et al. (2000). "Dietary polyunsaturated fatty acids and inflammatory mediator production." Am J Clin Nutr 71(1 Suppl): 343S-8S.

            Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = 90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.


Innis, S. M. (2000). "The role of dietary n-6 and n-3 fatty acids in the developing brain." Dev Neurosci 22(5-6): 474-80.

            The dietary requirements for essential fatty acids and the possibility of a specific role for the polyunsaturated fatty acid docosahexaenoic acid (DHA) is one of the most controversial areas in infant nutrition. DHA is found in unusually high concentrations in the brain and is selectively accumulated during fetal and infant brain growth. DHA can be synthesised through a complex series of chain elongation-desaturation reactions from alpha-linolenic acid, but the efficiency of this process in young infants is not clear. Clinical studies on the potential benefits to neural development of dietary DHA have yielded conflicting results. Recent studies have provided evidence that plasma DHA is available to developing brain and that DHA is involved in dopamine and serotonin metabolism. These findings should guide clinical studies to more sensitive measures of the functional roles of dietary n-3 fatty acids and to clinical conditions where n-3 fatty acids may have benefit.


Hornstra, G. (2000). "Essential fatty acids in mothers and their neonates." Am J Clin Nutr 71(5 Suppl): 1262S-9S.

            Essential fatty acids (EFAs) and their long-chain polyenes (LCPs) are indispensable for human development and health. Because humans cannot synthesize EFAs and can only ineffectively synthesize LCPs, EFAs need to be consumed as part of the diet. Consequently, the polyunsaturated fatty acid (PUFA) status of the developing fetus depends on that of its mother, as confirmed by the positive relation between maternal PUFA consumption and neonatal PUFA status. Pregnancy is associated with a decrease in the biochemical PUFA status, and normalization after delivery is slow. This is particularly true for docosahexaenoic acid (DHA) because, on the basis of the current habitual diet, birth spacing appeared to be insufficient for the maternal DHA status to normalize completely. Because of the decrease in PUFA status during pregnancy, the neonatal PUFA status may not be optimal. This view is supported by the lower neonatal PUFA status after multiple than after single births. The neonatal PUFA status can be increased by maternal PUFA supplementation during pregnancy. For optimum results, the supplement should contain both n-6 and n-3 PUFAs. The PUFA status of preterm neonates is significantly lower than that of term infants, which is a physiologic condition. Because the neonatal DHA status correlates positively with birth weight, birth length, and head circumference, maternal DHA supplementation during pregnancy may improve the prognosis of preterm infants. In term neonates, maternal linoleic acid consumption correlates negatively with neonatal head circumference. This suggests that the ratio of n-3 to n-6 PUFAs in the maternal diet should be increased. Consumption of trans unsaturated fatty acids appeared to be associated with lower maternal and neonatal PUFA status. Therefore, it seems prudent to minimize the consumption of trans fatty acids during pregnancy.


Gulumian, M. (2000). "The ability of mineral dusts and fibres to initiate lipid peroxidation. Part II: relationship to different particle-induced pathological effects." Redox Rep 5(6): 325-51.

            Exposure to pathogenic mineral dusts and fibres is associated with pulmonary changes including fibrosis and cancer. Investigations into aetiological mechanisms of these diseases have identified modifications in specific macromolecules as well as changes in certain early processes, which have preceded fibrosis and cancer. Peroxidation of lipids is one such modification, which is observed following exposure to mineral dusts and fibres. Their ability to initiate lipid peroxidation and the parameters that determine this ability have recently been reviewed. Part II of this review examines the relationship between the capacity of mineral dusts and fibres to initiate lipid peroxidation and a number of pathological changes they produce. The oxidative modification of polyunsaturated fatty acids is a major contributor to membrane damage in cells and has been implicated in a great variety of pathological processes. In most pathological conditions where an induction of lipid peroxidation is observed it is assumed to be the consequence of disease, without further establishing if the induction of lipid peroxidation may have preceded or accompanied the disease. In the great majority of instances, however, despite the difficulty in proving this association, a causal relationship between lipid peroxidation and disease cannot be ruled out.


Gogos, C. A., A. Skoutelis, et al. (2000). "The effects of lipids on the immune response of patients with cancer." J Nutr Health Aging 4(3): 172-5.

            The role of diet and certain nutritional factors in the etiology or promotion of various malignant diseases has widely been studied. A link between dietary fat and cancer has long been proposed through various human epidemiologic and experimental data. High fat diets are associated with a high incidence and accelerated development of certain tumors, while there is evidence that dietary w-3 fatty acids have beneficial effects in cancer growth and metastasis. The relation between the different lipid formulations and cancer appears to be mainly related to the influence of specific fatty acids on the synthesis of the immunosuppressive prostaglandin E2. Omega-3 polyunsaturated fatty acids seem to have an anti-tumor effect through their immunomodulating, anti-inflammatory action and direct inhibition of tumor cell proliferation via alteration in prostaglandin E2 production.


Gibson, R. A. and M. Makrides (2000). "n-3 polyunsaturated fatty acid requirements of term infants." Am J Clin Nutr 71(1 Suppl): 251S-5S.

            The benchmarks for human nutrient requirements are the recommended dietary intakes (RDIs). However, the RDIs are set to prevent a clinical deficiency state in an otherwise healthy population and there are few nutrient recommendations set with the goal of achieving an optimal or maximal state of nutrition and health. This is becoming an increasing challenge with the introduction of many nutraceuticals and functional foods, a prime example being the debate surrounding the introduction of long-chain polyunsaturated fatty acids (LCPUFAs) into infant formulas. Most expert nutrition committees have used the fatty acid composition of breast milk as a basis for recommendations for infant formulas, with little information on the minimum absolute requirement for essential PUFAs. It has been difficult to determine a minimum requirement for fatty acids because 1) LCPUFAs can be synthesized from precursor fatty acids, 2) plasma n-3 LCPUFA concentrations representing deficiency and sufficiency are not clearly defined, and 3) there are no recognized clinical tests for n-3 LCPUFA deficiency and sufficiency. Therefore, there is a clear need to associate a measure of LCPUFA status with a specific functional outcome before any recommendations can be made for achieving optimal or maximal LCPUFA status.


Freeman, M. P. (2000). "Omega-3 fatty acids in psychiatry: a review." Ann Clin Psychiatry 12(3): 159-65.

            Omega-3 fatty acids are long-chain, polyunsaturated fatty acids found in plant and marine sources. Unlike saturated fats, which have been shown to have negative health consequences, omega-3 fatty acids are polyunsaturated fatty acids that have been associated with many health benefits. Omega-3 fatty acids may prove to be efficacious in a number of psychiatric disorders. Mood disorders have been associated with abnormalities in fatty acid composition. Several lines of evidence suggest that diminished omega-3 fatty acid concentrations are associated with mood disorders. Clinical data are not yet available regarding omega-3 fatty acids in the treatment of major depression. However, one double-blind treatment trial has been conducted in bipolar disorder. Also, substantial evidence does exist supporting a potential role of omega-3 fatty acids in schizophrenia, although treatment data are needed. A case has been reported in which a patient with schizophrenia was successfully treated with omega-3 fatty acids. Controlled studies are necessary to explore the potential treatment of schizophrenia with omega-3 fatty acids. Omega-3 fatty acids may also be helpful in the treatment of dementia. Furthermore, omega-3 fatty acids may prove to be a safe and efficacious treatment for psychiatric disorders in pregnancy and in breastfeeding.


Fidler, N. and B. Koletzko (2000). "The fatty acid composition of human colostrum." Eur J Nutr 39(1): 31-7.

            We reviewed 15 studies reporting on the fatty acid composition of colostrum lipids from 16 geographic regions: 11 European studies and one study each from Central America, the Caribbean, Australia and Asia. The contents of essential fatty acids, saturates and polyunsaturates were similar in the southern European countries Spain, Slovenia and France. Colostrum of St. Lucian women was high in saturates and low in oleic acid, reflecting a high-carbohydrate, low-fat diet. Abundant fish intake was reflected in high contents of docosahexaenoic acid and total n-3 long-chain polyunsaturated fatty acids in St. Lucia. Two French studies published with an interval of two years showed a very similar colostrum fatty acid composition, whereas two German studies obtained with an interval of 14 years showed higher docosahexaenoic acid and arachidonic acid contents in the later study, with an unchanged n-6/n-3 long-chain polyunsaturated fatty acid ratio. Studies from Spain reported a decline of alpha-linolenic acid in colostrum over a time period of 13 years. Colostrum of Australian women contained the lowest polyunsaturated/saturated and n-6/n-3 long-chain polyunsaturated fatty acids ratios (0.28 and 1.58) and the lowest contents of linoleic and alpha-linolenic acids (7.8 and 0.4 wt.%). In contrast, the contents of docosahexaenoic acid, eicosapentaenoic acid and total n-3 long-chain polyunsaturated fatty acids (0.6, 0.4 and 1.4 wt.%) were higher in Australian than in European samples. Fatty acid composition of human colostrum appears to be markedly influenced by geographic differences in maternal dietary composition.


Farooqui, A. A., L. A. Horrocks, et al. (2000). "Glycerophospholipids in brain: their metabolism, incorporation into membranes, functions, and involvement in neurological disorders." Chem Phys Lipids 106(1): 1-29.

            Neural membranes contain several classes of glycerophospholipids which turnover at different rates with respect to their structure and localization in different cells and membranes. The glycerophospholipid composition of neural membranes greatly alters their functional efficacy. The length of glycerophospholipid acyl chain and the degree of saturation are important determinants of many membrane characteristics including the formation of lateral domains that are rich in polyunsaturated fatty acids. Receptor-mediated degradation of glycerophospholipids by phospholipases A(l), A(2), C, and D results in generation of second messengers such as arachidonic acid, eicosanoids, platelet activating factor and diacylglycerol. Thus, neural membrane phospholipids are a reservoir for second messengers. They are also involved in apoptosis, modulation of activities of transporters, and membrane-bound enzymes. Marked alterations in neural membrane glycerophospholipid composition have been reported to occur in neurological disorders. These alterations result in changes in membrane fluidity and permeability. These processes along with the accumulation of lipid peroxides and compromised energy metabolism may be responsible for the neurodegeneration observed in neurological disorders.


Farooqui, A. A., L. A. Horrocks, et al. (2000). "Deacylation and reacylation of neural membrane glycerophospholipids." J Mol Neurosci 14(3): 123-35.

            The deacylation-reacylation cycle is an important mechanism responsible for the introduction of polyunsaturated fatty acids into neural membrane glycerophospholipids. It involves four enzymes, namely acyl-CoA synthetase, acyl-CoA hydrolase, acyl-CoA: lysophospholipid acyltransferase, and phospholipase A2. All of these enzymes have been purified and characterized from brain tissue. Under normal conditions, the stimulation of neural membrane receptors by neurotransmitters and growth factors results in the release of arachidonic acid from neural membrane glycerophospholipids. The released arachidonic acid acts as a second messenger itself. It can be further metabolized to eicosanoids, a group of second messengers involved in a variety of neurochemical functions. A lysophospholipid, the second product of reactions catalyzed by phospholipase A2, is rapidly acylated with acyl-CoA, resulting in the maintenance of the normal and essential neural membrane glycerophospholipid composition. However, under pathological situations (ischemia), the overstimulation of phospholipase A2 results in a rapid generation and accumulation of free fatty acids including arachidonic acid, eicosanoids, and lipid peroxides. This results in neural inflammation, oxidative stress, and neurodegeneration. In neural membranes, the deacylation-reacylation cycle maintains a balance between free and esterified fatty acids, resulting in low levels of arachidonic acid and lysophospholipids. This is necessary for not only normal membrane integrity and function, but also for the optimal activity of the membrane-bound enzymes, receptors, and ion channels involved in normal signal-transduction processes.


Eritsland, J. (2000). "Safety considerations of polyunsaturated fatty acids." Am J Clin Nutr 71(1 Suppl): 197S-201S.

            The n-6 and n-3 polyunsaturated fatty acids (PUFAs) are essential nutrients; intake of relatively small amounts of these fatty acids prevents nutritional deficiencies. Replacing dietary saturated fat with PUFAs may confer health gains. Experimental data support the notion that high intake of n-6 PUFAs may increase in vivo lipid peroxidation. This effect may be counteracted by dietary antioxidant supplementation. The influence of a high n-3 PUFA intake on measures of lipid peroxidation has been equivocal. In clinical trials, subjects who consumed diets rich in n-6 or n-3 PUFAs had fewer atherothrombotic endpoints than did control groups. In this report, data regarding the influence of PUFAs on lipid peroxidation as well as on cholesterol and glucose metabolism, hemostasis, and other aspects of interest are reviewed and discussed. Currently, daily intake of PUFAs as >10% of total energy is not recommended. Below this ceiling there is little evidence that high dietary intake of n-6 or n-3 PUFAs implies health risks.


Edwards, P. A., D. Tabor, et al. (2000). "Regulation of gene expression by SREBP and SCAP." Biochim Biophys Acta 1529(1-3): 103-13.

            Sterol regulatory element binding proteins (SREBPs) function as transcription factors that activate specific genes involved in cholesterol synthesis, endocytosis of low density lipoproteins, the synthesis of both saturated and unsaturated fatty acids and glucose metabolism. As such, these proteins provide a link between lipid and carbohydrate metabolism. There are three SREBPs, SREBP-1a, SREBP-1c and SREBP-2, that are encoded by two genes. SREBPs are synthesized as 125 kDa precursor proteins that are localized to the endoplasmic reticulum. The precursor is transported to the Golgi by a chaperone protein (SREBP-cleavage activating protein) and then cleaved by two proteases to release the mature, transcriptionally active 68 kDa amino terminal domain. Recent studies have shown that formation of mature SREBP is controlled at multiple levels in response to changes in the levels of oxysterols, insulin/glucose and polyunsaturated fatty acids. These recent findings have important clinical implications relevant to hyperlipidemia and diabetes and are the topic of this review.


Dutta-Roy, A. K. (2000). "Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta." Am J Clin Nutr 71(1 Suppl): 315S-22S.

            To understand the placental role in the processes responsible for the preferential accumulation of maternal long-chain polyunsaturated fatty acids (LCPUFAs) in the fetus, we investigated fatty acid uptake and metabolism in the human placenta. A preference for LCPUFAs over nonessential fatty acids has been observed in isolated human placental membranes as well as in BeWo cells, a human placental choriocarcinoma cell line. A placental plasma membrane fatty acid binding protein (p-FABP(pm)) with a molecular mass of approximately 40 kDa was identified. The purified p-FABP(pm) preferentially bound with essential fatty acids (EFAs) and LCPUFAs over nonessential fatty acids. Oleic acid was taken up least and docosahexaenoic acid (DHA) most by BeWo cells, whereas no such discrimination was observed in HepG2 liver cells. Studies on the distribution of radiolabeled fatty acids in the cellular lipids of BeWo cells showed that DHA is incorporated mainly into the triacylglycerol fraction, followed by the phospholipid fraction; the reverse is true for arachidonic acid (AA). The greater cellular uptake of DHA and its preferential incorporation into the triacylglycerol fraction suggests that both uptake and transport modes of DHA by the placenta to the fetus are different from those of AA. p-FABP(pm) antiserum preferentially decreased the uptake of LCPUFAs and EFAs by BeWo cells compared with preimmune serum. Together, these results show the preferential uptake of LCPUFAs by the placenta that is most probably mediated via the p-FABP(pm).


Donadio, J. V., Jr. (2000). "Use of fish oil to treat patients with immunoglobulin a nephropathy." Am J Clin Nutr 71(1 Suppl): 373S-5S.

            This review describes the use of fish oil in the treatment of patients with immunoglobulin (Ig) A nephropathy. IgA nephropathy is the most common glomerular disease worldwide. It has a variable course and leads to end-stage renal disease in a substantial number of cases. Among the 4 published randomized clinical trials that tested the efficacy of fish-oil treatment of IgA nephropathy, 2 reported beneficial effects on renal function and 2 showed negative results. In the largest trial conducted by my collaborative study group, convincing evidence was provided for protection against progressive renal disease after daily treatment for 2 y with fish oil providing 1.8 g eicosapentaenoic acid and 1.2 g docosahexaenoic acid-the 2 major n-3 polyunsaturated fatty acids in fish oil. Oral prednisone has also been advocated, especially in the treatment of children with IgA nephropathy. Two randomized trials are currently underway in the United States to resolve the discrepancy of results in previous fish-oil trials and to determine whether corticosteroids or fish oil is the better treatment of patients at risk for developing progressive disease; results of these studies are not yet available.


Decsi, T. and B. Koletzko (2000). "Effects of protein-energy malnutrition and human immunodeficiency virus-1 infection on essential fatty acid metabolism in children." Nutrition 16(6): 447-53.

            This report summarizes data on the availability of essential fatty acids (EFAs) and their long-chain polyunsaturated fatty acid (LCPUFA) metabolites in protein-energy malnutrition (PEM), in human immunodeficiency virus-1 (HIV-1) infection for which less information is available, and the combination of both PEM and HIV-1. The contribution of different EFAs and LCPUFAs to the fatty-acid composition of plasma and erythrocyte membrane lipids was found to be reduced in children with PEM in comparison with well-nourished children. In addition to limited dietary EFA supply, reduced bioconversion of EFAs to their respective LCPUFA metabolites and/or peroxidative degradation of LCPUFAs may contribute to the reduction of LCPUFA status in malnourished children. Restoration of normal energy, protein, and EFA intakes does not appear to readily correct abnormalities of plasma and erythrocyte membrane LCPUFA values. Enhanced dietary supply of LCPUFAs and/or improved supply of antioxidant vitamins may represent novel therapeutic modalities in severe PEM. With and without PEM, HIV infection was related to altered availability of various EFAs and LCPUFAs in HIV-seropositive children. The plasma total lipid fatty-acid profiles seen in well-nourished children with HIV infection were compatible with an HIV infection-related enhancement of the metabolic activity of the conversion of EFAs to their respective LCPUFA metabolites. However, the plasma phospholipid EFA and LCPUFA profiles seen in severely malnourished children with HIV infection more closely resembled those seen in children with PEM but without HIV infection than in those in children with HIV infection but no PEM. Metabolic studies using stable isotope-labeled fatty acids may contribute to better understanding of the HIV-related changes in EFA metabolism and clearly are needed before therapeutic conclusions can be drawn.


Decsi, T. (2000). "[Long-chain polyunsaturated fatty acids in the early development of the human nervous system]." Orv Hetil 141(51): 2767-73.

            The role of long-chain polyunsaturated fatty acids (LCPUFA) in the early development of the human nervous system was put forward by the better cognitive development observed in breast-fed than in formula fed infants in parallel with the presence of LCPUFA in human milk but not in formula. The role of LCPUFA in early human neurodevelopment can be investigated by comparing data obtained in formula fed infants randomly assigned to receive formula with or without LCPUFA. Investigations in preterm infants indicate that the presence of LCPUFA in the formula offers benefits for the early postnatal development of visual and cognitive functions. The unequivocal results obtained in preterm infants led to the recommendation of LCPUFA supplementation to formulae for preterm infants. In several studies in full-term infants, enhanced dietary intake of LCPUFA was accompanied with better visual acuity and better results in various cognitive tests. However, other studies did not show visual or cognitive differences between full-term infants fed formula with or without LCPUFA. It is a question under current debate whether supplementation of LCPUFA to formulae for full-term infants is required to lessen the difference between the intellectual development of breast-fed and formula fed infants.


De Caterina, R., J. K. Liao, et al. (2000). "Fatty acid modulation of endothelial activation." Am J Clin Nutr 71(1 Suppl): 213S-23S.

            Dietary balance of long-chain fatty acids may influence processes involving leukocyte-endothelial interactions, such as atherogenesis and inflammation, that involve increased endothelial expression of leukocyte adhesion molecules, or endothelial activation. We compared the ability of various saturated, monounsaturated, and polyunsaturated fatty acids to modulate endothelial activation. Consumption of the n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3) reduced endothelial expression of vascular cell adhesion molecule 1 (VCAM-1), E-selectin, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), and IL-8 in response to IL-1, IL-4, tumor necrosis factor, or bacterial endotoxin, with a half-maximal inhibitory concentration (IC(50)) of 1-25 micromol, ie, in the range of nutritionally achievable plasma concentrations. The magnitude of this effect paralleled its incorporation into cellular phospholipids. DHA also reduced the adhesion of human monocytes and monocytic U937 cells to cytokine-stimulated endothelial cells. These effects were accompanied by a reduction in VCAM-1 messenger RNA, indicating a pretranslational effect. To assess structural fatty acid determinants of VCAM-1 inhibitory activity, we compared various saturated, monounsaturated, and n-6 and n-3 polyunsaturated fatty acids for their VCAM-1 inhibitory activity. Saturated fatty acids did not inhibit cytokine-induced expression of adhesion molecules. However, a progressive increase in inhibitory activity was observed with dietary intake of fatty acids with the same chain length but increasing double bonds, ie, from monounsaturated to n-6 and, further, to n-3 fatty acids. Thus, the greater number of double bonds seems critical for the greater activity of n-3 compared with n-6 fatty acids in inhibiting endothelial activation. These properties are likely to be relevant to the antiatherogenic and antiinflammatory properties of n-3 fatty acids.


Das, U. N. (2000). "Free radicals, cytokines and nitric oxide in cardiac failure and myocardial infarction." Mol Cell Biochem 215(1-2): 145-52.

            Myocardial infarction is the most common cause of congestive cardiac failure. Free radicals, cytokines, nitric oxide (NO) and antioxidants play a major role both in atherosclerosis and myocardial damage and preservation. In the early stages of atherosclerosis, neutrophils and monocytes infiltrate the intima and generate free radicals which damage the endothelial cells. As a result, production of NO and prostacyclin by the endothelial cells declines, which have cardioprotective actions. This also has relevance to the beneficial action of aspirin since, it can modulate both prostanoid and L-arginine-NO systems and NF-kB translocation. In both acute myocardial infarction and chronic congestive cardiac failure, the plasma levels of various inflammatory mediators such as interleukins and tumour necrosis factor-alpha (TNFalpha) are elevated. TNFalpha, produced by the inflammatory cells and the myocardium, can suppress myocardial contractility and induce the production of free radicals, which in turn can further damage the myocardium. Transforming growth factor beta (TGFbeta), polyunsaturated fatty acids and the glucose-insulin-potassium regimen can antagonize the harmful actions of TNFalpha and protect the myocardium. This explains why efforts made to reduce the levels of pro-inflammatory cytokines have beneficial action and preserve the myocardium.


Cravo, M. L., L. M. Gloria, et al. (2000). "Metabolic responses to tumour disease and progression: tumour-host interaction." Clin Nutr 19(6): 459-65.

            The progressive nutritional deterioration frequently found in cancer patients, is often referred to as cancer cachexia. In contrast to starvation, where it is possible to reverse the body composition changes by the provision of extra calories, in cancer cachexia this reversal is not observed, suggesting that anorexia alone is unlikely to be responsible for this wasting syndrome. Over the past decades a number of studies have focused on the possible mediators which may be responsible for metabolic abnormalities observed in cancer patients. Pro-inflammatory cytokines have been strongly implicated, but evidence supporting such a direct role is lacking. Recently, exciting work regarding molecules produced by tumour cells, and which may induce lipolysis and proteolysis, has been published. There is also evidence that increased metabolism of host resources may provide substrates which might promote tumour growth. A number of studies have demonstrated that polyunsaturated fatty acids, such as linoleic and arachidonic acid, are able to promote tumour cell growth either by directly stimulating mitosis or by inhibiting apoptosis. Even more interesting is the discovery of antagonists of these catabolic factors such as eicosapentanoic acid for the lipolytic factor, which may play a role in the treatment of these patients in the near future.


Clarke, S. D. (2000). "Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance." Br J Nutr 83 Suppl 1: S59-66.

            This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the n-3 family, play essential roles in the maintenance of energy balance and glucose metabolism. The data discussed indicate that dietary PUFA function as fuel partitioners in that they direct glucose toward glycogen storage, and direct fatty acids away from triglyceride synthesis and assimilation and toward fatty acid oxidation. In addition, the n-3 family of PUFA appear to have the unique ability to enhance thermogenesis and thereby reduce the efficiency of body fat deposition. PUFA exert their effects on lipid metabolism and thermogenesis by upregulating the transcription of the mitochondrial uncoupling protein-3, and inducing genes encoding proteins involved in fatty acid oxidation (e.g. carnitine palmitoyltransferase and acyl-CoA oxidase) while simultaneously down-regulating the transcription of genes encoding proteins involved in lipid synthesis (e.g. fatty acid synthase). The potential transcriptional mechanism and the transcription factors affected by PUFA are discussed. Moreover, the data are interpreted in the context of the role that PUFA may play as dietary factors in the development of obesity and insulin resistance. Collectively the results of these studies suggest that the metabolic functions governed by PUFA should be considered as part of the criteria utilized in defining the dietary needs for n-6 and n-3 PUFA, and in establishing the optimum dietary ratio for n-6:n-3 fatty acids.


Carpentier, Y. A. and I. E. Dupont (2000). "Advances in intravenous lipid emulsions." World J Surg 24(12): 1493-7.

            Over the past decade, our views have considerably evolved with respect to the metabolism of intravenous lipid emulsions and their composition. Substantial progress has been made in understanding the metabolic pathways of emulsion particles and the delivery of their various components (fatty acids and vitamins) to specific tissues or cells. Although soybean long-chain triglycerides represent a valuable source of energy, concerns have been raised about their high content of polyunsaturated fatty acids (mainly n-6 essential fatty acids), which may adversely affect immune functions and antioxidant status. Introduction of medium-chain triglycerides or olive oil to lipid emulsions can largely help bypass these disadvantages. Recently, incorporation of n-3 fatty acids in lipid preparations was suggested to have potential application in several chronic and acute diseases because of their ability to reduce inflammatory and thrombotic responses and cell sensitivity to various stimuli. Hence lipid emulsions should no longer be considered only as a means of providing energy substrates; they also modulate key metabolic functions. Such improved knowledge may lead to optimizing the metabolic care of certain patients.


Carlson, S. E. (2000). "Behavioral methods used in the study of long-chain polyunsaturated fatty acid nutrition in primate infants." Am J Clin Nutr 71(1 Suppl): 268S-74S.

            Domains of behavior may be broadly categorized as sensory, motor, motivational and arousal, cognitive, and social. Differences in these domains occur because of changes in brain structure and function. Docosahexaenoic acid (DHA; 22:6-23) and arachidonic acid (AA; 20:4-26) are major structural components of the brain that decrease when diets deficient in the essential fatty acids (EFA) alpha-linolenic acid and linoleic acid are consumed. Early electrophysiologic and behavioral studies in EFA-deficient rodents showed behavioral effects attributable to lower-than-normal accumulation of DHA and AA in the brain. More recently, electrophysiologic and behavioral studies in EFA-deficient primate infants and analogous studies in human infants have been conducted. The human infants were fed formulas that could result in lower-than-optimal accumulation of long-chain polyunsaturated fatty acids (LCPUFAs) in the brain during critical periods of development. This article describes the behavioral methods that have been used to study primate infants. These methods may be unfamiliar to many physicians and nutritionists who wish to read and interpret the human studies. The behavioral outcomes that have been evaluated in LCPUFA studies represent only a fraction of those available in the behavioral sciences. Specific developmental domains have been studied less often than global development, even though studies of nonhuman primates deficient in EFAs suggest that the former provide more information that could help target the underlying mechanisms of action of LCPUFAs in the brain.


Cantwell, M. M. (2000). "Assessment of individual fatty acid intake." Proc Nutr Soc 59(2): 187-91.

            Dietary assessment of individual fatty acid intake is difficult due to a number of limitations. Information regarding the type, quantity and brand-name of fat used in cooking and at the table is required. In addition, margarine manufacturers may change the component oils used for reasons of cost, which changes the fatty acid composition of their products from season-to-season. Independent markers of fatty acid intake are required, therefore, to compensate for these limitations. Adipose tissue concentrations have been used as a measure of habitual intake of fatty acid groups and individual fatty acids in numerous studies. Saturated (SFA) and monounsaturated fatty acids (MUFA) are generally poorly correlated with adipose tissue concentrations, which can be explained partly by endogenous synthesis. In general, adipose tissue concentrations of exogenously-produced fatty acids (n-3 and n-6 polyunsaturated fatty acids (PUFA)) are well correlated with estimates of habitual intake. Correlations between dietary trans unsaturated fatty acids (TUFA) and adipose tissue concentrations vary between countries, which may be due to differences in dietary sources. Correlations may be affected by differences in bioavailability or selective retention of fatty acids in certain tissue lipids.


Cabre, E. and M. A. Gassull (2000). "Nutritional and metabolic issues in cirrhosis and liver transplantation." Curr Opin Clin Nutr Metab Care 3(5): 345-54.

            In the last year some relevant papers on nutrition and metabolism in chronic liver disease and transplantation have been published. Studies investigating the reliability of predicting energy expenditure in cirrhosis, and some relevant contributions to the understanding of metabolic consequences of liver transplantation, deserve particular mention. These include the first direct evidence that liver transplantation corrects the insulin resistance present in cirrhosis, as well as studies on the role of genetic polymorphism of the vitamin D receptor gene in bone loss after transplantation. Other papers have dealt with body composition, polyunsaturated fatty acid and antioxidant status in cirrhosis. However, relevant contributions in the field of nutritional support in cirrhosis are surprisingly lacking.


Burgess, J. R., L. Stevens, et al. (2000). "Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder." Am J Clin Nutr 71(1 Suppl): 327S-30S.

            Attention-deficit hyperactivity disorder (ADHD) is the diagnosis used to describe children who are inattentive, impulsive, and hyperactive. ADHD is a widespread condition that is of public health concern. In most children with ADHD the cause is unknown, but is thought to be biological and multifactorial. Several previous studies indicated that some physical symptoms reported in ADHD are similar to symptoms observed in essential fatty acid (EFA) deficiency in animals and humans deprived of EFAs. We reported previously that a subgroup of ADHD subjects reporting many symptoms indicative of EFA deficiency (L-ADHD) had significantly lower proportions of plasma arachidonic acid and docosahexaenoic acid than did ADHD subjects with few such symptoms or control subjects. In another study using contrast analysis of the plasma polar lipid data, subjects with lower compositions of total n-3 fatty acids had significantly more behavioral problems, temper tantrums, and learning, health, and sleep problems than did those with high proportions of n-3 fatty acids. The reasons for the lower proportions of long-chain polyunsaturated fatty acids (LCPUFAs) in these children are not clear; however, factors involving fatty acid intake, conversion of EFAs to LCPUFA products, and enhanced metabolism are discussed. The relation between LCPUFA status and the behavior problems that the children exhibited is also unclear. We are currently testing this relation in a double-blind, placebo-controlled intervention in a population of children with clinically diagnosed ADHD who exhibit symptoms of EFA deficiency.


Brown, A. C. (2000). "Lupus erythematosus and nutrition: a review of the literature." J Ren Nutr 10(4): 170-83.

            The purpose of this review was to search the scientific literature for dietary compounds that alleviate or exacerbate symptoms of lupus erythematosus (LE) in both animal and human models. A detailed literature review was undertaken to find articles showing a relationship between LE and nutrition by using MEDLINE/INDEX MEDICUS (1950-March 2000) for English-language articles, followed by cross-referencing. Aggravating substances appear to include excess calories, excess protein, high fat (especially saturated and omega-6 polyunsaturated fatty acids), zinc, iron, and L-canavanine found in alfalfa tablets. Possible beneficial dietary compounds include vitamin E, vitamin A (beta-carotene), selenium, fish oils (omega-3 polyunsaturated fatty acids), evening primrose oil, flaxseed, a plant herb (Tripterygium wilfordii), dehydroepiandrosterone, and calcium plus vitamin D (if taking corticosteroids). Some people with systemic LE placed on food allergy elimination diets reported improvement in their LE symptoms; however, this may be related to a decrease of other substances in the diet. Also, although no direct evidence was reported on the beneficial effects of either bromelain or a vegetarian diet (possibly allowing fish), it is suggested that they might be beneficial. Limitations to this research are that the findings are based on relatively few studies, many of which were without control groups or extrapolated from animal models. No large-scale studies have been performed with LE patients to substantiate the benefit, if any, of these individual dietary interventions, and if they were conducted, the remission and exacerbation pattern of LE may interfere with elucidating their effectiveness. Also, dietary changes should not be attempted without a physician's approval/monitoring.


Brousseau, M. E. and E. J. Schaefer (2000). "Diet and coronary heart disease: clinical trials." Curr Atheroscler Rep 2(6): 487-93.

            Dietary intervention trials using coronary heart disease (CHD) mortality and morbidity as endpoints have demonstrated that restriction of dietary total and saturated fat or replacement of the latter with polyunsaturated fatty acids (PUFAs), in particular n-3 PUFAs, is of great benefit with respect to CHD risk. This is likewise the case for intervention trials using angiographic endpoints, with many studies showing that such diets not only retard progression of coronary atherosclerosis but can cause regression as well. The role that antioxidants, such as vitamin E, may play in the development and progression of CHD is less clear. The results of large-scale clinical trials evaluating the effect of vitamin E supplementation on CHD risk do not support the concept that this agent is cardioprotective. The purpose of this report is to review dietary intervention trials that support a direct relationship between diet, lipoproteins, and CHD risk.


Bishop-Bailey, D. (2000). "Peroxisome proliferator-activated receptors in the cardiovascular system." Br J Pharmacol 129(5): 823-34.

            Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARalpha, -delta, and -gamma, which are members of the steriod receptor superfamily. The first member of the family (PPARalpha) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARalpha being involved in beta-oxidation pathways, and PPARgamma in the differentiation of adipocytes. Little is known about the functions of PPARdelta, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands.


Bhathena, S. J. (2000). "Relationship between fatty acids and the endocrine system." Biofactors 13(1-4): 35-9.

            Significant interactions exist between fatty acids and the endocrine system. Hormones affect the metabolism of fatty acids and the fatty acid composition of tissue lipids. The principal hormones involved in lipid metabolism are insulin, glucagon, catecholamines, cortisol and growth hormone. The concentrations of these hormones are altered in chronic degenerative conditions such as diabetes and cardiovascular disease, which in turn lead to alterations in tissue lipids. Lipogenesis and lipolysis, which modulate fatty acid concentrations in plasma and tissues, are under hormonal control. Neuropeptides are involved in lipid metabolism in brain and other tissues. Polyunsaturated fatty acids (PUFA) are also precursors for eicosanoids including prostaglandins, leukotrienes, and thromboxanes, which have hormone-like activities. Fatty acids in turn alter both hormone and neuropeptide concentrations and their receptors. Saturated and trans fatty acids (TFA) decrease insulin concentration leading to insulin resistance. In contrast, PUFA increase plasma insulin concentration and decrease insulin resistance. In humans, omega-3 PUFA alter the levels of opioid peptides in plasma.


Belluzzi, A., S. Boschi, et al. (2000). "Polyunsaturated fatty acids and inflammatory bowel disease." Am J Clin Nutr 71(1 Suppl): 339S-42S.

            The rationale for supplementation with n-3 fatty acids to promote the health of the gastrointestinal tract lies in the antiinflammatory effects of these lipid compounds. The first evidence of the importance of dietary intake of n-3 polyunsaturated fatty acids was derived from epidemiologic observations of the low incidence of inflammatory bowel disease in Eskimos. The aim of this paper was to briefly review the literature on the use of n-3 fatty acids in inflammatory bowel disease (ulcerative colitis and Crohn disease), the results of which are controversial. The discrepancies between studies may reside in the different study designs used as well as in the various formulations and dosages used, some of which may lead to a high incidence of side effects. Choosing a formulation that lowers the incidence of side effects, selecting patients carefully, and paying strict attention to experimental design are critical when investigating further the therapeutic potential of these lipids in inflammatory bowel disease.


Beatty, S., H. Koh, et al. (2000). "The role of oxidative stress in the pathogenesis of age-related macular degeneration." Surv Ophthalmol 45(2): 115-34.

            Age-related macular degeneration (AMD) is the leading cause of blind registration in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress and that the antioxidant vitamins A, C, and E protect against this type of injury. Furthermore, there is strong evidence suggesting that lipofuscin is derived, at least in part, from oxidatively damaged photoreceptor outer segments and that it is itself a photoreactive substance. However, the relationships between dietary and serum levels of the antioxidant vitamins and age-related macular disease are less clear, although a protective effect of high plasma concentrations of alpha-tocopherol has been convincingly demonstrated. Macular pigment is also believed to limit retinal oxidative damage by absorbing incoming blue light and/or quenching ROIs. Many putative risk-factors for AMD have been linked to a lack of macular pigment, including female gender, lens density, tobacco use, light iris color, and reduced visual sensitivity. Moreover, the Eye Disease Case-Control Study found that high plasma levels of lutein and zeaxanthin were associated with reduced risk of neovascular AMD. The concept that AMD can be attributed to cumulative oxidative stress is enticing, but remains unproven. With a view to reducing oxidative damage, the effect of nutritional antioxidant supplements on the onset and natural course of age-related macular disease is currently being evaluated.


Baugh, M. A. (2000). "HIV: reactive oxygen species, enveloped viruses and hyperbaric oxygen." Med Hypotheses 55(3): 232-8.

            This paper demonstrates that there are many examples in the literature of contradictory data concerning reactive oxygen intermediates (ROIs), responsible for producing cellular oxidative stress (OS), and their enhancement or diminution of viral replication. Nevertheless, ROIs repeatedly have been shown to be virucidal against enveloped-viruses, like the human immunodeficiency virus (HIV). Hyperbaric oxygen therapy (HBOT) increases the production of ROIs throughout the body, leaving no safe harbor for the virus to hide outside the genome. This technique already has been tried on acquired immune deficiency syndrome (AIDS) patients, with exciting results. Historically, the biggest setback to demonstrating HBO's antiviral effects has been the investigator's folly of studying non-enveloped viruses or failing to initiate ROI production. ROIs specifically attack areas of unsaturation occurring in the polyunsaturated fatty acids of cell membranes and viral envelopes. Moreover, it consistently has been shown that a peroxidized viral envelope breaches, and a breached viral envelope causes viral disintegration.


Balet Duat, M. A. and D. Cardona Pera (2000). "[Oxidation of lipids contained in total parental nutrition]." Nutr Hosp 15(4): 140-7.

            The components used in parenteral nutrition mixtures are subject to oxidation. The oxidation of polyunsaturated lipids leads to the formation of toxic lipoperoxides. This toxicity is of particular significance in new-born children, because of the lack of maturity of their defensive systems against oxidative processes, and also in critically-ill patients, whose oxidative metabolism is increased. A review of the literature is effected to assess the following: toxicity of lipoperoxides, factors involved in the oxidation of parenteral nutrition mixtures and the analytical methods used to determine the peroxides present in parenteral nutrition mixtures. The factors influencing the oxidation of parenteral nutrition mixtures include: the amount of polyunsaturated fatty acids, the presence of bisulphite, vitamin complexes and their polysorbate content, temperature, type of bag and exposure to light. The analytical methods found for the analysis of peroxides in TPN mixtures are: iodine measurement analysis, high resolution liquid chromatography, the thiobarbituric acid test, and oxidation of the ferrous cation in the presence of xylenol orange. Depending on the method, it is possible to determine total peroxides or only lipoperoxides. The literature reviewed does not establish a threshold level of peroxide concentration below which a parenteral nutrition mixture can be considered safe.


Balazy, M. (2000). "Trans-arachidonic acids: new mediators of inflammation." J Physiol Pharmacol 51(4 Pt 1): 597-607.

            Inflammation and many other pathological processes lead to increased production of free radicals that target critical macromolecules such as proteins, DNA and lipids. Structural modifications of these molecules, induced by free radicals, typically result in alterations of vital biochemical processes. Hydroxyl radical-initiated lipid peroxidation is known to generate a variety of toxic oxidized lipids, many of which originate from polyunsaturated fatty acids esterified to cellular membrane phospholipids. Recent interests have focused on a group of lipids known as isoeicosanoids that are formed from peroxidation of arachidonic acid, and share structural similarity to enzymatically-derived prostaglandins and leukotrienes. However, little is known about lipid peroxidation processes initiated by nitrogen free radicals. NO2 is a toxic free radical and an abundant urban air pollutant, which is also generated in vivo from oxidations of nitric or nitrite and decomposition of peroxynitrite. The NO2-induced lipid peroxidation mechanisms involving arachidonic acid have not been characterized. Described here is the isomerization of arachidonic acid, a new process induced by NO2, which leads to a mixture of trans-arachidonic acids. We observed that the levels of trans-arachidonic acids in rat plasma increased following infusion of bacterial endotoxin; therefore, the isomerization of arachidonic acid is likely to occur in vivo by a mechanism involving NO2.


Archer, D. B. (2000). "Filamentous fungi as microbial cell factories for food use." Curr Opin Biotechnol 11(5): 478-83.

            The knowledge base that will underpin the more efficient use of filamentous fungi as cell factories in food has increased during the past year in the areas of gene regulation, protein secretion, safety and synthesis of ingredients such as long-chain polyunsaturated fatty acids.


Angerer, P. and C. von Schacky (2000). "n-3 polyunsaturated fatty acids and the cardiovascular system." Curr Opin Lipidol 11(1): 57-63.

            n-3 Polyunsaturated fatty acids, mainly those contained in fish oils, are candidates for inclusion in secondary prevention programmes for coronary heart disease, based on the results of recent randomized trials in humans. Marine n-3 polyunsaturated fatty acids retard coronary atherosclerosis and appear to prevent fatal arrhythmias; and they decrease mortality subsequent to myocardial infarction.


Angerer, P. and C. von Schacky (2000). "n-3 polyunsaturated fatty acids and the cardiovascular system." Curr Opin Clin Nutr Metab Care 3(6): 439-45.

            n-3 Polyunsaturated fatty acids, mainly those contained in fish oils, are candidates for inclusion in secondary prevention programmes for coronary heart disease, based on the results of recent randomized trials in humans. Marine n-3 polyunsaturated fatty acids retard coronary atherosclerosis and appear to prevent fatal arrhythmias; and they decrease mortality subsequent to myocardial infarction.


Al, M. D., A. C. van Houwelingen, et al. (2000). "Long-chain polyunsaturated fatty acids, pregnancy, and pregnancy outcome." Am J Clin Nutr 71(1 Suppl): 285S-91S.

            During pregnancy, essential long-chain polyunsaturated fatty acids (LCPUFAs) play important roles as precursors of prostaglandins and as structural elements of cell membranes. Throughout gestation, accretion of maternal, placental, and fetal tissue occurs and consequently the LCPUFA requirements of pregnant women and their developing fetuses are high. This is particularly true for docosahexaenoic acid (DHA; 22:6n-3). The ratio of DHA to its status marker, docosapentaenoic acid (22:5n-6), in maternal plasma phospholipids decreases significantly during pregnancy. This suggests that pregnancy is associated with maternal difficulty in coping with the high demand for DHA. The DHA status of newborn multiplets is significantly lower than that of singletons; the same is true for infants of multigravidas as compared with those of primigravidas and for preterm compared with term neonates. Because the LCPUFA status at birth seems to have a long-term effect, the fetus should receive an adequate supply of LCPUFAs. Data from an international comparative study indicated that, especially for n-3 LCPUFAs, the fetus is dependent on maternal fatty acid intake; maternal supplementation with LCPUFAs, their precursors, or both increased LCPUFA concentrations in maternal and umbilical plasma phospholipids. However, significant competition between the 2 LCPUFA families was observed, which implies that effective supplementation requires a mixture of n-6 and n-3 fatty acids. Further research is needed to determine whether higher LCPUFA concentrations in plasma phospholipid will have functional benefits for mothers and children.


Agostoni, C., E. Riva, et al. (2000). "Dietary fats and cholesterol in italian infants and children." Am J Clin Nutr 72(5 Suppl): 1384S-1391S.

            The fat intake of Italian infants has peculiar characteristics that begin quite early because their mothers' milk has a monounsaturated fat content (45%) at the upper limit of the values found in Europe. Comparison studies in breast-fed and formula-fed infants were conducted to evaluate growth and developmental correlates and differences in fat intakes in the early months of life. Breast-fed infants have higher blood lipid concentrations at 4 mo of age than do formula-fed infants. The addition of long-chain polyunsaturated fatty acids (LCPUFAs) and cholesterol to formulas for term infants may affect concentrations of circulating blood lipids as well as the LCPUFA composition of the lipids during the breast-feeding period. The addition of LCPUFAs does not seem to affect the growth rate of formula-fed infants. Although an initial benefit of LCPUFA feeding on eye-hand coordination was observed, this effect was not sustained; by 24 mo, different feeding groups had similar developmental scores. Other peculiarities of the Italian experience are presented, including body weights from infancy to early childhood in 147 children, the nutrient densities of different diets in Italian schoolchildren, and the effects of nutritional education on dietary intakes. The diets of these children were high in animal protein and supplied approximately 30-35% of energy from fats throughout childhood. Both the dietary protein intakes at 1 y of age and parental body mass indexes were associated with 5-y body mass index values. Classroom education may be useful to lower the plasma lipid concentrations in healthy, primary school-age children. It is not known whether this early modification can be maintained and whether it influences the later development of cardiovascular disorders.


Actis, A. B. and A. R. Eynard (2000). "Influence of environmental and nutritional factors on salivary gland tumorigenesis with a special reference to dietary lipids." Eur J Clin Nutr 54(11): 805-10.

            Salivary gland cancer is a rare condition whose incidence varies according to different geographical regions. Several environmental factors, such as ionizing radiation and some occupational aspects, as well as habits like smoking and alcohol consumption, are related to salivary tumorigenesis. Both acinar and ductal cells may be involved in the origin of salivary gland tumours. Even though laboratory and epidemiological evidence indicates that diet and nutritional habits may modulate the tumorigenesis at different sites, little is known about this effect on salivary glands, mainly in regard to dietary lipids. However, the fact that monounsaturated fatty acids behave as protumorigenic and, on the contrary, certain polyunsaturated fatty acids exert beneficial effects, demonstrated on breast, colon and even oral cancer, gives support to our hypothesis. The suggested relationship between environmental and nutritional factors, mainly dietary lipids, and salivary gland cancer constitutes the aim of the present work.


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