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Docosahexaenoic acid (DHA) Reviews

(121 References)

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.

Terry, P. D., T. E. Rohan, et al. (2003). "Intakes of fish and marine fatty acids and the risks of cancers of the breast and prostate and of other hormone-related cancers: a review of the epidemiologic evidence." Am J Clin Nutr 77(3): 532-43.

            Marine fatty acids, particularly the long-chain eicosapentaenoic and docosahexaenoic acids, have been consistently shown to inhibit the proliferation of breast and prostate cancer cell lines in vitro and to reduce the risk and progression of these tumors in animal experiments. However, whether a high consumption of marine fatty acids can reduce the risk of these cancers or other hormone-dependent cancers in human populations is unclear. Focusing primarily on the results of cohort and case-control studies, we reviewed the current epidemiologic literature on the intake of fish and marine fatty acids in relation to the major hormone-dependent cancers. Despite the many epidemiologic studies that have been published, the evidence from those studies remains unclear. Most of the studies did not show an association between fish consumption or marine fatty acid intake and the risk of hormone-related cancers. Future epidemiologic studies will probably benefit from the assessment of specific fatty acids in the diet, including eicosapentaenoic and docosahexaenoic acids, and of the ratio of these to n-6 fatty acids, dietary constituents that have not been examined individually very often.

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.

Qiu, X. (2003). "Biosynthesis of docosahexaenoic acid (DHA, 22:6-4, 7,10,13,16,19): two distinct pathways." Prostaglandins Leukot Essent Fatty Acids 68(2): 181-6.

            Docosahexaenoic acid (DHA) has long been recognized for its beneficial effect in humans, but its biosynthetic pathway has not been clearly established until recently. According to Sprecher, in mammals, DHA is synthesized via a retro-conversion process in peroxisomes-the aerobic delta4 desaturation-independent pathway. Recent identification of a Thraustochytrium delta4 desaturase indicates that delta4 desaturation is indeed involved in DHA synthesis in Thraustochytrium. More interestingly, an alternative pathway for DHA biosynthesis-the anaerobic polyketide synthase pathway was also reported recently to occur in Schizochytrium, another member of the Thraustochytriidae. This mini-review attempts to assess the latest research on these distinct pathways for DHA biosynthesis.

Nakamura, M. T. and T. Y. Nara (2003). "Essential fatty acid synthesis and its regulation in mammals." Prostaglandins Leukot Essent Fatty Acids 68(2): 145-50.

            The tissue content of highly unsaturated fatty acids (HUFA) such as arachidonic acid and docosahexaenoic acid is maintained in a narrow range by feedback regulation of synthesis. Delta-6 desaturase (D6D) catalyzes the first and rate-limiting step of the HUFA synthesis. Recent identification of a human case of D6D deficiency underscores the importance of this pathway. Sterol regulatory element binding protein-1c (SREBP-1c) is a key transcription factor that activates transcription of genes involved with fatty acid synthesis. We recently identified sterol regulatory element (SRE) that is required for activation of the human D6D gene by SREBP-1c. Moreover, the same SRE also mediates the suppression of the D6D gene by HUFA. The identification of SREBP-1c as a key regulator of D6D suggests that the major physiological function of SREBP-1c in liver may be the regulation of phospholipid synthesis rather than triglyceride synthesis. Peroxisome proliferators (PP) induce fatty acid oxidation enzymes and desaturases in rodent liver. However, the induction of desaturases by PP is slower than the induction of oxidation enzymes. This delayed induction may be a compensatory reaction to the increased demand of HUFA caused by increased HUFA oxidation and peroxisome proliferation in PP administration. Recent studies have demonstrated a critical role of peroxisomal beta-oxidation in DHA synthesis, and identified acyl CoA oxidase and D-bifunctional protein as the key enzymes.

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).

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).

Davis, B. C. and P. M. Kris-Etherton (2003). "Achieving optimal essential fatty acid status in vegetarians: current knowledge and practical implications." Am J Clin Nutr 78(3 Suppl): 640S-646S.

            Although vegetarian diets are generally lower in total fat, saturated fat, and cholesterol than are nonvegetarian diets, they provide comparable levels of essential fatty acids. Vegetarian, especially vegan, diets are relatively low in alpha-linolenic acid (ALA) compared with linoleic acid (LA) and provide little, if any, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Clinical studies suggest that tissue levels of long-chain n-3 fatty acids are depressed in vegetarians, particularly in vegans. n-3 Fatty acids have numerous physiologic benefits, including potent cardioprotective effects. These effects have been demonstrated for ALA as well as EPA and DHA, although the response is generally less for ALA than for EPA and DHA. Conversion of ALA by the body to the more active longer-chain metabolites is inefficient: < 5-10% for EPA and 2-5% for DHA. Thus, total n-3 requirements may be higher for vegetarians than for nonvegetarians, as vegetarians must rely on conversion of ALA to EPA and DHA. Because of the beneficial effects of n-3 fatty acids, it is recommended that vegetarians make dietary changes to optimize n-3 fatty acid status.

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.

Chen, W. J. and S. L. Yeh (2003). "Effects of fish oil in parenteral nutrition." Nutrition 19(3): 275-9.

            OBJECTIVE: Fish oil is a rich source of omega-3 fatty acids (FAs), especially eicosapentaenoic acid and docosahexaenoic acid. The existing data suggest that eicosapentaenoic acid and docosahexaenoic acid are the active agents in fish oil. A number of clinical trials have shown that dietary fish oil supplementation has antiatherogenic properties and immunomodulation effects. Fish oils are not used widely in parenteral nutrition because fish oil emulsions have not been commercially available until very recently. Studies concerning the use of fish oil in parenteral route are rare. METHODS: We reviewed the effect of parenteral fish oil infusion on lipid metabolism and immune response in normal and disease conditions. RESULTS: Studies showed that the main effects of parenteral infusion of fish oil are: 1) incorporation of omega-3 FAs into cellular membranes of many cell populations that consequently influence the disease process of some disease conditions, 2) an effect on eicosanoid metabolism leading to a decrease in platelet aggregation and thrombosis, 3) amelioration of the severity of diet-induced hepatic steatosis, 4) less accumulation of lipid peroxidation products in liver tissue, and 5) immunomodulation effects and therapeutic benefits in animal disease models or various disease conditions of humans. Most of these studies suggested that parenteral infusion of omega-3 FAs have clinical beneficial effects comparable to those of dietary administration. However, different effects of omega-3 and omega-6 FAs in some situations has been reported. For example, plasma triacylglycerol levels were not lowered after fish oil infusion in normal or diabetic rats when compared with those of safflower oil or soybean oil infusion. The reason for the difference remain unclear. CONCLUSION: The metabolic and immunologic effects of parenteral use of omega-3 FAs requires further evaluation, especially in some disease conditions.

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.

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.

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.

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.

Strucinska, M. (2002). "[Vegetarian diets of breastfeeding women in the light of dietary recommendations]." Rocz Panstw Zakl Hig 53(1): 65-79.

            The literature review concerning selected nutritional and health aspects of applying different vegetarian diets by breastfeeding women was presented. The only two types of vegetarian diets: lactoovo- and semi-vegetarian, when properly composed, seem to be relatively safe for mother and her child. The most threatening vegetarian diets for lactating women are those including exclusively products of plant origin (so called restricted diets: vegan or macrobiotic). The results of studies performed on mothers consuming these vegetarian diets showed deficiencies in: vitamin B12 and vitamin D (in mothers and their infants) and calcium (only in lactating women). The low intake of docosahexaenoic acid (DHA) was also characteristic in this group. Additionally the endogenous metabolism of DHA is inhibited due to high proportion of linoleic vs. linolenic acid intake. It considered that lactating women on vegetarian diet should have a greater nutritional knowledge in order to avoid deficiencies which would adversely affect mother's and her child's health.

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.

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.

Roberts, L. J., 2nd and J. D. Morrow (2002). "Products of the isoprostane pathway: unique bioactive compounds and markers of lipid peroxidation." Cell Mol Life Sci 59(5): 808-20.

            We previously reported the discovery of prostaglandin F2-like compounds (F2-isoprostanes) formed by nonenzymatic free-radical-induced peroxidation of arachidonic acid. Quantification of F2-isoprostanes has proven to be a major advance in assessing oxidative stress status in vivo. Central in the pathway of formation of isoprostanes are prostaglandin H2-like endoperoxides, which also undergo rearrangement in vivo to form E-ring, D-ring, and thromboxane-ring compounds. E2- and D2-isoprostanes also undergo dehydration in vivo to form reactive cyclopentenone A2- and J2-isoprostanes, which are susceptible to Michael addition reactions with thiols. Recently, we described the formation of highly reactive gamma-ketoaldehydes (now termed isoketals) as products of isoprostane endoperoxide rearrangement which readily adduct to lysine residues on proteins and induce cross-links at rates that far exceed other aldehyde products of lipid peroxidation. Isoprostane-like compounds (neuroprostanes) and isoketal-like compounds (neuroketals) are formed from oxidation of docosahexaenoic acid, which is enriched in the brain, and measurement of neuroprostanes may provide a unique marker of oxidative neuronal injury.

Renaud, S. and D. Lanzmann-Petithory (2002). "Dietary fats and coronary heart disease pathogenesis." Curr Atheroscler Rep 4(6): 419-24.

            The intake of saturated fat seems to be the main environmental factor for coronary heart disease (CHD). However, decreasing the intake of saturated fat and replacing it in part with linoleic acid in primary or secondary intervention trials did not satisfactorily reduce CHD clinical manifestations. It is only when omega-3 fatty acids, alpha-linolenic acid (ALA), or eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were added to the diet that sudden cardiac death (ALA, EPA plus DHA) and nonfatal myocardial infarction (only ALA) were significantly lowered. The protective effect of omega-3 fatty acids occurs rapidly, within weeks. The mechanism for preventing ventricular fibrillation seems to be through a direct effect on myocytes. The additional effect of ALA on nonfatal myocardial infarction may be through thrombosis, at least partly caused by an effect on platelets.

Ren, C. L. (2002). "Use of modulators of airways inflammation in patients with CF." Clin Rev Allergy Immunol 23(1): 29-39.

            One of the hallmarks of cystic fibrosis (CF) lung disease is the presence of intense, neutrophil-dominated airway inflammation, and many researchers have focused on developing therapies to reduce inflammation in CF lung disease. Systemic corticosteroids can delay progression of lung disease, but at the cost of unacceptable side effects. Inhaled corticosteroids are widely used, but their efficacy has yet to be demonstrated in a controlled fashion. Ibuprofen has also been shown to delay disease progression, but its use has been limited by the need to obtain individual pharmacokinetics and concern about side effects. Other treatments with potential anti-inflammatory effects include pentoxifylline, leukotriene antagonists, docosahexaenoic acid, and azithromycin. Few, if any, large clinical studies of these therapies have been published, but several are presently underway. Because neutrophil elastase appears to be a key mediator of tissue damage in CF lung disease, anti-elastase compounds have also been studied, including alpha-1-protease inhibitor, secretory leukocyte protease inhibitor, and small molecule inhibitors. There have been no large-scale controlled trials of these therapies in CF. More recently, investigators have focused on cytokine modulation, using either interleukin-10 or interferon gamma. Some complementary and alternative medicine therapies may also have anti-inflammatory effects, although their clinical value has yet to be demonstrated in a rigorously-controlled fashion. In summary, numerous anti-inflammatory therapies have been applied to CF lung disease, but more large, well-controlled studies will need to be performed to determine their true clinical usefulness.

Rapoport, S. I. and F. Bosetti (2002). "Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder?" Arch Gen Psychiatry 59(7): 592-6.

            BACKGROUND: Lithium and certain anticonvulsants, including carbamazepine and valproic acid, are effective antimanic drugs for treating bipolar disorder, but their mechanisms of action remain uncertain. EXPERIMENTAL OBSERVATIONS: Feeding rats lithium chloride for 6 weeks, to produce a brain lithium concentration of 0.7mM, reduced arachidonic acid turnover within brain phospholipids by 75%. The effect was highly specific, as turnover rates of docosahexaenoic acid and palmitic acid were unaffected. Arachidonate turnover in rat brain also was reduced by long-term valproic acid administration. Lithium's reduction of arachidonate turnover corresponded to its down-regulating gene expression and enzyme activity of cytosolic phospholipase A(2), an enzyme that selectively liberates arachidonic but not docosahexaenoic acid from phospholipids. Lithium also reduced the brain protein level and activity of cyclooxygenase 2, as well as the brain concentration of prostaglandin E(2), an arachidonate metabolite produced via cyclooxygenase 2. CONCLUSIONS: These results give rise to the hypothesis that lithium and antimanic anticonvulsants act by targeting parts of the "arachidonic acid cascade," which may be functionally hyperactive in mania. Thus, drugs that target enzymes in the cascade, such as cyclooxygenase 2 inhibitors, might be candidate treatments for mania. Also, in view of competition between arachidonic and docosahexaenoic acids in a number of functional processes, docosahexaenoic acid or its precursors would be expected to be therapeutic. Neither of these predictions is evident from other current hypotheses for the antimanic action of lithium and anticonvulsant drugs.

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.

Nordoy, A. (2002). "Statins and omega-3 fatty acids in the treatment of dyslipidemia and coronary heart disease." Minerva Med 93(5): 357-63.

            Dyslipidemia including hypercholesterolemia and hypertriglyceridemia often associated with low levels of HDL-cholesterol is a common and important cluster of risk factors for coronary heart disease. Dyslipidemia is also commonly associated with hypertension, hyperinsulinemia and central obesity in the metabolic syndrome. Lifestyle adjustments including increased physical activity and dietary modifications leading to weight reduction are important first steps in the prevention of coronary heart disease in patients with such abnormalities in lipid metabolism. When these adjustments are insufficient to achieve desirable results, the combined treatment with statins and omega-3 fatty acids is an efficient treatment alternative. Both statins and omega-3 fatty acids have documented their effects against coronary heart disease (CHD) both in primary and secondary prevention trials. The mechanisms involved are only partly explained, however, the synergistic effects of statins and omega-3 fatty acids significantly reduce the risk for CHD in patients with dyslipidemia.

Nakamura, M. T. and T. Y. Nara (2002). "Gene regulation of mammalian desaturases." Biochem Soc Trans 30(Pt 6): 1076-9.

            Stearoyl-CoA desaturase (SCD) catalyses the synthesis of oleic acid (18:1, n -9), which is mostly esterified into triacylglycerols (TAGs) as an energy reserve. Delta-6 Desaturase (D6D) and Delta-5 desaturase (D5D) are the key enzymes for the synthesis of highly unsaturated fatty acids (HUFAs), such as arachidonic acid (20:4, n -6) and docosahexaenoic acid (22:6, n -3), that are incorporated in phospholipids (PLs) and perform essential physiological functions. Despite these different physiological roles of SCD and D6D/D5D, these desaturases share common regulatory features, including dependence of expression on insulin, suppression by HUFAs, and induction by peroxisome proliferators (PPs). A key regulator of desaturase gene expression is sterol-regulatory element binding protein-1c (SREBP-1c), which mediates transcriptional activation of the SCD and D6D genes by insulin and inhibition by HUFAs. Because HUFAs are poorly incorporated into TAGs, the primary role of SREBP-1c in liver may be monitoring and regulating fatty acid composition in PLs rather than the regulation of TAG synthesis. The induction of desaturases by PPs is enigmatic because the major effect of PPs is induction of fatty acid oxidation enzymes by activating PP-activated receptor-alpha (PPARa). To our knowledge, no other gene that is induced by both SREBP-1 and PP has been identified. It is yet to be determined whether PPARa mediates the process directly. Available data suggest that the induction of desaturases by PPs may be a compensatory response to an increased demand for unsaturated fatty acids because PPs increase fatty acid degradation and induce proliferation of peroxisomes.

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.

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.

Kimura, S., H. Saito, et al. (2002). "Docosahexaenoic acid attenuated hypertension and vascular dementia in stroke-prone spontaneously hypertensive rats." Neurotoxicol Teratol 24(5): 683-93.

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.

Hammond, B. G., D. A. Mayhew, et al. (2002). "Safety assessment of DHA-rich microalgae from Schizochytrium sp." Regul Toxicol Pharmacol 35(2 Pt 1): 255-65.

            The purpose of this series of studies was to assess the genotoxic potential of docosahexaenoic acid-rich microalgae from Schizochytrium sp. (DRM). DRM contains oil rich in highly unsaturated fatty acids (PUFAs). Docosahexaenoic acid (DHA n-3) is the most abundant PUFA component of the oil ( approximately 29% w/w of total fatty acid content). DHA-rich extracted oil from Schizochytrium sp. is intended for use as a nutritional ingredient in foods. All in vitro assays were conducted with and without mammalian metabolic activation. DRM was not mutagenic in the Ames reverse mutation assay using five different Salmonella histidine auxotroph tester strains. Mouse lymphoma suspension assay methodology was found to be inappropriate for this test material because precipitating test material could not be removed by washing after the intended exposure period and the precipitate interfered with cell counting. The AS52/XPRT assay methodology was not subject to these problems and DRM was tested and found not to be mutagenic in the CHO AS52/XPRT gene mutation assay. DRM was not clastogenic to human peripheral blood lymphocytes in culture. Additionally, DRM did not induce micronucleus formation in mouse bone marrow in vivo further supporting its lack of any chromosomal effects. Overall, the results of this series of mutagenicity assays support the conclusion that DRM does not have any genotoxic potential.

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.

Calder, P. C., P. Yaqoob, et al. (2002). "Fatty acids and lymphocyte functions." Br J Nutr 87 Suppl 1: S31-48.

            The immune system acts to protect the host against pathogenic invaders. However, components of the immune system can become dysregulated such that their activities are directed against host tissues, so causing damage. Lymphocytes are involved in both the beneficial and detrimental effects of the immune system. Both the level of fat and the types of fatty acid present in the diet can affect lymphocyte functions. The fatty acid composition of lymphocytes, and other immune cells, is altered according to the fatty acid composition of the diet and this alters the capacity of those cells to produce eicosanoids, such as prostaglandin E2, which are involved in immunoregulation. A high fat diet can impair lymphocyte function. Cell culture and animal feeding studies indicate that oleic, linoleic, conjugated linoleic, gamma-linolenic, dihomo-gamma-linolenic, arachidonic, alpha-linolenic, eicosapentaenoic and docosahexaenoic acids can all influence lymphocyte proliferation, the production of cytokines by lymphocytes, and natural killer cell activity. High intakes of some of these fatty acids are necessary to induce these effects. Among these fatty acids the long chain n-3 fatty acids, especially eicosapentaenoic acid, appear to be the most potent when included in the human diet. Although not all studies agree, it appears that fish oil, which contains eicosapentaenoic acid, down regulates the T-helper 1-type response which is associated with chronic inflammatory disease. There is evidence for beneficial effects of fish oil in such diseases; this evidence is strongest for rheumatoid arthritis. Since n-3 fatty acids also antagonise the production of inflammatory eicosanoid mediators from arachidonic acid, there is potential for benefit in asthma and related diseases. Recent evidence indicates that fish oil may be of benefit in some asthmatics but not others.

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.

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.

Abhyankar, B. (2002). "Further reduction in mortality following myocardial infarction." Hosp Med 63(10): 610-4.

            Omacor is a new omega-3 fatty acid product that is licensed for secondary prevention post-myocardial infarction. It confers an additional 20% reduction in all-cause mortality, based on the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico prevenzione (GISSI-P) study data. The GISSI-P results are compared with other trials of secondary prevention.

Yazawa, K. (2001). "Recent development of health foods enriched with DHA, EPA and DPA in Japan." World Rev Nutr Diet 88: 249-52.

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.

Yavin, E., S. Glozman, et al. (2001). "Docosahexaenoic acid sources for the developing brain during intrauterine life." Nutr Health 15(3-4): 219-24.

            Docosahexaenoic acid (DHA, 22: 6n-3) and arachidonic acid (AA, 20: 4n-6) provision to the developing fetus, with emphasis towards brain and vascular system growth, is a subject of increasing concern particularly under pathological conditions associated with premature birth or in utero growth restriction following obstruction of the maternal-fetal blood flow. Most of DHA, but also AA accretion under physiological conditions, is maternally dependent and requires adequate maternal nutrition and normally functioning placental-fetal circulation. It has been demonstrated that unlike other fatty acids (FA), DHA is preferentially transported across the placenta into the fetal circulation. The selective transplacental DHA transfer is probably mediated by specific carrier proteins. While some of the latter may be acting in fetal organs, the mechanism(s) for the selective accumulation of DHA in brain is still unknown. The fetal brain and also the fetal liver are capable of producing DHA from linolenic (LnA, 18:3 n-3) acid. How effective this local elongation-desaturation mechanism for DHA provision is and to what degree this route is activated in premature births is not clear. Transfer of DHA via the fetal gastrointestinal tract is an additional route to provide DHA to other fetal organs. As indicated by animal model studies, it holds the potential for DHA supply when the maternal pathway is compromised.

Valenzuela, A. and M. S. Nieto (2001). "[Docosahexaenoic acid (DHA) in fetal development and in infant nutrition]." Rev Med Chil 129(10): 1203-11.

            Docosahexanoic acid (C22:6, DHA) is a highly unsaturated omega-3 fatty acid that forms part of the central nervous and visual system structures. DHA is synthesized from its precursor, alfa-linolenic acid, that is also a omega-3 fatty acid and can be obtained from vegetable oils. Marine organisms, specially fish, are good nutritional sources of DHA and eicosapentanoic acid (EPA), another omega-3 fatty acid that has a role in vascular homeostasis. DHA increases membrane fluidity, improving neurogenesis, synaptogenesis and the activity of retinal photoreceptors. The fetus, specially during the last trimester of pregnancy, has high DHA requirements. It is provided by the mother, since fetal DHA synthesis is negligible in this stage of development. Breast feeding provides DHA to the child, but most replacement artificial formulas do not provide this fatty acid. At the present moment, many products for infant nutrition contain DHA.

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.

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.

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

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.

Salem, N., Jr., B. Litman, et al. (2001). "Mechanisms of action of docosahexaenoic acid in the nervous system." Lipids 36(9): 945-59.

            This review describes (from both the animal and human literature) the biological consequences of losses in nervous system docosahexaenoate (DHA). It then concentrates on biological mechanisms that may serve to explain changes in brain and retinal function. Brief consideration is given to actions of DHA as a nonesterified fatty acid and as a docosanoid or other bioactive molecule. The role of DHA-phospholipids in regulating G-protein signaling is presented in the context of studies with rhodopsin. It is clear that the visual pigment responds to the degree of unsaturation of the membrane lipids. At the cell biological level, DHA is shown to have a protective role in a cell culture model of apoptosis in relation to its effects in increasing cellular phosphatidylserine (PS); also, the loss of DHA leads to a loss in PS. Thus, through its effects on PS, DHA may play an important role in the regulation of cell signaling and in cell proliferation. Finally, progress has been made recently in nuclear magnetic resonance studies to delineate differences in molecular structure and order in biomembranes due to subtle changes in the degree of phospholipid unsaturation.

Rudolph, I. L., D. S. Kelley, et al. (2001). "Regulation of cellular differentiation and apoptosis by fatty acids and their metabolites." Nutr Res 21(1-2): 381-93.

            We have reviewed the literature regarding the effects of fatty acids and their metabolites on cellular differentiation and apoptosis. Results obtained in different studies have been variable, but some generalizations can be made. Differentiation was increased by incubation of cells with arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), or leukotriene D4 (LTD4). Effects of these agents on differentiation could be magnified with the simultaneous addition of other differentiation-inducing agents like dimethylsulfoxide or retinoic acid. AA and gamma-linolenic acid increased apoptosis while the effects of n-3 fatty acids (EPA and DHA) and of eicosanoids varied from stimulation to inhibition. These inconsistencies are attributed to the differences in methods used to evaluate differentiation and apoptosis, concentrations of fatty acids and serum, exposure time and the cell models used. Studies using the physiological concentrations of the fatty acids and standardized experimental conditions need to be conducted to establish effects of fatty acids and their metabolites on these cellular processes.

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.

Nestel, P. (2001). "Fish oil fatty acids beneficially modulate vascular function." World Rev Nutr Diet 88: 86-9.

Mori, T. A. and L. J. Beilin (2001). "Long-chain omega 3 fatty acids, blood lipids and cardiovascular risk reduction." Curr Opin Lipidol 12(1): 11-7.

            Increasing evidence suggests that omega 3 fatty acids derived from fish and fish oils may play a protective role in coronary heart disease and its many complications, through a variety of actions, including effects on lipids, blood pressure, cardiac and vascular function, prostanoids, coagulation and immunological responses. Interesting differences between the effects of highly purified eicosapentaenoic acid and docosahexaenoic acid are emerging, which may be relevant in the choice of omega 3 fatty acid for incorporation into food products. On the basis of our current knowledge, we believe it is justified to recommend, particularly to high-risk populations, an increased dietary intake of omega 3 fatty acids through the consumption of fish.

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.

McLennan, P. L. (2001). "Myocardial membrane fatty acids and the antiarrhythmic actions of dietary fish oil in animal models." Lipids 36 Suppl: S111-4.

            Epidemiologic studies, animal studies, and more recently, clinical intervention trials all suggest a role for regular intake of dietary fish oil in reducing cardiovascular morbidity and mortality. Prevention of cardiac arrhythmias and sudden death is demonstrable at fish or fish oil intakes that have little or no effect on blood pressure or plasma lipids. In animals, dietary intake of fish oil [containing both eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3)] selectively increases myocardial membrane phospholipid content of DHA, whereas low dose consumption of purified fatty acids shows antiarrhythmic effects of DHA but not EPA. Ventricular fibrillation induced under many conditions, including ischemia, reperfusion, and electrical stimulation, and even arrhythmias induced in vitro with no circulating fatty acids are prevented by prior dietary consumption of fish oil. The preferential accumulation of DHA in myocardial cell membranes, its association with arrhythmia prevention, and the selective ability of pure DHA to prevent ventricular fibrillation all point to DHA as the active component of fish oil. The antiarrhythmic effect of dietary fish oil appears to depend on the accumulation of DHA in myocardial cell membranes.

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.

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.

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.

Lanzmann-Petithory, D. (2001). "Alpha-linolenic acid and cardiovascular diseases." J Nutr Health Aging 5(3): 179-83.

            The intake of saturated fat was postulated to be the main environmental factor for coronary heart disease. It was also postulated that the noxious effects of saturated fatty acids (FA) was primarily through the increase in serum cholesterol. Nevertheless intervention trials either in coronary patients or even in primary prevention did not observe significant reduction in cardiac mortality, especially sudden death, when the diet was markedly enriched in linoleic acid (LA), the most efficient FA to lower serum cholesterol. In intervention trials, It is only when the diet was enriched in n-3 FA, especially alphalinolenic acid (ALA) that cardiac death was reduced. Studies in animals as well as in vitro on myocytes in culture, have shown that ALA was preventing ventricular fibrillation, the chief mechanism of cardiac death. Furthermore, studies in rats have observed that among n-3 FA, ALA, the precursor of the n-3 family, may be more efficient to prevent ventricular fibrillation than eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In addition it was demonstrated that ALA was the main FA lowering platelet aggregation, an important step in thrombosis, i. e. non fatal myocardial infarction and stroke. Thus, without side effects, a higher intake of ALA (2g / day) with a ratio of 5/1 for LA/ALA, could possibly constitute a nutritional answer to the main cause of morbidity and mortality in industrialized countries.

Lagarde, M., N. Bernoud, et al. (2001). "Lysophosphatidylcholine as a preferred carrier form of docosahexaenoic acid to the brain." J Mol Neurosci 16(2-3): 201-4; discussion 215-21.

            The metabolic fate of docosahexaenoic acid (DHA) was evaluated from its intake as a nutrient in triglycerides and phosphatidylcholines to its uptake by target tissues, especially the brain. Several approaches were used including the kinetics and tissue distribution of ingested 13C-labeled DHA, the incorporation of radiolabeled DHA injected as its nonesterified form compared to the fatty acid esterified in lysophosphatidylcholine (lysoPC), and the capacity of the two latter forms to cross a reconstituted blood-brain barrier (BBB) consisting of cocultures of brain-capillary endothelial cells and astrocytes. The results obtained allow us to raise the hypothesis that lysoPC may represent a preferred physiological carrier of DHA to the brain.

Lagarde, M., N. Bernoud, et al. (2001). "Lysophosphatidylcholine as a carrier of docosahexaenoic acid to target tissues." World Rev Nutr Diet 88: 173-7.

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.

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.

Kelley, D. S. (2001). "Modulation of human immune and inflammatory responses by dietary fatty acids." Nutrition 17(7-8): 669-73.

            I review the effects of the amount and composition of dietary fat on indices of human immune and inflammatory responses. A reduction in the amount of fat intake enhanced several indices of immune response, including lymphocyte proliferation, natural-killer-cell activity, cytokine production, and delayed-type hypersensitivity. When total fat intake was held constant, an increase in the intake of linoleic acid (18:2 omega-6) or arachidonic acid (20:4 omega-6) by healthy human volunteers did not inhibit many indices of immune response tested but did increase the production of inflammatory eicosanoids (prostaglandin E2 and leukotriene B4). Supplementation of human diets with omega-3 fatty acids reduced several aspects of neutrophil, monocyte, and lymphocyte functions, including the production of inflammatory mediators. Most of the studies have indicated reductions in these functions, with a minimum of 1.2 g/d of supplementation with eicosapentaenoic acid and docosahexaenoic acid for 6 wk. However, other studies concomitantly supplementing with 205 mg/d of vitamin E did not find inhibition of immune-cell functions, even with larger amounts and longer durations of supplementation with these fatty acids. One study reported that supplementation with docosahexaenoic acid selectively inhibits inflammatory responses without inhibiting T- and B-cell functions. Despite some discrepancies, fish oils have been used successfully in the management of several inflammatory and autoimmune diseases. The potential for the use of fish oils in the management of these diseases is tremendous, even though further studies are needed to establish safe and adequate intake levels of omega-3 fatty acids.

Jeffrey, B. G., H. S. Weisinger, et al. (2001). "The role of docosahexaenoic acid in retinal function." Lipids 36(9): 859-71.

            An important role for docosahexaenoic acid (DHA) within the retina is suggested by its high levels and active conservation in this tissue. Animals raised on n-3-deficient diets have large reductions in retinal DHA levels that are associated with altered retinal function as assessed by the electroretinogram (ERG). Despite two decades of research in this field, little is known about the mechanisms underlying altered retinal function in n-3-deficient animals. The focus of this review is on recent research that has sought to elucidate the role of DHA in retinal function, particularly within the rod photoreceptor outer segments where DHA is found at its highest concentration. An overview is also given of human infant studies that have examined whether a neonatal dietary supply of DHA is required for the normal development of retinal function.

Infante, J. P. and V. A. Huszagh (2001). "Zellweger syndrome knockout mouse models challenge putative peroxisomal beta-oxidation involvement in docosahexaenoic acid (22:6n-3) biosynthesis." Mol Genet Metab 72(1): 1-7.

            The putative involvement of peroxisomal beta-oxidation in the biosynthetic pathway of docosahexaenoic acid (22:6n-3, DHA) synthesis is critically reviewed in light of experiments with two recently developed knockout mouse models for Zellweger syndrome, a peroxisomal disorder affecting brain development. These mice were generated by targeted disruption of the PEX2 and PEX5 peroxisomal assembly genes encoding targeting signal receptor peroxins for the recognition and transport of a set of peroxisomal enzymes, including those of peroxisomal beta-oxidation, to the peroxisomal matrix. Analysis of esterified 22:6n-3 concentrations in PEX2-/- and PEX5-/- mice do not support the hypothesized requirement of peroxisomal beta-oxidation in 22:6n-3 synthesis, as only brain, but not liver or plasma, 22:6n-3 levels were decreased. Supplementation of PEX5+/- dams with 22:6n-3, although restoring the levels of brain 22:6n-3 in total lipids to that of controls, did not normalize the phenotype. These decreased brain 22:6n-3 concentrations appear to be secondary to impaired plasmalogen (sn-1-alkyl-, alkenyl-2-acyl glycerophospholipids) synthesis, probably at the level of the dihydroxyacetonephosphate acyltransferase (DHAP-AT), a peroxisomal enzyme catalyzing the first step in the synthesis of 22:6n-3-rich plasmalogens. To diminish the confounding effects of impaired plasmalogen synthesis in the brains of these Zellweger syndrome mouse models, kinetic experiments with labeled precursors, such as 18:3n-3 or 20:5n-3, in liver or isolated hepatocytes, which have negligible amounts of plasmalogens, are suggested to establish the rates of 22:6n-3 biosynthesis and precursor-product relationships. Similar experiments using brain of the acyl-CoA oxidase knockout mouse model are proposed to confirm the lack of peroxisomal beta-oxidation involvement in 22:6n-3 synthesis, since this mutation would not impair plasmalogen synthesis.

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.

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.

Hamazaki, T., S. Sawazaki, et al. (2001). "Effect of docosahexaenoic acid on hostility." World Rev Nutr Diet 88: 47-52.

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.

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 benefit