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Eicosapentaenoic acid (EPA) Reviews

(83 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.

 

Takatsuka, H., T. Iwasaki, et al. (2003). "Intestinal graft-versus-host disease: mechanisms and management." Drugs 63(1): 1-15.

            Allogeneic haematopoietic stem cell transplantation remains the treatment of choice for a number of malignancies. However, graft-versus-host disease (GVHD) has long been regarded as a serious complication of this procedure. Although GVHD may affect any organ, intestinal GVHD is particularly important because of its frequency, severity and impact on the general condition of the patient. Recent studies have led to progressive elucidation of the mechanism of GVHD. Donor T cells are critical for the induction of GVHD, because depletion of T cells from bone marrow grafts effectively prevents GVHD but also results in an increase of leukaemia relapse. It has been shown that the gastrointestinal tract plays a major role in the amplification of systemic disease because gastrointestinal damage increases the translocation of endotoxins, which promotes further inflammation and additional gastrointestinal damage. Consequently, the management of intestinal GVHD (and the intestine itself) is a subject that should be highlighted. In this article, approaches to the prevention of intestinal GVHD are discussed after being classified into three categories: regimens in common clinical use, regimens under investigation and original regimens used at our hospital. The standard regimen that is used most widely for prevention of GVHD is cyclosporin plus short-term methotrexate. Corticosteroids can be added to this regimen but careful consideration of the adverse effects of these hormones should be considered. Tacrolimus is a newer, more potent alternative to cyclosporin. T-cell depletion (TCD) after transplantation has been shown to prevent acute GVHD, however, the survival benefit of TCD has not been as great as expected. Mycophenolate mofetil can be useful for the treatment of acute GVHD as part of combination therapy. Regimens currently under investigation in animal experiments include suppression of inflammatory cytokines and inhibition of T-cell activation, and, specifically at our institution, hepatocyte growth factor gene therapy. The evidence-based therapy used at our institution includes systemic antibacterial therapy (including eradication of intestinal bacteria) to prevent the intestinal translocation of lipopolysaccharide and avoid the subsequent increase of various inflammatory cytokines. In addition, because of the similarities between intestinal GVHD and ulcerative colitis, sulfasalazine, betamethasone enemas and eicosapentaenoic acid have been used to treat intestinal GVHD in some patients.

 

Spector, S. L. and M. E. Surette (2003). "Diet and asthma: has the role of dietary lipids been overlooked in the management of asthma?" Ann Allergy Asthma Immunol 90(4): 371-7; quiz 377-8, 421.

            OBJECTIVE: This article discusses the role of diet in the management of asthma. Readers will gain an understanding of how evolution of the western diet has contributed to increased asthma prevalence and how dietary modification that includes management of dietary lipids may reduce symptoms of asthma. DATA SOURCES: Relevant studies published in English were reviewed. STUDY SELECTION: Medline search to identify peer-reviewed abstracts and journal articles. RESULTS: Asthma and obesity, which often occur together, have increased in prevalence in recent years. Studies suggest adaption of a western diet has not only contributed to obesity, but that increased intake of specific nutrients can cause changes in the frequency and severity of asthma. Increased asthma prevalence has also been proposed to arise from increased exposure to diesel particles or lack of exposure to infectious agents or endotoxins during childhood, generating a biased Th2 immune response, and increased cytokine and leukotriene production. Antagonists directed against these pro-inflammatory mediators include anticytokines and antileukotrienes. A reduction in the levels of inflammatory mediators associated with asthma has also been seen with dietary interventions, such as the administration of oils containing gamma-linolenic acid and eicosapentaenoic acid. CONCLUSIONS: Evidence suggests elevated body mass index and dietary patterns, especially intake of dietary lipids, contribute to symptoms of asthma. Dietary modification may help patients manage their asthma as well as contribute to their overall health.

 

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.

 

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).

 

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

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

 

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.

 

Calder, P. C. (2003). "Long-chain n-3 fatty acids and inflammation: potential application in surgical and trauma patients." Braz J Med Biol Res 36(4): 433-46.

            Lipids used in nutritional support of surgical or critically ill patients have been based on soybean oil, which is rich in the n-6 fatty acid linoleic acid (18:2n-6). Linoleic acid is the precursor of arachidonic acid (20:4n-6). In turn, arachidonic acid in cell membrane phospholipids is the substrate for the synthesis of a range of biologically active compounds (eicosanoids) including prostaglandins, thromboxanes, and leukotrienes. These compounds can act as mediators in their own right and can also act as regulators of other processes, such as platelet aggregation, blood clotting, smooth muscle contraction, leukocyte chemotaxis, inflammatory cytokine production, and immune function. There is a view that an excess of n-6 fatty acids should be avoided since this could contribute to a state where physiological processes become dysregulated. One alternative is the use of fish oil. The rationale of this latter approach is that fish oil contains long chain n-3 fatty acids, such as eicosapentaenoic acid. When fish oil is provided, eicosapentaenoic acid is incorporated into cell membrane phospholipids, partly at the expense of arachidonic acid. Thus, there is less arachidonic acid available for eicosanoid synthesis. Hence, fish oil decreases production of prostaglandins like PGE2 and of leukotrienes like LTB4. Thus, n-3 fatty acids can potentially reduce platelet aggregation, blood clotting, smooth muscle contraction, and leukocyte chemotaxis, and can modulate inflammatory cytokine production and immune function. These effects have been demonstrated in cell culture, animal feeding and healthy volunteer studies. Fish oil decreases the host metabolic response and improves survival to endotoxin in laboratory animals. Recently clinical studies performed in various patient groups have indicated benefit from this approach.

 

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.

 

Woods, R. K., F. C. Thien, et al. (2002). "Dietary marine fatty acids (fish oil) for asthma in adults and children." Cochrane Database Syst Rev(3): CD001283.

            BACKGROUND: Epidemiological studies suggest that a diet high in marine fatty acids (fish oil) may have beneficial effects on inflammatory conditions such as rheumatoid arthritis and possibly asthma. OBJECTIVES: 1. To determine the effect of marine n-3 fatty acid (fish oil) supplementation in asthma. 2. To determine the effect of a diet high in fish oil in asthma. SEARCH STRATEGY: The Cochrane Airways Review Group register was searched using the terms: marine fatty acids OR diet OR nutrition OR fish oil OR eicosapentaenoic acid OR EPA. Bibliographies of retrieved trials were searched and fish oil manufacturers contacted. SELECTION CRITERIA: Randomised controlled trials in patients with asthma more than two years of age were included. The study duration had to be in excess of four weeks. Double blind trials were preferred, but single-blind and open trials were also reviewed for possible inclusion. Three reviewers read each paper, blind to its identity. Decisions concerning inclusion were made by simple majority. Quality assessment was performed by all three reviewers independently. DATA COLLECTION AND ANALYSIS: The only comparison possible was between marine n-3 fatty acid supplementation and placebo. There were insufficient trials to examine dietary manipulation alone. MAIN RESULTS: Nine randomised controlled trials conducted between 1986 and 2001 satisfied the inclusion criteria. Seven were of parallel design and two were cross-over studies. Eight compared fish oil with placebo whilst one compared high dose vs low dose marine n-3 fatty acid supplementation. Two studies were conducted in children, whilst the remaining seven studies were conducted in adults. None of the included studies reported asthma exacerbations, health status or hospital admissions. There was no consistent effect on any of the analysable outcomes: FEV1, peak flow rate, asthma symptoms, asthma medication use or bronchial hyper reactivity. One of the studies performed in children which combined dietary manipulation with fish oil supplementation showed improved peak flow and reduced asthma medication use. There were no adverse events associated with fish oil supplements. REVIEWER'S CONCLUSIONS: There is little evidence to recommend that people with asthma supplement or modify their dietary intake of marine n-3 fatty acids (fish oil) in order to improve their asthma control. Equally, there is no evidence that they are at risk if they do so.

 

Von Hoff, D. D. and D. Bearss (2002). "New drugs for patients with pancreatic cancer." Curr Opin Oncol 14(6): 621-7.

            This past year has proved to be a relatively disappointing one for the development of agents that could improve the survival rates of patients with advanced pancreatic cancer. A well designed randomized trial of treatment of patients with gemcitabine with or without a farnesyl transferase inhibitor (tried because pancreatic cancers have a high incidence of K- abnormalities) showed no improvement in survival rates. A definitive randomized controlled trial with a histone deacetylase inhibitor also proved negative. There are some signs of hope in that in early nonrandomized studies there are some new agents that appear to have some activity against the disease. These agents include the thymidylate synthase inhibitor capecitabine (which is possibly activated at the tumor site), the antigastrin immunogen G17DT (which is an immunization designed to neutralize the pancreatic growth factor gastrin), and the topoisomerase I inhibitor 9-nitrocamptothecin. In addition, the combination of the new agent oxaliplatin to high-dose 5FU plus leucovorin, which gave a median survival rate of 12.5 months, is also worthy of further study. Supportive care findings of interest for the patient with advanced pancreatic cancer of note include: the study in which eicosapentaenoic acid (fish oil) caused a modest weight gain (median of 1 kg), and the finding that ofloxacin plus ursodeoxycholic acid was not superior to ursodeoxycholic acid alone for the prevention or occlusion of biliary stents.

 

Tisdale, M. J. (2002). "Biochemical mechanisms of cellular catabolism." Curr Opin Clin Nutr Metab Care 5(4): 401-5.

            PURPOSE OF REVIEW: To provide an in-depth analysis of current developments concerning biochemical mechanisms of cellular catabolism. There have been a number of important developments in this area over the past 12 months, particularly with respect to protein catabolism. RECENT FINDINGS: Protein degradation in a range of catabolic conditions is mediated primarily through the ubiquitin-proteasome proteolytic pathway. Glucocorticoids have been suggested to activate this system in sepsis, while in cancer cachexia a tumour-produced sulphated glycoprotein, proteolysis-inducing factor, induces protein catabolism in skeletal muscle by increasing expression of proteasome subunits and the ubiquitin carrier protein, E2(14k). Apoptosis may also be important in the loss of muscle protein during the early stage of cachexia. Induction of proteasome expression by glucocorticoids appears to be a direct result of the downregulation of the activity of nuclear factor kappaB, while proteolysis-inducing factor acts through 15-hydroxyeicosatetraenoic acid as an intracellular transducer. SUMMARY: Formation of 15-hydroxyeicosatetraenoic acid is inhibited by eicosapentaenoic acid, which has been shown to attenuate the development of weight loss in patients with pancreatic cancer. When eicosapentaenoic acid is combined with an energy dense nutritional supplement, there is an increase in body weight of cachectic cancer patients through an increase in lean body mass. Eicosapentaenoic acid also prevents protein catabolism and activation of the ubiquitin-proteasome proteolytic pathway during acute starvation in mice, suggesting a similar pathway is involved. Thus eicosapentaenoic acid may be effective in the treatment of protein catabolism in conditions other than cancer.

 

Tisdale, M. J. (2002). "Cachexia in cancer patients." Nat Rev Cancer 2(11): 862-71.

           

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.

 

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.

 

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.

 

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.

 

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

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

 

Kinoshita, M. (2002). "[Anti-hyperlipidemic agents]." Nippon Rinsho 60(5): 968-74.

            There are several drugs for hyperlipidemia except for statin and fibrate. Resin is a commonly used drug for hypercholesterolemia and is known to very useful for the prevention of coronary heart disease(CHD). Probucol is also used for hypercholesterolemia and recently is known that it prevent the restenosis of the coronary artery after PTCA. Nicotinic acid is used for hypertriglyceridemia and hypercholesterolemia, both. It is also known to very useful for the prevention of CHD. Eicosapentaenoic acid is effective for hypertriglyceridemia and also shows an inhibition of platelets aggregation. These drugs as well as statin and fibrate are used in combination with each other for severe hyperlipidemia.

 

Horrobin, D. F. (2002). "A new category of psychotropic drugs: neuroactive lipids as exemplified by ethyl eicosapentaenoate (E-E)." Prog Drug Res 59: 171-99.

            New treatments for psychiatric disorders are urgently required. Recent reviews show that there have been no improvements in efficacy of drugs for either affective disorders or schizophrenia since the first compounds were introduced over 40 years ago. Neuroactive lipids represent an entirely novel class of psychotropic compounds. Ethyl eicosapentaenoate is the first example of this group. Placebo-controlled studies have found it to be effective in depression, in treatment-unresponsive schizophrenia and in tardive dyskinesia. It is extremely well tolerated with none of the usual side-effects of either antidepressants or neuroleptics. It probably works by modulating postreceptor signal transduction processes.

 

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

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

 

Fujita, T. (2002). "[Formation and removal of reactive oxygen species, lipid peroxides and free radicals, and their biological effects]." Yakugaku Zasshi 122(3): 203-18.

            It is well known that biomembranes and subcellular organelles are susceptible to lipid peroxidation. There is a steadily increasing body of evidence indicating that lipid peroxidation is involved in basic deteriorative mechanisms, e.g., membrane damage, enzyme damage, and nucleic acid mutagenicity. The formation of lipid peroxides can be induced by enzymatic or nonenzymatic peroxidation in the presence of oxygen. The mechanisms of formation and removal of reactive oxygen species, lipid peroxides, and free radicals in biological systems are briefly reviewed. In recent years, there has been renewed interest in the role played by lipid peroxidation in many disease states. Xanthine oxidase has been shown to generate reactive oxygen species, superoxide (O2-.), and hydrogen peroxide (H2O2) that are involved in the peroxidative damage to cells that occurs in ischemia-reperfusion injury. During ischemia, this enzyme is induced from xanthine dehydrogenase. We have shown that peroxynitrite (a reactive nitrogen species) has the potential to convert xanthine dehydrogenase to oxidase. The following biological effects of lipid peroxidation were found: a) the lipid peroxidation induced by ascorbic acid and Fe2+ affects the membrane transport in the kidney cortex and the cyclooxygenase activity in the kidney medulla, and b) the hydroperoxy adducts of linoleic acid and eicosapentaenoic acid inhibit the cyclooxygenase activity in platelets. The balance between the formation and removal of lipid peroxides determines the peroxide level in cells. This balance can be disturbed if cellular defenses are decreased or if there is a significant increase in peroxidative reactions. Once lipid peroxidation is initiated, the reactive intermediate formed induces cell damage.

 

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

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

 

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.

 

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.

 

Berger, G. E., S. J. Wood, et al. (2002). "Implications of lipid biology for the pathogenesis of schizophrenia." Aust N Z J Psychiatry 36(3): 355-66.

            OBJECTIVE: Preclinical and clinical data suggest that lipid biology is integral to brain development and neurodegeneration. Both aspects are proposed as being important in the pathogenesis of schizophrenia. The purpose of this paper is to examine the implications of lipid biology, in particular the role of essential fatty acids (EFA), for schizophrenia. METHODS: Medline databases were searched from 1966 to 2001 followed by the cross-checking of references. RESULTS: Most studies investigating lipids in schizophrenia described reduced EFA, altered glycerophospholipids and an increased activity of a calcium-independent phospholipase A2 in blood cells and in post-mortem brain tissue. Additionally, in vivo brain phosphorus-31 Magnetic Resonance Spectroscopy (31P-MRS) demonstrated lower phosphomonoesters (implying reduced membrane precursors) in first- and multi-episode patients. In contrast, phosphodiesters were elevated mainly in first-episode patients (implying increased membrane breakdown products), whereas inconclusive results were found in chronic patients. EFA supplementation trials in chronic patient populations with residual symptoms have demonstrated conflicting results. More consistent results were observed in the early and symptomatic stages of illness, especially if EFA with a high proportion of eicosapentaenoic acid was used. CONCLUSION: Peripheral blood cell, brain necropsy and 31P-MRS analysis reveal a disturbed lipid biology, suggesting generalized membrane alterations in schizophrenia. 31P-MRS data suggest increased membrane turnover at illness onset and persisting membrane abnormalities in established schizophrenia. Cellular processes regulating membrane lipid metabolism are potential new targets for antipsychotic drugs and might explain the mechanism of action of treatments such as eicosapentaenoic acid.

 

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.

           

Tsushima, M. (2001). "[Eicosapentaenoic acid]." Nippon Rinsho 59 Suppl 3: 650-6.

           

Tisdale, M. J. (2001). "Loss of skeletal muscle in cancer: biochemical mechanisms." Front Biosci 6: D164-74.

            Patients with cancer often undergo a specific loss of skeletal muscle mass, while the visceral protein reserves are preserved. This condition known as cachexia reduces the quality of life and eventually results in death through erosion of the respiratory muscles. Nutritional supplementation or appetite stimulants are unable to restore the loss of lean body mass, since protein catabolism is increased mainly as a result of the activation of the ATP-ubiquitin-dependent proteolytic pathway. Several mediators have been proposed. An enhanced protein degradation is seen in skeletal muscle of mice administered tumour necrosis factor (TNF), which appears to be mediated by oxidative stress. There is some evidence that this may be a direct effect and is associated with an increase in total cellular-ubiquitin-conjugated muscle proteins. Another cytokine, interleukin-6 (IL-6), may play a role in muscle wasting in certain animal tumours, possibly through both lysosomal (cathepsin) and non-lysosomal (proteasome) pathways. A tumour product, proteolysis-inducing factor (PIF) is produced by cachexia-inducing murine and human tumours and initiates muscle protein degradation directly through activation of the proteasome pathway. The action of PIF is blocked by eicosapentaenoic acid (EPA), which has been shown to attenuate the development of cachexia in pancreatic cancer patients. When combined with nutritional supplementation EPA leads to accumulation of lean body mass and prolongs survival. Further knowledge on the biochemical mechanisms of muscle protein catabolism will aid the development of effective therapy for cachexia.

 

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

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

 

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

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

 

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

           

Shimokawa, H. (2001). "Beneficial effects of eicosapentaenoic acid on endothelial vasodilator functions in animals and humans." World Rev Nutr Diet 88: 100-8.

           

Senzaki, H., A. Tsubura, et al. (2001). "Effect of eicosapentaenoic acid on the suppression of growth and metastasis of human breast cancer cells in vivo and in vitro." World Rev Nutr Diet 88: 117-25.

           

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.

 

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.

 

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.

 

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.

 

Kaboyashi, J. (2001). "[The importance of the quality and quantity of fatty acids in food]." Nippon Rinsho 59 Suppl 3: 543-8.

           

Jatoi, A., Jr. and C. L. Loprinzi (2001). "Current management of cancer-associated anorexia and weight loss." Oncology (Huntingt) 15(4): 497-502, 508; discussion 508-10.

            Loss of appetite and weight predict a poor prognosis for cancer patients. Although caloric supplementation might benefit subgroups of patients--specifically, perioperative, severely malnourished cancer patients, stem cell and bone marrow transplant patients and head and neck cancer patients--its use remains controversial and is not recommended for the majority of patients with cancer-associated weight loss. Most patients with advanced cancer, anorexia, and/or weight loss do not appear to benefit from nutritional supplementation. Instead, discussions with patients and families about realistic eating goals ans, at time armacologic interventions with progestational agents or corticosteroids--both of which are aimed at palliating anorexia--provide clinical benefit. Other phamalogic interventions such as eicosapentaenoic acid, thalidomide (Thalomid), adenosine triphosphate and nonsteriodal anti-inflammatory agents focus on the fact that cancer-assciated weight loss is an enitty dintinct for simple starvation These interventions promise to replenish lean tissue but require further investigation before they can be recommndedas standard clinical practice.

 

Gadducci, A., S. Cosio, et al. (2001). "Malnutrition and cachexia in ovarian cancer patients: pathophysiology and management." Anticancer Res 21(4B): 2941-7.

            In ovarian cancer patients the poor nutritional status and cachexia are caused by the metabolic effects of the enlarging tumor masses and bowel obstruction. These patients may have a high resting energy expenditure due to increase in Cori cycle activity, glucose and triglyceride-fatty acid cycling and gluconeogenesis. Biochemical mediators of cachexia include cytokines, such as tumor necrosis factor and interleukin-6, and tumor-produced catabolic factors, such as lipid-mobilizing factor, proteolysis-inducing factor, and anemia-inducing factor. Mechanisms involved in the pathogenesis of obstruction may include extrinsic occlusion of the bowel due to pelvic, mesenteric omental masses, or intestinal motility disorders due to infilor tration of the mesentery or bowel muscle and nerves. The relief of malnutrition and cachexia may be attempted through nutritional support, pharmacological approach (megestrol acetate, cyclooxygenase inhibitors) and palliative treatment of bowel obstruction. Very few agents have been demonstrated to have true anticachectic activity, so future research should be addressed to the identification of drugs able to block the activity of tumor-produced catabolic factors. The decision regarding optimum management of bowel obstruction should be individualized. Krebs' and Goplerud's score (based on age, nutritional status, tumor status, ascites, previous chemotherapy and irradiation) seems to offer reliable eligibility criteria for those patients who can benefit from surgery.

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

Woods, R. K., F. C. Thien, et al. (2000). "Dietary marine fatty acids (fish oil) for asthma." Cochrane Database Syst Rev(2): CD001283.

            BACKGROUND: Epidemiological studies suggest that a diet high in marine fatty acids (fish oil) may have beneficial effects on inflammatory conditions such as rheumatoid arthritis and possibly asthma. OBJECTIVES: 1. To determine the effect of marine n-3 fatty acid (fish oil) supplementation in asthma. 2. To determine the effect of a diet high in fish oil in asthma. SEARCH STRATEGY: The Cochrane Airways Review Group register was search using the terms: marine fatty acids OR diet OR nutrition OR fish oil OR eicosapentaenoic acid OR EPA. Bibliographies of retrieved trials were searched and fish oil manufacturers contacted. SELECTION CRITERIA: Randomised controlled trials in patients with asthma more than two years of age were included. The study duration had to be in excess of 4 weeks. Double blind trials were preferred, but single-blind and open trials were also reviewed for possible inclusion. Three reviewers read each paper, blind to its identity. Decisions concerning inclusion were made by simple majority. Quality assessment was performed by all three reviewers independently. DATA COLLECTION AND ANALYSIS: The only comparison possible was between marine n-3 fatty acid supplementation and placebo. There were insufficient trials to examine dietary manipulation alone. MAIN RESULTS: Eight randomised controlled trials conducted between 1986 and 1998 satisfied the inclusion criteria. Six were of parallel design and two were cross-over studies. Seven compared fish oil with placebo whilst one compared high dose vs low dose marine n-3 fatty acid supplementation. None of the included studies reported asthma exacerbations, health status or hospital admissions. There was no consistent effect on any of the analyzable outcomes: FEV1, peak flow rate, asthma symptoms, asthma medication use or bronchial hyper reactivity. The single study performed in children also combined dietary manipulation with fish oil supplementation and showed improved peak flow and reduced asthma medication use. There were no adverse events associated with fish oil supplements. REVIEWER'S CONCLUSIONS: There is little evidence to recommend that people with asthma supplement or modify their dietary intake of marine n-3 fatty acids (fish oil) in order to improve their asthma control. Equally, there is no evidence that they are at risk if they do so.

 

Woods, R. K., F. C. Thien, et al. (2000). "Dietary marine fatty acids (fish oil) for asthma." Cochrane Database Syst Rev(4): CD001283.

            BACKGROUND: Epidemiological studies suggest that a diet high in marine fatty acids (fish oil) may have beneficial effects on inflammatory conditions such as rheumatoid arthritis and possibly asthma. OBJECTIVES: 1. To determine the effect of marine n-3 fatty acid (fish oil) supplementation in asthma. 2. To determine the effect of a diet high in fish oil in asthma. SEARCH STRATEGY: The Cochrane Airways Review Group register was search using the terms: marine fatty acids OR diet OR nutrition OR fish oil OR eicosapentaenoic acid OR EPA. Bibliographies of retrieved trials were searched and fish oil manufacturers contacted. SELECTION CRITERIA: Randomised controlled trials in patients with asthma more than two years of age were included. The study duration had to be in excess of 4 weeks. Double blind trials were preferred, but single-blind and open trials were also reviewed for possible inclusion. Three reviewers read each paper, blind to its identity. Decisions concerning inclusion were made by simple majority. Quality assessment was performed by all three reviewers independently. DATA COLLECTION AND ANALYSIS: The only comparison possible was between marine n-3 fatty acid supplementation and placebo. There were insufficient trials to examine dietary manipulation alone. MAIN RESULTS: Eight randomised controlled trials conducted between 1986 and 1998 satisfied the inclusion criteria. Six were of parallel design and two were cross-over studies. Seven compared fish oil with placebo whilst one compared high dose vs low dose marine n-3 fatty acid supplementation. None of the included studies reported asthma exacerbations, health status or hospital admissions. There was no consistent effect on any of the analyzable outcomes: FEV1, peak flow rate, asthma symptoms, asthma medication use or bronchial hyper reactivity. The single study performed in children also combined dietary manipulation with fish oil supplementation and showed improved peak flow and reduced asthma medication use. There were no adverse events associated with fish oil supplements. Updated Search conducted August 2000. No new trials were found. REVIEWER'S CONCLUSIONS: There is little evidence to recommend that people with asthma supplement or modify their dietary intake of marine n-3 fatty acids (fish oil) in order to improve their asthma control. Equally, there is no evidence that they are at risk if they do so.

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

Okabe, H. (2000). "[Ageing society and laboratory medicine]." Rinsho Byori 48(9): 783-96.

            An interest in the ageing process has increased greatly with increasing the population of the aged. The goal of this interest is to improve the quality of life(QOL) in the aged. In this paper, the presidential address "Ageing Society and Laboratory Medicine" at the 46th annual meeting of JSCP in Kumamoto'99 was summarized on the important research for ageing in the past decades. The paper presented was age- and gene-related changes, the latent variation of serum constituents and lipids abnormality in the ageing process. Concerning to the definition of reference value of healthy populations and the subjects who had no combined ailments, the reference interval of individuals(intra-personal), followed 5 years categorized by age, sex, and social conditions, gave a narrow range of variation than did a larger mixed populations(inter-personal). The reference intervals set would be a more sensitive reference than is the customary "normal range" for values occurring in inter-personal. Concerning to the study of the relationship between laboratory test and activity of daily living(ADL), the higher serum levels for TP, Alb, Hb, Glu, TC were observed in the higher ADL. The basic research techniques were also evaluated in the paper. The serum lipoperoxides were correlated with serum lipoprotein free radicals which caused atherosclerosis. The higher frequency of cerebral- and myocardial-infarction in the aged were observed in the higher serum LDL-C and lower serum level of arachidonic acid(AA), eicosapentaenoic acid(EPA), and AA/EPA ratio were observed in AMI patients with lower HDL-C groups than the healthy aged. Although Alzheimer(AD)'s disease had a progressive memory loss and immobile dementia and was reported the decrease of acetyltransferase activity in the brain, decrease of serum level of free choline, lyso-phosphatidylcholine, phosphatidylcholine(PC) and sphingomyelin(SM)/PC ratio were observed in spite of keeping normal serum level of SM. The decreased serum levels of pseudocholin esterase and albumin, especially mercaptoalbumin were observed in the healthy aged with advancing age. The early diagnosis and prediction of prognosis for the latent ailments in the aged was stressed. As to the study of variations of serum protein levels in the healthy aged, variations of serum proteins were classified into three types, 1) mainly acute phase reactant proteins such as alpha 1AT increased with advancing age, 2) transporting proteins such an albumin decreased and 3) proteins with no significant variation these were useful proteins for the early finding of latent ailments. The higher increase of alpha 1AT/beta 2III in the healthy aged over 60 y.o. was suspected to become severe in near future.

 

McMurray, D. N., C. A. Jolly, et al. (2000). "Effects of dietary n-3 fatty acids on T cell activation and T cell receptor-mediated signaling in a murine model." J Infect Dis 182 Suppl 1: S103-7.

            A short-term feeding paradigm in mice, with diets enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was used to study the modulation of T cell activation via the T cell receptor (TcR) and the downstream pathways of intracellular signaling. Diets enriched in EPA and DHA suppressed antigen-specific delayed hypersensitivity reactions and mitogen-induced proliferation of T cells. Cocultures of accessory cells and T cells from mice given different diets revealed that purified fatty acid ethyl esters acted directly on the T cell, rather than through the accessory cell. The loss of proliferative capacity was accompanied by reductions in interleukin (IL)-2 secretion and IL-2 receptor alpha chain mRNA transcription, suggesting that dietary EPA and DHA act, in part, by interrupting the autocrine IL-2 activation pathway. Dietary EPA and DHA blunted the production of intracellular second messengers, including diacylglycerol and ceramide, following mitogen stimulation in vitro. Dietary effects appear to vary with the agonist employed (i.e., anti-CD3 [TcR], anti-CD28, exogenous IL-2, or phorbol myristate acetate and ionomycin).

 

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

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

 

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

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

 

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

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

 

Kremer, J. M. (2000). "n-3 fatty acid supplements in rheumatoid arthritis." Am J Clin Nutr 71(1 Suppl): 349S-51S.

            Ingestion of dietary supplements of n-3 fatty acids has been consistently shown to reduce both the number of tender joints on physical examination and the amount of morning stiffness in patients with rheumatoid arthritis. In these cases, supplements were consumed daily in addition to background medications and the clinical benefits of the n-3 fatty acids were not apparent until they were consumed for > or =12 wk. It appears that a minimum daily dose of 3 g eicosapentaenoic and docosahexaenoic acids is necessary to derive the expected benefits. These doses of n-3 fatty acids are associated with significant reductions in the release of leukotriene B(4) from stimulated neutrophils and of interleukin 1 from monocytes. Both of these mediators of inflammation are thought to contribute to the inflammatory events that occur in the rheumatoid arthritis disease process. Several investigators have reported that rheumatoid arthritis patients consuming n-3 dietary supplements were able to lower or discontinue their background doses of nonsteroidal antiinflammatory drugs or disease-modifying antirheumatic drugs. Because the methods used to determine whether patients taking n-3 supplements can discontinue taking these agents are variable, confirmatory and definitive studies are needed to settle this issue. n-3 Fatty acids have virtually no reported serious toxicity in the dose range used in rheumatoid arthritis and are generally very well tolerated.

 

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

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

 

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

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

 

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

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

 

Heller, A. and T. Koch (2000). "[Immunonutrition with omega-3-fatty acids. Are new anti-inflammatory strategies in sight?]." Zentralbl Chir 125(2): 123-36.

            In the early phase of sepsis and SIRS an overwhelming activation of humoral and cellular mediator systems can alter vascular resistance and causes capillary leakage increasing the risk of organ dysfunction. omega-6-arachidonic acid is released from lipid pools of cellular membranes during inflammation and is metabolized to pro-inflammatory prostaglandins and leukotriens, which are key mediators in the pathogenesis of organ dysfunction. omega-3-eicosapentaenoic acid-derived lipid mediators present altered biologic effects. Thus, omega-3-fatty acid application enables anti-inflammatory intervention on the level of lipid mediators. The current article reviews experimental and clinical data on omega-3-fatty acids. Besides the decrease of pro-inflammatory mediators, fish oil supplementation lowered post operative infection rates and showed a tendency to reduce hospital stay in surgical patients. It is believed that the decreased formation of LTB4 and TXA2 during sepsis after administration of omega-3-fatty acids accounts for improved microcirculatory perfusion and declined lactate acidosis.

 

Hedqvist, P., N. Gautam, et al. (2000). "Interactions between leukotrienes and other inflammatory mediators/modulators in the microvasculature." Am J Respir Crit Care Med 161(2 Pt 2): S117-9.

           

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

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

 

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

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

 

Connor, W. E. (2000). "Importance of n-3 fatty acids in health and disease." Am J Clin Nutr 71(1 Suppl): 171S-5S.

            In the past 2 decades, views about dietary n-3 fatty acids have moved from speculation about their functions to solid evidence that they are not only essential nutrients but also may favorably modulate many diseases. Docosahexaenoic acid (22:6n-3), which is a vital component of the phospholipids of cellular membranes, especially in the brain and retina, is necessary for their proper functioning. n-3 Fatty acids favorably affect atherosclerosis, coronary heart disease, inflammatory disease, and perhaps even behavioral disorders. The 38 articles in this supplement document the importance of n-3 fatty acids in both health and disease.

 

Babcock, T., W. S. Helton, et al. (2000). "Eicosapentaenoic acid (EPA): an antiinflammatory omega-3 fat with potential clinical applications." Nutrition 16(11-12): 1116-8.

 

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