Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study.

RATIONALE: Specialized pro-resolving mediators (SPM-lipoxins, resolvins, protectins, and maresins) are produced via the enzymatic conversion of essential fatty acids, including the omega-3 fatty acids docosahexaenoic acid and n-3 docosapentaenoic acid. These mediators exert potent leukocyte directed actions and control vascular inflammation. Supplementation of animals and humans with essential fatty acids, in particular omega-3 fatty acids, exerts protective actions reducing vascular and systemic inflammation. Of note, the mechanism(s) activated by these supplements in exerting their protective actions remain poorly understood. OBJECTIVE: Given that essential fatty acids are precursors in the biosynthesises of SPM, the aim of the present study was to establish the relationship between supplementation and peripheral SPM concentrations. We also investigated the relationship between changes in plasma SPM concentrations and peripheral blood platelet and leukocyte responses. METHODS AND RESULTS: Healthy volunteers were enrolled in a double-blinded, placebo-controlled, crossover study, and peripheral blood was collected at baseline, 2, 4, 6, and 24 hours post administration of placebo or one of 3 doses of an enriched marine oil supplement. Assessment of plasma SPM concentrations using lipid mediator profiling demonstrated a time- and dose-dependent increase in peripheral blood SPM concentration. Supplementation also led to a regulation of peripheral blood cell responses. Here we found a dose-dependent increase in neutrophil and monocyte phagocytosis of bacteria and a decrease in the diurnal activation of leukocytes and platelets, as measured by a reduction in adhesion molecule expression. In addition, transcriptomic analysis of peripheral blood cells demonstrated a marked change in transcript levels of immune and metabolic genes 24 hours post supplementation when compared with placebo. CONCLUSIONS: Together, these findings demonstrate that supplementation with an enriched marine oil leads to an increase in peripheral blood SPM concentrations and reprograms peripheral blood cells, indicating a role for SPM in mediating the immune-directed actions of this supplement. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03347006.

Novel mediators and mechanisms in the resolution of infectious inflammation: evidence for vagus regulation.

Excessive chronic inflammation is linked to many diseases and considered a stress factor in humans (Robbins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Co., 1999, Proc Natl Acad Sci USA, 2008, 105: 17949, Immunity, 44, 2016, 44: 463, N Engl J Med, 2011, 364: 656). Today, the resolution of inflammation is widely recognized as a cellular biochemically active process involving biosynthesis of a novel superfamily of endogenous chemical signals coined specialized pro-resolving mediators (SPMs; Nature, 2014, 510:92). Herein, we review recent evidence, indicating a role for the vagus nerve and vagotomy in the regulation of lipid mediators. Vagotomy reduces pro-resolving mediators, including the lipoxins, resolvins, protectins and maresins, delaying resolution in mouse peritonitis. Vagotomy also delays resolution of Escherichia coli infection in mice. Specifically, right vagus regulates peritoneal Group 3 innate lymphoid cell (ILC-3) number and peritoneal macrophage responses with lipid mediator profile signatures with elevated pro-inflammatory eicosanoids and reduced resolvins, including the novel protective immunoresolvent agonist protectin conjugate in tissue regeneration1 (PCTR1). Acetylcholine upregulates PCTR biosynthesis, and administration of PCTR1 to vagotomized mice restores tissue resolution and host responses to E. coli infections. Results obtained with human vagus ex vivo indicate that vagus can produce both pro-inflammatory eicosanoids, such as prostaglandins and leukotrienes, as well as the SPM. Electrical stimulation of human vagus in vitro reduces both prostaglandins and leukotrienes and enhances resolvins and the other SPM. These results elucidate a host protective mechanism mediated by vagus stimulation of SPM that includes resolvins and PCTR1 to regulate myeloid antimicrobial functions and resolution of infection. Moreover, they define a new pro-resolution of inflammation reflex operative in mice and human tissue that involves a vagus SPM circuit.

Hemp (Marijuana) reverted Copper-induced toxic effects on the essential fatty acid profile of Labeo rohita and Cirrhinus mrigala.

Heavy metals pollution affects the nutritive value of fish. This study examined if the inclusion of dietary hempseed (HS) and hempseed oil (HO) in the diet of the fish could revert the copper-induced toxic effects on muscle fatty acid profile of rohu (Labeo rohita) and mrigal (Cirrhinus mrigala). Fingerlings of both species were exposed to a sub-lethal concentration of copper i.e., 20% of LC50 (1.34 ppm for rohu and 1.52 ppm for mrigal) for 96 h for 30 days. Following exposure, fish were maintained on graded levels of HO (1, 2 and 3%) or on HS (5, 10 and 15%) for 50 days. Copper exposure showed a significant effect on the fatty acid composition of both species; increased their saturated (SFA) to unsaturated (USFA) and altered their omega-3/omega-6 (ω-3/ω-6) ratios. However, feeding graded levels of hempseed products reverted the toxic effects of copper on the fatty acid profile of both the species, significantly increased muscle total fatty acid contents, improved ω-3/ω-6 ratios, and decreased SFA / USFA ratio in % inclusion dependent manner. Furthermore, hempseed product showed a species-specific effect on USFA. The ω-3/ω-6 ratios decreased in the muscle of C. mrigala whereas an increasing trend with an increase in hempseed product % inclusion was observed in L. rohita. Moreover, HS showed a higher impact on both species as compared to HO. With the findings of this study, hempseed product could be recommended as a feed ingredient for enhancing the essential fatty acid contents of fish which in turn can have a good impact on consumer health.

The Role of Essential Fatty Acids in Anorexia Nervosa and Obesity.

The two basic questions in food intake study are what we eat, and how much do we eat. Most research is directed toward the control of how much is eaten. This is likely the result of the increased number of individuals with eating disorders in the Western world. Feeding behavior is highly complex, and is controlled by many psychological, physiological, biochemical, and immunological factors. The aim of this review is to clarify the involvement of fatty acids in eating disorders such as anorexia and binge eating disorder. The review will describe the modified fatty acid profile observed in individuals with anorexia or binge eating disorder, and discuss on what factors fatty acids can exert beneficial effects. In addition, the differences and similarities between anorexia and binge eating disorder will be discussed. We suggest that beneficial effects of essential fatty acids on both anorexia and binge eating disorder can be explained by the stabilizing effect of those fatty acids on the neuronal membrane fluidity index.

Nutritionally essential fatty acids and biologically indispensable cyclooxygenases.

The study of cyclooxygenases (COXs), targets of aspirin and related drugs, is rooted in the discovery of essential fatty acids (EFAs). There are two COXs that convert EFAs, primarily arachidonic acid, to prostaglandins. Each COX is involved with distinct biologies. COX-1 expression is constitutive while COX-2 is inducible. The two COXs might have evolved partly to permit prostaglandin formation at different tissue sites. However, COX-2 is sometimes induced in cells already expressing COX-1, and in these instances, COX-2 functions while COX-1 is latent. This can occur because of unique biochemical properties of COX-2 that enable cells to form prostaglandins when arachidonic acid comprises a small fraction of available fatty acids and the concentrations of peroxides that are necessary for COX to function are low.

The role of essential fatty acids in the control of coronary heart disease.

PURPOSE OF REVIEW: Evidence from various research paradigms supports the cardiovascular benefits of a high intake of n-3 polyunsaturated fatty acids (PUFAs), especially the long-chain, marine-derived n-3 PUFA, eicosapentaenoic acids and docosahexaenoic acids. The effect of the plant-derived alpha-linolenic acid (ALA) is, however, not clear. Concerns about a high n-6 PUFA intake has been raised, because n-6 PUFA may weaken the effects of n-3 PUFA. RECENT FINDINGS: Most previous observational studies on the intake of PUFA and the risk of coronary heart disease (CHD) did not specify the replacement nutrient. A recent meta-analysis of cohort studies suggested that replacing saturated fatty acids with PUFA may lower the risk of CHD. On the other hand, recently published studies do not suggest that higher linoleic acid intake is associated to a lower risk of CHD or to give support for a negative association between ALA and CHD. Furthermore, recent studies do not suggest that the association between ALA and CHD is modified by linoleic acid. SUMMARY: Recent meta-analyses of cohort studies have reported a lower risk of CHD when PUFA replaces SFA in the diet. However, recent studies do not suggest that a higher linoleic acid intake is related to a lower risk of CHD. The effect of ALA on the risk of CHD is not clear.

[Essential fatty acids and lipid mediators. Endocannabinoids]. / Acidi grassi essenziali, mediatori lipidici ed endocannabinoidi.

In 1929 Burr and Burr discovered the essential fatty acids omega-6 and omega-3. Since then, researchers have shown a growing interest in polyunsaturated fatty acids (PUFA) as precursors of "lipid mediator" molecules, often with opposing effects, prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipossines, resolvines, protectines, maresins that regulate immunity, platelet aggregation, inflammation, etc. They showed that the balance between omega-3 and omega-6 acids has a profound influence on all the body's inflammatory responses and a raised level of PUFA omega-3 in tissue correlate with a reduced incidence of degenerative cardiovascular disease, some mental illnesses such as depression, and neuro-degenerative diseases such as Alzheimer's. The CYP-catalyzed epoxidation and hydroxylation of arachidonic acid (AA) were established recently as the so-called third branch of AGE cascade. Cytochrome P450 (CYP) epoxygenases convert AA to four epoxyeicosatrienoic acid (EET) regioisomers, that produce vascular relaxation anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are accessible to CYP enzymes in the same way as AA. Metabolites derived from EPA include epoxye-icosatetraenoic acids (EETR) and hydroxyeicosapentaenoic acids (19- and 20-HEPE), whereas DHA include epoxydocosapentaenoic acids (EDPs) hydroxydocosahexaenoic acids (21- and 22-HDoHE). For many of the CYP isoforms, the n-3 PUFAs are the preferred substrates and the available data suggest that some of the vasculo- and cardioprotective effects attributed to dietary n-3 PUFAs may be mediated by CYP-dependent metabolites of EPA and DHA. From AA derives also endocannabinoids like anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol, capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as hashish and marijuana (-)-Delta9-tetrahydrocannabinol. They act as true 'endogenous cannabinoids' by binding and functionally activating one or both cannabinoid receptor present on nervous and peripheral cell membranes. Enzymes that carry out anandamide oxidation are the same fatty acid oxygenases that are known to act on endogenous arachidonic acid namely, the members of the COX, LOX, and P450 families of enzymes. Recent advances in the biochemistry and pharmacology of the endocannabinoid system, also for its central and peripheral roles in regulating food intake, will offer the development of novel therapeutic agents.

Essential fatty acid depletion of renal allografts and prevention of rejection.

A central hypothesis in transplantation biology is that resident leukocytes expressing class II histocompatibility antigens may determine the immunogenicity of an organ. By means of a novel method to deplete the kidney of resident leukocytes, essential fatty acid deficiency (EFAD), this hypothesis was tested in an intact, vascular organ. Kidneys subjected to EFAD and thus depleted of resident Ia-positive macrophages survived and functioned when transplanted across a major histocompatibility antigen barrier in the absence of immunosuppression of the recipient. Control allografts were rejected promptly. Allografts from donors subjected to EFAD normalized their lipid composition and were repopulated with host macrophages by 5 days. Administration of Ia-positive cells at the time of transplantation established that the resident leukocyte depletion induced by EFAD was responsible for the protective effect. These observations may provide insights into the mechanisms underlying tissue immunogenicity and the population of normal tissues with resident leukocytes.

Essential fatty acids and human brain.

The human brain is nearly 60 percent fat. We've learned in recent years that fatty acids are among the most crucial molecules that determine your brain's integrity and ability to perform. Essential fatty acids (EFAs) are required for maintenance of optimal health but they can not synthesized by the body and must be obtained from dietary sources. Clinical observation studies has related imbalance dietary intake of fatty acids to impaired brain performance and diseases. Most of the brain growth is completed by 5-6 years of age. The EFAs, particularly the omega-3 fatty acids, are important for brain development during both the fetal and postnatal period. Dietary decosahexaenoic acid (DHA) is needed for the optimum functional maturation of the retina and visual cortex, with visual acuity and mental development seemingly improved by extra DHA. Beyond their important role in building the brain structure, EFAs, as messengers, are involved in the synthesis and functions of brain neurotransmitters, and in the molecules of the immune system. Neuronal membranes contain phospholipid pools that are the reservoirs for the synthesis of specific lipid messengers on neuronal stimulation or injury. These messengers in turn participate in signaling cascades that can either promote neuronal injury or neuroprotection. The goal of this review is to give a new understanding of how EFAs determine our brain's integrity and performance, and to recall the neuropsychiatric disorders that may be influenced by them. As we further unlock the mystery of how fatty acids affect the brain and better understand the brain's critical dependence on specific EFAs, correct intake of the appropriate diet or supplements becomes one of the tasks we undertake in pursuit of optimal wellness.

Fatty acid facts, Part I. Essential fatty acids as treatment for depression, or food for mood?

The epidemic character of depressive disorders has prompted further research into dietary habits that could make an etiological contribution. One clear change in the diet of the population in developed countries has been the replacement of omega-3 polyunsaturated fatty acids by saturated fats and trans-fats as well as by omega-6 polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids are essential fatty acids, and the members of the -3 and -6 series are crucial for human health. In biochemical processes there is a competition between these two series. A higher dietary intake of omega-6 results in the excessive incorporation of these molecules in the cell membrane with numerous pathological consequences, presumably due to the formation of proinflammatory eicosanoids. Members of the omega-3 family and their derivatives modulate the inflammatory action. Essential fatty acids play a major role in brain development and brain functioning. The omega-3 series members docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) provide fluidity to the cell membrane, facilitating certain processes including neurotransmission and ion channel flow. It is thought that omega-3 deficiency during the fetal and postnatal period may have a long-term effect at various levels. Epidemiological studies have demonstrated a positive association between omega-3 deficits and mood disorders. As for treatment, there is convincing evidence that add-on omega-3 fatty acids to standard antidepressant pharmacotherapy results in improved mood. There is no evidence that fatty acid monotherapy has a mood-elevating effect, with a possible exception for childhood depression. There are indications that omega-3 has a prophylactic effect on perinatal depression and has a negative effect on natural killer cell activity and T-lymphocyte function. These observations need further study in view of the popularity of self-medication.

Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules.

Lowering plasma low density lipoprotein-cholesterol (LDL-C), blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor each at half standard dose; folic acid; and aspirin-called as polypill- was estimated to reduce cardiovascular events by approximately 80%. Essential fatty acids (EFAs) and their long-chain metabolites: gamma-linolenic acid (GLA), dihomo-GLA (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and other products such as prostaglandins E1 (PGE1), prostacyclin (PGI2), PGI3, lipoxins (LXs), resolvins, protectins including neuroprotectin D1 (NPD1) prevent platelet aggregation, lower blood pressure, have anti-arrhythmic action, reduce LDL-C, ameliorate the adverse actions of homocysteine, show anti-inflammatory actions, activate telomerase, and have cytoprotective properties. Thus, EFAs and their metabolites show all the classic actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules present in almost all tissues, have no significant or few side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and infants, children, and adults; and have been known to reduce the incidence cardiovascular diseases including stroke. In addition, various EFAs and their long-chain metabolites not only enhance nitric oxide generation but also react with nitric oxide to yield their respective nitroalkene derivatives that produce vascular relaxation, inhibit neutrophil degranulation and superoxide formation, inhibit platelet activation, and possess PPAR-gamma ligand activity and release NO, thus prevent platelet aggregation, thrombus formation, atherosclerosis, and cardiovascular diseases. Based on these evidences, I propose that a rational combination of omega-3 and omega-6 fatty acids and the co-factors that are necessary for their appropriate action/metabolism is as beneficial as that of the combined use of a statin, thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor, folic acid, and aspirin. Furthermore, appropriate combination of omega-3 and omega-6 fatty acids may even show additional benefits in the form of protection from depression, schizophrenia, Alzheimer's disease, and enhances cognitive function; and serve as endogenous anti-inflammatory molecules; and could be administered from childhood for life long.

[The importance of essential fatty acids and the effect of trans fatty acids in human milk on fetal and neonatal development]. / Importância dos ácidos graxos essenciais e os efeitos dos ácidos graxos trans do leite materno para o desenvolvimento fetal e neonatal.

Breastfeeding has a major impact on public health, since human breast milk is the best food for infants up to six months of age. The lipid fraction in human milk is the main source of energy for the infant and supplies essential nutrients such as fat-soluble vitamins and polyunsaturated fatty acids (PUFA). Essential fatty acids (EFA), specifically linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (ALA, 18:3n-3), are precursors of long-chain polyunsaturated fatty acids (LC-PUFA), including docosahexaenoic (DHA) and arachidonic (ARA) acids. Quality of lipids in secreted milk is precisely related to maternal ingestion. LC-PUFAs protect against allergy and infection and are important for visual and cognitive development in infancy. Industrial food processing has introduced the trans fatty acids (TFA) among the nutrients available to the population. TFA can interfere with the metabolism of essential fatty acids by decreasing LC-PUFA synthesis. It is thus important to raise population awareness on the importance of adequate PUFA consumption and reduced TFA intake during prenatal and postnatal development.

Nutrition in brain development and aging: role of essential fatty acids.

The essential fatty acids (EFAs), particularly the n-3 long-chain polyunsaturated fatty acids (LCPs), are important for brain development during both the fetal and postnatal period. They are also increasingly seen to be of value in limiting the cognitive decline during aging. EFA deficiency was first shown over 75 years ago, but the more subtle effects of the n-3 fatty acids in terms of skin changes, a poor response to linoleic acid supplementation, abnormal visual function, and peripheral neuropathy were only discovered later. Both n-3 and n-6 LCPs play important roles in neuronal growth, development of synaptic processing of neural cell interaction, and expression of genes regulating cell differentiation and growth. The fetus and placenta are dependent on maternal EFA supply for their growth and development, with docosahexaenomic acid (DHA)-supplemented infants showing significantly greater mental and psychomotor development scores (breast-fed children do even better). Dietary DHA is needed for the optimum functional maturation of the retina and visual cortex, with visual acuity and mental development seemingly improved by extra DHA. Aging is also associated with decreased brain levels of DHA: fish consumption is associated with decreased risk of dementia and Alzheimer's disease, and the reported daily use of fish-oil supplements has been linked to improved cognitive function scores, but confirmation of these effects is needed.

Long-chain polyunsaturated fatty acids in maternal and infant nutrition.

Homo sapiens has evolved on a diet rich in alpha-linolenic acid and long chain polyunsaturated fatty acids (LCP). We have, however, gradually changed our diet from about 10,000 years ago and accelerated this change from about 100 to 200 years ago. The many dietary changes, including lower intake of omega3-fatty acids, are related to 'typically Western' diseases. After a brief introduction in essential fatty acids (EFA), LCP and their functions, this contribution discusses our present low status of notably LCPomega3 in the context of our rapidly changing diet within an evolutionary short time frame. It then focuses on the consequences in pregnancy, lactation and neonatal nutrition, as illustrated by some recent data from our group. We discuss the concept of a 'relative' EFA/LCP deficiency in the fetus as the outcome of high transplacental glucose flux. This flux may in the fetus augment de novo synthesis of fatty acids, which not only dilutes transplacentally transported EFA/LCP, but also causes competition of de novo synthesized oleic acid with linoleic acid for delta-6 desaturation. Such conditions were encountered by us in mothers with high body mass indices, diabetes mellitus and preeclampsia. The unifying factor might be compromised glucose homeostasis. In search of the milk arachidonic acid (AA) and docosahexaenoic acid (DHA) contents of our African ancestors, we investigated women in Tanzania with high intakes of freshwater fish as only animal lipid source. These women had milk AA and DHA contents that were well above present recommendations for infant formulae. Both studies stimulate rethinking of 'optimal homeostasis'. Subtle signs of dysbalanced maternal glucose homeostasis may be important and observations from current Western societies may not provide us with an adequate basis for dietary recommendations.

The biological actions and potential clinical significance of dietary omega-3 fatty acids.

The exploration of the effects of fish oil in cardiovascular disease and inflammation seems to be a promising avenue of research. There is evidence indicating the role of marine oils in inhibiting coagulation and platelet, leukocyte, and T-lymphocyte function. Moderate amounts of fish oil reduce serum triglyceride and very-low-density lipoprotein levels, while effects on cholesterol, high-density lipoprotein, and low-density lipoprotein levels are unpredictable except at extremely large doses. Putative actions in lowering blood pressure and limiting myocardial infarct size require further study. The clinician needs to be aware of the dose- and time-dependent nature of the measurable effects of fish oil. The folly of recommending two to four capsules per day is contrasted with the ten to 30 capsules required to produce a specific desired effect.

Do essential fatty acids play a role in brain and behavioral development?

The membrane phospholipids of the brain contain high levels of polyunsaturated fatty acids (PUFA), particularly arachidonic acid, 20:4n-6 and docosahexaenoic acid, 22:6n-3. These long-chain PUFA are synthesized from their respective essential fatty acid (EFA) precursors, linoleic acid, 18:2n-6 and linolenic acid, 18:3n-3. Although the necessity of n-6 fatty acids for optimum growth has been established, a similar requirement for those of the n-3 family is less clear. The rapid accumulation of the long-chain n-3 PUFA in the brain during prenatal and preweaning development suggests that the provision of n-3 fatty acids to the developing brain may be necessary for normal growth and functional development. The intent of this review is to assess the experimental work which addresses this question, most of which has been conducted on rodents. The emphasis will be on studies which measure behavioral outcomes, and particular attention will be paid to methodological issues which affect the interpretation of these data. An integration of the research findings will be presented and discussed in light of possible implications for therapeutic interventions.

Long-chain polyunsaturated fatty acids, pregnancy, and pregnancy outcome.

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

Evening primrose oil and borage oil in rheumatologic conditions.

Diets rich in arachidonic acid (20:4n-6) lead to the formation of 2-series prostaglandins (PGs) and 4-series leukotrienes (LTs), with proinflammatory effects. Nonsteroidal antiinflammatory drugs are used in rheumatoid arthritis to inhibit cyclooxygenase (prostaglandin-endoperoxide synthase), thereby decreasing production of 2-series PGs. Lipoxygenase activity remains intact, however, allowing LT production (eg, synthesis of LTB(4), a potent inflammatory mediator) to continue. Altering the essential fatty acid (EFA) content of the diet can modify some of these effects. Ingestion of a diet rich in evening primrose oil elevates concentrations of dihomo-gamma-linolenic acid (DGLA; 20:3n-6), which results in the production of 1-series PGs, eg, PGE(1). DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LTs. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-series PGs and 4-series LTs and thus suppress inflammation. The results of in vitro and animal work evaluating EFAs in inflammatory situations are encouraging, which has stimulated clinical workers to evaluate these compounds in rheumatoid arthritis. Several well-controlled, randomized clinical studies have now been completed in which various EFAs were evaluated as treatments. The results of most of these studies suggest some clinical benefit to these treatments; these data are reviewed here.

Importance of n-3 fatty acids in health and disease.

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.