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n-3 fatty acids and cardiovascular disease. Breslow JL. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1477S-1482S. Review. PMID: 16841857 The results of prospective cohort studies indicate that consuming fish or fish oil containing the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is associated with decreased cardiovascular death, whereas consumption of the vegetable oil-derived n-3 fatty acid {alpha}-linolenic acid is not as effective. Randomized control trials (RCTs) in the context of secondary prevention also indicate that the consumption of EPA plus DHA is protective at doses 3 g/d, EPA plus DHA can improve cardiovascular disease risk factors, including decreasing plasma triacylglycerols, blood pressure, platelet aggregation, and inflammation, while improving vascular reactivity. Mainly on the basis of the results of RCTs, the American Heart Association recommends that everyone eat oily fish twice per week and that those with coronary heart disease eat 1 g/d of EPA plus DHA from oily fish or supplements. Directions for future research include 1) RCTs to confirm the initial trials showing that EPA plus DHA decreases cardiovascular death and additional studies to determine whether this effect is due to EPA, DHA, or the combination; the dosage of the effective components; and whether the mechanism of action in humans is prevention of fatal arrhythmias. 2) Clinical studies to determine whether the reduction in cardiovascular disease risk factors is due to EPA, DHA, or the combination and the dosage of the effective components. 3) Clinical studies to determine whether vegetable oil-derived {alpha}-linolenic acid added to a diet enriched in n-6 fatty acids can effectively substitute for fish oil-derived EPA plus DHA.

n-3 fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits. Gebauer SK, Psota TL, Harris WS, Kris-Etherton PM. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1526S-1535S. Review. PMID: 16841863 Dietary recommendations have been made for n-3 fatty acids, including {alpha}-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) to achieve nutrient adequacy and to prevent and treat cardiovascular disease. These recommendations are based on a large body of evidence from epidemiologic and controlled clinical studies. The n-3 fatty acid recommendation to achieve nutritional adequacy, defined as the amount necessary to prevent deficiency symptoms, is 0.6-1.2% of energy for ALA; up to 10% of this can be provided by EPA or DHA. To achieve recommended ALA intakes, food sources including flaxseed and flaxseed oil, walnuts and walnut oil, and canola oil are recommended. The evidence base supports a dietary recommendation of {approx}500 mg/d of EPA and DHA for cardiovascular disease risk reduction. For treatment of existing cardiovascular disease, 1 g/d is recommended. These recommendations have been embraced by many health agencies worldwide. A dietary strategy for achieving the 500-mg/d recommendation is to consume 2 fish meals per week (preferably fatty fish). Foods enriched with EPA and DHA or fish oil supplements are a suitable alternate to achieve recommended intakes and may be necessary to achieve intakes of 1 g/d.

Are omega-3 fatty acids options for prevention and treatment of cognitive decline and dementia? Cederholm T, Palmblad J. Curr Opin Clin Nutr Metab Care. 2009 Dec 16. [Epub ahead of print] PMID: 20019606 PURPOSE OF REVIEW: To report recent data on the potential role of omega-3 fatty acids (n-3 FA) found in oily fish, especially docosahexaenoic acid (DHA), to prevent and treat cognitive decline and Alzheimer's disease. RECENT FINDINGS: Observational studies still provide conflicting results, in which the majority indicate beneficial effects on cognition, both when assessed as a continuous variable or as incident dementia, mainly Alzheimer's disease. Experimental studies have demonstrated potentially ameliorating effects of eicosapentaenoic acid (EPA) and DHA on amyloid fragment formation, signal transduction including upregulation of the apolipoprotein receptor SorLA, as well as on angiogenesis. The role of EPA and DHA metabolites on Alzheimer's disease pathology is under investigation. Recently, three randomized intervention studies, with duration up to 6 months have been reported. In contrast to a small study from Taiwan, no positive overall effects were reported from the Swedish OmegAD Study or from a Dutch study, although post hoc analyses indicate that selected individuals with mild forms of Alzheimer's disease or cognitive decline may respond to treatment. SUMMARY: No firm conclusions can be drawn. Based on epidemiological data, fish including oily fish could be advised as part of a balanced diet for public health purpose, although the evidence for better cognition is only fairly consistent. It is unlikely that n-3 FA will emerge as a treatment option in general for improving cognitive function in patients with Alzheimer's disease. n-3 FA, especially DHA, may turn out as an adjuvant therapy in selected cases. Further long-term intervention studies on individuals with mild cognitive reductions are awaite"

The combination effects index (CI) analysis confirmed the synergy of clioquinol and clofibrate on inhibiting cancer cell viability. Using inhibitors to block PPARalpha signaling diminished the synergistic cytotoxicity of clioquinol and DHA. These results provide pharmacological evidence that the synergistic anticancer action of clioquinol and DHA is mediated by PPARalpha signaling in human cancer cells. PPARalpha signaling mediates the synergistic cytotoxicity of clioquinol and docosahexaenoic acid in human cancer cells. Tuller ER, Brock AL, Yu H, Lou JR, Benbrook DM, Ding WQ. Biochem Pharmacol. 2009 May 1;77(9):1480-6. Epub 2009 Feb 13. PMID: 19426685

Quantitative analysis of the benefits and risks of consuming farmed and wild salmon. Foran JA, Good DH, Carpenter DO, Hamilton MC, Knuth BA, Schwager SJ. J Nutr. 2005 Nov;135(11):2639-43. PMID: 16251623 Contaminants in farmed Atlantic and wild Pacific salmon raise important questions about the competing health benefits and risks of fish consumption. A benefit-risk analysis was conducted to compare quantitatively the cancer and noncancer risks of exposure to organic contaminants in salmon with the (n-3) fatty acid-associated health benefits of salmon consumption. Recommended levels of (n-3) fatty acid intake, as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be achieved by consuming farmed or wild salmon while maintaining an acceptable level of noncarcinogenic risk. However, the recommended level of EPA+DHA intake cannot be achieved solely from farmed or wild salmon while maintaining an acceptable level of carcinogenic risk. Although the benefit-risk ratio for carcinogens and noncarcinogens is significantly greater for wild Pacific salmon than for farmed Atlantic salmon as a group, the ratio for some subgroups of farmed salmon is on par with the ratio for wild salmon. This analysis suggests that risk of exposure to contaminants in farmed and wild salmon is partially offset by the fatty acid-associated health benefits. However, young children, women of child-bearing age, pregnant women, and nursing mothers not at significant risk for sudden cardiac death associated with CHD but concerned with health impairments such as reduction in IQ and other cognitive and behavioral effects, can minimize contaminant exposure by choosing the least contaminated wild salmon or by selecting other sources of (n-3) fatty acids.

Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events: the Kuopio ischaemic heart disease risk factor study. Rissanen T, Voutilainen S, Nyyssönen K, Lakka TA, Salonen JT. Circulation. 2000 Nov 28;102(22):2677-9. PMID: 11094031 Methods and Results-We studied this association in the Kuopio Ischaemic Heart Disease Risk Factor Study, a prospective population study in Eastern Finland. Subjects were randomly selected and included 1871 men aged 42 to 60 years who had no clinical coronary heart disease at baseline examination. A total of 194 men had a fatal or nonfatal acute coronary event during follow-up. In a Cox proportional hazards' model adjusting for other risk factors, men in the highest fifth of the proportion of serum DHA+DPA in all fatty acids had a 44% reduced risk (P=0.014) of acute coronary events compared with men in the lowest fifth. Men in the highest fifth of DHA+DPA who had a low hair content of mercury (2.0 µg/g). There was no association between proportion of eicosapentaenoic acid and the risk of acute coronary events. Conclusions-Our data provide further confirmation for the concept that fish oil-derived fatty acids reduce the risk of acute coronary events. However, a high mercury content in fish could attenuate this protective effect.

Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M, Keck PE Jr, Marangell LB, Richardson AJ, Lake J, Stoll AL. J Clin Psychiatry. 2006 Dec;67(12):1954-67. Review. Erratum in: J Clin Psychiatry. 2007 Feb;68(2):338. PMID: 17194275 Conclusions: The preponderance of epidemiologic and tissue compositional studies supports a protective effect of omega-3 EFA intake, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mood disorders. Meta-analyses of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p=.02). The results were highly heterogeneous, indicating that it is important to examine the characteristics of each individual study to note the differences in design and execution. There is less evidence of benefit in schizophrenia. EPA and DHA appear to have negligible risks and some potential benefit in major depressive disorder and bipolar disorder, but results remain inconclusive in most areas of interest in psychiatry. Treatment recommendations and directions for future research are described. Health benefits of omega-3 EFA may be especially important in patients with psychiatric disorders, due to high prevalence rates of smoking and obesity and the metabolic side effects of some psychotropic medications.

It was concluded that omega-3 fatty acid could inhibit the proliferation of pancreatic cancer cell line SW1990 cells and promote their apoptosis. The down-regulation of the cyclin E expression by omega-3 fatty acid might be one of the mechanisms for its anti-tumor effect on pancreatic cancer. Modulatory effects of EPA and DHA on proliferation and apoptosis of pancreatic cancer cells. Zhang W, Long Y, Zhang J, Wang C. J Huazhong Univ Sci Technolog Med Sci. 2007 Oct;27(5):547-50. PMID: 18060632

Chemopreventive and renal protective effects for docosahexaenoic acid (DHA): implications of CRP and lipid peroxides. Elmesery ME, Algayyar MM, Salem HA, Darweish MM, El-Mowafy AM. Cell Div. 2009 Apr 2;4(1):6. [Epub ahead of print] PMID: 19341447 doi:10.1186/1747-1028-4-6

Docosahexaenoic acid-enriched egg consumption induces accretion of arachidonic acid in erythrocytes of elderly patients. Payet M, Esmail MH, Polichetti E, Le Brun G, Adjemout L, Donnarel G, Portugal H, Pieroni G. Br J Nutr. 2004 May;91(5):789-96. PMID: 15137931 doi:10.1079/BJN20041106

The present study, thus, raises the possibility that DHA may exert pro-apoptotic and antitumoral effects through proteasomal regulation of beta-catenin levels and alterations in the expression of TCF-beta-catenin target genes. Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2. Calviello G, Resci F, Serini S, Piccioni E, Toesca A, Boninsegna A, Monego G, Ranelletti FO, Palozza P. Carcinogenesis. 2007 Jun;28(6):1202-9. Epub 2006 Dec 20. PMID: 17183061 doi:10.1093/carcin/bgl254

DHA and EPA generally modulated different sets of genes, although a few common effects were noted. In our approach, we used preneoplastic adenoma cells which are a relevant model for target cells of chemoprevention. If verified with real time PCR, these results identify genes and targets for chemoprevention of colon cancer. Modulation of gene expression in eicosapentaenoic acid and docosahexaenoic acid treated human colon adenoma cells. Habermann N, Lund EK, Pool-Zobel BL, Glei M. Genes Nutr. 2009 Mar;4(1):73-6. Epub 2009 Feb 21. PMID: 19234733 doi: 10.1007/s12263-009-0112-y.

Our findings suggest that administration of n-3 FA (EPA and DHA) in doses of at least 1.5 g/day for a prolonged period of time to patients with advanced cancer is associated with an improvement in clinical, biological and QoL parameters. N-3 fatty acids, cancer and cachexia: a systematic review of the literature. Colomer R, Moreno-Nogueira JM, García-Luna PP, García-Peris P, García-de-Lorenzo A, Zarazaga A, Quecedo L, del Llano J, Usán L, Casimiro C. Br J Nutr. 2007 May;97(5):823-31. Review. PMID: 17408522 doi:10.1017/S000711450765795X

Egg fortification with n-3 polyunsaturated fatty acids (PUFA): nutritional benefits versus high n-6 PUFA western diets, and consumer acceptance. Shapira N, Weill P, Loewenbach R. Isr Med Assoc J. 2008 Apr;10(4):262-5. PMID: 18548978 Egg fortification with n-3 polyunsaturated fatty acids (PUFA): nutritional benefits versus high n-6 PUFA western diets, and consumer acceptance. Shapira N, Weill P, Loewenbach R. Isr Med Assoc J. 2008 Apr;10(4):262-5. PMID: 18548978 CONCLUSIONS: Effective concentration and transformation of supplemental n-3 PUFA/LCPUFA from feed to egg substantially enhanced egg n-3 PUFA %DRI, particularly of DHA, critical for health but often deficient. Such land-based n-3 PUFA/LCPUFA fortification may be applicable to high n-6 PUFA diets, fitting within cholesterol limitations and market criteria. It may contribute to general health and specific requirements (i.e., pregnancy and lactation), with possibilities of wide accessibility and standardization.

Mercury, fish oils, and the risk of myocardial infarction. Guallar E, Sanz-Gallardo MI, van't Veer P, Bode P, Aro A, Gómez-Aracena J, Kark JD, Riemersma RA, Martín-Moreno JM, Kok FJ; Heavy Metals and Myocardial Infarction Study Group. N Engl J Med. 2002 Nov 28;347(22):1747-54. PMID: 12456850 Conclusions The toenail mercury level was directly associated with the risk of myocardial infarction, and the adipose-tissue DHA level was inversely associated with the risk. High mercury content may diminish the cardioprotective effect of fish intake.

n-3 Fatty acids and cardiovascular disease: mechanisms underlying beneficial effects. Jung UJ, Torrejon C, Tighe AP, Deckelbaum RJ. Am J Clin Nutr. 2008 Jun;87(6):2003S-9S. PMID: 18541602 Dietary n-3 fatty acids, particularly eicosapentaenoic acid and docosahexaenoic acid, are important nutrients through the life cycle. Evidence from observational, clinical, animal, and in vitro studies indicates a beneficial role of n-3 fatty acids in the prevention and management of cardiovascular disease. Although the precise mechanisms are still unclear, clinical and preclinical studies indicate that the cardioprotective effects of n-3 fatty acids may be attributed to a number of distinct biological effects on lipid and lipoprotein metabolism, blood pressure, platelet function, arterial cholesterol delivery, vascular function, and inflammatory responses. Substantial evidence supports n-3 fatty acids as a practical, therapeutic adjuvant for promoting cardiovascular health and preventing and treating disease. n-3 Fatty acids modulate a number of important physiologic responses that can contribute to their cardioprotective effects. The multiple and complex mechanisms through which DHA and EPA exert their action appear to be distinct but also complementary. However, more studies are needed to quantify their protective effects and to define exact mechanisms of action.

Omega 3 fatty acids and the brain: review of studies in depression. Sinclair AJ, Begg D, Mathai M, Weisinger RS. Asia Pac J Clin Nutr. 2007;16 Suppl 1:391-7. Review. PMID: 17392137 This paper discusses the clinical studies conducted in the area of depression and omega 3 PUFA and the possible mechanisms of action of these PUFA. It is clear from the literature that DHA is involved in a variety of processes in neural cells and that its role is far more complex than simply influencing cell membrane properties.

Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: a randomized controlled trial. Carney RM, Freedland KE, Rubin EH, Rich MW, Steinmeyer BC, Harris WS. JAMA. 2009 Oct 21;302(15):1651-7. PMID: 19843899 Conclusions Treatment of patients with CHD and major depression with sertraline and omega-3 fatty acids did not result in superior depression outcomes at 10 weeks, compared with sertraline and placebo. Whether higher doses of omega-3 or sertraline, a different ratio of EPA to DHA, longer treatment, or omega-3 monotherapy can improve depression in patients with CHD remains to be determined

Fatty acid intake and the risk of community-acquired pneumonia in U.S. women. Alperovich M, Neuman MI, Willett WC, Curhan GC. Nutrition. 2007 Mar;23(3):196-202. Epub 2007 Jan 22. PMID: 17236748 doi: 10.1016/j.nut.2006.11.007. Conclusions Fatty acid intake may affect the risk of community-acquired pneumonia in young and middle-aged women. Higher dietary intake of palmitic acid and possibly DHA and EPA may increase the risk of community-acquired pneumonia in women while higher oleic acid intake may decrease the risk.

The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential. Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, Spencer D, Berry D, Steward W, Dennison A. Eur J Cancer. 2009 Aug;45(12):2077-86. Epub 2009 Jun 1. Review. PMID: 19493674 Omega-3 fatty acid (omega-3 FA) consumption has long been associated with a lower incidence of colon, breast and prostate cancers in many human populations. Human trials have demonstrated omega-3 FA to have profound anti-inflammatory effects in those with cancer. In vitro and small animal studies have yielded a strong body of evidence establishing omega-3 FA as having anti-inflammatory, anti-apoptotic, anti-proliferative and anti-angiogenic effects. This review explores the evidence and the mechanisms by which omega-3 FA may act as angiogenesis inhibitors and identifies opportunities for original research trialling omega-3 FAs as anti-cancer agents in humans. The conclusions drawn from this review suggest that omega-3 FAs in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found principally in oily fish have potent anti-angiogenic effects inhibiting production of many important angiogenic mediators namely; Vascular Endothelial Growth Factor (VEGF), Platelet-Derived Growth Factor (PDGF), Platelet-Derived Endothelial Cell Growth Factor (PDECGF), cyclo-oxygenase 2 (COX-2), prostaglandin-E2 (PGE2), nitric oxide, Nuclear Factor Kappa Beta (NFKB), matrix metalloproteinases and beta-catenin