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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.

Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD. Nat Med. 2004 Dec;10(12):1344-51. Epub 2004 Nov 7. PMID: 15531889 doi:10.1038/nm1135 We identify berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemic patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, we show that BBR upregulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the 5' proximal section of the LDLR mRNA 3' untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.

Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils. Leaf A, Kang JX, Xiao YF, Billman GE. Circulation. 2003 Jun 3;107(21):2646-52. Review. PMID: 12782616 doi: 10.1161/01.CIR.0000069566.78305.33 This review will be limited specifically to the beneficial prevention by the n-3 polyunsaturated fatty acids (PUFAs) of arrhythmic deaths, including sudden cardiac death, which annually causes some 300 000 deaths in the United States and millions more worldwide. We will also show that the growing body of positive clinical studies is supported by what has been learned in animal and laboratory studies regarding the mechanism by which n-3 PUFAs prevent cardiac arrhythmias.

The effect of select nutrients on serum high-density lipoprotein cholesterol and apolipoprotein A-I levels. Mooradian AD, Haas MJ, Wong NC. Endocr Rev. 2006 Feb;27(1):2-16. Epub 2005 Oct 21. Review. PMID: 16243964 One of the factors contributing to the increased risk of developing premature atherosclerosis is low plasma concentrations of high-density lipoprotein (HDL) cholesterol (HDLc). Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein A-I (apo A-I). The low plasma concentrations of HDL could be the result of increased fractional clearance and reduced expression of apo A-I. To this end, nutrients play an important role in modulating the fractional clearance rate, as well as the rate of apo A-I gene expression. Because medical nutrition therapy constitutes the cornerstone of management of dyslipidemias, it is essential to understand the mechanisms underlying the changes in HDL level in response to alterations in dietary intake. In this review, we will discuss the effect of select nutrients on serum HDLc and apo A-I levels. Specifically, we will review the literature on the effect of carbohydrates, fatty acids, and ketones, as well as some of the nutrient-related metabolites, such as glucosamine and the prostanoids, on apo A-I gene expression. Because there are multiple mechanisms involved in the regulation of serum HDLc levels, changes in gene transcription do not necessarily correlate with clinical observations on serum levels of HDLc.

Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. Tang J, Feng Y, Tsao S, Wang N, Curtain R, Wang Y. J Ethnopharmacol. 2009 Oct 29;126(1):5-17. Epub 2009 Aug 15. PMID: 19686830 doi:10.1016/j.jep.2009.08.009 Conclusions The modern evidences of treating cancer with Huanglian and berberine have a strong linkage with traditional concept and rules of using Huanglian in CM practice. As anticancer candidates with low toxicity, berberine and its altered structure, as well as Huanglian and its formulae, will attract scientists to pursue the potential anticancer effects and the mechanisms by using technologies of genomics, proteomics and other advanced approaches. On the other hand, relatively few in vivo studies have been conducted on anticancer effects of Huanglian and berberine. The clinical application of berberine or Huanglian as novel cancer therapeutic agents requires in vivo validations and further investigations of their anticancer mechanisms.

Fernandez ML, West KL. Mechanisms by which dietary fatty acids modulate plasma lipids. J Nutr. 2005 Sep;135(9):2075-8. Review. PMID: 16140878 [PubMed - indexed for MEDLINE]

Libby P. Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr. 2006 Feb;83(2):456S-460S. Review. PMID: 16470012 [PubMed - indexed for MEDLINE]

Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A. Am J Clin Nutr. 2004 Jun;79(6):935-45. Review. PMID: 15159222

Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. Volvert ML, Seyen S, Piette M, Evrard B, Gangolf M, Plumier JC, Bettendorff L. BMC Pharmacol. 2008 Jun 12;8:10. PMID: 18549472 doi:10.1186/1471-2210-8-10 Conclusion Our results show that, though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain. This would explain why beneficial effects of benfotiamine have only been observed in peripheral tissues, while sulbutiamine, a lipid-soluble thiamine disulfide derivative, that increases thiamine derivatives in the brain as well as in cultured cells, acts as a central nervous system drug. We propose that benfotiamine only penetrates the cells after dephosphorylation by intestinal alkaline phosphatases. It then enters the bloodstream as S-benzoylthiamine that is converted to thiamine in erythrocytes and in the liver. Benfotiamine, an S-acyl derivative practically insoluble in organic solvents, should therefore be differentiated from truly lipid-soluble thiamine disulfide derivatives (allithiamine and the synthetic sulbutiamine and fursultiamine) with a different mechanism of absorption and different pharmacological properties.

Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. Li Y, Liu L, Tollefsbol TO. FASEB J. 2009 Dec 17. [Epub ahead of print] PMID: 20019239 doi: 10.1096/fj.09-149328 Cancer cells metabolize glucose at elevated rates and have a higher sensitivity to glucose reduction. However, the precise molecular mechanisms leading to different responses to glucose restriction between normal and cancer cells are not fully understood. We analyzed normal WI-38 and immortalized WI-38/S fetal lung fibroblasts and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells. Moreover, in WI-38/S cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16(INK4a). Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction. The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as antiaging approaches.

n-3 Fatty acids and cardiovascular disease: actions and molecular mechanisms. Torrejon C, Jung UJ, Deckelbaum RJ. Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):319-26. Epub 2007 Dec 3. Review. Erratum in: Prostaglandins Leukot Essent Fatty Acids. 2008 Feb;78(2):157. PMID: 18060753 In conclusion, a growing body of evidence, encompassing human to cellular and molecular studies are defining the roles for n-3 FA as bioactive agents for reducing the risks of and treating CVD.

The pathobiology of diabetic complications: a unifying mechanism. Brownlee M. Diabetes. 2005 Jun;54(6):1615-25. PMID: 15919781 doi: 10.2337/diabetes.54.6.1615

Strong correlations have been noted between cardiovascular diseases and low bone density / osteoporosis-connections so strong that the presence of one type of pathology is considered a likely predictor of the other. This potentially causal relationship has led to the hypothesis that these conditions share core mechanisms. Recent advances in our understanding of the complimentary roles played by vitamin D3 and vitamin K2 in vascular and bone health provide support for this hypothesis, along with insight into key metabolic dysfunctions underlying cardiovascular disease and osteoporosis. Part I of this review summarizes current research linking vitamin D deficiency to cardiovascular disease, the physiological mechanisms underlying vitamin D's cardiovascular effects, and leading vitamin D researchers' recommendations for significantly higher supplemental doses of the pro-hormone. Part II reviews the vitamin K connection to cardiovascular disease; the ways in which vitamin D and vitamin K pair up to prevent inflammation, vascular calcification and osteoporosis; and the necessity of providing vitamin K along with vitamin D to preclude adverse effects associated with hypervitaminosis D, which include vascular and other soft tissue calcification.

Vitamin D toxicity redefined: vitamin K and the molecular mechanism. Masterjohn C. Med Hypotheses. 2007;68(5):1026-34. Epub 2006 Dec 4. PMID: 17145139 doi:10.1016/j.mehy.2006.09.051

Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism. Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Fierro IM. Thromb Haemost. 2007 Jan;97(1):88-98. PMID: 17200775 DOI: 10.1160/TH06-06-0315

Murck H, Manku M. Ethyl-EPA in Huntington disease: potentially relevant mechanism of action. Brain Res Bull. 2007 Apr 30;72(2-3):159-64. Epub 2006 Nov 15. Review. PMID: 17352940 [PubMed - indexed for MEDLINE]

Effects of pistachios on cardiovascular disease risk factors and potential mechanisms of action: a dose-response study. Gebauer SK, West SG, Kay CD, Alaupovic P, Bagshaw D, Kris-Etherton PM. Am J Clin Nutr. 2008 Sep;88(3):651-9. PMID: 18779280

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 acids and cardiovascular disease: evidence explained and mechanisms explored. Calder PC. Clin Sci (Lond). 2004 Jul;107(1):1-11. Review. PMID: 15132735 DIETARY RECOMMENDATIONS FOR INTAKE OF LONG-CHAIN n-3 PUFAS It is clear from the forgoing discussion that long-chain n-3 fatty acids have been proven to be effective in secondary prevention of MI, with a particularly marked effect on sudden death. Thus it would be prudent to advise post-MI patients to increase long-chain n-3 PUFA consumption. Epidemiological studies, studies investigating effects on classic and emerging risk factors and mechanistic studies indicate that long-chain n-3 fatty acids also play a key role in primary prevention. This is supported by studies in animal models, including monkeys. Thus long-chain n-3 fatty acid consumption should be promoted for all individuals especially those at risk of developing cardiovascular disease. This is the reason why a number of organizations have now made recommendations relating to the intake of fatty fish (for example [3]) and of long-chain n-3 PUFAs (Table 6). It is clear that there is a wide gap between current intakes of long-chain n-3 PUFAs and many of these recommendations (Table 6). To meet these recommendations strategies other than increased consumption of fatty fish may be required.