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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.

Metabolic effects of conjugated linoleic acid in humans: the Swedish experience. Riserus U, Smedman A, Basu S, Vessby B. Am J Clin Nutr. 2004 Jun;79(6 Suppl):1146S-1148S. PMID: 15159248 CONCLUSIONS CLA and specifically the isolated isomers are interesting model fatty acids for studies of the effects of (structural differences of) unsaturated fatty acids in humans. Today, there is no clear indication for human use of CLA concentrates. The possible importance of the small reduction of body fat after supplementation with the commercially available CLA products, without evidence of an associated improvement in the metabolic profile, has to be weighed against the apparent reduction of HDL cholesterol and an increased lipid peroxidation. The possible health consequences of prolonged treatment periods are at present unknown. Human supplementation with high doses of the trans-10,cis-12 CLA isomer should be avoided while awaiting further information on possible effects and side effects. However, it cannot be excluded that future studies could point to clinical applications, eg, as a result of antitumorigenic properties or as a tool to prevent weight gain. This possibility certainly requires more research to increase the understanding of the mechanisms behind the effects of CLA and specific CLA isomers on a molecular level. More controlled studies in defined populations are needed, as are controlled studies for comparisons of the effects of different and well-defined (mixtures of) isomers and human studies of longer duration to secure long-term effects and safety.

Effect of fish oil on heart rate in humans: a meta-analysis of randomized controlled trials. Mozaffarian D, Geelen A, Brouwer IA, Geleijnse JM, Zock PL, Katan MB. Circulation. 2005 Sep 27;112(13):1945-52. Epub 2005 Sep 19. PMID: 16172267 doi: 10.1161/CIRCULATIONAHA.105.556886 Conclusions- In randomized controlled trials in humans, fish oil reduces HR, particularly in those with higher baseline HR or longer treatment duration. These findings provide firm evidence that fish oil consumption directly or indirectly affects cardiac electrophysiology in humans. Potential mechanisms such as effects on the sinus node, ventricular efficiency, or autonomic function deserve further investigation.

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, Dyachenko A, Zhang W, McGahan JP, Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano T, Beysen C, Hellerstein MK, Berglund L, Havel PJ. J Clin Invest. 2009 May;119(5):1322-34. Epub 2009 Apr 20. PMID: 19381015 doi: 10.1172/JCI37385. Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

Conjugated linoleic acid improves insulin sensitivity in young, sedentary humans. Eyjolfson V, Spriet LL, Dyck DJ. Med Sci Sports Exerc. 2004 May;36(5):814-20. PMID: 15126715 CONCLUSIONS: Our results indicate that a common dosage of a commercially available CLA supplement can improve ISI in young, sedentary individuals. However, there is considerable individual variability in the response. Additional studies are required to identify underlying metabolic changes in human skeletal muscle.

Opposing effects of cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid on blood lipids in healthy humans. Tricon S, Burdge GC, Kew S, Banerjee T, Russell JJ, Jones EL, Grimble RF, Williams CM, Yaqoob P, Calder PC. Am J Clin Nutr. 2004 Sep;80(3):614-20. PMID: 15321800 Conclusion: Divergent effects of cis-9,trans-11 CLA and trans-10,cis-12 CLA appear on the blood lipid profile in healthy humans: trans-10,cis-12 CLA increases LDL:HDL cholesterol and total:HDL cholesterol, whereas cis-9,trans-11 CLA decreases them.

[Vitamin K2] Ishida Y. Clin Calcium. 2008 Oct;18(10):1476-82. Review. Japanese. PMID: 18830045 "Vitamin K2 has been approved for the treatment of osteoporosis in Japan since 1995. Vitamin K2 treatment in osteoporosis has been shown to inhibit the occurrence of new bone fractures and to maintain BMD. The uniqueness of the prevention of bone fractures by vitamin K2 is that there has been no direct evidence of the relationship between increase of BMD and a decrease in the occurrence of bone fractures. A recent systematic review of seven Japanese randomized controlled trials by Cockayne has also shown that supplementation with phytonadione (Vitamin K1) and menaquinone (Vitamin K2) , particularly menaquinone-4, is associated with increased BMD and reduced fracture incidence. To confirm these results, a larger well design RCT using fractures as the primary endpoint is clearly needed."

Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12. Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njølstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE. JAMA. 2009 Nov 18;302(19):2119-2126. v PMID: 19920236 Conclusion Treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods.

Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects. Wallace FA, Miles EA, Calder PC. Br J Nutr. 2003 May;89(5):679-89. PMID: 12720588

Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. Hollis BW, Wagner CL, Drezner MK, Binkley NC. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):631-4. Epub 2007 Jan 10. PMID: 17218096 In the present study, we sought to investigate what circulating 25(OH)D levels would result in populations exhibiting no substrate limitations to the vitamin D-25-hydroxylase. To perform this, we chose two distinct populations. The first were individuals from a year-found sunny environment who spent a good deal of time outdoors. The second were a group of lactating women receiving a substantial daily oral dose of vitamin D3. Surprisingly, a study such as this previously had not been undertaken. There are several reasons for this. First, finding a group of sun-exposed individuals is not an easy task; in fact, we had to go to Hawaii to find them. Secondly, very few studies have been performed where subjects actually received adequate vitamin D3 supplementation to make them replete. Finally, it is very difficult and costly to measure circulating vitamin D3 and relate it to circulating 25(OH)D. The results of our study are far-reaching. This study also demonstrates that individuals can be vitamin D deficient with significant sun exposure if the skin area exposed is limited as was suggested several years ago (19). Finally, whether one receives their vitamin D3 orally or through UV exposure, the vitamin D-25-hydroxylase appears to handle it in an equivalent fashion with respect to maintaining circulating 25(OH)D levels. Thus, we believe that the relationship between circulating vitamin D and 25(OH)D may define adequate nutritional vitamin D status.

Vitamin D2 is much less effective than vitamin D3 in humans. Armas LA, Hollis BW, Heaney RP. J Clin Endocrinol Metab. 2004 Nov;89(11):5387-91. PMID: 15531486 Vitamin D2 potency is less than one third that of vitamin D3. Physicians resorting to use of vitamin D2 should be aware of its markedly lower potency and shorter duration of action relative to vitamin D3.

Bioavailability and Kinetics of Sulforaphane in Humans after Consumption of Cooked versus Raw Broccoli Martijn Vermeulen*, Ineke W. A. A. Klpping-Ketelaars†, Robin van den Berg‡ and Wouter H. J. Vaes J. Agric. Food Chem., 2008, 56 (22), pp 10505-10509 Publication Date (Web): October 24, 2008 (Article) DOI: 10.1021/jf801989e

Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Chiang N, Bermudez EA, Ridker PM, Hurwitz S, Serhan CN. Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15178-83. Epub 2004 Oct 7. PMID: 15471991 doi: 10.1073/pnas.0405445101

Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Kew S, Mesa MD, Tricon S, Buckley R, Minihane AM, Yaqoob P. Am J Clin Nutr. 2004 Apr;79(4):674-81. PMID: 15051614

Supplementation with oral probiotic bacteria protects human cutaneous immune homeostasis after UV exposure-double blind, randomized, placebo controlled clinical trial. Peguet-Navarro J, Dezutter-Dambuyant C, Buetler T, Leclaire J, Smola H, Blum S, Bastien P, Breton L, Gueniche A. Eur J Dermatol. 2008 Sep-Oct;18(5):504-11. Epub 2008 Aug 8. PMID: 18693151

Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans.\nDulloo AG, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, Chantre P, Vandermander J.\nAm J Clin Nutr. 1999 Dec;70(6):1040-5.\nPMID: 10584049

Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans. Mursu J, Voutilainen S, Nurmi T, Rissanen TH, Virtanen JK, Kaikkonen J, Nyyssönen K, Salonen JT. Free Radic Biol Med. 2004 Nov 1;37(9):1351-9. PMID: 15454274 doi:10.1016/j.freeradbiomed.2004.06.002 Cocoa polyphenols may increase the concentration of HDL cholesterol, whereas chocolate fatty acids may modify the fatty acid composition of LDL and make it more resistant to oxidative damage.

Fish consumption shifts lipoprotein subfractions to a less atherogenic pattern in humans. Li Z, Lamon-Fava S, Otvos J, Lichtenstein AH, Velez-Carrasco W, McNamara JR, Ordovas JM, Schaefer EJ. J Nutr. 2004 Jul;134(7):1724-8. PMID: 15226460 The effect of fish consumption on plasma lipoprotein subfraction concentrations was studied in 22 men and women (age > 40 y). Subjects were provided an average American diet (AAD, 35% of energy as fat, 14% as saturated fat, and 35 mg cholesterol/MJ) for 6 wk before being assigned to a National Cholesterol Education Program (NCEP) Step 2 high-fish diet (n = 11, 26% of energy as fat, 4.5% as saturated fat, and 15 mg cholesterol/MJ) or a NCEP Step 2 low-fish diet (n = 11, 26% of energy as fat, 4.0% as saturated fat, and 11 mg cholesterol/MJ) for 24 wk. All food and drink were provided to study participants. Consumption of the high-fish NCEP Step 2 diet was associated with a significant reduction in medium and small VLDL, compared with the AAD diet, whereas the low-fish diet did not affect VLDL subfractions. Both diets significantly reduced LDL cholesterol concentrations, without modifying LDL subfractions. Both diets also lowered HDL cholesterol concentrations. However, the high-fish diet significantly lowered only the HDL fraction containing both apolipoprotein (apo) AI and AII (LpAI:AII) and did not change HDL subfractions assessed by NMR, whereas the low-fish diet significantly lowered the HDL fraction containing only apo AI (LpAI) and the large NMR HDL fractions, resulting in a significant reduction in HDL particle size. Neither diet affected VLDL and LDL particle size. Our data indicate that within the context of a diet restricted in fat and cholesterol, a higher fish content favorably affects VLDL and HDL subspecies

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.

Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Frassetto LA, Schloetter M, Mietus-Synder M, Morris RC Jr, Sebastian A. Eur J Clin Nutr. 2009 Aug;63(8):947-55. Epub 2009 Feb 11. PMID: 19209185 doi:10.1038/ejcn.2009.4 Conclusions: Even short-term consumption of a paleolithic type diet improves BP and glucose tolerance, decreases insulin secretion, increases insulin sensitivity and improves lipid profiles without weight loss in healthy sedentary humans.