Combating oxidative stress in diabetic complications with Nrf2 activators: How much is too much?

References

• Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94(3):311–21.
   PubMed Web of Science ®Google Scholar
• Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414(6865):813–20.
   PubMed Web of Science ®Google Scholar
• Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 2002;23(5):599–622.
   PubMed Web of Science ®Google Scholar
• Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010;107(9):1058–70.
   PubMed Web of Science ®Google Scholar
• Schaffer SW, Jong CJ, Mozaffari M. Role of oxidative stress in diabetes-mediated vascular dysfunction: unifying hypothesis of diabetes revisited. Vascul Pharmacol 2012;57(5–6):139–49.
   PubMed Web of Science ®Google Scholar
• Ceriello A, Dello Russo P, Amstad P, Cerutti P. High glucose induces antioxidant enzymes in human endothelial cells in culture; Evidence linking hyperglycemia and oxidative stress. Diabetes 1996;45(4):471–7.
   PubMed Web of Science ®Google Scholar
• Ceriello A, Morocutti A, Mercuri F, Quagliaro L, Moro M, Damante G, et al. Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy. Diabetes 2000;49(12):2170–7.
   PubMed Web of Science ®Google Scholar
• Hodgkinson AD, Bartlett T, Oates PJ, Millward BA, Demaine AG. The response of antioxidant genes to hyperglycemia is abnormal in patients with type 1 diabetes and diabetic nephropathy. Diabetes 2003;52(3):846–51.
   PubMed Web of Science ®Google Scholar
• Palsamy P, Subramanian S. Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochim Biophys Acta 2011;1812(7):719–31.
   PubMed Web of Science ®Google Scholar
• Luo ZF, Qi W, Feng B, Mu J, Zeng W, Guo YH, et al. Prevention of diabetic nephropathy in rats through enhanced renal antioxidative capacity by inhibition of the proteasome. Life Sci 2011;88(11–12):512–20.
   PubMed Web of Science ®Google Scholar
• El-Bab MF, Zaki NS, Mojaddidi MA, Al-Barry M, El-Beshbishy HA. Diabetic retinopathy is associated with oxidative stress and mitigation of gene expression of antioxidant enzymes. Int J Gen Med 2013;19(6):799–806.
   Google Scholar
• Ray PD, Huang B-W, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 2012;24(5):981–90.
   PubMed Web of Science ®Google Scholar
• Winterbourn CC. Reconciling the chemistry and biology of reactive oxygen species. Nat Chem Biol 2008;4(5):278–86.
   PubMed Web of Science ®Google Scholar
• Terentis AC, Thomas SR, Burr JA, Liebler DC, Stocker R. Vitamin E oxidation in human atherosclerotic lesions. Circ Res 2002;90(3):333–9.
   PubMed Web of Science ®Google Scholar
• Song Y, Cook NR, Albert CM, Van Denburgh M, Manson JE. Effects of vitamins C and E and β-carotene on the risk of type 2 diabetes in women at high risk of cardiovascular disease: a randomized controlled trial. Am J Clin Nutr 2009;90(2):429–37.
   PubMed Web of Science ®Google Scholar
• Mayer-Davis EJ, Monaco JH, Marshall JA, Rushing J, Juhaeri MS. Vitamin C intake and cardiovascular disease risk factors in persons with non-insulin-dependent diabetes mellitus. Prev Med 1997;26(3):277–83.
   PubMed Web of Science ®Google Scholar
• Tessier DM, Khalil A, Trottier L, Fülöp T. Effects of vitamin C supplementation on antioxidants and lipid peroxidation markers in elderly subjects with type 2 diabetes. Arch Gerontol Geriatr 2009;48(1):67–72.
   PubMed Web of Science ®Google Scholar
• Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342(3):154–60.
   PubMed Web of Science ®Google Scholar
• Lonn E, Yusuf S, Hoogwerf B, Pogue J, Yi Q, Zinman B, et al. Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE Substudy. Diabetes Care 2002;25(11):1919–27.
   PubMed Web of Science ®Google Scholar
• de Haan JB. Nrf2 activators as attractive therapeutics for diabetic nephropathy. Diabetes 2011;60(11):2683–4.
   PubMed Web of Science ®Google Scholar
• McMahon M, Itoh K, Yamamoto M, Hayes JD. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem 2003;278(24):21592–600.
   PubMed Web of Science ®Google Scholar
• He X, Kan H, Cai L, Ma Q. Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes. J Mol Cell Cardiol 2009;46(1):47–58.
   PubMed Web of Science ®Google Scholar
• Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, Zhang DD. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 2010;59(4):850–60.
   PubMed Web of Science ®Google Scholar
• Ungvari Z, Bailey-Downs L, Gautam T, Jimenez R, Losonczy G, Zhang C, et al. Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol 2011;300(4):H1133–40.
   PubMed Web of Science ®Google Scholar
• Xue M, Qian Q, Adaikalakoteswari A, Rabbani N, Babaei-Jadidi R, Thornalley PJ. Activation of NF-E2–Related Factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 2008;57(10):2809–17.
   PubMed Web of Science ®Google Scholar
• Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 2011;60(11):3055–66.
   PubMed Web of Science ®Google Scholar
• Zhong Q, Mishra M, Kowluru RA. Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 2013;54(6):3941–8.
   PubMed Web of Science ®Google Scholar
• Tan Y, Ichikawa T, Li J, Si Q, Yang H, Chen X, et al. Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes 2011;60(2):625–33.
   PubMed Web of Science ®Google Scholar
• Bitar MS, Al-Mulla F. A defect in Nrf2 signaling constitutes a mechanism for cellular stress hypersensitivity in a genetic rat model of type 2 diabetes. Am J Physiol Endocrinol Metab 2011;301(6):E1119–29.
   Google Scholar
• Bai Y, Cui W, Xin Y, Miao X, Barati MT, Zhang C, et al. Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation. J Mol Cell Cardiol 2013;57:82–95.
   PubMed Web of Science ®Google Scholar
• Miao X, Bai Y, Sun W, Cui W, Xin Y, Wang Y, et al. Sulforaphane prevention of diabetes-induced aortic damage was associated with the up-regulation of Nrf2 and its down-stream antioxidants. Nutr Metab (Lond) 2012;9(1):84.
   PubMed Web of Science ®Google Scholar
• Cui W, Bai Y, Miao X, Luo P, Chen Q, Tan Y, et al. Prevention of diabetic nephropathy by sulforaphane: possible role of Nrf2 upregulation and activation. Oxid Med Cell Longev 2012; Sep; ID: 821936, 1–12.
   PubMed Web of Science ®Google Scholar
• Chan K, Han X-D, Kan YW. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci 2001;98(8):4611–6.
   PubMed Web of Science ®Google Scholar
• Aleksunes LM, Reisman SA, Yeager RL, Goedken MJ, Klaassen CD. Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice. J Pharmacol Exp Ther 2010;333(1):140–51.
   PubMed Web of Science ®Google Scholar
• Yoh K, Hirayama A, Ishizaki K, Yamada A, Takeuchi M, Yamagishi S-i, et al. Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells 2008;13(11):1159–70.
   PubMed Web of Science ®Google Scholar
• Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, et al. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 2010;299(1):H18–24.
   PubMed Web of Science ®Google Scholar
• He X, Ma Q. Redox regulation by nuclear factor erythroid 2-related factor 2: gatekeeping for the basal and diabetes-induced expression of thioredoxin-interacting protein. Mol Pharmacol 2012;82(5):887–97.
   PubMed Web of Science ®Google Scholar
• Thomas M. A preliminary evaluation of bardoxolone methyl for the treatment of diabetic nephropathy. Expert Opin Drug Metab Toxicol 2012;8(8):1015–22.
   PubMed Web of Science ®Google Scholar
• Dreger H, Westphal K, Weller A, Baumann G, Stangl V, Meiners S, et al. Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res 2009;83(2):354–61.
   PubMed Web of Science ®Google Scholar
• Tamasi V, Jeffries JM, Arteel GE, Falkner KC. Ebselen augments its peroxidase activity by inducing nrf-2-dependent transcription. Arch Biochem Biophys 2004;431(2):161–8.
   PubMed Web of Science ®Google Scholar
• Chew P, Yuen DYC, Koh P, Stefanovic N, Febbraio MA, Kola I, et al. Site-specific antiatherogenic effect of the antioxidant ebselen in the diabetic apolipoprotein E–deficient mouse. Arterioscler Thromb Vasc Biol 2009;29(6):823–30.
   PubMed Web of Science ®Google Scholar
• Chew P, Yuen DYC, Stefanovic N, Pete J, Coughlan MT, Jandeleit-Dahm KA, et al. Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse. Diabetes 2010;59(12):3198–207.
   PubMed Web of Science ®Google Scholar
• Honda T, Rounds BV, Gribble GW, Suh N, Wang Y, Sporn MB. Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Bioorg Med Chem Letters 1998;8(19):2711–4.
   PubMed Web of Science ®Google Scholar
• Honda T-i, Rounds BV, Bore L, Favaloro FG Jr, Gribble GW, Suh N, et al. Novel synthetic oleanane triterpenoids: a series of highly active inhibitors of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett 1999;9(24):3429–34.
   PubMed Web of Science ®Google Scholar
• Hong F, Freeman ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 2005;18(12):1917–26.
   PubMed Web of Science ®Google Scholar
• Song MY, Kim EK, Moon WS, Park JW, Kim HJ, So HS, et al. Sulforaphane protects against cytokine- and streptozotocin-induced β-cell damage by suppressing the NF-κB pathway. Toxicol Appl Pharmacol 2009;235(1):57–67.
   PubMed Web of Science ®Google Scholar
• Bahadoran Z, Mirmiran P, Hosseinpanah F, Rajab A, Asghari G, Azizi F. Broccoli sprouts powder could improve serum triglyceride and oxidized LDL/LDL-cholesterol ratio in type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial. Diabetes Res Clin Pract 2012;96(3):348–54.
   PubMed Web of Science ®Google Scholar
• Mirmiran P, Bahadoran Z, Hosseinpanah F, Keyzad A, Azizi F. Effects of broccoli sprout with high sulforaphane concentration on inflammatory markers in type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial. J Functional Foods 2012;4(4):837–41.
   Web of Science ®Google Scholar
• Bahadoran Z, Mirmiran P, Hosseinpanah F, Hedayati M, Hosseinpour-Niazi S, Azizi F. Broccoli sprouts reduce oxidative stress in type 2 diabetes: a randomized double-blind clinical trial. Eur J Clin Nutr 2011;65(8):972–7.
   PubMed Web of Science ®Google Scholar
• Liu Y, Chan F, Sun H, Yan J, Fan D, Zhao D, et al. Resveratrol protects human keratinocytes HaCaT cells from UVA-induced oxidative stress damage by downregulating Keap1 expression. Eur J Pharmacol 2011;650(1):130–7.
   PubMed Web of Science ®Google Scholar
• Huang K, Huang J, Xie X, Wang S, Chen C, Shen X, et al. Sirt1 resists advanced glycation end products-induced expressions of fibronectin and TGF-β1 by activating the Nrf2/ARE pathway in glomerular mesangial cells. Free Radic Biol Med 2013;65:528–40.
   PubMed Web of Science ®Google Scholar
• Jiang B, Guo L, Li BY, Zhen JH, Song J, Peng T, et al. Resveratrol attenuates early diabetic nephropathy by down-regulating glutathione S-transferases Mu in diabetic rats. J Med Food 2013;16(6):481–6.
   PubMed Web of Science ®Google Scholar
• Ghanim H, Sia CL, Korzeniewski K, Lohano T, Abuaysheh S, Marumganti A, et al. A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J Clin Endocrinol Metab 2011;96(5):1409–14.
   PubMed Web of Science ®Google Scholar
• Brasnyó P, Molnár GA, Mohás M, Markó L, Laczy B, Cseh J, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr 2011;106(3):383–9.
   PubMed Web of Science ®Google Scholar
• Pervaiz S, Holme AL. Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal 2009;11(11):2851–97.
   PubMed Web of Science ®Google Scholar
• Turan B, Tuncay E, Vassort G. Resveratrol and diabetic cardiac function: focus on recent in vitro and in vivo studies. J Bioenerg Biomembr 2012;44(2):281–96.
   PubMed Web of Science ®Google Scholar
• Khan HY, Zubair H, Faisal M, Ullah MF, Farhan M, Sarkar FH, et al. Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: a mechanism for cancer chemopreventive action. Mol Nutr Food Res 2013 Oct; [Epub ahead of print].
   PubMed Web of Science ®Google Scholar
• Zheng LF, Wei QY, Cai YJ, Fang JG, Zhou B, Yang L, et al. DNA damage induced by resveratrol and its synthetic analogues in the presence of Cu (II) ions: mechanism and structure-activity relationship. Free Radic Biol Med 2006;41(12):1807–16.
   PubMed Web of Science ®Google Scholar
• de la Lastra CA, Villegas I. Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans 2007;35(5):1156–60.
   PubMed Web of Science ®Google Scholar
• Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, et al. What is new for an old molecule? systematic review and recommendations on the use of resveratrol. PLoS ONE 2011;6(6):e19881.
   PubMed Web of Science ®Google Scholar
• Hu J, Klein JD, Du J, Wang XH. Cardiac muscle protein catabolism in diabetes mellitus: activation of the ubiquitin-proteasome system by insulin deficiency. Endocrinology 2008;149(11):5384–90.
   PubMed Web of Science ®Google Scholar
• Marfella R, Filippo CD, Portoghese M, Siniscalchi M, Martis S, Ferraraccio F, et al. The ubiquitin–proteasome system contributes to the inflammatory injury in ischemic diabetic myocardium: the role of glycemic control. Cardiovasc Pathol 2009;18(6):332–45.
   PubMed Web of Science ®Google Scholar
• Wang X, Hu Z, Hu J, Du J, Mitch WE. Insulin resistance accelerates muscle protein degradation: activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology 2006;147(9):4160–8.
   PubMed Web of Science ®Google Scholar
• Wang Y, Sun W, Du B, Miao X, Bai Y, Xin Y, et al. Therapeutic effect of MG-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of Nrf2 and NF-κB. Am J Physiol Heart Circ Physiol 2013;304(4):H567–78.
   PubMed Web of Science ®Google Scholar
• Cui W, Li B, Bai Y, Miao X, Chen Q, Sun W, et al. Potential role for Nrf2 activation in the therapeutic effect of MG132 on diabetic nephropathy in OVE26 diabetic mice. Am J Physiol Endocrinol Metab 2013;304(1):E87–99.
   PubMed Web of Science ®Google Scholar
• Miao X, Cui W, Sun W, Xin Y, Wang B, Tan Y, et al. Therapeutic effect of MG132 on the aortic oxidative damage and inflammatory response in OVE26 type 1 diabetic mice. Oxid Med Cell Longev. 2013 March; ID: 879516, 1–12.
   Web of Science ®Google Scholar
• Guo N, Peng Z. MG132, a proteasome inhibitor, induces apoptosis in tumor cells. Asia Pac J Clin Oncol 2013;9(1):6–11.
   PubMed Web of Science ®Google Scholar
• Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, et al. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 2005;102(12):4584–9.
   PubMed Web of Science ®Google Scholar
• Sporn MB, Liby KT, Yore MM, Fu L, Lopchuk JM, Gribble GW. New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 2011;74(3):537–45.
   PubMed Web of Science ®Google Scholar
• Ichikawa T, Li J, Meyer CJ, Janicki JS, Hannink M, Cui T. Dihydro-CDDO-trifluoroethyl amide (dh404), a novel Nrf2 activator, suppresses oxidative stress in cardiomyocytes. PLoS ONE 2009;4(12):e8391.
   Google Scholar
• Zoja C, Corna D, Nava V, Locatelli M, Abbate M, Gaspari F, et al. Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. Am J Physiol Renal Physiol 2013;304(6):F808–19.
   PubMed Web of Science ®Google Scholar
• Chin M, Lee C-YI, Chuang J-C, Bumeister R, Wigley WC, Sonis ST, et al. Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity. Am J Physiol Renal Physiol 2013;304(12):F1438–46.
   Google Scholar
• Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011;365(4):327–36.
   PubMed Web of Science ®Google Scholar
• McCullough PA, Ali S. Cardiac and renal function in patients with type 2 diabetes who have chronic kidney disease: potential effects of bardoxolone methyl. Drug Des Devel Ther 2012;6:141–9.
   PubMed Web of Science ®Google Scholar
• Upadhyay A, Sarnak MJ, Levey AS. Bardoxolone methyl, chronic kidney disease, and type 2 diabetes. N Engl J Med 2011;365(18):1746.
   PubMedGoogle Scholar
• Ding Y, Stidham RD, Bumeister R, Trevino I, Winters A, Sprouse M, et al. The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells. Kidney Int [Commentary] 2013;83(5):845–54.
   PubMed Web of Science ®Google Scholar
• Abboud HE. Synthetic oleanane triterpenoids: magic bullets or not? Kidney Int 2013;83(5):785–7.
   PubMed Web of Science ®Google Scholar
• Hong DS, Kurzrock R, Supko JG, He X, Naing A, Wheler J, et al. A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer Res 2012;18(12):3396–406.
   PubMed Web of Science ®Google Scholar
• Pergola PE, Krauth M, Huff JW, Ferguson DA, Ruiz S, Meyer CJ, et al. Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. Am J Nephrol 2011;33(5):469–76.
   PubMed Web of Science ®Google Scholar
• McMahon G, Forman J. Bardoxolone methyl, chronic kidney disease, and type 2 diabetes. N Engl J Med 2011;365(18):1746.
   PubMedGoogle Scholar
• de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013;369(26):2492–503.
   PubMed Web of Science ®Google Scholar
• Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 2003;35(3):238–45.
   PubMed Web of Science ®Google Scholar
• Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1–Nrf2 pathway. Trends Pharmacol Sci 2013;34(6):340–6.
   PubMed Web of Science ®Google Scholar
• Xu J, Kulkarni SR, Donepudi AC, More VR, Slitt AL. Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes 2012;61(12):3208–18.
   PubMed Web of Science ®Google Scholar
• Xue P, Hou Y, Chen Y, Yang B, Fu J, Zheng H, et al. Adipose deficiency of Nrf2 in ob/ob mice results in severe metabolic syndrome. Diabetes 2013;62(3):845–54.
   PubMed Web of Science ®Google Scholar
• Pi J, Zhang Q, Fu J, Woods CG, Hou Y, Corkey BE, et al. ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function. Toxicol Appl Pharmacol 2010;244(1):77–83.
   PubMed Web of Science ®Google Scholar
• Bjelakovic G, Nikolova D, Gluud L, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297(8):842–57.
   PubMed Web of Science ®Google Scholar