Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) as A Therapeutical Target in Type-2 Diabetes Mellitus: A Review

Asri Hendrawati


BACKGROUND: Increasing free radicals and oxidative stress due to chronic hyperglycemia in type-2 diabetes mellitus (DM) promotes the activity of endogenic antioxidative genes. Nuclear factor erythroid 2-related factor 2 (Nrf2) expression and activity are important to regulate the production of endogenic antioxidative enzymes.

CONTENT: Normally, Nrf2 is bound by protein Kelchlike ECH-associated protein-1 (Keap1) in the cytosol. Stimulation from oxidative stress causes the release of Nrf2 from Keap1. When activated, Nrf2 enters the nucleus and activates the antioxidant response element (ARE). This will further increase the production of antioxidative enzymes, such as catalase, nitrite oxydase and heme oxygenase-1. The discovery of oxidative stress, as the cause of complications in DM, gives rise to the idea of developing a treatment which can increase the expression and activity of Nrf2, one of which is a flavonoid antioxidant.

SUMMARY: Currently, nuclear factor erythroid 2-related factor 2 is an important target in the therapy of DM.

KEYWORDS: Nrf2, type-2 diabetes mellitus, endogenic antioxidative enzymes, oxidative stress, antioxidants

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Murugesh KV, Yeligar DK, Dash P, Sengupta BC, Maity TK. Antidiabetic, antioxidant and antihyperlipidemic status of Heliotropium zeylanicum extract on streptozotocin-induced diabetic rats. Biol Pharm Bull. 2006; 29: 2202-5, CrossRef.

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: 311-21, CrossRef.

Riaz S. Diabetes mellitus. Sci Res Essays. 2009; 4: 367-73, article.

Perkumpulan Endokrinologi Indonesia. Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia. Jakarta: PB. PERKENI; 2015, article.

Goh SY, Cooper ME. The role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab. 2008; 93:1143-52, CrossRef.

Murarka S, Movahed MR. Diabetic cardiomyopathy. J Card Fail. 2010; 16: 971-9, CrossRef.

Pi J, Zhang Q, Fu J, Woods CG, Hou Y, Corkey BE. ROS signaling, oxidative stres and Nrf2 in pancreatic beta-cell function. Toxicol Appl Pharmacol. 2010; 244:77-83, CrossRef.

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: 47-58, CrossRef.

He X, Ma Q. Disruption of Nrf2 synergizes with high glucose to cause heightened myocardial oxidative stres and severe cardiomyopathy in diabetic mice . J Diabetes Metab. 2012; 2012 (Suppl 7): 1-9, CrossRef.

Zhi WY, Dan L, Wen HL, Tian RJ. Role of nuclear factor (erythroidderived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment? World J Diabetes. 2012; 3: 19-28, CrossRef.

Kawai Y, Garduno L, Theodore M, Yang J, Arinze IJ. Acetylationdeacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J. Biol. Chem. 2011; 286:7629-40, CrossRef.

Yu R, Lei W, Mandlekar S, Weber MJ, Der CJ, Wu J, et al. Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. J Biol Chem. 1999; 274: 27545-52, CrossRef.

Yu R, Chen C, Mo YY, Hebbar V, Owuor ED, Tan TH, et al. Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. J Biol Chem. 2000; 275: 39907-13, CrossRef.

Brunt KR, Fenrich KK, Kiani G, Tse MY, Pang SC, Ward CA, et al. Protection of human vascular smooth muscle cells from H2O2-induced apoptosis through functional codependence between HO-1 and AKT. Arterioscler Thromb Vasc Biol. 2006; 26: 2027-34, CrossRef.

Sykiotis GP, Bohmann D. Keap1/Nrf2 signaling regulates oxidative stres tolerance and lifespan in Drosophila. Dev Cell. 2008; 14: 76-85, CrossRef.

Chang CL, Au LC, Huang SW, Kwok CF, Ho LT, Juan CC. Insulin upregulates heme oxygenase-1 expression in 3T3-L1 adipocytes via PI3-kinase- and PKC-dependent pathways and heme oxygenase-1-associated microRNA downregulation. Endocrinology. 2011; 152: 384-93, CrossRef.

Bashan N, Kovsa, J, Kachko I, Ovadia H, Rudich A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev. 2009; 89: 27-71, CrossRef.

Ducluzeau PH, Priou M, Weitheimer M, Flamment M, Duluc L, Iacobazi F, et al. Dynamic regulation of mitochondrial network and oxidative functions during 3T3-L1 fat cell differentiation. J Physiol Biochem. 2011; 67: 285-96, CrossRef.

Shin S, Wakabayashi J, Yates MS, Wakabayashi N, Dolan PM, Aja S, et al. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmacol. 2009; 620: 138-44, CrossRef.

Nerland DE. The antioxidant/electrophile response element motif. Drug Metab Rev. 2007; 39: 235-48, CrossRef.

Negi G, Kumar A, Joshi RP, Sharma SS. Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: old perspective with a new angle. Biochem Biophys Res Commun. 2011; 408(1): 1-5, CrossRef.

Moskaug JO, Carlsen H, Myhrstad M, Blomhoff R. Molecular imaging of the biological effects of quercetin and quercetin-rich foods. Mech Ageing Dev. 2004; 125: 315-24, CrossRef.

McNally SJ, Harrison EM, Ross JA, Garden OJ, Wigmore SJ. Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition. Int J Mol Med. 2007; 19: 165-72, CrossRef.

Aggarwal BB. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu Rev Nutr. 2010; 30: 173-99, CrossRef.

Hayes JD, McMahon M. Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett. 2001; 174: 103-13, CrossRef.

Nishida C, Uauy, R, Kumanyika, S and Shetty P. Joint WHO/FAO Expert consultation on Diet, Nutrition and the prevention of chronic diseases: process, product and policy implications. Public Health Nutrition. 2004; 7: 245-50, CrossRef.

Duncan J G. Mitochondrial dysfunction in diabetic cardiomyopathy. Biochim Biophys Acta. 2011; 1813: 1351-9, CrossRef.

Li J, Ichikawa T, Villacorta L. Nrf2 protects against maladaptive cardiac responses to hemodynamic stres. Arterioscler Thromb Vasc Biol. 2009; 29: 1843-50, CrossRef.

Parabathina RK, Raja GV, Rao MN, Rao GS, Rao KS. Cardioprotective effects of vitamin E, morin, rutin and quercetin against Doxorubicin induced oxidative stres of rabbits: A biochemical study. J Chem Pharm Res. 2010; 2: 754-65, article.


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