The emerging role of redox-sensitive Nrf2-Keap1 pathway in diabetes

Pharmacological Research

Volumn 91, Issue , 2015, Pages 104-114

  Bhakkiyalakshmi, Elango ^a   Sireesh, Dornadula ^a   Rajaguru, Palanisamy ^b   Paulmurugan, Ramasamy ^c   Ramkumar, Kunka Mohanram ^a  

^a SRM INSTITUTE OF SCIENCE AND TECHNOLOGY   (India)

^b ANNA UNIVERSITY   (India)

^c STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Antioxidants; Diabetes; Nrf2 activators; Nrf2 Keap1 pathway; Oxidative stress

Indexed keywords

ANTIOXIDANT; BARDOXOLONE METHYL; BENZYLOXYCARBONYLLEUCYLLEUCYLLEUCINAL; CATECHIN; CINNAMALDEHYDE; CURCUMIN; INSULIN; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MAGNESIUM LITHOSPERMATE; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN KINASE C; PTEROSTILBENE; RESVERATROL; STILBENE DERIVATIVE; SULFORAPHANE; TERT BUTYLHYDROQUINONE; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; KEAP1 PROTEIN, HUMAN; NFE2L2 PROTEIN, HUMAN; SIGNAL PEPTIDE;

ANTIOXIDANT ACTIVITY; AUTOIMMUNITY; CELL DEATH; CELL DESTRUCTION; DIABETES MELLITUS; DIABETIC NEPHROPATHY; DIABETIC RETINOPATHY; DISORDERS OF MITOCHONDRIAL FUNCTIONS; HUMAN; INSULIN DEFICIENCY; INSULIN RESISTANCE; MOLECULAR MECHANICS; NONHUMAN; OXIDATION REDUCTION STATE; OXIDATIVE STRESS; PANCREAS ISLET BETA CELL; PATHOGENESIS; PROTEIN DEGRADATION; PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; METABOLISM; OXIDATION REDUCTION REACTION; PHYSIOLOGICAL STRESS;

ANIMALS; DIABETES MELLITUS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; NF-E2-RELATED FACTOR 2; OXIDATION-REDUCTION; SIGNAL TRANSDUCTION; STRESS, PHYSIOLOGICAL;

EID: 84921032016     PISSN: 10436618     EISSN: 10961186     Source Type: Journal    
DOI: 10.1016/j.phrs.2014.10.004     Document Type: Review

References (148)

1. Guariguata L. Contribute data to the 6th edition of the IDF Diabetes Atlas. Diabetes Res Clin Pract 2013;100:280-1.
2. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-49.
3. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35(Suppl. 1):S64-71.
4. Johnson JD, Luciani DS. Mechanisms of pancreatic beta-cell apoptosis in diabetes and its therapies. Adv Exp Med Biol 2010;654:447-62.
5. Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 2005;54(Suppl. 2):S97-107.
6. Donath MY, Halban PA. Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia 2004;47:581-9.
7. Donath MY, Storling J, Maedler K, Mandrup-Poulsen. T. Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med (Berl) 2003;81:455-70.
8. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010;107:1058-70.
9. Ramkumar K, Vijayakumar R, Vanitha P, Suganya N, Manjula C, Rajaguru P, et al. Protective effect of gallic acid on alloxan-induced oxidative stress and osmotic fragility in rats. Hum Exp Toxicol 2013;33:638-49.
10. Ramkumar KM, Lee AS, Krishnamurthi K, Devi SS, Chakrabarti T, Kang KP, et al. Gymnema montanum H. protects against alloxan-induced oxidative stress and apoptosis in pancreatic beta-cells. Cell Physiol Biochem 2009;24:429-40.
11. Latha M, Pari L, Ramkumar KM, Rajaguru P, Suresh T, Dhanabal T, et al. Antidiabetic effects of scoparic acid D isolated from Scoparia dulcis in rats with streptozotocin-induced diabetes. Nat Prod Res 2009;23:1528-40.
12. Golbidi S, Ebadi SA, Laher I. Antioxidants in the treatment of diabetes. Curr Diabetes Rev 2011;7:106-25.
13. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 2007;47:89-116.
14. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997;236:313-22.
15. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 1999;274:26071-8.
16. McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, et al. The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 2001;61:3299-307.
17. Nioi P, McMahon M, Itoh K, Yamamoto M, Hayes JD. Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence. Biochem J 2003;374:337-48.
18. Wild AC, Moinova HR, Mulcahy RT. Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 1999;274:33627-36.
19. Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003;43:233-60.
20. Wu KC, McDonald PR, Liu JJ, Chaguturu R, Klaassen CD. Implementation of a high-throughput screen for identifying small molecules to activate the Keap1-Nrf2-ARE pathway. PLoS ONE 2012;7:e44686.
21. Ramkumar KM, Sekar TV, Foygel K, Elango B, Paulmurugan R. Reporter protein complementation imaging assay to screen and study Nrf2 activators in cells and living animals. Anal Chem 2013;85:7542-9.
22. Sakurai T, Kanayama M, Shibata T, Itoh K, Kobayashi A, Yamamoto M, et al. Ebselen, a seleno-organic antioxidant, as an electrophile. Chem Res Toxicol 2006;19:1196-204.
23. 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;2012:821936.
24. Lee Y, Shin DH, Kim JH, Hong S, Choi D, Kim YJ, et al. Caffeic acid phenethyl ester-mediated Nrf2 activation and IkappaB kinase inhibition are involved in NFkappaB inhibitory effect: structural analysis for NFkappaB inhibition. Eur J Pharmacol 2010;643:21-8.
25. Huang TC, Chung YL, Wu ML, Chuang SM. Cinnamaldehyde enhances Nrf2 nuclear translocation to upregulate phase II detoxifying enzyme expression in HepG2 cells. J Agric Food Chem 2011;59:5164-71.
26. Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, et al. The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res 2005;65:4789-98.
27. Bhakkiyalakshmi E, Shalini D, Sekar TV, Rajaguru P, Paulmurugan R, Ramkumar KM. Therapeutic potential of pterostilbene against pancreatic beta-cell apoptosis mediated through Nrf2. Br J Pharmacol 2014;171:1747-57.
28. 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;60:3055-66.
29. Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 2006;38:769-89.
30. Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 1991;266:11632-9.
31. Villeneuve NF, Lau A, Zhang DD. Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases. Antioxid Redox Signal 2010;13:1699-712.
32. Calabrese V, Cornelius C, Dinkova-Kostova AT, Iavicoli I, Di Paola R, Koverech A, et al. Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochim Biophys Acta 2012;1822:753-83.
33. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 1999;13:76-86.
34. Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 2001;6:857-68.
35. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD. Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. J Biol Chem 2004;279:31556-67.
36. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 2004;24:7130-9.
37. Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 2004;24:10941-53.
38. Huang HC, Nguyen T, Pickett CB. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem 2002;277:42769-74.
39. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, et al. Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci U S A 2004;101:2040-5.
40. He X, Ma Q. NRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activation. Mol Pharmacol 2009;76:1265-78.
41. Nioi P, Nguyen T, Sherratt PJ, Pickett CB. The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol 2005;25:10895-906.
42. Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. Neuromol Med 2008;10:236-46.
43. Wang L, Chen Y, Sternberg P, Cai J. Essential roles of the PI3 kinase/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE. Investig Ophthalmol Vis Sci 2008;49:1671-8.
44. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129:1261-74.
45. Brunet A, Datta SR, Greenberg ME. Transcription-dependent and - independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 2001;11:297-305.
46. Jiang BH, Aoki M, Zheng JZ, Li J, Vogt PK. Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B. Proc Natl Acad Sci U S A 1999;96:2077-81.
47. Nakaso K, Yano H, Fukuhara Y, Takeshima T, Wada-Isoe K, Nakashima K. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett 2003;546:181-4.
48. Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A. Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 2006;281:14841-51.
49. Bloom DA, Jaiswal AK. Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression. J Biol Chem 2003;278:44675-82.
50. Niture SK, Jain AK, Jaiswal AK. Antioxidant-induced modification of INrf2 cysteine 151 and PKC-delta-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance. J Cell Sci 2009;122:4452-64.
51. Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene 2007;26:3100-12.
52. McCubrey JA, Lahair MM, Franklin RA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal 2006;8:1775-89.
53. Owuor ED, Kong AN. Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol 2002;64:765-70.
54. Jain AK, Jaiswal AK. Phosphorylation of tyrosine 568 controls nuclear export of Nrf2. J Biol Chem 2006;281:12132-42.
55. Sun Z, Huang Z, Zhang DD. Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS ONE 2009;4:e6588.
56. Hur W, Sun Z, Jiang T, Mason DE, Peters EC, Zhang DD, et al. A smallmolecule inducer of the antioxidant response element. Chem Biol 2010;17:537-47.
57. Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci U S A 2001;98:3404-9.
58. Talalay P, De Long MJ, Prochaska HJ. Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci U S A 1988;85:8261-5.
59. Dinkova-Kostova AT, Fahey JW, Talalay P. Chemical structures of inducers of nicotinamide quinone oxidoreductase 1 (NQO1). Methods Enzymol 2004;382:423-48.
60. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A 2002;99:11908-13.
61. Dinkova-Kostova AT, Holtzclaw WD, Wakabayashi N. Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry 2005;44:6889-99.
62. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 2004;10:549-57.
63. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 2009;284:13291-5.
64. Baird L, Dinkova-Kostova, AT. The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 2011;85:241-72.
65. Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P, et al. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem 2013;21:4011-9.
66. Li Y, Paonessa JD, Zhang Y. Mechanism of chemical activation of Nrf2. PLoS ONE 2012;7:e35122.
67. Liu H, Yu S, Xu W, Xu J. Enhancement of 26S proteasome functionality connects oxidative stress and vascular endothelial inflammatory response in diabetes mellitus. Arterioscler Thromb Vasc Biol 2012;32:2131-40.
68. 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:E87-99.
69. 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-kappaB. Am J Physiol Heart Circ Physiol 2013;304:H567-78.
70. Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci U S A 1992;89:2399-403.
71. Negi G, Kumar A, Sharma Nrf2 SS. NF-kappaB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Curr Neurovasc Res 2011;8:294-304.
72. Angeloni C, Leoncini E, Malaguti M, Angelini S, Hrelia P, Hrelia S. Modulation of phase II enzymes by sulforaphane: implications for its cardioprotective potential. J Agric Food Chem 2009;57:5615-22.
73. Ping Z, Liu W, Kang Z, Cai J, Wang Q, Cheng N, et al. Sulforaphane protects brains against hypoxic-ischemic injury through induction of Nrf2-dependent phase 2 enzyme. Brain Res 2010;1343:178-85.
74. Hong F, Freeman ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 2005;18:1917-26.
75. Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 2013;1:45-9.
76. Song MY, Kim EK, Moon WS, Park JW, Kim HJ, So HS, et al. Sulforaphane protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway. Toxicol Appl Pharmacol 2009;235:57-67.
77. Bai Y, Cui W, Xin Y, Miao X, Barati MT, Zhang C, et al. Prevention by sulforaphane of diabetic cardiomyopathy is associated with upregulation of Nrf2 expression and transcription activation. J Mol Cell Cardiol 2013;57:82-95.
78. Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R, Phisalaphong C, Jirawatnotai S. Curcumin extract for prevention of type 2 diabetes. Diabetes Care 2012;35:2121-7.
79. Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G. Curcumin-from molecule to biological function. Angew Chem Int Ed Engl 2012;51:5308-32.
80. Gonzalez-Reyes S, Guzman-Beltran S, Medina-Campos ON, Pedraza-Chaverri. J. Curcumin pretreatment induces Nrf2 and an antioxidant response and prevents hemin-induced toxicity in primary cultures of cerebellar granule neurons of rats. Oxid Med Cell Longev 2013;2013:801418.
81. Yang C, Zhang X, Fan H, Liu Y. Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res 2009;1282:133-41.
82. Wu J, Li Q, Wang X, Yu S, Li L, Wu X, et al. Neuroprotection by curcumin in ischemic brain injury involves the Akt/Nrf2 pathway. PLOS ONE 2013;8:e59843.
83. Carmona-Ramirez I, Santamaria A, Tobon-Velasco JC, Orozco-Ibarra M, Gonzalez-Herrera IG, Pedraza-Chaverri J, et al. Curcumin restores Nrf2 levels and prevents quinolinic acid-induced neurotoxicity. J Nutr Biochem 2013;24:14-24.
84. Molina-Jijon E, Tapia E, Zazueta C, El Hafidi M, Zatarain-Barron ZL, Hernandez-Pando R, et al. Curcumin prevents Cr(VI)-induced renal oxidant damage by a mitochondrial pathway. Free Radic Biol Med 2011;51:1543-57.
85. Seo KI, Choi MS, Jung UJ, Kim HJ, Yeo J, Jeon SM, et al. Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice. Mol Nutr Food Res 2008;52:995-1004.
86. He HJ, Wang GY, Gao Y, Ling WH, Yu ZW, Jin TR. Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. World J Diabetes 2012;3:94-104.
87. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm 2007;4:807-18.
88. Bansal SS, Goel M, Aqil F, Vadhanam MV, Gupta RC. Advanced drug delivery systems of curcumin for cancer chemoprevention. Cancer Prev Res (Phila) 2011;4:1158-71.
89. Maradana MR, Thomas R, O'Sullivan. BJ. Targeted delivery of curcumin for treating type 2 diabetes. Mol Nutr Food Res 2013;57:1550-6.
90. 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 U S A 2005;102:4584-9.
91. 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;74:537-45.
92. Ahmad R, Raina D, Meyer C, Kharbanda S, Kufe D. Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem 2006;281:35764-9.
93. 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;365:327-36.
94. 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;369:2492-503.
95. Abiko Y, Miura T, Phuc BH, Shinkai Y, Kumagai Y. Participation of covalent modification of Keap1 in the activation of Nrf2 by tert-butylbenzoquinone, an electrophilic metabolite of butylated hydroxyanisole. Toxicol Appl Pharmacol 2011;255:32-9.
96. Lee JM, Moehlenkamp JD, Hanson JM, Johnson JA. Nrf2-dependent activation of the antioxidant responsive element by tert-butylhydroquinone is independent of oxidative stress in IMR-32 human neuroblastoma cells. Biochem Biophys Res Commun 2001;280:286-92.
97. Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J. Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci 2005;83:313-28.
98. Yan D, Dong J, Sulik KK, Chen SY. Induction of the Nrf2-driven antioxidant response by tert-butylhydroquinone prevents ethanol-induced apoptosis in cranial neural crest cells. Biochem Pharmacol 2010;80:144-9.
99. Li H, Zhang L, Wang F, Shi Y, Ren Y, Liu Q, et al. Attenuation of glomerular injury in diabetic mice with tert-butylhydroquinone through nuclear factor erythroid 2-related factor 2-dependent antioxidant gene activation. Am J Nephrol 2011;33:289-97.
100. Zhong Q, Mishra M, Kowluru RA. Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. Investig Ophthalmol Vis Sci 2013;54:3941-8.
101. Gharavi N, El-Kadi AO. tert-Butylhydroquinone is a novel aryl hydrocarbon receptor ligand. Drug Metab Dispos 2005;33:365-72.
102. Hirose M, Yada H, Hakoi K, Takahashi S, Ito N. Modification of carcinogenesis by alpha-tocopherol, t-butylhydroquinone, propyl gallate and butylated hydroxytoluene in a rat multi-organ carcinogenesis model. Carcinogenesis 1993;14:2359-64.
103. Chao LK, Hua KF, Hsu HY, Cheng SS, Lin IF, Chen CJ, et al. Cinnamaldehyde inhibits pro-inflammatory cytokines secretion from monocytes/macrophages through suppression of intracellular signaling. Food Chem Toxicol 2008;46:220-31.
104. Gowder SJ, Devaraj H. Effect of the food flavour cinnamaldehyde on the antioxidant status of rat kidney. Basic Clin Pharmacol Toxicol 2006;99:379-82.
105. Akira T, Tanaka S, Tabata M. Pharmacological studies on the antiulcerogenic activity of Chinese cinnamon. Planta Med 1986;44:0-3.
106. Ooi LS, Li Y, Kam SL, Wang H, Wong EY, Ooi VE. Antimicrobial activities of cinnamon oil and cinnamaldehyde from the Chinese medicinal herb Cinnamomum cassia Blume. Am J Chin Med 2006;34:511-22.
107. Cabello CM, Bair 3rd WB, Lamore SD, Ley S, Bause AS, Azimian S, et al. The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth. Free Radic Biol Med 2009;46:220-31.
108. Subash Babu P, Prabuseenivasan S, Ignacimuthu S. Cinnamaldehyde - a potential antidiabetic agent. Phytomedicine 2007;14:15-22.
109. Kim SH, Hyun SH, Choung SY. Anti-diabetic effect of cinnamon extract on blood glucose in db/db mice. J Ethnopharmacol 2006;104:119-23.
110. El-Bassossy HM, Fahmy A, Badawy D. Cinnamaldehyde protects from the hypertension associated with diabetes. Food Chem Toxicol 2011;49:3007-12.
111. Wondrak GT, Cabello CM, Villeneuve NF, Zhang S, Ley S, Li Y, et al. Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress. Free Radic Biol Med 2008;45:385-95.
112. Wondrak GT, Villeneuve NF, Lamore SD, Bause AS, Jiang T, Zhang DD. The cinnamon-derived dietary factor cinnamic aldehyde activates the Nrf2-dependent antioxidant response in human epithelial colon cells. Molecules 2010;15:3338-55.
113. Sun W, Wang W, Kim J, Keng P, Yang S, Zhang H, et al. Anti-cancer effect of resveratrol is associated with induction of apoptosis via a mitochondrial pathway alignment. Adv Exp Med Biol 2008;614:179-86.
114. Movahed A, Nabipour I, Lieben Louis X, Thandapilly SJ, Yu L, Kalantarhormozi M, et al. Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. Evid Based Complement Altern Med 2013;2013:851267.
115. Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Sener M, et al. Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem 2007;294:137-44.
116. Das S, Fraga CG, Das DK. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB. Free Radic Res 2006;40:1066-75.
117. Lee JH, Song MY, Song EK, Kim EK, Moon WS, Han MK, et al. Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes 2009;58:344-51.
118. 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;1812:719-31.
119. Palsamy P, Subramanian S. Ameliorative potential of resveratrol on proinflammatory cytokines, hyperglycemia mediated oxidative stress, and pancreatic beta-cell dysfunction in streptozotocin-nicotinamide-induced diabetic rats. J Cell Physiol 2010;224:423-32.
120. Cheng AS, Cheng YH, Chiou CH, Chang TL. Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells. J Agric Food Chem 2012;60:9180-7.
121. Maurya R, Singh R, Deepak M, Handa SS, Yadav PP, Mishra PK. Constituents of Pterocarpus marsupium: an ayurvedic crude drug. Phytochemistry 2004;65:915-20.
122. Paul B, Masih I, Deopujari J, Charpentier C. Occurrence of resveratrol and pterostilbene in age-old darakchasava, an ayurvedic medicine from India. J Ethnopharmacol 1999;68:71-6.
123. Sehadri R. Polyphenols of Pterocarpus and Dalbergia woods. Phytochemistry 1984;11:881-98.
124. Langcake P, Cornford CA, Pryce RJ. Identification of Pterostilbene as a phytoalexin from Vitisvinifera leaves. Phytochemistry 1979;1979:1025-7.
125. Rimando AM, Nagmani R, Feller DR, Yokoyama W. Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J Agric Food Chem 2005;53:3403-7.
126. Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, et al. Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer's disease. Neurobiol Aging 2012;33:2062-71.
127. Pan MH, Chang YH, Badmaev V, Nagabhushanam K, Ho CT. Pterostilbene induces apoptosis and cell cycle arrest in human gastric carcinoma cells. J Agric Food Chem 2007;55:7777-85.
128. Amarnath Satheesh M, Pari L. The antioxidant role of pterostilbene in streptozotocin-nicotinamide-induced type 2 diabetes mellitus in Wistar rats. J Pharm Pharmacol 2006;58:1483-90.
129. Zhang L, Zhou G, Song W, Tan X, Guo Y, Zhou B, et al. Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo. Apoptosis 2012;17:25-36.
130. Pari L, Satheesh MA. Effect of pterostilbene on hepatic key enzymes of glucose metabolism in streptozotocin- and nicotinamide-induced diabetic rats. Life Sci 2006;79:641-5.
131. Modak M, Dixit P, Londhe J, Ghaskadbi S, Devasagayam TP. Indian herbs and herbal drugs used for the treatment of diabetes. J Clin Biochem Nutr 2007;40:163-73.
132. Grover JK, Vats V, Yadav SS. Pterocarpus marsupium extract (Vijayasar) prevented the alteration in metabolic patterns induced in the normal rat by feeding an adequate diet containing fructose as sole carbohydrate. Diabetes Obes Metab 2005;7:414-20.
133. Halagappa K, Girish HN, Srinivasan BP. The study of aqueous extract of Pterocarpus marsupium Roxb. on cytokine TNF-alpha in type 2 diabetic rats. Indian J Pharmacol 2010;42:392-6.
134. Jahromi MA, Ray AB. Antihyperlipidemic effect of flavonoids from Pterocarpus marsupium. J Nat Prod 1993;56:989-94.
135. Chiou YS, Tsai ML, Nagabhushanam K, Wang YJ, Wu CH, Ho CT, et al. Pterostilbene is more potent than resveratrol in preventing azoxymethane (AOM)-induced colon tumorigenesis via activation of the NF-E2-related factor 2 (Nrf2)-mediated antioxidant signaling pathway. J Agric Food Chem 2011;59:2725-33.
136. Rosen T. Green tea catechins: biologic properties, proposed mechanisms of action, and clinical implications. J Drugs Dermatol 2012;11:e55-60.
137. Wolfram S, Raederstorff D, Preller M, Wang Y, Teixeira SR, Riegger C, et al. Epigallocatechin gallate supplementation alleviates diabetes in rodents. J Nutr 2006;136:2512-8.
138. Waltner-Law ME, Wang XL, Law BK, Hall RK, Nawano M, Granner DK. Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. J Biol Chem 2002;277:34933-40.
139. Han MK. Epigallocatechin gallate, a constituent of green tea, suppresses cytokine-induced pancreatic beta-cell damage. Exp Mol Med 2003;35:136-9.
140. Song EK, Hur H, Han MK. Epigallocatechin gallate prevents autoimmune diabetes induced by multiple low doses of streptozotocin in mice. Arch Pharm Res 2003;26:559-63.
141. Na HK, Kim EH, Jung JH, Lee HH, Hyun JW, Surh YJ. (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Arch Biochem Biophys 2008;476:171-7.
142. Sahin K, Tuzcu M, Gencoglu H, Dogukan A, Timurkan M, Sahin N, et al. Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sci 2010;87:240-5.
143. Lee GT, Ha H, Jung M, Li H, Hong SW, Cha BS, et al. Delayed treatment with lithospermate B attenuates experimental diabetic renal injury. J Am Soc Nephrol 2003;14:709-20.
144. Hur KY, Kim SH, Choi MA, Williams DR, Lee YH, Kang SW, et al. Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. Atherosclerosis 2010;211:69-76.
145. Fish JM, Welchons DR, Kim YS, Lee SH, Ho WK, Antzelevitch C. Dimethyl lithospermate B, an extract of Danshen, suppresses arrhythmogenesis associated with the Brugada syndrome. Circulation 2006;113:1393-400.
146. Goldberg AL. Development of proteasome inhibitors as research tools and cancer drugs. J Cell Biol 2012;199:583-8.
147. 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;88:512-20.
148. Cui W, Bai Y, Luo P, Miao L, Cai L. Preventive and therapeutic effects of MG132 by activating Nrf2-ARE signaling pathway on oxidative stress-induced cardiovascular and renal injury. Oxid Med Cell Longev 2013;2013:306073.