Role of the Nrf2 signaling system in health and disease

Clinical Genetics

Volumn 86, Issue 5, 2014, Pages 447-452

  Hybertson, B M ^a   Gao, B ^a  

^a UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

Author keywords

Antioxidant; Keap1; Nrf2; Oxidative stress

Indexed keywords

BETA TRANSDUCIN REPEAT CONTAINING PROTEIN; GLYCOGEN SYNTHASE KINASE 3; I KAPPA B BETA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; KELCH LIKE ECH ASSOCIATED PROTEIN 1; TRANSCRIPTION FACTOR NRF2; UBIQUITIN PROTEIN LIGASE E3;

ANTIOXIDANT RESPONSIVE ELEMENT; ENZYME ACTIVATION; GENE CONTROL; GENE MUTATION; HEART RHYTHM; HUMAN; NONHUMAN; OXIDATIVE STRESS; PROMOTER REGION; PROTEIN AGGREGATION; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SYNTHESIS; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; CIRCADIAN RHYTHM; DISEASES; GENETICS; HEALTH; METABOLISM;

ANIMALS; ANTIOXIDANT RESPONSE ELEMENTS; CIRCADIAN RHYTHM; DISEASE; HEALTH; HUMANS; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

EID: 84911970444     PISSN: 00099163     EISSN: 13990004     Source Type: Journal    
DOI: 10.1111/cge.12474     Document Type: Review

References (114)

1. Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A 1994: 91 (21): 9926-9930.
2. Sykiotis GP, Bohmann D. Stress-activated cap'n'collar transcription factors in aging and human disease. Sci Signal 2010: 3 (112): re3.
3. Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 2006: 46: 113-140.
4. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 2002: 62 (18): 5196-5203.
5. Itoh K, Chiba T, Takahashi S 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 (2): 313-322.
6. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 2014: 39 (4): 199-218.
7. Ma Q, He X. Molecular basis of electrophilic and oxidative defense: promises and perils of Nrf2. Pharmacol Rev 2012: 64 (4): 1055-1081.
8. Chartoumpekis DV, Kensler TW. New player on an old field; the keap1/Nrf2 pathway as a target for treatment of type 2 diabetes and metabolic syndrome. Curr Diabetes Rev 2013: 9 (2): 137-145.
9. Malhotra D, Portales-Casamar E, Singh A et al. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 2010: 38 (17): 5718-5734.
10. Bryan HK, Olayanju A, Goldring CE, Park BK. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol 2013: 85 (6): 705-717.
11. Niture SK, Khatri R, Jaiswal AK. Regulation of Nrf2 - an update. Free Radic Biol Med 2014: 66: 36-44.
12. Suzuki T, Shibata T, Takaya K et al. Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels. Mol Cell Biol 2013: 33 (12): 2402-2412.
13. Kwak MK, Itoh K, Yamamoto M, Kensler TW. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 2002: 22 (9): 2883-2892.
14. Itoh K, Wakabayashi N, Katoh Y et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 1999: 13 (1): 76-86.
15. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 2004: 10 (11): 549-557.
16. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 2011: 16 (2): 123-140.
17. Takaya K, Suzuki T, Motohashi H et al. Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic Biol Med 2012: 53 (4): 817-827.
18. Wakabayashi N, Skoko JJ, Chartoumpekis DV et al. Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling. Mol Cell Biol 2014: 34 (4): 653-663.
19. Itoh K, Mimura J, Yamamoto M. Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal 2010: 13 (11): 1665-1678.
20. Rada P, Rojo AI, Evrard-Todeschi N et al. Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis. Mol Cell Biol 2012: 32 (17): 3486-3499.
21. Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A. Glycogen synthase kinase-3β inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 2006: 281 (21): 14841-14851.
22. Chen W, Sun Z, Wang X-J et al. Direct interaction between Nrf2 and p21Cip1/WAF1 upregulates the Nrf2-mediated antioxidant response. Mol Cell 2009: 34 (6): 663-673.
23. Gorrini C, Gang BP, Bassi C et al. Estrogen controls the survival of BRCA1-deficient cells via a PI3K-NRF2-regulated pathway. Proc Natl Acad Sci U S A 2014: 111 (12): 4472-4477.
24. Gorrini C, Baniasadi PS, Harris IS et al. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J Exp Med 2013: 210 (8): 1529-1544.
25. Gan L, Johnson DA, Johnson JA. Keap1-Nrf2 activation in the presence and absence of DJ-1. Eur J Neurosci 2010: 31 (6): 967-977.
26. Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci U S A 2006: 103 (41): 15091-15096.
27. Jiang ZY, Lu MC, Xu LL et al. Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem 2014: 57 (6): 2736-2745.
28. Jiang ZY, Chu HX, Xi MY et al. Insight into the intermolecular recognition mechanism between Keap1 and IKKbeta combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation. PLoS One 2013: 8 (9): e75076.
29. Gao B, Doan A, Hybertson BM. The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders. Clin Pharmacol 2014: 6: 19-34.
30. Rushworth SA, Zaitseva L, Murray MY, Shah NM, Bowles KM, MacEwan DJ. The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance. Blood 2012: 120: 5188-5198.
31. Thimmulappa RK, Lee H, Rangasamy T et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 2006: 116 (4): 984-995.
32. Cuadrado A, Martín-Moldes Z, Ye J, Lastres-Becker I. Transcription factors NRF2 and NF-κB are coordinated effectors of the rho family, GTP-binding protein RAC1 during inflammation. J Biol Chem 2014: 289 (22): 15244-15258.
33. Hybertson BM, Gao B, Bose SK, McCord JM. Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Mol Aspects Med 2011: 32 (4-6): 234-246.
34. Kawamura T, Wakabayashi N, Shigemura N et al. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol 2013: 304 (10): L646-L656.
35. Cimino F, Speciale A, Anwar S et al. Anthocyanins protect human endothelial cells from mild hyperoxia damage through modulation of Nrf2 pathway. Genes Nutr 2013: 8 (4): 391-399.
36. Cho HY, van Houten B, Wang X et al. Targeted deletion of nrf2 impairs lung development and oxidant injury in neonatal mice. Antioxid Redox Signal 2012: 17 (8): 1066-1082.
37. Reddy NM, Potteti HR, Mariani TJ, Biswal S, Reddy SP. Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. Am J Respir Cell Mol Biol 2011: 45 (6): 1161-1168.
38. Kaidery NA, Banerjee R, Yang L et al. Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson's disease. Antioxid Redox Signal 2013: 18 (2): 139-157.
39. Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson's disease. J Parkinsons Dis 2013: 3 (4): 461-491.
40. Rojo AI, Innamorato NG, Martin-Moreno AM, De Ceballos ML, Yamamoto M, Cuadrado A. Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease. Glia 2012: 58 (5): 588-598.
41. Chaturvedi RK, Flint Beal M. Mitochondrial diseases of the brain. Free Radic Biol Med 2013: 63: 1-29.
42. Ellrichmann G, Petrasch-Parwez E, Lee D-H et al. Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease. PLoS One 2011: 6 (1): e16172.
43. Petri S, Korner S, Kiaei M. Nrf2/ARE signaling pathway: key mediator in oxidative stress and potential therapeutic target in ALS. Neurol Res Int 2012: 2012: 7.
44. Arnold P, Mojumder D, Detoledo J, Lucius R, Wilms H. Pathophysiological processes in multiple sclerosis: focus on nuclear factor erythroid-2-related factor 2 and emerging pathways. Clin Pharmacol 2014: 6: 35-42.
45. Bar-Or A, Gold R, Kappos L et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study. J Neurol 2013: 260 (9): 2297-2305.
46. Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev 2013: 27 (20): 2179-2191.
47. Seo H-A, Lee I-K. The role of Nrf2: adipocyte differentiation, obesity, and insulin resistance. Oxid Med Cell Longev 2013: 2013: 7.
48. Chapple SJ, Siow RC, Mann GE. Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. Int J Biochem Cell Biol 2012: 44 (8): 1315-1320.
49. 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: 10.
50. Saito H. Toxico-pharmacological perspective of the Nrf2-Keap1 defense system against oxidative stress in kidney diseases. Biochem Pharmacol 2013: 85 (7): 865-872.
51. Bauer AK, Hill T 3rd, Alexander CM. The involvement of NRF2 in lung cancer. Oxid Med Cell Longev 2013: 2013: 746432.
52. Muller T, Hengstermann A. Nrf2: friend and foe in preventing cigarette-smoking-dependent lung disease. Chem Res Toxicol 2012: 25 (9): 1805-1824.
53. Harvey CJ, Thimmulappa RK, Sethi S et al. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci Transl Med 2011: 3 (78): 78ra32.
54. Boutten A, Goven D, Boczkowski J, Bonay M. Oxidative stress targets in pulmonary emphysema: focus on the Nrf2 pathway. Expert Opin Ther Targets 2010: 14 (3): 329-346.
55. Sandford AJ, Malhotra D, Boezen HM et al. NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease. Physiol Genomics 2012: 44 (15): 754-763.
56. Wu T, Zhao F, Gao B et al. Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev 2014: 28 (7): 708-722.
57. Shin SM, Yang JH, Ki SH. Role of the Nrf2-ARE pathway in liver diseases. Oxid Med Cell Longev 2013: 2013: 763257.
58. Page A, Volchkova Valentina A, Reid Saint P et al. Marburgvirus hijacks Nrf2-dependent pathway by targeting Nrf2-negative regulator Keap1. Cell Rep 2014: 6 (6): 1026-1036.
59. Gill AJ, Kolson DL. Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy. Crit Rev Immunol 2013: 33 (4): 307-359.
60. Magesh S, Chen Y, Hu L. Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 2012: 32 (4): 687-726.
61. Su ZY, Shu L, Khor TO, Lee JH, Fuentes F, Kong AN. A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Top Curr Chem 2013: 329: 133-162.
62. Kwak MK, Kensler TW. Targeting NRF2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol 2010: 244 (1): 66-76.
63. Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention? Carcinogenesis 2010: 31 (1): 90-99.
64. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal 2010: 13 (11): 1713-1748.
65. Yamadori T, Ishii Y, Homma S et al. Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers. Oncogene 2012: 31 (45): 4768-4777.
66. Homma S, Ishii Y, Morishima Y et al. Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 2009: 15 (10): 3423-3432.
67. Wang XJ, Sun Z, Villeneuve NF et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 2008: 29 (6): 1235-1243.
68. Niture SK, Jaiswal AK. Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med 2013: 57: 119-131.
69. Ji L, Li H, Gao P et al. Nrf2 pathway regulates multidrug-resistance-associated protein 1 in small cell lung cancer. PLoS One 2013: 8 (5): e63404.
70. Rajasekaran NS, Varadharaj S, Khanderao GD et al. Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice. Antioxid Redox Signal 2011: 14 (6): 957-971.
71. Kannan S, Muthusamy VR, Whitehead KJ et al. Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy. Cardiovasc Res 2013: 100 (1): 63-73.
72. Wang W, Li S, Wang H et al. Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins. J Mol Cell Cardiol 2014: 72: 305-315.
73. Bogaard HJ, Natarajan R, Henderson SC et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 2009: 120 (20): 1951-1960.
74. Pekovic-Vaughan V, Gibbs J, Yoshitane H et al. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis. Genes Dev 2014: 28 (6): 548-560.
75. O'Neill JS, Feeney KA. Circadian redox and metabolic oscillations in Mammalian systems. Antioxid Redox Signal 2014: 20 (18): 2966-2981.
76. Gillette MU, Wang TA. Brain circadian oscillators and redox regulation in mammals. Antioxid Redox Signal 2014: 20 (18): 2955-2965.
77. Tamaru T, Hattori M, Ninomiya Y et al. ROS stress resets circadian clocks to coordinate pro-survival signals. PLoS One 2013: 8 (12): e82006.
78. Stangherlin A, Reddy AB. Regulation of circadian clocks by redox homeostasis. J Biol Chem 2013: 288 (37): 26505-26511.
79. Edgar RS, Green EW, Zhao Y et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature 2012: 485 (7399): 459-464.
80. Yang G, Wright CJ, Hinson MD et al. Oxidative stress and inflammation modulate Rev-erbalpha signaling in the neonatal lung and affect circadian rhythmicity. Antioxid Redox Signal 2014: 21 (1): 17-32.
81. Luchetti F, Canonico B, Betti M et al. Melatonin signaling and cell protection function. FASEB J 2010: 24 (10): 3603-3624.
82. Ding K, Wang H, Xu J et al. Melatonin stimulates antioxidant enzymes and reduces oxidative stress in experimental traumatic brain injury: the Nrf2-ARE signaling pathway as a potential mechanism. Free Radic Biol Med 2014: 73C: 1-11.
83. Xu YQ, Zhang D, Jin T et al. Diurnal variation of hepatic antioxidant gene expression in mice. PLoS One 2012: 7 (8): e44237.
84. Cajochen C, Kräuchi K, Wirz-Justice A. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol 2003: 15 (4): 432-437.
85. Paroni R, Terraneo L, Bonomini F et al. Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling. J Pineal Res 2014: 57 (1): 43-52.
86. Aparicio-Soto M, Alarcon-de-la-Lastra C, Cardeno A, Sanchez-Fidalgo S, Sanchez-Hidalgo M. Melatonin modulates microsomal PGE synthase 1 and NF-E2-related factor-2-regulated antioxidant enzyme expression in LPS-induced murine peritoneal macrophages. Br J Pharmacol 2014: 171 (1): 134-144.
87. Kilic U, Kilic E, Tuzcu Z et al. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway. Nutr Metab (Lond) 2013: 10 (1): 7.
88. Haghjooy Javanmard S, Ziaei A, Ziaei S, Ziaei E, Mirmohammad-Sadeghi M. The effect of preoperative melatonin on nuclear erythroid 2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery. Oxid Med Cell Longev 2013: 2013: 676829.
89. Wang Z, Ma C, Meng CJ et al. Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model. J Pineal Res 2012: 53 (2): 129-137.
90. Hur W, Gray NS. Small molecule modulators of antioxidant response pathway. Curr Opin Chem Biol 2011: 15 (1): 162-173.
91. 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 (10): e44686.
92. Zenkov NK, Menshchikova EB, Tkachev VO. Keap1/Nrf2/ARE redox-sensitive signaling system as a pharmacological target. Biochemistry (Mosc) 2013: 78 (1): 19-36.
93. Kobayashi M. Harnessing the antioxidant power with ARE-inducing compounds. Chem Biol 2010: 17 (5): 419-420.
94. Zhuang C, Miao Z, Sheng C, Zhang W. Updated research and applications of small molecule inhibitors of Keap1-Nrf2 protein-protein interaction: a review. Curr Med Chem 2014: 21 (16): 1861-1870.
95. Stangel M, Linker RA. Dimethyl fumarate (BG-12) for the treatment of multiple sclerosis. Expert Rev Clin Pharmacol 2013: 6 (4): 355-362.
96. Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012: 367 (12): 1098-1107.
97. Wang R, Mason DE, Choe KP, Lewin AS, Peters EC, Luesch H. In vitro and in vivo characterization of a tunable dual-reactivity probe of the Nrf2-ARE pathway. ACS Chem Biol 2013: 8 (8): 1764-1774.
98. Liby KT, Sporn MB. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev 2012: 64 (4): 972-1003.
99. Zhang DD. Bardoxolone brings Nrf2-based therapies to light. Antioxid Redox Signal 2013: 19 (5): 517-518.
100. Ren D, Villeneuve NF, Jiang T et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A 2011: 108 (4): 1433-1438.
101. Arlt A, Sebens S, Krebs S et al. Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 2013: 32 (40): 4825-4835.
102. Boettler U, Sommerfeld K, Volz N et al. Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression. J Nutr Biochem 2011: 22 (5): 426-440.
103. Wang XJ, Hayes JD, Henderson CJ, Wolf CR. Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc Natl Acad Sci U S A 2007: 104 (49): 19589-19594.
104. Wang H, Liu K, Geng M et al. RXRalpha inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res 2013: 73 (10): 3097-3108.
105. Chian S, Thapa R, Chi Z, Wang XJ, Tang X. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochem Biophys Res Commun 2014: 447 (4): 602-608.
106. Chian S, Li YY, Wang XJ, Tang XW. Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway. Asian Pac J Cancer Prev 2014: 15 (6): 2911-2916.
107. Zhang YC, Gan FF, Shelar SB, Ng KY, Chew EH. Antioxidant and Nrf2 inducing activities of luteolin, a flavonoid constituent in Ixeris sonchifolia Hance, provide neuroprotective effects against ischemia-induced cellular injury. Food Chem Toxicol 2013: 59: 272-280.
108. Tang X, Wang H, Fan L et al. Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med 2011: 50 (11): 1599-1609.
109. Xiang M, Namani A, Wu S, Wang X. Nrf2: bane or blessing in cancer? J Cancer Res Clin Oncol 2014: 140 (8): 1251-1259.
110. Komatsu M, Kurokawa H, Waguri S et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 2010: 12 (3): 213-223.
111. Taguchi K, Fujikawa N, Komatsu M et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc Natl Acad Sci U S A 2012: 109 (34): 13561-13566.
112. Kosmider B, Messier EM, Janssen WJ et al. Nrf2 protects human alveolar epithelial cells against injury induced by influenza A virus. Respir Res 2012: 13: 43.
113. Cho HY, Imani F, Miller-DeGraff L et al. Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease. Am J Respir Crit Care Med 2009: 179 (2): 138-150.
114. Barajas B, Che N, Yin F et al. NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection. Arterioscler Thromb Vasc Biol 2011: 31 (1): 58-66.