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Molecular Mechanisms of Nrf2 in Inflammation: Interactions Between Nrf2 and Inflammatory Mediators

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Nrf2 and its Modulation in Inflammation

Part of the book series: Progress in Inflammation Research ((PIR,volume 85))

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Abstract

Inflammation is a common feature of chronic age-related diseases. Therefore, controlling inflammation by manipulation in the molecular mechanisms that cause the inflammatory process becomes critical to improve human health by preventing various diseases such as cancer, metabolic syndrome, neurodegenerative diseases, and many others. The transcription factor Nrf2 is essential for protection against oxidative/xenobiotic stress. However, Nrf2 also decreases inflammation through a cross talk with the NFκB signaling pathway. Although the mechanism by which Nrf2 mediates anti-inflammatory response is not fully elucidated, new insights have identified that in addition to regulating the expression of cytoprotective genes that have an established and well-known “antioxidant response element, ARE,”, Nrf2 can also regulate over six hundred additional genes that do not have an ARE sequence, including genes coding for proinflammatory cytokines. In this chapter, we summarize and discuss the direct and indirect role of Nrf2 in the regulation of inflammatory response and the development of therapeutic targets by identifying new molecular mechanisms.

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References

  1. Brooks-Worrell B, Palmer JP. Immunology in the clinic review series; focus on metabolic diseases: development of islet autoimmune disease in type 2 diabetes patients: potential sequelae of chronic inflammation. Clin Exp Immunol. 2012;167:40–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stolp HB, Dziegielewska KM. Review: role of developmental inflammation and blood–brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases. Neuropathol Appl Neurobiol. 2009;35:132–46.

    Article  CAS  PubMed  Google Scholar 

  3. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428–35.

    Article  CAS  PubMed  Google Scholar 

  4. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology: Series A. 2014;69:S4–9.

    Article  Google Scholar 

  5. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011;16:123–40.

    Article  CAS  PubMed  Google Scholar 

  8. Kobayashi E, Suzuki T, Yamamoto M. Roles Nrf2 plays in myeloid cells and related disorders. Oxidative Med Cell Longev. 2013;2013:529219.

    Article  CAS  Google Scholar 

  9. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as anticancer strategy. Nat Rev Drug Discov. 2013:931–47.

    Google Scholar 

  10. Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M, Takahashi S. Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int. 2001;60:1343–53.

    Article  CAS  PubMed  Google Scholar 

  11. Ma Q, Battelli L, Hubbs AF. Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am J Pathol. 2006;168:1960–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Johnson DA, Amirahmadi S, Ward C, Fabry Z, Johnson JA. The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol Sci. 2010;114:237–46.

    Article  CAS  PubMed  Google Scholar 

  13. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Investig. 2004;114:1248–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005;202:47–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garbin U, Fratta Pasini A, Stranieri C, Cominacini M, Pasini A, Manfro S, Lugoboni F, Mozzini C, Guidi G, Faccini G. Cigarette smoking blocks the protective expression of Nrf2/ARE pathway in peripheral mononuclear cells of young heavy smokers favouring inflammation. PLoS One. 2009;4:e8225.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Cho HY, Reddy SP, Yamamoto M, Kleeberger SR. The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J. 2004;18:1258–60.

    Article  CAS  PubMed  Google Scholar 

  17. He X, Ma Q. Disruption of Nrf2 synergizes with high glucose to cause heightened myocardial oxidative stress and severe cardiomyopathy in diabetic mice. J Diabetes Metab. 2012;002(Suppl 7)

    Google Scholar 

  18. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Talalay P, Fahey JW, Healy ZR, Wehage SL, Benedict AL, et al. Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation. Proc Natl Acad Sci U S A. 2007;104:17500–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ma Q, Kinneer K. Chemoprotection by phenolic antioxidants. Inhibition of tumor necrosis factor α induction in macrophages. J Biol Chem. 2002;277:2477–84.

    Article  CAS  PubMed  Google Scholar 

  21. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Ann Rev Immunol. 1996;14:649–83.

    Article  CAS  Google Scholar 

  22. Smale ST. Hierarchies of NF-kappa B target-gene regulation. Nat Immunol. 2011;12:689–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sakurai H, Suzuki S, Kawasaki N, Nakano H, Okazaki T, Chino A, Doi T, Saiki I. Tumor necrosis factor-alpha-induced IKK phosphorylation of NF-kappaB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway. J Biol Chem. 2003;278(38):36916–23.

    Article  CAS  PubMed  Google Scholar 

  24. Perkins ND. The Rel/NF-kappa B family: friend and foe. Trends Biochem Sci. 2000;25:434–40.

    Article  CAS  PubMed  Google Scholar 

  25. Manea A, Manea SA, Gafencu AV, Raicu M. Regulation of NADPH oxidase subunit p22(phox) by NF-kB in human aortic smooth muscle cells. Arch Physiol Biochem. 2007;113:163–72.

    Article  CAS  PubMed  Google Scholar 

  26. Mauro C, Leow SC, Anso E, Rocha S, Thotakura AK, Tornatore L, Moretti M, De Smaele E, Beg AA, Tergaonkar V, et al. NF-kappaB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol. 2011;13:1272–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wardyn JD, Ponsford AH, Sanderson CM. Dissecting molecular cross-talk between Nrf2 and NF-kB response pathways. Biochem Soc Trans. 2015;43:621–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pan H, Wang H, Wang X, Zhu L, Mao L. The absence of Nrf2 enhances NF-kappaB-dependent inflammation following scratch injury in mouse primary cultured astrocytes. Mediat Inflamm. 2012;217580

    Google Scholar 

  29. Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP, et al. Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron. 2014;81:1009–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, Liby KT, Risingsong R, Sporn M, Beal MF, Kiaei M. Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med. 2011;51:88–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, Biswal S. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest. 2006;116:984–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ganesh YV, Negi G, Sharma SS, Kumar A. Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-kappaB pathways in diabetic neuropathy. Redox Biol. 2013;1:394–7.

    Article  CAS  Google Scholar 

  33. Lin W, Wu RT, Wu T, Khor TO, Wang H, Kong AN. Sulforaphane suppressed LPS-induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway. Biochem Pharmacol. 2008;76:967–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, Shen J, Chen CT, Huo L, Hsu MC, Li CW, Ding Q, Liao TL, Lai CC, Lin AC, Chang YH, Tsai SF, Li LY, Hung MC. KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta, Mol. Cell. 2009;36:131–40.

    CAS  Google Scholar 

  35. Brigelius-Flohe R, Flohe L. Basic principles and emerging concepts in the redox control of transcription factors. Antioxid Redox Signal. 2011;15:2335–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Banning A, Brigelius-Flohe R. NF -kappaB, Nrf2, and HO-1 interplay in redox-regulated VCAM-1 expression. Antioxid Redox Signal. 2005;7:889–99.

    Article  CAS  PubMed  Google Scholar 

  37. Arbibe L, Mira JP, Teusch N, Kline L, Guha M, Mackman N, Godowski PJ, Ulevitch RJ, Knaus UG. Toll-like receptor 2-mediated NF-κB activation requires a Rac1-dependent pathway. Nat Immunol. 2000;1:533–40.

    Article  CAS  PubMed  Google Scholar 

  38. Bokoch GM. Regulation of innate immunity by rho GTPases. Trends Cell Biol. 2005;15:163–71.

    Article  CAS  PubMed  Google Scholar 

  39. Ohsawa K, Imai Y, Kanazawa H, Sasaki Y, Kohsaka S. Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J Cell Sci. 2000;113:3073–84.

    Article  CAS  PubMed  Google Scholar 

  40. 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;281:14841–51.

    Article  CAS  PubMed  Google Scholar 

  41. Cuadrado A, Martín-Moldes Z, Ye J, Lastres-Becker I. Transcription factors NRF2 and NF-kB are coordinated effectors of the rho family, GTP-binding protein RAC1 during inflammation. J Biol Chem. 2014;289:15244–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10:210–5.

    Article  CAS  PubMed  Google Scholar 

  43. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–91.

    Article  CAS  PubMed  Google Scholar 

  44. Wang H, Liu K, Geng M, Gao P, Wu X, Hai Y, Li Y, Li Y, Luo L, Hayes JD, Wang XJ, Tang X. RXRalpha inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res. 2013;73:3097–108.

    Article  CAS  PubMed  Google Scholar 

  45. Shi F, Kouadir M, Yang Y. NALP3 inflammasome activation in protein misfolding diseases. Life Sci. 2015;135:9–14.

    Article  CAS  PubMed  Google Scholar 

  46. Kolb R, Liu GH, Janowski AM, Sutterwala FS, Zhang W. Inflammasomes in cancer: a double-edged sword. Protein Cell. 2014;5:12–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016;13:148–59.

    Article  CAS  PubMed  Google Scholar 

  48. Liu X, Zhang X, Ding Y, Zhou W, Tao L, Lu P, Wang Y, Hu R. Nuclear factor E2-related factor-2 negatively regulates NLRP3 inflammasome activity by inhibiting reactive oxygen species-induced NLRP3 priming. Antioxid Redox Signal. 2017;26:28–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tsai PY, Ka SM, Chang JM, Chen HC, Shui HA, Li CY, Hua KF, Chang WL, Huang JJ, Yang SS, Chen A. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic Biol Med. 2011;51:744–54.

    Article  CAS  PubMed  Google Scholar 

  50. Ka SM, Lin JC, Lin TJ, Liu FC, Chao LK, Ho CL, Yeh LT, Sytwu HK, Hua KF, Chen A. Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation. Arthritis Res Ther. 2015;17:331.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. He L, Peng X, Zhu J, Chen X, Liu H, Tang C, Dong Z, Liu F, Peng Y. Mangiferin attenuate sepsis-induced acute kidney injury via antioxidant and anti-inflammatory effects. Am J Nephrol. 2014;40:441–50.

    Article  CAS  PubMed  Google Scholar 

  52. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Freigang S, Ampenberger F, Spohn G, Heer S, Shamshiev AT, et al. Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur J Immunol. 2011;41:2040–51.

    Article  CAS  PubMed  Google Scholar 

  54. Zhao C, Gillette DD, Li X, Zhang Z, Wen H. Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation. J Biol Chem. 2014;289(24):17020–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yachie A, Toma T, Mizuno K, Okamoto H, Shimura S, Ohta K, Kasahara Y, Koizumi S. Heme oxygenase-1 production by peripheral blood monocytes during acute inflammatory illnesses of children. Exp Biol Med. 2003;228:550–6.

    Article  CAS  Google Scholar 

  56. Pae HO, Ae Ha Y, Chai KY, Chung HT. Heme oxygenase-1 attenuates contact hypersensitivity induced by 2,4-dinitrofluorobenzene in mice. Immunopharmacol Immunotoxicol. 2008;30:207–16.

    Article  CAS  PubMed  Google Scholar 

  57. Patil K, Bellner L, Cullaro G, Gotlinger KH, Dunn MW, Schwartzman ML. Heme oxygenase-1 induction attenuates corneal inflammation and accelerates wound healing after epithelial injury. Invest Ophthalmol Vis Sci. 2008;49:3379–86.

    Article  PubMed  Google Scholar 

  58. Kim J, Surh YJ. The role of Nrf2 in cellular innate immune response to inflammatory injury. Toxicological Research. 2009;25(4):159–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wagener FA, Volk HD, Willis D, Abraham NG, Soares MP, Adema GJ, Figdor CG. Different faces of the heme-heme oxygenase system in inflammation. Pharmacol Rev. 2003;55:551–71.

    Article  CAS  PubMed  Google Scholar 

  60. Ahmed SM, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta. 1863;2017:585–97.

    Google Scholar 

  61. Chi X, Yao W, Xia H, Jin Y, Li X, Cai J, Hei Z. Elevation of HO-1 expression mitigates intestinal ischemia-reperfusion injury and restores tight junction function in a rat liver transplantation model. Oxidative Med Cell Longev. 2015;986075

    Google Scholar 

  62. Choi H. The cytoprotective effect of isorhamnetin against oxidative stress is mediated by the upregulation of the Nrf2-dependent HO-1 expression in C2C12 myoblasts through scavenging reactive oxygen species and ERK inactivation. Gen Physiol Biophys. 2016;35:145–54.

    Article  CAS  PubMed  Google Scholar 

  63. Kuhn AM, Tzieply N, Schmidt MV, von Knethen A, Namgaladze D, Yamamoto M, Brune B. Antioxidant signaling via Nrf2 counteracts lipopolysaccharide-mediated inflammatory responses in foam cell macrophages. Free Radic Biol Med. 2011;50:1382–91.

    Article  CAS  PubMed  Google Scholar 

  64. Lee DS, Jeong GS. Arylbenzofuran isolated from Dalbergia odorifera suppresses lipopolysaccharide-induced mouse BV2 microglial cell activation, which protects mouse hippocampal HT22 cells death from neuroinflammation-mediated toxicity. Eur J Pharmacol. 2014;728:1–8.

    Article  CAS  PubMed  Google Scholar 

  65. Brandsma CA, Hylkema MN, van der Strate BW, Slebos DJ, Luinge MA, Geerlings M, Timens W, Postma DS, Kerstjens HA. Heme oxygenase-1 prevents smoke-induced B-cell infiltrates: a role for regulatory T cells? Respir Res. 2008;9:17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Xia ZW, Xu LQ, Zhong WW, Wei JJ, Li NL, Shao J, Li YZ, Yu SC, Zhang ZL. Heme oxygenase-1 attenuates ovalbumin-induced airway inflammation by up-regulation of foxp3 T-regulatory cells, interleukin-10, and membrane-bound transforming growth factor-1. Am J Pathol. 2007;171:1904–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu Y, Zhu B, Wang X, Luo L, Li P, Paty DW, Cynader MS. Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis. J Neuroimmunol. 2003;139:27–35.

    Article  CAS  PubMed  Google Scholar 

  68. Sawada K, Ohnishi K, Kosaka T, Chikano S, Egashira A, Okui M, Shintani S, Wada M, Nakasho K. Shimoyama T exacerbated autoimmune hepatitis successfully treated with leukocytapheresis and bilirubin adsorption therapy. J Gastroenterol. 1997;32:689–95.

    Article  CAS  PubMed  Google Scholar 

  69. Kadl A, Pontiller J, Exner M, Leitinger N. Single bolus injection of bilirubin improves the clinical outcome in a mouse model of endotoxemia. Shock. 2007;28:582–8.

    Article  CAS  PubMed  Google Scholar 

  70. Lanone S, Bloc S, Foresti R, Almolki A, Taillé C, Callebert J, Conti M, Goven D, Aubier M, Dureuil B, El-Benna J, Motterlini R, Boczkowski J. Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats. FASEB J. 2005;19:1890–2.

    Article  CAS  PubMed  Google Scholar 

  71. Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, Yu J, Tsui TY, Bach FH. Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. J Immunol. 2004;172:3553–63.

    Article  CAS  PubMed  Google Scholar 

  72. Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, Tanaka N, Moriguchi T, Motohashi H, Nakayama K, Yamamoto M. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016;7:11624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, Sporn MB, Yamamoto M, Kensler TW, Biswal S. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun. 2006;351:883–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Levonen AL, Inkala M, Heikura T, Jauhiainen S, Jyrkkänen HK, Kansanen E, Määttä K, Romppanen E, Turunen P, Rutanen J, Yla-Herttuala S. Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo. Arterioscler Thromb Vasc Biol. 2007;27:741–7.

    Article  CAS  PubMed  Google Scholar 

  75. Pae HO, Oh GS, Lee BS, Rim JS, Kim YM, Chung HT. 3-Hydroxyanthranilic acid, one of L-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells. Atherosclerosis. 2006;187:274–84.

    Article  CAS  PubMed  Google Scholar 

  76. Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW. ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow. Blood. 2005;106:584–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen XL, Dodd G, Thomas S, Zhang X, Wasserman MA, Rovin BH, Kunsch C. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol. 2006:H1862–70.

    Google Scholar 

  78. Chen XL, Varner SE, Rao AS, Grey JY, Thomas S, Cook CK, Wasserman MA, Medford RM, Jaiswal AK, Kunsch C. Kunsch Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism. J Biol Chem. 2003;278(2):703–11.

    Article  CAS  PubMed  Google Scholar 

  79. Yang PM, Wu ZZ, Zhang YQ, Wung BS. Lycopene inhibits ICAM-1 expression and NF-kappaB activation by Nrf2-regulated cell redox state in human retinal pigment epithelial cells. Life Sci. 2016;155:94–101.

    Article  CAS  PubMed  Google Scholar 

  80. Lee SH, Sohn DH, Jin XY, Kim SW, Choi SC, Seo GS. Seo2’,4′,6′-tris(methoxymethoxy) chalcone protects against trinitrobenzene sulfonic acid-induced colitis and blocks tumor necrosis factor-alpha-induced intestinal epithelial inflammation via heme oxygenase 1-dependent and independent pathways. Biochem Pharmacol. 2007;74:870–80.

    Article  CAS  PubMed  Google Scholar 

  81. Kim BC, Jeon WK, Hong HY, Jeon KB, Hahn JH, Kim YM, Numazawa S, Yosida T, Park EH, Lim CJ. The anti-inflammatory activity of Phellinus linteus (Berk. & M.a. Curt.) is mediated through the PKCdelta/Nrf2/ARE signaling to up-regulation of heme oxygenase-1. J Ethnopharmacol. 2007;113:240–7.

    Article  PubMed  Google Scholar 

  82. Gan FF, , Ling H , Ang X , Reddy SA , Lee SS , Yang H , Tan SH , Hayes JD , Chui WK , Chew EH A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-kappaB and Nrf2-Keap1 signaling pathways, Toxicol Appl Pharmacol2013; 272: 852–862.

    Article  CAS  PubMed  Google Scholar 

  83. Harvey CJ, Thimmulappa RK, Sethi S, Kong X, Yarmus L, Brown RH, Feller-Kopman D, Wise R, Biswal S. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci Transl Med. 2011;3:78ra32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Ishii T, Itoh K, Ruiz E, Leake DS, Unoki H, Yamamoto M, Mann GE. Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal. Circ Res. 2004;94:609–16.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Steinbaugh MJ, Sun LY, Bartke A, Miller RA. Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan. Am J Physiol Endocrinol Metab. 2012;4:E488–95.

    Article  CAS  Google Scholar 

  87. Onken B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010;5:e8758.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2008;294:L478–88.

    Article  CAS  PubMed  Google Scholar 

  89. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A. 2004;101:3381–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Duan W, Zhang R, Guo Y, Jiang Y, Huang Y, Jiang H, Li C. Nrf2 activity is lost in the spinal cord and its astrocytes of aged mice. In Vitro Cell Dev Biol Anim. 2009;45:388–97.

    Article  CAS  PubMed  Google Scholar 

  91. Kapeta S, Chondrogianni N, Gonos ES. Nuclear erythroid factor 2-mediated proteasome activation delays senescence in human fibroblasts. J Biol Chem. 2010;285:8171–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cristofalo VJ. Ten years later: what have we learned about human aging from studies of cell cultures? The Cerontologist. 1996;36:737–41.

    Article  CAS  Google Scholar 

  93. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685–705.

    Article  CAS  PubMed  Google Scholar 

  94. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, Van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Coppé JP, Patil CK, Rodier F, Krtolica A, Beauséjour CM, Parrinello S, Hodgson JG, Chin K, Desprez PY, Campisi J. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS One. 2010;5(2):e9188.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Ishii Y, Itoh K, Morishima Y, Kimura T, Kiwamoto T, Iizuka T, Hegab AE, Hosoya T, Nomura A, Sakamoto T, Yamamoto M, Sekizawa K. Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema. J Immunol. 2005;175:6968–75.

    Article  CAS  PubMed  Google Scholar 

  97. Khor TO, Huang MT, Prawan A, Liu Y, Hao X, Yu S, Cheung WK, Chan JY, Reddy BS, Yang CS, Kong AN. Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res (Phila). 2008;1:187–91.

    Article  CAS  Google Scholar 

  98. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med. 2004;10:549–57.

    Article  CAS  PubMed  Google Scholar 

  99. Wang R, Yu Z, Sunchu B, Shoaf J, Dang I, Zhao S, Caples K, Bradley L, Beaver LM, Ho E, Löhr CV, Perez VI. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell. 2017;16:564–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest. 2004;114:1248–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Itoh K, Mochizuki M, Ishii Y, Ishii T, Shibata T, Kawamoto Y, Kelly V, Sekizawa K, Uchida K, Yamamoto M. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2). Mol Cell Biol. 2004;24:36–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Freigang F, Ampenberger G, Spohn S, Heer AT, Shamshiev J, Kisielow M, Hersberger M, Yamamoto MF, Bachmann M. KopfNrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis. Eur J Immunol. 2016;41:2040–51.

    Article  CAS  Google Scholar 

  103. Xue WL, Bai X. Zhang L rhTNFR:fc increases Nrf2 expression via miR-27a mediation to protect myocardium against sepsis injury. Biochem Biophys Res Commun. 2016;464:855–61.

    Article  CAS  Google Scholar 

  104. Keleku-Lukwete N, Suzuki M, Otsuki A, Tsuchida K, Katayama S, Hayashi M, Naganuma E, Moriguchi T, Tanabe O, Engel JD, Imaizumi M, Yamamoto M. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation. Proc Natl Acad Sci U S A. 2016;112:12169–74.

    Article  CAS  Google Scholar 

  105. Maicas N, Ferrándiz ML, Brines R, Ibáñez L, Cuadrado A, Koenders MI, van den Berg WB, Alcaraz MJ. Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid Redox Signal. 2016;15:889–901.

    Article  CAS  Google Scholar 

  106. Nagai N, Thimmulappa RK, Cano M, Fujihara M, Izumi-Nagai K, Kong X, Sporn MB, Kensler TW, Biswal S, Handa JT. Nrf2 is a critical modulator of the innate immune response in a model of uveitis. Free Radic Biol Med. 2009;47:300–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Braun S, Hanselmann C, Gassmann MG, auf dem Keller U, Born-Berclaz C, Chan K, Kan YW, Werner S. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol Cell Biol. 2002;22:5492–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wang CY, Wang ZY, Xie JW, Cai JH, Wang T, Xu Y, Wang X, An L. CD36 upregulation mediated by intranasal LV-NRF2 treatment mitigates hypoxia-induced progression of Alzheimer's-like pathogenesis. Antioxid Redox Signal. 2016;21:2208–30.

    Article  CAS  Google Scholar 

  109. Pareek TK, Belkadi A, Kesavapany S, Zaremba A, Loh SL, Bai L, Cohen ML, Meyer C, Liby KT, Miller RH, Sporn MB, Letterio JJ. Triterpenoid modulation of IL-17 and Nrf-2expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Sci Rep. 2011;1:201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Escartin C, Brouillet E. The Nrf2 pathway as a potential therapeutic target for Huntington disease a commentary on “Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington disease”. Free Radic Biol Med. 2016;49:144–6.

    Article  CAS  Google Scholar 

  111. Brandenburg LO, Kipp M, Lucius R, Pufe T, Wruck CJ. Sulforaphane suppresses LPS-induced inflammation in primary rat microglia. Inflamm Res. 2010;59:443–50.

    Article  CAS  PubMed  Google Scholar 

  112. Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee J-M, Li J, Johnson JA. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009;11:497–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Innamorato NG, Rojo AI, Garcia-Yague AJ, Yamamoto M, de Ceballos ML, Cuadrado A. The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol. 2008;181:680–9.

    Article  CAS  PubMed  Google Scholar 

  114. Buendia I, Michalska P, Navarro E, Gameiro I, Egea J, León R. Nrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol Ther. 2016;157:84–104.

    Article  CAS  PubMed  Google Scholar 

  115. Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Jordan-Sciutto KL. Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol. 2007;66:75–85.

    Article  CAS  PubMed  Google Scholar 

  116. Kanninen K, Malm TM, Jyrkkänen HK, Goldsteins G, Keksa-Goldsteine V, Tanila H, Yamamoto M, Ylä-Herttuala S, Levonen AL, Koistinaho J. Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol Cell Neurosci. 2008;39:302–13.

    Article  CAS  PubMed  Google Scholar 

  117. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM. Author information:phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging. 2001;22:993–1005.

    Article  CAS  PubMed  Google Scholar 

  118. Rojo AI, Sagarra MR, Cuadrado A. GSK-3beta down-regulates the transcription factor Nrf2 after oxidant damage: relevance to exposure of neuronal cells to oxidative stress. J Neurochem. 2008;105:192–202.

    Article  CAS  PubMed  Google Scholar 

  119. 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.

    Article  CAS  PubMed  Google Scholar 

  120. Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat Med. 2004;10(Suppl):S18–25.

    Article  PubMed  CAS  Google Scholar 

  121. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.

    Article  CAS  PubMed  Google Scholar 

  122. Gan L, Johnson JA. Oxidative damage and the Nrf2–ARE pathway in neurodegenerative diseases. Biochim Biophys Acta. 1842;2014:1208–18.

    Google Scholar 

  123. Colle D, Hartwig JM, Soares FA, Farina M. Probucol modulates oxidative stress and excitotoxicity in Huntington's disease models in vitro. Brain Res Bull. 2012;87:397–405.

    Article  CAS  PubMed  Google Scholar 

  124. Lou H, Jing X, Wei X, Shi H, Ren D, Zhang X. Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway. Neuropharmacology. 2014;79:380–8.

    Article  CAS  PubMed  Google Scholar 

  125. Jin YN, Yu YV, Gundemir S, Jo C, Cui M, Tieu K, Johnson GV. Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin. PLoS One. 2013;8:e57932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX. Mutations in cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362:59–62.

    Article  CAS  PubMed  Google Scholar 

  127. Contestabile A. Amyotrophic lateral sclerosis: from research to therapeutic attempts and therapeutic perspectives. Curr Med Chem. 2011;18:5655–65.

    Article  CAS  PubMed  Google Scholar 

  128. Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med. 2010;48:629–41.

    Article  CAS  PubMed  Google Scholar 

  129. Pehar VMR, Robinson KM, Cassina P, Díaz-Amarilla PJ, Hagen TM, Radi R, Barbeito L, Beckman JS. Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J Neurosci. 2007;27:7777–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Sarlette A, Krampfl K, Grothe C, Neuhoff N, Dengler R, Petri S. Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2008;67:1055–62.

    Article  CAS  PubMed  Google Scholar 

  131. Milani P, Ambrosi G, Gammoh O, Blandini F, Cereda C. SOD1 and DJ-1 converge at Nrf2 pathway: a clue for antioxidant therapeutic potential in neurodegeneration. Oxidative Med Cell Longev. 2013;836760

    Google Scholar 

  132. Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci. 2008;28:13574–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Barber SC, Mead RC, Shaw PG. Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2006;1762:1051–67.

    Article  CAS  Google Scholar 

  134. Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease. Pharmacol Exp Ther. 2008;326(1):196–208.

    Article  CAS  Google Scholar 

  135. Caesar I, Jonson M, Nilsson KP, Thor S, Hammarström P. Curcumin promotes Abeta fibrillation and reduces neurotoxicity in transgenic Drosophila. PLoS One. 2012;7(2):e31424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Liu J, Wu Q, Lu YF, Pi J. New insights into generalized hepatoprotective effects of oleanolic acid: key roles of metallothionein and Nrf2 induction. Biochem Pharmacol. 2008;76:922–8.

    Article  CAS  PubMed  Google Scholar 

  137. Li L, Zhang X, Cui L, Wang L, Liu H, Ji H, Du Y. Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain Res. 2013;1497:32–9.

    Article  CAS  PubMed  Google Scholar 

  138. Kim V, Kim HY, Ehrlich HY, Choi SY, Kim DJ, Kim Y. Amelioration of Alzheimer's disease by neuroprotective effect of sulforaphane in animal model. Amyloid. 2013;20:7–12.

    Article  CAS  PubMed  Google Scholar 

  139. Zhang R, Miao QW, Zhu CX, Zhao Y, Liu L, Yang J. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid beta deposits and peroxidation in mice with Alzheimer-like lesions. Am J Alzheimers Dis Other Dement. 2015;30:183–91.

    Article  Google Scholar 

  140. Heo HJ, Kim DO, Shin SC, Kim MJ, Kim BG, Shin DH. Effect of antioxidant flavanone, naringenin, from Citrus junoson neuroprotection. J Agric Food Chem. 2004;52:1520–5.

    Article  CAS  PubMed  Google Scholar 

  141. Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease. Free Radic Res. 2005;39:1119–25.

    Article  CAS  PubMed  Google Scholar 

  142. Gao X, Cassidy A, Schwarzschild MA, Rimm EB, Ascherio A. Habitual intake of dietary flavonoids and risk of Parkinson disease. Neurology. 2012;78:1138–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima M, Nabeshima Y. 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.

    Article  CAS  PubMed  Google Scholar 

  144. Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, Wong PK, Zhang DD. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008;29:1235–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT. Cancer chemoprevention mechanisms mediated through the Keap1–Nrf2 pathway. Antioxid Redox Signal. 2010;13:1713–48.

    Article  CAS  PubMed  Google Scholar 

  146. Hu R, Saw CL, Yu R, Kong AN. Regulation of NF-E2-related factor 2 signaling for cancer chemo-prevention: antioxidant coupled with anti-inflammatory. Antioxid Redox Signal. 2010;13:1679–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012;12:564–71.

    Article  CAS  PubMed  Google Scholar 

  148. Satoh H, Moriguchi T, Taguchi K, Takai J, Maher JM, Suzuki T, Winnard PT Jr, Raman V, Ebina M, Nukiwa T, Yamamoto M. Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis. 2010;31:1833–43.

    Article  CAS  PubMed  Google Scholar 

  149. Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhauser C. Nuclear factor κB is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem. 2001;276(34):32008–15.

    Article  CAS  PubMed  Google Scholar 

  150. Dickinson SE, et al. Inhibition of activator protein-1 by sulforaphane involves interaction with cysteine in the cFos DNA-binding domain: implications for chemoprevention of UVB-induced skin cancer. Cancer Res. 2009;69:7103–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 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;408:1–5.

    Article  CAS  PubMed  Google Scholar 

  152. Shin S, Wakabayashi J, Yates MS, Wakabayashi N, Dolan PM, Aja S, Liby KT, Sporn MB, Yamamoto M, Kensler TW. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmacol. 2009;620:138–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, Tuveson DA. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475(7354):106–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2016;39:199–218.

    Article  CAS  Google Scholar 

  155. Papp D, Lenti K, Módos D, Fazekas D, Dúl Z, Türei D, Földvári-Nagy L, Nussinov R, Csermely P, Korcsmáros T. The NRF2-related interactome and regulome contain multifunctional proteins and fine-tuned autoregulatory loops. FEBS Lett. 2012;586:1795–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Gao B, Doan A, Hybertson BM. The clinical potential of influencing Nrf2 signaling in degenerative and immunological disorders. Clin Pharm. 2016;6:19–34.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Linus Pauling Institute, Oregon State University, Corvallis, OR, USA

    Rong Wang & Viviana I. Perez

  2. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA

    Viviana I. Perez

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    Huai Deng

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Wang, R., Perez, V.I. (2020). Molecular Mechanisms of Nrf2 in Inflammation: Interactions Between Nrf2 and Inflammatory Mediators. In: Deng, H. (eds) Nrf2 and its Modulation in Inflammation. Progress in Inflammation Research, vol 85. Springer, Cham. https://doi.org/10.1007/978-3-030-44599-7_1

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