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Chemical and Biological Mechanisms of Phytochemical Activation of NRF2 and Importance in Disease Prevention

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50 Years of Phytochemistry Research

Part of the book series: Recent Advances in Phytochemistry ((RAPT,volume 43))

Abstract

Plants are an incredibly rich source of compounds that activate the Nrf2 transcription factor, leading to upregulation of a battery of cytoprotective genes. This perspective surveys established and proposed molecular mechanisms of Nrf2 activation by phytochemicals with a special emphasis on a common chemical property of Nrf2 activators: the ability as “soft” electrophiles to modify cellular thiols, either directly or as oxidized biotransformants. In addition, the role of reactive oxygen/nitrogen species as secondary messengers in Nrf2 activation is discussed. While the uniquely reactive C151 of Keap1, an Nrf2 repressor protein, is highlighted as a key target of cytoprotective phytochemicals, also reviewed are other stress-responsive proteins, including kinases, which play nonredundant roles in the activation of Nrf2 by plant-derived agents. Finally, the Perspective presents two key factors accounting for the enhanced therapeutic windows of effective phytochemical activators of the Keap1–Nrf2 axis: enhanced selectivity toward sensor cysteines and reversibility of addition to thiolate molecules.

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Notes

  1. 1.

    ClinicalTrials.gov identifiers, in order as listed above—amelioration studies: NCT01474993, NCT01315665, NCT01269723, NCT01183923, and NCT00994604; prevention studies: NCT00982319, NCT00255775, NCT00607932, NCT01437501, and NCT00252018.

  2. 2.

    Clinicaltrials.gov identifier NCT01315665.

  3. 3.

    Clinicaltrials.gov identifier NCT01335971.

References

  1. Pashkow FJ (2011) Oxidative stress and inflammation in heart disease: do antioxidants have a role in treatment and/or prevention? Int J Inflam 2011:514623

    PubMed  Google Scholar 

  2. Kasai H, Kawai K (2006) Oxidative DNA damage: mechanisms and significance in health and disease. Antioxid Redox Signal 8:981–983

    PubMed  CAS  Google Scholar 

  3. Rappaport SM, Li H, Grigoryan H, Funk WE, Williams ER (2012) Adductomics: characterizing exposures to reactive electrophiles. Toxicol Lett 213:83–90

    PubMed  CAS  Google Scholar 

  4. Malhotra D, Portales-Casamar E, Singh A, Srivastava S, Arenillas D, Happel C, Shyr C, Wakabayashi N, Kensler TW, Wasserman WW, Biswal S (2010) Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 38:5718–5734

    PubMed  CAS  Google Scholar 

  5. Hayes JD, McMahon M (2009) NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34:176–188

    PubMed  CAS  Google Scholar 

  6. Zhao Z, Chen Y, Wang J, Sternberg P, Freeman ML, Grossniklaus HE, Cai J (2011) Age-related retinopathy in NRF2-deficient mice. PLoS ONE 6:e19456

    PubMed  CAS  Google Scholar 

  7. Chen P-C, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A 106:2933–2938

    PubMed  CAS  Google Scholar 

  8. Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, Biswal S (2009) Targeting Nrf2 with the triterpenoid CDDO—imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci U S A 106:250–255

    PubMed  CAS  Google Scholar 

  9. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, de Cabo R, Csiszar A (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299:H18–24

    PubMed  CAS  Google Scholar 

  10. Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A (2002) Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[α]pyrene-induced stomach tumors. Proc Natl Acad Sci U S A 99:7610–7615

    PubMed  CAS  Google Scholar 

  11. Becks L, Prince M, Burson H, Christophe C, Broadway M, Itoh K, Yamamoto M, Mathis M, Orchard E, Shi R, McLarty J, Pruitt K, Zhang S, Kleiner-Hancock H (2010) Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene. BMC Cancer 10:540

    PubMed  Google Scholar 

  12. Xu C, Huang M-T, Shen G, Yuan X, Lin W, Khor TO, Conney AH, Kong A-NT (2006) Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2–related factor 2. Cancer Res 66:8293–8296

    PubMed  CAS  Google Scholar 

  13. Zhao J, Moore AN, Redell JB, Dash PK (2007) Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci 27:10240–10248

    PubMed  CAS  Google Scholar 

  14. Aoki Y, Sato H, Nishimura N, Takahashi S, Itoh K, Yamamoto M (2001) Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust. Toxicol Appl Pharmacol 173:154–160

    PubMed  CAS  Google Scholar 

  15. Chan K, Kan YW (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci U S A 96:12731–12736

    PubMed  CAS  Google Scholar 

  16. Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, Harada T, Yamamoto M (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 59:169–177

    PubMed  CAS  Google Scholar 

  17. Braun S, Hanselmann C, Gassmann MG, auf dem Keller U, Born-Berclaz C, Chan K, Kan YW, Werner S (2002) 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 22:5492–5505

    PubMed  CAS  Google Scholar 

  18. Sykiotis GP, Bohmann D (2010) Stress-activated cap’n’collar transcription factors in aging and human disease. Sci Signal 3:re3

    Google Scholar 

  19. Prochaska HJ, Santamaria AB, Talalay P (1992) Rapid detection of inducers of enzymes that protect against carcinogens. Proc Natl Acad Sci U S A 89:2394–2398

    PubMed  CAS  Google Scholar 

  20. Kinghorn AD, Su BN, Jang DS, Chang LC, Lee D, Gu JQ, Carcache-Blanco EJ, Pawlus AD, Lee SK, Park EJ, Cuendet M, Gills JJ, Bhat K, Park HS, Mata-Greenwood E, Song LL, Jang M, Pezzuto JM (2004) Natural inhibitors of carcinogenesis. Planta Med 70:691–705

    PubMed  CAS  Google Scholar 

  21. Fahey JW, Zalcmann AT, Talalay P (2001) The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 56:5–51

    PubMed  CAS  Google Scholar 

  22. Hecht SS (2000) Inhibition of carcinogenesis by isothiocyanates. Drug Metab Rev 32:395–411

    PubMed  CAS  Google Scholar 

  23. Burow M, Wittstock U (2009) Regulation and function of specifier proteins in plants. Phytochem Rev 8:87–99

    CAS  Google Scholar 

  24. Agerbirk NN, De Vos M, Kim JH, Jander G (2009) Indole glucosinolate breakdown and its biological effects. Phytochem Rev 8:101–120

    CAS  Google Scholar 

  25. Talalay P, De Long MJ, Prochaska HJ (1988) Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci U S A 85:8261–8265

    PubMed  CAS  Google Scholar 

  26. Murakami A, Takahashi D, Kinoshita T, Koshimizu K, Kim HW, Yoshihiro A, Nakamura Y, Jiwajinda S, Terao J, Ohigashi H (2002) Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the α,β-unsaturated carbonyl group is a prerequisite. Carcinogenesis 23:795–802

    PubMed  CAS  Google Scholar 

  27. Su BN, Jung Park E, Vigo JS, Graham JG, Cabieses F, Fong HH, Pezzuto JM, Kinghorn AD (2003) Activity-guided isolation of the chemical constituents of Muntingia calabura using a quinone reductase induction assay. Phytochemistry 63:335–341

    PubMed  CAS  Google Scholar 

  28. Uda Y, Price KR, Williamson G, Rhodes MJ (1997) Induction of the anticarcinogenic marker enzyme, quinone reductase, in murine hepatoma cells in vitro by flavonoids. Cancer Lett 120:213–216

    PubMed  CAS  Google Scholar 

  29. Su BN, Gu J-Q, Kang Y-H, Park E-J, Pezzuto JM, Kinghorn AD (2004) Induction of the phase II enzyme, quinone reductase, by withanolides and norwithanolides from Solanaceous species. Mini-Rev Org Chem 1:115–123

    CAS  Google Scholar 

  30. Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P (2001) 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 98:3404–3409

    PubMed  CAS  Google Scholar 

  31. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86

    PubMed  CAS  Google Scholar 

  32. Prochaska HJ, Bregman HS, De Long MJ, Talalay P (1985) Specificity of induction of cancer protective enzymes by analogues of tert-butyl-4-hydroxyanisole (BHA). Biochem Pharmacol 34:3909–3914

    PubMed  CAS  Google Scholar 

  33. Jacobs H, Moalin M, Bast A, van der Vijgh WJF, Haenen GRMM (2010) An essential difference between the flavonoids monoHER and quercetin in their interplay with the endogenous antioxidant network. PLoS ONE 5:e13880

    PubMed  Google Scholar 

  34. Awad HM, Boersma MG, Boeren S, van Bladeren PJ, Vervoort J, Rietjens IMCM (2003) Quenching of quercetin quinone/quinone methides by different thiolate scavengers: stability and reversibility of conjugate formation. Chem Res Toxicol 16:822–831

    PubMed  CAS  Google Scholar 

  35. Galati G, Moridani MY, Chan TS, O’Brien PJ (2001) Peroxidative metabolism of apigenin and naringenin versus luteolin and quercetin: glutathione oxidation and conjugation. Free Radic Biol Med 30:370–382

    PubMed  CAS  Google Scholar 

  36. van Zanden JJ, Ben Hamman O, van Iersel MLPS, Boeren S, Cnubben NHP, Lo Bello M, Vervoort J, van Bladeren PJ, Rietjens IMCM (2003) Inhibition of human glutathione S-transferase P1–1 by the flavonoid quercetin. Chem Biol Interact 145:139–148

    PubMed  CAS  Google Scholar 

  37. Ishii T, Mori T, Tanaka T, Mizuno D, Yamaji R, Kumazawa S, Nakayama T, Akagawa M (2008) Covalent modification of proteins by green tea polyphenol (-)-epigallocatechin-3-gallate through autoxidation. Free Radic Biol Med 45:1384–1394

    PubMed  CAS  Google Scholar 

  38. Muzolf-Panek M, Gliszczyńska-Świgło A, de Haan L, Aarts JMMJG, Szymusiak H, Vervoort JM, Tyrakowska B, Rietjens IMCM (2008) Role of catechin quinones in the induction of EpRE-mediated gene expression. Chem Res Toxicol 21:2352–2360

    PubMed  CAS  Google Scholar 

  39. Sang S, Lambert JD, Hong J, Tian S, Lee M-J, Stark RE, Ho C-T, Yang CS (2005) Synthesis and structure identification of thiol conjugates of (-)-epigallocatechin gallate and their urinary levels in mice. Chem Res Toxicol 18:1762–1769

    PubMed  CAS  Google Scholar 

  40. Nakamura Y, Kumagai T, Yoshida C, Naito Y, Miyamoto M, Ohigashi H, Osawa T, Uchida K (2003) Pivotal role of electrophilicity in glutathione S-transferase induction by tert-butylhydroquinone. Biochemistry 42:4300–4309

    PubMed  CAS  Google Scholar 

  41. Bensasson RV, Zoete V, Dinkova-Kostova AT, Talalay P (2008) Two-step mechanism of induction of the gene expression of a prototypic cancer-protective enzyme by diphenols. Chem Res Toxicol 21:805–812

    PubMed  CAS  Google Scholar 

  42. Wang XJ, Hayes JD, Higgins LG, Wolf CR, Dinkova-Kostova AT (2010) Activation of the NRF2 signaling pathway by copper-mediated redox cycling of para- and ortho-hydroquinones. Chem Biol 17:75–85

    PubMed  Google Scholar 

  43. Dinkova-Kostova AT, Wang XJ (2011) Induction of the Keap1/Nrf2/ARE pathway by oxidizable diphenols. Chem Biol Interact 192:101–106

    PubMed  CAS  Google Scholar 

  44. Sparnins VL, Barany G, Wattenberg LW (1988) Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse. Carcinogenesis 9:131–134

    PubMed  CAS  Google Scholar 

  45. Brady JF, Ishizaki H, Fukuto JM, Lin MC, Fadel A, Gapac JM, Yang CS (1991) Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites. Chem Res Toxicol 4:642–647

    PubMed  CAS  Google Scholar 

  46. Gurtoo HL, Marinello AJ, Struck RF, Paul B, Dahms RP (1981) Studies on the mechanism of denaturation of cytochrome P-450 by cyclophosphamide and its metabolites. J Biol Chem 256:11691–11701

    PubMed  CAS  Google Scholar 

  47. Jin L, Baillie TA (1997) Metabolism of the chemoprotective agent diallyl sulfide to glutathione conjugates in rats. Chem Res Toxicol 10:318–327

    PubMed  CAS  Google Scholar 

  48. Cavin C, Bezencon C, Guignard G, Schilter B (2003) Coffee diterpenes prevent benzo[a]pyrene genotoxicity in rat and human culture systems. Biochem Biophys Res Commun 306:488–495

    PubMed  CAS  Google Scholar 

  49. Hwang YP, Jeong HG (2008) The coffee diterpene kahweol induces heme oxygenase-1 via the PI3K and p38/Nrf2 pathway to protect human dopaminergic neurons from 6-hydroxydopamine-derived oxidative stress. FEBS Lett 582:2655–2662

    PubMed  CAS  Google Scholar 

  50. van Cruchten STJ, de Haan LHJ, Mulder PPJ, Kunne C, Boekschoten MV, Katan MB, Aarts JMMJG, Witkamp RF (2010) The role of epoxidation and electrophile-responsive element-regulated gene transcription in the potentially beneficial and harmful effects of the coffee components cafestol and kahweol. J Nutr Biochem 21:757–763

    PubMed  CAS  Google Scholar 

  51. Boyd MR (1981) Toxicity mediated by reactive metabolites of furans. Adv Exp Med Biol 136 Pt B:865–879

    Google Scholar 

  52. Avonto C, Taglialatela-Scafati O, Pollastro F, Minassi A, Di† Marzo V, De Petrocellis L, Appendino G (2011) An NMR spectroscopic method to identify and classify thiol-trapping agents: revival of Michael acceptors for drug discovery? Angewandte Chemie Int Ed 50:467–471

    Google Scholar 

  53. Khojasteh-Bakht SC, Chen W, Koenigs LL, Peter RM, Nelson SD (1999) Metabolism of (R)-(+)-pulegone and (R)-(+)-menthofuran by human liver cytochrome P-450s: evidence for formation of a furan epoxide. Drug Metab Dispos 27:574–580

    PubMed  CAS  Google Scholar 

  54. Saw CL-L, Cintrón M, Wu T-Y, Guo Y, Huang Y, Jeong W-S, Kong A-NT (2011) Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates. Biopharm Drug Dispos 32:289–300

    PubMed  CAS  Google Scholar 

  55. Aggarwal BB, Ichikawa H (2005) Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 4:1201–1215

    PubMed  CAS  Google Scholar 

  56. Leibelt DA, Hedstrom OR, Fischer KA, Pereira CB, Williams DE (2003) Evaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced 3,3†²-diindolylmethane in sprague-dawley rats. Toxicol Sci 74:10–21

    PubMed  CAS  Google Scholar 

  57. Fordtran JS, Scroggie WB, Polter DE (1964) Colonic absorption of tryptophan metabolites in man. J Lab Clin Med 64:125–132

    PubMed  CAS  Google Scholar 

  58. Thornton-Manning J, Appleton ML, Gonzalez FJ, Yost GS (1996) Metabolism of 3-methylindole by vaccinia-expressed P450 enzymes: correlation of 3-methyleneindolenine formation and protein-binding. J Pharmacol Exp Ther 276:21–29

    PubMed  CAS  Google Scholar 

  59. Regal KA, Laws GM, Yuan C, Yost GS, Skiles GL (2001) Detection and characterization of DNA adducts of 3-methylindole. Chem Res Toxicol 14:1014–1024

    PubMed  CAS  Google Scholar 

  60. Grose KR, Bjeldanes LF (1992) Oligomerization of indole-3-carbinol in aqueous acid. Chem Res Toxicol 5:188–193

    PubMed  CAS  Google Scholar 

  61. Staub RE, Onisko B, Bjeldanes LF (2006) Fate of 3,3†-diindolylmethane in cultured MCF-7 human breast cancer cells. Chem Res Toxicol 19:436–442

    PubMed  CAS  Google Scholar 

  62. Sepkovic DW, Bradlow HL, Bell M (2001) Quantitative determination of 3,3†²-diindolylmethane in urine of individuals receiving indole-3-carbinol. Nutr Cancer 41:57–63

    PubMed  CAS  Google Scholar 

  63. Ben-Dor A, Steiner M, Gheber L, Danilenko M, Dubi N, Linnewiel K, Zick A, Sharoni Y, Levy J (2005) Carotenoids activate the antioxidant response element transcription system. Mol Cancer Ther 4:177–186

    PubMed  CAS  Google Scholar 

  64. Lewinsohn E, Sitrit Y, Bar E, Azulay Y, Meir A, Zamir D, Tadmor Y (2005) Carotenoid pigmentation affects the volatile composition of tomato and watermelon fruits, as revealed by comparative genetic analyses. J Agric Food Chem 53:3142–3148

    PubMed  CAS  Google Scholar 

  65. Kondratyuk TP, Park E-J, Marler LE, Ahn S, Yuan Y, Choi Y, Yu R, van Breemen RB, Sun B, Hoshino J, Cushman M, Jermihov KC, Mesecar AD, Grubbs CJ, Pezzuto JM (2011) Resveratrol derivatives as promising chemopreventive agents with improved potency and selectivity. Mol Nutr Food Res 55:1249–1265

    PubMed  CAS  Google Scholar 

  66. Kode A, Rajendrasozhan S, Caito S, Yang S-R, Megson IL, Rahman I (2008) 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 294:L478–L488

    PubMed  CAS  Google Scholar 

  67. Piver B, Fer M, Vitrac X, Merillon JM, Dreano Y, Berthou F, Lucas D (2004) Involvement of cytochrome P450 1A2 in the biotransformation of trans-resveratrol in human liver microsomes. Biochem Pharmacol 68:773–782

    PubMed  CAS  Google Scholar 

  68. Potter GA, Patterson LH, Wanogho E, Perry PJ, Butler PC, Ijaz T, Ruparelia KC, Lamb JH, Farmer PB, Stanley LA, Burke MD (2002) The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. Br J Cancer 86:774–778

    PubMed  CAS  Google Scholar 

  69. Rushmore TH, Kong AN (2002) Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Curr Drug Metab 3:481–490

    PubMed  CAS  Google Scholar 

  70. Casper RF, Quesne M, Rogers IM, Shirota T, Jolivet A, Milgrom E, Savouret J-F (1999) Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity. Mol Pharmacol 56:784–790

    PubMed  CAS  Google Scholar 

  71. Miao W, Hu L, Kandouz M, Batist G (2003) Oltipraz is a bifunctional inducer activating both phase I and phase II drug-metabolizing enzymes via the xenobiotic responsive element. Mol Pharmacol 64:346–354

    PubMed  CAS  Google Scholar 

  72. Montano MM, Katzenellenbogen BS (1997) The quinone reductase gene: A unique estrogen receptor-regulated gene that is activated by antiestrogens. Proc Natl Acad Sci U S A 94:2581–2586

    PubMed  CAS  Google Scholar 

  73. Montano MM, Jaiswal AK, Katzenellenbogen BS (1998) Transcriptional regulation of the human quinone reductase gene by antiestrogen-liganded estrogen receptor-alpha and estrogen receptor-beta. J Biol Chem 273:25443–25449

    PubMed  CAS  Google Scholar 

  74. Montano MM, Deng H, Liu M, Sun X, Singal R (2004) Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications. Oncogene 23:2442–2453

    PubMed  CAS  Google Scholar 

  75. Bianco NR, Chaplin LJ, Montano MM (2005) Differential induction of quinone reductase by phytoestrogens and protection against oestrogen-induced DNA damage. Biochem J 385:279–287

    PubMed  CAS  Google Scholar 

  76. Buryanovskyy L, Fu Y, Boyd M, Ma Y, Hsieh T-c, Wu JM, Zhang Z (2004) Crystal structure of quinone reductase 2 in complex with resveratrol. Biochemistry 43:11417–11426

    PubMed  CAS  Google Scholar 

  77. Boutin JA, Chatelain-Egger F, Vella F, Delagrange P, Ferry G (2005) Quinone reductase 2 substrate specificity and inhibition pharmacology. Chem Biol Interact 151:213–228

    PubMed  CAS  Google Scholar 

  78. Dinkova-Kostova AT, Talalay P (2008) Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol Nutr Food Res 52:S128–S138

    PubMed  Google Scholar 

  79. Nakamura Y, Miyoshi N (2010) Electrophiles in foods: the current status of isothiocyanates and their chemical biology. Biosci Biotechnol Biochem 74:242–255

    PubMed  CAS  Google Scholar 

  80. Holland R, Navamal M, Velayutham M, Zweier JL, Kensler TW, Fishbein JC (2009) Hydrogen peroxide is a second messenger in phase 2 enzyme induction by cancer chemopreventive dithiolethiones. Chem Res Toxicol 22:1427–1434

    PubMed  CAS  Google Scholar 

  81. Winterbourn CC (1993) Superoxide as an intracellular radical sink. Free Radic Biol Med 14:85–90

    PubMed  CAS  Google Scholar 

  82. Holland R, Hawkins AE, Eggler AL, Mesecar AD, Fabris D, Fishbein JC (2008) Prospective type 1 and type 2 disulfides of Keap1 protein. Chem Res Toxicol 21:2051–2060

    PubMed  CAS  Google Scholar 

  83. Mieyal JJ, Gallogly MM, Qanungo S, Sabens EA, Shelton MD (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal 10:1941–1988

    PubMed  CAS  Google Scholar 

  84. Na H-K, Surh Y-J (2006) Transcriptional regulation via cysteine thiol modification: A novel molecular strategy for chemoprevention and cytoprotection. Mol Carcinog 45:368–380

    PubMed  CAS  Google Scholar 

  85. Janssen-Heininger YMW, Mossman BT, Heintz NH, Forman HJ, Kalyanaraman B, Finkel T, Stamler JS, Rhee SG, van der Vliet A (2008) Redox-based regulation of signal transduction: Principles, pitfalls, and promises. Free Radic Biol Med 45:1–17

    PubMed  CAS  Google Scholar 

  86. Nakagawa H, Hasumi K, Woo J-T, Nagai K, Wachi M (2004) Generation of hydrogen peroxide primarily contributes to the induction of Fe(II)-dependent apoptosis in Jurkat cells by (-)-epigallocatechin gallate. Carcinogenesis 25:1567–1574

    PubMed  CAS  Google Scholar 

  87. Yang G-Y, Liao J, Li C, Chung J, Yurkow EJ, Ho C-T, Yang CS (2000) Effect of black and green tea polyphenols on c-jun phosphorylation and H2O2 production in transformed and non-transformed human bronchial cell lines: possible mechanisms of cell growth inhibition and apoptosis induction. Carcinogenesis 21:2035–2039

    PubMed  CAS  Google Scholar 

  88. Hou Z, Sang S, You H, Lee M-J, Hong J, Chin K-V, Yang CS (2005) Mechanism of action of (-)-epigallocatechin-3-gallate: auto-oxidation-dependent inactivation of epidermal growth factor receptor and direct effects on growth inhibition in human esophageal cancer KYSE 150 cells. Cancer Res 65:8049–8056

    PubMed  CAS  Google Scholar 

  89. Wu CC, Hsu MC, Hsieh CW, Lin JB, Lai PH, Wung BS (2006) Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. Life Sci 78:2889–2897

    PubMed  CAS  Google Scholar 

  90. Lee-Hilz YY, Boerboom A-MJF, Westphal AH, van Berkel WJH, Aarts JMMJG, Rietjens IMCM (2006) Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression. Chem Res Toxicol 19:1499–1505

    PubMed  CAS  Google Scholar 

  91. Galati G, Moridani MY, Chan TS, O‚ÄôBrien PJ (2001) Peroxidative metabolism of apigenin and naringenin versus luteolin and quercetin: glutathione oxidation and conjugation. Free Radic Biol Med 30:370–382

    PubMed  CAS  Google Scholar 

  92. Galati G, Chan T, Wu B, O’Brien PJ (1999) Glutathione-dependent generation of reactive oxygen species by the peroxidase-catalyzed redox cycling of flavonoids. Chem Res Toxicol 12:521–525

    PubMed  CAS  Google Scholar 

  93. Liby KT, Yore MM, Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7:357–369

    PubMed  CAS  Google Scholar 

  94. Forman HJ, Fukuto JM, Torres M (2004) Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am J Physiol Cell Physiol 287:C246–256

    PubMed  CAS  Google Scholar 

  95. Magder S (2006) Reactive oxygen species: toxic molecules or spark of life? Crit Care 10:208

    PubMed  Google Scholar 

  96. Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, Williams CR, Royce DB, Honda T, Honda Y, Gribble GW, Hill-Kapturczak N, Agarwal A, Sporn MB (2005) The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res 65:4789–4798

    PubMed  CAS  Google Scholar 

  97. Calabrese EJ (2005) Cancer biology and hormesis: human tumor cell lines commonly display hormetic (biphasic) dose responses. Crit Rev Toxicol 35:463–582

    PubMed  CAS  Google Scholar 

  98. LoPachin RM, Barber DS, Gavin T (2008) Molecular mechanisms of the conjugated alpha, beta-unsaturated carbonyl derivatives: relevance to neurotoxicity and neurodegenerative diseases. Toxicol Sci 104:235–249

    PubMed  CAS  Google Scholar 

  99. Brandes N, Schmitt S, Jakob U (2009) Thiol-based redox switches in eukaryotic proteins. Antioxid Redox Signal 11:997–1014

    PubMed  CAS  Google Scholar 

  100. Sporn MB, Liby KT, Yore MM, Fu L, Lopchuk JM, Gribble GW (2011) New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 74:537–545

    PubMed  CAS  Google Scholar 

  101. Almazari I, Park J-M, Park S-A, Suh J-Y, Na H-K, Cha Y-N, Surh Y-J (2012) Guggulsterone induces heme oxygenase-1 expression through activation of Nrf2 in human mammary epithelial cells: PTEN as a putative target. Carcinogenesis 33:368–376

    PubMed  CAS  Google Scholar 

  102. Lin D, Saleh S, Liebler DC (2008) Reversibility of covalent electrophile-protein adducts and chemical toxicity. Chem Res Toxicol 21:2361–2369

    PubMed  CAS  Google Scholar 

  103. Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88

    PubMed  CAS  Google Scholar 

  104. Talalay P, Fahey JW, Holtzclaw WD, Prestera T, Zhang Y (1995) Chemoprotection against cancer by phase 2 enzyme induction. Toxicol Lett 82–83:173–179

    Google Scholar 

  105. Thornalley PJ (2002) Isothiocyanates: mechanism of cancer chemopreventive action. Anticancer Drugs 13:331–338

    PubMed  CAS  Google Scholar 

  106. Klaić L, Morimoto RI, Silverman RB (2012) Celastrol analogues as inducers of the heat shock response. Design and synthesis of affinity probes for the identification of protein targets. ACS Chem Biol 7:928–937

    PubMed  Google Scholar 

  107. Zhang DD, Hannink M (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23:8137–8151

    PubMed  CAS  Google Scholar 

  108. Karapetian RN, Evstafieva AG, Abaeva IS, Chichkova NV, Filonov GS, Rubtsov YP, Sukhacheva EA, Melnikov SV, Schneider U, Wanker EE, Vartapetian AB (2005) Nuclear oncoprotein prothymosin alpha is a partner of Keap1: Implications for expression of oxidative stress-protecting genes. Mol Cell Biol 25:1089–1099

    PubMed  CAS  Google Scholar 

  109. Velichkova M, Hasson T (2005) Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol Cell Biol 25:4501–4513

    PubMed  CAS  Google Scholar 

  110. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT (2010) Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal 13:1713–1748

    PubMed  CAS  Google Scholar 

  111. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M (2006) Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol 26:2887–2900

    PubMed  CAS  Google Scholar 

  112. Zhang DD, Lo S-C, Cross JV, Templeton DJ, Hannink M (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24:10941–10953

    PubMed  CAS  Google Scholar 

  113. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2006) Dimerisation of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a ‘tethering’ mechanism: A two-site interaction model for the Nrf2-Keap1 complex. J Biol Chem 281:24756–24768

    PubMed  CAS  Google Scholar 

  114. McMahon M, Lamont DJ, Beattie KA, Hayes JD (2010) Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc Natl Acad Sci U S A 107:18838–18843

    PubMed  CAS  Google Scholar 

  115. Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, Eguchi M, Wada Y, Kumagai Y, Yamamoto M (2009) The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol 29:493–502

    PubMed  CAS  Google Scholar 

  116. Kansanen E, Bonacci G, Schopfer FJ, Kuosmanen SM, Tong KI, Leinonen H, Woodcock SR, Yamamoto M, Carlberg C, Ylä-Herttuala S, Freeman BA, Levonen A-L (2011) Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism. J Biol Chem 286:14019–14027

    PubMed  CAS  Google Scholar 

  117. Sakurai T, Kanayama M, Shibata T, Itoh K, Kobayashi A, Yamamoto M, Uchida K (2006) Ebselen, a seleno-organic antioxidant, as an electrophile. Chem Res Toxicol 19:1196–1204

    PubMed  CAS  Google Scholar 

  118. Ohnuma T, Nakayama S, Anan E, Nishiyama T, Ogura K, Hiratsuka A (2010) Activation of the Nrf2/ARE pathway via S-alkylation of cysteine 151 in the chemopreventive agent-sensor Keap1 protein by falcarindiol, a conjugated diacetylene compound. Toxicol Appl Pharmacol 244:27–36

    PubMed  CAS  Google Scholar 

  119. Satoh T, Okamoto S-I, Cui J, Watanabe Y, Furuta K, Suzuki M, Tohyama K, Lipton SA (2006) From the cover: activation of the Keap1/Nrf2 pathway for neuroprotection by electrophillic phase II inducers. Proc Natl Acad Sci U S A 103:768–773

    PubMed  CAS  Google Scholar 

  120. Eggler AL, Small E, Hannink M, Mesecar AD (2009) Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem J 422:171–180

    PubMed  CAS  Google Scholar 

  121. Hur W, Sun Z, Jiang T, Mason DE, Peters EC, Zhang DD, Luesch H, Schultz PG, Gray NS (2010) A small-molecule inducer of the antioxidant response element. Chem Biol 17:537–547

    PubMed  CAS  Google Scholar 

  122. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 28:2758–2770

    PubMed  CAS  Google Scholar 

  123. Luo Y, Eggler AL, Liu D, Liu G, Mesecar AD, van Breemen RB (2007) Sites of alkylation of human Keap1 by natural chemoprevention agents. J Am Soc Mass Spectrom 18:2226–2232

    PubMed  CAS  Google Scholar 

  124. Hu C, Eggler AL, Mesecar AD, van Breemen RB (2011) Modification of Keap1 cysteine residues by sulforaphane. Chem Res Toxicol 24:515–521

    PubMed  CAS  Google Scholar 

  125. Hong F, Freeman ML, Liebler DC (2005) Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 18:1917–1926

    PubMed  CAS  Google Scholar 

  126. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P (2002) 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 99:11908–11913

    PubMed  CAS  Google Scholar 

  127. Abiko Y, Miura T, Phuc BH, Shinkai Y, Kumagai Y (2011) Participation of covalent modification of Keap1 in the activation of Nrf2 by tert-butylbenzoquinone, an electrophilic metabolite of butylated hydroxyanisole. Toxicol Appl Pharmacol 255:32–39

    PubMed  CAS  Google Scholar 

  128. Eggler AL, Liu G, Pezzuto JM,van Breemen RB , Mesecar AD (2005) Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci U S A 102:10070–10075

    PubMed  CAS  Google Scholar 

  129. Niture SK, Jain AK, Jaiswal AK (2009) 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 122:4452–4464

    PubMed  CAS  Google Scholar 

  130. Kobayashi A, Kang M-I, Watai Y, Tong KI, Shibata T, Uchida K, Yamamoto M (2006) Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 26:221–229

    PubMed  CAS  Google Scholar 

  131. Ichikawa T, Li J, Meyer CJ, Janicki JS, Hannink M, Cui T (2009) Dihydro-CDDO-trifluoroethyl amide (dh404), a novel Nrf2 activator, suppresses oxidative stress in cardiomyocytes. PLoS ONE 4:e8391

    PubMed  Google Scholar 

  132. Tanigawa S, Fujii M, Hou D-X (2007) Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 42:1690–1703

    PubMed  CAS  Google Scholar 

  133. Dreger H, Westphal K, Wilck N, Baumann G, Stangl V, Stangl K, Meiners S (2010) Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res 85:395–403

    PubMed  CAS  Google Scholar 

  134. Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, Freeman ML (2008) Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol 21:705–710

    PubMed  CAS  Google Scholar 

  135. Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, Talalay P (2004) 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 101:2040–2045

    PubMed  CAS  Google Scholar 

  136. Fourquet S, Guerois R, Biard D, Toledano MB (2010) Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J Biol Chem 285:8463–8471

    PubMed  CAS  Google Scholar 

  137. Lund MN, Luxford C, Skibsted LH, Davies MJ (2008) Oxidation of myosin by haem proteins generates myosin radicals and protein cross-links. Biochem J 410:565–574

    PubMed  CAS  Google Scholar 

  138. Martin D, Rojo AI, Salinas M, Diaz R, Gallardo G, Alam J, De Galarreta CM, Cuadrado A (2004) Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J Biol Chem 279:8919–8929

    PubMed  CAS  Google Scholar 

  139. Na H-K, Kim E-H, Jung J-H, Lee H-H, Hyun J-W, Surh Y-J (2008) (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Arch Biochem Biophys 476:171–177

    PubMed  CAS  Google Scholar 

  140. Lee H-H, Park S-A, Almazari I, Kim E-H, Na H-K, Surh Y-J (2010) Piceatannol induces heme oxygenase-1 expression in human mammary epithelial cells through activation of ARE-driven Nrf2 signaling. Arch Biochem Biophys 501:142–150

    PubMed  CAS  Google Scholar 

  141. Pitha-Rowe I, Liby K, Royce D, Sporn M (2009) Synthetic triterpenoids attenuate cytotoxic retinal injury: cross-talk between Nrf2 and PI3K/AKT signaling through inhibition of the lipid phosphatase PTEN. Invest Ophthalmol Vis Sci 50:5339–5347

    PubMed  Google Scholar 

  142. Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A (2006) 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 281:14841–14851

    PubMed  CAS  Google Scholar 

  143. Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD, Cuadrado A (2011) SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol 31:1121–1133

    PubMed  CAS  Google Scholar 

  144. Gericke A, Munson M, Ross AH (2006) Regulation of the PTEN phosphatase. Gene 374:1–9

    PubMed  CAS  Google Scholar 

  145. Jain AK, Jaiswal AK (2007) GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. J Biol Chem 282:16502–16510

    PubMed  CAS  Google Scholar 

  146. Sun Z, Huang Z, Zhang DD (2009) Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS ONE 4:e6588

    PubMed  Google Scholar 

  147. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209

    PubMed  CAS  Google Scholar 

  148. Cullinan SB, Diehl JA (2006) Coordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol 38:317–332

    PubMed  CAS  Google Scholar 

  149. Pi J, Bai Y, Reece JM, Williams J, Liu D, Freeman ML, Fahl WE, Shugar D, Liu J, Qu W, Collins S, Waalkes MP (2007) Molecular mechanism of human Nrf2 activation and degradation: Role of sequential phosphorylation by protein kinase CK2. Free Radic Biol Med 42:1797–1806

    PubMed  CAS  Google Scholar 

  150. Apopa PL, He X, Ma Q (2008) Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells. J Biochem Mol Toxicol 22:63–76

    PubMed  CAS  Google Scholar 

  151. McNally SJ, Harrison EM, Ross JA, Garden OJ, Wigmore SJ (2007) Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition. Int J Mol Med 19:165–172

    PubMed  CAS  Google Scholar 

  152. Rushworth SA, Ogborne RM, Charalambos CA, O’Connell MA (2006) Role of protein kinase C δ in curcumin-induced antioxidant response element-mediated gene expression in human monocytes. Biochem Biophys Res Commun 341:1007–1016

    PubMed  CAS  Google Scholar 

  153. Wung B-S, Hsu M-C, Wu C-C, Hsieh C-W (2006) Piceatannol upregulates endothelial heme oxygenase-1 expression via novel protein kinase C and tyrosine kinase pathways. Pharmacol Res 53:113–122

    PubMed  CAS  Google Scholar 

  154. Ogborne RM, Rushworth SA, O’Connell MA (2008) Epigallocatechin activates haem oxygenase-1 expression via protein kinase Cdelta and Nrf2. Biochem Biophys Res Commun 373:584–588

    PubMed  CAS  Google Scholar 

  155. Numazawa S, Ishikawa M, Yoshida A, Tanaka S, Yoshida T (2003) Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress. Am J Physiol Cell Physiol 285:C334–C342

    PubMed  CAS  Google Scholar 

  156. Sherratt PJ, Huang HC, Nguyen T, Pickett CB (2004) Role of protein phosphorylation in the regulation of NF-E2-related factor 2 activity. Methods Enzymol 378:286–301

    PubMed  CAS  Google Scholar 

  157. Zhu M, Zhang Y, Bowden GT (2006) Involvement of mitogen-activated protein kinases and protein kinase C in regulation of antioxidant response element activity in human keratinocytes. Cancer Lett 244:220–228

    PubMed  CAS  Google Scholar 

  158. Chen C, Pung D, Leong V, Hebbar V, Shen G, Nair S, Li W, Kong AN (2004) Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals. Free Radic Biol Med 37:1578–1590

    PubMed  CAS  Google Scholar 

  159. Kern JT, Hannink M, Hess JF (2007) Disruption of the Keap1-containing ubiquitination complex as an antioxidant therapy. Curr Top Med Chem 7:972–978

    PubMed  CAS  Google Scholar 

  160. Eggler AL, Gay KA, Mesecar AD (2008) Molecular mechanisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2. Mol Nutr Food Res 52(Suppl 1):S84–S94

    Google Scholar 

  161. Hou DX, Kumamoto T (2010) Flavonoids as protein kinase inhibitors for cancer chemoprevention: direct binding and molecular modeling. Antioxid Redox Signal 13:691–719

    PubMed  CAS  Google Scholar 

  162. Velmurugan K, Alam J, McCord JM, Pugazhenthi S (2009) Synergistic induction of heme oxygenase-1 by the components of the antioxidant supplement Protandim. Free Radic Biol Med 46:430–440

    PubMed  CAS  Google Scholar 

  163. Murakami A, Ohnishi K (2012) Target molecules of food phytochemicals: Food science bound for the next dimension. Food Funct 3:462–476

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Young-Joon Surh, Mark Hannink, Wendy A. Peer, Andrew D. Mesecar, and Albena Dinkova-Kostova for their thoughtful comments on this Perspective. We are grateful to the National Institutes of Health for financial support through the R03 CA128095 grant.

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Authors and Affiliations

  1. Department of Chemistry, Villanova University, 19085, Villanova, PA, USA

    Aimee L. Eggler

  2. Purdue University Center for Cancer Research, 47907, West Lafayette, IN, USA

    Sergey N. Savinov

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  1. Aimee L. Eggler
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  2. Sergey N. Savinov
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Correspondence to Aimee L. Eggler .

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  1. Institute of Biological Chemistry, Washington State University, Pullman, Washington, USA

    David R. Gang

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Eggler, A., Savinov, S. (2013). Chemical and Biological Mechanisms of Phytochemical Activation of NRF2 and Importance in Disease Prevention. In: Gang, D. (eds) 50 Years of Phytochemistry Research. Recent Advances in Phytochemistry, vol 43. Springer, Cham. https://doi.org/10.1007/978-3-319-00581-2_7

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