Nrf2 as a Master Redox Switch in Turning on the Cellular Signaling Involved in the Induction of Cytoprotective Genes by Some Chemopreventive Phytochemicals

A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities. Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5'-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed. This review highlights the cytoprotective gene expression induced by some representative dietary chemopreventive phytochemicals with the Nrf2-Keap1 system as a prime molecular target.

[1]  Jie Wu,et al.  Role of a Mitogen-activated Protein Kinase Pathway in the Induction of Phase II Detoxifying Enzymes by Chemicals* , 1999, The Journal of Biological Chemistry.

[2]  Takafumi Suzuki,et al.  Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity , 2008, Molecular and Cellular Biology.

[3]  L. Wattenberg.  Chemoprophylaxis of carcinogenesis: a review. , 1966, Cancer research.

[4]  C. B. Pickett,et al.  Phosphorylation of Nrf2 at Ser-40 by Protein Kinase C Regulates Antioxidant Response Element-mediated Transcription* , 2002, The Journal of Biological Chemistry.

[5]  A. Murakami,et al.  Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes , 2004, FEBS letters.

[6]  Abhinav K. Jain,et al.  GSK-3beta acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2. , 2007, The Journal of biological chemistry.

[7]  M. Kwak,et al.  Role of increased expression of the proteasome in the protective effects of sulforaphane against hydrogen peroxide-mediated cytotoxicity in murine neuroblastoma cells. , 2007, Free radical biology & medicine.

[8]  M. Imamura,et al.  Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol. , 2002, Carcinogenesis.

[9]  Masayuki Yamamoto,et al.  Nrf2-Keap1 defines a physiologically important stress response mechanism. , 2004, Trends in molecular medicine.

[10]  A. Kong,et al.  Mechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2 , 2006, Molecular Cancer Therapeutics.

[11]  G. Sudhandiran,et al.  Chromium (VI)‐induced oxidative stress and apoptosis is reduced by garlic and its derivative S‐allylcysteine through the activation of Nrf2 in the hepatocytes of Wistar rats , 2008, Journal of applied toxicology : JAT.

[12]  M. Sporn.  Approaches to prevention of epithelial cancer during the preneoplastic period. , 1976, Cancer research.

[13]  T. Kensler,et al.  Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  G. Jeong,et al.  Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells , 2007, Experimental & Molecular Medicine.

[15]  A. I. Rojo,et al.  Glycogen Synthase Kinase-3β Inhibits the Xenobiotic and Antioxidant Cell Response by Direct Phosphorylation and Nuclear Exclusion of the Transcription Factor Nrf2* , 2006, Journal of Biological Chemistry.

[16]  M. Kwak,et al.  Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers. , 2004, Mutation research.

[17]  Y. Surh,et al.  Transcriptional regulation via cysteine thiol modification: A novel molecular strategy for chemoprevention and cytoprotection , 2006, Molecular carcinogenesis.

[18]  Anuj Sharma,et al.  Multiple molecular targets in cancer chemoprevention by curcumin , 2006, The AAPS Journal.

[19]  E. Heiss,et al.  Mechanism-based in vitro screening of potential cancer chemopreventive agents. , 2003, Mutation research.

[20]  A. Kong,et al.  Modulation of nuclear factor E2-related factor 2–mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin , 2006, Molecular Cancer Therapeutics.

[21]  P. Lai,et al.  Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. , 2006, Life sciences.

[22]  N. Kitteringham,et al.  The Nrf2-Keap1 defence pathway: role in protection against drug-induced toxicity. , 2008, Toxicology.

[23]  D. Hou,et al.  Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. , 2007, Free radical biology & medicine.

[24]  Y. Surh,et al.  Cancer chemopreventive effects of curcumin. , 2007, Advances in experimental medicine and biology.

[25]  H. Mukhtar,et al.  The novel antioxidant 3-O-caffeoyl-1-methylquinic acid induces Nrf2-dependent phase II detoxifying genes and alters intracellular glutathione redox. , 2006, Free radical biology & medicine.

[26]  A. Dinkova-Kostova,et al.  Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes. , 1999, Carcinogenesis.

[27]  Sanjeev Banerjee,et al.  Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. , 2002, Cancer research.

[28]  H. Huang,et al.  Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  R. Cole,et al.  Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[30]  A. Dinkova-Kostova,et al.  Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers. , 1998, Journal of medicinal chemistry.

[31]  C. Wolf,et al.  The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. , 2001, Cancer research.

[32]  P. Bowen,et al.  Can the Consumption of Tomatoes or Lycopene Reduce Cancer Risk? , 2002, Integrative cancer therapies.

[33]  Y. Surh,et al.  Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. , 2008, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[34]  J. Alam,et al.  Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse beta-cells. , 2007, American journal of physiology. Endocrinology and metabolism.

[35]  A. I. Rojo,et al.  GSK-3beta down-regulates the transcription factor Nrf2 after oxidant damage: relevance to exposure of neuronal cells to oxidative stress. , 2008, Journal of neurochemistry.

[36]  B. Longley,et al.  Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease? , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  Y. Surh,et al.  Cancer chemoprevention with dietary phytochemicals , 2003, Nature Reviews Cancer.

[38]  Mark Hannink,et al.  Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex , 2004, Molecular and Cellular Biology.

[39]  I. Rahman,et al.  Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[40]  M. Kwak,et al.  Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Y. Surh,et al.  Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. , 2005, Biochemical and biophysical research communications.

[42]  B. Halliwell,et al.  Artifacts in cell culture: rapid generation of hydrogen peroxide on addition of (-)-epigallocatechin, (-)-epigallocatechin gallate, (+)-catechin, and quercetin to commonly used cell culture media. , 2000, Biochemical and biophysical research communications.

[43]  J. Fahey,et al.  Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M. Alcaraz,et al.  Role of nuclear factor‐κB and heme oxygenase‐1 in the mechanism of action of an anti‐inflammatory chalcone derivative in RAW 264.7 cells , 2004 .

[45]  Norman R. Farnsworth,et al.  Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes , 1997, Science.

[46]  Y. Hwang,et al.  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 , 2008, FEBS letters.

[47]  X. He,et al.  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 , 2008, Journal of biochemical and molecular toxicology.

[48]  Yan-qing Li,et al.  Inhibition of Epigallocatechin Gallate on Orthotopic Colon Cancer by Upregulating the Nrf2-UGT1A Signal Pathway in Nude Mice , 2007, Pharmacology.

[49]  A. Mesecar,et al.  Molecular mechanisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2. , 2008, Molecular nutrition & food research.

[50]  Y. Surh,et al.  Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential. , 1995, Life sciences.

[51]  M. Lieberman,et al.  Ubiquitination of Keap1, a BTB-Kelch Substrate Adaptor Protein for Cul3, Targets Keap1 for Degradation by a Proteasome-independent Pathway* , 2005, Journal of Biological Chemistry.

[52]  Y. Surh,et al.  (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. , 2008, Archives of biochemistry and biophysics.

[53]  Hongqiao Zhang,et al.  Curcumin alters EpRE and AP‐1 binding complexes and elevates glutamate‐cysteine ligase gene expression , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[54]  John M Pezzuto,et al.  Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[55]  A. Mesecar,et al.  Sites of alkylation of human Keap1 by natural chemoprevention agents , 2007, Journal of the American Society for Mass Spectrometry.

[56]  M. Inoue,et al.  Green tea and coffee intake and risk of pancreatic cancer in a large-scale, population-based cohort study in Japan (JPHC study) , 2007, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[57]  Sanjay Gupta,et al.  Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action. , 2008, Carcinogenesis.

[58]  Donna D. Zhang,et al.  Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity. , 2007, Toxicology and applied pharmacology.

[59]  M. Hannink,et al.  Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling , 2006, The EMBO journal.

[60]  Jae Heun Lee,et al.  Up-regulation of aldose reductase expression mediated by phosphatidylinositol 3-kinase/Akt and Nrf2 is involved in the protective effect of curcumin against oxidative damage. , 2007, Free radical biology & medicine.

[61]  R. Yu,et al.  Induction of xenobiotic enzymes by the map kinase pathway and the antioxidant or electrophile response element (ARE/EpRE),†,‡ , 2001, Drug metabolism reviews.

[62]  J. K. Kundu,et al.  Molecular basis of chemoprevention by resveratrol: NF-kappaB and AP-1 as potential targets. , 2004, Mutation research.

[63]  S. Biswal,et al.  Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. , 2002, Cancer research.

[64]  C. Kunsch,et al.  Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. , 2004, Current pharmaceutical design.

[65]  Vincent Zoete,et al.  Two-step mechanism of induction of the gene expression of a prototypic cancer-protective enzyme by diphenols. , 2008, Chemical research in toxicology.

[66]  J. Ross,et al.  Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition. , 2007, International journal of molecular medicine.

[67]  N. Juge,et al.  Molecular basis for chemoprevention by sulforaphane: a comprehensive review , 2007, Cellular and Molecular Life Sciences.

[68]  A. Mesecar,et al.  Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase. , 2005, Chemical research in toxicology.

[69]  R. Brigelius-Flohé,et al.  The GI-GPx Gene Is a Target for Nrf2 , 2005, Molecular and Cellular Biology.

[70]  Y. Surh,et al.  Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. , 2007, Antioxidants & redox signaling.

[71]  A. Conney,et al.  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. , 2006, Cancer research.

[72]  Ha Won Kim,et al.  Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice , 2004, International journal of cancer.

[73]  A. I. Rojo,et al.  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* , 2004, Journal of Biological Chemistry.

[74]  J. K. Kundu,et al.  International Conference on Diet , Nutrition , and Cancer Redox-Sensitive Transcription Factors as Prime Targets for Chemoprevention with Anti-Inflammatory and Antioxidative Phytochemicals 1 – 3 , 2005 .

[75]  Paul Talalay,et al.  Direct and indirect antioxidant properties of inducers of cytoprotective proteins. , 2008, Molecular nutrition & food research.

[76]  B. Wung,et al.  Cinnamaldehyde inhibits the tumor necrosis factor-alpha-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-kappaB activation: effects upon IkappaB and Nrf2. , 2008, Toxicology and applied pharmacology.

[77]  K. Itoh,et al.  Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. , 2003, Carcinogenesis.

[78]  J M Lee,et al.  Chemoprotective properties of some pungent ingredients present in red pepper and ginger. , 1998, Mutation research.

[79]  Y. Surh,et al.  Nrf2 as a novel molecular target for chemoprevention. , 2005, Cancer letters.

[80]  K. Itoh,et al.  Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein. , 2008, Toxicology and applied pharmacology.

[81]  Junjie Xing,et al.  Protection of chlorophyllin against oxidative damage by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2 , 2008, Free radical research.

[82]  M. Kwak,et al.  Induction of Nrf2-regulated genes by 3H-1, 2-dithiole-3-thione through the ERK signaling pathway in murine keratinocytes. , 2007, European journal of pharmacology.

[83]  A. Kong,et al.  Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. , 2006, Cancer research.

[84]  Yan-qing Li,et al.  Protective Effects of Epigallocatechin Gallate on Colon Preneoplastic Lesions Induced by 2-Amino-3-Methylimidazo(4,5-f)Quinoline in Mice , 2008, Molecular medicine.

[85]  D. Sohn,et al.  2′,4′,6′-Tris(methoxymethoxy) chalcone protects against trinitrobenzene sulfonic acid-induced colitis and blocks tumor necrosis factor-α-induced intestinal epithelial inflammation via heme oxygenase 1-dependent and independent pathways , 2007 .

[86]  A. Nussler,et al.  Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. , 2007, Journal of hepatology.

[87]  R. Yu,et al.  Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death , 2000, Archives of pharmacal research.

[88]  A. Kong,et al.  Comparison of (−)-Epigallocatechin-3-Gallate Elicited Liver and Small Intestine Gene Expression Profiles Between C57BL/6J Mice and C57BL/6J/Nrf2 (−/−) Mice , 2005, Pharmaceutical Research.

[89]  Bok-Ryang Kim,et al.  Upregulation of heme oxygenase-1 by brazilin via the phosphatidylinositol 3-kinase/Akt and ERK pathways and its protective effect against oxidative injury. , 2008, European journal of pharmacology.

[90]  Y. Kan,et al.  Nrf2 is essential for protection against acute pulmonary injury in mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[91]  M. Sporn,et al.  Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. , 2006, Biochemical and biophysical research communications.

[92]  S H Moolgavkar,et al.  The multistage theory of carcinogenesis and the age distribution of cancer in man. , 1978, Journal of the National Cancer Institute.

[93]  M. Sporn,et al.  Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). , 1976, Federation proceedings.

[94]  M. Hannink,et al.  Structure of the Keap 1 : Nrf 2 interface provides mechanistic insight into Nrf 2 signaling , 2006 .

[95]  C. Ho,et al.  Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. , 2001, Biochemical pharmacology.

[96]  A. Kong,et al.  Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals. , 2004, Free radical biology & medicine.

[97]  W. Willett,et al.  Coffee, tea, and caffeine consumption and incidence of colon and rectal cancer. , 2005, Journal of the National Cancer Institute.

[98]  P. Maher,et al.  Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. , 2006, Investigative ophthalmology & visual science.

[99]  D. Spitz,et al.  Redox signaling in cancer biology. , 2006, Antioxidants & redox signaling.

[100]  X. Lu,et al.  Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of transcription factor Nrf2. , 2006, Medicinal chemistry (Shariqah (United Arab Emirates)).

[101]  T. Ishii,et al.  Sulforaphane, an activator of Nrf2, suppresses cellular accumulation of arsenic and its cytotoxicity in primary mouse hepatocytes , 2006, FEBS letters.

[102]  Y. Surh,et al.  Chemopreventive potential of epigallocatechin gallate and genistein: evidence from epidemiological and laboratory studies. , 2004, Toxicology letters.

[103]  A. Kong,et al.  Dietary chemopreventive compounds and ARE/EpRE signaling. , 2004, Free radical biology & medicine.

[104]  C. Yabe-Nishimura,et al.  Curcumin activates human glutathione S-transferase P1 expression through antioxidant response element. , 2007, Toxicology letters.

[105]  W. Mitzner,et al.  Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice , 2005, The Journal of experimental medicine.

[106]  B. Wung,et al.  Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile. , 2007, Life sciences.

[107]  Bok-Ryang Kim,et al.  Piperine protects cisplatin-induced apoptosis via heme oxygenase-1 induction in auditory cells. , 2007, The Journal of nutritional biochemistry.

[108]  P. Engstrom,et al.  Chemoprevention of cancer. , 1994, Current problems in cancer.

[109]  J. Jakubikova,et al.  Role of PI3K/Akt and MEK/ERK signaling pathways in sulforaphane- and erucin-induced phase II enzymes and MRP2 transcription, G2/M arrest and cell death in Caco-2 cells. , 2005, Biochemical pharmacology.

[110]  Jawed Alam,et al.  Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. , 2003, The Biochemical journal.

[111]  K. Itoh,et al.  An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. , 1997, Biochemical and biophysical research communications.

[112]  P. P. Chang,et al.  Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells. , 2006, Cancer research.

[113]  U. Sohn,et al.  The protective effect of eupatilin on indomethacin-induced cell damage in cultured feline ileal smooth muscle cells: involvement of HO-1 and ERK. , 2008, Journal of ethnopharmacology.

[114]  A. I. Rojo,et al.  GSK‐3β down‐regulates the transcription factor Nrf2 after oxidant damage: relevance to exposure of neuronal cells to oxidative stress , 2008 .

[115]  R. Brigelius-Flohé,et al.  Part of the Series: From dietary antioxidants to regulators in cellular signaling and gene regulation , 2006, Free radical research.

[116]  Wen-Sen Lee,et al.  Mechanism of concentration-dependent induction of heme oxygenase-1 by resveratrol in human aortic smooth muscle cells. , 2005, Biochemical pharmacology.

[117]  D. Sohn,et al.  2',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. , 2007, Biochemical pharmacology.

[118]  R. Brigelius-Flohé,et al.  Modulation of pregnane X receptor- and electrophile responsive element-mediated gene expression by dietary polyphenolic compounds. , 2007, Free radical biology & medicine.

[119]  M. Alcaraz,et al.  Role of nuclear factor-kappaB and heme oxygenase-1 in the mechanism of action of an anti-inflammatory chalcone derivative in RAW 264.7 cells. , 2004, British journal of pharmacology.

[120]  Masayuki Yamamoto,et al.  Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. , 2006, Advances in enzyme regulation.

[121]  L. Howells,et al.  Involvement of Nrf2, p38, B-Raf, and Nuclear Factor-κB, but Not Phosphatidylinositol 3-Kinase, in Induction of Hemeoxygenase-1 by Dietary Polyphenols , 2006, Molecular Pharmacology.

[122]  C. Klaassen,et al.  Induction of Drug-Metabolizing Enzymes by Garlic and Allyl Sulfide Compounds via Activation of Constitutive Androstane Receptor and Nuclear Factor E2-Related Factor 2 , 2007, Drug Metabolism and Disposition.

[123]  Y. Surh,et al.  Intracellular signaling network as a prime chemopreventive target of (-)-epigallocatechin gallate. , 2006, Molecular nutrition & food research.

[124]  K. Itoh,et al.  A Sulforaphane Analogue That Potently Activates the Nrf2-dependent Detoxification Pathway* , 2002, The Journal of Biological Chemistry.

[125]  D. Liebler,et al.  Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. , 2005, Chemical research in toxicology.

[126]  T. Mak,et al.  DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2 , 2006, Proceedings of the National Academy of Sciences.

[127]  M. Danilenko,et al.  Carotenoids activate the antioxidant response element transcription system. , 2004, Molecular cancer therapeutics.

[128]  W. Berkel,et al.  Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression. , 2006, Chemical research in toxicology.

[129]  S. Larsson,et al.  Coffee consumption and risk of liver cancer: a meta-analysis. , 2007, Gastroenterology.

[130]  Ik-Soo Lee,et al.  Isoorientin induces Nrf2 pathway-driven antioxidant response through phosphatidylinositol 3-kinase signaling , 2007, Archives of pharmacal research.

[131]  A. Cederbaum,et al.  Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. , 2004, Archives of biochemistry and biophysics.

[132]  M. O'Connell,et al.  Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes. , 2006, Biochemical and biophysical research communications.

[133]  A. Kong,et al.  Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. , 2006, Cancer letters.