Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment for 48 h of murine Hepa 1c1c7 cells in culture with the cancer chemopreventive oltipraz (1) followed by addition of CD(3)I and immediate cell lysis yields, by LC/MS analysis, three isotopomers of the methylated pyrrolopyrazine (2), a known human metabolite of oltipraz. The major isotopomer (58%) is the one containing two CD(3)- groups attached to the pendant sulfur atoms of the pyrrolopyrazine ring, the others containing one CD(3)- and one CH(3)- group or two CH(3)- groups. It is concluded from this that the unmethylated pyrrolopyrazine (4) is the major metabolite of oltipraz. Prodrugs 5 and 6, which have been shown to rapidly generate 4 in the presence of GSH at physiological pH, induce the phase 2 enzyme NQO1 in Hepa 1c1c7 cells with potencies on par with oltipraz itself: CD(NQO1) = 14.4 +/- 1.3, 20.1 +/- 4.6, and 23.6 +/- 1.6 microM for oltipraz, 5, and 6, respectively. Pretreatment of oltipraz, 5, and 6 in cell culture media with 1 mM GSH, which is shown to immediately convert 5 and 6 to 4, followed by incubation with Hepa 1c1c7 cells shows similar potencies for oltipraz and the (decomposed) produrgs, with CD(NQO1) = 18.0 +/- 4.4 microM for 5, 17.8 +/- 0.2 microM for 6, and 13.5 +/- 1.4 microM for oltipraz. Treatment with compound 6 of murine hepatoma cells containing a luciferase gene under the control of the antioxidant response element (ARE) from the mouse heme oxygenase (ho-1) gene elicits induction of luciferase activity, CD = 35.8 +/- 2.8 microM, somewhat greater than the potency than oltipraz itself. Western blots of nuclear proteins isolated from Hepa 1c1c7 cells and probed with anti-Nrf2 indicate that as compared to vehicle DMSO, compound 6 stimulates nuclear translocation of Nrf2 from the cytosol. From this study, it is concluded that the major metabolite of the cancer chemopreventive oltipraz is a phase 2 enzyme inducer of comparable potency that activates the ARE and initiates nuclear translocation of transcription factor Nrf 2.
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PMID:Phase 2 enzyme induction by the major metabolite of oltipraz. 1461 73

In the last decade, it has become recognized that reactive oxygen species (ROS) play important roles in the multiple biological processes involved in the pathophysiology of chronic inflammation such as cell proliferation, adhesion molecule expression, cytokine and chemoattractant production and matrix metalloproteinase generation. Intracellular redox homeostasis is maintained by balancing the production of ROS with their removal through cellular antioxidant defense systems. The antioxidant response element (ARE) is a cis-acting DNA regulatory element located in the regulatory regions of multiple genes including phase II detoxification enzymes as well as antioxidant proteins including glutathione-S-transferases, NAD(P)H:quinone oxidoreductase-1, gamma-glutamylcysteine synthase, ferritin, and heme oxygenase-1. Nrf2 is the primary transcription factor that binds to the ARE, and through heterodimerization with other leucine-zipper containing transcription factors, activates the expression of these genes. It is evident that activation of ARE-regulated genes contributes to the regulation of cellular antioxidant defense systems. More importantly, there is a growing body of evidence suggesting that modulation of these cytoprotective genes has profound effects on immune and inflammatory responses. Activation of cytoprotective Nrf2/ARE-regulated genes can suppress inflammatory responses, whereas decreased expression of these genes results in autoimmune disease and enhanced inflammatory responses to oxidant insults. Thus, coordinate induction of cytoprotective genes through Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of immune and inflammatory diseases.
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PMID:Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. 1503 91

The retinal pigment epithelial cell (RPE cell) layer protects the photoreceptors of the retina against oxidative stress. The decline of this capacity is believed to be a major factor in the impairment of vision in age-related macular degeneration. Exposure of human adult RPE cells to UV light at predominantly 320-400 nm (UVA light) in the presence of all-trans-retinaldehyde results in photooxidative cytotoxicity. Significant protection of RPE cells was obtained by prior treatment with phase 2 gene inducers, such as the isothiocyanate sulforaphane or a bis-2-hydroxybenzylideneacetone Michael reaction acceptor. The degree of protection was correlated with the potencies of these inducers in elevating cytoprotective glutathione levels and activities of NAD(P)H:quinone oxidoreductase. In embryonic fibroblasts derived from mice in which the genes for the transcription factor Nrf2, the repressor Keap1, or both Nrf2 and Keap1 were disrupted, the magnitude of resistance to photooxidative damage paralleled the basal levels of glutathione and NAD(P)H:quinone oxidoreductase in each cell type. Demonstration of protection of RPE cells against photooxidative damage by induction of phase 2 proteins may shed light on the role of oxidative injury in ocular disease. Moreover, the finding that dietary inducers provide indirect antioxidant protection suggests novel strategies for preventing chronic degenerative diseases, such as age-related macular degeneration.
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PMID:Induction of phase 2 genes by sulforaphane protects retinal pigment epithelial cells against photooxidative damage. 1522 24

Antioxidant-response element (ARE) and nuclear factor Nrf2-mediated expression and coordinated induction of genes encoding chemopreventive proteins, including NQO1, are critical mechanisms in chemoprotection. Recently, Nrf3, a new member of the Nrf family with substantial homology to Nrf2, was identified and cloned. In this report, we have investigated the role of Nrf3 in ARE-mediated gene expression and induction of NQO1 in response to antioxidants. Overexpression of Nrf3 in Hep-G2 cells led to a concentration-dependent decrease in transfected and endogenous NQO1 gene expression and induction in response to antioxidant tert-butylhydroquinone (t-BHQ). Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3. Bandshift and supershift assays with in vitro transcribed and translated proteins and nuclear extracts from Hep-G2 cells treated with Me2SO and t-BHQ and immunoprecipitation assays demonstrated that Nrf3 associates with small Maf proteins to bind to the ARE. RNA interference specific to Nrf3 reduced intracellular Nrf3 leading to increased expression and induction of transfected and endogenous NQO1 gene expression in response to t-BHQ. These results combined suggest that Nrf3 is a negative regulator of ARE-mediated gene expression.
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PMID:Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. 1538 60

Epidemiologic studies have found an inverse association between consumption of tomato products and the risk of certain types of cancers. However, the mechanisms underlying this relationship are not completely understood. One mechanism that has been suggested is induction of phase II detoxification enzymes. Expression of phase II enzymes is regulated by the antioxidant response element (ARE) and the transcription factor Nrf2 (nuclear factor E2-related factor 2). In this study, we determined the role of this transcription system in the induction of phase II enzymes by carotenoids. We found that in transiently transfected cancer cells, lycopene transactivated the expression of reporter genes fused with ARE sequences. Other carotenoids such as phytoene, phytofluene, beta-carotene, and astaxanthin had a much smaller effect. An increase in protein as well as mRNA levels of the phase II enzymes NAD(P)H:quinone oxidoreductase and gamma-glutamylcysteine synthetase was observed in nontransfected cells after carotenoid treatment. Ethanolic extract of lycopene containing unidentified hydrophilic derivatives of the carotenoid activated ARE with similar potency to lycopene. The potency of the carotenoids in ARE activation did not correlate with their effect on intracellular reactive oxygen species and reduced glutathione level, which may indicate that ARE activation is not solely related to their antioxidant activity. Nrf2, which is found predominantly in the cytoplasm of control cells, translocated to the nucleus after carotenoid treatment. Interestingly, part of the translocated Nrf2 colocalized with the promyelocytic leukemia protein in the promyelocytic leukemia nuclear bodies. The increase in phase II enzymes was abolished by a dominant-negative Nrf2, suggesting that carotenoid induction of these proteins depends on a functional Nrf2 and the ARE transcription system.
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PMID:Carotenoids activate the antioxidant response element transcription system. 1565 64

The antioxidant response element (ARE) and Nrf2 are known to regulate the expression and coordinated induction of genes encoding detoxifying enzymes including NAD(P)H:quinone oxidoreductase1 (NQO1) in response to antioxidants. In this report, we demonstrate that overexpression of the transcription factor Bach1 in Hep-G2 cells negatively regulated NQO1 gene expression and induction in response to antioxidant t-BHQ. Bandshift and supershift assays revealed that Bach1 binds to the ARE as a heterodimer with small Maf proteins but not as a homodimer or heterodimer with Nrf2. The transfection and ChIP assays revealed that Bach1 and Nrf2 competed with each other to regulate ARE-mediated gene expression. Heme, a negative regulator of Bach1 relieved the Bach1 repression of NQO1 gene expression in transfected cells. The transcription of Bach1 and Nrf2 did not change in response to t-BHQ. Immunofluorescence assays and Western blot analysis revealed that both Bach1 and Nrf2 localized in the cytoplasm and nucleus of the untreated cells. The treatment of cells with t-BHQ resulted in the nuclear accumulation of both Bach1 and Nrf2. Interestingly, the t-BHQ-induced nuclear accumulation of Bach1 was significantly delayed over that of Nrf2. These results led to the conclusion that a balance of Nrf2 versus Bach1 inside the nucleus influences up- or down-regulation of ARE-mediated gene expression. The results further suggest that antioxidant-induced delayed accumulation of Bach1 contributes to the down-regulation of ARE-regulated genes, presumably to reduce the antioxidant enzymes to normal levels.
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PMID:Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. 1573 32

A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-gamma of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress. Moreover, like previously identified phase 2 inducers, the TP analogues use the antioxidant response element-Nrf2-Keap1 signaling pathway. Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2(-/-) and keap1(-/-) mouse embryonic fibroblasts. The high potency of TP analogues in inducing the phase 2 response and blocking inflammation depends on the presence of activated Michael reaction (enone) functions at critical positions in rings A and C. The most potent TP doubles NAD(P)H-quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC(50) for suppression of iNOS induction in primary mouse macrophages of 0.0035 nM. The direct interaction of this TP with thiol groups of the Keap1 sensor for inducers is demonstrated spectroscopically. The antiinflammatory and phase 2 inducer potencies of 18 TP are closely linearly correlated (r(2) = 0.91) over 6 orders of magnitude of concentration. Thus, in addition to blocking inflammation and promoting differentiation, these TP exhibit another very important protective property: the induction of the phase 2 response.
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PMID:Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. 1576 73

Aerobic cells produce reactive oxygen species as a consequence of normal cellular metabolism, and an array of antioxidant systems are in place to maintain the redox balance. When the redox equilibrium of the cell is upset by pro-oxidant environmental stimuli, adaptive responses to the redox stress take place, which can result in up-regulation of antioxidant proteins and detoxification enzymes. Over the past few years, it has become apparent that members of the CNC (cap 'n' collar)-basic leucine zipper family of transcription factors are principal mediators of defensive responses to redox stress. In mammals, the CNC family members nuclear factor-erythroid 2 p45-related factors 1 and 2 (Nrf1 and Nrf2) have been shown to be involved in the transcriptional up-regulation of cytoprotective genes including those encoding glutamate cysteine ligase, NAD(P)H:quinone oxidoreductase, glutathione S-transferases and aldo-keto reductases. An evolutionarily conserved system exists in Caenorhabditis elegans, and it is possible that Drosophila melanogaster may also utilize CNC transcription factors to induce antioxidant genes in response to pro-oxidant chemicals. The advent of microarray and proteomic technologies has advanced our understanding of the gene batteries regulated by oxidative insult, but has highlighted the complexity of gene regulation by environmental factors. This review focuses on the antioxidant response to environmental stress, and the impact that microarrays and proteomics have made in this field.
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PMID:Antioxidant and cytoprotective responses to redox stress. 1577 20

Understanding the molecular pathway(s) of antioxidant gene regulation is of crucial importance for developing antioxidant-inducing agents for the intervention of oxidative cardiac disorders. Accordingly, this study was undertaken to determine the role of Nrf2 signaling in the basal expression as well as the chemical inducibility of endogenous antioxidants and phase 2 enzymes in cardiac fibroblasts. The basal expression of a scope of key cellular antioxidants and phase 2 enzymes was significantly lower in cardiac fibroblasts derived from Nrf2-/- mice than those from wild type control. These include catalase, reduced glutathione (GSH), glutathione reductase (GR), GSH S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NQO1). Incubation of Nrf2+/+ cardiac fibroblasts with 3H-1,2-dithiole-3-thione (D3T) led to a significant induction of superoxide dismutase (SOD), catalase, GSH, GR, glutathione peroxidase (GPx), GST, and NQO1. The inducibility of SOD, catalase, GSH, GR, GST, and NQO1, but not GPx by D3T was completely abolished in Nrf2-/- cells. The Nrf2-/- cardiac fibroblasts were much more sensitive to reactive oxygen and nitrogen species-mediated cytotoxicity. Upregulation of antioxidants and phase 2 enzymes by D3T in Nrf2+/+ cardiac fibroblasts resulted in a dramatically increased resistance to the above species-induced cytotoxicity. In contrast, D3T-treatment of the Nrf2-/- cells only provided a slight cytoprotection. Taken together, this study demonstrates for the first time that Nrf2 is critically involved in the regulation of the basal expression and chemical induction of a number of antioxidants and phase 2 enzymes in cardiac fibroblasts, and is an important factor in controlling cardiac cellular susceptibility to reactive oxygen and nitrogen species-induced cytotoxicity.
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PMID:Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: protection against reactive oxygen and nitrogen species-induced cell injury. 1589 89

The Nrf2-Keap1 system coordinately regulates cytoprotective gene expression via the antioxidant responsive element (ARE). The expression of several ARE-regulated genes was found to be up-regulated in endothelial cells by laminar shear stress, suggesting that Nrf2 contributes to the anti-atherosclerosis response via the ARE. To gain further insight into the roles that Nrf2 plays in the development of atherosclerosis, we examined how Nrf2 regulates gene expression in response to anti-atherogenic laminar flow (L-flow) or pro-atherogenic oscillatory flow (O-flow). Exposure of human aortic endothelial cells (HAECs) to L-flow, but not to O-flow, induced the expression of cytoprotective genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1) by 5-fold and heme oxygenase-1 by 8-fold. The critical contribution of Nrf2 to the expression induced by L-flow was ascertained in siRNA-mediated knock-down experiments. Two cyclooxygenase-2 (COX-2) specific inhibitors attenuated Nrf2 nuclear accumulation in the acute phase of L-flow exposure. A downstream product of COX-2, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), activated the Nrf2 regulatory pathway in HAECs through binding to the cysteines of Keap1. These results demonstrate that 15d-PGJ2 is essential for L-flow to activate Nrf2 and induce anti-atherosclerotic gene expression. Whereas both L-flow and O-flow induced the nuclear accumulation of Nrf2 to comparable levels, chromatin immunoprecipitation analysis revealed that Nrf2 binding to the NQO1 ARE was significantly diminished in the case of O-flow compared with that of L-flow. These results suggest that O-flow inhibits Nrf2 activity at the DNA binding step, thereby suppressing athero-protective gene expression and hence predisposing the blood vessels to the formation of atherosclerosis.
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PMID:Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. 1591 55


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