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)

We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GST micro-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.
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PMID:Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin. 1648 34

Spices and herbs often contain active phenolic substances endowed with potent antioxidative properties. We had previously shown that curcumin, the yellow pigment in curry, strongly induced HO-1 expression and activity in rat astrocytes. In the CNS, HO-1 has been reported to operate as a fundamental defensive mechanism for neurons exposed to an oxidant challenge. Treatment of astrocytes with curcumin upregulated expression of HO-1 protein at both cytoplasmic and nuclear levels, as shown by immunofluorescence analysis under laser-scanning confocal microscopy. A significant expression of quinone reductase and glutathione S transferase, two members of phase II detoxification enzymes, was found in astrocytes exposed to 5-15 microM curcumin. Moreover, the effects of curcumin on HO-1 activity were explored in cultured hippocampal neurons. Elevated expression of HO-1 mRNA and protein were detected after 6 h incubation with 5-25 microM curcumin. Higher concentrations of curcumin (50-100 microM) caused a substantial cytotoxic effect with no change in HO-1 protein expression. Interestingly, pre-incubation (18 h) with curcumin resulted in an enhanced cellular resistance to glucose oxidase-mediated oxidative damage; this cytoprotective effect was considerably attenuated by zinc protoporphyrin IX, an inhibitor of heme oxygenase activity. This study gives additional support to the possible use of curcumin as a dietary preventive agent against oxidative stress-related diseases.
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PMID:Curcumin activates defensive genes and protects neurons against oxidative stress. 1667 86

We have previously reported that antioxidant response element (ARE)-regulated genes, such as heme oxygenase 1 (HO-1), sequestosome 1 (SQSTM1), and NAD(P)H quinone oxidoreductase 1 (NQO1), are induced in human umbilical vein endothelial cells (HUVEC) upon exposure to laminar shear stress. In the present study, we have confirmed a critical role for NF-E2-related factor 2 (Nrf2) in the induction of gene expression in HUVEC exposed to laminar shear stress. Although the mRNA levels of Nrf2 were unchanged during exposure to shear stress, the protein levels of Nrf2 were markedly increased. Small interfering RNA (SiRNA) against Nrf2 significantly attenuated the expression of Nrf2-regulated genes such as HO-1, SQSTM1, NQO1, glutamate-cysteine ligase modifier subunit (GCLM), and ferritin heavy chain. Nrf2 was rapidly degraded in cells treated with cycloheximide under static conditions, but shear stress decreased the rate of Nrf2 degradation. Incubation with the thiol antioxidant N-acetylcysteine strongly inhibited both the Nrf2 accumulation and the expression of Nrf2-regulated genes such as HO-1, GCLM, and SQSTM1. Nitric oxide (NO) production was increased with the strength of shear stress but neither the inhibitor of endothelial NO synthase (eNOS) nor the siRNA against eNOS affected the expression of Nrf2-regulated genes. A xanthine oxidase inhibitor oxypurinol and the flavoprotein inhibitor diphenyleneiodonium, which inhibits NAD(P)H oxidase and mitochondrial respiratory chain, markedly suppressed the expression of these genes. Moreover, diphenylpyrenlphosphine, a reducing compound of lipid hydroperoxides, also significantly suppressed Nrf2-regulated gene expression. Taken together, these findings suggest that shear stress stabilizes Nrf2 protein via the lipid peroxidation elicited by xanthine oxidase and flavoprotein mediated generation of superoxide, resulting in gene induction by the Nrf2-ARE signaling pathway.
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PMID:Shear stress stabilizes NF-E2-related factor 2 and induces antioxidant genes in endothelial cells: role of reactive oxygen/nitrogen species. 1718 31

Consumers of higher levels of Brassica vegetables, particularly those of the genus Brassica (broccoli, Brussels sprouts and cabbage), reduce their susceptibility to cancer at a variety of organ sites. Brassica vegetables contain high concentrations of glucosinolates that can be hydrolyzed by the plant enzyme, myrosinase, or intestinal microflora to isothiocyanates, potent inducers of cytoprotective enzymes and inhibitors of carcinogenesis. Oral administration of either the isothiocyanate, sulforaphane, or its glucosinolate precursor, glucoraphanin, inhibits mammary carcinogenesis in rats treated with 7,12-dimethylbenz[a]anthracene. In this study, we sought to determine whether sulforaphane exerts a direct chemopreventive action on animal and human mammary tissue. The pharmacokinetics and pharmacodynamics of a single 150 mumol oral dose of sulforaphane were evaluated in the rat mammary gland. We detected sulforaphane metabolites at concentrations known to alter gene expression in cell culture. Elevated cytoprotective NAD(P)H:quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1) gene transcripts were measured using quantitative real-time polymerase chain reaction. An observed 3-fold increase in NQO1 enzymatic activity, as well as 4-fold elevated immunostaining of HO-1 in rat mammary epithelium, provides strong evidence of a pronounced pharmacodynamic action of sulforaphane. In a subsequent pilot study, eight healthy women undergoing reduction mammoplasty were given a single dose of a broccoli sprout preparation containing 200 mumol of sulforaphane. Following oral dosing, sulforaphane metabolites were readily measurable in human breast tissue enriched for epithelial cells. These findings provide a strong rationale for evaluating the protective effects of a broccoli sprout preparation in clinical trials of women at risk for breast cancer.
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PMID:Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. 1734 38

The isothiocyanate sulforaphane was isolated from broccoli extracts in a bioactivity-guided fractionation as the principal and very potent inducer of cytoprotective phase 2 enzymes and subsequently shown to inhibit tumor development in animal models that involve various carcinogens and target organs. Because broccoli and broccoli sprouts are widely consumed, extracts obtained from them are viewed as convenient vehicles for sulforaphane delivery to humans. In relation to our current interest in devising strategies for protection against UV light-induced skin cancer, it was necessary to examine the safety and efficacy of topical application of sulforaphane-containing broccoli sprout extracts as single and multiple doses in both mice and humans. Topical application of an extract delivering 100 nmol sulforaphane/cm(2) increased the protein levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase A1, and heme oxygenase 1, three representative phase 2 enzymes, in mouse skin epidermis. Quantitative assessment of the activity of NQO1 24 h after dosing showed increases of 1.5- and 2.7-fold after application of single and multiple (thrice, every 24 h) doses, respectively. A dose-escalation safety study in healthy human subjects revealed no adverse reactions when doses as high as 340 nmol of sulforaphane in the form of broccoli sprout extracts were applied topically to the center of a 1-cm-diameter circle drawn on the volar forearm. A subsequent efficacy study showed that despite the interindividual differences in basal levels, the enzyme activity of NQO1 in homogenates of 3-mm full thickness skin punch biopsies increased in a dose-dependent manner, with maximum increases of 1.5- and 4.5-fold after application of 150 nmol doses, once or three times (at 24 h-intervals), respectively, thus providing direct evidence for induction of the phase 2 response in humans.
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PMID:Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts. 1741 83

Increased generation of reactive oxygen species (ROS) in vascular diseases such as atherosclerosis, diabetes, chronic renal failure and preeclampsia readily leads to impaired endothelium-dependent relaxation and vascular injury. To counteract ROS- and electrophile-mediated injury, cells can induce a number of genes encoding phase II detoxifying enzymes and antioxidant proteins. A cis-acting transcriptional regulatory element, designated as antioxidant response element (ARE) or electrophile response element (EpRE), mediates the transcriptional activation of genes such as heme oxygenase-1, gamma-glutamylcysteine synthethase, thioredoxin reductase, glutathione-S-transferase and NAD(P)H:quinone oxidoreductase. Other antioxidant enzymes such as superoxide dismutase and catalase and non-enzymatic scavengers such as glutathione are also involved in scavenging ROS. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap nno Collar family of basic region-leucine zipper (bZIP) transcription factors, plays an important role in ARE-mediated antioxidant gene expression. Kelch-like ECH-associated protein-1 (Keap1) normally sequesters Nrf2 in the cytoplasm in association with the actin cytoskeleton, but upon oxidation of cysteine residues Nrf2 dissociates from Keap1, translocates to the nucleus and binds to ARE sequences leading to transcriptional activation of antioxidant and phase II detoxifying genes. Protein kinase C (PKC), mitogen-activated protein kinases (MAPKs) and phosphotidylinositol 3-kinase (PI3K) have been implicated in the regulation of Nrf2/ARE signaling. We here review the evidence that the Nrf2/ARE signaling pathway plays an important role in vascular homeostasis and the defense of endothelial and smooth muscle cells against sustained oxidative stress associated with diseases such as atherosclerosis and preeclampsia.
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PMID:Nrf2/ARE regulated antioxidant gene expression in endothelial and smooth muscle cells in oxidative stress: implications for atherosclerosis and preeclampsia. 1743 32

Spanish black radish (Raphanus sativus L. var. niger) is a member of the Cruciferae family that also contains broccoli and Brussels sprouts, well-known to contain health-promoting constituents. Spanish black radishes (SBR) contain high concentrations of a glucosinolate unique to the radish family, glucoraphasatin, which represents >65% of the total glucosinolates present in SBR. The metabolites of glucosinolates, such as isothiocyanates, are implicated in health promotion, although it is unclear whether glucosinolates themselves elicit a similar response. The crude aqueous extract from 0.3 to 3 mg of dry SBR material increased the activity of the phase II detoxification enzyme quinone reductase in the human hepatoma HepG2 cell line with a maximal effect at a concentration of 1 mg/mL. Treatment of HepG2 cells with the crude aqueous extract of 1 mg of SBR per mL also significantly induced the expression of mRNA corresponding to the phase I detoxification enzymes: cytochrome P450 (CYP) 1A1, CYP1A2, and CYP1B1 as well as the phase II detoxification enzymes: quinone reductase, heme oxygenase 1, and thioredoxin reductase 1. Previous studies have shown that the myrosinase metabolites of different glucosinolates vary in their ability to induce detoxification enzymes. Here, we show that while glucoraphasatin addition was ineffective, the isothiocyanate metabolite of glucoraphasatin, 4-methylthio-3-butenyl isothiocyanate (MIBITC), significantly induced phase II detoxification enzymes at a concentration of 10 microM. These data demonstrate that the crude aqueous extract of SBR and the isothiocyanate metabolite of glucoraphasatin, MIBITC, are potent inducers of detoxification enzymes in the HepG2 cell line.
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PMID:Aqueous extract from Spanish black radish (Raphanus sativus L. Var. niger) induces detoxification enzymes in the HepG2 human hepatoma cell line. 1761 35

In the central nervous system oxidative stress has been implicated in the pathology of several neurological disorders. The ability to withstand reactive oxygen species and oxidative stress are essential for survival and therefore all aerobic cells are endowed with chemical and enzymatic antioxidative defense systems. The purpose of the present study was to investigate the antioxidative response at the transcriptional level following exposure of primary astrocytes to a pro-oxidant, Paraquat (PQ). This was done by investigating the time-dependent expression of selected genes encoding the antioxidative enzymes Mn- and CuZn superoxide dismutase (SOD) and catalase as well as the transcription factor component AP-1. Paraquat induced the expression of Mn- and CuZn SOD, catalase and decreases the expression of c-jun (a part of AP-1). Furthermore, the gene expression profiles were investigated after exposure to PQ using a commercial cDNA membrane array containing 207 genes from key oxidative stress pathways. The gene expression pattern clearly indicated that 60 microM PQ for 48 h induces genes related to oxidative stress, detoxification, mitotic arrest, DNA repair, and apoptosis. The PQ (48 h)-induced expressions of genes identified in cDNA array were confirmed by Northern blot analysis, which revealed a statistical significant up-regulation of genes involved in oxidative stress, detoxification, and DNA repair/synthesis and includes heme oxygenase-1 (11-fold), NAD(P)H dehydrogenase (8-fold), glutathione S-transferase P (7-fold), glucose-regulated 78-kDa protein (7-fold), glucose-regulated 75-kDa protein (6-fold), and growth-arrest and DNA-damage-inducible protein 45 (4.5-fold) and minor changes for heat shock 10-kDa protein, NADPH-cytochrome P450 reductase, heme oxygenase-2, proliferating cell nuclear antigen, and Bcl-2-associated death promoter. Thus, we could demonstrate a PQ-inducible effect of the mRNA of antioxidative enzymes, as well as the mRNAs of possible enzymes involved in the protection against oxidative stress.
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PMID:Characterization of the transcriptional profile in primary astrocytes after oxidative stress induced by Paraquat. 1793 86

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a major pungent ingredient of red pepper, is reported to have antimutagenic and anticarcinogenic properties. However, the mechanisms underlying its chemoprotective effects remain largely unresolved. In the present study, we found that capsaicin induced expression of heme oxygenase-1 (HO-1) in HepG2 cells. Capsaicin treatment resulted in a transient increase in the phosphorylation of Akt and subsequently nuclear translocation of NF-E2-related factor 2 (Nrf2), enhancing its binding to antioxidant response element (ARE). HepG2 cells treated with capsaicin exhibited increased production of reactive oxygen species (ROS). Prior exposure of cells to N-acetyl-L -cysteine blocked not only the ROS production but also the nuclear translocation of Nrf2 and its ARE binding, as well as HO-1 induction by capsaicin. Immunoblot analysis showed that whereas the level of HO-1 protein was elevated, that of NAD(P)H:quinone oxidoreductase (NQO1) was decreased after the treatment with capsaicin or the inhibitor of NQO1, dicumarol. We hypothesize that quinone metabolites or other reactive forms of capsaicin may bind covalently to NQO1 and thereby inhibit its activity, leading to production of ROS. This, in turn, would trigger the activation of Akt via phosphorylation, increase the nuclear translocation and ARE binding of Nrf2, and upregulate the expression of HO-1.
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PMID:Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. 1797 24

Secondary brain injury plays a pivotal role in the outcome of patients suffering from traumatic brain injury (TBI). The mechanisms underlying secondary brain injury are complex and interrelated. Previous studies focused on one of these mechanisms have been proved to be ineffective in clinical practice. Therefore, a target, which can interrupt multi-mechanisms underlying TBI, is desirable. Nrf2-ARE pathway has been proved to be the key regulator in reducing oxidative stress, inflammatory damage and accumulation of toxic metabolites, which are all involved in TBI. However, whether Nrf2-ARE pathway is activated after TBI has not been studied. In the present study, the nuclear Nrf2 protein level was detected by Western blot, and the mRNA levels of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1), two Nrf2-regulated gene products, were determined using reverse-transcriptase polymerase chain reaction (RT-PCR) 24h after TBI. Furthermore, we also localized the expression of Nrf2 and HO-1 using immunohistochemical study. After TBI, the nuclear Nrf2 protein level was significantly increased, and the mRNA levels of both HO-1 and NQO1 were also up regulated. Moreover, both Nrf2 and HO-1 were localized in the same types of cells. According to these results, it could be postulated that Nrf2-ARE pathway was activated in brain after TBI.
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PMID:Activation of Nrf2-ARE pathway in brain after traumatic brain injury. 1816 15


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