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:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among five members of the NADPH oxidase (Nox) family, Nox1 confers mitogenic properties and is implicated to participate in the process of cell transformation. We have established two phenotypes of carcinogenesis model by ethanol treatment of human gingival keratinocytes immortalized with E6/E7 oncogenes of human papillomavirus type16: immortalized (EPI) nontransformed cells with epithelium-like morphology and more advanced transformed (FIB) cells with spindle fibroblastic-shape morphology. FIB membranes possessed a 63-kDa Nox1 protein at higher levels and exhibited 2.8-fold higher capability for superoxide and hydroxyl radical generation, compared with EPI membranes. Both EPI and FIB cells expressed more abundant Nox1 protein at a proliferating stage than that at a quiescent confluent phase. Immunofluorescence staining with an anti-Nox1 antibody showed that immunoreactive materials were distributed in the whole interior of both types of cells, while they were preferentially localized in the nuclei of FIB cells. Nuclei isolated from EPI and FIB cells contained a 63 kDa-Nox1 protein. Compared with EPI cells, FIB cells expressed elevated levels of Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase proteins. Furthermore, JNK2 was constitutively phosphorylated in FIB cells. Together, our data strongly implicate Nox1 in redox-mediated signaling related to cellular activation of human keratinocytes at a more advanced stage of transformation.
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PMID:Association of gp91phox homolog Nox1 with anchorage-independent growth and MAP kinase-activation of transformed human keratinocytes. 1295 83

Inhibitors of excessive superoxide (O2-) generation have been indicated to be more effective antioxidants than radical scavengers because O2- anion is one of the precursors of several types of reactive oxygen species (ROS). We demonstrated here that benzyl isothiocyanate (BITC) is a potent inhibitor of leukocytic NADPH oxidase generating a great amount of O2- in oxidative burst. The exposure of BITC to the differentiated HL-60 cells resulted in the inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced O2- generation, while the methylthiocarbamate analog of BITC, hardly reactive with thiols including glutathione and protein sulfhydryl, did not show any effect. Pre-treatment of the cells with diethyl maleate significantly potentiated the BITC-induced inhibition, while pre-treatment with N-acetyl-cysteine counteracted it. These results led us to assume that a plausible intracellular target molecule(s) having a reactive sulfhydryl moiety might be regulated by the covalent attachment with BITC. In spite of no ability to affect the translocation of protein kinase C beta to the membrane, BITC probably modifies the electron transport system of cytochrome b558, consistent with the observation that BITC inhibited the substrate utilization. Pre-treatments of mouse skin with BITC significantly attenuated the TPA-enhanced hydrogen peroxide level, suggesting that BITC indeed acts as an inhibitor of O2- generation in mouse skin. A histological study also demonstrated that BITC inhibited TPA-induced leukocyte infiltration in the dermis. Because we have found several O2- generation inhibitors to be effective chemopreventors against mouse skin carcinogenesis, the modifying effect of the topical application of BITC on TPA-induced mouse skin tumor promotion was investigated. We demonstrated for the first time that the pre-treatment with BITC 40 min prior to each TPA treatment significantly inhibited the number of papillomas per mouse. In conclusion, the results from this study provided biological evidence that BITC has a potential to prevent inflammation-related carcinogenesis including skin cancer.
Carcinogenesis 2004 Apr
PMID:Benzyl isothiocyanate inhibits excessive superoxide generation in inflammatory leukocytes: implication for prevention against inflammation-related carcinogenesis. 1468 23

The gastric inflammatory response provoked by Helicobacter pylori (H. pylori) consists of infiltrations by neutrophils, lymphocytes, and macrophages, resulting in varying degrees of epithelial cell damage. H. pylori-associated inflammation not only activates various oxidant-producing enzymes such as NADPH oxidase and inducible nitric oxide synthase, but also lowers the antioxidant ascorbic acid in the stomach. Reactive oxygen metabolites and nitrogen metabolites generated by these enzymes react with each other to generate new or more potent reactive species. The specific types of cellular damage resulting from reactive oxygen metabolites include lipid peroxidation, protein oxidation, and oxidative DNA damage. All of these oxidative products can result in biochemical changes leading to cancer. A positive association has been demonstrated between H. pylori infection and gastric adenocarcinoma with increased oxidative stress. Therefore, appropriate treatment to reduce oxidative stress would be expected to prevent subsequent gastric carcinogenesis through lessening of H. pylori-associated inflammation. This review will provide evidence that antiinflammatory regimens can decrease the development of tumors and the amelioration of gastric inflammation might lead to chemoprevention strategies by the attenuation of oxidative stress.
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PMID:Amelioration of oxidative stress with ensuing inflammation contributes to chemoprevention of H. pylori-associated gastric carcinogenesis. 1513 Feb 81

The persistent infection caused by hepatitis C virus (HCV) is presumably explained by a deficient immune response to the infection, but the basis for the inefficiency of immune-mediated virus eradication is not known in detail. This study addresses mechanisms of relevance to dysfunction of cytotoxic lymphocytes in HCV infection, with a focus on the role of phagocyte-derived oxygen radicals. We show that NS3, a nonstructural, HCV-encoded protein, induces a prolonged release of oxygen radicals from mononuclear and polymorphnuclear phagocytes by activating a key enzyme in radical formation, the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The NS3-activated phagocytes, in turn, induced dysfunction and/or apoptosis in three major subsets of lymphocytes of relevance to defense against HCV infection: CD3+/56- T cells, CD3-/56+ natural killer (NK) cells, and CD3+/56+ NKT cells. Two inhibitors of the NADPH oxidase, histamine and diphenylene iodonium, suppressed the NS3-induced oxygen radical production and efficiently protected lymphocytes against NS3-induced apoptosis and dysfunction. In conclusion, we propose that NS3, by triggering oxygen radical formation in phagocytes, may contribute to the dysfunction of antiviral lymphocytes in HCV-infected liver tissue and that strategies to circumvent oxidative stress may be useful in preventing HCV-associated carcinogenesis and facilitating lymphocyte-mediated clearance of infected cells.
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PMID:A hepatitis C virus-encoded, nonstructural protein (NS3) triggers dysfunction and apoptosis in lymphocytes: role of NADPH oxidase-derived oxygen radicals. 1537 90

We hypothesized that superoxide from Kupffer cells (KC) contributes to hepatocarcinogenesis. p47phox(-/-) mice, deficient in phagocyte NADPH oxidase and superoxide generation, received a single dose of the hepatocarcinogen diethylnitrosamine (DEN). The following hepatic effects were observed at time points between 30 min and 35 days. Liver damage after DEN was manifested by loss of body and liver mass and of liver DNA and by an increase in apoptosis, necrosis and signs of inflammation. These effects were massive in wild-type (wt) male mice, but only very mild in p47phox(-/-) mice. Regenerative DNA synthesis subsequent to liver damage was high in wt male mice, but weak in p47phox(-/-) mice. In females the apparent protection by p47phox(-/-) was less pronounced than in males. Therefore, further experiments were performed with males. In KC isolated from wt mice superoxide production was enhanced by DEN pretreatment in vivo. Also, in vitro addition of DEN to KC cultures induced superoxide release, similarly to lipopolysaccharide, a standard KC activator. Thus, DEN directly activates wt KC to produce superoxide. KC from p47phox(-/-) mice did not release superoxide. TNFalpha production by isolated KC was transiently depressed 0.5 h after DEN treatment in vivo, but recovered rapidly. In blood serum TNFalpha levels of wt mice were elevated for the initial 6 h. TNFalpha in KC cultures and in serum of p47phox(-/-) mice was reduced. DEN in vivo induced DNA damage ('comets') in hepatocytes. This damage was extensive in wt mice but much less in p47phox(-/-) mice. These studies suggest two conclusions: (i) superoxide generation by phagocytes during liver damage and inflammation aggravates genotoxic and cytotoxic effects in hepatocytes and may thus contribute to tumor initiation and promotion; (ii) DEN has a direct stimulatory effect on KC to release superoxide and TNFalpha.
Carcinogenesis 2005 Feb
PMID:Superoxide generation from Kupffer cells contributes to hepatocarcinogenesis: studies on NADPH oxidase knockout mice. 1551 30

Paradoxically, reactive oxygen species (ROS) can promote normal cellular proliferation and carcinogenesis, and can also induce apoptosis of tumor cells. In this report, we study the contribution of ROS to various cellular signals depending on the nature and the level of ROS produced. In nontransformed NIH 3T3 cells, ROS are at low levels and originate from NADPH oxidase. Hydrogen peroxide (H(2)O(2)), controlled by the glutathione system, is pivotal for the modulation of normal cell proliferation. In CT26 (colon) and Hepa 1-6 (liver) tumor cells, high levels of ROS, close to the threshold of cytotoxicity, are produced by mitochondria and H(2)O(2) is controlled by catalase. N-acetylcysteine, which decreases H(2)O(2) levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H(2)O(2) concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H(2)O(2) levels through superoxide anion dismutation, as well as in vitro proliferation of normal cells, but kill tumor cells. CT26 tumors were implanted in mice and treated by oxaliplatin in association with one of the three SOD mimics manganese(III)tetrakis(4-benzoic acid) porphyrin, copper(II)(3,5-diisopropylsalicylate)2, or manganese dipyridoxyl diphosphate. After 1 month, the volumes of tumors were respectively 35%, 31%, and 63% smaller than with oxaliplatin alone (P < 0.001). Similar data were gained with Hepa 1-6 tumors. In conclusion, antioxidant molecules may have opposite effects on tumor growth. SOD mimics can act in synergy with cytotoxic drugs to treat colon and liver cancers.
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PMID:Controlling tumor growth by modulating endogenous production of reactive oxygen species. 1639 77

Neutrophil oxidants are hypothesized to damage the gastric mucosa and promote carcinogenesis in people infected with Helicobacter pylori. To investigate this process we used wild-type and chronic granulomatous disease (CGD) mice with a targeted disruption of the gp91(phox) subunit of the NADPH oxidase. The mice were inoculated with a mouse-adapted strain of H. pylori and changes in gastric pathology were examined 12 and 30 weeks after infection. Glandular atrophy, a precursor lesion in the development of intestinal-type gastric carcinoma, and epithelial cell proliferation were both dramatically increased in the gastric body of CGD animals within 12 weeks. This correlated strongly with increased numbers of neutrophils in the mucosa (Pearson coefficient 0.97, P < 0.001). H. pylori is a noninvasive bacterium, and there was no increase in bacterial numbers in the CGD animals. Closer examination of the gastric tissue indicated the presence of degenerate neutrophils associated with atrophy. We hypothesize that the release of granule constituents from these neutrophils contributes to tissue damage. This is exacerbated by the absence of a functional NADPH oxidase, and is consistent with this enzyme complex having an important role in dampening the inflammatory response.
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PMID:NADPH oxidase involvement in the pathology of Helicobacter pylori infection. 1580 16

The following describes a novel screening method for "new chemical entities" (NCEs), suitable for ADMET studies, that measures ability to form prooxidant radicals on metabolism and their ability to induce oxidative stress in intact cells. The accelerated molecular cytotoxic mechanism screening (ACMS) techniques used with isolated rat hepatocytes showed that cytotoxicity is usually initiated as a result of macromolecular covalent binding or macromolecular oxidative stress. While P450 is likely responsible for drug metabolic activation in the liver, intestine, lung, and in other nonhepatic tissues, where P450 levels are low, peroxidases including prostaglandin synthetase peroxidase can catalyze xenobiotic one-electron oxidation to form prooxidant free radicals that may cause toxicity or carcinogenesis. Inflammation markedly activates H2O2, generating NADPH oxidase and peroxidase of certain immune cells when they infiltrate tissues including the liver. Myeloperoxidase and NADPH oxidase in the Kupffer cells (resident macrophages of the liver) also become activated during inflammation. The addition of noncytotoxic concentrations of peroxidase/H2O2 to the hepatocyte incubate markedly increased drug cytotoxicity and prooxidant radical formation as shown by glutathione or lipid oxidation. Many drugs that have hepato- or gastrointestinal (GI) toxicity problems or were withdrawn from the market for safety problems, e.g., troglitazone, tolcapone, mefenamic acid, diclofenac, and phenylbutazone, were markedly more toxic and prooxidant in this inflammation model system, whereas other drugs, e.g., entacapone, were not toxic in this inflammation model. Some of the idiosyncratic hepatotoxicity responsible for recent drug withdrawals may therefore result from commonplace sporadic inflammatory episodes during drug therapy.
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PMID:Oxidative stress mediated idiosyncratic drug toxicity. 1593 67

Reactive oxygen species (ROS) signal cascades involved in cell growth, cell death, mitogenesis, angiogenesis and carcinogenesis. ROS are produced as a byproduct of oxidative phosphorylation (OXPHOS) in the mitochondria. It is estimated that 2-4% of the oxygen consumed during OXPHOS is converted to ROS. Besides mitochondria, NADPH-oxidase 1 (Nox1) also generates a significant amount of ROS in the cell. In this paper, we tested the hypothesis that mitochondria control Nox 1 redox signaling and the loss of control of this signaling contributes to tumorigenesis. We analyzed Nox1 expression in a mitochondrial gene knockout (rho(0)) cell line and in the isogenic cybrid cell line in which mitochondrial genes were restored by transfer of wild type mitochondria into rho(0) cells. Our study revealed, for the first time, that the inactivation of mitochondrial genes leads to down-regulation of Nox1 and that the transfer of wild type mitochondrial genes restored the Nox1 expression to a level comparable to that in the parental cell line. Consistent with Nox1 down-regulation, we found that rho(0) cells contained low levels of superoxide anion and that superoxide levels reversed to parental levels in cybrid cells when Nox1 expression was restored by transfer of wild type mitochondria. Increasing mitochondrial superoxide levels also increased the expression of Nox1 in parental cells. Confocal microscopy studies revealed that Nox1 localizes in the mitochondria. Nox1 was highly expressed in breast (86%) and ovarian (71%) tumors and that its expression positively correlated with expression of cytochrome C oxidase encoded by mtDNA. Our study, described in this paper demonstrates the existence of cross talk between the mitochondria and NADPH oxidase. Furthermore, our studies suggest that mitochondria control Nox1 redox signaling and the loss of control of this signaling contributes to breast and ovarian tumorigenesis.
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PMID:Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors. 1629 28

We previously conducted screening tests of the chloroform extracts from a total of 89 species of Japanese plant food items for their suppressive effects on superoxide (O(2) ()) generation through both NADPH oxidase and xanthine oxidase, and reported that mioga ginger (Zingiber mioga Roscoe) indicated the strongest suppressive activities. In this study, the suppressive effects of mioga ginger constituents, aframodial, and galanal B, together with [6]-gingerol and galanolactone occurring in ginger, on free radical generation and inducible proinflammatory gene expressions were investigated. Of these constituents, aframodial (20 microM) exhibited marked suppressive effects on 12-O-tetradecanoylphorbol-13-acetate-induced O(2) () generation in HL-60 cells and lipopolysaccharide (LPS)/interferon-gamma-induced nitric oxide (NO) generation in RAW264.7 cells (inhibition rates [IRs]=84.6% and 95.9%, respectively). Aframodial also strongly suppressed the stimulated HL-60 cell-induced mutagenicity in AS52 cells (IR=95.9%). The LPS-induced expression of inducible proinflammatory genes such as inducible NO synthase, interleukin (IL)-1beta, IL-6, and granulocyte-macrophage colony-stimulating factor was significantly abolished (IRs=99.1%, 74.6%, 74.0%, and 64.4%, respectively) by aframodial. In addition, degradation of the inhibitor of nuclear factor kappaB was suppressed by this compound (IR=100%), suggesting that the suppression of nuclear factor kappaB activation, at least in part, is involved. Taken together, these results suggest that aframodial has potent antioxidative and anti-inflammatory potentials, and may be a promising candidate in prevention and/or therapy for chronic inflammationassociated carcinogenesis.
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PMID:Suppressive effects of mioga ginger and ginger constituents on reactive oxygen and nitrogen species generation, and the expression of inducible pro-inflammatory genes in macrophages. 1635 25


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