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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 (COX-2) expression is induced in the neurons of the pathologic brain and elevated COX-2 expressions can lead to neuronal death. Here, we report that COX-2 induction in cortical neurons induced by LPS pretreatment for more than 12 h increased the neurotoxic effects of low doses of Fe2+ by more than 2.5-fold. Moreover, the neurotoxicity induced by 30 muM Fe2+ in LPS-pretreated cells exceeded that induced by 100 microM Fe2+ in LPS-untreated cells. LPS pretreatment also similarly aggravated the neurotoxic effects of low doses of H2O2, Zn2+, and sodium nitroprusside. This LPS-induced Fe2+ -toxicity enhancement was blocked by trolox, vitamin C, the SOD mimetic MnTBAP, and by the COX-2-specific inhibitor NS398, but not by inhibitors of xanthine oxidase, NADPH oxidase, NOS, and monoamine oxidase. Cortical neurons with enhanced COX-2 expression showed superoxide generation, GSH depletion, and lipid peroxidation in response to low doses of Fe2+, and all of these changes were repressed by MnTBAP or NS398. Consistent with this pharmacological data, cortical neurons prepared from COX-2 knockout mice showed marked reductions in LPS-induced Fe2+ -toxicity enhancement and superoxide generation. These results suggest that COX-2 functions as a cellular factor which induces superoxide-mediated cell death in primary cortical neurons.
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PMID:Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation. 1693 79

Exposure of human umbilical endothelial cells (ECs) to cigarette smoke extract (CSE) activated the NADPH-oxidase enzyme and increased the production of superoxide (O-2) as well as reactive oxygen species (ROS). CSE also inhibited the prostacyclin (PGI2) formation by ECs. Preincubation of ECs with diphenylene iodonium (DPI), the inhibitor of NADPH oxidase, blocked the increase of O-2 production, but neither lowered the ROS level nor prevented the inhibition of PGI2 formation in CSE-treated cells. Preincubation of ECs with a medium supplemented with 1 mM vitamin C did not decrease, but rather increased the O-2 production in CSE-treated cells. However, adding 1 mM glutathione (GSH) to vitamin C decreased the O-2 production, indicating that vitamin C was overwhelmed by the prooxidant in CS, and GSH enhanced the recycling process and spared vitamin C. The ROS level remained high in CSE-treated cells even after preincubation with vitamin C or vitamin C + GSH compared to the control cells. These results are discussed in light of the possible decrease of antioxidant enzyme activities in CSE-treated cells and the increase of cellular hydrogen peroxide (H2O2) generated from the CSE, which cause an imbalance between oxidizing species and the antioxidants producing oxidative stress in CSE-treated cells. These results demonstrate that CSE has a direct inhibitory effect on PGI2 formation and enhances the level of ROS in CSE-treated ECs, regardless of the activation of NADPH-oxidase.
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PMID:Inhibition of prostacyclin release by cigarette smoke extract in endothelial cells is not related to enhanced superoxide generation and NADPH-oxidase activation. 1707 61

Apocynin has been used as an efficient inhibitor of the NADPH oxidase complex and its mechanism of inhibition is linked to prior activation through the action of peroxidases. Here we studied the oxidation of apocynin catalyzed by myeloperoxidase (MPO) and activated neutrophils. We found that apocynin is easily oxidized by MPO/H2O2 or activated neutrophils and has as products dimer and trimer derivatives. Since apocynin impedes the migration of the cytosolic component p47phox to the membrane and this effect could be related to its conjugation with essential thiol groups, we studied the reactivity of apocynin and its MPO-catalyzed oxidation products with glutathione (GSH). We found that apocynin and its oxidation products do not react with GSH. However, this thiol compound was efficiently oxidized by the apocynin radical during the MPO-catalyzed oxidation. We suggest that the reactivity of apocynin radical with thiol compounds could be involved in the inhibitory effect of this methoxy-catechol on NADPH oxidase complex.
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PMID:The oxidation of apocynin catalyzed by myeloperoxidase: proposal for NADPH oxidase inhibition. 1716 80

Ammonium is a central intermediate in the nitrogen metabolism of plants. We have previously shown that methyl jasmonate (MJ) not only increases the content of H(2)O(2), but also causes NH(4)(+) accumulation in rice leaves. More recently, H(2)O(2) is thought to constitute a general signal molecule participating in the recognition of and the response to stress factors. In this study, we examined the role of H(2)O(2) as a link between MJ and subsequent NH(4)(+) accumulation in detached rice leaves. MJ treatment resulted in an accumulation of NH(4)(+) in detached rice leaves, which was preceded by a decrease in the activity of glutamine synthetase (GS) and an increase in the specific activities of protease and phenylalanine ammonia-lyase (PAL). GS, PAL, and protease appear to be the enzymes responsible for the accumulation of NH(4)(+) in MJ-treated detached rice leaves. Dimethylthiourea (DMTU), a chemical trap for H(2)O(2), was observed to be effective in inhibiting MJ-induced NH(4)(+) accumulation in detached rice leaves. Scavengers of free radicals (sodium benzoate, SB, and glutathione, GSH), nitric oxide donor (N-tert-butyl-alpha-phenylnitrone, PBN), the inhibitors of NADPH oxidase (diphenyleneiodonium chloride, DPI, and imidazole, IMD), and inhibitors of phosphatidylinositol 3-kinase (wortmannin, WM, and LY 294002, LY), which have previously been shown to prevent MJ-induced H(2)O(2) production in detached rice leaves, inhibited MJ-induced NH(4)(+) accumulation. Similarly, changes in enzymes responsible for NH(4)(+) accumulation induced by MJ were observed to be inhibited by DMTU, SB, GSH, PBN DPI, IMD, WM, or LY. Seedlings of rice cultivar Taichung Native 1 (TN1) are jasmonic acid (JA)-sensitive and those of cultivar Tainung 67 (TNG67) are JA-insensitive. On treatment with JA, H(2)O(2) accumulated in the leaves of TN1 seedlings but not in the leaves of TNG67. Ethylene action inhibitor, silver thiosulfate, was observed to inhibit MJ- and abscisic acid-induced accumulation of NH(4)(+) and changes in enzymes responsible for NH(4)(+) accumulation in detached rice leaves, suggesting that the action of MJ and ABA is ethylene dependent.
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PMID:The participation of hydrogen peroxide in methyl jasmonate-induced NH(4)(+) accumulation in rice leaves. 1721 59

Disruption of leptin signaling in the heart may contribute to obesity-related cardiac disease, as leptin deficient (oblob) mice display cardiac hypertrophy, increased cardiac apoptosis and reduced survival. Since leptin maintains a tonic level of neuronal nitric oxide synthase (NOS1) expression in the brain, we hypothesized that leptin deficiency would decrease NOS1 cardiac expression, in turn activating xanthine oxidoreductase (XOR) and creating nitroso-redox imbalance. We studied 2- to 6-month-old oblob (n=26) and C57Bl/6 controls (n=27). Cardiac NOS1 protein abundance (P<0.01) and mRNA expression (P=0.03) were reduced in oblob (n=10 and 6, respectively), while NOS3 protein abundance and mRNA expression were unaltered. Importantly, cardiac NOS1 protein abundance was restored towards normal in oblob mice after leptin treatment (n=3; P<0.05 vs leptin untreated oblob mice). NO metabolite (nitrite and nitrate) production within the myocardium was also reduced in oblob mice (n=5; P=0.02). Furthermore, oxidative stress was increased in oblob mice as GSH/GSSG ratio was decreased (n=4; P=0.02). Whereas XOR activity measured by Amplex Red fluorescence was increased (n=8; P=0.04), XOR and NADPH oxidase subunits protein abundance were not changed in oblob mice (n=6). Leptin deficiency did not disrupt NOS1 subcellular localization, as NOS1 co-localized with ryanodine receptor but not with caveolin-3. In conclusion, leptin deficiency is linked to decreased cardiac expression of NOS1 and NO production, with a concomitant increase in XOR activity and oxidative stress, resulting in nitroso-redox imbalance. These data offer novel insights into potential mechanisms of myocardial dysfunction in obesity.
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PMID:Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice. 1730 68

When activated by proinflammatory stimuli, microglia release substantial levels of glutamate, and mounting evidence suggests this contributes to neuronal damage during neuroinflammation. Prior studies indicated a role for the Xc exchange system, an amino acid transporter that antiports glutamate for cystine. Because cystine is used for synthesis of glutathione (GSH) synthesis, we hypothesized that glutamate release is an indirect consequence of GSH depletion by the respiratory burst, which produces superoxide from NADPH oxidase. Microglial glutamate release triggered by lipopolysaccharide was blocked by diphenylene iodonium chloride and apocynin, inhibitors of NADPH oxidase. This glutamate release was also blocked by vitamin E and elicited by lipid peroxidation products 4-hydroxynonenal and acrolein, suggesting that lipid peroxidation makes crucial demands on GSH. Although NADPH oxidase inhibitors also suppressed nitrite accumulation, vitamin E did not; moreover, glutamate release was largely unaffected by nitric oxide donors, inhibitors of nitric oxide synthase, or changes in gene expression. These findings indicate that a considerable degree of the neurodegenerative consequences of neuroinflammation may result from conversion of oxidative stress to excitotoxic stress. This phenomenon entails a biochemical chain of events initiated by a programmed oxidative stress and resultant mass-action amino acid transport. Indeed, some of the neuroprotective effects of antioxidants may be due to interference with these events rather than direct protection against neuronal oxidation.
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PMID:Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. 1740 30

This study was designed to explore the role of losartan, an angiotensin II receptor blocker, in hypertensive injuries of blood vessels and the potential mechanisms related to the vascular advanced glycosylation end product (AGE)/receptor (RAGE) system, oxidative stress and endothelial proinflammatory factors. Spontaneously hypertensive rats (SHR) were employed for our study, and age-matched Wistar-Kyoto rats (WKY) were used for control experiments. After losartan treatment for 12 weeks, we observed by immunofluorescence that the vascular AGE level in the losartan group was significantly lower than that of the SHR group and that the vascular mRNA expression of RAGE, NF-kappaB, NADPH oxidase p47phox and ET-1, as detected by RT-PCR, was significantly lower in losartan group than in the SHR group. Meanwhile, we found that the expression of RAGE and NF-kappaB proteins in the losartan group and the WKY group was remarkably lower than that of the SHR group. Compared with the SHR group, the activities of plasma superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) and the NO level were robustly increased, while the plasma malondialdehyde (MDA) and ET-1 were substantially reduced. These findings suggest that losartan decreases the vascular AGE level, suppresses RAGE and NF-kappaB activation, and enhances the antioxidant capacity thereby improving the endothelial function, which induce hypertensive vascular remodeling.
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PMID:Beneficial effects of losartan on vascular injury induced by advanced glycosylation end products and their receptors in spontaneous hypertension rats. 1748 57

Growth inhibitory effects of 15-lipoxygenase-1 [13-(S)-HPODE and 13-(S)-HODE] and 15-lipoxygenase-2 [15-(S)-HPETE and 15-(S)-HETE] (15-LOX-1 and LOX-2) metabolites and the underlying mechanisms were studied on chronic myeloid leukemia cell line (K-562). The hydroperoxy metabolites, 15-(S)-HPETE and 13-(S)-HPODE rapidly inhibited the growth of K-562 cells by 3h with IC(50) values, 10 and 15microM, respectively. In contrast, the hydroxy metabolite of 15-LOX-2, 15-(S)-HETE, showed 50% inhibition only at 40microM by 6h and 13-(S)-HODE, hydroxy metabolite of 15-LOX-1, showed no significant effect up to 160microM. The cells exposed to 10microM of 15-(S)-HPETE and 40microM of 15-(S)-HETE showed typical apoptotic features like release of cytochrome c, caspase-3 activation and PARP-1 (poly(ADP) ribose polymerase-1) cleavage. A flow cytometry based DCFH-DA analysis and inhibitory studies with DPI, a pharmacological inhibitor of NADPH oxidase, NAC (N-acetyl cysteine) and GSH revealed that NADPH oxidase-mediated generation of ROS is responsible for caspase-3 activation and subsequent induction of apoptosis in the K-562 cell line.
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PMID:Effect of 15-lipoxygenase metabolites, 15-(S)-HPETE and 15-(S)-HETE on chronic myelogenous leukemia cell line K-562: reactive oxygen species (ROS) mediate caspase-dependent apoptosis. 1751 76

Redox processes are involved in the mechanism of action of NADPH oxidase inhibitors such as diphenyleneiodonium and apocynin. Here, we studied the structure-activity relationship for apocynin and analogous ortho-methoxy-substituted catechols as inhibitors of the NADPH oxidase in neutrophils and their reactivity with peroxidase. Aiming to alter the reduction potential, the ortho-methoxy-catechol moiety was kept constant and the substituents at para position related to the hydroxyl group were varied. Two series of compounds were employed: methoxy-catechols bearing electron-withdrawing groups (MC-W) such as apocynin, vanillin, 4-nitroguaiacol, 4-cyanoguaiacol, and methoxy-catechol bearing electron-donating groups (MC-D) such as 4-methylguaiacol and 4-ethylguaiacol. We found that MC-D were weaker inhibitors compared to MD-W. Furthermore, the radicals generated by oxidation of MC-W via MPO/H(2)O(2), but not for MC-D, were able to oxidize glutathione (GSH) as verified by the formation of thiyl radicals, depletion of GSH, and recycling of the ortho-methoxy-catechols during their oxidations. The capacity of oxidizing sulfhydryl (SH) groups was also verified when ovalbumin was incubated with MC-W, but not for MC-D. Since the effect of apocynin has been correlated with inactivation of the cytosolic fractions of the NADPH oxidase complex and its oxidation during the inhibitory process develops a special role in this process, we suggest that the close relationship between the reactivity of the radicals of MC-W compounds with thiol groups and their efficacy as NADPH oxidase inhibitor could be the chemical pathway behind the mechanism of action of apocynin and should be taken into account in the design of new and specific NADPH oxidase inhibitors.
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PMID:The reactivity of ortho-methoxy-substituted catechol radicals with sulfhydryl groups: contribution for the comprehension of the mechanism of inhibition of NADPH oxidase by apocynin. 1754 76

The link between chronic alcohol consumption and cardiovascular injury including hypertension is well known. However, molecular mediators implicated with alcohol-induced elevation in blood pressure (BP) remain elusive. The aim of this study was to investigate the relationship of chronic ethanol-induced endothelial injury and elevation in BP with angiotensin II levels in rats. Male Fisher rats were divided into two groups of seven animals each and treated as follows: (1) Control (5% sucrose, orally) daily for 12 weeks and (2) ethanol (4 g kg(-1), orally) daily for 12 weeks. The BP (systolic, diastolic, and mean) was recorded every week. The animals were anesthetized with pentobarbital after 12 weeks; blood and thoracic aorta were isolated and analyzed for aortic reactivity response, angiotensin II levels, and oxidative endothelial injury. The results show that the systolic, diastolic, and mean BP were significantly elevated 12 weeks after ethanol ingestion. The increased BP was related to elevated angiotensin II levels in the plasma and aorta of alcohol treated group compared to control. The aortic NADPH oxidase activity, ratio of oxidized to reduced glutathione (GSSG/GSH) and lipid peroxidation significantly increased, whereas nitric oxide (NO), endothelial NO synthase (eNOS), and vascular endothelial growth factor (VEGF) protein expressions were depressed in alcohol group compared to control. The phenylephrine-mediated vasoconstriction response was not altered, while acetylcholine-mediated vasorelaxation response was depressed in the aorta of ethanol treated rats compared to control. It is concluded that chronic ethanol ingestion induces hypertension which is correlated with elevated tissue angiotensin II levels, activation of NADPH oxidase activity causing endothelial injury, depletion of endothelial NO generating system, and impaired vascular relaxation in rats.
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PMID:Chronic alcohol-induced oxidative endothelial injury relates to angiotensin II levels in the rat. 1772 10


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