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)

The strong ROS (reactive oxygen species) production, part of an antioxidant response of human fibroblasts triggered by DHA (docosahexaenoic acid; C(22:6,n-3), served as a model for deciphering the relative contribution of NOX (NADPH oxidase) to ROS production, as the role of this enzymatic system remains controversial. Using hydroxyethidium fluorescence for fibroblast ROS production, RT (reverse transcriptase)-PCR for NOX 4 mRNA quantification and mRNA silencing, we show that ROS production evolves in parallel with the catalytic activity of NOX and is suppressed by siNOX 4 (small interference oligonucleotide RNA directed against NOX 4) silencing. Apocynin and plumbagin, specific inhibitors of NOX, prevent ROS production in this cellular model and confirm the role of NOX 4 for this production. Furthermore, we show that, in cell lysates, NOX 4 activity can be modulated by PUFAs (polyunsaturated fatty acids) at the micromolar level in the presence of calcium: NOX 4 activity is increased by arachidonic acid (C20:4,n-6) (approximately 175% of the control), and conjugated linoleic acid (C18:2 [9Z,11E]) is a potent inhibitor (50% of the control). Unexpectedly, intracellular superoxide dismutase does not participate in the modulation of this ROS production and the opposite effects of some PUFAs, described in our experiments, could suggest another way of regulating NOX activity.
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PMID:Polyunsaturated fatty acids modulate NOX 4 anion superoxide production in human fibroblasts. 1747 80

The purpose of this study was to investigate the mechanisms that regulate superoxide (O(2)(*-)) production as a function of an acute elevation of intravascular pressure and age. Mesenteric arteries isolated from young (6 mo) and aged (24 mo) male Fischer 344 rats were used. O(2)(*-) production in vessels in response to 80 (normal pressure, NP) and 180 (high pressure, HP) mmHg was determined by the superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction assay. In vessels exposed to NP, O(2)(*-) production was significantly higher in aged than in young vessels (32.7 +/- 7.0 vs. 15.4 +/- 2.4 nmol.mg(-1).30 min(-1)). HP enhanced O(2)(*-) production in vessels of both groups, but the enhancement was significantly greater in aged than in young vessels (63.4 +/- 6.7 vs. 32.7 +/- 4.3 nmol.mg(-1).30 min(-1)). Apocynin (100 micromol/l) attenuated HP-induced increases in O(2)(*-) production in both groups, whereas allopurinol (100 micromol/l) and N(omega)-nitro-L-arginine methyl ester (100 mumol/l) inhibited the response only in aged vessels. Confocal microscopy showed increases in O(2)(*-) in response to HP in endothelial and smooth muscle layers of both groups, with much greater fluorescent staining in aged than in young rats and in the endothelium than in smooth muscle cells. No significant changes in NAD(P)H oxidase gene and protein expressions were observed in vessels of the two groups. Upregulation of protein expression of xanthine oxidase was detected in aged vessels. We conclude that NAD(P)H oxidase contributes importantly to HP-induced enhanced O(2)(*-) production in vessels of both young and aged rats, whereas xanthine oxidase and nitric oxide synthase-dependent O(2)(*-) production also contribute to the enhancement in mesenteric arteries of aged rats.
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PMID:Aging enhances pressure-induced arterial superoxide formation. 1755 15

Increases in NADPH oxidase activity, oxidative stress, and myocyte apoptosis coexist in failing hearts. In cardiac myocytes in vitro inhibition of NADPH oxidase reduces apoptosis. In this study, we tested the hypothesis that NADPH oxidase inhibition reduces myocyte apoptosis and improves cardiac function in heart failure after myocardial infarction (MI). Rabbits with heart failure induced by MI and sham-operated animals were randomized to orally receive apocynin, an inhibitor of NADPH oxidase (15 mg per day) or placebo for 4 weeks. Left ventricular (LV) dimension and function were assessed by echocardiography and hemodynamics. Myocardial NADPH oxidase activity was measured by superoxide dismutase-inhibitable cytochrome c reduction assay, NADPH oxidase subunit p47phox expression by Western blot and immunofluorescence analysis, myocardial oxidative stress evaluated by 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) using immunohistochemistry, and myocyte apoptosis by TUNEL assay. MI rabbits exhibited LV dilatation and systolic dysfunction measured by LV fractional shortening and the maximal rate of LV pressure rise (dP/dt). These changes were associated with increases in NADPH oxidase activity, p47phox protein expression, 8-OHdG expression, 4-HNE expression, myocyte apoptosis, and Bax protein and a decrease in Bcl-2 protein. Apocynin reduced NADPH oxidase activity, p47phox protein, oxidative stress, myocyte apoptosis, and Bax protein, increased Bcl-2 protein, and ameliorated LV dilatation and dysfunction after MI. The results suggest that inhibition of NADPH oxidase may represent an attractive therapeutic approach to treat heart failure.
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PMID:Inhibition of NADPH oxidase reduces myocardial oxidative stress and apoptosis and improves cardiac function in heart failure after myocardial infarction. 1760 36

1. In the present study, we investigated whether the administration of apocynin, an NADPH oxidase inhibitor, provided brain protection in a rat model of intracerebral haemorrhage (ICH). 2. Rats were divided into sham, ICH untreated, ICH treated with vehicle (ethanol) and ICH treated with apocynin groups. Intracerebral haemorrhage was induced by collagenase injection. Neurological function, haemorrhage volume and brain oedema were measured 24 h after ICH. 3. Intracerebral haemorrhage caused significant neurological deficit associated with brain oedema. Apocynin (3, 10 and 30 mg/kg) failed to reduce brain injury after ICH. Low dose ethanol (0.2 g/kg) improved neurological function and reduced brain oedema (ICH-vehicle vs ICH-untreated, P < 0.05). 4. In conclusion, apocynin has no neuroprotective effect when administered intraperitoneally after ICH.
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PMID:Effects of apocynin and ethanol on intracerebral haemorrhage-induced brain injury in rats. 1764 27

The vascular NAD(P)H oxidase contributes to endothelial dysfunction and high blood pressure in the spontaneously hypertensive rat by enhancing superoxide production. We investigated the effects of apocynin, a NAD(P)H oxidase inhibitor, on blood pressure and vascular radical and nitric oxide formation in SHR and compared its effects to the calcium channel blocker nifedipine. Apocynin (over four weeks) lowered systolic blood pressure significantly and as effectively as nifedipine. Both apocynin and nifedipine significantly reduced superoxide production. In parallel, vascular nitric oxide production and ecNOS activity was significantly increased by apocynin treatment. Therefore, apocynin may be an effective antihypertensive drug in essential hypertension.
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PMID:The NAD(P)H oxidase inhibitor apocynin improves endothelial NO/superoxide balance and lowers effectively blood pressure in spontaneously hypertensive rats: comparison to calcium channel blockade. 1765 64

Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP+), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67phox cytosolic subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKCdelta) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKCdelta inhibitor, also inhibited paraquat-induced translocation of p67phox. Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKCdelta- and ERK-dependent pathways.
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PMID:Cytotoxicity of paraquat in microglial cells: Involvement of PKCdelta- and ERK1/2-dependent NADPH oxidase. 1766 68

This study investigated whether inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase attenuates cerebral infarction after transient focal ischaemia in rats. Focal ischaemia (1.5 h) was produced in male Sprague-Dawley rats (250 - 280 g) by middle cerebral artery occlusion. Some rats also received treatment with 50 mg/kg apocynin, a NADPH oxidase inhibitor, by intraperitoneal injection 30 min prior to reperfusion. Two hours after reperfusion, brains were harvested to measure NADPH oxidase activity and superoxide levels. After 24 h, the remaining brains were harvested to investigate infarct size. NADPH oxidase activity and superoxide level were all augmented 2 h after reperfusion compared with controls. Apocynin treatment significantly reduced NADPH oxidase activity and superoxide levels. Cerebral infarct size was significantly smaller in the apocynin-treated group compared with those undergoing ischaemia/reperfusion alone. These results indicate that inhibition of NADPH oxidase attenuates cerebral infarction after transient focal ischaemia in rats, suggesting that inhibition of NADPH oxidase may provide a therapeutic strategy for ischaemic stroke.
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PMID:Apocynin attenuates cerebral infarction after transient focal ischaemia in rats. 1769 29

The tonic contraction of human and guinea pig gallbladder (GB) is dependent on basal levels of PGE(2) and thromboxane A(2) (TxA(2)). The pathway involved in the genesis of these prostaglandins has not been elucidated. We aimed to examine the source of reactive oxygen species (ROS) and whether they contribute to the genesis of GB tonic contraction by generating basal prostaglandin levels. Tonic contraction was studied in human and guinea pig GB muscle strips treated with ROS scavengers (Tiron and catalase), apocynin (an inhibitor of NADPH oxidase), and NOX-1 small interference RNA (siRNA). The subunits of NADPH oxidase and their functional roles were determined with specific antibodies in GB muscle cells. ROS scavengers reduced the GB tonic contraction and H(2)O(2) and PGE(2) levels. Apocynin also inhibited the tonic contraction. Antibodies against subunits of NADPH oxidase present in GB muscle cells lowered H(2)O(2) and PGE(2) levels. NOX-1 siRNA transfection reduced the tonic contraction, NOX-1 expression, and levels of H(2)O(2) and PGE(2). Tiron and apocynin inhibited the expected increase in tension and H(2)O(2) levels induced by stretching of muscle strips. H(2)O(2) increased the levels of PGE(2) and TxA(2) by increasing platelet-activating factor-like lipids that phosphorylate p38 and cPLA(2) sequentially. H(2)O(2) generated by NADPH oxidase participates in a signal transduction pathway that maintains the GB tonic contraction by activating PAF, p38, and cPLA(2) to generate prostaglandins.
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PMID:Reactive oxygen species are messengers in maintenance of human and guinea pig gallbladder tonic contraction. 1862 97

Apocynin (4-hydroxy-3-methoxyacetophenone) is a major active ingredient from the rhizomes of Picrorhiza kurroa, a botanical plant used as an herbal medicine for treatment of a number of inflammatory diseases. Recently, apocynin is regarded as a specific inhibitor for NADPH oxidase in cell and animal models. In vitro studies indicated conversion of apocynin to diapocynin in the presence of peroxidases, e.g., myloperoxidase, posing the possibility that diapocynin also contributes to the anti-oxidative action of apocynin. The objectives of this study are to examine the bioavailability of apocynin to plasma, liver and brain tissue after intraperitoneal (i.p.) injection, and to examine whether apocynin is converted to diapocynin in vivo. Diapocynin was chemically synthetized and characterized by NMR and IR. Apocynin (5mg/kg body wt) was injected i.p. to adult male Sprague-Dawley rats and plasma, liver and brain were collected at different times (30min, 1 and 2h) after injection. Samples were treated with beta-glucuronidase to hydrolyze the glycosyl linkage and analyzed by HPLC/MS. At 30min and 1h after injection, approximately 50% of apocynin was converted to its glycosyl derivative and was distributed in plasma, liver and brain. No diapocynin was detected in any samples. These results indicate rapid glycosylation of apocynin and its transport to blood and other organs but no apparent conversion to diapocynin in vivo.
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PMID:Bioavailability of apocynin through its conversion to glycoconjugate but not to diapocynin. 1797 2

Reactive oxygen species participate in the pathogenesis of inflammatory airway diseases, in which increased arginase may play a role by interfering with nitric oxide (NO) synthesis and providing substrate for collagen synthesis. Therefore a modulatory role of reactive oxygen species for arginase was explored in alveolar macrophages using the NADPH oxidase inhibitor apocynin. The effects of lipopolysacharides (LPS) and apocynin on nitrite accumulation, arginase activity and mRNA for inducible NO synthase (iNOS), arginase I and II were determined. Superoxide anion (O(2)(-)) release was analysed by the iodonitrotetrazolium (INT) formazan assay. LPS (1 microg/ml) caused a 55%, transient increase in INT formation, i.e. O(2)(-) release which was inhibited by apocynin (500 microM). LPS caused a 2 fold increase in arginase activity and a marked increase in mRNA encoding arginase I, the predominant isoenzyme. Both effects were largely attenuated by apocynin. Apocynin did not affect the stability of arginase I mRNA, but accelerated the decline of arginase activity when protein synthesis was inhibited by cycloheximide. Apocynin also reduced LPS-induced nitrite accumulation (by 30%) and iNOS mRNA expression, but the magnitude of these effects was smaller than that on arginase I. Arginase I mRNA was also increased following exposure to hydrogen peroxide (H(2)O(2), 200 muM). In conclusion, inhibition of NADPH oxidase in alveolar macrophages causes down-regulation of arginase, indicating that reactive oxygen species exert stimulatory effects on arginase. Enhanced transcription of arginase mRNA and prolongation of the life time of the active enzyme appear to contribute to the enhanced arginase activity.
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PMID:Inhibition of NADPH oxidase by apocynin inhibits lipopolysaccharide (LPS) induced up-regulation of arginase in rat alveolar macrophages. 1800 8


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