Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A substantial proportion of individuals with coronary artery disease (CAD) has concomitant hypercholesterolemia. A large-scale association study was performed to identify separately genes that confer susceptibility to CAD in the absence or presence of nonfamilial hypercholesterolemia. The study population comprised 5248 unrelated Japanese individuals, including 3085 subjects with CAD (2350 men, 735 women) and 2163 controls (1329 men, 834 women). Among all study subjects, 2541 individuals (1688 men, 853 women) had nonfamilial hypercholesterolemia, and 2707 individuals (1991 men, 716 women) did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperuricemia revealed that three polymorphisms [994G --> T (Val279Phe) in the platelet-activating factor acetylhydrolase gene, 242C --> T (His72Tyr) in the NADH/NADPH oxidase p22 phox gene, and 1100C --> T in the apolipoprotein C-III gene] were significantly associated with CAD in men with hypercholesterolemia. Genotyping of these three polymorphisms may prove informative for prediction of the genetic risk for CAD in men with nonfamilial hypercholesterolemia.
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PMID:Association of gene polymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. 1470 72

Aging and estrogen deficiency increase the risk for developing cardiovascular disease (CVD). Oxidative stress has also been implicated in the pathophysiology of CVD and in ischemia-reperfusion (I/R) injury. We tested the hypothesis that chronic in vivo estrogen treatment or superoxide inhibition with the SOD mimetic EUK-8 improves cardiac functional recovery after I/R in the aged female rat. Sprague-Dawley rats (12-14 mo) were used as follows: intact (n = 6), ovariectomized + placebo (OVX, n = 6), OVX + EUK-8 (EUK-8, 3 mg/kg, n = 6), and OVX + estrogen (1.5 mg/pellet, 60 days release, n = 6). Perfused isolated hearts were subjected to global ischemia (25 min) followed by reperfusion (40 min). Functional recovery after I/R and myocardial protein expression of NADPH oxidase (p22, p67, and gp91(phox)), inducible nitric oxide synthase (NOS), endothelial NOS, and SOD1, as well as nitrotyrosine levels (as a marker for peroxynitrite), were assessed. Compared with OVX, EUK-8 and estrogen markedly improved functional recovery after I/R, which was associated with a decrease in NADPH oxidase expression and nitrotyrosine staining. However, estrogen increased inducible NOS expression, whereas EUK-8 had little effect. There were no significant changes in endothelial NOS and SOD1 expression among the groups. These results indicate that EUK-8 and estrogen improved cardiac recovery after I/R. Given the controversy surrounding hormone replacement therapy, EUK-8 may be an alternative to estrogen in protecting those at risk for myocardial ischemia in the aging population.
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PMID:Cardioprotection by chronic estrogen or superoxide dismutase mimetic treatment in the aged female rat. 1498 70

Oxidative stress (OxSt) is a major damaging factor in arterial hypertension and its long-term complications. This is why considerable attention is paid to the possible effects of antihypertensive drugs on OxSt. Manidipine is a dihydropiridine calcium channel blocker with reported nephroprotective activities, but no information is available on its effect on OxSt and related mechanisms. This study assessed the effect of manidipine on normal subjects' monocyte gene and protein expression of OxSt-related proteins such as p22(phox), a NAD(P)H oxidase system subunit, critical in generating O2-, and heme oxygenase-1 (HO-1), induced by and protective from OxSt, and compared manidipine with the ACE inhibitor captopril and the calcium channel blocker nifedipine, in the presence and absence of sodium arsenite (NaAsO2) as an inducer of OxSt.Co-incubation of manidipine with NaAsO2 dose-dependently decreased p22(phox) mRNA production from basal: 0.87 +/- 0.1 d.u., 0.69 +/- 0.06 and 0.66 +/- 0.09 at 100, 300 and 500 nM respectively versus 0.99 +/- 0.2, P < 0.04, while HO-1 mRNA production was increased by the same concentrations of the drug: 0.87 +/- 0.1 d.u., 0.92 +/- 0.1, 0.98 +/- 0.1 respectively versus 0.63 +/- 0.07; P < 0.03. Monocyte p22(phox) mRNA production was reduced both by manidipine and captopril: 0.48 +/- 0.04 d.u. and 0.43 +/- 0.08, respectively versus 0.58 +/- 0.07, P < 0.006, while no changes were induced by nifedipine (0.61 +/- 0.07, P = ns). Manidipine increased monocyte HO-1 mRNA production (1.6 +/- 0.4 versus 1.2 +/- 0.4, P < 0.008), while nifedipine and captopril showed no effect (1.2 +/- 0.3 and 1.1 +/- 0.3, respectively). The effects of M on p22(phox) and HO-1 gene expression in the presence of OxSt were also paralleled by the same effects at protein level. In conclusion, manidipine decreases p22(phox) and increases HO-1 mRNA production and protein level. The manidipine-induced increase of HO-1 gene and protein expression seems to be a peculiar effect of this drug since it is not observed with captopril and nifedipine. This effect, together with the reduction of p22(phox) mRNA production, could play a role in its protective mechanism against OxSt.
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PMID:Effect of manidipine on gene expression and protein level of oxidative stress-related proteins: p22phox and HO-1: relevance for antihypertensive and anti-remodeling effects. 1508 64

The phagocyte NADPH oxidase is a multisubunit enzyme responsible for the generation of superoxide anions (O(2).) that kill invading microorganisms. p47(phox) is a cytosolic subunit of the phagocyte NADPH oxidase, which plays a crucial role in the assembly of the activated NADPH oxidase complex. The molecular shapes of the p47(phox) tandem SH3 domains either with or without a polybasic/autoinhibitory region (PBR/AIR) at the C terminus were studied using small angle x-ray scattering. The tandem SH3 domains with PBR/AIR formed a compact globular structure, whereas the tandem SH3 domains lacking the PBR/AIR formed an elongated structure. Alignment anisotropy analysis by NMR based on the residual dipolar couplings revealed that the tandem SH3 domains with PBR/AIR were in good agreement with a globular module corresponding to the split half of the intertwisted dimer in crystalline state. The structure of the globular module was elucidated to represent a solution structure of the tandem SH3 domain in the autoinhibited form, where the PBR/AIR bundled the tandem SH3 domains and the linker forming a closed structure. Once PBR/AIR is released by phosphorylation, rearrangements of the SH3 domains may occur, forming an open structure that binds to the cytoplasmic proline-rich region of membrane-bound p22(phox).
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PMID:Solution structure of the tandem Src homology 3 domains of p47phox in an autoinhibited form. 1512 2

Plain old balloon angioplasty (POBA) is a useful therapeutic strategy especially for angioplasty of small coronary arteries. An association study was performed to identify genes that confer susceptibility to restenosis after POBA. The study population comprised 730 individuals (424 men, 306 women) who underwent successful POBA in at least one major coronary artery and were examined angiographically 6 months after the procedure. A total of 469 subjects (273 men, 196 women) exhibited no restenosis after POBA for any of the coronary lesions, whereas 261 subjects (151 men, 110 women) manifested restenosis for all lesions. The genotypes for 40 polymorphisms of 34 genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (242C --> T in the NADH/NADPH oxidase p22 phox (p22-PHOX) gene and 2136C --> T in the thrombomodulin (THBD) gene) in men and two polymorphisms (584G --> A in the paraoxonase 1 (PON1) gene and 2445G --> A in the fatty acid-binding protein 2 (FABP2) gene) in women were significantly associated with restenosis after POBA. A stepwise forward selection procedure revealed that the effects of these polymorphisms on restenosis were statistically independent of conventional risk factors for coronary artery disease. Genotyping of these polymorphisms may prove informative for assessment of genetic risk for restenosis after POBA.
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PMID:Genetic risk for restenosis after coronary balloon angioplasty. 1513 68

The phagocyte NADPH oxidase is a multisubunit enzyme responsible for the production of reactive oxygen species. p47(phox) is a cytosolic component of the NADPH oxidase and plays an important role in the assembly of the activated complex. The structural determination of the tandem SH3 domains of p47(phox) is crucial for elucidation of the molecular mechanism of the activation of p47(phox). We determined the X-ray crystal structure of the tandem SH3 domains with the polybasic/autoinhibitory region (PBR/AIR) of p47(phox). The GAPPR sequence involved in PBR/AIR forms a left-handed polyproline type-II helix (PPII) and interacts with the conserved SH3 binding surfaces of the SH3 domains simultaneously. These SH3 domains are related by a 2-fold pseudosymmetry axis at the centre of the binding groove and interact with the single PPII helix formed by the GAPPR sequence with opposite orientation. In addition, a number of intra-molecular interactions among the SH3 domains, PBR/AIR and the linker tightly hold the architecture of the tandem SH3 domains into the compact structure and stabilize the autoinhibited form synergistically. Phosphorylation of the serine residues in PBR/AIR could destabilize and successively release the intra-molecular interactions. Thus, the overall structure could be rearranged from the autoinhibitory conformation to the active conformation and the PPII ligand binding surfaces on the SH3 domains are now unmasked, which enables their interaction with the target sequence in p22(phox).
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PMID:A molecular mechanism for autoinhibition of the tandem SH3 domains of p47phox, the regulatory subunit of the phagocyte NADPH oxidase. 1514 73

We previously observed that the respiratory burst of human monocytes (THP-1 cell line) triggered by phorbol myristate acetate was strongly enhanced by a priming of the cells by Chlamydia pneumoniae [Biochem. Biophys. Res. Commun. 287 (2001) 781]. We describe here the modifications of the responses of Chlamydia-primed THP-1 cells to hydrocortisone (HCT) and methylprednisolone (MPL). HCT and MPL inhibited the production of the cytokines TNFalpha and IL-8. But HCT, which inhibited the respiratory burst in LPS-primed monocytes, paradoxically stimulated the phenomenon in Chlamydia-primed cells; MPL exerted no significant effect. Both glucocorticoids did not significantly modify the triggering effect of Chlamydia on NF-kappaB binding activity. On the expression of p22(phox), a protein subunit of the NADPH oxidase, HCT had an increasing and MPL a decreasing effect. Glucocorticoids thus had unexpected effects on the inflammatory response of Chlamydia-primed monocytes.
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PMID:Effects of glucocorticoids on the respiratory burst of Chlamydia-primed THP-1 cells. 1514 63

The objective of the present study was to examine the role of the angiotensin II type 1 receptor (AT(1)-R) in the diabetes-aggravated oxidative stress and brain injury observed in a rat model of combined diabetes and focal cerebral ischemia. Diabetes was induced by an injection of streptozotoxin (STZ; 55 mg/kg iv) at 8 wk of age. Two weeks after the induction of diabetes, some animals received continuous subcutaneous infusion of the AT(1)-R antagonist candesartan (0.5 mg.kg(-1).day(-1)) for 14 days. Focal cerebral ischemia, induced by middle cerebral artery occlusion/reperfusion (MCAO), was conducted at 4 wk after STZ injection. Male Sprague-Dawley rats (n = 189) were divided into five groups: normal control, diabetes, MCAO, diabetes + MCAO, and diabetes + MCAO + candesartan. The major observations were that 1) MCAO produced typical cerebral infarction and neurological deficits at 24 h that were accompanied by elevation of NAD(P)H oxidase gp91(phox) and p22(phox) mRNAs, and lipid hydroperoxide production in the ipsilateral hemisphere; 2) diabetes enhanced NAD(P)H oxidase gp91(phox) and p22(phox) mRNA expression, potentiated lipid peroxidation, aggravated neurological deficits, and enlarged cerebral infarction; and 3) candesartan reduced the expression of gp91(phox) and p22(phox), decreased lipid peroxidation, lessened cerebral infarction, and improved the neurological outcome. We conclude that diabetes exaggerates the oxidative stress, NAD(P)H oxidase induction, and brain injury induced by focal cerebral ischemia. The diabetes-aggravated brain injury involves AT(1)-Rs. We have shown for the first time that candesartan reduces brain injury in a combined model of diabetes and cerebral ischemia.
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PMID:Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. 1514 62

Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome caused by a profound defect in the oxygen metabolic burst machinery. Activity of NADPH oxidase is absent or profoundly diminished, as at least one of its components (gp91(phox), p22(phox), p47(phox) and p67(phox)) is lacking or non-functional. This review explains the molecular basis of NADPH oxidase dysfunction by the effects of mutations in genes coding for particular oxidase components. Among the four types of CGD, the most common is X-linked CGD (approximately 65%), with defects in the CYBB gene encoding gp91(phox). A wide spectrum of mutations has been described in the CYBB gene with no predominant genotype. The second most common subtype of CGD caused by NCF1 mutation accounts for 30% of CGD patients and is inherited in an autosomal recessive manner, with predominance of a homozygotous deltaGT deletion in the genotype. The other two CGD subtypes having an autosomal recessive pattern together account for no more than 10% of CGD cases. A strategy for the molecular diagnostics in CGD patients is proposed and principles of genetic counseling are discussed here.
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PMID:Genetic and biochemical background of chronic granulomatous disease. 1517 25

The purpose of this study was to determine the role of NADPH oxidase in H(+) secretion by airway epithelia. In whole cell patch clamp recordings primary human tracheal epithelial cells (hTE) and the human serous gland cell line Calu-3 expressed a functionally similar zinc-blockable plasma membrane H(+) conductance. However, the rate of H(+) secretion of confluent epithelial monolayers measured in Ussing chambers was 9-fold larger in hTE compared with Calu-3. In hTE H(+) secretion was blocked by mucosal ZnCl(2) and the NADPH oxidase blockers acetovanillone and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), whereas these same blockers had no effect in Calu-3. We determined levels of transcripts for the NADPH oxidase transmembrane isoforms (Nox1 through -5, Duox1 and -2, and p22(phox)) and found Duox1, -2, and p22(phox) to be highly expressed in hTE, as well as the intracellular subunits p40(phox), p47(phox), and p67(phox). In contrast, Calu-3 lacked transcripts for Duox1, p40(phox), and p47(phox). Anti-Duox antibody staining resulted in prominent apical staining in hTE but no significant staining in Calu-3. When treated with amiloride to block the Na(+)/H(+) exchanger, intracellular pH in hTE acidified at significantly higher rates than in Calu-3, and treatment with AEBSF blocked acidification. These data suggest a role for an apically located Duox-based NADPH oxidase during intracellular H(+) production and H(+) secretion, but not in H(+) conduction.
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PMID:NADPH oxidase-dependent acid production in airway epithelial cells. 1521 Jun 97


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