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)

Thiourea and diethylthiourea, two compounds which react with hydroxyl radicals, inhibited NADPH-dependent microsomal oxidation of ethanol and 1-butanol. Inhibition by both compounds was more effective in the presence of the catalase inhibitor, azide. Inhibition by thiourea was noncompetitive with respect to ethanol in the absence of azide but was competitive in the presence of azide. Urea, a compound which does not react with hydroxyl radicals or H2O2, was without effect. Thiourea had no effect on NADH- and NADH-cytochrome c reductase, NADPH oxidase, and NADH- and NADPH-dependent oxygen uptake. Thiourea inhibited the activities of aniline hydroxylase and aminopyrine demethylase. Thiourea, but no other hydroxyl radical scavengers, e.g., dimethyl sulfoxide, mannitol, and benzoate, reacted directly with H202 and decreased H2O2 accumulation in the presence of azide. Therefore the actions of thiourea are complex because it can react with both hydroxyl radicals and H2O2. Differences between the actions of thiourea and those previously reported for dimethyl sulfoxide, mannitol, and benzoate, e.g., effects on drug metabolism, effectiveness of inhibition in the absence of azide, or kinetics of the inhibition, probably reflect the fact that thiourea reacts directly with H2O2 whereas the other agents do not. The current results remain consistent with the concept that microsomal oxidation of alcohols involves interactions of the alcohols with hydroxyl radicals generated from microsomal electron transfer.
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PMID:Effect of thiourea on microsomal oxidation of alcohols and associated microsomal functions. 42 8

The influence of hyperosmolarity on superoxide production by polymorphonuclear leukocytes (PMNL) was examined using NaCl and urea as osmotic substances. Superoxide production was inhibited in a hyperosmotic environment produced by high concentrations of these substances with the following IC50: 440 +/- 75 (SD) mOsm/kg for NaCl and 660 +/- 100 for urea. In the case of NaCl, this inhibition was time-dependent and abolished at 4 degrees C. Since PMNL pump out Na+ ion for maintenance of cellular volume in an energy dependent fashion, it was suggested that the inhibition of superoxide production was due to the exhaustion of energy stores. On the other hand, urea inhibition was almost immediate and remained even when preincubation was performed at 4 degrees C. Because the transport of urea through the cell membrane is known to be energy independent, these findings suggested that urea was either an inhibitor of the NADPH oxidase or a scavenger of superoxide anion.
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PMID:Effect of NaCl and urea concentration comparable to renal medulla on superoxide production by human polymorphonuclear leukocytes. 284 27

Hyperosmotic environment in the renal medulla seems important for bacterial pyelonephritis because it exerts inhibitory influences upon the function of polymorphonuclear leukocytes (PMN). Urea and NaCl primarily contribute to high osmolarity in the renal medulla. We previously reported that PMN function was actually suppressed in phagocytosis, intracellular bacterial killing and superoxide generation in the hyperosmotic solution of urea and NaCl. In the present report, to verify the mechanism of this inhibitory effect, a kinetic study for NADPH oxidase in the cell membrane, the key enzyme complex of superoxide generation, was carried out in the cell membrane-solubilizing system under the hyperosmotic condition caused by urea or NaCl. Urea directly denaturated NADPH oxidase, and its inhibitory mechanism was reversible and uncompetitive with a decrease in Vmax and Km, while NaCl had no effect upon it, maintaining Lineweaver-Burk plots in the same position as those of the control. This result suggests that urea at least produces an inhibitory effect upon PMN through the direct inactivation of NADPH oxidase, although NaCl was unable to do so.
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PMID:Influence of hyperosmotic environment comparable to the renal medulla upon membrane NADPH oxidase of human polymorphonuclear leukocytes. 793 18

Hyperosmolarity in the renal medulla inhibits host defenses against bacterial pyelonephritis. Urea and NaCl contribute most to high osmolarity in the renal medulla. We therefore examined the inhibitory mechanism of urea on superoxide generation by human polymorphonuclear leukocytes. Superoxide production was inhibited by high concentration of urea. This inhibition was found to be direct and immediate. In addition, direct inactivation of NADPH oxidase, the key enzyme complex of superoxide generation, was shown by an NADPH oxidase activity assay using cell lysates of polymorphonuclear leukocytes stimulated by phorbol myristate acetate. The inhibitory effect of urea on NADPH oxidase was reversed by washing urea out of the assay system of cell lysates. Kinetic analysis of the inhibition of NADPH oxidase activity by urea showed decreased Vmax and Km, suggesting uncompetitive inhibition. These findings suggested that urea inactivated polymorphonuclear leukocyte superoxide production through a direct and uncompetitive inhibition of NADPH oxidase.
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PMID:Direct inactivation of human polymorphonuclear leukocyte by hyperosmotic urea comparable to the renal medulla. 838 Nov 92

A NAD(P)H oxidase has been isolated from the archaeon Sulfolobus solfataricus. The enzyme is a homodimer with M(r) 38,000 per subunit (SsNOX38) containing 1 FAD molecule/subunit. It oxidizes NADH and, less efficiently, NADPH with the formation of hydrogen peroxide. The enzyme was resistant against chemical and physical denaturating agents. The temperature for its half-denaturation was 93 and 75 degrees C in the absence or presence, respectively, of 8 M urea. The enzyme did not show any reductase activity. The SsNOX38 encoding gene was cloned and sequenced. It accounted for a product of 36.5 kDa. The translated amino acid sequence was made of 332 residues containing two putative betaalphabeta-fold regions, typical of NAD- and FAD-binding proteins. The primary structure of SsNOX38 did not show any homology with the N-terminal amino acid sequence of a NADH oxidase previously isolated from S. solfataricus (SsNOX35) (Masullo, M., Raimo, G., Dello Russo, A., Bocchini, V. and Bannister, J. V. (1996) Biotechnol. Appl. Biochem. 23, 47-54). Conversely, it showed 40% sequence identity with a putative thioredoxin reductase from Bacillus subtilis, but it did not contain cysteines, which are essential for the activity of the reductase.
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PMID:A NAD(P)H oxidase isolated from the archaeon Sulfolobus solfataricus is not homologous with another NADH oxidase present in the same microorganism. Biochemical characterization of the enzyme and cloning of the encoding gene. 1062 24

In this study, the cellular localization of the inhibitory effect of a natural flavonoid cirsimaritin against formyl-methionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst in rat neutrophils was investigated. Cirsimaritin concentration-dependently inhibited the superoxide anion (O(*-)(2))generation and O(2) consumption (IC(50) 11.5+/-2.2 micro M and 17.0+/-3.9 micro M, respectively) of neutrophils. Cirsimaritin did not reduce, but slightly enhanced the O(*-)(2) generation in phorbol 12-myristate 13-acetate (PMA)-activated or arachidonic acid-stimulated NADPH oxidase preparation as well as during the autoxidation of dihydroxyfumaric acid. Cirsimaritin did not elevate cellular cAMP levels, and only partially inhibited the fMLP-induced [Ca(2+)](i) changes in the presence or absence of extracellular Ca(2+). The phosphorylation of protein tyrosine, extracellular signal-regulated protein kinase and Akt caused by fMLP were attenuated by cirsimaritin in a concentration-dependent manner. In contrast, cirsimaritin had no effect on the phosphorylation of p38 mitogen-activated protein kinase. Cirsimaritin produced a concentration-dependent reduction in the formation of phosphatidic acid and phosphatidylethanol, in the presence of ethanol, from fMLP-stimulated neutrophils (IC(50) 15.1+/-6.5 micro M and 15.6+/-3.4 micro M, respectively), but did not affect the phosphatidylethanol formation in response to PMA. Under the similar concentration range, cirsimaritin attenuated the membrane translocation of ARF and Rho A. However, the GTPgammaS-stimulated membrane-associated ARF and Rho in cell lysate were unaffected by cirsimaritin. Collectively, these results indicate that the inhibition of fMLP-induced respiratory burst by cirsimaritin in rat neutrophils is likely mainly through the blockade of phospholipase D signaling pathway.
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PMID:Inhibition of formyl-methionyl-leucyl-phenylalanine-stimulated respiratory burst by cirsimaritin involves inhibition of phospholipase D signaling in rat neutrophils. 1223 43

Despite their beneficial effects, aminoglycosides including gentamicin (GEN) have considerable nephrotoxic side-effects. The toxicity of GEN at the level of the kidney seems to relate to the generation of reactive oxygen species (ROS). ROS have been reported to be involved in the activation of protein kinase C (PKC). The unique structural aspects of PKC cause it to function as a sensor for oxidative stress. It seems likely that the increased NAD(P)H oxidase-derived superoxide (O2) production is at least in part mediated by PKC. We investigated the effects of chelerythrine, a commonly used PKC inhibitor, on GEN-induced changes of renal malondialdehyde (MDA), nitric oxide (NO) generation, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, glutathione (GSH) content, and serum creatinine (Cr), blood urea nitrogen (BUN) levels. Morphological changes in the kidney were also examined. GEN administration to control rats increased MDA and NO generation but decreased CAT, SOD and GSH-Px activities, and GSH content. Chelerythrine administration with GEN caused significantly decreased MDA, NO generation and increased CAT, SOD and GSH-Px activities, and GSH content when compared with GEN alone. Chelerythrine also significantly decreased serum Cr and BUN levels. Morphological changes in the kidney including tubular necrosis were evaluated qualitatively. Both biochemical findings and histopathological evidence showed that administration of chelerythrine reduced the GEN-induced kidney damage. We propose that chelerythrine acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GEN via the inhibition of a PKC pathway.
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PMID:Protective effect of chelerythrine on gentamicin-induced nephrotoxicity. 1558 91

1. Liver slices from rats treated with thyroxine show an increased rate of O(2) consumption. The extra consumption, but not the basal respiration, can be abolished by ouabain. 2. Dinitrophenol is not effective in increasing the rate of O(2) consumption of liver slices from thyroxine-treated animals but its effectiveness can be recovered in the presence of ouabain. 3. (Na(+)+K(+))-stimulated adenosine triphosphatase activity of liver was increased by administration of thyroxine in vivo. No changes were found in total Mg(2+)-stimulated adenosine triphosphatase activity. 4. Mitochondrial alpha-glycerophosphate dehydrogenase and microsomal NADPH oxidase activity were increased by both thyroxine and chronic ethanol treatment. 5. Liver slices from animals chronically treated with ethanol synthesize urea at an increased rate. 6. Mitochondrial size (section area) is markedly increased in the liver of animals chronically treated with ethanol. 7. Acute administration of ethanol in doses of 4 and 6g/kg significantly increases the uptake of (131)I-labelled thyroxine by the liver. 8. Work reported here, along with results from other investigators, indicates marked similarities between the effects produced in the liver by chronic administration of ethanol and by thyroid hormones.
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PMID:Metabolic alterations produced in the liver by chronic ethanol administration. Comparison between the effects produced by ethanol and by thyroid hormones. 1674 13

Progressive renal damage and hypertension are associated with oxidative and nitrosative stress. On the other hand, S-allylcysteine (SAC), the most abundant organosulfur compound in aged garlic extract (AG), has antioxidant properties. The effects of SAC and AG on blood pressure, renal damage, and oxidative and nitrosative stress were studied in five-sixths nephrectomized rats treated with SAC (200 mg/kg ip) and AG (1.2 ml/kg ip) every other day for 30 days. Proteinuria and serum creatinine and blood urea nitrogen concentrations were measured on days 0, 5, 10, 15, and 30, and systolic blood pressure was recorded on days 0, 15, and 30. The degree of glomerulosclerosis and tubulointerstitial damage, the immunostaining for inducible nitric oxide synthase, 3-nitrotyrosine, poly(ADP-ribose), and the subunits of NADPH oxidase p22phox and gp91phox, and the activity of SOD were determined on day 30. SAC and AG reduced hypertension, renal damage, and the abundance of inducible nitric oxide synthase, 3-nitrotyrosine, poly(ADP-ribose), p22phox, and gp91phox and increased SOD activity. Our data suggest that the antihypertensive and renoprotective effects of SAC and AG are associated with their antioxidant properties and that they may be used to ameliorate hypertension and delay the progression of renal damage.
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PMID:Renoprotective and antihypertensive effects of S-allylcysteine in 5/6 nephrectomized rats. 1768 53

Cis-diamminedichloroplatinum (II) (cisplatin) is an effective chemotherapeutic agent successfully used in the treatment of a wide range of tumors; however, nephrotoxicity has restricted its clinical use. Several studies have shown that reactive oxygen species are involved in cisplatin-induced nephrotoxicity, including hydrogen peroxide, hydroxyl radical and superoxide anion (O(2)(-)). The source of O(2)(-) in cisplatin-induced renal damage has not been established. The aim of this study was to investigate if NADPH oxidase is involved in cisplatin-induced nephrotoxicity using apocynin, a widely used NADPH oxidase inhibitor. Rats were studied 3 days after a single injection of cisplatin (7.5mg/kg, i.p.). Apocynin was given in the drinking water (2g/L) 7 days before and 3 days after cisplatin injection. Apocynin treatment was able to ameliorate the renal histological damage and the increase in blood urea nitrogen, serum creatinine, and urinary excretion of total protein, N-acetyl-beta-d-glucosaminidase and glutathione-S-transferase induced by cisplatin. In addition, the protective effect of apocynin was associated with the amelioration of cisplatin-induced oxidative and nitrosative stress. Our data suggest that O(2)(-) derived from NADPH oxidase triggers some of the side effects due to cisplatin administration.
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PMID:Protective effects of apocynin against cisplatin-induced oxidative stress and nephrotoxicity. 1824 69


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