Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of new 6-(alkylthio)ascorbic acids was synthesized, and their inhibitory effects on lipid peroxidation and the oxidative burst of human neutrophils were tested. Of 12 structurally different lipophilic ascorbic acid derivatives 6-S-n-hexadecyl-2-O-methyl-6-deoxy-6-thio-L-ascorbic acid (7b; B-003) inhibited the Fe2+/ADP-induced lipid peroxidation of rat liver microsomes with an IC50 value of 2 microM. In human neutrophils, 7b most potently inhibited the fMLP-induced oxidative burst in a cell density-dependent manner with an IC50 value of 0.6 microM at 5 x 10(5) cells/mL. Shorter alkyl chain lengths decreased the inhibitory potency for both lipid peroxidation and oxidative burst, but in general no correlation was found between the two parameters. Likewise, 6-S-n-hexadecyl-3-O-methyl-6-thio-L-ascorbic acid (7c; B-015), the regioisomer of 7b, was a potent antioxidant but did not affect the oxidative burst. Since superoxide anions generated by xanthine/xanthine oxidase were not quenched by 7b, it became evident that its target was somewhere between receptor stimulation and NADPH-oxidase activation. By measuring the cellular concentrations of 7b and 7c, an accumulation of the first was found explaining its potency and the dependence on cell density. Expecting a pKa value of 3.3 for 7b and 7.7 for 7c a protonophore action of 7b was likely and could be verified by the drop in intracellular pH (pHi) which did not occur with 7c. Ionophores such as nigericin, CCCP, or propionic acid also lowered the pHi but did not inhibit the oxidative burst, indicating that the pHi drop was not the cause for this inhibition. 7b also strongly inhibited the fMLP-induced secretion of azurophilic (IC50 = 7 microM) and specific (IC50 = 2.5 microM) granules.
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PMID:Antioxidant and neutrophil-inhibiting properties of new 2-O-methyl-6-(alkylthio)ascorbic acid derivatives. 825 24

Human spermatozoa possess a specialized capacity to generate reactive oxygen species (ROS) that is thought to be of significance in the redox regulation of sperm capacitation (De Lamirande and Gagnon, 1993; Aitken et al., 1995). However, the mechanisms by which ROS are generated by these cells are not understood. In this study we have examined the possible significance of NADPH as a substrate for ROS production by human spermatozoa. Addition of NADPH to viable populations of motile spermatozoa induced a sudden dose-dependent increase in the rate of superoxide generation via mechanisms that could not be disrupted by inhibitors of the mitochondrial electron transport chain (antimycin A, rotenone, carbonyl cyanide m-chlorophenylhydrazone [CCCP], and sodium azide), diaphorase (dicoumarol) xanthine oxidase (allopurinol), or lactic acid dehydrogenase (sodium oxamate). However, NADPH-induced ROS generation could be stimulated by permeabilization and was negatively correlated with sperm function. Both NADH and NADPH were active electron donors in this system, while NAD+ and NADP+ exhibited little activity. Stereo-specificity was evident in the response in that only the beta-isomer of NADPH supported superoxide production. The involvement of a flavoprotein in the electron transfer process was indicated by the high sensitivity of the oxidase to inhibition by diphenylene iodonium and quinacrine. These results indicate that NAD(P)H can serve as an electron donor for superoxide generation by human spermatozoa and present a simple strategy for the production of motile populations of free radical generating cells with which to study the significance of these molecules in the control of normal and pathological sperm function.
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PMID:Reactive oxygen species generation by human spermatozoa is induced by exogenous NADPH and inhibited by the flavoprotein inhibitors diphenylene iodonium and quinacrine. 921 32

Vascular superoxide anion (O(2)(*-)) levels are increased in DOCA-salt hypertensive rats. We hypothesized that the endothelin (ET)-1-induced generation of ROS in the aorta and resistance arteries of DOCA-salt rats originates partly from xanthine oxidase (XO) and mitochondria. Accordingly, we blocked XO and the mitochondrial oxidative phosphorylation chain to investigate their contribution to ROS production in mesenteric resistance arteries and the aorta from DOCA-salt rats. Systolic blood pressure rose in DOCA-salt rats and was reduced after 3 wk by apocynin [NAD(P)H oxidase inhibitor and/or radical scavenger], allopurinol (XO inhibitor), bosentan (ET(A/B) receptor antagonist), BMS-182874 (BMS; ET(A) receptor antagonist), and hydralazine. Plasma uric acid levels in DOCA-salt rats were similar to control unilaterally nephrectomized (UniNx) rats, reduced with allopurinol and bosentan, and increased with BMS. Levels of thiobarbituric acid-reacting substances were increased in DOCA-salt rats versus UniNx rats, and BMS, bosentan, and hydralazine prevented their increase. Dihydroethidium staining showed reduced O(2)(*-) production in mesenteric arteries and the aorta from BMS- and bosentan-treated DOCA-salt rats compared with untreated DOCA-salt rats. Increased O(2)(*-) derived from XO was reduced or prevented by all treatments in mesenteric arteries, whereas bosentan and BMS had no effect on aortas from DOCA-salt rats. O(2)(*-) generation decreased with in situ treatment by tenoyltrifluoroacetone and CCCP, inhibitors of mitochondrial electron transport complexes II and IV, respectively, whereas rotenone (mitochondrial complex I inhibitor) had no effect. Our findings demonstrate the involvement of ET(A) receptor-modulated O(2)(*-) derived from XO and from mitochondrial oxidative enzymes in arteries from DOCA-salt rats.
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PMID:Xanthine oxidase and mitochondria contribute to vascular superoxide anion generation in DOCA-salt hypertensive rats. 1848 45

Inflammatory brain disease may damage cerebral vascular endothelium leading to cerebral blood flow dysregulation. The proinflammatory cytokine TNF-alpha causes oxidative stress and apoptosis in cerebral microvascular endothelial cells (CMVEC) from newborn pigs. We investigated contribution of major cellular sources of reactive oxygen species to endothelial inflammatory response. Nitric oxide synthase and xanthine oxidase inhibitors (N(omega)-nitro-l-arginine and allopurinol) had no effect, while mitochondrial electron transport inhibitors (CCCP, 2-thenoyltrifluoroacetone, and rotenone) attenuated TNF-alpha-induced superoxide (O(2)(*-)) and apoptosis. NADPH oxidase inhibitors (diphenylene iodonium and apocynin) greatly reduced TNF-alpha-evoked O(2)(*-) generation and apoptosis. TNF-alpha rapidly increased NADPH oxidase activity in CMVEC. Nox4, the cell-specific catalytic subunit of NADPH oxidase, is highly expressed in CMVEC, contributes to basal O(2)(*-) production, and accounts for a burst of oxidative stress in response to TNF-alpha. Nox4 small interfering RNA, but not Nox2, knockdown prevented oxidative stress and apoptosis caused by TNF-alpha in CMVEC. Nox4 is colocalized with HO-2, the constitutive isoform of heme oxygenase (HO), which is critical for endothelial protection against TNF-alpha toxicity. The products of HO activity, bilirubin and carbon monoxide (CO, as a CO-releasing molecule, CORM-A1), inhibited Nox4-generated O(2)(*-) and apoptosis caused by TNF-alpha stimulation. We conclude that Nox4 is the primary source of inflammation- and TNF-alpha-induced oxidative stress leading to apoptosis in brain endothelial cells. The ability of CO and bilirubin to combat TNF-alpha-induced oxidative stress by inhibiting Nox4 activity and/or by O(2)(*-) scavenging, taken together with close intracellular compartmentalization of HO-2 and Nox4 in cerebral vascular endothelium, may contribute to HO-2 cytoprotection against inflammatory cerebrovascular disease.
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PMID:Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-alpha in cerebral vascular endothelial cells. 1911 62