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)

1. The potential protective effect of several antioxidants [Cu/Zn superoxide dismutase (Cu/Zn SOD), ascorbate, reduced glutathione (GSH), and alpha-tocopherol (alpha-TOC)] on relaxations of the mouse anococcygeus muscle to nitric oxide (NO; 15 microM) and, where appropriate, nitrergic field stimulation (10 Hz; 10 s trains) was investigated. 2. The superoxide anion generating drug duroquinone (100 microM) reduced relaxations to exogenous NO by 54 +/- 6%; this inhibition was partially reversed by Cu/Zn SOD (250 u ml-1), and by ascorbate (500 microM). Following inhibition of endogenous Cu/Zn SOD activity with diethyldithiocarbamate (DETCA), duroquinone (50 microM) also reduced relaxations to nitrergic field stimulation (by 53 +/- 6%) and this effect was again reversed by Cu/Zn SOD and by ascorbate. Neither GSH (500 microM) nor alpha-TOC (400 microM) afforded any protection against duroquinone. 3. Xanthine (20 mu ml-1); xanthine oxidase (100 microM) inhibited NO-induced relaxations by 73 +/- 14%, but had no effect on those to nitrergic field stimulation, even after DETCA treatment. The inhibition of exogenous NO was reduced by Cu/Zn SOD (250 u ml-1) and ascorbate (400 microM), but was unaffected by GSH or alpha-TOC (both 400 microM). 4. Hydroquinone (100 microM) also inhibited relaxations to NO (by 52 +/- 10%), but not nitrergic stimulation. In this case, however, the inhibition was reversed by GSH (5-100 microM) and ascorbate (100-400 microM), although Cu/Zn SOD and alpha-TOC were ineffective. 5. 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO, 50 microM) inhibited NO-induced relaxations by 50 +/- 4%, but had no effect on nitrergic responses; the inhibition was reduced by ascorbate (2-200 microM) and alpha-TOC (10-200 microM), but not by Cu/Zn SOD or GSH. 6. Hydroxocobalamin (5-100 microM) inhibited, equally, relaxations to both NO (-logIC40 3.14 +/- 0.33) and nitrergic stimulation (-logIC40 3.17 +/- 0.22). 7. Thus, a number of physiological antioxidants protected NO from superoxide anions, and from direct NO-scavengers. The possibility that the presence of these antioxidants within nitrergically-innervated tissues might explain the lack of effect of the NO inhibitors on nerve-induced relaxation, without the need to invoke a transmitter other than free radical NO, is discussed.
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PMID:Antioxidant protection of NO-induced relaxations of the mouse anococcygeus against inhibition by superoxide anions, hydroquinone and carboxy-PTIO. 888 31

We have studied the activity of substances (superoxide dismutase [SOD], catalase [Cat], malonaldehyde, xanthine oxidase [XO], nitric oxide [NOx]) participating in oxidative stress. Seminal plasma samples of 147 ejaculates obtained from normal and from infertile males were examined. Activities of SOD, Cat, and XO were measured chemiluminometrically while malonaldehydes and NOx were measured by spectrophotometer in seminal plasma samples. Ejaculates were previously characterized according to World Health Organization andrological criteria (sperm number, motility, and morphology). Procedures were performed in a university laboratory. Statistically significant changes (in comparison to normozoospermic samples) were noted in activities of SOD, XO, and malonaldehyde levels. The SOD activity exceeded values obtained for normozoospermic samples only in oligozoospermia. Otherwise low SOD levels in analyzed infertile subgroups inversely related to elevated malonaldehydes. Because diminished activity of SOD in seminal plasma was associated with increased levels of malonaldehydes and XO, we could postulate some significance of these monitored substances in evaluation of the cause of male infertility.
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PMID:Oxidative stress and male infertility. 888 9

1. The effects of oxygen free radical scavengers and endothelial cell-derived nitric oxide (EDNO) on the death of porcine cultured aortic endothelial cells exposed to exogenous superoxide-[xanthine (0.4 mM)/xanthine oxidase (0.04 unit ml-1) + diethylenetriaminepentaacetic acid (DTPA, 10 microM)] or hydroxyl radical-generating system(s) [superoxide generating system+ferric iron (Fe3+, 0.1 mM) or peroxynitrite (0-100 microM)] have been evaluated. 2. Spin trapping studies using 5,5-dimethyl-l-pyrroline-N-oxide (DMPO) with electron paramagnetic resonance spectrometry were also conducted to determine qualitatively the oxidant species generated by the oxidant generating systems. 3. Endothelial cell injury provoked by the exogenous superoxide generating system was inhibited by catalase, DTPA and a hydroxyl radical scavenger (dimethyl sulphoxide, DMSO), but not by superoxide dismutase (SOD). Addition of Fe3+ to the superoxide generating system enhanced the cell injury. These suggested that the direct cytotoxicity of exogenous superoxide is limited, and that endogenous transition metal-dependent hydroxyl radical formation is involved in the cell injury. 4. An inhibitor of the constitutive NO-pathway, NG-monomethyl-L-arginine, did not influence cell injury induced by the superoxide generating system, suggesting that basal NO production is not responsible for the cytotoxicity. 5. Stimulation of endothelial cells with bradykinin enhanced cell injury provoked by the exogenous superoxide generating system, but not by the exogenous hydroxyl radical generating system. The enhancement by bradykinin was inhibited by NG-monomethyl-L-arginine and bradykinin B2-receptor antagonist, D-Arg-[Hyp3, Thi5,8, D-Phe7] bradykinin, suggesting that an interaction of NO with superoxide is involved in the enhanced cytotoxicity. A possible intermediate of this reaction, peroxynitrite, also caused endothelial cell injury in a concentration-dependent manner. 6. The modulatory effects of NO on hydroxyl radical-like activity (= formaldehyde production) from the superoxide generating system was also evaluated in a cell-free superoxide/NO generating system, consisting of xanthine/xanthine oxidase, DTPA, DMSO, and various amounts of a spontaneous NO generator, sodium nitroprusside (SNP) and were compared with those of Fe3+. At doses up to 10 microM, SNP concentration-dependently increased the formaldehyde production while the higher concentrations of SNP decreased. The maximum amount of formaldehyde produced by SNP was 5 fold less than that produced by Fe3+ (0.1 mM). Peroxynitrite-induced formaldehyde formation was concentration-dependently inhibited by SNP. 7. We conclude that agonist-stimulated but not basal NO production acts as cytotoxic hydroxyl radical donor as well as the endogenous transition metal when endothelial cells are exposed to exogenous superoxide anion, while the modulatory effect of EDNO is limited by a secondary reaction with hydroxyl radicals.
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PMID:Self-limiting enhancement by nitric oxide of oxygen free radical-induced endothelial cell injury: evidence against the dual action of NO as hydroxyl radical donor/scavenger. 889 64

Not all possible mediators of lung I/R injury that have been studied, such as cyclooxygenase and lipoxygenase products, have been presented in this review, but it is very clear that oxygen free radicals are the primary mediators of the damage, regardless of their origin. Oxygen radicals are generated by neutrophils, which are sequestered and activated in the ischemic-reperfused pulmonary tissue, and by xanthine oxidase, which is upregulated by ischemia and/or activated neutrophils. The contributions to lung injury by different species of oxygen radicals may very depending upon the lung model used to study I/R. Also, nitric oxide may be injurious or protective in lung I/R injury, depending upon some critical alveolar PO2 level present either during ischemia or at reperfusion. I/R-induced lung microvascular injury ultimately depends upon some balance between lung metabolic stress, the extent of the I/R-induced inflammatory response, endogenous antioxidant levels, and the timing, magnitude, and duration of oxygen free radical generation during both periods of ischemia and reperfusion. The final common pathway causing microvascular permeability to increase after lung I/R is the activation of the endothelial cell's contractile machinery. Particularly, endothelial contraction may occur in a MLCK-dependent fashion. Endothelial contraction may also be related to an intracellular Ca++ increase and subsequent calmodulin activation. The initiating event causing increased intracellular Ca++ is not known, but may be due to endothelial cell/leukocyte interactions, oxygen radical-mediated Ca++ transients, mobilization of intracellular Ca++ pools by various second messengers, or stimulation of Ca++ influx secondarily to changes in the activity of membrane ion pumps such as the Na+/H+ antiport. Increasing cAMP levels in the postischemic lung can prevent and actually reverse I/R-induced microvascular injury, by affecting MLCK, the endothelial cell cytoskeleton, and/or the function of sequestered leukocytes. Also, cAMP elevation aids the resolution of pulmonary edema by facilitating capillary fluid reabsorption. Whatever the mechanism, elevation of cAMP in the setting of lung I/R injury represents a potentially useful therapy for improving early lung function following lung transplantation. Finally, additional studies are necessary to elucidate the complete mechanisms responsible for producing microvascular injury during lung I/R. Specifically, a better understanding of the relationships between the many factors required to produce lung damage is needed. Many interventions into the lung I/R process provide protection against microvascular injury, suggesting that regulation of the endothelial barrier permeability to fluid, protein, and leukocytes is accomplished by several redundant systems. This situation may be similar to mechanisms reported to regulate the immune response mediated by T cells (62a), where T cell activation depends upon multiple signal inputs for the full immune response to occur. Thus, multiple signals in a correct sequence delivered to the endothelium may be necessary to produce the microvascular injury associated with lung ischemia and reperfusion.
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PMID:Endothelial damage caused by ischemia and reperfusion and different ventilatory strategies in the lung. 890 6

Since nitric oxide (NO) has been widely accepted as a novel neuromodulator, which activates soluble forms of guanylate cyclase to increase in guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels, the effect of water-soluble substance in cigarette smoke on cyclic GMP levels were investigated using nerve terminals prepared from rat cerebral cortex. Although the smoke-substance itself failed to affect cyclic GMP levels in the synaptosomes, the smoke-substance significantly inhibited the increases in cyclic GMP levels induced by NO donors. The blocking effect of the smoke-substance was inhibited by concomitant incubation with superoxide dismutase, but not with mannitol. In addition, the effect of smoke-substance was mimicked by products of the xanthine/xanthine oxidase system, but not by nicotine. The effect of smoke-substance was preserved at least 7 days after they were stored at room temperature. Therefore, these results suggest that the smoke-substance may possess long half-lives to produce the radicals which inactivate NO, and to inhibit the increase in cyclic GMP levels in nerve terminals. The interference with NO may explain the part of mechanism in effects of cigarette smoke on neuronal functions.
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PMID:Effects of cigarette smoke on nitric oxide-induced increase in cyclic GMP in nerve terminals of rat cerebral cortex. 891 78

In the present study we investigated the effect of metabolic activation on the susceptibility of isolated rat pancreatic islet cells to the alkylating beta-cell toxin streptozocin (SZ), reactive oxygen intermediates (ROI), and nitric oxide (NO). The latter two represent physiologically occurring mediators involved in the autoimmune destruction of islet cells. ROI were generated by the enzyme xanthine oxidase, and NO was released from sodium nitroprusside. During 18 h of culture at a physiological glucose concentration (5 mmol/L), 75% of the islet cells were lysed by SZ, 81% by ROI, and 74% by NO, as determined by the trypan blue exclusion assay. Increasing concentrations of glucose or the nonnutrient stimulators theophylline and glibenclamide dose-dependently reduced SZ- and ROI-mediated islet cell lysis. In the presence of 29 mmol/L glucose, 5.5 mmol/L theophylline, or 10 micrograms/mL glibenclamide, SZ-induced lysis was reduced to 15%, 22%, or 15%, and ROI-induced lysis was reduced to 20%, 34%, or 15%, respectively. In contrast, stimulation by glucose, theophylline, or glibenclamide did not improve resistance against NO. The protection against SZ and ROI was associated with preserved mitochondrial activity, as determined by the ability of the islet cells to convert the tetrazolium salt 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide into its formazan. Elevation of the glucose concentration from 5.5 to 29 mmol/L increased the residual mitochondrial activity from 45% to 80% in SZ-exposed islet cells and from 21% to 78% in ROI-exposed cells. Conversely, the lack of protection against NO correlated with no preservation of mitochondrial activity in the presence of high concentrations of glucose, theophylline, or glibenclamide. In conclusion, our results show that metabolic stress does not render islet cells more susceptible to inflammatory insults in vitro. Rather, an increased mitochondrial energy supply improves the resistance against SZ and ROI, whereas the toxicity of NO was independent of islet cell activity.
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PMID:Metabolic activation of islet cells improves resistance against oxygen radicals or streptozocin, but not nitric oxide. 892 45

Reactive oxygen species (ROS) have been implicated in the pathogenesis of a wide variety of respiratory diseases. We investigated mechanisms of ROS-induced mucin secretion by guinea pig tracheal epithelial (GPTE) cells in primary culture, and ROS-induced activation of the second messenger-producing enzyme phospholipase C (PLC), in GPTE cells and in a virally transformed cell line (BEAS-2B) derived from human bronchial epithelium. Mucin secretion was measured by a monoclonal antibody-based enzyme-linked immunosorbent assay, and PLC activation was assessed by anion exchange chromatography. ROS generated enzymatically by xanthine oxidase (XO, 500 microM) in the presence of purine (500 microM) enhanced release of mucin by GPTE cells and activated PLC in GPTE and BEAS cells. Hypersecretion of mucin and activation of PLC in response to purine + XO appeared to occur via an intracellular pathway(s) dependent on endogenously produced nitric oxide and possibly intracellularly generated oxidants. Both responses could be blocked or attenuated by preincubation of the cells with NG-monomethyl-L-arginine, an inhibitor of the enzyme nitric oxide synthase, or with dimethylthiourea, a compound that can react with a variety of intracellular oxidant species. Reactive nitrogen species generated chemically also stimulated secretion of mucin and activated PLC via a mechanism dependent (at least in part) on intracellular oxidant-mediated process(es). The results suggest that intracellularly generated radical species of nitrogen and oxygen may be important modulators of the response of airway epithelial cells to external oxidant stress.
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PMID:Oxidant stress stimulates mucin secretion and PLC in airway epithelium via a nitric oxide-dependent mechanism. 894 30

We have previously shown that nitric oxide (NO) donors, such as nitrosoglutathione, inhibit endothelial cell (EC) xanthine dehydrogenase (XD)/xanthine oxidase (XO) activity. The purpose of this study was to assess whether endothelial-derived NO plays any role in the regulation of intracellular XD/XO. We exposed rat pulmonary microvascular EC to L-arginine (precursor of NO) or inhibitors of nitric oxide synthase (NOS), i.e., NG-nitro-L-arginine methyl esther (L-NAME) and NG-nitro-L-arginine, in conditions of normoxia, hypoxia, and hypoxia followed by reoxygenation. Hypoxia alone caused a 1.9- and a 6.6-fold increase in XO and a 5-fold increase in XO + XD activities after 24 and 48 h of exposure, respectively. The combination of hypoxia and L-NAME (300 microM) treatment amounted at 48 h to a 10- and 7.5-fold increase in XO and XO + XD activities, respectively, compared with normoxic untreated cells. L-NAME also prevented the decline in XD/XO activity that occurred in untreated EC after hypoxia-reoxygenation. On the other hand, treatment with L-arginine caused a dose-dependent decrease in XD/XO activity in hypoxic EC compared with cells provided with L-arginine-free medium. In separate experiments, we assessed the role of L-arginine supplementation on the in vivo regulation of lung XD/XO by exposing male adult Sprague-Dawley rats for a period of 5 days to a hypoxic hypobaric atmosphere (0.5 atm). Exposure to hypoxia produced a significant increase in lung tissue XO activity and an increase in the ratio of XO to XD. L-Arginine supplementation in the drinking water prevented the increase in lung XO and the XO-to-XD ratio in hypoxic rats and caused a significant decrease in XO and XD in rats exposed to normoxia. In conclusion, this study suggests that endogenous NO has a significant role in the regulation of XD/XO both in vitro and in vivo. By inhibiting XD/XO activity, NO may have a modulating effect in conditions of hypoxia and hypoxia-reoxygenation, where this enzyme is thought to be important.
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PMID:Regulation of intracellular xanthine oxidase by endothelial-derived nitric oxide. 894 32

Vulnerable areas of atherosclerotic plaques often contain lipid-laden macrophages and display matrix metalloproteinase activity. We hypothesized that reactive oxygen species released by macrophage-derived foam cells could trigger activation of latent proforms of metalloproteinases in the vascular interstitium. We showed that in vivo generated macrophage foam cells produce superoxide, nitric oxide, and hydrogen peroxide after isolation from hypercholesterolemic rabbits. Effects of these reactive oxygens and that of peroxynitrite, likely to result from simultaneous production of nitric oxide and superoxide, were tested in vitro using metalloproteinases secreted by cultured human vascular smooth muscle cells. Enzymes in culture media or affinity-purified (pro-MMP-2 and MMP-9) were examined by SDS-PAGE zymography, Western blotting, and enzymatic assays. Under the conditions used, incubation with xanthine/xanthine oxidase increased the amount of active gelatinases, while nitric oxide donors had no noticeable effect. Incubation with peroxynitrite resulted in nitration of MMP-2 and endowed it with collagenolytic activity. Hydrogen peroxide treatment showed a catalase-reversible biphasic effect (gelatinase activation at concentrations of 4 microM, inhibition at > or = 10-50 microM). Thus, reactive oxygen species can modulate matrix degradation in areas of high oxidant stress and could therefore contribute to instability of atherosclerotic plaques.
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PMID:Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. 895 20

In this study we attempted to demonstrate whether endothelial cell nitric oxide synthase (eNOS) and xanthine oxidase (XO) could be activated to release nitric oxide (NO) and peroxynitrite (ONOO-) following exposure to ultraviolet B (UVB) radiation and to define whether this light-induced response could be involved in the pathogenesis of sunburn erythema and inflammation. Treatment of human endothelial cells with UVB (290-320 nm) radiation (up to 100 mJ/cm2) resulted in an increase of both NO and ONOO- release that was inhibited by NG-monomethyl-L-arginine (L-NMMA). Treatment of cell cytosol with various doses of UVB radiation (up to 20 mJ/cm2) resulted in a threefold increase of XO activity that was inhibited (approximately 90% by oxypurinol. In reconstitution experiments, when purified eNOS was added to purified XO, an almost fourfold increase in ONOO- production at 20 mj/cm2 UVB radiation was observed. UVB radiation (100 mg/cm2) decreased cell membrane fluidity, indicating changes in the physicochemical characteristics of the membranes. In in vivo experiments, when human volunteers were subjected to UVB light, a protection factor (PF) of 3.90 +/- 0.85 was calculated when an emulsified cream formulation containing nitro-L-arginine (L-NA; 2%) and L-NMMA (2%) was applied to their skin. The present studies indicate that UVB radiation acts as a potent stimulator of eNOS and XO in human endothelial cells. The cytotoxic effects of NO and ONOO- may be the main factors in the integrated response of the skin leading to vasodilatation, the first key event of erythema production and the inflammation process.
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PMID:Nitric oxide and peroxynitrite released by ultraviolet B-irradiated human endothelial cells are possibly involved in skin erythema and inflammation. 896 Jul 7


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