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)

Nitric oxide (.NO) is a signal transducing free radical which can modify oxidant stress by limiting superoxide (O2.-)-mediated injury. However, the product of .NO reaction with O2.-, peroxynitrite (ONOO-), is a potent oxidizing and nitrating agent. Exposure of a mixture containing phosphatidylcholine liposomes and surfactant apoprotein A (SP-A; 10% by weight) to increasing concentrations of .NO, generated by spermine NONOate, and constant O2.- levels, produced by the action of xanthine oxidase on lumazine, suppressed O2.(-)-induced lipid peroxidation in the presence of Fe3(+)- EDTA. On the other hand, an increase in the .NO/O2.- value resulted in nitration of SP-A tyrosine residues, located in the carbohydrate recognition domain (CRD), and decreased the ability of SP-A to aggregate lipids and bind mannose, two functions that require an intact CRD. SP-A was also nitrated to a large extent following exposure to 3-morpholinosydnonimine (SIN-1) or tetranitromethane at pH 8. In each case, increased nitrotyrosine content correlated in a monotonic fashion with inhibition of lipid aggregation and mannose binding, correlated with the extent of functional inhibition. Superoxide dismutase (2400 U/ml) and urate (100 microM; nonspecific scavenger of both ONOO- and hydroxyl radical), but not mannitol (50 mM; hydroxyl radical scavenger), prevented the SIN-1-induced injury to SP-A. In contrast, spermine NON-Oate or xanthine oxidase plus lumazine alone neither inhibited SP-A function nor nitrated the protein. These results indicate that at high concentrations, .NO inhibit O2.-induced lipid peroxidation. However, ONOO., formed by the reaction of .NO and O2.-, nitrates SP-A leading to decreased ability to aggregate lipids and bind mannose.
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PMID:Nitration of surfactant protein A (SP-A) tyrosine residues results in decreased mannose binding ability. 880 82

This study was designed to test the hypothesis that nitric oxide (NO) is the relaxant metabolite produced by metabolic activation of glyceryl trinitrate (GTN) in rabbit aortic strip (RAS). Superoxide anion, an inactivator of NO, was included in a two-tissue bioassay in which rabbit Taenia coli strip (RTCS) relaxed to GTN in the presence of RAS. Superoxide as generated by xanthine (10 microM)/ xanthine oxidase (20 mU/ml) failed to attenuate relaxations of RTCS to GTN (0.1 nM-10 microM) and RAS, compared with the untreated control. In contrast, superoxide attenuated the relaxation of RTCS to both authentic NO gas and to SIN-1 (0.1 nM-10 microM), a known spontaneous releaser of NO; the attenuation of RTCS relaxation to NO gas was reversed by superoxide dismutase (100 units/ml). In addition, another drug that has been reported to scavenge NO, hydroquinone, did not attenuate the RTCS relaxation to GTN. These results suggest that biotransformation of GTN in vascular smooth muscle that leads to relaxation is caused by a NO-containing species (i.e. a S-nitrosothiol). Such a molecule would be less susceptible to inactivation by superoxide anion and hydroquinone.
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PMID:Superoxide does not inhibit glyceryl trinitrate-rabbit aortic strip-mediated relaxation of rabbit Taenia coli. Evidence against a role for nitric oxide itself as the smooth muscle active drug metabolite? 881 76

Giardia lamblia trophozoites were incubated for 2 h with activated murine macrophages, nitric oxide (NO) donors or a superoxide anion generator (20 mU/ml xanthine oxidase plus 1 mM xanthine). Activated macrophages were cytotoxic to Giardia trophozoites (approximately 60% dead trophozoites). The effect was inhibited (> 90%) by an NO synthase inhibitor (200 microM) and unaffected by superoxide dismutase (SOD, 300 U/ml). Giardia trophozoites were killed by the NO donors, S-nitroso-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) in a dose-dependent manner (LD50 300 and 50 microM, respectively). A dual NO-superoxide anion donor, 3-morpholino-sydnonimine hydrochloride (SIN-1), did not have a killing effect in concentrations up to 1 mM. However, when SOD (300 U/ml) was added simultaneously with SIN-1 to Giardia, a significant trophozoite-killing effect was observed (approximately 35% dead trophozoites at 1 mM). The mixtures of SNAP or SNP with superoxide anion, which yields peroxynitrite, abolished the trophozoite killing induced by NO donors. Authentic peroxynitrite only killed trophozoites at very high concentrations (3 mM). These results indicate that NO accounts for Giardia trophozoites killing and this effect is not mediated by peroxynitrite.
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PMID:Role of nitric oxide and superoxide in Giardia lamblia killing. 922 10

Nitric oxide (NO.) is a free radical characterized by a high spontaneous chemical reactivity with many other molecules including the superoxide radical (O2.-). This complex interaction may generate a peroxynitrite anion (ONOO-), which behaves as an important mediator of oxidative stress in many pathological states. In the present study, in vitro experiments were performed to assess directly the O2.- and hydroxyl (.OH) radical scavenging effects of various NO. donor drugs, i.e. sodium nitroprusside (SNP), sodium nitrite (NaNO2), molsidomine and SIN 1, at pH 7.4, 7 or 6. Concentrations of NO. in the incubation medium containing the different NO. donor drugs were measured by the assay based on the reaction of Fe-N-methyl-D-glucamine dithiocarbamate (MGD) with NO. that yields a stable spin-adduct measured by electron paramagnetic resonance (EPR). O2.- and .OH generation was characterized by EPR spin trapping techniques, using the spin trap 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). These free radicals were generated from the enzymatic system xanthine-xanthine oxidase, in phosphate buffer adjusted at pH 7.4, 7 and 6. Under these experimental conditions, SNP exhibited the strongest superoxide scavenging properties, characterized by IC50 values expressed in the micromolar range, which decreased at low pH. Addition of SNP (800 microM) to solution containing MGD and Fe2+ (5:1) at pH 7 4 produced a three line EPR spectrum which is identified to [(MGD)2-Fe2+-NO]. In control experiments no EPR signal was observed. We obtained the same results with NaNO2 and an augmentation of the spin-adduct level was noted with the prolongation of the incubation period. In return, molsidomine (2 mM) did not produce, in our conditions, a detectable production of NO.. NaNO2 displayed a significant superoxide scavenging effect only at pH 6, whilst neither molsidomine nor SIN 1 had any effect. Therefore, the superoxide scavenging properties of SNP, NaNO2, and molsidomine appeared to be closely related to their potential for NO release, which partially depends on the pH conditions. The behaviour of SIN 1 is more complicated, the speed of oxygen diffusion probably acting as a limiting factor in NO. formation in our conditions. The production of NO. was detected in presence of SIN 1. The intensity of the complex is comparable with the signal founded with NaNO2. By contrast, all molecules exhibited hydroxyl radical scavenging properties, highlighting the capacity of .OH to react with a wide range of molecules. In conclusion, considering the poor chemical reactivity of O2.-, the NO. donor drugs/O2.- interactions suggest a special relationship between these two radical species, which, in certain pathological states, could lead to the generation of cytotoxic end-products with strong oxidizing properties.
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PMID:In vitro studies of interactions of NO. donor drugs with superoxide and hydroxyl radicals. 945 Jun 62

Many of the cytopathic effects of nitric oxide (NO*) are mediated by peroxynitrite (PN), a product of the reaction between NO* and superoxide radical (O2*-). In the present study, we investigated the role of PN, O2*- and hydroxyl radical (OH*) as mediators of epithelial hyperpermeability induced by the NO* donor, S-nitroso-N-acetylpenicillamine (SNAP), and the PN generator, 3-morpholinosydnonimine (SIN-1). Caco-2BBe enterocytic monolayers were grown on permeable supports in bicameral chambers. Epithelial permeability, measured as the apical-to-basolateral flux of fluorescein disulfonic acid, increased after 24 h of incubation with 5.0 mM SNAP or SIN-1. Addition of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, an NO* scavenger, or Tiron, an O2*- scavenger, reduced the increase in permeability induced by both donor compounds. The SNAP-induced increase in permeability was prevented by allopurinol, an inhibitor of xanthine oxidase (a source of endogenous O2*-). Diethyldithiocarbamate, a superoxide dismutase inhibitor, and pyrogallol, an O2* generator, potentiated the increase in permeability induced by SNAP. Addition of the PN scavengers deferoxamine, urate, or glutathione, or the OH* scavenger mannitol, attenuated the increase in permeability induced by both SNAP and SIN-1. Both donor compounds decreased intracellular levels of glutathione and protein-bound sulfhydryl groups, suggesting the generation of a potent oxidant. These results support a role for PN, and possibly OH*, in the pathogenesis of NO* donor-induced intestinal epithelial hyperpermeability.
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PMID:Nitric oxide donor-induced hyperpermeability of cultured intestinal epithelial monolayers: role of superoxide radical, hydroxyl radical, and peroxynitrite. 981 20

We have reported that peroxynitrite (PON) selectively inactivated prostacyclin synthase (PGIS) by a mechanism of tyrosine nitration at the active site [Zou, Martin and Ullrich (1997) Biol. Chem. Hoppe-Seyler 378, 707-713]. We have now extended our studies on rat mesangial cells (RMC) and show that nitration can occur under the influence of cytokines. Pretreatment of RMC with interleukin 1beta (IL-1beta), which up-regulated cyclo-oxygenase 2 and inducible nitric oxide synthase (NOS-2), significantly attenuated the conversion of [14C]prostaglandin H2 (PGH2) into the stable prostacyclin (PGI2) metabolite 6-oxo-prostaglandin F1alpha (6-oxo-PGF1alpha). The presence of superoxide dismutase (SOD, 100 units/ml) or the NOS synthase inhibitor Nomega-monomethyl-l-arginine (100 microM) as well as cycloheximide (10 microM) plus actinomycin (10 microM) abolished IL-1beta-mediated down-regulation of 6-oxo-PGF1alpha from PGH2. At the same time, 6-oxo-PGF1alpha production from arachidonate (AA) increased at the expense of prostaglandin E2 (PGE2). Neither NO alone generated from different NO donors nor superoxide from xanthine/xanthine oxidase (1-100 m-units/ml) inhibited PGI2 synthesis, either from PGH2 or from AA. Bolus additions of chemically synthesized PON or the PON generator 3-morpholinosydnonimine N-ethylcarbamide (SIN-1) exhibited a potent inhibition of 6-oxo-PGF1alpha release from both PGH2 and AA. In addition, immunoprecipitation of nitrotyrosine-containing proteins from PON- and SIN-1-treated RMC yielded distinct nitrated PGIS bands but also from IL-1beta-pretreated cells alone, compared with a lack of nitrated PGIS in control cells. Taken together, our results strongly suggest that IL-1beta pretreatment of RMC via NOS-2 leads to the production of PON with the consequence of a partial nitration and inhibition of PGIS.
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PMID:Interleukin 1beta decreases prostacyclin synthase activity in rat mesangial cells via endogenous peroxynitrite formation. 982 Aug 30

We have previously shown that surfactant protein A (SP-A) mediates in vitro killing of mycoplasmas by alveolar macrophages (AMs) from resistant C57BL/6 mice through a nitric oxide (.NO)-dependent mechanism. Herein, SP-A-deficient [SP-A(-/-)] and inducible.NO synthase-deficient [iNOS(-/-)] mice were infected intranasally with 10(5) or 10(7) colony-forming units of Mycoplasma pulmonis. SP-A(-/-) mice were as susceptible to mycoplasmal infection as highly susceptible C3H/He mice, and far more susceptible than resistant C57BL/6 mice. iNOS(-/-) mice had significantly greater numbers of mycoplasmas and severity of lung lesions than iNOS(+/+) controls. In vitro, AMs isolated from C57BL/6 mice, activated with IFN-gamma, incubated with SP-A (25 micrograms/ml), and infected with 10(10) colony-forming units of M. pulmonis, killed mycoplasmas within 6 h. Mycoplasmal killing was abrogated by 1,000 units/ml of copper-zinc superoxide dismutase. In the absence of AMs, incubation of M. pulmonis with the peroxynitrite generator 3-morpholinosynodiomine.HCl (SIN-1) effected complete killing of mycoplasmas by 90 min in a dose-dependent manner. Addition of copper-zinc superoxide dismutase (3,000 units/ml), which converts SIN-1 to a.NO donor, prevented this killing. Neither of the reactive oxygen species generated by xanthine oxidase (10 milliunits/ml, plus 500 microM xanthine and 100 microM FeCl3), nor.NO generated by 1-propanamine-3-(2-hydroxy-2-nitroso-1-propylhydrazine (PAPA NONOate) (100 microM) killed mycoplasmas. These data establish that peroxynitrite generation by AMs is necessary for the killing of a pathogen in vitro and in vivo.
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PMID:Surfactant protein A mediates mycoplasmacidal activity of alveolar macrophages by production of peroxynitrite. 1022 Apr

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is covalently modified by NAD in the presence of nitric oxide (NO) and dithiothreitol. Replacement of NAD with NADH in the presence of SIN-1 (3-morpholinosydnonimine) and dithiothreitol increased modification 25-fold. We now demonstrate that in contrast to NO-mediated attachment of NAD, covalent attachment of NADH to GAPDH proceeds in the presence of low molecular weight thiols, independent of NO. Removal of oxygen and transition metal ions inhibited modification, consistent with a role for reactive oxygen species; inhibition by superoxide dismutase, stimulation by xanthine oxidase/hypoxanthine, and the lack of an effect of catalase supported the hypothesis that superoxide, generated from thiol oxidation, was involved. Electrospray mass spectrometry showed covalent linkage of the NADH molecule to GAPDH. Characterization of the product of phosphodiesterase cleavage demonstrated that linkage to GAPDH occurred through the nicotinamide of NADH. Lys-C digestion of GAPDH, followed by peptide isolation by high performance liquid chromatography, matrix-assisted laser desorption ionization time-of-flight analysis, and Edman sequencing, demonstrated that NADH attachment occurred at Cys-149, the active-site thiol. This thiol linkage was stable to HgCl2. Thus, linkage of GAPDH to NADH, in contrast to NAD, occurs in the presence of thiol, is independent of NO, and is mediated by superoxide.
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PMID:Thiols mediate superoxide-dependent NADH modification of glyceraldehyde-3-phosphate dehydrogenase. 1039 84

The effects of cortical tissue preparations (CTP) from human brain on the production of reactive oxygen species (ROS) has been investigated with several biochemical model reactions. As indicators for ROS, fragmentation of the methionine derivatives, alpha-keto-gamma-methylthiobutyric acid (KMB) or 1-amino-cyclopropane-1-carboxylic acid (ACC), yielding ethene have been used. With these systems we have shown that production of OH-radical-type oxidants by the xanthine oxidase (XOD)-system is strongly stimulated by CTP. This activity is due to intrinsic iron ions since ethene formation from KMB is stimulated by EDTA, inhibited by desferrioxamine (Desferal) and also visible with heat-denatured CTP. CTP by themselves have no XOD activity. 3-Hydroxykynurenine (3HK) is another possible substrate for XOD but produces H2O2 without XOD-catalysis, whereas allopurinol is not inhibiting. CTP contain measurable NAD(P)H oxidoreductase activity, producing OH- radical- type oxidants at the expense of NADPH and (to a lesser extent) NADH as electron donors, shown as redox-cycling of 2-methyl-5-hydroxy-1,4-naphthoquinone, plumbagin. Ethene formation from KMB is also driven by both morpholinosydnonimine (SIN) or ONOOH. The reaction driven by SIN is stimulated by CTP and inhibited by catalase, SOD and hemoglobin. Since ethene release from KMB driven by ONOOH is inhibited by CTP the mechanisms driving KMB fragmentation are different for SIN and ONOOH. Furthermore CTP contain approx. 4 U catalase activity per mg protein and very weak peroxidase (POD) activity shown as ACC fragmentation yielding ethene in the presence of both H2O2 and KBr or NaCl. Since ACC binds to CTP and both compounds, ACC and KMB are natural products, present in food (ACC) or synthesized from methionine in vivo (KMB), these compounds may represent protecting agents in systems where reactive oxygen species are formed. One might even speculate that the production of ethene at these membrane receptor sites may have biological functions, since ethene is known to possess anaesthetic activities.
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PMID:Pro- and antioxidative properties of cortical tissue preparations from human brain exhibiting NMDA-receptor characteristics. 1043 95

Peroxynitrite, formed by the reaction between nitric oxide (NO) and superoxide, has been implicated in the pathogenesis of numerous disease processes. Several studies have shown that peroxynitrite-induced protein nitration may compromise enzyme and protein function. We hypothesized that peroxynitrite may regulate cytokine function during inflammation. To test this hypothesis, the neutrophil and monocyte chemotactic responses of macrophage inflammatory protein-1alpha (MIP-1alpha) incubated with and without peroxynitrite were evaluated. Peroxynitrite attenuated neutrophil chemotactic activity (NCA) and monocyte chemotactic activity (MCA) by MIP-1alpha in a dose-dependent manner (P < .05). The inhibitory effects were not significant on NCA and MCA induced by leukotriene B4 or complement-activated serum incubated with peroxynitrite. The reducing agents deferoxamine, dithiothreitol, and exogenous L-tyrosine abrogated the NCA and MCA inhibition by peroxynitrite. Papa-NONOate, an NO donor, or a combination of xanthine and xanthine oxidase to generate superoxide, did not show an inhibitory effect on NCA and MCA induced by MIP-1alpha. In contrast, 3-morpholinosydnonimine (SIN-1), a peroxynitrite generator, elicited a concentration-dependent reduction in NCA and MCA induced by MIP-1alpha. Consistent with its capacity to reduce NCA and MCA, peroxynitrite treatment reduced MIP-1alpha binding to neutrophils and monocytes. Nitrotyrosine was detected in the MIP-1alpha incubated with peroxynitrite. These findings are consistent with nitration of tyrosine by peroxynitrite with subsequent inhibition of MIP-1alpha binding to neutrophils and monocytes and a reduction in NCA and MCA. These data demonstrate that peroxynitrite modulates the inflammatory cell migration by MIP-1alpha, and they suggest that oxidants may play an important role in the regulation of MIP-1alpha-induced inflammatory cell chemotaxis.
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PMID:Inhibition of MIP-1alpha-induced human neutrophil and monocyte chemotactic activity by reactive oxygen and nitrogen metabolites. 1069 61


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