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

The authors have previously reported that intratracheal instillation of staphylococcal enterotoxin-B (SEB) induced interstitial pneumonia (IP) in autoimmune-prone mice. SEB-reactive T-cells were critically involved in the development of IP in this model. Concern has arisen about the hazards of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the process of lung injury and fibrosis. Therefore, the involvement of nitric oxide (NO) and superoxide anion (O2-) in the pathogenesis of IP in this autoimmune-prone model has been investigated. Nitrite/nitrate levels were increased in bronchoalveolar lavage (BAL) fluid and serum from SEB-injected mice. The signal of the NO-(N-(dithiocarboxy) sarcosine)2-Fe2+ complex was detected in the SEB-injected lung and whole blood by electron paramagnetic resonance (EPR) spectroscopy. NO production was significantly decreased by aminoguanidine (AG) treatment. Xanthine oxidase (XO) activity in the lung, BAL fluid, and plasma was increased with instillation of SEB, and 4-amino-6-hydroxypyrazolo(3,4-d)-pyrimidine (AHPP) significantly inhibited XO activity. Moreover, both AG and AHPP significantly decreased production of pro-inflammatory cytokines, numbers of infiltrated cells in BAL fluid, and the area of thickened alveolar septa in the SEB-injected lung. In conclusion, the overproduction of nitric oxide and super oxide anion were implicated in the pathogenesis of interstitial pneumonia, and inducible nitric oxide synthase and xanthine oxidase inhibitors had protective effects against interstitial pneumonia in this model.
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PMID:Effects of inducible nitric oxide synthase and xanthine oxidase inhibitors on SEB-induced interstitial pneumonia in mice. 1193 21

Four terpenylnaphthoquinones were found to enhance the rate of superoxide production in the presence of ascorbate as detected from the superoxide dismutase (SOD)-inhibitable initial oxygen consumption rates. Initial rates of oxygen consumption in the presence of ascorbate plus quinone increase with an increase in the half-wave reduction potentials of the quinones. These quinones also enhance the rate of Cyt(III)c reduction by xanthine/xanthine oxidase (X/XO) in both air- and nitrogen-saturated aqueous solutions at pH 7.4. Maximum rates of Cyt(III)c reduction in nitrogen and oxygen-saturated solutions (V(max)), in the presence of X/XO, increase with an increase in the half-wave reduction potentials of the quinones. SOD inhibits Cyt(III)c reduction rates in the presence of these quinones and X/XO in a manner which is also dependent on the quinone half-wave redox potential. The relative antineoplastic activity of two of these quinones follows the order in rates of oxygen consumption or Cyt(III)c reduction. This is consistent with an antineoplastic action of these quinones through the mechanism of redox cycling or possible interference or inhibition of mitochondrial respiration.
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PMID:Reductive activation of terpenylnaphthoquinones. 1204 45

In the intestine, epithelial cells continually produce and secrete low levels of nitric oxide (NO). Salmonella sp. invade epithelium by responding to environmental stimuli. The aims of this study were to determine the effect of reactive nitrogen intermediates (RNIs) on S. dublin and S. typhimurium growth and invasion of T84 epithelial monolayers. Intracellular NO formation was inhibited by 7-nitroindazole (7-NI) or N(G)-monomethyl-L-arginine, monoacetate (L-NMMA); extracellular NO and peroxynitrite were scavenged with ferro-hemoglobin or urate. The effect of authentic peroxynitrite (ONOO-); 3-morpholino-sydnonimine (SIN-1), which releases ONOO- via NO and superoxide; spermine NONOate, which releases only NO; or superoxide generated by xanthine oxidase and pterin on S. dublin and S. typhimurium growth and invasion were examined. Inhibition of NO synthesis and scavenging of extracellular NO or peroxynitrite reduced S. dublin invasion into T84 monolayers and enhanced bacterial growth. Pre-exposure of S. dublin to ONOO- and SIN-1 increased subsequent bacterial invasion into T84 monolayers. Conversely, exposure of bacteria to spermine NONOate or superoxide did not affect S. dublin invasion. In contrast, S. typhimurium invasion was not affected by pre-treatment with NO donors. In conclusion, exposure of S. dublin to ONOO- enhances the ability of the bacteria to invade epithelial cells. These results suggest that luminal ONOO- may have a novel role as an extracellular signal between invasive bacteria and epithelial cells.
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PMID:Peroxynitrite enhances the ability of Salmonella dublin to invade T84 monolayers. 1209 42

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are signal-transducing molecules that regulate the activities of a variety of proteins. In the present investigation, we have compared the effects of superoxide (O2-), nitric oxide (NO), and hydrogen peroxide (H2O2) on the activities of three highly homologous serine/threonine phosphatases, protein phosphatase type 1 (PP1), protein phosphatase type 2A (PP2A), and calcineurin (protein phosphatase type 2B). Although superoxide, generated from xanthine/xanthine oxidase or paraquat, and NO, generated from (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide or sodium nitroprusside, potently inhibited the phosphatase activity of calcineurin in neuroblastoma cell lysates, they had relatively little effect on the activities of PP1 or PP2A. In contrast, H2O2 inhibited the activities of all three phosphatases in lysates but was not a potent inhibitor for any of the enzymes. Calcineurin inactivated by O2-, NO, and H2O2 could be partially reactivated by the reducing agent ascorbate or by the thiol-specific reagent dithiothreitol (DTT). Maximal reactivation was achieved by the addition of both reagents, which suggests that ROS and RNS inhibit calcineurin by oxidizing both a catalytic metal(s) and a critical thiol(s). Reactivation of H2O2-treated PP1 also required the combination of both ascorbate and DTT, whereas PP2A required only DTT for reactivation. These results suggest that, despite their highly homologous structures, calcineurin is the only major Ser/Thr phosphatase that is a sensitive target for inhibition by superoxide and nitric oxide and that none of the phosphatases are sensitive to inhibition by hydrogen peroxide.
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PMID:Differential susceptibilities of serine/threonine phosphatases to oxidative and nitrosative stress. 1214 65

The effect of reactive oxygen/nitrogen species (ROS/RNS)(hydrogen peroxide -- H(2)O(2), superoxide anion radical O(2)*- and hydroxyl radical *OH -- the reaction products of hypoxanthine/xanthine oxidase system), nitric oxide (NO* from sodium nitroprusside -- SNP), and peroxynitrite (ONOO(-) from 3-morpholinosydnonimine -- SIN-1) on insulin mitogenic effect was studied in L6 muscle cells after one day pretreatment with/or without antioxidants. ROS/RNS inhibited insulin-induced mitogenicity (DNA synthesis). Insulin (0.1 microM), however, markedly improved mitogenicity in the muscle cells treated with increased concentrations (0.1, 0.5, 1 mM) of donors of H(2)O(2), O(2)*-, *OH, ONOO(-) and NO*. Cell viability assessed by morphological criteria was also monitored. Massive apoptosis was induced by 1 mM of donors of H(2)O(2) and ONOO(-), while NO* additionally induced necrotic cell death. Taken together, these results have shown that ROS/RNS provide a good explanation for the developing resistance to the growth promoting activity of insulin in myoblasts under conditions of oxidative or nitrosative stress. Cell viability showed that neither donor induced cell death when given below 0.5 mM. In order to confirm the deleterious effects of ROS/RNS prior to the subsequent treatment with ROS/RNS plus insulin one day pretreatment with selected antioxidants (sodium ascorbate - ASC (0.01, 0.1, 1 mM), or N-acetylcysteine - NAC (0.1, 1, 10 mM) was carried out. Surprisingly, at a low dose (micromolar) antioxidants did not abrogate and even worsened the concentration-dependent effects of ROS/RNS. In contrast, pretreatment with millimolar dose of ASC or NAC maintained an elevated mitogenicity in response to insulin irrespective of the ROS/RNS donor type used.
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PMID:Preconditioning with millimolar concentrations of vitamin C or N-acetylcysteine protects L6 muscle cells insulin-stimulated viability and DNA synthesis under oxidative stress. 1215 Oct 57

The impact of nitric oxide (NO) synthesis on different biological cascades can rapidly change dependent on the rate of NO formation and composition of the surrounding milieu. With this perspective, we used diaminonaphthalene (DAN) and diaminofluorescein (DAF) to examine the nitrosative chemistry derived from NO and superoxide (O2-) simultaneously generated at nanomolar to low micromolar per minute rates by spermine/NO decomposition and xanthine oxidase-catalyzed oxidation of hypoxanthine, respectively. Fluorescent triazole product formation from DAN and DAF increased as the ratio of O2- to NO approached equimolar, then decreased precipitously as O2- exceeded NO. This pattern was also evident in DAF-loaded MCF-7 carcinoma cells and when stimulated macrophages were used as the NO source. Cyclic voltammetry analysis and inhibition studies by using the N2O3 scavenger azide indicated that DAN- and DAF-triazole could be derived from both oxidative nitrosylation (e.g., DAF radical + NO) and nitrosation (NO+ addition). The latter mechanism predominated with higher rates of NO formation relative to O2-. The effects of oxymyoglobin, superoxide dismutase, and carbon dioxide were examined as potential modulators of reactant availability for the O2- + NO pathway in vivo. The findings suggest that the outcome of NO biosynthesis in a scavenger milieu can be focused by O2- toward formation of NO adducts on nucleophilic residues (e.g., amines, thiols, hydroxyl) through convergent mechanisms involving the intermediacy of nitrogen dioxide. These modifications may be favored in microenvironments where the rate of O2- production is temporally and spatially contemporaneous with nitric oxide synthase activity, but not in excess of NO generation.
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PMID:Focusing of nitric oxide mediated nitrosation and oxidative nitrosylation as a consequence of reaction with superoxide. 1217 14

We have examined the mechanism of 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced gastric cancer with respect to the production of hydroxyl free radical (OH). Nucleophilic attack by H2O2 on the nitroso group of MNNG produces 1-methyl-3-nitroguanidine (MNG) and the intermediate peroxynitric acid (ONOOH), which splits into hydroxyl free radical (OH) and nitrogen dioxide leading to the formation of nitric and nitrate ions in water. Xanthine oxidase (XO) induces the production of O2.- or H2O2 from molecular oxygen, depending on the overall level of enzyme reduction. In this study, we examined OH production by the reaction of MNNG with H2O2 derived from the XO-HX system containing XO and the purine substrate hypoxanthine by ESR using the spin trapping reagent 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO). OH was produced in the XO-HX-DMPO system with addition of MNNG (the MNNG-XO-HX-DMPO system) under aerobic conditions, but was not in the XO-HX-DMPO system, and production of OH was inhibited by catalase but not by superoxide dismutase, suggesting that OH was produced by the reaction of MNNG with H2O2 derived from the XO-HX system. The production of OH was significantly increased with increase in the reducing activity of XO, though that of O2.- was not, also suggesting the O2(.-)-independent .OH production. The productions of nitrite ion and MNG in the MNNG-XO-HX system were determined by the colorimetric method and HPLC, respectively. Based on these findings, we conclude that .OH was produced by homolytic split of the intermediate ONOOH formed by nucleophilic attack of H2O2 derived from the XO-HX system on MNNG.
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PMID:Production of hydroxyl free radical in the xanthine oxidase system with addition of 1-methyl-3-nitro-1-nitrosoguanidine. 1218 Jan 89

It is established, that in rat organism nitrites and nitrates can be restored in nitrogen oxide due to nitrate and nitrite reductase activity of xanthine oxidase system. The rat thymocytes were shown in the experiment in vitro to have nitrate reductase activity, which was activated by hypoxanthine and inhibited by allopurinol. As a result of thymocytes apoptosis, provoked by papaverine, there is an essential increase of nitrate reductase activity of xanthine oxidase. The comparative research of thymocytes destruction character under the action of sodium nitroprusside (NP), N-nitrosodimethylamine (NDMA), NaNO2 and NaNO3 has been revealed, that their cytotoxicity, is dose-dependent and it decreases in order of these compounds mentioning. Synergism is revealed at the action on thymocytes of NP combined with sodium nitrite. These data as the results of investigation of EPR-spectrometry as well as use of thymocytes, containing a trap--complex of diethyldithiocarbamate-iron (DETK-Fe), allow to assume, that cytotoxic effect of NP is caused by the action of liberated from it. Cytotoxic action of nitrate is connected with reducibility to nitrite which influences on the cells independently, and nitrite action doesn't depend on its transformation to NO. The death of thymocytes caused by N-nitrosodimethylamine is not a result of its denitrozation.
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PMID:[The role of xanthine oxidase in the cytotoxic action of nitrates and nitrites]. 1219 68

Abstract: Carboplatin, a second-generation platinum-containing anticancer drug, is currently being used against a variety of cancers. High-dose carboplatin chemotherapy can cause renal tubular injury in cancer patients. However, the biochemical mechanism of carboplatin-induced renal injury has not been well studied. This study investigated the dose response of carboplatin-induced changes in endogenous antioxidants, lipid peroxidation and platinum content in rat kidney. Male Wistar rats (250-300 g) were divided into five groups and treated as follows: (1) control (saline, intraperitoneally); (2) carboplatin (64 mg/kg, intraperitoneally); (3) carboplatin (128 mg/kg, intraperitoneally); (4) carboplatin (192 mg/kg, intraperitoneally); and (5) carboplatin (256 mg/kg, intraperitoneally). The animals were sacrificed four days after treatment. The blood and kidneys were isolated and analyzed. Plasma creatinine and blood urea nitrogen levels were increased significantly in response to carboplatin in a dose-dependent manner. Renal superoxide dismutase and catalase activities were decreased significantly due to carboplatin at dosages of 128 mg/kg and above. The protein expressions of renal copper/zinc-superoxide dismutase and manganese-superoxide dismutase significantly depleted after carboplatin. Carboplatin (192 and 256 mg/kg) significantly increased lipid peroxidation (malondialdehyde concentration) in rat kidneys. Carboplatin dose-dependently increased the renal platinum concentration, with significance at dosages of 128 mg/kg and above. Carboplatin (256 mg/kg) significantly increased renal xanthine oxidase activity, while ratio of reduced to oxidized glutathione depleted significantly. The data suggested that carboplatin caused dose-dependent oxidative renal injury, as evidenced by renal antioxidant depletion, enhanced lipid peroxidation, platinum content, plasma creatinine and blood urea nitrogen levels in rats.
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PMID:Dose response of carboplatin-induced nephrotoxicity in rats. 1242 Jul 97

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a master regulator to sense decreased oxygen partial pressure. HIF-1 alpha stability regulation initiates a complex biological response that allows cells to act appropriately to meet patho-physiological situations of decreased oxygen availability. Recently, nitric oxide emerged as a messenger with the ability to stabilize HIF-1 alpha and to transactivate HIF-1 under normoxia. Considering that reactive nitrogen species are recognized for post-translation protein modifications, among others S-nitrosation, we asked whether HIF-1 alpha is a target for S-nitrosation. In vitro NO+ donating NO donors such as GSNO and SNAP provoked massive S-nitrosation of purified HIF-1 alpha. All 15 free thiol groups found in human HIF-1 alpha are subjected to S-nitrosation. Thiol modification is not shared by spermine-NONOate, a NO radical donating compound. However, spermine-NONOate in the presence of O(2)(-), generated by xanthine/xanthine oxidase, regained S-nitrosation, most likely via formation of a N(2)O(3)-like species. In vitro, S-nitrosation of HIF-1 alpha was attenuated by the addition of GSH or ascorbate. In RCC4 and HEK293 cells GSNO or SNAP reproduced S-nitrosation of HIF-1 alpha, however with a significantly reduced potency that amounted to modification of three to four thiols, only. Importantly, endogenous formation of NO in RCC4 cells via inducible NO synthase elicited S-nitrosation of HIF-1 alpha that was sensitive to inhibition of inducible NO synthase activity with N-monomethyl-L-arginine. NO-stabilized HIF-1 alpha was susceptible to the addition of N-acetyl-cysteine that destabilized HIF-1 alpha in close correlation to the disappearance of S-nitrosated HIF-1 alpha. In conclusion, HIF-1 alpha is a target for S-nitrosation by exogenously and endogenously produced NO.
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PMID:HIF-1 alpha protein as a target for S-nitrosation. 1256 87


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