Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The generation of oxygen-derived free radicals has been implicated in the disordered vascular regulation of inflammation and reperfusion. In the vasculature, oxygen-derived free radicals are vasodilatory. The mechanisms underlying this effect remain unclear. To examine the cellular processes involved, we studied the effects of hydrogen peroxide (H2O2) on adenylyl cyclase activity in A10 cells, a murine vascular smooth muscle cell line. Pretreatment with H2O2 caused a dose-dependent enhancement of forskolin-stimulated adenylyl cyclase activity (ED50, 44 mumol/L to a maximum of 166% of control activity; n = 4). This enhancement was attenuated by iron chelation with deferoxamine and by the intracellular hydroxyl scavenger dimethylthiourea and mimicked by preincubation with purine/xanthine oxidase either alone or in the presence of superoxide dismutase. The effects of H2O2 were completely blocked by the tyrosine kinase inhibitors genistein and tyrphostin A9 but not by its inactive analogue tyrphostin A1 (H2O2 alone, 149 +/- 13%; H2O2 + tyrphostin A9, 100 +/- 9%; H2O2 + tyrphostin A1, 171 +/- 21%; n = 4). H2O2 comparably enhanced adenylyl cyclase activity stimulated by isoproterenol (166 +/- 17% of control, n = 5) and sodium fluoride (177 +/- 18% of control, n = 5). Thus oxygen-derived free radicals enhance adenylyl cyclase activation, probably via tyrosine kinase-mediated effects on the catalytic subunit of adenylyl cyclase. Sensitization of adenylyl cyclase activation may be an important mechanism by which free radicals modulate hormone-mediated vasodilation.
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PMID:Oxidant stress enhances adenylyl cyclase activation. 755 17

The cytotoxic effect of lipopolysaccharide (LPS) was examined on bovine aortic endothelial cell proliferation in vitro. These LPS-induced cytotoxicity (IC50 = 20 ng/ml) was not inhibitable by substances regulating the formation of nitric oxide (NO). e.g. by NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis, and by the glucocorticoid dexamethasone, an inhibitor of the induction of NO synthase. Also other substances which inhibit the generation or action of oxygen radicals, as glutathion and the xanthine oxidase inhibitor allopurinol did not prevent the cytotoxic effect of LPS. Only tyrphostin B46, an inhibitor of tyrosine kinase, attenuated the toxic LPS effect, suggesting that the LPS-induced cytotoxicity in bovine aortic endothelial cell cultures is mediated by a specific tyrosine kinase, and not by NO or oxygen radicals.
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PMID:Investigations into the mechanism of toxicity of lipopolysaccharide (LPS) in bovine aortic endothelial cells. 756 18

We have demonstrated that the endothelial cell-derived superoxide anion is deeply involved in the endothelial cell injury induced by activated neutrophils (Fujita, H., Morita, I. and Murota, S. (1994) Arch. Biochem. Biophys. 309, 62-69). To clarify the mechanism underlying the increase in the endothelial cell-derived superoxide anion induced by activated neutrophils, the conversion of xanthine dehydrogenase (XD) to xanthine oxidase (XO) in cultured endothelial cells isolated from bovine carotid arteries was investigated. Although the endothelial cells expressed both XD and XO activity, the XO activity of unstimulated cells comprised about 12% of the total (XD + XO) activity. When endothelial cells were exposed to neutrophils activated with phorbol 12-myristate 13-acetate (PMA), XO activity rapidly increased about 3-fold over the control. Whereas treatment of endothelial cells with PMA alone or unstimulated neutrophils alone did not increase the XO activity at all. The increase in XO activity in endothelial cells was also observed on the treatment of the cells with neutrophils activated with leukotriene B4 or thrombin. To determine whether or not proteases released from activated neutrophils are involved in the increased conversion of XD to XO in endothelial cells, the effects of the elastase specific inhibitor, ONO-5046, and protease inhibitors, such as aprotinin, gabexate mesylate and urinastatin, were examined. However, these protease inhibitors did not suppress the conversion of XD to XO induced by PMA-activated neutrophils. Moreover, the treatment of endothelial cells with purified human neutrophil elastase and H2O2 also did not affect the conversion at all. In contrast, monoclonal antibodies against CD11a and CD18 significantly inhibited the increased conversion of XD to XO induced by PMA-activated neutrophils. Moreover, tyrosine kinase inhibitors such as staurosporin and herbimysine also inhibited the increased conversion of XD to XO induced by PMA-activated neutrophils. These results indicate that the adhesion of activated neutrophils to endothelial cells via CD11a/CD18-ICAM-1 is involved in the conversion of XD to XO in endothelial cells induced by activated neutrophils.
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PMID:Conversion of xanthine dehydrogenase to xanthine oxidase in bovine carotid artery endothelial cells induced by activated neutrophils: involvement of adhesion molecules. 769 38

Addition of PMA (phorbol myristate acetate)-stimulated neutrophils to an endothelial cell monolayer caused a significant increase in the intracellular peroxide level of the endothelial cells after 15 minutes and endothelial cell injury after 5 hours. Both the early and the late events were abolished in the presence of specific antibodies against CD (cluster of differentiation) 11a, CD11b, CD18 and ICAM (intercellular adhesion molecule) 1, but not CD11c. These antibodies affected neither the production of active oxygen species by the neutrophils nor the rate of adhesion of neutrophils to endothelial cells. Pretreatment of endothelial cells with allopurinol caused significant inhibition of both the early and the late events, suggesting that the binding of adhesion molecules may trigger the activation of XO (xanthine oxidase) of endothelial cells, and have the cells produce more hydrogen peroxide and ferrous ions, followed by producing more hydrogen peroxide. The hydrogen peroxide produced by endothelial cells themselves and by neutrophils may be converted to hydroxyl radicals by ferrous ions, which may cause lethal cell damage. Examination of XO activity in endothelial cells showed that the enzyme activity increased double within 15 minutes after the addition of PMA activated neutrophils. Monoclonal antibodies against CD11a and CD18 significantly inhibited the increased conversion of XD (xanthine dehydrogenase) to XO induced by PMA-activated neutrophils. Moreover, tyrosine kinase inhibitors also inhibited the increased conversion of XD to XO. These results indicate that the adhesion of activated neutrophils to endothelial cells via CD11a/CD18-ICAM-1 is involved in the conversion of XD to XO in endothelial cells, which results in endothelial cell injury.
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PMID:Cell adhesion molecule mediates endothelial cell injury caused by activated neutrophils. 889 63

In the mammary gland of virgin mice, xanthine oxidoreductase (XOR) enzymic activity is barely measurable. a high increase in the levels of the enzyme is observed during the last days of pregnancy and during lactation, and this is parallelled by an elevation in the amounts of the respective protein and transcript. In situ hybridization experiments demonstrate that the XOR mRNA is specifically expressed in the alveolar epithelial cells of the mammary gland. In HC11 cells, a model culture system for normal breast epithelium, the levels of XOR enzymic activity are dose- and time-dependently induced by dexamethasone, and a further synergistic augmentation is observed in the presence of dexamethasone plus prolactin. Increased XOR gene expression is consequent on glucocorticoid receptor activation, as indicated by sensitivity to the specific receptor antagonist RU486. In addition, the phenomenon is likely to involve protein phosphorylation and dephosphorylation events, as suggested by modulation of XOR mRNA by tyrosine kinase and phosphatase inhibitors.
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PMID:Expression of xanthine oxidoreductase in mouse mammary epithelium during pregnancy and lactation: regulation of gene expression by glucocorticoids and prolactin. 892 Sep 83

Proinflammatory cytokines and chemotactic peptides are strongly implicated as mediators of the pathophysiologic responses of asbestosis and other chronic inflammatory lung diseases. Recent studies in our laboratory have demonstrated that asbestos fibers stimulate lung epithelial cells to produce interleukin-8 (IL-8), the major neutrophil chemoattractant in the lung. The mechanisms by which asbestos regulates IL-8 expression were studied using the pulmonary type II-like epithelial cell line A549. Membrane permeable hydroxyl scavengers inhibited asbestos induced IL-8 expression. Using A549 cells transfected with the -546 IL-8 construct linked to a chloramphenicol acetyl transferase reporter gene, we have shown that these antioxidants directly inhibited asbestos-stimulated IL-8 promoter-dependent transcription. Asbestos fibers as well as reactive oxygen species generating systems hypoxanthine-xanthine oxidase and hydrogen peroxide stimulated DNA binding activity to the regulatory elements in the IL-8 promoter, binding sites of nuclear factor (NF)-kappaB- and NF-IL-6-like transcription factors. Asbestos-inducible DNA binding activity was partially inhibited by tetramethylthiourea, a hydroxyl radical scavenger. IL-8 secretion was also suppressed by staurosporine, an inhibitor of protein kinase C, and by inhibitors of tyrosine kinase such as herbimycin A and genistein. The suppression paralleled the effect of these inhibitors on asbestos-induced DNA binding to the NF-kappaB- and NF-IL-6-like binding sites of the IL-8 promoter. Taken together, the results suggest that asbestos-induced redox changes and phosphorylation events, mediated by staurosporine-sensitive and tyrosine kinase(s), activate nuclear proteins which recognize the NF-kappaB/NF-IL-6 binding sites of the IL-8 promoter and contribute to the regulation of IL-8 gene expression.
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PMID:Asbestos induction of nuclear transcription factors and interleukin 8 gene regulation. 896 74

Although the involvement of free radicals in the development of endothelial dysfunction under pathological conditions, like diabetes and hypercholesterolemia, has been proposed frequently, there is limited knowledge as to how superoxide anions (O2-) might affect endothelial signal transduction. In this study, we investigated the effects of preincubation with the O2(-)-generating system xanthine oxidase/hypoxanthine (XO/HX) on mechanisms for Ca2+ signaling in cultured porcine aortic endothelial cells. Incubation of cells with XO/HX yielded increased intracellular Ca2+ release and capacitative Ca2+ entry in response to bradykinin and ATP in a time- and concentration-dependent manner. This effect was prevented by superoxide dismutase but not by the tyrosine kinase inhibitor tyrphostin A48. In addition, capacitative Ca2+ entry induced by the receptor-independent stimulus 2,5-di-(tert-butyl)-1,4-benzohydroquinone or thapsigargin was enhanced in O2(-)-exposed cells (+38% and +32%, respectively). Increased Ca2+ release in response to bradykinin in XO/HX-pretreated cells might be due to enhanced formation of inositol-1,4,5-trisphosphate (+140%). Exposure to XO/HX also affected other signal transduction mechanisms involved in endothelial Ca2+ signaling, such as microsomal cytochrome P450 epoxygenase and membrane hyperpolarization to Ca2+ store depletion with thapsigargin (+103% and +48%, respectively) and tyrosine kinase activity (+97%). A comparison of bradykinin-initiated intracellular Ca2+ release and thapsigargin-induced hyperpolarization with membrane viscosity modulated by XO/HX (decrease in viscosity) or cholesterol (increase in viscosity) reflected a negative correlation between bradykinin-initiated Ca2+ release and membrane viscosity. Because intracellular Ca2+ is a main regulator of endothelial vascular function, our data suggest that O2- anions are involved in regulation of the vascular endothelium.
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PMID:Effects of superoxide anions on endothelial Ca2+ signaling pathways. 974 37

Reactive oxygen species (ROS), particularly hydroxyl radical (HO*), increase neutrophil adherence to hypoxanthine-xanthine oxidase (HX-XO)-treated human umbilical vein endothelial cells (HUVEC) in culture. This adherence is inhibited by the tyrosine kinase inhibitors genistein (30 microM) and herbimycin A (0.9 microM), suggesting the involvement of tyrosine kinase. Phosphorylation of several HUVEC proteins in the range of 120-130 and 70 kDa was found to depend on the XO concentration and stimulation time. This phosphorylation was inhibited by the antioxidants dimethylthiourea (DMTU, 0.75 to 7.5 mM) and pentoxifylline (Ptx, 0.1 mM), and by the iron chelators desferrioxamine (DF, 1 mM) and hydroxybenzyl ethylene diamine (HBED, 0.5 mM), suggesting the involvement of HO*. Three tyrosine-phosphorylated proteins, focal adhesion kinase (p125FAK), paxillin (PAX) and p130cas were isolated and characterized by immunoprecipitation and western blotting. Antioxidants and iron chelators reduced their phosphorylation. HUVEC treated with ROS for 15 min showed actin stress fiber formation. Cytochalasin D (5 microM) inhibited tyrosine phosphorylation and PMN-HUVEC adherence, showing the importance of cytoskeleton integrity in these two functions. In conclusion, HO*, which is involved in increased PMN-HUVEC adhesion, also increases tyrosine phosphorylation on three major cytoskeleton proteins which seem to play a role in this adhesion.
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PMID:Reactive oxygen species activate focal adhesion kinase, paxillin and p130cas tyrosine phosphorylation in endothelial cells. 987 May 55

The effect of epidermal growth factor (EGF) on the H202-induced increase in paracellular permeability in Caco-2 and T-84 cell monolayers was evaluated to examine the role of EGF in intestinal mucosal protection from oxidative stress. Oxidative stress was induced by exposing cell monolayers to H2O2 or a mixture of xanthine oxidase + xanthine (XO + X). Paracellular permeability was assessed by measuring transepithelial electrical resistance (TER), sodium chloride dilution potential, and unidirectional flux of [3H]mannitol. H2O2 (0.1 to 5.0 mM) reduced TER and dilution potential and increased mannitol flux. Administration of EGF delayed H2O2 and XO + X-induced changes in TER, dilution potential, and [3H]mannitol flux. This protective effect of apically or basally administered EGF was concentration-related, with A50 (95% confidence limits) values of 2.1 (1.17 to 4.34) and 6.0 (4.37 to 8.34) nM, respectively. The EGF-mediated protection was prevented by treatment of cell monolayers with genistein (10 microM), a tyrosine kinase inhibitor. H2O2 and XO + X also induced tyrosine phosphorylation of a number of proteins in Caco-2 and T-84 cell monolayers. EGF treatment inhibited the oxidant-induced tyrosine phosphorylation of proteins, particularly those with a molecular mass of 110-220 kDa. Treatment of Caco-2 cells with anti-transforming growth factor-alpha antibodies potentiated the H2O2-induced changes in TER, dilution potential, and mannitol flux. These studies demonstrated that an EGF receptor-mediated mechanism delays oxidant-induced disruption of the epithelial barrier function, possibly by suppressing the oxidant-induced tyrosine phosphorylation of proteins.
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PMID:Inhibition of oxidant-induced barrier disruption and protein tyrosine phosphorylation in Caco-2 cell monolayers by epidermal growth factor. 1003 55

The effects of hypoxanthine and xanthine oxidase-induced superoxide anion were evaluated on various signal transduction pathways in aortic smooth muscle cells (SMCs) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Superoxide increased inositol 1,4,5-tris-phosphate (IP(3)) formation in a concentration- and time-dependent manner in both strains but more markedly in SMCs from SHR. Various antioxidants significantly decreased the superoxide-induced IP(3) formation in both strains. In addition, tyrosine kinase inhibitors, genistein and tyrphostin A25, inhibited the superoxide-induced IP(3) formation more markedly in SHR than in WKY. Moreover, superoxide decreased the basal level of cGMP to a greater extent in SHR and also suppressed the rise in cGMP induced by S-nitroso-N-acetylpenicillamine. In addition, the superoxide-induced increase in IP(3) formation was significantly inhibited by guanylyl cyclase stimulator S-nitroso-N-acetylpenicillamine but was potentiated by ODQ (a guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one) and KT5823 (a cGMP-dependent protein kinase inhibitor), with a greater effect in SHR. Finally, the superoxide-enhanced IP(3) formation was not accompanied by simultaneous changes in cAMP levels, and inhibition of the adenylyl cyclase pathway did not modify the superoxide-induced IP(3) formation. Our results thus demonstrate a stimulatory effect of superoxide on IP(3) formation, mediated by the tyrosine kinase-coupled phospholipase C(gamma) activity, and an inhibitory effect of superoxide on cGMP formation in vascular SMCs. The increased reactivity of the phospholipase C pathway and the decreased cross inhibition of the IP(3) pathway by cGMP in the presence of superoxide may underlie the altered functions of vascular SMCs in SHR.
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PMID:Effects of superoxide on signaling pathways in smooth muscle cells from rats. 1060 Nov 26


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