Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing evidence that oxidative stress is of pathophysiological importance in cardiovascular disease. Mechanical forces such as pulsatility may also contribute. Using human coronary artery smooth muscle cells (HCAS), we tested the hypothesis that stretch-induced cell proliferation is associated with oxidative stress. Stretch induced DNA synthesis in HCAS, and this was prevented by the antioxidants N-acetylcysteine and pyrrolidinedithiocarbamate (PDTC). Pulsatile stretch also increased superoxide production from HCAS in a time- and stretch dependent manner. Stretch-induced superoxide production was inhibited by diphenyleneiodoniumchloride, an NADPH oxidase inhibitor, and p-chloromercuriphenylsulfonic acid, an NADH oxidase inhibitor, but not by the xanthine oxidase inhibitor oxypurinol or the cyclooxygenase inhibitor indomethacin. In electrophoretic mobility shift assays, tumor necrosis factor-alpha activated nuclear factor-kappa B (NF-kappa B) with a peak at approximately 3 hours, whereas pulsatile stretch showed sustained activation during stimulation for up to 24 hours. The sustained activation of NF-kappa B was abolished by cotreatment with N-acetylcysteine or PDTC. Furthermore, treatment of HCAS with antisense p65 and p50 oligodeoxynucleotides of NF-kappa B inhibited stretch-induced DNA synthesis. We propose that pulsatile stretch increases oxidative stress and, in turn, promotes DNA synthesis via NF-kappa B in cultured human coronary artery smooth muscle cells.
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PMID:Pulsatile stretch stimulates superoxide production and activates nuclear factor-kappa B in human coronary smooth muscle. 935 51

The aim of this study was to examine and compare the potential influence of cyclooxygenase or lipoxygenase derived metabolites of arachidonic acid on myocardial injury produced either by a free radical generating system consisting of purine plus xanthine oxidase or that produced by hydrogen peroxide. A free radical generating system consisting of purine (2.3 mM) and xanthine oxidase (10 U/L) as well as hydrogen peroxide (75 microM) produced significant functional changes in the absence of either significant deficits in high energy phosphates or ultrastructural damage. Prostaglandin F2 alpha (30 nM) significantly attenuated both the negative inotropic effect of purine plus xanthine oxidase as well as the ability of the free radical generator to elevate diastolic pressure. An identical concentration of prostaglandin 12 (prostacyclin) significantly reduced diastolic pressure elevation only and had no effect on contractile depression. The salutary effects of the two PGs occurred in the absence of any inhibitory influence on superoxide anion generation produced by the purine and xanthine oxidase reaction. None of prostaglandins modulated the response to hydrogen peroxide. In addition, neither prostaglandin E2 nor leukotrienes exerted any effect on changes produced by either type of oxidative stress. A 5 fold elevation in the concentrations of free radical generators or hydrogen peroxide produced extensive injury as characterized by a virtual total loss in contractility, 400% elevation in diastolic pressure, ultrastructural damage and significant depletions in high energy phosphate content. None of these effects were modulated by eicosanoid treatment. Our results therefore demonstrate a selective ability of both prostaglandin F2 alpha and to a lesser extent prostacyclin, to attenuate dysfunction produced by purine plus xanthine oxidase but not hydrogen peroxide. It is possible that these eicosanoids may represent endogenous protective factors under conditions of enhanced oxidative stress associated with superoxide anion generation.
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PMID:Prostaglandins attenuate cardiac contractile dysfunction produced by free radical generation but not by hydrogen peroxide. 940 59

We studied the mechanism of reoxygenation injury of cerebral microvessels in cultured rat brain capillary endothelial cells (BCECs). BCECs were isolated from rat cerebral cortices by a two step enzymatic treatment. The monolayers of BCECs were subjected to anoxia for 20 minutes followed by reoxygenation for 3 hours. Cell damage was assessed by measuring the leakage of intracellular lactic dehydrogenase (LDH). The control group was anoxia/reoxygenated BCECs without any protective reagents. To study the protective effect of free radical scavengers and antioxidants, superoxide dismutase, catalase, deferoxamine, oxypurinol, indomethacin, or NG-nitro-L-arginine methyl ester (L-NAME) was applied during anoxia/reoxygenation. Thus 7 experimental conditions were established. Lactic dehydrogenase (LDH) leaked from reoxygenated BCECs due to cell membrane damage. This leakage was almost totally suppressed by superoxide dismutase, indicating that reoxygenation injury of BCECs is mediated by superoxide generation. The other scavengers and antioxidants partially suppressed LDH leakage. Reduction of Ca2+ in the culture medium from 1.6 mM to 0.016 mM also suppressed LDH leakage. These results indicate that BCECs subjected to anoxia/reoxygenation become potent generators of superoxide anion, which is thought to be responsible for reoxygenation injury. The superoxide generation partially depends on the xanthine oxidase and cyclooxygenase pathways. As L-NAME partially suppressed LDH leakage peroxynitrite may contribute to reoxygenation injury of BCECs. The extracellular Ca2+ concentration also plays a critical role in the reoxygenation injury of BCECs.
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PMID:The mechanism of free radical generation in brain capillary endothelial cells after anoxia and reoxygenation. 941 71

The aim of the study was to investigate the time course of neutrophil activation after skeletal muscle ischemia in humans and to assess the effect of xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. In patients undergoing tourniquet ischemia of the upper limb, polymorphonuclear neutrophils (PMN) were simultaneously isolated from antecubital vein blood of both the contralateral control arm and the tourniquet arm. PMN-superoxide production (PMN-SOP) was determined by a cytochrome C reduction assay, PMN-myeloperoxidase activity (PMN-MPO) by guaiacol oxidation and serum PMN-elastase concentration by an enzyme immunoassay. At 60 min after release of the tourniquet, significant increases of PMN-SOP, PMN-MPO, and serum elastase concentrations were observed in tourniquet arms as compared with control arms (p < .05). Allopurinol (300 mg orally, 12 and 2 h before ischemia) significantly inhibited the increase of PMN-SOP, PMN-MPO, and serum elastase (p < .05). Indomethacin (50 mg orally, 2 h before ischemia) prevented increased PMN-MPO and serum elastase, but prevented increased PMN-SOP only when neutrophils were incubated in the presence of their autologous plasma. These findings suggest that ischemia/reperfusion of human skeletal muscle involves both xanthine oxidase-dependent oxygen free radicals and cyclooxygenase metabolites. These pathways could activate circulating neutrophils which potentially inflict local and remote endothelial injury.
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PMID:Neutrophil activation after skeletal muscle ischemia in humans. 946 69

Decreases in the alveolar O2 tension commonly follow gram-negative bacteremic shock that progresses to the acute respiratory distress syndrome (ARDS). To examine the effects of alveolar hypoxia and reoxygenation (H/R) on postbacteremic pulmonary cytokine expression, lungs from Sprague-Dawley rats (n = 43) were perfused over 180 min after hematogenous infection with 10(9) live Escherichia coli serotype O55:B5 (EC) or infusion of 0.9% NaCl (NS). Compared with normoxic EC and NS controls, EC + H/R and NS + H/R lungs received 90 min of constant-flow hypoxia followed by 60 min of reoxygenation. Perfusates were cultured and analyzed for TNF-alpha, IL-1alpha, IL-1beta, and PGE2 while monitoring pulmonary artery pressure (Ppa). Changes in the filtration coefficient (Kf) were evaluated at 180 min when cytokine mRNA levels were assessed in lung homogenates. Transcripts of the anti-inflammatory cytokine TGF-beta1 and of inducible cyclooxygenase (COX-2) were similarly analyzed. For equivalent EC clearance, Ppa, and Kf as in normoxic EC, postbacteremic H/R increased TNF-alpha gene expression and doubled the export of TNF-alpha from the lungs, an effect not blocked by allopurinol. IL-1alpha transcripts were also increased in EC + H/R versus EC lungs, in contrast to the lack of change in IL-1beta, TGF-beta, or COX-2 mRNA levels, or in cell-associated or circulating IL-1beta and PGE2. Thus, gram-negative bacteremic lung infection and secondary alveolar H/R upregulate the expression of specific inflammatory cytokines compared with pulmonary infection under normoxic conditions, independently of xanthine oxidase-induced O2 radicals. These findings identify the alveolar PO2 as a potent immunomodulatory signal whose reductions early after gram-negative sepsis may enhance lung inflammation in ARDS.
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PMID:Upregulation of postbacteremic TNF-alpha and IL-1alpha gene expression by alveolar hypoxia/reoxygenation in perfused rat lungs. 947 82

Reoxygenation and reperfusion after severe hypoxia and ischemia (HI) contribute substantially to birth asphyxia-related brain injury. Excess production of free radicals via metabolization of arachidonic acid, xanthine oxidase, and non-protein-bound iron play an important role. Cerebral reperfusion injury is characterized by a decrease in perfusion, oxygen consumption, and electrical activity of the brain. Reduction of free radical production may attenuate these features. We therefore induced severe HI in 35 newborn lambs, and upon reperfusion the lambs received a placebo [control (CONT), n = 7], the cyclooxygenase inhibitor indomethacin (INDO, 0.3 mg/kg/i.v., n = 7), the xanthine oxidase inhibitor allopurinol (ALLO, 20 mg/kg/i.v., n = 7), the iron chelator deferoxamine (DFO, 2.5 mg/kg/i.v., n = 7), or a combination of these drugs (COMB, n = 7). In each group changes (%) from pre-HI values were investigated for brain perfusion [measured by carotid artery flow (Qcar, mL/min)], (relative) cerebral O2 metabolism (CMR(O2)), and electrocortical brain activity (ECBA, microV) at 15, 60, 120, and 180 min post-HI. Qcar decreased significantly at 120 and 180 min post-HI in CONT (p < 0.05), but not in INDO, ALLO, DFO, and COMB groups. CMR(O2) decreased significantly in CONT at 60 min post-HI (p < 0.05), remained stable in DFO and INDO, and was significantly higher in ALLO and COMB (p < 0.05) at 120 and 180 min post-HI. ECBA was significantly lower in CONT during the whole post-HI period (p < 0.05), ECBA in INDO and COMB were significantly decreased at 60 and 120 min post-HI (p < 0.05), but recovered afterward, whereas DFO and ALLO remained stable during the post-HI period. In conclusion preservation of Qcar and CMR(O2), and recovery of ECBA occurred after treatment with INDO, ALLO, and DFO; combination of these drugs did not have an additional positive effect.
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PMID:The effect of antioxidative combination therapy on post hypoxic-ischemic perfusion, metabolism, and electrical activity of the newborn brain. 966 81

Nonsteroidal antiinflammatory drugs such as aspirin and indomethacin are known to induce gastric mucosal damage including bleeding, ulceration, and perforation in humans and animals. Although it has been proposed that a deficiency of endogenous prostaglandins due to inhibition of cyclooxygenase by the drug is involved in these effects, the exact pathogenic mechanism remains to be elucidated. It has recently been proposed that neutrophil- and oxygen radical-dependent microvascular injuries may be important prime events that lead to mucosal injury induced by nonsteroidal antiinflammatory drugs. Lipid peroxidation mediated by oxygen radicals, especially hydroxyl radicals, plays a crucial role in the development of the gastric mucosal injury induced by indomethacin. Both allopurinol, an inhibitor of xanthine oxidase, and neutrophil depletion by intraperitoneal injection of antineutrophil antibody significantly attenuates indomethacin-induced gastric injury. In this paper, we have reviewed the recent data that assess the role of oxygen radical and lipid peroxidation in the pathogenesis of indomethacin-induced gastric mucosal injury in rats and humans.
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PMID:Role of oxygen radical and lipid peroxidation in indomethacin-induced gastric mucosal injury. 975 23

Recent studies indicate that arsenic may generate reactive oxygen species to exert its toxicity. However, the mechanism is still unclear. In this study, we demonstrate that arsenite is able to induce apoptosis in a concentration- and time-dependent manner; however, arsenate is unable to do so. An increase of intracellular peroxide levels was accompanied with arsenite-induced apoptosis, as demonstrated by flow cytometry using DCFH-DA. N-Acetyl-L-cysteine (a thiol-containing antioxidant), diphenylene iodonium (an inhibitor of NADPH oxidase), 4,5-dihydro-1,3-benzene disulfonic acid (a selective scavenger of O2-), and catalase significantly inhibit arsenite-induced apoptosis and intracellular fluorescence intensity. In contrast, allopurinol (an inhibitor of xanthine oxidase), indomethacin (an inhibitor of cyclooxygenase), superoxide dismutase, or PDTC had no effect on arsenite-induced cell death. Activation of CPP32 activity, PARP (a DNA repair enzyme) degradation, and release of cytochrome c from mitochondria to the cytosol are involved in arsenite-induced apoptosis, and Bcl-2 antagonize arsenite-induced apoptosis by a mechanism that interferes in the activity of CPP32. These results lead to a working hypothesis that arsenite-induced apoptosis is triggered by the generation of hydrogen peroxide through activation of flavoprotein-dependent superoxide-producing enzymes (such as NADPH oxidase), and hydrogen peroxide might play a role as a mediator to induce apoptosis through release of cytochrome c to cytosol, activation of CPP32 protease, and PARP degradation.
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PMID:Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis. 976 29

The effects of a new type of nitric oxide (NO)-releasing compound, 1-hydroxyl-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC7), and peroxynitrite (ONOO-) on the formation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), thromboxane (TX) B2 and 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) from exogenous arachidonic acid in washed rabbit platelets have been compared. At concentrations of 5 microM and below, NOC7 inhibited 12-HETE formation (56.5-98.8% inhibition). Moreover, NOC7 inhibited TXB2 and HHT formation at concentrations ranging from 5 to 20 microM (TXB2, 62.2-88.1% inhibition; HHT, 11.6-62.2% inhibition). ONOO- had little or no effect on the production of these three metabolites at concentrations of up to 50 microM. Experiments utilizing a new class of NO antidote, carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, revealed that the observed effects of NOC7 are caused by NO. The effects of NO were reversed by addition of the superoxide generating system (xanthine plus xanthine oxidase and catalase), indicating that superoxide is a vital modulator of the action of NO. These results suggest that NO, but not ONOO- (up to 50 microM), can be a potent dual inhibitor of the 12-lipoxygenase and cyclooxygenase activities in platelets and that superoxide is an important regulator of the action of NO.
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PMID:Comparison of the effects of nitric oxide and peroxynitrite on the 12-lipoxygenase and cyclooxygenase metabolism of arachidonic acid in rabbit platelets. 977 72

Calcium influx via the NMDA receptor has been proposed as a mechanism of hypoxia-induced neuronal injury. The present study tests the hypothesis that the increase of [Ca2+]i observed under hypoxic conditions is the result of an NMDA-mediated Ca2+ influx. Changes of [Ca2+]i, measured fluorometrically with Fura-2, were followed after activation of the NMDA receptor with NMDA and glutamate, in the presence of glycine, in cortical synaptosomes prepared from six normoxic and six hypoxic guinea pig fetuses. [Ca2+]i was significantly higher in hypoxic vs normoxic synaptosomes, at baseline and in the presence of glycine as well as following activation of the NMDA receptor. Increase in [Ca2+]i was not observed in a Ca2+ free medium and was significantly decreased by MK-801 and thapsigargin. These results demonstrate that hypoxia-induced modifications of the NMDA receptor ion-channel results in increased [Ca2+]i in hypoxic vs normoxic synaptosomes. This increased accumulation may be due to an initial influx of Ca2+ via the altered NMDA receptor with subsequent release of Ca2+ from intracellular stores. Increase in intracellular calcium may initiate several pathways of free radical generation including cyclooxygenase, lipoxygenase, xanthine oxidase and nitric oxide synthase, and lead to membrane lipid peroxidation resulting in neuronal cell damage.
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PMID:NMDA receptor-mediated calcium influx in cerebral cortical synaptosomes of the hypoxic guinea pig fetus. 1021 19


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