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)

Reactive oxygen species are considered important regulators in the pathogenesis and in the development of pancreatitis. The transcription factor nuclear factor kappaB (NF-kappaB) is activated by reactive oxygen species and regulates the gene expressions of inflammatory cytokines. The present study investigates (1) the susceptibility of isolated rat pancreatic acinar cells to oxidant attacks produced by adenosine diphosphate/ferrous iron, hypoxanthine/xanthine oxidase, and neutrophils primed with 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA) and (2) the potential of small-molecule antioxidants (N-acetylcysteine, beta-carotene, rebamipide, allopurinol) and superoxide dismutase (SOD) to prevent such injury and oxidant-mediated NF-kappaB activation and inflammatory cytokine production in the cells. As a result, oxidative stress resulted in a time-dependent increase in lipid peroxide production in pancreatic acinar cells which was inhibited by small-molecule antioxidants and SOD. PMA-primed neutrophils induced NF-kappaB activation and increased the production of cytokines (IL-6, TNF-alpha) in the cells. This was in parallel with lipid peroxide production. Small-molecule antioxidants and SOD inhibited NF-kappaB activation and cytokine production in acinar cells caused by PMA-primed neutrophils. In conclusion, oxidative stress activates NF-kappaB, resulting in upregulation of inflammatory cytokines in pancreatic acinar cells. Small-molecule antioxidants might be clinically useful anti-inflammatory agents by inhibiting oxidant-induced cytokine production.
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PMID:Oxidative stress induced cytokine production in isolated rat pancreatic acinar cells: effects of small-molecule antioxidants. 1180 45

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

Dendritic cells play a key role in immune responses. There is growing evidence that reactive oxygen species participate in signaling pathways involving nuclear factor (NF)-kappaB, leading to expression of important immune system genes. We found that, unlike H2O2, reactive oxygen species generated by the reaction of oxidase on xanthine induced early phenotypic maturation of dendritic cells by upregulating specific markers CD80, CD83, and CD86 and downregulating mannose receptor-mediated endocytosis. Maturation induced by xanthine oxidase was prevented by allopurinol, an inhibitor of xanthine oxidase activity, and by N-acetylcysteine. The proteasome inhibitor MG-132, which blocks NF-kappaB activation, also inhibited CD86 upregulation, but not endocytosis downregulation by reactive oxygen species. Finally, xanthine-xanthine oxidase enhanced or blocked antigen presentation by dendritic cells depending on whether they had been prepulsed or not with the antigen. Taken together, these results demonstrate that oxidative stress induces phenotypic and functional maturation of dendritic cells, partly through an NF-kappaB-dependent mechanism.
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PMID:Superoxide anions induce the maturation of human dendritic cells. 1255 28

Reactive oxygen intermediates (ROI) and cytokines, particularly tumor necrosis factor (TNF) have been implicated in the pathogenesis of influenza. Using a murine model of influenza, we have studied the levels of TNF, interleukin 6 (IL-6) and of superoxide-generating xanthine oxidase (XO). Mice infected intranasally with influenza virus APR/8 had high levels of XO, TNF and IL-6 in the broncoalveolar lavage, as early as 3 d after infection. XO was elevated also in serum and lung tissue. Administration of the antioxidant N-acetylcysteine (NAC,1 g/kg per day, orally) significantly decreased the mortality in infected mice, indicating a role for RO1 in the lethality associated with influenza infection.
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PMID:Protective effect of n-acetylcysteine in a model of influenza infection in mice. 1265 1

OBJECTIVE: To delineate biochemical details of graded xanthine oxidase stress toward cultured alveolar type II cells, particularly oxidant-mediated damage of type II cell nucleic acid, protein, and lipid, as an in vitro model of distant ischemia-reperfusion lung injury. DESIGN: In vitro injury model using native rat and immortalized mouse alveolar type II cells and exogenous xanthine oxidase. SETTING: Research laboratory. Measurement: Cultured type II cells were subjected to xanthine oxidase-derived reactive oxygen stress at variable concentrations and incubation times. Reduction of type II cell double-stranded DNA, inhibition of de novo phosphatidyl choline synthesis, enhancement of lipid peroxidation, and suppression of mitochondrial redox capacity were analyzed in relation to high-intensity (xanthine oxidase, 25 munits/mL) oxidant stress. Alterations in type II cell cellular glutathione-related antioxidant repertoire were assessed at both high-intensity and low-intensity (xanthine oxidase, 1 munits/mL) oxidant stress. MAIN RESULTS: High-intensity xanthine oxidase stress significantly increased type II cell DNA strand breakage, inhibited de novo phosphatidyl choline synthesis, diminished mitochondrial integrity, and enhanced lipid peroxidation in the absence of overt cytolysis. This injury was modulated with addition of exogenous glutathione peroxidase, or catalase/superoxide dismutase, but not glutathione or N-acetylcysteine. Although aspects of the glutathione antioxidant repertoire were similarly diminished with high-intensity xanthine oxidase stress, low-dose (long duration) xanthine oxidase stress augmented the activities of type II cell glutathione peroxidase and gamma-glutamyl transferase (the rate-limiting enzyme in glutathione synthesis). CONCLUSION: High-intensity xanthine oxidase stress (in vitro model of in vivo ischemia-reperfusion) may overwhelm type II cell antioxidant defenses and mediate oxidant injury to nucleic acid, protein, and lipid in the absence of cell lysis. Immortalized murine type II cells seem to appropriately model xanthine oxidase-mediated nucleic acid and protein injury of native rat type II cells. Exogenous glutathione peroxidase reduces oxidant injury in this in vitro model. Depending on magnitude (and possibly duration) of the xanthine oxidase stress, type II cell glutathione antioxidant elements may be diminished or enhanced.
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PMID:Global effects of xanthine oxidase stress on alveolar type II cells. 1278 Sep 70

Human LDL were used to study the protective action of four organosulfur compounds (diallyl sulfide, DAS; diallyl disulfide, DADS; S-ethylcysteine, SEC; N-acetylcysteine, NAC) derived from garlic against oxidation and glycation. The four organosulfur compounds significantly inhibited superoxide production by xanthine-xanthine oxidase (P < 0.05) and showed marked copper-chelating capability. DAS and DADS exhibited greater antioxidant activities against copper- and amphotericin B-induced LDL oxidation (P < 0.05) than SEC and NAC. However, SEC and NAC were more effective in sparing LDL alpha-tocopherol (P < 0.05). When oxidation was minimized, SEC was the most powerful agent against LDL glycation (P < 0.05); however, DADS was superior to other agents in suppressing both oxidation and glycation when LDL oxidation occurred simultaneously with glycation. These results suggest that the four organosulfur compounds derived from garlic are potent agents for protecting LDL against oxidation and glycation, and that they may benefit patients with diabetes mellitus or cardiovascular diseases by preventing complications.
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PMID:Protective action on human LDL against oxidation and glycation by four organosulfur compounds derived from garlic. 1278 61

The novel antioxidant 3-O-caffeoyl-one-methylquinic acid (MCGA3) is a methyl chlorogenic acid derivative isolated from bamboo leaves. MCGA3 scavenges reactive oxygen species (ROS) and inhibits lipid peroxidation and xanthine oxidase in vitro. In this study, we evaluated the cytoprotective effect of MCGA3, which occurs via heme oxygenase-1 (HO-1) induction in bovine vascular endothelial cells exposed to tert-butylhydroperoxide (tBHP). Cells treated with 1 mM tBHP (6-18 h) generated substantial ROS and concomitantly lost most intracellular lactate dehydrogenase (LDH), which then caused necrotic cell death. Of the several MCGA antioxidants and structurally related phenolic acids examined in this study, MCGA3 (0.01-0.15 mM) was found to completely block this necrosis and generation of ROS by tBHP. Surprisingly, MCGA3 by itself was found to be a potent inducer of HO-1. We observed the time- and dose-dependent induction of HO-1 mRNA and protein, which was closely associated with decreased intracellular ROS and necrosis against tBHP. Deesterified or Al-chelated MCGA3 or co-treatment with MCGA3 and actinomycin D abolished HO-1 induction and the antinecrotic effect of MCGA3. Zinc protoporphyrin IX and cycloheximide attenuated the cytoprotection afforded by MCGA3, but did not reduce HO-1 mRNA. Interestingly, N-acetylcysteine (1 mM) enhanced the HO-1 induction of MCGA3, but N-acetylcysteine itself did not induce HO-1. These results suggested that not only ortho-dihydroxyl groups but also aromatic ester and methoxyl ester moieties are necessary for full HO-1 induction and cytoprotection against toxic tBHP-derived ROS. Ferritin mRNA was also upregulated during all HO-1 induction by MCGA3, which might decrease iron and lower ROS levels. Consequently, the combined action of HO-1 and ferritin may protect cells from toxic tBHP-mediated necrosis.
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PMID:Cytoprotective effects of heme oxygenase-1 induction by 3-O-caffeoyl-1-methylquinic acid. 1473 89

15-Deoxy-delta(12,14)-prostaglandin J(2) (15dPGJ(2) has been recently proposed as a potent anti-inflammatory agent. However, the mechanisms by which 15dPGJ(2) mediates its therapeutic effects in vivo are unclear. We demonstrate that 15dPGJ(2) at micromolar (2.5-10 microm) concentrations induces the expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme, at both mRNA and protein levels in human lymphocytes. In contrast, troglitazone and ciglitazone, two thiazolidinediones that mimic several effects of 15dPGJ(2) through their binding to the peroxisome proliferator-activated receptor (PPAR)-gamma, did not affect HO-1 expression, and the positive effect of 15dPGJ(2) on this process was mimicked instead by other cyclopentenone prostaglandins (PG), such as PGD(2) (the precursor of 15dPGJ(2)) and PGA(1) and PGA(2) which do not interact with PPAR-gamma. Also, 15dPGJ(2) enhanced the intracellular production of reactive oxygen species (ROS) and increased xanthine oxidase activity in vitro. Inhibition of intracellular ROS production by N-acetylcysteine, TEMPO, Me(2)SO, 1,10-phenanthroline, or allopurinol resulted in a decreased 15dPGJ(2)-dependent HO-1 expression in the cells. Furthermore, buthionine sulfoximine, an inhibitor of reduced glutathione synthesis, or Fe(2+)/Cu(2+) ions enhanced the positive effect of 15dPGJ(2) on HO-1 expression. On the other hand, the inhibition of phosphatidylinositol 3-kinase or p38 mitogen-activated protein kinase, or the blockade of transcription factor NF-kappaB activation, hindered 15dPGJ(2)-elicited HO-1 expression. Collectively, the present data suggest that 15dPGJ(2) anti-inflammatory actions at pharmacological concentrations involve the induction of HO-1 gene expression through mechanisms independent of PPAR-gamma activation and dependent on ROS produced via the xanthine/xanthine oxidase system and/or through Fenton reactions. Both phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase signaling pathways also appear implicated in modulation of HO-1 expression by 15dPGJ(2).
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PMID:15-deoxy-delta 12,14-prostaglandin J2 induces heme oxygenase-1 gene expression in a reactive oxygen species-dependent manner in human lymphocytes. 1502 26

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates target gene transcription in a ligand-dependent manner. The in vivo effects of lipopolysaccharide (LPS) on expression of PXR and its target gene cytochrome P450 3A (CYP3A) in mouse liver were investigated in this study. Mice were injected intraperitoneally with different doses of LPS (0.1-5.0 mg/kg). PXR and CYP3A11 mRNA levels were measured using reverse transcription polymerase chain reaction. Results indicate that LPS significantly inhibits the expression of PXR mRNA in a dose-dependent manner, followed by suppression of CYP3A11 mRNA in mouse liver. LPS also represses the upregulation of CYP3A11 mRNA levels and erythromycin N-demethylase (ERND) catalytic activity in mice pretreated with PXR ligands dexamethasone, rifampicin, mifepristone, and phenobarbital. LPS-induced downregulation of PXR and CYP3A11 mRNA in liver was significantly attenuated in mice pretreated with gadolinium chloride, a selective Kupffer cell toxicant. Pretreatment with a single dose of gadolinium chloride (10 mg/kg) also significantly attenuated LPS-induced downregulation of dexamethasone-, rifampicim-, mifepristone-, and phenobarbital-inducible, CYP3A11 mRNA expression and ERND activity in mouse liver. Furthermore, LPS-induced downregulation of PXR and CYP3A11 mRNA was significantly attenuated in mice pretreated with allopurinol, an inhibitor of xanthine oxidase, and diphenyleneiodonium chloride, an inhibitor of NADPH oxidase. Allopurinol and diphenyleneiodonium chloride pretreatment also attenuated the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver. However, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, has no effect on LPS-induced downregulation of PXR and CYP3A11 mRNA. Finally, LPS-induced downregulation of PXR and CYP3A11 mRNA was prevented in mice pretreated with either N-acetylcysteine or ascorbic acid. These antioxidants also prevented the repressive effects of LPS on dexamethasone-, rifampicin-, mifepristone-, and phenobarbital-inducible CYP3A11 mRNA expression and ERND catalytic activity in mouse liver. These results indicate that Kupffer cells contribute to LPS-induced downregulation of PXR and CYP3A in mouse liver. Reactive oxygen species, produced possibly by NADPH oxidase and perhaps by xanthine oxidase, are involved in LPS-induced downregulation of nuclear receptor PXR and its target gene CYP3A in mouse liver.
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PMID:Kupffer cells and reactive oxygen species partially mediate lipopolysaccharide-induced downregulation of nuclear receptor pregnane x receptor and its target gene CYP3a in mouse liver. 1518 91

The present study investigated the protective effect of N-acetylcysteine (NAC) against oxygen radical-mediated coronary artery injury. Vascular contraction and relaxation were determined in canine coronary arteries immersed in Kreb's solution (95% O2-5% CO2), incubated or not with NAC (10 mM), and exposed to free radicals (FR) generated by xanthine oxidase (100 mU/ml) plus xanthine (0.1 mM). Rings not exposed to FR or NAC were used as controls. The arteries were contracted with 2.5 microM prostaglandin F2alpha. Subsequently, concentration-response curves for acetylcholine, calcium ionophore and sodium fluoride were obtained in the presence of 20 microM indomethacin. Concentration-response curves for bradykinin, calcium ionophore, sodium nitroprusside, and pinacidil were obtained in the presence of indomethacin plus Nomega-nitro-L-arginine (0.2 mM). The oxidative stress reduced the vascular contraction of arteries not exposed to NAC (3.93 +/- 3.42 g), compared to control (8.56 +/- 3.16 g) and to NAC group (9.07 +/- 4.0 g). Additionally, in arteries not exposed to NAC the endothelium-dependent nitric oxide (NO)-dependent relaxation promoted by acetylcholine (1 nM to 10 microM) was also reduced (maximal relaxation of 52.1 +/- 43.2%), compared to control (100%) and NAC group (97.0 +/- 4.3%), as well as the NO/cyclooxygenase-independent receptor-dependent relaxation provoked by bradykinin (1 nM to 10 microM; maximal relaxation of 20.0 +/- 21.2%), compared to control (100%) and NAC group (70.8 +/- 20.0%). The endothelium-independent relaxation elicited by sodium nitroprusside (1 nM to 1 microM) and pinacidil (1 nM to 10 microM) was not affected. In conclusion, the vascular dysfunction caused by the oxidative stress, expressed as reduction of the endothelium-dependent relaxation and of the vascular smooth muscle contraction, was prevented by NAC.
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PMID:Protective effect of N-acetylcysteine against oxygen radical-mediated coronary artery injury. 1527 23


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