UNIPROT:P47989 - FACTA Search

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)

The growing evidence that glutamate may be an important agent mediating ischemic damage to neurons, led us to investigate the possible protective effects of pharmacological agents against glutamate in a model system of cortical neurons. In this study we examined, in particular, the cytoprotective effect of prostaglandins. Experiments were carried out in vitro by using rat cortical neurons in culture for 10 days. They were incubated for 3h with glutamate (10 microM) in the presence or absence of various pharmacological agents including prostaglandins (PGD2, PGE1, PGE2, PGF2 alpha, PGI2, 6-Keto-PGF1 alpha, carba-TXA2, carba-PGI2 and PGF2 alpha-methylester). Increase in lacticodehydrogenase (LDH) release into the culture medium has been measured as an index of cell injury. When neurons were incubated with glutamate they released LDH due to NMDA-receptor activation since D-L-2-amino-5-phosphonovaleric acid, a specific receptor antagonist, protected the cells. The protective activity of oxypurinol, amflutizole, superoxide dismutase, NG nitro-L-arginine and quinacrine, also suggests that xanthine oxidase activation, the generation of superoxide radical, and nitrix oxide, as well as phospholipase A2 stimulation are responsible for neuron injury (i.e. LDH release). All the tested prostaglandins, except PGF2 alpha-methylester, afforded significant protection at concentrations between 0.1 and 10 microM. The order of potency of the prostanoids was: PGF2 alpha = PGE2 > Carba-TXA2 > PGE1 > PGD2 > PGI2 = Carba-PGI2 > 6-Keto-PGF1 alpha. Additional experiments showed that prostaglandins did not compete for the NMDA binding site and that they did not inhibit free radical-related membrane damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protection by prostaglandins from glutamate toxicity in cortical neurons. 791 88

The transcription factor NF-kB may play an important role in the response to tissue injury and activation of cytokines. We therefore examined the regulation of NF-kB in mesangial cells. Treatment of mesangial cells with TNF-alpha increased nuclear proteins that bound to an NF-kB-specific DNA oligonucleotide. IgG aggregates also increased nuclear NF-kB demonstrating Fc-tau receptor-mediated activation of NF-kB. Treatment of a cytosolic preparation with the detergent deoxycholate also activated NF-kB. The binding characteristics were typical for NF-kB transcription factors as determined by competition experiments with NF-kB-binding wild type kB DNA oligonucleotides or mutated oligonucleotides. Furthermore, a monoclonal antibody against the p65 subunit of NF-kB prevented the binding of NF-kB to the kB oligonucleotide. To evaluate the potential role of reactive oxygen intermediates in the activation of NF-kB, we used PDTC as a scavenger and HMAP as an inhibitor of NADPH-dependent oxidase. Both PDTC and HMAP attenuated the increase in nuclear NF-kB in response to either TNF-alpha or IgG complexes. Finally, generation of superoxide anion by xanthine oxidase activated NF-kB, an effect also mitigated by PDTC. In contrast, exogenous H2O2 did not activate NF-kB. Preincubation of cells with 8 br-cAMP, forskolin, or PGE2 attenuated the increase in nuclear NF-kB in response to TNF-alpha, aggregated IgG, or superoxide anion. Our results provide support for a role of reactive oxygen intermediates as mediators for activation of NF-kB in MC after stimulation with TNF-alpha or IgG aggregates. As an unexpected novel finding we report that cAMP can inhibit activation of NF-kB in MC. These observations may help to explain effects of TNF-alpha, IgG aggregates and cAMP on generation of cytokines by mesangial cells and the resulting glomerular pathophysiology.
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PMID:Activation and attenuation of transcription factor NF-kB in mouse glomerular mesangial cells in response to tumor necrosis factor-alpha, immunoglobulin G, and adenosine 3':5'-cyclic monophosphate. Evidence for involvement of reactive oxygen species. 792 39

The aim of this study was to investigate the effects of nitroglycerin (NTG), a nitric oxide (NO) donor used as a vasodilating agent, on prostanoid [e.g., prostaglandin (PG)] release in the O2(-)-pretreated rat heart. Perfusion of O2-, generated by a xanthine oxidase-purine coupling, caused elevation (P < 0.05) of the coronary perfusion pressure (CPP) after 20 min (from 57.1 +/- 3.9 during the control period to 72.2 +/- 3.9 mmHg, P < 0.05). O2- caused increased release of PGF2 alpha from 3.6 +/- 0.7 to 20.6 +/- 4.4 pmol.min-1.g-1 and of thromboxane A2 (TxA2) from 2.4 +/- 0.4 to 9.6 +/- 1.6 pmol.min-1.g-1 (P < 0.001) with no significant changes in PGE2 and PGI2 release. During the 20-min washout of O2- from the heart with normal Krebs solution, release of PGF2 alpha and TxA2 decreased to 8.7 +/- 1.4 and 6.3 +/- 1.7 pmol.min-1.g-1, respectively, and the release of PGE2 and PGI2 markedly increased from 11.1 +/- 2.9 to 25.4 +/- 3.6 and 157.2 +/- 16.4 to 413.2 +/- 41.4 pmol.min-1.g-1, respectively (P < 0.05), without lowering the elevated CPP. Administration of 4 microM NTG during the washout period paradoxically augmented the elevated CPP to 133.3 +/- 0.6% and was associated with a doubling (P < 0.05) of PGF2 alpha and TxA2 release with no significant changes in PGE2 and PGI2 release. The NTG-induced CPP elevation was inhibited (P < 0.05) by indomethacin, a cyclooxygenase inhibitor, or ONO-3708, a TxA2 receptor blocker, whereas arachidonic acid, a substrate for PG synthesis, augmented the CPP elevation. These results indicate that NTG stimulates the synthesis of vasoconstrictive PG in the O2(-)-pretreated rat heart, inducing a paradoxical elevation in CPP.
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PMID:Superoxide and nitroglycerin stimulate release of PGF2 alpha and TxA2 in isolated rat heart. 899 4

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

This study was performed to clarify the mechanism of vasoconstriction induced by oxygen-derived free radicals in spontaneously hypertensive rats. The isometric tension of aortic rings from spontaneously hypertensive rats and Wistar-Kyoto rats was measured in Krebs-Henseleit solution. Oxygen-derived free radicals were generated by mixing xanthine and xanthine oxidase. The removal of endothelium enhanced the contractions induced by oxygen-derived free radicals. The inhibition of nitric oxide production with NG-nitro-L-arginine methyl ester (10(-4) M) enhanced the contractions. Treatment with the thromboxane A2 (TXA2) synthetase inhibitor OKY-046 (10(-4) M) or RS-5186 (10(-4) M) markedly reduced the contractions. Treatment with the cyclooxygenase inhibitor indomethacin (10(-5) M) and a TXA2/prostaglandin H2 (PGH2) receptor antagonist, ONO-3708 (10(-6) M), completely abolished the oxygen-derived free radical-induced contractions. In contrast, treatment with the PGI2 synthetase inhibitor tranylcypromine (10(-4) M) did not attenuate the oxygen-derived free radical-induced contractions. Whether endothelium was present or not, the release of TXB2, PGE2, and 6-keto-PGF1alpha, but not PGF2alpha, was increased by the production of oxygen-derived free radicals. Catalase and the hydroxyl radical scavenger deferoxamine plus mannitol markedly inhibited the oxygen-derived free radical-induced contractions. These results suggest that oxygen-derived free radical-induced vasoconstriction in spontaneously hypertensive rat aorta is caused by TXA2 and PGH2 released in smooth muscle.
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PMID:Oxygen-derived free radical-induced vasoconstriction by thromboxane A2 in aorta of the spontaneously hypertensive rat. 1021 31

The isoprostanes are a group of biologically active arachidonic acid metabolites initially thought to be formed under conditions of oxidative stress and independently of cyclooxygenase. However, recent studies have demonstrated isoprostane production under conditions in which cyclooxygenase is intentionally activated/induced. Here we describe for the first time formation of isoprostanes by human vascular cells via independent pathways of oxidative stress and cyclooxygenase induction. We compared the release of the isoprostane with that of the traditional prostaglandin, prostaglandin E2. Cyclooxygenase-2 induction was confirmed by Western blot. When cells were stimulated with cytokines, the release of isoprostanes was inhibited by the cyclooxygenase-1 and -2 inhibitor indomethacin as well by as the cyclooxygenase-2 selective inhibitor L-745,337. However, treatment of cells with the superoxide-producing enzyme xanthine oxidase also resulted in isoprostane release, which was not affected by cyclooxygenase inhibition, unlike PGE2 release under the same condition. Thus, two independent pathways relating to oxidative stress and cyclooxygenase-2 induction form isoprostanes. These findings may have particular importance in diseases such as sepsis and ARDS in which oxidant stress occurs and cyclooxygenase is induced.
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PMID:Isoprostanes and PGE2 production in human isolated pulmonary artery smooth muscle cells: concomitant and differential release. 1033 84

The oxidative stress in placental tissues during late pregnancy, as well as the relationship between reactive oxygen species (ROS) and the arachidonic acid (AA) pathway was evaluated in a neonatal streptozotocin (STZ)-induced diabetic rat model. Lipoperoxide levels are increased in diabetic tissues compared with control tissues (P<0.001) and they seem to increase throughout the development of gestation both in control (P<0.05) and STZ-induced diabetic (P<0.001) rats. Superoxide dismutase (SOD) activity is not modified on different days of pregnancy, but enzymatic activity is lower in diabetic tissues than in control tissues (P<0.01). Labour is preceded by an increase in placental 14C-prostaglandin conversion from 14C-AA in control and diabetic animals (P<0.05) and the thromboxane B2 (TXB2)/6-keto-prostaglandin F1alpha (PGF1alpha) ratio is higher in diabetic placental tissues than in controls. The addition of SOD and glutathione to the incubation medium does not modify prostanoid levels in control rats, but does decrease the AA conversion to PGF2alpha, PGE2 and TXB2 (P<0.05) in diabetic placenta. Superoxide radical generation (hypoxanthine/xanthine oxidase or hydrogen peroxide added to the incubation medium) produces a decrease in 6-keto-PGF1alpha (P<0.05) in control and diabetic tissues, whereas PGF2alpha, PGE2 and TXB2 levels, and PGF2alpha and TXB2 production are increased in control and diabetic animals respectively (P<0.05). Diabetic pregnant rats supplemented with a diet containing 400 mg day(-1) of alpha-tocopherol (vitamin E) have diminished placental PGF2alpha and TXB2 production and lipoperoxide levels. The results show a higher TXB2 and a decreased 6-keto-PGF1alpha placental production that may be linked to increased oxidative stress and to a reduced antioxidant capacity in STZ-induced diabetic rats. These imbalances, probably involved in abnormal placental structure and function, may potentially be corrected with dietary supplementation of alpha-tocopherol in diabetic pregnancies.
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PMID:Oxidative stress and altered prostanoid production in the placenta of streptozotocin-induced diabetic rats. 1205 17

Hydrophobic bile acids impair gallbladder emptying in vivo and inhibit gallbladder muscle contraction in response to CCK-8 in vitro. This study was aimed at determining the mechanisms of muscle cell dysfunction caused by bile acids in guinea pig gallbladders. Muscle cells were obtained by enzymatic digestion. Taurochenodeoxycholic acid (TCDC), a hydrophobic bile acid, caused a contraction of up to 15% and blocked CCK-induced contraction. Indomethacin abolished the TCDC-induced contraction. Hydrophilic bile acid tauroursodeoxycholic acid (TUDC) had no effect on muscle contraction but prevented the TCDC-induced contraction and its inhibition on CCK-induced contraction. Pretreatment with NADPH oxidase inhibitor PH2I, xanthine oxidase inhibitor allopurinol, and free-radical scavenger catalase also prevented TCDC-induced contraction and its inhibition of the CCK-induced contraction. TCDC caused H2O2 production, lipid peroxidation, and increased PGE2 synthesis and activities of catalase and SOD. These changes were significantly inhibited by pretreatment of PH2I or allopurinol. Inhibitors of cytosolic phospholipase A2 (cPLA2), protein kinase C (PKC), and mitogen-activating protein kinase (MAPK) also blocked the TCDC-induced contraction. It is concluded that hydrophobic bile acids cause muscle cell dysfunction by stimulating the formation of H2O2 via activation of NADPH and xanthine oxidase. H2O2 causes lipid peroxidation and activates cPLA2 to increase PGE2 production, which, in turn, stimulates the synthesis of free-radical scavengers through the PKC-MAPK pathway.
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PMID:Effects of bile acids on the muscle functions of guinea pig gallbladder. 1206 95

The aim of this study was to compare the effects of two nonsteroidal anti-inflammatory drugs (NSAID), members of the same family with a different cyclooxygenase (COX) inhibition selectivity, meloxicam, preferent COX-2 inhibitor, and piroxicam, preferent COX-1 inhibitor, on oxygen radical generation in rat gastric mucosa. Therefore, the activity of oxidative stress-related enzymes such as xanthine oxidase (XO), superoxide dismutase (SOD) and glutathione (GSH) homeostasis were studied in rats. Gastric prostaglandins (PG) were also assessed as a measure of COX-1 inhibition. Both oxicams produced a similar extent of the gastric mucosal damage and a significant decrease in PGE2 synthesis, however only piroxicam induced an increase of both myeloperoxidase (MPO) activity and tumor necrosis factor (TNF)-alpha content in the gastric mucosa, indicating that neutrophil-derived free radicals were involved in gastric injury. Furthermore, both compounds reduced SOD activity and increased XO activity in gastric mucosa. Our results also revealed modifications in GSH metabolism: although glutathione peroxidase (GSH-px) activity was unaffected by meloxicam or piroxicam administration, both glutathione reductase (GSSG-rd) activity and total GSH content were significantly decreased after dosing. These results suggest that under our experimental conditions, meloxicam, preferential COX-2 inhibitor causes rates of gastric lesion in rats comparable to those seen with the traditional NSAID piroxicam, preferential COX-1 inhibitor. In addition to suppression of systemic COX activity, oxygen radicals, probably derived via the XO, and neutrophils play an important role in the production of damage induced by both oxicams. Moreover, the decrease in SOD activity and changes in glutathione homeostasis in gastric mucosa may also contribute to pathogenesis of meloxicam- or piroxicam-induced gastropathy.
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PMID:Effects of oxicam inhibitors of cyclooxygenase on oxidative stress generation in rat gastric mucosa. A comparative study. 1218 Jan 28

Type 1, or cellular, immune response is characterized by overproduction of TNF-alpha, IFN-gamma, IL-1, IL-2 and IL-8 and is the underlying immune mechanism of psoriasis, alopecia areata, rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin-dependent diabetes mellitus and experimental autoimmune uveitis (EAU). Type 2 immune response is seen in antibody-mediated autoimmune diseases. Based on the pharmacokinetic effects of cetirizine and allopurinol, this paper introduces these two safe and inexpensive drugs as novel potential agents against cell-mediated autoimmune disorders. Cetirizine, supposed to inhibit DNA binding activity of NF-kappa B, inhibits the expression of adhesion molecules on immunocytes and endothelial cells and the production of IL-8 and LTB4, two potent chemoattractants, by immune cells. It induces the release of PGE2, a suppressor of antigen presentation and MHC class II expression, from monocyte/macrophages and reduces the number of tryptase positive mast cells in inflammation sites. Tryptase is a chemoattractant, generates kinins from kininogen, activates mast cells, triggers maturation of dendritic cells and stimulates the release of IL-8 from endothelial cells and the production of Th1 lymphokines by mononuclear immunocytes. Allopurinol is a free radical scavenger, suppresses the production of TNF-alpha and downregulates the expression of ICAM-1 and P2X(7) receptors on monocyte/macrophages. ICAM-1 serves as a ligand for LFA-1 (on T lymphocytes), allowing proper antigen presentation. P2X(7) receptors are thought to be involved in IL-1beta release, mitogenic stimulation of T lymphocytes and the probable cytoplasmic communication between macrophages and lymphocytes at inflammation sites. Allopurinol was markedly more effective than prednisolone in treating experimental autoimmune uveitis and in combination with cyclosporine suppressed the inflammatory reaction of this condition more effectively than either agent alone. As allopurinol is a competitive inhibitor of xanthine oxidase and decreases serum levels of uric acid, which is protective against multiple sclerosis, it should preferably be coadministered with uric acid precursors in the treatment of this condition. Cetirizine and allopurinol may prove of benefit in the treatment of various cellular autoimmune disorders.
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PMID:Cetirizine and allopurinol as novel weapons against cellular autoimmune disorders. 1503 12

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