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)

Progressive tissue necrosis is a unique reaction to spinal cord trauma in which the site of injury is gradually transformed into a large, cavity-filled lesion. The earliest histopathological changes after injury include a widely disseminated extravasation of erythrocytes and neutrophils. To test whether such an inflammatory reaction might initiate progressive necrosis, we examined the effects of the following anti-inflammatory treatments: allopurinol (Ap) to inhibit injury-induced xanthine oxidase, indomethacin (I) or naproxen to inhibit constitutive and inducible cyclooxygenase, aminoguanidine (Ag) to inhibit inducible nitric oxide synthase, pregnenolone (P) as a precursor steroid, and a bacterial lipopolysaccharide (L) to stimulate secretory activities of glial cells and macrophages. The spinal cord of adult rats was crushed at T8 with jeweler's forceps and, after 3 or 21 days of treatment, the cords were studied quantitatively by light microscopical image analysis. Ag, Ag+I, or Ap significantly reduced the size of the primary lesion at 3 days postoperatively, while P+L+I did so only after 21 days of treatment. A secondary lesion developed in the dorsal column and gradually extended for many millimeters rostral and caudal from the primary lesion. The size of the dorsal column lesion was diminished by 3-day treatment with Ap and by 21-day treatment with Ap or P+L+I, but Ag or Ag+I had no effect. We conclude that (a) progressive necrosis is initiated and maintained by inflammatory mechanisms and (b) for this reason, treatment with specific anti-inflammatory agents selectively attenuates various components of the necrotizing process.
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PMID:Experimental analysis of progressive necrosis after spinal cord trauma in the rat: etiological role of the inflammatory response. 900 Apr 53

The functional changes in macrophages (Mphi) following exposure to a high dose (6 Gy) of gamma-rays in vitro were investigated. Resident peritoneal Mphi obtained from C57BL/6 mice were irradiated with gamma-rays (137Cs, 0.3 Gy/min). High-dose irradiation enhanced nitric oxide (NO) production from Mphi treated with interferon-gamma and their cytotoxic activity. The enhancement of NO production by irradiation was attributed to high levels of expression of the inducible nitric oxide synthase. Furthermore, the participation of reactive oxygen intermediates in NO production was examined. Nitric oxide production was not enhanced by treatment with the membrane-oxidizing agent tert-butyl hydroperoxide or the hypoxanthine/xanthine oxidase superoxide (O2.-)-generating system. On the other hand, NO production was enhanced by treatment with a low dose of hydrogen peroxide (H2O2), which can diffuse passively through the cell membrane and can be converted into hydroxyl radicals (HO.) that cause DNA breaks. In addition, treatment with low-dose actinomycin D, which induces DNA strand breaks, enhanced NO production, but hydroxyurea, which stops DNA replication without DNA strand breaks, had no such effect. These findings suggest that DNA strand breaks caused by hydroxyl radicals formed inside the cells by gamma-irradiation, or strand breaks caused directly by radiation, plays an important role in the enhancement of NO production, but peroxidation of cell membranes has little effect.
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PMID:Enhancement of NO production from resident peritoneal macrophages by in vitro gamma-irradiation and its relationship to reactive oxygen intermediates. 903 42

Nitric oxide (NO.) and superoxide (O2-) are inflammatory mediators. Their formation seems to be associated with apoptotic and/or necrotic cell death in diseases such as mesangioproliferative glomerulonephritis in which the early phase of mesangiolysis is linked to significant NO. production. Notably, mesangial cells (MC) not only generate NO. but also O2- after cytokine stimulation. Here we investigated the interrelation between NO. and O2- in MC death by generating both radicals with the use of NO donors (S-nitrosoglutathione, spermine-NO) and O2(-)-generating systems (2,3-dimethoxy-1,4-naphtoquinone, hypoxanthine/xanthine oxidase). Exogenously supplied NO. or O2- in a concentration-dependent manner induced apoptosis and/or necrosis. Apoptosis is characterized by chromatin condensation and DNA fragmentation in contrast to necrotic cytoplasmatic membrane rupture. Noteworthy, coincubation of NO. and O2- was cross-protective. Maximum protection required the existence of a balanced NO./O2- ratio. Analysis in cytokine-stimulated MC suggests endogenous radical formation, which may participate in modulating apoptosis. Manipulation of the endogenous NO./O2- ratio by exogenous, sublethal S-nitrosoglutathione in addition to cytokines produced death, which was antagonized by inducible nitric oxide synthase (iNOS) inhibition. Moreover, pyrrolidine dithiocarbamate supplementation, which down-regulates iNOS expression and blocks superoxide dismutase activity, initiates apoptosis. Our results imply the participation of reactive nitrogen and oxygen species in determining life and death of MC.
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PMID:The balance between nitric oxide and superoxide determines apoptotic and necrotic death of rat mesangial cells. 914 12

1. The mechanisms involved in mediating bacterial endotoxin lipopolysaccharide (LPS)-induced injury in the colon of neonatal rat pups aged 10-12 days was examined. 2. Administration of LPS (3 mg kg(-1), i.p.) caused a time-related increase in the plasma concentration of rat mast cell protease-II (RMCP-II) which was attenuated dose-dependently, by the non-selective mast cell stabilizer doxantrazole (0.05-5 mg kg(-1), i.p.). The selective connective tissue mast cell stabilizer ketotifen (5-25 mg kg(-1), i.p.) was without effect at the lower dose and had only a limited inhibitory effect at the higher dose. 3. In addition, doxantrazole (5 mg kg(-1), i.p.) inhibited mast cell degranulation in response to LPS in sections of neonatal rat colon, but ketotifen (5 mg kg(-1), i.p.) was without effect. 4. The increase in plasma RMCP-II concentration in response to LPS treatment preceded increases in tissue myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS) activity and tissue lipid peroxidation. These events were all attenuated by pretreatment with doxantrazole (5 mg kg(-1), i.p.), antineutrophil serum (100 microl kg(-1), i.p.), dexamethasone (2 mg kg(-1), i.p.) and the selective iNOS inhibitor, aminoguanidine (25 mg kg(-1), i.p.). 5. In addition, lipid peroxidation was inhibited by pre-administration of the antioxidant enzymes superoxide dismutase (2000 u kg(-1), i.p.) and catalase (2000 u kg(-1), i.p.), the xanthine oxidase inhibitor allopurinol (100 mg kg(-1), i.p.) and the peroxyl scavenger deferoxamine (10 mg kg(-1), i.p.), suggesting the involvement of reactive oxygen metabolites in the colonic injury. 6. These findings suggest that the sequence of events resulting in colonic damage in the neonatal rat following administration of LPS include mast cell degranulation, neutrophil infiltration, elevation in iNOS activity and subsequent lipid peroxidation.
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PMID:Role of mast cells, neutrophils and nitric oxide in endotoxin-induced damage to the neonatal rat colon. 948 51

Intracellularly generated reactive species of both oxygen (ROS) and nitrogen (RNS) have been implicated in signaling responses in airway epithelial cells, but these radicals have not been measured directly in such cells. In this study, intracellular production of both ROS and RNS were measured in the same cell lysates of guinea pig tracheal epithelial (GPTE) cells maintained in primary culture. ROS and RNS were quantified under basal (constitutive) conditions and in response to different stimuli: LPS and TNFalpha [activators of inducible nitric oxide synthase (iNOS)]; several activators of calcium-dependent cNOS (ATP, bradykinin, ionophore A23187, and thapsigargin); and exogenous oxidant stress generated by addition of xanthine oxidase to purine (p + XO). Studies with LPS and TNFalpha also were performed using the murine macrophage cell line, RAW 264.7, as a positive control. Intracellular oxidant production was detected from oxidation of dihydrorhodamine to rhodamine. NOx was quantified by either chemiluminescent or fluorescent detection. NOS activity was measured as citrulline production from arginine. Basal production of oxidants by GPTE cells (0.08 + 0.00 nmol rhodamine) was less than 10% that of RAW.267 cells (0.91 + 0.03 nmol rhodamine). TNFalpha and LPS significantly increased intracellular oxidant production in GPTE cells, as did p + XO, but none of the cNOS activators affected production of oxidants in these cells. Concentrations of NO2 after 4 h in unstimulated RAW 264.7 and GPTE cells were similar and comprised 63% of total NOx in GPTE and 62% in RAW cells. TNFalpha and LPS both increased NO2 in GPTE cells, but none of the Ca++-mobilizing agents nor p + XO significantly affected intracellular RNS. The results suggest both ROS and RNS can be measured in the same lysates from airway epithelial cells, and that both ROS and RNS are produced in these cells in response to different stimuli.
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PMID:Concurrent production of reactive oxygen and nitrogen species by airway epithelial cells in vitro. 958 18

Exposure of mesangial cells to superoxide, generated by the hypoxanthine/xanthine oxidase system or by the redox cycler 2,3-dimethoxy-1,4-naphthoquinone caused a concentration-dependent amplification of interleukin (IL)-1beta-stimulated nitrite production. The effect of superoxide was accompanied by an increase in inducible nitric oxide synthase (iNOS) protein and iNOS mRNA levels. Incubation of mesangial cells with superoxide alone did not induce iNOS expression. To elucidate whether the increase of iNOS expression is due to transcriptional upregulation we fused a 4.5-kb genomic iNOS fragment that contains the transcriptional start site of the rat iNOS gene to a luciferase reporter gene. In transient transfection studies, superoxide caused a 10-fold augmentation of iNOS promoter activity in IL-1beta-challenged mesangial cells. Our data identify superoxide as a co-stimulatory factor amplifying cytokine-induced iNOS gene expression and subsequent nitric oxide (NO) synthesis.
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PMID:Potentiation of nitric oxide synthase expression by superoxide in interleukin 1 beta-stimulated rat mesangial cells. 975 54

We have reported that peroxynitrite (PON) selectively inactivated prostacyclin synthase (PGIS) by a mechanism of tyrosine nitration at the active site [Zou, Martin and Ullrich (1997) Biol. Chem. Hoppe-Seyler 378, 707-713]. We have now extended our studies on rat mesangial cells (RMC) and show that nitration can occur under the influence of cytokines. Pretreatment of RMC with interleukin 1beta (IL-1beta), which up-regulated cyclo-oxygenase 2 and inducible nitric oxide synthase (NOS-2), significantly attenuated the conversion of [14C]prostaglandin H2 (PGH2) into the stable prostacyclin (PGI2) metabolite 6-oxo-prostaglandin F1alpha (6-oxo-PGF1alpha). The presence of superoxide dismutase (SOD, 100 units/ml) or the NOS synthase inhibitor Nomega-monomethyl-l-arginine (100 microM) as well as cycloheximide (10 microM) plus actinomycin (10 microM) abolished IL-1beta-mediated down-regulation of 6-oxo-PGF1alpha from PGH2. At the same time, 6-oxo-PGF1alpha production from arachidonate (AA) increased at the expense of prostaglandin E2 (PGE2). Neither NO alone generated from different NO donors nor superoxide from xanthine/xanthine oxidase (1-100 m-units/ml) inhibited PGI2 synthesis, either from PGH2 or from AA. Bolus additions of chemically synthesized PON or the PON generator 3-morpholinosydnonimine N-ethylcarbamide (SIN-1) exhibited a potent inhibition of 6-oxo-PGF1alpha release from both PGH2 and AA. In addition, immunoprecipitation of nitrotyrosine-containing proteins from PON- and SIN-1-treated RMC yielded distinct nitrated PGIS bands but also from IL-1beta-pretreated cells alone, compared with a lack of nitrated PGIS in control cells. Taken together, our results strongly suggest that IL-1beta pretreatment of RMC via NOS-2 leads to the production of PON with the consequence of a partial nitration and inhibition of PGIS.
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PMID:Interleukin 1beta decreases prostacyclin synthase activity in rat mesangial cells via endogenous peroxynitrite formation. 982 Aug 30

We have previously shown that surfactant protein A (SP-A) mediates in vitro killing of mycoplasmas by alveolar macrophages (AMs) from resistant C57BL/6 mice through a nitric oxide (.NO)-dependent mechanism. Herein, SP-A-deficient [SP-A(-/-)] and inducible.NO synthase-deficient [iNOS(-/-)] mice were infected intranasally with 10(5) or 10(7) colony-forming units of Mycoplasma pulmonis. SP-A(-/-) mice were as susceptible to mycoplasmal infection as highly susceptible C3H/He mice, and far more susceptible than resistant C57BL/6 mice. iNOS(-/-) mice had significantly greater numbers of mycoplasmas and severity of lung lesions than iNOS(+/+) controls. In vitro, AMs isolated from C57BL/6 mice, activated with IFN-gamma, incubated with SP-A (25 micrograms/ml), and infected with 10(10) colony-forming units of M. pulmonis, killed mycoplasmas within 6 h. Mycoplasmal killing was abrogated by 1,000 units/ml of copper-zinc superoxide dismutase. In the absence of AMs, incubation of M. pulmonis with the peroxynitrite generator 3-morpholinosynodiomine.HCl (SIN-1) effected complete killing of mycoplasmas by 90 min in a dose-dependent manner. Addition of copper-zinc superoxide dismutase (3,000 units/ml), which converts SIN-1 to a.NO donor, prevented this killing. Neither of the reactive oxygen species generated by xanthine oxidase (10 milliunits/ml, plus 500 microM xanthine and 100 microM FeCl3), nor.NO generated by 1-propanamine-3-(2-hydroxy-2-nitroso-1-propylhydrazine (PAPA NONOate) (100 microM) killed mycoplasmas. These data establish that peroxynitrite generation by AMs is necessary for the killing of a pathogen in vitro and in vivo.
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PMID:Surfactant protein A mediates mycoplasmacidal activity of alveolar macrophages by production of peroxynitrite. 1022 Apr

We examined the mechanism of the time- and protein synthesis-dependent decline in cardiac mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer for 120 min in the presence or absence of the protein synthesis inhibitor cycloheximide (CX; 10 microM). Cardiac work remained stable for 60 min and then spontaneously decreased during 60-120 min of perfusion. This was accompanied by an increase in myocardial inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO) activities and enhanced dityrosine formation in the perfusate, an indicator of peroxynitrite generation. CX markedly attenuated the loss in contractile function and prevented the increase in iNOS and XO activities and dityrosine level. Despite the decline in cardiac work in control hearts, the coupling between tricarboxylic acid (TCA) cycle activity and oxygen consumption remained constant in both groups. ATP, creatine phosphate, and glycogen levels were not different between control and CX groups and did not differ over 120 min of perfusion. We concluded that the delayed and spontaneous loss in myocardial mechanical function in isolated working rat hearts is 1) attenuated by CX treatment, 2) accompanied by a concomitant increase in both iNOS and XO activities and peroxynitrite generation in the heart, and 3) not dependent on a direct impairment in myocardial ATP production, myocardial oxygen consumption, or TCA cycle acetyl-CoA production but may be due to an inefficiency of the heart to utilize ATP for contractile work.
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PMID:Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts. 1036 64

In continuing studies of limb effects resulting from fetal exposure to N(G)-nitro-(L)-arginine methyl ester (L-NAME), we examined the early time course of vascular changes and the effectiveness of fetal intraamniotic injection. Vascular engorgement and hemorrhage occurred within 4 hr of L-NAME treatment on gestational day (gd) 17, and direct injection appeared to be as effective as maternal intraperitoneal injection in inducing limb hemorrhage. Further studies examined protein nitration and electron transport inhibition in tissues of exposed fetuses. L-NAME caused significant increases in nitrotyrosine (NT) formation in limb but not in heart or brain, and reduced electron transport rates in limb. Three agents, alpha-phenyl-N-t-butylnitrone (PBN), a radical trap and inhibitor of inducible nitric oxide synthase (iNOS), allopurinol, an inhibitor of xanthine oxidase, and aminoguanidine, a relatively specific inhibitor of iNOS, significantly moderated limb hemorrhage and protein nitration in distal limb. These results suggest that L-NAME works directly on the fetal limb vasculature and indicate a cytotoxic role for peroxynitrite, a potent oxidant and nitrating agent that is the reaction product of nitric oxide and superoxide anion radical. We propose that L-NAME and other vasoactive toxicants disrupt the fetal limb in a sequential process. Initially, nitric oxide (NO) is depleted, causing hemorrhage and edema in the limb. Within hours, iNOS is induced, resulting in cytotoxic tissue concentrations of NO and reactive nitrogen species that induce apoptosis and/or necrosis in the limb. We suggest that L-NAME exposure may serve as a model of vascular disruptive limb malformations.
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PMID:Role of free radicals in the limb teratogenicity of L-NAME (N(G)-nitro-(L)-arginine methyl ester): a new mechanistic model of vascular disruption. 1047


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