Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the description of bronchopulmonary dysplasia (BPD) in premature infants, the supplemental oxygen administered has been suspect in the etiology of BPD. This has prompted studies on the effect of hyperoxia on lung growth in neonatal animals. So far, these have not led to a treatment which either prevents or mitigates BPD. Another approach to investigate the effect of hyperoxia on the immature lung is to use lung explants from 12-d gestation mouse fetuses. Exposing explants to different concentrations of oxygen for 48 h, we found that exposures to oxygen both below (10%) and above (35% or greater) normoxia adversely affected branching morphogenesis and growth. The effect was irreversible at exposures of 50% oxygen and greater. To determine the role of reactive oxygen species (ROS) in the effect of hyperoxia, antioxidants and inhibitors of ROS formation were added to the incubating explants, and their influence on reducing the adverse effect of 50% oxygen was assessed. The combination of CuZn superoxide dismutase (SOD) and catalase, manganese SOD, manganese-3-tetrakis(1-methyl-4-pyridyl)porphorin, a low molecular weight SOD mimetic, and to a lesser extent, deferoximine, an antioxidant and inhibitor of hydroxyl radical formation, were successful in reducing the effect of 50% oxygen on morphogenesis. Not successful were N-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase); allopurinol (an inhibitor of xanthine oxidase); N-acetylcysteine and ebselen (a glutathione peroxidase mimetic); Trolox (a synthetic tocopherol); catalase, and CuZnSOD used alone. These results provide evidence that superoxide anion and possibly hydroxyl radical are the ROS most likely responsible for the growth effects of hyperoxia on mouse fetal lung morphogenesis.
 ...
PMID:Oxygen toxicity to the developing lung of the mouse: role of reactive oxygen species. 882 70

Hypoxia increases the activity of xanthine oxidase (XO) and its precursor, xanthine dehydrogenase (XDH), but the mechanism of regulation is unclear. In hypoxic Swiss 3T3 cells, an early (0-24 h) cycloheximide-insensitive increase in XO-XDH activity, coupled with a lack of increase in de novo XO-XDH synthesis (immunoprecipitation) or mRNA levels (quantitative RT-PCR), demonstrated a posttranslational effect of hypoxia. Similarly, hyperoxia decreased XO-XDH activity faster than could be accounted for by cessation of XO-XDH protein synthesis. In further support of a posttranslational effect, cells transfected with a constitutively driven XDH construct displayed an exaggerated increase in activity in hypoxia but no increase in activity in hyperoxia. However, more prolonged exposure to hypoxia (24-48 h) induced an increase in XO-XDH mRNA levels and de novo XO-XDH protein synthesis, suggesting an additional pretranslational effect. Finally, hypoxic induction of XO-XDH activity was found to be cell-type-restricted. We conclude that control of XO-XDH levels by oxygen tension is a complex process which involves several points of regulation.
 ...
PMID:Hypoxia regulates xanthine dehydrogenase activity at pre- and posttranslational levels. 939 Jan 87

The effects of respiratory hyperoxia (RH) and xanthine oxidase (XO) during localized hyperthermia (HT) were investigated by determining markers of oxidative damage to lipids and proteins and tumor growth. Anesthetized rats with s.c. DS-sarcomas underwent one of the following treatments: (a) localized saline-bath HT (60 min, 44 degrees C); (b) HT + RH (100% O2); and (c) HT + RH + XO (15 units/kg i.v.). Sham-treated animals served as controls. Tumors were investigated for: (a) thiobarbituric acid-reactive substance formation and protein-bound 4-hydroxynonenal, as indicators of lipid peroxidation; (b) reactive oxygen-mediated protein modifications; (c) apoptosis; and (d) tumor volume growth. Upon treatment, increases in thiobarbituric acid-reactive substances, protein-bound 4-hydroxynonenal, protein-associated carbonyl functions, and number of cells undergoing apoptosis were found in tumor tissue, together with an inhibition of tumor growth. When treatment groups were compared, effects in the group HT + RH + XO were generally most pronounced. These findings indicate that the antitumor effect of HT is at least partially mediated through the selective induction of lipid peroxidation and oxidative injury in tumor cells, leading to apoptosis. This effect was enhanced by adding RH or RH + XO, presumably due to enhanced tissue damage following an increased formation of reactive oxygen species, with higher levels of lipid peroxidation and protein oxidation.
 ...
PMID:Enhancement of oxidative cell injury and antitumor effects of localized 44 degrees C hyperthermia upon combination with respiratory hyperoxia and xanthine oxidase. 966 74

We studied the regulation of GSH and the enzymes involved in GSH regulation, gamma-glutamylcysteine synthetase (gamma-GCS) and gamma-glutamyl transpeptidase (gamma-GT), in response to the oxidants menadione, xanthine/xanthine oxidase, hyperoxia, and cigarette smoke condensate in human alveolar epithelial cells (A549). Menadione (100 microM), xanthine/xanthine oxidase (50 microM/10 mU), and cigarette smoke condensate (10%) exposure produced increased GSH levels (240 +/- 6, 202 +/- 12, and 191 +/- 2 nmol/mg protein, respectively; P < 0.001) compared with the control level (132 +/- 8 nmol/mg protein), which were associated with a significant increase in gamma-GCS activity (0.18 +/- 0.006, 0.16 +/- 0.01, and 0.17 +/- 0. 008 U/mg protein, respectively; P < 0.01) compared with the control level (0.08 +/- 0.001 U/mg protein) at 24 h. Exposure to hyperoxia (95% O2) resulted in a time-dependent increase in GSH levels. gamma-GCS activity increased significantly at 4 h (P < 0.001), returning to control values after 12 h of exposure. Dexamethasone (3 microM) exposure produced a significant time-dependent decrease in the levels of GSH and gamma-GCS activity at 24-96 h. The activity of gamma-GT did not change after oxidant treatment; however, it was decreased significantly by dexamethasone at 24-96 h. Thus oxidants and dexamethasone modulate GSH levels and activities of gamma-GT and gamma-GCS by different mechanisms. We suggest that the increase in gamma-GCS activity but not in gamma-GT activity may be required for the increase in intracellular GSH under oxidative stress in alveolar epithelial cells.
 ...
PMID:Differential regulation of glutathione by oxidants and dexamethasone in alveolar epithelial cells. 968 38

To test whether exogenous oxidants alter intracellular oxidant levels in skeletal muscle fibres, we exposed rat diaphragm to donors of nitric oxide (NOx), reactive oxygen species (ROS) or hyperoxia, and monitored intracellular oxidant levels using a fluorescent probe. Fibre bundles were dissected from the diaphragm and loaded with 2', 7'-dichlorodihydrofluorescein (DCFH); emissions were monitored using a fluorescence microscope. DCFH-loaded muscles were exposed to either a NOx donor (1 mM S-nitroso-N-acetyl penicillamine, SNAP; 1 mM sodium nitroprusside, SNP; 400 microM 1-hydroxy-2-oxo-3-(N-3-methyl-aminopropyl)-3-methyl-1-triazen, NOC-7), an ROS donor (100 microM hydrogen peroxide, H2O2; 100 microM tert-butyl hydroperoxide; 1 mM hypoxanthine plus 0.01 U mL-1 xanthine oxidase, HXXO) or a range of PO2s (25, 60 or 95% O2 oxygenating Krebs-Ringer solution) for 40 min; time-matched control bundles remained in Krebs-Ringer solution. Control muscles oxidized DCFH at a rate of 0.32 +/- 0.1 greyscale units min-1. SNAP (766%), SNP (1244%), NOC-7 (851%), H2O2 (543%), and HXXO (541%) increased DCFH oxidation from control levels. The increase in emissions caused by NOC-7 and SNP were blunted by the NOx scavenger haemoglobin (1 microM). DCFH oxidation by HXXO was unaffected by 1000 U mL-1 superoxide dismutase but was significantly decreased by 1000 U mL-1 catalase and 1 mM salicylate. PO2 had no effect on intracellular oxidant levels. Therefore, extracellular NOx and ROS can alter intracellular oxidant status in skeletal muscle fibres. These observations suggest that intrafibre oxidant levels could be the result of both intracellular and extracellular oxidant production.
 ...
PMID:Exogenous reactive oxygen and nitric oxide alter intracellular oxidant status of skeletal muscle fibres. 1038 90

Recent evidence indicates that hypoxia enhances the generation of oxidants. Little is known about the role of free radicals in contractility of the rat diaphragm during hypoxia. We hypothesized that antioxidants improve contractility of the hypoxic rat diaphragm and that xanthine oxidase (XO) is an important source of free radicals in the hypoxic diaphragm. The effects of N-acetylcysteine (NAC; 18 mM), Tiron (10 mM), and the XO inhibitor allopurinol (250 microM) were studied on isometric and isotonic force generation during hypoxia (PO(2) approximately 7 kPa). NAC and Tiron decreased maximal force generation, slowed the shortening velocity, and decreased the power output. Fatigue rate was decreased in the presence of either NAC or Tiron. Allopurinol did not alter the contractility or fatigability of the diaphragm. During hyperoxia (PO(2) approximately 85 kPa), neither NAC nor allopurinol affected the contractility or fatigability of the diaphragm. Thus free radicals play a significant role in diaphragm contractility during hypoxia. Whether antioxidants exert a beneficial or harmful effect on muscle performance depends on the contraction pattern of the muscle. Free radicals generated by XO do not play a role in diaphragm contractility during either hypoxia or hyperoxia.
 ...
PMID:Free radicals in hypoxic rat diaphragm contractility: no role for xanthine oxidase. 1170 36

In an investigation of the antitumor effects of 2-methoxyestradiol (2-ME) in combination with other reactive oxygen generating treatments, 2-ME (0.5 microM) was found to completely inhibit cell proliferation of rat DS-sarcoma cells in vitro, with 71% of cells dying after exposure to 5 microM 2-ME. Concentration-dependent increases in ROS-formation, lipid peroxidation and mitochondrial changes were also observed, and an elevation in caspase-3 activity resulted in DNA fragmentation and apoptosis. Combination of 2-ME with hypoxanthine and xanthine oxidase enhanced in vitro cytotoxicity. In vivo, 2-ME caused a slight inhibition of tumor growth, with no tumors cured. Combination of 2-ME treatment with localized 44 degrees C hyperthermia, respiratory hyperoxia and xanthine oxidase caused a tumor growth delay with 51% of tumors cured. These results suggest that amplifying the levels of reactive oxygen species within tumor tissue with substances such as 2-ME may prove to be a promising strategy for adjuvant treatment of solid tumors.
 ...
PMID:2-Methoxyestradiol enhances reactive oxygen species formation and increases the efficacy of oxygen radical generating tumor treatment. 1243 19

Many tumor treatment modalities such as ionizing radiation or some chemotherapy induce reactive oxygen species (ROS) resulting in therapeutic cell damage. The aim of this study was to analyze whether such ROS induction may affect the mechanical stability of solid tumor tissue by degradation of the extracellular matrix proteins or by a loss of cell adhesion molecules. Additionally, the protective impact of alpha-tocopherol treatment on these processes was studied. Experimental DS-sarcomas in rats were treated with a combination of localized 44 degrees C hyperthermia, inspiratory hyperoxia and xanthine oxidase in order to induce pronounced oxidative stress. A second group of animals were pretreated with alpha-tocopherol. The in vivo expression of E- and N-cadherin, alpha-catenin, integrins alphav, beta3 and beta5 as well as the expression of the integrin dimer alphavbeta3 were assessed by flow cytometry. The activity of the matrix metalloproteinases MMP-2 and -9 and the activity of the urokinase-type plasminogen activator (uPA) were determined by zymography. The expression of E-cadherin, the alphav-, beta3-integrin and the alphavbeta3-integrin dimer was significantly reduced by ROS induction, an effect which was at least partially reversible by alpha-tocopherol. N-cadherin, alpha-catenin and the beta5-integrin expression was not affected by ROS. In addition, MMP-2, MMP-9 and uPA activities were markedly reduced immediately after hyperthermia. Whereas 24 h later the effects on MMP-2 and -9 were no longer evident, for uPA the impact of oxidative stress became even more pronounced at this time. These results show that several processes responsible for the structural stability of the tumor tissue are affected by therapeutic ROS generation. Changes in some of the markers assessed suggested a decrease in tissue stability upon ROS induction, whereas others indicated changes which could lead to a more stable tumor cell cluster. Depending on the individual tumor entity ROS may therefore influence the mechanical stability of solid tumors and by this affect metastatic behavior.
 ...
PMID:Impact of therapeutically induced reactive oxygen species and radical scavenging by alpha-tocopherol on tumor cell adhesion. 1778 61

Many non-surgical tumor treatments induce reactive oxygen species (ROS) which result in cell damage. This study investigated the impact of ROS induction on the expression of adhesion molecules and whether alpha-tocopherol pre-treatment could have a protective effect. Experimental rat DS-sarcomas were treated with a combination of localized 44 degrees C-hyperthermia, inspiratory hyperoxia and xanthine oxidase which together lead to a pronounced ROS induction. Further animals were pre-treated with alpha-tocopherol. The in vivo expression of E- and N-cadherin, alpha-catenin, integrins alpha v, beta 3 and beta 5 as well as of the integrin dimer alpha v beta 3 was assessed by flow cytometry. The expression of alpha v-, beta 3-integrin, of the alpha v beta 3-integrin dimer and of E-cadherin was significantly reduced by the ROS-inducing treatment. This effect was partially reversible by alpha-tocopherol, indicating that ROS play a role in this process. N-cadherin, alpha-catenin and beta 5-integrin expression were unaffected by ROS. These results indicate that the expression of several adhesion molecules is markedly reduced by ROS and may result in a decrease in the structural stability of tumor tissue. Further studies are needed to clarify the impact of ROS induction on the metastatic behavior of tumors.
 ...
PMID:Impact of reactive oxygen species on the expression of adhesion molecules in vivo. 1922 56

Most mammalian tissue cells experience oxygen partial pressures in vivo equivalent to 1-6% O2 (i.e., physioxia). In standard cell culture, however, headspace O2 levels are usually not actively regulated and under these conditions are ~18%. This drives hyperoxia in cell culture media that can affect a wide variety of cellular activities and may compromise the ability of in vitro models to reproduce in vivo biology. Here, we review and discuss some specific O2-consuming organelles and enzymes, including mitochondria, NADPH oxidases, the transplasma membrane redox system, nitric oxide synthases, xanthine oxidase, and monoamine oxidase with respect to their sensitivities to O2 levels. Many of these produce reactive oxygen and/or nitrogen species (ROS/RNS) as either primary end products or byproducts and are acutely sensitive to O2 levels in the range from 1% to 18%. Interestingly, many of them are also transcriptional targets of hypoxia-inducible factors (HIFs) and chronic cell growth at physioxia versus 18% O2 may alter their expression. Aquaporins, which facilitate hydrogen peroxide diffusion into and out of cells, are also regulated by HIFs, indicating that O2 levels may affect intercellular communication via hydrogen peroxide. The O2 sensitivities of these important activities emphasize the importance of maintaining physioxia in culture.
 ...
PMID:How Supraphysiological Oxygen Levels in Standard Cell Culture Affect Oxygen-Consuming Reactions. 3036 17


<< Previous 1 2 3