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)

Reactive oxygen species (ROS) and caspases have been implicated as potential mediators of cell death. However, their mechanistic relationship remains to be elucidated. Here we investigated the roles of caspases in apoptosis and necrosis induced by ROS, generated by the mixture of xanthine and xanthine oxidase (X/XO). A low concentration of XO (0.025 U/ml) induced DNA fragmentation with little cellular membrane damage 3 h after treatment, suggesting the induction of apoptosis. The same treatment induced membrane blebbing, a morphological change typical of apoptosis, 15 min after treatment. A high concentration of XO (0.1 U/ml) damaged cell membranes with little concomitance of DNA fragmention, suggesting the induction of necrosis. ROS also activated caspase 3-like proteases and caspase 3 itself together with the release of cytochrome c which might be the cause of caspase activation. Apoptosis induced by low concentrations of XO and necrosis induced by high concentrations of XO was inhibited by z-DEVD-CH2F, an irreversible inhibitor of caspase 3. However, rapid induction of membrane blebbing was not inhibited by z-DEVD-CH2F. These results suggest that both apoptosis and necrosis could be induced by ROS through the activation of caspase 3-like protease; however, caspase 3 activation is not needed for ROS-induced membrane blebbing.
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PMID:Regulation of reactive oxygen species-induced apoptosis and necrosis by caspase 3-like proteases. 984 Sep 39

Cigarette smoking is a major risk factor for gastric cancer and peptic ulcer. The aim of our study was to investigate the relationship between exposure to cigarette smoke and apoptosis in the rat gastric mucosa and the mechanism involved. Rats were exposed to different concentrations of cigarette smoke (0, 2, and 4%) once daily for a different number of 1 h periods (1, 3, 6, and 9 d). Apoptosis was identified by the terminal deoxy-transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) method and caspase-3 activity. The mucosal xanthine oxidase (XO) activity and p53 level were also measured. The results showed that exposure to cigarette smoke produced a time- and concentration-dependent increase in apoptosis in the rat gastric mucosa that was accompanied by an increase in XO activity. The increased apoptosis and XO activity could be detected after even a single exposure. In contrast, the level of p53 was elevated only in the later stage of cigarette smoke exposure. The apoptotic effect could be blocked by pretreatment with an XO inhibitor (allopurinol, 20 mg/kg intraperitoneally) or a hydroxyl free radical scavenger (DMSO, 0.2%, 1 ml/kg intravenously). However, neither of these treatments had any effect on the p53 level of the mucosa. In summary, we conclude that exposure to cigarette smoke can increase apoptosis in the rat gastric mucosa through a reactive oxygen species- (ROS) mediated and a p53-independent pathway.
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PMID:Exposure to cigarette smoke increases apoptosis in the rat gastric mucosa through a reactive oxygen species-mediated and p53-independent pathway. 1083 74

Although clinical studies have demonstrated that EGb 761, a standard extract of Ginkgo biloba, was effective in mild-to-moderate dementia of the Alzheimer's disease patients, the mechanism underlying its neuroprotective effect remains unclear. In this study, effects of bilobalide, the main constituent of the nonflavone fraction of EGb 761, on reactive oxygen species (ROS)-induced apoptosis in PC12 cells was studied. Exposure of cells to xanthine (100 microM)/xanthine oxidase (150 mU/ml) (ROS producer) resulted in a characteristic DNA fragmentation and an increase in the apoptosis rate. When p53, c-Myc, Bcl-2, Bcl-x(L), and Bax were measured by flow cytometry and the activities of caspase-1- and caspase-3-like protease determined with Ac-YVAD-AMC or Ac-DEVD-AMC as substrates, the profile of ROS-induced changes in these apoptosis regulatory and effector proteins suggests that elevation of c-Myc, p53, and Bax and activation of caspase-3 play an important role in the apoptosis. When cells were treated with ROS and bilobalide (25-100 microM) simultaneously, a dose-dependent reduction in the apoptotic rate was found. The percentage of cells with positive staining for c-Myc and p53 decreased from 27.8 and 50.1% to 16.7 and 23.2%, respectively, when bilobalide (25 microM) was present. Bilobalide also reduced ROS-induced elevation of Bax and activation of caspase-3 effectively. Our results provide the first direct evidence that bilobalide can protect neurons against oxidative stress. Bilobalide may block the apoptosis in the early stage and then attenuate the elevation of c-Myc, p53, and Bax and activation of caspase-3 in cells.
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PMID:Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide. 1086 1

There is growing evidence which suggests that dysregulation of apoptosis may lead to several disease states including cancer. To investigate the mechanism controlling the induction of cell death, apoptosis defective/resistant (Apt-) mutants were isolated and characterized in this study. FDC-P1, a mouse myeloid cell line that depends upon IL-3 for survival and growth but undergoes apoptosis when deprived of growth factor, was mutagenized by treatment with ethyl methane sulfonate. We selected cells that survived the growth factor deprivation but did not grow without the factor. Surviving cells were cloned by limiting dilution and four clones that showed the least morphological characteristics and biochemical changes of apoptosis were chosen. Unlike the parent FDC-P1, these mutants were cross resistant to apoptosis induced by a variety of antitumor drugs such as Adriamycin, Dexamethasone, VP-16, as well as reactive oxygen species (ROS) generated by xanthine/xanthine oxidase (X/XO). We used one of these Apt- mutant to test candidate death genes. Our findings suggest that the preferential increase in Bax/Bcl-2 ratio, p53, c-Myc, Caspase-3 and decrease in AP-1 on treatment with various anticancer drugs may contribute to the preferential apoptotic response in FDC-P1 cells but to varying degrees. Whereas, the higher constitutive level of antioxidant enzymes superoxide dismutase and catalase in the Apt- mutant may contribute at least in part to its resistance.
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PMID:Differential sensitivity of murine myeloid FDC-P1 cells and apoptosis resistant mutant(s) to anticancer drugs. 1123 67

When cultured cerebellar granule neurons (CGN) are transferred from 25 mM KCl (K25) to 5 mM KCl (K5) caspase-3 and caspase-8, but not caspase-1 or caspase-9,activities are induced and cells die apoptotically. CGN death was triggered by a [Ca(2+)](i) modification when [Ca(2+)](i) was reduced from 300 nM to 50 nM in a K5 medium. The [Ca(2+)](i) changes were followed by an increase in ROS levels. The generation of both cytosolic and mitochondrial reactive oxygen species (ROS) occurred at three different times, 10 min, 30 min and 3--4 hr but only those ROS produced after 3--4 hr are involved in the process of cell death. When CGN cultured in a K5 medium are treated with different antioxidants like scavengers of ROS (mannitol, DMSO) or antioxidant enzymes (superoxide dismutase and catalase) phosphatidylserine translocation, caspase activity, chromatin condensation and cell death is markedly diminished. The protective effect of antioxidants is not mediated through a modification in [Ca(2+)](i). Caspase activation, PS translocation and chromatin condensation were downstream of ROS production. In contrast to H(2)O(2), ROS produced by a xanthine/xanthine oxidase system in CGN cultured in K25 were able to directly induce caspase-3 activation and death that resulted sensitive to z-VAD, a caspase inhibitor. These findings indicate that a reduction in [Ca(2+)](i) triggers CGN death by inducing a generation of ROS after 3--4 hr, which could play a critical role in the initial phases of the apoptotic process including PS translocation, chromatin condensation and the activation of initiator and executor caspases.
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PMID:Role of oxidative stress in the apoptotic cell death of cultured cerebellar granule neurons. 1131 73

Gallic acid (GA) derivatives, 3,4-methylenedioxyphenyl 3,4,5-trihydroxybenzoate (GD-1) and S-(3,4-methylenedioxyphenyl)3,4,5-trihydroxythiobenzoate (GD-3), were previously reported to induce apoptosis in tumor cells with IC50s of 14.5 microm and 3.9 microm, respectively. To elucidate the mechanism by which these gallic acid derivatives (GDs) induce apoptosis, we studied whether GD-1 and GD-3 can activate caspases. When promyelocytic leukemia HL-60RG cells were treated with GD-1 and GD-3, poly(ADP-ribose)polymerase (PARP), a substrate of caspase-3, was cleaved into 85 kDa of degradative product with increasing incubation time. GA also activated PARP cleavage, which was inhibited by catalase, N-acetyl-L-cysteine (NAC), and intracellular Ca2+ chelator 1,2-bis(2-aminophenoxyethane)-N,N,N,N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), in addition to a caspase inhibitor, Z-VAD-FMK. Its inhibitory pattern was identical with that of hypoxanthine/xanthine oxidase. On the other hand, GD-1- and GD3-induced PARP cleavage was not suppressed by catalase or NAC, but by BAPTA-AM. This suggested that the GD-elicited signaling pathway is different from GA's. Taken together, GDs activated caspase-3 following intracellular Ca2+ elevation independent of reactive oxygen species. Thus, it became evident that the signaling pathway leading to apoptosis was regulated by GDs in a different manner from GA.
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PMID:Ca2+-Dependent caspase activation by gallic acid derivatives. 1145 29

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.
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PMID:2-Methoxyestradiol enhances reactive oxygen species formation and increases the efficacy of oxygen radical generating tumor treatment. 1243 19

Exposure of cerebellar granule cells (CGCs) to 1-methyl-4-phenylpyridinium (MPP+) results in apoptotic cell death, which is markedly attenuated by co-treatment of CGCs with the radical scavenger vitamin E. Analysis of free radical production and mitochondrial transmembrane potential (DeltaPsim), using specific fluorescent probes, showed that MPP+ mediates early radical oxygen species (ROS) production without a loss of DeltaPsim. Exposure to MPP+ also produces an early increase in Bad dephosphorylation and translocation of Bax to the mitochondria. These events are accompanied by cytochrome c release from mitochondria to cytosol, which is followed by caspase 3 activation. Exposure of the neurons to vitamin E maintains Bad phosphorylation and attenuates Bax translocation, inhibiting cytochrome c release and caspase activation. MPP+-mediated cytochrome c release is also prevented by allopurinol, suggesting the participation of xanthine oxidase in the process. Our results indicate that free radicals play an active role in the MPP+-induced early events that culminate with cell death.
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PMID:Vitamin E blocks early events induced by 1-methyl-4-phenylpyridinium (MPP+) in cerebellar granule cells. 1255 93

Pentagalloylglucose (5GG) is a potent and specific inhibitor of NADPH dehydrogenase or xanthine oxidase. In our previous study, we showed that 5GG was able to induce apoptosis in HL-60 cells in a time- and concentration-dependent manner via the activation of caspase-3. Recently, we found that 5GG was capable of perturbing the cell cycle of the human breast cancer cell line MCF-7. DNA flow cytometric analysis showed that 5GG exhibited the ability of blocking MCF-7 cell cycle progression at the G1 phase. The level of several G1 phase-related cyclins and cyclin-dependent kinases did not change in these cells during a 24-hr exposure to 5GG. However, the activity of cyclin E/CDK2 was decreased in a concentration- and time-dependent manner and the activity of cyclin D/CDK4 was inhibited when serum-starved synchronized cells were released from synchronization. p27(Kip) and p21(Cip), inhibitors of cyclin/CDK complexes in G1-phase, were gradually increased after 5GG treatment in a time-dependent manner and the induction of p21(Cip) was correlated with an increase in p53 levels. These results suggest that the suppression of cell-cycle progression in the G1 phase by 5GG was mediated in MCF-7 cells, at least in part, by either the inhibition of cyclin D/CDK4 and cyclin E/CDK2 activity or the induction of the CDK inhibitors p27(Kip) and p21(Cip).
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PMID:Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip). 1278 29

The hypothesis was tested that treatment with allopurinol, a xanthine oxidase inhibitor, or deferoxamine, a chelator of nonprotein-bound iron, preserved cerebral energy metabolism, attenuated development of edema, and improved histologic outcome in the newborn piglet at 24 h after hypoxia-ischemia. Thirty-two newborn piglets were subjected to 1 h of hypoxia-ischemia by occluding both carotid arteries and reducing the fraction of inspired oxygen; five newborn piglets served as sham-operated controls. The depth of hypoxia-ischemia was controlled by phosphorous magnetic resonance spectroscopy. Upon reperfusion and reoxygenation, piglets received vehicle (n= 12), allopurinol (30 mg/kg/d, n = 10), or deferoxamine (12.5 mg/kg/d, n = 10). The cerebral energy status was determined with phosphorous magnetic resonance spectroscopy. The presence of vasogenic edema was assessed by T2-weighted magnetic resonance imaging. Brain cell injury was assessed with caspase-3 activity, histology, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end (TUNEL)-labeling. At 24 h after hypoxia-ischemia, the phosphocreatine/inorganic phosphate ratios were significantly decreased in vehicle-treated, but not in allopurinol- or deferoxamine-treated piglets. Water T2 values were significantly increased at 24 h after hypoxia-ischemia in cerebral cortex, thalamus, and striatum of vehicle-treated piglets, but not in allopurinol- and deferoxamine-treated piglets. No differences in caspase-3 activity, histologic outcome, or TUNEL-labeling were demonstrated between the three treatment groups. We suggest that allopurinol and deferoxamine may have an additional value in the treatment of perinatal hypoxia-ischemia with other neuroprotective agents or in combination with hypothermia.
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PMID:Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia. 1281 12


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