Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Superoxide dismutase is well known to act as an effective antioxidant enzyme against cellular damage caused by oxidative stresses including ischemia/reperfusion-induced cerebral injury. However, it is still controversial whether or not the activity of endogenous superoxide dismutase changes during cerebral ischemia and reperfusion. In order to elucidate this phenomenon, we assayed the superoxide dismutase activity in the cerebral tissues of gerbils using the chemiluminescence method with a Cypridina luciferin analog. This method was demonstrated to be a sensitive and specific assay for the enzymatic activity of superoxide dismutase in cerebral tissues, which was not subject to interference from proteins or ascorbate. After 3 h of focal and global ischemia, there were no changes in the cerebral tissue superoxide dismutase activities. After 24 h of reperfusion following 1 h of ischemia, the superoxide dismutase activity decreased only approx 20%, whereas the adenylate kinase activities, measured in the same cerebral tissues as those used for superoxide dismutase assay, started to decline 1 h after reperfusion commenced and were approx 50% of the control levels after 24 h. These results show that almost all the activity of endogenous superoxide dismutase is maintained and does not decrease significantly as a result of ischemia/reperfusion-induced cerebral injury.
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PMID:The superoxide dismutase activities of cerebral tissues, assayed by the chemiluminescence method, in the gerbil focal ischemia/reperfusion and global ischemia models. 836 36

Complete, reversible forebrain ischemia was induced with a seven-vessel occlusion rat model. Previous studies of ischemic (M. A. Sciamanna, J. Zinkel, A. Y. Fabi, and C. P. Lee, 1992, Biochim. Biophys. Acta 1134, 223-232) rat brain mitochondria (RBM) showed that ischemia of 30 min caused an approximately 60% decrease in State 3 respiratory rates with both succinate and NAD-linked substrates and also in energy-linked Ca2+ transport. No significant change was seen in the State 4 rates. The inhibition of respiration could be prevented by EGTA or ruthenium red. In this paper it is shown that reperfusion (5 h) following ischemia (30 min) further impaired RBM respiratory activities (succinate and NAD-linked substrates). The presence of EGTA or ruthenium red in the assay medium did not protect against ischemia/reperfusion-induced injury. The effects of ascorbate, an oxygen radical scavenger, were studied. RBM isolated from ascorbate-treated animals (0.8 mg ascorbate/kg body weight) after ischemia (30 min) alone showed only a slight increase in State 3 (approximately 25%) and a decrease in State 4 (approximately 20%) activities with succinate, when compared to untreated 30-min ischemic animals, whereas, with glutamate+malate little or no effect was seen. The respiratory activities of RBM from ascorbate-treated, ischemic/reperfused (30 min/5 h) rats were restored to approximately 65% of controls levels. Ascorbate protection was dose-dependent with maximum protection at 0.8 mg ascorbate/kg body weight of rat. The k of succinate oxidase-supported Ca2+ uptake also returned to 62% of control values. Protection by ascorbate was most effective when administered prior to the onset of ischemia and provided partial protection when administered after the onset of reperfusion. These results suggest that ischemia-induced injury is primarily mediated by disruption of cellular Ca2+ homeostasis, and reperfusion-induced injury by peroxidative events.
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PMID:Ischemia/reperfusion-induced injury of forebrain mitochondria and protection by ascorbate. 837 58

Leukocyte adhesion may play a central role in the pathogenesis of preservation-reperfusion injury to liver grafts. We previously showed that lymphocyte adhesion to sinusoids is dependent on the length of cold ischemia. In the present study we examined the mechanisms of lymphocyte adherence after harvesting combined with a short and a long preservation time. The effects of lymphocyte adherence on liver function were also examined. Rat livers were stored at 1 degrees C in University of Wisconsin solution for 45 min or 30 hr and then reperfused at 37 degrees C in the isolated perfused rat liver with isogeneic lymphocytes in an asanguineous perfusate. The role of reactive oxygen intermediates was investigated with allopurinol, a vitamin E analog and ascorbate or superoxide dismutase and catalase. For us to determine the role of Kupffer cells, Kupffer cell blockade was produced by gadolinium chloride. Leukotriene B4 effects were examined with the lipooxygenase inhibitor, nordihydroguaiaretic acid. We evaluated the possible presence of mechanical obstruction by studying flow rates and the circulation of red blood cells. We examined the role of adhesion molecules by pretreating lymphocytes with trypsin or neuraminidase and by exposing livers to arabinogalactan. We investigated the effects of lymphocyte adhesion on liver function by comparing perfusate liver enzymes in livers reperfused with and without lymphocytes, with trypsinized lymphocytes and with an increased number of lymphocytes. Allopurinol significantly reduced hypoxanthine degradation, and nordihydroguaiaretic acid inhibited leukotriene B4 release into the perfusate. The ability of gadolinium chloride to inhibit Kupffer cells was shown by colloid carbon uptake. In livers harvested and preserved for 45 min, lymphocytes decreased about 40% during reperfusion. In livers preserved for 30 hr, the reduction was significantly greater (about 80%). Lymphocyte adherence was lessened in livers preserved for 45 min by all three of the reactive oxygen intermediate protectants and by gadolinium chloride. In contrast, neither reactive oxygen intermediate protectants nor gadolinium chloride reduced adherence in livers preserved for 30 hr. Nordihydroguaiaretic acid had no effect in livers preserved for either 45 min or 30 hr. Portal flow in livers preserved for 45 min and 30 hr was similar, suggesting an absence of mechanical obstruction, and this finding was supported by a complete absence of red cell trapping. Trypsinization of lymphocytes and exposure of livers to arabinogalactan significantly lessened lymphocyte adherence in livers preserved for 30 hr but not in those preserved for 45 min.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lymphocyte adherence in the reperfused rat liver: mechanisms and effects. 838 Jul 89

Direct evidence for substantial mobilization of copper in the coronary flow immediately following prolonged, but not short, cardiac ischemia is presented. In the first coronary flow fraction (CFF) of reperfusion (0.15 ml), after 35 min of ischemia, the level of copper (as well as of iron) was 8- to 9-fold higher than the preischemic value. The levels in subsequent CFFs decreased and reached the preischemic value, indicating that both metals appear in a burst at the resumption of coronary flow. When the first CFF was used in a reaction mixture containing ascorbate and salicylate, the latter underwent chemical hydroxylation and was converted to its dihydroxybenzoate derivatives. Likewise, this CFF promoted the ascorbate-driven DNA degradation. Subsequent 150 CFFs were serially collected and demonstrated low activities. Following 18 min of ischemia, the copper level in the first CFF of reperfusion was only 15% over the preischemic value. In contrast, the mobilization of iron into coronary flow was significant but markedly lower than after 35 min. The levels of copper and the redox activity of the first CFF correlated well with the degree of loss of cardiac function, after 18 and 35 min of ischemia, respectively. After 18 min of ischemia, cardiac function was about 50% and the damage is considered reversible, whereas after 35 min the functional loss exceeded 80% and is considered irreversible. These results are in accord with the causative role that copper and iron can play in heart injury following ischemia, by virtue of their capacity to catalyze the production of hydroxyl radicals, and could lead to the development of new modalities for intervention in tissue injury.
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PMID:Copper and iron are mobilized following myocardial ischemia: possible predictive criteria for tissue injury. 843 81

Iron is believed to contribute to the process of cell damage and death resulting from ischemic and traumatic insults by catalyzing the oxidation of protein and lipids. Exposure of cultured rat hippocampal neurons to iron (FeSO4) caused a dose-dependent reduction in neuronal survival, which was potentiated by ascorbate. Damage to neurons was associated with a significant level of oxygen radical in the culture medium. The iron chelator desferal prevented both the neuronal degeneration caused by FeSO4 and the production of oxygen radical, demonstrating that ionic iron was responsible for the cell damage. Iron neurotoxicity was associated with an elevation of [Ca2+]i and was attenuated by NMDA receptor antagonists. Since recent findings demonstrated neuroprotective effects of growth factors in cell culture and in vivo models of ischemia, we examined the effects of growth factors on iron-induced damage. Basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and insulin-like growth factors (IGF-I and IGF-II) each protected neurons against iron-induced damage. Both rat hippocampal and human cortical neurons were protected by these growth factors. Taken together, the data suggest that the neuroprotective effects of growth factors against excitotoxic/ischemic insults may result, in part, from a prevention or attenuation of oxidative damage.
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PMID:Basic FGF, NGF, and IGFs protect hippocampal and cortical neurons against iron-induced degeneration. 847 96

A newly introduced compound, EPC-K1, represents a phosphate diester linkage of vitamin E and vitamin C. The effect of EPC-K1 on the reperfusion injury was evaluated in a heterotopic cardiac transplantation model using syngenic combination rats. Prior to the warm ischemia, 12mg EPC-K1/kg was administered intravenously to donor rats. After 15 min of warm ischemic time, hearts were harvested and perfused with 4 degrees C saline. After completion of the transplantation, recipient rats were also treated with intravenous 12 mg EPC-K1/kg, before reperfusion. Saline was used instead of EPC-K1 for both donors and recipients in the control group. On the 7th post-transplantation day, graft survival was 7 out of 8 in EPC-K1 group, versus 1 out of 9 in the control group (p < 0.001). Thiobarbituric acid-reactive substance levels in the recipient serum, three hours after reperfusion, were significantly limited, in the group in which EPC-K1 was administered only to donors. But it was not possible to clarify whether the effect of EPC-K1 is primarily at the donor or recipient levels at this time. These results indicate that EPC-K1 may reduce reperfusion injury after cardiac transplantation. This beneficial effect may be mediated by the hydroxyl radical scavenging properties of EPC-K1.
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PMID:Beneficial effect of EPC-K1 on the survival of warm ischemic damaged graft in rat cardiac transplantation. 850 49

The aim of this study was to elucidate the mechanisms by which retinal cells release endogenous amino acids in response to ascorbate/Fe(2+)-induced oxidative stress, as compared with chemical hypoxia or ischemia. In the absence of stimulation, oxidative stress increased the release of aspartate, glutamate, taurine, and GABA only when Ca2+ was present. Under hypoxia or ischemia, the release of aspartate, glutamate, glycine, alanine, taurine, and GABA increased mainly by a Ca(2+)-independent mechanism. The increased release observed in N-methyl-D-glucamine+ medium suggested the reversal of the Na+-dependent amino acid transporters. Upon oxidative stress, the release of aspartate, glutamate, and GABA, occurring through the reversal of the Na(+)-dependent transporters, was reduced by about 30%, although the release of taurine was enhanced. An increased release of [3H]arachidonic acid and free radicals seems to affect the Na+-dependent transporters for glutamate and GABA in oxidized cells. All cell treatments increased [Ca2+]i (1.5 to twofold), although no differences were observed in membrane depolarization. The energy charge of cells submitted to hypoxia or oxidative stress was not changed. However, ischemia highly potentiated the reduction of the energy charge, as compared with hypoglycemia or hypoxia alone. The present work is important for understanding the mechanisms of amino acid release that occur in vivo upon oxidative stress, hypoxia, or ischemia, frequently associated with the impairment of energy metabolism.
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PMID:Oxidative stress, hypoxia, and ischemia-like conditions increase the release of endogenous amino acids by distinct mechanisms in cultured retinal cells. 863 76

The effect of acute endotoxin-induced septic shock on myocardium oxidative stress after low or high vitamin C and/or E dietary supplementation was studied in guinea pigs, laboratory animals which, like human, do not have capacity for ascorbate synthesis. Neither the antioxidant enzymes or GSH were modified by endotoxin and vitamin treatments. Vitamin E showed a strong capacity to protect the myocardium against both enzymatic and non-enzymatic lipid peroxidation even in the presence of endotoxin. Vitamin C supplementation increased heart ascorbate whereas endotoxic shock totally depleted the heart ascorbate of vitamin C supplemented animals without changing vitamin E. Endotoxin significantly increased myocardium uric acid, a marker of ischemia induced oxidative stress, in animals fed with low vitamin C levels. This increase was totally prevented in vitamin C supplemented, but not in vitamin E supplemented animals. Strongly depressed levels of plasma vitamin C have been recently described in sepsis in human patients. The results suggest that ascorbate is a primary antioxidant target in the heart of endotoxin treated mammals lacking the capacity to synthesize ascorbate and that ascorbate can have a protective value against endotoxin-induced free radical damage in the myocardium. Implications of these results for the possible preventive role of vitamin C in humans during sepsis are discussed.
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PMID:Endotoxin depletes ascorbate in the guinea pig heart. Protective effects of vitamins C and E against oxidative stress. 876 Oct 15

Under aerobic conditions the addition of (C2N5)2N(N[O]NO)-.Na+(DEA/NO), S-nitroso-N-acetyl penicillamine and nitric oxide (NO)-saturated buffer, but not S-nitroso-L-glutathione, to dopamine solutions resulted in dopamine o-semiquinone formation that was dependent on the formation of a NO/oxygen intermediate. High pressure liquid chromatography (HPLC) electrochemical analysis of dopamine demonstrated that the DEA/NO-induced oxidation of dopamine was abrogated in the presence of the antioxidants, ascorbate and glutathione. NO spontaneously released from DEA/NO decreased [3H]dopamine accumulation in primary cultures of mesencephalic neurons in a dose-dependent fashion. In contrast, [3H] gamma-aminobutyric acid uptake by mesencephalic neurons tested under the same conditions was unchanged. When DEA/NO was added to incubation buffer that contained [3H]dopamine and the antioxidant, ascorbate or glutathione, [3H]dopamine uptake was also inhibited. These data excluded that oxidation of extracellular [3H]dopamine by the intermediates of the NO/O2 reaction could have caused this decrease. Instead, NO may have acted directly on a not yet identified target operative in the regulation of dopamine storage and release. Analysis of the rate constants for the NO reaction with ascorbate, glutathione and dopamine revealed that dopamine quinone formation was delayed by the presence of antioxidants. Since the formation of NO as well as neurotransmitter release are activated during ischemia reperfusion injury, it is possible that prolonged NO exposure could deplete antioxidants and facilitate the oxidation of dopamine and thereby cause neurotoxicity.
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PMID:Role of antioxidants in the nitric oxide-elicited inhibition of dopamine uptake in cultured mesencephalic neurons. Insights into potential mechanisms of nitric oxide-mediated neurotoxicity. 879 43

Free radicals are thought to be involved in the onset of neuronal disturbances such as Alzheimer's disease, Parkinson's disease, and neuronal ceroid lipofuscinosis. It is also assumed that they play a role in cerebral injury caused by ischemia or trauma. Plasma and cerebrospinal fluid (CSF), Total (peroxyl) Radical-trapping Antioxidant Parameter (TRAP), and the known antioxidant components of TRAP, for instance, ascorbic acid, uric acid, protein sulfhydryl groups, tocopherol, and ubiquinol were analyzed and the remaining unidentified fragment was calculated in five healthy volunteers before and after 4 weeks of ascorbate and ubiquinone (Q-10) supplementation. In CSF, TRAP was significantly lower than in plasma. The major contributor to plasma's antioxidant capacity was uric acid (UA), whereas in CSF it was ascorbic acid (AA). In CSF, AA concentrations were four times higher than in plasma. Oral supplementation of AA (500 mg/d first 2 weeks, 1,000 mg/d following 2 weeks) and Q-10 (100 mg/d first 2 weeks, 300 mg/d following 2 weeks) induced a significant increase in plasma AA and Q-10. Surprisingly, in spite of the high lipophilicity of Q-10, its concentration did not change in CSF. The supplementation of AA increased its concentration in CSF by 28% (p < .05). However, the increase in AA did not result in an increase in CSF TRAP. This indicates that AA had lost one-third of its radical trapping capacity as compared to that in plasma. The facts that AA is the highest contributor to CSF TRAP and its effect on TRAP is concentration dependent could indicate that the peroxyl radical-trapping capacity of CSF is buffered by AA.
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PMID:The effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity. 881 36


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