Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stroke is the third leading cause of death in the US, with a prevalence of 750,000 patients per year, and a social cost estimated at $50 billion. Current therapeutics are targeted at restoring blood flow rather than on preventing the actual mechanisms associated with neuronal cell death. Here, we show that, following transient (2 h) middle cerebral artery occlusion (tMCAO) in male, Wistar rats, neuronal damage determined using MAP-2 staining increased progressively after the tMCAO. Notably, such neuronal degeneration was first associated with a decrease in p-Akt in both the focus and penumbra of the infarct region and, later with an increase in cytosolic cytochrome C levels in cortical neurons in the infarct area. These findings implicate that Akt alterations and consequent release of cytochrome C are involved in neuronal death. To further address this issue, NXY-059 (disodium 4-[(tert.-butylimino)methyl]benzene-1,3-disulfonate N-oxide) administered i.v. (30 mg/kg bolus, followed by 30 mg/kg/h infusion for up to 24 h), commencing 1 h after reperfusion, not only prevented the increase in infarct area but also attenuated the postreperfusion increase in neuronal cytosolic cytochrome C and the postperfusion decrease in neuronal p-Akt. Thus, NXY-059, by preventing mitochondrial cytochrome C release by maintaining activation of the Akt pathway, appears to protect neurons from damage after ischemia.
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PMID:NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia. 1217 60

Cerebral ischemia initiates a program of cell death known as apoptosis. Early steps in these death promoting events are the release of cytochrome c from the mitochondria and activation of caspase-9. The purpose of this report is to determine if the administration of a specific caspase-9 inhibitor, Z-Leu-Glu(Ome)-His-Asp(Ome)-FMK x TFA (Z-LEHD-FMK) would attenuate apoptosis and the resultant brain injury after ischemia. Adult Wistar rats underwent 3 h of temporary middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. An intraventricular injection of 4.8 microg of Z-LEHD-FMK was given 15-min postreperfusion. Administration of the caspase-9 inhibitor, Z-LEHD-FMK, to the experimental group (n = 12) reduced total infarction volume by 49% (p < 0.05) and improved neurological outcome by 63% (p < 0.01) as compared to the control group (n = 12). Western blot analysis of animals that underwent ischemia-reperfusion showed the appearance of the active form of caspase-9. Inhibition of caspase-9, the apical caspase in cytochrome-c-dependent apoptosis, is an effective intervention to attenuate neurological injury after focal ischemia.
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PMID:Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia. 1232 85

Liver damage ranges from acute hepatitis to hepatocellular carcinoma, through apoptosis, necrosis, inflammation, immune response, fibrosis, ischemia, altered gene expression and regeneration, all processes that involve hepatocyte, Kupffer, stellate, and endothelial cells. Reactive oxygen and nitrogen species (ROS, RNS) play a crucial role in the induction and in the progression of liver disease, independently from its etiology. They are involved in the transcription and activation of a large series of cytokines and growth factors that, in turn, can contribute to further production of ROS and RNS. The main sources of free radicals are represented by hepatocyte mitochondria and cytochrome p450 enzymes, by endotoxin-activated macrophages (Kupffer cells), and by neutrophils. The consequent alteration of cellular redox state is potentiated by the correlated decrease of antioxidant and energetic reserves. Indices of free radical-mediated damage, such as the increase of malondialdehyde, 4-hydroxynonenal, protein-adducts, peroxynitrite, nitrotyrosine, etc., and/or decrease of glutathione, vitamin E, vitamin C, selenium, etc., have been documented in patients with viral or alcoholic liver disease. These markers may contribute to the monitoring the degree of liver damage, the response to antiviral therapies and to the design of new therapeutic strategies. In fact, increasing attention is now paid to a possible "redox gene therapy." By enhancing the antioxidant ability of hepatocytes, through transgene vectors, one could counteract oxidative/nitrosative stress and, in this way, contribute to blocking the progression of liver disease.
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PMID:Oxidative stress in viral and alcoholic hepatitis. 1249 74

We have developed a perfusion bioreactor system that allows the formation of steady state oxygen gradients in cell culture. In this study, gradients were formed in cultures of rat hepatocytes to study the role of oxygen in modulating cellular functions. A model of oxygen transport in our flat-plate reactor was developed to estimate oxygen distribution at the cell surface. Experimental measurements of outlet oxygen concentration from various flow conditions were used to validate model predictions. We showed that cell viability was maintained over a 24-h period when operating with a physiologic oxygen gradient at the cell surface from 76 to 5 mmHg O(2) at the outlet. Oxygen gradients have been implicated in the maintenance of regional compartmentalized metabolic and detoxification functions in the liver, termed zonation. In this system, physiologic oxygen gradients in reactor cultures contributed to a heterogeneous distribution of phosphoenolpyruvate carboxykinase (predominantly localized upstream) and cytochrome p450 2B (predominantly localized downstream) that correlates with the distribution of these enzymes in vivo. The oxygen gradient chamber provides a means of probing the oxygen effects in vitro over a continuous range of O(2) tensions. In addition, this system serves as an in vitro model of zonation that could be further extended to study the role of gradients in ischemia-reperfusion injury, toxicity, and bioartificial liver design.
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PMID:Formation of steady-state oxygen gradients in vitro: application to liver zonation. 1259 51

Intracellular recordings were made from hippocampal CA1 neurons in rat slice preparations. Superfusion with oxygen- and glucose-deprived medium (in vitro ischemia) produced a rapid depolarization approximately 5 min after the onset of the superfusion. Even when oxygen and glucose were reintroduced immediately after rapid depolarization, the membrane depolarized further (persistent depolarization) and reached 0 mV (irreversible depolarization) after 5 min from the reintroduction. The pretreatment of the slice preparation with a phospholipase A2 (PLA2) inhibitor, para-bromophenacyl bromide, or a cytochrome p-450 inhibitor, 17-octadecynoic acid, significantly restored the membrane to the preexposure potential level after the reintroduction of oxygen and glucose. The administration of 14,15-epoxyeicosatrienoic acid or 20-hydroxyeicosatetraenoic acid did not change the latency of the rapid depolarization and did not allow the membrane potential to recover after the ischemic exposure. In contrast, after pretreatment with cyclooxygenase or lipoxygenase inhibitors, such as indomethacin, resveratrol, Dup-697, nordihydroguaiaretic acid, and 3,4-dihydrophenyl ethanol, a minority of neurons tested showed postischemic recovery from the persistent depolarization. Improved recovery was also seen after treatment with the free radical scavengers, edaravone and alpha-tocopherol. These results suggest that the activation of the arachidonic acid cascade via PLA2 and the free radicals produced by arachidonic acid metabolism contribute to the irreversible depolarization produced by in vitro ischemia.
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PMID:Arachidonic acid metabolites contribute to the irreversible depolarization induced by in vitro ischemia. 1291 87

This in vitro study was designed to examine the efficacy of exogenous pyruvate and glucose as a fuel substrate to protect rat astrocytes from post-ischemic injury. Astrocytes were incubated in Kreb's buffer deprived of oxygen and glucose for 6 h (ischemia) followed by incubation with added pyruvate or glucose and normoxia for the next 6 h (reperfusion). The transformation of reactive astrocytes in response to various treatments was examined by immunostaining with glial fibrillary acidic protein. The extent of cell damage was evaluated in terms of lactate dehydrogenase leakage from the cells and altered intracellular redox status. The mechanism of cell death was determined by immunoblotting with cytochrome C, caspase-3 and PARP antibodies. The mechanism of the action of pyruvate was determined by measuring the activity of pyruvate dehydrogenase complex, and cellular metabolic status by measuring ATP levels. In comparison to glucose, supply of exogenous pyruvate restored the morphological integrity of post-ischemic astrocytes and prevented gliosis. Pyruvate prevented the cell death of post-ischemic astrocytes by inhibiting the leakage of lactate dehydrogenase, decreasing the redox ratio and restraining the activation of apoptotic events such as release of mitochondrial cytochrome c and fragmentation of caspase-3 and PARP. This study also suggests that pyruvate may accelerate its own metabolism by increasing the activity of pyruvate dehydrogenase and thus restores the cellular ATP levels in post-ischemic astrocytes. Use of pyruvate as an alternate fuel substrate may provide a possibility for the novel therapeutic approach to the treatment of cerebral ischemia.
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PMID:Pyruvate ameliorates post ischemic injury of rat astrocytes and protects them against PARP mediated cell death. 1460 78

The effects of KR-31378, a neuroprotective agent for ischemia-reperfusion damage, on liver microsomal cytochrome P450s (CYPs) were investigated in male Sprague Dawley rats. When rats were treated orally with KR-31378 for 7 consecutive days, CYP3A-selective erythromycin N-demethylase (ERDM) activity was significantly induced in a dose-dependent manner. In Western immunoblotting, CYP 3A proteins were clearly induced by treatment with KR-31378. Within 24 h after treatment with 80 mg/kg of KR-31378, ERDM activity was induced in liver microsomes in accompanied by induction of the level of CYP 3A proteins. The present results suggest that KR-31378 might modulate the expression of CYP 3A enzymes in humans.
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PMID:Effects of a new neuroprotective agent KR-31378 on liver cytochrome P450s in male Sprague Dawley rats. 1460 26

In contrast to traditional therapy (beta-adrenoblocker and nitrates), energostim improves the systolic and diastolic functions of myocardium during 120-min occlusion of the left descending coronary artery. The energostim-induced improvement in the central hemodynamics is correlated with an adaptive increase in activity of the antioxidant system enzymes in response to the ischemic production of reactive oxygen species, which is evidence of the mobilization of reserves of the enzymatic link in the antioxidant defense system of cardiomyocytes. Analogous pattern is observed in the blood. In the control group of traditional therapy, a decrease in the superoxide dismutase (SOD) activity and the redox potential (NAD/NADH) in myocardium are correlated with a decrease in the maximum rate of pressure increase in the left ventricle (R 6.4, p < 0.01) observed 2 h after the coronary occlusion. In the energostim treated group, there is a correlation between the SOD activity and the content of cytochrome C in mitochondria (R 6.1, p < 0.01): a change in the level of cytochrome C during 2-h acute ischemia is correlated with the decrease in redox potential (NAD/NADH) and in the ratio of glutathione peroxidase to Mn-dependent SOD (r 0.64, p < 0.01). Thus, disturbances in the antioxidant defense system of both myocardium and blood plasma of the patients with acute myocardium infarction are correlated with inability of the energy supply system to utilize oxygen in the process of glycolysis and oxidative phosphorylation in mitochondria. Stable adaptive increase in activity of the antioxidant defense system enzymes and a decrease in the content of cytochrome C in the blood plasma are probably the independent indications of beneficial prognosis and high efficacy of the proposed treatment of the ischemic damage of myocardium.
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PMID:[Effect of energostim on myocardial damage during coronary artery occlusion]. 1465 Feb 8

The efflux of mitochondrial protein cytochrome C to cytoplasm is one of the key events of mitochondrial dysfunction observed in post-ischemic pathology. We investigated the effect of intra-carotid infusion of 5-10 mg/kg of cyclosporin A (CsA) on the neuronal survival in CA1 sector of hippocampus and on the subcellular localization of cytochrome C in the model of 5 min gerbil brain ischemia. To discriminate between the immunosuppressive and the mitochondria protecting component of CsA action, we compared the effect of CsA with one other immunosuppressant FK506. Almost 75% of neurons in ischemia-affected brain area were saved after CsA but not after FK506 treatment. This protective effect was only observed when the drug was infused immediately upon reperfusion. Early CsA treatment was able to block an initial phase of cytochrome C release, occurring transiently at 30 min post-ischemia, an effect never observed after FK506 administration. We assessed the neuroprotective potency of CsA vs. FK506 in rat cortical primary culture treated with compounds that mimic destructive signals induced by brain ischemia. In all cases, neuronal death and cytochrome C release were evidently suppressed by CsA applied not later than 30 min after the initial insult. Thus, early treatment with CsA in vitro and after bolus intra-carotid injection in vivo can save neurons by inhibition of cytochrome C efflux to cytoplasm.
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PMID:Neuroprotection by cyclosporin A following transient brain ischemia correlates with the inhibition of the early efflux of cytochrome C to cytoplasm. 1496 36

Mitochondria play a key role in the regulation of cell death, necrosis, and apoptosis. It is well known that the opening of the mitochondrial permeability transition pore (PTP) induces the cytochrome C release and results in apoptosis. Also, it has been reported that the inhibition of PTP by cyclosporin A prevents the ischemia/reperfusion-induced necrosis. Thus, the opening of mitochondrial PTP may be a central coordinating event of apoptotic and necrotic cell death. However, the relationship between PTP opening and both modes of cell death remains elusive. In this paper, we report the recent state of our research method and the role of mitochondrial PTP in cardiac cell death.
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PMID:[The research method for investigating the role of the mitochondrial permeability transition pore in cell death]. 1511 57


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