Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Recent advances in clinical islet transplantation have allowed patients with type 1 diabetes to become insulin independent, but the procedure is limited since islets from two donors per recipient are typically required. This limitation arises because within a few days of the islets being embolized into the portal circulation, at least half of the transplanted beta-cells have undergone apoptotic cell death triggered by hypoxic and chemokine/cytokine-mediated stress. We hypothesized that the survival of beta-cells in the early post-transplant period would be enhanced if naturally occurring inhibitor of apoptosis proteins (IAPs) were transiently overexpressed in the grafts. In the present study, we used a growth-regulatable beta-cell line (betaTC-Tet) as a model for beta-cells within islets, and examined whether adenovirally delivered XIAP (X-linked IAP-a highly potent IAP) could enhance beta-cell survival. In vitro, XIAP-expressing betaTC-Tet cells were markedly resistant to apoptosis in an ischemia-reperfusion injury model system and following exposure to cytokines. When Ad-XIAP transduced betaTC-Tet cells were transplanted subcutaneously into immunodeficient mice, the grafts were able to reverse diabetes in 3 days, vs. 21 days for Ad-betaGal transduced cells. This approach may allow more efficient use of the limited existing supply of human islets.
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PMID:XIAP overexpression in islet beta-cells enhances engraftment and minimizes hypoxia-reperfusion injury. 1588 33

1alpha,25-(OH)(2)-vitamin-D(3) (1,25-D(3)) and 17beta-estradiol are both known to act neuroprotective in certain experimental in vitro and in vivo settings. We studied the effects of 1,25-D(3) or 17beta-estradiol or their combined application on heat shock protein-27 (HSP-27) distribution after focal cortical ischemia using the photothrombosis model. HSP-27 is a well-established marker of the cerebral oxidative stress response and a potent inhibitor of apoptosis. Lesioned rats were injected i.p. one hour after injury with either 1 microg 1,25-D(3)/kg or 7 microg 17beta-estradiol/kg or a combination of both steroids. Groups of non-lesioned steroid-treated rats and lesioned, solvent-treated rats served as controls. Treatment with both steroids did not affect the size of the lesion. In addition, 17beta-estradiol resulted in significant reduction of HSP-27 induction, whereas the combination of 1,25-D(3)+17beta-estradiol resulted in a highly significant reduction of HSP-27 within the infracted cerebral cortex, indicating that both steroids act synergistically in a protective manner.
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PMID:1alpha,25-dihydroxy-vitamin D3 in combination with 17beta-estradiol lowers the cortical expression of heat shock protein-27 following experimentally induced focal cortical ischemia in rats. 1592 86

Previous work has shown that puerarin (Pur), extracted from the dried root of Pueraria lobata (Wild) Ohwi, increases cerebral blood flow in dogs and attenuates cerebral and spinal cord injury resulting from ischemia and reperfusion in rats and rabbits. The present study further demonstrates the neuroprotective effects of Pur on cerebral ischemic injury in rats and the mechanisms underlying the protective effects. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAo) for 50 min followed by reperfusion for 24 h. Pur (50, 100 mg/kg, i.p) was administered at the onset of MCAo. Twenty-four hours after reperfusion, neurological deficits were evaluated in Pur- and vehicle-treated rats. The infarct volume and edema ratios were assessed from stained brain slices. The results showed that Pur (100 mg/kg) markedly decreased the infarct volume by 34 % ( P < 0.01) in cerebral cortex and improved the neurological functions ( P < 0.05) after MCAo. Furthermore, flow cytometric analysis of annexin-V and PI labeling cells showed that the percentages of apoptosis and necrosis in the dorsolateral cortex were significantly reduced by 38.6 % and 28.5 % ( P < 0.01 and P < 0.05) following treatment with Pur (100 mg/kg) in MCAo rats. Caspase-3 activity, a biochemical marker of apoptosis, was significantly inhibited after treatment with Pur in the dorsolateral cortex. In agreement with this result, the expression of the X-chromosome-linked inhibitor of apoptosis protein (XIAP) was obviously up-regulated after administration of Pur (100 mg/kg), while caspase-3 gene was down-regulated in the dorsolateral cortex. These results suggest that the neuroprotection of puerarin against cerebral ischemia is associated with anti-apoptosis.
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PMID:The Neuroprotection of puerarin against cerebral ischemia is associated with the prevention of apoptosis in rats. 1604 41

Oxidative stress may cause apoptosis of cardiomyocytes in ischemia-reperfused myocardium, and heat shock pretreatment is thought to be protective against ischemic injury when cardiac myocytes are subjected to ischemia or simulated ischemia. However, the detailed mechanisms responsible for the protective effect of heat shock pretreatment are currently unclear. The aim of this study was to determine whether heat shock pretreatment exerts a protective effect against hydrogen peroxide(H2O2)-induced apoptotic cell death in neonatal rat cardiomyocytes and C2C12 myogenic cells and whether such protection is associated with decreased release of second mitochondria-derived activator of caspase-direct IAP binding protein with low pl (where IAP is inhibitor of apoptosis protein) (Smac/DIABLO) from mitochondria and the activation of caspase-9 and caspase-3. After heat shock pretreatment (42 +/- 0.3 degrees C for 1 hour, recovery for 12 hours), cardiomyocytes and C2C12 myogenic cells were exposed to H2O2 (0.5 mmol/L) for 6, 12, 24, and 36 hours. Apoptosis was evaluated by Hoechst 33258 staining and DNA laddering. Caspase-9 and caspase-3 activities were assayed by caspase colorimetric assay kit and Western analysis. Inducible heat shock proteins (Hsp) were detected using Western analysis. The release of Smac/DIABLO from mitochondria to cytoplasm was observed by Western blot and indirect immunofluorescence analysis. (1) H2O2 (0.5 mmol/L) exposure induced apoptosis in neonatal rat cardiomyocytes and C2C12 myogenic cells, with a marked release of Smac/DIABLO from mitochondria into cytoplasm and activation of caspase-9 and caspase-3, (2) heat shock pretreatment induced expression of Hsp70, Hsp90, and alphaB-crystallin and inhibited H2O2-mediated Smac/DIABLO release from mitochondria, the activation of caspase-9, caspase-3, and subsequent apoptosis. H2O2 can induce the release of Smac/DIABLO from mitochondria and apoptosis in cardiomyocytes and C2C12 myogenic cells. Heat shock pretreatment protects the cells against H2O2-induced apoptosis, and its mechanism appears to involve the inhibition of Smac release from mitochondria.
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PMID:Heat shock pretreatment inhibited the release of Smac/DIABLO from mitochondria and apoptosis induced by hydrogen peroxide in cardiomyocytes and C2C12 myogenic cells. 1618 70

The extracellular signal-regulated kinase (ERK) and Akt have been reported to be activated by ischemia/reperfusion in vivo. However, the signaling pathways involved in activation of these kinases and their potential roles were not fully understood in the postischemic kidney. In the present study, we observed that these kinases are activated by hypoxia/reoxygenation (H/R), an in vitro model of ischemia/reperfusion, in opossum kidney (OK) cells and elucidated the signaling pathways of these kinases. ERK and Akt were transiently activated during the early phase of reoxygenation following 4-12h of hypoxia. The ERK activation was inhibited by U0126, a specific inhibitor of ERK upstream MAPK/ERK kinase (MEK), but not by LY294002, a specific inhibitor of phosphoinositide 3-kinase (PI3K), whereas Akt activation was blocked by LY294002, but not by U0126. Inhibitors of epidermal growth factor receptor (EGFR) (AG 1478), Ras and Raf, as well as antioxidants inhibited activation of ERK and Akt, while the Src inhibitor PP2 had no effect. PI3K/Akt activation was shown to be associated with up-regulation of X chromosome-linked inhibitor of apoptosis (XIAP), but not survivin. Reoxygenation following 4-h hypoxia-stimulated cell proliferation, which was dependent on ERK and Akt activation and was also inhibited by antioxidants and AG 1478. Taken together, these results suggest that H/R induces activation of MEK/ERK and PI3K/Akt/XIAP survival signaling pathways through the reactive oxygen species-dependent EGFR/Ras/Raf cascade. Activation of these kinases may be involved in the repair process during ischemia/reperfusion.
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PMID:Signal transduction of MEK/ERK and PI3K/Akt activation by hypoxia/reoxygenation in renal epithelial cells. 1686 Apr 36

High temperature requirement A2 (HtrA2)/Omi is a mitochondrial serine protease that is released into the cytosol from mitochondria and in turn promotes caspase activation by proteolyzing inhibitor of apoptosis proteins. Here we asked whether treatment with an HtrA2/Omi inhibitor, 5-[5-(2-nitrophenyl)furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101), restores heart dysfunction following ischemia/reperfusion injury in vivo. Rats underwent a 30-min ischemia by occluding the left anterior descending artery, followed by 24 h reperfusion. UCF-101 (0.75 or 1.5 micromol/kg, i.p.) was administered 10 min before reperfusion. UCF-101 treatment significantly recovered the mean arterial blood pressure and ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion with concomitant reduction of infarct size. Cardio-protection mediated by UCF-101 was correlated with reduced X-linked inhibitor of apoptosis protein (XIAP) degradation and inhibition of Caspase-9, Caspase-3, and Caspase-7 processing. Furthermore, UCF-101 prevented loss of membrane integrity by inhibiting fodrin breakdown in cardiomyocytes. UCF-101-induced cytoprotection was also correlated with reduced Fas ligand expression and inhibition of FLIP degradation following ischemia/reperfusion. These results suggest that UCF-101 rescues cardiomyocytes from ischemia/reperfusion injury by inhibiting XIAP degradation and Fas/Fas-ligand-induced apoptosis, thereby ameliorating ischemia/reperfusion-induced myocardial dysfunction.
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PMID:Inhibition of HtrA2/Omi ameliorates heart dysfunction following ischemia/reperfusion injury in rat heart in vivo. 1718 30

We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.
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PMID:X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants. 1805 85

Although cap-dependent translation initiation is the prevalent mode of ribosome binding to mRNAs in eukaryotes, some mRNAs exhibit the ability to bypass the requirement for the cap structure. The translation of X-chromosome-linked inhibitor of apoptosis protein (XIAP) mRNA is controlled by an internal ribosome entry site (IRES) element, which requires the interaction of the heterogeneous nuclear ribonucleoprotein C1-C2 (hnRNP-C1/C2). We analyze, at the protein level, the time course and distribution of XIAP and hnRNP-C1/C2 upon ischemia in mice or staurosporine (STP)-induced apoptosis in HT22 cells. Both ischemia and STP induced a parallel upregulation of XIAP and hnRNP-C1/C2 protein levels in the penumbra and in HT22 cells. These results suggest that the increased levels of hnRNP C1/C2 may modulate XIAP translation, probably by interacting with the XIAP-IRES. The up-regulation of hnRNP-C1/C2 may foster the synthesis of XIAP as a protective pathway by which neurons try to counteract the initial deleterious effects of apoptosis.
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PMID:Concomitant transitory up-regulation of X-linked inhibitor of apoptosis protein (XIAP) and the heterogeneous nuclear ribonucleoprotein C1-C2 in surviving cells during neuronal apoptosis. 1836 99

A plethora of apoptotic stimuli converge on the mitochondria and affect their membrane integrity, thereby eliciting release of multiple death-promoting factors residing in the mitochondrial intermembrane space into the cytosol. Among the death-promoting factors, a serine protease, high temperature requirement A2 (HtrA2) has drawn attention as a key player in the apoptosis pathways in different pathological conditions including myocardial ischemia/reperfusion injury. Heart ischemia/reperfusion results in HtrA2 translocation from the mitochondria to the cytosol, where it promotes cardiomyocyte apoptosis via a protease activity-dependent and caspase-mediated pathway. Once released, cytosolic HtrA2 causes X-chromosome-linked inhibitor of apoptosis protein (XIAP) degradation, caspase activation, and subsequent apoptosis. Consistent with the hypothesis, inhibition of HtrA2 improved postischemic myocardial contractile functions along with reduction of myocardial infarct size. The precise mechanism underlying HtrA2-induced apoptosis in mammalian cells has been studied through biochemical, structural, and genetic studies, in which HtrA2 promotes proteolytic activation of caspases through multiple pathways in heart ischemia. Therapeutic interventions that inhibit HtrA2 expression, translocation, or protease activity (such as by using the ucf-101 inhibitor) may provide an attractive therapeutics in the treatment of cardiovascular diseases.
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PMID:Activation of HtrA2, a mitochondrial serine protease mediates apoptosis: current knowledge on HtrA2 mediated myocardial ischemia/reperfusion injury. 1878 92

The purpose of the present study was to investigate the potential cardioprotective effects of an original approach based on the properties of the X chromosome-linked Inhibitor of Apoptosis (XIAP), the most effective endogenous inhibitor of apoptosis. For this purpose, the C-terminal part of XIAP (BIR3 and RING domains) was fused to the protein transduction domain (PTD) of the HIV1 transactivator of transcription, which confers to fused protein the ability to cross cell membranes. This protein, so-called PTD-BIR3/RING, was administered intravenously in C57BL/6J mice subjected to 30 min coronary artery occlusion and 24 h of reperfusion. Administration of PTD-BIR3/RING at 5 min before and 30 min after the onset of reperfusion reduced infarct size vs control (23+/-2% vs 41+/-4% and 27+/-4% vs 41+/-3%, respectively, p<0.05). Similar reduction in infarct size was observed when PTD-BIR3/RING was administered prior to ischemia (28+/-1% vs 44+/-3%). In addition to inhibition of caspase-3 and -9 activities, PTD-BIR3/RING induced an inhibition of caspase-8 and several other actors of the apoptotic pathways. In conclusion, this study demonstrates that the administration of PTD-BIR3/RING reduces myocardial infarct size even when injected during reperfusion through interruption of caspase activation by pharmacologically mimicking endogenous XIAP.
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PMID:Cardioprotection against myocardial infarction with PTD-BIR3/RING, a XIAP mimicking protein. 1923 93


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