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)

A previous exposure to a non-harmful ischemic insult (preconditioning) protects the brain against subsequent harmful ischemia (ischemic tolerance). In contrast to delayed gene-mediated ischemic tolerance, little is known about the molecular mechanisms that regulate rapid ischemic tolerance, which occurs within 1 h following preconditioning. Here we have investigated the degradation of the pro-apoptotic Bcl-2 family member Bim as a mechanism of rapid ischemic tolerance. Bim protein levels were reduced 1 h following preconditioning and occurred concurrent with an increase in Bim ubiquitination. Ubiquitinated proteins are degraded by the proteasome, and inhibition of the proteasome with MG132 (a proteasome inhibitor) prevented Bim degradation and blocked rapid ischemic tolerance. Inhibition of p42/p44 mitogen-activated protein kinase activation by U0126 reduced Bim ubiquitination and Bim degradation and blocked rapid ischemic tolerance. Finally, inhibition of Bim expression using antisense oligonucleotides also reduced cell death following ischemic challenge. Our results suggest that following preconditioning ischemia, Bim is rapidly degraded by the ubiquitin-proteasome system, resulting in rapid ischemic tolerance. This suggests that the rapid degradation of cell death-promoting proteins by the ubiquitin-proteasome pathway may represent a novel therapeutic strategy to reduce cell damage following neuropathological insults, e.g. stroke.
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PMID:Rapid degradation of Bim by the ubiquitin-proteasome pathway mediates short-term ischemic tolerance in cultured neurons. 1643 16

Ischemia-reperfusion activates ERK and p38 MAPK in cardiac membranes, but the role of caveolae in MAPK signaling during this stress has not been studied. The purpose of this study was to determine the effect of in vivo myocardial ischemia-reperfusion on the level and distribution of caveolin-1 and -3 and cholesterol as well as MAPK activation in caveolin-enriched fractions. Adult male rats were subjected to in vivo regional myocardial ischemia induced by 25 min of coronary artery occlusion and 10 min (n = 5) or 2 h (n = 4) of reperfusion. Another group of rats served as appropriate nonischemic time controls (n = 4). A discontinuous sucrose density gradient was used to isolate caveolae/lipid rafts from ischemic and nonischemic heart tissue. Caveolin-1 and -3, as well as cholesterol, were enriched in the light fractions. A redistribution of caveolin-3 and a reduction in caveolin-1 and cholesterol levels in the light fractions occurred after 10 min of reperfusion. The ERKs were activated in ischemic zone light and heavy fractions by 10 min of reperfusion. p44 ERK was activated after 2 h of reperfusion only in the light fractions, whereas p42 ERK phosphorylation was increased in the light and heavy fractions. Although no p38 MAPK activation occurred after 10 min of reperfusion, 2 h of reperfusion caused significant activation of p38 MAPK in nonischemic zone light and heavy fractions. These results show the importance of caveolar membrane/lipid rafts in MAPK signaling and suggest that subcellular compartmentation of p44/p42 ERKs and p38 MAPK may play distinct roles in the response to myocardial ischemia-reperfusion.
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PMID:Regional myocardial ischemia-induced activation of MAPKs is associated with subcellular redistribution of caveolin and cholesterol. 1656 1

Treatment of organ donors with catecholamines reduces acute rejection episodes and improves long-term graft survival after renal transplantation. The aim of this study was to investigate the effect of catecholamine pre-treatment on ischemia/reperfusion (I/R)- and cold preservation injury in rat kidneys. I/R-injury was induced by clamping the left kidney vessels for 60 min along with a contralateral nephrectomy. Cold preservation injury was induced by storage of the kidneys for 24 h at +4 degrees Celsius in University of Wisconsin solution, followed by syngeneic transplantation. Rats were pre-treated with either dopamine (DA), dobutamine (DB), or norepinephrine (2, 5, and 10 microg/kg/min, each group) intravenously via an osmotic minipump for 24 h before I/R- and cold preservation injury. Pre-treatment with DA (2 or 5 microg/kg/min) and DB (5 microg/kg/min) improved recovery of renal function after I/R-injury and dose dependently reduced mononuclear and major histocompatibility complex class II-positive cells infiltrating the kidney after I/R-injury. One day after I/R-injury, upregulation of transforming growth factor (TGF)-beta 1 and 2 and phosphorylation of p42/p44 mitogen-activated protein kinases was observed in kidneys of animals treated with DA or DB. DA (5 microg/kg/min) and DB (5 microg/kg/min) pre-treatment reduced endothelial cell damage after 24 h of cold preservation. Only DA pre-treatment improved renal function and reduced renal inflammation after 24 h of cold preservation and syngeneic transplantation. Our results demonstrate a protective effect of pre-treatment with catecholamines on renal inflammation and function after I/R- or cold preservation injury. This could help to explain the potent organoprotective effects of catecholamine pre-treatment observed in human kidney transplantation.
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PMID:Effect of pre-treatment with catecholamines on cold preservation and ischemia/reperfusion-injury in rats. 1676 Sep 13

Caspase-3 (32 kDa) is one of the primary protease executioners of apoptosis and is activated by intra-chain proteolytic cleavage, which generates a large subunit (17 kDa) and a small subunit (12 kDa). Typically, after apoptotic stimuli, the level of cleaved caspase-3 increases while that of caspase-3 decreases. It has been shown that caspase-3 mRNA levels increase in cortex following traumatic brain injury or focal ischemia. In the present study, we demonstrate that both caspase-3 mRNA and protein increase in apoptotic PC12 cells following exposure to manganese which strongly induces caspase-3 cleavage. Up-regulation of caspase-3 protein was evident in manganese-treated PC12 cells and was moderate in cisplatin-, rotenone- and A23187-treated cells but was not observed in serum deprivation-, anisomycin-, camptothecin-, cycloheximide- or staurosporine-treated cells in which all treatments induced extensive DNA fragmentation. Manganese-induced up-regulation of caspase-3 mRNA was partially attenuated by the pretreatment with the MEK inhibitor U0126, but not with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. In contrast, the increase in caspase-3 protein was suppressed by both U0126 and SP600125. These results suggest that p44/42 MAPK contributes to the up-regulation of caspase-3 mRNA and the JNK pathway regulates caspase-3 protein levels posttranslationally in manganese-induced apoptosis in PC12 cells.
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PMID:p44/42 MAP kinase and c-Jun N-terminal kinase contribute to the up-regulation of caspase-3 in manganese-induced apoptosis in PC12 cells. 1678 41

Ischemia-reperfusion (I/R) injury associated with liver transplantation remains a serious complication in clinical practice, in spite of several attempts to solve the problem. The present review focuses on the complexity of I/R injury, summarizing conflicting results obtained from the literature about the mechanisms responsible for it. We also review the therapeutic strategies designed in past years to reduce I/R injury, attempting to explain why most of them have not been applied clinically. These strategies include improvements in pharmacological treatments, modifications of University of Wisconsin (UW) preservation solution based on a variety of additives, and gene therapy. Finally, we will consider new potential protective strategies using trimetazidine, 5-amino-4-imidazole carboxamide riboside (AICAR), melatonin, modulators of the renin-angiotensin system (RAS) and the phosphatidylinositol-3-OH kinase (PI3K)-Akt and the p42/p44 extracellular signal-regulated kinases (Erk 1/2) pathway. These strategies have shown promising results for I/R injury but have not been tested in experimental liver transplantation to date. Moreover, we will review ischemic preconditioning, taking into account the recent clinical studies that suggest that this surgical strategy could be appropriate for liver transplantation.
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PMID:Past and future approaches to ischemia-reperfusion lesion associated with liver transplantation. 1682 7

The aim of the present article is to review the cardioprotective properties of cannabinoids, with an emphasis on the signaling pathways involved. Cannabinoids have been reported to protect against ischemia in rat isolated hearts, as well as in rats and mice in vivo. Although these effects have been observed mostly with a pre-treatment of a cannabinoid, we report that the selective CB(2)-receptor agonist JWH133 is able to reduce infarct size when administered either before ischemia, during the entire ischemic period, or just upon reperfusion. Little is known about the signaling pathways involved in these cardioprotective effects. Likely candidates include protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) since they are activated during ischemia-reperfusion and contribute to the protective effect ischemic preconditioning. The use of pharmacological inhibitors suggests that PKC, p38 MAPK, and p42/p44 MAPK (ERK1/2) contribute to the protective effect of cannabinoids. In addition, perfusion with JWH133 in healthy hearts caused an increase in both p38 MAPK phosphorylation level and activity, whereas the CB(1)-receptor agonist ACEA was associated with an increase in the phosphorylation status of both ERK1 and ERK2 without any change in activity. During ischemia, both agonists doubled p38 MAPK activity, whereas ERK1/2 phosphorylation level and activity during reperfusion were enhanced only by the CB(1)-receptor agonist. Finally, although nitric oxide (NO) was shown to exert both pro and anti-apoptotic effects on cardiomyocytes, with an apparently controversial effect on myocardial survival, our data suggest that NO may contribute to the cardioprotective effect of some cannabinoids.
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PMID:Signaling pathways involved in the cardioprotective effects of cannabinoids. 1703 Oct 75

A variety of harmful stimuli, among them energy depletion occurring during transient brain ischemia, are thought to unbalance protein kinase cascades, ultimately leading to neuronal damage. In superfused, electrically stimulated rat cerebral cortex slices, chemical ischemia (CI) was induced by a 5-min treatment with the mitochondrial toxin, sodium azide (10 mM), combined with the glycolysis blocker, 2-deoxyglucose (2 mM). Thereafter, 1 h reperfusion (REP) with normal medium followed. Western blot analysis of p21Ras, extracellular signal-regulated protein kinases (ERK)1/2 (p44/42), phospho-ERK1/2, mitogen-activated protein kinase (MAPK)-p38, phospho-p38, stress-activated protein kinases/c-Jun NH2-terminal protein kinases (SAPK/JNK), phospho-SAPK/JNK was carried out. The level of p21Ras was increased by 40% immediately after CI, and did not return to control values following REP. Both ERK1 and ERK2 levels were reduced by CI and recovered to control values following REP; no significant change in their phosphorylation degree (phosphorylated to total level ratio, about 50% in the controls) was observed. Neither p38 levels, nor phosphorylation degree were changed following CI/REP. The activation of SAPK/JNK was significantly reduced under CI, and did not recover following REP. All CI/REP-induced effects were prevented by the NMDA receptor antagonist MK-801, 10 microM, suggesting the involvement of glutamate. The present findings show that although CI stimulates the p21Ras protein, MAPK levels and/or phosphorylation are reduced, possibly because of acute energy depletion. Because the activation of SAPK/JNK has been related to both apoptosis and neuroprotection, the decrease observed under CI/REP conditions may instead be related to nonapoptotic neuronal death. These results could be of interest in developing preventive treatments for ischemia/REP-induced brain damage.
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PMID:Effects of chemical ischemia on cerebral cortex slices: focus on mitogen-activated protein kinase cascade. 1738 88

Transforming growth factor (TGF)-beta(1) is one of the most pleiotropic and multifunctional peptides known. While the cardioprotective effect of TGF-beta(1) during ischemia is well known, the specific role of TGF-beta(1) in altering the cardiac remodeling process remains unclear. This study was designed to examine the regulation of hypoxia-reoxygenation-mediated collagen type I expression and activity of matrix metalloproteinases (MMPs) by overexpression of TGF-beta(1) in cultured HL-1 mouse cardiomyocytes. TGF-beta(1) was overexpressed in cardiomyocytes by transfection with adeno-associated virus (AAV)/TGF-beta(1)(Latent) or with AAV/TGF-beta(1)(ACT) (active TGF-beta(1)). Twenty-four hours of hypoxia followed by 3 h of reoxygenation (H-R) markedly enhanced (pro)collagen type I expression and activity of MMPs concomitant with an increase in reactive oxygen species (ROS) release and LOX-1 expression. Overexpression of TGF-beta(1) reduced these alterations induced by H-R. TGF-beta(1) overexpression also blocked H-R-mediated p38 and p44/42 MAPK activation. Transfection with AAV/TGF-beta(1)(ACT) was superior to that with AAV/TGF-beta(1)(Latent). These data for the first time demonstrate that H-R induces signals for cardiac remodeling in cardiomyocytes and TGF-beta(1) can modulate, possibly via antioxidant mechanism, these signals. These findings contribute to further understanding of the role of TGF-beta(1) in the cardiac remodeling process.
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PMID:Blockade of hypoxia-reoxygenation-mediated collagen type I expression and MMP activity by overexpression of TGF-beta1 delivered by AAV in mouse cardiomyocytes. 1758 16

Extracellular signal-regulated kinases (ERK) such as ERK1 [p44 mitogen-activated protein kinase (MAPK)] and ERK2 (p42 MAPK) are activated in the central nervous system under physiological and pathological conditions such as ischemia and epilepsy. Our aim is to investigate ERK1, ERK2, and phosphorylated ERK (p-ERK) (Thr202/Tyr 204) expression in the temporal lobe of patients with intractable epilepsy (IE) and to explore its possible role of ERK in it. Tissue samples from temporal neocortices of 40 patients who had surgery for IE were used to detect ERK1, ERK2, and p-ERK (Thr 202/Tyr 204) expression through immunohistochemistry and western blot. We compared these tissues against 17 histological normal temporal lobes from head-trauma patients. ERK1, ERK2, and p-ERK in IE were significantly higher than those in the controls. They were mainly expressed in the cytoplasm of neurons and glial cells. There was also increased detection of p-ERK in the gliotic cortex of IE compared with the non-gliotic cortex. These findings were consistently observed in western blot and immunohistochemistry techniques. ERK expression in patients with IE was significantly increased compared with the controls. This suggested a probable role of ERK in the pathogenesis of IE.
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PMID:Extracellular signal-regulated protein kinase in human intractable epilepsy. 1766 6

The lanthanide cation, gadolinium (Gd) attenuates post-ischemic myocardial stunning. This study tests the hypothesis that Gd also preconditions the myocardium against infarction following ischemia-reperfusion (IR) and explores potential mechanisms underlying Gd-induced cardioprotection. Regional myocardial infarction was induced in rats by occluding the left anterior descending artery for 30 min and reperfusing for 120 min. Rats (n=6/group) were administered intravenous Gd (1 to 100 micromol/kg) 15 min prior to ischemia. Hearts were excised after reperfusion to determine infarct size (IS) and area at risk (AAR). The ratio IS/AAR (%) was reduced by Gd in a "U"-shaped, dose-dependent manner. The minimum dose that reduced IS/AAR was 5 micromol/kg (52+/-5% vs. 64+/-4%), while the dose that reduced IS/AAR maximally was 20 micromol/kg (44+/-4%). Gd also reduced IS/AAR when given 1 min before reperfusion (47+/-3%) but not when given 10 s after reperfusion (60+/-3%). Cardioprotection was maintained if IR was delayed 24-72 h after Gd administration. Cardioprotection by Gd was abolished by inhibition of JAK-2 with AG-490, of p42/44 MAPK with PD98059 or of K(ATP) channels with glibenclamide. None of these agents given alone altered IS/AAR compared with controls. Inhibition of JAK-2 also blocked Gd-induced delayed cardioprotection. Gd may have broad potential roles in IR, as it conferred immediate cardioprotection when given prior to ischemia or prior to reperfusion and delayed cardioprotection for up to 72 h after administration. The mechanism underlying Gd-induced preconditioning appears to be multi-factorial, involving JAK-2, STAT-3 and p44 MAPK pathways, as well as K(ATP) channels.
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PMID:Gadolinium limits myocardial infarction in the rat: dose-response, temporal relations and mechanisms. 1808 88


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