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)

Succinyl-Leu-Leu-Val-Tyr-4-methylcoumaryl-7-amide (Suc-LLVY-MCA) hydrolyzing activities of the 20S and 26S proteasomes in the gerbil cortex following transient forebrain ischemia were examined. Using extraction solutions without ATP, only 20S proteasome activity was noted after separation with glycerol gradient centrifugation. When these extracts were incubated with ATP and an ATP-regenerating system prior to glycerol gradient separation, both 20S and 26S proteasome activities were detected. Following 10 min of ischemia, the activity of the 26S proteasomes decreased, whereas the 20S proteasome activity increased after 30 min of reperfusion. These changes returned to the control level after 1 h. The active 26S proteasomes were formed with ATP-dependent association with the 20S proteasomes and several subunits and the 26S proteasomes degraded ubiquitin-protein conjugates. These results indicate that proteasome activity might not be irreversibly impaired after transient ischemia. However, transient inhibition of ATP-dependent conversion of 20S to 26S proteasomes in vitro must be one of the causes of the accumulation of the ubiquitin-protein conjugates in the early reperfusion period.
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PMID:Changes in proteasome activity following transient ischemia. 871 10

Endothelial cell death may contribute to tissue injury from ischemia. Little is known, however, about the characteristics of endothelial cell death in response to hypoxia. Using an in vitro model, we found that human umbilical vein endothelial cells were resistant to hypoxia-induced cell death with only a 2% reduction in viability at 24 h and 45% reduction in viability at 48 h. Overexpression of a mutant, IkappaBalpha, via adenoviral vector did not potentiate cell death in hypoxia, indicating that nuclear factor-kappaB activation was not involved in cytoprotection. Cell death in hypoxia was determined to be apoptotic by 3' labeling of DNA using terminal deoxynucleotidyl transferase staining and reversibility of cell death with a caspase inhibitor. Exposure of endothelial cells to hypoxia did not alter levels of proapoptotic and antiapoptotic Bcl-2 family members Bax and Bcl-XL by immunoblot analysis. In contrast, changes in p53 protein levels correlated with the induction of apoptosis in hypoxic endothelial cells. Inhibition of the proteasome increased p53 protein levels and accelerated cell death in hypoxia. Overexpression of p53 by adenoviral transduction was sufficient to initiate apoptosis of normoxic endothelial cells. These data provide a framework for the study of factors regulating endothelial cell survival and death in hypoxia.
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PMID:Mechanisms of hypoxia-induced endothelial cell death. Role of p53 in apoptosis. 1007 3

The authors used mRNA differential display to identify genes whose expression levels are altered in the adult rat hippocampus 24 hours after global ischemia. At this time after challenge, the basic helix-loop-helix transcription factor, SEF-2, and the 26S proteasome complex subunit, p112, were identified as genes whose expression levels are decreased and increased, respectively, in the hippocampus. To determine the spatial and temporal patterns of expression change for each gene, the authors antisense in situ hybridization to paired brain sections of sham-operated and global ischemia-challenged rats at 6, 12, and 24 hours after reperfusion SEF-2 expression was not significantly altered from that of sham-operated controls in any hippocampal subfield at or before 12 hours after challenge. At 24 hours after ischemia, however, SEF-2 expression levels were significantly diminished in the vulnerable CA1 subfield, but not in the less vulnerable CA3 or dentate granule cell subfields. The proteasome p112 subunit gene displayed no change in expression levels at 6 hours after insult; however, an elevated expression was observed at 12 hours after challenge in the dentate granule cell subfield. By 24 hours after challenge, p112 expression was significantly elevated in both the CA1 and dentate granule cell subfields. These results demonstrate that a member of the basic helix-loop-helix family of transcription factors, SEF-2, and the major subunit of the 26S proteasome complex, p112, display altered gene expression in the hippocampus after transient cerebral ischemia.
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PMID:Altered expression levels of SEF-2 and p112 in the rat hippocampus after transient cerebral ischemia: identification by mRNA differential display. 1019 13

Acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow and urinary osmolality were measured to test the effectiveness of drugs. Renal function in untreated acute renal failure rats markedly decreased at 24 h after reperfusion. The administration of PSI, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, a proteasome inhibitor, at a dose of 1 mg/kg before the occlusion abolished the decreases in the renal function of acute renal failure rats. Calpeptin (1 mg/kg), a calpain inhibitor, attenuated the deterioration of renal function to the same extent as 0.1 mg/kg PSI, but no significant difference was observed between the untreated and calpeptin-treated acute renal failure groups. Histopathological examination of the kidney of untreated acute renal failure rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were significantly suppressed by PSI (1 mg/kg) treatment. In contrast, calpeptin, at the same dose, was ineffective against the development of renal lesions. These results suggest that proteasome participates in the pathogenesis of ischemic acute renal failure. Thus, proteasome may be a potential target for the identification of agents that may be useful in the treatment of diseases whose etiology is dependent on ischemia/reperfusion.
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PMID:Proteasome participates in the pathogenesis of ischemic acute renal failure in rats. 1061 18

The ubiquitin-proteasome protein degradation pathway is crucial in controlling intracellular levels of a variety of short-lived proteins and maintaining cellular growth and metabolism. In a previous study, we showed the accumulation of conjugated ubiquitin in CA1 neurons of the gerbil after 5 min of forebrain ischemia (; ). The accumulation of conjugated ubiquitin may reflect proteasome malfunction. In the present study, we investigated the effects of proteasome inhibitors on primary neuronal cultures to determine whether proteasomal malfunction induces neuronal death. When carbobenzoxy-Leu-Leu-Leu-aldehyde or lactacystin, two different types of proteasome inhibitors, were separately used to suppress proteasome activity, we observed induction of apoptotic neuronal cell death in both cases. During the apoptotic process, mitochondrial membrane potential was disrupted, cytochrome-c was released from mitochondria into the cytosol, and caspase-3-like proteases were activated. Apoptosis was inhibited by pretreatment with acetyl-aspartyl-glutamyl-valyl-aspart-1-aldehyde or overexpression of Bcl-x/(L). These results demonstrated that suppression of proteasome function induces neuronal apoptosis via the release of cytochrome c from mitochondria and activation of caspase-3-like proteases.
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PMID:Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. 1062 3

Nuclear factor-kappa B (NF-kappaB) is a multisubunit transcription factor that when activated induces the expression of genes encoding acute-phase proteins, cell adhesion molecules, cell surface receptors, and cytokines. NF-kappaB is composed of a variety of protein subunits of which p50-and p65-kDa (RelA) are the most widely studied. Under resting conditions, these subunits reside in the cytoplasm as an inactive complex bound by inhibitor proteins, IkappaB alpha and IkappaB beta. On activation, IkappaB is phosphorylated by IkappaB kinase and ubiquitinated and degraded by the proteasome; simultaneously, the active heterodimer translocates to the nucleus where it can initiate gene transcription. In the periphery, NF-kappaB is involved in inflammation through stimulation of the production of inflammatory mediators. The role of NF-kappaB in the brain is unclear. In vitro, NF-kappaB activation can be either protective or deleterious. The role of NF-kappaB in ischemic neuronal cell death in vivo was investigated. Adult male rats were subjected to 2 hours of focal ischemia induced by middle cerebral artery occlusion (MCAO). At 2, 6, and 12 hours after reperfusion, the expression and transactivation of NF-kappaB in ischemic versus nonischemic cortex and striatum were determined by immunocytochemistry and by electrophoretic mobility gel-shift analysis. At all time points studied, p50 and p65 immunoreactivity was found exclusively in the nuclei of cortical and striatal neurons in the ischemic hemisphere. The contralateral nonischemic hemisphere showed no evidence of nuclear NF-kappaB immunoreactivity. Double immunofluorescence confirmed expression of p50 in nuclei of neurons. Increased NF-kappaB DNA-binding activity in nuclear extracts prepared from the ischemic hemisphere was further substantiated by electrophoretic mobility gel-shift analysis. Because the activation of NF-kappaB by many stimuli can be blocked by antioxidants in vitro, the effect of the antioxidant, LY341122, previously shown to be neuroprotective, on NF-kappaB activation in the MCAO model was evaluated. No significant activation of NF-kappaB was found by electrophoretic mobility gel-shift analysis in animals treated with LY341122. These results demonstrate that transient focal cerebral ischemia results in activation of NF-kappaB in neurons and supports previous observations that neuroprotective antioxidants may inhibit neuronal death by preventing the activation of NF-kappaB.
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PMID:Transcription factor nuclear factor-kappa B is activated in neurons after focal cerebral ischemia. 1072 23

Ischemic epithelial cells are characterized by disruption of intercellular junctions and loss of apical-basolateral protein polarity, which are normally dependent on the integrity of the adherens junction (AJ). Biochemical analysis of both whole ischemic kidneys and ATP-depleted Madin-Darby canine kidney (MDCK) cells demonstrated a striking loss of E-cadherin (the transmembrane protein of the AJ) with the appearance and accumulation of an approximately 80-kDa fragment reactive with anti-E-cadherin antibodies on Western blots of ATP-depleted MDCK cells. This apparent ischemia-induced degradation of E-cadherin was not blocked by either inhibitors of the major proteolytic pathways (i.e., proteasome, lysosome, or calpain), or by chelation of intracellular calcium, suggesting the involvement of a protease capable of functioning at low ATP and low calcium levels. Immunocytochemistry revealed the movement of several proteins normally comprising the AJ, including E-cadherin and beta-catenin, away from lateral portions of the plasma membrane to intracellular sites. Moreover, rate-zonal centrifugation and immunoprecipitation with anti-E-cadherin and anti-beta-catenin antibodies indicated that ATP depletion disrupted normal E-cadherin-catenin interactions, resulting in the dissociation of alpha- and gamma-catenin from E-cadherin and beta-catenin-containing complexes. Because the generation and maintenance of polarized epithelial cells are dependent upon E-cadherin-mediated cell-cell adhesion and normal AJ function, we propose that the rapid degradation of E-cadherin and dissolution of the AJ is a key step in the development of the ischemic epithelial cell phenotype. Furthermore, we hypothesize that the reassembly of the AJ after ischemia/ATP depletion may require a novel bioassembly mechanism involving recombination of newly synthesized and sorted E-cadherin with preexisting pools of catenins that have (temporally) redistributed intracellularly.
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PMID:Selective degradation of E-cadherin and dissolution of E-cadherin-catenin complexes in epithelial ischemia. 1080 98

Induction of NF-kappaB-dependent gene expression plays an important role in a number of biological processes including inflammation and ischemia-reperfusion injury. However, few attempts aimed at selective regulation of this transcription factor have been successful. We report here that a naturally occurring antibacterial peptide PR39 reversibly binds to the alpha 7 subunit of the 26S proteasome and blocks degradation of NF-kappa B inhibitor I kappa B alpha by the ubiquitin-proteasome pathway without affecting overall proteasome activity. I kappa B alpha phosphorylation and ubiquitination occur normally after PR39 treatment, and binding of valosin-containing proteins is not impaired. The inhibition of I kappa B alpha degradation abolishes induction of NF-kappa B-dependent gene expression in cell culture and in mouse models of acute pancreatitis and myocardial infarction, including upregulation of endothelial adhesion proteins VCAM-1 and ICAM-1. In the latter model, sustained infusion of PR39 peptide resulted in significant reduction of myocardial infarct size. PR39 and related peptides may provide novel means to regulate cellular function and to control of NF-kappa B-dependent gene expression for therapeutic purposes.
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PMID:Inhibition of ubiquitin-proteasome pathway-mediated I kappa B alpha degradation by a naturally occurring antibacterial peptide. 1093 Apr 47

Numerous studies indicate a role for oxidative stress in the neuronal degeneration and cell death that occur during ischemia-reperfusion injury. Recent data suggest that inhibition of the proteasome may be a means by which oxidative stress mediates neuronal cell death. In the current study, the authors demonstrate that there is a time-dependent decrease in proteasome activity, which is not associated with decreased expression of proteasome subunits, after cerebral ischemia-reperfusion injury. To determine the role of oxidative stress in mediating proteasome inhibition, ischemia-reperfusion studies were conducted in mice that either overexpressed the antioxidant enzyme glutathione peroxidase [GPX 1(+)], or were devoid of glutathione peroxidase activity (GPX -/-). After ischemia-reperfusion, GPX 1(+) mice displayed decreased infarct size, attenuated neurologic impairment, and reduced levels of proteasome inhibition compared with either GPX -/- or wild type mice. In addition, GPX 1(+) mice displayed lower levels of 4-hydroxynonenal-modified proteasome subunits after ischemia-reperfusion injury. Together, these data indicate that proteasome inhibition occurs during cerebral ischemia-reperfusion injury and is mediated, at least in part, by oxidative stress.
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PMID:Oxidative stress-associated impairment of proteasome activity during ischemia-reperfusion injury. 1104 9

The objectives of this study were (1) to assess the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF) induced by ischemia-reperfusion, and (2) to determine the involvement of this proteolytic pathway in the enhanced production of renal endothelin-1 (ET-1) in this model of ARF. ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured to test the effectiveness of drugs used. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. In addition, a marked increase in renal ET-1 content was evident in the ARF rats, compared to the sham-operated rats. Intraperitoneal injection of a proteasome inhibitor (PSI), N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, at a dose of 1 mg/kg, 1 h before the clamping, significantly attenuated the renal function impairment in the ischemic ARF rats, and the effect was accompanied by a decrease in renal ET-1 content. On the other hand, a calpain inhibitor, calpeptin, had little effect at the same dose. These results suggest that a proteasome-dependent proteolytic pathway is involved in the enhanced production of ET-1 in the kidney and the consequent renal functional damage in ischemic ARF.
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PMID:Proteasome inhibition attenuates renal endothelin-1 production and the development of ischemic acute renal failure in rats. 1107 83


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