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)

The essential social and academic task of legal medicine is to devote itself to a multidisciplinary approach to problems at the interface of medicine and law. It includes forensic medical activity, in which one of the social concerns is to investigate the fatal mechanisms, survival time and physical activity, especially in traumatic and unexpected sudden death, by means of forensic pathological procedures. To meet the social requirements through reliable interpretation of those issues, systematic practical investigations are necessary, establishing the evidence-based assessment in forensic pathology. For that purpose, an approach based on the pathophysiochemistry of fatal mechanisms may be useful to aid or support pathomorphological observations. Essential markers in forensic pathophysiochemistry are the indicators of systemic responses involving acute phase reaction to traumas, i.e., circulatory, respiratory and central nervous system (CNS) functions. A comprehensive study based on previous investigations is necessary to establish practical markers and to promote their use in routine forensic casework. In the present paper, reviewing the literature, our data in routine casework are summarized. Routine forensic casework at our institute includes biochemistry on automated analyzer systems, immunohistochemistry using commercial kits and molecular biology by means of RT-PCR: 1) blood and urine biochemistry in general, 2) oxymetry, 3) serum and pericardial myocardial markers (creatine kinase MB, troponin I and T), 4) serum pulmonary surfactants (SP-A and -D), 5) other serum markers including C-reactive protein, neopterin, catecholamines, cortisol, erythropoietin and S-100 protein, 6) pericardial natriuretic peptides, 7) urinary myoglobin, 8) immunohistochemistry of a pulmonary surfactant (SP-A) in the lungs, ubiquitin, S-100 protein and ssDNA in the brain, and 9) RT-PCR for a pulmonary surfactant (SP-A) in the lungs, ischemia- and hypoxia-related factors (hypoxia-inducible factor 1A, vascular endothelial growth factor and erythropoietin) in the brain, heart and kidneys. Further accumulation of practical data may be essentially important to establish evidence for medico-legal assessment in individual cases and to renew forensic pathology in response to potential social requirements.
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PMID:[Pathophysiochemistry of acute death: an approach to evidence-based assessment in forensic pathology]. 1552 66

The mechanisms underlying neurologic deficits and delayed neuronal death after ischemia are not fully understood. In the present study, we report that transient cerebral ischemia induces accumulation of ubiquitinated proteins (ubi-proteins) in postsynaptic densities (PSDs). By immunoelectron microscopy, we demonstrated that ubi-proteins were highly accumulated in PSD structures after ischemia. On Western blots, ubi-proteins were markedly increased in purified PSDs at 30 minutes of reperfusion, and the increase persisted until cell death in the CA1 region after ischemia. In the resistant DG area, however, the changes were transient and significantly less pronounced. Deposition of ubi-proteins in PSDs after ischemia correlates well with PSD structural damage in the CA1 region as viewed by electron microscopy. These results suggest that the ubiquitin-proteasome system fails to repair and remove damaged proteins in PSDs. The changes may demolish synaptic neurotransmission, contribute to neurologic deficits, and eventually lead to delayed neuronal death after transient cerebral ischemia.
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PMID:Protein ubiquitination in postsynaptic densities after transient cerebral ischemia. 1554 15

Using ubiquitin immunohistochemistry and impregnative Nauta method we demonstrated that ubiquitin positivity and Nauta positivity in the neurons affected with ischemic injury in the lumbosacral spinal cord of rabbits and dogs may be of the same origin. Increased number of ubiquitin-positive aggregates was found in the cytoplasm of neurons in the intermediate zone and lamina IX of ventral horns of spinal cord in rabbits after 30 min of ischemia followed by 24 h lasting reperfusion. Nauta-positive, flocculent, intracytoplasmic, dark clusters appeared in the same localization in the canine lumbosacral spinal cord neurons after 30 min of ischemia and 24 h of reperfusion. Ubiquitin aggregates and Nauta-positive dark clusters in the injured spinal cord neurons could be the first light microscopic signs of slow neuronal death following spinal cord ischemia and reperfusion.
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PMID:Visualization of protein aggregation in nerve cells after ischemia/reperfusion by ubiquitin immunohistochemistry and impregnative Nauta method. 1556 42

Our prior work demonstrated that geldanamycin (GA) reduced injury due to oxygen-glucose deprivation (OGD) in primary astrocyte cultures. Using medium with an ionic composition similar to that observed during in vivo global ischemia, the selectivity and temporal profile of CA1 neuronal damage seen in vivo was mimicked with OGD in mouse hippocampal organotypic slice cultures. The present study tested the ability of GA to reduce delayed neuronal death in such cultures. Treating organotypic cultures with 100 nM GA for 24 h prior to OGD induced Hsp70 and significantly reduced CA1 neuronal damage. Staining with ubiquitin to identify protein aggregates revealed reduced redistribution of ubiquitin, consistent with reduced protein aggregation likely due at least in part to induction of Hsp70 by GA.
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PMID:Geldanamycin treatment reduces delayed CA1 damage in mouse hippocampal organotypic cultures subjected to oxygen glucose deprivation. 1586 91

Transient cerebral ischemia leads to protein aggregation mainly in neurons destined to undergo delayed neuronal death after ischemia. This study utilized a rat transient cerebral ischemia model to investigate whether ischemic preconditioning is able to alleviate neuronal protein aggregation, thereby protecting neurons from ischemic neuronal damage. Ischemic preconditioning was introduced by a sublethal 3 min period of ischemia followed by 48 h of recovery. Brains from rats with either ischemic preconditioning or sham-surgery were then subjected to a subsequent 7 min period of ischemia followed by 30 min, 4, 24, 48 and 72 h of reperfusion. Protein aggregation and neuronal death were studied by electron and confocal microscopy, as well as by biochemical analyses. Seven minutes of cerebral ischemia alone induced severe protein aggregation after 4 h of reperfusion mainly in CA1 neurons destined to undergo delayed neuronal death (which took place after 72 h of reperfusion). Ischemic preconditioning reduced significantly protein aggregation and virtually eliminated neuronal death in CA1 neurons. Biochemical analyses revealed that ischemic preconditioning decreased accumulation of ubiquitin-conjugated proteins (ubi-proteins) and reduced free ubiquitin depletion after brain ischemia. Furthermore, ischemic preconditioning also reduced redistribution of heat shock cognate protein 70 and Hdj1 from cytosolic fraction to protein aggregate-containing fraction after brain ischemia. These results suggest that ischemic preconditioning decreases protein aggregation after brain ischemia.
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PMID:Ischemic preconditioning prevents protein aggregation after transient cerebral ischemia. 1593 39

Protein turnover represents the balance between protein synthesis and degradation. It can be controlled quantitatively, for instance by an activation of protein synthesis during cardiac hypertrophy or by activating protein degradation during ventricular unloading. It can also be regulated qualitatively by changing the steady state concentration of specific proteins and enzymes. The recent literature points to an emerging role for the mammalian target of rapamycin (mTOR) and for the ubiquitin-proteasome system (UPS) in this process, and both pathways interact in the regulation of cell growth and survival. We highlight the critical role played by such interaction in different cellular functions, including insulin signaling, stress response to hypoxia, adaptation to variations in workload, regulation of protein phosphatase activity, apoptosis and post-ischemic recovery. A deregulation of these pathways participates in the mechanisms of cardiac ischemia, hypertrophy and failure, and controlling their activity represents an opportunity for novel therapeutic avenues.
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PMID:Protein turnover in cardiac cell growth and survival. 1606 Dec 15

Protein aggregation and misfolding are central mechanisms of both acute and chronic neurodegeneration. Overexpression of chaperone Hsp70 protects from stroke in animal and cell culture models. Although it is accepted that chaperones protect cells, the mechanism of protection by chaperones in ischemic injury is poorly understood. In particular, the relative importance of preventing protein aggregation compared to facilitating correct protein folding during ischemia and recovery is not known. To test the importance of protein folding and minimize interaction with co-chaperones we studied the bacterial chaperonin GroEL (HSPD1) and a folding-deficient mutant D87K. Both molecules protected cells from ischemia-like injury, and reduced infarct volume and improved neurological outcome after middle cerebral artery occlusion in rats. Protection was associated with reduced protein aggregation, assessed by ubiquitin immunohistochemistry. Marked neuroprotection by the folding-deficient chaperonin demonstrates that inhibition of aggregation is sufficient to protect the brain from ischemia. This suggests that strategies to maintain protein solubility and inhibit aggregation in the face of acute insults such as stroke may be a useful protective strategy.
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PMID:Chaperonin GroEL and its mutant D87K protect from ischemia in vivo and in vitro. 1625 78

Heat shock protein (Hsp)70 can suppress both necrosis and apoptosis induced by various injuries in vivo and in vitro. However, the relative importance of different functions and binding partners of Hsp70 in ischemic protection is unknown. To explore this question, we tested the ability of Hsp70-K71E, an adenosine triphosphate (ATP)ase-deficient point mutant, and Hsp70-381-640, a deletion mutant lacking the ATPase domain and encoding the carboxyl-terminal portion, to protect against ischemia-like injury in vivo and in vitro. Heat shock protein 70-wild type (-WT), -K71E, -381-640, and control vector plasmid LXSN were expressed in primary murine astrocyte cultures. Astrocytes overexpressing Hsp70-WT, -K71E, or -381-640 were all significantly protected from 4 h combined oxygen-glucose deprivation and 24 h reperfusion when assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay or propidium iodide staining and cell counting (P < 0.05). Brains of rats were transfected with plasmids encoding Hsp70-WT, -K71E, -381-640, or LXSN 24 h before 2 h middle cerebral artery occlusion followed by 24 h reperfusion. Animals that overexpressed either of the mutant proteins or Hsp70-WT had significantly better neurological scores and smaller infarcts than control animals. Protection by both mutants was associated with reduced protein aggregation, as assessed by ubiquitin immunohistochemistry and reduced nuclear translocation of apoptosis-inducing factor. The results show that the carboxyl-terminal portion of Hsp70 is sufficient for neuroprotection. This indicates that neither the ability to fold denatured proteins nor interactions with cochaperones or other proteins that bind the amino-terminal half of Hsp70 are essential to ischemic protection.
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PMID:The carboxyl-terminal domain of inducible Hsp70 protects from ischemic injury in vivo and in vitro. 1629 51

Numerous proteins are known to be lost following myocardial ischemia/reperfusion yet little is known about the mediating proteinases. This study examines the hypothesis that proteasome plays a significant role in the removal of proteins oxidized during myocardial ischemia. Proteasome was inhibited by perfusing isolated rat hearts with buffer containing lactacystin, 2 micromol/L, for 10 min, which resulted in 51 and 42% decreases in 20S and 26S proteasome activities that persisted for a minimum of 90 min. Lactacystin pretreatment had minor effects on postischemic recovery of isolated hearts exposed to 30 min global ischemia and 60 min reperfusion. Protein carbonyl content of lactacystin-pretreated ischemic hearts was significantly (P < 0.05) increased. One band with approximate molecular mass of 50 kDa is known to contain oxidized actin. Actin degradation was quantitated by analysis of 3-methylhistidine which was significantly (P < 0.05) decreased by 15% following 30 min ischemia and 60 min reperfusion. Pretreatment of ischemic hearts with lactacystin prevented much of the loss (-6.5%) of 3-methylhistidine. Probing immunoprecipitated actin with an antibody specific for ubiquitin revealed no bands containing ubiquitinated homologues of this protein. These observations support the conclusion that proteasome mediates removal of some of the proteins oxidized during myocardial ischemia/reperfusion, and that at least oxidized actin is removed by the 20S proteasome.
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PMID:Proteasome mediates removal of proteins oxidized during myocardial ischemia. 1633 89

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


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