UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of the immediate early genes (IEG)s c-fos, c-jun and zif/268, and the genes coding for ornithine decarboxylase (ODC) and its regulatory protein antizyme (AZ), was studied in rat small intestine following transient ischemia. The ischemic stimulus for 10 min alone did not alter the expression of these genes. A rapid and transitory induction of all IEG mRNAs occurred in a coordinated manner peaking at 30 min following recirculation and returned to basal levels 3 hr after recirculation. Protein products of the IEGs accumulated in the smooth muscle layer of the intestine by 2-3 hr after recirculation. Expression of both ODC and AZ mRNAs initially decreased to 70% of control levels 1 hr after recirculation but markedly increased at 2 to 4 hr after recirculation. The functional significance of these changes in gene expression in relation to tissue integrity and function after the ischaemia/reperfusion is discussed.
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PMID:Induction of immediate-early, ornithine decarboxylase and antizyme gene expression in the rat small intestine after transient ischaemia. 864 18

The expression of the immediate early genes (IEGs) c-fos and e-jun have been hypothesized to potentially play key roles in mediating cellular responses following injury to the liver. In this study, we sought to evaluate the potential involvement of c-jun and c-fos as determinants either of cellular regeneration or programmed cell death following ischemia/reperfusion (I/R) in mouse liver. To this end, we have analyzed the in situ messenger RNA (mRNA) expression patterns of c-jun and c-fos following lobar I/R in mouse liver. The expression patterns of c-jun and c-fos were correlated with four criteria for tissue repair and injury, including: 1) morphological determinations of regeneration using immunocytochemical detection of proliferating cell nuclear antigen (PCNA), 2) programmed cell death (apoptosis) using the in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, 3) histopathologic assessment of hepatocellular necrosis, and 4) serum glutamic pyruvic transaminase (GPT) levels. Increasing lengths of lobar ischemia for 3, 60, and 90 minutes followed by reperfusion directly correlated with the extent of liver injury as determined by serum transaminases and hepatocellular necrosis. PCNA expression in the liver was elevated at 1 to 6 hours following liver reperfusion and returned to baseline levels by 20 hours in both ischemic and nonischemic lobes. In contrast, apoptotic responses peaked only in ischemic lobes at 6 hours' postreperfusion and remained elevated out to 20 hours. Two distinct patterns of c-jun and c-fos expression were observed during the acute (1-3 hours) and subacute (6-20 hours) phases of liver responses to I/R including: 1) coexpression of c-jun and c-fos mRNA within damaged regions of the liver at 1 to 3 hours' postreperfusion, and 2) a decline in c-fos expression with sustained high levels of c-jun expression within a subset of cells bordering necrotic/apoptotic regions of the liver at 6 to 20 hours' postreperfusion. These findings suggest that coexpression of both c-jun and c-fos may be involved in mediating early tissue repair processes in liver remodeling following I/R. In contrast, the onset of hepatocellular apoptosis correlated with sustained c-jun expression, in the absence of c-fos, and suggests that these changes in the molecular profile of immediate early gene expression may regulate cellular responses that signal hepatocytes for programmed cell death.
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PMID:Expression of c-fos and c-jun during hepatocellular remodeling following ischemia/reperfusion in mouse liver. 867 76

In recent years much has been learned about the cellular and molecular events underlying cerebral hypoxia-ischemia (HI). We review, from a molecular standpoint, the main pathogenetic theories in hypoxic-ischemic cerebral injury, including excitotoxicity, free radical damage, and the role of growth factors, proto-oncogenes and heat shock proteins. The various forms of cell death in the developing and adult brain (necrosis, apoptosis and delayed neuronal death) are reviewed, with an emphasis on gene regulation of naturally-occurring and HI-associated cell death. We report the expression of the immediate early gene c-fos and c-jun mRNAs and of HSP72 mRNA and protein in several models of cerebral HI. Gel agarose electrophoresis of extracted DNA and in situ end-labeling of fragmented DNA revealed that cell death in these models was associated with endonuclease(s) activation. We also pre-treated some animals with dexamethasone, a neuroprotective drug in a model of perinatal HI. High-dose dexamethasone prevented c-fos induction in cerebral regions sensitive to HI. This effect may be due to a functional antagonism, at the transcriptional level, between Fos and the glucocorticoid receptor.
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PMID:[Molecular factors of cerebral hypoxia-ischemia]. 868 Dec 2

We examined the effect of reversible ischemia on the transcription of prostaglandin endoperoxide synthase (PGHS-1) and c-fos mRNA in rat cerebral cortex. The level of PGHS-1 mRNA climaxed after 30 min of ischemia whereas transcription of c-fos mRNA peaked after 60 min of postischemic reperfusion. We conclude that cerebral ischemia causes early transcription of PGHS-1, without modulation by the c-fos gene or its translated product.
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PMID:Induction of PGH synthase and c-fos mRNA during early reperfusion of ischemic rat brain. 871 74

Molecular events underlying the mechanism by which brain injury elicits delayed transneuronal degeneration of neurons remote from the site of initial injury are not well understood. In rats, acute injury of the caudate nucleus (CN) and globus pallidus (GP) by local injection of excitotoxic ibotenic acid (IA) or by transient forebrain ischemia resulted in delayed cell death of neurons in the substantia nigra reticulata (SNr). To elucidate the involvement of glutamate receptor mediated hyperactivity of neurons produced by loss of inhibitory inputs in this delayed degeneration of SNr neurons, the region-specific expression of an immediate early gene, c-fos, and the effect of glutamate receptor antagonists on the c-fos expression were examined by using immunocytochemical and in situ hybridization analysis. Following unilateral IA-injection into the CN and GP, a robust expression of c-fos mRNA and Fos protein was induced specifically in neurons of both subthalamic nucleus (STN) and SNr deafferented by the IA-lesions 36 h after IA-injection. The delayed expression of Fos-protein in SNr neurons lasted for 48 h longer than that in STN neurons. Following unilateral IA-injection confined to the CN, an intense but short-term expression of Fos-protein was exhibited only in neurons of the deafferented SNr. c-fos mRNA and Fos protein were not expressed in neurons of the substantia nigra compacta at any time points examined. The induction of c-fos mRNA and Fos protein in neurons of the STN and SNr following IA-lesions of the CN and GP was reduced markedly by non-NMDA receptor antagonist (GYKI52466), but not by NMDA receptor antagonist (MK-801). The region-specific c-fos expression implies that deprivation of inhibitory afferents (disinhibition) due to destruction of presynaptic neurons can induce increased activity of postsynaptic neurons. The effect of GYKI52466 on the c-fos gene expression in neurons of the deafferented STN and SNr suggests that activation of non-NMDA receptors may be involved in a pathophysiological cascade for the transneuronal degeneration of SNr neurons.
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PMID:Deafferentiation-induced c-fos gene expression in subthalamic nucleus and substantia nigra reticulata is reduced by non-NMDA receptor antagonist. 871 29

The occurrence of blood-brain barrier (BBB) permeability alterations and neovascularization are well documented in the cerebral cortical cold-injury model. This model was used to determine whether the glucose transporter (glutI) protein was present in endothelium of cerebral vessels with breakdown of BBB to protein and when regenerating endothelial cells become immunoreactive for glutI protein. Secondly, the protein products of c-fos and c-jun were localized to determine whether these early immediate genes are activated in this model. Observations were made over a period of 12 hours to 14 days after the cold-injury. Blood-brain barrier permeability was assessed using horseradish peroxidase (HRP) as a tracer. Since HRP may not be able to enter thrombosed vessels within the cold lesion, immunohistochemistry was used to detect extravasation of endogenous serum proteins using antisera to rat serum proteins. The proteins-glut1, GFAP, c-fos and c-jun-were localized by immunohistochemistry. Endothelium of vessels which were permeable to protein, whether in the cold-injury site or in the perilesional area, all contained glut1 protein; hence, the presence of glut1 did not appear to correlate with an intact BBB to protein. An interesting point is that in the process of neovascularization, regenerating endothelial cells become immunoreactive for glut1 at 5 days and this coincides with the presence of tight junctions in these cells. Immunoreactivity for c-fos was observed in regenerating endothelium within the lesion site, in astrocytes, and to a lesser extent in endothelial cells and neurons in the perilesional area. Few astrocytes showed immunoreactivity for c-jun at 4 and 5 days. Possibly, the growth factors generated to promote angiogenesis and repair led to activation of the c-fos gene with deposition of c-fos protein. The results suggest that during nervous system development or endothelial regeneration, the presence of glut1 in cerebral endothelium coincides with the presence of an intact BBB to protein and protein tracers. However, in pathological states presence of glut1 in cerebral endothelium does not appear to correlate with an intact BBB to protein. This model lends itself to the study of angiogenesis and repair processes in the cerebral cortex in an environment unaffected by ischemia and thus the findings may be relevant to traumatic injuries of the human cerebral cortex.
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PMID:Cold-injury of the cerebral cortex: immunolocalization of cellular proteins and blood-brain barrier permeability studies. 875 77

Following transient forebrain ischemia selective and delayed neuronal degeneration occurs in the CA1 sector of the hippocampus. It is presently unclear whether this cell death is related to programmed cell death (PCD), which occurs in neurons during development of the CNS. Recently, the expression of various genes, such as c-fos, c-jun mkp-1, cyclin D1, and hsp70 was found to be associated with PCD in model systems. We and others have described that these genes are also upregulated in the hippocampus following ischemia. Most notably, c-fos, c-jun, and hsp70 are expressed specifically in CA1 neurons at survival times shortly preceding cell degeneration in rat models of global ischemia. In addition, the gene products could be detected by immunohistochemical methods, despite a general impairment of protein synthesis. These finding are especially relevant, since recent report suggests a functional role for Fos family proteins and c-jun in PCD in neurons of the superior cervical ganglion. These results could be indicative for the occurrence of a PCD-related program in CA1 neurons ad corroborate several other lines of evidences, such as occurrence of DNA fragmentation. Clearly, further studies are necessary to elucidate the functional role of the gene inductions following ischemia in vivo.
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PMID:Molecular correlates of delayed neuronal death following transient forebrain ischemia in the rat. 878 Jul 89

Protein tyrosine phosphorylation is thought to play an important role in the regulation of neural function. We reported previously that CL100, a cytoplasmic type protein tyrosine phosphatase (PTP), was induced after transient forebrain ischemia. In the present study, changes in the mRNA levels after ischemia of PRL-1, a cytoplasmic type PTP and immediate-early gene similar to CL100, was examined. In situ hybridization histochemistry showed that PRL-1 mRNA was expressed in normal adult rats in neurons and oligodendrocytes in widespread regions including the cerebral cortex, hippocampus and cerebellum. PRL-1 mRNA was expressed in the developing brains on embryonic days 15 and 19 and postnatal day 1. Northern blot analysis showed that PRL-1 mRNA was induced from 6 h to 9 h after reperfusion in the cerebral cortex of postischemic rats. These findings suggest that PRL-1 plays a role in neurons and oliogodendrocytes, and that expression of PRL-1 mRNA is regulated by a mechanism different from those of other immediate-early genes such as c-fos and c-jun.
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PMID:PRL-1, a protein tyrosine phosphatase, is expressed in neurons and oligodendrocytes in the brain and induced in the cerebral cortex following transient forebrain ischemia. 884 18

The redox status of the cell plays an essential role in regulating signal transduction, transcription factor activity, and expression of cell surface molecules. In this study, we show that pyrrolidine dithiocarbamate (PDTC), a potent antioxidant agent, upregulated the cell surface expression of intercellular adhesion molecule-1 (ICAM-1) in human endothelial cells (EC). Further analysis of PDTC-mediated ICAM-1 up-regulation revealed that PDTC increased ICAM-1 mRNA levels and augmented its gene promoter activity. Transfection experiments in EC with reporter constructs harboring nested deletion fragments of the ICAM-1 promoter indicated the presence of a functional PDTC-responsive region located between positions -136 to -353 of the promoter. Gel retardation assays together with supershift analysis revealed that PDTC induced the binding of c-fos and c-jun to a consensus activating protein-1 (AP-1) binding site located at position -284. PDTC alone or in combination with TNF-alpha enhanced AP-1-dependent transactivation in HUVEC, as determined by DNA binding assays. The functional implication of AP-1 in the transcription of the ICAM-1 gene was further demonstrated by cotransfection experiments in which a c-jun expression vector induced the promoter activity of the PDTC-responsive element of the ICAM-1 promoter. Taken together, these results indicate that the antioxidant PDTC induces transcriptional activation of ICAM-1 and that this induction is mediated at least in part by the transcription factor AP-1. This mechanism might be operative in pathologic conditions in which a redox imbalance plays a key role, such as ischemia/reperfusion injury or arteriosclerosis.
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PMID:Transcriptional up-regulation of intracellular adhesion molecule-1 in human endothelial cells by the antioxidant pyrrolidine dithiocarbamate involves the activation of activating protein-1. 887 59

Selective phospholipids of synaptic membranes are reservoirs for lipid second messengers. 1-Alkyl-2 arachidonoyl glycero-3-phosphocholine is hydrolyzed by phospholipase A2 (PLA2) into two products: lyso-PAF, which is transacetylated to yield platelet-activating factor (PAF), and free arachidonic acid (20:4), which can undergo oxidative metabolism to eicosanoids. Alternative pathways of PAF synthesis, such as CoA-independent transacylase and the de novo route of synthesis, remain to be explored and compared to the PLA2-dependent route. At low concentrations, PAF is a retrograde messenger of LTP in CA1 hippocampal neurons, and is also a memory enhancer in inhibitor avoidance tasks. PAF enhances excitatory amino acid release in synaptic pairs from primary hippocampal cultures by a presynaptic mechanism. Ischemia and convulsions activate synaptic PLA2. Thus, increased concentrations of PAF promote massive glutamate exocytosis, glutamate receptor activation, and elevated intracellular calcium levels in target cells. As a result, calcium-sensitive cascades are affected. PAF thus had dual roles as a lipid mediator: under physiological conditions it modulates neurotransmitter release, but at high concentrations it becomes neurotoxic. Through an intracellular high affinity binding site, PAF activates the expression of immediate-early genes. Some of these genes encode transcription factors (e.g. zif-268, c-fos), and others encode enzymes (COX-2 or inducible prostaglandin synthase). PAF also activates the expression of metalloproteinases which participate in the remodeling of the extracellular matrix. These effects have been studied in cells in culture as well as in the brain. A PAF antagonist specific for the intracellular binding site inhibits COX-2 expression elicited by a single electroconvulsive shock or vasogenic edema. COX-1, the constitutive prostaglandin synthase, is not induced and is unaffected by the antagonist. Most of the cerebral induction occurs in the hippocampus and results from transcriptional activation. PAF mediated gene expression may be involved in neural plasticity as well as in pathophysiological conditions in which the neural tissue activates repair-injury pathways.
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PMID:Platelet-activating factor in the modulation of excitatory amino acid neurotransmitter release and of gene expression. 890 78

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