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)

C-Jun expression in the hippocampus of gerbils subjected to 5 min of transient forebrain ischemia was examined with immunohistochemistry and western blotting using two c-Jun antibodies raised against two different amino acid sequences. Both c-Jun antibodies showed increased immunoreactivity at 6 and 12 h postischemia in the stratum pyramidale of CA3 and granule cell layer of the dentate gyrus. No immunostaining was detected in CA1 up to the 7th day. Western blots showed increased c-Jun immunoreactivity at 6 and 12 h. However, the antibody c-Jun (AB-1) detected a single band at about p39 in normal and post-ischemic states, whereas the antibody c-Jun/AP-1 (N) recognized a band at about p39 in normal and post-ischemic gerbils, and a p62 phosphorylated double-band at 6 and 12 h following ischemia. In addition, increased c-Jun N-terminal kinase-1 (JNK-1) expression was observed on western blots at 6 and 12 h postischemia. These results suggest that different c-Jun-related responses, some of which probably indicate post-translational changes of the c-Jun protein, occur in the hippocampus of the gerbil following transient forebrain ischemia.
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PMID:Transient forebrain ischemia in the adult gerbil is associated with a complex c-Jun response. 926 13

The Ref-1 protein is a bifunctional nuclear enzyme involved in repair of DNA lesions and in redox regulation of DNA-binding activity of AP-1 family members, such as Fos and Jun transcription factors. In the present study, we demonstrate by in situ hybridization that transient global ischemia induced by cardiac arrest activates ref-1 mRNA expression in the granular cells of the rat dentate gyrus after 6 h and in CA1 pyramidal neurons of the hippocampus proper after 24 h, respectively. Immunohistochemical analysis revealed nuclear accumulation of Ref-1 protein in granular cells of the ischemia-resistant dentate gyrus, whereas Ref-1 protein expression progressively decreased in vulnerable CA1 neurons of the post-ischemic hippocampus from 24 h onwards. At the same time point, intense nuclear c-Jun immunoreactivity was observed in both neuronal cell populations. Our data suggest that oxidative stress induced by ischemia-reperfusion may increase neuronal ref-1 expression. However, inability of ref-1 mRNA translation and nuclear translocation of encoded protein in CA1 pyramidal neurons may inhibit repair of oxidative DNA damage or cellular adaptive responses leading to delayed neuronal cell death.
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PMID:Expression of nuclear redox factor ref-1 in the rat hippocampus following global ischemia induced by cardiac arrest. 949 40

Apoptosis in the nervous system is a necessary event during the development of the nervous system and is also present after genotoxic events, be they chronic as in aging or more acute after trauma and ischemia. Apoptotic events reflect an interplay between intrinsic signaling events that rely on cytokines, neurotransmitters, and growth factors and responses to extrinsic events that increase levels of radical oxygen species. Both intrinsically and extrinsically driven signal-transduction pathways act via transcription factors that regulate the coordinated timely expression of stress-response genes as part of a decision-making process that can commit cells to apoptosis or survival. Here we discuss the role of two transcription factors that participate in apoptosis in the nervous system: the activator protein AP-1 and nuclear factor kappaB.
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PMID:Signal transduction in neuronal death. 968 34

For many inherited and acquired hepatic diseases, liver transplantation is the only possible therapeutic strategy. Ischemia/reperfusion (I/R) damage to donor tissue is thought to be one component that may play a role in the decline of posttransplant tissue function and ultimately rejection. The transcription factors, AP-1 and nuclear factor kappaB (NF-kappaB), play important roles in the acute cellular responses to tissue damage, as well as the inflammatory phase following I/R. We have found that the DNA binding activity of AP-1 was dramatically increased following warm ischemia at 1 to 3 hours postreperfusion. Induced DNA binding activity was composed of predominately c-Jun and JunD hetero- and homodimers as determined by electrophoretic mobility supershift assays. This increase in AP-1 activity occurred in the absence of significant changes in the steady-state protein levels of c-Jun and JunB. Maximal activation of Jun amino-terminal kinase ( JNK) occurred within the 25 to 30 minutes postreperfusion, just before the peak in AP-1 DNA binding. These findings suggest that phosphorylation may play an important role in regulating AP-1 transcriptional complexes. Furthermore, JunD protein levels slightly increased at 3 hours postreperfusion, concordant with changes in AP-1 DNA binding activity. The activation of NF-kappaB at 1 hour postreperfusion was independent of proteolytic degradation of IkappaB- or IkappaB-beta. This activation of NF-kappaB DNA binding activity in the nucleus was preceded by an increase in tyrosine phosphorylation of IkappaB-. These studies suggest that JNK, IkappaB tyrosine kinase, and JunD are potential targets for therapeutic intervention during liver I/R injury.
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PMID:Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor kappaB independently of IkappaB degradation. 975 39

Synaptic activation leads to the formation of arachidonic acid, platelet-activating factor (PAF, 1-O-alkyl-2-acyl-sn-3-phosphocholine) and other lipid messengers. PAF is a potent bioactive phospholipid in synaptic plasticity. PAF enhances presynaptic glutamate release, is a retrograde messenger in long-term potentiation and enhances memory formation. PAF also couples synaptic events with gene expression by stimulating a FOS/JUN/AP-1 transcriptional signaling system, as well as transcription of COX-2 (inducible prostaglandin synthase). Since the COX-2 gene is also involved in synaptic plasticity, the PAF-COX-2 pathway may have physiological significance. Seizures, ischemia and other forms of brain injury promote phospholipase A2 (PLA2) overactivation, resulting in the accumulation of bioactive lipids at the synapse. PAF, under these pathological conditions, behaves as a neuronal injury messenger by at least two mechanisms: (a) enhancing glutamate release; and, (b) by sustained augmentation of COX-2 transcription. These events link PAF with neurodegeneration. The upstream intracellular pathways of signal transduction involved in neuronal or photoreceptor cell apoptosis are not well understood and involve stress sensitive kinases. PAF is a transcriptional activator of the COX-2 gene. BN 50730, a potent intracellular PAF antagonist, blocks COX-2 induction. COX-2 transcription and protein expression are upregulated in the hippocampus in kainic acid induced epileptogenesis. There is a selectively elevated induction of COX-2 (72-fold) by kainic acid preceding neuronal cell death. BN 50730 administered by i.c.v. injection blocks seizure-induced COX-2 induction. Overall, PAF is a dual modulator of neural function and becomes an endogenous neurotoxin when over produced.
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PMID:The neuromessenger platelet-activating factor in plasticity and neurodegeneration. 993 49

Oxidative stress causes cardiac damage following ischemia/reperfusion and in response to anthracyclines. Extracellular signal-regulated kinases (ERK) 1/2 are activated by oxidative stress in cardiac myocytes and protect cardiac myocytes from apoptosis. Prostaglandins (PG) also protect cells from injury in a number of tissues, including the cardiomyocyte. Cyclooxygenase (COX) the rate-limiting enzyme in PG biosynthesis has two isoforms, the constitutive COX-1 and an inducible COX-2. Here, we examined the effects of two oxidative stresses, hydrogen peroxide (H2O2) and the anthracycline doxorubicin on the activity of ERK1/2 and the expression of COX isoforms and PG formation in neonatal rat primary cardiomyocytes. These cells expressed COX-1 at rest and both COX isoforms on treatment with phorbol 12-myristate 13-acetate. Exposure to 50 microM H2O2 for 10 min or doxorubicin at 10 and 100 micrograms/ml caused expression of COX-2 that was prevented by free radical scavengers. COX-2 induction was associated with activation of ERK1/2 and the specific ERK-inhibitor PD098059 abolished COX-2 expression. Treatment of cells with decoy oligonucleotides corresponding to COX-2 promoter elements implicated the AP-1 and NF-kappaB-2 but not the NF-kappaB-1 in the transcription of COX-2. Induction of COX-2 mRNA and protein was accompanied by increased prostacyclin formation, which was abolished by the selective COX-2 inhibitor, NS-398, and PD098059. H2O2 and doxorubicin enhanced the release of lactate dehydrogenase and free radical scavengers prevented this. NS-398 enhanced the release of lactate dehydrogenase in response to H2O2 and doxorubicin, whereas the injury was prevented by iloprost, a stable prostacyclin analogue. In cardiomyocytes cell injury by H2O2 and doxorubicin is limited by an increase in prostacyclin formation that reflects induction of COX-2 mediated by ERK1/2 activation.
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PMID:Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. 998 50

Acute ischemia followed by prolonged reperfusion has been shown to induce cardiomyocyte apoptosis. In this report, we demonstrate that myocardial adaptation to ischemia induced by repeated cyclic episodes of short-term ischemia each followed by another short duration of reperfusion reduced cardiomyocyte apoptosis and DNA fragmentation. This was associated with the induction of the expression of Bcl-2 mRNA and translocation and activation of NF-kappaB. Another transcription factor, AP-1, remained unaffected by repeated ischemia and reperfusion, but exhibited significant upregulation by a single episode of 30 min ischemia followed by 2 h of reperfusion. This activation of AP-1 was inhibited by a scavenger of oxygen free radicals, DMTU. Thirty minutes ischemia and 120 min reperfusion downregulated the induction of the expression of Bcl-2 mRNA, but moderately activated NF-kappaB binding activity. This was associated with an increased number of apoptotic cells and DNA fragmentation in cardiomyocytes which were attenuated by DMTU. The results of this study indicate that Bcl-2, AP-1 and NF-kappaB differentially regulate cardiomyocyte apoptosis mediated by acute ischemia and prolonged reperfusion.
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PMID:Differential regulation of Bcl-2, AP-1 and NF-kappaB on cardiomyocyte apoptosis during myocardial ischemic stress adaptation. 1002 58

The immediate early genes (IEGs), c-jun, junB and c-fos are expressed after global ischemia in the gerbil. The role of these genes remains unclear. Whilst moderate ischemia (7 min) causes delayed CA1 neuronal death, pre-conditioning with mild ischemia (2 min) neuroprotects the CA1 subfield. This differential response allows the specific expression patterns of IEGs to be associated with either delayed neuronal death, or cell survival, depending upon the insult severity. Using a graded insult strategy we have shown that (1) early IEG expression is prominent in the neuronal layers of the CA3, hilar and dentate regions, and (2) a delayed, secondary wave of JunB expression is localized to the selectively vulnerable CA1 neuronal layer after moderate ischemia. This expression precedes the histological and histochemical features of neuronal death. Delayed JunB expression was not observed in animals subject to 2 min ischemia. The glial fibrillary acidic protein (GFAP) promotor possesses an AP-1 binding site, the target for IEG dimers. To examine the possible link between IEG expression and astrocyte activation the transcriptional activation of GFAP was assessed. GFAP mRNA was evident within 8 h of ischemia after both insults. The extent of the astrocytic reaction was dependent upon the severity of the ischemia. The temporospatial distribution of IEG and GFAP expression differed, indicating that glial activation is unlikely to be regulated by the hippocampal expression of IEGs. We conclude that early IEG expression is involved in signalling mechanisms that invoke neuroprotective effects in the dentate and CA3 regions, and that delayed JunB expression in the CA1 subfield is associated with neuronal death, and may be involved in the commitment or execution phases of cell death. Early astrocytic responses may play a role in the mechanism of ischaemic tolerance.
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PMID:Delayed induction of JunB precedes CA1 neuronal death after global ischemia in the gerbil. 1008 31

Activation of c-fos, an immediate early gene, and the subsequent upregulation of Fos protein expression occur following neural injury, including focal cerebral ischemia (fci). Fos and Jun form a heterodimer known as activator protein 1, which regulates the expression of many late effector genes. To study the downstream effects of c-fos expression following ischemia, we suppressed the translation of c-fos by administering an antisense oligonucleotide (AO) to c-fos mRNA. Eighteen hours prior to fci, male, Long Evans (LE) rats received intraventricular injections of AO, mismatched AO (MS) or artificial cerebrospinal fluid (aCSF). Fci was induced by permanent right middle cerebral artery occlusion. At 24-h post-occlusion, neurological function was assessed, and the animals were sacrificed. The brains were removed and stained with triphenyltetrazolium chloride for infarct volume determination. Fos immunohistochemistry was performed in separate animals to determine the effects of treatment on Fos expression number of Fos positive cells. AO administration reduced the number of cells with fci-induced Fos expression by approximately 75%. No differences in neurological scores existed between any of the groups. AO-treated LE developed larger infarcts (40.1+/-1.0%, mean+/-S.D., p<0.001) than MS- or aCSF-treated controls (34.3+/-1.0%, 34.6+/-1.0%, respectively). These results suggest that c-fos activation and subsequent Fos protein expression exerts a neuroprotective effect, which is likely via upregulation of neurotrophins, following focal cerebral ischemia. This response, among others, may contribute to brain adaptation to injury that underlies functional recovery after stroke.
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PMID:Suppression of post-ischemic-induced fos protein expression by an antisense oligonucleotide to c-fos mRNA leads to increased tissue damage. 1037 56

Cells respond to external stimuli by changes in gene expression that are largely dependent on transcription factors (TFs). We studied the behavior of some TFs in rat liver during ischemia, postischemic reperfusion, and heat shock. Knowledge of the conditions at the end of ischemia is essential to understand changes occurring at reperfusion. The TFs investigated are known to be typically responsive to heat shock (HSF), hypoxia (HIF-1), pro- and antioxidant conditions (AP-1), or to various environmental changes (HNF-1 and ATF/CREB family). The most relevant new information includes the following: 1) Liver ischemia activates extremely rapidly the DNA binding capacity of HSF, soon followed by analogous activation of HIF-1 and AP-1. 2) After a certain lag time from the activation of HIF-1, mRNAs accumulate for two glycolytic enzymes, in particular Aldolase A and Heme Oxygenase 1, which contain HIF-1 sequences in their promoters. 3) Reperfusion, which is known to further increase the binding of HSF and to induce NFkappaB binding, abrogates or decreases the binding of HIF-1 and AP-1, stimulated by ischemia, and activates the binding of ATF/CREB. Later on, a second peak of AP-1 binding is induced. 4) Heat shock activates both ischemia-responsive and reperfusion-responsive TFs. 5) Preliminary experiments of supergelshift reveal that the activation of AP-1 at reperfusion or upon heat shock may result from the different involvement of the component subunits.
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PMID:Differential activation of some transcription factors during rat liver ischemia, reperfusion, and heat shock. 1039 95


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