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)

MyD116 is the murine homologue of growth arrest- and DNA damage-inducible genes (gadd34), a gene family implicated in growth arrest and apoptosis induced by endoplasmic reticulum dysfunction. The present study investigated changes in MyD116 mRNA levels induced by transient forebrain ischemia. MyD116 mRNA levels were measured by quantitative PCR. After 2 h of recovery following 30 min forebrain ischemia, MyD116 mRNA levels rose to about 550% of control both in the cortex and hippocampus. In the cortex, MyD116 mRNA levels gradually declined to 290% of control 24 h after ischemia, whereas in the hippocampus they remained high (538% of control after 24 h of recovery). To elucidate the possible mechanism underlying this activation process, MyD116 mRNA levels were also quantified in primary neuronal cell cultures under two different experimental conditions, both leading to a depletion of endoplasmic reticulum (ER) calcium pools. Changes in cytoplasmic calcium activity were assessed by fluorescence microscopy of fura-2-loaded cells, and protein synthesis (PS) was evaluated by measuring the incorporation of l-[4,5-3H]leucine into proteins. The first procedure, exposure to thapsigargin (Tg), an irreversible inhibitor of ER Ca2+-ATPase, produced a parallel increase in cytoplasmic calcium activity and a long-lasting suppression of PS, while the second, immersion in a calcium-free medium supplemented with the calcium chelator EGTA, caused a parallel decrease in cytoplasmic calcium levels and a short-lasting suppression of PS. Exposure of neurons to Tg induced a permanent increase in MyD116 mRNA levels. Exposure of cells to calcium-free medium supplemented with EGTA produced only a transient rise in MyD116 mRNA levels peaking after 6 h of recovery. The results demonstrate that depletion of ER calcium stores without any increase in cytoplasmic calcium activity is sufficient to activate MyD116 expression. A similar mechanism may be responsible for the increase in MyD116 mRNA levels observed after transient forebrain ischemia. It is concluded that those pathological disturbances triggering the activation of MyD116 expression after transient forebrain ischemia are only transient in the cerebral cortex but permanent in the hippocampus.
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PMID:Activation of MYD116 (gadd34) expression following transient forebrain ischemia of rat: implications for a role of disturbances of endoplasmic reticulum calcium homeostasis. 987 49

The brain's response to ischemia, which helps determine clinical outcome after stroke, is regulated partly by competing genetic programs that respectively promote cell survival and delayed cell death. Many genes involved in this response have been identified individually or systematically, providing insights into the molecular basis of ischemic injury and potential targets for therapy. The development of microarray systems for gene expression profiling permits screening of large numbers of genes for possible involvement in biological or pathological processes. Therefore, we used an oligodeoxynucleotide-based microarray consisting of 374 human genes, most implicated previously in apoptosis or related events, to detect alterations in gene expression in the hippocampus of rats subjected to 15 minutes of global cerebral ischemia followed by up to 72 hours of reperfusion. We found 1.7-fold or greater increases in the expression of 57 genes and 1.7-fold or greater decreases in the expression of 34 genes at 4, 24, or 72 hours after ischemia. The number of induced genes increased from 4 to 72 hours, whereas the number of repressed genes decreased. The induced genes included genes involved in protein synthesis, genes mutated in hereditary human diseases, proapoptotic genes, antiapoptotic genes, injury-response genes, receptors, ion channels, and enzymes. We detected transcriptional induction of several genes implicated previously in cerebral ischemia, including ALG2, APP, CASP3, CLU, ERCC3, GADD34, GADD153, IGFBP2, TIAR, VEGF, and VIM, as well as other genes not so implicated. We also found coinduction of several groups of related genes that might represent functional modules within the ischemic neuronal transcriptome, including VEGF and its receptor, NRP1; the IGF1 receptor and the IGF1-binding protein IGFBP2; Rb, the Rb-binding protein E2F1, and the E2F-related transcription factor, TFDP1; the CACNB3 and CACNB4 beta-subunits of the voltage-gated calcium channel; and caspase-3 and its substrates, ACINUS, FEM1, and GSN. To test the hypothesis that genes identified through this approach might have roles in the pathophysiology of cerebral ischemia, we measured expression of the products of two induced genes not heretofore implicated in cerebral ischemia-GRB2, an adapter protein involved in growth-factor signaling pathways, and SMN1, which participates in RNA processing and is deleted in most cases of spinal muscular atrophy. Western analysis showed enhanced expression of both proteins in hippocampus at 24 to 72 hours after ischemia, and SMN1 was localized by immunohistochemistry to hippocampal neurons. These results suggest that microarray analysis of gene expression may be useful for elucidating novel molecular mediators of cell death and survival in the ischemic brain.
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PMID:Microarray analysis of hippocampal gene expression in global cerebral ischemia. 1145 15

Excessive nitric oxide (NO) has been implicated in neurotoxicity after stresses such as ischemia. NO toxicity is generally thought to be mediated by the DNA damage-p53 pathway or mitochondrial dysfunction. We investigated the mechanism of NO toxicity by using murine microglial MG5 cells established from p53-deficient mice. When MG5 cells were exposed to bacterial lipopolysaccharide plus interferon-gamma, mRNA and protein for inducible NO synthase (iNOS) were markedly induced, and apoptosis occurred. Under these conditions, we found that mRNA and protein for CHOP/GADD153, a C/EBP family transcription factor which is involved in endoplasmic reticulum (ER) stress-induced apoptosis, are induced. iNOS mRNA was induced 2 h after treatment, whereas CHOP mRNA began to increase at 6 h with a time lag. CHOP mRNA was also induced by NO donors S-nitroso-N-acetyl-DL-penicillamine (SNAP) or NOC18, or a peroxynitrite generator 3-(4-morpholinyl)-sydnonimine hydrochloride (SIN-1). Bip/GRP78, an ER chaperone which is known to be induced by ER stress, was also induced by SNAP or SIN-1, indicating that NO causes ER stress. These results suggest that NO-induced apoptosis in MG5 cells occurs through the ER stress pathway involving CHOP, but is independent of p53.
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PMID:Induction of CHOP and apoptosis by nitric oxide in p53-deficient microglial cells. 1159 87

Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrest- and DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.
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PMID:Roles of CHOP/GADD153 in endoplasmic reticulum stress. 1468 63

Genome-wide gene expression analysis of the hippocampal CA1 region was conducted in a rat global ischemia model for delayed neuronal death and induced ischemic tolerance using an oligonucleotide-based DNA microarray containing 8,799 probes. The results showed that expression levels of 246 transcripts were increased and 213 were decreased following ischemia, corresponding to 5.1% of the represented probe sets. These changes were divided into seven expression clusters using hierarchical cluster analysis, each with distinct conditions and time-specific patterns. Ischemic tolerance was associated with transient up-regulation of transcription factors (c-Fos, JunB Egr-1, -2, -4, NGFI-B), Hsp70 and MAP kinase cascade-related genes (MKP-1), which are implicated cell survival. Delayed neuronal death exhibited complex long-lasting changes of expression, such as up-regulation of proapoptotic genes (GADD153, Smad2, Dral, Caspase-2 and -3) and down-regulation of genes implicated in survival signaling (MKK2, and PI4 kinase, DAG/PKC signaling pathways), suggesting an imbalance between death and survival signals. Our study provides a differential gene expression profile between delayed neuronal death and induced ischemic tolerance in a genome-wide analysis, and contributes to further understanding of the complex molecular pathophysiology in cerebral ischemia.
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PMID:Genome-wide gene expression analysis for induced ischemic tolerance and delayed neuronal death following transient global ischemia in rats. 1474 48

Endoplasmic reticulum (ER) stress-induced cell death plays an important role in cerebral ischemia. In the present study, we investigated whether edaravone (3-methyl-1-phenyl-pyrazolin-5-one), a free radical scavenger, can protect against ER damage induced by cerebral ischemia. In a mouse model of hypoxia/ischemia, treatment with edaravone reduced edema-corrected infarction volume, attenuated hemispheric swelling, and improved neurological status. Moreover, edaravone suppressed ER stress-mediated apoptosis by inhibiting eukaryotic initiation factor alpha phosphorylation, C/EBP homologous protein (CHOP) induction, and caspase-12 activation. In mouse primary cultured glial cells, edaravone attenuated ER stress as evidenced by inhibition of the induction of glucose regulated protein 78 and CHOP and XBP-1 splicing under treatment with tunicamycin (Tm), which induces ER stress. Tm did not induce the production of reactive oxygen species in primary cultured glial cells. In addition, the free radical scavengers N-acetyl-l-cysteine and ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] did not affect ER stress response caused by Tm. These results demonstrated a novel action of edaravone that can protect against ER dysfunction in cerebral ischemia.
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PMID:Edaravone protects against hypoxia/ischemia-induced endoplasmic reticulum dysfunction. 1517 95

Oxidative stress is the main cause of cardiac injury during ischemia/reperfusion but the molecular mechanism for this process is unclear. In this study, it was found that hypoxia induces apoptosis in rat embryonic heart-derived H9c2 cells leading to the induction of GADD153, which is an apoptosis-related gene. Therefore, this study addressed the molecular role of GADD153 in hypoxia-induced apoptosis. The stable or inducible overexpression of GADD153 sensitized the H9c2 cells to apoptotic cell death. The results suggest that the transactivation domain of the GADD153 might be responsible for this cell execution and play a role in the nucleoplasmic localization of GADD153. The cells transiently transfected with the antisense GADD153 were more resistant to hypoxia-induced apoptosis than the vector control cells. Furthermore, GADD153 transcriptionally down-regulated the expression of the cardiac ankyrin repeat protein gene (CARP), which is a nuclear transcriptional co-factor that negatively regulates the expression of the cardiac gene. The ectopic expression of CARP in H9c2 cells increased the resistance to hypoxia-induced apoptosis. These results suggest that GADD153 overexpression and the concomitant down-regulation of CARP might have a causative role in the apoptotic cell injury of hypoxic H9c2 cells.
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PMID:Involvement of GADD153 and cardiac ankyrin repeat protein in hypoxia-induced apoptosis of H9c2 cells. 1582 45

The thalamus degenerates following cerebral infarction in the territory supplied by the middle cerebral artery (MCA), and apoptosis is suspected to be the mechanism of this phenomenon. The author studied the role of the growth arrest and DNA damage-inducible gene (GADD) 153 in this thalamic degeneration. The MCA was occluded in stroke-prone spontaneously hypertensive rats. The expression of GADD 153 and Bcl-2, and the release of cytochrome c from the mitochondria to cytosol, were examined in the thalamus until 7 days after ischemia using in situ hybridization, immunoblot, immunohistochemistry and RT-PCR analyses. Gadd153 mRNA expression and GADD153 protein increased transiently at 2, 3, 5 and 7 days, and at 3 and 5 days after ischemia. Bcl-2 mRNA expression and Bcl-2 protein decreased at 3 and 5 days. The release of cytochrome c from the mitochondria was detected at 5 days. These results suggest that increased GADD 153 suppresses Bcl-2 expression, which causes the release of cytochrome c from the mitochondria and leads to thalamic degeneration.
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PMID:Growth arrest and DNA damage-inducible gene 153 increases transiently in the thalamus following focal cerebral infarction. 1583 16

Ischemia-reperfusion (IR) injury induces endoplasmic reticulum (ER) stress and cell death. Bax Inhibitor-1 (BI-1) is an evolutionarily conserved ER protein that suppresses cell death and that is abundantly expressed in both liver and kidney. We explored the role of BI-1 in protection from ER stress and IR injury by using bi-1 knockout mice, employing models of transient hepatic or renal artery occlusion. Compared to wild-type bi-1 mice, bi-1 knockout mice subjected to hepatic IR injury exhibited these characteristics: (i) increased histological injury; (ii) increased serum transaminases, indicative of more hepatocyte death; (iii) increased percentages of TUNEL-positive hepatocytes; (iv) greater elevations in caspase activity; and (v) more activation of ER stress proteins inositol-requiring enzyme 1 and activating transcription factor 6 and greater increases in expression of ER stress proteins C/EBP homologous protein and spliced XBP-1 protein. Moreover, hepatic IR injury induced elevations in bi-1 mRNA in wild-type liver, suggesting a need for bi-1 gene induction to limit tissue injury. Similar sensitization of kidney to ER stress and IR injury was observed in bi-1(-/-) mice. We conclude that bi-1 provides endogenous protection of liver and kidney from ER stress and IR injury. Analysis of components of the bi-1-dependent pathway for protection from IR injury may therefore reveal new strategies for organ preservation.
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PMID:Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. 1647 5

Both prostaglandin A(1) (PGA(1)) and lithium have been reported to protect neurons against excitotoxic and ischemic injury. The present study was undertaken to examine the effects of lithium and PGA1 on heat shock proteins (HSP) and the growth arrest and DNA-damage-inducible gene (GADD153) and to evaluate if lithium could potentiate PGA(1)'s neuroprotective effects against cerebral ischemia. Rats were pretreated with a subcutaneous injection of lithium for 2 days and a single intracerebral ventricle administration of PGA(1) 15 min before ischemic insult. Brain ischemia was induced by a permanent middle cerebral artery occlusion. The infarct volume, motor behavior deficits and brain edema were analyzed 24 h after ischemic insult. The result showed that PGA(1) significantly reduced infarct volume, neurological deficits and brain edema. Except for neurological deficit, lithium enhanced PGA(1)'s neuroprotection. The neuroprotective effects of PGA(1) were associated with an up-regulation of cytoprotective heat shock proteins HSP70 and GRP78 in the ischemic brain hemisphere as determined by immunoblotting and immunofluorescence. The induction of HSP70 and GRP78 was enhanced by lithium. However, although the expression of GADD153 was enhanced significantly after pMCAO, it was not influenced by either PGA(1) or lithium or their combination. These studies suggest that lithium can potentiate PGA(1)'s neuroprotective effects and thus may have potential clinical value for the treatment of stroke in combination with other neuroprotective agents.
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PMID:Enhancement of neuroprotection and heat shock protein induction by combined prostaglandin A1 and lithium in rodent models of focal ischemia. 1679 96


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