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)

Forkhead box transcription factor, class O (FOXO) is a mammalian homologue of DAF-16, which is known to regulate the lifespan of Caenorhabditis elegans and includes subfamilies of forkhead transcription factors such as AFX, FKHRL1, and FKHR. FKHR is phosphorylated on three sites (Thr-24, Ser-256, and Ser-319) in a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner, thereby inhibiting death signals. We here documented dephosphorylation of FKHR following transient forebrain ischemia with its concomitant translocation into the nucleus in neurons in gerbil and mouse brains. The activation of FKHR preceded delayed neuronal death in the vulnerable hippocampal regions following ischemic brain injury. The FKHR activation was accompanied by an increase in DNA binding activity for FKHR-responsive element on the Fas ligand promoter. We also defined FKHR-induced downstream targets such as Fas ligand and Bim in brain ischemia. Therefore, we propose a new strategy to rescue neurons from delayed neuronal death by promoting the survival signaling. Sodium orthovanadate, a protein tyrosine phosphatase inhibitor, up-regulated Akt activity in the brain and in turn rescue neurons from delayed neuronal death by inhibiting FKHR-dependent or -independent death signals in neurons.
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PMID:Transcriptional regulation of neuronal genes and its effect on neural functions: expression and function of forkhead transcription factors in neurons. 1600 42

Warm ischemia and reperfusion (WI/R) results in the release of destructive proinflammatory cytokines and oxygen free radicals, which in turn cause injury to the liver. Apoptosis is regarded as the central mechanism of liver injury during WI/R. Oxymatrine, an extract from a traditional Chinese herb, Sophora flavescens Ait, has been widely used for the treatment of chronic hepatitis, by virtue of its anti-inflammatory and anti-apoptotic activity. The objective of this study was to investigate whether administration of oxymatrine could protect livers against WI/R. The experimental design consisted of three groups of rats (each group contained 10 Wistar rats): one group were treated by sham-operation; the second (control) group with WI/R were administrated saline, and the third group, rats with WI/R, were administered oxymatrine). Oxymatrine was intravenously administered before a 30-minute period of ischemia. Blood samples were collected for biochemical assay. Liver samples taken at different time points underwent histological examination for detection of apoptotic cells, and Western blotting analysis for Fas and Fas ligand, the key factors in the upper apoptotic pathways. Histologic alteration of the liver was attenuated in oxymatrine-treated rats, and the serum levels of AST and ALT were significantly (P < 0.01) reduced (73% and 61%, respectively). Oxymatrine significantly inhibited cell apoptosis, as examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), and it reduced the apoptotic index by 65% (P < 0.05%) as detected by flow cytometry. The anti-apoptotic activity of oxymatrine depends mainly on downregulation of Fas and Fas ligand. The results of this study indicate that oxymatrine may represent a potent drug to protect the liver against WI/R injury.
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PMID:Anti-apoptosis effects of oxymatrine protect the liver from warm ischemia reperfusion injury in rats. 1622 47

Death of hepatocytes and other hepatic cell types is a characteristic feature of liver diseases as diverse as cholestasis, viral hepatitis, ischemia/reperfusion, liver preservation for transplantation and drug/toxicant-induced injury. Cell death typically follows one of two patterns: oncotic necrosis and apoptosis. Necrosis is typically the consequence of acute metabolic perturbation with ATP depletion as occurs in ischemia/reperfusion and acute drug-induced hepatotoxicity. Apoptosis, in contrast, represents the execution of an ATP-dependent death program often initiated by death ligand/death receptor interactions, such as Fas ligand with Fas, which leads to a caspase activation cascade. A common event leading to both apoptosis and necrosis is mitochondrial permeabilization and dysfunction, although the mechanistic basis of mitochondrial injury may vary in different settings. Prevention of these modes of cell death is an important target of therapy, but controversies still exist regarding which mode of cell death predominates in various forms of liver disease and injury. Resolution of these controversies may come with the recognition that apoptosis and necrosis frequently represent alternate outcomes of the same cellular pathways to cell death, especially for cell death mediated by mitochondrial permeabilization. An understanding of processes leading to liver cell death will be important for development of effective interventions to prevent hepatocellular death leading to liver failure and to promote cancer and stellate cell death in malignancy and fibrotic disease.
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PMID:Apoptosis and necrosis in the liver: a tale of two deaths? 1644 72

Apoptosis has been shown in cardiac cells under divergent physiological and pathological conditions. However, there has been an ongoing debate upon the relative contribution of cardiomyocyte apoptosis to the myocardial infarct size after ischemia-reperfusion (I-R) injury. We tested the hypothesis that blocking the death receptor pathway of apoptosis through genetic deletion of Fas receptors or Fas ligands would reduce myocardial infarct size caused by acute I-R injury. The hearts isolated from Fas receptor or Fas ligand knockout (KO) mice as well as the C57BL/6J wild-type control mice (N = 6-8 per group) were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. Our results show that the infarct size, determined with triphenyltetrazolium chloride staining, was not significantly different between the three groups (i.e., 30.2 +/- 3.9% for wild-type controls, 30.0 +/- 2.1% for Fas ligand KOs, and 23.8 +/- 3.6% for Fas receptor KOs; mean +/- SEM, p > 0.05). Postischemic leakage of lactate dehydrogenase, another marker of necrotic cellular injury, also was not significantly different between these groups (p > 0.05). In addition, postischemic ventricular contractile function as well as coronary flow were similar for all the experimental groups (p > 0.05). In conclusion, contrary to our original hypothesis, the present study in the gene KO mice suggests that the Fas ligand- and Fas receptor-mediated death receptor pathway of apoptosis is not the primary determinant of myocardial infarct size and ventricular dysfunction caused by acute global I-R injury in the isolated perfused mouse heart.
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PMID:Genetic deletion of fas receptors or Fas ligands does not reduce infarct size after acute global ischemia-reperfusion in isolated mouse heart. 1645 39

Our previous studies and the others have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. Here we reported that Tat-JNK binding domain (JBD) of JNK-interacting protein-1 (JIP-1), a smaller 11-mer peptide corresponding to residues 153-163 of murine JIP-1 conjugated to Tat peptide, perturbed the assembly of JIP-1-JNK3 complexes, thus inhibiting the activation of JNK3 induced by ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. As a result, Tat-JBD diminished the increased phosphorylation of c-Jun (a nuclear substrate of JNK) and the increased expression of Fas ligand induced by ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. At the same time, through inhibiting phosphorylation of Bcl-2 (a cytosolic target of JNK) and the release of Bax from Bcl-2/Bax dimers, Tat-JBD attenuated Bax translocation to mitochondria and the release of cytochrome c induced by ischemia/reperfusion. Furthermore, the activation of caspase3 and hydrolyzation of poly-ADP-ribose-polymerase induced by brain ischemia/reperfusion were also significantly suppressed by preinfusion of the peptide Tat-JBD. Importantly, Tat-JBD showed neuroprotective effects on ischemic brain damage in vivo, and administration of the peptide after ischemia also achieved the same effects as preinfusion of the peptide did. Thus, our findings imply that Tat-JBD induced neuroprotection against ischemia/reperfusion in rat hippocampal CA1 region via inhibiting nuclear and non-nuclear pathways of JNK signaling. Taken together, these results indicate that Tat-JBD peptide provides a promising therapeutic approach for ischemic brain injury.
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PMID:Neuroprotection against ischemic brain injury by a small peptide inhibitor of c-Jun N-terminal kinase (JNK) via nuclear and non-nuclear pathways. 1650 11

We have previously demonstrated that fasting and ischemia-reperfusion (I/R) induced apoptosis in rat intestinal mucosa. It is widely accepted that apoptosis is induced through two main pathways. This study aimed to compare apoptotic pathways following fasting and I/R. Rats were divided into two groups: the I/R group involved occlusion of the superior mesenteric artery for 60 min, followed by 60-min reperfusion, whereas the fasting group involved fasting for 24 or 48 h. Intestinal apoptosis was assessed as percentage of fragmented DNA, by electrophoresis and by a terminal deoxynucleotidyl transferase mediated dUDP-biotin nick- end labeling (TUNEL) assay. Apoptotic proteins including death ligands/receptors and caspases were evaluated by Western blot analysis. Small intestinal mucosal height and mitochondrial dehydrogenase function were assessed. Fasting and I/R significantly induced intestinal apoptosis. Mucosal height was significantly decreased in fasting rats, and mitochondrial dysfunction was induced only by I/R. Expressions of Fas, Fas ligand, and TNF-alpha type 1 receptor were enhanced in fasting and I/R rats. After I/R, expressions of cytochrome c and cleaved caspase-9 were significantly increased. In contrast, expressions of cleaved caspase-8 and cleaved caspase-3 increased in fasting rats. Fasting promoted mucosal apoptosis via a receptor-mediated type I apoptotic pathway in the rat small intestine, and I/R induced apoptosis via a mitochondria-mediated type II pathway.
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PMID:Apoptotic pathway in the rat small intestinal mucosa is different between fasting and ischemia-reperfusion. 1657 89

Activation of Akt/protein kinase B has been recently reported to play an important role in ischemic tolerance. We here demonstrate that the decreased protein expression and phosphorylation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) underlie the increased Akt-Ser-473 phosphorylation in the hippocampal CA1 subfield in ischemic preconditioning (IPC). Co-immunoprecipitation analysis reveals that Akt physically interacts with Rac1, a small Rho family GTPase required for mixed lineage kinase 3 (MLK3) autophosphorylation, and both this interaction and Rac1-Ser-71 phosphorylation induced by Akt are promoted in preconditioned rats. In addition, we show that Akt activation results in the disassembly of the plenty of SH3s (POSH)-MLK3-Rac1 signaling complex and down-regulation of the activation of MLK3/c-Jun N-terminal kinase (JNK) pathway. Akt activation results in decreased serine phosphorylation of 14-3-3, a cytoplasmic anchor of Bax, and prevents ischemia-induced mitochondrial translocation of Bax, release of cytochrome c, and activation of caspase-3. The expression of Fas ligand is also decreased in the CA1 region. Akt activation protects against apoptotic neuronal death as shown in TUNEL staining following IPC. Intracerebral infusion of LY294002 before IPC reverses the increase in Akt phosphorylation and the decrease in JNK signaling activation, as well as the neuroprotective action of IPC. Our results suggest that activation of pro-apoptotic MLK3/JNK3 cascade can be suppressed through activating anti-apoptotic phosphoinositide 3-kinase/Akt pathway induced by a sublethal ischemic insult, which provides a functional link between Akt and the JNK family of stress-activated kinases in ischemic tolerance.
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PMID:Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt. 1697 99

Numerous studies have demonstrated the neuroprotective effects of estrogen in experimental cerebral ischemia. To investigate molecular mechanisms of estrogen neuroprotection in global ischemia, immunoblotting, immunohistochemistry and Nissel-staining analysis were used. Our results showed that chronic pretreatment with beta-estradiol 3-benzoate (E2) enhanced Akt1 activation and reduced the activation of mixed-lineage kinase 3 (MLK3), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase 1/2 (JNK1/2) in the hippocampal CA1 subfield during reperfusion after 15 min of global ischemia. In addition, E2 reduced downstream JNK nuclear and non-nuclear components, c-Jun and Bcl-2 phosphorylation and Fas ligand protein expression induced by ischemia/reperfusion. Administration of phosphoinositide 3-kinase (PI3K) inhibitor LY 294,002 prevented both activation of Akt1 and inhibition of MLK3, MKK4/7 and JNK1/2. The interaction between ERalpha and the p85 subunit of PI3K was also examined. E2 and antiestrogen ICI 182,780 promoted and prevented this interaction, respectively. Furthermore, ICI 182,780 blocked both the activation of Akt1 and the inhibition of MLK3, MKK4/7 and JNK1/2. Photomicrographs of cresyl violet-stained brain sections showed that E2 reduced CA1 neuron loss after 5 days of reperfusion, which was abolished by ICI 182,780 and LY 294,002. Our data indicate that in response to estrogen, ERalpha interacts with PI3K to activate Akt1, which may inhibit the MLK3-MKK4/7-JNK1/2 pathway to protect hippocampal CA1 neurons against global cerebral ischemia in male rats.
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PMID:Inhibition of MLK3-MKK4/7-JNK1/2 pathway by Akt1 in exogenous estrogen-induced neuroprotection against transient global cerebral ischemia by a non-genomic mechanism in male rats. 1706 55

The S-nitrosylated forms of certain proteins such as albumin have been thought to be circulating endogenous reservoirs of nitric oxide (NO) and may have potential as NO donors in therapeutic applications. In this study, we investigated the characteristics of R410C, a genetic variant of human serum albumin with two free thiols at positions 34 (Cys-34) and 410 (Cys-410), as a NO carrier via S-nitroso formation. A biotin switch assay revealed that Cys-410 was more rapidly and efficiently nitrosylated than was Cys-34. Nitrosylation of Cys-410 introduced only small conformational changes in the protein, which were detected by far-UV circular dichroism but not by near-UV circular dichroism. In addition, both native R410C and S-nitrosylated R410C did not induce molecular heterogeneity through oligomerization. S-Nitrosylated R410C exhibited strong antibacterial activity against Salmonella typhimurium in vitro and suppressed apoptosis of U937 human promonocytic cells induced by Fas ligand. In a rat ischemia-reperfusion liver injury model, S-nitrosylated R410C treatment significantly reduced liver damage, as indicated by markedly decreased release of liver enzymes (aspartate aminotransferase and alanine aminotransferase). Pharmacokinetic analyses indicated retention of the S-nitroso moiety of S-nitrosylated R410C in circulation after i.v. injection, with an approximate half-life of 20.4 min in the mouse. These data suggest that R410C can be a useful NO carrier and can be regarded as a new class of S-nitrosylated proteins possessing antibacterial and cytoprotective properties with a circulation time sufficient for in vivo biological activity.
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PMID:S-Nitrosylation of human variant albumin Liprizzi (R410C) confers potent antibacterial and cytoprotective properties. 1713 41

High temperature requirement A2 (HtrA2)/Omi is a mitochondrial serine protease that is released into the cytosol from mitochondria and in turn promotes caspase activation by proteolyzing inhibitor of apoptosis proteins. Here we asked whether treatment with an HtrA2/Omi inhibitor, 5-[5-(2-nitrophenyl)furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101), restores heart dysfunction following ischemia/reperfusion injury in vivo. Rats underwent a 30-min ischemia by occluding the left anterior descending artery, followed by 24 h reperfusion. UCF-101 (0.75 or 1.5 micromol/kg, i.p.) was administered 10 min before reperfusion. UCF-101 treatment significantly recovered the mean arterial blood pressure and ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion with concomitant reduction of infarct size. Cardio-protection mediated by UCF-101 was correlated with reduced X-linked inhibitor of apoptosis protein (XIAP) degradation and inhibition of Caspase-9, Caspase-3, and Caspase-7 processing. Furthermore, UCF-101 prevented loss of membrane integrity by inhibiting fodrin breakdown in cardiomyocytes. UCF-101-induced cytoprotection was also correlated with reduced Fas ligand expression and inhibition of FLIP degradation following ischemia/reperfusion. These results suggest that UCF-101 rescues cardiomyocytes from ischemia/reperfusion injury by inhibiting XIAP degradation and Fas/Fas-ligand-induced apoptosis, thereby ameliorating ischemia/reperfusion-induced myocardial dysfunction.
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PMID:Inhibition of HtrA2/Omi ameliorates heart dysfunction following ischemia/reperfusion injury in rat heart in vivo. 1718 30


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