Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 c-Jun NH(2)-terminal kinase (JNK) pathway of the mitogen-activated protein kinase (MAPK) signaling cascade regulates cell function and survival after stress stimulation. Equally robust studies reported dichotomous results suggesting both protective and detrimental effects of JNK during myocardial ischemia-reperfusion (I/R). The lack of a highly specific JNK inhibitor contributed to this controversy. We recently developed a cell-penetrating, protease-resistant peptide inhibitor of JNK, d-JNKI-1. Here we report on the effects of d-JNKI-1 in myocardial I/R. d-JNKI-1 was tested in isolated-perfused adult rat hearts. Increased activation of JNK, p38-MAPK, and extracellular signal-regulated kinase-1/2 (ERK1/2), as assessed by kinase assays and Western blotting, occurred during I/R. d-JNKI-1 delivered before onset of ischemia prevented the increase in JNK activity while not affecting ERK1/2 and p38-MAPK activation. JNK inhibition reduced ischemic injury, as manifested by increased time to contracture (P < 0.05) and decreased left ventricular end-diastolic pressure during ischemia (P < 0.01), and enhanced posthypoxic recovery of systolic and diastolic function (P < 0.01). d-JNKI-1 reduced mitochondrial cytochrome-c release, caspase-3 activation, and the number of apoptotic cells determined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (P < 0.05), indicating suppression of the mitochondrial machinery of apoptosis. d-JNKI-1 delivered at the time of reperfusion did not improve functional recovery but still prevented apoptosis. In vivo, d-JNKI-1 reduced infarct size after coronary artery occlusion and reperfusion by approximately 50% (P < 0.01). In conclusion, d-JNKI-1 is an important compound that can be used in preclinical models to investigate the role of JNK signaling in vivo. Inhibition of JNK during I/R is cardioprotective in anesthetized rats in vivo.
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PMID:A peptide inhibitor of c-Jun NH2-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo. 1715 45

JNK signaling pathway is activated and involved in the selective neuronal death in the hippocampal CA1 subfield following cerebral ischemia. However, little is known about upstream partner controlling the pathway. Here we reported that ischemia/reperfusion significantly elevated Cdc42 activity, enhanced assembly of the Cdc42-MLK3 complex and activation of JNK pathway. Most importantly, knock-down endogenous Cdc42 selectively suppressed the MLK3/MKK7/JNK3 cascade, and subsequently blocked the phosphorylation of c-Jun and FasL expression. Meanwhile, Bcl-2 was inactivated and the release of cytochrome c was diminished. These alterations eventually perturbed the caspase-3 activation as well as post-ischemic neuronal cell death. Taken together, our findings strongly suggest that Cdc42 serves as an upstream activator and modulates JNK-mediated apoptosis machinery in vivo, which ultimately results in neuronal apoptosis via nuclear and non-nuclear pathways. Thus, Cdc42 may be a potential therapeutic target in ischemic brain injury.
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PMID:Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus. 1716 86

Bacteria have developed mechanisms to sequester host iron via chelators such as deferoxamine (DFO). Interestingly, DFO has been shown to stimulate acute intestinal epithelial cell inflammatory cytokine production in the absence of bacteria; however, this mechanism has not been elucidated. Intestinal epithelial cell production of IL-6 and TNF-alpha is elevated in various gastrointestinal pathologies, including acute intestinal ischemia. Similarly, VEGF and HGF are essential to intestinal epithelial cell integrity. Therapeutic strategies that decrease IL-6 and TNF-alpha while increasing VEGF and HGF therefore have theoretical appeal. We hypothesized that 1) fetal human intestinal epithelial cells acutely produce increased IL-6, TNF-alpha, VEGF, and HGF during iron chelation and 2) the MAPK pathway mediates these effects. Fetal human intestinal epithelial cells were stimulated by iron chelation (1 mM DFO) with and without p38 MAPK, ERK, or JNK inhibition. Supernatants were harvested after 24 h of incubation, and IL-6, TNF-alpha, VEGF, and HGF levels were quantified by ELISA. Activation of MAPK pathways was confirmed by Western blot analysis. DFO stimulation resulted in a significant increase in epithelial cell IL-6 and VEGF production while yielding a decrease in HGF production (P<0.05). Unexpectedly, TNF-alpha was not detectable. p38 MAPK, ERK, and JNK inhibition significantly decreased IL-6, VEGF, and HGF production (P<0.05). In conclusion, DFO acutely increases fetal human intestinal epithelial cell IL-6 and VEGF expression while causing an unexpected decrease in HGF expression and no detectable TNF-alpha production. Furthermore, chelator-induced intestinal epithelial cell cytokine expression depends on p38, ERK, and JNK MAPK pathways.
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PMID:Iron chelation acutely stimulates fetal human intestinal cell production of IL-6 and VEGF while decreasing HGF: the roles of p38, ERK, and JNK MAPK signaling. 1720 43

c-Jun NH(2)-terminal kinase (JNK), a member of the MAPK family of protein kinases, is a stress-response kinase that is activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through nonreceptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We recently demonstrated that the activation of JNK by this condition is initiated by ROI generated by mitochondrial electron transport and involves sequential activation of the proline-rich kinase 2 and the small GTP-binding factors Rac-1 and Cdc42. Here we present evidence that protein kinase C (PKC) and transforming growth factor-beta-activated kinase-1 (TAK-1) are also components of this pathway. Inhibition of PKC with the broad-range inhibitor calphostin C, the PKC-alpha/beta-selective inhibitor Go9367, or adenovirus-expressing dominant-negative PKC-alpha blocked the phosphorylation of proline-rich kinase 2 and JNK. Reoxygenation activated the mitogen-activated protein kinase kinase kinase, TAK-1, and promoted the formation of a complex containing Rac-1, TAK-1, and JNK but not apoptosis-stimulating kinase-1 or p21-activated kinase-1, which was detected within the first 10 min of reoxygenation. These results identify two new components, PKC and TAK-1, that have not been previously described in this signaling pathway.
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PMID:PKC-alpha and TAK-1 are intermediates in the activation of c-Jun NH2-terminal kinase by hypoxia-reoxygenation. 1720 6

JNK pathway is an important pro-apoptotic kinase cascade mediating cell death in response to a variety of extracellular stimuli including excitotoxicity, which results in selective and delayed neuronal death in the hippocampal CA1. On the contrary, activation of the protein kinase Akt, which is controlled by the opposing actions of PI3K and PTEN, contributes to enhanced resistance to apoptosis through multiple mechanisms. We here demonstrate that the temporal pattern of Akt activation reversely correlates with JNK1/2 activation following various time points of ischemic reperfusion. However, the activation of JNK1/2 could be decreased by the elevation of Akt activation via increasing the tyrosine phosphorylation of PTEN by bpv(pic), a potent PTPases inhibitor for PTEN, or by intracerebroventricular infusion of PTEN antisense oligodeoxynucleotides (AS-ODNs). In contrast, JNK1/2 activation was significantly increased by preventing PTEN degradation after pretreatment with proteasome inhibitor. The neuroprotective effects of bpv(pic) and PTEN AS-ODNs were significant in the CA1 subfield after transient global ischemia. In conclusion, the present results clearly show that PTEN plays a key regulatory role in the cross-talk between cell survival PI3K/Akt pathway and pro-death JNK pathway, and raise a new possibility that agents targeting phosphatase PTEN may offer a great promise to expand the therapeutic options in protecting neurons form ischemic brain damage.
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PMID:Critical role of PTEN in the coupling between PI3K/Akt and JNK1/2 signaling in ischemic brain injury. 1723 58

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK), which plays a pivotal role in cell apoptosis. To determine the mechanism of ASK1 induction during reperfusion of ischemic spinal tissue, we used a model of rabbit spinal cord ischemia and reperfusion. To assess the role of ASK1 in spinal cord ischemia-reperfusion injuries, we examined alterations in spinal tissue morphology, protein-protein interactions, and activation of key members of the ASK1-mediated signaling pathway. Changes in spinal cord morphology were observed with hematoxylin and eosin (H&E) staining and electron microscopy. The phosphorylation levels of ASK1, JNK, and p38 were assessed by immunoblotting proteins from animals that received 30 min of ischemia followed by 1 or 24h of reperfusion. We observed increased phosphorylation of ASK1, JNK, and p38 after reperfusing ischemic spinal cords. Immunohistochemical studies were performed to determine the cellular localization of phosphorylated ASK1 (pASK1) and 14-3-3. Following reperfusion for 24h, we observed increased cytoplasmic localization of pASK1 and decreased cytoplasmic localization of 14-3-3. Immunoprecipitation analyses suggested that 14-3-3 dissociates from ASK1 during reperfusion of ischemic spinal cords. These results indicate that activation of ASK1 may play an important role in the apoptotic signaling mechanisms that occur in reperfused spinal cord injuries.
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PMID:Activation of ASK1 during reperfusion of ischemic spinal cord. 1729 65

Our previous study indicates that global ischemia facilitates the assembly of the GluR6.PSD-95.MLK3 signaling module, which in turn activated MLK3, leading to exacerbated ischemic neuron death. In addition, JIP1, functioning as a scaffold protein, could couple MLK3-MKK7-JNK to form a specific signaling module and facilitate the activation of the JNK signal pathway. However, the organization, regulation, and function between the two signaling modules and the effects they have on MLK3 activation remain incompletely understood. Here, we show that JIP1 maintains MLK3 in an inactive and monomeric state; once activated, MLK3 binds to PSD-95 and then dimerizes and autophosphorylates. In addition, a GluR6 C-terminus-containing peptide (Tat-GluR6-9c) and antisense oligonucleotides (AS-ODNs) against PSD-95 inhibit the integration of PSD-95 and MLK3 and the dimerization of MLK3, facilitate the interaction of JIP1 and MLK3, and, consequently, perform neuroprotection on neuron death. However, AS-ODNs against JIP1 play a negative role compared to that mentioned above. The findings show that the crosstalk occurs between PSD-95 and the JIP1-mediated signaling module, which may be involved in brain ischemic injury and contribute to the regulation of MLK3 activation. Thus, specific blockade of PSD-95-MLK3 coupling may reduce the extent of ischemia-reperfusion-induced neuronal cell death.
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PMID:Crosstalk between PSD-95 and JIP1-mediated signaling modules: the mechanism of MLK3 activation in cerebral ischemia. 1734 86

A variety of harmful stimuli, among them energy depletion occurring during transient brain ischemia, are thought to unbalance protein kinase cascades, ultimately leading to neuronal damage. In superfused, electrically stimulated rat cerebral cortex slices, chemical ischemia (CI) was induced by a 5-min treatment with the mitochondrial toxin, sodium azide (10 mM), combined with the glycolysis blocker, 2-deoxyglucose (2 mM). Thereafter, 1 h reperfusion (REP) with normal medium followed. Western blot analysis of p21Ras, extracellular signal-regulated protein kinases (ERK)1/2 (p44/42), phospho-ERK1/2, mitogen-activated protein kinase (MAPK)-p38, phospho-p38, stress-activated protein kinases/c-Jun NH2-terminal protein kinases (SAPK/JNK), phospho-SAPK/JNK was carried out. The level of p21Ras was increased by 40% immediately after CI, and did not return to control values following REP. Both ERK1 and ERK2 levels were reduced by CI and recovered to control values following REP; no significant change in their phosphorylation degree (phosphorylated to total level ratio, about 50% in the controls) was observed. Neither p38 levels, nor phosphorylation degree were changed following CI/REP. The activation of SAPK/JNK was significantly reduced under CI, and did not recover following REP. All CI/REP-induced effects were prevented by the NMDA receptor antagonist MK-801, 10 microM, suggesting the involvement of glutamate. The present findings show that although CI stimulates the p21Ras protein, MAPK levels and/or phosphorylation are reduced, possibly because of acute energy depletion. Because the activation of SAPK/JNK has been related to both apoptosis and neuroprotection, the decrease observed under CI/REP conditions may instead be related to nonapoptotic neuronal death. These results could be of interest in developing preventive treatments for ischemia/REP-induced brain damage.
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PMID:Effects of chemical ischemia on cerebral cortex slices: focus on mitogen-activated protein kinase cascade. 1738 88

Exposure to hypoxia before hypoxia-ischemia (HI) confers substantial protection referred to as preconditioning (PC). We hypothesized that PC induces critical changes of genes related to apoptotic cell death to render the brain more resistant. PC hypoxia (8% O2, 36 degrees C, 3 h) was induced in rats on postnatal day (PND) 6, and the rats were killed at 0, 2, 8, and 24 h. Total RNA was extracted from cerebral cortex and analyzed using Affymetrix rat genome 230 2.0 array. PC induced significant changes in 906 genes at 0 h, 927 at 2 h, 389 at 8 h, and 114 at 24 h. Ontology analysis revealed significant alterations in genes involved in cell communication, signal transduction, transcription, phosphorylation, and transport. Genes involved in cell death/apoptosis as well as those related to brain development (cell differentiation, neurogenesis, organogenesis, blood vessel development) were overrepresented. A detailed analysis demonstrated that 77 significantly regulated genes were involved in apoptosis, specifically related to the Bcl-2 family, JNK pathway, trophic factor pathways, inositol triphosphate (PI3) kinase/Akt pathway, extrinsic or intrinsic pathway, or the p53 pathway. The study supports that the epidermal growth factor receptor family, mitogen-activated protein kinase phosphatases, and Bcl-2-related proteins and the PI3 kinase/Akt pathway may have roles in providing resistance in the developing central nervous system (CNS).
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PMID:Global gene expression in the developing rat brain after hypoxic preconditioning: involvement of apoptotic mechanisms? 1751 69

Increasing evidence suggests that the Bcl-2 family proteins play pivotal roles in regulation of the mitochondria cell-death pathway on transient cerebral ischemia. Bad, a BH3-only proapoptotic Bcl-2 family protein, has been shown to be phosphorylated extensively on serine by kinds of kinases. However, the exact mechanisms of the upstream kinases in regulation of Bad signaling pathway remain unknown. Here, we reported that Bad could be phosphorylated not only by Akt1 but also by JNK1/2 after transient global ischemia in rat hippocampal CA1 region. Our data demonstrated that Akt1 mediated the phosphorylation of Bad at serine 136, which increased the interaction of serine 136-phosphorylated Bad with 14-3-3 proteins and prevented the dimerization of Bad with Bcl-Xl, inhibited the release of cytochrome c to the cytosol and the death effector caspase-3 activation, leading to the survival of neuron. In contrast, JNK1/2 induced the phosphorylation of Bad at a novel site of serine 128 after brain ischemia/reperfusion, which inhibited the interaction of PI3K/Akt-induced serine 136-phosphorylated Bad with 14-3-3 proteins, thereby promoted the apoptotic effect of Bad. In addition, activated Akt1 inhibited the activation of Bad(S128) through downregulating JNK1/2 activation, thus inhibiting JNK-mediated Bad apoptosis pathway. Furthermore, the fate of cell to survive or to die was determined by a balance between prosurvival and proapoptotic signals. Taken together, our studies reveal that Bad phosphorylation at two distinct sites induced by Akt1 and JNK1/2 have opposing effects on ischemic brain injury, and present the possibility of Bad as a potential therapeutic target for stroke treatment.
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PMID:Opposing effects of Bad phosphorylation at two distinct sites by Akt1 and JNK1/2 on ischemic brain injury. 1755 43


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