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 protein kinase C (PKC) family of serine/threonine kinases plays a role in a variety of physiological and pathophysiological processes in the brain including development, synaptic plasticity, epilepsy, ischemia, and neuronal cell death. The subgroup of atypical PKCs (aPKCs) comprises of three members, PKCiota/lambda, PKCzeta, and PKMzeta, with high amino acid homology. We used specific RNA probes and in situ hybridization to determine the expression patterns of all the three isoforms in the adult mouse brain. PKCiota and PKMzeta were found to be broadly expressed in most of the cortex, the limbic system, and the thalamus. In contrast, PKCzeta transcription was restricted to distinct forebrain areas and the cerebellum. Here we present a first comprehensive overview of isotype-specific aPKC distribution in the central nervous system, thereby providing a solid ground for further studies on the functional implications of the different aPKCs in the neuronal system.
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PMID:Differential expression of atypical PKCs in the adult mouse brain. 1530 23

Cardiovascular and neurologic surgeries often involve a temporary reduction in cerebral blood flow. In these conditions, as well as during cerebral ischemia and traumatic brain injury, the temporary loss of oxygen and glucose initiates a cascade of cellular events that culminate in neuronal death and damage. Understanding the mechanisms that contribute to neuronal death after hypoxia/ischemia is critically important for treatment of such brain injury. Here, we use a model of combined cerebral hypoxia/ischemia (H/I) to examine the role of protease-activated receptor-1 (PAR-1) in hypoxic/ischemic neuronal damage. Our data show that PAR-1-deficient mice have smaller lesion volumes than wild-type controls after 45 minutes of H/I. The results of the genetic block of PAR-1 were corroborated using a PAR-1 antagonist, which decreased infarct volume in wild-type C57Bl6 mice. Examination of cellular responses to H/I reveals that PAR-1 -/- animals have less cellular death and diminished glial fibrillary acidic protein expression. Additionally, PAR-1 -/- mice exhibit less motor behavior impairment in rotorod and inverted wire-hang tests. These data suggest that PAR-1 contributes to hypoxic/ischemic brain injury and are consistent with other studies that implicate serine proteases and their receptors in neuropathology after cerebral insults.
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PMID:PAR-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia. 1535 17

Ghrelin, a 28-amino acid peptide mainly produced by the stomach, is a natural ligand of the type 1a growth hormone secretagogue receptor (GHS-R1a) that also binds synthetic peptidyl and nonpeptidyl GHSs. GHS-R1a and various GHS-R1a-related receptor subtypes are widely distributed in central and peripheral tissues, particularly in the cardiovascular system. In agreement with this distribution of GHS-R, ghrelin and synthetic GHSs exert a wide spectrum of actions, including cardiac and vascular activities. Ghrelin, as well as peptidyl and nonpeptidyl GHSs, is able to increase cardiac performances both in animals and in humans and to exert protective effects on ischemia/reperfusion injury of isolated rat heart. Moreover, both ghrelin and synthetic GHSs have been shown as able to act as survival factors, protecting cardiomyocytes and endothelial cells from doxorubicin-induced apoptosis. Despite the fact that the neuroendocrine actions of ghrelin are dependent on its acylation in serine 3, these cardiovascular effects are exerted by unacylated as well as by acylated ghrelin. This evidence indicates that these actions are not likely to be mediated by a type 1a GHS-R, which, by definition, binds acylated ghrelin only. However, synthetic peptidyl GHSs, but not nonpeptidyl, and even ghrelin itself are able to reduce atherosclerotic lesion development in apolipoprotein-E-deficient mice. This action seems to be mediated by a specific receptor for synthetic peptidyl GHSs only, identified as CD36, a multifunctional B-type scavenger receptor involved in atherogenesis and mainly expressed in cardiomyocytes and microvascular endothelial cells. Thus, there are similarities, but also differences, between ghrelin and synthetic GHSs, in terms of cardiac actions that are likely to be related to the existence of multiple GHS-R subtypes that mediate the cardiovascular actions of the above substances. These actions indicate their potential pharmacotherapeutic implications in cardiovascular diseases.
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PMID:Ghrelin and synthetic growth hormone secretagogues are cardioactive molecules with identities and differences. 1547 30

Ischemia-reperfusion (IR) of the testis results in testicular oxidative stress and germ cell-specific apoptosis. Nuclear factor kappa B (NF-kappaB) is a nuclear transcription factor involved in the control of a number of cellular processes, and its activation is part of the cellular stress response to a variety of factors including cytokine stimulation, irradiation, and IR. The present study investigates NF-kappaB activation after IR of the murine testis and potential downstream target genes of that activation. Mice were subjected to a period of testicular ischemia followed by 0-4 hours of reperfusion. Activation of NF-kappaB was assessed by 1) Western blot analysis of the NF-kappaB inhibitory protein, IkappaBalpha; 2) immunohistochemistry for IkappaBalpha; and 3) TranSignal NF-kappaB target gene array (107 genes) analysis. Results demonstrate that IkappaBalpha is phosphorylated on serine 32 reaching a peak by 2 hours after IR of the testis. A decrease in total IkappaBalpha was also noted at 2 hours after IR, consistent with the rapid degradation of the phosphorylated protein. Phosphorylation and degradation of IkappaBalpha is indicative of NF-kappaB activation. Immunolocalization revealed IkappaBalpha specifically in Sertoli cells of the murine testis. Results of the TranSignal target gene array revealed that the expression of 9 genes was consistently changed 2 hours after IR of the testis, 3 of which increased in expression and 6 of which were down-regulated. Most notably, high-mobility group nucleosomal binding domain 1 increased in expression while platelet-derived growth factor B and Wilms tumor homolog decreased. These results suggest that testicular IR releases the suppression of NF-kappaB by IkappaBalpha in Sertoli cells. Activation of the NF-kappaB pathway in the testis resulted in an alteration of expression of potential NF-kappaB target genes, some increased while others decreased. The specific roles of these genes in the testicular response to IR remains to be determined.
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PMID:Activation of the nuclear factor kappa B pathway following ischemia-reperfusion of the murine testis. 1561 77

Focal adhesion kinase (FAK) is a 125 kDa protein tyrosine kinase (PTK) associated with focal adhesion in many cells, which plays a major role in the integrity of cytoskeletal structure. Reactive oxygen species produced during ischemia and reperfusion injury has been found to be an important mediator of signal transduction process. We found that low dose H2O2 induced increased FAK production in pulmonary microvascular endothelial cells, which could be blocked by cycloheximide (CHX), a protein synthesis inhibitor. Pulmonary endothelial cells were cultured on DMEM medium till 100% confluent. H2O2 was added at 100 uM for 30 min. The cells were collected and lysed, then immuno-blotted with anti-FAK antibody. After 30 min treatment, we found a 30%+/-6% (N=5) increase of FAK in H2O2 treated endothelial cells. This increase could be blocked by pretreatment of cells with CHX at 5 ug/ml for 60 min. In both groups, increased phosphorylation of ERK was observed. Immuno-fluorescence revealed increased staining of FAK in the peri-nuclear region of the H2O2 treated endothelial cells. These findings suggest that H2O2 activated MAP kinase pathway leading to increased FAK production at the protein level. FAK is a 125 kDa PTK associated with focal adhesion in many cells, and it plays a major role in the integrity of cytoskeletal structure. FAK is discretely localized to focal adhesions via its C-terminal focal adhesion-targeting (FAT) sequence. FAK is regulated by integrin-dependent cell adhesion and can control tyrosine phosphorylation of downstream substrates, like paxillin. The reactive oxygen species produced during ischemia and reperfusion injury has been found to be an important mediator of the signal transduction process. Although the signaling pathways leading to hydrogen peroxide induced endothelial monolayer permeability remain ambiguous, cytoskeletal proteins are known to be essential for maintaining endothelial integrity and regulating solute flux through the monolayer. Recent evidence has shown that H2O2 stimulates cytoskeleton reorganization, cell growth/proliferation, and DNA synthesis in various cells. In our previous study, we found a significantly increased amount of FAK in endothelial cells treated with low doses of H2O2. Mitogen-activated protein (MAP) kinases are a group of 30- to 110-kDa serine/threonine kinases. MAPKs belong to the group of kinases that are rapidly activated in response to growth factor stimulation. This family of MAPKs includes ERK, and ERK2. The activated MAPK can translocate to the nucleus where it can regulate transcription factors. Activation of p44 and p42 extracellular signal-regulated protein kinases (ERK1 and ERK2) is an important step in the cascade leading to cell growth and proliferation. In order to determine the mechanism of increased FAK production, we investigated the relationship of FAK production and ERK activation.
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PMID:Reactive oxygen species increased focal adhesion kinase production in pulmonary microvascular endothelial cells. 1563 12

The cyclin-dependent kinases (CDK) CDK1, CDK2, CDK4, and CDK6 are serine/threonine protein kinases targeted in cancer therapy due to their role in cell cycle progression. The postmitotic CDK5 is involved in biological pathways important for neuronal migration and differentiation. CDK5 represents an attractive pharmacological target as its deregulation is implicated in various neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. We have generated an improved crystal form of CDK5 in complex with p25, a segment of the p35 neuronal activator. The crystals were used to solve the structure of CDK5/p25 with (R)-roscovitine and aloisine at a resolution of 2.2 and 2.3 A, respectively. The structure of CDK5/p25/roscovitine provides a rationale for the preference of CDK5 for the R over the S stereoisomer. Furthermore, roscovitine stabilized an unusual collapsed conformation of the glycine-rich loop, an important site of CDK regulation, and we report an investigation of the effects of glycine-rich loop phosphorylation on roscovitine binding. The CDK5/p25 crystals represent a valuable new tool for the identification and optimization of selective CDK inhibitors.
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PMID:Mechanism of CDK5/p25 binding by CDK inhibitors. 1568 52

The role of NF-kappaB in cardiac physiology and pathophysiology has been difficult to delineate due to the inability to specifically block NF-kappaB signaling in the heart. Cardiac-specific transgenic models have recently been developed that repress NF-kappaB activation by preventing phosphorylation at specific serine residues of the inhibitory kappaB (IkappaB) protein isoform IkappaBalpha. However, these models are unable to completely block NF-kappaB because of a second signaling pathway that regulates NF-kappaB function via Tyr42 phosphorylation of IkappaBalpha. We report the development of transgenic (3M) mouse lines that express the mutant IkappaBalpha(S32A,S36A,Y42F) in a cardiac-specific manner. NF-kappaB activation in cardiomyopathic TNF-1.6 mice is completely blocked by the 3M transgene but only partially blocked (70-80%) by the previously described double-mutant 2M [IkappaBalpha(S32A,S36A)] transgene, which demonstrates the action of two proximal pathways for NF-kappaB activation in TNF-alpha-induced cardiomyopathy. In contrast, after acute stimuli including administration of TNF-alpha and ischemia-reperfusion (I/R), NF-kappaB activation is blocked in both 2M and 3M transgenic mice. This result suggests that phosphorylation of the regulatory Ser32 and Ser36 predominantly mediates NF-kappaB activation in these situations. We show that infarct size after I/R is reduced by 70% in 3M transgenic mice, which conclusively demonstrates that NF-kappaB is involved in I/R injury. In summary, we have engineered novel transgenic mice that allow us to distinguish two major proximal pathways for NF-kappaB activation. Our results demonstrate that the serine and tyrosine phosphorylation pathways are differentially activated during different pathophysiological processes (cardiomyopathy and I/R injury) and that NF-kappaB contributes to infarct development after I/R.
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PMID:Cardiac-specific blockade of NF-kappaB in cardiac pathophysiology: differences between acute and chronic stimuli in vivo. 1569 59

c-Jun N-terminal kinase (JNK) is an important stress-responsive kinase that is activated by various forms of brain insults. In this study, we have examined the role of JNK activation in neuronal cell death in a murine model of focal ischemia and reperfusion; furthermore, we investigated the mechanism of JNK in apoptosis signaling, focusing on the mitochondrial-signaling pathway. We show here that JNK activity was induced in the brain 0.5 to 24 h after ischemia. Systemic administration of SP600125, a small molecule JNK-specific inhibitor, diminished JNK activity after ischemia and dose-dependently reduced infarct volume. c-Jun N-terminal kinase inhibition also attenuated ischemia-induced expression of Bim, Hrk/DP5, and Fas, but not the expression of Bcl-2 or FasL. In strong support of a role for JNK in promoting the mitochondrial apoptosis-signaling pathway, JNK inhibition prevented ischemia-induced mitochondrial translocation of Bax and Bim, release of cytochrome c and Smac, and activation of caspase-9 and caspase-3. The potential mechanism by which JNK promoted Bax translocation after ischemia was further studied using coimmunoprecipitation, and the results revealed that JNK activation caused serine phosphorylation of 14-3-3, a cytoplasmic sequestration protein of Bax, leading to Bax disassociation from 14-3-3 and subsequent translocation to mitochondria. These results confirm the role of JNK as a critical cell death mediator in ischemic brain injury, and suggest that one of the mechanisms by which JNK triggers the mitochondrial apoptosis-signaling pathway is via promoting Bax and Bim translocation.
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PMID:Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. 1571 57

Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and/or IGF-I on the serine/threonine kinases Akt and glycogen synthase kinase 3beta (GSK3beta) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3beta (pGSK3beta) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3beta remained low 4 h after HI. Administration of IGF-I (50 microg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3beta decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3beta in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3- and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3beta, may explain the attenuated activation of caspases and reduction of injury in the immature brain.
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PMID:IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta? 1584 77

Serine/threonine kinase Akt, or protein kinase B, has been shown to regulate a number of neutrophil functions. We sought to identify Akt binding proteins in neutrophils to provide further insights into understanding the mechanism by which Akt regulates various neutrophil functions. Proteomic and immunoprecipitation studies identified gamma-amino butyric acid (GABA) type B receptor 2 (GABA(B)R2) as an Akt binding protein in human neutrophils. Neutrophil lysates subjected to Akt immunoprecipitation followed by immunoblotting with anti-GABA(B)R2 demonstrated Akt association with the intact GABA(B)R. Similar results were obtained when reciprocal immunoprecipitations were performed with anti-GABA(B)R2 Ab. Additionally, GABA(B)R2 and Akt colocalization was demonstrated by confocal microscopy. A GABA(B)R agonist, baclofen, activated Akt and stimulated neutrophil-directed migration in a PI3K-dependent manner, whereas CGP52432, a GABA(B)R antagonist blocked such effects. Baclofen, stimulated neutrophil chemotaxis and tubulin reorganization in a PI3K-dependent manner. Additionally, a GABA(B)R agonist failed to stimulate neutrophil superoxide burst. We are unaware of the association of GABA(B)R with Akt in any cell type. The present study shows for the first time that a brain-specific receptor, GABA(B)R2 is present in human neutrophils and that it is functionally associated with Akt. Intraventricular baclofen pretreatment in rats subjected to a stroke model showed increased migration of neutrophils to the ischemic lesion. Thus, the GABA(B)R is functionally expressed in neutrophils, and acts as a chemoattractant receptor via an Akt-dependent pathway. The GABA(B)R potentially plays a significant role in the inflammatory response and neutrophil-dependent ischemia-reperfusion injury such as stroke.
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PMID:Gamma-amino butyric acid type B receptors stimulate neutrophil chemotaxis during ischemia-reperfusion. 1590 70

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