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: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic GMP-dependent protein kinases protein kinase G (PKG) Ialpha and PKGIbeta are major mediators of cGMP signaling in the cardiovascular system. PKGIalpha is present in the heart, although its role in protection against ischemia/reperfusion injury is not known. We investigated the direct effect of PKGIalpha against necrosis and apoptosis following simulated ischemia (SI) and reoxygenation (RO) in cardiomyocytes. Adult rat cardiomyocytes were infected with adenoviral vectors containing hPKGIalpha or catalytically inactive mutant hPKGIalphaK390A. After 24 h, the cells were subjected to 90 min of SI and 2 h RO for necrosis (trypan blue exclusion and lactate dehydrogenase release) or 18 h RO for apoptosis studies. To evaluate the role of K(ATP) channels, subgroups of cells were treated with 5-hydroxydecanoate (100 microm), HMR1098 (30 microm), or glibenclamide (50 microm), the respective blockers of mitochondrial, sarcolemmal, or both types of K(ATP) channels prior to SI. The necrosis observed in 33.7 +/- 1.6% of total myocytes in the SI-RO control group was reduced to 18.6 +/- 0.8% by PKGIalpha (mean +/- S.E., n = 7, p < 0.001). The apoptosis observed in 17.9 +/- 1.3% of total myocytes in the SI-RO control group was reduced to 6.0 +/- 0.6% by PKGIalpha (mean +/- S.E., n = 7, p < 0.001). In addition, PKGIalpha inhibited the activation of caspase-3 after SI-RO in myocytes. Myocytes infected with the inactive PKGIalphaK390A mutant showed no protection. PKGIalpha enhanced phosphorylation of Akt, ERK1/2, and JNK, increased Bcl-2, inducible nitric-oxide synthase, endothelial nitric-oxide synthase, and decreased Bax expression. 5-Hydroxydecanoate and glibenclamide abolished PKGIalpha-mediated protection against necrosis and apoptosis. However, HMR1098, had no effect. A scavenger of reactive oxygen species, as well as inhibitors of phosphatidylinositol 3-kinase, ERK, JNK1, and NOS, also blocked PKGIalpha-mediated protection against necrosis and apoptosis. These results show that opening of mitochondrial K(ATP) channels and generation of reactive oxygen species, in association with phosphorylation of Akt, ERK, and JNK, and increased expression of NOS and Bcl-2, play an essential role in the protective effect of PKGIalpha.
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PMID:Cyclic GMP-dependent protein kinase Ialpha attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocyte. 1703 26

This study examined Ca(2+) handling mechanisms involved in cardioprotection induced by chronic intermittent hypoxia (CIH) against ischemia-reperfusion (I/R) injury. Adult male Sprague-Dawley rats were exposed to 10% inspired O(2) continuously for 6 h daily from 3, 7, and 14 days. In isolated perfused hearts subjected to I/R, CIH-induced cardioprotection was most significant in the 7-day group with less infarct size and lactate dehydrogenase release, compared with the normoxic group. The I/R-induced alterations in diastolic Ca(2+) level, amplitude, time-to-peak, and the decay time of both electrically and caffeine-induced Ca(2+) transients measured by spectrofluorometry in isolated ventricular myocytes of the 7-day CIH group were less than that of the normoxic group, suggesting an involvement of altered Ca(2+) handling of the sarcoplasmic reticulum (SR) and sarcolemma. We further determined the protein expression and activity of (45)Ca(2+) flux of SR-Ca(2+)-ATPase, ryanodine receptor (RyR) and sarcolemmal Na(+)/Ca(2+) exchange (NCX) in ventricular myocytes from the CIH and normoxic groups before and during I/R. There were no changes in expression levels of the Ca(2+)-handling proteins but significant increases in the RyR and NCX activities were remarkable during I/R in the CIH but not the normoxic group. The augmented RyR and NCX activities were abolished, respectively, by PKA inhibitor (0.5 microM KT5720 or 0.5 microM PKI(14-22)) and PKC inhibitor (5 microM chelerythrine chloride or 0.2 microM calphostin C) but not by Ca(2+)/calmodulin-dependent protein kinase II inhibitor KN-93 (1 microM). Thus, CIH confers cardioprotection against I/R injury in rat cardiomyocytes by altered Ca(2+) handling with augmented RyR and NCX activities via protein kinase activation.
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PMID:Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion. 1726 48

The aim of this study was to investigate the cardioprotective effects and the possible mechanisms of delayed preconditioning induced by tetramethylpyrazine (TMP) in cultured neonatal rat cardiomyocytes subjected to anoxia-reoxygenation injury. Cultured neonatal rat cardiomyocytes were preconditioned using TMP at different concentrations (100, 200 and 500 microM). Cell viability, lactate dehydrogenase release, malondialdehyde formation, superoxide dismutase activity and glutathione peroxidase activity were measured to determine the protective effects against anoxia-reoxygenation injury. The expression of heat shock protein 70 (Hsp70) was measured 24 hr after TMP preconditioning by Western blot analysis. The results showed that TMP decreased lactate dehydrogenase release, increased cell viability, suppressed malondialdehyde formation and augmented activities of superoxide dismutase and glutathione peroxidase in a concentration-dependent manner. Moreover, the delayed protection was abolished by pre-treating with either protein kinase C inhibitor chelerythrine chloride or PD98059, a selective inhibitor of extracellular signal-regulated protein kinase 1/2, respectively, and the expression of Hsp70 was significantly increased in 24 hr after TMP preconditioning that was also suppressed by chelerythrine chloride or PD98059. These results suggest that TMP can induce delayed cardioprotective effects by activation of protein kinase C and extracellular signal-regulated protein kinase 1/2 signalling pathways and subsequent increased expression of Hsp70 in rat neonatal cardiomyocytes.
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PMID:Delayed protection of tetramethylpyrazine on neonatal rat cardiomyocytes subjected to anoxia-reoxygenation injury. 1751 88

Nucleoside diphosphate kinase A (NDPK-A) regulates the alpha1 isoform of the AMP-activated protein kinase (AMPK alpha1) selectively, independent of [AMP] and surrounding [ATP], by a process termed substrate channelling. Here, we show, using a range of empirically validated biochemical techniques, that the muscle form (M-LDH or LDH-A) and the heart form (H-LDH or LDH-B) of lactate dehydrogenase are physically associated with the liver cytosolic substrate-channelling complex such that M-LDH associates with NDPK-A, AMPK alpha1 and casein kinase 2 (CK2), whereas H-LDH associates with local NDPK-B. We find that the species of LDH bound to the substrate-channelling complex regulates the in vivo enzymatic activities of both AMPK and CK2, and has a downstream effect on the phospho-status of acetyl CoA carboxylase, a key regulator of cellular fat metabolism known to be a part of the cytosolic substrate-channelling complex in vivo. We hypothesise that the regulatory presence of LDH in the complex couples the substrate-channelling mechanism to both the glycolytic and redox states of the cell, allowing for efficient sensing of cell metabolic status, interfacing with the substrate-channelling complex and regulating the enzymatic activities of AMPK and CK2, two critical protein kinases.
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PMID:M-LDH serves as a regulatory subunit of the cytosolic substrate-channelling complex in vivo. 1757 40

The lysosomal destabilization that precedes mitochondrial apoptotic changes is an important step in cell death, particularly in oxidative cell death. This study describes the novel pharmacological effects of zaprinast, a cGMP-elevating phosphodiesterase inhibitor, on the inhibition of oxidative cell death in astrocyte cultures. H2O2-induced oxidative cytotoxicity was measured grossly by monitoring lactate dehydrogenase (LDH) release, and was found to be associated with lysosomal acridine orange relocation, lysosomal cathepsin D release into cytosol, and reduced mitochondrial potentials. Moreover, zaprinast (100 microM) inhibited all of these cytotoxic phenomena. In addition, H2O2-induced LDH release was not inhibited by 8-pCPT-cGMP, and the inhibition of this release by zaprinast was unaffected by Rp-8-pCPT-cGMP, a protein kinase G inhibitor. Zaprinast was found to inhibit sphingosine-induced lysosomal acridine orange relocation and the induced decrease in mitochondrial potential, but zaprinast had no effect on rotenone-induced mitochondrial collapse, which was not associated with lysosomal destabilization. However, zaprinast did not inhibit the cellular increase of reactive oxygen species induced by H2O2, which suggests that its protective mechanism differs from that of desferrioxamine, which does inhibit such cellular increase of oxygen free radicals. We suggest that the novel protective effect of zaprinast on H2O2-induced oxidative cell death is primarily associated with its inhibition of lysosomal destabilization.
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PMID:Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes. 1764 12

Neurosteroids are important regulators of central nervous system function and may be involved in processes of neuronal cell survival. This study was undertaken to test the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL), pregnenolone sulfate (PGLS), and allopregnanolone (Allo) on hydrogen peroxide- and staurosporine-induced toxicity in SH-SY5Y cells. It has been found that DHEAS inhibited the hydrogen peroxide toxicity in a concentration-dependent manner, whereas DHEA was active only at higher doses. PGL and PGLS showed neuroprotective effects only at the lowest concentration. Allo had no significant effect on hydrogen peroxide-evoked lactate dehydrogenase release and at the highest concentration aggravated its toxic effects. Next part of this study evaluated neurosteroid effects on staurosporine-induced apoptosis. DHEAS, DHEA, and PGL significantly antagonized effects of staurosporine on both caspase-3 activity and mitochondrial membrane potential. PGLS and Allo inhibited the staurosporine-induced changes in both apoptotic parameters only at the lowest concentration. Antiapoptotic properties of neurosteroids were positively verified by Hoechst staining. Furthermore, as shown by calcein assay, DHEA, DHEAS, and PGL increased viability of staurosporine-treated cells, and these effects were attenuated by specific inhibitors of phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated protein kinase (ERK)-mitogen activated protein kinase (MAPK). These data indicate that neurosteroids prevent SH-SY5Y cell damage related to oxidative processes and activation of mitochondrial apoptotic pathway. Moreover, neuroprotective effects of DHEA, DHEAS seem to depend on PI3-K and ERK/MAPK signaling pathways. It can be suggested that, at physiological concentrations, all studied neurosteroids participate in the inhibition of neuronal apoptosis, but with various potencies.
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PMID:Effects of neurosteroids on hydrogen peroxide- and staurosporine-induced damage of human neuroblastoma SH-SY5Y cells. 1818 15

Steroid hormones have been reported to activate various signal transducers that trigger a variety of cellular responses. Among these hormones, testosterone has been identified as an antioxidant that protects against cellular damage. Therefore, using mouse embryonic stem (ES) cells as a model system, this study evaluated the effects of dihydrotestosterone (DHT), a biologically active testosterone metabolite, on H2O2-induced apoptosis. H2O2 increased the release of lactate dehydrogenase (LDH) and DNA fragmentation but reduced the cell viability in a time-dependent manner (> or =8 h). Moreover, H2O2 decreased the level of DNA synthesis and the levels of the cell cycle regulatory proteins [cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 2, and CDK 4]. These effects of H2O2 were inhibited by a pretreatment with DHT. However, a treatment with flutamide (androgen receptor inhibitor, 10(-3) M) abolished the protective effects of DHT. This result was supported by the presence of the androgen receptor in mouse ES cells. The activity of the antioxidant enzyme, catalase, was increased by the DHT treatment but not by a co-treatment with DHT and flutamide. Using CM-H(2)DCFDA (DCF-DA) for the detection of intracellular H2O2, DHT decreased the intracellular H2O2 levels but flutamide blocked this effect. H2O2 also increased the level of p38 MAPK, JNK/SAPK, and NF-kappaB phosphorylation, which were inhibited by the DHT pretreatment. Catalase inhibited the effect of H2O2 on MAPKs and NF-kappaB. However, the flutamide treatment abolished the inhibitory effects of DHT on the H2O2-induced increase in the levels of p38 MAPK, JNK/SAPK, and NF-kappaB phosphorylation. DHT inhibited the H2O2-induced increase in caspase-3 expression and decreased the level of Bcl-2 and the cellular inhibitor of apoptosis protein (cIAP)-2. These effects were abolished by the flutamide treatment. In conclusion, DHT prevents the H2O2-induced apoptotic cell death of mouse ES cells through the activation of catalase and the downregulation of p38 MAPK, JNK/SAPK, and NF-kappaB via the androgen receptor.
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PMID:Effect of dihydrotestosterone on hydrogen peroxide-induced apoptosis of mouse embryonic stem cells. 1833 Aug 93

The protein tyrosine kinase inhibitor, genistein, has been reported to inhibit proliferation and to induce cell death in various non-solid and solid cancer cell lines. Herein, we examined the effects of genistein in several human malignant glioma cell lines. We found that genistein inhibited the proliferation of LN-18, LNT-229, LN-308 and T98G cells at EC50 concentrations of 25-80 microM (72 h of exposure). The growth of a non-neoplastic immortalized human astrocyte cell line, SV-FHAS, was inhibited at similar concentrations. There was a reduction in [3H]-methylthymidine incorporation and a moderate lactate dehydrogenase release as a sign of cell death in genistein-treated glioma cells. Electron microscopy showed morphological changes with mitochondrial swelling and apoptosis in glioma cells treated with high concentrations of genistein. Genistein-induced cytotoxicity was associated with an increased DNA/topoisomerase II complex formation. Furthermore, genistein induced cell cycle arrest in G2/M. There was an increase in the p53 and p21 levels in response to genistein. However, there was no difference in genistein sensitivity between p21-deficient colon carcinoma cells and isogenic control cells. Genistein-induced cell death in LN-18 and LNT-229 was unaffected by the ectopic expression of the preferential caspase 1/8 inhibitor, crm-A, or co-exposure to the pan-specific pseudosubstrate caspase inhibitor, zVAD-fmk. The ectopic expression of the anti-apoptotic BCL-2 protein attenuated the cytotoxic effects of genistein. Moreover, the ectopic expression of temperature-sensitive p53V135A, which acts as a dominant-negative p53 mutant at 38.5 degrees C but assumes p53 wild-type properties at 32.5 degrees C, in LN-18 or LNT-229 cells, had no effect on genistein cytotoxicity at either temperature. Genistein did not act in synergy with CD95 ligand-induced apoptosis or various cancer chemotherapy drugs in cytotoxic or clonogenic cell death assays. Thus, genistein-like protein kinase inhibitors are promising agents for the experimental treatment of malignant gliomas.
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PMID:The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines. 1835 97

The aim of the present paper was to examine, in a comparative way, the occurrence and the mechanisms of the interactions between adenosine A(2A) receptors (A(2A)Rs) and metabotropic glutamate 5 receptors (mGlu5Rs) in the hippocampus and the striatum. In rat hippocampal and corticostriatal slices, combined ineffective doses of the mGlu5R agonist 2-chloro-5-hydroxyphenylglycine (CHPG) and the A(2A)R agonist CGS 21680 synergistically reduced the slope of excitatory postsynaptic field potentials (fEPSPs) recorded in CA1 and the amplitude of field potentials (FPs) recorded in the dorsomedial striatum. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway appeared to be involved in the effects of CGS 21680 in corticostriatal but not in hippocampal slices. In both areas, a postsynaptic locus of interaction appeared more likely. N-methyl-D: -aspartate (NMDA) reduced the fEPSP slope and FP amplitude in hippocampal and corticostriatal slices, respectively. Such an effect was significantly potentiated by CHPG in both areas. Interestingly, the A(2A)R antagonist ZM 241385 significantly reduced the NMDA-potentiating effect of CHPG. In primary cultures of rat hippocampal and striatal neurons (ED 17, DIV 14), CHPG significantly potentiated NMDA-induced lactate dehydrogenase (LDH) release. Again, such an effect was prevented by ZM 241385. Our results show that A(2A) and mGlu5 receptors functionally interact both in the hippocampus and in the striatum, even though different mechanisms seem to be involved in the two areas. The ability of A(2A)Rs to control mGlu5R-dependent effects may thus be a general feature of A(2A)Rs in different brain regions (irrespective of their density) and may represent an additional target for the development of therapeutic strategies against neurological disorders.
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PMID:Is the functional interaction between adenosine A(2A) receptors and metabotropic glutamate 5 receptors a general mechanism in the brain? Differences and similarities between the striatum and the hippocampus. 1840 64

Increasingly, published evidence links glutamate with the pathogenesis of Alzheimer's disease. We investigated the molecular mechanism underlying glutamate-induced neurotoxicity in hippocampus, which is primarily linked to cognitive dysfunction in Alzheimer's disease. Acute exposure of rat hippocampal slices to glutamate significantly induced cell death, as determined by media lactate dehydrogenase levels and PI staining. Moreover, this was accompanied by Ca2+ influx and calpain-1 activation, as confirmed by the proteolytic pattern of spectrin. Notably, glutamate-induced calpain-1 activation decreased the level of beta-catenin, and this process appeared to be independent of glycogen synthase kinase 3beta (GSK-3beta), since glutamate also led to loss of GSK-3beta. Calpeptin, a calpain inhibitor, attenuated the glutamate-mediated degradations of spectrin, synaptophysin, and beta-catenin except GSK-3beta and modestly increased cell survival. In contrast, the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) effectively reduced all glutamate-evoked responses, i.e., the breakdowns of spectrin, synaptophysin, beta-catenin and GSK-3beta, and cell death. Pharmacological studies and in vitro calpain-1 proteolysis confirmed that in the glutamate-treated hippocampus, calpain-1-mediated decrease of beta-catenin could occur independently of GSK-3beta and of proteasome, and that GSK-3beta degradation is independent of calpain-1. These findings together provide the first direct evidence that glutamate promotes the down-regulations of beta-catenin and GSK-3beta, which potently contribute to neurotoxicity in hippocampus during excitotoxic cell death, and a molecular basis for the protection afforded by calpeptin and APV from the neurotoxic effect of glutamate.
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PMID:Concomitant degradation of beta-catenin and GSK-3 beta potently contributes to glutamate-induced neurotoxicity in rat hippocampal slice cultures. 1844 33


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