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)

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

5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a phylogenetically conserved serine/threonine protein kinase. AMPK may inhibit cell growth and proliferation and also regulates apoptosis. 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a cell-permeable AMPK activator. Activation of AMPK with AICAR has been shown to induce apoptosis of the rat hepatoma cell line FTO2B cells and almost completely inhibited HepG2 cells growth. In this study, a HepG2 cell line, which was transfected with a vector containing human CYP2E1 cDNA (E47 cells), was treated with AICAR. Cell proliferation was blocked, and apoptosis and necrosis were elevated as assessed by cellular morphology, DNA content assay, and lactate dehydrogenase leakage. AICAR treatment significantly increases CYP2E1 activity (20-fold) and expression (5.5-fold) in E47 cells. Iodotubericidin, which inhibits the conversion of AICAR to its activated form AICAR monophosphate, the antioxidants trolox and MnTMPyP, and 4-methylpyrazole, an inhibitor of CYP2E1, all can protect the E47 cells from AICAR-induced necrosis. Production of intracellular reactive oxygen species was increased by AICAR treatment in E47 cells. The cytotoxicity mechanism of AICAR in E47 cells is suggested to include AMPK activation, p53 phosphorylation, p21 expression, overexpression of CYP2E1, and intracellular ROS accumulation.
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PMID:Overexpression of CYP2E1 induces HepG2 cells death by the AMP kinase activator 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). 1847 82

The present study was designed to investigate the modulatory effects of rottlerin on ischemia reperfusion induced myocardial injury. Isolated rat hearts were exposed to 30 min of global ischemia followed by 120 min of reperfusion using Langendorff apparatus. Myocardial injury was assessed in the terms of infarct size, release of lactate dehydrogenase (LDH), creatine kinase (CK) enzymes. Rottlerin, a selective PKCdelta inhibitor, did not modulate ischemia-reperfusion (I/R) induced myocardial injury at low dose (3 microM). However, at moderate dose (6 microM) it significantly produced cardioprotective effects. On the contrary, rottlerin at high dose (12 microM) significantly enhanced I/R induced myocardial injury. However, administration of FR-167653 (1.1 microM, 2.2 microM), a selective p-38 mitogen activated protein kinase (p-38 MAPK) inhibitor, attenuated rottlerin (12 microM) mediated enhancement in I/R induced myocardial injury in a dose dependent manner. Per se administration of FR-167653 (1.1 microM, 2.2 microM) also attenuated I/R induced myocardial injury in a dose dependent manner. Pretreatment with rottlerin (6 microM) did not enhance the cardioprotective effects of FR-167653 (2.2 microM). It may be concluded that rottlerin mediated cardioprotective effects at moderate dose, possible due to inhibition of PKCdelta; while at high dose it enhanced I/R induced myocardial injury which may be attributed to activation of p-38 MAPK.
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PMID:Possible mechanism of rottlerin induced modulation of ischemia reperfusion injury in isolated rat hearts. 1875 70

Genetic selection for improved growth and overall meatiness has resulted in the occurrence of 2 major mutations in pigs, the Rendement Napole (RN) and Halothane (Hal) gene mutations. At the tissue level, these mutations influence energy metabolism in skeletal muscle and muscle fiber type composition, yet also influence total body composition. The RN mutation affects the adenosine monophosphate-activated protein kinase gamma subunit and results in increased glycogen deposition in the muscle, whereas the Hal mutation alters sarcoplasmic calcium release mechanisms and results in altered energy metabolism. From a meat quality standpoint, these mutations independently influence the extent and rate of muscle energy metabolism postmortem, respectively. Even though these mutations alter overall muscle energy metabolism and histochemically derived muscle fiber type independently, their effects have not been yet fully elucidated in respect to myosin heavy chain (MyHC) isoform content and those enzymes responsible for defining energetics of the tissue. Therefore, the objective of this study was to determine the collective effects of the RN and Hal genes on genes and gene products associated with different muscle fiber types in pig skeletal muscle. To overcome potential pitfalls associated with traditional muscle fiber typing, real-time PCR, gel electrophoresis, and Western blotting were used to evaluate MyHC composition and several energy-related gene expressions in muscles from wild-type, RN, Hal, and Hal-RN mutant pigs. The MyHC mRNA levels displayed sequential transitions from IIb to IIx and IIa in pigs bearing the RN mutation. In addition, our results showed MyHC protein isoform abundance is correlated with mRNA level supporting the hypothesis that MyHC genes are transcriptionally controlled. However, transcript abundance of genes involved in energy metabolism, including lactate dehydrogenase, citrate synthase, glycogen synthase, and peroxisome proliferator-activated receptor alpha, was not different between genotypes. These data show that the RN and Hal gene mutations alter muscle fiber type composition and suggest that muscle fiber energy metabolism and speed of contraction, the 2 determinants of muscle fiber type, can be uncoupled.
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PMID:Myosin heavy chain isoform content and energy metabolism can be uncoupled in pig skeletal muscle. 1882 Jan 56

Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame-retardant additives, especially in electrical appliances and textiles. Because of their structural similarity, PBDEs are thought to have toxicities similar to those of polychlorinated biphenyls (PCBs), which are well-known persistent compounds. Both 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) and 2,2',4,4',5, 5'-hexachlorobiphenyl (PCB153) can coexist in the environment and human tissues as dominant congeners of PBDEs and PCBs, respectively. To explore the mechanisms of the neurotoxic effect of PBDE-47 and the interaction in combination with PCB153, cell viability, lactate dehydrogenase (LDH) leakage, intracellular Ca2+ concentration ([Ca2+]i), apoptosis and expression levels of death associated protein kinase (DAPK), caspase3, caspase12 and cytochrome c mRNA and proteins were measured in SH-SY5Y cells treated with PBDE-47 (0, 1, 5, 10 micromol/L) and/or PCB153 (5 micromol/L) for 24 h. Compared to controls, the cell viabilities were clearly decreased (P<0.05), and LDH leakage, [Ca2+]i and apoptosis were significantly increased (P<0.05). Furthermore, expression levels of DAPK and caspase3 mRNA, caspase12, as well as cytochrome c mRNA and proteins were markedly increased (P<0.05), while pro-caspase3 proteins were significantly decreased (P<0.05). A positive correlation between [Ca2+]i and percentage of apoptotic cells (r=0.86, P<0.05) and an interaction between PBDE-47 and PCB153 (P<0.05) were observed. We conclude that PBDE-47 can induce SH-SY5Y cell apoptosis via three classic apoptosis pathways and interact with PCB153 to enhance neurotoxicity.
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PMID:Mechanism of the neurotoxic effect of PBDE-47 and interaction of PBDE-47 and PCB153 in enhancing toxicity in SH-SY5Y cells. 1902 89

Previously, we found that neurosteroids inhibited hydrogen peroxide- and staurosporine-induced damage of undifferentiated human neuroblastoma SH-SY5Y cells. However, differentiated neuroblastoma cells morphologically and functionally resemble neuronal cells, and are thus considered to be a model system for studying neuronal apoptotic processes. In the present study, we examined the effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and pregnenolone (PGL) on the viability of retinoic acid-differentiated human neuroblastoma SH-SY5Y cells. Mitochondrial and extracellular apoptotic processes in these cells were induced by staurosporine and doxorubicin, respectively. Calcein viability assays showed that doxorubicin (0.5 microM for 24 h) decreased cell viability by ca. 20% as compared to control cultures. DHEA and DHEAS at 0.1 and 1 microM concentrations, respectively, significantly inhibited the doxorubicin toxicity. PGL showed a neuroprotective effect only at 0.1 microM, whereas it was inactive at a higher concentration (1 microM). Staurosporine (1 microM for 24 h) decreased SH-SY5Y cell viability by ca. 50%. DHEA (0.1 and 1 microM) and DHEAS (0.1 and 1 microM) significantly antagonized the toxic effects of staurosporine, whereas these compounds showed no activity at the lowest concentration (0.01 microM). PGL inhibited the staurosporine-induced decrease in cell viability only at the concentration of 0.1 microM. Since staurosporine generated a stronger detrimental effect on SH-SY5Y cell viability than doxorubicin, we studied the mechanisms of neurosteroid action only in the former model. Staurosporine (1 microM for 24 h) enhanced lactate dehydrogenase (LDH) release by ca. 40% and this effect was inhibited by DHEA (0.01, 0.1, and 1 microM), DHEAS (0.1 and 1 microM) and PGL (0.01 and 01 microM). In order to verify an involvement of phosphatidylinositol-3-kinase (PI3-K) in the antiapoptotic action of neurosteroids, a specific inhibitor of this protein kinase (LY294002 at 10 microM) was used. Pretreatment of the cells with LY294002 antagonized the ameliorating effects of DHEA, DHEAS, and PGL on staurosporine-induced LDH release. These data indicated that at physiological concentrations, DHEA, DHEAS, and PGL prevented RA-differentiated SH-SY5Y cell damage produced by activation of both mitochondrial and extracellular apoptotic pathways. Furthermore, this study confirmed that the neuroprotective effects of neurosteroids in a staurosporine model of cytotoxicity appeared to be dependent upon PI3-K activity.
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PMID:Neurosteroids enhance the viability of staurosporine and doxorubicin treated differentiated human neuroblastoma SH-SY5Y cells. 1906 15


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