Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to study the role of protein kinase in the proliferation of lung fibroblasts induced by crocidolite. An in vitro model was established by rabbit alveolar macrophage (AM) and human embryonic pulmonary fibroblasts (HEPF). Using MTT color response method to measure HEPF proliferation, the influence of the inhibitor or activator of protein kinase (PKA, PKC and TPK) on the proliferation of crocidolite-induced HEPF were investigated. TiO2 was taken as negative control and SiO2 positive control. The results showed that the inhibitors of PKA, PKC and TPK could all inhibit the proliferation of HEPF induced by crocidolite, their activators could also promote the proliferation of HEPF. There all existed significant dose-effect relationships (P < 0.01), and the intensity in crocidolite group was inhibited or activated more than that in the controls. Through acting intensity analysis, the intensity was found as follows: TPK > PKC > PKA. It was suggested that TPK, PKC and PKA signal pathways were all involved in the process of the proliferation of crocidolite-induced HEPF, but TPK maybe played a key role in this process. This study provide leads for further research on identifying the bioactive factors of proliferation of crocidolite-induce HEPF.
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PMID:[Role of protein kinase in the proliferation of human embryonic pulmonary fibrolasts stimulated by the supernatants of crocidolite-exposed alveolar macrophages]. 1125 51

The effects of epigallocatechin gallate (EGCG) on the phosphoinositide 3-kinase (PI3K)/Akt and glycogen synthase kinase-3 (GSK-3) pathway during oxidative-stress-induced injury were studied using H2O2-treated PC12 cells, which were differentiated by nerve growth factor (NGF). Following 100 microM H2O2 exposure, the viability of differentiated PC12 cells (EGCG or z-VAD-fmk pretreated vs. not pretreated) was evaluated the number of viable cell with Trypan blue and 3,4,5-dimethylthiazol-2-yl (MTT). Additionally, expression of cytochrome c, caspase-3, poly(ADP-ribose) polymerase (PARP), PI3K/Akt and GSK-3 was examined using Western blot analyses. EGCG or z-VAD-fmk-pretreated PC12 cells showed an increase of viability compared to untreated PC12 cells, and pretreatment of PC12 cells with either agent induced a dose-dependent inhibition of caspase-3 activation and PARP cleavage. However, inhibition of cytochrome c release was only detected in EGCG-pretreated cells. Upon examination of the PI3K/Akt and GSK-3 upstream pathway, Western blots of EGCG pretreated cells showed decreased immunoreactivity (IR) of Akt and GSK-3 and increased IR of p85a PI3K, phosphorylated Akt and phosphorylated GSK-3. In contrast, no changes were seen in z-VAD-fmk-pretreated cells. These results show that EGCG affects the PI3K/Akt, GSK-3 pathway as well as downstream signaling, including the cytochrome c and caspase-3 pathways. Therefore, it is suggested that EGCG-mediated activation of PI3K/Akt and inhibition of GSK-3 could be a new potential therapeutic strategy for neurodegenerative diseases associated with oxidative injury.
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PMID:Epigallocatechin gallate protects nerve growth factor differentiated PC12 cells from oxidative-radical-stress-induced apoptosis through its effect on phosphoinositide 3-kinase/Akt and glycogen synthase kinase-3. 1455 56

Glycogen synthase kinase-3beta (GSK-3beta) is implicated in regulating apoptosis and tau protein hyperphosphorylation in Alzheimer's disease (AD). We investigated the effects of two key AD molecules, namely apoE (E3 and E4 isoforms) and beta-amyloid (Abeta) 1-42 on GSK-3beta and its major upstream regulators, intracellular calcium and protein kinases C and B (PKC and PKB) in human SH-SY5Y neuroblastoma cells. ApoE3 induced a mild, transient, Ca2+-independent and early activation of GSK-3beta. ApoE4 effects were biphasic, with an early strong GSK-3beta activation that was partially dependent on extracellular Ca2+, followed by a GSK-3beta inactivation. ApoE4 also activated PKC-alpha and PKB possibly giving the subsequent GSK-3beta inhibition. Abeta(1-42) effects were also biphasic with a strong activation dependent partially on extracellular Ca2+ followed by an inactivation. Abeta(1-42) induced an early and potent activation of PKC-alpha and a late decrease of PKB activity. ApoE4 and Abeta(1-42) were more toxic than apoE3 as shown by MTT reduction assays and generation of activated caspase-3. ApoE4 and Abeta(1-42)-induced early activation of GSK-3beta could lead to apoptosis and tau hyperphosphorylation. A late inhibition of GSK-3beta through activation of upstream kinases likely compensates the effects of apoE4 and Abeta(1-42) on GSK-3beta, the unbalanced regulation of which may contribute to AD pathology.
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PMID:Apolipoprotein E and beta-amyloid (1-42) regulation of glycogen synthase kinase-3beta. 1462 95

This study was undertaken to evaluate the effect of the G93A mutation in the human Cu/Zn-superoxide dismutase gene (hSOD1) on the phosphatidylinositol-3-kinase (PI3K)/Akt and glycogen synthase kinase-3 (GSK-3) pathway in motoneuron, and to determine the role of epigallocatechin gallate (EGCG) on oxidative stress-injured motoneurons. The viability of G93A mutant cells was less than that of wild-type cells, and the activation of PI3K and the phosphorylation of Akt and GSK-3 in G93A mutant cells decreased compared with wild-type hSOD1 4.1 cells. In the experiment to evaluate the effect of oxidative stress and/or EGCG on these motoneurons, after exposure to 400 microM H2O2, the MTT assay revealed greatly reduced viability of G93A mutant cells compared with wild-type cells, and pre-treatment of these cells with EGCG before H2O2 exposure increased the viability of both cell lines. Western blot analysis showed that the G93A mutation and oxidative stress decreased survival signals including PI3K/Akt but increased death signals including GSK-3; however, pre-treatment with EGCG increased survival signals but decreased death signals. These results suggest that PI3K/Akt and GSK-3 activities are altered in G93A mutant cells and EGCG-induced activation of PI3K/Akt and inhibition of GSK-3 could be a new potential therapeutic strategy for ALS associated with oxidative injury.
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PMID:Epigallocatechin gallate prevents oxidative-stress-induced death of mutant Cu/Zn-superoxide dismutase (G93A) motoneuron cells by alteration of cell survival and death signals. 1533 84

The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-beta-peptide (A beta), which plays a critical role in the neurodegeneration that triggers the disease. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which are members of the nuclear receptor family. We report here that (1) PPAR gamma is present in rat hippocampal neurons in culture. (2) Activation of PPAR gamma by troglitazone and rosiglitazone protects rat hippocampal neurons against A beta-induced neurodegeneration, as shown by the 3-[4,5 -2yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay, immunofluorescence using an anti-heavy neurofilament antibody, and quantitative electron microscopy. (3) Hippocampal neurons treated with several PPAR gamma agonists, including troglitazone, rosiglitazone, and ciglitazone, prevent the excitotoxic A beta-induced rise in bulk-free Ca2+. (4) PPAR gamma activation results in the modulation of Wnt signaling components, including the inhibition of glycogen synthase kinase-3beta (GSK-3beta) and an increase of the cytoplasmic and nuclear beta-catenin levels. We conclude that the activation of PPAR gamma prevents A beta-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPAR gamma and the Wnt signaling pathway. More important, the fact that the activation of PPAR gamma attenuated A beta-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective.
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PMID:Peroxisome proliferator-activated receptor gamma is expressed in hippocampal neurons and its activation prevents beta-amyloid neurodegeneration: role of Wnt signaling. 1570 77

The effects of diallyl disulfide (DADS), a garlic-derived compound, on the viability of neuronal cells and cell signals, including phosphatidylinositol 3-kinase (PI3K)/Akt, glycogen synthase kinase-3 (GSK-3), cytochrome c, caspase-3, and poly(ADP-ribose) polymerase (PARP), were investigated in PC12 cells neuronally differentiated by nerve growth factor. To evaluate the toxicity of DADS itself, nPC12 cells were treated with several concentrations of DADS, and 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue stain revealed that the viability was not affected by low concentration of DADS, up to 20 microM, but it was decreased at higher than this concentration. The levels of free radicals and membrane lipid peroxidation were significantly increased in nPC12 cells when treated with more than 50 microM DADS, and treatment of PC12 cells with 100 microM DADS killed the cells by inhibiting PI3K/Akt and by promoting activation of GSK-3 and caspase-3, release of cytochrome c, and cleavage of PARP. To evaluate the protective effects of low concentration of DADS on oxidative stress-injured nPC12 cells, the viability of the cells (pretreated with DADS for 2 h vs. not pretreated) was evaluated 24 h after exposure to 100 microM H2O2 for 30 min. Compared to the cells treated with 100 microM H2O2 only, pretreatment of the cells with 20 microM DADS before exposure to 100 microM H2O2 increased the viability and induced activation of PI3K and Akt, inactivation of GSK-3, and inhibition of cytochrome c release, caspase-3 activation, and PARP cleavage. These results indicate that low concentration of DADS has neuroprotective effects by activating PI3K/Akt and by inhibiting GSK-3 activation, cytochrome c release, caspase-3 activation, and PARP cleavage, whereas high concentration is rather cytotoxic. Therefore, some specific optimum concentration of DADS may be a new potential therapeutic strategy for oxidative stress injured in vitro model of neurodegenerative diseases.
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PMID:Protective effect of diallyl disulfide on oxidative stress-injured neuronally differentiated PC12 cells. 1571 Feb 34

HIV-1 protease inhibitor (PI), nelfinavir (NFV) induced growth arrest and apoptosis of NCI-H460 and -H520, A549, EBC-1 and ABC-1 non-small-cell lung cancer (NSCLC) cells in association with upregulation of p21waf1, p27kip1 and p53, and downregulation of Bcl-2 and matrix metalloproteinase (MMP)-2 proteins. We found that NFV blocked Akt signalling in these cells as measured by Akt kinase assay with glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) as a substrate. To explore the role of Akt signalling in NFV-mediated growth inhibition of NSCLC cells, we blocked this signal pathway by transfection of Akt small interfering RNA (siRNA) in these cells; transient transfection of Akt siRNA in NCI-H460 cells decreased the level of Bcl-2 protein and slowed their proliferation compared to the nonspecific siRNA-transfected cells. Conversely, forced-expression of Akt partially reversed NFV-mediated growth inhibition of these cells, suggesting that Akt may be a molecular target of NFV in NSCLC cells. Also, we found that inhibition of Akt signalling by NFV enhanced the ability of docetaxel to inhibit the growth of NCI-H460 and -H520 cells, as measured by MTT assay. Importantly, NFV slowed the proliferation and induced apoptosis of NCI-H460 cells present as tumour xenografts in nude mice without adverse systemic effects. Taken together, this family of compounds might be useful for the treatment of individuals with NSCLC.
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PMID:NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines. 1713 72

Recently we demonstrated that IGF-1 expression is increased in the diabetic kidney and that it may involve in renal hypertrophy and extracellular matrix protein (ECM) accumulation in mesangial cells as seen in diabetic glomerulopathy. The present study investigates the molecular mechanism(s) of IGF-1 and Akt/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway in the regulation of fibronectin and cyclin D1 expression and survival of renal mesangial cells. A proteomic approach is also employed to identify protein targets of IGF-1 signaling via GSK-3beta inhibition in mesangial cells. We show that IGF-1 (100 ng/ml) significantly increases the protein kinase Akt/PKB activity (1.5-2-fold, p<0.05) within 1-5 minutes, which is completely blocked by the presence of 100 nM Wortmannin (phosphatidyl-inositol 3-kinase inhibitor). Akt activation is coupled with Ser9 phosphorylation and inactivation of its down-stream target GSK-3beta. IGF-1 increases the cyclic AMP-responsive element (CRE) binding transcription factor CREB phosphorylation at Ser 133 and CRE-binding activity in mesangial cells, which parallels cyclin D1 and fibronectin expressions. Both proteins are known to have CRE-sequences in their promoter regions upstream of the transcription start site. Suppression of GSK-3beta by SB216763 (100 nM) increases CREB phosphorylation, cyclin D1 and fibronectin levels. Two dimensional gel electrophoresis followed by MALDI-TOF mass spectrometric analysis of mesangial proteins reveals that IGF-1 treatment or an inhibition of GSK-3beta increases the expression of the phosphorylated Ser/Thr binding signal adapter protein 14-3-3zeta. Immuno-precipitation of 14-3-3zeta followed by Western blotting validates the association of phosphorylated GSK-3beta with 14-3-3zeta in renal mesangial cells. Stable expression of a constitutively active GSK-3beta(Ser9Ala) induces cell death while overexpression of HA-tagged 14-3-3zeta increases cell viability as measured by MTT assays. These results indicate that the Akt/GSK-3beta pathway and the adapter protein 14-3-3zeta may play an important role in IGF-1 signaling and survival of mesangial cells in diabetic nephropathy.
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PMID:Proteomic identification of 14-3-3zeta as an adapter for IGF-1 and Akt/GSK-3beta signaling and survival of renal mesangial cells. 1720 Jun 89

The phosphatidylinositol-3-kinase (PI3-K) pathway has been suggested to play a pivotal role in neuronal survival. Although PI3-K has been recently identified as a neuroprotectant, there are no reports regarding the effect of a direct PI3-K activator on Abeta-induced neurotoxicity. We investigated whether direct PI3-K activation prevents Abeta-induced neurotoxicity. To evaluate the effect of Abeta on neuronal cells, we treated primary cultured cortical neurons with several doses of Abeta for 72 h. To investigate the protective effect that PI3-K activation has on Abeta-induced neurotoxicity, cells were simultaneously treated with several doses of a PI3-K activator for 72 h. An MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, and DAPI staining showed that Abeta decreased neuronal cell viability in a concentration-dependent manner and also that PI3-K activation effectively prevented Abeta-induced neuronal cell death. Abeta significantly decreased survival signals, including phosphorylated Akt, glycogen synthase kinase-3beta, and heat shock transcription factor-1. Abeta also increased death signals, such as phosphorylated tau (pThr231) and activated caspase-3. Treatment with a PI3-K activator restored the survival signals and inhibited the death signals. These results suggest that the neurotoxic effect of Abeta can be partially prevented by PI3-K activation.
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PMID:Phosphatidylinositol-3-kinase activation blocks amyloid beta-induced neurotoxicity. 1798 Apr 76

Cell therapy has been extensively studied as an approach to repair damage in nervous system diseases. Multipotent stromal cells [MSCs] are well known to have neuroprotective effects and neural differentiation potential. The ability to induce migration of MSCs near nervous system damage via direct transplantation or via intravenous injections and increase the secretion of neurotrophic factors from MSCs might improve our ability to repair damage to the nervous system through cell therapy. In the present study, we investigated whether recombinant human erythropoietin [rhEPO], known to have a hematopoietic effect, could increase the motility of human bone marrow [hBM]-MSCs and enhance production of neurotrophic factors from hBM-MSCs. Based on the results of our MTT assay, trypan blue staining, and bromodeoxyuridine ELISA, rhEPO treatment increases the viability of MSCs but not their proliferation. With a migration assay kit, we demonstrated that the motility of hBM-MSCs was enhanced in rhEPO-treated cells. Immunoblotting assays revealed increased expression of phospho-Akt, phospho-GSK-3beta, phospho-extracellular signal-regulated kinase (ERK), beta PAK-interacting exchange factor (PIX), CXCR4, phospho tyrosine kinase B (TrkB), and vascular endothelial growth factor receptor-2 [VEGFR-2] in rhEPO-treated cells. Reverse transcription-polymerase chain reaction and gelatin zymography demonstrated that rhEPO treatment induces MMP-2 mRNA level and activity. In the studies using ELISAs, we found that rhEPO could increase levels of stromal cell-derived factor-1alpha, VEGF, and brain-derived neurotrophic factors. These findings suggest that rhEPO can increase the viability and motility of hBM-MSCs by affecting various intracellular signals including Akt, ERK, beta-PIX, CXCR4, TrkB, VEGFR-2, and MMP-2 and can enhance the production of neurotrophic factors from hBM-MSCs.
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PMID:Erythropoietin increases the motility of human bone marrow-multipotent stromal cells (hBM-MSCs) and enhances the production of neurotrophic factors from hBM-MSCs. 1859 Mar 75


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