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

Since the generation of nitric oxide (NO) is an essential step in the trigger phase of ischemic preconditioning, short-term inhalation of NO before ischemia should ameliorate ischemia/reperfusion (I/R) injury of the lung. We tested this hypothesis in high oxygen (>99%) ventilated rats in order to additionally evaluate compatibility of NO and exposure to hyperoxia. Male adult Sprague-Dawley rats inhaled NO (15 ppm, 10 min) before the left lung hilum was clamped for 1 h, and the reperfusion phase was observed for 4 h (NO group). Animals in the I/R group underwent the same treatment, but without NO inhalation. A third group without I/R served as time-matched controls. Animals in the I/R group showed severe I/R injury in terms of arterial pO2 (apO2), which was reduced to 22% of surgical controls (SCs) at time point 30 min reperfusion, and increased endothelial permeability (Evans blue procedure). The pretreatment with NO attenuated these effects. The pO2 after 4 h reperfusion was still 3.0-fold higher in the NO group compared to I/R. In contrast, the I/R- and hyperoxia-induced invasion of leukocytes, as determined by measuring myeloperoxidase (MPO) activity, was not affected by NO. These data were correlated with the activity of major cellular signaling pathways by measuring the phosphorylation at activating and inhibitory sites of extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, protein kinase B (AKT), and glycogen synthase kinase 3beta (GSK-3beta), and by determination of cGMP in plasma and lung tissue. Inhalation of NO partly prevented the loss of activation by I/R and hyperoxic ventilation of ERK, JNK, and AKT, and it reduced the I/R-induced activation of GSK-3beta. The level of cGMP in plasma and lung tissue was increased in the NO group after 4 h reperfusion. In conclusion, application of inhaled NO in the preconditioning mode prevented I/R injury in the rat lung without interfering effects of hyperoxic ventilation. The effects of NO on cellular signaling pathways resemble mechanisms of ischemic preconditioning, but further studies have to evaluate the physiological relevance of these results.
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PMID:Preconditioning by inhaled nitric oxide prevents hyperoxic and ischemia/reperfusion injury in rat lungs. 1845 45

Thiadiazolidinones (TDZDs) are small molecules that inhibit glycogen synthase kinase 3-beta (GSK3-beta) activity in a non competitive manner to ATP. NP00111, a new TDZD, besides causing inhibition of GSK-3beta, has also shown to be an agonist of PPARgamma . Since phosphorylation and consequent inhibition of GSK-3beta by PI-3K/Akt and agonism of PPARgamma have shown to afford neuroprotection in several in vitro and in vivo models, we have studied the potential neuroprotective effect of NP00111 in an "in vitro" model of ischemia-reperfusion. NP00111, at the concentration of 10 microM, significantly protected adult rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) for 1 h followed by 3 h re-oxygenation, measured as lactic dehydrogenase (LDH) released to the extracellular media. The protective effects of NP00111 were more pronounced during the re-oxygenation period in comparison to the OGD period. Other GSK-3beta inhibitors like lithium or AR-A014418 did not afford protection in this model. However, the PPARgamma agonist rosiglitazone was protective at 3 microM. Protection afforded by NP00111 and rosiglitazone were prevented by the PPARgamma antagonist GW9662, suggesting that both NP00111 and rosiglitazone were preventing cell death caused by oxygen-glucose deprivation via activation of PPARgamma. NP00111 increased by two fold phosphorylation of ERK1/2 and its protective effects were lost when the hippocampal slices were co-incubated with the mitogen-activated protein kinase (MAPK) inhibitor PD98059. In conclusion, the novel TDZD NP00111 was protective against OGD in rat hippocampal slices by a mechanism related to phosphorylation of ERK1/2 via activation of PPARgamma.
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PMID:Neuroprotective effect of the new thiadiazolidinone NP00111 against oxygen-glucose deprivation in rat hippocampal slices: implication of ERK1/2 and PPARgamma receptors. 1847 12

Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist D-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3beta (GSK-3beta). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of beta-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3beta and stabilization of beta-catenin contribute to the anti-apoptotic effects of ghrelin.
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PMID:Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. 1854 46

25-hydroxycholesterol (25-OH-chol) induces apoptosis in many cell types. The present study investigated the possible involvement of mitochondria-dependent apoptotic signalling molecules in the death of PC12 cells treated with 25-OH-chol. 25-OH-chol increased the production of reactive oxygen species and opened mitochondrial permeability transition pore, resulting in release of cytochrome c and subsequent activation of caspase-9 and -3. 25-OH-chol induced the activation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-3beta (GSK-3beta). The JNK inhibitor SP600125 attenuated the activation of caspase-9 and -3 and reduced 25-OH-chol-induced cell death. GSK inhibitors SB415286 and SB216763 significantly down-regulated JNK activity and attenuated the cytotoxicity of 25-hydroxycholesterol. However, SP600125 did not alter the activity of GSK-3beta. The results indicate that 25-OH-chol induces cell death via activation of GSK-3beta and subsequent up-regulation of JNK. Pharmacological intervention of GSK-3beta-JNK-caspase signalling pathway may be useful for the reduction of cytotoxicity of oxysterols.
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PMID:25-hydroxycholesterol induces mitochondria-dependent apoptosis via activation of glycogen synthase kinase-3beta in PC12 cells. 1856 12

Repetitive cycles of reflow/reocclusion in the initial 2 min following release of a prolonged coronary occlusion, i.e., ischemic postconditioning (IPoC), salvages ischemic myocardium. We have proposed that the intermittent ischemia prevents formation of mitochondrial permeability transition pores (MPTP) by maintaining an acidic myocardial pH for several minutes until survival kinases can be activated. To determine other requisites of IPoC, isolated rabbit hearts were subjected to 30 min of regional myocardial ischemia and 120 min of reperfusion. Infarct size was determined by staining with triphenyltetrazolium chloride. During the first 2 min of reperfusion the perfusate was either at pH 7.4 following equilibration with 95% O(2)/5% CO(2), pH 6.9 following equilibration with 80% N(2)/20% CO(2), or pH 7.8 following equilibration with 100% O(2). Whereas acidic, oxygenated perfusate for the first 2 min of reperfusion was cardioprotective, protection was lost when acidic perfusate was hypoxic. However, the acidic, hypoxic hearts could be rescued by addition of phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, to the perfusate. Therefore, both low pH and restoration of oxygenation are necessary for protection, and the signaling step requiring combined oxygen and H(+) must be upstream of PKC. To gain further insight into the mechanism of IPoC, the latter was effected with 6 cycles of 10-s reperfusion/10-s reocclusion. Its protective effect was abrogated by either making the oxygenated perfusate alkaline during the reperfusion phases or making the reperfusion buffer hypoxic. Presumably the repeated coronary occlusions during IPoC keep myocardial pH low while the resupply of oxygen during the intermittent reperfusion provides fuel for the redox signaling that acts to prevent MPTP formation even after restoration of normal myocardial pH. Hearts treated simultaneously with IPoC and alkaline perfusate could not be rescued by addition to the perfusate of either PMA or SB216763 which inhibits GSK-3beta, the putative last cytoplasmic signaling step in the signal transduction cascade leading to MPTP inhibition. Yet cyclosporin A which also inhibits MPTP formation does rescue hearts made alkaline during IPoC. In view of prior studies in which the ROS scavenger N-2-mercaptopropionyl glycine aborts IPoC's protection, our data reveal that IPoC's reperfusion periods are needed to support redox signaling rather than improve metabolism. The low pH, on the other hand, is equally necessary and seems to suppress MPTP directly rather than through upstream signaling.
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PMID:Acidosis, oxygen, and interference with mitochondrial permeability transition pore formation in the early minutes of reperfusion are critical to postconditioning's success. 1862 79

Epithelial-mesenchymal transition (EMT) and hypoxia are considered as crucial events favouring invasion and metastasis of many cancer cells. In this study, different human neoplastic cell lines of epithelial origin were exposed to hypoxic conditions in order to investigate whether hypoxia per se may trigger EMT programme as well as to mechanistically elucidate signal transduction mechanisms involved. The following human cancer cell lines were used: HepG2 (from human hepatoblastoma), PANC-1 (from pancreatic carcinoma), HT-29 (from colon carcinoma) and MCF-7 (from breast carcinoma). Cancer cells were exposed to carefully controlled hypoxic conditions and investigated for EMT changes and signal transduction by using morphological, cell and molecular biology techniques. All cancer cells responded to hypoxia within 72 h by classic EMT changes (fibroblastoid phenotype, SNAIL and beta-catenin nuclear translocation and changes in E-cadherin) and by increased migration and invasiveness. This was involving very early inhibition of glycogen synthase kinase-3beta (GSK-3beta), early SNAIL translocation as well as later and long-lasting activation of Wnt/beta-catenin-signalling machinery. Experimental manipulation, including silencing of hypoxia-inducible factor (HIF)-1alpha and the specific inhibition of mitochondrial generation of reactive oxygen species (ROS), revealed that early EMT-related events induced by hypoxia (GSK-3beta inhibition and SNAIL translocation) were dependent on transient intracellular increased generation of ROS whereas late migration and invasiveness were sustained by HIF-1alpha- and vascular endothelial growth factor (VEGF)-dependent mechanisms. These findings indicate that in cancer cells, early redox mechanisms can switch on hypoxia-dependent EMT programme whereas increased invasiveness is sustained by late and HIF-1alpha-dependent release of VEGF.
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PMID:Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells. 1879 Nov 99

Proline oxidase (POX), a flavoenzyme localized at the inner mitochondrial membrane, catalyzes the first step of proline degradation by converting proline to pyrroline-5-carboxylate (P5C). POX is markedly elevated during p53-induced apoptosis and generates proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, to induce apoptosis through both mitochondrial and death receptor pathways. These previous studies also showed suppression of the mitogen-activated protein kinase pathway leading us to broaden our exploration of proliferative signaling. In our current report, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter and found that three pathways which cross talk with each other were downregulated by POX: the cyclooxygenase-2 (COX-2) pathway, the epidermal growth factor receptor (EGFR) pathway and the Wnt/beta-catenin pathway. First, POX markedly reduced COX-2 expression, suppressed the production of prostaglandin E2 (PGE(2)) and importantly, the growth inhibition by POX was partially reversed by treatment with PGE(2.) Phosphorylation of EGFR was decreased with POX expression and the addition of EGF partially reversed the POX-dependent downregulation of COX-2. Wnt/beta-catenin signaling was decreased by POX in that phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was decreased on the one hand and phosphorylation of beta-catenin was increased on the other. There changes led to decreased accumulation of beta-catenin and decreased beta-catenin/TCF/LEF-mediated transcription. Our newly described POX-mediated suppression of proliferative signaling together with the previously reported induction of apoptosis suggested that POX could function as a tumor suppressor. Indeed, in human colorectal tissue samples, immunohistochemically-monitored POX was dramatically decreased in tumors compared with normal counterparts. Thus, POX metabolism of substrate proline affects multiple signaling pathways, modulating both apoptosis and tumor growth, and could be an attractive target to metabolically control the cancer phenotypes.
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PMID:Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers. 1879 9

Here, we provide the first evidence that sphingosine kinase 1 (SphK1), an oncogenic lipid kinase balancing the intracellular level of key signaling sphingolipids, modulates the transcription factor hypoxia inducible factor 1alpha (HIF-1alpha), master regulator of hypoxia. SphK1 activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1alpha levels is mediated by the Akt/glycogen synthase kinase-3beta signaling pathway that prevents its von Hippel-Lindau protein-mediated degradation by the proteasome. The pharmacologic and RNA silencing inhibition of SphK1 activity prevents the accumulation of HIF-1alpha and its transcriptional activity in several human cancer cell lineages (prostate, brain, breast, kidney, and lung), suggesting a canonical pathway. Therefore, we propose that SphK1 can act as a master regulator for hypoxia, giving support to its inhibition as a valid strategy to control tumor hypoxia and its molecular consequences.
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PMID:Sphingosine kinase 1: a new modulator of hypoxia inducible factor 1alpha during hypoxia in human cancer cells. 1892 40

The protein kinase-mediated actions of peptide growth factors such as IGF-1 and bFGF protect cultured neurons from being killed by the oxygen and glucose deprivations (OGD) that prevail in the 'stroked brain'. Here, we show that neuroprotection by IGF-1 is mediated by PI-3K/Akt, whereas that of bFGF is mediated by MAPK. IGF-1 and bFGF together did not further increase protection suggesting a downstream convergence of their pathways. Since protein kinases mediated the protection, a phosphatase inhibitor such as okadaic acid (OA) might be as protective as the growth factors against OGD. Here, we show that OA is actually a much more effective protector. It increased the phosphorylation of both PI-3K/Akt and MAPK, and stimulated new protein synthesis. OA also acted independently of the CREB activation and FKHRL1 and GSK-3 inactivation which have been implicated in IGF-1 actions.
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PMID:The phosphatase inhibitor, okadaic acid, strongly protects primary rat cortical neurons from lethal oxygen-glucose deprivation. 1902 14

We previously demonstrated that cadmium (Cd) is able to induce autophagic cell death through a calcium-extracellular signal-regulated kinase pathway. Here, the object of this study is to investigate the role of glycogen synthase kinase-3beta (GSK-3beta) in the induction of autophagy. After treatment with Cd, MES-13 mesangial cells were determined to have undergone autophagy based on the formation of acidic vesicular organelles and autophagosomes as well as on the processing of microtubule-associated protein 1 light chain 3, using flow cytometry with acridine orange staining, electron microscopy, and immunoblot, respectively. Use of the GSK-3beta inhibitor SB 216763 or the small interfering RNA technique to knockdown the expression of GSK-3beta resulted in a decrease of Cd-induced autophagy. In contrast, overexpression of GSK-3beta by transient transfection potentiated Cd toxicity toward the mesangial cells, suggesting that GSK-3beta plays a crucial role in regulating Cd-induced autophagy. Moreover, a decrease of the phosphorylated level at Ser9 of GSK-3beta was observed by immunoblot after treatment with Cd, indicating GSK-3beta was activated by Cd. This phenomenon was reversed by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC), demonstrated that ROS might activate GSK-3beta. In fact, intracellular hydrogen peroxide (H(2)O(2)) was 2.6-fold elevated after 3 h of exposure to Cd. Both Cd-induced ROS bursts and autophagy were reduced by NAC and vitamin E. In summary, this study demonstrated that, in MES-13 mesangial cells, Cd-induced autophagy was mediated through the ROS-GSK-3beta signaling pathway.
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PMID:Cadmium toxicity toward autophagy through ROS-activated GSK-3beta in mesangial cells. 1912 99


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