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)

3-Aminobenzamide (3-AB), an inhibitor of poly(ADP-ribose) polymerase (PARP), has been proved to have neuroprotective properties. In this study, we examined the role of 3-AB in rat hippocampal neuron death induced by seizures. Our data showed that the seizures resulted in PARP activation and translocation of the apoptosis-inducing factor from the mitochondria to the nucleus, leading to neuron death. These effects could, however, all be abolished by 3-AB. Moreover, we showed that 3-AB facilitated Akt activation and decreased the activity of its downstream target, glycogen synthase kinase-3beta. Altogether, our data suggested that 3-AB might have a therapeutic value in seizure-induced hippocampal neuron damage, probably due to the inhibition of apoptosis and activation of Akt cell survival signaling.
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PMID:Poly(ADP-ribose) polymerase inhibitor is neuroprotective in epileptic rat via apoptosis-inducing factor and Akt signaling. 1763 84

Glycogen synthase kinase-3 (GSK-3) plays important roles in the regulation of glycogen and protein synthesis. In Alzheimer's disease it is responsible for hyperphosphorylation of tau. However, the role of GSK-3beta in brain aging and in neurodegenerative diseases is not fully elucidated. Our aim was to determine the protein level of GSK-3beta and its active, tyrosine 216-phosphorylated form in adult and aged brain parts. Moreover, lipid and protein oxidation and nuclear NF-kappaB translocation were measured and correlated with the activity of PARP-1, the nuclear target for free radical signalling. The GSK-3beta/PARP-1 relationship was investigated. Adult (4 months) and old (24 months) rats were used. PARP-1 inhibitor 3-aminobenzamide (3-AB) was injected subcutaneously for 5 days in a dose of 10 and 30 mg/kg b.w. On the 8th day object recognition test and open field test were performed.Biochemical,radiochemical,immunochemical and spectrophotometric methods were applied. Our data indicated similar protein level and activity of GSK-3beta in aged and adult brain cortex, hippocampus, striatum and cerebellum. A significantly higher level of p65NF-kappaB subunit was found in the nuclei of aged hippocampus. Moreover, our previous study presented higher PARP-1 activity in aged hippocampus and brain cortex versus adult. These results indicated an enhancement of oxidative stress and altered susceptibility of macromolecules to oxidative stress in aged brain. Subsequently it was found that 3-AB significantlychangedthelevelofactiveformofGSK-3beta(Tyr216) in the hippocampus and brain cortex and at high dose decreased the locomotor activity of aged rats. These results indicated that PARP-1 may play an important role in the regulation of GSK-3beta. Under massive oxidative stress PARP inhibitor(s) may protect the brain against both excessive poly(ADP-ribosy)lation and GSK-3beta activation.
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PMID:GSK-3beta and oxidative stress in aged brain. Role of poly(ADP- -ribose) polymerase-1. 1817 96

Arachidonic acid (AA, a proinflammatory fatty acid) in combination with iron promotes excess reactive oxygen species (ROS) production and exerts a deleterious effect on mitochondria. We have shown previously that activation of AMP-activated protein kinase (AMPK) protects hepatocytes from AA + iron-induced apoptosis. Resveratrol, a polyphenol in grapes, has beneficial effects mediated through SIRT1, LKB1, and AMPK. This study investigated the potential of resveratrol to protect against the mitochondrial impairment induced by AA + iron and the underlying mechanism for this cytoprotection. Resveratrol treatment inhibited apoptosis, ROS production, and glutathione depletion elicited by AA + iron in HepG2 cells. In addition, resveratrol attenuated superoxide generation in mitochondria and inhibited mitochondrial dysfunction induced by AA + iron. Overall, AMPK activation by resveratrol contributed to cell survival, as supported by the reversal of its restoration of mitochondrial membrane potential by either overexpression of a dominant-negative mutant of AMPKalpha or compound C treatment. Resveratrol increased inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK3beta) downstream of AMPK, which contributed to mitochondrial protection and cell survival. Likewise, small interfering RNA knockdown of LKB1, an upstream kinase of AMPK, reduced the ability of resveratrol to protect cells from mitochondrial dysfunction. Furthermore, this LKB1-dependent mitochondrial protection resulted from resveratrol's poly(ADP-ribose)polymerase activation, but not SIRT1 activation, as supported by the experiment using 3-aminobenzamide, a poly(ADP-ribose)polymerase inhibitor. Other polyphenols, such as apigenin, genistein, and daidzein, did not activate AMPK or protect mitochondria against AA + iron. Thus, resveratrol protects cells from AA + iron-induced ROS production and mitochondrial dysfunction through AMPK-mediated inhibitory phosphorylation of GSK3beta downstream of poly(ADP-ribose)polymerase-LKB1 pathway.
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PMID:Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. 3061 99

The study aimed to investigate the effect of inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) activity on tau phosphorylation in HEK293/tau441 cells and its mechanism. HEK293/tau441 cells were treated with 3-aminobenzamide (3-AB), a PARP-1 inhibitor, at different doses (0.5, 1, 2, 4 mmol/L). After 24 h, the cell morphology was observed under phase contrast microscope, tau phosphorylation level in different sites (tau-1, tau-5, Thr231) and the activity of glycogen synthase kinase 3 (GSK-3) were detected by Western blotting. The results showed: (1) 3-AB at different doses failed to change the morphology of cells; (2) The 3-AB-induced decrease in activity of PARP-1 resulted in increase of unphosphorylation level in tau-1(Ser195/198/199/202) sites; (3) The phosphorylation of tau was decreased in Thr231 site, while the total tau was slightly changed after 3-AB treatment; (4) With the increased phosphorylation of GSK-3 at Ser9 site, the activity of GSK-3 was decreased after 3-AB treatment. The results suggest that the inhibition of PARP-1 by 3-AB could decrease tau phosphorylation in HEK293/tau441 cells probably through decreasing GSK-3 activity.
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PMID:[Suppressing poly(ADP-ribose)polymerase-1 inhibits tau phosphorylation in HEK293/tau441 cells]. 2219 45