No abstract

No abstract

No abstract

This study examines the signaling mechanism by which cilostazol prevents neuronal cell death. Cilostazol (ϳ0.1-100 M) prevented tumor necrosis factor-␣ (TNF-␣)-induced decrease in viability of SK-N-SH and HCN-1A cells, which was antagonized by 1 M iberiotoxin, a maxi-K channel blocker. TNF-␣ did not suppress the viability of the U87-MG cell, a phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-null glioblastoma cell, but it did decrease viability of U87-MG cells transfected with expression vectors for the sense PTEN, and this decrease was also prevented by cilostazol. Cilostazol as well as 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619) and (3S)-(ϩ)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one (BMS 204352), maxi-K channel openers, prevented increased DNA fragmentation evoked by TNF-␣, which were antagonizable by iberiotoxin. TNF-␣-induced increased PTEN phosphorylation and decreased Akt/ cyclic AMP response element-binding protein (CREB) phosphorylation were significantly prevented by cilostazol, those of which were antagonized by both iberiotoxin and paxilline, maxi-K channel blockers. The same results were evident in U87-MG cells transfected with expression vectors for sense PTEN. Cilostazol increases the K ϩ current in SK-N-SH cells by activating maxi-K channels without affecting the ATP-sensitive K ϩ channel. Thus, our results for the first time provide evidence that cilostazol prevents TNF-␣-induced cell death by suppression of PTEN phosphorylation and activation of Akt/CREB phosphorylation via mediation of the maxi-K channel opening.Recent research has shown that the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is implicated in the regulation of several cellular functions, including cell viability from apoptosis (Li et al., 1998;Stambolic et al., 1998;Cantley and Neel, 1999). PTEN is capable of dephosphorylating both phospho-tyrosine and phospho-serine/threonine-containing substrates (Myers et al., 1997) and also of dephosphorylating the phosphatidylinositol-3,4,5-triphosphate [PI(3,4,5)P 3 ], a direct product of phosphatidylinositol 3-kinase (PI3-K) activity, thereby converting the PI(3,4,5)P 3 to phosphatidylinositol 3,4-diphosphate [PI(3,4)P 2 ], an inactive state (Maehama and Dixon, 1998;Stambolic et al., 1998). Huang et al. (2001) have demonstrated that transient transfection of PTEN into the PTEN-null cells results in decrease in Bcl-2 mRNA and protein, and loss of PTEN leads to up-regulation of the Bcl-2 gene. Overexpression of PI3-K and its downstream effector Akt (serine/threonine kinase) have been documented to mediate growth factor-induced neuronal survival (Crowder and Freeman, 1998) and to up-regulate Bcl-2 promoter activity associated with increased Bcl-2

The objective of this study was to assess the possible beneficial skeletal muscle preserving effects of ethanol extract of Schisandrae Fructus (EESF) on sciatic neurectomy- (NTX-) induced hindlimb muscle atrophy in mice. Here, calf muscle atrophy was induced by unilateral right sciatic NTX. In order to investigate whether administration of EESF prevents or improves sciatic NTX-induced muscle atrophy, EESF was administered orally. Our results indicated that EESF dose-dependently diminished the decreases in markers of muscle mass and activity levels, and the increases in markers of muscle damage and fibrosis, inflammatory cell infiltration, cytokines, and apoptotic events in the gastrocnemius muscle bundles are induced by NTX. Additionally, destruction of gastrocnemius antioxidant defense systems after NTX was dose-dependently protected by treatment with EESF. EESF also upregulated muscle-specific mRNAs involved in muscle protein synthesis but downregulated those involved in protein degradation. The overall effects of 500 mg/kg EESF were similar to those of 50 mg/kg oxymetholone, but it showed more favorable antioxidant effects. The present results suggested that EESF exerts a favorable ameliorating effect on muscle atrophy induced by NTX, through anti-inflammatory and antioxidant effects related to muscle fiber protective effects and via an increase in protein synthesis and a decrease in protein degradation.