This study examined the protective effects of cilostazol on cerebral infarcts produced by subjecting rats to 2-h occlusion of the left middle cerebral artery followed by 24-h reperfusion. The ischemic cerebral infarct consistently involved the cortex and striatum. The infarct size was significantly reduced, when rats received 10 mg/kg cilostazol intravenously 5 min or 1 h after the completion of 2-h ischemia. Cyclic AMP level was significantly elevated in the cortex of 4-and 12-h reperfusion (P Ͻ 0.01) following treatment with cilostazol (10 mg/kg, 5 min after 2-h ischemia) accompanied by decreased tumor necrosis factor-␣ level. Samples from the regions corresponding to the penumbra showed markedly reduced Bcl-2 protein level and, in contrast, high levels of Bax protein and cytochrome c release. Cilostazol decreased Bax protein and cytochrome c release and increased the levels of Bcl-2 protein. Cilostazol (10

This work describes the pharmacological inhibition by cilostazol and its metabolites, OPC-13015 and OPC-13213, of the apoptosis in the human umbilical vein endothelial cells (HUVECs) damaged by lipopolysaccharide (LPS) in comparison with its analog, cilostamide. Cilostazol and OPC-31213 caused a significant suppression of cell death induced by LPS (1 g/ml) in a concentration-dependent manner but a modest suppression by cilostamide and OPC-13015. These compounds potently inhibited the 5,5-dimethyl-1-pyrroline-1-oxide (DMPO)/ ⅐ OH adduct formation and significantly reduced the increased intracellular reactive oxygen species (ROS) and tumor necrosis factor-␣ (TNF-␣) production induced by LPS (1 g/ml). An apoptotic death of HUVECs by 1 g/ml LPS (DNA ladders on electrophoresis) was strongly suppressed by all these compounds. Incubation with LPS caused a marked decrease in Bcl-2 protein, which was significantly reversed by cilostazol and its analogs. The greatly increased Bax protein expression and cytochrome c release by LPS were, in contrast, suppressed by cilostazol and, to a lesser degree, by others. In conclusion, cilostazol and its analogs exert a strong protection against apoptotic cell death by scavenging hydroxyl radicals and intracellular ROS with reduction in TNF-␣ formation and by increasing Bcl-2 protein expression and decreasing Bax protein and cytochrome c release.

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

KMS4034 may be an effective analgesic for various pain conditions.

Liver transplantation is the best treatment option for early-stage hepatocellular carcinoma, liver cirrhosis, fulminant liver failure, and end-stage liver diseases. Even though advances in surgical techniques and perioperative care have improved postoperative outcomes, perioperative cardiovascular complications are a leading cause of postoperative morbidity and mortality following liver transplantation. Ischemic coronary artery disease (CAD) and cardiomyopathy are the most common cardiovascular diseases and could be negative predictors of postoperative outcomes in liver transplant recipients. Therefore, comprehensive cardiovascular evaluations are required to assess perioperative risks and prevent concomitant cardiovascular complications that would preclude good outcomes in liver transplant recipients. The two major types of cardiac computed tomography are the coronary artery calcium score (CACS) and coronary computed tomography angiography (CCTA). CCTA in combination with the CACS is a validated noninvasive alternative to coronary angiography for diagnosing and grading the severity of CAD. A CACS > 400 is associated with significant CAD and a known important predictor of posttransplant cardiovascular complications in liver transplant recipients. In this review article, we discuss the usefulness, advantages, and disadvantages of CCTA combined with CACS as a noninvasive diagnostic tool for preoperative cardiac evaluation and for maximizing the perioperative outcomes of liver transplant recipients.

SUMMARY BackgroundClinical factors were previously identified as predictors of short-term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7-year trial provides an opportunity to study predictors of short-and long-term clinical remission among CD patients treated with certolizumab pegol (CZP).

The purpose of this experiment was to examine whether the cAMP-adenosine pathway is implicated in the autoregulatory vasodilation in response to hypotension. Suffusion with cAMP (1–100 μmol/l) or adenosine (0.01–10 μmol/l) caused a sustained vasodilation of the resting pial arteries in a concentration-dependent manner. In contrast, N 6,2′- O-dibutyryl-cAMP and 8-bromo-cAMP exerted a weak dilation at high concentration (100 μmol/l). The vasodilation to cAMP (1–100 μmol/l), adenosine (0.01–10 μmol/l), and hypotension was significantly reduced by pretreatment with 3,7-dimethyl-1-propargylxanthine (1 μmol/l), an A2 receptor antagonist, as well as 3-isobutyl-1-methylxanthine (3 μmol/l), an inhibitor of endo- and ectophosphodiesterase, 1,3-dipropyl-8- p-sulfophenylxanthine (100 μmol/l), an inhibitor of ecto-5′-phosphodiesterase, or α,β-methylene-adenosine 5′-diphosphate (100 μmol/l), an inhibitor of ecto-5′-nucleotidase. However, 8-cyclopentyltheophylline (1 μmol/l), an A1 antagonist, did not elicit a similar response. The increased release of adenosine when the cortical surface was suffused with cAMP (100 μmol/l) was significantly reduced by 3-isobutyl-1-methylxanthine, 1,3-dipropyl-8- p-sulfophenylxanthine, and α,β-methylene-adenosine 5′-diphosphate (each 100 μmol/l). These results indicate that the cAMP-adenosine pathway as a viable metabolic mechanism is implicated in the production of adenosine in the rat pial artery and contributes to the regulation of vasodilation in response to hypotension.

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