Cerebral ischemia/reperfusion injury is partially mediated by thrombin, which causes brain damage through protease-activated receptor 1（PAR1）. However, the role and mechanisms underlying the effects of PAR1 activati...Cerebral ischemia/reperfusion injury is partially mediated by thrombin, which causes brain damage through protease-activated receptor 1（PAR1）. However, the role and mechanisms underlying the effects of PAR1 activation require further elucidation. Therefore, the present study investigated the effects of the PAR1 antagonist SCH79797 in a rabbit model of global cerebral ischemia induced by cardiac arrest. SCH79797 was intravenously administered 10 minutes after the model was established. Forty-eight hours later, compared with those administered saline, rabbits receiving SCH79797 showed markedly decreased neuronal damage as assessed by serum neuron specific enolase levels and less neurological dysfunction as determined using cerebral performance category scores. Additionally, in the hippocampus, cell apoptosis, polymorphonuclear cell infiltration, and c-Jun levels were decreased, whereas extracellular signal-regulated kinase phosphorylation levels were increased. All of these changes were inhibited by the intravenous administration of the phosphoinositide 3-kinase/Akt pathway inhibitor LY29004（3 mg/kg） 10 minutes before the SCH79797 intervention. These findings suggest that SCH79797 mitigates brain injury via anti-inflammatory and anti-apoptotic effects, possibly by modulating the extracellular signal-regulated kinase, c-Jun N-terminal kinase/c-Jun and phosphoinositide 3-kinase/Akt pathways.展开更多
目的探讨蛋白酶激活受体1(PAR1)在胰腺癌细胞株Bxpc-3的表达及意义。方法采用反转录聚合酶链反应(RT-PCR)扩增法检测胰腺癌细胞株Bxpc-3中PAR1 mRNA的表达;设置对照组与实验组,实验组加PAR1激动剂(PAR1-AP),而对照组不加PAR1-AP,利用PAR...目的探讨蛋白酶激活受体1(PAR1)在胰腺癌细胞株Bxpc-3的表达及意义。方法采用反转录聚合酶链反应(RT-PCR)扩增法检测胰腺癌细胞株Bxpc-3中PAR1 mRNA的表达;设置对照组与实验组,实验组加PAR1激动剂(PAR1-AP),而对照组不加PAR1-AP,利用PAR1-AP观察其对胰腺癌细胞迁移和增殖能力的影响。结果胰腺癌细胞中存在PAR1 m RNA的高表达;实验组细胞迁移比对照组明显增快,实验组和对照组平均每视野细胞数为(148.425±16.123)个vs(54.012±4.614)个(t=21.950,P<0.01)。实验组细胞增殖也高于对照组,实验组和对照组每分钟闪烁值为8450±1159 vs 4098±671(t=7.330,P<0.05)。结论PAR1在胰腺癌细胞中高表达,并能促进其迁移和增殖,表明PAR1与胰腺癌的转移能力和恶性程度密切相关;PAR1可以作为判断胰腺癌预后的生物学指标及治疗的新靶点。展开更多
Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previou...Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previous works have shown that it is possible to develop potent thrombin receptor antagonists to compete effectively with the receptor’s internal “tethered” ligand to block platelet activation. Vorapaxar (SCH 530348) from Schering-Plough (now Merck) and atopaxar (E5555) from Eisai have been advanced to human clinical trials. Recently, the pivotal phase III clinical trial results for vorapaxar were published. In this article we review these results plus the phase II results from atopaxar. Several newly described thrombin receptor antagonists from the literature will also be discussed. The phase III results from vorapaxar demonstrated that a thrombin receptor antagonist can achieve efficacy in addition to current standard- of-care in treating atherothrombotic patients, especially those with previous myocardial infarction (MI). However, the increased moderate and severe bleeding, especially intracranial bleeding, point to the limitations of current thrombin receptor antagonists. Future thrombin receptor antagonists that can improve on the efficacy and bleeding profile of current ones should have a promising place in meeting the unmet medical need in treating atherothrombotic patients using current standard therapy.展开更多
基金supported by the Natural Science Foundation of Hubei Province of China,No.2010CDB09101
文摘Cerebral ischemia/reperfusion injury is partially mediated by thrombin, which causes brain damage through protease-activated receptor 1（PAR1）. However, the role and mechanisms underlying the effects of PAR1 activation require further elucidation. Therefore, the present study investigated the effects of the PAR1 antagonist SCH79797 in a rabbit model of global cerebral ischemia induced by cardiac arrest. SCH79797 was intravenously administered 10 minutes after the model was established. Forty-eight hours later, compared with those administered saline, rabbits receiving SCH79797 showed markedly decreased neuronal damage as assessed by serum neuron specific enolase levels and less neurological dysfunction as determined using cerebral performance category scores. Additionally, in the hippocampus, cell apoptosis, polymorphonuclear cell infiltration, and c-Jun levels were decreased, whereas extracellular signal-regulated kinase phosphorylation levels were increased. All of these changes were inhibited by the intravenous administration of the phosphoinositide 3-kinase/Akt pathway inhibitor LY29004（3 mg/kg） 10 minutes before the SCH79797 intervention. These findings suggest that SCH79797 mitigates brain injury via anti-inflammatory and anti-apoptotic effects, possibly by modulating the extracellular signal-regulated kinase, c-Jun N-terminal kinase/c-Jun and phosphoinositide 3-kinase/Akt pathways.
文摘目的探讨蛋白酶激活受体1(PAR1)在胰腺癌细胞株Bxpc-3的表达及意义。方法采用反转录聚合酶链反应(RT-PCR)扩增法检测胰腺癌细胞株Bxpc-3中PAR1 mRNA的表达;设置对照组与实验组,实验组加PAR1激动剂(PAR1-AP),而对照组不加PAR1-AP,利用PAR1-AP观察其对胰腺癌细胞迁移和增殖能力的影响。结果胰腺癌细胞中存在PAR1 m RNA的高表达;实验组细胞迁移比对照组明显增快,实验组和对照组平均每视野细胞数为(148.425±16.123)个vs(54.012±4.614)个(t=21.950,P<0.01)。实验组细胞增殖也高于对照组,实验组和对照组每分钟闪烁值为8450±1159 vs 4098±671(t=7.330,P<0.05)。结论PAR1在胰腺癌细胞中高表达,并能促进其迁移和增殖,表明PAR1与胰腺癌的转移能力和恶性程度密切相关;PAR1可以作为判断胰腺癌预后的生物学指标及治疗的新靶点。
文摘Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previous works have shown that it is possible to develop potent thrombin receptor antagonists to compete effectively with the receptor’s internal “tethered” ligand to block platelet activation. Vorapaxar (SCH 530348) from Schering-Plough (now Merck) and atopaxar (E5555) from Eisai have been advanced to human clinical trials. Recently, the pivotal phase III clinical trial results for vorapaxar were published. In this article we review these results plus the phase II results from atopaxar. Several newly described thrombin receptor antagonists from the literature will also be discussed. The phase III results from vorapaxar demonstrated that a thrombin receptor antagonist can achieve efficacy in addition to current standard- of-care in treating atherothrombotic patients, especially those with previous myocardial infarction (MI). However, the increased moderate and severe bleeding, especially intracranial bleeding, point to the limitations of current thrombin receptor antagonists. Future thrombin receptor antagonists that can improve on the efficacy and bleeding profile of current ones should have a promising place in meeting the unmet medical need in treating atherothrombotic patients using current standard therapy.
