Apoptosis induced by endoplasmic reticulum(ER)stress plays a crucial role in mediating brain damage after ischemic stroke.Recently,Hes1(hairy and enhancer of split 1)has been implicated in the regulation of ER stress,...Apoptosis induced by endoplasmic reticulum(ER)stress plays a crucial role in mediating brain damage after ischemic stroke.Recently,Hes1(hairy and enhancer of split 1)has been implicated in the regulation of ER stress,but whether it plays a functional role after ischemic stroke and the underlying mechanism remain unclear.In this study,using a mouse model of ischemic stroke via transient middle cerebral artery occlusion(tMCAO),we found that Hes1 was induced following brain injury,and that siRNA-mediated knockdown of Hes1 increased the cerebral infarction and worsened the neurological outcome,suggesting that Hes1 knockdown exacerbates ischemic stroke.In addition,mechanistically,Hes1 knockdown promoted apoptosis and activated the PERK/eIF2a/ATF4/CHOP signaling pathway after tMCAO.These results suggest that Hes1 knockdown promotes ER stress-induced apoptosis.Furthermore,inhibition of PERK with the specific inhibitor GSK2606414 markedly attenuated the Hes1 knockdown-induced apoptosis and the increased cerebral infarction as well as the worsened neurological outcome following tMCAO,implying that the protection of Hes1 against ischemic stroke is associated with the amelioration of ER stress via modulating the PERK/eIF2a/ATF4/CHOP signaling pathway.Taken together,these results unveil the detrimental role of Hes1 knockdown after ischemic stroke and further relate it to the regulation of ER stress-induced apoptosis,thus highlighting the importance of targeting ER stress in the treatment of ischemic stroke.展开更多
General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有...General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有关键的调节作用,与肿瘤、心肌损伤、肺纤维化等的发生发展有一定的相关性。综述GCN2的生物学功能、结构特征、作用机制和疾病关联性,并总结分析GCN2抑制剂或激动剂的研发现状,重点阐述GCN2抑制剂或激动剂在抗肿瘤方向的临床应用潜力,为靶向GCN2激酶的新药开发提供参考。展开更多
基金supported by grants from the Guangxi Zhuang Autonomous Region Health and Family Planning Commission Science and Technology Project(Z2016419)Guangxi Natural Science Foundation Project(No.:2018JJA140853)the Science and Technology Project of Hunan Province,China(2014FJ4233).
文摘Apoptosis induced by endoplasmic reticulum(ER)stress plays a crucial role in mediating brain damage after ischemic stroke.Recently,Hes1(hairy and enhancer of split 1)has been implicated in the regulation of ER stress,but whether it plays a functional role after ischemic stroke and the underlying mechanism remain unclear.In this study,using a mouse model of ischemic stroke via transient middle cerebral artery occlusion(tMCAO),we found that Hes1 was induced following brain injury,and that siRNA-mediated knockdown of Hes1 increased the cerebral infarction and worsened the neurological outcome,suggesting that Hes1 knockdown exacerbates ischemic stroke.In addition,mechanistically,Hes1 knockdown promoted apoptosis and activated the PERK/eIF2a/ATF4/CHOP signaling pathway after tMCAO.These results suggest that Hes1 knockdown promotes ER stress-induced apoptosis.Furthermore,inhibition of PERK with the specific inhibitor GSK2606414 markedly attenuated the Hes1 knockdown-induced apoptosis and the increased cerebral infarction as well as the worsened neurological outcome following tMCAO,implying that the protection of Hes1 against ischemic stroke is associated with the amelioration of ER stress via modulating the PERK/eIF2a/ATF4/CHOP signaling pathway.Taken together,these results unveil the detrimental role of Hes1 knockdown after ischemic stroke and further relate it to the regulation of ER stress-induced apoptosis,thus highlighting the importance of targeting ER stress in the treatment of ischemic stroke.
文摘目的:探讨2型糖尿病(T2DM)小鼠骨形成变化及不同运动对T2DM小鼠骨中环磷酸腺苷(c AMP)/环磷腺苷效应元件结合蛋白(CREB)/激活转录因子4(ATF4)途径和骨形成的影响。方法:40只4周龄C57BL/6雄性小鼠,适应性喂养1周后随机分为正常对照组(ZC,10只)和T2DM造模组(30只)。T2DM造模组小鼠造模成功后随机分为T2DM对照组(TC组,9只)、T2DM游泳组(TS组,9只)和T2DM下坡跑组(TD组,9只)。利用游泳和下坡跑对TS组和TD组小鼠进行8周训练。结束后,取小鼠血清并利用ELISA法检测c AMP浓度;取右侧股骨并利用RT-PCR法检测CREB、ATF4、骨钙素(OC)、骨钙蛋白(OCN)和骨涎蛋白(BSP)的m RNA表达;取右侧胫骨并利用West-blotting法检测CREB蛋白表达;取小鼠骨髓间充质干细胞(BMSCs)并诱导其向骨细胞(OB)分化,利用碱性磷酸酶(ALP)染液对OB染色;取左侧股骨并用Micro-CT对股骨远端BMD进行扫描。结果:与ZC组相比,TC组c AMP浓度下降,CREB、ATF4、OC、OCN和BSP m RNA及CREB蛋白表达均显著下降(P<0.05或P<0.01),OB成骨能力和BMD显著下降(P<0.01)。与TC组相比,TS组OC和OCN m RNA表达上调(P<0.05或P<0.01),OB骨形成能力增强;TD组c AMP浓度下降,CREB、ATF4、OC和OCN m RNA及CREB蛋白表达均显著上调(P<0.05或P<0.01),OB骨形成能力和BMD显著增加(P<0.01)。与TS组相比,TD组c AMP浓度升高,CREB、ATF4和OC的m RNA表达显著上调(P<0.05或P<0.01),OB骨形成能力增强。结论:2型糖尿病小鼠骨形成代谢被抑制;下坡跑通过激活2型糖尿病小鼠骨中c AMP/CREB/ATF4途径,促进成骨细胞分化及骨形成能力,提高骨密度,且其作用效果优于游泳。
文摘General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有关键的调节作用,与肿瘤、心肌损伤、肺纤维化等的发生发展有一定的相关性。综述GCN2的生物学功能、结构特征、作用机制和疾病关联性,并总结分析GCN2抑制剂或激动剂的研发现状,重点阐述GCN2抑制剂或激动剂在抗肿瘤方向的临床应用潜力,为靶向GCN2激酶的新药开发提供参考。
