Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
为探讨小鼠植入前胚胎组蛋白乙酰化酶GCN5(general control of nucleotide synthesis,GCN5) 和组蛋白去乙酰化酶1(histone deacetyluse1,HDAC1)的表达模式及常规体外培养对它们表达的影响,应用荧光免疫细胞化学技术,检测了体内和体外培...为探讨小鼠植入前胚胎组蛋白乙酰化酶GCN5(general control of nucleotide synthesis,GCN5) 和组蛋白去乙酰化酶1(histone deacetyluse1,HDAC1)的表达模式及常规体外培养对它们表达的影响,应用荧光免疫细胞化学技术,检测了体内和体外培养的小鼠2、4、8细胞期卵裂胚胎、桑葚胚和囊胚GCN5和HDAC1的表达。结果显示,GCN5在体内组各细胞期卵裂胚胎和桑葚胚的细胞浆内均呈高表达,细胞核内未见明显表达,而囊胚细胞的细胞浆和细胞核内均无表达:HDAC1在体内组小鼠2细胞期胚胎中以细胞浆内表达为主,在其他各期胚胎均以细胞核内表达为主．囊胚期内细胞团部分细胞的细胞核内未见HDAC1表达。GCN5在体外组小鼠植入前各期胚胎均不表达,而 HDAC1的表达强度明显低于体内组的。提示体外培养抑制小鼠植入前胚胎GCN5和明显降低 HDAC1的表达,影响胚胎基因的正确性表达。展开更多
目的:探讨干扰组蛋白去乙酰化酶1(HDAC1)对皮肤鳞癌细胞凋亡的影响。方法:皮肤鳞癌细胞A431分别转染HDAC1小干扰RNA(HDAC1 si RNA)和小干扰RNA阴性对照(si RNA NC),RT-PCR和Western blot检测转染后细胞中HDAC1的表达水平,MTT检测细胞活...目的:探讨干扰组蛋白去乙酰化酶1(HDAC1)对皮肤鳞癌细胞凋亡的影响。方法:皮肤鳞癌细胞A431分别转染HDAC1小干扰RNA(HDAC1 si RNA)和小干扰RNA阴性对照(si RNA NC),RT-PCR和Western blot检测转染后细胞中HDAC1的表达水平,MTT检测细胞活力,流式细胞术检测细胞凋亡,Western blot检测信号转导及转录激活因子3(STAT3)、磷酸化STAT3(p-STAT3)和cleaved caspase-3的蛋白水平。同时用STAT3信号通路抑制剂作用于转染HDAC1 si RNA的A431细胞,MTT法检测细胞活力,流式细胞术检测细胞凋亡,Western blot检测STAT3、p-STAT3和cleaved caspase-3的蛋白水平。结果:HDAC1 si RNA能够抑制A431细胞中HDAC1的m RNA和蛋白表达。干扰HDAC1表达后细胞活力和细胞中p-STAT3水平下降,而细胞凋亡率和细胞中cleaved caspase-3水平升高。STAT3信号通路抑制剂作用后,转染HDAC1 si RNA的A431细胞活力及p-STAT3水平下降,细胞凋亡率及细胞中cleaved caspase-3水平升高。结论:干扰HDAC1表达可能通过调控STAT3信号通路抑制皮肤鳞癌细胞活力,促进皮肤鳞癌细胞凋亡。展开更多
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
文摘目的探讨乳酸脱氢酶A(LDH-A)与组蛋白去乙酰化酶1(HDAC1)在肠型胃癌中表达的相关性及其与预后的关系。方法应用Western blotting法检测HDAC1蛋白在慢病毒介导的LDH-A siRNA转染肠型胃癌细胞株SGC7901中表达的变化;应用免疫组织化学方法检测661例肠型胃癌组织及癌旁正常组织中LDH-A与HDAC1蛋白的表达情况并分析其表达与预后的关系。结果 Western blotting检测结果显示,LDH-A蛋白在SGC7901细胞株中的表达明显上调,且LDH-A的沉默可显著下调HDAC1的表达。肠型胃癌组织中LDH-A蛋白的高表达率为54.8%(362/661),明显高于癌旁正常组织的12.9%(85/661),两者差异有统计学意义(P<0.01);肠型胃癌组织中HDAC1的高表达率为51.3%(339/661),明显高于癌旁正常组织的15.4%(102/661),两者差异有统计学意义(P<0.01)。LDH-A与HDAC1蛋白在肠型胃癌组织中的表达呈正相关(r=0.324,P<0.001)。单因素生存分析结果显示,LDH-A与HDAC1均低表达患者的生存曲线明显优于其他组合(P<0.001);多因素生存分析结果显示LDH-A与HDAC1表达均为肠型胃癌独立的预后因素。结论在肠型胃癌中,LDH-A与HDAC1的表达呈正相关,采用LDH-A和HDAC1双靶点抑制治疗可能具有潜在的生存获益。
文摘为探讨小鼠植入前胚胎组蛋白乙酰化酶GCN5(general control of nucleotide synthesis,GCN5) 和组蛋白去乙酰化酶1(histone deacetyluse1,HDAC1)的表达模式及常规体外培养对它们表达的影响,应用荧光免疫细胞化学技术,检测了体内和体外培养的小鼠2、4、8细胞期卵裂胚胎、桑葚胚和囊胚GCN5和HDAC1的表达。结果显示,GCN5在体内组各细胞期卵裂胚胎和桑葚胚的细胞浆内均呈高表达,细胞核内未见明显表达,而囊胚细胞的细胞浆和细胞核内均无表达:HDAC1在体内组小鼠2细胞期胚胎中以细胞浆内表达为主,在其他各期胚胎均以细胞核内表达为主．囊胚期内细胞团部分细胞的细胞核内未见HDAC1表达。GCN5在体外组小鼠植入前各期胚胎均不表达,而 HDAC1的表达强度明显低于体内组的。提示体外培养抑制小鼠植入前胚胎GCN5和明显降低 HDAC1的表达,影响胚胎基因的正确性表达。
文摘目的:探讨干扰组蛋白去乙酰化酶1(HDAC1)对皮肤鳞癌细胞凋亡的影响。方法:皮肤鳞癌细胞A431分别转染HDAC1小干扰RNA(HDAC1 si RNA)和小干扰RNA阴性对照(si RNA NC),RT-PCR和Western blot检测转染后细胞中HDAC1的表达水平,MTT检测细胞活力,流式细胞术检测细胞凋亡,Western blot检测信号转导及转录激活因子3(STAT3)、磷酸化STAT3(p-STAT3)和cleaved caspase-3的蛋白水平。同时用STAT3信号通路抑制剂作用于转染HDAC1 si RNA的A431细胞,MTT法检测细胞活力,流式细胞术检测细胞凋亡,Western blot检测STAT3、p-STAT3和cleaved caspase-3的蛋白水平。结果:HDAC1 si RNA能够抑制A431细胞中HDAC1的m RNA和蛋白表达。干扰HDAC1表达后细胞活力和细胞中p-STAT3水平下降,而细胞凋亡率和细胞中cleaved caspase-3水平升高。STAT3信号通路抑制剂作用后,转染HDAC1 si RNA的A431细胞活力及p-STAT3水平下降,细胞凋亡率及细胞中cleaved caspase-3水平升高。结论:干扰HDAC1表达可能通过调控STAT3信号通路抑制皮肤鳞癌细胞活力,促进皮肤鳞癌细胞凋亡。
