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
程序性死亡配体1(Programmed cell death ligand 1,PD-L1)是一种Ⅰ型跨膜蛋白,与程序性死亡受体1(Programmed cell death protein 1,PD-1)结合,诱导肿瘤免疫逃逸。靶向PD-1/PD-L1通路的临床免疫治疗逐渐开展,但在部分肿瘤治疗中未能取...程序性死亡配体1(Programmed cell death ligand 1,PD-L1)是一种Ⅰ型跨膜蛋白,与程序性死亡受体1(Programmed cell death protein 1,PD-1)结合,诱导肿瘤免疫逃逸。靶向PD-1/PD-L1通路的临床免疫治疗逐渐开展,但在部分肿瘤治疗中未能取得满意的效果。近年来研究发现PD-L1不仅定位于细胞膜,还定位在细胞质、细胞核或者细胞外,并且发挥相应的功能。本文结合近年来国内外的研究,从细胞核PD-L1(Nuclear PD-L1,nPD-L1)的表达、转运、功能、检测及临床意义等方面进行综述。文献复习结果表明,PD-L1在多种肿瘤细胞核中表达。在外界刺激因素作用下,PD-L1可通过核转运蛋白、信号转导及转录激活蛋白3、蛋白激酶B、细胞外调节蛋白激酶等多个信号通路转运至细胞核内,调控肿瘤增殖和死亡、免疫、血管及干细胞生成。通过免疫组化等方法检测nPD-L1的表达,对肿瘤诊断、治疗、预后、监测及随访均有重要意义,nPD-L1有可能成为新的治疗靶点并进入临床应用。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.
文摘程序性死亡配体1(Programmed cell death ligand 1,PD-L1)是一种Ⅰ型跨膜蛋白,与程序性死亡受体1(Programmed cell death protein 1,PD-1)结合,诱导肿瘤免疫逃逸。靶向PD-1/PD-L1通路的临床免疫治疗逐渐开展,但在部分肿瘤治疗中未能取得满意的效果。近年来研究发现PD-L1不仅定位于细胞膜,还定位在细胞质、细胞核或者细胞外,并且发挥相应的功能。本文结合近年来国内外的研究,从细胞核PD-L1(Nuclear PD-L1,nPD-L1)的表达、转运、功能、检测及临床意义等方面进行综述。文献复习结果表明,PD-L1在多种肿瘤细胞核中表达。在外界刺激因素作用下,PD-L1可通过核转运蛋白、信号转导及转录激活蛋白3、蛋白激酶B、细胞外调节蛋白激酶等多个信号通路转运至细胞核内,调控肿瘤增殖和死亡、免疫、血管及干细胞生成。通过免疫组化等方法检测nPD-L1的表达,对肿瘤诊断、治疗、预后、监测及随访均有重要意义,nPD-L1有可能成为新的治疗靶点并进入临床应用。
