The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed...The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.展开更多
目的探讨超声脐血流收缩末期峰值(S)与舒张末期峰值(D)的比值(S/D)联合血清可溶性CD40配体(sCD40L)、热休克蛋白70(HSP70)对妊娠期高血压母婴结局的预测价值。方法回顾性分析2020年6月至2022年6月于保定第一中心医院诊治的160例妊娠期...目的探讨超声脐血流收缩末期峰值(S)与舒张末期峰值(D)的比值(S/D)联合血清可溶性CD40配体(sCD40L)、热休克蛋白70(HSP70)对妊娠期高血压母婴结局的预测价值。方法回顾性分析2020年6月至2022年6月于保定第一中心医院诊治的160例妊娠期高血压患者临床资料。根据母婴结局将患者分为母婴结局正常组(n=120)和母婴结局异常组(n=40)。所有患者均行超声检查脐血流S/D比值;酶联免疫吸附(ELISA)法测定患者血清中sCD40L、HSP70水平;对影响妊娠期高血压母婴结局的因素进行Logistic回归分析;受试者工作特征(ROC)曲线分析超声脐血流S/D比值联合血清sCD40L、HSP70对妊娠期高血压母婴结局的预测价值。结果与母婴结局正常组比较,异常组妊娠期高血压患者超声脐血流S/D比值显著升高(3.86±1.01 vs 2.57±0.65,P<0.05),血清sCD40L[(3.65±0.91)ng/L vs(6.04±1.42)ng/L]、HSP70水平[(2.01±0.46)μg/L vs(2.90±0.52)μg/L]均明显升高(P<0.05);Logistic回归分析发现,超声脐血流S/D比值、sCD40L、HSP70是影响妊娠期高血压患者母婴结局的危险因素(P<0.05)。超声脐血流S/D比值联合血清sCD40L、HSP70预测妊娠期高血压母婴结局的ROC曲线下面积(AUC)为0.993,均优于其各自单独预测(Z三者联合-超声脐血流S/D比值=4.030,P<0.001;Z三者联合-sCD40L=2.409,P=0.008;Z三者联合-HSP70=4.302,P<0.001)。结论妊娠期高血压患者超声脐血流S/D比值、血清sCD40L、HSP70水平升高,且与母婴结局有关,临床可用以预测患者母婴结局。展开更多
基金supported by the National Natural Science Foundation of China,Nos.91849115 and U1904207(to YX),81974211 and 82171247(to CS)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No.2020-PT310-01(to YX).
文摘The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.
文摘目的探讨超声脐血流收缩末期峰值(S)与舒张末期峰值(D)的比值(S/D)联合血清可溶性CD40配体(sCD40L)、热休克蛋白70(HSP70)对妊娠期高血压母婴结局的预测价值。方法回顾性分析2020年6月至2022年6月于保定第一中心医院诊治的160例妊娠期高血压患者临床资料。根据母婴结局将患者分为母婴结局正常组(n=120)和母婴结局异常组(n=40)。所有患者均行超声检查脐血流S/D比值;酶联免疫吸附(ELISA)法测定患者血清中sCD40L、HSP70水平;对影响妊娠期高血压母婴结局的因素进行Logistic回归分析;受试者工作特征(ROC)曲线分析超声脐血流S/D比值联合血清sCD40L、HSP70对妊娠期高血压母婴结局的预测价值。结果与母婴结局正常组比较,异常组妊娠期高血压患者超声脐血流S/D比值显著升高(3.86±1.01 vs 2.57±0.65,P<0.05),血清sCD40L[(3.65±0.91)ng/L vs(6.04±1.42)ng/L]、HSP70水平[(2.01±0.46)μg/L vs(2.90±0.52)μg/L]均明显升高(P<0.05);Logistic回归分析发现,超声脐血流S/D比值、sCD40L、HSP70是影响妊娠期高血压患者母婴结局的危险因素(P<0.05)。超声脐血流S/D比值联合血清sCD40L、HSP70预测妊娠期高血压母婴结局的ROC曲线下面积(AUC)为0.993,均优于其各自单独预测(Z三者联合-超声脐血流S/D比值=4.030,P<0.001;Z三者联合-sCD40L=2.409,P=0.008;Z三者联合-HSP70=4.302,P<0.001)。结论妊娠期高血压患者超声脐血流S/D比值、血清sCD40L、HSP70水平升高,且与母婴结局有关,临床可用以预测患者母婴结局。
