目的基于淀粉样β前体蛋白(amyloid beta precursor protein,APP)家族、淀粉样β前体蛋白结合蛋白A(amyloid beta precursor protein binding family A,APBA)家族和淀粉样β前体蛋白结合蛋白B(amyloid beta precursor protein binding f...目的基于淀粉样β前体蛋白(amyloid beta precursor protein,APP)家族、淀粉样β前体蛋白结合蛋白A(amyloid beta precursor protein binding family A,APBA)家族和淀粉样β前体蛋白结合蛋白B(amyloid beta precursor protein binding family B,APBB)家族构建胃癌预后评估模型。方法从基因表达综合(gene expression omnibus,GEO)数据库下载GSE62254胃癌数据集作为训练集,GSE15459作为验证集。利用Cox回归分析筛选APP家族、APBA家族和APBB家族中胃癌预后的独立危险因素;分别建立基于三家族独立预后因素的风险评分1(risk score 1,RS1)、RS1联合病理学参数的RS2、传统TNM分期的RS3;卡方检验分析RS1与胃癌患者临床病理特征的关系;利用单细胞在线分析网站,分析纳入RS1模型的基因在不同细胞亚群中的表达情况;利用CIBERSORT分析RS1对不同免疫细胞浸润的影响;利用基因集富集分析(gene set enrichment analysis,GSEA)进行通路富集分析。结果APLP2、APBB1、APBB2是胃癌患者预后的独立危险因素(P<0.05),基于三者的风险评分RS1高组患者生存期明显短于RS1低组患者。联合临床病理学参数的Cox回归分析显示,N分期、M分期、Lauren分型和RS1是胃癌患者预后的独立危险因素(P<0.05)。基于此构建的RS2(AUC=0.767)比仅基于T分期、N分期、M分期构建的RS3(AUC=0.719)预测准确率提高了4.8%。RS1和肿瘤T分期呈正相关(P<0.05),RS1高组CD4静息细胞浸润较高,激活细胞浸润较低,M2巨噬细胞浸润较高。GSEA通路分析显示,高RS1组患者富集于MAPK、MTOR和WNT等通路。结论本研究成功构建了基于APP、APBA和APBB家族的胃癌预后评估模型,该模型能够较准确地判断胃癌患者预后。展开更多
Abnormalities in insulin metabolism, characteristic of T2DM, are among the major factors thought to mechanistically influence the onset of AD. These abnormalities are thought to play a role in AD via their influence o...Abnormalities in insulin metabolism, characteristic of T2DM, are among the major factors thought to mechanistically influence the onset of AD. These abnormalities are thought to play a role in AD via their influence on the synthesis and degradation of Aβ and as a consequence of the cascade of neuronal alterations resulting from the effects of danger/alarm signals from oligomeric amyloid species. Additionally, recent studies have indicated that certain signal transduction pathways downstream of the InsR may also promote the generation of Aβ peptides by modulating the cleavage of the parent Aβ precursor protein (AβPP) at the γ-secretase site, a cleavage site necessary for Aβ amyloidogenicity. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia;this condition persists for several years before becoming full blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and reduced insulin signaling in brain, altering all of insulin’s actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition enhancing effect on patient with AD.展开更多
目的:探讨绞股蓝对海马注射Aβ1-40大鼠脑内细胞周期蛋白异常表达和钙稳态变化的影响。方法:动物随机分为绞股蓝组、模型组、对照组。运用淀粉样β蛋白双侧海马注射,模拟阿尔茨海默病脑内Aβ对神经系统的损害。Y型迷宫测试大鼠学习记忆...目的:探讨绞股蓝对海马注射Aβ1-40大鼠脑内细胞周期蛋白异常表达和钙稳态变化的影响。方法:动物随机分为绞股蓝组、模型组、对照组。运用淀粉样β蛋白双侧海马注射,模拟阿尔茨海默病脑内Aβ对神经系统的损害。Y型迷宫测试大鼠学习记忆能力,免疫组织化学染色和积分吸光度分析检测细胞周期蛋白A、B1(cyc linA、cyc lin B1),Fura-2/AM-荧光法测定海马细胞内Ca2+含量;并对绞股蓝组大鼠给予绞股蓝皂苷灌胃,观察其对AD大鼠上述各项指标变化的影响。结果:Aβ1-40海马注射大鼠学习记忆能力明显低于对照组(P<0.05),脑内细胞周期蛋白A、B1蛋白水平明显高于对照组,海马神经元内Ca2+含量显著高于对照组;而给予绞股蓝在一定程度上能改善大鼠学习记忆能力,降低cyc lin A、cyc lin B1蛋白和Ca2+含量的水平(P<0.05)。结论:绞股蓝对Aβ引起的动物学习记忆能力减退、海马神经元内异常表达细胞周期蛋白和钙稳态失衡有一定的逆转作用。展开更多
文摘目的基于淀粉样β前体蛋白(amyloid beta precursor protein,APP)家族、淀粉样β前体蛋白结合蛋白A(amyloid beta precursor protein binding family A,APBA)家族和淀粉样β前体蛋白结合蛋白B(amyloid beta precursor protein binding family B,APBB)家族构建胃癌预后评估模型。方法从基因表达综合(gene expression omnibus,GEO)数据库下载GSE62254胃癌数据集作为训练集,GSE15459作为验证集。利用Cox回归分析筛选APP家族、APBA家族和APBB家族中胃癌预后的独立危险因素;分别建立基于三家族独立预后因素的风险评分1(risk score 1,RS1)、RS1联合病理学参数的RS2、传统TNM分期的RS3;卡方检验分析RS1与胃癌患者临床病理特征的关系;利用单细胞在线分析网站,分析纳入RS1模型的基因在不同细胞亚群中的表达情况;利用CIBERSORT分析RS1对不同免疫细胞浸润的影响;利用基因集富集分析(gene set enrichment analysis,GSEA)进行通路富集分析。结果APLP2、APBB1、APBB2是胃癌患者预后的独立危险因素(P<0.05),基于三者的风险评分RS1高组患者生存期明显短于RS1低组患者。联合临床病理学参数的Cox回归分析显示,N分期、M分期、Lauren分型和RS1是胃癌患者预后的独立危险因素(P<0.05)。基于此构建的RS2(AUC=0.767)比仅基于T分期、N分期、M分期构建的RS3(AUC=0.719)预测准确率提高了4.8%。RS1和肿瘤T分期呈正相关(P<0.05),RS1高组CD4静息细胞浸润较高,激活细胞浸润较低,M2巨噬细胞浸润较高。GSEA通路分析显示,高RS1组患者富集于MAPK、MTOR和WNT等通路。结论本研究成功构建了基于APP、APBA和APBB家族的胃癌预后评估模型,该模型能够较准确地判断胃癌患者预后。
文摘Abnormalities in insulin metabolism, characteristic of T2DM, are among the major factors thought to mechanistically influence the onset of AD. These abnormalities are thought to play a role in AD via their influence on the synthesis and degradation of Aβ and as a consequence of the cascade of neuronal alterations resulting from the effects of danger/alarm signals from oligomeric amyloid species. Additionally, recent studies have indicated that certain signal transduction pathways downstream of the InsR may also promote the generation of Aβ peptides by modulating the cleavage of the parent Aβ precursor protein (AβPP) at the γ-secretase site, a cleavage site necessary for Aβ amyloidogenicity. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia;this condition persists for several years before becoming full blown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and reduced insulin signaling in brain, altering all of insulin’s actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognition enhancing effect on patient with AD.
文摘目的:探讨绞股蓝对海马注射Aβ1-40大鼠脑内细胞周期蛋白异常表达和钙稳态变化的影响。方法:动物随机分为绞股蓝组、模型组、对照组。运用淀粉样β蛋白双侧海马注射,模拟阿尔茨海默病脑内Aβ对神经系统的损害。Y型迷宫测试大鼠学习记忆能力,免疫组织化学染色和积分吸光度分析检测细胞周期蛋白A、B1(cyc linA、cyc lin B1),Fura-2/AM-荧光法测定海马细胞内Ca2+含量;并对绞股蓝组大鼠给予绞股蓝皂苷灌胃,观察其对AD大鼠上述各项指标变化的影响。结果:Aβ1-40海马注射大鼠学习记忆能力明显低于对照组(P<0.05),脑内细胞周期蛋白A、B1蛋白水平明显高于对照组,海马神经元内Ca2+含量显著高于对照组;而给予绞股蓝在一定程度上能改善大鼠学习记忆能力,降低cyc lin A、cyc lin B1蛋白和Ca2+含量的水平(P<0.05)。结论:绞股蓝对Aβ引起的动物学习记忆能力减退、海马神经元内异常表达细胞周期蛋白和钙稳态失衡有一定的逆转作用。
