Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The...Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.展开更多
目的:评估急诊冠状动脉介入治疗术(PCI)后循环microRNA-26b-5p水平和血糖水平变化的趋势及相关性。方法:根据入选标准和排除标准,共入选接受急诊PCI术的急性前壁心肌梗死患者38例。详细记录临床相关资料,分别于术前、术后24h、术后72h...目的:评估急诊冠状动脉介入治疗术(PCI)后循环microRNA-26b-5p水平和血糖水平变化的趋势及相关性。方法:根据入选标准和排除标准,共入选接受急诊PCI术的急性前壁心肌梗死患者38例。详细记录临床相关资料,分别于术前、术后24h、术后72h行循环血microRNA-26b-5p和血糖水平检测。Real Time PCR法检测血液样本中microRNA-26b-5p表达量的变化。结果:对于成功行急诊PCI的急性心肌梗死患者,术后microRNA-26b-5p表达水平较术前明显升高(P<0.01),术后血糖水平逐渐下降(P<0.01),两者之间存在负相关(r=-0.332,P<0.01)。结论:急性心肌梗死患者往往存在应激性高血糖,microRNA-26b-5p可能参与血糖水平的相关。展开更多
目的探讨葛根素调控miR-30b-5p表达对类固醇诱导的兔股骨头坏死(osteonecrosis of the femoral head,ONFH)的作用及机制。方法将84只新西兰大白兔分为对照组、ONFH组、葛根素低剂量组、葛根素高剂量组、阳性对照组、葛根素高剂量+antago...目的探讨葛根素调控miR-30b-5p表达对类固醇诱导的兔股骨头坏死(osteonecrosis of the femoral head,ONFH)的作用及机制。方法将84只新西兰大白兔分为对照组、ONFH组、葛根素低剂量组、葛根素高剂量组、阳性对照组、葛根素高剂量+antagomir NC组、葛根素高剂量+miR-30b-5p antagomir组,每组12只。通过Micro-CT检测大白兔股骨头骨小梁数量、骨小梁厚度及骨小梁分离度;HE染色检测股骨头组织病理变化;ELISA法检测股骨头组织中超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量;TUNEL染色检测股骨头组织中骨细胞凋亡;qRT-PCR检测股骨头组织中miR-30b-5p表达;Western Blot检测股骨头组织中Dickkopf-1(DKK-1)蛋白表达。结果与对照组比较,ONFH组骨小梁数量、骨小梁厚度、SOD活性、miR-30b-5p表达降低,骨小梁分离度、空骨陷窝率、MDA含量、骨细胞凋亡率及DKK-1蛋白表达升高(P<0.05);与ONFH组比较,葛根素低、高剂量组、阳性对照组骨小梁数量、骨小梁厚度、SOD活性、miR-30b-5p表达升高,骨小梁分离度、空骨陷窝率、MDA含量、骨细胞凋亡率及DKK-1蛋白表达降低(P<0.05);miR-30b-5p antagomir减弱了高剂量葛根素对ONFH兔氧化应激及细胞凋亡的抑制作用。结论葛根素可抑制氧化应激及细胞凋亡进而发挥对ONFH兔的保护作用,其机制可能与上调miR-30b-5p表达有关。展开更多
基金supported by the National Natural Science Foundation of China,Nos. 82173806 and U1803281Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science,Nos. 2021-I2M-1-030 and 2022-I2M-2-002Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-JKCS-08 (all to RL)。
文摘Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.
文摘目的:评估急诊冠状动脉介入治疗术(PCI)后循环microRNA-26b-5p水平和血糖水平变化的趋势及相关性。方法:根据入选标准和排除标准,共入选接受急诊PCI术的急性前壁心肌梗死患者38例。详细记录临床相关资料,分别于术前、术后24h、术后72h行循环血microRNA-26b-5p和血糖水平检测。Real Time PCR法检测血液样本中microRNA-26b-5p表达量的变化。结果:对于成功行急诊PCI的急性心肌梗死患者,术后microRNA-26b-5p表达水平较术前明显升高(P<0.01),术后血糖水平逐渐下降(P<0.01),两者之间存在负相关(r=-0.332,P<0.01)。结论:急性心肌梗死患者往往存在应激性高血糖,microRNA-26b-5p可能参与血糖水平的相关。
文摘目的探讨葛根素调控miR-30b-5p表达对类固醇诱导的兔股骨头坏死(osteonecrosis of the femoral head,ONFH)的作用及机制。方法将84只新西兰大白兔分为对照组、ONFH组、葛根素低剂量组、葛根素高剂量组、阳性对照组、葛根素高剂量+antagomir NC组、葛根素高剂量+miR-30b-5p antagomir组,每组12只。通过Micro-CT检测大白兔股骨头骨小梁数量、骨小梁厚度及骨小梁分离度;HE染色检测股骨头组织病理变化;ELISA法检测股骨头组织中超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量;TUNEL染色检测股骨头组织中骨细胞凋亡;qRT-PCR检测股骨头组织中miR-30b-5p表达;Western Blot检测股骨头组织中Dickkopf-1(DKK-1)蛋白表达。结果与对照组比较,ONFH组骨小梁数量、骨小梁厚度、SOD活性、miR-30b-5p表达降低,骨小梁分离度、空骨陷窝率、MDA含量、骨细胞凋亡率及DKK-1蛋白表达升高(P<0.05);与ONFH组比较,葛根素低、高剂量组、阳性对照组骨小梁数量、骨小梁厚度、SOD活性、miR-30b-5p表达升高,骨小梁分离度、空骨陷窝率、MDA含量、骨细胞凋亡率及DKK-1蛋白表达降低(P<0.05);miR-30b-5p antagomir减弱了高剂量葛根素对ONFH兔氧化应激及细胞凋亡的抑制作用。结论葛根素可抑制氧化应激及细胞凋亡进而发挥对ONFH兔的保护作用,其机制可能与上调miR-30b-5p表达有关。
