Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rode...Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.展开更多
Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-met...Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-methyladenosine(m^(6)A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein(METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.展开更多
目的:探讨RNA m^(6)A甲基化修饰在脂肪细胞胰岛素抵抗中的作用及机制。方法:收集2型糖尿病患者术中赘余皮下脂肪组织,以非2型糖尿病患者同样组织为对照,检测组间RNA m^(6)A水平。高脂饮食诱导C57BL/6J小鼠构建胰岛素抵抗(in⁃sulin resis...目的:探讨RNA m^(6)A甲基化修饰在脂肪细胞胰岛素抵抗中的作用及机制。方法:收集2型糖尿病患者术中赘余皮下脂肪组织,以非2型糖尿病患者同样组织为对照,检测组间RNA m^(6)A水平。高脂饮食诱导C57BL/6J小鼠构建胰岛素抵抗(in⁃sulin resistance,IR)模型(HFD组,n=5,60%高脂饲料喂养16周),对照组10%低脂饲料喂养16周(CD组,n=5)。模型构建成功后,取附睾周围脂肪组织行表观转录组学m^(6)A甲基化修饰芯片检测,并借助MeRIP-qPCR实验、RT-qPCR以及RNA结合蛋白免疫沉淀测定(RNA Binding Protein Immunoprecipitation Assay,RIP)实验验证胰岛素信号转导相关基因变化;进一步观察METTL3小分子抑制剂STM2457对高脂饮食诱导下小鼠胰岛素信号转导基因的影响。结果:2型糖尿病患者和小鼠IR模型脂肪组织中总体m^(6)A修饰水平均升高(患者200 ng RNA t=-8.375,P<0.001;患者100 ng RNA t=-3.722,P=0.006;患者50 ng RNA t=-4.937;P=0.001;小鼠100 ng RNA t=-3.590,P=0.023;小鼠50 ng RNA t=-2.760,P=0.025)。表观转录组学检测证实IR的脂肪组织中1175个基因发生高m^(6)A修饰,55个基因发生低m^(6)A修饰,同时有182个基因呈现高m^(6)A修饰且低表达,包括AKT2、INSR、PIK3R1、ACACA、SREBF1等5个胰岛素信号转导关键基因,其中AKT2、INSR、ACACA、SREBF1等4个基因被确证并证实其与METTL3存在直接结合,其m^(6)A修饰水平受METTL3正向调控。STM2457作用下,胰岛素敏感性提高,且AKT2、INSR、ACACA、SREBF1转录水平上调,提示IR表型改善明显。结论:高脂饮食通过METTL3诱导脂肪细胞胰岛素信号转导基因AKT2、INSR、ACACA、SREBF1发生m^(6)A高甲基化修饰,诱导其低表达,阻滞胰岛素信号转导,进而参与诱发IR。展开更多
原发性肝癌(hepatocellular carcinoma,HCC)是全球发病率和死亡率居高不下的恶性肿瘤之一,其患者通常因为耐药性产生而不能从新兴的免疫、靶向治疗中持续受益。研究表明,目前常用的单一生物标志物,例如甲胎蛋白、肿瘤突变负荷(tumor mut...原发性肝癌(hepatocellular carcinoma,HCC)是全球发病率和死亡率居高不下的恶性肿瘤之一,其患者通常因为耐药性产生而不能从新兴的免疫、靶向治疗中持续受益。研究表明,目前常用的单一生物标志物,例如甲胎蛋白、肿瘤突变负荷(tumor mutation burden,TMB)和程序性死亡受体-1(programmed cell death protein 1,PD-1)/程序性死亡配体-1(programmed death ligand 1,PD-L1)等缺乏指示HCC免疫、靶向治疗效果的效力。为了进一步优化临床决策,寻找能够准确预测HCC免疫、靶向治疗疗效的生物标志物尤为重要。最近研究表明,N6-甲基腺嘌呤(N6-methyladenosine,m^(6)A)作为真核生物最普遍的RNA修饰方式之一,在HCC免疫治疗和靶向治疗耐药性产生过程中发挥重要作用。本文总结了m^(6)A修饰参与HCC免疫治疗、靶向治疗耐药的机制及相关研究进展,并且阐述了m^(6)A修饰相关特征作为潜在生物标志物,对这两种新兴治疗方法疗效的预测作用,从m^(6)A修饰的角度提出改善HCC治疗效果及预测疗效的潜在方案,以期为临床治疗及有效决策提供新思路。展开更多
基金supported by the National Institutes of Health,Nos.AA025919,AA025919-03S1,and AA025919-05S1(all to RAF).
文摘Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China,Nos.82030071 (to JH),82272495 (to YC)Science and Technology Major Project of Changsha,No.kh2103008 (to JH)Graduate Students’ Independent Innovative Projects of Hunan Province,No.CX20230311 (to YJ)。
文摘Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-methyladenosine(m^(6)A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein(METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.
文摘目的:探讨RNA m^(6)A甲基化修饰在脂肪细胞胰岛素抵抗中的作用及机制。方法:收集2型糖尿病患者术中赘余皮下脂肪组织,以非2型糖尿病患者同样组织为对照,检测组间RNA m^(6)A水平。高脂饮食诱导C57BL/6J小鼠构建胰岛素抵抗(in⁃sulin resistance,IR)模型(HFD组,n=5,60%高脂饲料喂养16周),对照组10%低脂饲料喂养16周(CD组,n=5)。模型构建成功后,取附睾周围脂肪组织行表观转录组学m^(6)A甲基化修饰芯片检测,并借助MeRIP-qPCR实验、RT-qPCR以及RNA结合蛋白免疫沉淀测定(RNA Binding Protein Immunoprecipitation Assay,RIP)实验验证胰岛素信号转导相关基因变化;进一步观察METTL3小分子抑制剂STM2457对高脂饮食诱导下小鼠胰岛素信号转导基因的影响。结果:2型糖尿病患者和小鼠IR模型脂肪组织中总体m^(6)A修饰水平均升高(患者200 ng RNA t=-8.375,P<0.001;患者100 ng RNA t=-3.722,P=0.006;患者50 ng RNA t=-4.937;P=0.001;小鼠100 ng RNA t=-3.590,P=0.023;小鼠50 ng RNA t=-2.760,P=0.025)。表观转录组学检测证实IR的脂肪组织中1175个基因发生高m^(6)A修饰,55个基因发生低m^(6)A修饰,同时有182个基因呈现高m^(6)A修饰且低表达,包括AKT2、INSR、PIK3R1、ACACA、SREBF1等5个胰岛素信号转导关键基因,其中AKT2、INSR、ACACA、SREBF1等4个基因被确证并证实其与METTL3存在直接结合,其m^(6)A修饰水平受METTL3正向调控。STM2457作用下,胰岛素敏感性提高,且AKT2、INSR、ACACA、SREBF1转录水平上调,提示IR表型改善明显。结论:高脂饮食通过METTL3诱导脂肪细胞胰岛素信号转导基因AKT2、INSR、ACACA、SREBF1发生m^(6)A高甲基化修饰,诱导其低表达,阻滞胰岛素信号转导,进而参与诱发IR。
文摘原发性肝癌(hepatocellular carcinoma,HCC)是全球发病率和死亡率居高不下的恶性肿瘤之一,其患者通常因为耐药性产生而不能从新兴的免疫、靶向治疗中持续受益。研究表明,目前常用的单一生物标志物,例如甲胎蛋白、肿瘤突变负荷(tumor mutation burden,TMB)和程序性死亡受体-1(programmed cell death protein 1,PD-1)/程序性死亡配体-1(programmed death ligand 1,PD-L1)等缺乏指示HCC免疫、靶向治疗效果的效力。为了进一步优化临床决策,寻找能够准确预测HCC免疫、靶向治疗疗效的生物标志物尤为重要。最近研究表明,N6-甲基腺嘌呤(N6-methyladenosine,m^(6)A)作为真核生物最普遍的RNA修饰方式之一,在HCC免疫治疗和靶向治疗耐药性产生过程中发挥重要作用。本文总结了m^(6)A修饰参与HCC免疫治疗、靶向治疗耐药的机制及相关研究进展,并且阐述了m^(6)A修饰相关特征作为潜在生物标志物,对这两种新兴治疗方法疗效的预测作用,从m^(6)A修饰的角度提出改善HCC治疗效果及预测疗效的潜在方案,以期为临床治疗及有效决策提供新思路。
