目的:研究线粒体分裂抑制剂1(Mdivi-1)在实验性自身免疫性脑脊髓炎(EAE)小鼠髓鞘保护中的作用,探讨Mdivi-1抑制髓鞘变性的机制。方法:小鼠经髓磷脂少突胶质细胞糖蛋白第35~55位肽段(MOG35-55)免疫后,随机分为DMSO模型组和Mdivi-1干预组...目的:研究线粒体分裂抑制剂1(Mdivi-1)在实验性自身免疫性脑脊髓炎(EAE)小鼠髓鞘保护中的作用,探讨Mdivi-1抑制髓鞘变性的机制。方法:小鼠经髓磷脂少突胶质细胞糖蛋白第35~55位肽段(MOG35-55)免疫后,随机分为DMSO模型组和Mdivi-1干预组。于免疫后第28天处死小鼠,行Luxol fast blue染色分析髓鞘丢失情况,免疫荧光染色和TUNEL染色小鼠脊髓组织和体外细胞实验分析Mdivi-1髓鞘保护机制。结果:与DMSO模型组比较,Mdivi-1处理明显减少EAE小鼠脊髓组织白质区髓鞘丢失,减少少突胶质细胞凋亡及线粒体凋亡相关蛋白cleaved caspase-3、caspase-9、cytochrome C和Bax的表达;体外MO3.13少突胶质细胞培养实验发现,Mdivi-1可以明显阻止星形孢菌素(staurosporine)处理诱导的线粒体膜电位去极化,减轻细胞损伤,增强细胞活力。结论:Mdivi-1可能通过抑制少突胶质细胞线粒体相关凋亡信号通路发挥髓鞘保护作用。展开更多
脊髓亚急性联合变性(subacute combined degeneration of the spinal cord,SCD)是维生素B12缺乏导致的神经系统变性[1~3]。SCD在老年人中更为常见,男女无明显差异,其患病率随着年龄的增长而增加,且患病率在发展中国家较发达国家高。SCD...脊髓亚急性联合变性(subacute combined degeneration of the spinal cord,SCD)是维生素B12缺乏导致的神经系统变性[1~3]。SCD在老年人中更为常见,男女无明显差异,其患病率随着年龄的增长而增加,且患病率在发展中国家较发达国家高。SCD是一种进行性和可逆性疾病,且隐匿起病、症状微妙,故强调早诊断、早治疗。但目前缺乏诊断价值高且可靠的实验室诊断,漏诊率达10%~26%[4],故临床医师必须持高度怀疑对SCD行早期诊治,避免因漏诊误诊而致神经功能的永久性损害。本文报道1例吉林省人民医院疼痛科治疗SCD病人的临床资料,旨在为临床医师提供诊疗经验,减少该病的漏诊及误诊。现报告如下。展开更多
Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal mus...Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal muscular atrophy-like clinical phenotype.The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies.Epithelial cells were isolated from urine samples from a spinal muscular atrophy(SMA)-like patient[MORC2 p.S87L),a CMT2Z patient[MORC2 p.Q400R),and a healthy control and induced to generate pluripotent stem cells,which were then differentiated into motor neuron precursor cells.Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAP K/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells.Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control.G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient.MORC2 p.S87Lspecific antisense oligonucleotides(p.S87L-ASO-targeting)showed significant efficacy in improving cell prolife ration and activating the PI3K/Akt and MAP K/ERK pathways in induced pluripotent stem cells.Howeve r,p.S87L-ASO-ta rgeting did not rescue prolife ration of motor neuron precursor cells.These findings suggest that downregulation of the PI3K/Akt and MAP K/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype.p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction.展开更多
Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo.As emerging bioengineering methods have...Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo.As emerging bioengineering methods have led to the optimization of cell culture protocols,spinal cord organoids technology has made remarkable advancements in the past decade.Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes.Moreover,fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment.These qualities make spinal cord organoids valuable tools for disease modeling,drug screening,and tissue regeneration.By utilizing this emergent technology,researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases.However,at present,spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine.Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.展开更多
文摘目的:研究线粒体分裂抑制剂1(Mdivi-1)在实验性自身免疫性脑脊髓炎(EAE)小鼠髓鞘保护中的作用,探讨Mdivi-1抑制髓鞘变性的机制。方法:小鼠经髓磷脂少突胶质细胞糖蛋白第35~55位肽段(MOG35-55)免疫后,随机分为DMSO模型组和Mdivi-1干预组。于免疫后第28天处死小鼠,行Luxol fast blue染色分析髓鞘丢失情况,免疫荧光染色和TUNEL染色小鼠脊髓组织和体外细胞实验分析Mdivi-1髓鞘保护机制。结果:与DMSO模型组比较,Mdivi-1处理明显减少EAE小鼠脊髓组织白质区髓鞘丢失,减少少突胶质细胞凋亡及线粒体凋亡相关蛋白cleaved caspase-3、caspase-9、cytochrome C和Bax的表达;体外MO3.13少突胶质细胞培养实验发现,Mdivi-1可以明显阻止星形孢菌素(staurosporine)处理诱导的线粒体膜电位去极化,减轻细胞损伤,增强细胞活力。结论:Mdivi-1可能通过抑制少突胶质细胞线粒体相关凋亡信号通路发挥髓鞘保护作用。
文摘脊髓亚急性联合变性(subacute combined degeneration of the spinal cord,SCD)是维生素B12缺乏导致的神经系统变性[1~3]。SCD在老年人中更为常见,男女无明显差异,其患病率随着年龄的增长而增加,且患病率在发展中国家较发达国家高。SCD是一种进行性和可逆性疾病,且隐匿起病、症状微妙,故强调早诊断、早治疗。但目前缺乏诊断价值高且可靠的实验室诊断,漏诊率达10%~26%[4],故临床医师必须持高度怀疑对SCD行早期诊治,避免因漏诊误诊而致神经功能的永久性损害。本文报道1例吉林省人民医院疼痛科治疗SCD病人的临床资料,旨在为临床医师提供诊疗经验,减少该病的漏诊及误诊。现报告如下。
基金supported by the National Natural Science Foundation of China,Nos.82171172(to RZ)and 81771366(to RZ)Fundamental Research Funds for the Central Universities of Central South University,Nos.2021zzts1095(to SZ)and 2022zzts0832(to HY)。
文摘Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal muscular atrophy-like clinical phenotype.The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies.Epithelial cells were isolated from urine samples from a spinal muscular atrophy(SMA)-like patient[MORC2 p.S87L),a CMT2Z patient[MORC2 p.Q400R),and a healthy control and induced to generate pluripotent stem cells,which were then differentiated into motor neuron precursor cells.Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAP K/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells.Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control.G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient.MORC2 p.S87Lspecific antisense oligonucleotides(p.S87L-ASO-targeting)showed significant efficacy in improving cell prolife ration and activating the PI3K/Akt and MAP K/ERK pathways in induced pluripotent stem cells.Howeve r,p.S87L-ASO-ta rgeting did not rescue prolife ration of motor neuron precursor cells.These findings suggest that downregulation of the PI3K/Akt and MAP K/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype.p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction.
基金supported by the sup-project of National Key R&D Program of China,No.2018YFA0108602CAMS Innovation Fund for Medical Sciences,No.CIFMS,2021-I2M-C&T-B-016National High Level Hospital Clinical Research Funding,No.2022-PUMCH-B-112(all to JG).
文摘Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo.As emerging bioengineering methods have led to the optimization of cell culture protocols,spinal cord organoids technology has made remarkable advancements in the past decade.Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes.Moreover,fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment.These qualities make spinal cord organoids valuable tools for disease modeling,drug screening,and tissue regeneration.By utilizing this emergent technology,researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases.However,at present,spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine.Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.
