TDP-43 proteinopathies and cryptic exons:Transactive response DNA binding protein of 43 kDa(TDP-43)is a ubiquitously expressed RNA/DNA binding protein crucial for coding and non-coding RNA metabolism including transcr...TDP-43 proteinopathies and cryptic exons:Transactive response DNA binding protein of 43 kDa(TDP-43)is a ubiquitously expressed RNA/DNA binding protein crucial for coding and non-coding RNA metabolism including transcription,splicing,transport,translation,and turnover.TDP-43 shuttles between the nucleus and cytoplasm,but is predominantly localized in the nucleus.Neurodegenerative diseases(NDs)may be accompanied by nuclear loss and possible cytoplasmic accumulation and aggregation of TDP-43 in vulnerable neurons and beyond.This neuropathology is the hallmark of most individuals suffering from amyotrophic lateral sclerosis(ALS),frontotemporal dementia(FTD)with TDP-43-immunoreactive pathology(FTD-TDP),limbic-predominant age-related TDP-43 encephalopathy(LATE)and Perry syndrome,but also coexists with the primary pathology in subsets of patients suffering from other NDs,such as Alzheimer’s disease,Lewy body dementias,or Huntington’s disease.Variants in the gene encoding TDP-43(TARDBP)are the cause of ALS and/or FTD in some rare cases substantiating the importance of this protein in aging neurons.It is still controversial if loss of nuclear,or increased cytoplasmic and/or aggregating TDP-43 is more harmful to neurons(Nag and Schneider,2023).Recently,the role of nuclear TDP-43 in repressing the inclusion of intronic sequences,named cryptic exons(CEs),into mature mRNAs gained much attention.展开更多
目的:分析TDP联合电脑中频并功能锻炼治疗护理慢性腰肌劳损的疗效。方法:从2023年10月~2024年9月,选取100例患有慢性腰肌劳损的疗养人员作为研究样本,进行随机分组,对照组50例进行功能锻炼结合常规指导,观察组50例在对照组的基础上使用...目的:分析TDP联合电脑中频并功能锻炼治疗护理慢性腰肌劳损的疗效。方法:从2023年10月~2024年9月,选取100例患有慢性腰肌劳损的疗养人员作为研究样本,进行随机分组,对照组50例进行功能锻炼结合常规指导,观察组50例在对照组的基础上使用TDP联合电脑中频并功能锻炼治疗与康复指导,对比两组相关指标。结果:观察组治疗总有效率高于对照组,治疗后1个疗程,观察组VAS评分低于对照组(P Objective: To analyze the efficacy of TDP combined with computerized intermediate frequency and functional exercise in the treatment of chronic lumbar muscle strain. Methods: From October 2023 to September 2024, 100 convalescents with chronic lumbar muscle strain were selected as research samples and randomized, 50 cases in the control group were treated with functional exercise combined with conventional guidance, and 50 cases in the observation group were treated with TDP combined with computer intermediate frequency and functional exercise treatment and rehabilitation guidance on the basis of the control group, and the relevant indexes of the two groups were compared. Results: The total effective rate of treatment in the observation group was higher than that in the control group, and the VAS score in the observation group was lower than that in the control group (P < 0.01) after one course of treatment, and the serum inflammatory factor level in the observation group was lower than that in the control group (P < 0.01). Conclusion: The application of TDP combined with computer intermediate frequency and functional exercise therapy and nursing for convalescents has obvious effects, which can effectively reduce pain and control the level of inflammation, which is worthy of promotion.展开更多
目的探索TAR DNA结合蛋白43(transactive response DNA binding protein 43,TDP-43)在氧化应激诱导的小鼠神经元(neuro-2a,N2a)细胞损伤及小鼠痛觉敏化中的作用及机制。方法①为评估最佳诱导浓度,不同浓度的H_(2)O_(2)处理N2a细胞分为4...目的探索TAR DNA结合蛋白43(transactive response DNA binding protein 43,TDP-43)在氧化应激诱导的小鼠神经元(neuro-2a,N2a)细胞损伤及小鼠痛觉敏化中的作用及机制。方法①为评估最佳诱导浓度,不同浓度的H_(2)O_(2)处理N2a细胞分为4组:对照组、200μmol/L H_(2)O_(2)组、400μmol/L H_(2)O_(2)组和800μmol/L H_(2)O_(2)组。②为评估最佳诱导时间,400μmol/L H_(2)O_(2)处理N2a细胞分为4组:对照组、6 h H_(2)O_(2)组、12 h H_(2)O_(2)组和24 h H_(2)O_(2)组。③为验证线粒体DNA(mitochondria DNA,mtDNA)释放途径,使用环孢素(cyclosporin,CsA)抑制线粒体通透性转换孔(mitochondrial permeability transition pore,mPTP)分为3组:对照组、24 h H_(2)O_(2)组和24 h H_(2)O_(2)+CsA组。④为验证TDP-43介导的细胞损伤机制,siRNA抑制TDP-43后分为3组:对照组、24 h H_(2)O_(2)组、24 h H_(2)O_(2)+siTDP-43组。⑤采用CCK-8检测细胞活性,EdU检测细胞增殖,Western blot检测TDP-43、神经元标志物(neuronal nuclei,NeuN)、环状GMP-AMP合酶(cylic GMP-AMP synthase,cGAS)和干扰素基因刺激因子(stimulator of interferon,STING)表达,qPCR检测mtDNA,免疫染色观察细胞内TDP-43表达变化,Calcein AM染色评估mPTP开放。⑥为验证TDP-43在神经病理性疼痛(neuropathic pain,NP)中的作用,将24只6~8周健康SPF级雄性C57BL/6J小鼠(体质量25~30 g)使用随机数字表法分为3组:对照组、慢性压迫性损伤(chronic constriction injury,CCI)组、CCI+siTDP-43组,术前1 d和术后7、14、21 d进行鞘内注射siTDP-43;术前1 d和术后1、3、5、7、14、21 d通过von Frey纤维丝和热辐射法测定小鼠机械痛阈值和热痛阈值,免疫荧光检测术后21 d腰段(L5-L6)脊髓背角中TDP-43与NeuN的变化。结果氧化应激刺激诱导N2a中TDP-43蛋白表达增加,刺激mtDNA通过mPTP释放,上调cGAS、STING的表达,影响N2a的细胞活性(P<0.05);CsA抑制mPTP通道的开放并减少mtDNA释放(P<0.05);下调TDP-43的表达后可显著降低mtDNA的释放,抑制cGAS和STING的表达,并恢复N2a细胞的增殖能力(P<0.05)。CCI术后5 d,小鼠机械痛阈值和热痛阈值出现明显下降并持续至21 d(P<0.05);CCI小鼠术后21 d脊髓背角神经元中TDP-43表达增加(P<0.05);鞘内注射siRNA抑制TDP-43后,可提高CCI小鼠的机械痛阈值和热痛阈值(P<0.05)。结论氧化应激诱导神经元细胞TDP-43蛋白增加,刺激mtDNA通过mPTP释放到细胞质,激活cGAS/STING通路,导致神经元损伤并加重CCI小鼠痛觉敏化。展开更多
基金supported by the Deutsche Forschungsgemeinschaft(DFGgrant#521487152)(to AF)。
文摘TDP-43 proteinopathies and cryptic exons:Transactive response DNA binding protein of 43 kDa(TDP-43)is a ubiquitously expressed RNA/DNA binding protein crucial for coding and non-coding RNA metabolism including transcription,splicing,transport,translation,and turnover.TDP-43 shuttles between the nucleus and cytoplasm,but is predominantly localized in the nucleus.Neurodegenerative diseases(NDs)may be accompanied by nuclear loss and possible cytoplasmic accumulation and aggregation of TDP-43 in vulnerable neurons and beyond.This neuropathology is the hallmark of most individuals suffering from amyotrophic lateral sclerosis(ALS),frontotemporal dementia(FTD)with TDP-43-immunoreactive pathology(FTD-TDP),limbic-predominant age-related TDP-43 encephalopathy(LATE)and Perry syndrome,but also coexists with the primary pathology in subsets of patients suffering from other NDs,such as Alzheimer’s disease,Lewy body dementias,or Huntington’s disease.Variants in the gene encoding TDP-43(TARDBP)are the cause of ALS and/or FTD in some rare cases substantiating the importance of this protein in aging neurons.It is still controversial if loss of nuclear,or increased cytoplasmic and/or aggregating TDP-43 is more harmful to neurons(Nag and Schneider,2023).Recently,the role of nuclear TDP-43 in repressing the inclusion of intronic sequences,named cryptic exons(CEs),into mature mRNAs gained much attention.
文摘目的:分析TDP联合电脑中频并功能锻炼治疗护理慢性腰肌劳损的疗效。方法:从2023年10月~2024年9月,选取100例患有慢性腰肌劳损的疗养人员作为研究样本,进行随机分组,对照组50例进行功能锻炼结合常规指导,观察组50例在对照组的基础上使用TDP联合电脑中频并功能锻炼治疗与康复指导,对比两组相关指标。结果:观察组治疗总有效率高于对照组,治疗后1个疗程,观察组VAS评分低于对照组(P Objective: To analyze the efficacy of TDP combined with computerized intermediate frequency and functional exercise in the treatment of chronic lumbar muscle strain. Methods: From October 2023 to September 2024, 100 convalescents with chronic lumbar muscle strain were selected as research samples and randomized, 50 cases in the control group were treated with functional exercise combined with conventional guidance, and 50 cases in the observation group were treated with TDP combined with computer intermediate frequency and functional exercise treatment and rehabilitation guidance on the basis of the control group, and the relevant indexes of the two groups were compared. Results: The total effective rate of treatment in the observation group was higher than that in the control group, and the VAS score in the observation group was lower than that in the control group (P < 0.01) after one course of treatment, and the serum inflammatory factor level in the observation group was lower than that in the control group (P < 0.01). Conclusion: The application of TDP combined with computer intermediate frequency and functional exercise therapy and nursing for convalescents has obvious effects, which can effectively reduce pain and control the level of inflammation, which is worthy of promotion.
文摘目的探索TAR DNA结合蛋白43(transactive response DNA binding protein 43,TDP-43)在氧化应激诱导的小鼠神经元(neuro-2a,N2a)细胞损伤及小鼠痛觉敏化中的作用及机制。方法①为评估最佳诱导浓度,不同浓度的H_(2)O_(2)处理N2a细胞分为4组:对照组、200μmol/L H_(2)O_(2)组、400μmol/L H_(2)O_(2)组和800μmol/L H_(2)O_(2)组。②为评估最佳诱导时间,400μmol/L H_(2)O_(2)处理N2a细胞分为4组:对照组、6 h H_(2)O_(2)组、12 h H_(2)O_(2)组和24 h H_(2)O_(2)组。③为验证线粒体DNA(mitochondria DNA,mtDNA)释放途径,使用环孢素(cyclosporin,CsA)抑制线粒体通透性转换孔(mitochondrial permeability transition pore,mPTP)分为3组:对照组、24 h H_(2)O_(2)组和24 h H_(2)O_(2)+CsA组。④为验证TDP-43介导的细胞损伤机制,siRNA抑制TDP-43后分为3组:对照组、24 h H_(2)O_(2)组、24 h H_(2)O_(2)+siTDP-43组。⑤采用CCK-8检测细胞活性,EdU检测细胞增殖,Western blot检测TDP-43、神经元标志物(neuronal nuclei,NeuN)、环状GMP-AMP合酶(cylic GMP-AMP synthase,cGAS)和干扰素基因刺激因子(stimulator of interferon,STING)表达,qPCR检测mtDNA,免疫染色观察细胞内TDP-43表达变化,Calcein AM染色评估mPTP开放。⑥为验证TDP-43在神经病理性疼痛(neuropathic pain,NP)中的作用,将24只6~8周健康SPF级雄性C57BL/6J小鼠(体质量25~30 g)使用随机数字表法分为3组:对照组、慢性压迫性损伤(chronic constriction injury,CCI)组、CCI+siTDP-43组,术前1 d和术后7、14、21 d进行鞘内注射siTDP-43;术前1 d和术后1、3、5、7、14、21 d通过von Frey纤维丝和热辐射法测定小鼠机械痛阈值和热痛阈值,免疫荧光检测术后21 d腰段(L5-L6)脊髓背角中TDP-43与NeuN的变化。结果氧化应激刺激诱导N2a中TDP-43蛋白表达增加,刺激mtDNA通过mPTP释放,上调cGAS、STING的表达,影响N2a的细胞活性(P<0.05);CsA抑制mPTP通道的开放并减少mtDNA释放(P<0.05);下调TDP-43的表达后可显著降低mtDNA的释放,抑制cGAS和STING的表达,并恢复N2a细胞的增殖能力(P<0.05)。CCI术后5 d,小鼠机械痛阈值和热痛阈值出现明显下降并持续至21 d(P<0.05);CCI小鼠术后21 d脊髓背角神经元中TDP-43表达增加(P<0.05);鞘内注射siRNA抑制TDP-43后,可提高CCI小鼠的机械痛阈值和热痛阈值(P<0.05)。结论氧化应激诱导神经元细胞TDP-43蛋白增加,刺激mtDNA通过mPTP释放到细胞质,激活cGAS/STING通路,导致神经元损伤并加重CCI小鼠痛觉敏化。
