Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein mal- function and mitochondrial dysfunction contribute to the loss...Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein mal- function and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracallular signaling pathways that can pro- tect against or delay this pathogenic process. Here, we show that the DYNClll deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF.MEK signaling protects against neuronal atrophy induced by DYNClll deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demon- strate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention.展开更多
背景:前期研究发现,电针能有效抑制凋亡调控基因p38及Fas m RNA的表达,并降低MAPK信号通路的表达,从而抑制软骨细胞凋亡,同时电针可影响骨性关节炎软骨细胞JAK-STAT信号通路,并有效增加转化生长因子β1含量及促进关节软骨中STAT3,Smad3...背景:前期研究发现,电针能有效抑制凋亡调控基因p38及Fas m RNA的表达,并降低MAPK信号通路的表达,从而抑制软骨细胞凋亡,同时电针可影响骨性关节炎软骨细胞JAK-STAT信号通路,并有效增加转化生长因子β1含量及促进关节软骨中STAT3,Smad3及Lep R m RNA的表达以延缓关节软骨退变。目的:观察电针对骨关节炎大鼠关节软骨超微结构及软骨组织中Ras,Raf,MEK1/2,ERK1/2 m RNA表达的影响。方法:建立膝骨关节炎大鼠模型,造模成功后2周随机分为4组,模型组不进行电针干预,电针15,30 min组取双侧膝关节内、外膝眼,分别经电针治疗15,30 min,PD98059组经静脉注射细胞外信号调节激酶抑制剂PD98059,另设正常饲养的大鼠作正常组对照,共干预3个月。结果与结论:(1)透射电镜检测显示,与模型组比,PD98059抑制剂组、电针15,30 min组软骨细胞形态变化较小,细胞核较大,部分内质网池扩张,线粒体结构仍较清晰;(2)ELISA结果显示,与模型组比,PD98059抑制剂组、电针15,30 min组的肿瘤坏死因子α水平降低(P<0.01);(3)RT-PCR结果显示,与模型组相比,PD98059抑制剂组、电针15,30 min组的Ras,Raf,MEK1/2及ERK1/2 m RNA表达显著降低(P<0.05或P<0.01);(4)结果说明,电针干预能够减轻膝骨关节炎模型大鼠软骨细胞损伤,降低膝关节部滑膜组织中肿瘤坏死因子α水平,下调关节软骨Ras,Raf,MEK1/2及ERK1/2 m RNA表达,从而对骨关节炎关节软骨发挥一定的保护作用。展开更多
文摘Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein mal- function and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracallular signaling pathways that can pro- tect against or delay this pathogenic process. Here, we show that the DYNClll deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF.MEK signaling protects against neuronal atrophy induced by DYNClll deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demon- strate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention.
文摘背景:前期研究发现,电针能有效抑制凋亡调控基因p38及Fas m RNA的表达,并降低MAPK信号通路的表达,从而抑制软骨细胞凋亡,同时电针可影响骨性关节炎软骨细胞JAK-STAT信号通路,并有效增加转化生长因子β1含量及促进关节软骨中STAT3,Smad3及Lep R m RNA的表达以延缓关节软骨退变。目的:观察电针对骨关节炎大鼠关节软骨超微结构及软骨组织中Ras,Raf,MEK1/2,ERK1/2 m RNA表达的影响。方法:建立膝骨关节炎大鼠模型,造模成功后2周随机分为4组,模型组不进行电针干预,电针15,30 min组取双侧膝关节内、外膝眼,分别经电针治疗15,30 min,PD98059组经静脉注射细胞外信号调节激酶抑制剂PD98059,另设正常饲养的大鼠作正常组对照,共干预3个月。结果与结论:(1)透射电镜检测显示,与模型组比,PD98059抑制剂组、电针15,30 min组软骨细胞形态变化较小,细胞核较大,部分内质网池扩张,线粒体结构仍较清晰;(2)ELISA结果显示,与模型组比,PD98059抑制剂组、电针15,30 min组的肿瘤坏死因子α水平降低(P<0.01);(3)RT-PCR结果显示,与模型组相比,PD98059抑制剂组、电针15,30 min组的Ras,Raf,MEK1/2及ERK1/2 m RNA表达显著降低(P<0.05或P<0.01);(4)结果说明,电针干预能够减轻膝骨关节炎模型大鼠软骨细胞损伤,降低膝关节部滑膜组织中肿瘤坏死因子α水平,下调关节软骨Ras,Raf,MEK1/2及ERK1/2 m RNA表达,从而对骨关节炎关节软骨发挥一定的保护作用。
