内质网应激与神经系统疾病

内质网是蛋白质修饰、折叠和钙储存场所，内质网中钙与离子紊乱和未折叠蛋白质蓄积可引发内质网应激，发生具有保护作用的未折叠蛋白反应，而长期过强的内质网应激诱导细胞凋亡，内质网应激直接影响应激细胞的转归，如适应、损伤或凋亡。神经系统许多疾病与内质网应激相关，本文主要将近年来与内质网应激相关的神经系统疾病的研究作一综述。     

帕金森病与内质网应激

在帕金森病(PD)的病理生理机制中,内质网应激作为新的关注点已经进入人们的视野.内质网应激反应中的未叠蛋白反应可以将细胞内的未叠和错叠蛋白进行正确折叠,另一方面,过度的应激会导致细胞的凋亡,而帕金森病中标志性的α-synuclein这一异常折叠蛋白的出现以及黑质多巴胺能神经元的减少也为内质网应激在帕金森病发病中的作用提供了可能的依据,目前的研究也表明在细胞和动物模型中,内质网应激确实参与了帕金森病的病理生理过程,因而针对内质网应激采取相应的治疗措施为帕金森病的治疗提供了一个新的方向.     

内质网应激与运动障碍性疾病

内质网是真核细胞蛋白质修饰、折叠、分泌和钙储存的场所。内质网腔内错误折叠与未折叠蛋白积存及钙平衡紊乱均可导致内质网应激,从而发生具有保护作用的未折叠蛋白反应,而长期、严重的内质网应激会导致细胞死亡。内质网应激在许多运动障碍性疾病的病理机制中起重要作用,而其作用机制目前并不清楚。本文就内质网应激在运动障碍性疾病中的发病机制和所起作用作一综述。     

未折叠蛋白反应与细胞转归

在低氧、葡萄糖饥饿、氧化及糖基化作用紊乱等刺激下,大量未折叠蛋白在内质网中堆积,导致内质网应激,产生未折叠蛋白反应,通过上调内质网伴侣蛋白的表达以保护细胞,但是长时间过强的内质网应激则启动凋亡途径,因此未折叠蛋白反应对应激细胞的转归包括生存适应和诱导凋亡起重要作用.本文就未折叠蛋白反应分子机制的研究进展作一综述,一并述及与未折叠蛋白反应有关的神经和肌肉疾病.     

未折叠蛋白反应与细胞转归

在低氧、葡萄糖饥饿、氧化及糖基化作用紊乱等刺激下,大量未折叠蛋白在内质网中堆积,导致内质网应激,产生未折叠蛋白反应,通过上调内质网伴侣蛋白的表达以保护细胞,但是长时间过强的应激则启动凋亡途径,因此未折叠蛋白反应对应激细胞的转归包括生存适应和诱导凋亡起重要作用.本文就未折叠蛋白反应分子机制的研究进展作一综述,同时述及与未折叠蛋白反应有关的神经和肌肉疾病.     

内质网应激在高血糖加重脑缺血再灌注损伤中的研究进展

正各种应激压力导致未折叠蛋白/错误折叠蛋白在内质网(endoplasmic reticulum,ER)腔内蓄积,引起内质网应激(endoplasmic reticulum stress,ERS)。高血糖与脑缺血再灌注损伤(cerebral ischemia-reperfusion injury,CIRI)通常一起出现,约占所有CIRI的53%,且可加重脑组织的缺血再灌注损伤,细胞凋亡是CIRI的中心环节。新近研究表明,高血糖对CIRI的恶化效应与内质网应激诱导的细胞凋亡密切相关~([1]),主要通过增加CAAT区/增强子结合蛋白同源蛋白(CAAT/enhance binding protein homologousprotein,CHOP)的表达和激活半胱氨酸的天冬氨酸蛋白水解酶12(cysteme aspartate specific protease 12,Caspase-12)来实现。故本文将阐     

阿尔茨海默病中内质网应激与Tau蛋白相关作用的研究进展

阿尔茨海默病（AD）是老年性高发的神经退行性疾病,严重影响人们生活质量并带来沉重 的经济负担。AD 的主要病理特征为由tau 蛋白异常磷酸化引起的神经原纤维缠结和由β 淀粉样蛋白 异常聚集形成的老年斑。近年来的研究发现,tau 蛋白的错误折叠及聚集与内质网应激相互作用,在AD 病理机制中起着重要的作用。现通过对内质网应激在AD 发病中的作用机制和tau 蛋白在AD 发病过程 中的病理机制的梳理,探讨内质网应激与tau 蛋白之间可能的关系,以期为AD 发病机制及新靶点药物 的研发和治疗提供新的思路和可能。     

内质网在神经细胞稳态中的作用

内质网是真核细胞中重要的细胞器之一,是蛋白质加工和钙储存的主要场所。内质网不仅本身参与Ca2+平衡的调节,还通过与其它细胞器如线粒体相互作用,共同调节神经细胞的各种活动。此外,细胞在内质网应激状态下启动的未折叠蛋白反应,与氧化应激、自噬等细胞反应联系密切,在对抗应激、促进细胞生存或凋亡过程中发挥关键作用。本文就上述各方面对内质网在神经细胞稳态方面的作用作一综述。     

内质网应激与癫痫脑损伤的研究进展

内质网是钙储存调节和蛋白加工的主要场所,各种细胞内外环境的改变如缺血缺氧、低血糖、Ca2 紊乱等,均可诱发内质网应激(ERS),后者可通过ERS自适应性保护通路和ERS反应性凋亡通路直接影响应激细胞的转归。癫痫发作后脑损伤主要表现为神经元程序性死亡,而惊厥的病理生理条件可激活启动ERS,从而介导神经元适应、损伤或凋亡,其作为一条新的重要细胞信号路径,为癫痫脑损伤的发病机制和防治研究提供新方向。     

未折叠蛋白反应及其在生理功能与疾病中的作用

未折叠或错误折叠的蛋白质在内质网(endoplasmic reticulum,ER)中聚集促使细胞做出适应性反应,包括上调位于内质网的各种酶和分子伴侣,这被称为未折叠蛋白反应(unfolded protein response,UPR)。未折叠蛋白反应存在于所有的真核细胞中,是人们了解最多的细胞器间信号传导系统模型。未折叠蛋白反应信号传导的基本机制最先在酵母中被阐明,在哺乳动物中有类似机制但表现得更为复杂。目前已经知道哺乳动物中有三条途径涉及UPR信号传导,分别是IRE1-XBP1路径,ATF6路径和PERK-elF2α磷酸化-ATF4路径。UPR在细胞生理病理中发挥重要作用。很多疾病如神经退行性疾病、糖尿病与高同型半胱氨酸血症等与蛋白折叠错误及由此引起的UPR有关。这些疾病也被称为错误折叠蛋白疾病。     

Cellular apoptosis and Caspase-12 expression in a rat model of progressive spinal cord compression

BACKGROUND： Studies have demonstrated that the mechanisms underlying cellular apoptosis signal transduction focus on two pathways： intracellular mitochondria and extracellular death receptor. The current evidence supports that signal transduction of cellular apoptosis also includes endoplasmic reticulum stress signal transduction. OBJECTIVE： To observe Caspase-12 expression and cellular apoptosis following ischemia in rats with progressive spinal cord compression, and to verify the influence of endoplasmic reticulum stress on the apoptosis induced by spinal cord injury. DESIGN, TIME AND SETTING： A randomized, controlled, animal trial was performed at the Institute of Neuroscience in Chongqing Medical University between January and October in 2006. MATERIALS： Immunohistochemical kit, diaminobenzidine, and TUNEL kit were purchased from Beijing Zhongshan Biotechnology, China; rabbit anti-rat Caspase-12 monoclonal antibody was provided by Santa Cruz, USA. METHODS： Sixty Wistar rats, aged 3-4 months, were randomly assigned to a model group （n = 50）, which underwent spinal cord compression in the L1 segment following L1 laminectomy and articular process excision to establish a model of progressive spinal cord compression, and a sham-surgery group （n = 10）, which underwent only laminectomy. Starting with the first day after surgery, the rats were locally anesthetized, the skin was opened, and the screw was rotated by 1/4 of a cycle, twice weekly. MAIN OUTCOME MEASURES： At 3, 7, 14, 21, and 28 days after surgery, rats from each group were anesthetized, and the spinal cords were resected. Pathological changes following spinal cord compression were determined using hematoxylin-eosin staining, Nissl dye, and transmission electron microscopy. The TUNEL method was used to observe neuronal apoptosis in the compressed spinal cord segments. Immunohistochemistry and Western blot were utilized to detect Caspase-12 expression in the compressed segments. RESULTS： Cellular swelling, neural degeneration, and altered endoplasmic reticulum structures were observed at 3 days following compression. Symptoms became gradually aggravated with increasing compression time. Compared with the sham-surgery group, the number of apoptotic neurons was remarkably increased in compressed segments of the model group （P 〈 0.05）, and Caspase-12 expression was also shown to increase （P 〈 0.05）. CONCLUSION： Neuronal apoptosis was a predominant pathological factor resulting in secondary spinal cord injury during progressive spinal cord compression, and Caspase-12 was shown to be possibly involved in neuronal apoptosis induced by progressive spinal cord compression.     

Environmental factors in the development and progression of late-onset Alzheimer＇s disease

Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.     

高血压脑出血的显微外科治疗进展

高血压脑出血（Hypertensive intrac-rebral hemorrhage,HICH）是具有高发病率、高病死率、高致残率的急性脑血管疾病,占所有脑卒中患者的10%-20%,早期病死率可高达49.4%。随着人口老龄化,其发病率逐年提高;而外科手术的干预,使其病死率有所下降,但致残率居高不下。如何提高手术疗效和患者生存质量,一直是神经外科医师努力的方向。微侵袭血肿清除术因其手术创伤小,恢复快,是目前国内治疗高血压脑出血的重要手段。     

神经内镜联合亚低温治疗高血压基底节区脑出血

目的 探讨神经内镜联合亚低温在治疗高血压基底节区脑出血中的临床应用价值.方法 回顾性分析我院神经内镜治疗高血压基底节区脑出血患者40例的临床资料,并对治疗结果进行分析.结果 神经内镜治疗组22例(甲组),神经内镜联合亚低温治疗组18例(乙组),术后3个月根据GCS评分,甲组恢复良好1例,中残4例,重残6例,植物生存6例,死亡5例;乙组恢复良好4例,中残8例,重残3例,植物生存1例,死亡2例,两组比较差异有统计学意义(P＜0.05).两组颅内压比较第1天两者差异不明显,但第2、3天亚低温组颅内压明显降低.结论 神经内镜是治疗高血压基底节区脑出血较为有效的手术方式,联合亚低温治疗能有效降低颅内压,改善术后神经功能恢复,具有较好的临床应用价值.     

Total saponins of Panax ginseng effects on proliferation and differentiation of human embryonic neural stem cells and in a Parkinson’s disease mouse model

BACKGROUND： Total saponins of Panax ginseng （TSPG） exhibits neuroprotection against Parkinson＇s disease in the substantia nigra. OBJECTIVE： To investigate the effects of TSPG on human embryonic neural stem cells （NSCs） proliferation and differentiation into dopaminergic neurons using in vitro studies, and to observe NSC differentiation in a mouse model of Parkinson＇s disease, as well as behavioral changes before and after transplantation. DESIGN, TIME AND SETTING： In vitro neural cell biology trial and in vivo randomized, controlled animal trial were performed at the Institute of Basic Medical Sciences, Chongqing Medical University between September 2004 and December 2007. MATERIALS： TSPG （purity 〉 95%） was isolated, extracted, and identified by Chongqing Academy of Chinese Materia Medica. Recombinant human basic fibroblast growth factor （bFGF） and recombinant human epidermal growth factor （EGF） were purchased from PeproTech, USA. A total of 25 C57/BL6J mice, aged 18-20 weeks were included. Twenty were used to establish a Parkinson＇s disease model with i.p. injection of MPTP （1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine） and TSPG alone or combined with interleukin-1 （IL-1）-treated NSCs prior to transplantation into the corpus striatum. The remaining five mice were pretreated for 3 days with TSPG prior to MPTP injection, serving as the TSPG prevention group. METHODS： Primary NSCs were isolated, cultured and purified from embryonic cerebral cortex. Immunocytochemistry was employed to detect specific antigen expression in the NSCs. In vitro experiment： （1） to induce proliferation, NSCs were treated with TSPG, EGF＋bFGF, or TSPG＋EGF＋bFGF, respectively; （2） to induce dopaminergic neuronal differentiation, NSCs were treated with TSPG, IL-1, or TSPG＋IL-1, respectively. MAIN OUTCOME MEASURES： In vitro experiment： the effects of TSPG on NSCs proliferation were evaluated with flow cytometry and MTT assay. Tyrosine hydroxylase expression was determined by immunocytochemistry assay to observe effects of TSPG on dopaminergic neuronal differentiation. In vivo experiment： differentiation of grafted NSCs in the mouse brain was determined by immunohistochemical staining. Behavioral changes were evaluated by spontaneous activity frequency, memory function, and score of paralysis agitans. RESULTS： （1） NSCs were cultured and passaged for more than three passages. Immunocytochemistry revealed positive nestin staining, as well as neurofilament protein and glial fibrillary acidic protein. （2） TSPG significantly increased NSC proliferation, in particular when combined with EGF and bFGF, which was twice as effective as FGF or bFGF alone. TSPG also induced dopaminergic differentiation in NSCs, in particular when TSPG was added together with IL-1, resulting in an effect five times greater than that of IL-1 alone. （3） At day 30 following transplantation, most NSCs in the TSPG prevention group differentiated into dopaminergic neurons, and the scores of paralysis agitans, spontaneous activity, and memory function were significantly increased compared with TSPG alone or TSPG＋IL-1 groups （P 〈 0.05）. CONCLUSION： TSPG stimulated NSC proliferation, in particular when combined with FGF and bFGF. TSPG significantly induced dopaminergic neuronal differentiation of NSCs, and the effect was greater when combined with IL-1. In addition, TSPG greatly improved behavior in the Parkinson＇s disease mouse model following NSC transplantation. Following NSC transplantation, TSPG pretreatment exhibited superior efficacy over either TSPG alone or TSPG in combination with IL-1, in terms of behavioral improvements in the Parkinson＇s disease mouse model.     

Dysfunctional autophagy in Alzheimer＇s disease： pathogenic roles and therapeutic implications

Neuronal autophagy is essential for neuronal survival and the maintenance of neuronal homeostasis. Increasing evidence has implicated autophagic dysfunction in the pathogenesis of Alzheimer＇s disease （AD）. The mechanisms underlying autophagic failure in AD involve several steps, from autophagosome formation to degradation. The effect of modulating autophagy is context-dependent. Stimulation of autophagy is not always beneficial. During the implementation of therapies that modulate autophagy, the nature of the autophagic defect, the timing of intervention, and the optimal level and duration of modulation should be fully considered.     

Oxidative stress in Alzheimer＇s disease

Oxidative stress plays a significant role in the pathogenesis of Alzheimer＇s disease （AD）, a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons （lipids, proteins, and nucleic acids） can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, inflammation, and β-amyloid （Aβ） peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.