溶酶体蛋白酶cathepsin B参与介导前列腺癌PC-3细胞凋亡

细胞凋亡是多细胞生物清除多余、损伤或有潜在危险细胞的一种主要生理机制.蛋白水解酶是细胞凋亡研究的重要对象,其中大部分工作都集中在探索caspases的功能和调控上.近年来,越来越多的证据显示一些非caspases蛋白酶如位于溶酶体中的cathepsins特别是cathepsin B(CTSB)参与细胞凋亡过程.溶酶体cathepsins既可以与caspases协同作用,也可以不依赖于caspases独立执行凋亡功能.选取人前列腺癌PC-3细胞株作为研究对象,通过检测PC-3细胞对TNFα、D-sphingosine两种凋亡诱导剂和caspases、cathepsins抑制剂的应答反应,以及细胞凋亡过程中溶酶体、线粒体的结构变化,证实了D-sphingosine引起PC-3细胞死亡的效应主要通过释放溶酶体中蛋白酶CTSB实现,CTSB和caspases均参与介导TNFα诱导的PC-3细胞凋亡过程,并且很可能在不同的凋亡信号通路中发挥作用.     

内质网应激源和雷帕霉素受体蛋白调控的自噬和凋亡

细胞自噬与凋亡是多细胞体生物维持自身稳态的重要生理反应机制。分别将自噬和凋亡诱导剂Beclin1和Caspases被引入到Kapuy等人建立的模型中,这个模型描述了内质网应激压力的条件,雷帕霉素受体蛋白(mammalian target of rapamycin,mTOR)调控Beclin1控制的自噬与Caspases导向的凋亡。另外,探讨了内质网应激源和mTOR相关的参数对自噬和凋亡的调控。结果显示,虽然mTOR会抑制细胞自噬活性,但内质网应激压力仍然会引发这一过程。当自噬切换到凋亡时,内质网应激压力与mTOR的共同作用下会加速细胞的死亡。     

创伤弧菌触发吞噬细胞细胞骨架重排和诱导细胞凋亡的研究进展

创伤弧菌(Vibrio vulnificus,V.vulnificus)感染是一种少见而又致命性的重要疾病.由于起病急、死亡率高,创伤弧菌感染的有效预防和治疗受到严峻的挑战,促使人们对创伤弧菌的致病机制进行更为深入地研究.吞噬细胞在机体抗感染免疫中起着重要的作用.由于感染后触发宿主吞噬细胞骨架改变及诱导其凋亡是多种病原菌入侵的机制之一,与疾病的发生、发展和结局有着密切关系.本文就创伤弧菌感染后,触发吞噬细胞细胞骨架改变及诱导细胞凋亡的研究进展作一综述.     

骨髓增生异常综合征的细胞凋亡分子机制(综述)

骨髓增生异常综合征的基本病理特征是骨髓的无效造血。骨髓造血细胞的凋亡增加是导致无效造血的主要原因之一。目前认为 ,骨髓基质细胞分泌的细胞因子如肿瘤坏死因子 (TNF -α)、转化生长因子 β(TGF - β) ,Fas受体 /配体的高表达 ,凋亡调节基因的异常 ,如促凋亡基因 (Bax、Bad)与抗凋亡基因 (Bcl- 2、Bcl-X)的比值增高 ,及半胱氨酸 /天冬氨酸特异的蛋白酶 (caspases)的过度激活等 ,与病人的骨髓造血细胞凋亡增加有关。     

凋亡抑制蛋白XIAP研究进展

X连锁凋亡抑制蛋白(XIAP)是哺乳动物中具有抑制细胞凋亡作用的蛋白,是IAPs家族的一员.XIAP通过杆状病毒IAP重复序列(BIR)直接与起始以及效应caspases结合,抑制了细胞凋亡的线粒体途径,也可以通过NF-κB途径抑制细胞表面受体介导的凋亡.XIAP具有不同于Bcl-2的作用机制,是IAPs家族中最具有抑制活性的一个.XIAP的作用受到线粒体释放的蛋白Smac的拮抗,以及受到自身具有泛素连接酶E3活性的RING指结构域的调节.阐述XIAP抑制caspase以及Smac等拮抗XIAP的机理对于治疗肿瘤以及过度凋亡疾病具有重要的意义.     

基质金属蛋白酶-1基因多态性在牙周炎中的研究进展

基质金属蛋白酶-1可以降解牙周基质的主要成分-1型胶原，在牙周炎的病理过程中起着重要作用。近年来研究表明在基质金属蛋白酶-1的启动子区存在基因多态性，其对基质金属蛋白酶-1基因表达的影响与结缔组织降解性疾病如牙周炎的易感性和严重程度存在联系。本文将就基质金属蛋白酶-1基因多态性对基因表达的影响及其调控机制和在牙周炎中的研究进展做一综述。     

基于化学位移和伪氨基酸组分信息预测抗凋亡蛋白质与促凋亡蛋白质

凋亡蛋白质是一种有着特殊功能的蛋白质,在生物体的生长和维持体内平衡中扮演着重要的角色.在细胞凋亡过程中抗与促凋亡蛋白质对细胞凋亡的调控起着不同的作用.如果抗凋亡蛋白质或者促凋亡蛋白质失活,将导致癌症和其它疾病的发生,所以对抗凋亡蛋白质和促凋亡蛋白质的识别,将有助于更好的了解凋亡蛋白的致病机理.建立一个新的凋亡蛋白质数据集,并基于化学位移信息和伪氨基酸组分信息采用支持向量机(SVM)方法对新的数据集进行了预测.融合后的特征信息用Jackknife检验预测成功率达到77.01%,从预测结果可以看出提取有效的特征信息是提高预测成功率的重要因素.     

一氧化氮与肺动脉高压的关系研究进展

肺动脉高压是肺心病发病过程中的中心环节,其产生及严重程度影响着慢性阻塞性肺疾病和肺心病的病程．虽然目前对其发病机制还没有全面清晰地了解,但众多细胞因子在其形成过程中的表达起重要作用已得到共识．一氧化氮作为一种信号物质,在血压调节、细胞凋亡、学习记忆过程形成等多个重大生命活动中起着积极的生物学意义,尤其对血管平滑肌舒张的作用机制显示了其在治疗肺动脉高压领域有着巨大潜力．     

色素上皮衍生因子在视网膜疾病中的应用研究进展

色素上皮衍生因子(pigment epithelium-derived factor, PEDF)是一种多效的神经营养因子和新生血管抑制因子,其在视网膜的生长发育及许多疾病病理过程中起着神经分化、神经营养、神经保护和抑制新生血管形成等作用,并可抗肿瘤和调控一些炎症反应.本文主要是综述目前对PEDF的生物学特点、作用及其在视网膜疾病中的应用研究状况,并推测其可能作用机制,展望其在视网膜疾病的临床治疗中的应用前景.     

鱼类溶菌酶和组织蛋白酶研究进展

溶菌酶和组织蛋白酶在鱼类先天性免疫系统中发挥重要作用。溶菌酶是一种具有生物活性的、能水解粘多糖的无毒、无公害小分子碱性酶,参与机体多种免疫反应,在抵抗外来病原细菌、真菌、病毒或肿瘤入侵中起重要作用。组织蛋白酶是半胱氨酸蛋白酶家族的主要成员,参与机体的多种生理和病理活动,目前在细胞凋亡中的作用日益受到重视。本综述主要介绍近年来鱼类溶菌酶和组织蛋白酶在生物学功能、基因克隆、组织分布及重组蛋白功能活性的新研究进展。     

Apoptosis in the nervous system

Neuronal apoptosis sculpts the developing brain and has a potentially important role in neurodegenerative diseases. The principal molecular components of the apoptosis programme in neurons include Apaf-1 (apoptotic protease-activating factor 1) and proteins of the Bcl-2 and caspase families. Neurotrophins regulate neuronal apoptosis through the action of critical protein kinase cascades, such as the phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase pathways. Similar cell-death-signalling pathways might be activated in neurodegenerative diseases by abnormal protein structures, such as amyloid fibrils in Alzheimer's disease. Elucidation of the cell death machinery in neurons promises to provide multiple points of therapeutic intervention in neurodegenerative diseases.     

A century-old debate on protein aggregation and neurodegeneration enters the clinic

The correlation between neurodegenerative disease and protein aggregation in the brain has long been recognized, but a causal relationship has not been unequivocally established, in part because a discrete pathogenic aggregate has not been identified. The complexity of these diseases and the dynamic nature of protein aggregation mean that, despite progress towards understanding aggregation, its relationship to disease is difficult to determine in the laboratory. Nevertheless, drug candidates that inhibit aggregation are now being tested in the clinic. These have the potential to slow the progression of Alzheimer's disease, Parkinson's disease and related disorders and could, if administered presymptomatically, drastically reduce the incidence of these diseases. The clinical trials could also settle the century-old debate about causality.     

Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.     

Rationalization of the effects of mutations on peptide and protein aggregation rates

In order for any biological system to function effectively, it is essential to avoid the inherent tendency of proteins to aggregate and form potentially harmful deposits. In each of the various pathological conditions associated with protein deposition, such as Alzheimer's and Parkinson's diseases, a specific peptide or protein that is normally soluble is deposited as insoluble aggregates generally referred to as amyloid. It is clear that the aggregation process is generally initiated from partially or completely unfolded forms of the peptides and proteins associated with each disease. Here we show that the intrinsic effects of specific mutations on the rates of aggregation of unfolded polypeptide chains can be correlated to a remarkable extent with changes in simple physicochemical properties such as hydrophobicity, secondary structure propensity and charge. This approach allows the pathogenic effects of mutations associated with known familial forms of protein deposition diseases to be rationalized, and more generally enables prediction of the effects of mutations on the aggregation propensity of any polypeptide chain.     

Neurodegenerative disease: amyloid pores from pathogenic mutations

Alzheimer's and Parkinson's diseases are associated with the formation in the brain of amyloid fibrils from beta-amyloid and alpha-synuclein proteins, respectively. It is likely that oligomeric fibrillization intermediates (protofibrils), rather than the fibrils themselves, are pathogenic, but the mechanism by which they cause neuronal death remains a mystery. We show here that mutant amyloid proteins associated with familial Alzheimer's and Parkinson's diseases form morphologically indistinguishable annular protofibrils that resemble a class of pore-forming bacterial toxins, suggesting that inappropriate membrane permeabilization might be the cause of cell dysfunction and even cell death in amyloid diseases.     

Caspase signalling controls microglia activation and neurotoxicity

Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.     

Inflammation and therapeutic vaccination in CNS diseases

The spectrum of inflammatory diseases of the central nervous system has been steadily expanding from classical autoimmune disorders such as multiple sclerosis to far more diverse diseases. Evidence now suggests that syndromes such as Alzheimer's disease and stroke have important inflammatory and immune components and may be amenable to treatment by anti-inflammatory and immunotherapeutic approaches. The notion of 'vaccinating' individuals against a neurodegenerative disorder such as Alzheimer's disease is a marked departure from classical thinking about mechanism and treatment, and yet therapeutic vaccines for both Alzheimer's disease and multiple sclerosis have been validated in animal models and are in the clinic. Such approaches, however, have the potential to induce unwanted inflammatory responses as well as to provide benefit.     

Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene

A mutation at codon 717 of the beta-amyloid precursor protein gene has been found to cosegregate with familial Alzheimer's disease in a single family. This mutation has been reported in a further five out of approximately 100 families multiply affected by Alzheimer's disease. We have identified another family, F19, in which we have detected linkage between the beta-amyloid precursor protein gene and Alzheimer's disease. Direct sequencing of exon 17 in affected individuals from this family has revealed a base change producing a Val----Gly substitution, also at codon 717. The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.     

Cell death in the nervous system

Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease trigger neuronal cell death through endogenous suicide pathways. Surprisingly, although the cell death itself may occur relatively late in the course of the degenerative process, the mediators of the underlying cell-death pathways have shown promise as potential therapeutic targets.     

用于“治疗性克隆”人胚胎干细胞研究面临的问题与可能的解决办法

利用培育的干细胞(SC)来实现组织再生和器官修复对于许多重大疾病如糖尿病、心脏疾病、老年性痴呆(AD)、帕金森病(PD)、神经损伤等的治疗具有重要意义,同时也是新药研发的重要工具.使用体细胞核转移技术(SCNT)克隆人类早期胚胎和提取干细胞,即所谓的"治疗性克隆"(Therapeutic cloning)技术,是目前进行干细胞个性化治疗的重要手段,具有广泛的临床应用前景.通过这种方法获得人胚胎干细胞的研究尚处于基础阶段,仍面临着许多有待解决的科学问题和技术挑战.在此主要就用于"治疗性克隆"人胚胎干细胞的研究进展做了简要综述,着重探讨了在该研究领域面临的主要困难,特别是在获得人成熟卵细胞方面,并提出了可能的解决办法.