弗林蛋白酶与心血管活性物质关系的研究进展

弗林蛋白酶是真核生物中一种广泛参与前体蛋白切割的内切蛋白酶,对分泌途径中许多重要的多肽和蛋白的前体进行剪切加工,使之具有生物活性.在维持机体正常生理过程、参与疾病的病理过程中,弗林蛋白酶起着重要作用.部分心血管活性物质的活化也需要弗林蛋白酶的参与,对维持机体的血压平衡可能起着重要作用.     

弗林蛋白酶与心血管活性物质关系的研究进展

弗林蛋白酶是真核生物中一种广泛参与前体蛋白切割的内切蛋白酶,对分泌途径中许多重要的多肽和蛋白的前体进行剪切加工,使之具有生物活性.在维持机体正常生理过程、参与疾病的病理过程中,弗林蛋白酶起着重要作用.部分心血管活性物质的活化也需要弗林蛋白酶的参与,对维持机体的血压平衡可能起着重要作用.     

跨损伤合成DNA聚合酶ζ-Rev7在肿瘤发展中的研究进展

跨损伤DNA合成(TLS)属于一种复制后修复过程,主要涉及DNA聚合酶κ、η和ζ等。跨损伤修复是细胞内一种DNA损伤耐受机制,DNA聚合酶ζ在这一过程中扮演着重要的角色,DNA聚合酶ζ主要由亚基Rev7和Rev3构成,在细胞代谢中的作用主要是参与跨损伤修复。Rev7(也称为MAD2L2)是一种多功能蛋白,能够与多种蛋白结合,参与DNA损伤修复、细胞的周期调节、基因表达和致癌作用。同时也参与调控多种不良肿瘤的预后过程。     

Sema 4D/CD100的基础和临床研究进展

Sema4D/CD100是一种免疫信号素,参与了免疫和非免疫系统的多种重要的生理功能.本文对Sema4D/CD100分子及其受体的结构、生物学功能及其参与的多种病理生理过程进行综述.     

逆行信使NO在突触长时程增强过程中的作用

NO作为一种重要的生物信使分子,广泛存在于外周和中枢神经系统(CNS).近年来,有关NO在CNS中的作用研究已取得一定进展,尤其在神经突触可塑性方面,它参与了长时程增强(LTP)过程的诱导和维持.作为一种逆行信使,通过一系列信号通路或分子,如:NO-cGMP-PKG、激发内源性ADP核糖苷化及影响C-FOS的表达,最终参与LTP的产生和维持.     

甘露糖受体与临床相关性研究进展

甘露糖受体作为参与免疫反应的一种模式识别受体，在识别病原体，递呈抗原和保持内环境稳定中发挥重要作用。甘露糖受体参与包括感染性、免疫性以及肿瘤等临床诸多疾病的病理生理过程，在认识疾病和临床治疗等方面具有极其突出的价值。     

细胞内钙成像和钙测定的基本原理及应用

钙位于元素周期表中第2列，属于碱土金属。钙离子是一种重要的二价阳离子，它和许多其它阳离子的物理学性质非常相似，但具有独特的生物学功能。表现在，钙离子不仅是电流的载体，作为二价阳离子维持胞内外电化学梯度，而且还是一种重要的细胞内第二信使，参与肌细胞收缩、腺细胞分泌、神经递质释放、受精、细胞分化和程序死亡等过程。事实上，真核生物几乎所有的细胞分子事件都有钙离子的参与．     

载脂蛋白E基因多态性与疾病的相关性研究

载脂蛋白E（ApoE）是一种重要的血浆脂蛋白,由3种等位基因构成：E2、E3和E4。ApoE作为一种载脂蛋白,在脂质运输和代谢过程中发挥重要作用,而目前越来越多的研究表明：ApoE在免疫调节方面发挥重要作用,从而参与到多种疾病的发生发展中。近年来发现,ApoE及其基因多态性与高脂血症、动脉粥样硬化、Alzheimer病、神经系统病变及脓毒血症等人类疾患的发生发展有着密切关系。     

血小板及其因子的免疫效应

血小板是参与止血和凝血过程的重要组成成分,同时也保护血管内皮,参与内皮修复、防止动脉粥样硬化.越来越多的研究表明,血小板在机体免疫中发挥重要作用.血小板的生成需要诸多因子参与,血小板相关因子也参与免疫调节和免疫应答.血小板可直接或间接通过对固有免疫和适应性免疫的调控发挥效应.它已被视为是一种固有免疫效应细胞,在各种细菌、真菌等病原体导致的感染性疾病过程中具有不可替代的作用.除此之外,调控血小板及其因子、受体将会使很多疾病的治疗和预防具有广阔的研究前景.     

FAK家族的新成员—Pyk2

Pyk2 ,FAK家族的新成员 ,是一种富含脯氨酸的非受体酪氨酸蛋白激酶 ,分布于多种组织和细胞 ,主要依赖Ca2 + 浓度或PKC参与细胞内的MAPK或PI3 K信号通路转导 ,将胞外信息传递到胞内 ,催化多种含SH2结构域的底物蛋白磷酸化 ,从而发挥重要的生理作用。Pyk2作为细胞内一种重要的效应分子 ,可促进基因转录 ,调节细胞的生长、增殖、分化 ,并且通过其特殊的生物学效应参与中枢神经系统、心血管系统、肾脏系统及炎症反应等疾病的发生发展 ,其具有重要的临床意义     

The functional role of stress proteins in ER stress mediated cell death

The endoplasmic reticulum (ER) is an intracellular organelle involved in biosynthesis and the secretory pathway. This organelle has many resident proteins including biosynthetic enzymes and secretory proteins. Recent studies have suggested that dysfunction of the ER or secretory pathway is involved in the pathogenesis of various human diseases. Some stresses acting on the ER, which are designated ER stress, induce the accumulation of unfolded/misfolded proteins in the ER, leading to cell death. Misfolded proteins are retained until they form their native conformation or returned to the cytosol for degradation by the proteasome. Among the ER-resident proteins, molecular chaperones prevent aggregation of proteins within the ER, and orchestrate the ER quality control systems. We have reported the roles of novel stress proteins, namely 150-kDa oxygen-regulated protein, 94-kDa glucose-regulated protein and RA410. These proteins are induced significantly by hypoxia or oxidative stress and have cytoprotective effects under these conditions. These findings suggest that hypoxia and oxidative stress target the ER and secretory pathway, resulting in ER stress, and that these proteins exert cytoprotective effects in various diseases associated with ER stress.     

Physiological roles of ASK1-mediated signal transduction in oxidative stress- and endoplasmic reticulum stress-induced apoptosis: advanced findings from ASK1 knockout mice

Apoptosis, a molecularly regulated form of cell death, is essential for the normal functioning and homeostasis of most multicellular organisms, and can be induced by a range of environmental, physical, and chemical stresses. As the cellular decision to live or to die is made by the coordinated action and balancing of many different pro- and antiapoptotic factors, defects in control of this coordination and balance may contribute to a variety of human diseases, including cancer and autoimmune and neurodegenerative conditions. In recent years, multiple factors associated with the execution of apoptosis, such as caspases and Bcl-2 family members, have been discovered and their complicated signaling and molecular interactions have been demonstrated; however, the precise mechanistic basis for intracellular and/or extracellular stress-induced apoptosis remains to be fully characterized. Protein kinases contribute to regulation of life and death decisions made in response to various stress signals, and the actions of pro- and antiapoptotic factors are often affected by modulation of the phosphorylation status of key elements in the execution of apoptosis. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein (MAP) kinase kinase kinase family, which activates both the MKK4/MKK7-JNK and MKK3/MKK6-p38 MAP kinase pathways and constitutes a pivotal signaling pathway in various types of stress-induced apoptosis. We have recently shown through ASK1 gene ablation in mice that ASK1 plays essential roles in oxidative stress- and endoplasmic reticulum (ER) stress-induced apoptosis. These stresses are closely linked to physiological phenomena in the control of cell fate, and the resultant apoptosis is implicated in the pathophysiology of a broad range of human diseases. This article reviews our new findings on the physiological roles of ASK1-mediated signal transduction in stress responses and the molecular mechanisms by which ASK1 determines cell fate such as survival, differentiation, or apoptosis, with special focus on the regulatory mechanisms of ASK1-mediated apoptosis induced by oxidative stress and ER stress.     

内质网应激在糖尿病及糖尿病肾病中的研究进展

内质网（ER）是细胞内重要的细胞器,多种因素可导致ER内稳态失衡,功能发生改变,称为内质网应激（ERS）。ERS首先触发未折叠蛋白反应,增强细胞的存活能力。如果ERS持续存在,各种刺激超出了细胞处理能力,则将启动相关凋亡途径诱导细胞凋亡。越来越多的研究表明,ERS在糖尿病及其并发症脏器损害过程中普遍存在并发挥着重要作用。     

Nitric oxide-mediated neuronal apoptosis in rats with recurrent febrile seizures through endoplasmic reticulum stress pathway

Nitric oxide (NO), as a neurotransmitter, exerts various physiological and pathological effects on the brain. Excess NO is toxic to neurons and may cause neuronal apoptosis. However, the cascade of NO-mediated apoptosis is not fully understood. We utilized a recurrent febrile seizures (FS) rat model and found that plasma NO was increased, neuronal apoptosis was evident, the expression of glucose-regulated protein78 (GRP78, a well-established marker of ER stress) was elevated, and caspase-12 (an ER stress-specific proapoptosis molecule) was activated in the hippocampus in a time-dependent manner after recurrent FS. Administration of sodium nitroprusside (SNP, an NO donor) enhanced neuronal apoptosis, down-regulated the expression of GRP78, and increased that of caspase-12 in FS+SNP groups compared with FS groups. In contrast, treatment with N(G)-nitrol-l-arginine methyl ester (l-NAME, a competitive NO synthase inhibitor) inhibited neuronal apoptosis, up-regulated the expression of GRP78, and decreased that of caspase-12 in FS+l-NAME groups compared with FS groups. These results suggest that NO mediates neuronal apoptosis caused by recurrent FS, and that the ER stress pathway is involved in NO-mediated neuronal apoptosis.     

内质网应激反应基因表达调控的多样性

内质网通过激活未折叠蛋白反应(unfolded protein response,UPR),包括蛋白合成暂停、内质网分子伴侣和折叠酶等蛋白表达上调、诱导内质网相关性降解(ER-associated degradation,ERAD),以至细胞功能不能恢复,最后诱导内质网相关性细胞凋亡,清除受损细胞,保护机体生存。所有这些内质网相关反应都是各种应激信号刺激内质网,引起多种内质网应激基因表达的结果。转录、翻译以及翻译后加工各个环节对内质网应激时基因的表达产生调控,且方式各不相同。     

Caspases involved in ER stress-mediated cell death

Caspases are cysteine proteases involved in apoptotic pathways. Excess endoplasmic reticulum (ER) stress, induced by the accumulation of unfolded or malfolded proteins, activates various apoptotic pathways. Crosstalk between the mitochondria and ER plays an essential role in ER stress-mediated cell death. The cytochrome c-dependent apoptotic pathway is activated by ER stress. On the other hand, caspase-12, which is located at the ER, is also activated by excess ER stress and results in cell death in the absence of the cytochrome c-dependent pathway. The predominant apoptotic pathway may differ among cell type and differentiation stage.     

内质网应激介导神经变性疾病错折叠蛋白的神经毒性

神经变性疾病(neurodegenerative diseases,NDD)的共同病变基础是细胞内的蛋白处理机制失效而出现错折叠蛋白的集聚并产生神经毒性[1].环境毒素作用、氧化损伤、线粒体功能失常、胞内Ca2 失衡等因素均可能与NDD的发病有关[2].但面对错折叠蛋白,细胞必然通过内质网启动未折叠蛋白反应(unfolded protein response,UPR),这就提示我们内质网应激(endoplasmic reticulum stress,ERstress)可能在NDD发病过程中起关键作用.近期研究表明,内质网应激广泛存在于各种NDD中,并介导错折叠蛋白产生神经毒性及细胞凋亡作用.这里我们主要对内质网应激在发病率最高的3种NDD中所起的作用加以阐述,以期为未来NDD的研究及治疗提供切实可行的思路.     

Embryo collection induces transient activation of XBP1 arm of the ER stress response while embryo vitrification does not

Embryo cryopreservation has become a standard procedure in the practice of assisted reproduction. While routinely performed in IVF labs, the effects of embryo vitrification on the molecular mechanisms governing preimplantation development remain largely unknown. The endoplasmic reticulum stress (ER stress) response is an evolutionary conserved mechanism that cells employ to manage ER stress. ER stress can be defined as an imbalance between protein synthesis and secretion within the ER. The primary focus of this study was to investigate whether standard embryo manipulations, including embryo collection, culture and vitrification, result in activation of the ER stress pathway in vitro and to determine whether the embryo utilizes the unfolded protein response as an adaptive response. Our results indicate that the major ER stress pathway constituents are present at all stages of preimplantation development and that the activation of ER stress pathways can be induced at the 8-cell, morula and blastocyst stages. Additionally, we have demonstrated that the IRE1α arm of the ER Stress pathway is activated in freshly collected embryos but contrastingly, this ER Stress arm is not activated following embryo vitrification. It is important to understand the possible stresses that Assisted Reproductive Technologies place on the embryo and the mechanisms the embryo employs to adapt to these stresses. This study indicates that among the adaptive pathways available, cultured mammalian embryos can employ the ER stress pathway. Assisted reproduction techniques should be aware that their activities may induce the ER stress pathway in their patients' early embryos.