受体相互作用蛋白激酶RIP1在细胞信号转导途径中作用的研究进展

 受体相互作用蛋白1是一类丝氨酸/苏氨酸蛋白激酶,是一种重要的细胞信号转导分子,从其被发现开始就成为了细胞信号转导的研究热点,但多集中在其在细胞凋亡中的作用,近年来的研究表明,受体相互作用蛋白1不仅参与了细胞的凋亡,还参与了细胞存活,细胞程序性坏死等多种信号的转导,是一类重要的调节细胞生存或死亡的信号分子,本文对受体相互作用蛋白1功能的研究进展做简要综述。     

程序性坏死研究进展

程序性坏死是近年来发现的一种由死亡受体介导的caspases非依赖性细胞死亡模式,通常在凋亡被抑制的情况下发生,具有坏死细胞的形态学特征。研究发现程序性坏死同细胞凋亡一样受细胞内信号因子的周密调节,激酶受体相互作用蛋白激酶1和受体相互作用蛋白激酶3是其关键的调控因子。程序性坏死在炎症性病变、缺血性心脑血管病、神经退行性疾病等多种疾病的发生发展及肿瘤细胞的耐药方面具有重要意义。     

TNF-α诱导MLO-Y4细胞发生RIP3介导的程序性坏死

目的:探讨肿瘤坏死因子α(TNF-α)能否诱导小鼠长骨骨样细胞株MLO-Y4发生程序性坏死及其发生机制。方法:将MLO-Y4细胞分为正常对照(control)组、TNF-α处理组、TNF-α+necrostatin-1(Nec-1)处理组、TNF-α+Z-VAD处理组和TNF-α+受体相互作用蛋白3(RIP3)-siRNA组。用流式细胞术检测各组细胞凋亡或坏死率,透射电镜鉴定细胞形态学变化,用Western blot法测定RIP1、RIP3和cleaved caspase-3的蛋白水平,应用激光共聚焦显微镜观察RIP1和RIP3蛋白的共表达,应用荧光标记法检测各组细胞活性氧(ROS)水平。结果:TNF-α诱导MLO-Y4细胞24 h,凋亡和坏死率明显高于control组(P0.01)。与TNF-α组相比,Nec-1、Z-VAD和RIP3-siRNA均能降低细胞的凋亡或坏死率(P0.01)。在TNF-α组可见大量坏死样细胞,在Z-VAD组仍可见到坏死样细胞,而在Nec-1和RIP3-siRNA组未见到坏死样细胞。Western blot实验结果显示Nec-1可有效抑制RIP1蛋白表达,而Z-VAD对RIP1和RIP3蛋白表达无影响,RIP3-siRNA可有效降低RIP3蛋白表达(P0.01)。与TNF-α组比较,Nec-1可有效降低RIP1-RIP3蛋白共表达阳性细胞百分率(P0.01),而Z-VAD对其无影响。与control组相比,TNF-α组的ROS水平明显增高(P0.01);与TNF-α组相比,Nec-1、Z-VAD及RIP3-siRNA均能有效抑制ROS水平(P0.01)。结论:TNF-α能诱导MLO-Y4细胞发生RIP3介导的程序性坏死;ROS可能是MLO-Y4细胞程序性坏死的执行者。     

B细胞程序性死亡的研究进展

Ｂ细胞程序性死亡是一个高度调节的过程，特异性受体信号控制着Ｂ细胞凋亡。Ｂ细胞是否凋亡取决于Ｂ细胞发育阶段及其凋亡激发因素。随着对Ｂ细胞凋亡机制的研究，对凋亡敏感性及抗性的分子机制已有了初步认识。     

程序性坏死机制与缺血再灌注损伤

程序性坏死是一种具有可调控的信号传导通路的细胞坏死方式。多种刺激可导致程序性坏死的发生,复合体Ⅰ、复合体Ⅱ和RIP1-RIP3坏死体是通路中的信号分子,而Necstatin-1是程序性坏死的特异性阻断剂。程序性坏死可能是缺血再灌注损伤中细胞死亡的重要方式。     

程序性死亡受体1在HIV感染和防治中的作用研究进展

程序性死亡受体1(programmed cell death-1,PD-1)是细胞表面的一种免疫抑制分子,与配体PD-L1或PD-L2相互作用,负向调控细胞和体液免疫应答。人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染后,PD-1在感染者外周血淋巴细胞表面表达上调,高水平表达的...     

B细胞程序性死亡的研究进展

Ｂ细胞程序性死亡是一个高度调节的过程，特异性受体信号控制着Ｂ细胞凋亡。Ｂ细胞是否凋亡取决于Ｂ细胞发育阶段及其凋亡的激发因素。随着对Ｂ细胞凋亡机制的研究，对凋亡敏感性及抗性的分子机制已有了初步认识。     

受体相互作用蛋白激酶调控非酒精性脂肪肝中细胞程序性坏死的研究进展

非酒精性脂肪性肝病（NAFLD）是一种常见的慢性肝病,如果得不到有效控制,则会进一步发展为非酒精性脂肪性肝炎（NASH）,进而引起肝纤维化、肝硬化,甚至癌变。程序性坏死是近年来发现的一种新型细胞程序性死亡方式,由受体相互作用蛋白激酶（RIPK）介导所致,最终可以导致细胞膜溶解破裂,引发炎症。RIPK家族作为细胞内和细胞外应激的重要传感器,诱导调控程序性坏死的发生,并参与炎症及其他免疫反应。近年来研究表明,RIPK调控的程序性坏死在非酒精性脂肪性肝病的发生发展中具有重要作用,在动物NAFLD/NASH模型中,RIPK的表达情况与肝脂肪变性程度密切相关。在一些临床研究中亦观察到,NAFLD/NASH患者比健康人RIPK表达水平上升。但程序性坏死到底是加速肝病进程的因素,还是肝病发展过程中的保护因素,仍然没有定论。有研究表明,RIPK抑制剂可能为NAFLD治疗提供方向。我们综述了程序性坏死的分子机制及与非酒精性脂肪性肝病的关系,以及RIPK在其中扮演的重要角色,并总结了其在NAFLD/NASH治疗方面的研究进展,为进一步探究其机制,探索新的治疗手段提供理论依据。     

程序性死亡受体1/程序性死亡配体1信号各组分在急性冠脉综合征患者外周血中的表达及意义

目的 探讨程序性死亡受体1/程序性死亡配体1信号各组分在急性冠脉综合征(ACS)患者外周血中的表达及意义.方法 采用流式细胞术检测CD4+ CD28-T细胞表面程序性死亡受体1(PD-1)以及单核细胞表面程序性死亡配体1(PD-L1)的表达;采用酶联免疫吸附实验(ELISA)检测外周血中可溶性程序性死亡受体1(sPD-1),可溶性程序性死亡配体1(sPD-L1)和干扰素-γ(IFN-γ)的浓度.结果 与稳定性心绞痛(SA)和正常对照组(HC)相比,ACS患者CD4+ CD28-T细胞表面PD-1和单核细胞表面PD-L1的表达明显上调(P＜0.05),外周血中sPD-1、sPD-L1和IFN-γ的水平显著升高(P＜0.05).其中,sPD-L1和IFN-γ的水平呈显著正相关(r=0.772,P＜0.05).sPD-1和IFN-γ的水平无相关性(r =0.306,P＜0.05).结论 ACS患者体内CD4+ CD28-T细胞过量产生的IFN-γ是单核细胞表面PD-L1表达上调和外周血sPD-L1水平升高的原因之一,为进一步研究CD4+ CD28-T细胞的增殖活化和防治ACS提供理论依据.     

程序性死亡蛋白配体-1/程序性死亡蛋白-1在老年胃癌患者外周血CD8+T淋巴细胞中的表达及临床意义

目的 通过分析程序性死亡蛋白配体-1/程序性死亡蛋白-1(programmed death ligand-1/programmed death-1,PD-L1/PD-1)在老年胃癌患者外周血CD8+T淋巴细胞中表达情况,探讨其临床意义.方法 选择同一时期90例老年胃癌患者(具有不同临床分期)及90例老年健康体检者,分别采取新鲜外周血后经流式细胞仪检测血中CD8+T淋巴细胞表面PD-L1/PD-1表达情况,结合老年胃癌患者的临床分期,分析PD-L1/PD-1在不同胃癌分期中的表达意义.结果 PD-L1/PD-1在老年胃癌患者外周血CD8+T淋巴细胞呈高表达,相较于老年健康者差异具有统计学意义(t=7.043,P<0.05);外周血CD8+T淋巴细胞的PD-L1/PD-1阳性表达均随着临床分期的增加而增加,呈明显的正相关性(r=0.883,P<0.05);外周血CD8+T淋巴细胞的PD-1阳性表达随着临床分期的增加而增加,两者之间呈正相关性(r=0.811,P<0.05);临床分期较晚的老年胃癌患者外周血CD8+T淋巴细胞PD-L1/PD-1表达比其他相对较早的临床分期老年胃癌患者显著上升(t=4.377,P<0.05).结论 PD-L1/PD-1信号通路异常在老年胃癌患者病变的发生发展过程中发挥了重要作用,外周血CD8+T淋巴细胞PD-L1/PD-1的表达对评判患者的预后具有指导作用.     

蜂毒肽诱导人肝癌细胞系SMMC-7721程序性坏死

目的 探讨蜂毒肽(MLT)对人肝癌细胞系SMMC-7721的杀伤作用及可能机制.方法 采用MTT法检测不同浓度蜂毒肽对人肝癌细胞系SMMC-7721的杀伤及程序性坏死特异性抑制剂-1(Nec-1)对蜂毒肽杀伤SMMC-7721细胞的抑制作用.Hoechst 33342及PI双染色观察细胞程序性坏死的发生,流式细胞术检测...     

Role of programmed cell death in normal neuronal development and function

The consequences of eliminating the process of programmed cell death during the development of the nervous system is examined by reviewing studies in the genetic model organisms Caenorhabditis elegans, Drosophila melanogaster, Danio rerio and Mus musculus, where mutations of cell death genes have eliminated or reduced programmed cell death in the nervous system. In many cases, genetic elimination of cell death leads to embryonic mortality or gross anatomical malformations; however, there are cases where animals develop normally but with excess neurons and glia in the nervous system. Undead cells either differentiate and function as working neurons, in some instances being of smaller size, or fail to differentiate and lack normal connections with their targets. Changes in motor control and sensory processing are generally not observed, except for during the most complex of behaviors. Examination of organisms where death genes have been genetically eliminated reveals that programmed cell death may play an important role in sculpting gross brain structure during early development of the neural tube. In contrast, the consequences of preventing neuronal cell death at later developmental stages (e.g. during vertebrate synapse formation) are just beginning to be understood.     

Mitochondrial fission proteins regulate programmed cell death in yeast

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.     

Involvement of programmed cell death in preimplantation embryo demise

Fragmentation is frequently observed in animal and human embryosobtained via in-vitro fertilization (IVF), and is known to beassociated with decreased pregnancy rates and poor survivalfollowing cryopreservation. We postulate that embryo fragmentationis a consequence of activated programmed cell death (PCD) andsubsequent apoptosis and discuss evidence of morphological,histological and biochemical features compatible with the occurrenceof PCD in preimplantation embryos. If PCD is an underlying causeof the high incidence of the fragmentation seen in human pre-embryos,it remains to be determined whether this is reflective of thenatural incidence of lethal chromo somes in the human populationor due to the IVF procedure and culture conditions.     

骨关节炎软骨细胞的新型程序性死亡

背景：骨关节炎是一种常见的关节退行性疾病,其发生机制复杂,目前尚未阐明。但已有的研究表明,骨关节炎的发生发展与软骨细胞程序性死亡有关。目的：总结骨关节炎软骨细胞新型程序性死亡的研究进展。方法：“Osteoarthritis,Pyroptosis,Necroptosis,Ferroptosis,ROS,L-ROS,Iron-overload”为英文检索词,以“骨关节炎、细胞焦亡、坏死性凋亡、铁死亡、铁超载、脂质活性氧”为中文检索词,使用计算机在CNKI、万方数据库、PubMed、维普数据库检索2012年7月至2022年7月有关于程序性细胞死亡的相关文章,并进行系统地归纳、总结和分析。结果与结论：焦亡与骨关节炎的关系近年来备受关注,目前的研究重点仍是NLRP3炎性小体和脂多糖。有关坏死性凋亡的研究中,骨关节炎的发展也已被证明与受体相互作用蛋白激酶1密切相关,受体相互作用蛋白激酶1有可能是治疗骨关节炎的潜在靶点。铁死亡是一种最新发现的细胞死亡方式,研究发现其通过铁超载和脂质过氧化介导了软骨细胞的死亡,但铁死亡的发生涉及多个基因的表达和调控,具有复杂的信号通路和机制,目前尚未完全阐明。细胞焦亡...     

细胞自噬的调控与自噬程序性死亡的研究进展

自噬(autophagy)是一种溶酶体依赖性降解途径,涉及细胞内长寿蛋白和受损伤细胞器的降解,其既是细胞保守的自我防御机制,又是一种程序性细胞死亡机制(PCD),与机体的多种疾病有密切关系.自噬具有独特的形态改变和特有的调控通路,自噬的调控涉及到多种机制、如翻译后修饰等.凋亡是研究最清楚的程序性细胞死亡机制,凋亡与细胞自噬程序性死亡之间存在着复杂的关系.对哺乳动物细胞自噬的分子调控机制,自噬程序性细胞死亡过程及其与凋亡的关系等方面进行探讨很有意义.     

Expression and prognostic significance of programmed death protein 1 and programmed death ligand‐1, and cytotoxic T lymphocyte‐associated molecule‐4 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. In this study, we assessed the correlation between clinicopathologic factors with programmed cell death protein 1 (PD‐1) and programmed cell death ligand‐1 (PD‐L1), and cytotoxic T lymphocyte‐associated molecule‐4 (CTLA‐4) expressions. Furthermore, we analyzed the prognostic significance of these proteins in a subgroup of patients. We retrospectively evaluated the PD‐1, PD‐L1, and CTLA‐4 expressions in 294 HCC tissue microarray samples using immunohistochemistry. PD‐1 and PD‐L1 expressions were significant related to high CD8+ tumor‐infiltrating lymphocytes (TILs) (r = 0.664, p < 0.001 and r = 0.149, p = 0.012). Only high Edmondson–Steiner grade was statistically related to high PD‐1 expression. High PD‐L1 expression was demonstrated as an independent poor prognostic factor for disease‐free survival in addition to previous known factors, size >5 cm and serum albumin ≤3.5 g/dL in high CD8+ TILs group. We have demonstrated that the combined high expression of PD‐L1 and CD8+ TIL is an important prognostic factor related to the immune checkpoint pathway in HCC and furthermore, there is a possibility that it could be used as a predictor of therapeutic response. Also, this result would be helpful in evaluating the applicable group of PD‐1/PD‐L1 blocking agent for HCC patients.