GSDMs家族蛋白介导细胞焦亡在抗肿瘤免疫中的作用

细胞焦亡是一种调节性细胞死亡方式。Gasdermine（GSDMs）是一类执行细胞焦亡的胞内蛋白质。虽然GSDMs表达后的完整蛋白质不具有活性,但能被某些蛋白水解酶激活。被激活的GSDMs N端在质膜上穿孔,导致细胞裂解,引起细胞内的促炎分子及损伤相关分子模式（danger-associated molecular patterns,DAMPs）迅速有效地从焦亡细胞中释放,从而引发炎症和免疫反应。焦亡细胞促进抗肿瘤免疫作用可能涉及细胞毒性T淋巴细胞对肿瘤细胞的杀伤。本文介绍GSDMs介导的细胞焦亡及细胞焦亡过程中引发促炎症和免疫反应的关键分子,并且探讨细胞焦亡对肿瘤治疗的有利及不利因素,以期更好地了解细胞焦亡对肿瘤免疫微环境的影响及对肿瘤免疫治疗的作用,有助于促进恶性肿瘤治疗策略的改进。     

北京生命科学研究所发现炎症性Caspase为细菌内毒素的胞内天然免疫受体

<正>北京生命科学研究所邵峰实验室近年来一直专注于研究宿主细胞质中感知细菌和病原细菌的分子免疫机制。2014年8月6日,该研究组最新的研究成果在Nature在线发表,他们发现人和小鼠的炎症性Caspase-4/5/11为胞内内毒素(Lipopolysac charide,LPS,脂多糖,俗称内毒素)的受体,直接结合LPS发生寡聚化而被激活,导致细胞炎症性坏死。在该项研究中,邵峰实验室研究人员首先建立了一个可以将LPS高效导入哺乳动物细胞内的转染     

炎性小体激活与细胞焦亡的研究进展

细胞焦亡是一种依赖天冬氨酸特异性半胱氨酸蛋白酶1(cysteinyl aspartate specific proteinase 1,caspase-1)/caspase-11的程序性细胞死亡方式。炎性小体的激活在细胞焦亡过程中扮演重要角色。当病原体入侵时,核苷酸结合寡聚化结构域样受体(nucleotide-binding oligomerization domain-like receptor,NLR)和黑色素瘤缺乏因子2(absent in melanoma 2,AIM2)等胞内模式识别受体(pattern recognition receptor,PRR)与相应配体结合,导致炎性小体多蛋白复合物组装和caspase-1/caspase-11激活,进而诱导细胞焦亡发生。深入研究炎性小体激活和细胞焦亡的相关机制,对认识炎症性疾病的发生发展非常重要。本文就炎性小体激活与细胞焦亡的研究进展进行综述。     

细胞焦亡的机制和功能

细胞焦亡(pyroptosis)是一种高度促炎性的细胞程序性死亡,最早是在受细菌感染或者细菌毒素处理后的巨噬细胞中观察到的,很长一段时间被误认为是一种巨噬细胞特异的、依赖于能够切割白介素1β的促炎性蛋白酶caspase-1的细胞死亡.后续的研究发现,胞浆内模式识别受体识别病原体来源的模式分子或者机体本身来源的危险信号分子形成炎症小体(inflammasomes),招募和激活caspase-1导致细胞焦亡;鼠的caspase-11和人的caspase-4/5直接作为模式识别受体识别细菌脂多糖类脂A组装的炎症小体也导致细胞焦亡,这一发现颠覆了传统炎症小体的概念.与caspase-1不同, caspase-11/4/5不能切割白介素且引起的细胞焦亡在非单核细胞中也普遍存在.最新的研究发现, caspase-1以及caspase-11/4/5都能切割共同的底物gasdermin D(GSDMD)导致裂解性细胞死亡.GSDMD属于一类具有膜打孔活性的gasdermin家族蛋白成员,细胞焦亡也被重新定义为gasdermin介导的程序性坏死样细胞死亡,开创了细胞焦亡研究的新领域.本文回顾了细胞焦亡研究的历史以及细胞焦亡概念的进化过程,总结了caspase-1和caspase-11/4/5上游目前已知的天然免疫通路,讨论了关于细胞焦亡的研究进展尤其是GSDMD以及其他gasdermin家族细胞焦亡执行蛋白的功能和作用机制,以及细胞焦亡和相关蛋白在对抗感染以及人的自身炎症性疾病过程中的作用.     

炎性小体在诱导脊髓损伤神经炎症中的作用

脊髓损伤的治疗与康复一直是医学领域的重大难题,尤其是在改善损伤的神经功能方面进展甚微。继发性损伤是造成脊髓损伤后神经功能障碍的主要原因,炎症反应是继发性损伤阶段最重要的病理过程。急性期通过抑制神经炎症来减轻继发性损伤被认为可减轻神经功能损害而达到神经保护作用。炎性小体是一类蛋白质复合体,由模式识别受体中的NLRs家族和PHYIN家族的受体蛋白质作为主要框架组装并命名,常见的炎性小体包括NLRP1、NLRP3、NLRC4(IPAF)、AIM2等。在感染或受到损伤刺激时,炎性小体在细胞质内组装,并激活促炎症蛋白酶胱天蛋白酶1(caspase-1),活化的胱天蛋白酶1一方面促进促炎症细胞因子IL-1β和IL-18的前体成熟和分泌,另一方面介导细胞焦亡。细胞焦亡以细胞肿胀破裂并释放细胞内容物为特征,是在炎症和应激的病理条件下诱导的程序性细胞死亡方式。促炎症细胞因子和焦亡释放的胞内物质都可作为促炎信号引发炎症反应。近期发现,炎性小体通过诱导促炎因子释放以及介导细胞焦亡等途径, 参与激活脊髓损伤后的炎症级联反应,加重继发性神经炎症。靶向抑制炎性小体的激活可减轻炎症反应,促进神经细胞存活,达到神经保护作用。因此,炎性小体有望成为脊髓损伤治疗的新靶点。本文拟从炎性小体的结构及其在脊髓损伤中的作用、激活机制和治疗前景进行综述,以期为后续研究提供思路。     

炎症小体的研究进展概述CSCD

炎症小体(inflammasome)是一种多蛋白质复合物,它的组装可以导致Caspase-1的激活,并促进炎性细胞因子白介素-1β(interleukin-1β,IL-1β)和白介素-18(interleukin-18,IL-18)的成熟与释放;同时,激活的Caspase-1还可以引发细胞焦亡(pyroptosis)。炎症小体在应答病原体相关分子模式(pathogenassociated molecular pattern,PAMP)或者危险相关分子模式(danger-associated molecular pattern,DAMP)的刺激中扮演着重要角色。炎症小体的异常会导致多种自发炎症及自身免疫性疾病的发生,但是关于其调控活化机制仍有诸多不明,相关研究有待进一步深入。     

细胞焦亡机制及与疾病的关系

细胞焦亡(pyroptosis)是近年来发现的一种区别于细胞凋亡的促炎程序性死亡方式。焦亡途径包括半胱天冬酶(caspase)-1介导的经典焦亡途径和Caspase-4/5/11介导的非经典焦亡途径。细胞焦亡涉及多种炎性小体的激活,如核苷酸结合寡聚化结构域样受体蛋白3(NLR pyrin domain containing 3,NLRP3)、核苷酸结合寡聚化结构域样受体蛋白C4 (NLR containing a caspase recruitment domain 4,NLRC4)以及黑色素瘤缺乏因子2 (absent in melanoma 2,AIM2)等。Gasdermin-D(GSDMD)是参与细胞焦亡的关键切割蛋白,最终导致膜蛋白通道开放、膜孔形成、白细胞介素(interleukins,ILs)释放,从而扩大炎症反应。细胞焦亡介导许多疾病如感染性疾病、神经系统疾病、心血管疾病、代谢性疾病以及炎症免疫性疾病等。本文综述了细胞焦亡机制及与疾病关系的研究进展。     

炎症小体的研究进展概述

炎症小体(inflammasome)是一种多蛋白质复合物,它的组装可以导致Caspase-1的激活,并促进炎性细胞因子白介素-1β(interleukin-1β,IL-1β)和白介素-18(interleukin-18,IL-18)的成熟与释放;同时,激活的Caspase-1还可以引发细胞焦亡(pyroptosis)。炎症小体在应答病原体相关分子模式(pathogenassociated molecular pattern,PAMP)或者危险相关分子模式(danger-associated molecular pattern,DAMP)的刺激中扮演着重要角色。炎症小体的异常会导致多种自发炎症及自身免疫性疾病的发生,但是关于其调控活化机制仍有诸多不明,相关研究有待进一步深入。     

NLRP3炎症小体的负向调控机制

NLRP3炎症小体是由NOD样受体(NOD-like receptor, NLR) NLRP3、接头蛋白ASC和胱冬肽酶-1(Caspase-1)所形成的多聚蛋白复合体,能够感受来自病原微生物的病原相关分子模式(pathogen-associated molecular patterns, PAMPs)和胞内自身危险信号-危险相关分子模式(danger-associated molecular patterns, DAMPs),促进细胞因子IL-1β和IL-18的成熟和分泌、引起细胞焦亡,从而在多种生理、病理过程中发挥重要作用. NLRP3炎症小体是目前研究最深入的炎症小体,其表达水平和活化强度与多种疾病的发生、发展密切相关,如感染性疾病、痛风、Ⅱ型糖尿病、动脉粥样硬化、阿尔兹海默症及癌症等.因此,阐明NLRP3炎症小体活化的调控机制,对于揭示这些疾病发生、发展的机理,寻找免疫调节治疗的新途径具有重要意义.本文详细介绍了NLRP3炎症小体的负向调控机制.     

病毒感染对NLRP3炎症小体活化、组装和效应的影响

炎症小体是存在于胞浆的大分子多蛋白复合物,在感染或应激状态下被激活,并触发IL-1β和IL-18等促炎细胞因子的释放,诱导细胞焦亡,从而参与先天免疫防御。NLRP3识别病毒复制过程中产生的各种病原体相关分子模式（PAMP）和危险相关分子模式（DAMP）,启动NLRP3炎症小体依赖的抗病毒免疫反应。但是,有些病毒也进化出复杂的策略而靶向炎症小体,以逃避天然免疫监视。本综述讨论了病毒感染过程对NLRP3炎症小体的活化、组装和效应的影响。     

Recent advances in the study of Kaposi's sarcoma-associated herpesvirus replication and pathogenesis

It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma-associated herpesvirus(KSHV; also known as human herpesvirus 8(HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis.     

The structure, reproduction and taxonomy of Vidalia and Osmundaria (Rhodophyta, Rhodomelaceae)

Comprises species occurring mostly in subtidal habitats in tropical, subtropical and warm-temperate areas of the world. An analysis of the type species, V. spiralis (Sonder) Lamouroux ex J. Agardh, a species from Australia, establishes basic characters for distinguishing species in the genus. These characters are (1) branching patterns of thalli, (2) flat blades that may be spiralled on their axis, (3) width of the blade, (4) primary or secondary derivation of sterile and fertile branchlets and (5) position of sterile and fertile branchlets on the thalli. Application of the latter two characters provides an important basic method for separation of species into three major groups. Osmundaria , a genus known only in southern Australia, was studied in relation to Vidalia , and its separation from the Vidalia assemblage is not accepted. Species of Vidalia therefore are transferred to the older genus name, Osmundaria. Two new species, Osmundaria papenfussii and Osmundaria oliveae are described from Natal. Confusion in the usage of the epithet, Vidalia fimbriala Brown ex Turner has been clarified, and Vidalia gregaria Falkenberg, described as an epiphyte on Osmundaria pro/ifera Lamouroux, is revealed to be young branches of the host, Osmundaria prolifera.     

New or rare chromosome counts in Artemisia L. (Asteraceae, Anthemideae) and related genera from Kazakhstan

Fifteen chromosome counts of six Artemisia taxa and one species of each of the genera Brachanthemum, Hippolytia, Kaschgaria, Lepidolopsis and Turaniphytum are reported from Kazakhstan. Three of them are new reports, two are not consistent with previous counts and the remainder are confirmations of very scarce (one to four) earlier records. All the populations studied have the same basic chromosome number, x = 9, with ploidy levels ranging from 2x to 6x. Some correlations between ploidy level, morphological characters and distribution are noted.     

肝癌中HBV和HCV基因和抗原的分布及意义

采用原位分子杂交方法检测HCV RNA及HBV X基因;采用免疫组织化学方法研究HCV核心抗原,非结构区C33c抗原及HBxAg在肝细胞肝癌中的定位及分布.结果表明(1)HCV RNA、HBV X基因在肝细胞肝癌组织检出率分别为40%(55/136)和82%(112/136).HCV RNA定位于癌细胞的胞浆内,阳性细胞呈散在、灶状及弥漫分布三种形式;HBV X基因在肝癌细胞中的分布呈胞浆型、核型及核浆型,阳性细胞也呈上述三种分布形式;(2)HCV C33c抗原、核心抗原在肝细胞肝癌中的阳性率为81%(133/164)及86%(141/164).C33c抗原定位于癌细胞及肝细胞的胞浆内;核心抗原既定位于癌细胞核中,又可定位于胞浆中.C33c抗原阳性细胞以灶状分布为主;而核心抗原阳性细     

Selection with two alleles and complete dominance

For a plant selection model with frequency-independent viabilities, fertilities and selfing rates, it is shown that apart from global fixation, for certain parameter combinations a protected polymorphism and facultative fixation (either allele may become fixed according to initial frequencies) may both occur. Facultative fixation requires different selling rates for the dominant and recessive type. Protection of the polymorphism requires resource allocation for male and female function. In this connection the problem of purely genetically caused population extinction is discussed.
For general frequency dependence and regular segregation, the chances for establishment of a completely recessive gene are compared to those of a completely dominant gene. It is proven that the process of establishment of the recessive gene, despite a fitness advantage, may be considerably endangered by drift effects if random mating prevails. The recessive gene may reach the same effectivity in establishment as a dominant gene, only if the recessive homozygote mates exclusively with its own type during the period of establishment.