焦亡在心脏疾病中的研究进展

焦亡是一种新发现并证实与炎症相关的细胞死亡方式,其特征为依赖于半胱天冬氨酸蛋白酶-1(cysteinyl aspartate specific proteinase-1,Caspase-1)的细胞程序性死亡,并伴有促炎症因子的释放,主要为白介素-1β(interleukin-1β,IL-1β)和白介素-18(interleukin-18,IL-18).越来越多的研究发现,焦亡相关信号通路在心脏疾病中起重要作用,包括心肌梗死、缺血再灌注损伤、心肌肥厚、心肌纤维化和心力衰竭等.本文就焦亡相关信号通路与心脏疾病关系研究进展作一综述.     

细胞焦亡:一种新的细胞死亡方式

细胞焦亡是近年来发现并证实的一种新的程序性细胞死亡方式,其特征为依赖于半胱天冬酶-1(caspase-1),并伴有大量促炎症因子的释放.细胞焦亡的形态学特征、发生及调控机制等均不同于凋亡、坏死等其他细胞死亡方式.研究表明,细胞焦亡广泛参与感染性疾病、神经系统相关疾病和动脉粥样硬化性疾病等的发生发展,并发挥重要作用.对细...     

机械力刺激诱导机体组织炎症反应机制研究进展

机械力刺激能够诱发机体中包括牙周组织在内的多种组织发生无菌性炎症反应,并能促进免疫细胞以及一些非免疫细胞如牙周膜细胞发生焦亡(pyroptosis)。现有研究表明,Gasdermin-D(GSDMD)在炎症反应、细胞焦亡发生中具有重要作用,但GSDMD是否参与机械力刺激引发的炎症反应和细胞焦亡尚未可知。综述机械力刺激诱导机体组织炎症反应以及焦亡的信号通路研究进展。     

细胞焦亡研究进展

细胞焦亡是一种新发现的依赖于Gasdermin蛋白家族成孔活性的细胞程序性炎症坏死,在抵抗外部病原体入侵和感知内源危险信号中发挥着不可替代的作用,其形态学特征、发生及作用机制与细胞凋亡等典型细胞死亡方式有显著不同。焦亡由炎症小体激活Caspase-1的经典细胞焦亡途径和胞质LPS激活Caspase-4/5/11的非经典细胞焦亡途径而诱发。本文就近年来细胞焦亡的发现和命名、形态学和分子特征、分子机制和焦亡相关的疾病进行综述,为疾病预防诊断及临床药物的靶向治疗提供理论依据和现实的可行性。     

细胞焦亡在肾间质纤维化中的作用机制北大核心CSCD

细胞焦亡是由caspase蛋白酶介导,经GSDMD切割细胞膜成孔,引起细胞破裂死亡、活性促炎因子释放的一种新型的细胞促炎性程序性死亡方式。细胞焦亡分为caspace-1相关的经典途径与caspase-4/5/11相关的非经典途径。细胞焦亡是肾间质纤维化的重要参与者,多种信号刺激激活炎性小体,诱发细胞焦亡,引起炎症反应和免疫细胞、肾固有细胞的相关应答,三者串联形成“焦亡-炎症-纤维化”轴,共同参与肾间质纤维化的发生;细胞焦亡还与自噬相互作用,影响纤维化进程。本文就细胞焦亡的分子机制及其在肾间质纤维化中的作用机制进行概述。     

细胞焦亡及相关疾病的研究进展

细胞焦亡是由Gasdermin蛋白介导的一种程序性炎性细胞死亡方式,分为依赖caspase-1的经典途径和依赖caspase-4/5/11的非经典途径。炎性小体的激活在此过程中扮演重要角色。细胞焦亡参与肾脏疾病、动脉粥样硬化、神经系统疾病、感染性疾病等的发生发展,并发挥重要作用。通过对细胞焦亡作用机制及相关疾病的研究,为临床疾病的防治提供新思路。     

炎症反应在细胞焦亡和动脉粥样硬化之间的作用

心血管疾病是全球慢性非传染性疾病中死亡率最高的一类疾病，而动脉粥样硬化（AS）在心血管疾病的发生发展中扮演了重要的角色。炎症反应与动脉粥样硬化形成密切相关，而其又广泛参与细胞焦亡过程。核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）、适配器凋亡相关微粒蛋白（apoptosis-associated speck-like protein containing CARD，ASC）以及Caspase-1等细胞焦亡的重要功能分子均参与AS形成，细胞焦亡的过程中伴随白细胞介素等炎症介质的产生及释放，而炎症反应又可反过来促进细胞焦亡的发生发展。我们分别从炎症反应在动脉粥样硬化、细胞焦亡形成中的作用，炎症反应在这两者之间的桥梁作用等3个方面进行综述。     

细胞焦亡调控与炎症和肿瘤病理机制的关系

细胞焦亡是近年来的研究热点,且在多种疾病中发挥关键作用,在机体炎症反应和免疫反应中普遍存在。该文回顾性综述近年来有关细胞焦亡机制及相关疾病的最新文献,系统而全面地阐述细胞焦亡研究的最新进展。     

细胞焦亡与组织纤维化

细胞焦亡是一种特异性依赖caspace-1的新型细胞程序性死亡方式。相关刺激激活炎性小体并启动细胞焦亡,最终致使细胞死亡并释放促炎因子IL-1β、IL-18。细胞焦亡在多种纤维化疾病中介导形成"焦亡-炎性反应-纤维化"轴样病理改变,扩大炎性级联反应,加重组织纤维化病程进程。因此,细胞焦亡的启动逐渐成为药物靶点研究的新方向。     

miRNA调控细胞焦亡在2型糖尿病及相关心血管病中的研究进展

<正>2型糖尿病（type 2 diabetes mellitus,T2DM）本质是一种无菌性炎症，不仅导致糖脂代谢紊乱、胰岛素抵抗等病理改变，还伴随多种心血管损害。大量研究发现，细胞焦亡通路激活推动T2DM及相关心血管疾病的病程演进，是连接T2DM代谢综合征和心肌损害的枢纽。随着多种微小RNA(micro RNA,mi RNA)调控细胞焦亡的作用被发现，miRNA通过调控细胞焦亡信号通路或蛋白表达，影响T2DM及相关心血管疾病的发生发展，成为糖尿病心肌保护策略的研究热点。本文就miRNA调控的细胞焦亡在2型糖尿病及相关心血管疾病中的研究进展进行综述。     

Macrophages and Recently Identified Forms of Cell Death

Recent advances in cell death biology have uncovered an ever increasing range of cell death forms. Macrophages have a bidirectional relationship with cell death that modulates the immune response. Thus, macrophages engulf apoptotic cells and secrete cytokines that may promote cell death in parenchymal cells. Furthermore, the presence of apoptotic or necrotic dead cells in the microenvironment elicits differential macrophage responses. Apoptotic cells elicit anti-inflammatory responses in macrophages. By contrast macrophages may undergo a proinflammatory form of cell death (pyroptosis) in response to damage-associated molecular patterns (DAMPs) released from necrotic cells and also in response to pathogen-associated molecular patterns (PAMPs). Pyroptosis is a recently identified form of cell death that occurs predominantly in subsets of inflammatory macrophages and is associated to the release of interleukin-1β (IL-1β) and IL-18. Deregulation of these processes may result in disease. Thus, failure of macrophages to engulf apoptotic cells may be a source of autoantigens in autoimmune diseases, excessive macrophage release of proapoptotic factors or sterile pyroptosis may contribute to tissue injury and failure of pathogen-induced pyroptosis may contribute to pathogen survival. Ongoing research is exploring the therapeutic opportunities resulting this new knowledge.     

Molecular mechanisms and functions of pyroptosis,inflammatory caspases and inflammasomes in infectious diseases

Cell death is a fundamental biological phenomenon that is essential for the survival and development of an organism. Emerging evidence also indicates that cell death contributes to immune defense against infectious diseases. Pyroptosis is a form of inflammatory programmed cell death pathway activated by human and mouse caspase-1, human caspase-4 and caspase-5, or mouse caspase-11. These inflammatory caspases are used by the host to control bacterial, viral, fungal, or protozoan pathogens. Pyroptosis requires cleavage and activation of the pore-forming effector protein gasdermin D by inflammatory caspases. Physical rupture of the cell causes release of the pro-inflammatory cytokines IL-1β and IL-18, alarmins and endogenous danger-associated molecular patterns, signifying the inflammatory potential of pyroptosis. Here, we describe the central role of inflammatory caspases and pyroptosis in mediating immunity to infection and clearance of pathogens.     

Pyroptotic cell death defends against intracellular pathogens

Inflammatory caspases play a central role in innate immunity by responding to cytosolic signals and initiating a twofold response. First, caspase-1 induces the activation and secretion of the two prominent pro-inflammatory cytokines, interleukin-1β (IL-1β) and IL-18. Second, either caspase-1 or caspase-11 can trigger a form of lytic, programmed cell death called pyroptosis. Pyroptosis operates to remove the replication niche of intracellular pathogens, making them susceptible to phagocytosis and killing by a secondary phagocyte. However, aberrant, systemic activation of pyroptosis in vivo may contribute to sepsis. Emphasizing the efficiency of inflammasome detection of microbial infections, many pathogens have evolved to avoid or subvert pyroptosis. This review focuses on molecular and morphological characteristics of pyroptosis and the individual inflammasomes and their contribution to defense against infection in mice and humans.     

Caspase-1-induced pyroptotic cell death

Programmed cell death is a necessary part of development and tissue homeostasis enabling the removal of unwanted cells. In the setting of infectious disease, cells that have been commandeered by microbial pathogens become detrimental to the host. When macrophages and dendritic cells are compromised in this way, they can be lysed by pyroptosis, a cell death mechanism that is distinct from apoptosis and oncosis/necrosis. Pyroptosis is triggered by Caspase-1 after its activation by various inflammasomes and results in lysis of the affected cell. Both pyroptosis and apoptosis are programmed cell death mechanisms but are dependent on different caspases, unlike oncosis. Similar to oncosis and unlike apoptosis, pyroptosis results in cellular lysis and release of the cytosolic contents to the extracellular space. This event is predicted to be inherently inflammatory and coincides with interleukin-1β (IL-1β) and IL-18 secretion. We discuss the role of distinct inflammasomes, including NLRC4, NLRP3, and AIM2, as well as the role of the ASC focus in Caspase-1 signaling. We further review the importance of pyroptosis in vivo as a potent mechanism to clear intracellular pathogens.     

Pyroptosis in cardiovascular diseases: Pumping gasdermin on the fire

Pyroptosis is a form of programmed cell death associated with activation of inflammasomes and inflammatory caspases, proteolytic cleavage of gasdermin proteins (forming pores in the plasma membrane), and selective release of proinflammatory mediators. Induction of pyroptosis results in amplification of inflammation, contributing to the pathogenesis of chronic cardiovascular diseases such as atherosclerosis and diabetic cardiomyopathy, and acute cardiovascular events, such as thrombosis and myocardial infarction. While engagement of pyroptosis during sepsis-induced cardiomyopathy and septic shock is expected and well documented, we are just beginning to understand pyroptosis involvement in the pathogenesis of cardiovascular diseases with less defined inflammatory components, such as atrial fibrillation. Due to the danger that pyroptosis represents to cells within the cardiovascular system and the whole organism, multiple levels of pyroptosis regulation have evolved. Those include regulation of inflammasome priming, post-translational modifications of gasdermins, and cellular mechanisms for pore removal. While pyroptosis in macrophages is well characterized as a dramatic pro-inflammatory process, pyroptosis in other cell types within the cardiovascular system displays variable pathways and consequences. Furthermore, different cells and organs engage in local and distant crosstalk and exchange of pyroptosis triggers (oxidized mitochondrial DNA), mediators (IL-1β, S100A8/A9) and antagonists (IL-9). Development of genetic tools, such as Gasdermin D knockout animals, and small molecule inhibitors of pyroptosis will not only help us fully understand the role of pyroptosis in cardiovascular diseases but may result in novel therapeutic approaches inhibiting inflammation and progression of chronic cardiovascular diseases to reduce morbidity and mortality from acute cardiovascular events.     

细胞焦亡：程序性死亡研究新热点

细胞焦亡(Pyroptosis)是一种以促炎性为特点的细胞程序性死亡方式,分为依赖半胱氨酸蛋白酶-1(Caspase-1)的经典细胞焦亡途径和依赖半胱氨酸蛋白酶-4/5/11(Caspase-4/5/11)的非经典细胞焦亡途径。研究表明细胞焦亡广泛参与到多种疾病的发生发展中。最近研究人员发现GSDMD和Pannexin-1可能是介导细胞焦亡的关键物质,但具体机制和相互关系仍有待进一步深入研究。     

焦亡介导高糖引起的小鼠胚胎成骨细胞MC3T3-E1炎症与损伤

目的:探讨细胞焦亡(pyroptosis)能否介导高糖(HG;45 mmol/L葡萄糖)引起的小鼠胚胎成骨细胞MC3T3-E1炎症和损伤。方法:应用细胞计数试剂盒8(CCK-8)检测成骨细胞活力;Western blot测定成骨细胞的核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)和胱天蛋白酶1(CASP1)的表达水平;ELISA法测定细胞培养上清液中白细胞介素18(IL-18)和IL-1β的水平;2',7'-二氯二氢荧光素二乙酯染色荧光显微镜照相法检测胞内活性氧(ROS)水平;罗丹明123染色荧光显微镜照相法测定线粒体膜电位(MMP)水平;碱性磷酸酶(ALP)试剂盒测定成骨细胞早期标志物ALP的活性;茜素红染色观察成骨细胞晚期标志物矿化结节的形成。结果:HG处理MC3T3-E1细胞24 h可明显促进NLRP3和CASP1的表达,引起IL-18和IL-1β的分泌增多,同时可使细胞活力降低,ROS生成和MMP丢失增加,成骨细胞分化与矿化功能下降(表现为ALP活性降低和矿化结节数量减少)。利用siRNA沉默CASP1表达可显著减轻HG引起的上述成骨细胞炎症和损伤。结论:焦亡可介导HG引起的MC3T3-E1细胞炎症和损伤。     

PM2.5 induced lung injury through upregulating ROS-dependent NLRP3 Inflammasome-Mediated Pyroptosis

The main cause of air pollution is PM_2.5, which directly causes lung injury through respiration. Oxidative stress and inflammation are considered to be the key mechanism of cell damage. Pyroptosis is a process of the programmed death of inflammatory cells and as a dangerous endogenous signal, it is widely involved in different inflammatory diseases. However, few studies have been conducted on PM_2.5 exposure and cell pyroptosis. In this study, we aimed to investigate the effect of PM_2.5 on apoptosis, pyroptosis and cell cycle arrest regulated by reactive oxygen species production. Balb/c mice were exposed to PM_2.5 dynamically and verified by the RAW264.7 cells in vitro. The results showed the activation of NF-κB and NLRP3 inflammasome and the release of IL-1β and reactive oxygen species were caused by exposure to PM_2.5. The maturation of IL-1β relied on Caspase-1, and the active Caspase-1 was related to cell pyroptosis. Oxidative stress, inflammation, apoptosis and pyroptosis all affected the cell cycle. This study describes a potentially important mechanism of PM_2.5-induced lung damage that PM_2.5 promotes lung injury via upregulating ROS-NLRP3-mediated the RAW264.7 cells pyroptosis.