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| 1 | Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis显示文摘Necroptosis 和 pyroptosis 是有血浆膜破裂的一个普通特征的规划房间死亡的二种形式。这里,我们与 necroptosis 比较学习了 pyroptosis 的形态学和机制。与 necroptosis 不同, pyroptosis 经历膜 blebbing 并且生产 apoptotic 在血浆膜以前的像身体的房间伸出(称为的 pyroptotic 身体) 破裂。在 necroptosis 的破裂是像爆炸的,而在 pyroptosis 它导致房间变平。necroptosis 的实行被混合的系 kinase 调停,这被知道像域(MLKL ) 在血浆膜的 oligomers,而 gasdermin-D (GSDMD ) 调停在它由 caspase-1 或 caspase-11 的劈开以后的 pyroptosis。我们显示出那 N 终端碎片 caspase 劈开产生的 GSDMD (GSDMD-N ) 也形成 oligomer 并且移居到血浆膜杀死房间。MLKL 和 GSDMD-N 是脂性的,两蛋白质的 N 终端序列为他们的 oligomerization 和血浆膜 translocation 是重要的。不同于在血浆膜上形成隧道的 MLKL,那导致渗透地胀大的选择离子的流入冲破的房间, GSDMD-N 形成非选择的毛孔并且不依靠增加的 osmolarity 破坏房间。我们的学习表明 GSDMD 的形成毛孔的活动和 MLKL 的形成隧道的活动在 pyroptosis 和 necroptosis 决定血浆膜破裂的不同方法。 | Xin Chen Wan-ting He Lichen Hu Jingxian Li Yuan Fang Xin Wang Xiaozheng Xu Zhuo Wang Kai Huang Jiahuai Han | 2016 | Cell Research2016，26，9： | 110 |
| 2 | Necroptosis, pyroptosis and apoptosis: an intricate game of cell death显示文摘Cell death is a fundamental physiological process in all living organisms.Its roles extend from embryonic development,organ maintenance,and aging to the coordination of immune responses and autoimmunity.In recent years,our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially.Different modalities of what has become known as‘programmed cell death’have been described,and some key players in these processes have been identified.We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death.These studies have highlighted the complex mechanisms tipping the balance between different cell fates.Here,we summarize the latest discoveries in the three most well understood modalities of cell death,namely,apoptosis,necroptosis,and pyroptosis,highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole. | Damien Bertheloot Eicke Latz Bernardo S.Franklin | 2021 | Cellular & Molecular Immunology2021，18，5： | 84 |
| 3 | NLRP3 inflammasome activation and cell death显示文摘The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3,adapter protein ASC,and inflammatory protease caspase-1 that responds to microbial infection,endogenous danger signals,and environmental stimuli.The assembled NLRP3 inflammasome can activate the protease caspase‐1 to induce gasdermin D-dependent pyroptosis and facilitate the release of IL-1β and IL-18,which contribute to innate immune defense and homeostatic maintenance.However,aberrant activation of the NLRP3 inflammasome is associated with the pathogenesis of various inflammatory diseases,such as diabetes,cancer,and Alzheimer’s disease.Recent studies have revealed that NLRP3 inflammasome activation contributes to not only pyroptosis but also other types of cell death,including apoptosis,necroptosis,and ferroptosis.In addition,various effectors of cell death have been reported to regulate NLRP3 inflammasome activation,suggesting that cell death is closely related to NLRP3 inflammasome activation.In this review,we summarize the inextricable link between NLRP3 inflammasome activation and cell death and discuss potential therapeutics that target cell death effectors in NLRP3 inflammasome-associated diseases. | Yi Huang Wen Xu Rongbin Zhou | 2021 | Cellular & Molecular Immunology2021，18，9： | 94 |
| 4 | Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis显示文摘Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death,such as ferroptosis,apoptosis and necroptosis. However,whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here,we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells,iron enhanced ROS signaling initiated by CCCP,causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20,which facilitates cytochrome c release to cytosol to activate caspase-3;eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore,ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME,iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above,we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover,no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis,but also implicates a novel iron-based intervention strategy for melanoma therapy. | Bo Zhou Jia-yuan Zhang Xian-shuo Liu Hang-zi Chen Yuan-li Ai Kang Cheng Ru-yue Sun Dawang Zhou Jiahuai Han Qiao Wu | 2018 | Cell Research2018，28，12： | 52 |
| 5 | Caspase-1在炎症及程序性细胞死亡过程中的作用显示文摘Caspase家族是一类半胱氨酸天冬氨酸特异性蛋白酶,其中caspase-1是最先在哺乳动物细胞中被鉴定出来的家族成员,介导了某些特定类型细胞的凋亡。在微生物感染或细胞内危险信号存在时,caspase-1可通过与炎性体结合而发生激活,从而加工pro-IL-1β和pro-IL-18等炎症因子使其成熟并释放,在炎症反应中起着核心调控作用。此外,caspase-1还能介导一种特殊的促炎症的程序性细胞死亡(Pyroptosis)。caspase-1参与的炎症及程序性细胞死亡能有效提高机体抵抗内源和外源各种刺激的能力,达到保护宿主的目的,而caspase-1的功能异常则与多种疾病密切相关。 | 邬皓晨 陈勇军 徐易尘 沈萍萍 | 2011 | 中国细胞生物学学报2011，33，2： | 36 |
| 6 | Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy显示文摘Diabetic nephropathy(DN)is characterized by sterile inflammation with continuous injury and loss of renal inherent parenchyma cells.Podocyte is an essential early injury target in DN.The injury and loss of podocytes are closely associated with proteinuria,the early symptom of renal injury in DN.However,the exact mechanism for podocyte injury and death in DN remains ambiguous.In this study we investigated whether pyroptosis,a newly discovered cell death pathway was involved in DN.Diabetic mice were generated by high-fat diet/STZ injections.We showed that the expression levels of caspase-11 and cleavage of gasdermin D(GSDMD-N)in podocytes were significantly elevated,accompanied by reduced expression of podocyte makers nephrin and podocin,loss and fusion in podocyte foot processes,increased inflammatory cytokines NF-κB,IL-1β,and IL-18,macrophage infiltration,glomerular matrix expansion and increased urinary albumin to creatinine ratio(UACR).All these changes in diabetic mice were blunted by knockout of caspase-11 or GSDMD.Cultured human and mouse podocytes were treated with high glucose(30 mM),which significantly increased the expression levels of caspase-11 or caspase-4(the homolog of caspase-11 in human),GSDMD-N,NF-κB,IL-1β,and IL-18,and decreased the expression of nephrin and podocin.Either caspase-4 or GSDMD knockdown by siRNA significantly blunted these changes.In summary,our results demonstrate that caspase-11/4 and GSDMD-mediated pyroptosis is activated and involved in podocyte loss under hyperglycemia condition and the development of DN. | Qian Cheng Jing Pan Zhuan-li Zhou Fan Yin Hong-yan Xie Pan-pan Chen Jing-yao Li Pei-qing Zheng Li Zhou Wei Zhang Jun Liu Li-min Lu | 2021 | Acta Pharmacologica Sinica2021，42，6： | 33 |
| 7 | GSDMB promotes non-canonical pyroptosis by enhancing caspase-4 activity显示文摘Gasdermin B (GSDMB) has been reported to be associated with immune diseases in humans, but the detailed molecular mechanisms remain unsolved. The N-terminus of GSDMB by itself, unlike other gasdermin family proteins, does not induce cell death. Here, we show that GSDMB is highly expressed in the leukocytes of septic shock patients, which is associated with increased release of the gasdermin D (GSDMD) N-terminus. GSDMB expression and the accumulation of the N-terminal fragment of GSDMD are induced by the activation of the non-canonical pyroptosis pathway in a human monocyte cell line. The downregulation of GSDMB alleviates the cleavage of GSDMD and cell death. Consistently, the overexpression of GSDMB promotes GSDMD cleavage, accompanied by increased LDH release. We further found that GSDMB promotes caspase-4 activity, which is required for the cleavage of GSDMD in non-canonical pyroptosis, by directly binding to the CARD domain of caspase-4. Our study reveals a GSDMB-mediated novel regulatory mechanism for non-canonical pyroptosis and suggests a potential new strategy for the treatment of inflammatory diseases. | Qin Chen Peiliang Shi Yufang Wang Dayuan Zou Xiuwen Wu Dingyu Wang Qiongyuan Hu Yujie Zou Zan Huang Jianan Ren Zhaoyu Lin Xiang Gao | 2019 | Journal of Molecular Cell Biology2019，11，6： | 22 |
| 8 | Eukaryotic elongation factor-2 kinase regulates the cross-talk between autophagy and pyroptosis in doxorubicin-treated human melanoma cells in vitro显示文摘Eukaryotic elongation factor-2 kinase (eEF-2K), a negative regulator of protein synthesis, has been shown to play an important role in modulating autophagy and apoptosis in tumor cells under various stresses. In this study, we investigated the regulatory role of eEF-2K in pyroptosis (a new form of programmed necrosis) in doxorubicin-treated human melanoma cells. We found that doxorubicin (0.5-5 μmol/L) induced pyroptosis in melanoma cell lines SK-MEL-5, SK-MEL-28, and A-375 with high expression of DFNA5, but not in human breast cancer cell line MCF-7 with little expression of DFNA5. On the other hand, doxorubicin treatment activated autophagy in the melanoma cells;inhibition of autophagy by transfecting the cells with siRNA targeting Beclin1 or by pretreatment with chloroquine (20 μmol/L) significantly augmented pyroptosis, thus sensitizing the melanoma cells to doxorubicin. We further demonstrated that doxorubicin treatment activated eEF-2K in the melanoma cells, and silencing of eEF-2K blunted autophagic responses, but promoted doxorubicin-induced pyroptotic cell death. Taken together, the above results demonstrate that eEF-2K dictates the cross-talk between pyroptosis and autophagy in doxorubicin-treated human melanoma cells;suppression of eEF-2K results in inhibiting autophagy and augmenting pyroptosis, thus modulating the sensitivity of melanoma cells to doxorubicin, suggesting that targeting eEF-2K may reinforce the antitumor ef?cacy of doxorubicin, offering a new insight into tumor chemotherapy. | Pian Yu Hai-yan Wang Min Tian Ao-xue Li Xi-sha Chen Xin-luan Wang Yi Zhang Yan Cheng | 2019 | Acta Pharmacologica Sinica2019，40，9： | 19 |
| 9 | Programmed cell death and its role in inflammation显示文摘Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases. | Yong Yang Ge-Ning Jiang Peng Zhang Jie Fan | 2015 | Journal of Medical Colleges of PLA(China)2015，30，2： | 17 |
| 10 | Kanglexin,a novel anthraquinone compound,protects against myocardial ischemic injury in mice by suppressing NLRP3 and pyroptosis显示文摘Pyroptosis is a form of inflammatory cell death that could be driven by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inflammasome activation following myocardial infarction(MI).Emerging evidence suggests the therapeutic potential for ameliorating MI-induced myocardial damages by targeting NLRP3 and pyroptosis.In this study,we investigated the myocardial protection effect of a novel anthraquinone compound(4,5-dihydroxy-7-methyl-9,10-anthraquinone-2-ethyl succinate)named Kanglexin(KLX)in vivo and in vitro.Male C57BL/6 mice were pre-treated either with KLX(20,40 mg·kg^?1per day,intragastric gavage)or vehicle for 7 consecutive days prior to ligation of coronary artery to induce permanent MI.KLX administration dose-dependently reduced myocardial infarct size and lactate dehydrogenase release and improved cardiac function as compared to vehicle-treated mice 24 h after MI.We found that MI triggered NLRP3 inflammasome activation leading to conversion of interleukin-1β(IL-1β)and IL-18 into their active mature forms in the heart,which could expand the infarct size and drive cardiac dysfunction.We also showed that MI induced pyroptosis,as evidenced by increased DNA fragmentation,mitochondrial swelling,and cell membrane rupture,as well as increased levels of pyroptosis-related proteins,including gasdermin D,N-terminal GSDMD,and cleaved caspase-1.All these detrimental alterations were prevented by KLX.In hypoxia-or lipopolysaccharide(LPS)-treated neonatal mouse ventricular cardiomyocytes,we showed that KLX(10μM)decreased the elevated levels of terminal deoxynucleotidyl transferase dUTP nick end labeling-and propidium iodide-positive cells,and pyroptosis-related proteins.We conclude that KLX prevents MI-induced cardiac damages and cardiac dysfunction at least partly through attenuating NLRP3 and subsequent cardiomyocyte pyroptosis,and it is worthy of more rigorous investigations for its potential for alleviating ischemic heart disease. | Yu Bian Xin Li Ping Pang Xue-ling Hu Shu-ting Yu Yi-ning Liu Xin Li Ning Wang Jin-hui Wang Wei Xiao Wei-jie Du Bao-feng Yang | 2020 | Acta Pharmacologica Sinica2020，41，3： | 15 |
| 11 | Exosomes derived from bone marrow mesenchymal stem cells protect the injured spinal cord by inhibiting pericyte pyroptosis显示文摘Mesenchymal stem cell(MSC)transplantation is a promising treatment strategy for spinal cord injury,but immunological rejection and possible tumor formation limit its application.The therapeutic effects of MSCs mainly depend on their release of soluble paracrine factors.Exosomes are essential for the secretion of these paracrine effectors.Bone marrow mesenchymal stem cell-derived exosomes(BMSC-EXOs)can be substituted for BMSCs in cell transplantation.However,the underlying mechanisms remain unclear.In this study,a rat model of T10 spinal cord injury was established using the impact method.Then,30 minutes and 1 day after spinal cord injury,the rats were administered 200μL exosomes via the tail vein(200μg/mL;approximately 1×106 BMSCs).Treatment with BMSC-EXOs greatly reduced neuronal cell death,improved myelin arrangement and reduced myelin loss,increased pericyte/endothelial cell coverage on the vascular wall,decreased bloodspinal cord barrier leakage,reduced caspase 1 expression,inhibited interleukin-1βrelease,and accelerated locomotor functional recovery in rats with spinal cord injury.In the cell culture experiment,pericytes were treated with interferon-γand tumor necrosis factor-α.Then,Lipofectamine 3000 was used to deliver lipopolysaccharide into the cells,and the cells were co-incubated with adenosine triphosphate to simulate injury in vitro.Pre-treatment with BMSC-EXOs for 8 hours greatly reduced pericyte pyroptosis and increased pericyte survival rate.These findings suggest that BMSC-EXOs may protect pericytes by inhibiting pyroptosis and by improving blood-spinal cord barrier integrity,thereby promoting the survival of neurons and the extension of nerve fibers,and ultimately improving motor function in rats with spinal cord injury.All protocols were conducted with the approval of the Animal Ethics Committee of Zhengzhou University on March 16,2019. | Yan Zhou Lu-Lu Wen Yan-Fei Li Kai-Min Wu Ran-Ran Duan Yao-Bing Yao Li-Jun Jing Zhe Gong Jun-Fang Teng Yan-Jie Jia | 2022 | Neural Regeneration Research2022，17，1： | 15 |
| 12 | Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies显示文摘Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases. | Wei-Tao Yan Yan-Di Yang Xi-Min Hu Wen-Ya Ning Lyu-Shuang Liao Shuang Lu Wen-Juan Zhao Qi Zhang Kun Xiong | 2022 | Neural Regeneration Research2022，17，8： | 15 |
| 13 | Punicalagin ameliorates collagen-induced arthritis by downregulating M1 macrophage and pyroptosis via NF-κB signaling pathway显示文摘Rheumatoid arthritis(RA)is a chronic inflammatory disease that eventually leads to disability.Inflammatory cell infiltration,severe joint breaking and systemic bone loss are the main clinical symptoms.In this study,we established a collagen-induced arthritis(CIA)model and found a large number of M1 macrophages and pyroptosis,which are important sources of proinflammatory cytokines.Punicalagin(PUN)is an active substance extracted from pomegranate peel.We found that it inhibited joint inflammation,cartilage damage and systemic bone destruction in CIA mice.PUN effectively alleviated the high expression of inflammatory cytokines in synovial tissue in vivo.PUN treatment shifted macrophages from the M1 phenotype to the M2 phenotype after stimulation with lipopolysaccharide(LPS)and interferon(IFN)-γ.The expression of inducible nitric oxide synthase(i NOS)and other proinflammatory cytokines released by M1 macrophages was decreased in the PUN treatment group.However,simultaneously,the expression of markers of anti-inflammatory M2 macrophages,such as arginase(Arg)-1 and interleukin(IL)-10,was increased.In addition,PUN treatment attenuated pyroptosis by downregulating the expression of NLRP3 and caspase-1,thereby preventing inflammatory cell death resulting from the release of IL-1βand IL-18.Mechanistically,PUN inhibited the activation of receptor activators of the nuclear factor-κB(NF-κB)signaling pathway,which contributes to M1 polarization and pyroptosis of macrophages.We concluded that PUN ameliorated pathological inflammation by inhibiting M1 phenotype polarization and pyroptosis and has great potential as a therapeutic treatment for human RA. | Gaoran Ge Jiaxiang Bai Qing Wang Xiaolong Liang Huaqiang Tao Hao Chen Minggang Wei Junjie Niu Huilin Yang Yaozeng Xu Yuefeng Hao Yi Xue Dechun Geng | 2022 | Science China(Life Sciences)2022，65，3： | 14 |
| 14 | Role of pyroptosis in inflammation and cancer显示文摘Pyroptosis is a form of programmed cell death mediated by gasdermin and is a product of continuous cell expansion until the cytomembrane ruptures,resulting in the release of cellular contents that can activate strong inflammatory and immune responses.Pyroptosis,an innate immune response,can be triggered by the activation of inflammasomes by various influencing factors.Activation of these inflammasomes can induce the maturation of caspase-1 or caspase-4/5/11,both of which cleave gasdermin D to release its N-terminal domain,which can bind membrane lipids and perforate the cell membrane.Here,we review the latest advancements in research on the mechanisms of pyroptosis,newly discovered influencing factors,antitumoral properties,and applications in various diseases.Moreover,this review also provides updates on potential targeted therapies for inflammation and cancers,methods for clinical prevention,and finally challenges and future directions in the field. | Xiang Wei Feng Xie Xiaoxue Zhou Yuchen Wu Haiyan Yan Ting Liu Jun Huang Fangwei Wang Fangfang Zhou Long Zhang | 2022 | Cellular & Molecular Immunology2022，19，9： | 11 |
| 15 | C1q和肿瘤坏死因子相关蛋白4(CTRP4)降低子痫前期大鼠滋养层细胞的caspase-1和IL-1β水平显示文摘目的探讨C1q和肿瘤坏死因子相关蛋白4(CTRP4)对子痫前期大鼠胎盘滋养层细胞的影响。方法构建子痫前期大鼠模型,采集正常孕鼠和模型大鼠胎盘滋养层组织,运用实时定量PCR和Western blot法检测CTRP4、白细胞介素1β(IL-1β)和caspase-1 mRNA和蛋白表达水平;分离培养正常孕鼠和模型鼠滋养层细胞,在不同时间点,运用流式细胞术检测碘化丙啶和caspase-1双阳性(PI+caspase-1+)细胞(pyroptosis),运用实时定量PCR和Western blot法检测IL-1β和caspase-1表达水平;在模型大鼠滋养层细胞培养基中分别加入(0.5、5、15、25、50)ng/m L CTRP4重组蛋白或(10、20)ng/m L CTRP4蛋白中和抗体,处理72 h后检测pyroptosis细胞数目和caspase-1、IL-1β水平。结果子痫前期大鼠胎盘滋养层组织caspase-1、IL-1β表达增强,CTRP4表达水平下调;CTRP4重组蛋白处理体外培养的大鼠滋养层细胞可显著减少PI+caspase-1+细胞数量并降低caspase-1、IL-1β水平,而CTRP4蛋白中和抗体处理显著增加PI+caspase-1+细胞数量并增强炎症反应。结论 CTRP4可显著抑制caspase-1/IL-1β炎症调节通路的活性,并抑制子娴前期大鼠胎盘滋养层细胞的pyroptosis。 | 段利利 刘子冬 王林 马斌芳 范忆冰 徐莹 郭芬芬 | 2016 | 细胞与分子免疫学杂志2016，32，11： | 9 |
| 16 | TP53-induced glycolysis and apoptosis regulator alleviates hypoxia/ischemia-induced microglial pyroptosis and ischemic brain damage显示文摘Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator(TIGAR)can protect neurons after cerebral ischemia/reperfusion.However,the role of TIGAR in neonatal hypoxic-ischemic brain damage(HIBD)remains unknown.In the present study,7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia.At 6 days before induction of HIBD,a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D(LV-sh_TIGAR or LV-sh_GSDMD)was injected into the left lateral ventricle and striatum.Highly aggressively proliferating immortalized(HAPI)microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation.Three days before in vitro HIBD induction,HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD.Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Lentivirusmediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro.Application of exogenous nicotinamide adenine dinucleotide phosphate(NADPH)increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation.Additionally,exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro.These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD.The study was approved by the Animal Ethics Committee of Soochow University of China(approval No.2017LW003)in 2017. | Lan-Lan Tan Xiao-Lu Jiang Li-Xiao Xu Gen Li Chen-Xi Feng Xin Ding Bin Sun Zheng-Hong Qin Zu-Bin Zhang Xing Feng Mei Li | 2021 | Neural Regeneration Research2021，16，6： | 9 |
| 17 | Sirt1-ROS-TRAF6 Signaling-Induced Pyroptosis Contributes to Early Injury in Ischemic Mice显示文摘Stroke is an acute cerebro-vascular disease with high incidence and poor prognosis,most commonly ischemic in nature.In recent years,increasing attention has been paid to inflammatory reactions as symptoms of a stroke.However,the role of inflammation in stroke and its underlying mechanisms require exploration.In this study,we evaluated the inflammatory reactions induced by acute ischemia and found that pyroptosis occurred after acute ischemia both in vivo and in vitro,as determined by interleukin-1β,apoptosis-associated speck-like protein,and caspase-1.The early inflammation resulted in irreversible ischemic injury,indicating that it deserves thorough investigation.Meanwhile,acute ischemia decreased the Sirtuin 1(Sirtl)protein levels,and increased the TRAF6(TNF receptor associated factor 6)protein and reactive oxygen species(ROS)levels.In further exploration,both Sirtl suppression and TRAF6 activation were found to contribute to this pyroptosis.Reduced Sirtl levels were responsible for the production of ROS and increased TRAF6 protein levels after ischemic exposure.Moreover,N-acetyl-L-cysteine,an ROS scavenger,suppressed the TRAF6 accumulation induced by oxygen-glucose deprivation via suppression of ROS bursts.These phenomena indicate that Sirtl is upstream of ROS,and ROS bursts result in increased TRAF6 levels.Further,the activation of Sirtl during the period of ischemia reduced ischemiainduced injury after 72 h of reperfusion in mice with middle cerebral artery occlusion.In sum,these results indicate that pyroptosis-dependent machinery contributes to the neural injury during acute ischemia via the Sirt1-ROS-TRAF6 signaling pathway.We propose that inflammatory reactions occur soon after oxidative stress and are detrimental to neuronal survival;this provides a promising therapeutic target against ischemic injuries such as a stroke. | Weijie Yan Wei Sun Jiahui Fan Haiqing Wang Song Han Junfa Li Yanling Yin | 2020 | Neuroscience Bulletin2020，36，8： | 9 |
| 18 | Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy显示文摘Diabetic mellitus(DM) is a common degenerative chronic metabolic disease often accompanied by severe cardiovascular complications(DCCs) as major causes of death in diabetic patients with diabetic cardiomyopathy(DCM) as the most common DCC. The metabolic disturbance in DCM generates the conditions/substrates and inducers/triggers and activates the signaling molecules and death executioners leading to cardiomyocyte death which accelerates the development of DCM and the degeneration of DCM to heart failure.Various forms of programmed active cell death including apoptosis, pyroptosis, autophagic cell death, autosis,necroptosis, ferroptosis and entosis have been identified and characterized in many types of cardiac disease.Evidence has also been obtained for the presence of multiple forms of cell death in DCM. Most importantly,published animal experiments have demonstrated that suppression of cardiomyocyte death of any forms yields tremendous protective effects on DCM. Herein, we provide the most updated data on the subject of cell death in DCM, critical analysis of published results focusing on the pathophysiological roles of cell death, and pertinent perspectives of future studies. | Jinjing Wei Yongting Zhao Haihai Liang Weijie Du Lihong Wang | 2022 | Acta Pharmaceutica Sinica B2022，12，1： | 8 |
| 19 | Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure显示文摘Programmed cell death(PCD),including apoptosis,apoptotic necrosis,and pyroptosis,is involved in various organ dysfunction syndromes.Recent studies have revealed that a substrate of caspase-3,gasdermin E(GSDME),functions as an effector for pyroptosis;however,few inhibitors have been reported to prevent pyroptosis mediated by GSDME.Here,we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD.Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity,exhibiting a lower IC50 than that of Z-DEVD-FMK.Functionally,Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3,preventing apoptotic and pyroptotic events in hepatocytes and macrophages.Furthermore,in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure,Ac-DMPD/DMLD-CMK significantly alleviated liver injury.Together,this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also,more importantly,shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD. | Wan-feng Xu Quan Zhang Chu-jie Ding Hui-yong Sun Yuan Che Hai Huang Yun Wang Jia-wei Wu Hai-ping Hao Li-juan Cao | 2021 | Acta Pharmacologica Sinica2021，42，1： | 7 |
| 20 | L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling显示文摘Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy.L-carnitine(LC)has been shown to protect against various types of renal injury.In this study,we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus(TAC)nephropathy.SD rats were injected with TAC(1.5 mg·kg^(−1)·d^(−1),sc)for 4 weeks.Renoprotective effects of LC were assessed in terms of renal function,histopathology,oxidative stress,expression of inflammatory and fibrotic cytokines,programmed cell death(pyroptosis,apoptosis,and autophagy),mitochondrial function,and PI3K/AKT/PTEN signaling.Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy.At a molecular level,TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney,induced oxidative stress,and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN.Coadministration of LC(200 mg·kg^(−1)·d^(−1),ip)caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats.Furthermore,LC exerted anti-inflammatory and antioxidant effects,prevented mitochondrial dysfunction,and modulated the expression of a series of apoptosis-and autophagy-controlling genes to promote cell survival.Human kidney proximal tubular epithelial cells(HK-2 cells)were treated with TAC(50μg/mL)in vitro,which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death(pyroptosis,apoptosis,and autophagy)through interfering with PI3K/AKT/PTEN signaling.The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002(25μM).In conclusion,LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling. | Hai-lan Zheng Hai-yue Zhang Chun-lian Zhu Hui-ying Li Sheng Cui Jian Jin Shang-guo Piao Yu-ji Jiang Mei-ying Xuan Ji-zhe Jin Ying-shun Jin Jung-pyo Lee Byung-ha Chung Bum-soon Choi Chul-woo Yang Can Li | 2021 | Acta Pharmacologica Sinica2021，42，1： | 7 |
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