<strong>Background: </strong>Pyroptosis is defined as programmed necrosis executed by gasdermin D or E (GSDMD or GSDME), which punches cellular membrane. Morphologically, pyroptosis is characterized by cel...<strong>Background: </strong>Pyroptosis is defined as programmed necrosis executed by gasdermin D or E (GSDMD or GSDME), which punches cellular membrane. Morphologically, pyroptosis is characterized by cell swelling and cell membrane rupture, leading to the release of cellular contents that triggers intense inflammatory response. More and more studies have found that pyroptosis may be involved in the pathogenesis of viral infection, which may be a determinant for inflammation observed in most viral diseases. <strong>Objective:</strong> This paper aims to summarize the roles of pyroptosis in the pathogenesis of viral infectious diseases and to provide potential drug targets for the treatment of viral diseases, which will contribute to medical research and public health. <strong>Measures:</strong> This paper mainly summarizes pyroptosis occurring in diseases caused by different viruses, including human immunodeficiency virus, hepatitis virus, enterovirus, influenza virus and dengue fever virus. Meanwhile, the reported mechanism underlying pyroptosis mediating pathogenesis of these viral diseases will also be described. <strong>Conclusion:</strong> Current studies have shown that pyroptosis is a double-edged sword in viral infectious diseases. On one hand, pyroptosis leads to pathogenic inflammation of many viral infectious diseases which aggravate tissue damage initiated by viral infection, and blocking proptosis usually relieves the inflammation, which exerts therapeutic effects on viral diseases. On the other hand, moderating pyroptosis can contribute to defense against pathogen infection by releasing immune epitopes and inducing antiviral immune response.展开更多
Inflammatory bowel disease(IBD)is a chronic relapsing gastrointestinal disorder,while the treatment effect is not satisfactory.Immune responsive gene 1(IRG1)is a highly ex-pressed gene in macrophage in response to inf...Inflammatory bowel disease(IBD)is a chronic relapsing gastrointestinal disorder,while the treatment effect is not satisfactory.Immune responsive gene 1(IRG1)is a highly ex-pressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate.Studies have reported that IRG1/itaconate has a significant antioxidant effect.This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate so-dium(DSS)-induced colitis in vivo and in vitro.In vivo experiments,we found IRG1/itaconate ex-erted protective effects against acute colitis by increasing mice weight,the length of colon,reducing disease activity index and colonic inflammation.Meanwhile,IRG1 deletion aggravated the macrophages/CD4+/CD8+T-cell accumulation,and increased the release of interleukin(IL)-1b,tumor necrosis factor-a(TNF-a),IL-6,the activation of nuclear factor-kB(NF-kB)/mitogen-activated protein kinase(MAPK)signaling pathway,and gasdermin D(GSDMD)mediated pyrop-tosis.Four-octyl itaconate(4-OI),a derivative of itaconate,attenuated these changes,therefore relieved DSS-induced colitis.In vitro experiment,we found 4-OI inhibited the reactive oxygen species production,thereby inhibiting the activation of MAPK/NF-kB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages.Simultaneously,we found 4-OI inhib-ited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines.Finally,we found anti-TNF-a agent reduced the severity of DSS-induced colitis and inhibited gasdermin E(GSDME)-mediated pyroptosis in vivo.Meanwhile,our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-a in vitro.Taken together,IRG1/itaconate exerted a pro-tective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-medi-ated pyroptosis,which could be a promising candidate for IBD therapy.展开更多
It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E(GSDME)-deficient cells,but pyroptosis in GSDME-sufficient cells.The high GSDME expression and apoptosis resistance of pancreatic ducta...It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E(GSDME)-deficient cells,but pyroptosis in GSDME-sufficient cells.The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma(PDAC)cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis.Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC.This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs.Based on this system,ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds.Concretely,they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells.Further,we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis via caspase-3/GSDME pathway both in vitro and in vivo.Collectively,this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.展开更多
细胞焦亡是细胞促炎程序性死亡,其强弱程度依赖于胱天蛋白酶(Caspases)活性。Caspases通过切割Gasdermin家族蛋白使其形成无活性的C端片段和有活性的N端片段,后者移位到膜上并形成穿孔,导致水分渗透和细胞肿胀并释放炎性因子,继而引发...细胞焦亡是细胞促炎程序性死亡,其强弱程度依赖于胱天蛋白酶(Caspases)活性。Caspases通过切割Gasdermin家族蛋白使其形成无活性的C端片段和有活性的N端片段,后者移位到膜上并形成穿孔,导致水分渗透和细胞肿胀并释放炎性因子,继而引发细胞焦亡。细胞焦亡的不同信号通路机制在各类疾病的发生发展过程中发挥着重要作用。多糖作为生物大分子对细胞核因子-κB、核苷酸结合寡聚化结构域样受体蛋白3(NOD-like receptor protein 3,NLRP3)及活性氧等信号分子均具有调节作用。但多糖能否通过影响相关信号通路达到抑制或激活细胞焦亡的作用有待进一步研究。本文综述细胞焦亡相关信号通路、细胞焦亡在疾病中的作用及多糖在细胞焦亡信号通路调节中的作用,旨在对多糖在细胞焦亡中的潜在作用进行探讨,为进一步开发功能性多糖提供新的思路。展开更多
文摘<strong>Background: </strong>Pyroptosis is defined as programmed necrosis executed by gasdermin D or E (GSDMD or GSDME), which punches cellular membrane. Morphologically, pyroptosis is characterized by cell swelling and cell membrane rupture, leading to the release of cellular contents that triggers intense inflammatory response. More and more studies have found that pyroptosis may be involved in the pathogenesis of viral infection, which may be a determinant for inflammation observed in most viral diseases. <strong>Objective:</strong> This paper aims to summarize the roles of pyroptosis in the pathogenesis of viral infectious diseases and to provide potential drug targets for the treatment of viral diseases, which will contribute to medical research and public health. <strong>Measures:</strong> This paper mainly summarizes pyroptosis occurring in diseases caused by different viruses, including human immunodeficiency virus, hepatitis virus, enterovirus, influenza virus and dengue fever virus. Meanwhile, the reported mechanism underlying pyroptosis mediating pathogenesis of these viral diseases will also be described. <strong>Conclusion:</strong> Current studies have shown that pyroptosis is a double-edged sword in viral infectious diseases. On one hand, pyroptosis leads to pathogenic inflammation of many viral infectious diseases which aggravate tissue damage initiated by viral infection, and blocking proptosis usually relieves the inflammation, which exerts therapeutic effects on viral diseases. On the other hand, moderating pyroptosis can contribute to defense against pathogen infection by releasing immune epitopes and inducing antiviral immune response.
基金supported by the National Natural Science Foundation of China(No.81701883,82072736,82172171)。
文摘Inflammatory bowel disease(IBD)is a chronic relapsing gastrointestinal disorder,while the treatment effect is not satisfactory.Immune responsive gene 1(IRG1)is a highly ex-pressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate.Studies have reported that IRG1/itaconate has a significant antioxidant effect.This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate so-dium(DSS)-induced colitis in vivo and in vitro.In vivo experiments,we found IRG1/itaconate ex-erted protective effects against acute colitis by increasing mice weight,the length of colon,reducing disease activity index and colonic inflammation.Meanwhile,IRG1 deletion aggravated the macrophages/CD4+/CD8+T-cell accumulation,and increased the release of interleukin(IL)-1b,tumor necrosis factor-a(TNF-a),IL-6,the activation of nuclear factor-kB(NF-kB)/mitogen-activated protein kinase(MAPK)signaling pathway,and gasdermin D(GSDMD)mediated pyrop-tosis.Four-octyl itaconate(4-OI),a derivative of itaconate,attenuated these changes,therefore relieved DSS-induced colitis.In vitro experiment,we found 4-OI inhibited the reactive oxygen species production,thereby inhibiting the activation of MAPK/NF-kB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages.Simultaneously,we found 4-OI inhib-ited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines.Finally,we found anti-TNF-a agent reduced the severity of DSS-induced colitis and inhibited gasdermin E(GSDME)-mediated pyroptosis in vivo.Meanwhile,our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-a in vitro.Taken together,IRG1/itaconate exerted a pro-tective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-medi-ated pyroptosis,which could be a promising candidate for IBD therapy.
基金financially supported by the National Natural Science Foundation of China(No.82174100)the National Key R&D Program of China(No.2022YFC3501601)。
文摘It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E(GSDME)-deficient cells,but pyroptosis in GSDME-sufficient cells.The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma(PDAC)cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis.Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC.This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs.Based on this system,ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds.Concretely,they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells.Further,we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis via caspase-3/GSDME pathway both in vitro and in vivo.Collectively,this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.
文摘细胞焦亡是细胞促炎程序性死亡,其强弱程度依赖于胱天蛋白酶(Caspases)活性。Caspases通过切割Gasdermin家族蛋白使其形成无活性的C端片段和有活性的N端片段,后者移位到膜上并形成穿孔,导致水分渗透和细胞肿胀并释放炎性因子,继而引发细胞焦亡。细胞焦亡的不同信号通路机制在各类疾病的发生发展过程中发挥着重要作用。多糖作为生物大分子对细胞核因子-κB、核苷酸结合寡聚化结构域样受体蛋白3(NOD-like receptor protein 3,NLRP3)及活性氧等信号分子均具有调节作用。但多糖能否通过影响相关信号通路达到抑制或激活细胞焦亡的作用有待进一步研究。本文综述细胞焦亡相关信号通路、细胞焦亡在疾病中的作用及多糖在细胞焦亡信号通路调节中的作用,旨在对多糖在细胞焦亡中的潜在作用进行探讨,为进一步开发功能性多糖提供新的思路。
