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
BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple b...BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple biological processes,including cellular senescence,apoptosis,sugar and lipid metabolism,oxidative stress,and inflammation.AIM To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.METHODS This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)testing.C57BL/6 mice were also intraperitoneally pretreated with SIRT1,p53,or glutathione peroxidase 4(GPX4)inducers and inhibitors and injected with lipopolysaccharide(LPS)/D-galactosamine(D-GalN)to induce ALF.Gasdermin D(GSDMD)^(-/-)mice were used as an experimental group.Histological changes in liver tissue were monitored by hematoxylin and eosin staining.ALT,AST,glutathione,reactive oxygen species,and iron levels were measured using commercial kits.Ferroptosis-and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction.SIRT1,p53,and GSDMD were assessed by immunofluorescence analysis.RESULTS Serum AST and ALT levels were elevated in patients with ALF.SIRT1,solute carrier family 7a member 11(SLC7A11),and GPX4 protein expression was decreased and acetylated p5,p53,GSDMD,and acyl-CoA synthetase long-chain family member 4(ACSL4)protein levels were elevated in human ALF liver tissue.In the p53 and ferroptosis inhibitor-treated and GSDMD^(-/-)groups,serum interleukin(IL)-1β,tumour necrosis factor alpha,IL-6,IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated.In mice with GSDMD knockout,p53 was reduced,GPX4 was increased,and ferroptotic events(depletion of SLC7A11,elevation of ACSL4,and iron accumulation)were detected.In vitro,knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels,the cytostatic rate,and GSDMD expression,restoring SLC7A11 depletion.Moreover,SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group,accompanied by reduced p53,GSDMD,and ACSL4,and increased SLC7A11 and GPX4.Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalNinduced in vitro and in vivo models.CONCLUSION SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.展开更多
In this editorial we comment on the article published in a recent issue of the World Journal of Gastroenterology.Acute liver failure(ALF)is a critical condition characterized by rapid hepatocellular injury and organ d...In this editorial we comment on the article published in a recent issue of the World Journal of Gastroenterology.Acute liver failure(ALF)is a critical condition characterized by rapid hepatocellular injury and organ dysfunction,and it often necessitates liver transplant to ensure patient survival.Recent research has eluci-dated the involvement of distinct cell death pathways,namely ferroptosis and pyroptosis,in the pathogenesis of ALF.Ferroptosis is driven by iron-dependent lipid peroxidation,whereas pyroptosis is an inflammatory form of cell death;both pathways contribute to hepatocyte death and exacerbate tissue damage.This comprehensive review explores the interplay between ferroptosis and pyroptosis in ALF,highlighting the role of key regulators such as silent information regulator sirtuin 1.Insights from clinical and preclinical studies provide valuable perspectives on the dysregulation of cell death pathways in ALF and the therapeutic potential of targeting these pathways.Collaboration across multiple disciplines is essential for translating the experimental insights into effective treatments for this life-threatening condition.展开更多
In this editorial,we comment on the article by Zhou et al published in a recent issue.We specifically focus on the crucial roles of ferroptosis and pyroptosis in acute liver failure(ALF),a disease with high mortality ...In this editorial,we comment on the article by Zhou et al published in a recent issue.We specifically focus on the crucial roles of ferroptosis and pyroptosis in acute liver failure(ALF),a disease with high mortality rates.Ferroptosis is the result of increased intracellular reactive oxygen species due to iron accumulation,glutathione(GSH)depletion,and decreased GSH peroxidase 4 activity,while pyroptosis is a procedural cell death mediated by gasdermin D which initiates a sustained inflammatory process.In this review,we describe the characteristics of ferroptosis and pyroptosis,and discuss the involvement of the two cell death modes in the onset and development of ALF.Furthermore,we summarize several interfering methods from the perspective of ferroptosis and pyroptosis for the alleviation of ALF.These observations might provide new targets and a theoretical basis for the treatment of ALF,which are also crucial for improving the prognosis of patients with ALF.展开更多
In this editorial,we comment on the article by Zhou et al.The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1(SIRT1)activation in acute liver fa...In this editorial,we comment on the article by Zhou et al.The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1(SIRT1)activation in acute liver failure(ALF).ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage,often posing a high risk of mortality.The predominant form of hepatic cell death in ALF involves apoptosis,ferroptosis,autophagy,pyroptosis,and necroptosis.Glutathione peroxidase 4(GPX4)inhibition sensitizes the cell to ferroptosis and triggers cell death,while Gasdermin D(GSDMD)is a mediator of pyroptosis.The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway,bridging the gap between the two processes.The inhibition of p53 elevates the levels of GPX4,reducing the levels of inflammatory and liver injury markers,ferroptotic events,and GSDMDN protein levels.Reduced p53 expression and increased GPX4 on deletion of GSDMD indicated ferroptosis and pyroptosis interaction.SIRT1 is a NAD-dependent deacetylase,and its activation attenuates liver injury and inflammation,accompanied by reduced ferroptosis and pyroptosis-related proteins in ALF.SIRT1 activation also inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation,attenuating LPS/D-GalN-induced ALF.展开更多
In this editorial,we comment on the article published in the recent issue of the World Journal of Gastroenterology.Acute liver failure(ALF)is a fatal disease that causes uncontrolled massive hepatocyte death and rapid...In this editorial,we comment on the article published in the recent issue of the World Journal of Gastroenterology.Acute liver failure(ALF)is a fatal disease that causes uncontrolled massive hepatocyte death and rapid loss of liver function.Ferroptosis and pyroptosis,cell death forms that can be initiated or blocked concurrently,can play significant roles in developing inflammation and various malignancies.However,their roles in ALF remain unclear.The article discovered the positive feedback between ferroptosis and pyroptosis in the progression of ALF,and revealed that the silent information regulator sirtuin 1(SIRT1)inhibits both pathways through p53,dramatically reducing inflammation and protecting hepatocytes.This suggests the potential use of SIRT1 and its downstream molecules as therapeutics for ALF.Thus,we will discuss the role of ferroptosis and pyroptosis in ALF and the crosstalk between these cell death mechanisms.Additionally,we address potential treatments that could alleviate ALF by simultaneously inhibiting both cell death pathways,as well as examples of SIRT1 activators being used as disease treatment strategies,providing new insights into the therapy of ALF.展开更多
Sepsis is a life-threatening disease of organ failure caused by dysregulated host responses to infection and other infectious factors.Multi-organ injury is the leading cause of high mortality and septic shock during s...Sepsis is a life-threatening disease of organ failure caused by dysregulated host responses to infection and other infectious factors.Multi-organ injury is the leading cause of high mortality and septic shock during sepsis.Recent studies suggest that noncanonical pyroptosis,characterized mainly by the direct activation of caspase-11-gasdermin D-mediated pyroptosis by cytoplastic lipopolysaccharide,is closely related to sepsis-related organ injury.Here,this review summarizes recent advances in the regulatory mechanisms and targeted natural products from traditional Chinese medicine of the noncanonical pyroptosis pathway in sepsis-related injury.展开更多
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Supported by National Natural Science Foundation of China,No.82060123Doctoral Start-up Fund of Affiliated Hospital of Guizhou Medical University,No.gysybsky-2021-28+1 种基金Fund Project of Guizhou Provincial Science and Technology Department,No.[2020]1Y299Guizhou Provincial Health Commission,No.gzwjk2019-1-082。
文摘BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple biological processes,including cellular senescence,apoptosis,sugar and lipid metabolism,oxidative stress,and inflammation.AIM To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.METHODS This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)testing.C57BL/6 mice were also intraperitoneally pretreated with SIRT1,p53,or glutathione peroxidase 4(GPX4)inducers and inhibitors and injected with lipopolysaccharide(LPS)/D-galactosamine(D-GalN)to induce ALF.Gasdermin D(GSDMD)^(-/-)mice were used as an experimental group.Histological changes in liver tissue were monitored by hematoxylin and eosin staining.ALT,AST,glutathione,reactive oxygen species,and iron levels were measured using commercial kits.Ferroptosis-and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction.SIRT1,p53,and GSDMD were assessed by immunofluorescence analysis.RESULTS Serum AST and ALT levels were elevated in patients with ALF.SIRT1,solute carrier family 7a member 11(SLC7A11),and GPX4 protein expression was decreased and acetylated p5,p53,GSDMD,and acyl-CoA synthetase long-chain family member 4(ACSL4)protein levels were elevated in human ALF liver tissue.In the p53 and ferroptosis inhibitor-treated and GSDMD^(-/-)groups,serum interleukin(IL)-1β,tumour necrosis factor alpha,IL-6,IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated.In mice with GSDMD knockout,p53 was reduced,GPX4 was increased,and ferroptotic events(depletion of SLC7A11,elevation of ACSL4,and iron accumulation)were detected.In vitro,knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels,the cytostatic rate,and GSDMD expression,restoring SLC7A11 depletion.Moreover,SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group,accompanied by reduced p53,GSDMD,and ACSL4,and increased SLC7A11 and GPX4.Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalNinduced in vitro and in vivo models.CONCLUSION SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.
基金Supported by China Medical University,No.CMU111-MF-10.
文摘In this editorial we comment on the article published in a recent issue of the World Journal of Gastroenterology.Acute liver failure(ALF)is a critical condition characterized by rapid hepatocellular injury and organ dysfunction,and it often necessitates liver transplant to ensure patient survival.Recent research has eluci-dated the involvement of distinct cell death pathways,namely ferroptosis and pyroptosis,in the pathogenesis of ALF.Ferroptosis is driven by iron-dependent lipid peroxidation,whereas pyroptosis is an inflammatory form of cell death;both pathways contribute to hepatocyte death and exacerbate tissue damage.This comprehensive review explores the interplay between ferroptosis and pyroptosis in ALF,highlighting the role of key regulators such as silent information regulator sirtuin 1.Insights from clinical and preclinical studies provide valuable perspectives on the dysregulation of cell death pathways in ALF and the therapeutic potential of targeting these pathways.Collaboration across multiple disciplines is essential for translating the experimental insights into effective treatments for this life-threatening condition.
文摘In this editorial,we comment on the article by Zhou et al published in a recent issue.We specifically focus on the crucial roles of ferroptosis and pyroptosis in acute liver failure(ALF),a disease with high mortality rates.Ferroptosis is the result of increased intracellular reactive oxygen species due to iron accumulation,glutathione(GSH)depletion,and decreased GSH peroxidase 4 activity,while pyroptosis is a procedural cell death mediated by gasdermin D which initiates a sustained inflammatory process.In this review,we describe the characteristics of ferroptosis and pyroptosis,and discuss the involvement of the two cell death modes in the onset and development of ALF.Furthermore,we summarize several interfering methods from the perspective of ferroptosis and pyroptosis for the alleviation of ALF.These observations might provide new targets and a theoretical basis for the treatment of ALF,which are also crucial for improving the prognosis of patients with ALF.
文摘In this editorial,we comment on the article by Zhou et al.The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1(SIRT1)activation in acute liver failure(ALF).ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage,often posing a high risk of mortality.The predominant form of hepatic cell death in ALF involves apoptosis,ferroptosis,autophagy,pyroptosis,and necroptosis.Glutathione peroxidase 4(GPX4)inhibition sensitizes the cell to ferroptosis and triggers cell death,while Gasdermin D(GSDMD)is a mediator of pyroptosis.The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway,bridging the gap between the two processes.The inhibition of p53 elevates the levels of GPX4,reducing the levels of inflammatory and liver injury markers,ferroptotic events,and GSDMDN protein levels.Reduced p53 expression and increased GPX4 on deletion of GSDMD indicated ferroptosis and pyroptosis interaction.SIRT1 is a NAD-dependent deacetylase,and its activation attenuates liver injury and inflammation,accompanied by reduced ferroptosis and pyroptosis-related proteins in ALF.SIRT1 activation also inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation,attenuating LPS/D-GalN-induced ALF.
基金Supported by The Hubei Provincial Natural Science Foundation of China,No.2020CFB656.
文摘In this editorial,we comment on the article published in the recent issue of the World Journal of Gastroenterology.Acute liver failure(ALF)is a fatal disease that causes uncontrolled massive hepatocyte death and rapid loss of liver function.Ferroptosis and pyroptosis,cell death forms that can be initiated or blocked concurrently,can play significant roles in developing inflammation and various malignancies.However,their roles in ALF remain unclear.The article discovered the positive feedback between ferroptosis and pyroptosis in the progression of ALF,and revealed that the silent information regulator sirtuin 1(SIRT1)inhibits both pathways through p53,dramatically reducing inflammation and protecting hepatocytes.This suggests the potential use of SIRT1 and its downstream molecules as therapeutics for ALF.Thus,we will discuss the role of ferroptosis and pyroptosis in ALF and the crosstalk between these cell death mechanisms.Additionally,we address potential treatments that could alleviate ALF by simultaneously inhibiting both cell death pathways,as well as examples of SIRT1 activators being used as disease treatment strategies,providing new insights into the therapy of ALF.
基金supported by the National Natural Science Foundation of China(No.82373919)the Natural Science Foundation of Chongqing,China(No.CSTB2022NSCQMSX0175)the Excellent Talents Pool Project of Army Medical University.
文摘Sepsis is a life-threatening disease of organ failure caused by dysregulated host responses to infection and other infectious factors.Multi-organ injury is the leading cause of high mortality and septic shock during sepsis.Recent studies suggest that noncanonical pyroptosis,characterized mainly by the direct activation of caspase-11-gasdermin D-mediated pyroptosis by cytoplastic lipopolysaccharide,is closely related to sepsis-related organ injury.Here,this review summarizes recent advances in the regulatory mechanisms and targeted natural products from traditional Chinese medicine of the noncanonical pyroptosis pathway in sepsis-related injury.
