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
The microscopic global nucleon–nucleus optical model potential(OMP)proposed by Whitehead,Lim,and Holt,the WLH potential(Whitehead et al.,Phys Rev Lett 127:182502,2021),which was constructed in the framework of many-b...The microscopic global nucleon–nucleus optical model potential(OMP)proposed by Whitehead,Lim,and Holt,the WLH potential(Whitehead et al.,Phys Rev Lett 127:182502,2021),which was constructed in the framework of many-body per-turbation theory with state-of-the-art nuclear interactions from chiral effective field theory(EFT),was tested with(p,d)transfer reactions calculated using adiabatic wave approximation.The target nuclei included both stable and unstable nuclei,and the incident energies reached 200 MeV.The results were compared with experimental data and predictions using the phenomenological global optical potential of Koning and Delaroche,the KD02 potential.Overall,we found that the micro-scopic WLH potential described the(p,d)reaction angular distributions similarly to the phenomenological KD02 potential;however,the former was slightly better than the latter for radioactive targets.On average,the obtained spectroscopic factors(SFs)using both microscopic and phenomenological potentials were similar when the incident energies were below approxi-mately 120 MeV.However,their difference tended to increase at higher incident energies,which was particularly apparent for the doubly magic target nucleus 40Ca.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
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
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 National Natural Science Foundation of China(Nos.U2067205 and 12205098)National Key Laboratory of Computational Physics(HX02021-35).
文摘The microscopic global nucleon–nucleus optical model potential(OMP)proposed by Whitehead,Lim,and Holt,the WLH potential(Whitehead et al.,Phys Rev Lett 127:182502,2021),which was constructed in the framework of many-body per-turbation theory with state-of-the-art nuclear interactions from chiral effective field theory(EFT),was tested with(p,d)transfer reactions calculated using adiabatic wave approximation.The target nuclei included both stable and unstable nuclei,and the incident energies reached 200 MeV.The results were compared with experimental data and predictions using the phenomenological global optical potential of Koning and Delaroche,the KD02 potential.Overall,we found that the micro-scopic WLH potential described the(p,d)reaction angular distributions similarly to the phenomenological KD02 potential;however,the former was slightly better than the latter for radioactive targets.On average,the obtained spectroscopic factors(SFs)using both microscopic and phenomenological potentials were similar when the incident energies were below approxi-mately 120 MeV.However,their difference tended to increase at higher incident energies,which was particularly apparent for the doubly magic target nucleus 40Ca.
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 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.
