BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its me...BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.展开更多
AIM:To investigate the expression and prognostic value of CCL2 in gastric cancer,as well as its relationshipwith tumor hypoxia.METHODS:Tumor tissues from 68 gastric cancer patients(GC)were analyzed,and the expression ...AIM:To investigate the expression and prognostic value of CCL2 in gastric cancer,as well as its relationshipwith tumor hypoxia.METHODS:Tumor tissues from 68 gastric cancer patients(GC)were analyzed,and the expression of CCL2and hypoxia-inducible factor 1 alpha(HIF-1α)in tumortissues was detected by immunohistochemistry.Statistical evaluations that were used included univariate logrank tests of Kaplan-Meier curves and multivariate Coxregression model analysis.RESULTS:CCL2 was highly expressed in 66.2%(45/68)of gastric cancer specimens.The distribution of CCL2expression in tumor tissue was consistent with thatof HIF-1α.Patients with high CCL2 expression in GChad a lower overall survival rate[50.6 mo(95%CI:44.44-56.93)vs 64.6 mo(95%CI:60.27-68.94),P=0.013].CONCLUSION:CCL2 expression correlates closely with HIF-1αexpression in gastric cancer.CCL2 may be an independent prognostic marker for GC.展开更多
基金Supported by the National Natural Science Foundation of China,No.81570543 and No.81560104
文摘BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.
基金Supported by National Natural Science Foundation of China,No.81101739China International Medical Foundation,No.CIMF-F-H001-023
文摘AIM:To investigate the expression and prognostic value of CCL2 in gastric cancer,as well as its relationshipwith tumor hypoxia.METHODS:Tumor tissues from 68 gastric cancer patients(GC)were analyzed,and the expression of CCL2and hypoxia-inducible factor 1 alpha(HIF-1α)in tumortissues was detected by immunohistochemistry.Statistical evaluations that were used included univariate logrank tests of Kaplan-Meier curves and multivariate Coxregression model analysis.RESULTS:CCL2 was highly expressed in 66.2%(45/68)of gastric cancer specimens.The distribution of CCL2expression in tumor tissue was consistent with thatof HIF-1α.Patients with high CCL2 expression in GChad a lower overall survival rate[50.6 mo(95%CI:44.44-56.93)vs 64.6 mo(95%CI:60.27-68.94),P=0.013].CONCLUSION:CCL2 expression correlates closely with HIF-1αexpression in gastric cancer.CCL2 may be an independent prognostic marker for GC.
