Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o ...Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o rganisms,plants and animals through direct or indirect exposure.However,the current understanding of the toxicity of copper is rather limited.Copper overload can perturb intracellular homeostasis and induce oxidative stress and e ven cell death.Recently,cuproptosis has been identified as a copper-dependent form of cell death induced by o xidative stress in mitochondria.We uncover here that zinc transporter 1(ZNT1)is an important regulator involved in cuproptosis.Firstly,we established the copper overload-induced cell death model with the overexpression of copper importer SLC31A1 in HeLa cells.Using this model,we conducted unbiased genome-wide CRISPR-Cas9 screens in cells treated with copper.Our results revealed a significant enrichment of ZNT1 gene in both library A and library B plasmids.Knocking out of ZNT1 in HeLa cells notably prevented cuproptosis.Subsequent knockout of metal transcription factor 1(MTF1)in ZNT1-deficient cells nearly abolished their ability to resist copper-induced cell death.However,overexpression of metallothionein 1X(MT1X)in the double-knockout cells could p artially restored the resistance to cuproptosis by loss of MTF1.Mechanistically,knockout of ZNT1 could promote MT1X expression by activating MTF1.As a consequence,the interaction between MT1X and copper was e nhanced,reducing the flow of copper into mitochondria and eliminating mitochondria damage.Taken together,this study reveals the important role of ZNT1 in cuproptosis and shows MTF1-MT1X axis mediated resistance to c uproptosis.Moreover,our study will help to understand the regulatory mechanism of cellular and systemic copper homeostasis under copper overload,and present insights into novel treatments for damages caused by both genetic copper overload diseases and environmental copper contamination.展开更多
AIM:To evaluate the predictive value of islet autoantibodies for the diagnosis of autoimmune uveitis(AU),as well as to characterize the association bet ween islet autoantibodies and AU.METHODS:Totally 97 patients with...AIM:To evaluate the predictive value of islet autoantibodies for the diagnosis of autoimmune uveitis(AU),as well as to characterize the association bet ween islet autoantibodies and AU.METHODS:Totally 97 patients with AU and 100 healthy persons without any autoimmune diseases as the control group were recruited.Multiple serum islet autoantibodies were measured using commercial enzyme-linked immunosorbent assay kits(ELISA).A supplementary questionnaire was used to complement the subject's demographics and clinical features.The level of glucose concentrations and white blood cells were measured.Conditional logistic regression was performed to estimate odds ratios(ORs),and 95%confidence intervals(CIs)of AU according to islet autoantibodies and to evaluate the predictive value of islet autoantibodies for AU diagnosis.Autoantibodies subgroups and other variables were included into analysis.RESULTS:In AU patients,the prevalence of detecting at least one of the autoantibodies was 31.9%(31/97).The most frequent autoantibody was ZnT8A(30.9%),followed by GADA(11.3%),IA-2A(4.1%),ICA(2.1%)and IAA(2.1%).Islet autoantibodies were found to be correlated positively with AU diagnosis[OR(95%CI):13.86(3.28,58.50),P<0.001].Moreover,Zn-T8A was remarkably correlated with AU diagnosis[OR(95%CI):6.13(1.96,19.17),P<0.001],In contrast,neither GADA nor other islet antibodies(IA-2A,ICA and IAA)showed any association with AU risk under an additive model.CONCLUSION:The prevalence of islet antibodies,especially ZnT8A,in patients with AU is higher.Islet antibodies as well as novel biomarkers should be included in routine evaluation at AU and is a valuable biological marker to classify newly-diagnosed uveitis.展开更多
文摘Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o rganisms,plants and animals through direct or indirect exposure.However,the current understanding of the toxicity of copper is rather limited.Copper overload can perturb intracellular homeostasis and induce oxidative stress and e ven cell death.Recently,cuproptosis has been identified as a copper-dependent form of cell death induced by o xidative stress in mitochondria.We uncover here that zinc transporter 1(ZNT1)is an important regulator involved in cuproptosis.Firstly,we established the copper overload-induced cell death model with the overexpression of copper importer SLC31A1 in HeLa cells.Using this model,we conducted unbiased genome-wide CRISPR-Cas9 screens in cells treated with copper.Our results revealed a significant enrichment of ZNT1 gene in both library A and library B plasmids.Knocking out of ZNT1 in HeLa cells notably prevented cuproptosis.Subsequent knockout of metal transcription factor 1(MTF1)in ZNT1-deficient cells nearly abolished their ability to resist copper-induced cell death.However,overexpression of metallothionein 1X(MT1X)in the double-knockout cells could p artially restored the resistance to cuproptosis by loss of MTF1.Mechanistically,knockout of ZNT1 could promote MT1X expression by activating MTF1.As a consequence,the interaction between MT1X and copper was e nhanced,reducing the flow of copper into mitochondria and eliminating mitochondria damage.Taken together,this study reveals the important role of ZNT1 in cuproptosis and shows MTF1-MT1X axis mediated resistance to c uproptosis.Moreover,our study will help to understand the regulatory mechanism of cellular and systemic copper homeostasis under copper overload,and present insights into novel treatments for damages caused by both genetic copper overload diseases and environmental copper contamination.
基金Supported by the Science Foundation of Shaanxi Province of China(No.2017SF-265)the Science Foundation of Xi’an of China[No.2017121SF/YX015(2)].
文摘AIM:To evaluate the predictive value of islet autoantibodies for the diagnosis of autoimmune uveitis(AU),as well as to characterize the association bet ween islet autoantibodies and AU.METHODS:Totally 97 patients with AU and 100 healthy persons without any autoimmune diseases as the control group were recruited.Multiple serum islet autoantibodies were measured using commercial enzyme-linked immunosorbent assay kits(ELISA).A supplementary questionnaire was used to complement the subject's demographics and clinical features.The level of glucose concentrations and white blood cells were measured.Conditional logistic regression was performed to estimate odds ratios(ORs),and 95%confidence intervals(CIs)of AU according to islet autoantibodies and to evaluate the predictive value of islet autoantibodies for AU diagnosis.Autoantibodies subgroups and other variables were included into analysis.RESULTS:In AU patients,the prevalence of detecting at least one of the autoantibodies was 31.9%(31/97).The most frequent autoantibody was ZnT8A(30.9%),followed by GADA(11.3%),IA-2A(4.1%),ICA(2.1%)and IAA(2.1%).Islet autoantibodies were found to be correlated positively with AU diagnosis[OR(95%CI):13.86(3.28,58.50),P<0.001].Moreover,Zn-T8A was remarkably correlated with AU diagnosis[OR(95%CI):6.13(1.96,19.17),P<0.001],In contrast,neither GADA nor other islet antibodies(IA-2A,ICA and IAA)showed any association with AU risk under an additive model.CONCLUSION:The prevalence of islet antibodies,especially ZnT8A,in patients with AU is higher.Islet antibodies as well as novel biomarkers should be included in routine evaluation at AU and is a valuable biological marker to classify newly-diagnosed uveitis.
