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
A novel route for dinitrification of N-phenylbenzenesulfonamide to synthesize N-(2,4-dinitrophenyl)benzenesulfonamide has been developed.The method features convenient operation and good functional group tolerance.Thi...A novel route for dinitrification of N-phenylbenzenesulfonamide to synthesize N-(2,4-dinitrophenyl)benzenesulfonamide has been developed.The method features convenient operation and good functional group tolerance.This reaction may go through a nitrogen dioxide radical(NO_(2)·)intermediate,which is generated by the thermal reaction process of sodium nitrate and ammonium persulfate.In addition,it provides direct approach for the preparation of 2,4-dinitroaniline derivatives which are crucial intermediate for the synthesis of benzimidazoles and quinoxaline derivatives.展开更多
As a systemic metabolic disease caused by a variety of factors,osteoporosis is characterized by reduced bone mass,bone tissue microstructural degradation,and decreased bone mechanical properties,accompanied by bone fr...As a systemic metabolic disease caused by a variety of factors,osteoporosis is characterized by reduced bone mass,bone tissue microstructural degradation,and decreased bone mechanical properties,accompanied by bone fragility and fracture,which is a common risk of senile disease.In China,osteoporosis has become a common disease and has frequent morbidity,with the incidence trend on the rise.Bisphosphates have received much attention in this field as inhibitory bone resorption agents,and sodium olpadronate belongs to the third-generation bisphosphonates.This experiment investigated the synthetic process and pharmacological activity of sodium olpadronate.Using 3-(N,N-dimethylamino)-propionitrile as the starting material,the synthesis process was improved to reduce cost with a total yield of 49.7%,which was 24.0%higher than that reported in the literature.Pharmacodynamic experiments showed that sodium olpadronate could be used to treat osteoporosis.Moreover,toxicology experiments showed no obvious toxic side effects.Taken together,sodium olpadronate had very promising development prospects.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.
文摘A novel route for dinitrification of N-phenylbenzenesulfonamide to synthesize N-(2,4-dinitrophenyl)benzenesulfonamide has been developed.The method features convenient operation and good functional group tolerance.This reaction may go through a nitrogen dioxide radical(NO_(2)·)intermediate,which is generated by the thermal reaction process of sodium nitrate and ammonium persulfate.In addition,it provides direct approach for the preparation of 2,4-dinitroaniline derivatives which are crucial intermediate for the synthesis of benzimidazoles and quinoxaline derivatives.
文摘As a systemic metabolic disease caused by a variety of factors,osteoporosis is characterized by reduced bone mass,bone tissue microstructural degradation,and decreased bone mechanical properties,accompanied by bone fragility and fracture,which is a common risk of senile disease.In China,osteoporosis has become a common disease and has frequent morbidity,with the incidence trend on the rise.Bisphosphates have received much attention in this field as inhibitory bone resorption agents,and sodium olpadronate belongs to the third-generation bisphosphonates.This experiment investigated the synthetic process and pharmacological activity of sodium olpadronate.Using 3-(N,N-dimethylamino)-propionitrile as the starting material,the synthesis process was improved to reduce cost with a total yield of 49.7%,which was 24.0%higher than that reported in the literature.Pharmacodynamic experiments showed that sodium olpadronate could be used to treat osteoporosis.Moreover,toxicology experiments showed no obvious toxic side effects.Taken together,sodium olpadronate had very promising development prospects.
