Epicatechin(EC)was used in this study to antagonize the cognitive dysfunction caused by lead(Pb)exposure in mice.Eight-week-old male Kunming mice were treated with PbCl_(2)(20 mg/kg)and/or EC(50 mg/kg)by gavage admini...Epicatechin(EC)was used in this study to antagonize the cognitive dysfunction caused by lead(Pb)exposure in mice.Eight-week-old male Kunming mice were treated with PbCl_(2)(20 mg/kg)and/or EC(50 mg/kg)by gavage administration for 4 weeks.Morris water maze test showed that EC could improve memory dysfunction induced by Pb.EC antagonized Ca^(2+)overload,activated Nrf2 signaling pathway and reduced the accumulation of Pb in the brain and serum,which suggested that EC might alter Pb distribution in mice.In vitro,spectroscopic analysis,potentiometric titration and docking studies were applied to inquiry into the interaction between bovine serum albumin(BSA)and Pb^(2+)in presence or absence of EC.EC was proved to chelate Pb^(2+)and reduced the interaction between BSA and Pb^(2+).In summary,EC might protect Pb-induced cognitive impairment by activating Nrf2 signaling pathway,and suppressing Pb accumulation via interference on the binding of Pb to albumin.展开更多
Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cyto...Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle(TCA cycle)to acetyl-CoA in the cytoplasm.Therefore,ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis.In this study,we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor,and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC_(50)=5.31±1.2μmol/L in vitro.326E treatment reduced de novo lipogenesis,and increased cholesterol efflux in vitro and in vivo.326E was rapidly absorbed after oral administration,exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid(BA)used for hypercholesterolemia.Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia.Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^(-/-)mice to a greater extent than that of BA treatment.Taken together,our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.展开更多
基金supported by the National Key Research and Development Program of China under Grant(2022YFF1102800)the Graduate Scientific Research Innovation Project of Tianji(2022SKY109)+1 种基金the Project of Tianjin Science and Technology Program(22JCYBJC00360)the Project of Tianjin Science and Technology Program(21ZYJDJC00060)。
文摘Epicatechin(EC)was used in this study to antagonize the cognitive dysfunction caused by lead(Pb)exposure in mice.Eight-week-old male Kunming mice were treated with PbCl_(2)(20 mg/kg)and/or EC(50 mg/kg)by gavage administration for 4 weeks.Morris water maze test showed that EC could improve memory dysfunction induced by Pb.EC antagonized Ca^(2+)overload,activated Nrf2 signaling pathway and reduced the accumulation of Pb in the brain and serum,which suggested that EC might alter Pb distribution in mice.In vitro,spectroscopic analysis,potentiometric titration and docking studies were applied to inquiry into the interaction between bovine serum albumin(BSA)and Pb^(2+)in presence or absence of EC.EC was proved to chelate Pb^(2+)and reduced the interaction between BSA and Pb^(2+).In summary,EC might protect Pb-induced cognitive impairment by activating Nrf2 signaling pathway,and suppressing Pb accumulation via interference on the binding of Pb to albumin.
基金supported by grants from the National Natural Science Foundation of China(92057116 and 82170872)the Medical Guidance Project of Shanghai Science and Technology Commission(20S11903400,China)+3 种基金the“Personalized Medicines-Molecular Signature-based Drug Discovery and Development”Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12040328,China)the“State Key Laboratory of Drug Research”Shanghai Institute of Materia Medica,Chinese Academy of Sciences(SIMM2105KF-02,China)Natural Science Foundation of Shanghai’s 2021“Science and Technology Innovation Action Plan”(21ZR1475300,China)the Lingang Laboratory(LG-QS-202205-01,China)。
文摘Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia,which results in atherosclerosis and cardiovascular disease(CVD).ATP-citrate lyase(ACLY)is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle(TCA cycle)to acetyl-CoA in the cytoplasm.Therefore,ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis.In this study,we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor,and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC_(50)=5.31±1.2μmol/L in vitro.326E treatment reduced de novo lipogenesis,and increased cholesterol efflux in vitro and in vivo.326E was rapidly absorbed after oral administration,exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid(BA)used for hypercholesterolemia.Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia.Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^(-/-)mice to a greater extent than that of BA treatment.Taken together,our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.
