Prenatal alcohol exposure, especially during early pregnancy, can lead to fetal alcohol syndrome. The pharmacological and toxicological mechanisms of ethanol are related to the effects of ceramide In this study, we es...Prenatal alcohol exposure, especially during early pregnancy, can lead to fetal alcohol syndrome. The pharmacological and toxicological mechanisms of ethanol are related to the effects of ceramide In this study, we established an alcohol exposure model in wild-type mice and in knockout mice for the key enzyme involved in ceramide metabolism, sphingomyelin synthase 2. This model received daily intragastric administration of 25% ethanol, and pups were used at postnatal days 0, 7, 14, 30 for experiments. Serology and immunofluorescence staining found that ethanol exposure dose-dependently reduced blood sphingomyelin levels in two genotypes of pups, and increased neural cell proliferation and the number of new neurons in the hippocampal dentate gyrus. Western blot analysis showed that the relative expression level of protein kinase C e increased in two genotypes of pups after ethanol exposure. Compared with witd-type pups, the expression level of the important activator protein of the ceramide/ceramide-l-phosphate pathway, protein kinase C a, was reduced in the hippocampus of sphingomyelin synthase 2 knockouts. Our findings illustrate that ceramide is involved in alcohol-induced neural proliferation in the hippocampal dentate gyrus of pups after prenatal ethanol exposure, and the mechanism may be associated with increased ex- pression of protein kinase C a activating the ceramide/ceramide-l-phosphate pathway.展开更多
The apical sodium-dependent bile acid transporter(ASBT) is the main transporter to promote re-absorption of bile acids from the intestinal tract into the enterohepatic circulation.Inhibition of ASBT could increase the...The apical sodium-dependent bile acid transporter(ASBT) is the main transporter to promote re-absorption of bile acids from the intestinal tract into the enterohepatic circulation.Inhibition of ASBT could increase the excretion of bile acids,thus increasing bile acid synthesis and consequently cholesterol consumption.Therefore,ASBT is an attractive target for developing new cholesterol-lowering drugs.In this report,a series of 1-(2,4-bifluorophenyl)-7-dialkylamino-1,8-naphthyridine-3-carboxamides were designed as inhibitors of ASBT.Most of them demonstrated potency against ASBT transport of bile acids.In particular,compound 4a_1 was found to have the best activity,resulting in 80.1%inhibition of ASBT at10μmol/L.展开更多
基金supported by the Technological Project of Science and Technology Department of Henan Province in China,No.122102310205the National Natural Science Foundation of China,No.30771140,31070952,U1204311
文摘Prenatal alcohol exposure, especially during early pregnancy, can lead to fetal alcohol syndrome. The pharmacological and toxicological mechanisms of ethanol are related to the effects of ceramide In this study, we established an alcohol exposure model in wild-type mice and in knockout mice for the key enzyme involved in ceramide metabolism, sphingomyelin synthase 2. This model received daily intragastric administration of 25% ethanol, and pups were used at postnatal days 0, 7, 14, 30 for experiments. Serology and immunofluorescence staining found that ethanol exposure dose-dependently reduced blood sphingomyelin levels in two genotypes of pups, and increased neural cell proliferation and the number of new neurons in the hippocampal dentate gyrus. Western blot analysis showed that the relative expression level of protein kinase C e increased in two genotypes of pups after ethanol exposure. Compared with witd-type pups, the expression level of the important activator protein of the ceramide/ceramide-l-phosphate pathway, protein kinase C a, was reduced in the hippocampus of sphingomyelin synthase 2 knockouts. Our findings illustrate that ceramide is involved in alcohol-induced neural proliferation in the hippocampal dentate gyrus of pups after prenatal ethanol exposure, and the mechanism may be associated with increased ex- pression of protein kinase C a activating the ceramide/ceramide-l-phosphate pathway.
基金supported by the National Natural Science Foundation of China(Nos.81473098 and 81473099)Hebei Provincial Key Research Project of Medical Science(Nos.ZD20140027 and 20150588)
文摘The apical sodium-dependent bile acid transporter(ASBT) is the main transporter to promote re-absorption of bile acids from the intestinal tract into the enterohepatic circulation.Inhibition of ASBT could increase the excretion of bile acids,thus increasing bile acid synthesis and consequently cholesterol consumption.Therefore,ASBT is an attractive target for developing new cholesterol-lowering drugs.In this report,a series of 1-(2,4-bifluorophenyl)-7-dialkylamino-1,8-naphthyridine-3-carboxamides were designed as inhibitors of ASBT.Most of them demonstrated potency against ASBT transport of bile acids.In particular,compound 4a_1 was found to have the best activity,resulting in 80.1%inhibition of ASBT at10μmol/L.
