Traditional drug development encounters profound challenges in tackling complex diseases.The process is notoriously time-consuming and resource-intensive,often lasting 10-15 years and requiring investments of billions...Traditional drug development encounters profound challenges in tackling complex diseases.The process is notoriously time-consuming and resource-intensive,often lasting 10-15 years and requiring investments of billions of dollars.This considerable burden not only places significant pressure on pharmaceutical companies but also results in the premature discontinuation of many potentially promising drugs due to insufficient funding.展开更多
Atherosclerosis is a chronic multifactorial cardiovascular disease.Western diets have been reported to affect atherosclerosis through regulating adipose function.In high cholesterol diet-fed ApoE^(−/−)mice,adipocyte H...Atherosclerosis is a chronic multifactorial cardiovascular disease.Western diets have been reported to affect atherosclerosis through regulating adipose function.In high cholesterol diet-fed ApoE^(−/−)mice,adipocyte HIF-1αdeficiency or direct inhibition of HIF-1αby the selective pharmacological HIF-1αinhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation,which lowers cholesterol levels and reduces inflammatory responses,resulting in improved dyslipidemia and atherogenesis.Smpd3,the gene encoding neutral sphingomyelinase,is identified as a new target gene directly regulated by HIF-1αthat is involved in ceramide generation.Injection of lentivirus-SMPD3 in epididymal adipose tissue reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1α-deficient mice.Therefore,HIF-1αinhibition may constitute a novel approach to slow atherosclerotic progression.展开更多
基金supported by the Key Research and Development Program,Ministry of Science and Technology of the People's Republic of China(No.2023YFC2606500)Open Fund from the State Key Laboratory of Antiviral Drugs(No.SKLAD-2024-0104,China)the Taishan Scholar Project of Shandong Province(tsqn202103108,China).
文摘Traditional drug development encounters profound challenges in tackling complex diseases.The process is notoriously time-consuming and resource-intensive,often lasting 10-15 years and requiring investments of billions of dollars.This considerable burden not only places significant pressure on pharmaceutical companies but also results in the premature discontinuation of many potentially promising drugs due to insufficient funding.
基金This work was supported by the National Key Research and Development Program of China(2018YFA0800700 and 2018YFC1003900)the National Natural Science Foundation of China(Nos.91857115,31925021,82022028 and 81921001).
文摘Atherosclerosis is a chronic multifactorial cardiovascular disease.Western diets have been reported to affect atherosclerosis through regulating adipose function.In high cholesterol diet-fed ApoE^(−/−)mice,adipocyte HIF-1αdeficiency or direct inhibition of HIF-1αby the selective pharmacological HIF-1αinhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation,which lowers cholesterol levels and reduces inflammatory responses,resulting in improved dyslipidemia and atherogenesis.Smpd3,the gene encoding neutral sphingomyelinase,is identified as a new target gene directly regulated by HIF-1αthat is involved in ceramide generation.Injection of lentivirus-SMPD3 in epididymal adipose tissue reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1α-deficient mice.Therefore,HIF-1αinhibition may constitute a novel approach to slow atherosclerotic progression.
