Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important...Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important regulator of cellular stress responses and has been confirmed to play a critical role in the occurrence of various diseases.However,the mechanisms by which hypoxia-inducible factor 1αis related to epilepsy and neuronal ferroptosis remain unclear.In this study,we used a pentylentetrazole-induced chronic epilepsy mouse model and treated the mice with intraperitoneal administration of PX-478,a hypoxia-inducible factor-1αinhibitor.Our results showed that PX-478 significantly prolonged the latency of epilepsy,reduced seizure severity,and shortened seizure duration.PX-478 also alleviated neuronal damage in the hippocampal CA1 and CA2 regions,reduced levels of reactive oxygen species and malondialdehyde,and increased levels of superoxide dismutase,catalase,and glutathione peroxidase.Transmission electron microscopy showed that PX-478 treatment reduced mitochondrial damage in the hippocampal neurons of epileptic mice,and significantly improved mitochondrial length and area.Additionally,PX-478 preferentially reduced Fe^(2+)levels and the expression of cyclooxygenase-2,ferritin heavy chain 1 and transferrin in the hippocampus of epileptic mice.It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway.In summary,these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway,alleviating oxidative stress,and reducing ferroptosis in hippocampal neurons.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 Science and Technology Development Plan Project of Jilin Province,No.YDZJ202401157ZYTS(to SL).
文摘Epilepsy is a prevalent neurological disorder in which hippocampal neuronal damage,particularly ferroptosis,plays a critical role.Previous studies have shown that hypoxia-inducible factor 1αis considered an important regulator of cellular stress responses and has been confirmed to play a critical role in the occurrence of various diseases.However,the mechanisms by which hypoxia-inducible factor 1αis related to epilepsy and neuronal ferroptosis remain unclear.In this study,we used a pentylentetrazole-induced chronic epilepsy mouse model and treated the mice with intraperitoneal administration of PX-478,a hypoxia-inducible factor-1αinhibitor.Our results showed that PX-478 significantly prolonged the latency of epilepsy,reduced seizure severity,and shortened seizure duration.PX-478 also alleviated neuronal damage in the hippocampal CA1 and CA2 regions,reduced levels of reactive oxygen species and malondialdehyde,and increased levels of superoxide dismutase,catalase,and glutathione peroxidase.Transmission electron microscopy showed that PX-478 treatment reduced mitochondrial damage in the hippocampal neurons of epileptic mice,and significantly improved mitochondrial length and area.Additionally,PX-478 preferentially reduced Fe^(2+)levels and the expression of cyclooxygenase-2,ferritin heavy chain 1 and transferrin in the hippocampus of epileptic mice.It also inhibited the activity of the hypoxia-inducible factor 1α/heme oxygenase-1 pathway.In summary,these findings suggest that PX-478 has the potential to treat epilepsy by inhibiting the hypoxia-inducible factor 1α/heme oxygenase-1 pathway,alleviating oxidative stress,and reducing ferroptosis in hippocampal neurons.
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.
