Accumulating data have revealed that abnormal activity of the mTOR(mammalian target of rapamycin)pathway plays an important role in epileptogenesis triggered by various factors. We previously reported that pretreatmen...Accumulating data have revealed that abnormal activity of the mTOR(mammalian target of rapamycin)pathway plays an important role in epileptogenesis triggered by various factors. We previously reported that pretreatment with perifosine, an inhibitor of Akt(also called protein kinase B), abolishes the rapamycin-induced paradoxical increase of S6 phosphorylation in a rat model induced by kainic acid(KA). Since Akt is an upstream target in the mTOR signaling pathway, we set out to determine whether perifosine has a preventive effect on epileptogenesis. Here, we explored the effect of perifosine on the model of temporal epilepsy induced by KA in rats and found that pretreatment with perifosine had no effect on the severity or duration of the KA-induced status epilepticus. However, perifosine almost completely inhibited the activation of p-Akt and p-S6 both acutely and chronically following the KA-induced status epilepticus.Perifosine pretreatment suppressed the KA-induced neuronal death and mossy fiber sprouting. The frequency of spontaneous seizures was markedly decreased in rats pretreated with perifosine. Accordingly, rats pretreated with perifosine showed mild impairment in cognitive functions. Collectively, this study provides novel evidence in a KA seizure model that perifosine may be a potential drug for use in anti-epileptogenic therapy.展开更多
It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E(GSDME)-deficient cells,but pyroptosis in GSDME-sufficient cells.The high GSDME expression and apoptosis resistance of pancreatic ducta...It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E(GSDME)-deficient cells,but pyroptosis in GSDME-sufficient cells.The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma(PDAC)cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis.Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC.This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs.Based on this system,ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds.Concretely,they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells.Further,we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis via caspase-3/GSDME pathway both in vitro and in vivo.Collectively,this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.展开更多
基金supported by the National Natural Science Foundation of China(81371429)the Public Welfare Technology Application Research Project of Zhejiang Province,China(2016C33211)the Science and Technology Commission of Hangzhou Municipality,Zhejiang Province,China(20140633B37and 20160533B73)
文摘Accumulating data have revealed that abnormal activity of the mTOR(mammalian target of rapamycin)pathway plays an important role in epileptogenesis triggered by various factors. We previously reported that pretreatment with perifosine, an inhibitor of Akt(also called protein kinase B), abolishes the rapamycin-induced paradoxical increase of S6 phosphorylation in a rat model induced by kainic acid(KA). Since Akt is an upstream target in the mTOR signaling pathway, we set out to determine whether perifosine has a preventive effect on epileptogenesis. Here, we explored the effect of perifosine on the model of temporal epilepsy induced by KA in rats and found that pretreatment with perifosine had no effect on the severity or duration of the KA-induced status epilepticus. However, perifosine almost completely inhibited the activation of p-Akt and p-S6 both acutely and chronically following the KA-induced status epilepticus.Perifosine pretreatment suppressed the KA-induced neuronal death and mossy fiber sprouting. The frequency of spontaneous seizures was markedly decreased in rats pretreated with perifosine. Accordingly, rats pretreated with perifosine showed mild impairment in cognitive functions. Collectively, this study provides novel evidence in a KA seizure model that perifosine may be a potential drug for use in anti-epileptogenic therapy.
基金financially supported by the National Natural Science Foundation of China(No.82174100)the National Key R&D Program of China(No.2022YFC3501601)。
文摘It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E(GSDME)-deficient cells,but pyroptosis in GSDME-sufficient cells.The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma(PDAC)cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis.Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC.This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs.Based on this system,ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds.Concretely,they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells.Further,we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis via caspase-3/GSDME pathway both in vitro and in vivo.Collectively,this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.
