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Stigmasterol protects human brain microvessel endothelial cells against ischemia-reperfusion injury through suppressing EPHA2 phosphorylation

查看全文 作　　者：LI [1]Suping;XU [1]Fei;YU [1]Liang;YU [2]Qian;YU [1]Nengwei;FU [2]Jing 高影响力作者 机构地区：[1]Department of Neurology,Sichuan Academy of Medical Sciences&Sichuan Provincial People’s Hospital,Chengdu 610072,China;[2]Department of Rehabilitation,Sichuan Academy of Medical Sciences&Sichuan Provincial People’s Hospital,Chengdu 610072,China高影响力机构 出　　处：《Chinese Journal of Natural Medicines》索引2023年第21卷第2期,共9页高影响力期刊 基　　金：supported by the Key Research Project of the Science&Technology Department of Sichuan Province,China(Nos.2021YFS0131 and 2020YFS0414). 摘　　要：Stigmasterol is a plant sterol with anti-apoptotic,anti-oxidative and anti-inflammatory effect through multiple mechanisms.In this study,we further assessed whether it exerts protective effect on human brain microvessel endothelial cells(HBMECs)against ischemia-reperfusion injury and explored the underlying mechanisms.HBMECs were used to establish an in vitro oxygen and glucose deprivation/reperfusion(OGD/R)model,while a middle cerebral artery occlusion(MCAO)model of rats were constructed.The interaction between stigmasterol and EPHA2 was detected by surface plasmon resonance(SPR)and cellular thermal shift assay(CETSA).The results showed that 10μmol·L−1 stigmasterol significantly protected cell viability,alleviated the loss of tight junction proteins and attenuated the blood-brain barrier(BBB)damage induced by OGD/R in the in vitro model.Subsequent molecular docking showed that stigmasterol might interact with EPHA2 at multiple sites,including T692,a critical gatekeep residue of this receptor.Exogenous ephrin-A1(an EPHA2 ligand)exacerbated OGD/R-induced EPHA2 phosphorylation at S897,facilitated ZO-1/claudin-5 loss,and promoted BBB leakage in vitro,which were significantly attenuated after stigmasterol treatment.The rat MCAO model confirmed these protective effects in vivo.In summary,these findings suggest that stigmasterol protects HBMECs against ischemia-reperfusion injury by maintaining cell viability,reducing the loss of tight junction proteins,and attenuating the BBB damage.These protective effects are at least meditated by its interaction with EPHA2 and inhibitory effect on EPHA2 phosphorylation. 关 键 词：Stigmasterol Oxygen and glucose deprivation/reperfusion EPHA2 Blood-brain barrier
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