title: Dioscin ameliorates cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via HMGB-1 inhibition.
abstract: We previously reported the promising effect of dioscin against hepatic ischemia/reperfusion (I/R) injury, but its effect on cerebral I/R injury remains unknown. In this work, an in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model and an in vivo middle cerebral artery occlusion (MCAO) model were used. The results indicated that dioscin clearly protected PC12 cells and primary cortical neurons against OGD/R insult and significantly prevented cerebral I/R injury. Further research demonstrated that dioscin-induced neuroprotection was accompanied by a significant inhibition in the expression and the nuclear to cytosolic translocation of HMGB-1, reflected by decreased TLR4 expression. Blockade of the TLR4/MyD88/TRAF6 signaling pathway by dioscin inhibited NF-κB and AP-1 transcriptional activities, MAPK and STAT3 phosphorylation, and pro-inflammatory cytokine responses, and upregulated the levels of anti-inflammatory factors. In addition, small interfering RNA (siRNA) and overexpressed genes of HMGB-1 and TLR4 were applied in in vitro experiments, respectively, and the results further confirmed that dioscin showed an efficient neuroprotection because of its inhibiting effects on HMGB-1/TLR4 signaling and subsequent suppressing inflammation. These findings provide new insights that will aid in elucidating the effect of dioscin against cerebral I/R injury and support the development of dioscin as a potential treatment for ischemic stroke.
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Tao
authors.affiliation: Department of Occupational and Environmental of Health, Dalian Medical University, No. 9 Western Section of Lushun South Road, Dalian, Liaoning, China.
authors.forename: Xiance
authors.initials: X
authors.lastname: Sun
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Lianhong
authors.initials: L
authors.lastname: Yin
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Xu
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China. Electronic address: jinyongpeng2005@163.com.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002470:Cell Survival; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018696:Neuroprotective Agents; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C019357:dioscin; D007770:L-Lactate Dehydrogenase; D004144:Diosgenin
keywords: Cerebral ischemia/reperfusion; Dioscin; HMGB-1; Inflammation; TLR4 signaling pathway