title: Upregulating the Expression of Survivin-HBXIP Complex Contributes to the Protective Role of IMM-H004 in Transient Global Cerebral Ischemia/Reperfusion.
abstract: IMM-H004, a 3-piperazinylcoumarin compound derived from coumarin, has been proved effective against CA1 cell loss and spatial learning impairments resulting from transient global ischemia/reperfusion (TGCI/R), while the mechanism is still largely unknown. Here, we confirmed that treatment of rats with IMM-H004 immediately after TGCI/R ameliorated delayed neuronal death (DND) in the CA1 of hippocampus and cortex. Further study suggested that IMM-H004 contributed to the expression of antiapoptotic protein survivin through the activation of PI3K-dependent protein kinase B (PKB/Akt), which led to the phosphorylation of forkhead box O1 (FoxO1), then relieved the inhibiting effect on survivin promoter. Additionally, IMM-H004 also enhanced the expression of hepatitis B X-interacting protein (HBXIP), which formed a complex with survivin to prevent the activation of caspase death cascade, thereby halting apoptotic cell death. Finally, we injected a HBXIP siRNA into hippocampus and performed microelectroporation before ischemia/reperfusion, which abolished the protective effect of IMM-H004. Further study revealed that HBXIP maintained the high expression of Akt and survivin. Collectively, our findings demonstrated that DND after TGCI/R was alleviated by IMM-H004 through promoting the formation of survivin-HBXIP complex, which further emphasized the importance of endogenous protein involved in self-repair after stroke.
authors.affiliation: Key Laboratory of Diagnostics of Traditional Chinese Medicine, Collaborative Innovation Center of Digital Traditional Chinese Medicine, College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.|State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Shi-Feng
authors.initials: SF
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Mei-Jin
authors.initials: MJ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Han
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zuo
authors.affiliation: Key Laboratory of Diagnostics of Traditional Chinese Medicine, Collaborative Innovation Center of Digital Traditional Chinese Medicine, College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.
authors.forename: Hui-Yong
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Key Laboratory of Diagnostics of Traditional Chinese Medicine, Collaborative Innovation Center of Digital Traditional Chinese Medicine, College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China. chennh@imm.ac.cn.|State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. chennh@imm.ac.cn.
authors.forename: Nai-Hong
authors.initials: NH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D003374:Coumarins / Q000008:administration & dosage*; D015870:Gene Expression; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000077022:Survivin; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C516989:Birc5 protein, rat; D003374:Coumarins; C588372:IMM-H004; C110719:LAMTOR5 protein, human; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D000077022:Survivin
keywords: Akt; Delayed neuronal death; Global cerebral ischemia; HBXIP; IMM-H004; Neuroprotective role; Survivin