PMID- 29895489 OWN - NLM STAT- MEDLINE DCOM- 20180702 LR - 20220408 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 44 DP - 2018 May 15 TI - Shengui Sansheng San extraction is an angiogenic switch via regulations of AKT/mTOR, ERK1/2 and Notch1 signal pathways after ischemic stroke. PG - 20-31 LID - S0944-7113(18)30125-9 [pii] LID - 10.1016/j.phymed.2018.04.025 [doi] AB - BACKGROUND: As a traditional Chinese herbal formula, Shengui Sansheng San (SSS) has been employed for stroke treatment more than 300 years. PURPOSE: We hypothesize that SSS extraction is an angiogenic switch in penumbra post-stroke, and corresponding mechanisms are investigated. METHODS: In present study, rats were subjected to permanent middle cerebral artery occlusion model (MCAo) and were treated with low, middle and high doses of SSS extraction. We assessed neurological function and survival rate, and measured infarct volume by 2,3,5-triphenyltetrazolium chloride staining on day 7 after ischemia. von Willebrand factor (vWF), stromal cell-derived factor-1 alpha (SDF-1alpha) /chemokine (C-X-C motif) receptor 4 (CXCR4) axis, vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) as well as protein kinase B (AKT)/mammalian target of rapamycin (mTOR) /hypoxia-inducible factor-1 alpha (HIF-1alpha), extracellular signal-regulated kinase 1/2 (ERK1/2) and Notch1 signaling pathways were respectively investigated by immunofluorescence assay or western blotting in vivo and oxygen-glucose-deprived (OGD) brain microvascular endothelial cells (BMECs); simultaneously, wound healing of BMECs and tube formation assay were administrated. RESULTS: Compared to MCAo group, SSS extraction could significantly improve neurological functional scores, survival rate and cerebral infarct volume, enhance vWF(+) vascular density and perimeter, SDF-1alpha/CXCR4 axis, VEGF expression, as well as activate AKT/mTOR/HIF-1alpha and ERK1/2 and inhibit Notch1 pathways in penumbra. In vitro, containing SSS extraction serum increased BMEC migration, capillary formation and VEGF expression via up-regulations of AKT/mTOR and ERK1/2 pathways in OGD BMECs, but ERK inhibitor (U0126) reversed the result of VEGF expression in high dose of SSS group. Additionally, VEGFR2 and Notch1 expressions were suppressed by containing SSS extraction serum. All results were in dose dependent manner. CONCLUSION: Our study firstly demonstrates that SSS extraction is an angiogenic switch. Due to suppressed VEGFR2/Notch1 cascades and activated AKT/mTOR and ERK1/2 signals in BMECs, a feedback loop of angiogenic homeostasis is established. Furthermore, the comprehensive mediations of SDF-1alpha/CXCR4 axis, AKT/mTOR/HIF-alpha, ERK1/2 and Notch1 pathways in penumbra contribute to the improvements of neurological function, survival rate and infarct volume post-stroke. CI - Copyright (c) 2018 Elsevier GmbH. All rights reserved. FAU - Liu, Bowen AU - Liu B AD - State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao. FAU - Luo, Cheng AU - Luo C AD - State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao. FAU - Zheng, Zhaoguang AU - Zheng Z AD - School of Stomatology and Medicine, Foshan University, Foshan, PR China. FAU - Xia, Zhenyan AU - Xia Z AD - State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao. FAU - Zhang, Qian AU - Zhang Q AD - State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao. FAU - Ke, Chienchih AU - Ke C AD - Biomedical Imaging Research Center, Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taiwan. FAU - Liu, Renshyan AU - Liu R AD - Biomedical Imaging Research Center, Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taiwan; Department of Nuclear Medicine and National PET/Cyclotron Center, Taipei Veterans General Hospital, Taipei, Taiwan. FAU - Zhao, Yonghua AU - Zhao Y AD - State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao. Electronic address: yhzhao@must.edu.mo. LA - eng PT - Journal Article DEP - 20180410 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (Chemokine CXCL12) RN - 0 (Cxcr4 protein, rat) RN - 0 (Drugs, Chinese Herbal) RN - 0 (Hif1a protein, rat) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Notch1 protein, rat) RN - 0 (Receptor, Notch1) RN - 0 (Receptors, CXCR4) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Brain Ischemia/*drug therapy/metabolism MH - Cells, Cultured MH - Chemokine CXCL12/metabolism MH - Disease Models, Animal MH - Drugs, Chinese Herbal/chemistry/*pharmacology MH - Endothelium, Vascular/cytology MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Infarction, Middle Cerebral Artery MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Mitogen-Activated Protein Kinases/metabolism MH - Neovascularization, Physiologic/*drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats MH - Receptor, Notch1/metabolism MH - Receptors, CXCR4/metabolism MH - Stroke/*drug therapy/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - Vascular Endothelial Growth Factor Receptor-2/metabolism OTO - NOTNLM OT - Angiogenesis OT - Homeostasis OT - Ischemic stroke OT - Shengui Sansheng San EDAT- 2018/06/14 06:00 MHDA- 2018/07/03 06:00 CRDT- 2018/06/14 06:00 PHST- 2017/08/22 00:00 [received] PHST- 2018/01/28 00:00 [revised] PHST- 2018/04/09 00:00 [accepted] PHST- 2018/06/14 06:00 [entrez] PHST- 2018/06/14 06:00 [pubmed] PHST- 2018/07/03 06:00 [medline] AID - S0944-7113(18)30125-9 [pii] AID - 10.1016/j.phymed.2018.04.025 [doi] PST - ppublish SO - Phytomedicine. 2018 May 15;44:20-31. doi: 10.1016/j.phymed.2018.04.025. Epub 2018 Apr 10.