title: Geniposide attenuates inflammatory response by suppressing P2Y14 receptor and downstream ERK1/2 signaling pathway in oxygen and glucose deprivation-induced brain microvascular endothelial cells.
abstract: BACKGROUND
  Fructus gardenia is widely used for treatment of stroke and infectious diseases in Chinese medicine. Geniposide is the key bioactive compound related to the pharmacodynamic actions of gardenia on ischemic stroke. The molecular mechanism by which geniposide improves the ischemic brain injury was observed in the study.
  
  
  OBJECTIVE
  Recent studies showed that geniposide had protective activities against the inflammatory response in ischemic stroke. However, the molecular mechanism of geniposide anti-inflammatory role has not yet been fully elucidated. In this study, we investigated the effect of geniposide on the expression of P2Y14 receptor and downstream signaling pathway in brain microvascular endothelial cells (BMECs).
  
  
  METHODS
  An in vitro model of cerebral ischemia in BMECs was established by oxygen-glucose-deprivation (OGD). To further confirm the specific effect of geniposide on P2Y14 receptor and downstream signaling pathways, we set up a UDP-glucose (an agonist of the P2Y14 receptor) stimulated model. After administration of geniposide, the expression of P2Y14 receptor, phosphorylation of RAF-1, mitogen activated protein kinase kinase1/2 (MEK1/2), extracellular signal-regulated kinase 1/2 (ERK1/2), level of interleukin-8 (IL-8), interleukin-1β (IL-1β), monocyte chemotactic protein 1 (MCP-1) in BMECs were determined.
  
  
  RESULTS
  The mRNA and protein expression of P2Y14 in the rat BMECs were up-regulated in OGD-induced injury. After administration of Geniposide, the expression of P2Y14 receptor was significantly down-regulated, the phosphorylation of RAF-1, MEK1/2, ERK1/2 were suppressed. Similar data were obtained in UDP-glc stimulated model. We also observed that geniposide markedly declined the production of IL-8, IL-1β and MCP-1 in OGD-induced BMECs.
  
  
  CONCLUSIONS
  Geniposide exerted anti-inflammatory effects by interfering with the expression of P2Y14 receptor, which subsequently inhibits the downstream ERK1/2 signaling pathways and the release of the pro-inflammatory cytokines IL-8, MCP-1, IL-1β. Therefore, this study provides the evidence for gardenia's clinical application in cerebral ischemia.
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: fhjingjing@qq.com.
authors.forename: Fanghe
authors.initials: F
authors.lastname: Li
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: liweihong.403@163.com.
authors.forename: Weihong
authors.initials: W
authors.lastname: Li
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: lixingguang@hotmail.com.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: lifeng95@vip.sina.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Clinical Medicine, Weifang Medical University, No 7166 Bao Tong Street, Weifang, Shandong Province 261053, China. Electronic address: zhanglinpeng1608@126.com.
authors.forename: Linpeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Xingzhi Academy, The Affiliated High School of Peking University, No 15 Da Ni Wan Road, Hai Dian District, Beijing 100080, China. Electronic address: wangbingce@stu.pkuschool.edu.cn.
authors.forename: Bingce
authors.initials: B
authors.lastname: Wang
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: Huangggr2011@126.com.
authors.forename: Guangrui
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, Beijing Tongzhou District Hospital of Integrated Chinese Medicine and Western Medicine, No 89 Che Zhan Road, Tong Zhou District, Beijing 101100, China. Electronic address: 597406909@qq.com.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Guo
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: 779264240@qq.com.
authors.forename: Liangqin
authors.initials: L
authors.lastname: Wan
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Temple University Health System, No 333 Cottman Avenue, Philadelphia, PA 19111, United States. Electronic address: Yongqiang.liu@fccc.edu.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: 735668409@qq.com.
authors.forename: Sai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: 2741510112@qq.com.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Kang
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, No 11 Bei San Huan Dong Road, Chao Yang District, Beijing 100029, China. Electronic address: mjbbjm0715@126.com.
authors.forename: Jiabao
authors.initials: J
authors.lastname: Ma
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D039823:Iridoids / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D039823:Iridoids; C528912:P2Y14 receptor, rat; D058470:Receptors, Purinergic P2Y; C007835:geniposide; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; D010100:Oxygen
keywords: Anti-inflammation; Brain microvascular endothelial cells; ERK1/2 signaling pathway; Geniposide; Geniposide (PubChem CID: 107848); P2Y(14) receptor