PMID- 29527168
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 9
DP  - 2018
TI  - Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome 
      Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has 
      Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats.
PG  - 134
LID - 10.3389/fphar.2018.00134 [doi]
LID - 134
AB  - Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma 
      (PPARgamma) are both potential targets for treatment of pulmonary arterial 
      hypertension (PAH). Expression of IP and PPARgamma decreases in PAH, suggesting that 
      screening of dual agonists of IP and PPARgamma might be an efficient method for drug 
      discovery. Virtual screening (VS) of potential IP-PPARgamma dual-targeting agonists 
      was performed in the ZINC database. Ten of the identified compounds were further 
      screened, and cefminox was found to dramatically inhibit growth of PASMCs with no 
      obvious cytotoxicity. Growth inhibition by cefminox was partially reversed by 
      both the IP antagonist RO113842 and the PPARgamma antagonist GW9662. Investigation of 
      the underlying mechanisms of action demonstrated that cefminox inhibits the 
      protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway 
      through up-regulation of the expression of phosphatase and tensin homolog (PTEN, 
      which is inhibited by GW9662), and enhances cyclic adenosine monophosphate (cAMP) 
      production in PASMCs (which is inhibited by RO113842). In a rat model of 
      hypoxia-induced pulmonary hypertension, cefminox displayed therapeutic efficacy 
      not inferior to that of the prostacyclin analog iloprost or the PPARgamma agonist 
      rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPARgamma 
      that significantly inhibits PASMC proliferation by up-regulation of PTEN and 
      cAMP, suggesting that it has potential for treatment of PAH.
FAU - Xia, Jingwen
AU  - Xia J
AD  - Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan 
      University, Shanghai, China.
FAU - Yang, Li
AU  - Yang L
AD  - Department of Anesthesiology, Chongqing Medical University, Chongqing, China.
FAU - Dong, Liang
AU  - Dong L
AD  - Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan 
      University, Shanghai, China.
FAU - Niu, Mengjie
AU  - Niu M
AD  - Department of Gastroenterology Medicine, Xi'an Third Hospital, Xi'an, China.
FAU - Zhang, Shengli
AU  - Zhang S
AD  - Department of Applied Physics, Xi'an Jiaotong University, Xi'an, China.
FAU - Yang, Zhiwei
AU  - Yang Z
AD  - Department of Applied Physics, Xi'an Jiaotong University, Xi'an, China.
FAU - Wumaier, Gulinuer
AU  - Wumaier G
AD  - Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan 
      University, Shanghai, China.
FAU - Li, Ying
AU  - Li Y
AD  - Department of Respiratory Medicine, Shaanxi Provincial Second People's Hospital, 
      Xi'an, China.
FAU - Wei, Xiaomin
AU  - Wei X
AD  - Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan 
      University, Shanghai, China.
FAU - Gong, Yi
AU  - Gong Y
AD  - Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan 
      University, Shanghai, China.
FAU - Zhu, Ning
AU  - Zhu N
AD  - Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan 
      University, Shanghai, China.
FAU - Li, Shengqing
AU  - Li S
AD  - Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan 
      University, Shanghai, China.
LA  - eng
PT  - Journal Article
DEP - 20180223
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC5829529
OTO - NOTNLM
OT  - cyclic adenosine monophosphate
OT  - hypoxia-induced pulmonary hypertension
OT  - peroxisome proliferator-activated receptor-gamma
OT  - phosphatase and tensin homolog
OT  - prostacyclin receptor
EDAT- 2018/03/13 06:00
MHDA- 2018/03/13 06:01
PMCR- 2018/02/23
CRDT- 2018/03/13 06:00
PHST- 2017/11/24 00:00 [received]
PHST- 2018/02/07 00:00 [accepted]
PHST- 2018/03/13 06:00 [entrez]
PHST- 2018/03/13 06:00 [pubmed]
PHST- 2018/03/13 06:01 [medline]
PHST- 2018/02/23 00:00 [pmc-release]
AID - 10.3389/fphar.2018.00134 [doi]
PST - epublish
SO  - Front Pharmacol. 2018 Feb 23;9:134. doi: 10.3389/fphar.2018.00134. eCollection 
      2018.