title: A pentapeptide monocyte locomotion inhibitory factor protects brain ischemia injury by targeting the eEF1A1/endothelial nitric oxide synthase pathway.
abstract: OBJECTIVE
  Ischemic stroke is a major cause of death worldwide but lacks viable treatment or treatment targets. Monocyte locomotion inhibitory factor (MLIF) is a small heat-stable pentapeptide produced by Entamoeba histolytica in axenic culture, which is supposed to protect the brain from ischemic injury; the mechanism, however, remains unknown. In this study, we further investigated the mechanism underlying the protective role of MLIF in brain ischemia.
  
  
  METHODS
  A middle cerebral artery occlusion model in rats was used for detecting the effect of MLIF in the brain ischemia in vivo. To identify targets of MLIF in brain endothelial cells, we performed immunoprecipitation of biotin-conjugated MLIF and mass spectrometry.
  
  
  RESULTS
  MLIF can protect the brain from ischemic injury in vivo, yielding decreased ischemic volume, prolonged survival, and improved neurological outcome. In vitro studies showed that MLIF displayed protective effects through inhibition of expression of pathological inflammatory adhesion molecules and enhancing endothelial nitric oxide synthase expression and nitric oxide release in the cerebrovascular endothelium. The target screening experiments demonstrated binding of MLIF to the ribosomal protein translation elongation factor eEF1A1. MLIF enhanced endothelial nitric oxide synthase expression through stabilization of endothelial nitric oxide synthase mRNA, and eEF1A1 was shown to be necessary for this enhanced expression. Knockdown of eEF1A1 or inhibition of endothelial nitric oxide synthase attenuated MLIF-mediated inhibition of adhesion molecule expression.
  
  
  CONCLUSIONS
  In this study, we identified a new potential pharmacologically targetable mechanism underlying MLIF's protective effects in brain ischemia through the eEF1A1/endothelial nitric oxide synthase pathway.
authors: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors: Yuefan
authors: Y
authors: Zhang
authors: Jun
authors: J
authors: Chen
authors: Fan
authors: F
authors: Li
authors: Dong
authors: D
authors: Li
authors: Qinhui
authors: Q
authors: Xiong
authors: Yang
authors: Y
authors: Lin
authors: Dazhi
authors: D
authors: Zhang
authors: Xiao-Fan
authors: XF
authors: Wang
authors: Pengyuan
authors: P
authors: Yang
authors: Yao-Cheng
authors: YC
authors: Rui
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000503:physiopathology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications* / Q000503:physiopathology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009842:Oligopeptides / Q000502:physiology*; D020648:Peptide Elongation Factor 1 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C577475:EEF1A1 protein, rat; D009842:Oligopeptides; D020648:Peptide Elongation Factor 1; C430647:monocyte locomotion inhibitory factor; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III