UM  > 中華醫藥研究院
Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin
Shang Li1,7; Nana Ai1; Mingyun Shen2,3; Yuanye Dang1; Cheong-Meng Chong1; Peichen Pan2; Yiu Wa Kwan4; Shun Wan Chan5; George Pak Heng Leung6; Maggie Pui Man Hoi1; Tingjun Hou2,3; Simon Ming-Yuen Lee1
2017
Source PublicationCELL DEATH DISCOVERY
ISSN2058-7716
Volume3
Abstract

Hemorrhagic stroke occurs when a weakened vessel ruptures and bleeds into the surrounding brain, leading to high rates of deathand disability worldwide. A series of complex pathophysiological cascades contribute to the risk of hemorrhagic stroke, and notherapies have proven effective to prevent hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potentialtherapeutic target for hemorrhagic stroke. ROCKs, which belong to the serine/threonine protein kinase family and participate in theorganization of actin cytoskeleton, have become attractive targets for the treatment of strokes. In this study,in vitroenzyme-basedassays revealed that a new compound (FPND) with a novel scaffold identified by docking-based virtual screening could inhibitROCK1 specifically at low micromolar concentration. Molecular modeling showed that FPND preferentially interacted with ROCK1,and the difference between the binding affinity of FPND toward ROCK1 and ROCK2 primarily resulted from non-polar contributions.Furthermore, FPND significantly prevented statin-induced cerebral hemorrhage in a zebrafish model. In addition,in vitrostudiesusing the xCELLigence RTCA system, immunofluorescence and western blotting revealed that FPND prevented statin-inducedcerebral hemorrhage by enhancing endothelial cell–cell junctions through inhibiting the ROCK-mediated VE-cadherin signalingpathway. As indicated by the extremely low toxicity of FPND against mice, it is safe and can potentially prevent vascular integrityloss-related diseases, such as hemorrhagic stroke.

DOI10.1038/cddiscovery.2017.51
Indexed BySCI
Language英语
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000463082900068
Fulltext Access
Citation statistics
Cited Times [WOS]:5   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, and Institute of Chinese Medical Sciences, University of Macau, Macau, China
2.College of PharmaceuticalSciences, Zhejiang University, Hangzhou, China
3.Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, China
4.School of Biomedical Sciences,Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
5.State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Department of AppliedBiology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
6.Pharmacology and Pharmacy, Faculty of Medicine, The University of HongKong, Hong Kong, China
7.Laboratory for Accelerated Vascular Research, Department of Surgery, Division of Vascular Surgery, University of California, San Francisco, CA 94143, USA
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Shang Li,Nana Ai,Mingyun Shen,et al. Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin[J]. CELL DEATH DISCOVERY,2017,3.
APA Shang Li.,Nana Ai.,Mingyun Shen.,Yuanye Dang.,Cheong-Meng Chong.,...&Simon Ming-Yuen Lee.(2017).Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin.CELL DEATH DISCOVERY,3.
MLA Shang Li,et al."Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin".CELL DEATH DISCOVERY 3(2017).
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Shang Li]'s Articles
[Nana Ai]'s Articles
[Mingyun Shen]'s Articles
Baidu academic
Similar articles in Baidu academic
[Shang Li]'s Articles
[Nana Ai]'s Articles
[Mingyun Shen]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Shang Li]'s Articles
[Nana Ai]'s Articles
[Mingyun Shen]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.