PMID- 36765040
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230214
IS  - 2058-7716 (Print)
IS  - 2058-7716 (Electronic)
IS  - 2058-7716 (Linking)
VI  - 9
IP  - 1
DP  - 2023 Feb 10
TI  - Repositioning linifanib as a potent anti-necroptosis agent for sepsis.
PG  - 57
LID - 10.1038/s41420-023-01351-y [doi]
LID - 57
AB  - Sepsis is a systemic inflammatory syndrome (SIRS) caused by acute microbial 
      infection, and it has an extremely high mortality rate. Tumor necrosis factor-alpha 
      (TNF-alpha)-induced necroptosis contributes to the pathophysiology of sepsis, so 
      inhibiting necroptosis might be expected to improve clinical outcomes in septic 
      patients. Here we predicted candidate drugs for treating sepsis in silico by 
      combining genes differentially expressed in septic patients and controls combined 
      with interrogation of the Library of Integrated Network-based Cellular Signatures 
      (LINCS) L1000 perturbation database. Sixteen candidate drugs were screened out 
      through bioinformatics analysis, and the top candidate linifanib was validated in 
      cellular and mouse models of TNF-alpha-induced necroptosis. Cell viability was 
      measured using a luminescent ATP assay, while the effects of linifanib on 
      necroptosis were investigated by western blotting, immunoprecipitation, and RIPK1 
      kinase assays. Linifanib effectively protected cells from necroptosis and rescued 
      SIRS mice from TNF-alpha-induced shock and death. In vitro, linifanib directly 
      suppressed RIPK1 kinase activity. In vivo, linifanib effectively reduced 
      overexpressed IL-6, a marker of sepsis severity, in the lungs of SIRS mice. Our 
      preclinical evidence using an integrated in silico and experimental drug 
      repositioning approach supports the potential clinical utility of linifanib in 
      septic patients. Further clinical validation is now warranted.
CI  - (c) 2023. The Author(s).
FAU - Yu, Liang
AU  - Yu L
AD  - School of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, 
      China.
FAU - Yang, Kai
AU  - Yang K
AD  - School of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, 
      China.
FAU - He, Xiaoyan
AU  - He X
AUID- ORCID: 0000-0002-4838-909X
AD  - Department of Neurology, Institute of Neural Regeneration and Repair, The First 
      Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China.
FAU - Li, Min
AU  - Li M
AD  - Department of Neurology, Institute of Neural Regeneration and Repair, The First 
      Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China.
FAU - Gao, Lin
AU  - Gao L
AD  - School of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, 
      China.
FAU - Zha, Yunhong
AU  - Zha Y
AUID- ORCID: 0000-0003-2899-226X
AD  - Department of Neurology, Institute of Neural Regeneration and Repair, The First 
      Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China. 
      yzha7808@ctgu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20230210
PL  - United States
TA  - Cell Death Discov
JT  - Cell death discovery
JID - 101665035
PMC - PMC9913023
COIS- The authors declare no competing interests.
EDAT- 2023/02/11 06:00
MHDA- 2023/02/11 06:01
PMCR- 2023/02/10
CRDT- 2023/02/10 23:27
PHST- 2022/11/01 00:00 [received]
PHST- 2023/01/30 00:00 [accepted]
PHST- 2023/01/26 00:00 [revised]
PHST- 2023/02/11 06:00 [pubmed]
PHST- 2023/02/11 06:01 [medline]
PHST- 2023/02/10 23:27 [entrez]
PHST- 2023/02/10 00:00 [pmc-release]
AID - 10.1038/s41420-023-01351-y [pii]
AID - 1351 [pii]
AID - 10.1038/s41420-023-01351-y [doi]
PST - epublish
SO  - Cell Death Discov. 2023 Feb 10;9(1):57. doi: 10.1038/s41420-023-01351-y.