Revised life science colitis Manuscript.pdf (492.78 kB)
Rigosertib potently protects against colitis-associated intestinal fibrosis and inflammation by regulating PI3K/AKT and NF-?B signaling pathways
journal contribution
posted on 2023-06-09, 21:07 authored by Farzad Rahmani, Fereshteh Asgharzadeh, Amir Avan, Farnaz Barneh, Mohammad Reza Parizadeh, Gordon FernsGordon Ferns, Mikhail Ryzhikov, Mohammad Reza Ahmadian, Elisa Giovannetti, Mohieddin Jafari, Majid Khazaei, Seyed Mahdi HassanianAims: Rigosertib (RGS) is a PI3K inhibitor that exerts protective effects against tumor progression and cancer-related inflammation. This study was aimed to explore the regulatory effects of RGS on proliferative, pro-fibrotic and inflammatory factors in DSS- induced colitis mice model. Materials and Methods: The present study integrates systems and molecular biology approaches to investigate the therapeutic potency of RGS in an experimental model of colitis specifically examining its effects on the PI3K/AKT and NF-?B signaling pathways. Key findings: Analysis of time-resolved proteome profiling showed that PI3K-AKT inhibitors regulate expression of many proteins in all stages of inflammation, fibrogenesis and extracellular matrix remodeling. Consistent with our in-silico findings, RGS improved colitis disease activity as assessed by changes in body weight, degree of stool consistency, rectal bleeding and prolapse. RGS also reduced oxidative stress markers and colon histopathological score by decreasing inflammatory responses in colon tissues. Moreover, expression of pro-fibrotic and pro-inflammatory factors including Acta 2, Col 1a1, Col 1a2, IL-1ß, TNF-a, INF-?, and MCP-1 were suppressed in the mice treated with RGS compared to the control group. The protective effects of RGS were mediated by inactivation of PI3K/AKT and NF-kB signaling pathways. Significance: This study clearly demonstrates the anti-proliferative, anti-inflammatory and anti-fibrotic effects of RGS in colitis, that may have implications for the treatment of colitis and colitis-associated cancer.
History
Publication status
- Published
File Version
- Accepted version
Journal
Life SciencesISSN
0024-3205Publisher
ElsevierExternal DOI
Volume
249Article number
a117470Department affiliated with
- Division of Medical Education Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-04-21First Open Access (FOA) Date
2021-03-03First Compliant Deposit (FCD) Date
2020-04-20Usage metrics
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