HJC0416 Attenuates Fibrogenesis in Activated Hepatic Stellate Cells via STAT3 and NF-κB Pathways
| Autor: | Omar Nunez Lopez, Ravi S. Radhakrishnan, Yanping Gu, Xiaofu Wang, Divya Ramdas, Claire B. Cummins, Christian Sommerhalder, Jia Zhou |
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| Rok vydání: | 2021 |
| Předmět: |
Liver Cirrhosis
STAT3 Transcription Factor Drug Evaluation Preclinical Thiophenes Article Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Hepatic Stellate Cells Animals Humans Propidium iodide Cell Cycle NF-kappa B NF-κB Cell cycle Rats Cell biology IκBα chemistry 030220 oncology & carcinogenesis Benzamides STAT protein Hepatic stellate cell Phosphorylation 030211 gastroenterology & hepatology Surgery Signal transduction |
| Zdroj: | J Surg Res |
| ISSN: | 0022-4804 |
| DOI: | 10.1016/j.jss.2020.12.045 |
| Popis: | Background Hepatic fibrosis is wound-healing response that is the result of hepatic stellate cell (HSC) activation and subsequent excess extracellular matrix deposition. HSCs can be activated by a variety of inflammatory stimuli as well as through the signal transducer and activator of transcription 3 (STAT3) pathway. HJC0416 is a novel, orally bioavailable small-molecule inhibitor of STAT3 that was developed by our team using a fragment-based drug design approach. Previously, our team has shown that HJC0416 has antifibrogenic effects in activated HSCs. Recently, increasing evidence suggests that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) plays an important role in the activation of HSCs. In the present study, we examined the role of NF-κB inhibition of HSC activation by HJC0416. Methods LX-2 (human) and HSC-T6 (rat) cell lines were used. Expression levels of extracellular proteins, NF-κB and STAT3 expression and DNA binding, and inflammatory cytokine levels were determined using western blot, ELISA, and immunofluorescence assay. Results HJC0416 decreased cell viability in a dose-dependent manner in both cell lines and arrested the cell cycle at the S phase. Increased apoptosis was seen in LX-2 cells through Yo-Pro-1 and propidium iodide immunofluorescent stating. HJC0416 significantly decreased expression of fibronectin and collagen I as well as markedly decreased α-SMA and laminin. HJC0416 inhibited the STAT3 pathway by decreasing phosphorylation of STAT3, as well as signal transduction pathway activation. Notably, HJC0416 also inhibited the classic and alternative pathways of NF-κB activation. HJC0416 inhibited LPS-induced p65 nuclear translocation and DNA binding, as well as prevented phosphorylation and degradation of inhibitory protein IκBα. HJC0416 also prevented phosphorylation of serine residue 536 on p65. Conclusions HJC0416, an inhibitor of STAT3, was found to have antifibrogenic properties in activated hepatic stellate cell lines. In addition, HJC0416 was found to inhibit the NF-κB pathway. Owing to this double effect, HJC0416 demonstrates promise for in vivo experimentation as an antifibrosis treatment. |
| Databáze: | OpenAIRE |
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