Details

Autor(en) / Beteiligte

• Zheng, Guang-Hao
• Liu, Jian
• Guo, Fang Yan
• Zhang, Zhi-Hong
• Jiang, Yin-Jing
• Lin, Yong-Ce
• Lan, Xiao-Qi
• Ren, Jie
• Wu, Yan-Ling
• Nan, Ji-Xing
• Jin, Cheng Hua
• Lian, Li-Hua

Titel

The in vitro and in vivo study of a pyrazole derivative, J-1063, as a novel anti-liver fibrosis agent: Synthesis, biological evaluation, and mechanistic analysis

Ist Teil von

• Bioorganic chemistry, 2022-05, Vol.122, p.105715-105715, Article 105715

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• [Display omitted] •J-1063 suppressed ECM deposition in HSCs, preventing the progress of HSCs transdifferentiation.•J-1063 exerted its anti-hepatic fibrosis activity by inhibiting the activation of TGF-β/Smad signaling pathway.•J-1063 prevented fibrotic inflammation by inhibiting the activation of NLRP3 inflammasome.•J-1063 inhibited the infiltration of macrophages and neutrophils in TAA-induced liver fibrosis. In the present study, we completed the synthesis of a pyrazole derivative J-1063 and evaluated the kinase inhibitory activity of J-1063 activin receptor-like kinase 5 (ALK5) and p38α mitogen-activated protein (MAP) in the enzymatic assay. We evaluated anti-fibrotic effects of J-1063 on TGF-β-induced hepatic stellate cells activation and TAA induced mice liver fibrosis. J-1063 showed much prior anti-fibrotic effects than those with LY2157299. Our data revealed that J-1063 exerted anti-fibrotic activity by inhibiting TGF-βR1 (ALK5), which is likely related to the inhibition of TGF-β--Smad signaling and NLRP3 inflammasome activation. The results suggest that J-1063 might be potential candidates for further anti-liver fibrosis drug development.