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- W4285992408 abstract "Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis (SSc); accounts for substantial morbidity and mortality; and lacks effective therapy. Recent findings implicated TGFβ-activated kinase 1 (TAK1), triggered by TGF-β and toll-like receptor signaling, in SSc pathogenesis. The objectives were to evaluate the activation of TAK1 signaling axis in SSc patients and to evaluate the antifibrotic ability of pharmacological TAK1 blockade in organ fibrosis. HS-276, a drug-like novel small molecule inhibitor of TAK1 was screened for its anti-fibrotic potential in cell cultures using foreskin, adult and SSc skin fibroblasts, and in bleomycin induced skin and lung fibrosis model. HS-276 treatment ameliorated dermal and pulmonary fibrosis and reduced the expression of several pro-fibrotic mediators in bleomycin-treated mice compared to vehicle-treated control. Importantly, HS-276 induced the regression of pre-established organ fibrosis. HS-276 abrogated TGF-β1-induced activation of collagen synthesis and myofibroblasts differentiation in explanted normal skin fibroblasts (neonatal and adult) and in constitutively active SSc fibroblasts. The antifibrotic effects of HS-276 were accompanied by reduced phosphorylation of p38 MAPK and JNK signaling as well as reduced expression IL-6 and other inflammatory markers. These findings implicate the significance of TAK1 signaling pathway in SSc skin and lung fibrosis and identify HS-276 as a potential antifibrotic agent for the treatment of SSc and other fibrotic diseases." @default.
- W4285992408 created "2022-07-21" @default.
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- W4285992408 date "2022-08-01" @default.
- W4285992408 modified "2023-09-28" @default.
- W4285992408 title "599 Selective inhibition Of fibro-inflammatory kinase TAK1: A potential therapeutic strategy to ameliorate systemic sclerosis" @default.
- W4285992408 doi "https://doi.org/10.1016/j.jid.2022.05.608" @default.
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