Abstract
The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet, and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation, and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor κB (NF-κB), interleukin (IL)-1, IL-6 and tumour necrosis factor-α by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-κB, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-κB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-β1, α-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-κB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future.
Highlights
The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF)
F, treatment with ST2825 or Pyrrolidine dithiocarbamate (PDTC) partially reversed the production of secreted collagen elicited by LPS. These results showed that the myeloid differentiation factor 88 (MyD88)-dependent inhibitory effect of hepatic stellate cells (HSCs) activation by dioscin might be associated with the nuclear factor κ B (NF-κ B) pathway
In contrast with the traditional view, ALF is a passive and irreversible pathological process induced by the necrosis of liver parenchymal cells, and recent evidences have shown that even advanced fibrosis is reversible[35,36]
Summary
The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). TLR4, one receptor for LPS, can trigger two different signaling pathways, in which one is a myeloid differentiation factor 88 (MyD88)-dependent pathway and leads to the rapid activation of nuclear factor κ B (NF-κ B) and increased tumour necrosis factor-α (TNF-α ) production, and the other is an MyD88-independent pathway requiring the Toll/interleukin-1 receptor (TIR)-containing adaptor molecule. Both pathways can stimulate downstream signal cascades, inducing the production of proinflammatory cytokines, chemokines, and type I interferon[17]
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