Novel anti‐fibrotic modalities for liver fibrosis: Molecular targeting and regenerative medicine in fibrosis therapy

Abstract

Based on the cellular and molecular mechanisms underlying hepatic fibrogenesis, several kinds of approaches have been proposed to treat liver fibrosis. Among a number of growth factors and cytokines that regulate collagen metabolism, transforming growth factor (TGF)-β is the most potent factor to accelerate liver fibrosis by activating hepatic stellate cells, stimulating collagen gene transcription, and suppressing matrix metalloproteinases expression. Thus, TGF-β as well as its intracellular mediators, Smad proteins, can be potential therapeutic targets for liver fibrosis. Constitutive phosphorylation and nuclear accumulation of Smad3 is the common feature of activated stellate cells. We have synthesized a novel small compound that inhibits Smad3-dependent collagen gene transcription by promoting nuclear import of a transcriptional repressor, YB-1. Another insight into anti-fibrotic strategies is the contribution of bone marrow-derived cells to the regression of liver fibrosis. Administration of granulocyte-colony stimulating factor enhanced the migration of bone marrow-derived cells into fibrotic liver tissue and accelerated the regression of experimental liver fibrosis. We have recently identified novel unknown factors expressed by bone marrow-derived cells that not only ameliorate liver fibrosis but also accelerate regeneration of fibrotic liver.

Astaxanthin prevents TGFβ1-induced pro-fibrogenic gene expression by inhibiting Smad3 activation in hepatic stellate cells

“…5A). Smad3 phosphorylation is an important determinant of its nuclear translocation [38]. Consistent with the reduction in phosphorylated Smad3 by ASTX, the nuclear translocation of Smad3 was also reduced by ASTX, whereas TGFβ1 treatment increased nuclear Smad3 levels (Fig.…”

Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients

“…Based on extensive in vitro and animal data, TGF-β has long been suspected as an important mediator of fibrosis in SSc as well as a variety of other fibrotic diseases, including renal, pulmonary, cardiac, and liver fibrosis (29)(30)(31). However, to our knowledge there has never previously been clinical data directly supporting its role in humans.…”

Strategies to prevent and reverse liver fibrosis in humans and laboratory animals

“…Another strategy using the traditional Chinese medicine Haobie Yangyin Ruanjian decoction (HYRD) inhibited liver fibrosis induced by CCl4 in rats, likely through downregulation of the TGF-β/Smad fibrogenic signaling pathway (Yang et al 2010). Another study indicated that Y-box protein-1 (YB-1) is a negative regulator of collagen expression by physically interacting with p300/ Smad3, thereby abrogating the stimulatory effect of TGF-β and liver fibrosis induced by CCl4 in mice (Inagaki et al 2012). The novel small compound HSc025 can bind to the C-terminal region of YB-1 and promote the nuclear import of YB-1, resulted in the suppression of collagen gene expression (Higashi et al 2011).…”

“…TGF-β induces the phosphorylation of Smad3 and reduces formation of the Smad3/4 complex, thereby inducing Smad DNA-binding activity to stimulate the expression of collagen and suppress MMP expression (Inagaki et al 2012). Therefore, nuclear accumulation of phosphorylated Smad3 is the most common feature observed in activated HSCs, and the inhibition of Smad3 accumulation or export to nuclear can suppress the transcriptional activity of the collagen gene (Inagaki et al 2012).…”