The Role of Butylidenephthalide in Targeting the Microenvironment Which
Contributes to Liver Fibrosis Amelioration
#MMPMID27199755
Chuang HM
; Su HL
; Li C
; Lin SZ
; Yen SY
; Huang MH
; Ho LI
; Chiou TW
; Harn HJ
Front Pharmacol
2016[]; 7
(?): 112
PMID27199755
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The treatment of liver fibrosis has clinical limitations because of its multiple
etiologies, such as epithelial-mesenchymal transition (EMT) promotion, cell
regeneration and remodeling dysfunction, inflammatory cell activation, and scar
tissue deposition. These factors might be considered as a new target for the
fibrotic microenvironment, leading to increased fibrogenesis and liver fibrosis.
Here, we investigate a small molecule named butylidenephthalide (BP) and its
multiple effects on liver fibrosis treatment. Thioacetamide was used in vivo to
induce chronic liver fibrosis. BP was administered orally in rats for a period of
2 and 4 weeks, which resulted in a significantly reduced fibrosis score (p <
0.05) and (p < 0.001), respectively. The inflammatory reaction of macrophage
infiltration were reduced in the administration of BP, which led to the decrease
in the transaminase levels. Moreover, we also found liver functions recovering
(due to the increased serum albumin and reduced prothrombin time) where liver
cells regenerated, which can be seen in the increase of Ki-67 on Oval cell. In
addition, the fibrotic scar was also reduced, along with the expression of matrix
metalloprotease by hepatic stellate cell. Furthermore, regarding the
mechanism/study of EMT reduced by BP, the knockdown of BMP-7, which could reduce
?-SMA expression, was mediated by the regulation of TGF-?, which implies its
major role on EMT. Finally, in the in vivo study, BP treatment of liver fibrosis
was reduced by Bmp7 knockdown in zebrafish, suggesting that BP leads to the
reduction of liver fibrosis, which also depends on BMP-7 induction. These results
suggest that BP had multiple targets for treating liver fibrosis in the following
ways: reduction of EMT, decreasing inflammatory reaction, and liver cell
proliferation. This multiple targets approach provided a new mechanism to treat
liver injury and fibrosis.
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