4-Methoxy Sulfonyl Paeonol Inhibits Hepatic Stellate Cell Activation and Liver Fibrosis by Blocking the TGF-β1/Smad, PDGF-BB/MAPK and Akt Signaling Pathways

Liver fibrosis initiates the progression of cirrhosis, and, finally, hepatocellular carcinoma (HCC). The increased proliferation and activation of hepatic stellate cells (HSCs) are crucial for hepatic fibrogenesis. Paeonol is the major vigorous component of Cortex Moutan, a traditional herbal medici...

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Published in:Applied sciences 2020-09, Vol.10 (17), p.5941
Main Authors: Liao, Yi-Jen, Wang, Yuan-Hsi, Liu, Chao-Lien, Fang, Cheng-Chieh, Hsu, Ming-Hua, Suk, Fat-Moon
Format: Article
Language:English
Subjects:
AKT protein
Apoptosis
Carbon tetrachloride
Cell activation
Cell culture
Cell proliferation
Cirrhosis
Collagen
Fibrosis
Gelatinase A
Gene expression
Growth factors
hepatic stellate cells (HSCs)
Hepatocellular carcinoma
Hepatocytes
Herbal medicine
Laboratory animals
Liver
Liver cancer
Liver cirrhosis
liver fibrosis
MAP kinase
paeonol derivative
Phosphorylation
Platelet-derived growth factor
Platelet-derived growth factor BB
Pretreatment
Signal transduction
Smad protein
Smad2 protein
Solvents
Stellate cells
Transforming growth factor-b1
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Summary:Liver fibrosis initiates the progression of cirrhosis, and, finally, hepatocellular carcinoma (HCC). The increased proliferation and activation of hepatic stellate cells (HSCs) are crucial for hepatic fibrogenesis. Paeonol is the major vigorous component of Cortex Moutan, a traditional herbal medicine widely used for treating various diseases. Here, we identified a novel paeonol derivative (4-methoxy sulfonyl paeonol, 4-MSP) that inhibits TGF-β1-induced Smad2/3 phosphorylation and collagen expression in HSCs. 4-MSP pretreatment suppressed the PDGF-BB–induced phosphorylation of MAPK pathway members (MEK/ERK, p38, JNK), Akt/p70S6K, and HSC proliferation. However, 4-MSP treatment had no effect on the induction of apoptosis in HSCs. The microarray experiments showed that 4-MSP treatment affects the TGF-β signaling, MAPK cascade, and other pathways related to HSCs activation and proliferation. The administration of 4-MSP to a liver fibrosis mouse model induced by CCl4 significantly decreased the expression of hepatic fibrosis markers (α-SMA, col1A2, TGF-β, and MMP2), and attenuated hepatic collagen deposition and liver damage. In addition, no adverse effects were observed in 4-MSP exposed mice. In conclusion, this novel paeonol-phenylsulfonyl derivative prevents the progression of liver fibrosis through blocking TGF-β1/Smad, PDGF-BB/MAPK, and Akt signaling, which suggests its use as a novel therapeutic against liver fibrosis.
ISSN:2076-3417
2076-3417
DOI:10.3390/app10175941