Abstract
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.
Highlights
Many etiologies lead to the formation of liver fibrosis, including viral hepatitis (HCV or/andHBV), nonalcoholic fatty liver disease, abuse in ethyl alcohol consumption, and nonalcoholic steatohepatitis [1,2,3]
We know that activated hepatic stellate cells (HSCs) are responsible for liver fibrosis, due to the deposition of excessive extracellular matrix (ECM) and increased collagen accumulation mediated by Transforming growth factor-β1 (TGF-β1) [11,13]
We first determined whether 4-methoxy sulfonyl paeonol (4-MSP) suppresses the HSC activation through inhibiting the TGF-β1 signaling pathway
Summary
Many etiologies lead to the formation of liver fibrosis, including viral hepatitis (HCV or/andHBV), nonalcoholic fatty liver disease, abuse in ethyl alcohol consumption (alcoholic steatohepatitis), and nonalcoholic steatohepatitis [1,2,3]. Many etiologies lead to the formation of liver fibrosis, including viral hepatitis Hepatic fibrosis corresponds to the proliferation of myofibroblasts, excessive amplification, and abnormal deposition of extracellular matrix (ECM) [4]. When a liver is injured, the activated hepatic stellate cells (HSCs), that produce a lot of ECM in the liver, are recognized as major cells in the progression of liver fibrosis [5]. HSCs maintain a quiescent phenotype, and are mainly discovered in the perisinusoidal space, with the function of vitamin A storage [6]. Transforming growth factor-β1 (TGF-β1), a key cytokine, is involved in the formation of liver fibrosis. TGF-β1 directly induces collagen 1 and α-smooth muscle actin (α-SMA) expressed in HSCs through a phosphorylation of downstream Smad2/3 proteins [11,12,13]
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