Tectona grandis Leaf Extract Ameliorates Hepatic Fibrosis: Modulation of TGF- β /Smad Signaling Pathway and Upregulating MMP3/TIMP1 Ratio

Chronic liver injury may result in hepatic fibrosis, which can progress to cirrhosis and eventually liver failure. There are no drugs that are specifically approved for treating hepatic fibrosis. The natural product honokiol (HNK), a bioactive compound extracted from Magnolia grandiflora, represents a potential tool in the management of hepatic fibrosis. Though HNK has been reported to exhibit suppressive effects in a rat fibrosis model, the mechanisms accounting for this suppression remain unclear. In the present study, the anti-fibrotic effects of HNK on the liver were evaluated in vivo and in vitro. In vivo studies utilized a murine liver fibrosis model, in which fibrosis is induced by treatment with carbon tetrachloride (CCl4). For in vitro studies, LX-2 human hepatic stellate cells (HSCs) were treated with HNK, and expression of markers of fibrosis, cell viability, the transforming growth factor-β (TGF-β1)/SMAD signaling pathway, and autophagy were analyzed. HNK was well tolerated and significantly attenuated CCl4-induced liver fibrosis in vivo. Moreover, HNK decreased HSC activation and collagen expression by downregulating the TGF-β1/SMAD signaling pathway and autophagy. These results suggest that HNK is a new potential candidate for the treatment of hepatic fibrosis through suppressing both TGF-β1/SMAD signaling and autophagy in HSCs.

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Effect of Oxymatrine on the TGFbeta-Smad signaling pathway in rats with CCl4-induced hepatic fibrosis

World Journal of Gastroenterology ◽

10.3748/wjg.14.2100 ◽

2008 ◽

Vol 14 (13) ◽

pp. 2100 ◽

Cited By ~ 28

Author(s):

Xiao-Ling Wu ◽

Wei-Zheng Zeng ◽

Ming-De Jiang ◽

Jian-Ping Qin ◽

Hui Xu

Keyword(s):

Signaling Pathway ◽

Hepatic Fibrosis ◽

Smad Signaling ◽

Smad Signaling Pathway

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Astragaloside Inhibits Hepatic Fibrosis by Modulation of TGF-β1/Smad Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/3231647 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Xingxing Yuan ◽

Zhiqiang Gong ◽

Bingyu Wang ◽

Xueying Guo ◽

Lei Yang ◽

...

Keyword(s):

Signaling Pathway ◽

Hepatic Fibrosis ◽

Collagen Fibers ◽

Control Group ◽

Smad Signaling ◽

Smad Proteins ◽

Smad Signaling Pathway ◽

Smad 3

Activation of HSC is a pivotal step in hepatic fibrosis. In the activation of HSC, the TGF-β1 plays a key role that can promote the occurrence of hepatic fibrosis by combining with Smad proteins. Astragaloside is the main active component extracted from Radix Astragali that has the effect of antioxidation and hepatoprotection. In the present study, we investigated the mechanism of astragalosides inhibiting hepatic fibrosis in vitro and in vivo. In vitro, astragalosides inhibited the activation of HSC and regulated the expression of MMP-2 and TIMP-2 and reduced the formation of collagen fibers. In vivo, administration of astragalosides decreased the serum ALT, AST, and TBiL in rats by reducing oxidative stress. Astragalosides also attenuated hepatic fibrosis by reducing the concentration of hydroxyproline and inhibiting the formation of collagen fibers. The expressions of TGF-β1, TβR-I, p-Smad 2, and p-Smad 3 were downregulated after astragalosides treatments, while Smad 7 was upregulated compared to the control group. The results indicated that the effect of astragaloside on hepatic fibrosis was related to the inhibition of HSC activation and the modulation of the TGF-β1/Smad signaling pathway.

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San-Cao Granule (三草颗粒) Ameliorates Hepatic Fibrosis through High Mobility Group Box-1 Protein/Smad Signaling Pathway

Chinese Journal of Integrative Medicine ◽

10.1007/s11655-015-2127-0 ◽

2015 ◽

Vol 24 (7) ◽

pp. 502-511 ◽

Cited By ~ 3

Author(s):

Shi-zhang Wei ◽

Sheng-qiang Luo ◽

Jian Wang ◽

Jia-bo Wang ◽

Rui-sheng Li ◽

...

Keyword(s):

Signaling Pathway ◽

Hepatic Fibrosis ◽

High Mobility ◽

High Mobility Group ◽

Smad Signaling ◽

Smad Signaling Pathway

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TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

Environmental Toxicology ◽

10.1002/tox.22878 ◽

2019 ◽

Vol 35 (4) ◽

pp. 419-429 ◽

Cited By ~ 5

Author(s):

Qiong Zhang ◽

Xuhong Chang ◽

Haibing Wang ◽

Yunlan Liu ◽

Xiaoxia Wang ◽

...

Keyword(s):

Signaling Pathway ◽

Hepatic Fibrosis ◽

Smad Signaling ◽

Smad Signaling Pathway ◽

Tgf Β1

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Neoagarooligosaccharide Protects against Hepatic Fibrosis via Inhibition of TGF-β/Smad Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22042041 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2041

Author(s):

Ji Hye Yang ◽

Sae Kwang Ku ◽

IL Je Cho ◽

Je Hyeon Lee ◽

Chang-Su Na ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Hepatic Fibrosis ◽

Inflammatory Responses ◽

Chronic Liver ◽

Mrna Levels ◽

Chronic Liver Injury ◽

Smad Signaling ◽

Smad Signaling Pathway

Hepatic fibrosis occurs when liver tissue becomes scarred from repetitive liver injury and inflammatory responses; it can progress to cirrhosis and eventually to hepatocellular carcinoma. Previously, we reported that neoagarooligosaccharides (NAOs), produced by the hydrolysis of agar by β-agarases, have hepatoprotective effects against acetaminophen overdose-induced acute liver injury. However, the effect of NAOs on chronic liver injury, including hepatic fibrosis, has not yet been elucidated. Therefore, we examined whether NAOs protect against fibrogenesis in vitro and in vivo. NAOs ameliorated PAI-1, α-SMA, CTGF and fibronectin protein expression and decreased mRNA levels of fibrogenic genes in TGF-β-treated LX-2 cells. Furthermore, downstream of TGF-β, the Smad signaling pathway was inhibited by NAOs in LX-2 cells. Treatment with NAOs diminished the severity of hepatic injury, as evidenced by reduction in serum alanine aminotransferase and aspartate aminotransferase levels, in carbon tetrachloride (CCl4)-induced liver fibrosis mouse models. Moreover, NAOs markedly blocked histopathological changes and collagen accumulation, as shown by H&E and Sirius red staining, respectively. Finally, NAOs antagonized the CCl4-induced upregulation of the protein and mRNA levels of fibrogenic genes in the liver. In conclusion, our findings suggest that NAOs may be a promising candidate for the prevention and treatment of chronic liver injury via inhibition of the TGF-β/Smad signaling pathway.

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Inhibitory Effect of Corilagin on miR-21-Regulated Hepatic Fibrosis Signaling Pathway

The American Journal of Chinese Medicine ◽

10.1142/s0192415x19500794 ◽

2019 ◽

Vol 47 (07) ◽

pp. 1541-1569 ◽

Cited By ~ 2

Author(s):

Xuan Zhou ◽

Jun Xiong ◽

Shi Lu ◽

Lei Luo ◽

Zhi-Lin Chen ◽

...

Keyword(s):

Growth Factor ◽

Liver Fibrosis ◽

Signaling Pathway ◽

Hepatic Fibrosis ◽

Type I ◽

Loss Of Function ◽

Smad Signaling ◽

Protein Levels ◽

Smad Signaling Pathway ◽

Liver Tissues

Corilagin is a polyphenol that can be extracted from many medicinal plants and shows multiple pharmacological effects. We aimed to investigate the role of corilagin on miR-21-regulated hepatic fibrosis, especially miR-21-regulated TGF-[Formula: see text]1/Smad signaling pathway, in hepatic stellate LX2 cell line and Sprague–Dawley rats. The mRNA or protein levels of miR-21, Smad7, connective tissue growth factor (CTGF), [Formula: see text]-smooth muscle actin ([Formula: see text]-SMA), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), collagen type I alpha 1 (COL1A1), Smad2, Smad3, Smad2/3, p-Smad2, p-Smad3, p-Smad2/3, and transforming growth factor-[Formula: see text]1 (TGF-[Formula: see text]1) in LX2 cells and liver tissues were determined. Furthermore, gain-of and loss-of function of miR-21 in miR-21-regulated TGF-[Formula: see text]1/Smad signaling pathway were analyzed in LX2 cells. Liver tissues and serum were collected for pathological analysis, immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Corilagin treatment reduced mRNA or protein levels of miR-21, CTGF, [Formula: see text]-SMA, TIMP-1, TGF-[Formula: see text]1, COL1A1, p-Smad2, p-Smad3, and p-Smad2/3 both in vitro and in vivo. While corilagin increased mRNA and protein levels of Smad7 and MMP-9. After gain-of and loss-of function of miR-21, the downstream effectors of miR-21-regulated TGF-[Formula: see text]1/Smad signaling pathway in LX2 cells changed accordingly, and the changes were inhibited by corilagin. Simultaneously, administration of corilagin not only ameliorated pathological manifestation of liver fibrosis but also reduced levels of [Formula: see text]-SMA and COL1A1 in liver tissues and TGF-[Formula: see text]1, ALT levels in serum. Corilagin is able to potentially prevent liver fibrosis by blocking the miR-21-regulated TGF-[Formula: see text]1/Smad signaling pathway in LX2 cells and CCl4-induced liver fibrosis rats, which may provide a novel therapeutic strategy for liver fibrosis.

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