NLRC5 regulates TGF-β1-induced proliferation and activation of hepatic stellate cells during hepatic fibrosis

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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Smad2 protects against TGF-β1/Smad3-mediated collagen synthesis in human hepatic stellate cells during hepatic fibrosis

Molecular and Cellular Biochemistry ◽

10.1007/s11010-014-2258-1 ◽

2014 ◽

Vol 400 (1-2) ◽

pp. 17-28 ◽

Cited By ~ 34

Author(s):

Lei Zhang ◽

Changwei Liu ◽

Xiao-ming Meng ◽

Cheng Huang ◽

Fengyun Xu ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Collagen Synthesis ◽

Stellate Cells ◽

Tgf Β1

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Schisandrin B Attenuates Hepatic Stellate Cell Activation and Promotes Apoptosis to Protect against Liver Fibrosis

Molecules ◽

10.3390/molecules26226882 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6882

Author(s):

Zhiman Li ◽

Lijuan Zhao ◽

Yunshi Xia ◽

Jianbo Chen ◽

Mei Hua ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Cell Activation ◽

Stellate Cell ◽

Stellate Cells ◽

Schisandrin B ◽

Proliferation And Apoptosis ◽

Induced Apoptosis ◽

Tgf Β1 ◽

Different Doses

The activation of hepatic stellate cells (HSC) plays a key role in the progression of hepatic fibrosis, it is essential to remove activated HSC through apoptosis to reverse hepatic fibrosis. Schisandrin B (Sch B) is the main chemical component of schisandrin lignan, and it has been reported to have good hepatoprotective effects. However, Schisandrin B on HSC apoptosis remains unclear. In our study, we stimulated the HSC-T6 and LX-2 cell lines with TGF-β1 to induce cell activation, and the proliferation and apoptosis of the activated HSC-T6 and LX-2 cells were detected after treatment with different doses of Schisandrin B. Flow cytometry results showed that Sch B significantly reduced the activity of activated HSC-T6 and LX-2 cells and significantly induced apoptosis. In addition, the cleaved-Caspase-3 levels were increased, the Bax activity was increased, and the Bcl-2 expression was decreased in HSC-T6 and LX-2 cells treated with Sch B. Our study showed that Sch B inhibited the TGF-β1-induced activity of hepatic stellate cells by promoting apoptosis.

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Forsythiaside A Regulates Activation of Hepatic Stellate Cells by Inhibiting NOX4-Dependent ROS

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/9938392 ◽

2022 ◽

Vol 2022 ◽

pp. 1-17

Author(s):

Mengting Zhou ◽

Xingtao Zhao ◽

Li Liao ◽

Ying Deng ◽

Meichen Liu ◽

...

Keyword(s):

Liver Fibrosis ◽

Western Blot ◽

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Antioxidant Activities ◽

Stellate Cells ◽

Tnf Α ◽

And Migration ◽

Tgf Β1 ◽

Proliferation And Migration

Hepatic stellate cells (HSCs) activation is an important step in the process of hepatic fibrosis. NOX4 and reactive oxygen species expressed in HSCs play an important role in liver fibrosis. Forsythiaside A (FA), a phenylethanoid glycoside extracted and isolated from Forsythiae Fructus, has significant antioxidant activities. However, it is not clear whether FA can play a role in inhibiting the HSCs activation through regulating NOX4/ROS pathway. Therefore, our purpose is to explore the effect and mechanism of FA on HSCs activation to alleviate liver fibrosis. LX2 cells were activated by TGF-β1 in vitro. MTT assay and Wound Healing assay were used to investigate the effect of FA on TGF-β1-induced LX2 cell proliferation and migration. Elisa kit was used to measure the expression of MMP-1 and TIMP-1. Western blot and RT-qPCR were used to investigate the expression of fibrosis-related COLI, α-SMA, MMP-1 and TIMP-1, and inflammation-related TNF-α, IL-6 and IL-1β. The hydroxyproline content was characterized using a biochemical kit. The mechanism of FA to inhibit HSCs activation and apoptosis was detected by DCF-DA probe, RT-qPCR, western blot and flow cytometry. NOX4 siRNA was used to futher verify the effect of FA on NOX4/ROS pathway. The results showed that FA inhibited the proliferation and migration of LX2 cells and adjusted the expression of MMP-1, TIMP-1, COLI, α-SMA, TNF-α, IL-6 and IL-1β as well as promoted collagen metabolism to show potential in anti-hepatic fibrosis. Mechanically, FA down-regulated NOX4/ROS signaling pathway to improve oxidation imbalances, and subsequently inhibited PI3K/Akt pathway to suppress proliferation. FA also promoted the apoptosis of LX2 cells by Bax/Bcl2 pathway. Furthermore, the effects of FA on TGF-β1-induced increased ROS levels and α-SMA and COLI expression were weaken by silencing NOX4. In conclusion, FA had potential in anti-hepatic fibrosis at least in part by remolding of extracellular matrix and improving oxidation imbalances to inhibit the activation of HSCs and promote HSCs apoptosis.

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The Combination of Schisandrol B and Wedelolactone Synergistically Reverses Hepatic Fibrosis Via Modulating Multiple Signaling Pathways in Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.655531 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yongqiang Ai ◽

Wei Shi ◽

Xiaobin Zuo ◽

Xiaoming Sun ◽

Yuanyuan Chen ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Inhibitory Effect ◽

Matrix Proteins ◽

Hepatocyte Injury ◽

Early Fibrosis ◽

Multiple Signaling ◽

Tgf Β1 ◽

Antifibrotic Drugs

Hepatic fibrosis represents an important event in the progression of chronic liver injury to cirrhosis, and is characterized by excessive extracellular matrix proteins aggregation. Early fibrosis can be reversed by inhibiting hepatocyte injury, inflammation, or hepatic stellate cells activation, so the development of antifibrotic drugs is important to reduce the incidence of hepatic cirrhosis or even hepatic carcinoma. Here we demonstrate that Schisandrol B (SolB), one of the major active constituents of traditional hepato-protective Chinese medicine, Schisandra sphenanthera, significantly protects against hepatocyte injury, while Wedelolactone (WeD) suppresses the TGF-β1/Smads signaling pathway in hepatic stellate cells (HSCs) and inflammation, the combination of the two reverses hepatic fibrosis in mice and the inhibitory effect of the combination on hepatic fibrosis is superior to that of SolB or WeD treatment alone. Combined pharmacotherapy represents a promising strategy for the prevention and treatment of liver fibrosis.

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