scholarly journals Dendropanoxide, a Triterpenoid from Dendropanax morbifera, Ameliorates Hepatic Fibrosis by Inhibiting Activation of Hepatic Stellate Cells through Autophagy Inhibition

Nutrients ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 98
Author(s):  
Yong-Joo Park ◽  
Dong-Min Kim ◽  
Hye-Been Choi ◽  
Mi-Ho Jeong ◽  
Seung-Hwan Kwon ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hepatic Fibrosis ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Autophagosome Formation ◽  
Chronic Liver Damage ◽  
Dendropanax Morbifera ◽  
Mrna And Protein Expression ◽  
Autophagy Inhibition ◽  
Excessive Accumulation

Hepatic fibrosis results from chronic liver damage and is characterized by excessive accumulation of extracellular matrix (ECM). In this study, we showed that dendropanoxide (DPX), isolated from Dendropanax morbifera, had anti-fibrotic effects on hepatic fibrosis by inhibiting hepatic stellate cell (HSC) activation. DPX suppressed mRNA and protein expression of α-SMA, fibronectin, and collagen in activated HSCs. Moreover, DPX (40 mg/kg) treatment significantly lowered levels of liver injury markers (aspartate aminotransferase and alanine transaminase), expression of fibrotic markers, and deposition of ECM in a carbon tetrachloride-induced mouse model. Anti-fibrotic effects of DPX were comparable to those of silymarin in a hepatic fibrosis mouse model. As a possible mechanism of anti-fibrotic effects, we showed that DPX inhibited autophagosome formation (LC3B-II) and degradation of p62, which have important roles in HSC activation. These findings suggest that DPX inhibits HSC activation by inhibiting autophagy and can be utilized in hepatic fibrosis therapy.

scholarly journals Mapping glycan-mediated galectin-3 interactions by live cell proximity labeling

2020 ◽  
Author(s):  
Eugene Joeh ◽  
Timothy O’Leary ◽  
Weichao Li ◽  
Richard Hawkins ◽  
Jonathan R. Hung ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Weak Interactions ◽  
Stellate Cell ◽  
Three Dimensional ◽  
Stellate Cells ◽  
Living Cells ◽  
Live Cells ◽  
Galectin 3

AbstractGalectin-3 is a glycan-binding protein (GBP) that binds β-galactoside glycan structures to orchestrate a variety of important biological events, including the activation of hepatic stellate cells to cause hepatic fibrosis. While the requisite glycan epitopes needed to bind galectin-3 have long been elucidated, the cellular glycoproteins that bear these glycan signatures remain unknown. Given the importance of the three-dimensional arrangement of glycans in dictating GBP interactions, strategies that allow the identification of GBP receptors in live cells, where the native glycan presentation and glycoprotein expression are preserved, possess significant advantages over static and artificial systems. Here, we describe the integration of a proximity labeling method and quantitative mass spectrometry to map the glycan and glycoprotein interactors for galectin-3 in live hepatic stellate cells. Understanding the identity of the glycoproteins and defining the structures of the glycans required for galectin-3 mediated hepatic stellate cell activation will empower efforts to design and develop selective therapeutics to mitigate hepatic fibrosis.SignificanceBecause of the weak interactions between individual glycan-binding proteins (GBP), such as galectin-3, and glycans, strategies that allow the direct interrogation of these interactions in living cells remain limited. Thus, the glycan and glycoprotein ligands that are physiologically relevant for galectin-3 binding are insufficiently described. Here, we used a proximity labeling approach that catalytically tags interactors for galectin-3 and identified its pertinent glycan and glycoprotein counter-receptors in live hepatic stellate cells. This study demonstrates that proximity labeling is a powerful tool for mapping GBP complexes in living cells, and when coupled with chemical inhibitors, it can discriminate between protein-protein and protein-glycan interactions.Graphical Abstract

scholarly journals Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis

2020 ◽  
Vol 26 (3) ◽  
pp. 280-293 ◽  
Author(s):  
Le Thi Thanh Thuy ◽  
Hoang Hai ◽  
Norifumi Kawada
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Radical Scavenger ◽  
History Of Research ◽  
Duct Ligation ◽  
History Of

Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis. In the livers of both humans and rodents, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development in mouse models of chronic liver injury including diethylnitrosamine-induced hepatocellular carcinoma, bile duct ligation-induced cholestasis, thioacetamide-induced hepatic fibrosis, and choline-deficient L-amino acid-defined diet-induced non-alcoholic steatohepatitis. This review focuses on the history of research into the role of reactive oxygen species and nitrogen species in liver fibrosis and discusses the current perception of Cygb as a novel radical scavenger with an emphasis on its role in hepatic stellate cell activation and fibrosis.

scholarly journals Saikosaponin D Inhibits the Proliferation and Promotes the Apoptosis of Rat Hepatic Stellate Cells by Inducing Autophagosome Formation

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Hong Jiang ◽  
Jia Liu ◽  
Kun Zhang ◽  
Qingxin Zeng
Keyword(s):  
Flow Cytometry ◽  
Hepatic Stellate Cells ◽  
Caspase 3 ◽  
Stellate Cell ◽  
Annexin V ◽  
Stellate Cells ◽  
Double Staining ◽  
Autophagosome Formation ◽  
Proliferation And Apoptosis ◽  
Normal Rat

Objective. This study aimed to investigate the effects of saikosaponin D (SSd) on the proliferation and apoptosis of the HSC-T6 hepatic stellate cell line and determine the key pathway that mediates SSd’s function. Methods. Cell viability was detected using the CCK-8 kit. The EdU kit and flow cytometry were used to examine cell proliferation. The Annexin V-FITC/PI double staining kit and flow cytometry were used to examine cell apoptosis. Western blot analysis was performed to analyze the expression levels of LC3, Ki67, cleaved caspase 3, Bax, and Bcl2. Autophagosome formation was detected by LC3-GFP adenovirus transfection. Results. SSd inhibits the proliferation and promotes the apoptosis of acetaldehyde-activated HSC-T6 cells. SSd treatment increased the expression of cleaved caspase 3 and Bax but reduced that of Ki67 and Bcl2. The same concentration of SSd barely influenced the growth of normal rat liver BRL-3A cells. SSd upregulated LC3-II expression and induced autophagosome formation. Autophagy agonist rapamycin had the same effect as SSd and autophagy inhibitor 3-methyladenine could neutralize the effect of SSd in acetaldehyde-activated HSC-T6 cells. Conclusions. SSd could inhibit the proliferation and promote the apoptosis of HSC-T6 cells by inducing autophagosome formation.

scholarly journals Curdione and Schisandrin C Synergistically Reverse Hepatic Fibrosis via Modulating the TGF-β Pathway and Inhibiting Oxidative Stress

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenzhang Dai ◽  
Qin Qin ◽  
Zhiyong Li ◽  
Li Lin ◽  
Ruisheng Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chinese Medicine ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Great Promise ◽  
Potential Candidate ◽  
Active Components

Hepatic fibrosis is the final pathway of several chronic liver diseases, which is characterized by the accumulation of extracellular matrix due to chronic hepatocyte damage. Activation of hepatic stellate cells and oxidative stress (OS) play an important role in mediating liver damage and initiating hepatic fibrosis. Hence, hepatic fibrosis can be reversed by inhibiting multiple channels such as oxidative stress, liver cell damage, or activation of hepatic stellate cells. Liuwei Wuling Tablets is a traditional Chinese medicine formula with the effect of anti- hepatic fibrosis, but the composition and mechanism of reversing hepatic fibrosis are still unclear. Our study demonstrated that one of the main active components of the Chinese medicine Schisandra chinensis, schisandrin C (Sin C), significantly inhibited oxidative stress and prevented hepatocyte injury. Meanwhile one of the main active components of the Chinese medicine Curdione inhibited hepatic stellate cell activation by targeting the TGF-β1/Smads signaling pathway. The further in vivo experiments showed that Sin C, Curdione and the combination of both have the effect of reversing liver fibrosis in mice, and the combined effect of inhibiting hepatic fibrosis is superior to treatment with Sin C or Curdione alone. Our study provides a potential candidate for multi-molecular or multi-pathway combination therapies for the treatment of hepatic fibrosis and demonstrates that combined pharmacotherapy holds great promise in the prevention and treatment of hepatic fibrosis.

scholarly journals MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1718-1727
Author(s):  
Shi-Ding Dou ◽  
Jiu-Na Zhang ◽  
Xiao-Li Xie ◽  
Ting Liu ◽  
Jun-Li Hu ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Intracellular Reactive Oxygen Species ◽  
Oxygen Species ◽  
Related Protein ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Intracellular Ros

Abstract Mitophagy affects the activation of hepatic stellate cells (HSCs). Mitochondria-targeted ubiquinone (MitoQ) is a mitochondria-targeted antioxidant that reduces the production of intracellular reactive oxygen species (ROS). However, its relationship with mitophagy remains unclear. This study evaluated mitophagy during HSC activation and the effects of MitoQ on mitophagy in cell culture and in an animal model of the activation of HSCs. We found that MitoQ reduced the activation of HSCs and alleviated hepatic fibrosis. PINK1 (PTEN-induced putative kinase 1) is a putative serine/threonine kinase located in the mitochondria’s outer membrane. While the activation of primary HSCs or LX-2 cells was associated with reduced PINK1/parkin-mediated mitophagy, MitoQ reduced intracellular ROS levels, enhanced PINK1/parkin-mediated mitophagy, and inhibited the activation of HSCs. After knocking down the key mitophagy-related protein, PINK1, in LX-2 cells to block mitophagy, MitoQ intervention failed to inhibit HSC activation. Our results showed that MitoQ inhibited the activation of HSCs and alleviated hepatic fibrosis by enhancing PINK1/parkin-mediated mitophagy.

scholarly journals Hepatic Stellate Cell Activation and Inactivation in NASH‑Fibrosis—Roles as Putative Treatment Targets?

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 365
Author(s):  
Alexandra Zisser ◽  
David H. Ipsen ◽  
Pernille Tveden-Nyborg
Keyword(s):  
Hepatic Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Treatment Modalities ◽  
Treatment And Prevention ◽  
Signaling Mechanisms ◽  
Cellular Pathways ◽  
Complex Signaling ◽  
Primary Predictor

Hepatic fibrosis is the primary predictor of mortality in patients with non-alcoholic steatohepatitis (NASH). In this process, the activated hepatic stellate cells (HSCs) constitute the principal cells responsible for the deposition of a fibrous extracellular matrix, thereby driving the hepatic scarring. HSC activation, migration, and proliferation are controlled by a complex signaling network involving growth factors, lipotoxicity, inflammation, and cellular stress. Conversely, the clearance of activated HSCs is a prerequisite for the resolution of the extracellular fibrosis. Hence, pathways regulating the fate of the HSCs may represent attractive therapeutic targets for the treatment and prevention of NASH-associated hepatic fibrosis. However, the development of anti-fibrotic drugs for NASH patients has not yet resulted in clinically approved therapeutics, underscoring the complex biology and challenges involved when targeting the intricate cellular signaling mechanisms. This narrative review investigated the mechanisms of activation and inactivation of HSCs with a focus on NASH-associated hepatic fibrosis. Presenting an updated overview, this review highlights key cellular pathways with potential value for the development of future treatment modalities.

scholarly journals Human Liver Stem Cell-Derived Extracellular Vesicles Target Hepatic Stellate Cells and Attenuate Their Pro-fibrotic Phenotype

2021 ◽  
Vol 9 ◽  
Author(s):  
Giulia Chiabotto ◽  
Elena Ceccotti ◽  
Marta Tapparo ◽  
Giovanni Camussi ◽  
Stefania Bruno
Keyword(s):  
Stem Cells ◽  
Hepatic Fibrosis ◽  
Extracellular Vesicles ◽  
Transforming Growth Factor Beta ◽  
Hepatic Stellate Cells ◽  
Human Liver ◽  
Adult Stem Cells ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Stellate Cells

Liver fibrosis occurs in response to chronic liver injury and is characterized by an excessive deposition of extracellular matrix. Activated hepatic stellate cells are primarily responsible for this process. A possible strategy to counteract the development of hepatic fibrosis could be the reversion of the activated phenotype of hepatic stellate cells. Extracellular vesicles (EVs) are nanosized membrane vesicles involved in intercellular communication. Our previous studies have demonstrated that EVs derived from human liver stem cells (HLSCs), a multipotent population of adult stem cells of the liver with mesenchymal-like phenotype, exert in vivo anti-fibrotic activity in the liver. However, the mechanism of action of these EVs remains to be determined. We set up an in vitro model of hepatic fibrosis using a human hepatic stellate cell line (LX-2) activated by transforming growth factor-beta 1 (TGF-β1). Then, we investigated the effect of EVs obtained from HLSCs and from human bone marrow-derived mesenchymal stromal cells (MSCs) on activated LX-2. The incubation of activated LX-2 with HLSC-EVs reduced the expression level of alpha-smooth muscle actin (α-SMA). Conversely, MSC-derived EVs induced an increase in the expression of pro-fibrotic markers in activated LX-2. The analysis of the RNA cargo of HLSC-EVs revealed the presence of several miRNAs involved in the regulation of fibrosis and inflammation. Predictive target analysis indicated that several microRNAs (miRNAs) contained into HLSC-EVs could possibly target pro-fibrotic transcripts. In particular, we demonstrated that HLSC-EVs shuttled miR-146a-5p and that treatment with HLSC-EVs increased miR-146a-5p expression in LX-2. In conclusion, this study demonstrates that HLSC-EVs can attenuate the activated phenotype of hepatic stellate cells and that their biological effect may be mediated by the delivery of anti-fibrotic miRNAs, such as miR-146a-5p.

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

Molecules ◽  
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.

Rat hepatic stellate cell expression of α2-macroglobulin is a feature of cellular activation: implications for matrix remodelling in hepatic fibrosis

1998 ◽  
Vol 95 (2) ◽  
pp. 179-186 ◽  
Author(s):  
C. A. KAWSER ◽  
J. P. IREDALE ◽  
P. J. WINWOOD ◽  
M. J. P. ARTHUR
Keyword(s):  
Protease Inhibitor ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Northern Analysis ◽  
Control Value ◽  
Α2 Macroglobulin ◽  
Cell Expression

1.Hepatic stellate cells are key mediators of hepatic fibrosis. We have studied hepatic stellate cell expression of the collagenase and general protease inhibitor α2-macroglobulin after activation in tissue culture and in response to certain cytokines. 2.Hepatic stellate cells isolated by Pronase–collagenase digestion were activated by culture on uncoated plastic. By Northern analysis hepatic stellate cells undergoing activation (5 days) expressed α2-macroglobulin mRNA and α2-macroglobulin could be immunolocalized to hepatic stellate cells from 5 to 15 days of culture. 3.By ELISA of cell culture supernatants hepatic stellate cell secretion of α2-macroglobulin was found to increase from 2.78±1.13 ;ng·ml-1·μg-1 DNA per 24 ;h at 5 days of culture (n = 8) to 13.55±4.64 ;ng·ml-1·μg-1 DNA per 24 ;h at 15 days of culture (n = 7). Stimulation of hepatic stellate cells with interleukin-6 at 5 days caused a significant increase in α2-macroglobulin expression as did exposure to Kupffer-cell conditioned medium. However, exposure of hepatic stellate cells to interleukin-1, transforming growth factor-β1 and tumour necrosis factor-α had no significant effect. 4.During profibrotic liver injury plasma α2-macroglobulin levels were found to increase to between 850% and 250% of the control value (100%) after bile duct ligation (72 ;h to 13 days respectively), and to 1166% and 1106% of the control value during progressive CCl4-induced fibrosis (24 ;h to 4 weeks respectively). 5.These data suggest that hepatic stellate cells are a potential source of the potent protease inhibitor α2-macroglobulin, expression of which may inhibit matrix remodelling during progressive fibrosis.

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