Dendropanoxide, a Triterpenoid from Dendropanax morbifera, Ameliorates Hepatic Fibrosis by Inhibiting Activation of Hepatic Stellate Cells through Autophagy Inhibition.
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ABSTRACT:
SUBMITTER: Park YJ
PROVIDER: S-EPMC8796030 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We explored the role of microRNA-30a (miR-30a) and the mechanism involved in hepatic fibrosis. MiR-30a overexpression was achieved by miR-30a mimics transfection in hepatic stellate cells (HSCs) (HSC-T6, LX-2), and miR-30a agomir (ago-miR-30a) treatment in mice. MiR-30a levels were measured using TaqMan miRNA assay system, and the localization of miR-30a was detected by fluorescence in situ hybridization (FISH). The interaction of miR-30a and Beclin1 was confirmed by dual-luciferase reporter assay. Autophagic flux was analysed using tandem mRFP-GFP-LC3 fluorescence microscopy, electron microscopy and Western blot of LC3-II/I ratio. MiR-30a was notably down-regulated in activated HSCs and LX-2-exosomes induced by TGF-β1; overexpression of miR-30a down-regulated extracellular matrix (ECM), such as α-SMA, TIMP-1, and Collagen I expression, and suppressed cell viability in HSCs. MiR-30a was significantly down-regulated in hepatic fibrosis mice and overexpression of miR-30a prevented BDL-induced fibrogenesis, concomitant with the down-regulation of ECM. MiR-30a inhibited HSCs autophagy and increased lipid accumulation in HSCs and in mice fibrotic hepatic tissues. MiR-30a inhibited its downstream effector of Beclin1 by direct targeting its 3'-UTR region. Moreover, Knock-down of Beclin1 by small interfering RNA (siRNA) inhibited HSC autophagy and activation in LX-2 cells. In conclusion, miR-30a is down-regulated in hepatic fibrosis models and its overexpression prevents liver fibrogenesis by directly suppressing Beclin1-mediated autophagy; therefore, miR-30a may be a new potential therapeutic target for controlling hepatic fibrosis.
| S-EPMC5706581 | biostudies-literature
Project description:Background: Liver fibrosis affects millions of people worldwide without an effective treatment. Although multiple cell types in the liver contribute to the fibrogenic process, hepatocyte death is considered to be the trigger. Multiple forms of cell death, including necrosis, apoptosis, and necroptosis, have been reported to co-exist in liver diseases. Mixed lineage kinase domain-like protein (MLKL) is the terminal effector in necroptosis pathway. Although necroptosis has been reported to play an important role in a number of liver diseases, the function of MLKL in liver fibrosis has yet to be unraveled. Methods and Results: Here we report that MLKL level is positively correlated with a number of fibrotic markers in liver samples from both patients with liver fibrosis and animal models. Mlkl deletion in mice significantly reduces clinical symptoms of CCl4- and bile duct ligation (BDL) -induced liver injury and fibrosis. Further studies indicate that Mlkl -/- blocks liver fibrosis by reducing hepatocyte necroptosis and hepatic stellate cell (HSC) activation. AAV8-mediated specific knockdown of Mlkl in hepatocytes remarkably alleviates CCl4-induced liver fibrosis in both preventative and therapeutic ways. Conclusion: Our results show that MLKL-mediated signaling plays an important role in liver damage and fibrosis, and targeting MLKL might be an effective way to treat liver fibrosis.
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Project description:BackgroundThis study investigated the mechanisms underlying the preventive effect of dihydromyricetin (DHM) against liver fibrosis involving hepatic stellate cells (HSCs) and hepatic natural killer (NK) cells.MethodsA carbon tetrachloride (CCl4)-induced liver fibrosis model was established in C57BL/6 mice to study the antifibrotic effect of DHM based on serum biochemical parameters, histological and immunofluorescence stainings, and the expression of several fibrosis-related markers. Based on the immunoregulatory role of DHM, the effect of DHM on NK cell activation ex vivo was evaluated by flow cytometry. Then, we investigated whether DHM-induced autophagy was involved in HSCs inactivation using enzyme-linked immunosorbent assays, transmission electron microscopy, and western blot analysis. Thereafter, the role of DHM in NK cell-mediated killing was studied by in vitro coculture of NK cells and HSCs, with subsequent analysis by flow cytometry. Finally, the mechanism by which DHM regulates NK cells was studied by western blot analysis.ResultsDHM ameliorated liver fibrosis in C57BL/6 mice, as characterized by decreased serum alanine transaminase and aspartate transaminase levels, decreased expressions of collagen I alpha 1 (CoL-1α1), collagen I alpha 2 (CoL-1α2), tissue inhibitor of metalloproteinases 1 (TIMP-1), α-smooth muscle actin (α-SMA) and desmin, as well as increased expression of matrix metalloproteinase 1 (MMP1). Interestingly, HSCs activation was significantly inhibited by DHM in vivo and in vitro. As expected, DHM also upregulated autophagy-related indicators in liver from CCl4-treated mice. DHM also prevented TGF-β1-induced activation of HSCs in vitro by initiating autophagic flux. In contrast, the autophagy inhibitor 3-methyladenine markedly abolished the antifibrotic effect of DHM. Surprisingly, the frequency of activated intrahepatic NK cells was significantly elevated by DHM ex vivo. Furthermore, DHM enhanced NK cell-mediated killing of HSCs by increasing IFN-γ expression, which was abolished by an anti-IFN-γ neutralizing antibody. Mechanistically, DHM-induced IFN-γ expression was through AhR-NF-κB/STAT3 pathway in NK cells.ConclusionThese results demonstrated that DHM can ameliorate the progression of liver fibrosis and inhibition of HSCs activation by inducing autophagy and enhancing NK cell-mediated killing through the AhR-NF-κB/STAT3-IFN-γ signaling pathway, providing new insights into the preventive role of DHM in liver fibrosis.
| S-EPMC8214786 | biostudies-literature
Project description:Persistent activation of hepatic stellate cells (HSCs) in the injured liver leads to the progression of liver injury from fibrosis to detrimental cirrhosis. In a previous study, we have shown that survivin protein is upregulated during the early activation of HSCs, which triggers the onset of liver fibrosis. However, the therapeutic potential of targeting survivin in a fully established fibrotic liver needs to be investigated. In this study, we chemically induced hepatic fibrosis in mice using carbon tetrachloride (CCl4) for 6 weeks, which was followed by treatment with a survivin suppressant (YM155). We also evaluated survivin expression in fibrotic human liver tissues, primary HSCs, and HSC cell line by histological analysis. αSMA+ HSCs in human and mice fibrotic liver tissues showed enhanced survivin expression, whereas the hepatocytes and quiescent (qHSCs) displayed minimal expression. Alternatively, activated M2 macrophage subtype induced survivin expression in HSCs through the TGF-β-TGF-β receptor-I/II signaling. Inhibition of survivin in HSCs promoted cell cycle arrest and senescence, which eventually suppressed their activation. In vivo, YM155 treatment increased the expression of cell senescence makers in HSCs around fibrotic septa such as p53, p21, and β-galactosidase. YM155 treatment in vivo also reduced the hepatic macrophage population and inflammatory cytokine expression in the liver. In conclusion, downregulation of survivin in the fibrotic liver decreases HSC activation by inducing cellular senescence and modulating macrophage cytokine expression that collectively ameliorates liver fibrosis.
| S-EPMC10964939 | biostudies-literature
Project description:The extract tea of Dendropanax morbifera is popular beverages in Korea, and their preventive and therapeutic roles in metabolic disorders have been reported. However, the molecular mechanism has not been studied despite the known efficacy of D. morbifera. Eleven fractions (fr.1-fr.11) were divided by MPLC to find the active compound. Among them, Fr.5 was superior to others in that the inhibitory efficacy of de novo triglyceride (TG) biosynthesis. NMR analysis revealed that Fr.5 is composed 98% or more (9Z,16S)-16-hydroxy-9,17-octadecadiene-12,14-diynoic acid (HOD). Treatment of HOD diminished oleic acid (OA)-induced TG accumulation in HepG2 hepatocytes and differentiation of 3T3-L1 preadipocytes by activating LKB1/AMPK. In addition, we determined the effect of the oral administration of the extract of D. morbifera on obesity and hepatic steatosis in high-fat diet (HFD)-induced obese mice. This study proved that D. morbifera containing HOD, the active substance, can show preventive or therapeutic efficacy on obesity and hepatic steatosis through the targeting LKB1/AMPK axis.
| S-EPMC5975361 | biostudies-literature
Project description:Aim:To investigate the mechanisms of Fuzheng Huayu (FZHY) Capsule in the treatment of hepatitis B (HBV)- associated fibrosis, HBV patients were divided into two groups, 50 cases were in the nucleotide analogues (NAs) group, while additional 50 cases were in the NAs?+?FZHY group. Methods:We assessed the curative effects of antifibrosis through liver function, FibroScan test, and liver biopsy and detected the ratio of lymphocyte subsets by flow cytometry. Peripheral blood lymphocyte and CD8+T, CD4+T, and natural killer cell subsets collected from patients were cocultured with LX-2 cells. Activation of LX-2 cells, production of the extracellular matrix, apoptosis, and proliferation of LX-2 cells were determined. Chronic liver injury models were established by ConA treatment. Results:It is evident that FZHY treatment significantly increased the percentage of NK cells, the rate of death, and apoptosis of LX-2 cells and decreased the FibroScan liver stiffness measurement value. The expressions of ?-SMA and procollagen type I mRNA in LX-2 cells of the FZHY treatment group as downregulated when they were cocultured with lymphocytes compared to those from the NAs group. The proliferation of LX-2 cells in the FZHY treatment group was inhibited compared to that in the NAs group. In a mouse model of hepatic fibrosis, PBLs and IHLs from ConA exposure plus FZHY treatment inhibited the ability of JS-1 cells to express ?-SMA. Conclusions:FZHY Capsule improved the disordered cellular immunity and postponed liver fibrosis possibly through inhibiting the interaction between lymphocyte and hepatic stellate cells.
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Project description:The aim of this study was to investigate the effect of quercetin on hepatic fibrosis, a characteristic response to acute or chronic liver injury. Mice were randomized to bile duct ligation (BDL) or carbon tetrachloride (CCl4) cirrhosis models. Quercetin (100?mg/kg or 200?mg/kg daily) was administered by gavage for 2 or 4 weeks. Liver tissue and blood samples were collected for histological and molecular analysis. The results of our experiments showed that quercetin reduced BDL or CCl4 liver fibrosis, inhibited extracellular matrix formation, and regulated matrix metallopeptidase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Quercetin attenuated liver damage by suppressing the TGF-?1/Smads signaling pathway and activating the PI3K/Akt signaling pathway to inhibit autophagy in BDL- or CCl4- induced liver fibrosis. Quercetin prevented hepatic fibrosis by attenuating hepatic stellate cell activation and reducing autophagy through regulating crosstalk between the TGF-?1/Smads and PI3K/Akt pathways.
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Project description:Recently, utilizing natural bioactive compounds for active ingredients in cosmetics has become a growing worldwide trend. More and more studies aim to identify the sources of herbal ingredients for applications in the pharmaceutical and cosmetic fields. Additionally, in order to optimize the safety of natural ingredients, choosing an environmentally friendly extraction method also plays an important role. In this work, an eco-friendly extraction technique for Dendropanax morbifera using microwave treatment and microwave-assisted Dendropanax morbifera extract (MA-DME) was investigated. The results indicate that higher yields of MA-DME were obtained than with conventional methods and that D. morbifera's antioxidant properties were enhanced. Moreover, we found that MA-DME exhibited extraordinary antioxidant, anti-aging, and skin-whitening activities. We suggest MA-DME as a potential cosmeceutical ingredient than could be utilized for comprehensive protection of human skin.
| S-EPMC9137482 | biostudies-literature
Project description:Background & aimsAutophagy plays a crucial role in hepatic homeostasis and its deregulation has been associated with chronic liver disease. However, the effect of autophagy on the release of fibrogenic extracellular vesicles (EVs) by platelet-derived growth factor (PDGF)-stimulated hepatic stellate cells (HSCs) remains unknown. Herein, we aimed to elucidate the role of autophagy, specifically relating to fibrogenic EV release, in fibrosis.MethodsIn vitro experiments were conducted in primary human and murine HSCs as well as LX2 cells. Small EVs were purified by differential ultracentrifugation. Carbon tetrachloride (CCl4) or bile duct ligation (BDL) were used to induce fibrosis in our mouse model. Liver lysates from patients with cirrhosis or healthy controls were compared by RNA sequencing.ResultsIn vitro, PDGF and its downstream molecule SHP2 (Src homology 2-containing protein tyrosine phosphatase 2) inhibited autophagy and increased HSC-derived EV release. We used this PDGF/SHP2 model to further investigate how autophagy affects fibrogenic EV release. RNA sequencing identified an mTOR (mammalian target of rapamycin) signaling molecule that was regulated by SHP2 and PDGF. Disruption of mTOR signaling abolished PDGF-dependent EV release. Activation of mTOR signaling induced the release of multivesicular body-derived exosomes (by inhibiting autophagy) and microvesicles (by activating ROCK1 signaling). These mTOR-dependent EVs promoted in vitro HSC migration. To assess the importance of this mechanism in vivo, SHP2 was selectively deleted in HSCs, which attenuated CCl4- or BDL-induced liver fibrosis. Furthermore, in the CCl4 model, mice receiving circulating EVs derived from mice with HSC-specific Shp2 deletion had less fibrosis than mice receiving EVs from control mice. Correspondingly, SHP2 was upregulated in patients with liver cirrhosis.ConclusionThese results demonstrate that autophagy in HSCs attenuates liver fibrosis by inhibiting the release of fibrogenic EVs.Lay summaryDuring liver fibrosis and cirrhosis, activated hepatic stellate cells (HSCs) are the key cell type responsible for fibrotic tissue deposition. Recently, we demonstrated that activated HSCs release nano-sized vesicles enriched with fibrogenic proteins. In the current study, we unveil the mechanism by which these fibrogenic vesicles are released, moving a step closer to the long-term goal of therapeutically targeting this process.
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Project description:Clusterin is a glycoprotein that is expressed in most human tissues and found in body fluids. In our previous studies we demonstrated that clusterin has a protective effect against hepatic lipid accumulation and renal fibrosis; however, the role of clusterin in hepatic fibrosis is unknown. Here, we examined whether clusterin had protective effects against hepatic fibrosis using in vitro and in vivo models. Clusterin was upregulated in the livers of human cirrhotic patients and in thioacetamide (TAA)-induced and bile duct ligation mouse models of liver fibrosis. Loss and overexpression of clusterin promoted and attenuated hepatic fibrosis after TAA injection, respectively. In addition, we found that clusterin attenuates hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Smad3 signaling pathways. Thus, clusterin plays an important role in hepatic fibrosis.
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