miR-488-5p mitigates hepatic stellate cell activation and hepatic fibrosis via suppressing TET3 expression
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Abstract:
Numerous studies have demonstrated that hepatic fibrosis, a progressive condition as an endpoint of multiple chronic hepatic diseases, is largely characterized with the extensive activation of hepatic stellate cells (HSCs). The precise effect of miR-488-5p in HSCs during hepatic fibrosis has not been elucidated.In our study, qRT-PCR was applied to assess the level of miR-488-5p in activated HSCs stimulated by TGF-β1. We built murine liver fibrosis models with carbon tetrachloride (CCl4), high-fat diet (HFD) and bile duct ligation (BDL). In vitro, the effects of miR-488-5p in HSCs were examined through cell proliferation assay and apoptosis. Luciferase reporter assay was applied to identify the underlying target of miR-488-5p. In vivo, the effects of miR-488-5p were explored through mouse liver fibrosis models.The reduction of miR-488-5p in the activated HSCs induced by TGF-β1 and three mouse hepatic fibrosis models were identified. The in vitro functional experimentations verified that miR-488-5p restrained expression of fibrosis-related markers and proliferative capacity in HSCs. Mechanically, we identified that miR-488-5p inhibited tet methylcytosine dioxygenase 3 (TET3) expression via straightly binding onto the 3' UTR of its mRNA, which sequentially restrained the TGF-β/Smad2/3 pathway. TET3 inhibition induced by the overexpression of miR-488-5p reduced extracellular matrix deposition, which contributed to mitigating mouse liver fibrosis.We highlight that miR-488-5p restrains the activation of HSCs and hepatic fibrosis via targeting TET3 which is involved in the TGF-β/Smad2/3 signaling pathway. Collectively, miR-488-5p is identified as a potential therapeutic target for hepatic fibrosis.Keywords:
Hepatic stellate cell
Hepatic fibrosis
Colorectal Surgery
Hepatic fibrosis is an essential pathological process involved in various chronic hepatic diseases that may deteriorate into hepatic cirrhosis and hepatic cancer.Thus,it has become hot topics to seek bioactive components against hepatic fibrosis.Many researches found that saponins from Panax notoginseng have the potential to be a bioactive agent against hepatic fibrosis.This review summarizes the research findings that saponins from Panax notoginseng showed a protection of hepatic cells from the fibrosis by inhibition of hepatic stellate cells and synthesis of extracellular matrix,promoting apoptosis of hepatic stellate cells and degradation of extracellular matrix.The prospects of saponins from Panax notoginseng in management of hepatic fibrosis are also elaborated.
Panax notoginseng
Hepatic stellate cell
Hepatic fibrosis
Chronic hepatic
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Colorectal Surgery
Surgical oncology
Acute hepatitis
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Surgical oncology
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Surgical oncology
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Surgical oncology
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Transforming growth factor-β1 (TGF-β1) is the strongest hepatic fibrosis promoter. It can inhibit the proliferation of hepatic cells, endothelial cells and epithelial cells, promote the synthesis of extracellular matrix (ECM), induce the apoptosis of hepatic cells, and promote the activation of hepatic stellate cells (HSC). Knowing the mechanism how TGF-β1 causes hepatic fibrosis has significance in the diagnosis and treatment of hepatic fibrosis.
Key words:
Transforming growth factor-β1; Hepatic fibrosis; Extracellular matrix; Hepatic stellate cells
Hepatic stellate cell
Hepatic fibrosis
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Hepatic fibrosis is the accumulation of excess collagen as a result of chronic liver injury. If left unabated, hepatic fibrosis can lead to the disruption of the liver architecture, portal hypertension, and increased risk of progression to cirrhosis and hepatocellular carcinoma. The thiazolidinedione class of antidiabetic drugs, through their target peroxisome proliferator-activated receptor γ (PPARγ), have protective effects against liver fibrosis, and can inhibit the profibrotic activity of hepatic stellate cells, the major collagen-producing liver cells. However, these drugs have been ineffective in the treatment of established fibrosis, possibly due to side effects such as increased weight and adiposity. Recently, selective PPARγ modulators that lack these side effects have been identified, but their role in treating fibrosis has not been studied. In this study, we tested the effectiveness of one of these selective modulators, SR1664, in the mouse carbon tetrachloride model of established hepatic fibrosis. Treatment with SR1664 reduced the total and type 1 collagen content without increasing body weight. The abundance of activated hepatic stellate cells was also significantly decreased. Finally, SR1664 inhibited the profibrotic phenotype of hepatic stellate cells. In summary, a selective PPARγ modulator was effective in the reduction of established hepatic fibrosis and the activated phenotype of hepatic stellate cells. This may represent a new treatment approach for hepatic fibrosis.
Hepatic stellate cell
Hepatic fibrosis
Thiazolidinedione
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Colorectal Surgery
Surgical oncology
Acute hepatitis
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Abstract Background: Activated hepatic stellate cells are the most critical cell responsible for liver fibrosis. In liver fibrogenesis, platelet-derived growth factor is the most prominent mitogen for hepatic stellate cells. This study aims to explore the potential of gadolinium (Gd)-labeled cyclic peptides (pPB) targeted to platelet-derived growth factor receptor-β (PDGFR-β) as a magnetic resonance imaging (MRI) radiotracer to identify the progress of liver fibrosis by imaging hepatic PDGFR-β expression. Results: Hepatic PDGFR-β expression level was found to be paralleled with the severity of liver fibrosis, which was increased with the progression of fibrosis and reduced with the regression. Majority of cells expressing PDGFR-β was determined to be activated hepatic stellate cells in fibrotic livers. Culture-activated human hepatic stellate cells expressed abundant PDGFR-β, and FITC-labeled pPB could bind to human hepatic stellate cells in a concentration and time dependent manner. With Gd-labeled pPB as a tracer, an MRI modality demonstrated that the relative hepatic T1-weighed MR signal value was increased progressively along with severity of hepatic fibrosis and reduced with the remission. Conclusion: Hepatic PDGFR-β expression reflects the progress of hepatic fibrosis, and MR imaging using Gd-labeled pPB as a tracer may distinguish different stages of liver fibrosis in mice.
Hepatic stellate cell
Hepatic fibrosis
Platelet-derived growth factor
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Colorectal Surgery
Surgical oncology
Acute hepatitis
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