The role of oxymatrine in regulating TGF-β1 in rats with hepatic fibrosis

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Abstract

Abstract Purpose: To investigate whether oxymatrine (OMT) prevents hepatic fibrosis in rats by regulating liver transforming growth factor β1 (TGF-β1) level. Methods: Hepatic fibrosis was induced in rats by thioacetamide (TAA). Blood was collected at the end of week 12 to determine the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and glutathione (GSH). Changes in liver tissue were observed after hematoxylin-eosin (HE) staining. Results: Fibrosis was confirmed by Masson’s collagen staining. Liver TGF-β1 level was determined by ELISA. OMT significantly reduced serum ALT and AST but increased GSH levels in rats with hepatic fibrosis. Moreover, it significantly improved liver histology in rats with TAA-induced hepatic fibrosis. It significantly decreased liver TGF-β1 level compared to that in the untreated group. It also significantly reduced collagen deposition in rats. Conclusion: Oxymatrine is effective in protecting rats from thioacetamide-induced hepatic fibrosis by regulating TGF-β1 expression.

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Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development.

Tao Han, Wei Xie, Wen Wen … (2012)

Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC). However, the mechanism underlying the progression from cirrhosis to HCC remains unclear. Herein we report the concurrent increase of liver progenitor cells (LPCs) and transforming growth factor-β (TGF-β) in diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis and cirrhotic livers of HCC patients. Using several experimental approaches, including 2-acetylaminofluorene/partial hepatectomy (2-AAF/PHx) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-elicited murine liver regeneration, we found that activation of LPCs in the absence of TGF-β induction was insufficient to trigger hepatocarcinogenesis. Moreover, a small fraction of LPCs was detected to coexpress tumor initiating cell (T-IC) markers during rat hepatocarcinogenesis and in human HCCs, and TGF-β levels were positively correlated with T-IC marker expression, which indicates a role of TGF-β in T-IC generation. Rat pluripotent LPC-like WB-F344 cells were exposed to low doses of TGF-β for 18 weeks imitating the enhanced TGF-β expression in cirrhotic liver. Interestingly, long-term treatment of TGF-β on WB-F344 cells impaired their LPC potential but granted them T-IC properties including expression of T-IC markers, increased self-renewal capacity, stronger chemoresistance, and tumorigenicity in NOD-SCID mice. Hyperactivation of Akt but not Notch, signal transducer and activator of transcription 3 (STAT3), or mammalian target of rapamycin (mTOR) was detected in TGF-β-treated WB-F344 cells. Introduction of the dominant-negative mutant of Akt significantly attenuated T-IC properties of those transformed WB-F344 cells, indicating Akt was required in TGF-β-mediated-generation of hepatic T-ICs. We further demonstrate that TGF-β-induced Akt activation and LPC transformation was mediated by microRNA-216a-modulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) suppression. Hepatoma-initiating cells may derive from hepatic progenitor cells exposed to chronic and constant TGF-β stimulation in cirrhotic liver, and pharmaceutical inhibition of microRNA-216a/PTEN/Akt signaling could be a novel strategy for HCC prevention and therapy targeting hepatic T-ICs. Copyright © 2012 American Association for the Study of Liver Diseases.

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Hepatic and serum levels of miR-122 after chronic HCV-induced fibrosis.

Inga Wedemeyer, Hans-Peter Dienes, Ingo Strack … (2013)

The progression of liver fibrosis in patients with chronic hepatitis C (CHC) is important to decide on the treatment of the virus. As liver biopsy and liver stiffness measurement for staging of fibrosis present limitations, circulating levels of miR-122 have been suggested as a novel biomarker to predict the extent of liver injury. We evaluated the potential of miR-122 as an indicator of fibrosis progression in CHC infection and performed, for the first time, a comprehensive analysis of hepatic and circulating miR-122 levels in patients with CHC. Patients with well-documented CHC infection were selected from the database of HepNet, the German-Competence-Network on Viral Hepatitis. All patients underwent blood sampling and liver biopsy with grading of inflammation and staging of fibrosis. RNA was extracted from 84 liver biopsies and 164 serum samples of CHC patients. miR-122 levels in liver and serum samples were quantified by real-time PCR normalized to RNU6 or spiked-in RNA, respectively. Hepatic levels of miR-122 decreased significantly with the severity of fibrosis (p = 0.001). In addition, circulating miR-122 levels correlated negatively with increasing stages of fibrosis, although the inverse correlation was moderate due to a two-phase miR-122 pattern during fibrosis progression. Thus, circulating miR-122 levels decreased in patients with severe fibrosis (F3, F4), while at early stages with distinct fibrotic structures (F2) and high inflammatory activity, miR-122 serum levels were elevated. We conclude that during progression of fibrosis less miR-122 is released into the blood stream due to the loss of liver cells and the decrease of hepatic miR-122 levels. Although the release of circulating miR-122 possibly mirrors acute liver injury, in chronic liver disease and fibrosis, the loss of liver cells and the decreased hepatocellular miR-122 expression render miR-122 an inappropriate marker, when exclusively used for interpretation of fibrosis progression. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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TGF-β/Smad signaling during hepatic fibro-carcinogenesis (Review)

Katsunori Yoshida, MIKI MURATA, Takashi Yamaguchi … (2014)

After hepatitis virus infection, plasma transforming growth factor (TGF)-β increases in either the acute or chronic inflammatory microenvironment. Although TGF-β is upregulated in patients with hepatocellular carcinoma, it is one of the most potent growth inhibitors for hepatocytes. This cytokine also upregulates extracellular matrix (ECM) production of hepatic stellate cells. Therefore, TGF-β is considered to be the major factor regulating liver carcinogenesis and accelerating liver fibrosis. Smad2 and Smad3 act as the intracellular mediators of TGF-β signal transduction pathway. We have generated numerous antibodies against individual phosphorylation sites in Smad2/3, and identified 3 types of phosphorylated forms (phospho-isoforms): COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2/3 (pSmad2L and pSmad3L) and dually phosphorylated Smad2/3 (pSmad2L/C and pSmad3L/C). These Smad phospho-isoforms are categorized into 3 groups: cytostatic pSmad3C signaling, mitogenic pSmad3L signaling and invasive/fibrogenic pSmad2L/C signaling. In this review, we describe differential regulation of TGF-β/Smad signaling after acute or chronic liver injuries. In addition, we consider how chronic inflammation associated with hepatitis virus infection promotes hepatic fibrosis and carcinogenesis (fibro-carcinogenesis), focusing on alteration of Smad phospho-isoform signaling. Finally, we show reversibility of Smad phospho-isoform signaling after therapy against hepatitis virus infection.

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Author and article information

Contributors

Jing Wu: Role: ND

Lin Pan: Role: ND

Xueqin Jin: Role: ND

Weihua Li: Role: ND

Hongbing Li: Role: ND

Jianmao Chen: Role: ND

Wen Yang: Role: ND

Journal

Journal ID (publisher-id): acb

Title: Acta Cirurgica Brasileira

Abbreviated Title: Acta Cir. Bras.

Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia (São Paulo, SP, Brazil )

ISSN (Print): 0102-8650

ISSN (Electronic): 1678-2674

Publication date (Print and electronic): March 2018

Volume: 33

Issue: 3

Pages: 207-215

Affiliations

[5] Yinchuan orgnameNingxia Medical University orgdiv1Laboratory Animal Center China

[4] Yinchuan orgnameNingxia Medical University orgdiv1Laboratory Animal Center China

[1] Yinchuan orgnameNingxia Medical University orgdiv1Laboratory Animal Center China

[2] Yinchuan orgnameNingxia Medical University orgdiv1The Affiliated Hospital China

[6] Yinchuan orgnameNingxia Medical University orgdiv1Laboratory Animal Center China

[3] Yinchuan orgnameNingxia Medical University orgdiv1Laboratory Animal Center China

Article

Publisher ID: S0102-86502018000300207

DOI: 10.1590/s0102-865020180030000002

PubMed ID: 29668780

SO-VID: 7bf5f245-047e-46e1-b000-fc9bae0234db

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This work is licensed under a Creative Commons Attribution 4.0 International License.

History

Date accepted : 20 February 2018

Date received : 22 November 2017

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Figures: 0, Tables: 0, Equations: 0, References: 27, Pages: 9

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SciELO Brazil

Keywords: Thioacetamide,Liver,Rats.,Transforming Growth Factor beta 1,Fibrosis

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Keywords: Thioacetamide, Liver, Rats., Transforming Growth Factor beta 1, Fibrosis

The role of oxymatrine in regulating TGF-β1 in rats with hepatic fibrosis

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Most cited references 25

Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development.

Hepatic and serum levels of miR-122 after chronic HCV-induced fibrosis.

TGF-β/Smad signaling during hepatic fibro-carcinogenesis (Review)

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