Molecular Biological Mechanisms of Action of Chrysophanol in Hepatic Stellate Cells Activated by Hepatic B Virus X Based on Network Pharmacology.

IF 3.2 4区 医学 Q3 VIROLOGY
Intervirology Pub Date : 2024-01-01 Epub Date: 2024-12-06 DOI:10.1159/000542355
Chih-Hung Lin, Ching-Feng Cheng, Yi-Shiou Chiou, Inga Wang, Chan-Yen Kuo
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引用次数: 0

Abstract

Introduction: Chrysophanol (Cho) is a natural anthraquinone with biological effects such as inducing ferroptosis and anticancer activity. The hepatitis B virus X protein (HBx) is essential for HBV replication. We aimed to identify the key pathways in HBx-induced hepatic stellate cell (HSC) activation and to characterize the potential mechanisms of action of Cho against liver fibrosis.

Methods: HSC-T6 cells were transfected with FLAG (control group) or FLAG-HBx (HBx group), and RNA sequencing and Western blotting analysis were conducted to assess the effects of HBx and Cho on specific molecular targets and signaling pathways.

Results: Gene ontology and pathway analyses indicated that the genes targeted by HBx participate in immunological responses, chemokine and cytokine activity, cell-substrate adhesion, extracellular matrix organization, growth factor binding, defense responses, and antigen processing and presentation. RNA-seq and Western blotting data revealed that HBx-activated HSC-T6 cells exhibited upregulated expression of mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR), S6, phosphorylated S6 (p-S6), peroxisome proliferator-activated receptor (PPAR-α), phosphorylated-PPAR-α (p-PPAR-α), CYP27, α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and Integrin-β1, which was reversed after treatment with Cho. These results were also verified in a HBx-activated HSC-T6 and LX-2 cell model and thioacetamide-induced liver fibrosis mouse model.

Conclusions: Thus, our findings indicate that Cho ameliorates HBx-induced HSC activation and liver fibrosis via inhibition of the mTOR and PPARs signaling pathways, suggesting that Cho is a potential therapeutic for chronic liver inflammation-mediated diseases.

基于网络药理学的大黄酚对乙型肝炎病毒激活的肝星状细胞作用的分子生物学机制
大黄酚(Cho)是一种天然蒽醌类物质,具有诱导铁下垂和抗癌等生物学作用。乙型肝炎病毒X蛋白(HBx)对HBV复制至关重要。我们旨在确定hbx诱导的肝星状细胞(HSC)激活的关键途径,并表征Cho抗肝纤维化的潜在作用机制。方法:用FLAG(对照组)或FLAG-HBx (HBx组)转染HSC-T6细胞,通过RNA测序和Western blotting分析,评估HBx和Cho对特定分子靶点和信号通路的影响。结果:基因本体和通路分析表明,HBx靶向基因参与免疫应答、趋化因子和细胞因子活性、细胞-底物粘附、细胞外基质组织、生长因子结合、防御应答、抗原加工和递呈等。RNA-seq和Western blotting数据显示,hbx激活的HSC-T6细胞表现出哺乳动物雷帕霉素靶蛋白(mTOR)、磷酸化mTOR (p-mTOR)、S6、磷酸化S6 (p-S6)、过氧化物酶体增殖物激活受体(PPAR-α)、磷酸化PPAR-α (p-PPAR-α)、CYP27、α-平滑肌肌动蛋白(α-SMA)、结结组织生长因子(CTGF)、整合素-β1的上调表达,经Cho处理后表达逆转。这些结果也在hbx激活的HSC-T6和LX-2细胞模型和硫代乙酰胺诱导的肝纤维化小鼠模型中得到验证。结论:因此,我们的研究结果表明,Cho通过抑制mTOR和PPARs信号通路改善hbx诱导的HSC激活和肝纤维化,表明Cho是慢性肝脏炎症介导疾病的潜在治疗药物。
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来源期刊
Intervirology
Intervirology 医学-病毒学
CiteScore
5.40
自引率
0.00%
发文量
13
审稿时长
6-12 weeks
期刊介绍: ''Intervirology'' covers progress in both basic and clinical virus research, and aims to provide a forum for the various disciplines within virology. Issues publishing original papers alternate with thematic issues, focusing on clearly defined topics. This thematic concentration serves to make timely reviews, research reports and controversy easily accessible to both specialists in the field and those who want to keep track of the latest developments outside their own area of interest. In addition to original papers, regular issues publish short communications and letters to the editor to provide readers with a forum for the exchange of ideas and comments. The scope encompasses work on the molecular biology of human and animal viruses, including genome organization and regulation, and the structure and function of viral proteins. The pathogenesis, immunology, diagnosis, epidemiology, prophylaxis and therapy of viral diseases are considered.
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