白桦酯酸通过阻断TLR4/NF-κB信号通路抑制肝纤维化及酒精性脂肪肝的实验研究

发布时间：2021-12-09 12:54

　　肝纤维化是发生在所有慢性肝病患者上的一种可逆的创伤性反应。肝纤维化是发展到肝硬化的必经阶段,并与肝癌有关,是所有慢性肝病晚期并发症的共同病理基础。在肝损伤的过程中,活化的肝星状细胞（HSC）是肝纤维化形成过程中产生胶原的主要细胞,关于HSC细胞增殖及ECM产生中的分子机制研究是近来关注的热点。抑制炎症反应,对抗氧化应激,调节相关细胞因子的活性,干扰细胞因子信号转导等途径能够有效地抑制HSC的增殖、活化,从而有效对抗肝纤维化。肝细胞是各种肝毒性介质作用的主要靶细胞,包括各种肝炎病毒,酒精的代谢物和胆汁酸等,破坏肝细胞并释放大量活性氧簇（ROS）和炎性介质,造成炎症细胞的活化并进一步激活HSC,加剧肝纤维化的发生。因此,发现肝保护药物是发展抗肝纤维化治疗的迫切需要。本实验采用硫代乙酰胺和酒精建立肝纤维化模型,通过体内、体外实验研究白桦酯酸的抗肝纤维化作用及潜在的作用机制。（1）使用硫代乙酰胺（200mg/kg）建立大鼠肝纤维化模型,腹腔注射硫代乙酰胺每周两次连续六周。白桦酯酸（20mg/kg or50mg/kg）与硫代乙酰胺同时给药或在其之后给药直至第六周或第八周,考察白桦酯酸的肝脏预防作... 

【文章来源】：延边大学吉林省 211工程院校

【文章页数】：75 页

【学位级别】：博士

【文章目录】：
List of Figures
Abbreviations
摘要
Abstract
Introduction
    1. Hepatic stellate cells in Liver fibrosis
    2. Liver fibrosis models in vivo
    3. TLR4/NF-κB signaling in Liver fibrosis and inflammation
Chapter 1. The anti-fibrotic effect of betulinic acid is mediated through the inhibition ofNF-KB nuclear protein translocation
    Abstract
    1.1 Introduction
    1.2 Materials and Methods
        1.2.1 Chemical
        1.2.2 In vivo study
            1.2.2.1 Animals
            1.2.2.2 Animal treatment
            1.2.2.3 Determination of biochemical parameters
            1.2.2.4 Assay of hydroxyproline
            1.2.2.5 Western blot analysis in vivo
            1.2.2.6 Histopathological and immunohistochemistry examination
        1.2.3 In vitro study
            1.2.3.1 Cell culture
            1.2.3.2 Cell viability assay
            1.2.3.3 Western blot analysis in vitro
    1.3 Statistical analysis
    1.4 Results
        1.4.1 In vivo experiments
            1.4.1.1 The effects of BA on body weight and liver weight induced by TAA
            1.4.1.2 The biochemical levels and hydroxyproline content of rats treated with BA for TAA-induced liver fibrosis
            1.4.1.3 Histopathological and immunohistochemical changes in rat livers after TAA treatment
            1.4.1.4 The anti-fibrosis effects of BA in downregulating the expression of α-SMA and collagen-Ⅰ
        1.4.2 In vitro experiment
            1.4.2.1 Effects of BA on cell viability
            1.4.2.2 The effects of BA on α-SMA, TIMP-1, MMP-13, caspase-8 and caspase-3 expression
            1.4.2.3 The effects of BA on inhibiting TNF-α induced TLR-4/MyD88 signal, p65 nucleus translocation and p65 phosphorylation in HSCs
    1.5 Discussion
Chapter 2.Betulinic acid and Betulin alleviated ethanol-induced fat accumulation viamodulation of TLR4/NF-κB signal pathway
    Abstract
    2.1 Introduction
    2.2 Materials and Methods
        2.2.1 Reagents
        2.2.2 In vivo study
            2.2.2.1 Animals and treatment
            2.2.2.2 Determination of biochemical parameters and serum triglyceride levels
            2.2.2.3 Histopathological examination
        2.2.3 In vitro study
            2.2.3.1 Cell cultures
            2.2.3.2 Influence of BA and BT on ethanol cytotoxicity to HSC-T6 cells
            2.2.3.3 Cell treatment on HSC-T6 cells with ethanol and BA or BT
        2.2.4 Western blotting analysis
        2.2.5 Statistical analysis
    2.3 Results
        2.3.1 In vivo
            2.3.1.1 The effect of BA and BT on serum aminotransferase activities and TG levels
            2.3.1.2 The effect of BA and BT on histopathological changes induced by ethanol in mice
            2.3.1.3 The effect of BA and BT on modulating CYP2E1, SREBP-1 and p-STAT3 expression
        2.3.2 In vitro
            2.3.2.1 The effect of BA and BT on HSC-T6 cells viability incubation with ethanol
            2.3.2.2 The inhibition of BA and BT on α-SMA and collagen-1 levels in ethanol activated HSCs
            2.3.2.3 The effects of BA and BT on inhibiting ethanol induced TLR4/MyD88 signal and p65 nucleus translocation in HSCs
            2.3.2.4 The effect of BA and BT on the expression of p-AMPK and p-STAT3 in ethanol activated HSCs
    2.4 Discussion
Conclusions
References
Publication
致谢



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