肝纖維化是發(fā)生在所有慢性肝病患者上的一種可逆的創(chuàng)傷性反應(yīng)。肝纖維化是發(fā)展到肝硬化的必經(jīng)階段,并與肝癌有關(guān),是所有慢性肝病晚期并發(fā)癥的共同病理基礎(chǔ)。在肝損傷的過程中,活化的肝星狀細(xì)胞（HSC）是肝纖維化形成過程中產(chǎn)生膠原的主要細(xì)胞,關(guān)于HSC細(xì)胞增殖及ECM產(chǎn)生中的分子機(jī)制研究是近來關(guān)注的熱點(diǎn)。抑制炎癥反應(yīng),對(duì)抗氧化應(yīng)激,調(diào)節(jié)相關(guān)細(xì)胞因子的活性,干擾細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)等途徑能夠有效地抑制HSC的增殖、活化,從而有效對(duì)抗肝纖維化。肝細(xì)胞是各種肝毒性介質(zhì)作用的主要靶細(xì)胞,包括各種肝炎病毒,酒精的代謝物和膽汁酸等,破壞肝細(xì)胞并釋放大量活性氧簇（ROS）和炎性介質(zhì),造成炎癥細(xì)胞的活化并進(jìn)一步激活HSC,加劇肝纖維化的發(fā)生。因此,發(fā)現(xiàn)肝保護(hù)藥物是發(fā)展抗肝纖維化治療的迫切需要。本實(shí)驗(yàn)采用硫代乙酰胺和酒精建立肝纖維化模型,通過體內(nèi)、體外實(shí)驗(yàn)研究白樺酯酸的抗肝纖維化作用及潛在的作用機(jī)制。（1）使用硫代乙酰胺（200mg/kg）建立大鼠肝纖維化模型,腹腔注射硫代乙酰胺每周兩次連續(xù)六周。白樺酯酸（20mg/kg or50mg/kg）與硫代乙酰胺同時(shí)給藥或在其之后給藥直至第六周或第八周,考察白樺酯酸的肝臟預(yù)防作... 

【文章來源】：延邊大學(xué)吉林省 211工程院校

【文章頁數(shù)】：75 頁

【學(xué)位級(jí)別】：博士

【文章目錄】：
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
致謝



本文編號(hào)：3530667