發(fā)布時間：2021-01-11 21:00

　　目的：肝纖維化是繼發(fā)于各種慢性致病因素引起的肝臟炎癥損傷后組織修復(fù)過程中的代償反應(yīng),以細(xì)胞外基質(zhì)的過度沉積為病理特征,是各種慢性肝病向肝硬化發(fā)展所共有的病理改變和必經(jīng)途徑。而肝纖維化發(fā)生的中心環(huán)節(jié)就是肝星狀細(xì)胞的激活。在肝損傷的過程中,活化的肝星狀細(xì)胞是肝纖維化形成過程中產(chǎn)生膠原的主要細(xì)胞。此外,長期過量飲酒可導(dǎo)致酒精性肝病的發(fā)生,使細(xì)胞外基質(zhì)和膠原蛋白過度沉積,進(jìn)而發(fā)展成肝纖維化以及肝硬化。酒精性肝病是世界范圍內(nèi)慢性肝病的最重要病因之一,嚴(yán)重危害人民健康。嚴(yán)重酗酒時可誘發(fā)廣泛肝細(xì)胞壞死或肝功能衰竭,甚至?xí)觿÷圆《拘愿窝滓约胺蔷凭愿尾〉陌l(fā)生。因此,發(fā)現(xiàn)更多新源藥物更深入的研究抗肝纖維化作用靶點(diǎn)是肝纖維化治療的迫切需要。本研究采用硫代乙酰胺誘導(dǎo)慢性肝纖維化模型和慢性酒精喂養(yǎng)加急性酒精灌胃的酒精性肝病小鼠模型,通過體外、體內(nèi)實(shí)驗(yàn)研究百里香醌以及白樺酯醇的肝保護(hù)作用及潛在的作用機(jī)制。方法：（1）百里香醌通過調(diào)節(jié)TLR4及LKB1-AMPK信號通路抑制肝纖維化實(shí)驗(yàn)研究。體外實(shí)驗(yàn)中用不同濃度的百里香醌預(yù)處理肝星狀細(xì)胞（T-HSC/CI-6）1小時后,加入1 pg/ml內(nèi)毒素（LPS）孵育2... 

【文章來源】：延邊大學(xué)吉林省 211工程院校

【文章頁數(shù)】：109 頁

【學(xué)位級別】：博士

【文章目錄】：
List of Figures
Abbreviations
Abstract in Chinese
Abstract
Introduct
    1. Chronic hepatic injury
    2. Hepatic stellate cells in hepatic fibrosis
    3. TLR4 signaling pathways in liver fibrosis
    4. LKB1-AMPK signaling pathways in hepatic injury
    5. Traditional Chinese medicine in liver disease
Chapter 1.Thymoquinone attenuates liver fibrosis via TLR4 and LKB1-AMPKsignaling pathways
    Abstract
    1.1 Introduction
    1.2 Materials and Methods
        1.2.1 Materials
        1.2.2 In vitro study
            1.2.2.1 Cell cultures
            1.2.2.2 Measurement of cell viability by MTT assay
        1.2.3 In vivo study
            1.2.3.1 Animals and treatments
            1.2.3.2 Serum biochemical parameters assay
            1.2.3.3 Histopathological analysis
            1.2.3.4 Immunohistochemistry examination
            1.2.3.5 Reverse Transcription Polymerase Chain Reaction（RT-PCR）
        1.2.4 Western blot analysis
        1.2.5 Statistical analysis
    1.3 Results
        1.3.1 In vitro results
            1.3.1.1 Effects of TQ on the Viability
            1.3.1.2 Effects of TQ on protein expression of CD14 and TLR4
            1.3.1.3 Effects of TQ on HSCs apoptosis
            1.3.1.4 Effects of TQ on protein expression of collagen-I and α-SMA
            1.3.1.5 Effects of TQ on LPS-induced protein expression of PI3K/Akt phosphorylation
        1.3.2 In vivo results
            1.3.2.1 Effects of TQ on ALT and AST activities
            1.3.2.2 Histopathological and immunohistochemical changes in mice livers after TAA treatment
            1.3.2.3 Effects of TQ on the expression of collagen-I,α-SMA and TIMP-1
            1.3.2.4 Effects of TQ on the expression of TLR4
            1.3.2.5 Effects of TQ on TAA treated protein expression of PI3K phosphorylation
            1.3.2.6 Effects of TQ on the activation of AMPK signaling pathways in TAA induced liver fibrosis
            1.3.2.7 Effects of TQ on proinflammatory cytokines levels
    1.4 Discussion
Chapter 2.Betulin alleviated ethanol-induced alcoholic liver steatosis throughLKB1-AMPK signaling pathways
    Abstract
    2.1 Introduction
    2.2 Materials and Methods
        2.2.1 Materials
        2.2.2 In vitro study
            2.2.2.1 Cell cultures
            2.2.2.2 Measurement of cell viability by MTT assay
        2.2.3 In vivo study
            2.2.3.1 Animals
            2.2.3.2 Chronic-binge ethanol feeding model
            2.2.3.3 Serum biochemical parameters and triglyceride assay
            2.2.3.4 Histopathological analysis
            2.2.3.5 Immunohistochemistry examination
            2.2.3.6 Immunofluorescence imaging assay
        2.2.4 Western blot analysis
        2.2.5 Statistical analysis
    2.3
        2.3.1
            2.3.1.3 AMPK signaling is implicated in the supp ression of ethanol-induced SREBP-1 expression by BT in LX-2 cells
            2.3.1.4 LKB1 signaling is implicated in the suppression of ethanol-induced SREBP-1 expression by BT in LX-2 cells
            2.3.1.5 Effects of BT on ethanol-induced protein expression of LKB1-AMPK phosphorylation
            2.3.1.6 Effect of BT on ethanol-induced SIRT1 expression
            2.3.1.7 Effects of BT on ethanol-induced collagen-I and α-SMA levels in LX-2 cells
        2.3.2 In vivo results
            2.3.2.1 Effects of BT on liver weight induced by chronic-binge ethanol
            2.3.2.2 Effects of BT on serum biochemical parameters and triglyceride assay
            2.3.2.3 Effects of BT on histopathological and Immunohistochemical changes induced by chronic-binge ethanol in mice
            2.3.2.4 Effect of BT on ch ronic-binge ethanol induced SREBP-1 expression
            2.3.2.5 Effects of BT on chronic-binge ethanol induced protein expression of LKB1-AMPK phosphorylation
            2.3.2.6 Effect of BT on chronic-binge ethanol induced SIRT1 expression
    2.4 Discussion
Conclusions
References
Publications
致謝


【參考文獻(xiàn)】：
期刊論文
[1]Pathogenesis of alcoholic liver disease:Role of oxidative metabolism[J]. Elisabetta Ceni,Tommaso Mello,Andrea Galli.  World Journal of Gastroenterology. 2014(47)
[2]Sophocarpine attenuates liver fibrosis by inhibiting the TLR4 signaling pathway in rats[J]. Hui Qian,Jian Shi,Ting-Ting Fan,Jiao Lv,Si-Wen Chen,Chun-Yan Song,Zhi-Wu Zheng,Wei-Fen Xie,Yue-Xiang Chen.  World Journal of Gastroenterology. 2014(07)
[3]Role of ethanol in the regulation of hepatic stellate cell function[J]. Robert G Batey,Jacob George.  World Journal of Gastroenterology. 2006(43)



本文編號：2971473