肝病之病程常伴隨著脂肪浸潤、脂肪肝、肝發炎等病狀，最終有可能惡化成肝纖維化、肝硬化甚至肝癌。有許多原因會導致肝病的發生，當飲酒過度時，體內大量代謝酒精所產生的氧化壓力，會引起酒精性肝病（alcoholic liver disease, ALD）之形成。金針花（Hemerocallis fulva L.）為台灣著名農產品之一，為中國傳統食療方，近年研究發現，金針花含有天然抗氧化物質，如類胡蘿蔔素、類黃酮及花青素等。此外，金針花萃取物已被證實在脂多醣（lipopolysaccharide, LPS）誘導巨噬細胞中可抑制nitric oxide（NO）的產生及降低誘導型一氧化氮合&;#37238;（inducible nitric oxide synthase, iNOS）表現，且具有清除活性氧能力。有研究指出，金針花經以95%之乙醇萃取後，與其水萃物相較之下，具有較佳之抗氧化活性，與其富含多酚類物質有關，其中又以芸香素（rutin）之含量為最高。因此，本研究的假說認為金針花乙醇萃取物因富含抗氧化活性而具有減緩酒精所造成肝損傷的效果。本研究以Lieber-DeCarli酒精液態飼料誘導小鼠酒精性肝損傷之動物模式，進行金針花乙醇萃取物之護肝功效評估。實驗動物分成五組，包括正常控制組（Control）、酒精誘導肝損傷負對照組（ALD）及酒精誘導肝損傷並同時給予金針花乙醇萃取物低劑量（400 mg/kg bw/day, ALD + LDFE）、高劑量（800 mg/kg bw/day, ALD + HDFE）及金針花乙醇萃取物中純物質-芸香素（2.6 mg/kg bw/day, ALD + Rutin）處理組。實驗結果顯示，相較於ALD組，餵食金針花乙醇萃取物低劑量及高劑量組，其血清中肝臟生化功能指標酵素天門冬胺酸轉胺&;#37238;（aspartate transaminase, AST）及丙胺酸轉胺&;#37238;（alanine transaminase, ALT）數值具有顯著降低的現象；肝臟組織病理學觀察方面，餵食低劑量及高劑量金針花乙醇萃取物，可改善肝臟中脂肪堆積之情形。此外，金針花乙醇萃取物亦可提高肝臟中抗氧化物質麩胱甘&;#32957;（glutathione, GSH）之含量，及提升肝臟中抗氧化酵素之活性，同時改善小鼠肝臟中脂質過氧化及發炎反應之情況，且向下調控肝中細胞激素P450 2E1（cytochrome P450 2E1, CYP2E1）酵素之活性。進一步以西方墨點法及免疫組織染色法，評估金針花乙醇萃取物之抗氧化機制，結果顯示金針花乙醇萃取物可提升NF-E2-related factor 2（Nrf2）於細胞核之表現量及其下游蛋白heme oxygenase-1（HO-1）表現量。綜合以上實驗結果，推測金針花乙醇萃取物可能藉由其抗氧化和抗發炎作用，以及向下調控CYP2E1之表現量，並活化Nrf2/HO-1，而具有改善酒精性肝損傷之護肝功效。

Liver disease is one of the most widely contracted diseases in Taiwan. There are many reasons result in liver disease, one of those are excessive alcohol consumption which will lead to alcoholic liver disease (ALD), such as in fatty liver, alcoholic hepatitis and end to cirrhosis, which results to hepatocyte dysfunction. The pathogenesis of ALD is related to lipid accumlation, oxidative stress, and inflammation. The flower of daylily (Hemerocallis fulva L.) is widely used in traditional medication and food material in eastern Asia. Previous studies indicated that the flowers of daylily are rich in variety of antioxidants such as carotenoids, flavonoids, anthocyanin, and so on. Furthermore, the extracts of daylily flowers have been reported to have the inhibition efficiency on the nitric oxide (NO) production, reducing the inducible nitric oxide synthase (iNOS) induction in lipopolysaccharide (LPS)-activated macrophages; and reative oxygen species (ROS) scavenging activity. Recent study found that the 95% ethanol extracts of daylily flowers content high level of polyphenols and exhibited better antioxidant activities than water extracts. The hypothesis of this study is ethanol extracts of daylily flower (DFE) may have the hepatoprotective effects on alcoholic liver disease mice by ameliorating the hepatic oxidative stress and inflammatory responses.. The aim of this study is to investigate the liver protective capability of ethanol extract of daylily flowers in male C57BL/6 mice which feed with Lieber-DeCarli alcohol-containing liquid diet, and its hepatoprotective mechanism. Mice were divided five groups: fed with normal liquid diet (normal control group), ethanol-containing liquid diet is (negative control group, ALD) or ethanol-containing liquid diet treated with low dosage of ethanol extract of daylily flower (DFE) at 400 mg/kg bw/day (ALD + LDFE group), high dosage of DFE at 800 mg/kg bw/day (ALD + HDFE group), and rutin which content as high dosage of DFE at 2.6 mg/kg bw/day (ALD + Rutin group) for 4 weeks. Our results showed that in comparison with the control group, the ALD group showed liver injury as evidenced by histological changes and elevation in serum biochemical, liver inflammation, and oxidative stress. These pathophysiological changes were attenuated by DFE supplementation. Further studies demonstrated an inhibitory effect of DFE on the critical role in ALD, cytochrome P450 2E1 (CYP2E1). DFE also attenuated alcohol-induced reduction in heme oxygenase-1 (HO-1) and NF-E2-related factor 2 (Nrf2). According to our results, the hepatoprotective effects of DFE were shown to be associated with antioxidative and anti-inflammatory effects as well as the downregulation expression of CYP2E1, and enhancement of HO-1 and Nrf2 expression in liver.

中文摘要 I
英文摘要 III
縮寫表 V
目錄 VIII
圖目錄 XII
表目錄 XIII
第一章 前言 1
第二章 文獻回顧 2
第一節 肝臟 2
一、肝臟之生理構造 2
二、肝臟功能 2
三、肝臟酵素 5
四、肝臟疾病 6
第二節 酒精性肝損傷 7
一、酒精代謝 7
二、酒精造成肝臟損傷之致病機致 8
三、Nuclear factor-eythroid 2–related factor 2（Nrf2） 12
四、誘導酒精性肝損傷之動物模式 14
第三節 金針花（Hemerocallis fulva L.） 16
一、簡介 16
二、植物性狀及加工技術 16
三、營養成分 19
四、植物化學成份（phytochemicals） 19
五、金針花之生理功效 24
六、金針花乙醇萃取物中多酚黃酮類之護肝功效 26
第三章 研究假說及目的 30
第一節 研究假說 30
第二節 研究目的 30
第四章、實驗架構 31
第五章　實驗材料與方法 32
第一節 實驗材料 32
一、金針花 32
二、實驗動物 32
三、飼料 32
四、實驗藥品 33
第二節 方法 35
一、金針花乙醇萃取物之萃取方法 35
二、金針花乙醇萃取物之動物實驗劑量篩選 36
三、金針花乙醇萃取物之成分分析 36
四、酒精液態飼料誘導酒精肝損傷之動物模式及分組 37
五、西方墨點法（Western blotting） 39
六、免疫組織化學染色法（Immunohistochemistry, IHC） 42
第三節 實驗步驟 44
一、組織病理學觀察 44
二、血液生化值測定 44
三、肝臟之蛋白質測定 45
四、肝臟之三酸甘油酯（triglyceride, TG）含量分析 45
五、肝臟之脂質過氧化程度（lipid peroxidation, LPO）分析 45
六、肝臟之麩胱甘&;#32957;（glutathione, GSH）含量測定 46
七、肝臟之麩胱甘&;#32957;過氧化&;#37238;（glutathione peroxidase, GPx）活性測定 46
八、肝臟之麩胱甘&;#32957;還原&;#37238;（glutathione reductase, GRd）活性測定 46
九、肝臟之過氧化氫&;#37238;（catalase, CAT）活性測定 47
十、肝臟之超氧化物歧化&;#37238;（superoxide dismutase, SOD）活性測定 47
十一、肝臟中細胞激素（cytokines）含量分析 48
十二、統計方法 48
第六章 結果 49
第一節 金針花乙醇萃取物之樣品分析 49
第二節 酒精液態飼料誘導小鼠酒精性肝損傷實驗 51
一、平均攝食量及平均體重變化 51
二、血清中AST（aspartate transaminase）及ALT（alanine transaminase）活性 51
三、血清中總膽固醇（total cholesterol, TC）及三酸甘油酯（triglyceride, TG）含量 51
四、組織病理學觀察結果 52
五、肝臟相對重量 52
六、肝臟中三酸甘油酯含量 53
七、肝臟中脂質過氧化程度 53
八、肝臟中麩胱甘&;#32957;含量 53
九、肝臟抗氧化酵素活性 54
十、肝臟發炎反應相關之細胞激素含量 55
十一、以西方墨點法探討小鼠肝中CYP2E1表現量 55
十二、以西方墨點法及免疫組織染色法探討小鼠肝中抗氧化路徑Nrf2/HO-1 56
第七章 討論 57
第一節 金針花乙醇萃取物之樣品分析 57
第二節 酒精液態飼料誘導小鼠酒精性肝損傷實驗 59
一、試驗間攝食量與體重變化 59
二、評估金針花乙醇萃取物對酒精性肝損傷之護肝功效 59
三、以免疫組織染色法及西方墨點法探討金針花乙醇萃取物改善酒精性肝損傷之抗氧化作用機轉 62
第八章 結論 63
第九章 未來研究 64
第十章 圖表 65
第十一章 參考文獻 88
第十二章 附錄 96

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