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研究生:黃筱尹
研究生(外文):Xiao-Yin Huang
論文名稱:體外和體內研究蓮蓬萃取物抵抗乙醯胺基苯酚誘導肝損傷之保護作用
論文名稱(外文):In vitro and in vivo protective effect of Lotus seedpod extract against acetaminophen-induced liver injury
指導教授:陳璟賢陳璟賢引用關係
指導教授(外文):Jing-Hsien Chen
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:營養學系碩士班
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:115
中文關鍵詞:乙醯胺基苯酚肝損傷蓮蓬萃取物表沒食子兒茶素細胞凋亡發炎
外文關鍵詞:acetaminophenliver injurylotus seedpod extractepigallocatechinapoptosisinflammation
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乙醯胺基苯酚(acetaminophen, APAP)是一種廣為使用的解熱鎮痛藥物。若APAP使用過量,將導致嚴重的肝損傷(liver injury)甚至造成急性肝衰竭。蓮蓬(lotus seedpod)為傳統中藥材,經研究顯示其富含多酚(polyphenol)物質且具有抗氧化、抗輻射與抗癌活性之作用,然而於保護肝臟方面之研究較少。本篇研究將透過體外與體內實驗探討蓮蓬水萃物(lotus seedpod extracts, LSE)對於APAP所誘導肝損傷之護肝作用及其分子機制作深入探討。首先於細胞實驗中,以APAP誘導人類肝細胞株HepG2細胞損傷,LSE或其主要所含的成分-表沒食子兒茶素(epigallocatechin,EGC)隨劑量增加可降低APAP對於肝細胞的傷害並提高細胞存活率。另外APAP誘導肝細胞凋亡(apoptosis)若有LSE或EGC介入可減少細胞凋亡之發生,其主要是經由抑制細胞凋亡之內在、外在與ASK 1/JNK訊息傳遞路徑進而達到抗細胞凋亡之作用。LSE亦可降低APAP所誘導的發炎調控蛋白iNOS的表現。動物實驗則以BALB/c小鼠每週給予兩次APAP (i.p.; 400 mg/kg)注射誘導肝臟損傷,並分別餵食1%與2% LSE共為期9週。實驗結果顯示,在血液生化數值方面,與APAP組相較,LSE試驗組其肝發炎指標(GOT、GPT)、三酸甘油酯(TG)與血清中發炎因子(IL-6和IL-1β)皆有顯著降低之趨勢。於肝臟抗氧化酵素方面,APAP注射會使小鼠glutathione (GSH)含量降低,但在餵食1% LSE組可顯著回復GSH含量且提升抗氧化酵素catalase和GRd活性。以西方墨點法分析肝臟中細胞凋亡相關蛋白,結果顯示LSE與NAC亦可減少因APAP所誘發的caspase-3、8、9蛋白表現。綜觀以上研究結果,LSE具有減少APAP所誘導肝臟細胞凋亡之效用,於未來可能具有治療藥物性肝損傷之潛力。

Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic drug in the world. APAP overdose will lead to severe liver injury and have potential to result in acute liver failure. Lotus seedpod, a traditional herbal, is rich in polyphenol and has been shown to possess antioxidant, radioprotective and anti-cancer activities. However, there were no significant reports on the hepatoprotective effect of LSE. In this study, we examined the hepatoprotective role of lotus seedpod extracts (LSE) in vitro and in vivo. Firstly, LSE or its main compound epigallocatechin (EGC) dose-dependently improved the survival of human hepatocyte HepG2 cells from APAP-induced loss of viability. LSE or EGC showed potential in reducing APAP-induced occurrence of apoptosis confirmed by morphological and biochemical features, including an increase in the distribution of hypodiploid phase, apoptotic bodies formation and caspases activation. Molecular data showed that antiapoptotic effects of LSE or EGC might be mediated via intrinsic, extrinsic and ASK 1/JNK apoptotic signaling pathways. Further data showed that LSE inhibited the APAP-induced the protein expression of iNOS. In vivo study, the BALB/c mice were supplemented with or without LSE (1% and 2%) during the 9-week treatment period in the presence or absence of APAP (i.p.; 400 mg/kg) twice per week. Our investigation demonstrated that LSE treatments significantly decreased the serum levels of the hepatic enzyme markers GOT and GPT, and triglyceride (TG) induced by APAP. LSE also inhibited the serum levels of inflammatory cytokines (IL-6 and IL-1β) during APAP treatment. LSE at 1% significantly restored the decrease in glutathione (GSH) content and elevated the levels of antioxidant enzymes, including catalase and glutathione reductase (GRd), in the liver. Western blotting data demonstrated that LSE and N-acetylcysteine (NAC) inhibited the expression of caspase -3, -8, -9 in APAP-induced liver injury. Our data imply that LSE reduced APAP-induced hepatocytes apoptosis, and these findings may open interesting perspectives to the strategy in treatment of liver injury.

目錄 I
圖表目錄 VI
中文摘要 VIII
Abstract X
縮寫檢索表 XI
第一章、緒論 1
第二章、文獻探討 2
2.1 肝臟生理(Liver physiology) 2
2.1.1 肝臟介紹 2
2.1.2 生理功能 4
2.1.3 肝損傷(Liver injury) 7
2.2 乙醯胺基苯酚(Acetaminophen, APAP)介紹 10
2.2.1 臨床用途與過量症狀 10
2.2.2 生理代謝途徑 10
2.2.3 臨床治療APAP服用過量的藥物: N-acetylcysteine (NAC) 12
2.2.4 流行病學調查 13
2.2.5 APAP與細胞凋亡(Apoptosis) 13
2.2.6 APAP與發炎(Inflammation) 14
2.2.7 APAP與多酚物質(Polyphenol)之相關研究 15
2.3 蓮蓬(Lotus seedpod) 16
2.3.1 蓮花植株介紹 16
2.3.2 蓮蓬成分與功效 17
2.3.3 表沒食子兒茶素(Epigallocatechin; EGC) 18
2.4 細胞凋亡(Apoptosis) 19
2.4.1 細胞凋亡的定義 19
2.4.2 細胞凋亡的形態與生化特徵 19
2.4.3 細胞凋亡的訊息傳遞路徑 20
2.4.4 外源性凋亡路徑(Extrinsic apoptosis pathway) 20
2.4.5 內源性凋亡路徑(Intrinsic apoptosis pathway) 21
2.4.6 凋亡蛋白酶(Cysteine aspartate protease, caspase) 22
2.5 體內抗氧化系統(Antioxidant system) 23
第三章、實驗架構與流程 26
3.1 細胞與動物實驗架構 26
3.2 細胞與動物實驗設計 27
第四章、材料與方法 28
4.1 實驗儀器與藥品試劑 28
4.1.1 實驗儀器與設備 28
4.1.2 實驗藥品與試劑 30
4.1.3 乙醯胺基苯酚(Acetaminophen, APAP)之配製 32
4.1.4 蓮蓬萃取物(Lotus seedpod extracts, LSE)之製備 33
4.1.5 表沒食子兒茶素(Epigallocatechin, EGC)製備 33
4.2 細胞培養 34
4.2.1 細胞株來源 34
4.2.2 實驗設計 34
4.2.3 培養條件 34
4.2.4 解凍細胞 35
4.2.5 繼代培養 35
4.2.6 細胞計數 36
4.2.7 冷凍細胞 36
4.3 細胞存活試驗(Cell viability) 37
4.4 細胞凋亡分析(4'',6-diamidino-2-phenylindole, DAPI stain) 37
4.5 細胞凋亡分析-雙染色法(Annexin V/PI stain) 38
4.6 細胞蛋白質萃取與定量 39
4.6.1 蛋白質萃取 39
4.6.2 蛋白質定量 39
4.7 西方墨點法(Western blotting) 40
4.7.1 樣品(sample)配製 40
4.7.2 鑄膠(SDS-PAGE) 40
4.7.3 電泳法(electrophoresis) 41
4.7.4 轉漬(transfer) 42
4.7.5 免疫墨點法(immunoblot) 42
4.8 免疫沉澱法(Immunoprecipitation, IP) 43
4.9 粒線體膜電位分析(Mitochondrial membrane potential assay, JC-1 staining) 44
4.10粒線體分離(Mitochondria isolation) 45
4.11活性氧物質生成分析(DCFH-DA staining) 45
4.12實驗動物 46
4.12.1 實驗設計與流程 46
4.12.2 飼料配製 47
4.12.3 APAP注射液配製 47
4.12.4 血液與組織樣本採集 48
4.13組織抗氧化能力分析 48
4.13.1 穀胱甘肽(Glutathione, GSH)含量測定 48
4.13.2 穀胱甘肽還原酶(Glutathione reductase, GRd)活性測定 49
4.13.3 過氧化氫酶(Catalase)活性測定 50
4.13.4 超氧歧化酶(Superoxide Dismutase, SOD)活性測定 51
4.13.5 穀胱甘肽過氧化酶(Glutathione peroxidase, GPx)活性測定 51
4.13.6 脂質過氧化程度測定(2-Thiobarbituric Acid Reactive Substances, TBARs) 52
4.14細胞激素(Cytokines)含量測定 53
4.15蘇木素-伊紅染色(Hematoxylin and eosin stain, H&E stain) 54
4.16纖維化染色(Masson''s trichrome stain) 56
4.17統計方法 57
第五章、實驗結果 58
5.1 探討不同濃度APAP及LSE單獨或合併處理對於HepG2細胞存活之影響 58
5.2 探討LSE對於APAP所誘導HepG2細胞凋亡之影響 59
5.3 探討LSE對於APAP所誘導HepG2細胞中凋亡蛋白酶表現之影響 59
5.4 探討LSE對於APAP所誘導HepG2細胞中凋亡外源性路徑蛋白之影響 60
5.5 探討LSE對於APAP所誘導HepG2細胞內粒線體膜電位改變之影響 61
5.6 探討LSE對於APAP所誘導HepG2細胞中凋亡內源性路徑蛋白之影響 61
5.7 探討LSE對於APAP所誘導HepG2細胞內粒線體凋亡因子之影響 62
5.8 探討LSE對於APAP處理的HepG2細胞在ASK 1/JNK傳遞路徑之影響 64
5.9 探討LSE對於APAP所誘發HepG2細胞內ROS生成之影響 65
5.10探討LSE對於APAP所誘發HepG2細胞中發炎相關蛋白表現之影響 65
5.11探討LSE對於APAP所誘發BALB/c小鼠血清生化數值變化的影響 66
5.12探討LSE對於APAP所誘發BALB/c小鼠血清發炎因子變化之影響 67
5.13探討LSE對於APAP所誘發BALB/c小鼠肝臟中抗氧化酵素與脂質過氧化程度的影響 68
5.14探討LSE對於APAP所誘發BALB/c小鼠肝臟病理組織之影響 69
5.15 LSE對於APAP所誘發BALB/c小鼠肝臟細胞凋亡相關蛋白表現之影響 70
第六章、討論 71
第七章、結論 79
第八章、參考文獻 80


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