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研究生:駱郁婷
研究生(外文):Yu-Ting Lo
論文名稱:人參皂苷Rb1對老鼠肝臟星狀HSC-T6細胞活化與纖維化之影響
論文名稱(外文):Effects of ginsenoside Rb1 on cell activation and liver fibrosis in rat hepatic stellate HSC-T6 cells
指導教授:趙振瑞趙振瑞引用關係
指導教授(外文):Jane C-J Chao
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:保健營養學研究所
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:2008
畢業學年度:96
語文別:中文
論文頁數:98
中文關鍵詞:人參皂苷Rb1肝臟星狀細胞肝纖維化
外文關鍵詞:ginsenoside Rb1hepatic stellate cellsliver fibrosis
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近年來,慢性肝炎及肝硬化已成為台灣十大死因之第七位,而其中肝纖維化的病症目前已被認為是可修復的。肝臟星狀細胞的活化及增生在肝纖維化的過程中扮演重要的角色,而肝臟星狀細胞因活化所產生大量細胞外基質的堆積則為造成肝纖維化的主要原因。人參皂苷Rb1為人參中最具有活性的物質,且被認為在許多生理功能皆具療效。因此本研究之目的在探討於過氧化氫的氧化壓力下,給予老鼠肝臟星狀HSC-T6細胞人參皂苷Rb1 (純度為98.8%),對於細胞的活化、增生及纖維化指標的影響。將細胞培養於Waymouth MB 752/1含10%胎牛血清之培養液中,並置於37℃、含5% CO2的環境下,24小時後以10 nM之H2O2誘導細胞更活化,再於24小時後更換為添加不同濃度人參皂苷Rb1之新鮮培養液,培養液中含人參皂苷Rb1之最終濃度分別為5、10、20、40及80 μg/mL。此外增設負控制組(添加0.08% dimethyl sulfoxide,為80 μg/mL Rb1組之劑量)及正控制組(添加5 mM之N-acetyl-L-cysteine)。細胞培養24小時後,收集細胞液及培養液進行細胞存活率、細胞活化指標α-平滑肌動蛋白(α-smooth muscle actin; α-SMA)、細胞增生情形及纖維化指標等分析。結果顯示:在給予細胞人參皂苷Rb1於5-40 μg/mL劑量下可降低由H2O2所誘導之α-SMA的表現(p < 0.05),且於5-80 μg/mL劑量下顯著抑制細胞的增生情形(p < 0.05)。纖維化指標方面,在5-80 μg/mL的劑量下,可顯著降低轉化生長因子-β1及膠原蛋白的表現;而在10-80 μg/mL的劑量下則可顯著抑制基質金屬蛋白酶-2及金屬蛋白酶組織抑制物-1等纖維化指標的蛋白質表現量(p < 0.05),且分別於10及80 μg/mL的劑量下能顯著抑制纖維化指標TGF-β1、type I與III collagen及TIMP-1之mRNA表現量(p < 0.05)。由結果得知,人參皂苷Rb1可藉由抑制肝臟星狀細胞的活化、增生及降低纖維化指標的表現,而達到抑制肝臟星狀細胞之致肝纖維化功能。
Chronic hepatitis and cirrhosis have been currently become the 7th leading cause of death in Taiwan. Recently, hepatic fibrosis is regarded as a reversible process in liver diseases. The activation and proliferation of hepatic stellate cells (HSCs) play important roles during liver fibrosis. The accumulated extracellular matrix proteins produced by activated HSCs are the major cause of liver fibrosis. Ginsenoside Rb1, the most active compound purified from ginseng, has been considered to be an effective regulator in many physiological functions. Accordingly, the present study investigated the effects of ginsenoside Rb1 (98.8% purity) on cell activation, proliferation, and liver fibrotic markers in rat hepatic stellate HSC-T6 cells under oxidative stress of H2O2. HSC-T6 cells were cultured in Waymouth MB 752/1 medium containing 10% fetal bovine serum at 37℃ in 5% CO2 atmosphere. HSC-T6 cells were induced more active by 10 nM H2O2. After 24 hours, the medium was replaced by fresh medium containing different concentrations of ginsenoside Rb1 (5, 10, 20, 40, and 80 μg/mL). Additionally, the medium containing 0.08% dimethylsulfoxide or 5 mM N-acetyl-L-cysteine was used as a negative or positive control. After 24 hours, cell suspension and medium were collected for cell viability assay, expression of cell activation marker - α-smooth muscle actin (α-SMA), cell proliferation assay, and expression of fibrotic markers. The results showed that ginsenoside Rb1 at 5-40 μg/mL significantly reduced α-SMA expression induced by H2O2 (p < 0.05) and inhibited cell proliferation at 5-80 μg/mL in HSC-T6 cells (p < 0.05). Transforming growth factor-β1 (TGF-β1) and collagen expression were reduced by ginsenoside Rb1 (5-80 μg/mL). Matrix metallo- proteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also suppressed by ginsenoside Rb1 (10-80 μg/mL). In addition, mRNA expression of TGF-β1, type I and III collagen, and TIMP-1 were inhibited by ginsenoside Rb1 (10 and 80 μg/mL). Therefore, ginsenoside Rb1 might be able to reverse fibrogenesis in hepatic stellate cells through reduction of cell activation, proliferation, and expression of fibrotic markers.
目錄
中文摘要..................................................Ⅰ
英文摘要..................................................Ⅲ
目錄......................................................Ⅴ
圖目次....................................................Ⅷ
表目次....................................................Ⅹ
第一章 緒論..............................................1
第二章 文獻回顧..........................................6
第一節 肝臟結構與細胞組成................................6
第二節 肝纖維化之機制...................................10
第三節 肝纖維化與氧化壓力...............................12
第四節 肝臟星狀細胞.....................................13
一、肝臟星狀細胞之簡介...................................13
二、肝臟星狀細胞之活化...................................13
三、肝臟星狀細胞HSC-T6...................................15
第五節 調控肝纖維化之重要因子...........................17
一、轉化生長因子-β.......................................17
二、基質金屬蛋白酶與金屬蛋白酶組織抑制物.................18
三、細胞外基質...........................................20
第六節 人參、人參皂苷Rb1及其相關研究....................27一、人參之簡介...........................................27
二、人參皂苷的種類與結構.................................27
三、人參皂苷Rb1之相關研究................................29
第七節 研究目的與動機...................................35
第三章 實驗材料與方法...................................36
第一節 實驗材料.........................................36
一、實驗細胞株...........................................36
二、人參皂苷Rb1..........................................36
三、試劑藥品.............................................36
第二節 細胞培養與實驗設計...............................38
第四章 分析項目.........................................40
第一節 細胞生長曲線.....................................40
第二節 細胞存活率之分析.................................41
第三節 細胞活化的測定-α-SMA的表現量....................42
ㄧ、酵素連結免疫吸附分析法...............................42
二、十二烷基硫酸鈉聚丙烯醯胺膠片電泳法...................42
第四節 細胞增生之分析...................................44
第五節 纖維化指標的測定.................................46
ㄧ、轉化生長因子-β1......................................46
二、總膠原蛋白...........................................47
三、基質金屬蛋白酶-2.....................................48
四、金屬蛋白酶組織抑制物-1...............................49
五、TGF-β1、第一型及第三型collagen及TIMP-1之mRNA表現量...50
第六節 統計方法.........................................52
第五章 結果.............................................53
第一節 細胞生長曲線.....................................53
第二節 細胞存活率之分析.................................55
第三節 細胞活化的測定...................................57
ㄧ、酵素連結免疫吸附分析法...............................57
二、十二烷基硫酸鈉聚丙烯醯胺膠片電泳法...................57
第四節 細胞增生的測定...................................60
第五節 纖維化指標的測定.................................62
ㄧ、轉化生長因子-β1......................................62
二、總膠原蛋白...........................................62
三、基質金屬蛋白酶-2.....................................63
四、金屬蛋白酶組織抑制物-1...............................63
五、TGF-β1、第一型及第三型collagen及TIMP-1之mRNA表現量...63
第六章 討論.............................................71
第一節 以HSC-T6細胞作為探討肝纖維化之模式...............71
第二節 人參皂苷Rb1對HSC-T6細胞活化的影響................74
第三節 人參皂苷Rb1對HSC-T6細胞增生的影響................76
第四節 人參皂苷Rb1對HSC-T6細胞纖維化的影響..............78
第五節 人參皂苷Rb1於體內有效之生理濃度..................82
第六節 未來研究方向.....................................84
第七章 結論.............................................85
第八章 參考文獻.........................................86
附錄.....................................................96
A. Waymouth MB 752/1培養液成份表.........................96
B. 人參皂苷Rb1之分析相關數據.............................98

圖目次
圖一 2007年台灣地區主要癌症死亡原因..................4
圖二 台灣地區歷年主要癌症死亡原因....................5
圖三 肝臟解剖圖......................................8
圖四 肝臟受到損傷時竇狀隙之變化......................9
圖五 肝纖維化之機制.................................11
圖六 肝臟星狀細胞於活化後之特徵.....................16
圖七 TGF-β 調節基因表現之訊號傳遞路徑...............22
圖八 TGF-β1 調節 MMPs 活化的途徑....................23
圖九 人類纖維化肝臟中細胞外基質組成份...............25
圖十 在人類正常肝臟與肝硬化中細胞外基質組成份的改變.26
圖十一 人參(A)人參葉(B)人參乾燥根.................31
圖十二 人參皂苷Rb1之化學結構..........................32
圖十三 人參皂苷的種類與結構...........................33
圖十四 人參皂苷Rb1於腸道中的代謝......................34
圖十五 MTS tetrazolium反應物與formazan生成............45
圖十六 肝臟星狀細胞HSC-T6之生長曲線圖.................54
圖十七 人參皂苷Rb1對HSC-T6細胞存活率之影響............56
圖十八A 人參皂苷Rb1對HSC-T6細胞活化之影響...............58
圖十八B 人參皂苷Rb1對HSC-T6細胞活化之影響...............59
圖十九 人參皂苷Rb1對HSC-T6細胞增生之影響..............61
圖二十 人參皂苷Rb1對HSC-T6細胞中TGF-β1含量之影響......65
圖二十一 人參皂苷Rb1對HSC-T6細胞中總膠原蛋白分泌量之影響66
圖二十二 人參皂苷Rb1對HSC-T6細胞中MMP-2含量之影響.......67
圖二十三 人參皂苷Rb1對HSC-T6細胞中TIMP-1含量之影響......68
圖二十四A人參皂苷Rb1對HSC-T6細胞中TGF-β1、第一型及第三型collagen、 及TIMP-1之mRNA表現量之影響...................69
圖二十四B人參皂苷Rb1對HSC-T6細胞中TGF-β1、第一型及第三型collagen、及TIMP-1之mRNA表現量定量之影響.................70

表目次
表一 2007年國人十大死因排名..........................3
表二 基質金屬蛋白酶家族.............................24
表三 TGF-β1、第一、第三型collagen、TIMP-1及甘油醛磷酸脫氫酶之primer序列........................................51
表四 肝臟星狀細胞株與初代星狀細胞之比較.............73
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