臺灣博碩士論文加值系統

五爪金英通常被稱為墨西哥菊或樹萬壽菊，其在藥理研究上顯示具有抗糖尿病、抗瘧疾、抗發炎、鎮痛、具腫瘤化學保護活性，也富含黃酮類（flavonoids）和倍半萜類（sesquiterpenoids），後者在細胞培養中被證實具有腫瘤化學保護劑的潛能。由於肝癌的罹患率位居台灣之首，且肝癌轉移往往是造成病患高死亡率的原因之一；本實驗室也已經證實五爪金英的主要活性成分-tagitinin C 在動物肝癌模式中具有毒殺效果，故進而想證實 tagitinin C 是否具抗肝癌轉移的效果。除此之外，本研究也進行了五爪金英高劑量服用對肝造成的毒性測試，發現會造成大鼠脂肪肝的情形，因此本研究分成以下兩部份進行探討：
本論文的第一部分先探討利用磁振頻譜（MRS）測試 tagitinin C是否具抗肝癌轉移效果。
利用細胞培養方式分別培養 Hep G2 及 Huh 7 兩株肝癌細胞一天後，進行細胞遷移能力（migration assay）及細胞質釋放至培養液的酵素基質金屬蛋白酶（MMP2及MMP9）活性的分析，發現 Hep G2 的轉移能力均比 Huh 7 能力好外，也發現 tagitinin C 均可抗此兩種肝癌細胞的轉移能力。
在動物實驗方面則取重量介於 26 ～ 30 克的嚴重免疫缺陷（Severe Combined Immunodeficiency, SCID）小鼠，將前述兩株肝癌細胞分別在小鼠腹部皮下注射造成小鼠肝癌模式後，分別將此兩種肝癌小鼠再隨機分成兩組，每一組十隻，分別為：控制組（只注射 0.2 ml DMSO）及實驗給藥組（給予 tagitinin C [75 μg/ml溶於 0.2 ml 的DMSO 中]）。每天皮下注射 5 天、15 天及 25 天後，先利用磁振頻譜量測腹部膽鹼（Cho）值及肌酸（Cr）值，然後分別抽取其血液測量肝功能指標（GOT 及 GPT）及肝癌指標（AFP），發現在血清中的 GPT 及 AFP 看不出這種抑制轉移現象時，膽鹼/肌酸值卻在此種癌鼠投與 tagitinin C 後均可降低，代表 tagitinin C 會抑制肝癌細胞的轉移。
論文的第二部分則探討過度服用五爪金英萃取物對肝造成的傷害及脂肪肝的情形。
取 280 ～ 320 克之 Sprague-Dawley 大鼠，隨機分為四組，每一組十隻。分別投與五爪金英萃取物成分[0、100、300、500 mg/ kg 分別溶於 1 ml 的橄欖油中]。連續餵食三週後研究使用磁振造影技術之 Dixon及磁振頻譜方法研究五爪金英萃取物高劑量服用對肝臟造成的影響。並於磁振檢查結束之後採取血液進行生化分析，及進行組織切片染色觀察。
結果顯示研究結果顯示：投藥組與對照組相比，證實 300 mg/ kg 會誘發脂肪肝且有時間相關（time dependent）效應。在劑量 300 mg/kg 連續投藥二週後，利用磁振造影技術我們發現脂肪對水的比值隨著劑量的增加而顯著增加。此現象在油紅（oil-red）組織切片染色也看到肝細胞有脂肪油滴的現象是相符合的。且在 300 ～ 500 mg/ kg 投藥三週後，利用上述磁振造影技術，我們發現脂肪對水的比值並沒有隨劑量增加而增加，反而降低。此現象與 Masson 組織切片看到組織纖維化的情形可能有關。

Tithonia diversifolia (Hemsl) A. Gray (Compositae) is commonly referred to as Mexican sunflower, or tree marigold. Pharmacological studies of Tithonia diversifolia showed that it has anti-diabetic, anti-malarial, anti-inflammatory, analgesic, and cancer chemo-preventive activity. They are particularly rich in sesquiterpenoids and flavonoids and these sesquiterpenoids were evaluated for their potential as cancer chemo-preventive agents in cell culture. Tagitinin C, a major sesquiterpenoid, was isolated from the leaves of Tithonia diversifolia. We have identified the anti-hepatoma of tagitinin C in our lab. Our thesis has two parts: One is to study the anti-metastatic activity of tagitinin C in xenograft models of hepatocellular carcinoma (HCC). The other is to study the toxicology of Tithonia diversifolia ethanolic extracts (TDE) at high dose in animal model.
At first, tagitinin C was isolated from TDE. The hepatoma Hep G2 and Huh 7 cells were treated with tagitinin C and assessed for viability by MTT assay, for migration by scratch migration assay and matrix metalloproteinases (MMP) activity assay, for metastasis assay in vivo study by MR techniques and Magnetic Resonance Spectroscopy (MRS) in tumorigenisity of xenografts inoculated by Hep G2 and Huh 7 cells. Tagitinin C was found to have cytotoxic activities against Hep G2 and Huh 7 with IC50 values at 2.0±0.1µg/ml and 1.2±0.1µg/ml individually. tagitinin C resulted in anti-migration and MMP activity decrease which suggested that this compound was anti-metastatic effect in vitro. Moreover, the tumorigenisity of xenografts derived from Hep G2 and Huh 7 cells were probably retarded and anti-migrated by the delivery of tagitinin C (15 μg/mouse/day) relative to the control counterparts by MRS assay. The conclusion in our first part of thesis is that tagitinin C demonstrated antitumor and antimetastatic activities in HCC xenograft model inoculated by two human hepatoma cells. This study provides an auxiliary or alternative therapy for clinical investigation in patients with HCC.
The second part is toxicological test: TDE were administered orally to male Sprague-Dawley rats at various dosages (0, 100, 300, 500 mg/ kg B. W., orally, 5 days/wk, 3 weeks). The animals were validated to have fatty liver compared to the control group (olive oil vehicle, per day, 3 weeks). A common finding in drug safety studies is fatty liver, which is the result of diet, stress, or compounds that modify lipid metabolism in the liver. Fatty liver will gradually develop into a very serious liver disease, such as cirrhosis, fulminant hepatitis, or HCC. With the increasing use of MRI for toxicological studies, this method should provide an improved, noninvasive method of identifying and monitoring individuals with fatty liver.
By use of MR techniques, including Dixon and MRS method, important results of the second study are: (i) the changes of fat content in rat liver after TDE treatment via MRS was time dependent at the dosage of 300 mg/kg, and this result was verified by oil-red stain in pathological observation. (ii) additional finding was that the fat content decreased after 3 weeks TDE treatment at the dose of 300 ～ 500 mg/kg, and this result may be associated with fibrosis in Masson stain.

中文摘要 I
Abstract III
致謝 V
目錄 VII
圖目錄 X
表目錄 XIII
第一章 緒論 1
1.1 研究動機 1
1.2 研究目的 2
1.3 實驗設計與架構 3
第二章 研究背景 4
2.1 肝臟疾病之介紹 4
2.1.1 肝癌 4
2.1.2 脂肪肝 6
2.1.3 肝臟疾病之臨床技術 8
2.2 五爪金英 9
2.3 磁振技術（MRI與MRS） 11
2.3.1 Dixon 效應 13
2.3.2 活體磁振頻譜（MRS） 15
2.3.3 多體素化學位移造影（CSI） 17
2.4 細胞遷移（Cell scratch migration） 21
2.5 基質金屬蛋白酶（matrix metalloproteinase, MMPs） 21
2.5.1 MMP分類 22
第三章 Tc 抗肝癌療效的評估 27
3.1 前言 27
3.2 實驗設計與架構 28
3.3 材料與方法 29
3.3.1 Tc 來源及配製方式 29
3.3.2 細胞來源 29
3.3.3 動物的處理 29
3.3.4 活體磁振掃描 31
3.3.5 活體磁振掃描試驗程序 32
3.3.6 磁振頻譜後處理 32
3.3.7 血液生化值 35
3.3.8 遷移試驗（migration assay） 36
3.3.9 基質金屬蛋白酶活性測定 36
3.3.10 統計分析 37
3.4 結果與討論 37
3.4.1 半致死劑量 37
3.4.2 血液生化數值 38
3.4.3 磁振頻譜 40
3.4.4 遷移試驗 44
3.4.5 基質金屬蛋白酶活性測定 46
3.5 結論 48
第四章 高劑量五爪金英服用後之肝臟毒性的評估 50
4.1 前言 50
4.2 實驗設計與架構 51
4.3 材料與方法 52
4.3.1 五爪金英材料來源及萃取方法 52
4.3.2 活體磁振掃描 54
4.3.3 毒理組磁振頻譜掃描部位 55
4.3.4 毒理測試組大鼠活體磁振掃描試驗程序 56
4.3.5 Dixon 影像分析 56
4.3.6 磁振頻譜後處理 56
4.3.7 血液生化值 57
4.3.8 病理切片 57
4.3.9 統計分析 58
4.4 結果與討論 59
4.4.1 Dixon 方法的結果 59
4.4.2 磁振頻譜 61
4.4.3 血液生化數值 63
4.4.4 病理切片 65
4.5 結論 69
第五章 綜合討論 70
5.1 抗肝癌療效的評估 70
5.2 過量五爪金英服用後之肝臟毒性的評估 70
5.3 總結及未來展望 71
參考文獻 72
附件一、磁振造影參數設定 79
附件二、多體素磁振頻譜後處理之方法步驟 84
附件三、基質金屬蛋白酶活性測定步驟 89

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