臺灣博碩士論文加值系統

糖尿病為現今常見之慢性代謝疾病之ㄧ，隨著生活品質提升，罹患糖尿病的人數有日益增加的趨勢，但目前糖尿病臨床上所使用之治療藥物種類有限並易伴隨多種副作用，有鑑於此，近年來學者積極從天然植物中萃取有效降低血糖的成分以應用於糖尿病之預防及治療。本實驗之目的為混合番石榴葉(Psidium guajava)及寬筋藤藤部(Tinospora cordifolia)之水萃取物，以期提高經濟價值並使降血糖效果達到相乘作用。實驗設計上，先分別探討兩者有效成分之最適萃取條件後，依照適當比例進行混合，以體外試驗方法測定混合植物水萃液對α-amylase的抑制率；再以Salmonella typhimurium TA97、TA100進行毒性試驗(Ames test)；並以MTT分析法（3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay）探討混合植物水萃液對初生小鼠正常肝細胞株(BNL CL.2)及人類肝癌細胞株(HepG2)之存活率是否具有影響；體內試驗參照行政院衛生署之健康食品調節血糖功能評估辦法進行，以六週齡雄性Wistar大鼠為對象，分成健康對照組(NC)及糖尿病誘發組(DC、1DC、5DC、10DC)，糖尿病誘發組以腹腔注射方式給予Nicotinamide (230 mg/kg) 及 Streptozotocin (75 mg/kg)誘發形成第二型糖尿病後，分別餵食不同劑量(1DC、5DC、10DC)之混合植物水萃液連續5週，經由空腹血糖值、口服葡萄糖耐受性試驗及各項血液生化分析評估混合植物水萃液之降血糖功
效。結果顯示，番石榴葉水萃液之半抑制濃度為3.24 mg/mL，寬筋藤水萃液之半抑制濃度為7.97 mg/mL，而兩者之混合液半抑制濃度則降低為3.16 mg/mL。毒性方面，在添加混合植物水萃取液0.3125~5.0 mg/plate之劑量下，無論S9添加與否，對於Salmonella typhimurium TA97和TA100並不具毒性，及致突變性之安全疑慮。細胞毒性試驗，加入5~300 μg/mL之混合植物水萃取液培養24、48及72小時後，能夠顯著提高初生小鼠正常肝細胞BNL CL.2之生存率，且其生存率呈現時間相關性及劑量依賴效應；而人類肝癌細胞HepG2之生存率則比控制組較為顯著降低。動物試驗方面，餵食混合植物水萃液5週後發現可減緩多吃、多喝、體重下降之糖尿病特徵，並顯著降低血中三酸甘油酯、低密度脂蛋白、肌酸酐濃度、提高血中高密度脂蛋白之濃度。無餵食混合植物水萃液之組別，其血糖值則持續升高，而有餵食混合植物水萃液之組別(1DC、5DC、10DC)於第3週可觀察到血糖濃度開始有降低之現象，並維持穩定至試驗期結束，顯示餵食混合植物水萃液能維持血糖值之穩定。病理組織切片方面，健康飲食控制組(NC)在眼球、腎臟、心臟、胰臟、腦部及肝臟結果均正常，而STZ誘導之糖尿病組(DC, 1DC, 5DC及10DC)則發現腎臟之腎絲球體發現嚴重程度不一之空泡化並伴隨有上皮細胞腫脹現象。
關鍵字：番石榴葉、寬筋藤、致突變試驗、降血糖

Diabetes mellitus (DM) is one of the metabolic disorders due to deficiency of insulin action. However, available drugs for DM have a number of limitations, such as adverse effects and high rates of secondary failure. Several studies have demonstrated many plants containing anti- hyperglycemic activity. The purpose of this study was to evaluate the anti-hyperglycemic activity of various plants. First, the inhibition of α-amylase activity was assayed in vitro. The results showed the water extracts from Psidium guajava leaves, Tinospora cordifolia stems and mixture of plant water extracts showed the highest inhibition of α-amylase activity and the IC50 was 3.24 mg/mL, 7.98 mg/mL and 3.14 mg/mL, respectively. In toxicity, mutagenicity of mixture of plant water extracts were investigated by Ames test. The results indicated that the mixture of plant water extracts (0.3125~5.0 mg/plate) couldn’t induce the toxicity and mutagenicity of Samlmonella typhimurium TA97 and TA100 with or without S9 mixture. In cytotoxicity, human hepatoma cell lines (HepG2) and murine embryonic liver cell line (BNL CL.2) which were treated with various concentrations of plant extracts, were used to investigate the cytotoxicity by MTT of assay（3- （ 4,5-dimethylthiazol-2-yl ）-2,5-diphenyltetrazolium bromide assay）.
When the cells of BNL CL.2 were treated with 5~300 μg/ml of mixture of plant water extracts for 24, 48 and 72 hours, the survival percentages were significantly higher than control group (p＜0.05), but no significant effect on HepG2 were observed. In vivo, the Wistar rats were employed and introduced nicotinamide (230 mg/kg) and streptozotocin (75 mg/kg) for diabetic induces. After continuous feeding for 5 weeks of mixture of plant water extracts showed to reduce eating and increase body weight, and had a significant decrease in triglyceride, LDL, and creatinine concentration in plasma, and increase in HDL concentration in plasma. The level of blood glucose and was decreased on the third week of feeding and continuously the level of blood glucose stable to the end of experiment. In histopathological study, normal histograms of eyes, kidney, heart, pancreas, brain and liver tissue were observed in NC group, while various intensity of renal tube epithelium cell hydropic degeneration was found in other diabetic-induced groups (DC, 1DC, 5DC and 10DC). However, no histopathological changes were observed in other organs, such as brain, liver and eyes.
Key words: Psidium guajava, Tinospora cordifolia, Ames test, anti-hyperglycemic

中文摘要 II
Abstract III
誌謝 V
目錄 VI
圖索引 X
表目錄 XIII
第壹章、前言 1
第貳章、文獻回顧 2
ㄧ、糖尿病介紹 2
(一)糖尿病之定義 2
(二)胰島素 4
(三)糖尿病之診斷與分類 11
(四)糖尿病之流行性學(Epidemiology) 19
二、番石榴之介紹 21
(一)番石榴簡介 21
(二)成分分析 22
(三)番石榴葉之生理活性 24
(四)番石榴葉降血糖之相關研究 25
三、寬筋藤之介紹 30
(一) 寬筋藤之簡介 30
(二)成分分析 31
(三)寬筋藤之生理活性 31
(三)寬筋藤降血糖之相關研究 35
四、致突變性試驗 36
(一)菌株突變特性 37
(二)其他突變特性 39
(三)轉化酵素(S9 mix) 40
五、植物萃取物對人體正常肝細胞及肝癌細胞存活率測定 42
(一)肝臟簡介 42

(二) MTT assay 43
六、糖尿病動物模式及評估指標 44
(一)第二型糖尿病動物模式之建立 44
(二) STZ致糖尿病機轉 45
(三)血糖評估指標 46
(四)血液生化值之評估及診斷之臨床意義 49
第参章、材料與方法 54
一、實驗設計 54
二、實驗材料 55
(一)植物材料 55
(二)體外試驗 55
(三)致突變性試驗 55
(四)細胞毒性試驗 56
(五)體內試驗 56
(六)器材與儀器設備 57
三、實驗方法 58
第一部份：利用In Vitro的方式篩選具有抑制α-amylase活性之植物 58
(一)植物萃取液樣品製備 58
(二)測定植物萃取液抑制α-amylase活性之方法 58
(三)實驗項目 60
(四)不同植物萃取液之總多酚類化合物(total phenolic compound)含量測定 63
第二部份：體外安全性試驗(Ames test) 64
(一)各種溶液之配製(Maron and others 1983) 64
(二)菌株保存 68
(三)菌株特性確認 68
(四)毒性試驗 68
(五)致突變性試驗 69
(六)抗致突變性試驗 69
第三部份：細胞毒性試驗 70
(一)細胞之解凍 70
(二)細胞之繼代培養 70
(三)細胞之保存 71
(四)細胞存活率測定方法 (MTT assay) 71
第五部份：體內試驗 72
(ㄧ)實驗分組方式 72
(二)以STZ誘導糖尿病模式之劑量測試 74
(三)混合植物萃取液調節血糖作用 75
四、統計分析 76
肆、結果與討論 77
第一部份：利用In Vitro的方式篩選具有抑制α-amylase活性之青草植物 77
ㄧ、不同植物水萃取液對抑制α-amylase活性之探討 77
二、不同植物之有機溶劑萃取液對抑制α-amylase活性之探討 77
三、不同溶劑之植物萃取液總酚類化合物含量 78
四、最適萃取條件對植物萃取液抑制α-amylase活性之探討 88
五、萃取率之計算 92
六、混合植物水萃取液對抑制α-amylase活性之探討 92
七、經不同pH處理之混合植物水萃取液對抑制α-amylase活性之探討 94
八、經不同溫度處理之混合植物水萃取液對抑制α-amylase活性之探討 94
九、植物水萃取液對α-amylase活性之半抑制濃度測定(IC50) 95
十、混合植物萃取液之模擬人工消化試驗 102
十一、不同儲存條件對混合植物萃取液抑制α-amylase 活性之影響 104
第二部份：體外安全性試驗(Ames test) 106
一、菌株基因型測試 106
二、毒性試驗 107
三、致突變性試驗 107
四、抗致突變性試驗 108
第三部份：細胞毒性試驗 118
ㄧ、植物水萃取液對初生小鼠肝細胞BNL CL.2生長之影響 118
二、植物水萃取液對人類肝癌細胞HepG2生長之影響 119
第四部份：體內試驗 127
ㄧ、大鼠實驗前後之體重變化 127
二、大鼠實驗前後之飲水、攝食量變化 127
三、空腹血糖值之監測 128
四、葡萄糖耐受性試驗 130
(一)以Nicotinamide及STZ進行誘發後ㄧ週之葡萄糖耐受性試驗 130
(二)餵食植物水萃取液五週後之葡萄糖耐受性試驗 131
五、餵食混合植物水萃液對大鼠血脂之影響 143
六、餵食混合植物水萃液對大鼠腎功能之影響 146
七、餵食混合植物水萃液對大鼠肝功能之評估 147
八、大鼠於實驗後之臟器重量變化 158
九、大鼠餵食混合植物水萃液五週後之臟器病理觀察 161
伍、結論 166
參考文獻 168
作者簡介 178

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