臺灣博碩士論文加值系統

高膽固醇血症(hypercholesterolemia）及高血脂(hyperlipidemia)被認為是影響動脈粥樣硬化症(atherosclerosis)與心血管相關疾病之形成及進展的主因。一些天然植物已被證實可有效降低血清中膽固醇或三酸甘油酯濃度進而延緩心血管疾病的形成或改善。丹參，在傳統醫學中屬於「活血化瘀(blood-quickening, stasis-dispelling )」的藥物並廣泛被使用於改善心血管類疾病(cardiovascular disorders )上，丹參酚酸B(Salvianolic acid B) 是從丹參(salvia miltiorrhiza bunge)根莖中萃取出來的化合物，在許多研究報告中指出其兼具抗氧化能力。近代研究更進一步指出，丹參酚酸B、薑黃素(curcumin)、葛根素(puerarin)及玫瑰花粹取物，皆被證實具有可降低心血管疾病風險因子。
本篇論文與實驗內容主要探討KDS718複方藥材對於餵食高脂肪食物6週或12週後的倉鼠(hamsters)，其降低血脂的效能。KDS718複方包含丹參酚酸B、薑黃素、葛根素及玫瑰花，實驗將不同濃度的KDS718與粉狀飼料混合後讓倉鼠自由攝食。實驗進行6週及12週後，採集倉鼠空腹血液並檢測其總膽固醇(total choleasterol)、三酸甘油酯(triglycerides)、低密度脂蛋白（low density lipoprotein，LDL）、極低密度脂蛋白（very low density lipoprotein，VLDL）的濃度以及其低密度脂蛋白的氧化反應(LDL oxidation)。此外，實驗中並進行沙門氏逆突變試驗(Ames revertant mutagenesis assay )、體外鼷鼠淋巴瘤tk分析(in vitro mouse lymphoma tk revertant mutagenesis assay) 及小鼠周邊血液微核試驗(the micronuclei assay in the mice peripheral blood)來測試KDS718是否會造成基因毒性。
實驗結果顯示，KDS718無法改善因餵食高脂肪食物所引發的高血脂，但KDS718並不具有任何基因毒性；此外，高脂肪食物無法誘發實驗的倉鼠形成動脈粥狀硬化斑塊。
綜合上述結果，KDS718無法降低血中脂質的濃度且高脂肪食物無法誘發粥狀硬化斑塊的形成，其可能的原因有以下3點:
（1）KDS718複方具有活性化合物的含量可能不足以改變血液中脂質的代謝機制；
（2）倉鼠選擇性攝取到不含有KDS718的粉狀飼料；
（3）含有膽酸的飼料可能更容易誘發倉鼠粥狀動脈硬化病灶的形成。

The hypercholesterolemia and hyperlipidemia were associated with the high incidence of the formation or development of atherosclerosis and related cardiovascular disorders. Some natural plants have proven they could reduce the concentration of cholesterol or triglycerides in blood serum so that postpone formation or development of cardiovascular disorders. Salvia miltiorrhiza bunge, a traditional Chinese herb which is taken as a blood-quickening, stasis-dispelling medicine, is widely used to improve cardiovascular disorders. Salvianolic acid B is extracted from Salvia miltiorrhiza bunge’s root and exhibites anti-oxidative activity in many assay models. Recent studies demonstrated that salvianolic acid B, curcumin, and the extracts of puerarin and rose had benefit for decreasing the risk factors of cardiovascular disorders.
In this study, we used the KDS718 complex to examine the hypolipidemia effects in hamster-fed with high fat diet for 6 or 12 weeks. The KDS718 consists of salvianolic acid B, curcumin, and the crude extract of puerarin and rose, and hamster was free access to powder diet containing various concentrations of powder KDS718. At the 6th weeks and the end, fasting blood was measured the levels of total choleasterol, triglycerides, LDL and VLDL, and the LDL oxidation. In addition, we also examined whether KDS718 had genotoxicity by Ames and mouse lymphoma tk revertant mutagenesis assay, and the micronuclei assay in the mice peripheral blood.
Our results suggest that KDS718 can’t improve the hyperlipidemia in hamster-fed with high fat diet, and it has no any genotoxicity. The high fat diet did not induce fatty streak in artery of high fat-fed hamster. KDS718 failed to reduce the lipid levels and induce fatty streak might result from the following reasons.
1. The amounts of active compounds of KDS718 might be not enough to change the lipid metabolism.
2. The hamster selectively ingested powder diet without KDS718 powder.
3. Atherosclerotic lesion might be easy formation with diets containing cholic acid in hamster.

縮寫表(Abbreviations)IV
第一章 Abstract 7
第二章 中文摘要 9
第三章 緒 論 11
第一節 研究目的 11
第二節 高血脂暨動脈粥狀硬化.13
一、前言 13
二、血漿脂質及脂蛋白 15
三、動脈粥樣硬化症(atherosclerosis) 流行病學 24
四、動脈血管介紹 29
五、動脈粥樣硬化症(atherosclerosis) 病理學 33
六、動脈粥樣硬化症假說(hypotheses of atherogenesis) 36
1.內皮損傷反應(response-to-injury of endothelium) 37
2. 低密度脂蛋白滯留反應(response-to-retention oF LDL) 39
3. 低密度脂蛋白氧化修飾(oxidative LDL modification） 42
七、單核球的遷移(monocyte migration) 44
八、平滑肌細胞的增生 47
第三節?中草藥複方(KDS718)成分介紹 49
一、丹參(Salvia miltiorrhiza bunge) 49
二、薑黃素(curcumin）55
三、葛根素(puerarin) 58
四、玫瑰花(rose rugosa thunb) 61
第四節?基因安全性指標評估 63
一、沙門氏逆突變試驗 63
二、體外鼷鼠淋巴瘤tk分析 65
三、小鼠周邊血液微核試驗 66
第四章 實驗材料與方法 68
第一節 實驗動物之血清生化參數測量 68
一、實驗儀器 68
二、實驗材料與試劑 68
三、實驗動物 69
四、實驗方法 69
第二節 基因安全性評估 75
壹、沙門氏逆突變試驗(AMES revertant mutagenesis test ) 75
一、實驗材料與試劑 75
二、實驗方法 76
三、結果分析與判定 78
貳、鼷鼠淋巴瘤TK分析 78
一、實驗材料與試劑 79
二、實驗方法 81
三、統計分析與結果判定 83
參、小鼠周邊血液微核試驗 83
一、實驗材料與試劑 84
二、實驗方法 84
三、統計分析與結果判定 86
第五章 實驗結果 88
第一節 血清生化參數結果 88
一、預試驗I 88
二、預試驗II 88
三、正式實驗 89
四、附加實驗 90
第二節 基因安全性評估 91
一、沙門氏逆突變試驗(AMES test) 91
二、鼷鼠淋巴瘤TK分析 93
三、小鼠周邊血液微核試驗 94
第六章 討論 96
第七章 圖表 102
FIG.1~ FIG.5 預試驗I：倉鼠餵食高脂肪飼料及KDS718，4 週後血中TG、TC、 HDL、LDL及VLDL的濃度 102
FIG.6~ FIG.10. 預試驗II：倉鼠餵食高脂肪飼料及KDS718，4 週後血中TG、TC、 HDL、LDL及VLDL的濃度 103
圖11~圖18. 正式試驗：倉鼠餵食高脂肪飼料及KDS718，6及12 週後血中TG、TC、GOT及GPT的濃度 104
圖19~圖21. 正式試驗：倉鼠餵食高脂肪飼料及KDS718，1、6及12 週體重的變化 106
FIG. 22~FIG. 23 正式試驗：倉鼠餵食高脂肪飼料及KDS718， 12週試驗之血清LDL OXIDATION結果 107
FIG. 24~FIG. 25 附加試驗: 倉鼠餵食高膽固醇飼料及KDS718，4 週後血中TOTAL CHOLESTEROL及TRIGLYCERIDES的濃度 108
TABLE 1~2. KDS718對於沙門氏菌的基因致突變性影響(AMES TEST)之結果 109
FIG. 26 KDS718濃度影響L5178Y TK+/-細胞存活率的結果 111
TABLE 3. 不同濃度的KDS718在不含S9條件下對於L5178Y TK+/-細胞基因突變的影響 112
TABLE 4. 不同濃度的KDS718在含有S9條件下對於L5178Y TK+/-細胞基因突變的影響 113
FIG. 27. 不同濃度的KDS718對於雄性小鼠周邊血液產生微核的結果 114
TABLE 5. 不同濃度的KDS718對於雄性小鼠周邊血液產生微核的數量 116
TABLE 6. 不同濃度的KDS718對於雄性小鼠周邊血液產生微核及網狀紅血球的百分比 117
第八章 參考文獻 118

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