臺灣博碩士論文加值系統

中 文 摘 要
許多的臨床研究和動物實驗報告顯示，高胰島血症和胰島素阻抗及其產生相關的代謝異常，如高三酸甘油酯血症，和臨床上常見的三大疾病，即非胰島素依賴型的糖尿病（NIDDM）、高血壓及冠狀動脈疾病，有極高的相關性，是故研究發展兼具改善高胰島素血症/胰島素阻抗的控制血壓相關的保健食品，不僅可改善上述三大疾病的控制，並能預防其併發症的發生。長期果糖餵食不僅會導致大白鼠的血壓升高，並且會伴隨有高胰島素血症、胰島素阻抗和高三酸甘油酯血症，是用來研究臨床上肥胖、糖尿病和高血壓之相關性及併發症極為有用的動物模式。
本實驗計劃的目的在於：評估高及低劑量M9011紅麴發酵液及菌絲體對果糖餵食誘發高血壓鼠之血壓及代謝的影響，及探討其影響血壓可能的機轉。
實驗結果顯示長期（十四週）經胃管餵食M9011紅麴發酵液，對於大白鼠心、肝及腎臟的細胞組織及肝、腎功能之生化指數均無顯著影響。低劑量M9011紅麴發酵液（其中含GABA1mg/kg/day）可預防果糖誘發高血壓發展的進程及降低高血壓的程度。其次，低或高劑量M9011紅麴菌絲體也能有效預防果糖誘發高血壓發展的進程。但是，高劑量的M9011紅麴發酵液（其中含GABA10mg/kg/day）卻無法預防果糖餵食鼠血壓的升高。在餵食純GABA組，無論是在果糖誘發高血壓鼠之高血壓發展期或是高血壓維持期，均可有效持續約2週且預防或抑制血壓的升高，但第3週後血壓又會回升到與Fructose only 組相同的狀態，因此推論M9011紅麴菌可能還含有其他除GABA以外的降血壓成分。另外，在果糖誘發的代謝方面，紅麴無法改善純果糖餵食組（Fructose only組）之高三酸甘油脂血症、高胰島素血症及胰島素阻抗的情況。但在本實驗中也發現，長期低劑量的紅麴發酵液不含Monacolins餵食可降低低密度脂蛋白膽固醇和非常低密度脂蛋白膽固醇的濃度，而且也增加高密度脂蛋白膽固醇的含量，顯示其成份中可能含有除Monacolins 外可改善膽固醇代謝異常的成分。
M9011紅麴菌株之菌絲體較其發酵液為較佳之，兼顧安全性及降血壓的功能的保健食品，其成份中可能含有除GABA外，另一重要，但未知的降血壓成分，而其作用機轉可能經由抑制交感神經系統的活性或改善血管內皮釋放一氣化氮的功能，而非作用在腎臟，這些都有待進一步的研究來釐清的課題。

ABSTRACT
Numerous clinical and experimental studies about non-insulin-dependent diabetes, hypertension and coronary artery diseases have suggested that a close correlation exists among hypertension, hyperinsulinemia/insulin resistance and dyslipidemia.Therefore, it is imperial to develop the new treatment to both improve hypertension and its associated metabolic disorders. In the present studies, we examined the effects of the aqueous extracts and cell mass of Monascus purpureus M9011 on fructose-induced hypertension associated with hyeprinsulinemia/insulin resistance and hypertriglyceridemia in rats. Furthermore, we examined the possible role of GABA (-aminobutyric acid) in the blood pressure lowering effect of M9011 and the effects of M9011 on the food and water intakes and renal function.
The present results showed that the gavages with low dose aqueous extracts （GABA 1mg/kg/day）or high （GABA 10mg/kg/day）and low doses of cell mass of M9011 daily for 8 wks could prevent the development of fructose-induced hypertension. It also could reduce the elevated blood pressure levels once it was established with low dose aqueous extracts of M9011. However, the high dose of aqueous extract of M9011 didn’t influence the development of fructose-induced hypertension. Nevertheless, M9011 could not improve fructose-induced hyperinsulinemia/insulin resistance and hypertriglycemia. The present data also implied that the antihypertensive effects of M9011 might not only mediate by GABA but also the other components. Chronic administration of low dose aqueous extract of M9011 without monacolins significantly attenuated the levels of LDL-cholesterol (low density lipoprotein- cholesterol) and VLDL- cholesterol (very low density lipoprotein-cholesterol), whereas increased the level of HDL-cholesterol. It implies that , in addition to monacolins, the other components of M9011 could improve the dysfunction of cholesterol metabolism in fructose-fed rats. Furthermore ,no significant changes in food intake、water intake and renal sodium and potassium excretions were observed in all of the fructose-fed rats.
In conclusion, the present results have demonstrated that cell mass of M9011 but not its aqueous extract is a safe and effective antihypertensive substance. We concluder that the presence of other components except GABA and monacolins might be responsible for the therapeutic effects of M9011 on hypertension and dyslipidemia in fructose-fed rats.

目 錄
頁數
中文摘要………………………………………………………………………Ⅰ
英文摘要………………………………………………………………………Ⅲ
第一章 前言………………………………………………………………..1
第一節 紅麴之特性及其在藥物上之應用………………………….…2
1-1紅麴菌之分類與生態………………………………………………….3
1-2 紅麴菌的代謝產物之特性與利用…………………………………..5
1-2-1菌體外水解酵素(高分子化合物分解酵素)………………….6
1-2-2 酸、醇及酯類化合物………………………………………..7
1-2-3 紅麴色素 …………………………………………………7
1-2-4 抗腐敗菌的狹效抗生素：桔黴素(monascidin)…………..8
1-2-5 膽固醇合成抑制劑………………………………………….9
1-2-5-1膽固醇合成之機制及其功能………………………… 9
1-2-5-2膽固醇合成抑制劑:Monacolin K ………………… .11
1-2-6 其他…………………………………………………………..13
1-2-6-1 降血糖…………………………………………..13
1-2-6-2 防癌及增強免疫的功效…………………………14
1-2-6-3 麥角固醇〈ergosterol〉………………………15
1-2-6-4、抗氧化物質…………………………………….16
1-2-6-4-1.長鏈脂肪酸…………………………….16
1-2-6-4-2.Dimerumic acid……………………….16
1-2-6-5 ankalactone…………………………………….17
1-2-6-6 Glucosamine:…………………………………..17
1-2-7 降血壓物質(GABA)…………………………………………17
1-2-7-1 GABA 的代謝…………………………………..17
1-2-7-2 真菌中的GABA……………………………………18
1-2-7-3 GABA的生理功能……………………………….19
1-3 紅麴食品之臨床運用………………………………………………23
1-3-1紅麴的降血脂功能臨床研究…………………………23
1-3-2紅麴的降血壓功能臨床研究……………………….26
1-4 紅麴的安全及毒性試驗……………………………………………27
第二節 紅麴在「X症狀」的治療與預防上之可能運用…………………..28
2-1 Syndrome X ……………………………………………………….28
2-2 胰島素阻抗/高胰島素血症和高血壓…………………………….29
2-3高三酸甘油酯血症與胰島素阻抗和高血壓……………………….31
2-4 紅麴 對「X症狀」的可能治療作用探討………………………..32
2-4-1 紅麴與高血壓可能治療作用及成分探討……………..32
2-4-2 紅麴降血糖的探討………………………………………34
2-4-3 紅麴與血脂及高胰島素血症/胰島素阻抗探討……….34
第三節 動物模式………………………………………………………….36
第二章 實驗動機、構想與目的…………………………………………...38
第三章 材料與方法………………………………………………...………40
第一節、實驗材料……………………………………………………..40
（一） 實驗動物：………………………………………………………40
（二） 本實驗菌株（M9011紅麴菌株）：………………………………40
（三） 飼料：……………………………………………………………41
第二節 化學試劑…………………………..……………………………41
第三節儀器設備……………………………………………..…………..42
第四節、實 驗 分 組 及 實 驗 步 驟 :………………………………44
第四章 實 驗 結 果………………………………………………………..60
第五章 討 論…………………………………………………………………73
第六章 結論………………………………………………………………….80
第七章 圖表與說明…………………………………………………….…….81
參考文獻……………………………………………………………………103

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