臺灣博碩士論文加值系統

隨著生活水準提高與醫療科技的進步，人類的平均壽命延長，伴隨著年齡增長而引發的慢性疾病與老化現象的研究議題逐漸受到國人的重視及探討。本研究以不同模式之代謝症候群老鼠同時給予紅麴山藥及控制血脂、血糖及血壓之藥物，探討是否會引起非預期性效應。在高血脂部份，以敘利亞倉鼠 (Syrian Hamster) 誘導高血脂模式老鼠，實驗結果得知，高膽固醇飲食倉鼠每百克體重餵食紅麴山藥一倍以上劑量可顯著降低血液中膽固醇濃度達 23.3% 以上 (p < 0.05)。以 streptozotocin 誘導並施打 nicotinamide 保護劑，誘導為第二型糖尿病之模式動物。在糖尿病大鼠每公斤體重餵食紅麴山藥 176.0 mg 之一倍以上劑量血液中胰島素含量與糖尿病組相比，可顯著增加 3.0 IU/mL 以上 (p < 0.05)。在糖化血色素方面與糖尿病組相比，則可顯著降低 3.4% 以上 (p < 0.05)。在高血壓部份，以自發性高血壓大鼠為模式老鼠，將紅麴山藥與 amlodipine 併用，以單次餵食紅麴山藥 (176 mg/kg) 顯著降低收縮壓與舒張壓 6.1% 和 7.0% (p<0.05)。在肝、腎功能方面，無論是正常組或是高血脂、糖尿病與高血壓組，在服用紅麴山藥或是紅麴山藥與藥物併用下，對於肝、腎代謝或是生理功能並未造成其負擔且未引發橫紋肌溶解症。
在第二部分，本研究經衛生福利部認可之可供食品使用且文獻曾記載具延緩老化之中藥作為素材，篩選出萃取物具高抗氧化力之中草藥，後續探討開發預防阿茲海默症之保健食品。以 IMR 32 神經細胞為模擬細胞，分析其細胞毒性與抗 Aβ 引起之細胞傷害。由 IMR 32 細胞試驗得知，雷公根與酸棗仁酒精萃取物對細胞不會產生毒性造成細胞凋亡的現象，再以聚集的Aβ1-40 所產生的神經毒素與細胞共培養也具有保護 IMR32 細胞免於受到 Aβ1-40 神經毒性傷害。
針對篩選出抗 Aβ 毒性之雷公根與酸棗仁兩種中草藥萃取物，以 8 週大之Sprague-Daw1ey 系雄性大鼠為模式動物，應用腦部手術以 ALZET 腦部輸注幫浦在大鼠腦部海馬迴處連續輸注類澱粉樣蛋白 (amyloid β-peptide, Aβ)，造成其在腦部沉積並破壞海馬迴組織，誘導大鼠產生阿茲海默症 (Alzheimer’s disease, AD)。除此之外，由本研究室先前利用傳統變異法篩選得到 Monascus purpureus NTU 568 之紅麴菌株，其以紅麴米發酵之產物經研究證實對阿茲海默症危險因子具改善作用，且已發表多篇期刊論文證實以山藥當基質之紅麴發酵物具改善數種氧化壓力及發炎反應相關代謝症候群疾病的能力，推測此菌株發酵生產之紅麴山藥對Aβ 腦部輸注之阿茲海默症大鼠記憶學習能力應具改善潛力，因此與篩選出之中藥一併進行各項試驗。經過連續餵飼 28 天酸棗仁、雷公根萃取物或紅麴山藥在記憶學習和行為能力皆有改善現象，達到延緩衰老之功效。實驗動物犧牲後分析血液中脂質含量、肝、腎功能和電解質均無顯著差異。再分析腦部海馬迴組織中連續輸注類澱粉樣蛋白會增加乙醯膽鹼酯&;#37238;活性和氧化壓力傷害，降低總抗氧化能力。由動物記憶、行為試驗和血液安全性與功效性指標實驗與分析結果得知，酸棗仁、雷公根萃取物與紅麴山藥，在科學性的多方試驗下，對於以 Aβ 誘導之阿茲海默症大鼠確實能減緩阿茲海默症產生的失憶，提供更充分的證據證實其功效，在治療上或許能達到輔助效果。未來將以此優勢開發多效性之延緩老化保健食品。

With improvements in living conditions and advances in medical technologies, humans are living longer. Aging puts people at a greater risk for health issues, metabolic syndrome and chronic diseases related to aging have an impact on society as a whole. The aging related issues have brought great attention to the world and have been discussed extensively.
In this study, we aimed to investigate the effects of interaction of red mold dioscorea (RMD), which has long been considered a food product, with medicines in different animal models of metabolic syndrome. Results obtained from hyperlipidemia groups indicated that the blood cholesterol levels in groups that feeding RMD more than 22.96 mg/100 g hamster were significantly decreased by 23.3% (p < 0.05). Rat models of streptozotocin (STZ)-induced type II diabetes were established. These animals were divided into groups that feeding RMD more than 176 mg/kg rat the insulin concentrations were increased significantly up to 3.0 IU/mL (p < 0.05). Furthermore, in glycated hemoglobin significant decreases 3.4% (p < 0.05). Further, we used RMD with amlodipine to investigate RMD’s effect on the anti-hypertension effect of amlodipine in a rat model of spontaneous hypertension. The results indicated that a single oral dose of RMD (176 mg/kg) administered over an 8-h period significantly (p < 0.05) decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 6.1% and 7.0%, respectively. No change in heart rate was observed. We did not observe rhabdomyolysis, a potentially dangerous side effect of statin drugs, in any experiments with animal models of metabolic syndrome. Furthermore, no animal exhibited signs of liver or kidney dysfunction.
In the second part, we aimed to develop functional foods by using Chinese herbs to counteract the effects of Alzheimer’s disease (AD). For this purpose, extracts of the Chinese herbs Rosa rugosa, Crataegus pinnatifida, Centella asiatica, and Semen Zizyphi spinosae were selected from their high antioxidant activity. In the aggregated Aβ1-40 neurotoxin model of IMR 32 cells, we found that Centella asiatica and the Semen Zizyphi spinosae ethanol extract had lower cell toxicity and protected IMR 32 cells from aggregation of the neurotoxic Aβ1-40 peptide.
We established an animal model of AD by continuously injecting Aβ into the hippocampus of SD rats by using an ALZET brain infusion pump. Groups fed Centella asiatica, Semen Zizyphi spinosae ethanol extract, or RMD demonstrated slight improvements in learning and memory capacity. After the animals were sacri&;#64257;ced, serum biochemical analyses for liver function, renal function, and electrolyte balance were performed. No changes were observed in any of these parameters. Serum and hippocampus samples were collected to examine AD risk factors. Aβ40 infusion increased acetylcholinesterase activity and decreased total antioxidant status and superoxide dismutase activity in the brain; however, these damages were potently reversed upon administration of Centella asiatica, Semen Zizyphi spinosae ethanol extract, or RMD. Moreover, the protection afforded by these herbs was more signi&;#64257;cant than that afforded by cholinesterase inhibitor drugs.
In conclusion, our study provides further efficacy data in support of traditional functional foods for the treatment of diseases. We found that Centella asiatica, Semen Zizyphi spinosae, and RMD inhibit Aβ-induced neurotoxicity and may play a role in preventing the deleterious effects associated with AD. On the basis of these findings, we recommend the development of functional foods for therapy or as adjuvant agents for the prevention of AD.

圖目錄……………………………………………………………… V

表目錄……………………………………………………………… VIII

摘要………………………………………………………………… X

Abstract…………………………………………………………… XII

第壹章 緒論………………………………………………………… 1
一、老化的定義…………………………………………………… 1
二、代謝症候群…………………………………………………… 2
三、高血脂症 (hyperlipidemia) 與血脂異常 (dyslipidemia) 3
四、糖尿病簡介…………………………………………………… 7
五、高血壓之簡介………………………………………………… 9
六、阿茲海默症………………………………………………… 10
七、中藥之開發與應用…………………………………………… 32
八、中草藥簡介…………………………………………………… 34
九、紅麴菌……………………………………………………… 37
第貳章 研究動機與目的……………… ………………………… 46
第參章 材料與方法………………………………………………… 49
一、實驗材料…………………………………………………………49
(一) 儀器…………………………………………………………… 49
(二) 藥品…………………………………………………………… 49
二、探討紅麴山藥與藥物併用對降血脂、血壓、血糖之功效及對引發橫紋肌溶解症之風險評估…………………………………… 51
(一) 紅麴山藥與降血脂藥物併用對高血脂倉鼠降血脂功效及其對生理之影響……………………………………………………………………51
(二) 紅麴山藥與降血糖藥物 thiazolidinedione 併用對糖尿病大鼠影響評估…………………………………………………………………………52
(三) 紅麴山藥與降血壓藥物amlodipine對高血壓大鼠降血壓之影響評估…………………………………………………………………… 55
三、中草藥對於改善記憶學習能力暨輔助治療阿茲海默症之研究 57
(一) 中藥對於阿茲海默症輔助治療之體外細胞試驗…………… 57
(二) 雷公根 20 %、酸棗仁 40 % 酒精萃取物與紅麴山藥改善阿茲海默症與記憶學習之動物試驗…………………………………… 62
(三) 雷公根飲品 (健康食品安全分類第二類) 安全性評估試驗 72
第肆章 結果與討論………………………………………………… 91
第一部份 探討紅麴山藥與藥物併用對降血脂、血壓、血糖之功效及對引發橫紋肌溶解症之風險評估…………………………………… 91
一、 RMD 與降血脂藥物併用對高血脂倉鼠降血脂之功效及其對生理之影響………………………………………………………………… 91
(一) 實驗動物體重與攝食量之變化……………………………… 91
(二) RMD 對血脂濃度變化情形…………………………………… 91
(三) 實驗動物肝臟中 TC 與 TG 濃度之變化…………………… 96
(四) 安全性分析—血液肝指數變化及肝功能檢測……………… 96
(五) 安全性分析—腎功能、電解質與橫紋肌溶解症…………… 101
二、 RMD產品與降血糖藥物併用對糖尿病大鼠血糖及其對生理之影響………………………………………………………………………103
(一) 實驗動物體重與攝食量之變化……………………………… 103
(二) 葡萄糖耐受性測試結果……………………………………… 103
(三) 實驗動物血液中血脂之濃度變化…………………………… 106
(四) 實驗動物血清胰島素和糖化血紅蛋白的變化情形………… 106
(五) 安全性分析—肝、腎功能與電解質………………………… 108
三、 RMD 與降血壓藥物併用對高血壓大鼠降血壓之影響評估… 113
(一) 試驗動物之單一餵食後 24 小時內收縮、舒張血壓及心律短期變化…………………………………………………………………… 113
(二) 試驗動物餵食 8 週後之收縮、舒張血壓及心律長期變化 113
(三) 實驗動物血液中脂質含量…………………………………… 116
(四) 安全性分析—肝、腎功能與電解質………………………… 116
第二部分、中藥與紅麴山藥對阿茲海默症輔助治療效益之研究 121
一、中藥對於阿茲海默症輔助治療之體外細胞試驗…………… 121
二、中草藥萃取物對 IMR-32 細胞存活率之影響……………… 121
三、聚合 Aβ1-40 濃度對IMR 32 之影響……………………… 123
四、雷公根、酸棗仁與玫瑰萃取物對 IMR-32 細胞抵抗聚合 Aβ1-40 神經毒性…………………………………………………………… 123
五、雷公根萃取物對 IMR 32 細胞之毒性與抗 Aβ1-40 毒性能力評估…………………………………………………………………… 123
(一) SOD 活性分析……………………………………………… 123
(二) Catalase 活性分析………………………………………… 127
(三) GPx 與 GR 活性分析………………………………………… 127
(四) GSH 與GSSG 含量分析……………………………………… 130
六、基原鑑定……………………………………………………… 130
(一) 雷公根之外觀鑑定與組織切片鑑定………………………… 130
(二) 酸棗仁之外觀鑑定與組織切片鑑定………………………… 134
(三) 雷公根與酸棗仁之 DNA 鑑定……………………………… 138
七、雷公根 20 %、酸棗仁 40 % 酒精萃取物與 RMD 改善阿茲海默症與記憶學習之體內動物試驗……………………………………… 138
(一) 實驗動物體重與攝食量之變化……………………………… 138
(二) 記憶學習能力試驗………………………………………… 138
八、大鼠血液與腦部海馬迴組織之各項功能檢測……………… 156
(一) 餵飼雷公根 20 % 與酸棗仁 40 % 酒精萃取物與 RMD 對大鼠血液中與腦部海馬迴組織之乙醯膽鹼&;#37238;活性之影響……………… 156
(二) 餵飼雷公根 20 % 與酸棗仁 40 % 酒精萃取物與 RMD 對大鼠血液與腦部海馬迴組織之乳酸脫氫&;#37238;活性之影響………………… 157
(三) 餵飼雷公根 20 % 與酸棗仁 40 % 酒精萃取物與 RMD 對大鼠血液中與腦部海馬迴組織之總抗氧化力活性之影響……………… 159
(四) 餵飼雷公根 20 % 與酸棗仁 40 % 酒精萃取物與 RMD 對大鼠血液與腦部海馬迴組織中過氧化氫&;#37238;活性之影響………………… 162
(五) 餵飼雷公根 20 % 與酸棗仁 40 % 酒精萃取物與 RMD 對大鼠血液與腦部海馬迴組織中超氧歧化&;#37238;活性之影響………………… 162
(六) 餵飼雷公根 20 % 與酸棗仁 40 % 酒精萃取物與 RMD 對大鼠血液與腦部海馬迴組織一氧化氮合成&;#37238;活性之影響……………… 166
九、安全性試驗分析……………………………………………… 170
(一) 血漿脂質含量分析…………………………………………… 170
(二) 肝功能分析…………………………………………………… 170
(三) 腎功能分析…………………………………………………… 170
(四) 電解質平衡狀態……………………………………………… 170
十、健康食品安全分類第二類產品雷公根飲品之安全性評估試驗……………………………………………………………… 176
(一) 評估雷公根飲品之沙門氏菌回復突變試驗………………… 176
(二) 評估雷公根飲品之體外哺乳類細胞染色體異常試驗……… 176
(三) 評估雷公根飲品之囓齒類週邊血液微核試驗……………… 177
(四) 評估雷公根飲品之大鼠28天重複劑量亞急性毒性試驗…… 183
第伍章 結論………………………………………………………… 190
第陸章 參考文獻…………………………………………………… 193
附錄—已發表之文章……………………………………………… 215

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