臺灣博碩士論文加值系統

自古以來，相傳綠豆篁其主要作用為保肝解毒、減輕疲勞、降火氣、養顏美容、增強免疫力等，是民間廣為流傳的偏方。雖然具有多種醫藥功能，但皆為口耳相傳，未經科學實驗認證。因此本研究目的分為兩部分，第一部分主要為藉由健康食品安全性評估方法中的28天餵食毒性試驗及基因毒性試驗評估綠豆篁食用之安全性，並對肝臟解毒表現進行研究。第二部分為利用體外(in vitro)實驗模式，評估綠豆篁乙醇粗萃物是否具有抗發炎效果。本篇研究方法在第一部分是以四週齡大的雄性及雌性BALB/c小鼠為實驗動物，使用管灌方式分別給予不同劑量的綠豆篁(0、25、50、100 mg/day)，其間並隨時紀錄體重變化。管灌至第四週後，將小鼠犧牲且收取血液及肝臟作檢測。利用自動血球計數儀及血清生化分析儀分析血液中血球相關數值及血清生化值，以Haematoxylin-Eosin stain判讀肝組織切片的病理學變化。基因毒性試驗則以TA97、TA98、TA100、TA102及TA1535為實驗菌株，分別添加不同濃度的綠豆篁(3、6、12、25、50 mg/mL)，最後再以微生物基因突變分析法檢測各菌株其反突變菌落數產生情形。雌性BALB/c小鼠肝臟乃利用酵素免疫測定法(ELISA)偵測肝臟中NADPH-CYP reductase與抗氧化酵素glutathione S-transferase (GST)、superoxide dismutase (SOD)及catalase活性，最後以real-time PCR assay分析肝臟中cytochrome P450 gene (CYP1A2、CYP2B10、CYP2E1、CYP3A11)表現。28天餵食毒性試驗結果顯示，隨著管灌綠豆篁週數增加，小鼠體重均有正常增加之趨勢，且每週各組間體重無顯著差異。所有血球相關數值及血清生化值皆在參考值範圍內。小鼠肝組織切片上未有任何顯著損傷之組織病理學變化。基因毒性試驗結果顯示，不論有無添加S9混合物，綠豆篁對各菌株的反突變菌落數產生，其各組間無顯著差異。肝臟解毒研究結果顯示，肝臟中NADPH-CYP reductase、抗氧化酵素GST、SOD與catalase活性及cytochrome P450 gene (CYP1A2、CYP2B10、CYP2E1、CYP3A11)相對於控制組皆有顯著差異。第二部分是藉由體外(in vitro)實驗模式，分別添加不同濃度的綠豆篁乙醇粗萃物(0、250、500、1000、1200 μg/mL)，利用分光光度計檢測DPPH自由基清除率。並以LPS誘發RAW264.7巨噬細胞產生發炎介質及細胞激素後，以ELISA偵測一氧化氮、前列腺素E2、促發炎細胞激素IL-1β、IL-6及TNF-α和抗發炎細胞激素IL-10的產生，接著以western blotting assay分析一氧化氮、前列腺素E2其合成酵素iNOS、COX-2蛋白質表現量。抗發炎研究結果顯示，綠豆篁乙醇粗萃物具有良好自由基清除率之能力，且有抑制LPS誘發RAW264.7巨噬細胞之發炎介質一氧化氮、前列腺素E2產生及其合成酵素iNOS、COX-2蛋白質表現與促發炎細胞激素IL-1β、IL-6及TNF-α產生之趨勢，並促進抗發炎細胞激素IL-10釋放。綜合本篇研究結果推論，綠豆篁為可安全食用的，且能促進肝臟達到解毒功效，並有抗發炎功能。

From time immemorial, the main function of Lvdou huang was used for the liver protection to counteract poison, reduce the tired feeling, back the fire and to lower internal heat, keep and improve looks, enhance immunity, etc.. Although has the many kinds of medicines function, but all for directly from master to disciple, has not authenticated after the scientific experiment. The aim of this study divided into two parts, the first part was to evaluate the safety of Lvdou huang by using oral administration Lvdou huang to examine gene toxicity test, and liver detoxification evaluation. The second part of this study was to evaluate anti-inflammation effect of the ethanol extract from Lvdou huang with RAW264.7 macrophage cell line. The four weeks old male and female BALB/c mice were divided into four groups and oral administered Lvdou huang at different dosage for 4 weeks. The body weight was recorded. After 4 weeks, mice were sacrificed and collected the blood and the liver. The blood cell counts and serum biochemistry value were analyzed by the automatic blood cell counter and the serum biochemical analyzer. Histopathological change of the liver tissue slice was assayed by Hematoxylin-Eosin stain. In the gene toxicity test, the Salmonella typhimurium TA97, TA98, TA100, TA102, and TA1535 either with or without S9 mix were treated different concentrations of Lvdou huang. The Ames test was used to detection the back mutation bacterial count. The activity of NADPH-CYP reductase, antioxidant enzyme activity of glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase in female mice liver were determined by ELISA assay. Finally, the expression of cytochrome P450 gene (CYP1A2、CYP2B10、CYP2E1、CYP3A11) was assayed by real-time PCR assay. 28 days oral administration toxicity test result showed that oral administration with different dosage of Lvdou huang did not significantly affect the body weight of mice. The correlation value of blood cell and serum biochemistry value were in the scope of reference value. Histopathological changes of mice liver did not show significant difference. The result of toxicity gene test result showed that treat mice with different dosage of Lvdou huang did not significantly affect the back mutation bacterial count of Salmonella typhimurium TA97, TA98, TA100, TA102, and TA1535 either with or without S9 mix. The activity of NADPH-CYP reductase, antioxidant enzyme such as GST, SOD and catalase ,and the expression of cytochrome P450 gene (CYP1A2、CYP2B10、CYP2E1、CYP3A11) showed significant difference when compared with control group. The second part of the experiment, the RAW264.7 macrophage cells were treated with different concentrations of the Lvdou huang ethanol extract. The free radical scavenging ability was analyzed by the spectrophotometer. The ELISA assay was used to determine nitric oxide, PGE2, proinflammatory cytokines such as IL-1β, IL-6 and TNF-α, and anti-inflammatory cytokine such as IL-10 secretion. The western blotting assay was to detection the protein expression of inducible NO (iNOS) and cyclooxygenase-2 (COX-2). The anti-inflammation result showed that Lvdou huang ethanol extract have the best free radical scavenging ability, and inhibited inflammatory mediators and proinflammatory cytokines, and advanced anti-inflammatory cytokine secretion in LPS-stimulated RAW264.7 macrophage cells. In conclusion, Lvdou huang was recognized as safe, and can promoted the effect of liver detoxification, and anti-inflammation.

中文摘要 7
Abstract 9
第一章、緒論 11
第一節、文獻回顧 11
1.1綠豆之簡介 11
(一)名稱及分類學 11
(二)產地及外型 11
(三)傳統藥理 12
(四)營養成分及機能性成分 12
(五)製程 13
1.2綠豆相關功能性研究 14
(一)抗腫瘤、癌症之功能 14
(二)免疫力之調節 14
(三)抗細菌、微生物及病毒之功能 15
(四)保肝之作用 16
(五)抗氧化、發炎之作用 16
(六)降血糖、血脂之功效 17
(七)其他 18
第二節、安全性評估 18
第三節、肝臟解毒基因表現 19
第四節、發炎相關因子表現 23
4.1巨噬細胞(Macrophage)與發炎反應 23
4.2巨噬細胞(Macrophage)的活化發炎反應之機制 24
4.3發炎反應相關因子 25
第五節、研究動機及目的 30
第六節、研究架構 32
第二章、材料與方法 34
第一節、實驗材料 34
1.1樣品 34
1.2實驗動物 34
1.3菌株 34
1.4細胞株 34
1.5試劑 34
1.5.1樣品配製 34
1.5.2 NADPH-CYP reductase活性測定 35
1.5.3 Glutathione S-transferase (GST)活性測定 35
1.5.4 Superoxide dismutase (SOD)活性分析 35
1.5.5 Catalase活性分析 35
1.5.6 Cytochrome P450 gene表現量分析 35
1.5.7肝組織切片判讀 36
1.5.8基因毒性之分析 36
1.5.9清除DPPH自由基能力分析 37
1.5.10細胞培養 37
1.5.11細胞毒性測試 37
1.5.12一氧化氮含量分析 38
1.5.13 Prostaglandin E2 (PGE2)含量測定 38
1.5.14 iNOS和COX-2蛋白質表現量分析 38
1.5.15細胞激素IL-1β、IL-6、IL-10及TNF-α分泌量分析 39
1.6儀器及器材 39
第二節、實驗方法 40
2.1動物實驗部分 40
2.1.1動物犧牲及檢體採取 40
2.1.2血液生化值分析 40
2.1.3肝臟微粒體(microsome)及細胞質液(cytosol)之製備 40
2.1.4 NADPH-CYP reductase活性測定 41
2.1.5 Glutathione S-transferase (GST)活性測定 41
2.1.6 Superoxide dismutase (SOD)活性分析 41
2.1.7 Catalase活性分析 42
2.1.8 Cytochrome P450 gene表現量分析 42
2.1.9肝組織切片判讀 43
2.1.10基因毒性之分析 44
2.2細胞實驗部分 44
2.2.1樣品配製 44
2.2.2清除DPPH自由基能力分析 44
2.2.3冷凍細胞活化 45
2.2.4細胞冷凍保存 45
2.2.5細胞繼代培養 46
2.2.6細胞毒性測試MTT assay 46
2.2.7一氧化氮含量分析 47
2.2.8前列腺素E2含量測定 47
2.2.9蛋白質定量分析 48
2.2.10 iNOS和COX-2蛋白質表現量測定 48
2.2.11細胞激素IL-1β、IL-6、IL-10及TNF-α分泌量分析 49
2.3統計分析 50
第三章、結果 51
第一部分：評估綠豆篁之安全性 51
第一節、餵食雄性BALB/c小鼠不同劑量之綠豆篁四週其體重之變化 51
第二節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週其體重之變化 51
第三節、餵食雄性BALB/c小鼠不同劑量之綠豆篁四週後其血液中血球分析之結果 51
第四節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週後其血液中血球分析之結果 53
第五節、餵食雄性BALB/c小鼠不同劑量之綠豆篁四週後其血清生化分析之結果 54
第六節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週後其血清生化分析之結果 55
第七節、餵食雄性BALB/c小鼠不同劑量之綠豆篁四週後其肝組織切片之判讀 56
第八節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週後其肝組織切片之判讀 56
第九節、綠豆篁溶液於含S9之代謝活化下進行微生物基因突變分析測試之結果 56
第十節、綠豆篁溶液於不含S9之代謝活化下進行微生物基因突變分析測試之結果 57
第二部分：評估綠豆篁對肝臟解毒能力 57
第一節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週後其肝臟NADPH-CYP reductase活性之測定 57
第二節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週後其肝臟glutathione S-transferase (GST)活性之測定 58
第三節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週後其肝臟抗氧化酵素superoxide dismutase (SOD)活性之測定 58
第四節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週後其肝臟抗氧化酵素catalase活性之測定 59
第五節、餵食雌性BALB/c小鼠不同劑量之綠豆篁四週後其肝臟cytochrome P450 gene之表現量 60
第三部分：探討綠豆篁抗發炎功效 61
第一節、不同濃度之綠豆篁乙醇粗萃物其清除DPPH自由基能力測定 61
第二節、RAW264.7巨噬細胞以不同濃度之綠豆篁乙醇粗萃物處理24小時後之細胞存活率測定 61
第三節、不同濃度之綠豆篁乙醇粗萃物對LPS誘發RAW264.7巨噬細胞釋放一氧化氮之影響 62
第四節、不同濃度之綠豆篁乙醇粗萃物對LPS誘發RAW264.7巨噬細胞iNOS蛋白質表現之影響 62
第五節、不同濃度之綠豆篁乙醇粗萃物對LPS誘發RAW264.7巨噬細胞釋放前列腺素E2之影響 63
第六節、不同濃度之綠豆篁乙醇粗萃物對LPS誘發RAW264.7巨噬細胞COX-2蛋白質表現之影響 63
第七節、不同濃度之綠豆篁乙醇粗萃物對LPS誘發RAW264.7巨噬細胞釋放細胞激素IL-1β之影響 64
第八節、不同濃度之綠豆篁乙醇粗萃物對LPS誘發RAW264.7巨噬細胞釋放細胞激素IL-6之影響 65
第九節、不同濃度之綠豆篁乙醇粗萃物對LPS誘發 RAW264.7巨噬細胞釋放細胞激素IL-10之影響 65
第十節、不同濃度之綠豆篁乙醇粗萃物對LPS誘發RAW264.7巨噬細胞釋放細胞激素TNF-α之影響 66
第四章、討論 67
第五章、結論 76
第六章、參考文獻 119

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