臺灣博碩士論文加值系統

苦丁茶(Ilex kudingcha)被當作傳統飲品已有超過兩千年的歷史，其具有止渴、提神及明目之功效，近年來多項研究指出苦丁茶具有許多藥理功效，包含作為抗氧化劑、保肝劑、抗菌劑、抗組織胺劑及神經保護劑等，此外，本研究室於先前實驗中已發現苦丁茶甲醇萃取物具有免疫調節之功效，然而，其潛在活性成分與免疫調節機制仍尚不明，因此，本實驗使用不同溶劑(正己烷及70%酒精)將苦丁茶甲醇萃取物再進行區分，並利用小鼠初代脾臟細胞與巨噬細胞體外試驗，評估樣品對Th1/Th2平衡及巨噬細胞活性之免疫調節作用，最後，以單獨添加及癌症免疫療法模式，探討苦丁茶甲醇萃取物及其區分物對PC-3細胞之影響。
結果顯示苦丁茶甲醇萃取物(IKME)及其正己烷區分物(HFIKME)與酒精處理之上清液(ESIKME)具有調節免疫反應使之傾向Th1平衡，而酒精處理之沉澱物(EPIKME)則是調節免疫反應使之傾向Th2平衡。再者，單獨添加苦丁茶甲醇萃取物及其不同區分物，具有稍微刺激巨噬細胞活性之作用，推測其可促進先天性免疫反應，此外，以脂多醣(LPS)刺激模擬發炎模式下，IKME與HFIKME可藉由降低(IL-1β + IL-6 + TNF-α)/IL-10細胞激素分泌之比值而達到抗發炎效果，然而，ESIKME可透過提升(IL-1β + IL-6 + TNF-α)/IL-10細胞激素分泌之比值而增加巨噬細胞之活性，顯示不同區分物可能具有不同的免疫調節屬性。
以單獨添加與癌症免疫療法模式探討樣品對PC-3細胞生長之影響，結果顯示在不同區分物之中，以ESIKME之抗癌活性最高，進一步使用即時定量聚合酶連鎖反應(qPCR)測定PC-3細胞凋亡相關基因之表現，結果發現ESIKME及其初代脾臟細胞/巨噬細胞條件培養液可顯著增加促凋亡(Bax)/抗凋亡(Bcl-2)基因表現之比值，且於相同濃度下，其促凋亡活性明顯高於IKME。
綜合本實驗結果，顯示ESIKME可能為IKME中具免疫調節及抗癌潛力之區分物，並且可能透過調節免疫反應使之傾向Th1平衡以及增加巨噬細胞活性，進而使其分泌特定細胞激素(如: IL-2, TNF-α及IL-6)，導致PC-3細胞促凋亡(Bax)/抗凋亡(Bcl-2)基因表現量之比值增加使其走向凋亡。

Ilex Kudingcha has been used for a traditional beverage to quench thirst, refresh the mind, and improve eyesight more than 2,000 years. In the recent years, a number of studies have reported that Ilex Kudingcha has numerous pharmacological properties, serving as antioxidants, hepatoprotectants, antibacterial agents, antihistamines and neuroprotective agents. Besides, our lab had demonstrated that Ilex Kudingcha methanol extract possessed immunomodulatory effects in the previous study. However, the potent active compounds in Ilex Kudingcha and its exact immunomodulatory mechanisms still remain unclear. To clarify the puzzle, in the present study Ilex Kudingcha methanol extract (IKME) was further fractionized using hexane and 70% alcohol. The crude extract and its fractions were then subjected to evaluate their immunomodulatory effects on Th1/Th2 balance and the activity of macrophages using mouse primary splenocytes and peritoneal macrophages in vitro. Next, in order to assess anti-cancer effects, the extract and its fractions were used to treat human prostate cancer PC-3 cells using direct addition and immunotherapy of primary splenocytes and peritoneal macrophages, respectively.
The results showed that IKME as well as its hexane fraction (HEIKME) and ethanol supernatant (ESIKME) fraction had potential to modulate Th1/Th2 immune response toward Th1 balance. In contrast to ESIKME, ethanol precipitate (EPIKME) fraction tended to regulate Th1/Th2 immune response toward Th2 balance. Moreover, IKME and its different fractions (HFIKME, EPIKME and ESIKME) treatments alone displayed a mild stimulatory activity to macrophages, suggesting that they might improve the innate immunity. Furthermore, in the presence of lipopolysaccharides (LPS), IKME and HFIKME treatments were identified to have an anti-inflammatory potency through decreasing (IL-1β + IL-6 + TNF-α)/IL-10 cytokines secretion ratio, however ESIKME treatment enhanced the activity of the LPS-stimulated macrophages through increasing (IL-1β + IL-6 + TNF-α)/IL-10 cytokines secretion ratio. Our results have indicated that different fractions of IKME might own distinct immunomodulatory properties.
Consequently, IKME and its different fractions (HFIKME, EPIKME and ESIKME) were further used to treat PC-3 cells by means of direct addition or immunotherapy. The results revealed that ESIKME showed the strongest anti-cancer activity among different fractions either by direct addition or immunotherapy. In order to elucidate mechanisms underlying the anticancer effect of ESIKME against PC-3 cells, the expression of genes associated with apoptosis were measured using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The results showed that expression ratios of pro-(Bax)/anti-apoptotic (Bcl-2) mRNA levels in PC-3 cells were significantly increased by ESIKME and its conditioned media of primary splenocytes and macrophages, respectively. The apoptosis-induced activity of ESIKME was significantly higher than that of IKME at the same concentration.
In conclusion, results from this study evidenced that ESIKME is a potent immunomodulatory and anti-cancer fraction from IKME. ESIKME prompted Th1/Th2 immune response toward Th1 balance and enhanced macrophages to secrete some specific cytokines, such as IL-2, TNF-α and IL-6, that could induced apoptosis of PC-3 cells via increasing Bax/Bcl-2 expression ratio.

摘要 i
Abstract iii
目錄 v
表目錄 x
圖目錄 xii
縮寫對照表 xiv
緒言 1
第一章 文獻回顧 2
第一節 免疫反應 2
一、 免疫系統 (Immune system) 2
二、 輔助型T細胞第一型與第二型之免疫平衡 6
三、 發炎反應 (Inflammation) 8
第二節 免疫與癌症 11
一、 免疫與癌症 11
二、 細胞死亡路徑-凋亡(apoptosis) 13
第三節 苦丁茶相關研究與介紹 15
第四節 多酚類之免疫調節作用 16
第五節 研究動機與目的 17
第六節 論文架構與實驗設計 18
第二章 苦丁茶甲醇萃取物及其不同區分物對初代脾臟細胞Th1/Th2免疫平衡之影響 19
第一節 前言 19
第二節 材料與方法 19
一、 樣品製備 19
二、 苦丁茶甲醇萃取物及其不同區分物之光譜掃描分析 22
三、 苦丁茶甲醇萃取物及其不同區分物之成分分析 22
四、 苦丁茶甲醇萃取物及其經酒精處理上清液之高效能液相層析法(HPLC)分析 26
五、 苦丁茶甲醇萃取物經酒精處理上清液之液相層析串聯質譜儀(LC/MS/MS)分析 28
六、 苦丁茶甲醇萃取物及其經酒精處理上清液之酚類化合物相對聚合程度測定 30
七、 苦丁茶甲醇萃取物及其不同區分物對BALB/c雌鼠初代脾臟細胞生長 之影響 31
八、 苦丁茶甲醇萃取物及其不同區分物對BALB/c雌鼠初代脾臟細胞分泌細胞激素之影響 35
九、 統計分析 39
第三節 結果 40
一、 苦丁茶甲醇萃取物及其不同區分物之萃取率 40
二、 苦丁茶甲醇萃取物及其不同區分物之光譜掃描 40
三、 苦丁茶甲醇萃取物及其不同區分物之成分分析 43
四、 以高效能液相層析法(HPLC)分析苦丁茶甲醇萃取物及其經酒精處理上清液之多酚類組成 45
五、 苦丁茶甲醇萃取物經酒精處理上清液(ESIKME)之液相層析串聯質譜儀(LC/MS/MS)分析 47
六、 苦丁茶甲醇萃取物及其經酒精處理上清液之酚類化合物相對聚合程度測定 51
七、 苦丁茶甲醇萃取物及其不同區分物對BALB/c雌鼠初代脾臟細胞生長 之影響 52
八、 苦丁茶甲醇萃取物及其不同區分物對BALB/c雌鼠初代脾臟細胞分泌細胞激素之影響 55
第四節 討論 61
第五節 結論 63
第三章 苦丁茶甲醇萃取物及其區分物對小鼠初代腹腔巨噬細胞發炎之影響 64
第一節 前言 64
第二節 材料與方法 64
一、 實驗架構 64
二、 苦丁茶甲醇萃取物及其區分物對BALB/c雌鼠初代巨噬細胞促發炎與抗發炎細胞激素之影響 65
三、 統計分析 68
第三節 結果 69
一、 苦丁茶甲醇萃取物及其區分物對BALB/c雌鼠初代巨噬細胞促發炎與抗發炎細胞激素之影響 69
(一) 模式A : 單獨添加樣品對初代巨噬細胞分泌細胞激素之影響 69
(二) 模式B : 模擬發炎模式下樣品對初代巨噬細胞分泌細胞激素之影響 75
第四節 討論 81
第五節 結論 83
第四章 苦丁茶甲醇萃取物及其不同區分物對人類前列腺癌PC-3細胞株生長之影響 84
第一節 前言 84
第二節 材料與方法 84
一、 實驗架構 84
二、 苦丁茶甲醇萃取物(IKME)及其區分物(HFIKME、EPIKME及ESIKME)製備 85
三、 苦丁茶甲醇萃取物(IKME)及其區分物(HFIKME、EPIKME及ESIKME)之初代脾臟細胞條件培養液製備 85
四、 苦丁茶甲醇萃取物(IKME)及其區分物(HFIKME、EPIKME及ESIKME)之初代巨噬細胞條件培養液製備 85
五、 人類前列腺癌PC-3細胞株之培養 86
六、 苦丁茶甲醇萃取物(IKME)及其區分物(HFIKME、EPIKME及ESIKME)與條件培養液對人類前列腺癌PC-3細胞株生長之影響 87
七、 苦丁茶甲醇萃取物(IKME)和其區分物(ESIKME)與免疫條件培養液對人類前列腺癌PC-3細胞株凋亡路徑相關基因mRNA表現量之影響 89
八、 統計分析 95
第三節 結果 96
一、 苦丁茶甲醇萃取物(IKME)及其區分物(HFIKME、EPIKME及ESIKME)與條件培養液對人類前列腺癌PC-3細胞株生長之影響 96
(一) 模式A : 直接添加樣品對人類前列腺癌細胞PC-3細胞株生長之影響 96
(二) 模式B : 初代脾臟細胞條件培養液對人類前列腺癌PC-3細胞株生長之影響 100
(三) 模式C : 初代巨噬細胞條件培養液對人類前列腺癌PC-3細胞株生長之影響 106
二、 苦丁茶甲醇萃取物(IKME)和其區分物(ESIKME)與免疫細胞條件培養液對人類前列腺癌PC-3細胞株凋亡路徑相關基因mRNA表現量之影響 112
(一) 模式A : 直接添加樣品對人類前列腺癌PC-3細胞株凋亡路徑相關基因mRNA表現之影響 112
(二) 模式B : 初代脾臟細胞條件培養液對人類前列腺癌PC-3細胞株凋亡路徑相關基因mRNA表現之影響 115
(三) 模式C : 初代巨噬細胞條件培養液對人類前列腺癌PC-3細胞株凋亡路徑相關基因mRNA表現之影響 118
三、 經苦丁茶甲醇萃取物(IKME)和其區分物(ESIKME)處理之免疫細胞條件培養液中細胞激素分泌量與人類前列腺癌細胞株促凋亡(Bax)與抗凋亡(Bcl-2)基因mRNA表現量比值之相關性分析 121
第四節 討論 124
第五節 結論 127
第五章 總討論與總結 128
第六章 參考文獻 129

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