臺灣博碩士論文加值系統

多醣已知具有不同生理功能，但在免疫調節功能仍未完全釐清，本研究為比較不同來源多醣之免疫調節活性，選用四種食材經熱水萃取，再以酒精沉澱分離出多醣，分別獲得蓮子心多醣(lotus plumule polysaccharide, LPPS)、黑木耳多醣(tree mushroom polysaccharide, TMPS)、白甘藍菜多醣(white cabbage polysaccharide, WCPS)及紫甘藍菜多醣(red cabbage polysaccharide, RCPS)，取這四種多醣非細胞毒性濃度進行研究，探討單獨添加或對以脂多醣(lipopolysaccharide, LPS)刺激脾臟細胞之影響，評估雌鼠初代脾臟細胞分泌促發炎與抗發炎細胞激素的變化，結果顯示，單獨添加LPPS與TMPS隨著添加濃度的增加，脾臟細胞促發炎的腫瘤壞死因子-α (tumor necrosis factor-α, TNF-α)/抗發炎的介白素-10 (interleukin-10, IL-10)細胞激素分泌比值隨之降低，顯示LPPS與TMPS均具有抗發炎潛力；在以LPS刺激脾臟細胞發炎模式下，四種多醣中，僅LPPS隨著添加濃度的增加，脾臟細胞TNF-α/IL-10細胞激素分泌比值隨之降低；顯示四種植物多醣中，以蓮子心多醣(LPPS)最具抗發炎潛力，黑木耳多醣(TMPS)次之。
進ㄧ步以蓮子心多醣(LPPS)於動物體外和體內模式探討其對非肥胖糖尿病(non-obese diabetes, NOD)雌鼠自發第1型糖尿病之抗發炎潛力，體外模式結果顯示，LPPS添加於NOD雌鼠初代脾臟細胞中，可藉由增加抗發炎(IL-10)/促發炎(IL-6)細胞激素分泌比値，而具有抗發炎活性；體內模式結果顯示，餵食LPPS試驗飲食十五週後可顯著降低NOD雌鼠自發性脾臟發炎現象，且有劑量反應關係；顯著抑制脾臟細胞促發炎細胞激素(IL-6與TNF-α)分泌量，顯著降低促發炎(IL-6)/抗發炎(IL-10)細胞激素分泌比値；顯著降低肝臟促發炎(IL-6與TNF-α)/抗發炎(IL-10)細胞激素mRNA相對表現量的比値；顯著增加胰島細胞數量，改善其基礎胰島素分泌能力；藉由相對增加血清HDL-C，降低LDL-C與總膽固醇含量，而改善血清脂質含量；綜合體外與體內實驗結果，推測LPPS可藉由調節脾臟細胞與肝臟之促發炎/抗發炎細胞激素基因表現，同時經由保護胰島細胞與調節血清脂質，而改善第1型糖尿病之病程發展及其併發症發生。
為瞭解蓮子心多醣(LPPS)之特性，進一步分離純化LPPS，分析其特性差異，膠體過濾(gel filtration)分析結果顯示LPPS含有兩個主要成分(fraction-1, F1與fraction-2, F2)，其分子量分別為> 2,000 kDa與25.7 kDa；分析LPPS中總蛋白質與總醣類組成比率，發現F1為LPPS中主要的蛋白多醣(proteopolysaccharide)成分，F2為LPPS中的醣蛋白(glycoprotein)成分。將已純化之物質(F1與F2)分別以RAW264.7巨噬細胞與初代脾臟細胞進行抗發炎功效評估，RAW264.7巨噬細胞結果顯示，在先添加樣品之預防模式下，以LPS誘導RAW264.7巨噬細胞發炎，LPPS之區分物(F1與F2)可藉由降低促發炎(IL-6)/抗發炎(IL-10)細胞激素分泌比値，具有強烈的抗發炎作用，且抗發炎功效F2優於F1；初代脾臟細胞結果顯示，LPPS之區分物(F1與F2)顯著降低促發炎(IL-1β與TNF-α)/抗發炎(IL-10)細胞激素分泌比值，抗發炎功效F2亦優於F1；綜合RAW264.7巨噬細胞與初代脾臟細胞之實驗結果，顯示F2最具抗發炎潛力，亦是LPPS中的主要抗發炎活性成分。
為瞭解蓮子心多醣及其區分物(F1與F2)抗發炎之作用機制，以初代脾臟細胞探討LPPS及其區分物可能的抗發炎機制，結果顯示，在以LPS刺激BALB/c小鼠初代脾臟細胞發炎模式與治療模式下，LPPS及其區分物(F1與F2)顯著降低脾臟細胞之類鐸接受器-2 (Toll-like receptor-2, TLR-2)或/與TLR-4 mRNA相對表現量，顯示LPPS及其區分物(F1與F2)可分別藉由降低TLR-2或/與TLR-4表現量，而抑制發炎。
綜合本論文研究結果，蓮子心多醣(LPPS)在體外與體內均具有抗發炎作用，LPPS含有兩個主要成分(F1與F2)，F1為蛋白多醣成分，F2為醣蛋白成分，亦是LPPS中的主要抗發炎活性成分，LPPS及其區分物(F1與F2)可能藉由降低脾臟細胞之TLR-2或/與TLR-4表現量，而抑制發炎作用。

Polysaccharides have been reported to have different physiological functions, but their immunological regulatory effects have not been fully clarified. To compare possible immunological regulatory effects of different plant polysaccharides, lotus plumule polysaccharides (LPPS), tree mushroom polysaccharide (TMPS), white cabbage polysaccharide (WCPS) and red cabbage polysaccharide (RCPS) were extracted with hot water and then precipitated using 70% alcohol. Non-cytotoxic doses of the polysaccharides were determined and administered to mouse primary splenocytes in the absence or presence of lipopolysaccharide (LPS) to investigate effects of different plant polysaccharides on pro- and anti-inflammatory cytokine secretions. The results showed that pro-/anti-inflammatory cytokine (TNF-α/IL-10) secretion ratios were significantly decreased in dose-dependent manners by LPPS and TMPS, respectively, in the absence of LPS, suggesting that LPPS and TMPS might have anti-inflammatory potential. However, only LPPS treated in the presence of LPS significantly decreased TNF-α/IL-10 secretion ratios in a dose-dependent manner. Our findings suggest that LPPS has the strongest anti-inflammatory effect among four different plant polysaccharides selected in this study, via decreasing pro-/anti-inflammatory cytokine secretion ratios by mouse primary splenocytes. TMPS also had a mild anti-inflammatory effect.
To confirm anti-inflammatory effects of LPPS, LPPS was further studied in vitro and in vivo for immunomodulatory functions using type 1 non-obese diabetes (NOD) female mice. The results showed that LPPS may have potential anti-inflammatory activity in vitro via increasing secretion ratios of anti-/pro-inflammatory (IL-10/IL-6) cytokines by splenocytes of NOD female mice. After a 15-week feeding experiment, the results showed that LPPS significantly (P < 0.05) decreased the absolute weights of the enlarged spleens in the NOD mice in a dose-dependent manner, inhibited pro-inflammatory TNF-α and IL-6 cytokine production and decreased the secretion ratio of IL-6/IL-10 in splenocyte cultures. LPPS markedly decreased the relative expression of pro-/anti-inflammatory cytokine genes (TNF-α/IL-10 and IL-6/IL-10) in the livers of NOD mice. Furthermore, LPPS significantly (P < 0.05) increased pancreatic islet cell numbers and slightly enhanced their basal insulin secretion ability compared to the control group. LPPS administration improved serum lipid profiles in the diabetic mice, via relatively increasing serum high density lipoprotein-cholesterol, but decreasing low density lipoprotein-cholesterol and total cholesterol levels. Overall, the results suggest that LPPS supplementation may in vivo ameliorate type 1 diabetes progress and its complications through modulating pro-/anti-inflammatory cytokine gene expression in spleen and liver, protecting pancreatic islets and modulating serum lipid profiles.
In order to understand the characteristics of LPPS, LPPS was further purified and characterized. Results showed that there were two major components fraction-1 (F1) and F2 in LPPS using gel filtration analysis. The molecular weights of native F1 and F2 approximately distributed at > 2,000 kDa and 25.7 kDa, respectively. The total protein and carbohydrate constituent ratios in LPPS, F1 and F2 revealed that F1 might be a major proteopolysaccharide component and F2 was a glycoprotein constituent in LPPS. To unravel the anti-inflammatory effects of LPPS and its purified components F1 and F2, in vitro experimental models using RAW264.7 macrophages and primary splenocytes from BALB/c mice were established. The results showed that purified components, F1 and F2 from LPPS, had strong anti-inflammatory effects on LPS-induced RAW264.7 macrophages in a preventive manner via decreasing pro-/anti- inflammatory (IL-6/IL-10) cytokine secretion ratios; however F2 was superior to F1. In addition, F1 and F2 from LPPS had strong anti-inflammatory effects on primary splenocytes via decreasing pro-/anti-inflammatory (IL-1β and TNF-α/IL-10) cytokine secretion ratios; however F2 was superior to F1. Our results indicated that F2 had the most potential anti-inflammatory effect, suggesting that F2 is a major active component in LPPS.
In order to further unravel the anti-inflammatory mechanism of LPPS and its purified components F1 and F2, in vitro experimental models using primary splenocytes from BALB/c mice were performed. The results showed that purified components, F1 and F2, significantly decreased Toll-like receptor-2 (TLR-2) or/and TLR-4 mRNA relative expression levels in the splenocytes under the inflammatory and repair experiments. The results suggested that LPPS, F1 and F2 exerted their anti-inflammatory effects possibly through decreasing TLR-2 or/and TLR-4 expression levels in splenocytes.
In summary, we found LPPS had anti-inflammatory potential in vitro and in vivo. There were two major components F1 and F2 in LPPS. F1 might be a major proteopolysaccharide component in LPPS. F2 was a glycoprotein constituent in LPPS and is suggested to be a major active component for the anti-inflammatory effect. F1 and F2 from LPPS exerted their anti-inflammatory effects possibly through decreasing TLR-2 or/and TLR-4 expression levels in the splenocytes.

總目錄
摘要 i
Abstract iii
表目錄 vii
圖目錄 x
縮寫對照表 xii
緒言 1
第一章 文獻回顧 2
第一節 免疫反應介紹 2
一、 免疫系統(immune system) 2
二、 T細胞(T cell) 3
三、 細胞激素(cytokines) 5
四、 巨噬細胞(macrophages) 8
五、 類鐸接受器(Toll-like receptors, TLRs) 11
第二節 第1型糖尿病介紹 14
一、 NOD小鼠之發病過程 15
二、 胰島素 16
三、 第1型糖尿病自體免疫攻擊β細胞之可能機制 18
四、 NOD小鼠與Th1和Th2免疫反應之相關研究 21
第三節 多醣與免疫調節 23
一、 蓮子心多醣(lotus plumule polysaccharide, LPPS) 23
二、 黑木耳多醣(tree mushroom polysaccharide, TMPS) 24
三、 甘藍菜多醣(cabbage polysaccharide, CPS) 24
第四節 本論文研究動機與目的 24
第五節 本論文實驗設計與研究架構 25
第二章 不同來源多醣對初代脾臟細胞免疫反應之影響 27
第一節 前言 27
第二節 材料與方法 27
一、 多醣製備 27
二、 BALB/c雌鼠初代脾臟細胞之取得與培養 29
三、 統計分析 36
第三節 結果 37
一、 不同來源多醣之萃取率 37
二、 不同來源多醣對BALB/c雌鼠初代脾臟細胞生長之影響 37
三、 比較不同來源植物多醣對BALB/c雌鼠初代脾臟細胞分泌細胞激素之影響 40
第四節 討論 44
第五節 結論 45
第三章 建立NOD雌鼠發病評估指標與探討蓮子心多醣對不同週鹷NOD雌鼠免疫細胞之影響 46
第一節 前言 46
第二節 材料與方法 46
一、 實驗動物 46
二、 NOD與BALB/c雌鼠初代脾臟細胞之取得與培養 47
三、 口服葡萄糖耐受試驗(oral glucose tolerance test, OGTT) 48
四、 小鼠犧牲與血清之取得及分析 49
五、 肝臟脂質含量測定 54
六、 以real time polymerase chain reaction (real-time PCR)分析肝臟與腎臟促發炎與抗發炎細胞激素mRNA相對表現量 54
七、 統計分析 59
第三節 結果 60
一、 不同週齡NOD與BALB/c雌鼠基本生理狀態之差異 60
二、 蓮子心多醣對不同週齡NOD與BALB/c雌鼠初代脾臟細胞細胞激素分泌之影響 74
第四節 討論 79
第五節 結論 82
第四章 餵食蓮子心多醣對第1型非肥胖糖尿病雌鼠免疫反應之影響 83
第一節 前言 83
第二節 材料與方法 83
一、 試驗飼料配製 83
二、 實驗動物來源 84
三、 口服葡萄糖耐受試驗(oral glucose tolerance test, OGTT) 86
四、 小鼠犧牲與樣品收集 86
五、 初代胰臟胰島細胞之取得與培養 87
六、 初代脾臟細胞之取得與培養 89
七、 血清之取得與分析 89
八、 以real time polymerase chain reaction (real-time PCR)分析肝臟與腎臟促發炎與抗發炎細胞激素mRNA相對表現量 91
九、 統計分析 91
第三節 結果 92
一、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠體重變化之影響 92
二、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠初始體重、最終體重、攝食量、能量攝取、飼料效率及能量效率之影響 92
三、 餵食蓮子心多醣試驗飲食於第零、七及十三週對NOD與ICR雌鼠口服葡萄糖耐受試驗之影響 95
四、 餵食蓮子心多醣試驗飲食於第零、七及十三週對NOD與ICR雌鼠禁食血糖之影響 95
五、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠臟器絕對與相對組織重量之影響 98
六、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠脾臟細胞Th1/Th2與促發炎/抗發炎細胞激素分泌比值之影響 98
七、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠肝臟細胞激素mRNA相對表現量之影響 101
八、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠腎臟細胞激素mRNA相對表現量之影響 104
九、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠胰島細胞數量及其胰島素分泌能力之影響 104
一〇、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠禁食血清脂質含量之影響 107
一一、 餵食蓮子心多醣試驗飲食十五週對NOD與ICR雌鼠血清生化指標之影響 110
第四節 討論 112
第五節 結論 116
第五章 蓮子心多醣及其區分物對RAW264.7巨噬細胞抗發炎之影響 117
第一節 前言 117
第二節 材料與方法 117
一、 蓮子心多醣之製備與其區分物之純化 117
二、 蓮子心多醣區分物之分子量測定 118
三、 蓮子心多醣及其區分物之總蛋白質與總醣類的組成比率分析 119
四、 RAW264.7巨噬細胞培養方法 120
五、 RAW264.7巨噬細胞倍增時間試驗 121
六、 蓮子心多醣及其區分物與脂多醣對RAW264.7巨噬細胞生長之影響 122
七、 蓮子心多醣及其區分物對RAW264.7巨噬細胞細胞激素分泌之影響 123
第三節 結果 126
一、 蓮子心多醣區分物之特性 126
二、 蓮子心多醣區分物之分子量測定 126
三、 蓮子心多醣及其區分物之總蛋白質與總醣類之組成比率分析 129
四、 RAW264.7巨噬細胞倍增時間曲線 129
五、 蓮子心多醣及其區分物與脂多醣對RAW264.7巨噬細胞生長之影響 132
六、 蓮子心多醣及其區分物對RAW264.7巨噬細胞細胞激素分泌之影響 135
第四節 討論 143
第五節 結論 144
第六章 蓮子心多醣及其區分物對初代脾臟細胞抗發炎機制之研究 145
第一節 前言 145
第二節 材料與方法 145
一、 初代脾臟細胞取得與培養 145
二、 蓮子心多醣及其區分物對BALB/c雌鼠初代脾臟細胞生長之影響 145
三、 蓮子心多醣及其區分物對BALB/c雌鼠初代脾臟細胞細胞激素分泌之影響 146
四、 LPS與BALB/c雌鼠初代脾臟細胞培養不同時間對TLR-2與TLR-4 mRNA相對表現量之影響 147
五、 蓮子心多醣及其區分物(F1與F2)對BALB/c雌鼠初代脾臟細胞TLR-2與TLR-4 mRNA相對表現量之影響 149
六、 統計分析 151
第三節 結果 151
一、 蓮子心多醣及其區分物對BALB/c雌鼠初代脾臟細胞生長之影響 151
二、 蓮子心多醣及其區分物對BALB/c雌鼠初代脾臟細胞細胞激素分泌之影響 153
三、 LPS與BALB/c雌鼠初代脾臟細胞培養不同時間對TLR-2與TLR-4 mRNA相對表現量之影響 157
四、 蓮子心多醣及其區分物對BALB/c雌鼠初代脾臟細胞TLR-2與TLR-4 mRNA相對表現量之影響 159
第四節 討論 167
第五節 結論 168
第七章 總討論與總結 169
第一節 總討論 169
一、 比較不同來源多醣之免疫調節活性 169
二、 蓮子心多醣對非肥胖糖尿病雌鼠自發第1型糖尿病之抗發炎潛力 169
三、 蓮子心多醣及其區分物對RAW264.7巨噬細胞與初代脾臟細胞抗發炎功效之評估 170
四、 蓮子心多醣及其區分物(F1與F2)抗發炎之作用機制探討 170
第二節 總結 171
第八章 參考文獻 173
第九章 個人簡介與著作發表 187
一、 個人簡介 187
二、 博士班就讀期間之著作發表 188

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