臺灣博碩士論文加值系統

潰瘍性結腸炎 (ulcerative colitis，UC) 是一種發炎性腸道疾病 (inflammatory bowel diseases，IBD)，其特徵為結腸黏膜慢性且反覆發炎，並且從結腸至直腸通常成連續性病變。目前發炎機制尚不清楚，被推測與免疫、腸道菌落、環境、遺傳、飲食、種族、藥物誘發等因素有關。此外，臺灣衛生福利部亦指出 UC 患者罹患結腸癌之相對風險會因此提升。現今社會，隨著飲食逐漸精緻化，其發生率及盛行率正逐年上升。臺灣為海島國家，因此周邊海域蘊含豐富藻類資源。研究指出褐藻萃取之多醣體具抗氧化、抗發炎等多種重要生理活性。本研究探討半葉馬尾藻水萃物 (Sargassum hemiphyllum water extracts, SHw) 對於潰瘍性結腸炎影響。SHw 主要成分為褐藻醣膠，其中包含 328 ± 13.52 mg/g 醣類及 61.39 ± 0.11 mg/g 硫酸酯基團。在 DPPH 自由基清除試驗及超氧陰離子清除試驗上，SHw 皆展現出優異的抗氧化能力；螯合亞鐵能力上則效果較差。細胞實驗部分使用結腸腺瘤細胞株 Caco-2 模擬腸道上皮細胞， SHw 展現提升傷口癒合的效果，並且有效抑制小鼠巨噬細胞株 RAW264.7 生成自由基 NO 及促發炎細胞因子 IL-6 達到抑制發炎作用。此外，SHw 在細胞共培養模型中也展現出提升單層膜屏障完整性的功效。動物實驗使用 2.5 % 及 5 % (w/v) Dextran sodium sulfate (DSS) 分別模擬輕微及嚴重腸道發炎現象。結果顯示，SHw 雖然只能在輕微發炎環境下改善小鼠體重減輕、健康狀況功效，但在改善結腸縮減現象方面皆有顯著改善效果。組織病理分析上，SHw 顯著改善 DSS 誘導造成之結腸柱狀結構受損及炎性細胞浸潤現象。促發炎細胞因子表現方面，DSS 誘導所造成 IL-6、 IL-1β 表現量上升現象皆顯著受到抑制。綜合上述， SHw 具有改善潰瘍性結腸炎症狀之潛力。

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), which is characterized by chronic and recurrent inflammation of the colonic mucosa, and it involves inflammation and ulcers along the superficial lining of your colon and rectum. The exact pathogenesis of UC has not confirmed. Several studies suggest that UC is triggered by multiple factors, including immunity, intestinal microbiota, environment, inheritance, diet, drug, and etc. Taiwan’s Ministry of Health and Welfare also pointed out that the relative risk of colon cancer for UC patients will increase as a result. Nowadays, with the gradual refinement of diet, UC's incidence and prevalence rates are increasing year by year. Since Taiwan is an island state, it is rich in algae resources. Recent research indicated that the polysaccharide extracted from brown algae has several bioactivities activities such as antioxidant and anti-inflammatory. In this study, we investigated the effect of Sargassum hemiphyllum water extracts (SHw) on ulcerative colitis. The main component of SHw is fucoidan, which contains 328 ± 13.52 mg/g carbohydrates and 61.39 ± 0.11 mg/g sulfate groups. SHw exhibited excellent antioxidant capacity in DPPH radical scavenging activities assay and superoxide anion scavenging activities test. In the cell-line experiment, SHw accelerated the wound healing in Caco-2 cell, and significantly decreased the production of nitric oxide and interleukin-6 in RAW264.7 cell induced by LPS stimulus. SHw also inhibited LPS-induced loss of monolayer permeability in co-culture model. We also evaluated the effects of SHw on dextran sodium sulfate salt (DSS)-induced colitis as an animal model. SHw treatment can only improve weight loss and health conditions in the 2.5 % DSS-induced model, instead of the 5 % DSS-induced model. In spite of the worse effect on maintaining health in the 5 % DSS model, SHw significantly reduced the severity of DSS-induced colitis by protecting mice from macroscopic damage and reduction of colon length in both two models. SHw also inhibited the pro-inflammatory cytokine expression, including IL-6, IL-1β and TNF-α. In summary, SHw has the potential to become the therapeutic agent for ulcerative colitis.

摘要 I
Abstract II
目次 III
圖目次 VII
表目次 VIII
前言 1
壹. 文獻回顧 2
一、 發炎性腸道疾病 2
二、 潰瘍性結腸炎 (Ulcerative colitis) 2
1. 潰瘍性結腸炎簡介 2
2. 潰瘍性結腸炎流行病學 2
3. 腸道黏膜屏障與潰瘍性結腸炎 2
4. 潰瘍性結腸炎免疫反應 3
5. 潰瘍性結腸炎之治療 3
6. DSS誘導潰瘍性結腸炎模型 3
三、 海藻 (Seaweed) 3
1. 海藻 (Seaweed) 簡介 3
2. 褐藻 (Brown seaweed) 4
3. 中國半葉馬尾藻 (Sargassum hemiphyllum) 4
3-1. 褐藻醣膠 (Fucoidan) 5
貳、實驗設計流程 6
一、 半葉馬尾藻特性分析 6
二、 細胞實驗 6
三、 動物實驗 7
參、實驗材料與方法 9
一、 實驗材料 9
1. 樣品原料 9
2. 結腸炎模型化學品 9
3. 凝膠滲透層析標準品 9
4. 抗氧化試驗 9
5. 細胞株 9
6. 細胞培養之培養基 10
7. 細胞存活率試劑 10
8. 一氧化氮生成試驗 10
9. 細胞氧化壓力試驗 10
10. 實驗動物 11
11. 組織切片 11
12. RNA 萃取套組 11
13. 反轉錄反應試劑 11
14. 即時定量聚合酶鏈鎖反應試劑 (Real-time PCR) 11
15. 細胞因子分析 12
二、 實驗器材 12
三、 實驗方法 13
1. 實驗樣品製備 13
1-1. 半葉馬尾藻熱水萃取物 13
2. 樣品特性分析 13
2-1. 凝膠滲透層析儀 (Gel Permeation Chromatography, GPC) 13
2-2. 總醣含量測定 (Total sugar content) 13
2-3. 硫酸根含量測定 14
2-4. 抗氧化能力試驗 14
2-4-1. DPPH (α,α-diphenyl-β-picryhydrazyl) 自由基清除能力測定 14
2-4-2. 清除超氧陰離子能力測定 14
2-4-3. 螯合亞鐵結合能力測定 15
3. 細胞實驗 (In vitro) 15
3-1. 細胞株活化 15
3-2. 細胞培養 (Cell culture) 15
3-2-1. 人類結腸腺瘤細胞株Caco-2 15
3-2-2. 小鼠巨噬細胞株 RAW 264.7 16
3-3. 細胞保存 16
3-4. 細胞毒性測試 (Cytotoxicity test) 16
3-5. 傷口癒合試驗 17
3-6. 細胞氧化壓力試驗 17
3-7. 細胞內一氧化氮 (Nitrate oxide, NO) 含量測定 17
3-8. Transepithelial electrical resistance (TEER) 17
4. 動物實驗 (In vivo) 18
4-1. 潰瘍性結腸炎小鼠之動物模式建立 18
4-1-1. 2.5 % DSS 誘導模型 18
4-1-2. 5 % DSS 誘導模型 18
4-2. 疾病活動指數（DAI） 18
4-3. ELISA 19
4-4. 分析組織中細胞因子之 mRNA 表現量 19
4-4-1. 抽取組織 RNA 19
4-4-2. 反轉錄反應 (Reverse transcription, RT) 20
4-4-3. 即時聚合酶連鎖反應 (Real-time polymerase chain reaction) 20
4-5. 組織病理切片 20
4-5-1. 石蠟切片 20
4-5-2. 蘇木素-伊紅染色 (Hematoxylin and eosin stain, H&E stain) 20
5. 統計分析 21
肆、結果 22
一、 半葉馬尾藻水萃物成分及生理活性分析 22
1. 半葉馬尾藻熱水萃取物之產率及成分分析 22
2. 半葉馬尾藻熱水萃取物之抗氧化能力分析 22
二、 半葉馬尾藻水萃物體外試驗 22
1. 半葉馬尾藻水萃物對於人類結腸腺瘤細胞株 (Caco-2) 之細胞存活率之影響 22
2. 半葉馬尾藻水萃物對於 Caco-2 細胞傷口癒合試驗之影響 23
3. 半葉馬尾藻水萃物對於受 H2O2 刺激的 Caco-2 細胞之影響 23
4. 半葉馬尾藻水萃物對於小鼠巨噬細胞株 RAW264.7之細胞存活率及一氧化氮(NO) 生成試驗 23
5. 半葉馬尾藻水萃物對於 Caco-2/RAW264.7 共培養模型之影響 24
6. 半葉馬尾藻水萃物對於受 LPS 刺激之 RAW264.7 生成細胞激素之影響 24
三、 半葉馬尾藻水萃物對潰瘍性結腸炎動物模式之探討 25
1. 2.5 % DSS 誘導結腸炎之動物模式 25
1-1. 半葉馬尾藻水萃物對於潰瘍性結腸炎小鼠的體重變化、健康指數之影響 25
1-2. 臟器重量及長度變化 25
1-3. 結腸組織切片分析 26
1-4. 促發炎細胞因子表現量變化 26
2. 5 % DSS 誘導結腸炎之動物模式 26
2-1. 半葉馬尾藻水萃物對於潰瘍性結腸炎小鼠的體重變化、健康指數之影響 26
2-2. 臟器重量及長度變化 27
2-3. 結腸組織切片分析 27
2-4. 促發炎細胞因子表現量變化 27
伍、討論 29
一、 半葉馬尾藻水萃物成分及生理活性分析 29
二、 半葉馬尾藻水萃物體外試驗 30
1. 探討半葉馬尾藻水萃物對於人類結腸線瘤細胞株 Caco-2 之影響 30
2. 探討半葉馬尾藻水萃物對於小鼠巨噬細胞 RAW264.7 之影響 30
3. 探討半葉馬尾藻水萃物對於Caco-2/RAW264.7 共培養模型之影響 31
三、 半葉馬尾藻水萃物對於 DSS 誘導結腸炎模型影響 32
1. 探討半葉馬尾藻水萃物對於 DSS 誘導腸道慢性發炎小鼠模型之影響 32
2. 探討半葉馬尾藻水萃物對於 DSS 誘導腸道急性發炎小鼠模型之影響 33
陸、結論 35
柒、參考文獻 36
捌、圖 47
玖、表 73
 
圖目次

圖一、半葉馬尾藻水萃物凝膠滲透層析 47
圖二、半葉馬尾藻水萃物之 DPPH 自由基清除能力試驗 48
圖三、半葉馬尾藻水萃物之超氧陰離子自由基清除能力試驗 49
圖四、半葉馬尾藻水萃物之螯合亞鐵能力試驗 50
圖五、半葉馬尾藻水萃物對於 Caco-2 細胞之存活率 51
圖六、SHw 對於 Caco-2 細胞之傷口癒合試驗 52
圖七、SHw 對於受 H2O2 刺激的 Caco-2 細胞之影響 53
圖八、SHw 對於小鼠巨噬細胞株 RAW264.7 之細胞存活率及一氧化氮 (NO) 生成影響 54
圖九、Caco-2/RAW264.7 共培養模型 55
圖十、SHw 對於 Caco-2/RAW264.7 共培養模型之 TEER (%) 的影響 56
圖十一、SHw 對於 LPS 誘導之 RAW 264.7 細胞生成促發炎細胞因子之影響 (A) IL-1β (B) IL-6 57
圖十二、2.5 % DSS 結腸炎小鼠模式誘導期間各組體重流失變化及疾病活動指數變化 58
圖十三、2.5 % DSS 結腸炎小鼠脾臟重量變化 59
圖十四、2.5 % DSS 結腸炎小鼠結腸長度變化 60
圖十五、2.5 % DSS 結腸炎小鼠各組結腸組織 H&E 染色結果 61
圖十六、2.5 % DSS 結腸炎小鼠各組結腸組織 H&E 染色結果 62
圖十七、2.5 % DSS 結腸炎小鼠各組結腸中促發炎細胞因子基因表現 63
圖十八、2.5 % DSS 結腸炎小鼠各組血清中促發炎細胞因子蛋白表現 64
圖十九、5 % DSS 結腸炎小鼠模式誘導期間各組體重流失變化及疾病活動指數變化 65
圖二十、5 % DSS 結腸炎小鼠脾臟重量變化 66
圖二十一、5 % DSS 結腸炎小鼠結腸長度變化 67
圖二十二、5 % DSS 結腸炎小鼠各組結腸組織 H&E 染色結果 68
圖二十三、5 % DSS 結腸炎小鼠各組結腸組織 H&E 染色結果 69
圖二十四、5 % DSS 結腸炎小鼠各組結腸組織 H&E 染色結果 70
圖二十五、5 % DSS 結腸炎小鼠各組結腸中促發炎細胞因子基因表現 71
圖二十六、5 % DSS 結腸炎小鼠各組血清中促發炎細胞因子蛋白表現 72
 
表目次

表一、半葉馬尾藻水萃物萃取率、總醣及硫酸根含量表 73
表二、疾病活動指數評分標準 74

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