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研究生:楊騏瑋
研究生(外文):Chi-Wei Yang
論文名稱:高硫酸基含量海藻寡醣之抗凝血與抗血小板凝集和抗病毒活性及被Caco-2 細胞吸收效果之探討
論文名稱(外文):Study on the Anti-thrombin, Anti-platelet Aggregation, and Antiviral Activity of Oversulfated Marine Algal Oligosaccharides and Its Adsorption Performance with Caco-2 Cell
指導教授:潘崇良
指導教授(外文):Chorng-Liang Pan
學位類別:碩士
校院名稱:國立臺灣海洋大學
系所名稱:食品科學系
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:155
中文關鍵詞:海藻寡醣高度硫酸化抗病毒抗凝血抗血小板凝集Caco-2 細胞
外文關鍵詞:Marin algal oligosaccharidesOversulfatedAntiviralAnti-thrombinAnti-platelet AggregationCaco-2 cell
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本研究目的在於探討馬尾藻、龍鬚菜、及石蓴熱萃液經酵素水解後區分不同聚合度的寡醣,利用氯磺酸-二甲基甲醯胺法 (Chlorsulfonic acid-N, N-dimethylformamide method, DMF),提升其硫酸基含量,並比較所得高硫酸基含量海藻寡醣對人血漿抗凝血與抗血小板凝集和抗病毒活性及對腸道細胞株 Caco-2 吸收之影響。馬尾藻、龍鬚菜、及石蓴於 121oC 熱萃 40 min 後以 3% 纖維素酶水解 6 hr,以及 2 U/mL 海藻熱萃多醣粉末誘導 Pseudomonas vesicularis MA103 及 Aeromonas salmonicida MAEF108 所產之酵素水解 24 hr 後,利用超過濾系統區分出小於 3 kDa 分子量之寡醣,經過 Sephadex G-10 膠體過濾層析 (Gel permeation chromatography, GPC) 及高效能液相層析儀 (High performance liquid chromatography, HPLC) 可初步分離出 9 種不同聚合度的寡醣,馬尾藻Sar-Y2、Sar-Y4、及 Sar-Y6,龍鬚菜 Gra-Y2、Gra-Y4、及Gra-Y6,石蓴寡醣 Ulva-Y2、Ulva-Y4、及Ulva-Y6。經區分後之海藻寡醣利用 DMF 法於 25℃ 下反應 4 小時,結果顯示Sar-Y2、Sar-Y4、及Sar-Y6硫酸基含量從 1.1-3.7% 提升至 17.8%-29.6%,Gra-Y2、Gra-Y4、及Gra-Y6從1.3-4.4% 提升至 13.7%-30.4%,Ulva-Y2、Ulva-Y4、及Ulva-Y6從0.9%-3.4% 提升至 14.7%-26.4%,而 Heparin (69.2 U/mL) 之硫酸基含量為 27.2%。經 HPLC分析得知,與標準品及分子質量檢量線比對初步可分得可能聚合度 (Degree of polymerization, DP) 為2、4、及6之寡醣,並進一步以揮發性光散射偵測器 (Evaporative light scattering detector, ELSD) 偵測,皆只有一個明顯之波峰 ; 且高硫酸基含量海藻寡醣以 HPLC 分析其滯留時間皆會提前,推測為寡醣接上硫酸基所造成。以傅立葉轉換紅外線光譜儀 (Fourier transform infrared spectroscopy, FT-IR) 分析,可在波長數 822 cm-1 及 1,250 cm-1 處左右有明顯之硫酸基團 C-O-S 及 S=O 之伸縮振動,推測為硫酸基添加所造成之結果。在人血漿之抗凝血實驗中,於活化部分凝血活酶時間 (Activated partial thromboplastin time, APTT),10 mg/mL Heparin 可延遲至 55 sec,而 20 mg/mL 的 Sar-Y4 DMF、 Sar-Y6 DMF、Gra-Y4 DMF、Gra-Y6 DMF、及 Ulva-Y6 DMF 可分別延遲至 66 sec、 99 sec 、55 sec、99 sec、及 77 sec,而在凝血酶原時間 (Prothrombin time, PT) 實驗中,高硫酸基含量之寡醣皆無延遲 PT 之活性,但會隨著硫酸基含量及寡醣濃度提高而降低凝血程度。於抗血小板凝集實驗中,20 mg/mL 的 Sar-Y2 DMF、Sar-Y4 DMF、Sar-Y6 DMF、Gra-Y6 DMF、與 Ulva-Y6 DMF 較相對應未添加硫酸基寡醣之凝集百分比分別降低了 12.2%、12.5%、11.7%、3.8%、與 11.6%,且皆與相對之控制組有顯著差異。而高硫酸基含量馬尾藻、龍鬚菜、及石蓴寡醣於抗日本腦炎病毒北京 1 型、登革熱病毒第 2 型、及腸病毒 71 型上,結果顯示主要的抑制效果在於抑制病毒吸附至宿主細胞上 (細胞存活率皆大於 92%),與單純病毒感染組 (Cell + Virus) 相較下皆有顯著性差異 (*p<0.05)。對腸道細胞株 Caco-2 細胞吸收測試之實驗上,以 HPLC 分析結果顯示,於 Transwell insert 吸收測試裝置之下層液,並未見到有寡醣被細胞吸收而穿透至下層液中,也未測得其醣量,但在上層液中,隨著作用時間 (0 min、30 min、及 90 min) 的增加,寡醣的含量則會隨之下降。
The aim of this study is to separate oligosaccharides (OS) with different degree of polymerization (DP) from hydrolysate of Sargassum sp., Gracilaria sp., and Ulva lactuca polysaccharides (PS), and using chlorsulfonic acid- N, N-dimethylformamide (DMF) method to increase sulfate contents of these OS. The effects of their anticoagulant, anti-platelet aggregation, antiviral activities, and its adsorption performance with intestinal cell line Caco-2 are examined. Sargassum sp., Gracilaria sp., and Ulva lactuca was extracted by 121oC hot water to obtain PS, and then added 3% cellulase, 2 U/mL crude PS degrading enzymes from Pseudomonas vesicularis MA103 and Aeromonas salmonicida MAEF108 (induced with Sargassum sp., Gracilaria sp., and Ulva lactuca PS) for enzyme hydrolysis (24 hr), Oligosaccharides hydrolysates with molecular mass < 3 kDa were collected by ultra filtration (UF) system, then though gel permeation chromatography (GPC) and high performance liquid chromatography (HPLC) to obtain isolated OS with different DP, such as Sar-Y2, Sar-Y4, and Sar-Y6 (from Sargassum sp.), Gra-Y2, Gra-Y4, and Gra-Y6 (from Gracilaria sp.), Ulva-Y2, Ulva-Y4, and Ulva-Y6 (from Ulva lactuca). The isolated OS then through DMF method (25oC for 4 hr) to increase sulfate contents. The sulfate contents of Sar-Y2, Y4, Y6 from 1.1 %-3.7% to 17.8%-29.6%, Gra-Y2, Y4, Y6 from 1.3%-4.4% to 13.7%-30.4%, Ulva-Y2, Y4, Y6 from 0.9%-3.4% to 14.7%-26.4%, and heparin (69.2 U/mL) was 27.02%. The HPLC analysis of isolated OS compare to standard and molecular mass calibration curve, the DP of OS may be DP 2, 4, 6, and using evaporative light scattering detector (ELSD) to detected,the results show only one obvious peak. The oversulfated algal OS analysis by HPLC, its retention time are earlier than original non-oversulfated OS. Fourier transform infrared spectroscopy (FT-IR) showed that was obvious sulfate ester group signal enhancement in wave numbers 822 cm-1 and 1,250 cm-1 are C-O-S and S=O stretching vibration, resulted from higher increase of sulfate contents. In the experiment of anticoagulant activities of human plasma, activated partial thromboplastin time (APTT) analysis of Heparin (10 g/mL) was delayed to 55 sec, however, APTT of Sar-Y4 DMF, Sar-Y6 DMF, and Gra-Y4, Gra-Y6 DMF, and Ulva-Y6 DMF (20 mg/mL) were delayed to 66 sec, 99 sec, 55 sec, 99 sec, and 77 sec, respectively. The anticoagulant activities of human plasma in prothrombin time (PT) analysis were examined, oversulfated OS were no obvious delayed in PT, but there were a tendency for reduction on absorbance value while OS concentration were increased. In anti-platelet aggregation analysis, percentage of platelet aggregation of 20 mg/mL Sar-Y2 DMF, Sar-Y4 DMF, Sar-Y6 DMF, Gra-Y6 DMF, and Ulva-Y6 DMF had lower 12.2%, 12.5%, 11.7%, 3.8%, and 11.6% than original related non-oversulfated OS, respectively, and had significant difference with control. In anti-japanese encephalitis virus Beijing 1 strain, dengue virus type 2, and enterovirus type 71 experiments, the results show the inhibition activity at prevent assay (cell viability>92%) and had significant difference with virus alone (*p<0.05). In the adsorption performance with Caco-2 cells testing experiment, the HPLC analysis showed that the basolateral fluid in the adsorption test device (Transwell insert), did not observe the OS uptake by cells and transfer to the basolateral fluid. But in the apical fluid, as the reaction time (0 min, 30 min, and 90 min) increased, that the OS contents were decreased.
目 錄

目錄 i
表目錄 vii
圖目錄 viii
附錄目錄 xiii
中文摘要 xiv
英文摘要 (Abstract) xvi
壹、前言 1
貳、文獻整理 3
一、海藻之來源與應用 3
1-1. 海藻簡介 3
1-2. 馬尾藻 4
1-3. 龍鬚菜 4
1-4. 石蓴 5
二、海藻寡醣 5
2-1. 海藻寡醣之萃取方法 5
2-2. 海藻寡醣之生理活性 6
2-2-1. 抗病毒 6
2-2-2. 抗氧化 7
2-2-3. 抗凝血及抗血小板凝集活性 8
2-2-4. 護肝作用 9
2-2-5. 益菌性 10
2-2-6. 調節免疫活性與抗腫瘤 10
2-2-7. 抑制血管收縮素轉化酵素 (Angiotesin
converting enzyme) 11
三、海藻寡醣高度硫酸化方法 11
四、海藻寡醣組成成分之鑑定 13
4-1. 高效能液相層析法 (High-performance liquid
chromatography, HPLC) 13
4-2. 傅立葉轉換紅外線光譜儀 (Fourier-transform
Infrared Spectroscopy, FTIR) 13
五、血液凝血機制 14
5-1. 內在途徑 15
5-2. 外在途徑 16
5-3. 最終共同路徑 16
5-4. 凝血酶的正回饋機制 17
5-5. 凝血作用的測試 17
5-6. 硫酸化多醣及寡糖對凝血的影響 18
5-7. 抗凝血系統 18
5-7-1. 抗凝血蛋白酶 III (Antithrombin III) 18
5-7-2. 蛋白質 C 與其輔因子蛋白質 S 18
5-7-3. 組織因子路徑抑制劑 (Tissue factor pathway
inhibitor, TFPI) 19
5-8. 纖維蛋白溶解系統 (Fibrinolytic or thrombolytic
system) 19
六、血小板 19
6-1. 血小板構造及其生理功能 19
6-2. 血小板凝集作用 (Aggregation) 20
七、日本腦炎病毒 21
7-1. 封套蛋白結構特性及作用機制 21
7-2. 感染細胞機制 22
八、登革熱病毒 22
8-1. 病毒特性及傳染模式 22
8-2. 感染細胞機制 23
九、 腸病毒 24
9-1. 病毒特性及增殖周期 24
9-2. 感染途徑及入侵途徑 25
十、腸道細胞株 Caco-2 25
10-1. Caco-2 細胞簡介 25
10-2. Caco-2 細胞之吸收模式 26
10-2-1. 藥物吸收模式 26
10-2-2. 醣類吸收模式 27
参、實驗設計 28
肆、材料方法 29
一、實驗材料 29
1-1. 原料 29
1-2. 試驗菌株 29
1-3. 試驗細胞株 29
1-4. 試驗病毒株 29
1-5. 試驗藥品 29
1-6. 儀器設備 31
1-7. 培養基組成 33
1-7-1. P. vesicularis MA 103 多醣降解酵素誘導
培養基 33
1-7-2. A. salmonicida MAEF108多醣降解酵素誘導
培養基 33
1-8. 細胞培養基 34
1-9. 海藻誘導酵素反應基質 34
1-10. DNS 溶液 35
二、實驗方法 35
2-1. 菌株之保存與活化 35
2-1-1. 菌株之保存 35
2-1-2. 菌株之活化 35
2-2. 海藻之一般成分分析 35
2-2-1. 水分含量 35
2-2-2. 灰分含量 36
2-2-3. 粗蛋白含量 36
2-2-4. 粗脂肪含量 36
2-2-5. 粗纖維含量 37
2-3. P. vesicularis MA103 或 A. salmonicida MAEF108 經
個別海藻熱萃多醣誘導所產之水解酵素與其活性測定 37
2-3-1. 個別海藻熱萃多醣之製備 37
2-3-2. 菌株活化與誘導 37
2-3-3. 個別海藻熱萃多醣誘導酵素之生產 38
2-3-4. 個別海藻熱萃多醣誘導酵素的活性測定 38
2-4. 個別海藻寡醣之分離與純化 39
2-4-1. 海藻寡醣水解物製備 39
2-4-2. 超過濾 (Ultra filtration, UF) 39
2-4-3. GPC 膠體過濾層析 39
2-5. 高度硫酸化 39
2-5-1. 氯磺酸–二甲基甲醯胺法 39
2-6. 海藻寡醣與高硫酸基含量海藻寡醣之成分分析 40
2-6-1. 還原糖含量 40
2-6-2. 總醣含量 40
2-6-3. 硫酸基含量測定 40
2-6-4. 高效能液相層析法 (High-performance liquid
chromatography, HPLC) 41
2-6-5. 傅立葉轉換紅外線光譜法 (Fourier transform
infrared spectroscopy, FT-IR) 42
2-7. 抗凝血測定 42
2-7-1. 活化部份凝血活酶時間 (Activited partial
thromboplastin time, APTT) 42
2-7-2. 凝血酶原時間 (Prothrombin time, PT) 42
2-8. 抗血小板凝集 (Platelet aggregation) 生理活性 43
2-8-1. 富含血小板血漿之製備 43
2-8-2. 血小板凝集測定 (Platelet aggregation
measurement) 43
2-9. 評估高硫酸基含量海藻寡醣抗病毒能力 44
2-9-1. 細胞株培養方法及繼代方法 44
2-9-2. 細胞毒性試驗 (MTT assay) 44
2-9-3. 抗日本腦炎病毒、登革熱病毒、及腸病毒試驗 45
2-9-3-1. 抑制病毒對宿主細胞吸附反應及抑制病毒
繁殖反應 45
2-10. 海藻寡醣腸道細胞吸收試驗 46
2-10-1. Caco-2 細胞株之活化 46
2-10-2. Caco-2 細胞株培養方法及繼代方法 46
2-10-3. 細胞數計數 47
2-10-4. 細胞之冷凍保存 47
2-10-5. Caco-2 細胞存活率分析 (MTT assay) 47
2-10-5-1. 不同 Caco-2 細胞接種數之細胞
存活率測定 48
2-10-5-2. 高硫酸基含量海藻寡醣對Caco-2 細胞
之毒性試驗 48
2-10-6. Transwell insert 培養法 48
2-10-7. Caco-2 細胞於吸收裝置其單層膜完整性測試 48
2-10-8. 高硫酸基含量海藻寡醣於腸道細胞吸收率測定 49
2-11. 統計分析 49
伍、結果與討論 50
陸、結論 66
柒、參考文獻 68

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