臺灣博碩士論文加值系統

松子油酸(Pinolenic acid; PNA)是一種來自松子的罕見不飽和脂肪酸(polyunsaturated fatty acid; PUFA)。PNA是亞麻油酸(linoleic acid; LA)經Δ5-去飽和酶(Δ5-Desaturase)代謝而成的產物，屬於非亞甲基間隔脂質肪酸(Non-methylene-interrupted fatty acid; NMIFA)。由於PNA的結構類似於具有抗發炎功效γ-次亞麻油酸(γ-linolenic acid; GLA)，先前的研究發現，PNA及其代謝產物在小鼠巨噬細胞中顯著取代了細胞磷脂質中的花生四烯酸(arachidonic acid; AA)，降低促發炎細胞介質的形成，如一氧化氮(nitric oxide; NO)與前列腺素E2 (prostaglandin E2; PGE2)，我們確定了PNA如何影響人體免疫細胞並調節促發炎介質的產生。結果表示，當細胞加入佛波醇-12-十四烷醯-13-乙酸酯(12-O-Tetradecanoylphorbol-13-acetate; TPA)時，THP-1單核球能夠完全分化成類巨噬細胞。在細胞培養基中加入50 μM的PNA，對細胞增殖無毒性影響。類巨噬細胞在培養基中攝取PNA，並且轉入至細胞磷脂質中。當使用脂多醣體(Lipopolysaccharide; LPS)刺激分化的THP-1巨噬細胞時，腫瘤壞死因子-α (tumor necrosis factor-α; TNF-α)與介白素-6(Interleukin-6; IL-6)的表現量會顯著增加。然而，在LPS刺激之前先將細胞培養於含PNA的培養基中會抑制兩種發炎介質的生成。綜合上述所說，PNA藉由轉入細胞磷脂質中，並且對TNF-α與IL-6生成造成影響。

Pinolenic acid (PNA) is a rare polyunsaturated fatty acid (PUFA) originally from pine seeds. PNA is a Δ5-desaturation product of linoleic acid (LA), and belongs to a group of non-methylene-separated fatty acids (NMIFA). Since the structure of PNA is similar to that of anti-inflammatory γ-linolenic acid (GLA) bioactive effects. Previous showed that PNA and its metabolites significantly substituted cellular phospholipid arachidonic acid (AA), and reduced pro-inflammatory mediator formation, such as nitric oxide (NO) and prostaglandin E2 (PGE2) in murine macrophages, we determined how PNA influence human immune cells and regulate the production of inflammatory mediators. Results showed that THP-1 monocytes were fully differentiated when the presence of 12-O-Tetradecanoylphorbol-13-acetate (TPA). Supplementation of the cell-culture medium with PNA (up to 50 μM) had no negative effect on cell proliferation. PNA was taken up rapidly from the medium by macrophages and incorporates into cellular phospholipids. When stimulated differentiated THP-1 macrophages with lipopolysaccharides (LPS), levels of tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) were significantly increased. However, incubation of cells with PNA before the LPS stimulation would suppress synthesis of both mediators. In summary, PNA would be taken up and incorporated into cellular phospholipids and exert anti-inflammatory effect on TNF-α and IL-6.

目錄
論文口試委員審定書 I
誌謝 II
縮寫對照表 IV
中文摘要 V
英文摘要 VII
圖目錄 XIV
表目錄 XVI

第一章 文獻回顧 1
1.1 前言 1
1.2 脂肪酸(Fatty acids) 2
1.2.1 脂肪酸分類 2
1.2.2 脂肪酸結構 2
1.2.3 脂肪酸來源 4
1.3 松科植物(Pinaceae)簡介 6
1.3.1 松子(Pine seed) 8
1.3.2 松子油酸(Pinolenic acid; PNA) 8
1.4 免疫系統(Immune system) 10
1.4.1 單核球與巨噬細胞分化 12
1.4.2 脂多醣體(Lipopolysaccharide; LPS) 13
1.4.3 發炎反應(Inflammation) 17
1.4.4 促發炎細胞介質(Proinflammatory mediators) 17
1.5 發炎路徑 (Inflammatory pathway) 22
1.5.1 核轉錄因子-kappa B (Nuclear transcription factor-kappa B;
NF-κB) 22
1.5.2 有絲分裂原活化蛋白激酶(Mitogen-activated protein
kinases; MAPK) 24
1.6 研究目的及動機 27
1.7 研究架構 28

第二章 材料與方法 29
2.1 儀器設備與藥品試劑 29
2.1.1 儀器與設備 29
2.1.2 藥品與溶劑 30
2.1.3 試劑套組 31
2.1.4 Western Blot Antiobody 32
2.2 實驗樣品與細胞 33
2.2.1 實驗樣品來源 33
2.2.2 實驗細胞株 33
2.3 細胞基礎培養 33
2.3.1 基礎培養條件 33
2.3.2 細胞活化 33
2.3.3 細胞繼代 35
2.3.4 細胞凍存 35
2.3.5 細胞計數 35
2.4 實驗條件 37
2.4.1 預先培養實驗條件 37
2.4.2 發炎刺激實驗條件 37
2.5 細胞脂質萃取 37
2.5.1 樣品處理 37
2.5.2 脂質萃取 38
2.5.3 脂質分離 38
2.5.4 脂質分析-氣相層析分析(Gas Chromatography; GC) 40
2.6 食用松子油精萃松子油酸 41
2.6.1 皂化(Saponification) 41
2.6.2 甲基化(Methylation) 41
2.6.3 薄層層析法(Thin layer chromatography; TLC) 42
2.6.4 管柱層析法(Column chromatography; CC) 43
2.6.5 銀離子管柱層析法 44
2.7 探討PNA脂肪酸對LPS誘發類巨噬細胞發炎物質的調控 45
2.7.1 細胞存活率分析(MTT assay) 45
2.7.2 細胞毒性分析(Lactate dehydrogenase assay; LDH assay) 46
2.7.3 酵素免疫分析法(Enzyme-linked immunoadsorbent assay;
ELISA assay) 47
2.7.4 前列腺素E2分析(Prostaglandin E2 assay; PGE2 assay) 48
2.7.5 蛋白質萃取與定量(Protein extraction and quantification) 50
2.7.6 聚丙烯醯胺凝膠電泳(Sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SDS-PAGE)與西方墨點法(Western blot assay; WB assay) 51
2.8 統計分析 56

第三章 結果與討論 57
3.1 探討TPA對THP-1單核球細胞分化過程之影響 57
3.1.1 細胞存活率測試MTT assay 57
3.1.2 細胞毒性測試LDH assay 59
3.2 探討TPA與LPS對THP-1類巨噬細胞發炎介質生成之影響 59
3.2.1 依序利用TPA與LPS雙刺激模式誘導TNF-α生成之影
響 59
3.2.2 不同時間與方式的雙刺激模式對TNF-α生成之影響 61
3.3 探討PNA對THP-1類巨噬細胞存活率及毒性之影響 64
3.3.1 細胞存活率測試MTT assay 64
3.3.2 細胞毒性測試LDH assay 64
3.4 探討PNA對THP-1類巨噬細胞的發炎介質生成之影響 66
3.4.1 TNF-α生成之影響 66
3.4.2 IL-6生成之影響 66
3.4.3 PGE2生成之影響 70
3.5 分析PNA對THP-1類巨噬細胞中脂肪酸的變化 72
3.6 探討不同濃度PNA對THP-1類巨噬細胞發炎之COX-2路徑的
影響 75
3.7 探討不同濃度PNA對THP-1類巨噬細胞發炎之MAPK路徑的
影響 79
3.7.1 探討LPS在不同時間下對於THP-1類巨噬細胞之MAPK
路徑的影響 79
3.7.2 探討PNA對於THP-1類巨噬細胞之MAPK路徑的影響 81

第四章 結論 84

參考文獻 87
一、 英文文獻 87
二、 中文文獻 93
三、 網路資料 95

附錄 96
附錄一、MTT assay 96
附錄二、LDH assay 96
附錄三、ELISA assay 96
附錄四、PGE2 assay 98



圖目錄
圖1- 1 脂肪酸分類 3
圖1- 2 脂肪酸基本結構圖 5
圖1- 3 亞甲基與多重亞甲基結構 5
圖1- 4 不同脂肪酸比例(%) 5
圖1- 5 脂肪酸特性之比較 7
圖1- 6 PNA與GLA化學結構之雙鍵差異圖 9
圖1- 7 免疫系統示意圖 11
圖1- 8 單核球分化為M1與M2巨噬細胞 14
圖1- 9 LPS的結構 16
圖1- 10 LPS誘導發炎反應途徑 18
圖1- 11 IL-6順向與反向訊號傳遞路徑示意圖 21
圖1- 12 TNF-α訊號傳遞路徑示意圖 23
圖1- 13 典型與替代活化NF-κB訊息傳遞路徑 23
圖1- 14 MAPK訊號傳遞路徑示意圖 25
圖1- 15 細胞實驗流程圖 28
圖2- 1人類急性白血病系單核細胞株THP-1型態 34
圖2- 2 血球計數區域示意圖 36
圖2- 3 血球計數公式 36
圖2- 4 Western blot實驗流程圖 52
圖3- 1不同TPA濃度對THP-1單核球細胞存活率的影響 58
圖3- 2 不同TPA濃度對THP-1單核球細胞毒殺的影響 60
圖3- 3 不同濃度的TPA對THP-1類巨噬細胞TNF-α生成的影響 62
圖3- 4 不同濃度的LPS對THP-1類巨噬細胞TNF-α生成的影響 62
圖3- 5 不同時間與方式的雙刺激模式實驗流程圖 63
圖3- 6 不同時間與方式培的雙刺激模式對TNF-α生成之影響 63
圖3- 7 不同PNA濃度對THP-1類巨噬細胞存活率的影響 65
圖3- 8 不同PNA濃度對THP-1類巨噬細胞毒殺的影響 67
圖3- 9 探討PNA對THP-1類巨噬細胞TNF-α生成之影響 68
圖3- 10 探討PNA對THP-1類巨噬細胞IL-6生成之影響 69
圖3- 11 探討PNA對THP-1類巨噬細胞PGE2生成之影響 71
圖3- 12 探討預先培養方式對THP-1類巨噬細胞中脂肪酸組成的影響 73
圖3- 13 探討發炎刺激實驗對THP-1類巨噬細胞中脂肪酸組成的影響 74
圖3- 14 探討PNA對THP-1類巨噬細胞內COX-2表現量的影響 78
圖3- 15 探討LPS在不同時間對THP-1類巨噬細胞內磷酸化MAPK表現量的影響 80
圖3- 16 探討PNA對THP-1類巨噬細胞內MAPK表現量的影響 82
圖4- 1 發炎相關蛋白質與路徑 86

 
表目錄
表2- 1 Western blot試劑與溶液配方 53
表2- 2 電泳膠片配方-分離膠體(Running gel) 54
表2- 3 電泳膠片配方-焦集膠體(Stacking gel) 54
表3- 1 探討預先培養方式對PNA與其代謝相關產物的影響 76
表3- 2 探討發炎刺激實驗對PNA與其代謝相關產物的影響 76

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三、網路資料
1.Oncohemakey, Mononuclear Phagocytes in Immune Defense.
https://oncohemakey.com/mononuclear-phagocytes-in-immune-defense/

2.Acharya, T., (2013) Microbiology for Beginners, Structure of bacterial cells.
https://microbeonline.com/lipopolysaccharide-lps-of-gram-negative-bacteria-characteristics-and-functions/

3.Mehal, W.Z., 2015，科學人雜誌第163期09月號。
http://sa.ylib.com/MagArticle.aspx?Unit=featurearticles&id=2788