臺灣博碩士論文加值系統

薑黃 (Curcuma longa L.) 為一種中草藥，廣泛作為食品添加物，如香料、天然色素等用途。近年研究指出薑黃中類薑黃素 (curcuminoids) 成分具有抗發炎、抗癌等多種生物活性。本研究目的為從薑黃萃取類薑黃素，並將其製備奈米微乳化液，再進一步探討類薑黃素奈米微乳化液對抑制肺癌細胞 (A549、H460) 之機制。結果顯示，以 99.5% 乙醇從薑黃萃取類薑黃素，並使用管柱Eclipse XDB-C18 (150 × 4.6 mm i.d.) 配合光電二極體陣列偵檢器 (diode-array detector, DAD)，動相為 0.1% 的甲酸水溶液 (A) 及氰甲烷 (B)，流速為1 mL/min，管柱溫度35oC，偵測波長425 nm，可於 15 分鐘內分離出去二甲氧基薑黃素 (bidemethoxycurcumin)、去甲氧基薑黃素 (demethoxycurcumin) 及薑黃素 (curcumin) 等三種薑黃素。以水及Tween 80 之適當比例能成功配製出奈米微乳化液，其平均粒徑為 12.6 nm，且經 90 天儲藏性試驗能保有良好之粒徑分布及粒徑大小。細胞實驗顯示，類薑黃素奈米微乳化液及薑黃萃取液均具有抑制肺癌細胞 (A549 及 H460) 增生之效果，對於 A549 肺癌細胞而言，其作用 48 小時後IC50值分別為 3.9 和 3.75 μg/mL，而 H460 肺癌細胞之 IC50值分別為2.9 和 2.9 μg/mL。細胞週期分析結果發現，A549 及 H460 細胞隨作用濃度增加，G2/M 期比例亦隨之提高，顯示類薑黃素奈米微乳化液及薑黃萃取液會使細胞停滯於 G2/M 期，此外 sub-G1 比例同樣會隨著作用濃度提高而增加。Annexin V/PI 雙染結果發現類薑黃素奈米微乳化液與薑黃萃取液可誘導細胞凋亡的產生。而 caspase-8、caspase-9 和 caspase-3 酵素活性會受到類薑黃素奈米微乳化液與薑黃萃取液的誘發而活化。相關蛋白表現方面，A549 及 H460 經薑黃素奈米微乳化液與薑黃萃取液作用 24 小時後，其 A549 之 cyclin B、p53、p21 和 cytochrome C 的表現量隨作用濃度提高而上升，CDK1 和 Bcl-2 表現量則隨作用濃度增加而下降；H460 之 p21 和 cytochrome C 的表現量隨作用濃度提高而上升，其中類薑黃素奈米微乳化液以非依賴 p53 途徑活化 p21 的蛋白表現，而薑黃萃取液是透過增加 p53 使 p21 蛋白表現增加，而 cyclin B、CDK1 和 Bcl-2的表現量隨作用濃度提高而下降。綜合上述結果，薑黃素奈米微乳化液與薑黃萃取液具有抑制人類肺癌細胞的細胞增生能力，且能引起細胞週期停滯於 G2/M 期和誘發細胞凋亡。

Turmeric (Curcuma longa L.), a kind of herbal medicine, is widely used as food additives for spicy taste and natural coloring. Recently, curcuminoids isolated from C. longa have been shown to possess several biological activities, including anti-inflammation and anti-cancer. The objectives of this study were to extract curcuminoid from C. longa, and prepare curcuminoid nanoemulsions for studying the inhibition mechanism on lung cancer cells (A549 and H460). Results showed that 99.5% ethanol could extract curcuminoid fraction containing bisdemethoxycurcumin, demethoxycurcumin and curcumin, which were then separated within 15 min by using an Eclipse XDB-C18 column (150 × 4.6 mm i.d.) and a diode-array detector as well as by employing a mobile phase of 0.1% formic acid in water (A) and acetonitrile (B) with flow rate at 1 mL/min, column temperature at 35oC and detection wavelength at 425 nm. Curcuminoid nanoemulsions using deionized water and Tween 80 as emulsifier, with a mean droplet size of 12.6 nm, were successfully prepared. Storage for 90 days did not show significant change in particle size distribution, indicating that a high stability of this nanoemulsions. The cell-culture experiments revealed that both curcuminoid nanoemulsions and extract could inhibit proliferation of A549 and H460 cells, with the IC50 value of the former being 3.9 and 3.75 μg/mL, respectively, and the latter being 2.9 and 2.9 μg/mL. Cell cycle analysis showed that the cell cycle arrest for both A549 and H460 cells occurred at G2/M phase. Also, the accumulation of both cells in sub-G1 phase increased in a dose-dependent manner. Annexin V/PI double stain analysis indicated the presence of numerous apoptoic bodies on treatment with curcuminoid nanoemulsions and extract, accompanied by a dose-dependent expression of caspase-8, caspase-9 and caspase-3. Western blot analysis revealed that A549 cell treated with curcuminoid nanoemulsions and extract could up-regulate cyclin B, p53, p21 and cytochrome C, while down-regulate CDK1 and Bcl-2 in a concentration-dependent manner. Whereas, H460 cell with the same treatment could up-regulate p21 and cytochrome C and down-regulate cyclin B, CDK1 and Bcl-2. In addition, H460 cell treated with curcuminoid nanoemulsions could elevate p21 level in a p53-independent manner, but the extract elevated p21 in a p53-dependent manner. These results suggested that curcuminoid nanoemulsions and extract could inhibit the proliferation of lung cancer cells by arresting the cell cycle in G2/M phase and inducing apoptosis.

目錄
頁次
第一章、緒言 1
第二章、文獻回顧 3
一、薑黃之簡介 3
(一) 薑黃之生長分布 3
(二) 薑黃之化學成分 3
(三) 薑黃之藥理作用 6
二、薑黃素之簡介 6
(一) 薑黃素之化學結構 6
(二) 薑黃素之生理活性 8
三、肺癌簡介 14
(一) 小細胞肺癌 14
(二) 非小細胞肺癌 14
(三) 肺癌病程 15
(四) 肺癌之治療方式 17
四、細胞週期 19
(一) 細胞週期調控蛋白 20
(二) 細胞週期檢查點 25
五、細胞凋亡 28
(一) 細胞凋亡訊息傳遞途徑 29
(二) 調控細胞凋亡之相關蛋白 31
六、奈米微乳化液 37
(一) 奈米科技之簡介 37
(二) 微乳化 37
(三) 奈米微乳化液之分類 38
(四) 奈米微乳化液之主要組成 38
(五) 藥物傳遞系統 40
第三章 材料與方法 42
一、研究架構 42
二、材料與儀器 43
(一) 試驗材料 43
(二) 化學藥品 43
(三) 儀器設備 45
三、實驗方法 47
(一) 薑黃之薑黃素萃取製備 47
(二) 薑黃素之HPLC-DAD-MS 分析 48
(三) 薑黃素之鑑定 48
(四) 薑黃素之定量 48
(五) 類薑黃素之奈米微乳化液製備 49
(六) 奈米微乳化液之奈米特性分析 50
(七) 奈米微乳化液之安定性 51
(八) 類薑黃素奈米微乳化液抑制肺癌細胞生長之測定 51
(九) 統計分析 61
第四章 結果與討論 62
一、薑黃中薑黃素成分之研究 62
(一) 薑黃萃取液成分之分析 62
(二) 薑黃萃取液成分之含量 63
二、類薑黃素奈米微乳化液之製備 68
(一) 粒徑大小分佈分析 69
(二) 顯微影像分析 69
(三) 儲藏性試驗 69
(四) 包覆率 70
三、類薑黃素奈米微乳化液抑制肺癌細胞生長之影響 76
(一) 細胞對樣品溶劑耐受性之評估 76
(二) 抑制細胞增生之效果 79
(三) A549 及 H460 肺癌細胞型態之影響 84
(四) A549 及 H460 細胞週期之影響 88
(五) A549 及 H460 細胞凋亡之影響 92
(六) A549 及 H460 細胞內細胞週期及凋亡相關蛋白表現之影響 99
(七) A549 及 H460 細胞之 caspase-3、caspase-8 和 caspase-9 酵素活性表現之影響 106
第五章、結論 115
第六章、參考文獻 116

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