臺灣博碩士論文加值系統

血管新生 (Angiogenesis 或稱為 Neovascularization) 意指形成新的微血管，是從現存分布的血管經由內皮細胞移行及增生所形成。在正常生理過程都需要血管新生，包括胎兒的發育、傷口的癒合。當血管新生失去調控，也會產生許多病理過程，包括糖尿病病人視網膜的病變、各種型式的發炎疾病等，此外腫瘤的生長是需要血管新生使腫瘤成長及轉移。常見的生長因子及細胞激素有血管內皮細胞生長因子 (Vascular Endothelial Growth Factor; VEGF)、纖維母細胞生長因子 (Basic Fibroblast Growth Factor; bFGF)、基質金屬蛋白酶 (Matrix Metalloproteinases; MMPs)、介白素-6 (Interleukin-6; IL-6) 和介白素-8 (Interleukin-8; IL-8)等。本研究主要探討芭樂心葉水萃取物 (Psidium guajava L. budding leaves aqueous extract; PE)對於攝護腺癌細胞 DU-145抗血管新生能力評估。實驗結果顯示，PE於 1 mg/mL 下可抑制 DU-145細胞移行(抑制 69.1%)及 VEGF之表現 (抑制 76.0%)。透過 Gelatin Zymography及 Elisa kit分析結果顯示，PE於 1 mg/mL 下幾乎可以完全抑制 MMPs，IL-6與 IL-8之表現，透過蛋白質電泳分析證實，MMPs表現量的下降可能因 PE增進基質金屬蛋白酶抑制酵素 (Tissues inhibitor of metalloproteinases; TIMP)之表現。此外，PE亦能抑制人類臍帶靜脈血管內皮細胞 (Human umbilical vascular endothelial cells; HUVEC)之細胞移行與管腔結構的形成，更切確的證據顯示於雞胚胎的尿囊 (Chicken Chorioallantoic Membrane Assay; CAM)上，當給予 PE 25 mg/mL下，可明顯觀察出 CAM上的血管明顯受到 PE之抑制。
綜合上述，PE具有抑制攝護腺癌細胞 (DU-145)血管新生之作用，將可提供研發為預防或降低癌症發生之保健劑。

Angiogenesis, the generation of new capillaries through a process of pre-existing microvessel sprouting, is under stringent control and normally occurs only during embryonic and post-embryonic development, reproductive cycle, and wound repair. Usually, an imbalance of the growth factors is involved in this process, resulting in the acceleration of several diseases including malignant, ocular, and inflammatory diseases. Moreover, angiogenesis has been considered to be involved ass an important step in cancer progression. The discovery of key molecular modulators of angiogenesis, notably Vascular Endothelial Growth Factor (VEGF), Basic Fibroblast Growth Factor (bFGF), Matrix Metalloproteinases (MMPs), Interleukin-6 (IL-6) and Interleukin-8 (IL-8) has in reality catalyzed the development of numerous neutralizing therapeutic agents. In this thesis, the effects of the aqueous extract of Psidium guajava L. budding leaves (PE) on antiangiogensis in prostate cancer DU145 cells were investigated using in vivo as well as in vitro models. At a concentration of 1 mg/mL, PE inhibited 69.1% and 76.0% of cell migration capability and expression of vascular endothelial growth factor (VEGF), respectively. At 1 mg/mL, complete inhibition on the expression of MMPs, upregulation of TIMP-2 and inhibition on MMPs were also simultaneously demonstrated. Alternatively, IL-6 and IL-8 were also examined by the Gelatin Zymography and the Elisa Kit Assay. PE inhibited migration and tube formation of Human umbilical vascular endothelial cells (HUVEC) in a concentration dependent manner. More importantly, PE at 25 mg/mL prominently inhibited angiogenesis when demonstrated by Chicken Chorioallantoic Membrane Assay (CAM assay).
To summarize, PE possesses a strong antiangiogenic activity, which on combining its antimigration and anti-invasive potentials may contribute to its cancer chemopreventive capability.

中文摘要 …………………………………………………………………… 01
英文摘要 …………………………………………………………………… 03
研究架構 …………………………………………………………………… 05
前言 ………………………………………………………………………… 07
研究動機 …………………………………………………………………… 09
文獻回顧 …………………………………………………………………… 11
1.1 芭樂心葉 …………………………………………………………… 11
2.1 攝護腺癌 …………………………………………………………… 15
2.2 抗氧化劑與攝護腺癌 ……………………………………………… 25
3.1 血管新生的生理機制及機轉 ……………………………………… 27
3.2 癌症與血管新生之關聯 …………………………………………… 28
3.3 血管新生與抗血管新生之因子 …………………………………… 30
3.4 抑制血管新生抗癌藥物 …………………………………………… 44
3.5 血管新生之動物實驗模式 ………………………………………… 49
材料與方法 ………………………………………………………………… 50
1. 實驗材料與試劑 ……………………………………………………… 50
1.1 保健中草藥來源 …………………………………………………… 50
1.2 藥品 ………………………………………………………………… 50
1.3 實驗儀器 …………………………………………………………… 52
1.4 細胞株 ……………………………………………………………… 53
1.5 受精雞蛋 …………………………………………………………… 53
2. 實驗步驟與方法 ……………………………………………………… 53
2.1 芭樂心葉水萃物製備 ……………………………………………… 53
2.2 芭樂心葉多醣體及小分子 ………………………………………… 54
2.3 常用溶液 …………………………………………………………… 54
2.4 細胞培養 …………………………………………………………… 55
2.5 細胞存活率之測定 ………………………………………………… 57
2.6 細胞外激素之測定 ………………………………………………… 58
2.7 基質金屬蛋白酶之測定 (MMPs) ………………………………… 59
2.8 細胞移行分析 (Migration) ………………………………………… 59
2.9 管腔形成分析 (Tube Formation) ………………………………… 60
2.10 蛋白質表現量測定 ………………………………………………… 60
2.11 雞胚胎尿囊膜試驗 ……………………………………………… 64
2.12 統計分析 ………………………………………………………… 64
結果與討論 ………………………………………………………………… 65
結論 ………………………………………………………………………… 75
參考文獻 …………………………………………………………………… 108

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