臺灣博碩士論文加值系統

第一部分
大腸直腸癌屬高度侵入性與轉移性之惡性腫瘤，是高死亡率的癌症之一，其中癌細胞轉移是造成約 40 % 大腸癌病患死亡的主因，可見若能有效抑制癌細胞發生轉移，將可延長大腸直腸癌病患的生命。基質金屬蛋白酶 (matrix metalloproteinases, MMPs) 是癌細胞發生轉移時用來分解基底質所產生的分解酵素，其中 MMP-2 及 -9 證實與癌症的侵入與轉移最有關聯，若能有效抑制細胞中 MMP-2 和 -9 的活性，應能間接抑制細胞轉移的發生。迷迭香酸 (rosmarinic acid, RA) 是一種多酚類，廣泛存在於唇型科和紫草科等天然植物，研究發現其具有多種生物活性，如抗氧化、抗病毒、抗發炎、抗細菌及抗癌等，但 RA 抑制癌細胞侵入轉移方面的文獻仍相當有限。本研究主要目的為探討 RA 對大腸直腸癌細胞 Colo205 及 HT-29 侵入能力的抑制功效。首先以 RA 對 Colo205 及 HT-29 不具細胞毒殺作用之劑量，進行 gelatin-zymography assay 及 casein zymography assay，進行 MMP-2、-9 及 uPA 活性測定，並利用 RT-PCR 測試 MMP-2、-9、TIMP-1、 -2 之 mRNA 的表現量；其次，分析 RA 對細胞黏附力之影響；再利用 wound healing assay、cell migration assay和cell invasion assay 分析 RA 對 Colo205 及 HT-29 細胞移行性及侵入性之作用。結果顯示，RA 在 50 μM 可顯著抑制 Colo205 及 HT-29 之 MMP-2 與 uPA 活性，並可抑制兩種細胞的移行與侵入能力。而在 mRNA 的表現量，RA在濃度大於 50 μM 時可顯著抑制 Colo205 及 HT-29 之 MMP-2 mRNA表現量，同時增加 HT-29 TIMP-1 與 -2 以及 Colo205 TIMP-1表現量。再由 Western blot 結果得知，RA可抑制 Colo205及 HT-29之 p-ERK 與 p-p38 蛋白表現量，但對於 p-JNK 則無作用；迷迭香酸對 Colo205 及 HT-29 之 AP-1 與 NF-κB 亦顯示具有抑制作用。經由以上結果顯示，RA 可能是一種有效抑制大腸直腸癌細胞侵入性的天然活性物，而此種抑制作用可藉由調控細胞內 MAPK 訊息傳遞路徑，調降 NF-κB 及 AP-1 的活化及表現量，進而降低大腸直腸癌細胞外 uPA 與 MMP-2 之酵素活性，而達到抑制移行與侵入能力。
第二部分
肺結核 (Tuberculosis, TB) 是一種接觸性傳染疾病，會造成嚴重的公共健康風險。世界衛生組織估計在 2008 年約有 9,400,000 個新發病肺結核案例，且在東南亞地區約占 34% 。多重抗藥性肺結核 (Multidrug-resistant TB, MDR-TB) 是結核病中特別危險的一種，也是結核病治療失敗的重要原因。Mcobacterium tuberculosis 是誘發TB的主要原因，而 uridine diphosphate-glucose pyrophosphorylase (UGPase; EC 2.7.7.9) 是參與桿菌細胞壁合成的主要酵素，因此推論當 UGPase 活性受到抑制時，或許亦能抑制多重抗藥性 M. tuberculosis 的生長。迷迭香酸 (Rosmarinic acid, RA) 是一種多酚類，廣泛存在於唇型科和紫草科等天然植物，研究發現其具有多種生物活性，如抗病毒、抗發炎、抗細菌。因此，本研究主要探討 RA 對多重抗藥性 M. tuberculosis 增生及 UGPase 活性表現之影響。由於許多活性物的生理活性都與其抗氧化力有關，本研究首先以 trolox equivalent antioxidant capacity (TEAC) 方法測試 RA 抗氧化力，另外以生長在 7H11 培養基上之菌落數進行存活率測定，並利用 reverse transcription polymerase chain reaction (RT-PCR) 分析 UGPase表現量。結果顯示 RA 具有顯著的抗氧化能力，使用濃度高於 250 μg/ml的 RA 處理菌體 24 小時，可抑制多重抗藥性 M. tuberculosis 的生長，且UGPase 的表現量也同樣受到抑制。根據以上結果顯示，RA 可用來抑制多重抗藥性 M. tuberculosis 的生長，而此種抑菌功效可能是藉由降低 UGPase 的表現量使M. tuberculosis 細胞壁無法合成而達成。

(I)
Colorectal cancer is the leading cause of cancer mortality, and metastasis is responsible for approximately 40% of death in colon cancer patients. Matrix metalloproteinases (MMPs) are key enzymes in the degradation of extracellular matrix, and MMP-2 and -9 are critical for cell migration leading to invasion and metastasis of cancer. The inhibition of MMP-2 and -9 is therefore considered that might depress the occurrence of tumor invasion and metastasis. Rosmarinic acid (RA) is a bioactive polyphenol that widely presented in Rosmarinus officinalis L. However, the literature regarding the effect of RA on invasion of cancer cells is still limited. In this study, we investigated the anti-invasion activity of RA against human colorectal adenocarcinoma Colo205 and HT-29 cells. The cells were treated with 0, 10, 50, 100, or 200 M of RA at 37C for 24 h, and the MMP-2, -9, and uPA activities as well as cell-matrix adhesion, motility, and invasion activities were determined. The MMP-2, -9, TIMP-1 and -2 mRNA levels were assayed by RT-PCR. The molecular signaling was determined by Weastern blot. The results showed that the MMP-2 and uPA activities of Colo205 and HT-29 cells were significantly inhibited by RA at a concentration of > 50 μM. The migration and invasion activities of Colo205 and HT-29 cells were also suppressed after treating with RA at a concentration higher than 50 M. The mRNA level of MMP-2 in HT-29 and Colo205 were significantly inhibited by RA at a concentration of > 50 M. The mRNA levels of TIMP-1 and -2 in HT-29 and TIMP-1 in Colo205 were significantly increased by RA. The signaling of p-ERK and p-p38 in Colo205 and HT-29 were signigicantly inhibited by RA. Furthermore, the activations of NF-κB and AP-1 in colorectal cancer cells were also suppressed by RA. Our results suggest that RA might be a bioactive with potential anti-invasive activity against colorectal cancer cells by inhibiting uPA and MMP-2 activity and reducing motility capabilities through inhibiting the activations of MAPKs signaling pathways and NF-κB and AP-1 transcription factors.
(II)
Tuberculosis (TB) is a contagious disease which causes a serious public health risk. WHO estimates that there were approximately 9,400,000 new TB cases globally in 2008, and South-East Asia Region accounted for 34% of incident cases. Multidrug-resistant TB (MDR-TB) is a particularly dangerous form of TB, which is responsible for the majority of failures in TB therapy. Mycobacterium tuberculosis is the major pathogeny of TB, and uridine diphosphate-glucose pyrophosphorylase (UGPase; EC 2.7.7.9) is the major enzyme that involved to the synthesis of cell wall. The inhibition of UGPase might depress the proliferation of the bacilli. Rosmarinic acid (RA), a polyphenol which is widely presented in natural plants of Lamiaceae and Boraginaceae family, has been reported that possesses several biological activities such as anti-virus, anti-inflammation, and anti-bacteria. The aim of this study was to investigate the inhibitory effects of RA on the viability of multidrug-resistant M. tuberculosis, and their impact on UGPase was also evaluated. Because the biological activity of a bioactive sometimes having an association with their antioxidant power, we therefore first determined the antioxidant activity of RA by trolox equivalent antioxidant capacity (TEAC) method. The viability of the bacilli was measured by counting the colony growing on 7H11 agar plates, and the expression of UGPase was performed by RT-PCR. The results showed RA having a strong antioxidant activity, and the viability of M. tuberculosis was reduced by treating with RA at a concentration of > 250 g/ml for 24 h. Furthermore, the expression of UGPase was also decreased by treating with 250 g/ml RA for 24 h. Based on the data mentioned above, it is suggested that RA can be used to inhibit the proliferation of multidrug-resistant M. tuberculosis, and the anti-proliferous activity of RA might be through inhibiting the expression of UGPase.

目錄
目錄………………………………………………………………………i
圖目錄 …………………………………………………………………iv
表目錄 …………………………………………………………………vi
第一部分：餐飲常用香料活性成分--迷迭香酸之生理功效
(I) 對人類大腸直腸癌細胞侵入性之抑制功效…………1
中文摘要 ……………………………………………………………… 2
英文摘要 ……………………………………………………………… 4
第一章、前言 ………………………………………………………… 6
第二章、文獻整理………………………………………………………8
壹、癌症………………………………………………………………8
貳、大腸直腸癌之簡介………………………………………………9
參、腫瘤轉移與侵入…………………………………………………17
肆、蛋白酶基因表現之調控…………………………………………28
伍、迷迭香酸之簡介…………………………………………………35
陸、研究目的…………………………………………………………38
柒、研究架構…………………………………………………………39
第三章、材料與方法……………………………………………………40
第四章、結果……………………………………………………………52
一、迷迭香酸對人類大腸直腸癌細胞 Colo205 與 HT-29 細胞存活率之影響 …………………………………………………52
二、迷迭香酸對人類大腸直腸癌細胞--基質間黏附力之影響…52
三、迷迭香酸對人類大腸直腸癌細胞MMP-2 與 MMP-9 活性之影響 …………………………………………………………52
四、迷迭香酸對人類大腸直腸癌細胞uPA 活性之影響……… 53
五、迷迭香酸對人類大腸直腸癌細胞傷口癒合之影響…………53
六、迷迭香酸對人類大腸直腸癌細胞移行能力之影響…………54
七、迷迭香酸對人類大腸直腸癌細胞侵入能力之影響…………54
八、迷迭香酸對人類大腸直腸癌細胞 MMPs 與 TIMPs 轉錄階段 mRNA 表現之影響 …………………………………… 55
九、迷迭香酸對人類大腸直腸癌細胞 MAPK 訊息蛋白表現之影響 …………………………………………………………… 56
十、迷迭香酸對人類大腸直腸癌細胞 NF-κB 及 AP-1 轉錄因子蛋白表現之影響 …………………………………………… 56
第五章、討論……………………………………………………………58
第二部分：餐飲常用香料活性成分--迷迭香酸之生理功效
(II) 對多重抗藥性結核菌生長抑制作用與機制 ………72
中文摘要 ………………………………………………………………73
英文摘要……………………………………………………………… 74
第一章、前言 ………………………………………………………76
第二章、文獻整理……………………………………………………77
壹、肺結核病菌之簡介……………………………………………77
貳、肺結核病的治療………………………………………………77
參、肺結核桿菌與 UGPase 之關係 ……………………………78
肆、研究目的………………………………………………………82
伍、實驗架構………………………………………………………83
第三章、材料與方法……………………………………………………84
第四章、結果……………………………………………………………89
一、迷迭香酸之萃取………………………………………………89
二、迷迭香酸抗氧化力能力………………………………………89
三、迷迭香酸對多重抗藥性結核病菌之抑菌效果………………90
四、偵測 UGPase 之基因………………………….…………….90
五、迷迭香酸對多重抗藥性結核病菌 UGPase表現量之影響..90
第五章、討論……………………………………………………………92
總結論 ………………………………………………………………100
參考文獻 ……………………………………………………………101

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