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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90695完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 潘敏雄 | zh_TW |
| dc.contributor.advisor | Min-Hsiung Pan | en |
| dc.contributor.author | 秦妍 | zh_TW |
| dc.contributor.author | Yan Qin | en |
| dc.date.accessioned | 2023-10-03T17:13:14Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-10-03 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-02 | - |
| dc.identifier.citation | Hahn, M. J. (2018). GRAS notice 791 for Urolithin A. Washington, DC: U.S. Food and Drug Administration
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90695 | - |
| dc.description.abstract | 大腸直腸癌 (colorectal cancer, CRC) 是世界範圍內發病率和死亡率最高的惡性腫瘤之一。加工食品的攝入是誘發大腸癌最主要的外源性因素。越來越多的證據表明，蔬果中的天然化合物可以阻止腸癌的進展。尿石素 (urolithins) 為蔬果中富含的鞣花單寧被生物體腸道菌群所代謝的產物。有研究顯示，urolithins透過誘導細胞粒線體自噬來保護神經細胞及延緩老化作用。此外urolithins也表現出出色的抗癌效果，然而鮮少有研究從自噬的角度去探討urolithins對腸癌細胞凋亡的影響。因此，本實驗旨在探討鞣花單寧的腸道微生物代謝物urolithin C (UC) 對腸癌細胞自噬與凋亡的影響。首先以細胞存活率實驗篩選出抗癌效果最佳之化合物以及對化合物最敏感之細胞株。接著再以流式細胞儀對細胞週期及粒線體功能進行分析。此外，以海馬能量測定儀分析在壓力狀況下粒線體的耗氧量，以螢光顯微鏡及RT-qPCR對粒線體自噬及相關基因表現進行偵測。隨後測定不同時間點尿石素對腸癌細胞自噬與凋亡相關表型及蛋白表現量。結果顯示，UC對HCT116細胞存活率表現出最佳之抑制效果，並且可以顯著降低HCT116細胞G0/G1期細胞數量並造成S期停滯。在UC處理12小時後HCT116粒線體呼吸功能、粒線體膜電位與粒線體質量顯著降低。粒線體與溶酶體的染色共定位表明粒線體自噬的發生。RT-qPCR結果顯示UC誘導粒線體自噬基因PARK及BINP3的表現量上調。在細胞自噬方面，UC在12及24小時增加細胞內酸性囊泡胞器水平，自噬蛋白LC3II表現量在24小時顯著上升，p62蛋白有下降的趨勢。p-AMPK及p53蛋白表現量自UC處理後始終高於控制組。在細胞凋亡方面，UC在72小時顯著提升HCT116細胞凋亡數量至30%，BAX、c-caspase 9、c-caspase 3、c-PARP蛋白表現量在UC處理48小時後顯著升高。最後，自噬抑制劑 (3-MA、CQ) 的加入提高了UC處理24小時凋亡細胞的數量，以及凋亡蛋白c-caspase 3與c-PARP的表現量。綜合以上結果表明，UC誘導HCT116腸癌細胞自噬與凋亡，粒線體功能的損傷可能是其機制之一。並建議UC可以與自噬抑制劑共同使用以利於UC發揮更好的抗癌效果。期望未來UC能夠作為臨床上的輔助治療劑，為抑制大腸直腸癌的發展提供新的見解。 | zh_TW |
| dc.description.abstract | Colorectal cancer (CRC) is widely recognized as one of the most common malignancies with a high incidence and mortality. The intake of processed foods is the main exogenous factor inducing CRC. More and more evidence suggesting that natural compounds present in fruits and vegetables can impede the progression of CRC. Urolithins are the metabolites of ellagic acid by gut microbiota, which have been reported to promote mitophagy in muscle and neurodegenerative diseases. Urolithins also shows excellent anticancer effect, however, there is limited research investigating the impact of urolithins on colorectal cancer cell apoptosis from the perspective of autophagy. Therefore, the aim of this study was to investigate the effects of urolithin C (UC) on autophagy and apoptosis of colorectal cancer cell. Firstly, the best anti-cancer compound and the most sensitive cell line were selected by cell viability assay. The cell cycle and mitochondria function were analyzed by flow cytometry. Moreover, the oxygen consumption of mitochondria was measured by seahorse analyzer. Mitophagy and related gene expression was detected by fluorescence microscopy and RT-qPCR. Finally, the phenotype and protein level of autophagy and apoptosis were determined by time course with urolithin treatment. The results showed that urolithin C exhibited the best inhibitory effect on cell viability of HCT116 cells, and significantly reduce cell number in G0/G1 phase and cause S phase arrest. Mitochondrial respiratory function, mitochondrial membrane potential and mitochondrial mass significantly decreased after UC treatment for 12 hours. Staining of mitochondria and lysosome elucidated that mitophagy was activated in colon cancer cells. RT-qPCR results showed that mitophagy genes PARK and BINP3 were upregulated by UC treatment. In terms of autophagy, UC increased intracellular acidic vesicular organelles levels at 12 and 24 hours, the protein level of LC3II increased significantly and p62 decreased at 24 hours. The protein level of p-AMPK and p53 were consistently higher than those of control group after UC treatment. In terms of apoptosis, UC significantly increased the apoptotic cells to 30% after 72 hours of treatment while the protein levels of BAX, c-caspase 9, c-caspase 3 and c-PARP were significantly increased at 48 hours. Finally, autophagy inhibitors (3-MA, CQ) and UC co-treatment increased apoptotic cells and the protein level of c-caspase 3 and c-PARP at 24 hours. In summary, UC induced autophagy and apoptosis in HCT116 colorectal cancer cells, and mitochondrial dysfunction may be one of the underlying mechanisms. It is suggested to co-treatment urolithin C with autophagy inhibitors to enhance its anticancer effects. Hopefully UC may inhibit colorectal cancer as an adjuvant therapeutic agent. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-10-03T17:13:14Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-10-03T17:13:14Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 謝誌 I
摘要 IV Abstract VI 目錄 VIII 附圖目錄 XI 附表目錄 XII 圖目錄 XIII 縮寫表 XIV 緒論 1 第一章、文獻回顧 2 1.1 大腸癌簡介 2 1.1.1 流行病學數據 2 1.1.2 大腸之生理構造及功能 3 1.1.3 大腸癌之形成、發展及分期 4 1.1.4 大腸癌相關之風險因子 7 1.1.5 大腸癌之預防及治療方法 8 1.2 細胞自噬 (Autophagy) 10 1.2.1 細胞自噬的誘導因素與特徵 10 1.2.2 細胞自噬的分類與分子機制 10 1.2.3 選擇性自噬—粒線體自噬 (Mitophagy) 12 1.3 細胞凋亡 (Apoptosis) 14 1.3.1 細胞凋亡的誘導因素與特徵 14 1.3.2 外源性細胞凋亡 (Extrinsic apoptosis pathway) 15 1.3.3 內源性細胞凋亡 (Intrinsic apoptosis pathway) 16 1.4 癌症中細胞自噬與凋亡之間的串擾 17 1.4.1 細胞自噬與凋亡的主要調控因子 17 1.4.2 細胞自噬與凋亡的相互作用 19 1.5 尿石素簡介 21 1.5.1 尿石素的來源、代謝及組織分佈 21 1.5.2 尿石素的生物活性及安全性 23 第二章、研究目的與實驗架構 25 2.1研究目的 25 2.2實驗架構 25 第三章、實驗材料與方法 27 3.3實驗材料 27 3.3.1 樣品來源及製備 27 3.3.2 實驗儀器 27 3.3.3 藥品試劑 28 3.3.4 商業化試劑盒 29 3.3.5 抗體 30 3.3.6 RT-qPCR引子 31 3.4 實驗方法 32 3.4.1細胞培養 32 3.4.2細胞存活率實驗 34 3.4.3流式細胞儀 (FLOW Cytometry) 分析 35 3.4.4粒線體壓力測試 38 3.4.5螢光顯微鏡分析 39 3.4.6 RNA萃取及純化 40 3.4.7即時定量聚合酶鏈式反應 (RT-qPCR) 42 3.4.8蛋白質萃取與定量 44 3.4.9西方墨點法 46 3.5 統計分析 49 第四章、結果與討論 50 4.1 尿石素對腸癌細胞存活率及細胞週期之影響 50 4.1.1三種尿石素對不同腸癌細胞之抗癌效果 50 4.1.2 Urolithin C處理不同時長對HCT116細胞生長之影響 53 4.1.3 Urolithin C對腸癌細胞HCT116細胞週期之影響 53 4.2 Urolithin C對人類腸癌細胞HCT116粒線體功能之影響 55 4.2.1 Urolithin C對人類腸癌細胞HCT116粒線體壓力之影響 55 4.2.2 Urolithin C降低人類腸癌細胞HCT116粒線體膜電位與粒線體質量 57 4.2.3 Urolithin C誘導人類腸癌細胞HCT116發生粒腺體自噬 58 4.3 Urolithin C誘導人類腸癌細胞HCT116早期細胞自噬與晚期細胞凋亡 59 4.3.1 Urolithin C誘導人類腸癌細胞HCT116細胞自噬 59 4.3.2 Urolithin C誘導人類腸癌細胞HCT116細胞凋亡 60 4.3.3 Urolithin C對人類腸癌細胞HCT116細胞自噬與凋亡蛋白隨時間變化的影響 61 4.4Urolithin C與自噬抑制劑共同作用對人類腸癌細胞HCT116細胞凋亡的影響 63 第五章、圖表 65 第六章、結論 80 第七章、參考文獻 82 | - |
| dc.language.iso | zh_TW | - |
| dc.title | Urolithin C藉由誘導HCT116人類結腸癌細胞中粒線體功能障礙與粒線體自噬有效調節細胞自噬及凋亡 | zh_TW |
| dc.title | Urolithin C potently modulates autophagy and apoptosis via inducing mitochondria dysfunction and mitophagy in HCT116 human colorectal cancer cells | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 何元順;黃步敏;郭靜娟;張嘉哲 | zh_TW |
| dc.contributor.oralexamcommittee | Yuan-Soon Ho;Bu-Miin Huang;Ching-Chuan Kuo;Chia-Che Chang | en |
| dc.subject.keyword | 大腸直腸癌,尿石素,粒線體,自噬,凋亡, | zh_TW |
| dc.subject.keyword | colorectal cancer,urolithins,mitochondria,autophagy,apoptosis, | en |
| dc.relation.page | 96 | - |
| dc.identifier.doi | 10.6342/NTU202302475 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-08-04 | - |
| dc.contributor.author-college | 生物資源暨農學院 | - |
| dc.contributor.author-dept | 食品科技研究所 | - |
| dc.date.embargo-lift | 2028-07-31 | - |
| 顯示於系所單位： | 食品科技研究所 | |
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