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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳玉怜 | zh_TW |
| dc.contributor.advisor | Yuh-Lien Chen | en |
| dc.contributor.author | 虞景筌 | zh_TW |
| dc.contributor.author | Chiang-Chuan Yu | en |
| dc.date.accessioned | 2023-09-26T16:08:29Z | - |
| dc.date.available | 2023-11-10 | - |
| dc.date.copyright | 2023-09-26 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-08 | - |
| dc.identifier.citation | Afshin, A., M. H. Forouzanfar, M. B. Reitsma, P. Sur, K. Estep et al., 2017 Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med 377: 13-27.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90295 | - |
| dc.description.abstract | 隨著人類生活的改變，肥胖人口日漸增加，空氣汙染也未被有效控制，而不論是高脂飲食還是空氣汙染都是導致心血管疾病 (Cardiovascular disease，CVD) 的危險因素。先前的研究發現，粒線體損傷與心血管疾病有著重要的關聯。然而，目前尚不清楚空氣懸浮微粒 (particulate matter，PM2.5，PM) 和棕櫚酸 (palmitic aicd，PA) 共同處理，是否會透過粒線體損傷增加內皮細胞的發炎情形。本實驗中，使用10 μg/mL PM 和 150 μM PA共同處理HUVECs 24小時作為體外模型，並加入褪黑激素 (Melatonin，50 μM)，一種抗氧化劑，來觀察對內皮細胞發炎的影響。首先，使用MTT測定，PA和PM共同處理降低了HUVECs的細胞存活率。透過western blot 、免疫染色及單核球細胞黏附實驗，觀察到PM+PA 處理後，ICAM-1 (Intercellular adhesion molecule-1) 的表達增加，則證實了細胞的發炎反應。然而，褪黑激素治療明顯減少了這些變化。此外，使用MitoSOX Red染色觀察發現PM+PA的處理，顯著增加HUVECs中的粒線體活性氧物質 (reactive oxygen species，ROS) 的產生，而褪黑激素也抑制了這種變化。利用JC-1染色，我們觀察到PM+PA導致粒線體膜電位改變，並且透過Mito-Tracker染色，PM+PA處理組的粒線體分裂情形增加，同時Western blot也觀察到粒線體分裂蛋白Drp1 (Dynamin-related protein 1) 表達上升。然而，加入褪黑激素可保護內皮細胞避免粒線體損傷和分裂。吖啶橙 (acridine orange)染色和Western blot顯示，褪黑激素降低了PM和PA處理造成的自噬相關蛋白 p62 和 LC3B (Microtubule-associated proteins 1A/1B light chain 3B) 以及粒線體自噬相關蛋白PINK1 (PTEN-induced kinase 1) 和Parkin的表達，減少自噬作用的發生。除此之外，過去研究指出miR-221和miR-222可以透過與ICAM-1 3'UTR結合抑制ICAM-1的轉譯作用，因此我們也觀察到，褪黑激素會透過增加miR-221和miR-222，來抑制ICAM-1表現。在動物實驗方面，透過高脂飲食 (high-fat diet，HFD) 和氣管注射 (intratracheal injection) PM及管餵 (oral gavage) 褪黑激素，觀察到褪黑激素降低活性氧物質、減少粒線體分裂蛋白Drp1、減少自噬相關蛋白p62、LC3B和Pink1，以及增加miR-221和miR-222含量，並減輕內皮細胞的發炎反應。綜上所述，PM和高脂環境的共同存在下，會誘導內皮細胞的粒線體活性氧物質產生、使粒線體分裂、損傷和自噬作用並造成血管內皮細胞的發炎反應，而褪黑激素可以作為一種抗氧化劑，透過清除粒線體的活性氧物質、減輕粒線體分裂和損傷、減少粒線體自噬，也可以透過增加miR-221和miR-222減輕內皮的發炎反應。期待持續的研究，實現褪黑激素成為一種抗發炎保健食品，透過保護心血管以維護國民整體健康，迎接美好生活。 | zh_TW |
| dc.description.abstract | Due to the shifts in lifestyles, the number of obese individuals continues to rise, and the effective control of air pollution remains a challenge. Both a high-fat diet and air pollution are risk factors for cardiovascular diseases (CVDs). Previous studies have demonstrated an association between mitochondrial damage and CVDs. However, it remains unclear whether the combined treatment of particulate matter (PM2.5，PM) and palmitic acid (PA) leads to an increase endothelial cell inflammation through mitochondrial damage. In this study, we used human umbilical vein endothelial cells (HUVECs) as an in vitro model and treated them with 10 μg/mL PM and 150 μM PA for 24 hours. To observe the effects on endothelial cell inflammation, we added melatonin (50 μM). The result of the MTT assay revealed that PM and PA combined treatment decreased the cell viability of HUVECs. The result of western blot analysis demonstrated an increase in ICAM-1 expression after PM+PA treatment. Monocyte adhesion experiments and immunostaining results supported the inflammatory response of the PM+PA-treated cells. On the other hand, treatment with melatonin significantly attenuated these changes. Furthermore, the results of MitoSOX Red staining indicated a substantial increase in the production of mitochondrial reactive oxygen species (ROS) in PM+PA-treated HUVECs, which was mitigated by melatonin administration. JC-1 staining results revealed a decrease in mitochondrial membrane potential caused by PM+PA treatment. MitoTracker staining results suggested an increase in mitochondrial fission in the PM+PA-treated group, while western blotting results revealed elevated expression levels of the mitochondrial fission protein Drp1. Melatonin, nevertheless, preserved mitochondrial integrity and prevented mitochondrial fission in endothelial cells. Additionally, melatonin decreased the levels of autophagy-related proteins p62 and LC3B, as well as mitophagy-related proteins PINK1 and Parkin, indicating a reduction in mitophagy. Moreover, previous research has shown that miR-221 and miR-222 can inhibit ICAM-1 translation by binding to the 3'UTR of ICAM-1. In our study, we observed that melatonin increased the expression levels of miR-221 and miR-222, resulting in reduced ICAM-1 expression levels. In animal experiments, we used a high-fat diet, intratracheal injection of PM, and oral gavage of melatonin. It was discovered that melatonin decreased ROS, mitochondrial fission protein Drp1, mitophagy-related proteins p62, LC3B, and Pink1, increased miR-221 and miR-222 levels, and decreased the inflammatory response of endothelial cells. Furthermore, melatonin increased the levels of miR-221 and miR-222, thus reducing the inflammatory response of endothelial cells. In conclusion, combined exposure to PM and a high-fat environment induced the production of ROS in the mitochondria of endothelial cells, leading to mitochondrial fission, damage, and mitophagy, ultimately resulting in the inflammatory response in vascular endothelial cells. Melatonin fulfills its potential as an antioxidant by scavenging mitochondrial reactive oxygen species, reducing mitochondrial fission and damage, mitigating mitophagy, and decreasing endothelial inflammation through upregulation of miR-221 and miR-222. We anticipate further research to establish melatonin as an anti-inflammatory food supplement, safeguarding the cardiovascular system and promoting overall population health for a better future. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-26T16:08:29Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-09-26T16:08:29Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口委審定書 I
致謝 II 摘要 III Abstract V 目錄 VII 壹、緒論 1 一、 懸浮微粒與心血管疾病的關係 1 二、 高血脂與心血管疾病的關係 1 三、 內皮細胞的發炎反應與心血管疾病的關係 2 四、 懸浮微粒和高脂飲食與粒線體活性氧物質的關係 3 五、 粒線體的功能及動態平衡 5 六、 細胞的自噬作用及粒線體自噬 6 七、 Micro RNA 221/222與內皮發炎的相關性 10 八、 褪黑激素的抗氧化特性 12 九、 研究動機與假說 13 貳、實驗材料 15 一、 儀器設備 15 二、材料與試劑 16 三、溶液配方 20 參、實驗方法 22 一、 PM的製備 (Preparation of PM) 22 二、 PA的製備 (Preparation of palmitic acid) 23 三、 Mel的製備 (Preparation of Melatonin) 23 四、 分離人類臍靜脈內皮細胞 (HUVECs isolation) 23 五、 細胞培養及處理 (Cell culture and treatment) 24 六、 細胞存活性分析法 (Cell viability assay) 26 七、 細胞免疫螢光染色 (Immunofluorescence staining in cells) 26 八、 單核球黏附試驗 (Monocyte adhesion assay) 27 九、 oil red o staining 27 十、 西方墨點法 (Western blot) 28 十一、 粒線體活性氧物質測定 (Mitochondrial ROS level assay) 30 十二、 粒線體膜電位測定 (Measurement of mitochondrial membrane potential) 31 十三、 ATP測定 (ATP assay) 31 十四、 粒線體長度分析 (analysis of mitochondrial length) 32 十五、 吖啶橙染色 (acridine orange staining，AO stain) 32 十六、 RNA萃取與逆轉錄聚合酶連鎖反應 (Reverse transcription quantitative polymerase chain reaction，RT- qPCR) 32 十七、 miR-221/222 mimic轉染 (Transfection of miR-221/222 mimics) 33 十八、 動物模式 (Animal model) 33 十九、 石蠟包埋 (Paraffin embedding) 34 二十、 免疫組織螢光染色 (Immunofluorescence staining in tissues) 35 二十一、 冷凍切片 (Frozen section) 36 二十二、 數據統計分析 (Statistical analysis) 36 肆、結果 37 PM、PA以及Mel處理對HUVECs的細胞存活率及發炎的影響 37 Mel降低PM和PA共同處理HUVECs所造成之粒線體ROS 38 PM和PA共同處理HUVECs造成ROS依賴型粒線體受損，而Mel可以減緩此傷害 40 PM和PA共同處理HUVECs造成粒線體自噬，而Mel可以減緩此作用 43 miR-221、miR-222在PM、HFD以及Mel處理的HUVECs中的作用 44 PM、HFD以及Mel處理對小鼠胸主動脈內皮細胞的影響 46 伍、討論與結論 49 陸、參考文獻 60 柒、圖 75 圖一、PM、PA以及Mel處理對HUVECs的細胞存活率及發炎的影響 77 圖二、Mel降低PM和PA共同處理HUVECs所造成之粒線體ROS增加 83 圖三、PM和PA共同處理HUVECs造成ROS依賴型粒線體受損，而Mel可以減緩此傷害 91 圖四、PM和PA共同處理HUVECs造成粒線體自噬，而Mel可以減緩此作用 97 圖五、miR-221、miR-222在PM、HFD以及Mel處理的HUVECs中的作用 102 圖六、PM、HFD以及Mel處理對小鼠胸主動脈內皮細胞的影響 109 | - |
| dc.language.iso | zh_TW | - |
| dc.title | 探討粒線體功能在懸浮微粒及高脂飲食誘導內皮細胞發炎時扮演的角色 | zh_TW |
| dc.title | To study the role of mitochondria in particulate matter 2.5 and high-fat diet induced endothelial inflammation. | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 莫凡毅;許美鈴;吳佳慶;王懷詩 | zh_TW |
| dc.contributor.oralexamcommittee | Fan-E Mo;Meei-Ling Sheu;Chia-Ching Wu;Hwai-Shi Wang | en |
| dc.subject.keyword | 懸浮微粒,棕櫚酸,高脂飲食,褪黑激素,粒線體活性氧物質,粒線體分裂,粒線體自噬,發炎反應, | zh_TW |
| dc.subject.keyword | particulate matter,palmitic acid,high fat diet,melatonin,ROS,mitochondrial fission,mitophagy,inflammation, | en |
| dc.relation.page | 120 | - |
| dc.identifier.doi | 10.6342/NTU202303628 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2023-08-09 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | - |
| dc.date.embargo-lift | 2028-08-08 | - |
| 顯示於系所單位： | 解剖學暨細胞生物學科所 | |
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