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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/83753完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳玉怜(Yuh-Lien Chen) | |
| dc.contributor.author | Szu-Ju Fu | en |
| dc.contributor.author | 傅斯? | zh_TW |
| dc.date.accessioned | 2023-03-19T21:16:43Z | - |
| dc.date.copyright | 2022-10-03 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-08-08 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/83753 | - |
| dc.description.abstract | 高脂飲食是誘發心血管疾病的風險因子之一。根據過去的研究指出，空氣中的細懸浮微粒 (particulate matter，PM) 進入呼吸道後，與肺泡接觸進入血液循環，進而導致心血管疾病的產生。目前對於PM在高脂飲食下對心臟功能及粒線體受損所造成的影響仍不清楚。本研究動物模式利用高脂飲食 (high-fat diet，HFD) 餵食小鼠，並利用氣管內注射PM 10 mg/kg模擬暴露空氣污染之環境。結果發現小鼠在共同處理HFD和PM後，在心臟收縮及舒張功能皆有受損的情形。細胞凋亡相關因子PUMA (p53 upregulated modulator of apoptosis) 及纖維化相關蛋白Fibronectin 表現量皆會因HFD或PM單獨處理而上升；而共同處理HFD及PM時，PUMA及Fibronectin表現量則更顯著增加。此外，我們利用大鼠心肌母細胞 (H9c2) 作為體外細胞模式，並以50 μM 棕梠酸 (palmitic acid，PA) 與10 μg/mL PM模擬高脂飲食與空氣汙染之環境。經由TUNEL及Annexin V/PI方法，發現心肌細胞處理PA及PM會加劇細胞凋亡。根據西方墨點法結果，發現細胞在PA+PM共同處理下，PUMA、CASPASE3顯著上升而BCL2 (B-cell lymphoma 2) 顯著下降。接著，透過MitoSOX Red染色，發現PA及PM處理後會顯著增加粒線體活性氧化物 (mitochondrial reactive oxygen species) 產生。此外，相較於個別處理組別，PA+PM處理後，觀察JC-1染色發現粒線體膜電位下降，且ATP產量減少。同時，在Mitotracker染色發現粒線體在經由PA+PM處理後粒線體長度明顯變短，表示分裂增加。經西方墨點法的實驗結果顯示，粒線體分裂相關蛋白：p-DRP1 (phospho-dynamin-related protein 1) 和FIS1 (mitochondrial fission 1 protein) 的表現與個別處理PA和PM組別相比，顯著上升。而粒線體自噬相關蛋白：p62、LC3B (microtubuleassociated protein 1 light chain 3 Beta)、BNIP3 (BCL2 interacting protein 3) 在PA+PM共同處理下則有表現量顯著增加。在纖維化相關蛋白Fibronectin 和ETS-1 (ETS proto-oncogene 1) 表現量均顯著增加。根據結果得知，高脂與PM的環境下會導致粒線體受損加重，進而使心肌產生凋亡及纖維化。此外，利用粒線體分裂抑制劑Mdivi-1及粒線體氧化壓力抑制劑MitoQ處理，結果發現可顯著減少PA+PM共同處理下導致的細胞凋亡、纖維化。進一步使用氧化壓力抑制劑褪黑激素 (melatonin) 進行處理，發現其可有效地改善PA+PM所造成的粒線體受損，氧化壓力下降和粒線體膜電位增加，而粒線體分裂和自噬相關蛋白p-DRP1、p62、LC3B及BNIP3表現量均會減少，凋亡因子PUMA及纖維化相關蛋白Fibronectin 和ETS-1表現也會下降。由上述結果可以證明，在共同處理高脂及細懸浮微粒下，細胞的氧化壓力、細線體分裂增加並使粒線體功能下降，並且加劇細胞凋亡因子和纖維化蛋白的表現，而褪黑激素則可顯著降低PA+PM所誘發的細胞凋亡及纖維化。未來仍需要更深入探討褪黑激素在心血管疾病中提供保護效用之機制，希望其可成為以後治療高脂及空氣汙染引起心血管疾病用藥的選擇。 | zh_TW |
| dc.description.abstract | High-fat diet (HFD) is a risk factor for cardiovascular disease. According to previous studies, particulate matter (PM) in the air enters the respiratory tract, contacts with the alveoli and enters the blood circulation, leading to the onset of cardiovascular disease. Currently, the affect of PM on cardiac function and mitochondrial damage under a high-fat diet is still unclear. In this study, the experimental animal model was established in mice fed with high-fat chow diet and intratracheal injection of PM 10 mg/kg to simulate the environment exposed to HFD and air pollution. These results showed that both HFD and PM deteriorated the systolic and diastolic cardiac function in mice. Apoptosis-related factor PUMA (p53 upregulated modulator of apoptosis) and fibrosis-related protein Fibronectin were both increased in mice treated either with HFD or PM alone, while in mice co-treated with HFD and PM, the expression of PUMA and Fibronectin were significantly increased. In addition, we used rat cardiomyocytes (H9c2) as an in vitro cell model, using 50 μM palmitic acid (PA) and 10 μg/ml PM to simulate the environment of high-fat diet and air pollution. Apoptosis aggravated in cardiomyocytes treated with PA and PM using TUNEL and Annexin V/PI assays. Western blot results showed that PUMA and CASPASE3 were significantly increased and BCL2 (B-cell lympha 2) was significantly decreased under the combined treatment of PA+PM. Combined exposure to PA and PM increased the production of mitochondrial reactive oxygen species (ROS) by MitoSOX Red staining. Moreover, PA+PM decreased the mitochondrial membrane potential by JC-1 staining and significantly diminished the ATP production compared with the singal treatment group. In addition, PA+PM treatment significantly shortened the mitochondrial length using Mitotracker staining, indicating the mitochondrial fission. The expression of mitochondrial fission-related proteins, p-DRP1 (phospho-dynamin-related protein 1) and FIS1 (mitochondrial fission 1 protein) were significantly increased compared with the PA or PM treated groups alone. Moreover, mitophagy-related proteins, p62, LC3B (microtubule-associated protein 1 light chain 3 beta) and BNIP3 (BCL2 interacting protein 3) were significantly increased under PA+PM co-treatment. Also, the expression of fibrosis-related proteins fibronectin and ETS-1 (ETS proto oncogene 1) were significantly increased in H9c2 cells treated with PA and PM. According to these results, combined exposure to PA and PM deteriorated mitochondrial function and led to cardiac apoptosis and fibrosis. In addition, mitochondrial division inhibitor (Mdivi-1) and mitochondrial ROS inhibitor (MitoQ) significantly reduced PA+PM-induced apoptosis and fibrosis. Finally, melatonin, a ROS scavenger was used in this study. Melatonin effectively improved the mitochondrial dysfunction induced by PA+PM, decreased the mitochondrial ROS and alleviated the collapse of mitochondrial membrane potential. In addition, melatonin decreased the PA+PM-induced upregulation of mitochondrial fission and mitophagy-related proteins p-DRP1, p62, LC3B and BNIP3, and apoptosis-related factors PUMA, CASPASE3 and fibrosis-related proteins Fibronectin and ETS-1. In summary, co-exposure to HFD (PA) and PM increased oxidative stress, mitochondrial fission and mitophagy, decreased mitochondrial function, and further aggravated cardiac apoptosis and fibrosis. Melatonin significantly reduced the cardiac apoptosis and fibrosis induced by HFD+PM or PA+PM. In the future, the mechanism of melatonin underlying the protective effects against HFD and PM-induced cardiovascular diseases warrants further investigation, and melatonin may become a therapeutic intervention against high-fat and air pollution-induced cardiovascular diseases. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T21:16:43Z (GMT). No. of bitstreams: 1 U0001-0808202209412800.pdf: 7428814 bytes, checksum: ace6cb150f747fc177aefbb79b2d9762 (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 口委審定書 II 致謝 III 摘要 IV Abstract VI 目錄 VIII 壹、緒論 1 心臟的構造和功能 1 心血管疾病 1 I懸浮微粒與心血管疾病的相關性 1 II高脂飲食與心血管疾病的相關性 2 懸浮微粒和高脂飲食與活性氧化物相關性 3 粒線體 4 I粒線體動態平衡(Mitochondrial dynamics) 4 II細胞自噬作用 6 III粒線體自噬作用 8 處理高脂或PM對心肌凋亡的影響 10 處理高脂或PM對心肌纖維化反應的影響 11 褪黑激素的治療成效 12 研究動機 13 貳、實驗材料 14 一、儀器 14 二、材料與試劑 15 三、溶液配方 18 參、實驗方法 20 製備PM2.5 20 動物模式 (Animal model) 21 組織石蠟包埋 (Paraffin embedding) 22 蘇木精-伊紅染色 (hematoxylin-eosin staining) 22 天狼星紅染色 (Sirius Red Staining) 22 Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay 23 免疫組織化學染色 (Immunohistochemistry) 24 組織冷凍包埋 25 使用Dihydroethidium staining (DHE) 和MitoSOX Red偵測活性氧 25 心臟功能分析 25 製備Palmitic acid (PA) 26 細胞培養及處理 (Cell culture and treatment) 26 細胞活性分析法 (Cell viability assay) 28 細胞凋亡偵測技術 (Annexin V/PI) 28 細胞免疫螢光染色 (Immunofluorescence staining) 29 西方墨點法 (Western blot) 29 粒線體活性氧化物測定 (Mitochondrial ROS level assay) 32 粒線體膜電位測定 (Measurement of mitochondrial membrane potential ΔΨm) 33 粒線體即時影像分析 (time-lapse imaging) 33 細胞ATP測定 (ATP assay) 34 ?啶橙螢光染色 (Acridine orange staining，AO staining) 34 數據統計分析 (Statistical analysis) 34 肆、結果 35 小鼠在共同處理HFD+PM加重心臟功能的失常 35 小鼠在共同處理HFD+PM加劇心臟凋亡反應 35 小鼠在共同處理HFD+PM後加劇心肌纖維化反應 35 小鼠在共同處理HFD+PM使ROS大量產生並加劇粒線體分裂和自噬 36 褪黑激素可增進小鼠心臟功能 36 褪黑激素可減輕小鼠心臟凋亡和纖維化反應 37 褪黑激素可以減少粒線體分裂和粒線體自噬反應 38 共同處理PA和PM可加重心肌細胞的凋亡和纖維化反應 38 心肌細胞經褪黑激素治療可減輕凋亡和纖維化反應 39 共同處理PA和PM會使ROS大量產生，褪黑激素治療可降低ROS 40 粒線體氧化壓力抑制劑減輕共同處理PA和PM產生的凋亡和纖維化反應 41 共同處理PA和PM顯著降低粒線體膜電位（Δψm），並加劇粒線體分裂 42 粒線體氧化壓力抑制劑可回復粒線體膜電位（Δψm），並減少粒線體分裂 43 粒線體分裂抑制劑可回復粒線體膜電位（Δψm），並減少粒線體分裂 43 粒線體分裂抑制劑減輕共通處理PA和PM產生的凋亡和纖維化反應 44 經褪黑激素治療可回復粒線體膜電位（Δψm），並減少粒線體分裂 45 共同處理PA和PM會大量產生粒線體自噬反應 45 細胞自噬抑制劑減緩細胞凋亡和纖維化反應 46 褪黑激素和粒線體分裂抑制劑減輕粒線體自噬反應 47 伍、討論與結論 48 陸、參考文獻 54 柒、圖 64 圖一、共同處理HFD+PM加重心臟功能的失常 65 圖二、共同處理HFD+PM加劇心臟凋亡反應 67 圖三、共同處理HFD+PM加劇心臟纖維化反應 69 圖四、共同處理HFD+PM使ROS大量產生並加劇粒線體分裂和自噬 71 圖五、褪黑激素可增進小鼠心臟功能 73 圖六、褪黑激素可減輕小鼠心臟凋亡和纖維化反應 75 圖七、褪黑激素可以減少粒線體分裂和粒線體自噬反應 77 圖八、共同處理PA和PM可加重心肌細胞的凋亡和纖維化反應 80 圖九、心肌細胞經褪黑激素治療可減輕凋亡和纖維化反應 83 圖十、共同處理PA和PM會使ROS大量產生，經褪黑激素治療可降低ROS 85 圖十一、粒線體氧化壓力抑制劑減輕共同處理PA和PM產生的凋亡和纖維化反應 88 圖十二、共同處理PA和PM顯著降低粒線體膜電位（Δψm），並加劇粒線體分裂 91 圖十三、粒線體氧化壓力抑制劑可回復粒線體膜電位（Δψm），並減少粒線體分裂 93 圖十四、粒線體分裂抑制劑可回復粒線體膜電位（Δψm），並減少粒線體分裂 95 圖十五、粒線體分裂抑制劑減輕共通處理PA和PM產生的凋亡和纖維化反應 98 圖十六、經褪黑激素治療可回復粒線體膜電位（Δψm），並減少粒線體分裂 100 圖十七、共同處理PA和PM會大量產生粒線體自噬反應 103 圖十八、細胞自噬抑制劑減緩細胞凋亡和纖維化反應 106 圖十九、共同處理PA和PM會大量產生粒線體自噬反應 109 | |
| dc.language.iso | zh-TW | |
| dc.subject | 褪黑激素 | zh_TW |
| dc.subject | 粒線體氧化壓力 | zh_TW |
| dc.subject | 粒線體分裂 | zh_TW |
| dc.subject | 粒線體自噬 | zh_TW |
| dc.subject | 棕梠酸 | zh_TW |
| dc.subject | 懸浮微粒 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | 纖維化 | zh_TW |
| dc.subject | melatonin | en |
| dc.subject | fibrosis | en |
| dc.subject | apoptosis | en |
| dc.subject | PM | en |
| dc.subject | PA | en |
| dc.subject | mitochondrial fission | en |
| dc.subject | mitophagy | en |
| dc.subject | mitochondrial ROS | en |
| dc.title | 探討共同處理懸浮微粒和高脂飲食所誘發之心肌受損及其相關機轉 | zh_TW |
| dc.title | To study the effects of combined exposure to particulate matter 2.5 and high fat diet-induced cardiac damage and the related mechanisms | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 莫凡毅(Fan-E Mo),吳佳慶(Chia-Ching Wu),江美治(Meei-Jyh Jiang),王懷詩(Hwai-Shi Wang) | |
| dc.subject.keyword | 棕梠酸,懸浮微粒,細胞凋亡,纖維化,粒線體氧化壓力,粒線體分裂,粒線體自噬,褪黑激素, | zh_TW |
| dc.subject.keyword | PA,PM,apoptosis,fibrosis,mitochondrial ROS,mitochondrial fission,mitophagy,melatonin, | en |
| dc.relation.page | 109 | |
| dc.identifier.doi | 10.6342/NTU202202132 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2022-08-08 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 解剖學暨細胞生物學科所 | |
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