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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72882完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 潘敏雄(Min-Hsiung Pan) | |
| dc.contributor.author | Ya-Chun Chou | en |
| dc.contributor.author | 周雅淳 | zh_TW |
| dc.date.accessioned | 2021-06-17T07:09:06Z | - |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-02-26 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72882 | - |
| dc.description.abstract | 柑橘果皮以及未成熟之柑橘幼果或稱生理性落果皆被視為農產廢棄物，這些廢棄的果實和果皮中含有相當豐富的次級代謝物如多酚類、黃酮類、生物鹼和揮發性油等活性成分。在細胞和動物實驗已有多篇文獻指出柑橘屬中的黃酮類化合物 (flavonoids) 具有抗發炎、抗氧化、預防心血管疾病甚至是抑制腫瘤生長等功效，因此本論文第一部分的研究將以動物模式探討柑橘幼果萃取物 (immature Citrus reticulata extract; ICRE) 抑制脂肪形成的功效和分子機制。由高效液相層析儀 (HPLC) 分析之結果顯示柑橘幼果的熱水萃取物中含有辛弗林 (p-synephrine)、柚皮苷 (narirutin)、橙皮苷 (hesperidin)、川陳皮素 (nobiletin) 和橘皮素 (tangeretin) 等，含量分別是16.0 ± 1.08、4.52 ± 0.31、9.14 ± 0.32、2.54 ± 0.07及1.67 ± 0.05 mg/g。動物實驗結果顯示餵食1%的柑橘幼果萃取物可顯著減少小鼠體重增加與內臟脂肪的重量，並且降低禁食血糖和血液中的三酸甘油酯與總膽固醇 (P < 0.05)。除此之外，由組織切片的結果可知餵食柑橘幼果萃取物的組別其肝臟內的脂肪空泡數量和大小明顯減少 (P < 0.05)。除此之外，我們也觀察到餵食柑橘幼果萃取物的小鼠在低溫的環境下具有較佳的耐寒性，且進一步研究發現米色脂肪組織中的去偶合蛋白 (uncoupling protein 1, UCP1) 和產熱基因 (thermogenic gene) 表現量皆增加，表示柑橘幼果萃取物具有提升適應性生熱作用 (adaptive thermogenesis) 的潛力。綜合前述，在高脂飲食誘導下柑橘幼果萃取物可藉由促進脂肪組織的棕色化 (browning) 來達到預防肥胖與減少脂肪堆積的效果。 本論文第二部分的研究聚焦在柑橘果皮中之一群結構特殊的黃酮類物質稱為多甲氧基黄酮類 (polymethoxyflavones, PMFs)，其中川陳皮素 (nobiletin) 和橘皮素 (tangeretin) 的比例佔大多數，近期的研究發現柑橘果皮中的5-去甲基橘皮素 (5-demethyltangeretin, 5-DTAN) 具有較佳的抑制腸癌細胞生長之活性，但因其溶解度極差，影響5-DTAN在生物體中的吸收與利用，故希望能藉由開發新型的載體來增加5-DTAN的吸收，因此我們導入自微乳化載藥系統 (self-microemulsifying drug delivery system, SMEDDS) 的設計概念，找出對5-DTAN溶解度較高的油脂與界面活性劑，利用模擬乳化試驗建立擬三相圖篩選出最理想的配方，其組成為ethyl oleate / d-limonene (10% / 5%)、Cremophor® EL (59.5%) 和PEG 400 (25.5%)，並以光散射儀測定載藥後之平均乳化粒徑約為97.1 ± 6.50 nm，最高5-DTAN承載量為3.01 ± 0.38 mg/mL，利用穿透式電子顯微鏡 (TEM) 觀察型態發現乳化顆粒大致呈圓球狀且分散均勻，僅部分有輕微聚集的現象。此外在小鼠體內試驗中，從血中濃度結果可證實經自微乳化載藥系統包載之5-DTAN其口服吸收程度明顯高於5-DTAN的水懸浮 (water suspension) 劑型，並且我們使用串聯式液相層析－固相萃取－核磁共振儀 (LC-SPE-NMR) 首次鑑定出5-DTAN的主要代謝物為TAN-O-glucuronide。不僅如此，在裸鼠異種移植模式 (xenograft model) 中，口服自微乳化載藥系統包載之5-DTAN可有效抑制腸癌腫瘤的生長。由此可知，自微乳化載藥系統確實可改善5-DTAN的生物可利用率 (bioavailability)，並提升其癌症預防的特性。綜合上述結果，我們認為柑橘幼果和柑橘果皮相當具有潛力可被開發為保健食品，藉此方式以增加農產廢棄物的經濟價值。 | zh_TW |
| dc.description.abstract | Citrus peels and natural drop of immature citrus fruits are considered as agricultural waste. These agricultural citrus waste contain various secondary metabolites, such as polyphenols, flavonoids, alkaloids, and limonoids. Numerous studies have shown that citrus flavonoids exhibit many biological activities, such as anti-inflammatory, anti-oxidant, anti-atherogenic and even anticancer activity. In the first part of this dissertation, we investigated the bioactive compounds in these immature citrus fruits and evaluated the molecular target on anti-obesity in mice. Our results showed that the main phytochemical components of immature Citrus reticulata in water extraction analyzed by HPLC are synephrine, narirutin, hesperidin, nobiletin, and tangeretin (16.0 ± 1.08, 4.52 ± 0.31, 9.14 ± 0.32, 2.54 ± 0.07, 1.67 ± 0.05 mg/g, respectively). Oral administration of 1% immature Citrus reticulata extract (ICRE) for 11 weeks markedly reduced body weight gain, epididymal fat weight, fasting blood glucose, serum triglyceride, and total cholesterol (P < 0.05 for all). In addition, histological analysis revealed that dietary ICRE decreased adipocyte size and hepatic steatosis compared to the HFD group (P < 0.05 for both). Furthermore, we found that mice treated with ICRE have improved cold tolerance during acute cold challenge. These effects were associated with increased expression of uncoupling protein 1 (UCP1) and thermogenic genes in inguinal WAT. These results suggest that ICRE can prevent obesity and lipid accumulation through induction of brown-like adipocyte formation. In the second part of this dissertation, citrus peels contain polymethoxyflavones (PMFs) mainly in nobiletin and tangeretin. Previous studies indicated that 5-demethyltangeretin (5-DTAN) found in citrus peel exhibits highly potent anti-cancer activity in vitro. However, 5-DTAN is a hydrophobic compound with poor aqueous solubility, which limits its oral bioavailability and efficacy. Therefore, we aimed to develop and characterize an optimal self-microemulsifying delivery system (SMEDS) formulation for 5-DTAN and assess its anticancer activity in a xenograft model. SMEDS is a lipid-based formulation and typically comprises oil, surfactant, and co-surfactant. The results from our solubility and compatibility test revealed that ethyl oleate and d-limonene were appropriate for use as oil phases. The optimal formulation comprised ethyl oleate / d-limonene (10% / 5%), Cremophor® EL (59.5%), and PEG 400 (25.5%). With this optimal formulation, the mean particle size was 97.1 ± 6.50 nm with the highest 5-DTAN loading (3.01 ± 0.38 mg/mL) determined by photon correlation spectroscopy. The transmission electron microscopy (TEM) morphology of 5-DTAN microemulsion droplets demonstrated a spherical shape and uniform size. In pharmacokinetic study, the plasma concentration profiles showed that 5-DTAN-loaded SMEDS could significantly increase the oral absorption of 5-DTAN compare with the water suspension group. Meanwhile, for the first time, we identified TAN-O-glucuronide as a major metabolite of 5-DTAN by using liquid chromatography-solid phase extraction-nuclear magnetic resonance (LC-SPE-NMR). More than that using 5-DTAN loading SMEDS is an effective approach for inhibiting tumor growth in colon cancer xenograft mice. These results suggest that SMEDS is a promising delivery system to enhance antitumor effects of 5-DTAN through increasing the oral bioavailability. According to our data, we consider that these young citrus fruits and citrus peels can be developed into nutraceuticals, thereby increasing the economic value of this agricultural waste. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T07:09:06Z (GMT). No. of bitstreams: 1 U0001-2602202115481300.pdf: 6314509 bytes, checksum: 89e40076f506b052b680cad4742b349e (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 中文摘要 i Abstract iii Contents v Figures list vii Tables list viii Appendices list viii Abbreviations ix Graphical abstract xi Background 1 CHAPTER I. Immature Citrus reticulata extract promotes browning of beige adipocytes in high-fat diet-induced obese C57BL/6 mice 2 1. Literature review 2 1.1. Biological compounds of citrus fruits and properties 2 1.2. Introduction of obesity 3 1.3. Adipose tissue classification 5 1.4. Mechanisms regulating the balance of adipose tissue 6 2. Objectives and experimental design 8 2.1. Objectives 8 2.2. Experimental design 8 3. Materials and methods 9 3.1. Chemicals 9 3.2. Preparation of Immature Citrus reticulata extract (ICRE) 9 3.3. HPLC analysis 9 3.4. Animals and experimental design 10 3.5. Biochemical Analysis 11 3.6. Histological analysis 12 3.7. Immunoblotting analysis 12 3.8. Quantitative real-time qPCR 13 3.9. Statistical analysis 14 4. Results 15 4.1. Content of phytochemical components in ICRE 15 4.2. ICRE reduces HFD-induced body weight gain 15 4.3. ICRE attenuates lipid accumulation in liver and WAT 16 4.4. ICRE improves insulin resistance and dyslipidemia 16 4.5. ICRE induces browning of inguinal WAT (iWAT) 17 5. Discussion and Conclusion 18 6. Tables 21 7. Figures 24 CHAPTER II. Identification a novel metabolite of 5-demethyltangeretin and as an anti-cancer agent using self-microemulsifying delivery system 29 1. Literature review 29 1.1. Polymethoxyflavones and properties 29 1.2. Metabolism of polymethoxyflavones 30 1.3. Emulsion-based delivery systems – self-microemulsifying drug delivery system (SMEDDS) 33 1.4. Introduction of colon cancer 35 2. Objectives and experimental design 36 2.1. Objectives 36 2.2. Experimental design 36 3. Materials and methods 37 3.1. Materials 37 3.2. Solubility measurement 37 3.3. Construction of pseudoternary phase diagrams 38 3.4. Particle size, polydispersity index, and zeta potential determination 38 3.5. Morphological observation 39 3.6. Tumor xenograft mouse model 39 3.7. Immunohistochemical analysis 40 3.8. UPLC-ESI-MS/MS analysis 41 3.8.1. Measurement the levels of 5-DTAN in plasma 41 3.8.2. Measurement the metabolite of 5-DTAN in cultured cells 42 3.9. Sample preparation for LC-SPE-NMR 42 3.10. Statistical analysis 43 4. Results 44 4.1. Synthesis of 5-DTAN 44 4.2. Selection of oils, surfactants, and co-surfactants by solubility test 44 4.3. Construction of pseudo-ternary phase diagrams 45 4.4. Formulation optimization 45 4.5. Physicochemical characterization of 5-DTAN loading SMEDS 46 4.6. 5-DTAN-loaded SMEDS inhibited tumor growth in xenograft nude mice 47 4.7. Identification of 5-DTAN metabolites in vitro and in vivo 48 5. Discussion and Conclusion 50 6. Tables 53 7. Figures 56 8. Appendices 64 References 67 | |
| dc.language.iso | en | |
| dc.subject | 5-去甲基橘皮素 | zh_TW |
| dc.subject | 大腸癌 | zh_TW |
| dc.subject | 代謝物 | zh_TW |
| dc.subject | 自微乳化載藥系統 | zh_TW |
| dc.subject | 產熱基因 | zh_TW |
| dc.subject | 柑橘幼果 | zh_TW |
| dc.subject | 肥胖 | zh_TW |
| dc.subject | metabolite | en |
| dc.subject | obesity | en |
| dc.subject | self-microemulsifying delivery system(SMEDS) | en |
| dc.subject | 5-demethyltangeretin(5-DTAN) | en |
| dc.subject | immature citrus fruits | en |
| dc.subject | thermogenic gene | en |
| dc.subject | colon cancer | en |
| dc.title | 柑橘萃取物預防肥胖及自體微乳化多甲氧基類黃酮抑制腫瘤生長之研究 | zh_TW |
| dc.title | Study on the Preventive Effect of Citrus Extract on Obesity and the Inhibitory Effect of Polymethoxyflavones-Loaded SMEDDS on Tumor Growth | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王朝鐘(Chau-Jong Wang),何元順(Yuan-Soon Ho),王應然(Ying-Jan Wang),黃步敏(Bu-Miin Huang),張嘉哲(Chia-Che Chang),徐丞志(Cheng-Chih Hsu | ccrhsu@ntu.edu.tw | 0000-0002-2892-5326),郭靜娟(Ching-Chuan Kuo) | |
| dc.contributor.oralexamcommittee-orcid | ,張嘉哲(0000-0003-3509-3713),徐丞志(0000-0002-2892-5326) | |
| dc.subject.keyword | 柑橘幼果,肥胖,產熱基因,5-去甲基橘皮素,自微乳化載藥系統,代謝物,大腸癌, | zh_TW |
| dc.subject.keyword | immature citrus fruits,obesity,thermogenic gene,5-demethyltangeretin(5-DTAN),self-microemulsifying delivery system(SMEDS),metabolite,colon cancer, | en |
| dc.relation.page | 79 | |
| dc.identifier.doi | 10.6342/NTU202100758 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2021-03-02 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 食品科技研究所 | zh_TW |
| 顯示於系所單位： | 食品科技研究所 | |
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