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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林峯輝(Feng-Huei Lin) | |
| dc.contributor.author | Xin-Ran Zhou | en |
| dc.contributor.author | 周欣然 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:48:58Z | - |
| dc.date.available | 2025-08-13 | |
| dc.date.copyright | 2020-08-26 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-13 | |
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J Urol 173, 267-270, doi:10.1097/01.ju.0000145891.35810.56 (2005). 21 Khan, M. E., Khan, M. M. Cho, M. H. J. S. r. Ce 3+-ion, surface oxygen vacancy, and visible light-induced photocatalytic dye degradation and photocapacitive performance of CeO 2-graphene nanostructures. 7, 1-17 (2017). 22 Celardo, I., Pedersen, J. Z., Traversa, E. Ghibelli, L. Pharmacological potential of cerium oxide nanoparticles. Nanoscale 3, 1411-1420, doi:10.1039/c0nr00875c (2011). 23 Hales, B. F. Comparison of the mutagenicity and teratogenicity of cyclophosphamide and its active metabolites, 4-hydroxycyclophosphamide, phosphoramide mustard, and acrolein. Cancer research 42, 3016--3021 (1982). 24 Low, J. E., Borch, R. F. Sladek, N. J. C. r. Conversion of 4-hydroperoxycyclophosphamide and 4-hydroxycyclophosphamide to phosphoramide mustard and acrolein mediated by bifunctional catalysts. 42, 830-837 (1982). 25 Chen, T.-L. et al. Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. 25, 544-551 (1997). 26 Boudes, M. et al. Functional characterization of a chronic cyclophosphamide-induced overactive bladder model in mice. Neurourol Urodyn 30, 1659-1665, doi:10.1002/nau.21180 (2011). 27 Golubeva, A. V., Zhdanov, A. V., Mallel, G., Dinan, T. G. Cryan, J. F. The mouse cyclophosphamide model of bladder pain syndrome: tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors. Physiol Rep 2, e00260, doi:10.1002/phy2.260 (2014). 28 Çetinel, B. Chemotherapy and Pelvic Radiotherapy-Induced Bladder Injury. Urologia Journal 82, S2-S5, doi:10.5301/uro.5000144 (2015). 29 Slobodov, G. et al. Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial cystitis. 171, 1554-1558 (2004). 30 Heinrich, M., Oberbach, A., Schlichting, N., Stolzenburg, J.-U. Neuhaus, J. J. P. O. Cytokine effects on gap junction communication and connexin expression in human bladder smooth muscle cells and suburothelial myofibroblasts. 6, e20792 (2011). 31 Erickson, D. R. et al. A comparison of multiple urine markers for interstitial cystitis. 167, 2461-2469 (2002). 32 Shie, J.-H., Liu, H.-T. Kuo, H.-C. J. U. Increased cell apoptosis of urothelium mediated by inflammation in interstitial cystitis/painful bladder syndrome. 79, 484. e487-484. e413 (2012). 33 Theoharides, T. C., Kempuraj, D. Sant, G. R. J. U. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. 57, 47-55 (2001). 34 Ener, K. et al. Evaluation of oxidative stress status and antioxidant capacity in patients with painful bladder syndrome/interstitial cystitis: preliminary results of a randomised study. Int Urol Nephrol 47, 1297-1302, doi:10.1007/s11255-015-1021-1 (2015). 35 Halliwell, B., Clement, M. V. Long, L. H. J. F. l. Hydrogen peroxide in the human body. FEBS Letters 486, 10-13 (2000). 36 Chen, S. et al. Cerium oxide nanoparticles protect endothelial cells from apoptosis induced by oxidative stress. Biol Trace Elem Res 154, 156-166, doi:10.1007/s12011-013-9678-8 (2013). 37 Das, M. et al. Auto-catalytic ceria nanoparticles offer neuroprotection to adult rat spinal cord neurons. Biomaterials 28, 1918-1925, doi:10.1016/j.biomaterials.2006.11.036 (2007). 38 Kong, L. et al. Nanoceria extend photoreceptor cell lifespan in tubby mice by modulation of apoptosis/survival signaling pathways. Neurobiol Dis 42, 514-523, doi:10.1016/j.nbd.2011.03.004 (2011). 39 Singh, S., Kumar, A., Karakoti, A., Seal, S. Self, W. T. Unveiling the mechanism of uptake and sub-cellular distribution of cerium oxide nanoparticles. Mol Biosyst 6, 1813-1820, doi:10.1039/c0mb00014k (2010). 40 Horie, M. et al. Protein adsorption of ultrafine metal oxide and its influence on cytotoxicity toward cultured cells. 22, 543-553 (2009). 41 Zhang, F. et al. Cerium oxide nanoparticles: Size-selective formation and structure analysis. Applied Physics Letters 80, 127-129, doi:10.1063/1.1430502 (2002). 42 Zhang, F., Jin, Q. Chan, S.-W. Ceria nanoparticles: Size, size distribution, and shape. Journal of Applied Physics 95, 4319-4326, doi:10.1063/1.1667251 (2004). 43 Held, P. J. T. R.-A. G. An introduction to reactive oxygen species. 802, 5-9 (2012). 44 de Oliveira, M. G. et al. Deletion or pharmacological blockade of TLR4 confers protection against cyclophosphamide-induced mouse cystitis. Am J Physiol Renal Physiol 315, F460-F468, doi:10.1152/ajprenal.00100.2018 (2018). 45 Abd‐Allah, A. R. et al. Protective effect of taurine against cyclophosphamide‐induced urinary bladder toxicity in rats. 32, 167-172 (2005). 46 de Oliveira, M. G. et al. Autonomic dysregulation at multiple sites is implicated in age‐associated underactive bladder in female mice. 38, 1212-1221 (2019). 47 Hirst, S. M. et al. Anti‐inflammatory properties of cerium oxide nanoparticles. 5, 2848-2856 (2009). | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78275 | - |
| dc.description.abstract | 背景: 間質性膀胱炎(Interstitial Cystitis, IC)，又稱膀胱痛症(Bladder Pain Syndrome, BPS)，是一種膀胱慢性發炎症狀，患者飽受骨盆疼痛和膀胱壓力導致的尿頻、尿急、漏尿的痛苦。研究發現，氧化壓力和活性自由基(Reactive Oxygen Species, ROS) 是間質性膀胱炎的誘因之一。而氧化鈰奈米粒子(Cerium Oxide Nanoparticles, CONP)具有可自我再生循環的抗氧化能力，具有抗細胞凋亡、抗發炎的效果，近年作為抗氧化物被廣泛研究。與目前臨床研究治療間質性膀胱炎的抗氧化物質，如，維他命D、兒茶素、褪黑激素等不同，CONP的抗氧化能力更持久。在本研究中通過施加ICR公鼠環磷酰胺(Cyclophosphamide，CYP)作為慢性膀胱疼痛的動物實驗的誘導劑。CYP可經由小鼠肝臟代謝成丙烯醛 (Acrolein)導致IC的發生。而細胞實驗則選取可在細胞培養液中自行水解生成丙烯醛的4-氫過氧環磷酰胺(4-hydroper-oxycyclophosphamide, 4-HC)誘導人類尿路上皮細胞T24產生氧化壓力。目的: 探討氧化鈰奈米粒子作為抗氧化劑，對由氧化損傷造成的間質性膀胱炎症狀是否具有治療效果。材料與方法: 利用金屬鹽水解法合成CONP，通過SEM、TEM分析粒徑大小；EDX進行成分分析；DLS方法測定CONP於溶液中的分散粒徑；XRD分析結晶構造；XPS進行表面元素價態分析，氮氣吸附法測定粒子的比表面積。細胞實驗組別分為: (1) 控制組; (2) 4-HC誘導組:以37.5 μM 4-HC加入細胞培養液4小時以誘導細胞產生氧化壓力; (3) CONP pre-treat組別:在4-HC誘導前施加5 μg/mL CONP 24小時，驗證CONP對於4-HC產生之氧化傷害的還原效果; (4) only CONP組:CONP的施加對於細胞毒性的探討。根據ISO-10993-5標準，利用WST-1 assay 和Live/Dead assay驗證CONP材料的生物相容性及各組別細胞存活率；DCFDA assay驗證CONP對細胞氧化損傷的還原效果；qRT-PCR驗證發炎反應及細胞凋亡相關基因表現。動物實驗分為: (1) 控制組：腹腔注射滅菌PBS 6次 (2) CYP誘導組: IP 注射80 mg/kg 之CYP藥物4次 (3) pre-treat CONP組：先IP 注射30 mg/ kg之CONP 2次後，與CYP誘導組同時間給予4次CYP藥物。犧牲當天通過Voiding spot assay，收集各組別小鼠3小內的排尿濾紙，拍照、量化以評估CONP的施加對尿頻的改善狀況。動物犧牲後取膀胱組織以H E染色組織切片觀察，並利用TEM拍攝膀胱表皮細胞的排列狀況；SEM觀察膀胱粘膜層的恢復。通過血液生化分析確認CONP是否造成肝腎毒性。結果與討論：合成之CONP符合ISO-10993-5標準對生醫材料生物相容性之要求規範。在細胞實驗中，預先施加5 μg/mL CONP 可有效緩解由37.5 μM的4-HC引發的T24細胞內ROS的累積，恢復細胞活性，且對由4-HC上調之IL-6、TNF-α等相關發炎、氧化損傷基因有顯著抑製作用。動物實驗中，組織染色切片及相應的SEM、TEM的結果證明CONP的施加恢復了膀胱表皮細胞間的緊密連接且幫助內皮粘膜結構恢復。血液生化分析結果證實CONP不會造成肝腎毒性。結論：氧化鈰奈米粒子可有效緩解膀胱表皮細胞之氧化損傷，緩解間質性膀胱炎引起的膀胱組織發炎及功能性缺失，是一種潛在的、可用於治療間質性膀胱炎的生物醫學材料。 | zh_TW |
| dc.description.abstract | Background: Interstitial Cystitis (IC), also known as Bladder Pain Syndrome (BPS), is a chronic inflammatory condition in which patients suffer from pelvic pain and bladder pressure, frequent urination, urgency, and nocturia. Oxidative stress and reactive oxygen species (ROS) have been confirmed to be one of the reasons for IC. Antioxidants in clinical studies such as vitamin D, catechins, and melatonin have poor therapeutic effects due to their short-term antioxidant capacity. Cerium Oxide Nanoparticles (CONP) have self-regenerating antioxidative, anti-apoptotic and anti-inflammatory properties, and have been widely studied as antioxidants in recent years. Contrary to the current clinical research on the treatment of interstitial cystitis with antioxidant substances, such as vitamin D, catechins, melatonin, etc., CONP's antioxidant capacity may more durable. Cyclophosphamide (CYP), which can be metabolized by the liver to product acrolein, inducing interstitial cystitis both in humans and mice, was used as an inducer for in vivo study. While 4-hydroperoxycyclophosphamide (4-HC), forming a precursor of acrolein in the medium, was used to induce the cell to generate ROS and apoptosis in vitro. Purpose: To verify the therapeutic effects of cerium oxide nanoparticles for interstitial cystitis caused by oxidative damage. Materials and Methods: CONP was synthesized by the mantel-salt hydrolysis method, and the particle size was analyzed by SEM and TEM and EDX were used for the component analysis. The hydrodynamic size of CONP was determined by the DLS method. XRD was used to analyze the crystal structure, while XPS was used to analyze the surface element valence state. The specific surface area was determined by a nitrogen adsorption method. In vitro, human urothelial cells T24, were cultured and divided into (1) control group, (2) 4-HC group: added 37.5 μM 4-HC, 4 hours to induce cell oxidative stress, (3) pre-treat CONP group: applied 5 μg/mL CONP for 24 hours before 37.5 μM 4-HC 4-hours induction, (4) only CONP group: only applied 5μg/mL CONP for 24 hours. The biocompatibility of CONP was verified by WST-1 assay and Live/Dead assay, following ISO-10993-5 standard. DCFDA assay analyzed the antioxidative effects of CONP. q-RTPCR verified the inflammatory response and antioxidative related gene expression. In vivo, evaluate the improvement of CONP to the frequency of urination by a 3-hour void spot assay. The bladder tissue morphology was taken and observed with HE stained and TEM. The recovery of the bladder mucosa was observed by SEM. Results and discussion: The synthesized CONP meets the ISO-10993-5 standard for biocompatibility of biomedical materials. In cell experiments, pre-treated cells with 5 μg/mL CONP can effectively alleviate the accumulation of ROS caused by 37.5 μM 4-HC, meanwhile, inhibit IL-6, TNF-α, and other inflammatory or oxidative damage related genes expression. In animal experiments, the HE tissue staining sections and the corresponding TEM proved that the application of CONP restored the tight junctions between bladder epidermal cells. SEM images showed that CONP helped restore the structure of bladder endothelial mucosa. The results of blood biochemical analysis confirmed that CONP does not cause liver and kidney toxicity. Conclusion: Cerium oxide nanoparticles can effectively alleviate oxidative damage of T24 cells and alleviate bladder tissue inflammation and dysfunctional caused by interstitial cystitis, which is a potential biomaterial for the treatment of interstitial cystitis. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:48:58Z (GMT). No. of bitstreams: 1 U0001-1008202023011800.pdf: 4701773 bytes, checksum: ab335efba8af5ec04ca69465b5c7dfb1 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 國立台灣大學碩士學位論文口試委員會審定書 II 致謝 III 中文摘要 IV ABSTRACT VI CONTENTS IX LIST OF FIGURES XI LIST OF TABLES XIII LIST OF ABBREVIATIONS XIV Chapter 1 INTRODUCTION 1 1.1 Interstitial cystitis 1 1.2 Therapy of IC/BPS 3 1.2.1 Intravesical therapies 3 1.2.2 Oral pentosan polysulfate sodium 4 1.2.3 Intravesical instillation of Hyaluronic acid 4 1.2.4 Antioxidants for IC/BPS 5 1.3 Cerium oxide nanoparticles 8 1.4 In vitro and in vivo IC model establishment 8 1.5 The purpose of the study 9 Chapter 2 THEORETICAL BASIS 11 2.1 Etiologies of IC/BPS 11 2.1.1 Glycosaminoglycans and epithelial permeability in IC/BPS 11 2.1.2 Inflammation in IC/BPS 12 2.1.3 Oxidative stress in IC/BPS 13 2.3 Cerium Oxide nanoparticles 15 2.3.1 Biochemical properties of CONP 15 2.3.2 Biosafety of CONP 18 2.4 The relationship between CYP, 4-HC, and acrolein 18 Chapter 3 MATERIALS AND METHODS 21 3.1 The flow chart of this study 21 3.2 Materials 22 3.2.1 The synthesis process of CONP 22 3.2.2 The SEM of CONP 24 3.2.3 The TEM of CONP 24 3.2.4 The hydrodynamic size of CONP 25 3.2.5 The XRD of CONP 25 3.2.6 The specific surface area of CONP 26 3.2.7 The surface characterization of CONP 26 3.3 In vitro study 26 3.3.1 Cell culture 26 3.3.2 CONP biocompatibility testing 27 3.3.3 The effects of 4-HC and CONP on T24 cell viability 30 3.3.4 Intracellular ROS Measurement 31 3.3.5 The effects of CONP on T24 cell gene expression 33 3.4 In vivo study 35 3.4.1 Experimental Animals 35 3.4.2 Experimental group design 35 3.4.3 Morphology of bladder and urothelium 36 3.4.4 Void spot assay 37 3.5 Statistical Analysis 38 Chapter 4 RESULTS AND DISCUSSION 39 4.1 Characterization of CONP 39 4.2 The biocompatibility of CONP 45 4.3 4-Hydroperoxycyclophosphamide decreased the cell viability of T24 cells and induced intracellular ROS generation 46 4.4 CONP inhibits the oxidative stress of 4-HC to T24 cells 48 4.5 Pre-treat CONP reduce IC bladder vascular engorgement and hemorrhage 52 4.6 CONP can protect the urothelium and the bladder mucosa 53 4.6 Pre-treat CONP improves frequent urination 56 4.7 Intraperitoneal injection of CONP can circulate systemically without causing liver toxicity 58 Chapter 5 CONCLUSIONS 61 Chapter 6 REFERENCE 62 | |
| dc.language.iso | en | |
| dc.subject | 氧化壓力 | zh_TW |
| dc.subject | 活性自由基 | zh_TW |
| dc.subject | 膀胱痛症 | zh_TW |
| dc.subject | 氧化鈰奈米粒子 | zh_TW |
| dc.subject | 間質性膀胱炎 | zh_TW |
| dc.subject | bladder pain syndrome | en |
| dc.subject | oxidative stress | en |
| dc.subject | ROS | en |
| dc.subject | interstitial cystitis | en |
| dc.subject | cerium oxide nanoparticles | en |
| dc.title | 探討氧化鈰奈米粒子對於間質性膀胱炎/膀胱痛症的治療效果 | zh_TW |
| dc.title | Therapeutic Effect of Cerium Oxide Nanoparticles on Interstitial Cystitis/Bladder Pain Syndrome | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 黃義侑(Yi-You Huang),曾靖孋(Ching-Li Tseng) | |
| dc.subject.keyword | 間質性膀胱炎,膀胱痛症,氧化鈰奈米粒子,氧化壓力,活性自由基, | zh_TW |
| dc.subject.keyword | interstitial cystitis,bladder pain syndrome,cerium oxide nanoparticles,oxidative stress,ROS, | en |
| dc.relation.page | 65 | |
| dc.identifier.doi | 10.6342/NTU202002879 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-14 | |
| dc.contributor.author-college | 工學院 | zh_TW |
| dc.contributor.author-dept | 醫學工程學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-08-13 | - |
| 顯示於系所單位： | 醫學工程學研究所 | |
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