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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89722完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李宗玄 | zh_TW |
| dc.contributor.advisor | Tzong-Shyuan Lee | en |
| dc.contributor.author | 郭倍佳 | zh_TW |
| dc.contributor.author | Bei-Chia Guo | en |
| dc.date.accessioned | 2023-09-18T16:09:09Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-09-18 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-07-10 | - |
| dc.identifier.citation | Adair-Kirk TL, Atkinson JJ, Senior RM. Smoke particulates stress lung cells. Nat Med. 2008;14(10):1024-1025. doi: 10.1038/nm1008-1024.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89722 | - |
| dc.description.abstract | 心血管事件的發生是末期腎臟病患主要的死因之一。末期腎臟病患可以藉由透析的醫療處置來清除血液中之有毒物質以延長壽命，然而在透析過程中所使用之醫療軟管因需具備高度塑形力，因此大多含有塑化劑的成份。過去研究發現不論是在透析過程中或是透析後的血漿中塑化劑及其代謝產物的濃度均有上升的情形，但塑化劑及其代謝產物是否會影響末期腎臟病相關症候群的病程發展及其詳細機制仍然未知。另一方面，臨床上醫師會以他汀類藥物來預防末期腎臟病病患心血管事件的發生。他汀類藥物是羥甲基戊二酸單醯輔酶A (HMG-CoA) 還原酶抑制劑，其主要治療機轉為透過增加肝臟低密度脂蛋白受體蛋白表達量來降低血中的膽固醇濃度以及改善內皮細胞功能，進而達到降低心血管事件的發生。然而，近期研究指出，在透析患者給予他汀類藥物來降低心血管事件的治療是無效的，其原因為何並不清楚。因此，我的論文欲探討塑化劑(鄰苯二甲酸二辛脂)是否影響他汀類藥物降血脂以及保護內皮細胞的療效。在本研究中，我們使用肝臟細胞與內皮細胞做為體外實驗之模型。首先，通過預處理肝臟細胞塑化劑後再給予他汀類藥物的實驗並檢測低密度脂蛋白受體蛋白表達量及其與低密度脂蛋白結合量的變化。我們發現塑化劑及其代謝產物均有抑制他汀類藥物所造成的低密度脂蛋白受體蛋白表達量及其與低密度脂蛋白結合量的情形除基因轉錄調控外。低密度脂蛋白受體蛋白主要透過過氧化物酶體增殖物活化受體-前蛋白轉化酶枯草溶菌素/ kexin 9 (PPAR-PCSK9) 和肝臟X受體-肌球蛋白調節性輕鏈相互作用蛋白(LXR-IDOL)這兩條路徑所調控。此外，瞬態電壓感受器錨蛋白亞型1陽離子通道(TRPA1)有降血脂的效果且其活化與菸鹼醯胺腺嘌呤二核苷酸磷酸氧化酶-活性氧類 (NOX-ROS)路徑的活化息息相關。因此，我們分別給予其相對應的抑制劑與小分子干擾核糖核酸後發現塑化劑是透過增加菸鹼醯胺腺嘌呤二核苷酸磷酸氧化酶-活性氧類路徑的活化來進一步活化瞬態電壓感受器錨蛋白亞型1陽離子通道(TRPA1)來達到提高低密度脂蛋白受體蛋白降解進而達到阻斷辛伐他汀降血脂的效果。另一方面，通過預處理內皮細胞塑化劑後再給予他汀類藥物之實驗並檢測血管新生與抗發炎功能的改變。我們發現他汀類藥物增加內皮細胞血管新生與抗發炎的功能幾乎全部被抑制。值得注意的是，塑化劑能增加香草精第一型瞬態電壓陽離子通道(TRPV1)的脫敏因子-蛋白磷酸酶2B (PP2B) 的活性與蛋白表達量。因此，我們透過給予相對應的抑制劑與小分子干擾核糖核酸後發現塑化劑透過活化菸鹼醯胺腺嘌呤二核苷酸磷酸氧化酶-活性氧類-蛋白磷酸酶2B來達到將香草精第一型瞬態電壓陽離子通道去活化的效果從而達到干擾辛伐他汀保護心血管的療效。根據我的實驗結果，可以得知為何他汀類藥物在末期腎臟病患中無法達到預期的療效提供一個詳細的解釋，期許未來能透過飲食調整給予後續處理以確保他汀類藥物之療效。 | zh_TW |
| dc.description.abstract | The occurrence of cardiovascular events is the leading cause of death in patients with end-stage renal disease (ESRD). Dialysis can be used to remove toxic substances in the blood to prolong the lifespan of these patients. Di-(2-ethylhexyl) phthalate (DEHP) is added into medical tubes to increase the elasticity. However, previous studies have reported that the concentrations of DEHP and its metabolites in plasma are increased during and after dialysis. However, whether DEHP and its metabolites affect the development of ESRD-related complications and underlying mechanisms are still unknown. On the other hand, statins are used to prevent cardiovascular events in patients with ESRD. Statins are a group of hydroxymethylglutarate-Coenzyme A (HMG-CoA) reductase inhibitor. Mechanically, statins reduce the circulating level of cholesterol by increasing the expression of liver low-density lipoprotein receptor (LDLR) and improving endothelial cell function, thereby preventing the occurrence of cardiovascular events. However, recent studies indicate that statins failed to reduce cardiovascular events in dialysis patients with unclear mechanism. Therefore, in my thesis I attempted to study whether DEHP and its metabolites affects the efficacy of statins in lipid-lowering effect in hepatocytes and the protective effect in endothelial cells (ECs). In this study, hepatocytes (Hepatocellular carcinoma cell, Huh7 cells) and ECs were used as my in vitro models. In Huh7 cells, treatment with DEHP and its metabolites mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (5-oxo-MEHP), mono-(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP), 2-ethylhexanol (2-EH), and phthalic acid (PA) abolished the simvastatin-conferred lipid-lowering effect. In addition to transcriptional regulation, the posttranscriptional regulation of LDLR protein is regulated by peroxisome proliferator activated receptor -proprotein convertase subtilisin/kexin 9 (PPAR-PCSK9) and liver X receptor -inducible degrader of LDLR (LXR-IDOL) signaling pathways. Pretreatment with the corresponding inhibitors and small interfering ribonucleic acid (siRNA) abolished the DEHP-mediated inhibition of the lipid-lowering effect of statin, suggesting the role of PPAR-PCSK9 and LXR-IDOL pathways. Moreover, nicotinic amine adenine dinucleotide phosphate oxidase-reactive oxygen species (NOX-ROS) signaling pathway is involved in transient receptor potential ankyrin 1 (TRPA1) activation, which has lipid-lowering effect. My results demonstrated that DEHP increases NOX activity and ROS production. Thus, determined whether NOX-ROS pathway is involved in DEHP restricts simvastatin-induced lipid lowering effect. Pretreatment with APO (NOX inhibitor) or NAC (antioxidant) recover LDLR protein and LDL binding activity but inhibit DEHP-induced the expression of PCSK9 and IDOL. Finally, in order to examine whether TRPA1 is involved in DEHP-activated NOX-ROS pathway. Pretreatment with TRPA1 inhibitor (A900679 and H033031) inhibit DEHP-induced calcium influx, the expression of PPAR, PCSK9, LXR, IDOL but recover the expression of LDLR and LDL binding activity. Collectively, DEHP blunts simvastatin-induced lipid lowering effect by activating NOX-ROS-TRPA1-Ca2+ pathway. In ECs, treatment with DEHP and its metabolites MEHP but not 5OH-MEHP, 5oxo-MEHP, 5cx-MEPP, 2-EH and PA abolished the simvastatin-induced NO bio-availability and angiogenesis. DEHP abrogated the anti-inflammatory effect of simvastatin on tumor necrosis factor -induced increase of adhesion molecules and monocyte adhesion onto ECs. Mechanically, DEHP inhibited the activation of transient potential receptor vanilloid type 1 (TPRV1), which is essential for NO production by simvastatin in ECs. Especially, DEHP enhanced protein phosphatase 2B (PP2B) activity and expression, which is required for TRPV1 desensitization. In addition, DEHP activated PP2B through activating NOX-ROS signaling pathway. Inhibition of PP2B activity by corresponding inhibitors and siRNA protected the inhibitory effect of DEHP on simvastatin-induced calcium influx, NO production, ECs migration, ECs proliferation, ECs tube formation and anti-inflammatory effect. In summary, DEHP abrogates the pleiotropic effect of simvastatin by activating NOX-ROS-PP2B pathway, which cause TRPV1 desensitization, contributing to the inhibition of simvastatin-interfered pleiotropic effects in ECs. Based on the results of my experiment, we provide a detailed explanation why statins failed to reduce the cardiovascular events in dialysis patients. In the future, I hope to ensure the efficacy of statins by adjusting of diet. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-18T16:09:09Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-09-18T16:09:09Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 中文摘要 i
英文摘要 iii Chapter 1. Introduction 1 1.1 Statins 1 1.2 Chronic kidney disease (CKD) 8 1.3 Di-(2-ethylhexyl) phthalate (DEHP) 13 1.4 Reactive oxygen species (ROS) 19 1.5 Transient receptor potential ankyrin 1(TRPA1) 26 1.6 Transient receptor potential vanilloid 1 (TRPV1) 33 1.7 Objectives 39 Chapter 2. Material and methods 41 2.1 Reagents and antibodies 41 2.2 Cell culture 42 2.3 Protein extraction 42 2.4 Western blot analysis 43 2.5 Dil-LDL binding assay 43 2.6 Quantitative real-time PCR (qRT-PCR) 44 2.7 Determination of PPARgamma and LXRalpha activity 44 2.8 Transfection of siRNAs 45 2.9 Measurement of intracellular ROS levels 45 2.10 Determination of NADP+/NADPH ratio 45 2.11 Detection of calcium influx 45 2.12 Detection of nitrite production 46 2.13 Immunoprecipitation (IP) 46 2.14 Cell proliferation assay 47 2.15 Trans-well migration assay 47 2.16 Tube formation assay 48 2.17 In vitro mononuclear-endothelial cell adhesion assay 48 2.18 Statistical analysis 49 Chapter 3. Results 50 3.1 DEHP and its metabolites limits lipid-lowering effect of simvastatin in Huh7 cells 50 3.2 PPARgamma-PCSK9 and LXRalpha-IDOL cascade are essential for DEHP restrict simvastatin-conferred lipid-lowering effect in Huh7 cells 50 3.3 DEHP inhibits the simvastatin-elicited lipid-lowering effect by activating the NOX-ROS signaling pathway 51 3.4 DEHP induces the activation of the NOX-ROS-TRPA1-Ca2+ signaling pathway 52 3.5 DEHP blunts the statin-conferred pleiotropic effects in ECs 52 3.6 DEHP prevents simvastatin-induced activation of TRPV1-Ca2+ signaling in ECs 53 3.7 PP2B is involved in the inhibitory effects of DEHP on simvastatin-induced Ca2+ influx in ECs 53 3.8 DEHP inhibits the simvastatin-elicited Ca2+ influx by activating the NOX-ROS signaling pathway in ECs 54 3.9 DEHP induces ROS production to activate the TRPV1-Ca2+-PP2B signaling pathway in ECs 54 Chapter 4. Discussion 56 Chapter 5. Conclusion 70 References 71 Figure legends 137 Tables 171 | - |
| dc.language.iso | en | - |
| dc.title | 探討塑化劑干擾史達汀類藥物療效之分子機轉 | zh_TW |
| dc.title | Molecular Mechanism of Di-(2-ethylhexyl) Phthalate in Interfering with the Therapeutic Efficacy of Statins | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 徐松錕;林恒;李學德;侯欣翰 | zh_TW |
| dc.contributor.oralexamcommittee | Song-Kun Shyue;Heng Lin;Hsueh-Te Lee;Hsin-Han Hou | en |
| dc.subject.keyword | 辛伐他汀,鄰苯二甲酸二辛脂,低密度脂蛋白受體,菸鹼醯胺腺嘌呤二核苷酸磷酸氧化酶-活性氧類,瞬態電壓感受器錨蛋白亞型1陽離子通道,過氧化物酶體增殖物活化受體-前蛋白轉化酶枯草溶菌素/ kexin 9,肝臟X受體-肌球蛋白調節性輕鏈相互作用蛋白,一氧化氮,蛋白磷酸酶2B,香草精第一型瞬態電壓陽離子通道, | zh_TW |
| dc.subject.keyword | Simvastatin,DEHP,LDLR,NOX-ROS,TRPA1,PPARg-PCSK9,LXRa-IDOL,NO,PP2B,TRPV1, | en |
| dc.relation.page | 172 | - |
| dc.identifier.doi | 10.6342/NTU202301411 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-07-11 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 生理學研究所 | - |
| 顯示於系所單位： | 生理學科所 | |
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