請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57848完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林思洸(Sze-Kwan Lin) | |
| dc.contributor.author | Wan-Yu Lu | en |
| dc.contributor.author | 盧宛瑜 | zh_TW |
| dc.date.accessioned | 2021-06-16T07:07:15Z | - |
| dc.date.available | 2016-10-15 | |
| dc.date.copyright | 2014-10-15 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-09 | |
| dc.identifier.citation | 1. Geboes K. From Inflammation to Lesion. Acta Gastro-Enterologica Belgica 1994;57:273-284.
2. Torabinejad M, Eby WC, Naidorf IJ. Inflammatory and Immunological Aspects of the Pathogenesis of Human Periapical Lesions. Journal of Endodontics 1985;11:479-488. 3. Byers MR, Taylor PE, Khayat BG, Kimberly CL. Effects of Injury and Inflammation on Pulpal and Periapical Nerves. Journal of Endodontics 1990;16:78-84. 4. Moldauer I, Velez I, Kuttler S. Upregulation of basic fibroblast growth factor in human periapical lesions. Journal of Endodontics 2006;32:408-411. 5. Carreau A, El Hafny-Rahbi B, Matejuk A, Grillon C, Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. Journal of Cellular and Molecular Medicine 2011;15:1239-1253. 6. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer and Metastasis Reviews 2007;26:225-239. 7. Ye JP, Gao ZG, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. American Journal of Physiology-Endocrinology and Metabolism 2007;293:E1118-E1128. 8. Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proceedings of the National Academy of Sciences of the United States of America 2006;103:18727-18732. 9. Savransky V, Nanayakkara A, Li JG, Bevans S, Smith PL, Rodriguez A, Polotsky VY. Chronic intermittent hypoxia induces atherosclerosis. American Journal of Respiratory and Critical Care Medicine 2007;175:1290-1297. 10. Konisti S, Kiriakidis S, Paleolog EM. Hypoxia-a key regulator of angiogenesis and inflammation in rheumatoid arthritis. Nature Reviews Rheumatology 2012;8:153-162. 11. Thornton RD, Lane P, Borghaei RC, Pease EA, Caro J, Mochan E. Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts. Biochemical Journal 2000;350:307-312. 12. Eltzschig HK, Carmeliet P. Hypoxia and Inflammation. New England Journal of Medicine 2011;364:656-665. 13. Giaccia AJ, Simon MC, Johnson R. The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease. Genes & Development 2004;18:2183-2194. 14. Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. Journal of Applied Physiology 2000;88:1474-1480. 15. Dery MAC, Michaud MD, Richard DE. Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. International Journal of Biochemistry & Cell Biology 2005;37:535-540. 16. Jezek P, Plecita-Hlavata L. Mitochondrial reticulum network dynamics in relation to oxidative stress, redox regulation, and hypoxia. International Journal of Biochemistry & Cell Biology 2009;41:1790-1804. 17. Ng KT, Li JP, Ng KM, Tipoe GL, Leung WK, Fung ML. Expression of hypoxia-inducible factor-1alpha in human periodontal tissue. J Periodontol 2011;82:136-141. 18. Muzylak M, Price JS, Horton MA. Hypoxia Induces Giant Osteoclast Formation and Extensive Bone Resorption in the Cat. Calcified Tissue International 2006;79:301-309. 19. DeLaurier A, Boyde A, Jackson B, Horton MA, Price JS. Identifying early osteoclastic resorptive lesions in feline teeth: a model for understanding the origin of multiple idiopathic root resorption. J Periodontal Res 2009;44:248-257. 20. Ernster L, Schatz G. Mitochondria - a Historical Review. Journal of Cell Biology 1981;91:S227-S255. 21. Mitchell P. Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-Osmotic Type of Mechanism. Nature 1961;191:144-&. 22. Hamanaka RB, Chandel NS. Mitochondrial reactive oxygen species regulate hypoxic signaling. Curr Opin Cell Biol 2009;21:894-899. 23. Orrenius S, Gogvadze A, Zhivotovsky B. Mitochondrial oxidative stress: Implications for cell death. Annual Review of Pharmacology and Toxicology 2007;47:143-183. 24. Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang GP, Iyer S, Smulson M. Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis - Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. Journal of Biological Chemistry 1999;274:22932-22940. 25. Solaini G, Baracca A, Lenaz G, Sgarbi G. Hypoxia and mitochondrial oxidative metabolism. Biochimica Et Biophysica Acta-Bioenergetics 2010;1797:1171-1177. 26. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008;451:1069-1075. 27. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death and Differentiation 2009;16:966-975. 28. Shintani T, Klionsky DJ. Autophagy in health and disease: A double-edged sword. Science 2004;306:990-995. 29. Ohsumi Y, Mizushima N. Two ubiquitin-like conjugation systems essential for autophagy. Seminars in Cell & Developmental Biology 2004;15:231-236. 30. Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Archives of Biochemistry and Biophysics 2007;462:245-253. 31. Reggiori. F, Komatsu. M, Finley. K, Simonsen. A. Autophagy: More Than a Nonselective Pathway. International Journal of Cell Biology 2012;2012:18. 32. Zhang Y, Qi HY, Taylor R, Xu WH, Liu LF, Jin SK. The role of autophagy in mitochondria maintenance - Characterization of mitochondrial functions in autophagy-deficient S-cerevisiae strains. Autophagy 2007;3:337-346. 33. Twig G, Elorza A, Molina AJA, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. Embo Journal 2008;27:433-446. 34. Lemasters JJ. Perspective - Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Research 2005;8:3-5. 35. Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, Kroemer G. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death and Differentiation 2009;16:87-93. 36. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K, Mizushima N. Autophagy-deficient mice develop multiple liver tumors. Genes & Development 2011;25:795-800. 37. Chen H, Chan DC. Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases. Human Molecular Genetics 2009;18:R169-R176. 38. Huang CQ, Andres AM, Ratliff EP, Hernandez G, Lee P, Gottlieb RA. Preconditioning Involves Selective Mitophagy Mediated by Parkin and p62/SQSTM1. Plos One 2011;6. 39. Ding WX, Yin XM. Mitophagy: mechanisms, pathophysiological roles, and analysis. Biological Chemistry 2012;393:547-564. 40. Ikeda F, Crosetto N, Dikic I. What Determines the Specificity and Outcomes of Ubiquitin Signaling? Cell 2010;143:677-681. 41. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392:605-608. 42. Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proceedings of the National Academy of Sciences 2003;100:4078-4083. 43. Whitworth AJ, Theodore DA, Greene JC, Beneš H, Wes PD, Pallanck LJ. Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proceedings of the National Academy of Sciences 2005;102:8024-8029. 44. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. Journal of Biological Chemistry 2004;279:18614-18622. 45. Grunewald A, Voges L, Rakovic A, Kasten M, Vandebona H, Hemmelmann C, Lohmann K, Orolicki S, Ramirez A, Schapira AHV, Pramstaller PP, Sue CM, Klein C. Mutant Parkin Impairs Mitochondrial Function and Morphology in Human Fibroblasts. Plos One 2010;5. 46. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1. Science 2004;304:1158-1160. 47. Clark IE, Dodson MW, Jiang CG, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 2006;441:1162-1166. 48. Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong MH, Kim JM, Chung JK. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 2006;441:1157-1161. 49. Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, Wang J-W, Yang L, Beal MF, Vogel H, Lu B. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proceedings of the National Academy of Sciences 2006;103:10793-10798. 50. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. Journal of Cell Biology 2008;183:795-803. 51. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin. Plos Biology 2010;8. 52. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou Y, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. Journal of Cell Biology 2010;189:211-221. 53. Narendra DP, Youle RJ. Targeting Mitochondrial Dysfunction: Role for PINK1 and Parkin in Mitochondrial Quality Control. Antioxidants & Redox Signaling 2011;14:1929-1938. 54. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AHV, Taanman JW. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy (vol 19, pg 4861, 2010). Human Molecular Genetics 2013;22:1697-1697. 55. Wang XN, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, LaVoie MJ, Schwarz TL. PINK1 and Parkin Target Miro for Phosphorylation and Degradation to Arrest Mitochondrial Motility. Cell 2011;147:893-906. 56. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacology & Therapeutics 1999;84:413-428. 57. Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE 2004;2004:RE13. 58. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature 2002;420:629-635. 59. Liao JK. Isoprenoids as mediators of the biological effects of statins. Journal of Clinical Investigation 2002;110:285-288. 60. Horiuchi N, Maeda T. Statins and bone metabolism. Oral Diseases 2006;12:85-101. 61. Zhang Y, Bradley AD, Wang D, Reinhardt RA. Statins, bone metabolism and treatment of bone catabolic diseases. Pharmacological Research. 62. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clinical Pharmacokinetics 2002;41:343-370. 63. Corti R, Fayad ZA, Fuster V, Worthley SG, Helft G, Chesebro J, Mercuri M, Badimon JJ. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions - A longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001;104:249-252. 64. Relja B, Meder F, Wilhelm K, Henrich D, Marzi I, Lehnert M. Simvastatin inhibits cell growth and induces apoptosis and G0/G1 cell cycle arrest in hepatic cancer cells. International Journal of Molecular Medicine 2010;26:733-739. 65. Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin decreases IL-6 and IL-8 production in epithelial cells. Journal of Dental Research 2006;85:520-523. 66. Yokota K, Miyazaki T, Hirano M, Akiyama Y, Mimura T. Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Journal of Rheumatology 2006;33:463-471. 67. Staal A, Frith JC, French MH, Swartz J, Gungor T, Harrity TW, Tamasi J, Rogers MJ, Feyen JH. The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. Journal of Bone and Mineral Research 2003;18:88-96. 68. Pradeep AR, Thorat MS. Clinical Effect of Subgingivally Delivered Simvastatin in the Treatment of Patients With Chronic Periodontitis: A Randomized Clinical Trial. Journal of Periodontology 2010;81:214-222. 69. Anbinder AL, Prado FdA, Prado MdA, Balducci I, Rocha RFd. The influence of ovariectomy, simvastatin and sodium alendronate on alveolar bone in rats. Brazilian Oral Research 2007;21:247-252. 70. von Stechow D, Fish S, Yahalom D, Bab I, Chorev M, Muller R, Alexander JM. Does simvastatin stimulate bone formation in vivo? Bmc Musculoskeletal Disorders 2003;4. 71. Tang QO, Tran GT, Gamie Z, Graham S, Tsialogiannis E, Tsiridis E, Linder T, Tsiridis E. Statins: under investigation for increasing bone mineral density and augmenting fracture healing. Expert Opinion on Investigational Drugs 2008;17:1435-1463. 72. Yazawa H, Zimmermann B, Asami Y, Bernimoulin JP. Simvastatin promotes cell metabolism, proliferation, and osteoblastic differentiation in human periodontal ligament cells. Journal of Periodontology 2005;76:295-302. 73. Lin SK, Kok SH, Lee YL, Hou KL, Lin YT, Chen MH, Wang CC, Hong CY. Simvastatin as a Novel Strategy To Alleviate Periapical Lesions. Journal of Endodontics 2009;35:657-662. 74. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 2011;333:1109-1112. 75. Goldman SJ, Taylor R, Zhang Y, Jin SK. Autophagy and the degradation of mitochondria. Mitochondrion 2010;10:309-315. 76. Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, May J, Tocilescu MA, Liu W, Ko HS, Magrane J, Moore DJ, Dawson VL, Grailhe R, Dawson TM, Li C, Tieu K, Przedborski S. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 2010;107:378-383. 77. Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D. Mitochondrial Parkin Recruitment Is Impaired in Neurons Derived from Mutant PINK1 Induced Pluripotent Stem Cells. Journal of Neuroscience 2011;31:5970-5976. 78. Baker MJ, Tatsuta T, Langer T. Quality Control of Mitochondrial Proteostasis. Cold Spring Harbor Perspectives in Biology 2011;3. 79. Lupattelli G, Scarponi AM, Vaudo G, Siepi D, Roscini AR, Gemelli F, Pirro M, Latini RA, Sinzinger H, Marchesi S, Mannarino E. Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women. Metabolism 2004;53:744-748. 80. Rejnmark L, Buus NH, Vestergaard P, Heickendorff L, Andreasen F, Larsen ML, Mosekilde L. Effects of simvastatin on bone turnover and BMD: a 1-year randomized controlled trial in postmenopausal osteopenic women. Journal of Bone and Mineral Research 2004;19:737-744. 81. Vaziri H, Naserhojjati-Roodsari R, Tahsili-Fahadan N, Khojasteh A, Mashhadi-Abbas F, Eslami B, Dehpour AR. Effect of simvastatin administration on periodontitis-associated bone loss in ovariectomized rats. Journal of periodontology 2007;78:1561-1567. 82. Seto H, Ohba H, Tokunaga K, Hama H, Horibe M, Nagata T. Topical administration of simvastatin recovers alveolar bone loss in rats. Journal of Periodontal Research 2008;43:261-267. 83. Price U, Le HO, Powell S, Schmid M, Marx D, Zhang Y, Wang D, Narayana N, Reinhardt R. Effects of local simvastatin–alendronate conjugate in preventing periodontitis bone loss. Journal of periodontal research 2013;48:541-548. 84. Azevedo LC, Park M, Schettino GP. Novel potential therapies for septic shock. Shock 2008;30 Suppl 1:60-66. 85. Giusti-Paiva A, Martinez MR, Cestari Felix JV, da Rocha MJA, Carnio EC, Elias LLK, Antunes-Rodrigues J. Simvastatin Decreases Nitric Oxide Overproduction and Reverts the Impaired Vascular Responsiveness Induced by Endotoxic Shock in Rats. Shock 2004;21:271-275. 86. Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 2004;110:880-885. 87. Gutierrez GE, Lalka D, Garrett IR, Rossini G, Mundy GR. Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporosis International 2006;17:1033-1042. 88. Ma B, Clarke SA, Brooks RA, Rushton N. The effect of simvastatin on bone formation and ceramic resorption in a peri-implant defect model. Acta Biomater 2008;4:149-155. 89. Andres AM, Hernandez G, Lee P, Huang C, Ratliff EP, Sin J, Thornton CA, Damasco MV, Gottlieb RA. Mitophagy is required for acute cardioprotection by simvastatin. Antioxidants & redox signaling 2013. 90. Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R, Haque ME, McBride HM, Park DS, Fon EA. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO reports 2012;13:378-385. 91. Whitworth AJ, Lee JR, Ho VM-W, Flick R, Chowdhury R, McQuibban GA. Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson’s disease factors Pink1 and Parkin. Disease models & mechanisms 2008;1:168-174. 92. Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. The Journal of cell biology 2010;191:933-942. 93. Thomas RE, Andrews LA, Burman JL, Lin W-Y, Pallanck LJ. PINK1-Parkin Pathway Activity Is Regulated by Degradation of PINK1 in the Mitochondrial Matrix. PLoS genetics 2014;10:e1004279. 94. Fukuda R, Zhang H, Kim J-w, Shimoda L, Dang CV, Semenza Gregg L. HIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells. Cell 2007;129:111-122. 95. Hisada T, Ayaori M, Ohrui N, Nakashima H, Nakaya K, Uto-Kondo H, Yakushiji E, Takiguchi S, Terao Y, Miyamoto Y, Adachi T, Nakamura H, Ohsuzu F, Ikewaki K, Sakurai Y. Statin inhibits hypoxia-induced endothelin-1 via accelerated degradation of HIF-1α in vascular smooth muscle cells. Cardiovascular Research 2012;95:251-259. 96. Zhu XY, Daghini E, Chade AR, Napoli C, Ritman EL, Lerman A, Lerman LO. Simvastatin prevents coronary microvascular remodeling in renovascular hypertensive pigs. Journal of the American Society of Nephrology 2007;18:1209-1217. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57848 | - |
| dc.description.abstract | 缺氧是面對發炎性疾病時所需處理的治療標的，而細胞中應付缺氧的主要胞器就是粒線體。Mitophagy是指粒線體經由自噬作用而降解的機制，細胞會透過這項作用藉以清除代謝失去功能的粒線體，進而維持細胞內粒線體的平衡和基因完整性。Simvastatin是臨床上一廣為被使用作為降血脂的藥物，它同樣也具備抗發炎的功能。在我們先前的研究已經證明simvastatin可以藉由調控成骨細胞中細胞自噬和細胞凋亡的作用進而減緩根尖病變的進展。然而，其中詳細的機轉仍待闡明。在本次的研究中，我們將目標集中在粒線體機制的探討。我們利用西方點墨法去觀察，以simvastatin處理過後的MC3T3-E1細胞，在缺氧刺激下對於MC3T3-E1細胞內PTEN-induced putative kinase 1（PINK1）/ parkin（聯手調控mitophagy）和poly (adenosine phosphate ribose) polymerase（PARP）片段（細胞凋亡的標記）的蛋白質表現。我們也以免疫螢光法去監測PINK1與parkin於細胞內的實際位置。在誘導根尖病變的大鼠模型，我們設計不同的投藥途徑，利用影像學分析以及組織免疫染色去探討simvastatin最佳的治療方式。研究結果發現，缺氧刺激同樣可以提高PINK1/parkin與PARP cleavage的表現，而simvastatin更促使缺氧刺激下PINK1/parkin的表現，但卻會抑制PARP cleavage的量。我們在共軛焦顯微鏡下可觀察到，於缺氧刺激下PINK1可以穩定聚集在粒線體上，parkin也從細胞質被誘導轉至粒線體，而simvastatin更是強化了PINK1/parkin這樣的集中粒線體分布。影像學分析的結果顯示simvastatin可以有效減小根尖病變的範圍，尤其是將之作為根管局部用藥時治療效果更加顯著。組織免疫染色的結果也確認了simvastatin會增強成骨細胞中PINK1/parkin的表現。總結以上所述，我們發現缺氧會刺激成骨細胞啟動mitophagy。此外，無論在in vitro或in vivo的研究，simvastatin都會增強mitophagy的進行。這樣的結果暗示simvastatin會藉由促使成骨細胞中mitophagy機制以防止細胞走向凋亡，進而減緩根尖病變中的發炎性骨吸收。 | zh_TW |
| dc.description.abstract | Mitochondria are the organelles that deal with hypoxia, a potential therapeutic target for the treatment of inflammatory diseases. Through mitophagy, a process of mitochondrial degradation by autophagy, cells rid themselves of dysfunctional components to maintain mitochondrial homeostasis and genetic integrity. Simvastatin is a widely used anti-hyperlipidemia drug that also possesses anti-inflammatory function. We had previously demonstrated that simvastatin diminished the progression of periapical lesions by modulating autophagy and apoptosis in osteoblasts. However, the underlying mechanisms remained to be elucidated. In this study, we focused on mitochondria. We examined the effect of simvastatin on hypoxia-stimulated expression of PTEN-induced putative kinase 1（PINK1）/ parkin（team players in promotion of mitophagy）and poly (adenosine phosphate ribose) polymerase (PARP) fragmentation (an apoptosis marker) in MC3T3-E1 by western analysis. We also monitored the subcellular localization of PINK1 and parkin with immunofluorescence. In rat models of induced periapical lesions, different routes of administration of simvastatin were assessed radiographically and immunohistochemically for its therapeutic potential. Western blot showed elevated levels of PINK/parkin and PARP cleavage after hypoxia stimulation. Simvastatin enhanced hypoxia-induced PINK1/parkin and decreased PARP fragmentation. We detected that PINK1 accumulated in the mitochondria and parkin was recruited to the mitochondria when treated in hypoxia and simvastatin promoted the redistribution under confocal microscope. Radiography revealed that simvastatin reduced the extension of periapical lesions in rats, especially when simvastatin used as local application. Immunohistopathology confirmed that the number of PINK1/parkin–synthesizing osteoblasts increased after simvastatin treatment. In conclusion, we found that hypoxia stimulated mitophagy mechanism in osteoblasts. In addition, simvastatin enhanced mitophagy both in vitro and in vivo. Our data implied that simvastatin might alleviate the progression of inflammatory bone resorption in periapical lesions by promoting mitophagy to protect osteoblasts from going to apoptosis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T07:07:15Z (GMT). No. of bitstreams: 1 ntu-103-R00422020-1.pdf: 5183785 bytes, checksum: 75d55ede458a0e2079b9d074086bfe95 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 口試委員審定書 i
謝誌 ii 中文摘要 iii 英文摘要 v 第一章 導論 1 1.1 根尖病變與發炎反應及缺氧之關係 1 1.1.1 發炎反應 1 1.1.2 缺氧 1 1.2 調控粒線體的重要機制：Mitophagy 3 1.2.1 粒線體 3 1.2.2 Mitophagy 4 1.2.3 PINK1與Parkin聯手調控mitophagy 6 1.3 Simvastatin與根尖病變 8 1.3.1 Statin 8 1.3.2 Simvastatin 8 第二章 實驗目的 10 第三章 材料與方法 11 3.1 實驗細胞株 11 3.2 蛋白質的萃取 11 3.2.1 細胞內蛋白質的萃取 11 3.2.2細胞內粒線體/細胞質蛋白質的萃取 11 3.3西方點墨法 13 3.4 免疫螢光法 15 3.5 誘導根尖病變動物模型 16 3.6 免疫組織染色 18 第四章 實驗結果 19 4.1 缺氧刺激成骨細胞中mitophagy機制的進行 19 4.1.1 缺氧誘導PINK1與Parkin的蛋白質表現 19 4.1.2 缺氧造成細胞走向apoptosis 19 4.1.3 缺氧促使PINK1的聚集以及Parkin的轉移 19 4.2 Simvastatin可調控成骨細胞中mitophagy的機制 21 4.2.1 Simvastatin可促進缺氧刺激下PINK1與Parkin的蛋白質表現 21 4.2.2 Simvastatin可以抑制缺氧刺激下apoptosis的進行 21 4.2.3 Simvastatin可促進缺氧刺激下PINK1的聚集以及Parkin的轉移 21 4.3 誘導根尖病變大鼠模型中simvastatin的作用 23 4.3.1 Simvastatin可以減緩根尖病變的進展 23 4.3.2 誘導根尖病變大鼠模型中PINK1與parkin的表現 23 第五章 討論 24 5.1 缺氧會啟動細胞內mitophagy機制 24 5.2 Simvastatin可以促進缺氧刺激下mitophagy的進行 25 參考文獻 28 附錄 40 | |
| dc.language.iso | zh-TW | |
| dc.subject | PINK1 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | parkin | zh_TW |
| dc.subject | simvastatin | zh_TW |
| dc.subject | mitophagy | zh_TW |
| dc.subject | parkin | en |
| dc.subject | mitophagy | en |
| dc.subject | PINK1 | en |
| dc.subject | apoptosis | en |
| dc.subject | simvastatin | en |
| dc.title | Simvastatin可以藉由調節成骨細胞中mitophagy的機制來減緩發炎性骨吸收 | zh_TW |
| dc.title | Simvastatin alleviates inflammatory bone resorption by modulating mitophagy pathway in osteoblasts | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蕭宏昇(Michael Hong-Shen Hsiao),洪志遠(Chi-Yuan Hong) | |
| dc.subject.keyword | simvastatin,mitophagy,PINK1,parkin,細胞凋亡, | zh_TW |
| dc.subject.keyword | simvastatin,mitophagy,PINK1,parkin,apoptosis, | en |
| dc.relation.page | 52 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-10 | |
| dc.contributor.author-college | 牙醫專業學院 | zh_TW |
| dc.contributor.author-dept | 臨床牙醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床牙醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-103-1.pdf 未授權公開取用 | 5.06 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。