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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 謝松蒼 | |
| dc.contributor.author | Hung-Wei Kan | en |
| dc.contributor.author | 甘弘偉 | zh_TW |
| dc.date.accessioned | 2021-06-17T03:28:21Z | - |
| dc.date.available | 2023-08-01 | |
| dc.date.copyright | 2018-08-01 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-03-23 | |
| dc.identifier.citation | 1. Bento CF, Pereira P (2011) Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes. Diabetologia 54(8):1946-1956. doi: 10.1007/s00125-011-2191-8
2. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813-820. doi: 10.1038/414813a 3. Cagliero E, Roth T, Roy S, Lorenzi M (1991) Characteristics and mechanisms of high-glucose-induced overexpression of basement membrane components in cultured human endothelial cells. Diabetes 40(1):102-110 4. Catrina SB, Okamoto K, Pereira T, Brismar K, Poellinger L (2004) Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes 53(12):3226-3232. doi: 10.2337/diabetes.53.12.3226 5. Chakrabarti S, Blair P, Freedman JE (2007) CD40-40L signaling in vascular inflammation. J Biol Chem 282(25):18307-18317. doi: 10.1074/jbc.M700211200 6. Crook M (2004) Type 2 diabetes mellitus: a disease of the innate immune system? An update. Diabet Med 21(3):203-207. doi: 10.1046/j.1464-5491.2003.01030.x 7. Deregibus MC, Buttiglieri S, Russo S, Bussolati B, Camussi G (2003) CD40-dependent activation of phosphatidylinositol 3-kinase/Akt pathway mediates endothelial cell survival and in vitro angiogenesis. J Biol Chem 278(20):18008-18014. doi: 10.1074/jbc.M300711200 8. Dormond O, Contreras AG, Meijer E, Datta D, Flynn E, et al (2008) CD40-induced signaling in human endothelial cells results in mTORC2- and Akt-dependent expression of vascular endothelial growth factor in vitro and in vivo. J Immunol 181(11), 8088-8095 9. Dyck PJ, Hansen S, Karnes J, O'Brien P, Yasuda H, Windebank A et al (1985) Capillary number and percentage closed in human diabetic sural nerve. Proc Natl Acad Sci USA 82(8):2513-2517 10. Edwards JL, Vincent AM, Cheng HT, Feldman EL (2008) Diabetic neuropathy: mechanisms to management. Pharmacol Ther 120(1):1-34. doi: 10.1016/j.pharmthera.2008.05.005 11. Emerling BM, Platanias LC, Black E, Nebreda AR, Davis RJ, Chandel NS (2005) Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling. Mol Cell Biol 25(12):4853-4862. doi: 10.1128/MCB.25.12.4853-4862.2005 12. Estrella JS, Nelson RN, Sturges BK, Vernau KM, Williams DC, LeCouteur RA et al (2008) Endoneurial microvascular pathology in feline diabetic neuropathy. Microvasc Res 75(3):403-410. doi: 10.1016/j.mvr.2007.12.002 13. Giannini C, Dyck PJ (1994) Ultrastructural morphometric abnormalities of sural nerve endoneurial microvessels in diabetes-mellitus. Ann Neurol 36(3):408-415 14. Grant PJ (2007) Diabetes mellitus as a prothrombotic condition. J Intern Med 262(2):157-172. doi: 10.1111/j.1365-2796.2007.01824.x 15. Halterman MW, Miller CC, Federoff HJ (1999) Hypoxia-inducible factor-1alpha mediates hypoxia-induced delayed neuronal death that involves p53. J Neurosci 19(16):6818-6824 16. Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC (1999) Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 53(8):1634-1640 17. Hsieh YL, Chiang H, Tseng TJ, Hsieh ST (2008) Enhancement of cutaneous nerve regeneration by 4-methylcatechol in resiniferatoxin-induced neuropathy. J Neuropathol Exp Neurol 67(2):93-104. doi: 10.1097/nen.0b013e3181630bb8 18. Hur J, Sullivan KA, Pande M, Hong Y, Sima AA, Jagadish HV et al (2011) The identification of gene expression profiles associated with progression of human diabetic neuropathy. Brain 134(Pt 11):3222-3235. doi: 10.1093/brain/awr228 19. Jolivalt CG, Fineman M, Deacon CF, Carr RD, Calcutt NA (2011) GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice. Diabetes Obes Metab 13(11):990-1000. doi: 10.1111/j.1463-1326.2011.01431.x 20. Kennedy JM, Zochodne DW (2005) Impaired peripheral nerve regeneration in diabetes mellitus. J Peripher Nerv Syst 10(2):144-157. doi: 10.1111/j.1085-9489.2005.0010205.x 21. Khandrika L, Lieberman R, Koul S, Kumar B, Maroni P, Chandhoke R et al (2009) Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1alpha levels contribute to emergence of an aggressive phenotype in prostate cancer. Oncogene 28(9):1248-1260. doi: 10.1038/onc.2008.476 22. Libby P, Simon DI (2001) Inflammation and thrombosis: the clot thickens. Circulation 103(13):1718-1720. doi: 10.1161/01.CIR.103.13.1718 23. Limbourg A, von Felden J, Jagavelu K, Krishnasamy K, Napp LC, Kapopara PR, et al (2015) MAP-Kinase Activated Protein Kinase 2 Links Endothelial Activation and Monocyte/macrophage Recruitment in Arteriogenesis. PLoS One 10(10):e0138542. doi: 10.1371/journal.pone.0138542 24. Loseth S, Stalberg E, Jorde R, Mellgren SI (2008) Early diabetic neuropathy: thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies. J Neurol 255(8):1197-1202. doi: 10.1007/s00415-008-0872-0 25. Lutgens E, Lievens D, Beckers L, Donners M, Daemen M (2007) CD40 and its ligand in atherosclerosis. Trends Cardiovasc Med 17(4):118-123. doi: 10.1016/j.tcm.2007.02.004 26. Mach F, Schonbeck U, Sukhova GK, Bourcier T, Bonnefoy JY, Pober JS et al (1997) Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA 94(5):1931-1936 27. Maynard MA, Ohh M (2007) The role of hypoxia-inducible factors in cancer. Cell Mol Life Sci 64(16):2170-2180. doi: 10.1007/s00018-007-7082-2 28. Nukada H, van Rij AM, Packer SG, McMorran PD (1996) Pathology of acute and chronic ischaemic neuropathy in atherosclerotic peripheral vascular disease. Brain 119(Pt 5):1449-1460. doi: 10.1093/brain/119.5.1449 29. Ostrowski D, Ehrenreich H, Heinrich R (2011) Erythropoietin promotes survival and regeneration of insect neurons in vivo and in vitro. Neuroscience 188:95-108. doi: 10.1016/j.neuroscience.2011.05.018 30. Park KK, Liu K, Hu Y, Kanter JL, He Z (2010) PTEN/mTOR and axon regeneration. Exp Neurol 223(1):45-50. doi: 10.1016/j.expneurol.2009.12.032 31. Patel H, Chen J, Das KC, Kavdia M (2013) Hyperglycemia induces differential change in oxidative stress at gene expression and functional levels in HUVEC and HMVEC. Cardiovasc Diabetol 12:142. doi: 10.1186/1475-2840-12-142 32. Price SA, Agthong S, Middlemas AB, Tomlinson DR (2004) Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy: interactions with aldose reductase. Diabetes 53(7):1851-1856. doi: 10.2337/diabetes.53.7.1851 33. Rubenstein DA, Maria Z, Yin W (2011) Glycated albumin modulates endothelial cell thrombogenic and inflammatory responses. J Diabetes Sci Technol 5(3):703-713 34. Said G (2006) Inflammation in diabetic neuropathies. Eur Neurol Rev 6(1):73-76. doi: 10.17925/ENR.2006.00.01.73 35. Sarkar K, Fox-Talbot K, Steenbergen C, Bosch-Marce M, Semenza GL (2009) Adenoviral transfer of HIF-1alpha enhances vascular responses to critical limb ischemia in diabetic mice. Proc Natl Acad Sci USA 106(44):18769-18774. doi: 10.1073/pnas.0910561106 36. Semenza GL (2000) Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest 106(7):809-812. doi: 10.1172/JCI11223 37. Shun CT, Chang YC, Wu HP, Hsieh SC, Lin WM, Lin YH et al (2004) Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments. Brain 127(Pt 7):1593-1605. doi: 10.1093/brain/awh180 38. Singh B, Singh V, Krishnan A, Koshy K, Martinez JA, Cheng C et al (2014) Regeneration of diabetic axons is enhanced by selective knockdown of the PTEN gene. Brain 137(Pt 4):1051-1067. doi: 10.1093/brain/awu031 39. Thomas PK, Kalaydjieva L, Youl B, Rogers T, Angelicheva D, King RH et al (2001) Hereditary motor and sensory neuropathy-russe: new autosomal recessive neuropathy in Balkan Gypsies. Ann Neurol 50(4):452-457. doi: 10.1002/ana.1137 40. Xu L, Chen S, Bergan RC (2006) MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 25(21):2987-2998. doi: 10.1038/sj.onc.1209337 41. Yan J, Zhang Z, Shi H (2012) HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells. Cell Mol Life Sci 69(1):115-128. doi: 10.1007/s00018-011-0731-5 42. Zochodne DW (1999) Diabetic neuropathies: features and mechanisms. Brain Pathol 9(2):369-391. doi: 10.1111/j.1750-3639.1999.tb00233.x | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69797 | - |
| dc.description.abstract | 為了解糖尿病性神經病變中微血管病變的病理學和分子機制，我們系統性和定量性地分析了腓腸神經微血管和神經病理的形態學。在糖尿病的神經內膜中，顯著的微血管病變表現為微血管管腔面積減小，微血管基底膜厚度增加以及表現纖維蛋白血管比例增加。此外，微血管基底膜厚度和表現纖維蛋白血管的比例與糖尿病神經中小髓鞘髓神經纖維密度相關。在糖尿病神經中，存在顯著的巨噬細胞和T細胞浸潤，並且CD40表達增加。此外，我們也發現缺氧誘導因子-1α（HIF-1α），絲裂原活化蛋白激酶—活化蛋白激酶2（MK2）和磷酸酶和張力蛋白同系物（PTEN）在糖尿病神經中顯著增加。HIF-1α與小髓鞘纖維密度和微血管腔面積密切相關，而MK2和PTEN均與糖尿病神經中微血管基底膜厚度相關。在暴露於高葡萄糖培養基的人類臍靜脈內皮細胞（HUVEC）的細胞培養物中進一步觀察到上述分子的表現增加和高血糖的環境有關。在高葡萄糖暴露後，CD40的抑制減弱了HIF-1α和PTEN的表達，進一步證實了上述分子之間的上下游關係。在糖尿病神經中，本研究表明（1）微血管病變，血栓形成和發炎細胞浸潤與神經退行性病變的相關性，以及（2）CD40是調控和微血管病變嚴重程度有關的HIF-1α和PTEN上游的關鍵分子。 | zh_TW |
| dc.description.abstract | To understand the pathology and molecular signatures of microangiopathy in diabetic neuropathy, we systemically and quantitatively examined the morphometry of microvascular and nerve pathologies of sural nerves. In the endoneurium of diabetic nerves, prominent microangiopathy was evidenced by reduced capillary luminal area, increased capillary basement membrane thickness, and increased proportion of fibrin(+) blood vessels. Furthermore, capillary basement membrane thickness and the proportion of fibrin(+) blood vessels were correlated with small myelinated fiber density in diabetic nerves. In diabetic nerves, there was significant macrophage and T cell infiltration, and cluster of differentiation 40 (CD40) expression was increased. Hypoxia-inducible factor-1α (HIF-1α), mitogen-activated protein kinase-activated protein kinase 2 (MK2), and phosphatase and tensin homolog (PTEN) were upregulated in diabetic nerves. HIF-1α was correlated with small myelinated fiber density and capillary luminal area, while both MK2 and PTEN were correlated with capillary basement membrane thickness in diabetic nerves. The molecular cascades were further demonstrated and replicated in cell cultures of human umbilical vein endothelial cells (HUVECs) exposed to high-glucose medium. The silencing of CD40 attenuated HIF-1α and PTEN following high-glucose exposure. In diabetic nerves, this study demonstrated (1) the association of microangiopathy, thrombosis, and inflammatory infiltrates with nerve degeneration and (2) CD40 as a key molecule for the upregulation of HIF-1α and PTEN underlying the severity of microangiopathy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T03:28:21Z (GMT). No. of bitstreams: 1 ntu-107-D01446003-1.pdf: 2318322 bytes, checksum: 5de379ef18e64bd317a8702958a78bec (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | Table of Contents i
Acknowledgement iii 中文摘要 iv Abstract v Chapter 1. Introduction 1 Chapter 2. Material and Methods 3 Chapter 3. Results 9 Chapter 4. Discussion 14 Reference 19 Table 1. Clinical profiles of diabetic patients 24 Table 2. Comparisons of nerve and vascular morphometry between amputated patients and non-amputated patients 25 Table 3. Target sequences of indicated shRNA in the current study 26 Figures and Figure legends 27 Figure 1. Microangiopathy in diabetic nerves 27 Figure 2. Thrombosis in diabetic blood vessels 29 Figure 3. Infiltration of inflammatory cells in diabetic nerves 31 Figure 4. CD40 expression in endothelial cells and inflammatory cells 33 Figure 5. Nerve degeneration in diabetes 35 Figure 6. Upregulation of hypoxia-inducible factor-1α (HIF-1α) in diabetic sural nerves 37 Figure 7. Upregulation of hypoxia-inducible factor-1α (HIF-1α) in diabetic sural nerves 39 Figure 8. Upregulation of mitogen-activated protein kinase-activated protein kinase 2 (MK2) in diabetic sural nerves 41 Figure 9. Upregulation of phosphatase and tensin homolog (PTEN) in diabetic sural nerves 43 Figure 10. Altered molecular signatures in human umbilical vein endothelial cell (HUVEC) cultures treated with high-glucose medium 45 Figure 11. Western blots of CD40 knockdown molecular expression in human umbilical vein endothelial cells (HUVECs) by lentiviral infection 47 Figure 12. Western blots of molecular expression by silencing hypoxia-inducible factor-1α (HIF-1α) and phosphatase and tensin homolog (PTEN) in human umbilical vein endothelial cells (HUVECs) by lentiviral infection 49 Figure 13. CD40 knockdown and putative signaling pathway in human umbilical vein endothelial cells (HUVECs) after exposed to high-glucose medium 51 | |
| dc.language.iso | en | |
| dc.subject | 局部缺血 | zh_TW |
| dc.subject | 發炎反應 | zh_TW |
| dc.subject | 血栓形成 | zh_TW |
| dc.subject | 微血管病變 | zh_TW |
| dc.subject | 糖尿病神經病變 | zh_TW |
| dc.subject | Ischemia | en |
| dc.subject | Inflammation | en |
| dc.subject | Diabetic neuropathy | en |
| dc.subject | Microangiopathy | en |
| dc.subject | Thrombosis | en |
| dc.title | 微血管病變在糖尿病神經病理的分子機制 | zh_TW |
| dc.title | Molecular mechanisms of microangiopathy in diabetic nerve pathology | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 趙啟超,潘俊良,謝侑霖,江皓郁,曾拓榮 | |
| dc.subject.keyword | 糖尿病神經病變,微血管病變,局部缺血,血栓形成,發炎反應, | zh_TW |
| dc.subject.keyword | Diabetic neuropathy,Microangiopathy,Ischemia,Thrombosis,Inflammation, | en |
| dc.relation.page | 52 | |
| dc.identifier.doi | 10.6342/NTU201800692 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-03-23 | |
| 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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