請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20689
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 龔秀妮(Hsiu-Ni Kung) | |
dc.contributor.author | Yi-Ting Su | en |
dc.contributor.author | 蘇意婷 | zh_TW |
dc.date.accessioned | 2021-06-08T02:58:46Z | - |
dc.date.copyright | 2017-09-12 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-07-28 | |
dc.identifier.citation | 1. Washington, R.E., R.M. Andrews, and R. Mutter, Emergency Department Visits for Adults with Diabetes, 2010: Statistical Brief #167, in Healthcare Cost and Utilization Project(HCUP) Statistical Briefs. 2006: Rockville(MD).
2. Rossini, A.A., et al., Studies of Streptozotocin-Induced Insulitis and Diabetes. Proceedings of the National Academy of Sciences of the United States of America, 1977. 74(6): p. 2485-2489. 3. Tao, Z., A. Shi, and J. Zhao, Epidemiological Perspectives of Diabetes. Cell Biochem Biophys, 2015. 73(1): p. 181-5. 4. Young, B., ed, Wheater's functional histology : a text and colour atlas. 2006: p. 299–301. 5. Constanzo, L.S., BRS physiology 4th edition. 6. ADA, http://www.diabetes.org/?referrer=https://www.google.com.tw/. 2016. 7. Wilcox, G., Insulin and insulin resistance. Clin Biochem Rev, 2005. 26(2): p. 19-39. 8. Ito, C., et al., Importance of OGTT for diagnosing diabetes mellitus based on prevalence and incidence of retinopathy. Diabetes Res Clin Pract, 2000. 49(2-3): p. 181-6. 9. Katsarou, A., et al., Type 1 diabetes mellitus. Nat Rev Dis Primers, 2017. 3: p. 17016. 10. Gubitosi-Klug, R.A., et al., The Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study. Diabetes Care, 2017. 11. Vitak, T., et al., Effect of medicinal mushrooms on blood cells under conditions of diabetes mellitus. World J Diabetes, 2017. 8(5): p. 187-201. 12. Laffel, L., Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes-Metabolism Research and Reviews, 1999. 15(6): p. 412-426. 13. Mandrup-Poulsen, T., beta-cell apoptosis - Stimuli and signaling. Diabetes, 2001. 50: p. S58-S63. 14. de Almagro, M.C. and D. Vucic, The inhibitor of apoptosis(IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Exp Oncol, 2012. 34(3): p. 200-11. 15. Krijnen, P.A.J., S. Simsek, and H.W.M. Niessen, Apoptosis in diabetes. Apoptosis, 2009. 14(12): p. 1387-1388. 16. Brownlee, M., The pathobiology of diabetic complications - A unifying mechanism. Diabetes, 2005. 54(6): p. 1615-1625. 17. Valko, M., et al., Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol, 2007. 39(1): p. 44-84. 18. McCord, J.M. and I. Fridovich, Superoxide dismutase. An enzymic function for erythrocuprein(hemocuprein). J Biol Chem, 1969. 244(22): p. 6049-55. 19. Mitsuishi, Y., H. Motohashi, and M. Yamamoto, The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol, 2012. 2: p. 200. 20. Magesh, S., Y. Chen, and L.Q. Hu, Small Molecule Modulators of Keap1-Nrf2-ARE Pathway as Potential Preventive and Therapeutic Agents. Medicinal Research Reviews, 2012. 32(4): p. 687-726. 21. Haskins, K., et al., Oxidative stress in type 1 diabetes. Immunology of Diabetes Ii: Pathogenesis from Mouse to Man, 2003. 1005: p. 43-54. 22. Sadek, K.M., et al., Spirulina platensis prevents hyperglycemia in rats by modulating gluconeogenesis and apoptosis via modification of oxidative stress and MAPK-pathways. Biomed Pharmacother, 2017. 92: p. 1085-1094. 23. Hu, L., et al., Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett, 2013. 23(10): p. 3039-43. 24. Turner, N., Mitochondrial Metabolism and Insulin Action. 2013 25. Haigis, M.C. and L.P. Guarente, Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev, 2006. 20(21): p. 2913-21. 26. Sun, C., et al., SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metabolism, 2007. 6(4): p. 307-319. 27. Sultana, M.R., et al., Garlic activates SIRT-3 to prevent cardiac oxidative stress and mitochondrial dysfunction in diabetes. Life Sciences, 2016. 164: p. 42-51. 28. Rees, D.A. and J.C. Alcolado, Animal models of diabetes mellitus. Diabet Med, 2005. 22(4): p. 359-70. 29. Bus, P., et al., The VEGF-A inhibitor sFLT-1 improves renal function by reducing endothelial activation and inflammation in a mouse model of type 1 diabetes. Diabetologia, 2017. 30. Islam, M.S., The islets of Langerhans. Preface. Adv Exp Med Biol, 2010. 654: p. vii-viii. 31. Li, Y., et al., MicroRNA-19a-3p enhances the proliferation and insulin secretion, while it inhibits the apoptosis of pancreatic cells via the inhibition of SOCS3. International Journal of Molecular Medicine, 2016. 38(5): p. 1515-1524. 32. Chen, M.J., et al., Apoptosis Induction in Primary Human Colorectal Cancer Cell Lines and Retarded Tumor Growth in SCID Mice by Sulforaphane. Evidence-Based Complementary and Alternative Medicine, 2012: p. 1-13. 33. Bressenot, A., et al., Assessment of Apoptosis by Immunohistochemistry to Active Caspase-3, Active Caspase-7, or Cleaved PARP in Monolayer Cells and Spheroid and Subcutaneous Xenografts of Human Carcinoma. Journal of Histochemistry & Cytochemistry, 2009. 57(4): p. 289-300. 34. Roh, S.S., et al., Allium hookeri root protects oxidative stress-induced inflammatory responses and beta-cell damage in pancreas of streptozotocin-induced diabetic rats. Bmc Complementary and Alternative Medicine, 2016. 16. 35. Raza, H., A. John, and F.C. Howarth, Increased oxidative stress and mitochondrial dysfunction in zucker diabetic rat liver and brain. Cell Physiol Biochem, 2015. 35(3): p. 1241-51. 36. Ou, X., et al., SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cells, 2014. 32(5): p. 1183-94. 37. Wang, Z.Y. and H. Gleichmann, GLUT2 in pancreatic islets - Crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice. Diabetes, 1998. 47(1): p. 50-56. 38. Schnedl, W.J., et al., Stz Transport and Cytotoxicity - Specific Enhancement in Glut2-Expressing Cells. Diabetes, 1994. 43(11): p. 1326-1333. 39. Chaudhry, Z.Z., et al., Streptozotocin is equally diabetogenic whether administered to fed or fasted mice. Laboratory Animals, 2013. 47(4): p. 257-265. 40. Glastras, S.J., et al., Mouse Models of Diabetes, Obesity and Related Kidney Disease. Plos One, 2016. 11(8). 41. Mittendorfer, B. and S. Klein, Absence of leptin triggers type 1 diabetes. Nat Med, 2014. 20(7): p. 705-6. 42. Reece J, C.N., Biology. 2002. 43. Shirakawa, J., et al., Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic beta Cell Proliferation. Cell Metabolism, 2017. 25(4): p. 868-+. 44. Feng, A.L., et al., Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes. Diabetologia, 2017. 60(6): p. 1033-1042. 45. Liakopoulou, P., et al., Fixed ratio combinations of glucagon like peptide 1 receptor agonists with basal insulin: a systematic review and meta-analysis. Endocrine, 2017. 56(3): p. 485-494. 46. Ganugula, R., et al., Nano-curcumin safely prevents streptozotocin-induced inflammation and apoptosis in pancreatic beta cells for effective management of Type 1 diabetes mellitus. Br J Pharmacol, 2017. 174(13): p. 2074-2084. 47. Saavedra-Avila, N.A., et al., Cyclin D3 promotes pancreatic beta-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes. Proceedings of the National Academy of Sciences of the United States of America, 2014. 111(33): p. E3405-E3414. 48. Muruganathan, U., S. Srinivasan, and V. Vinothkumar, Antidiabetogenic efficiency of menthol, improves glucose homeostasis and attenuates pancreatic beta-cell apoptosis in streptozotocin-nicotinamide induced experimental rats through ameliorating glucose metabolic enzymes. Biomed Pharmacother, 2017. 92: p. 229-239. 49. Beesoo, R., et al., Apoptosis inducing lead compounds isolated from marine organisms of potential relevance in cancer treatment. Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 2014. 768: p. 84-97. 50. Iskender, H., et al., The effect of hesperidin and quercetin on oxidative stress, NF-kappaB and SIRT1 levels in a STZ-induced experimental diabetes model. Biomed Pharmacother, 2017. 90: p. 500-508. 51. Zheng, H., et al., Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes, 2011. 60(11): p. 3055-66. 52. Uruno, A., et al., The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol Cell Biol, 2013. 33(15): p. 2996-3010. 53. Yagishita, Y., et al., Nrf2 protects pancreatic beta-cells from oxidative and nitrosative stress in diabetic model mice. Diabetes, 2014. 63(2): p. 605-18. 54. Marchetti, P., et al., Pancreatic Beta Cell Identity in Humans and the Role of Type 2 Diabetes. Front Cell Dev Biol, 2017. 5: p. 55. 55. Nicholls, D.G., The Pancreatic beta-Cell: A Bioenergetic Perspective. Physiol Rev, 2016. 96(4): p. 1385-447. 56. Lombard, D.B., D.X. Tishkoff, and J. Bao, Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation. Handb Exp Pharmacol, 2011. 206: p. 163-88. 57. Brenmoehl, J. and A. Hoeflich, Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3. Mitochondrion, 2013. 13(6): p. 755-61. 58. Xiong, X., et al., Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells. Diabetologia, 2016. 59(1): p. 151-60. 59. Kim, M., et al., SIRT3 Overexpression Attenuates Palmitate-Induced Pancreatic beta-Cell Dysfunction. Plos One, 2015. 10(4). 60. Kulkarni, S.R., et al., Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human. Antioxid Redox Signal, 2014. 20(1): p. 15-30. 61. Kanzaki, H., et al., Molecular regulatory mechanisms of osteoclastogenesis through cytoprotective enzymes. Redox Biology, 2016. 8: p. 186-191. 62. Do, M.T., et al., Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1 alpha/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radical Biology and Medicine, 2014. 74: p. 21-34. 63. Fan, W., et al., Endothelial deletion of mTORC1 protects against hindlimb ischemia in diabetic mice via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation. Free Radic Biol Med, 2017. 108: p. 725-740. 64. Wang, S., et al., N-Acetylcysteine Attenuates Diabetic Myocardial Ischemia Reperfusion Injury through Inhibiting Excessive Autophagy. Mediators of Inflammation, 2017. 65. Caton, P.W., et al., Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients. Diabetologia, 2013. 56(5): p. 1068-1077. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20689 | - |
dc.description.abstract | 第一型糖尿病是一種代謝異常的疾病,會使體內胰島素分泌量不足,進而讓血糖高居不下。目前治療第一型糖尿病的方法包括注射胰島素、幹細胞治療、胰島移植及藥物治療等,但往往因其副作用及併發症使病患存活率未得改善。先前研究得知,分泌胰島素的β 細胞損傷或死亡可能源自於氧化壓力的上升,使細胞產生發炎、細胞自噬以及粒線體的損傷。若可抑制其胞內氧化壓力的上升,則可保護β 細胞,維持其胰島素分泌功能。
HN242是一種天然萃取物,取自一種南美洲植物的樹幹,在先前的研究中已知其功用包括抗氧化以及抗發炎等,因此我們想知道HN242是否能藉由降低氧化壓力及發炎來達到保護 β 細胞的存活與胰島素的功能,最終維持血糖平衡。 當細胞內氧化壓力增加時,會啟動一連串機制,製造解毒及抗氧化酵素,而細胞內抗氧化機轉的主要調控者即是Nrf2(Nuclear factor erythroid 2-related factor 2, NFE2L2),因此本研究目標為探討HN242是否能藉由Nrf2調整細胞內氧化壓力進而保護β 細胞,維持胰島素的分泌,最終可以穩定血糖。 實驗結果發現,在動物實驗上,我們成功的以STZ模擬第一型糖尿病,並且同時以口服的方式餵食HN242五天,不但顯著降低老鼠血糖,在GTT(葡萄糖耐受性測試)實驗中也得到改善。並以免疫染色觀察到胰島素分泌量的差異,也從TUNEL實驗證實這是由於減少細胞凋亡所造成。組織染色也發現HN242藉由增加Nrf2下游抗氧化因子NQO1的表現來對抗STZ產生的氧化壓力傷害,最終減少細胞的凋亡。接著,利用INS-1細胞(大鼠胰臟β 細胞株)實驗證明加入HN242組不論在STZ直接處理或是高糖環境下,都可增加細胞存活率、減少細胞週期sub G0/G1凋亡的細胞及細胞凋亡指標蛋白cleaved caspase3/7。也證明HN242是藉由提升Nrf2的表現及活性,一併活化其下游抗氧化因子,像是SOD1, NQO1, GCLC 及SIRT1/3來對抗過高的氧化壓力產生。我們還觀察到HN242可以在COX4, JC-1, 麩醯胺酸吸收這些與粒線體相關實驗中保護粒線體不受損傷。最後也利用過氧化物的清除劑(DTT)及NQO1 抑制劑(Dicumarol) 證明HN242的確是藉由提高抗氧化的能力來對抗第一型糖尿病所產生的過高氧化壓力,進而保護β細胞,維持胰島素的分泌。 總結上述結果,加入HN242不僅可以活化NRF2,也提升其下游抗氧化因子NQO1和GCLC的表現量,還有SIRT家族蛋白也受到調控,最終可保護 β細胞對抗氧化壓力,使細胞正常運作,穩定血糖。因此,HN242有做為治療第一型糖尿病藥物之潛力。 | zh_TW |
dc.description.abstract | Type I diabetes mellitus(insulin-dependent diabetes mellitus, DM), a kind of metabolic disorder, results in β-cell damage and high blood glucose level. There are many treatments for type Ⅰ diabetes including insulin injection, stem cell therapy, islet transplantation, and drug treatment, however, most are not efficient enough due to the side effects and complications.Previous studies indicate that insulin secreting islet β-cells loss their function and be damaged by the oxidative stress-induced cell inflammation, autophagy, mitochondrial damage, and apoptosis. Therefore, decreasing the oxidative stress level may decelerate the progression of type I diabetes.
HN242, a nature compound extracted from the bark of a plant grown in South America, is well known for its anti-oxidative and anti-inflammatory activities. The major regulator of cellular antioxidant mechanism is Nrf2(Nuclear factor erythroid 2-related factor 2, NFE2L2) and the activation of Nrf2 increases the production of downstream anti-oxidant enzymes, such as NQO1 and GCLC. Since the effect of HN242 on β-cell is not understood, we want to know whether HN242 can protect the function of β-cells through upregulating the Nrf2 pathway, and stabilize the blood glucose through increasing the insulin secretion. In the in vivo mice model, our results showed that oral administration of HN242, for 5 days, decreased blood glucose and increased the insulin secretion level in STZ-induced type Ⅰ diabetes mice in GTT(glucose tolerance test) assay. Morover the immunohistochemical studies showed that the insulin production and the expression levels of the antioxidant enzyme NQO1 were increased by HN242.The apoptosis of β-cell leading by STZ was also decreased in TUNEL staining. In the in vitro cell model, the expression of p-Nrf2 was increased in STZ+HN242 group, so as the following anti-oxidant enzymes, including SOD1, NQO1, GCLC and SIRT1/3, by HN242 in STZ- or high-glucose-treated β-cells. The mitochondrial activity indicators, COX4 and JC-1, the level of glutamine uptake, and the cell apoptosis marker, cleaved caspase3/7, were also reversed by HN242 under treated-STZ or -high glucose treatment. ROS scavenger, DTT, and NQO1 inhibitor, dicumarol, were also used to monitor cells with HN242 in high glucose or STZ conditions, results showed that HN242 protected β-cells from STZ-induced cell apoptosis and functional damage mainly through inhibiting the ROS production, by upregulating the Nrf2 signaling pathway. In conclusion, HN242 can protect β-cell from damage, improve the insulin secretion, and stabilize the blood glucose in type I DM through upregulating the Nrf2, the down-stream anti-oxidant enzymes, and SIRT pathways. HN242 may become a potential treatment for type I diabetes mellitus. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:58:46Z (GMT). No. of bitstreams: 1 ntu-106-R04446003-1.pdf: 4192800 bytes, checksum: c6fbf77933d104f6aa19bae5d86d7b84 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 誌謝……………………………………………………………………………. i
中文摘要…………………………………………………………………….… ii 英文摘要……………………………………………………………………..... iv 縮寫表…………………………………………………………………………. vi 第一章 緒論………………………………………………………………….. 1 第一節 引言………………………………………………………. 1 第二節 胰臟………………………………………………….…… 1 第三節 糖尿病概況與簡介………………………………….…… 3 第四節 糖尿病診斷…………………………………………….… 3 第五節 第一型糖尿病與治療……………………………………. 4 第六節 第一型糖尿病與細胞凋亡………………………………. 4 第七節 第一型糖尿病起因於過高的氧化壓力…………………. 5 第八節 SIRT家族與粒線體功能維持…………………………… 7 第九節 糖尿病動物模式的發展…………………………………. 8 第十節 研究目的…………………………………………………. 9 第二章 實驗材料與方法……………………………………………………. 10 第一節 實驗藥品、動物與試劑來源……………………………. 10 第二節 動物實驗流程……………………………………………. 13 第三節 血糖測量與IPGTT………………………………………. 14 第四節 組織石蠟包埋法…………………………………………. 15 第五節 組織化學免疫染色法(Immunohistochemistry, IHC)……. 16 第六節 胰島素分泌測定(Insulin secretion)……………………… 18 第七節 組織TUNEL(Terminal deoxynucleotidyl transferase dUTP nick end labeling)染色…………………………….. 19 第八節 結晶紫染色(Crystal violet stain)………………………… 21 第九節 流式細胞儀分析(Flow Cytometry)……………………… 21 第十節 細胞免疫螢光染色(ICC)………………………………… 23 第十一節 西方墨點法分析(Western blot)………………………….. 24 第十二節 麩醯胺酸吸收(Glutamine uptake assay)………………… 27 第十三節 統計分析…………………………………………………. 27 第三章 實驗結果…………………………………………………………….. 28 第一節 口服HN242 降低STZ誘導第一型糖尿病引致之高血 糖…………………………………………………..……… 28 第二節 HN242藉由維持胰島素及升糖素之間的平衡來穩定血 糖…………………………………………………………. 28 第三節 STZ導致β細胞細胞凋亡,HN242有效提高β細胞的 存活………………………………………………………. 29 第四節 HN242 提升抗氧化能力降低STZ引致之β細胞凋亡.. 30 第五節 HN242藉由活化NRF2及下游抗氧化因子來對抗氧化 壓力………………………………………………………. 30 第六節 氧化壓力造成粒線體損傷,HN242提高SIRT表現量 維持粒線體功能…………………………………………. 31 第四章 討論…………………………………………………………………. 33 第一節 STZ引發第一型糖尿病…………………………………. 33 第二節 胰島素與升糖素之間的平衡……………………………. 34 第三節 第一型糖尿病與β細胞大量死亡………………………. 35 第四節 第一型糖尿病與氧化壓力……………………………..... 36 第五節 Nrf2(Nuclear factor E2-related factor 2) 與第一型糖尿 病所引發的氧化壓力傷害………………………………. 37 第六節 第一型糖尿病引發粒線體損傷,SIRT(Sirtuin)家族扮 演重要角色………………………………………………. 37 第七節 Nrf2與SIRT家族之間的調控路徑-direct 或indirect…. 41 第八節 HN242是藉由對抗或是增加細胞自噬(Autophagy)及發 炎(Inflammation)的可能性………………………………. 41 第五章 結論………………………………………………………………..... 43 第六章 附圖…………………………………………………………………. 44 第七章 參考文獻……………………………………………………………. 73 第八章 補充資料……………………………………………………………. 80 | |
dc.language.iso | zh-TW | |
dc.title | HN242 藉由上調Nrf2 訊息傳遞路徑保護胰臟中β 細胞免受STZ引致之傷害 | zh_TW |
dc.title | HN242 protects pancreatic β-cells from STZ-induced damage through upregulating Nrf2 signaling pathway | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 周逸鵬(Yat-Pang Chau),劉興華(Shing-Hwa Liu),許美鈴(Mei-Ling Sheu),王淑慧(Shu-Huei Wang) | |
dc.subject.keyword | 第一型糖尿病,細胞凋亡,氧化壓力,抗氧化,HN242,INS1, | zh_TW |
dc.subject.keyword | Type I diabetes mellitus,Apoptosis,Oxidative stress,Antioxidant,HN242,INS1, | en |
dc.relation.page | 86 | |
dc.identifier.doi | 10.6342/NTU201702147 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-07-28 | |
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 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-106-1.pdf 目前未授權公開取用 | 4.09 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。