請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23391
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭彥彬 | |
dc.contributor.author | Yu-Miao Siao | en |
dc.contributor.author | 蕭宇妙 | zh_TW |
dc.date.accessioned | 2021-06-08T05:00:21Z | - |
dc.date.copyright | 2010-09-09 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-08-17 | |
dc.identifier.citation | Adachi-Yamada, T., Nakamura, M., Irie, K., Tomoyasu, Y., Sano, Y., Mori, E., Goto, S., Ueno, N., Nishida, Y., and Matsumoto, K. (1999). p38 mitogen-activated protein kinase can be involved in transforming growth factor beta superfamily signal transduction in Drosophila wing morphogenesis. Mol Cell Biol 19, 2322-2329.
Ambalavanan, N., Nicola, T., Hagood, J., Bulger, A., Serra, R., Murphy-Ullrich, J., Oparil, S., and Chen, Y. F. (2008). Transforming growth factor-beta signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung. Am J Physiol Lung Cell Mol Physiol 295, L86-95. Bakin, A. V., Rinehart, C., Tomlinson, A. K., and Arteaga, C. L. (2002). p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 115, 3193-3206. Benard, V., Bohl, B. P., and Bokoch, G. M. (1999). Characterization of rac and cdc42 activation in chemoattractant-stimulated human neutrophils using a novel assay for active GTPases. J Biol Chem 274, 13198-13204. Black, S. A., Jr., and Trackman, P. C. (2008). Transforming growth factor-beta1 (TGFbeta1) stimulates connective tissue growth factor (CCN2/CTGF) expression in human gingival fibroblasts through a RhoA-independent, Rac1/Cdc42-dependent mechanism: statins with forskolin block TGFbeta1-induced CCN2/CTGF expression. J Biol Chem 283, 10835-10847. Bonniaud, P., Margetts, P. J., Kolb, M., Schroeder, J. A., Kapoun, A. M., Damm, D., Murphy, A., Chakravarty, S., Dugar, S., Higgins, L., et al. (2005). Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am J Respir Crit Care Med 171, 889-898. Bourgier, C., Haydont, V., Milliat, F., Francois, A., Holler, V., Lasser, P., Bourhis, J., Mathe, D., and Vozenin-Brotons, M. C. (2005). Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression. Gut 54, 336-343. Bradham, D. M., Igarashi, A., Potter, R. L., and Grotendorst, G. R. (1991). Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol 114, 1285-1294. Brigstock, D. R., Steffen, C. L., Kim, G. Y., Vegunta, R. K., Diehl, J. R., and Harding, P. A. (1997). Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor. J Biol Chem 272, 20275-20282. Brodin, G., ten Dijke, P., Funa, K., Heldin, C. H., and Landstrom, M. (1999). Increased smad expression and activation are associated with apoptosis in normal and malignant prostate after castration. Cancer Res 59, 2731-2738. Cheifetz, S. (1999). BMP receptors in limb and tooth formation. Crit Rev Oral Biol Med 10, 182-198. Chen, Y., Shi-wen, X., Eastwood, M., Black, C. M., Denton, C. P., Leask, A., and Abraham, D. J. (2006). Contribution of activin receptor-like kinase 5 (transforming growth factor beta receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum 54, 1309-1316. Dennler, S., Goumans, M. J., and ten Dijke, P. (2002). Transforming growth factor beta signal transduction. J Leukoc Biol 71, 731-740. Denton, C. P., Khan, K., Hoyles, R. K., Shiwen, X., Leoni, P., Chen, Y., Eastwood, M., and Abraham, D. J. (2009). Inducible lineage-specific deletion of TbetaRII in fibroblasts defines a pivotal regulatory role during adult skin wound healing. J Invest Dermatol 129, 194-204. Derynck, R., and Zhang, Y. E. (2003). Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425, 577-584. Duncan, M. R., Frazier, K. S., Abramson, S., Williams, S., Klapper, H., Huang, X., and Grotendorst, G. R. (1999). Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J 13, 1774-1786. Engel, M. E., McDonnell, M. A., Law, B. K., and Moses, H. L. (1999). Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem 274, 37413-37420. Gao, R., Ball, D. K., Perbal, B., and Brigstock, D. R. (2004). Connective tissue growth factor induces c-fos gene activation and cell proliferation through p44/42 MAP kinase in primary rat hepatic stellate cells. J Hepatol 40, 431-438. Gao, R., and Brigstock, D. R. (2003). Low density lipoprotein receptor-related protein (LRP) is a heparin-dependent adhesion receptor for connective tissue growth factor (CTGF) in rat activated hepatic stellate cells. Hepatol Res 27, 214-220. Gao, R., and Brigstock, D. R. (2004). Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin alpha(v)beta(3) and heparan sulfate proteoglycan. J Biol Chem 279, 8848-8855. Goel, A., Boland, C. R., and Chauhan, D. P. (2001). Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer Lett 172, 111-118. Grainger, D. J., and Frow, E. K. (2000). Thrombospondin 1 does not activate transforming growth factor beta1 in a chemically defined system or in smooth-muscle-cell cultures. Biochem J 350 Pt 1, 291-298. Greenwood, J., Walters, C. E., Pryce, G., Kanuga, N., Beraud, E., Baker, D., and Adamson, P. (2003). Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 17, 905-907. Gressner, O. A., and Gressner, A. M. (2008). Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases. Liver Int 28, 1065-1079. Grotendorst, G. R., and Duncan, M. R. (2005). Individual domains of connective tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation. FASEB J 19, 729-738. Grotendorst, G. R., Okochi, H., and Hayashi, N. (1996). A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ 7, 469-480. Hardie, W. D., Le Cras, T. D., Jiang, K., Tichelaar, J. W., Azhar, M., and Korfhagen, T. R. (2004). Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 286, L741-749. Hawkins, P. T., Eguinoa, A., Qiu, R. G., Stokoe, D., Cooke, F. T., Walters, R., Wennstrom, S., Claesson-Welsh, L., Evans, T., Symons, M., and et al. (1995). PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase. Curr Biol 5, 393-403. Heldin, C. H., Miyazono, K., and ten Dijke, P. (1997). TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465-471. Higashiyama, H., Yoshimoto, D., Kaise, T., Matsubara, S., Fujiwara, M., Kikkawa, H., Asano, S., and Kinoshita, M. (2007). Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis. Exp Mol Pathol 83, 39-46. Holmes, A., Abraham, D. J., Sa, S., Shiwen, X., Black, C. M., and Leask, A. (2001). CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem 276, 10594-10601. Huang, M. T., Ma, W., Lu, Y. P., Chang, R. L., Fisher, C., Manchand, P. S., Newmark, H. L., and Conney, A. H. (1995). Effects of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion. Carcinogenesis 16, 2493-2497. Kennedy, L., Parapuram, S., Greenspoon, J., and Leask, A. (2008). Ceramide inhibits CCN2 expression in fibroblasts. J Cell Commun Signal 2, 19-23. Laskaris, G., Bovopoulou, O., and Nicolis, G. (1981). Oral submucous fibrosis in a Greek female. Br J Oral Surg 19, 197-201. Leask, A., and Abraham, D. J. (2003). The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology. Biochem Cell Biol 81, 355-363. Leask, A., and Abraham, D. J. (2004). TGF-beta signaling and the fibrotic response. FASEB J 18, 816-827. Leask, A., Chen, S., Pala, D., and Brigstock, D. R. (2008). Regulation of CCN2 mRNA expression and promoter activity in activated hepatic stellate cells. J Cell Commun Signal 2, 49-56. Leask, A., Holmes, A., and Abraham, D. J. (2002). Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis. Curr Rheumatol Rep 4, 136-142. Leask, A., Holmes, A., Black, C. M., and Abraham, D. J. (2003). Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts. J Biol Chem 278, 13008-13015. Leivonen, M., Nordling, S., Lundin, J., von Boguslawski, K., and Haglund, C. (2001). p27 expression correlates with short-term, but not with long-term prognosis in breast cancer. Breast Cancer Res Treat 67, 15-22. Liu, R. M., Choi, J., Wu, J. H., Gaston Pravia, K. A., Lewis, K. M., Brand, J. D., Mochel, N. S., Krzywanski, D. M., Lambeth, J. D., Hagood, J. S., et al. (2010). Oxidative modification of nuclear mitogen-activated protein kinase phosphatase 1 is involved in transforming growth factor beta1-induced expression of plasminogen activator inhibitor 1 in fibroblasts. J Biol Chem 285, 16239-16247. Mani, N. J., and Singh, B. (1976). Studies on Oral Submucous Fibrosis .3. Epithelial Changes. Oral Surg Oral Med O 41, 203-214. Massague, J. (1990). The transforming growth factor-beta family. Annu Rev Cell Biol 6, 597-641. Mori, T., Kawara, S., Shinozaki, M., Hayashi, N., Kakinuma, T., Igarashi, A., Takigawa, M., Nakanishi, T., and Takehara, K. (1999). Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell Physiol 181, 153-159. Pindborg, J. J., Chawla, T. N., Srivastava, A. N., and Gupta, D. (1965). Epithelial Changes in Oral Submucous Fibrosis. Acta Odontol Scand 23, 277-286. Pindborg, J. J., Chawla, T. N., Srivastava, A. N., Gupta, D., and Mehrotra, M. L. (1964). Clinical Aspects of Oral Submucous Fibrosis. Acta Odontol Scand 22, 679-691. Rajalalitha, P., and Vali, S. (2005). Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder. J Oral Pathol Med 34, 321-328. Ravanti, L., Hakkinen, L., Larjava, H., Saarialho-Kere, U., Foschi, M., Han, J., and Kahari, V. M. (1999). Transforming growth factor-beta induces collagenase-3 expression by human gingival fibroblasts via p38 mitogen-activated protein kinase. J Biol Chem 274, 37292-37300. Safina, A., Vandette, E., and Bakin, A. V. (2007). ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene 26, 2407-2422. Segarini, P. R., Nesbitt, J. E., Li, D., Hays, L. G., Yates, J. R., 3rd, and Carmichael, D. F. (2001). The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor. J Biol Chem 276, 40659-40667. Shishodia, S., Singh, T., and Chaturvedi, M. M. (2007). Modulation of transcription factors by curcumin. Adv Exp Med Biol 595, 127-148. Smith, M. R., Gangireddy, S. R., Narala, V. R., Hogaboam, C. M., Standiford, T. J., Christensen, P. J., Kondapi, A. K., and Reddy, R. C. (2010). Curcumin inhibits fibrosis-related effects in IPF fibroblasts and in mice following bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol. Verrecchia, F., Pessah, M., Atfi, A., and Mauviel, A. (2000). Tumor necrosis factor-alpha inhibits transforming growth factor-beta /Smad signaling in human dermal fibroblasts via AP-1 activation. J Biol Chem 275, 30226-30231. Vicencio, A. G., Lee, C. G., Cho, S. J., Eickelberg, O., Chuu, Y., Haddad, G. G., and Elias, J. A. (2004). Conditional overexpression of bioactive transforming growth factor-beta1 in neonatal mouse lung: a new model for bronchopulmonary dysplasia? Am J Respir Cell Mol Biol 31, 650-656. Zhang, Y. E. (2009). Non-Smad pathways in TGF-beta signaling. Cell Res 19, 128-139. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23391 | - |
dc.description.abstract | 口腔黏膜下纖維化症 (Oral submucous fibrosis, 或簡稱OSF),是一種慢性隱伏性的口腔黏膜纖維性病變。臨床上,本症的主要特徵是口腔黏膜變白、變僵硬。導致不能張口,說話、咀嚼及吞嚥發生困難。流行病學研究指出,嚼檳榔是口腔黏膜下纖維化症的最主要致病因子。除了檳榔萃取物本身以外,嚼檳榔不論是由於檳榔萃取物產生的細胞毒性或是由於檳榔的粗纖維造成的微小外傷都足以使結締組織中出現不等程度的慢性發炎細胞浸潤,釋放細胞激素,刺激纖維母細胞合成膠原蛋白。細胞激素中以轉型生長因子β (TGF-β) 及結締組織生長因子(CTGF)在OSF病變過程中扮演一個最重要角色。 CTGF是TGF-β的下游基因產物。 但是關於口腔黏膜中TGF-β1誘導CTGF表現的訊息傳遞路徑仍不清楚。
本研究發現在正常成人頰黏膜纖維母細胞中,TGF-β1 亦可以誘導CTGF的表現。且濃度愈高,誘導效應就愈明顯。 前處理 TGF-β1 receptor ALK5抑制劑 ( SB431542 )、ras-related small GTPase Rac1抑制劑 ( NSC23766 )、JNK抑制劑 ( SP600125 ) 可以幾乎完全阻斷TGF-β1誘導的CTGF表現。進一步研究確認, TGF-β 可促進Rac1 及 JNK的活化, 但抑制Rac1的活性不會對smad3的磷酸化造成影響。 因此,Rac-1並非透過smad3參與TGF-β1誘導CTGF 之表現。 TGF-β1可能透過 ALK5,Rac1及 JNK路徑誘導CTGF的表現。 另外我們亦發現薑黃素 (curcumin)可抑制口腔黏膜中TGF-β1誘導CTGF的表現 。冀望未來可以藉由抑制這些訊息傳遞路徑成員來達到抑制或治療口腔黏膜下纖維化症。 | zh_TW |
dc.description.abstract | Oral submucous fibrosis (OSF) is a chronic oral mucosal disease characterized by epithelial atrophy and progressive accumulation of collagen fibers in the lamina propria and the underlying submucosal layer. It has been shown that TGF-β is the main trigger for both the increased collagen production and decreased degradation pathways in OSF. However, the pathogenesis of OSF is still not well understood. In fibroblasts, connective tissue growth factor (CTGF) is a downstream target of TGF-β and synergizes with TGF-β to promote a sustained fibrotic response in vivo. Neutralizing antibody to human CTGF inhibited TGF-β-induced fibrosis, suggesting that CTGF is essential for the fibrotic response to TGF-β. Suppression of CTGF might prevent a progressive fibrotic response to stimulation by TGF-β. Previously, we have showed the presence of CTGF in fibroblasts, epithelial and endothelial cells of OSF tissues. In this study, we showed that TGF-β stimulated CTGF synthesis in a dose- and time- dependent manner in buccal mucosal fibroblasts. Pretreatment with TGF-β1 receptor ALK5 inhibitor SB431542, ras-related small GTPase Rac1 inhibitor NSC23766, JNK inhibitor SP600125 and antioxidant N-acetyl-L-cysteine (NAC), but not ERK inhibitor PD98059, p38 MAPK inhibitor SB203580, significantly reduced TGF-β induced CTGF synthesis. Furthermore, curcumin almost completely inhibited TGF-β-induced CTGF synthesis and the inhibition is dose-dependent. These results indicated that arecoline induced CTGF synthesis was mediated by Rac 1, ROS, JNK pathways and curcumin could be a useful agent in controlling OSF. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T05:00:21Z (GMT). No. of bitstreams: 1 ntu-99-R97450011-1.pdf: 1247724 bytes, checksum: 36c7810c40a75fdfbc16942b61bd5025 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 中文摘要 1
Abstract 2 導論 3 第一節 口腔黏膜下纖維化 3 1-1 口腔黏膜下纖維化 3 1-2 口腔黏膜下纖維化的流行病學 3 1-3 口腔黏膜下纖維化的病理學 3 1-4 口腔黏膜下纖維化的致病機制 4 1-5 口腔黏膜下纖維化的治療 4 第二節 轉型生長因子β1 ( Transforming growth factor β1 ) 5 2-1 TGF-β1的簡介 5 2-2 TGF-β的訊息傳遞路徑 6 2-3 TGF-β與纖維化 6 第三節 結締組織生長因子 ( connective tissue growth factor ) 7 3-1 CTGF的介紹 7 3-2 CTGF的訊息傳遞路徑 9 3-3 CTGF與纖維化 9 第四節 薑黃素 ( Curcumin ) 10 實驗目的 12 材料與方法 13 第一節 細胞株與細胞培養 13 第二節 藥物處理 13 第三節 西方墨點法 14 第四節 Rac1 activity assay 16 結果 18 TGF-β1 誘導人類頰黏膜纖維母細胞中CTGF蛋白的表現 18 ROS、Rac-1與JNK抑制劑會抑制TGF-β1對於CTGF的誘導 18 Rac-1、JNK 並非透過Smad參與TGF-β1誘導CTGF 表現 19 TGF-β1 會促進 Ras-related Small GTPase Rac1 的活化 19 TGF-β1 會促進JNK蛋白磷酸化 20 Curcumin可以抑制TGF-β1 誘導BMF之CTGF蛋白的表現 20 討論 22 結論 25 圖與表 26 References 35 | |
dc.language.iso | zh-TW | |
dc.title | TGF-β 誘導頰黏膜纖維母細胞 CTGF 表現機轉及以Curcumin 治療口腔黏膜下纖維化症之研究 | zh_TW |
dc.title | TGF-β stimulated connective tissue growth factor production in human buccal mucosal fibroblasts: Modulation by Curcumin | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 周涵怡,蕭宏昇 | |
dc.subject.keyword | 口腔黏膜下纖維化症,TGF-β1,CTGF,curcumin, | zh_TW |
dc.subject.keyword | OSF,TGF-β1,CTGF,curcumin, | en |
dc.relation.page | 43 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2010-08-17 | |
dc.contributor.author-college | 牙醫專業學院 | zh_TW |
dc.contributor.author-dept | 口腔生物科學研究所 | zh_TW |
顯示於系所單位: | 口腔生物科學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-99-1.pdf 目前未授權公開取用 | 1.22 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。