跳到主要內容

臺灣博碩士論文加值系統

(44.200.82.149) 您好!臺灣時間:2023/06/11 01:11
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:劉怡婷
研究生(外文):Liu, Yiting
論文名稱:研究不同酚類化合物對肝纖維化星狀細胞生長之調控與治療: 利用玻尿酸-聚乳酸奈米粒子包覆薑黃素之藥物傳遞
論文名稱(外文):Regulation Of Activated Hepatic Stellate Cytotoxicity By Polyphenolic Compounds And Their Targeting Delivery Using Hyaluronic Acid-polylactic Acid Nanoparticles
指導教授:吳立真
口試委員:廖明淵吳志哲何佳安
口試日期:2011-12-14
學位類別:碩士
校院名稱:國立暨南國際大學
系所名稱:應用化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:105
中文關鍵詞:槲皮素沒食子酸玻尿酸聚乳酸奈米粒子CD44肝纖維化
外文關鍵詞:QuercetinGallic acidHyaluronic acidPolylactic acidNanoparticleCD44Liver fibrosis
相關次數:
  • 被引用被引用:0
  • 點閱點閱:305
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
本研究主要探討酚類化合物對活化之肝星狀細胞生長的調控,並藉由奈米粒子作為藥物傳遞載體以提升纖維化治療之效率為目的。論文共分三部分進行研究: (1) 黃酮類化合物-槲皮素 (Quercetin)是否有效抑制活化之肝星狀細胞增殖、(2) 酚酸類化合物-沒食子酸 (Gallic acid)如何誘導肝星狀細胞死亡以減緩肝纖維化表徵、(3) 以玻尿酸-聚乳酸奈米粒子包覆疏水性酚類化合物(薑黃素)應用於肝纖維化治療之可行性。
研究中將細胞分別與槲皮素 (Quercetin)、沒食子酸 (Gallic acid)共培養24小時後,偵測細胞存活率 (MTT assay)、DNA合成速率分析 (BrdU assay),證實槲皮素與沒食子酸能有效抑制活化之肝星狀細胞生長;在細胞週期分析中也發現槲皮素與沒食子酸會使細胞週期停滯於G1期,且透過Fas/Fas ligand pathway誘導細胞走向凋亡。此外,在基因微陣列系統分析中除了證實沒食子酸具抗氧化能力外,也發現沒食子酸可能藉由增加氧化壓力,促使胞內鈣離子濃度過高,進而活化Calpain、引發細胞凋亡,最終使細胞膜受損、脹破、細胞死亡。活化的肝星狀細胞在肝纖維化過程中扮演重要角色,因此我們進行膠原蛋白定量與纖維化標的蛋白α-SMA (α-smooth muscle actin)表現量分析,證實沒食子酸可減緩肝纖維化表徵,有利於肝纖維化治療。
傳統的給藥系統大多是透過口服、注射或塗抹方式,唯有藥物進入血液才能循環至患部,故藥效取決於血液中藥物濃度,然而藥物半衰期短,加上人體新陳代謝作用,需多次給藥才能維持送入細胞內作用的藥物濃度,以提升肝纖維化治療效率。本研究利用HA-PADH-PLA 為藥物載體,傳送酚類化合物-薑黃素到活化之肝星狀細胞。實驗包含玻尿酸奈米粒子的製備,以粒徑儀、掃描式電子顯微鏡 (SEM)等確定粒子形成顆粒以及大小後,包埋螢光物質 (Coumarin 6)或抗纖維化藥物 (Curcumin)對肝臟組織細胞進行體外測試 (in vitro)。從實驗中證實HA-ADH-PLA polymer對細胞毒性甚小,可視為無毒性 ; 且以玻尿酸奈米粒子作為載體後,可降低薑黃素對活化的肝星狀細胞之半致死濃度 (IC50)降低30倍之多 (由 80.4 μM降低至 2.6 μM) ; 以 CD44 抗體進行定量分析,證實活化的肝星狀細胞其表面 CD44 較未活化的肝星狀細胞多; 於靶向試驗中也發現到隨著肝星狀細胞活化程度的不同,細胞所攝入之螢光玻尿酸奈米粒持在有效範圍。因此本論文第三部分作以下假設:若可以使用生物可降解的高分子-玻尿酸 (HA)包埋對肝纖維化具治癒效果的薑黃素 (Curcumin),利用肝竇中活化的肝星狀細胞表面有大量之玻尿酸接受器 CD44 會和 HA 結合的機轉,將薑黃素子亦具有顯著差異。
綜合以上研究結果可知,多酚類化合物-槲皮素、沒食子酸抑制活化之肝星狀細胞生長,並透過Fas/Fas ligand pathway或Intracellular Calcium signaling誘導細胞走向死亡。本研究更發展出新穎之藥物載體 HA-ADH-PLA奈米粒子,藉由HA對CD44具靶向作用,增加疏水性藥物於身體可用率,以提升纖維化治療之效率。

Hepatic stellate cells (HSCs), a central role of fibrosis process, transform from quiescent types to activated (aHSCs) ones, concomitantly with the production of significant amount of ECM. Significant aHSC apoptosis engaged can be observed after the recovery of acute hepatitis. Thus the eradication of aHSC potentially becomes a mean for hepatofibrosis treatment. Herein phenolic compounds (quercetin, gallic acid) were evaluated to investigate their effect on the proliferation and apoptosis of aHSCs. Meanwhile phenolic compound (curcumin) encapsulated nanoformulation by HA-PLA nanoparticle drug delivery system was established to enhance the efficacy on aHSC eradication. Treatment of aHSCs with quercetin and gallic acid inhibited cell viability in a dose- and time-dependent manner. Results revealed that increased BrdU incorporation suggested quercetin and gallic acid restrained aHSC proliferation. Additionally, quercetin limited aHSC proliferation by inducing a G1 arrest as evidenced by decreased expression of cyclin D1、D2、A、B1、E. Moreover quercetin and gallic acid induced aHSC apoptosis via Fas/Fas ligand-mediated extrinsic pathway. Gallic acid also decreased SMA expression as well as collagen production, and caused cell death by calcium signaling-induced ER stress. Gene microarray analysis showed that gallic acid induced several regulations on aHSC including extrinsic apoptosis as evidenced by the increase of Fas/Fas ligand expression, promotion of anti-fibrotic and anti-oxidative gene expression. For nanoformulation, the physicochemical properties such as size and shape of HA-PLA nanoparticles were characterized by particle size analyzer and scanning electron microscopy (SEM). Fluorescent dye (coumarin-6) and curcumin-encapsulated nanoparticles were treated with cancer cell line or HSCs (qHSC and aHSC) in vitro. Nanoparticle cellular binding efficiency was examined on several cell types such as MDA-MB-231 (CD44+), ZR-75-1 (CD44-), A549, aHSCs and qHSCs. High fluorescent intensity was shown in aHSCs due to the elevated expression of CD44, the receptor of HA, on aHSCs but not the normal cell types. These results also suggested that the binding efficiency was positively correlated to the abundance of cell surface CD44. Moreover cytotoxicity assay revealed that the carrier HA-ADH-PLA was toxic free and suitable for hepatofibrosis treatment. The IC50 of curcumin reduced 30-fold (from 80.4 μM reduce to 2.6 μM) by using the nanoformulation on aHSC, whereas no toxicity observed on other cell types (hepatic cells, clone 9, qHSC). These results indicated the excellence of curcumin-encapsulated HA-ADH-PLA nanoformulation. In summary, phenolic compounds can exert their effects on the eradication of aHSC, especially by nanoformulation.
論文摘要 I
英文摘要 III
圖目錄 VIII
表目錄 IX
第一章 緒論 - 1 -
1-1前言 - 1 -
1-2肝纖維化與肝硬化 - 2 -
1-3肝星狀細胞 - 3 -
1-4槲皮素 - 7 -
1-5沒食子酸 - 9 -
1-6薑黃素 - 10 -
1-7細胞凋亡 - 11 -
1-8生物可降解材料 - 14 -
1-9聚乳酸 - 15 -
1-10玻尿酸 - 16 -
1-11藥物釋放系統 - 23 -
1-12研究動機與目的 - 25 -
第二章 實驗材料 - 26 -
2-1動物品系 - 26 -
2-2細胞來源 - 26 -
2-3實驗器材 - 27 -
2-4實驗藥品 - 29 -
第三章 實驗方法與步驟 - 36 -
3-1肝星狀細胞的萃取分離 - 36 -
3-2細胞實驗 - 37 -
3-2-1細胞活化 - 37 -
3-2-2細胞繼代培養 - 37 -
3-2-3細胞冷凍保存 - 37 -
3-2-4細胞計數 - 38 -
3-2-5細胞存活率分析 (Cell Viability assay) - 38 -
3-2-6細胞週期分析 (Flow cytometry) - 39 -
3-2-7西方墨點轉漬法 (Western Blot assay) - 39 -
3-2-8膠原蛋白生合成分析 - 39 -
3-2-9細胞毒性分析-乳酸去氫酶活性測定 - 40 -
3-2-10細胞靶向測試 - 40 -
3-2-11 CD44 接受器定量 - 41 -
3-3玻尿酸-聚乳酸奈米粒子之合成 - 41 -
3-3-1酸水解玻尿酸 - 41 -
3-3-2玻尿酸-ADH之合成方法 - 41 -
3-3-3玻尿酸-ADH-聚乳酸之合成方法 - 41 -
3-3-4製作包覆螢光之奈米粒子 (溶劑揮發法) - 42 -
3-4奈米粒子之特性分析 - 42 -
3-4-1粒徑分析 - 42 -
3-4-2界面電位分析(Zeta potential) - 42 -
3-4-3掃描式電子顯微鏡拍攝 - 42 -
3-4-4膠體滲透層析儀 (Gel-Permeation Chromatography,GPC) - 43 -
3-4-5分光光度計 - 43 -
3-4-6原子力顯微鏡(Atomic force microscopy, AFM) - 43 -
3-5螢光染料包覆效率與釋放率分析 - 44 -
3-5-1測量螢光染料之最佳吸收波長及標準曲線 - 44 -
3-5-2包覆之螢光染料濃度分析 - 44 -
3-5-3包覆效率計算 - 44 -
第四章 實驗結果 - 45 -
4-1 槲皮素 - 45 -
4-1-1不同劑量槲皮素對肝星狀細胞存活之影響 - 45 -
4-1-2不同劑量槲皮素對肝星狀細胞增殖之影響 - 45 -
4-1-3槲皮素促使肝星狀細胞之細胞週期停滯於G1期 - 45 -
4-2 沒食子酸 - 46 -
4-2-1不同劑量沒食子酸對肝星狀細胞存活之影響 - 46 -
4-2-2不同劑量沒食子酸對肝星狀細胞增殖之影響 - 46 -
4-2-3食子酸有效降低活化態肝星狀細胞之膠原蛋白分泌量 - 47 -
4-2-4沒食子酸有效降低肝星狀細胞活化指標蛋白α-SMA的表現 - 47 -
4-2-5沒食子酸作用於肝星狀細胞之毒性分析 - 47 -
4-2-6沒食子酸對肝星狀細胞之細胞週期的影響 - 48 -
4-2-7以基因微陣列系統分析肝星狀細胞之基因表現 - 48 -
4-3玻尿酸奈米粒子包覆薑黃素 - 49 -
4-3-1玻尿酸-ADH-聚乳酸核磁共振光譜(NMR)與紅外線光譜分析 - 49 -
4-3-2 HA-ADH-PLA 奈米粒子的形成 - 49 -
4-3-3奈米粒子包覆率探討 (PVA添加與粒徑大小的關係) - 50 -
4-3-4 玻尿酸-ADH-聚乳酸奈米粒子界面電位 (Zeta potential) - 50 -
4-3-5薑黃素濃度對奈米粒子合成之影響 - 51 -
4-3-6 HA-ADH-PLA polymer對癌細胞株與肝組織細胞之毒性分析 - 51 -
4-3-7包覆薑黃素之奈米粒子對肝臟實質與非實質細胞之毒殺效率 - 51 -
4-3-8薑黃素對各細胞之半致死濃度 (IC50) - 52 -
4-3-9細胞表面CD44 含量分析 - 52 -
4-3-10包覆螢光物質之奈米粒子靶向試驗 - 53 -
第五章 討論 - 54 -
5-1不同酚類化合物抑制肝星狀細胞的生長增殖探討 - 54 -
5-2不同酚類化合物抑制肝星狀細胞的細胞週期停滯 - 54 -
5-3不同酚類化合物誘導肝星狀細胞凋亡及其途徑 - 55 -
5-4沒食子酸促使肝星狀細胞凋亡的其他途徑 - 55 -
5-6玻尿酸奈米粒子作為藥物載體對肝纖維化治療之應用 - 56 -
第六章 結論 - 57 -
第七章 參考文獻 - 58 -
第八章 圖表 - 68 -
附圖 - 89 -

1.行政院衛生署2010年台灣區十大死因與癌症統計資料
2.Meo, C.D., Panza, L., Capitani, D., Mannina. L., Banzato, A., Rondina, M., Renier, D., Rosato, A., Crescenzi, V., Hyaluronan as carrier of carboranes for tumor targeting in boron neutron capture therapy. Biomacromolecules. 2007. 8(2):552-9
3.Cheong, I., Huang, X., Bettegowda, C., Diaz Jr., L. A., Kinzler, K.W., Zhou, S., Vogelstein, B., A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science. 2006. 314(5803):1308-11
4.Andresen, T.L., Jensen, S.S., Kaasgaard, T., Jørgensen, K., Triggered activation and release of liposomal prodrugs and drugs in cancer tissue by secretory phospholipase A2. Curr Drug Deliv. 2005. 2(4):353-62
5.Schacht, E.H., Using biodegradable polymers in advanced drug delivery systems. Med Device Technol. 1990. 1(1):15-21
6.Zambaux, M.F., Bonneaux, F., Gref, R., Maincent, P., Dellacherie, E., Alonso, M.J., Labrude, P., Vigneron, C., Influence of experimental parameters on the characteristics of poly(lactic acid) nanoparticles prepared by a double emulsion method. J Control Release. 1998. 50(1-3):31-40
7.Khanna, S.C., Speiser, P., Epoxy resin beads as a pharmaceutical dosage form. I. Method of preparation. J Pharm Sci. 1969. 58(9):1114-7
8.Khanna, S.C., Speiser, P., Epoxy resin beads as a pharmaceutical dosage form. II. Dissolution studies of epoxy-amine beads and release of drug. J Pharm Sci. 1969. 58(11):1385-8
9.Shapiro,G.I., Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006. 24(11):1770-83
10.Platt, V.M., Szoka, Jr.F.C., Anticancer therapeutics: targeting macromolecules and nanocarriers to hyaluronan or CD44, a hyaluronan receptor. Mol Pharm. 2008. 5(4): 474-86
11.Hyung, W., Ko, H., Park, J., Lim, E., Park, S.B., Park, Y.J., Yoon, H.G., Suh, J.S., Haam, S., Huh, Y.M., Novel hyaluronic acid (HA) coated drug carriers (HCDCs) for human breast cancer treatment. Biotechnol Bioeng. 2008. 99(2):442-5
12.Asari, A., Morita, M., Sekiguchi, T., Okamura, K., Horie, K., Miyauchi, S., Hyaluronan, CD44 and fibronectin in rabbit corneal epithelial wound healing. Jpn J Ophthalmol. 1996. 40(1):18-25
13.Hans, M., Shimoni, K., Danino, D., Siegel, S.J., Lowman, A., Synthesis and characterization of mPEG-PLAprodrug micelles. Biomacromolecules. 2005. 6(5):2708-17
14.Friedman, S.L., Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 2000. 275(4):2247-50
15.Von Kupffer C: Uber Sternzellen der Leber. Briefliche Mitteilung an Professor Waldeyer. Arch mile Anat. 1876. 12:353-358
16.Weiner, F.R., Giambrone, M.A., Czaja, M.J., Shah, A., Annoni, G., Zern, M.A., Ito cell gene expression and collagen regulation. Hepatology. 1990. 11:111
17.Senoo, H., Imai, K., Matano, Y., Sato, M., Molecular mechanisms in the reversible regulation of morphology, proliferation and collagen metabolism in hepatic stellate cells by the three-dimensional structure of the extracellular matrix. J Gastroenterol Hepatol. 1998. 13 Suppl:S19-32
18.Friedman, S.L., Hepatic stellate cells. Prog Liver Dis. 1996. 14:101-30
19.Ueno,T., Sata, M., Sakata, R., Torimura, T., Sakamoto, M., Sugawara, H., Tanikawa, K., Hepatic stellate cells and intralobular innervation in human liver cirrhosis. Hum Pathol. 1997. 28 (8):953-9
20.Li, J.T., Liao, Z.X., Ping, J., Xu, D., Wang, H., Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies. J Gastroenterol. 2008. 43(6):419-28
21.Gresser, A.M., Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis. Kidney Int Suppl. 1996. 54:S39-45
22.Friedman, S.L., Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med. 1993. 328(25):1828-35
23.Maher, J.J., Leukocytes as modulators of stellate cell activation. Alcohol Clin Exp Res. 1999. 23 (5):917-21
24.Nieto, N., Friedman, S.L., Greenwel, P., Cederbaum, A.I., CYP2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells. Hepatology. 1999. 30(4):987-96
25.Lee, K.S., Buck, M., Houglum, K., Chojkier, M., Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest. 1995. 96:2461-8
26.Schnabl, B., Brandl, K., Fink, M., Gross, P., Taura, K., Gäbele, E., Hellerbrand, C., Falk, W., A TLR4/MD2 fusion protein inhibits LPS-induced pro-inflammatory signaling in hepatic stellate cells. Biochem Biophys Res Commun. 2008. 375(2):210-4
27.Bataller, R., Brenner, D.A., Liver fibrosis. J Clin Invest. 2005. 115(2):209-218
28.Marra, F., DeFranco, R., Grappone, C., Milani, S., Pastacaldi, S., Pinzani, M., Romanelli, R.G., Laffi, G., Gentilini, P., Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol. 1998. 152:423-30
29.Burt, A.D., Griffiths, M.R., Schuppan, D., Voss, B., MacSween, R.N., Ultrastructural localization of extracellular matrix proteins in liver biopsies using ultracryomicrotomy and immune-gold labeling. Histopathology. 1990. 16(1):53-8
30.Schuppan, D., Structure of the extracellular matrix in normal and fibrotic liver: collagens and glycoproteins. Semin Liver Dis. 1990. 10 (1):1-10
31.Bataller, R., Brenner, D.A., Liver fibrosis. J Clin Invest. 2005. 115(2):209-18
32.Smith, C., Lombard, K.A., Peffley, E. B., Liu, W., Genetic Analysis of Quercetin in Onion (Allium cepa L.) Lady Raider. The Texas Journal of Agriculture and Natural Resource. 2003. 16:24-8
33.Smith, C., Lombard, K.A., Peffley, E. B., Liu, W., Genetic Analysis of Quercetin in Onion (Allium cepa L.) Lady Raider. The Texas Journal of Agriculture and Natural Resource. 2003. 16:24-8
34.Zhu, J.X., Wang, Y., Kong, L.D., Yang, C., Zhang, X., Effects of Biota orientalis extract and its flavonoid constituents, quercetin and rutin on serum uric acid levels in oxonate-induced mice and xanthine dehydrogenase and xanthine oxidase activities in mouse liver. J Ethnopharmacol. 2004. 93(1):133-40
35.Negre-Salvayre, A., Salvayre, R., Quercetin prevents the cytotoxicity of oxidized LDL on lymphoid cell lines. Free Radic Biol Med. 1992. 12(2):101-6
36.Alarconde la Lastra, C., Martin, M.J., Motilva, V., Antiulcer and gastroprotective effects of quercetin: a gross and histologic study. Pharmacology. 1994. 8(1):56-62
37.Martin, M.J., La-Casa, C., Alarcon-de-Lastra, C., Cabeza, J., Villegas, I., Motilva, V., Anti-oxidant mechanisms involved in gastroprotetive effects of quercetin. Z Naturforsch Sec C J Biosci. 1998. 53:82-88
38.Yoon, J.S., Lee, H.J., Choi, S.H., Chang, E.J., Lee, S.Y., Lee, E.J., Quercetin Inhibits IL-1β-Induced Inflammation, Hyaluronan Production and Adipogenesis in Orbital Fibroblasts from Graves' Orbitopathy. PLoS One. 2011. 6(10):e26261
39.Boots, A.W., Drent, M., de Boer, V.C.J., Bast, A., Haenen, G.R.M.M., Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. Clin Nutr. 2011. 30(4):506-12
40.de Whalley, C.V., Rankin, S.M., Hoult, J.R., Jessup, W., Leake, D.S., Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages. Biochem Pharmacol. 1990. 39 (11):1743-50
41.Fuhrman, B., Aviram, M., Flavonoids protect LDL from oxidation and attenuate atherosclerosis. Curr Opin Lipidol. 2001. 12 (1):41-8
42.Edwards, R.L., Lyon, T., Litwin, S.E., Rabovsky, A., Symons, J.D., Jalili, T., Quercetin reduces blood pressure in hypertensive subjects. J Nutr. 2007. 137 (11):2405-11
43.Lopez-Reyes, A.G., Arroyo-Curras, N., Cano, B.G., Lara-Diaz, V.J., Guajardo-Salinas, G.E., Islas, J.F., Morales-Oyarvide, V., Morales-Garza, L.A., Galvez-Gastelum, F.J., Grijalva, G., Moreno-Cuevas, J.E., Black bean extract ameliorates liver fibrosis in rats with CCl4-induced injury. Ann Hepatol. 2008. 7 (2):130-5
44.el-Gammal, A.A., Mansour, R.M., Antimicrobial activities of some flavonoid compounds. Zentralbl Mikrobiol. 1986. 141 (7):561-5
45.Cushnie, T.P., Lamb, A.J., Antimicrobial activity of flavonoids. Int J Antimicrob Agents. 2005. 26(5):343–356
46.Meerbach, A., Neyts, J., Balzarini, J., Helbig, B., De Clercq, E., Wutzler, P., In vitro activity of polyhydroxycarboxylates against herpesviruses and HIV. Antiviral Chem Chemother. 2001. 12:337–345
47.Savi, L.A., Leal, P.C., Vieira, T.O., Rosso, R., Nunes, R.J., Yunes, R.A., Creczynski-Pasa, T.B., Barardi, C.R., Simoes, C.M., Evaluation of anti-herpetic and antioxidant activities, and cytotoxic and genotoxic effects of synthetic alkyl-esters of gallic acid. Arzneimittelforschung. 2005. 55, 66–75
48.Cha´vez, J.H., Leal, Yunes, P.C., Yunes, R.A., Nunes, R.J., Barardi, C.R.M., Pinto, A.R., Simo˜es, C. M.O., Zanetti, C.R., Evaluation of antiviral activity of phenolic compounds and derivatives against rabies virus. Veterinary Microbiology. 2006. 116:53–59
49.Labieniec, M., Gabryelak, T., Study of interactions between phenolic compounds and H2O2 or Cu (II) ions in B14 Chinese hamster cells. Cell Biol. Int. 2006. 30:761-768
50.Labieniec, M., Gabryelak, T., Antioxidative and oxidative changes in the digestive gland cells of freshwater mussels Unio tumidus caused by selected phenolic compounds in the presence of H2O2 or Cu 2+ ions. Toxicol. In Vitro. 2007. 21: 146-156
51.Kim, S.H., Jun, C.D., Suk, K., Choi, B.J., Lim, H., Park, S., Lee, S.H., Shin, H.Y., Kim, D.K., Shin, T.Y., Gallic Acid Inhibits Histamine Release and Pro-inflammatory Cytokine Production in Mast Cells. Toxicol Sci. 2006. 91(1), 123–131
52.Roy, G., Lombardia, M., Palacios, C., Serrano, A., Cespón, C., Ortega, E., Eiras, P., Luján, S., Revilla, Y., González-Porqué, P., Mechanistic aspects of induction of apoptosis by lauryl gallate in murine B-cell lymphoma line Wehi 231. Arch Biochem Biophys 2000. 383:206–214
53.Lee, K.W., Hur, H.J., Lee, H.J., Lee, C.Y., Antiproliferative effects of dietary phenolic substances and hydrogen peroxide. J Agric Food Chem 2005. 53:1990-1995
54.Qiu, X., Takemura, G., Koshiji, M., Hayakawa, Y., Maruyama, R., Ohno, Y., Minatoguchi, S., Akao., Fukuda, K., Fujiwara, T., Fuhiwara, H., Gallic acid induces vascular smooth muscle cell death via hydroxyl radical production. Heart Vessels 2000. 15:90-99
55.Isuzugawa, K., Inoue, M., Ogihara, Y., Catalase contents in cells determine sensitivity to apoptosis inducer gallic acid. Biol Pharm Bull 2001. 24:1022-1026
56.Labieniec, M., Gabryelak, T., Study of interactions between phenolic compounds and H2O2 or Cu (II) ions in B14 Chinese hamster cells. Cell Biol. Int. 2006, 30, 761-768.
57.Labieniec, M., Gabryelak, T., Antioxidative and oxidative changes in the digestive gland cells of freshwater mussels Unio tumidus caused by selected phenolic compounds in the presence of H2O2 or Cu 2+ ions. Toxicol In Vitro 2007. 21:146-156
58.Rao C.V., Regulation of COX and LOX by curcumin. Advances in experimental medicine and biology. 2007. 595: 213-26.
59.Sharma, C., Kaur, J., Shishodia, S., Aggarwal, B.B., Ralhan, R., Curcumin down regulates smokeless to induced NF-kappaB activation and COX-2 expression in human oral premalignant and cancer cells, Toxicology. 2006. 228:1–15
60.Roy, M., Chakraborty, S., Siddiqi, M., Bhattacharya, R.K., Induction of apoptosis in tumor cells by natural phenolic compounds. Asian Pac J Cancer Prevention. 2002. 361–67
61.Kim, K.R., Liu, M.J., Choi, Y.K., GADD153-mediated anticancer effects of N-(4-hydroxyphenyl) retinamide on human hepatoma cells. Biol Chem.2002. 277: 38930 –38938
62.Lengwehasatit, I., Dickson, A.J., Analysis of the role of GADD153 in the control of apoptosis in NS0 myeloma cells. Biotechnol Bioeng. 2002. 80:719–730
63.Rashmi, R., Santhosh Kumar, T.R., Karunagaran, D., Human colon cancer cells differin their sensitivity to curcumin-induced apoptosis and heat shock protects them by inhibiting the release of apoptosis -inducing factor and caspases. FEBS Lett. 2003. 528:19–24.
64.Vaux, D.L., Korsmeyer, S.J., Cell death in development. Cell. 1999. 96 (2):245-54.
65.Kamesaki, H., Mechanisms involved in chemotherapy-induced apoptosis and their implications in cancer chemotherapy. Int J Hematol. 1998. 68 (1):29-43
66.Huerta, S., Goulet, E.J., Huerta-Yepez, S., Livingston EH. Screening and detection of apoptosis. J Surg Res. 2007. 139 (1):143-56
67.Bedi, A., On the TRAIL from death receptors to prostate cancer therapy. Cancer Biol Ther. 2002. 1 (6):638-9
68.Belka, C., Rudner, J., Wesselborg, S., Stepczynska, A., Marini, P., Lepple-Wienhues, A., Faltin, H., Bamberg, M., Budach, W., Schulze-Osthoff, K., Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis. Oncogene. 2000. 19 (9):1181-90
69.Wallace-Brodeur, R.R., Lowe, S.W., Clinical implications of p53 mutations. Cell Mol Life Sci. 1999. 55 (1):64-75
70.Lowe, S.W., Schmitt, E.M., Smith, S.W., Osborne, B.A., Jacks, T., p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993. 362 (6423):847-9
71.Evan, G.I., Vousden, K.H., Proliferation, cell cycle and apoptosis in cancer. Nature. 2001. 411 (6835):342-8
72.Sun, X.M., MacFarlane, M., Zhuang, J., Wolf, B.B., Green, D.R., Cohen, G.M., Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem. 1999. 274 (8):5053-60
73.Janicke, R.U., Ng, P., Sprengart, M.L., Porter, A.G., Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. J Biol Chem. 1998. 273 (25):15540-5
74.McConnell, B.B., Gregory, F.J., Stott, F.J., Hara, E., Peters, G., Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes. Mol Cell Biol. 1999. 19(3):1981-9
75.Lin, Y.L., Lin, C.Y., Chi, C.W., Huang, Y.T., Study on antifibrotic effects of curcumin in rat hepatic stellate cells. 2009. Phytother Res. 23:927-932
76.Friedman, S.L., Cytokines and fibrogenesis. Semin Liver Dis. 1999. 19(2):129-40
77.Selway, J.W., Antiviral activity of flavones and flavans. Prog Clin Biol Res. 1986. 213:521-36
78.Manach, C., Williamson, G., Morand, C., Scalbert, A., Remesy, C., Bioavailability and bioefficacy of polyphenols in humans.I. Review of bioavailability studsies. Am J Clin Nutr. 2005. 81(1Suppl):230S-42S
79.Li, L., Braiteh, F. S., Kurzrock, R., Liposome-encapsulated curcumin-in vitro and in vivo effects on proliferation,apoptosis,signaling,and angiogenesis. Cancer sep. 2005. 104(6):1322-1331
80.朱一民,黃恩琪,葡聚醣接枝聚已內酯之兩性高分子及其奈米粒子應用於包覆藥物的研究。國立清華大,化學工程研究所,2008年碩士論文。
81.LI, L., Effect of Hyaluronan-activation of CD44 on Cell Signaling and Tumorigenesis. Acta Universitatis Upsaliensis Uppsala, 2006.
82.Morimoto, K., Yamaguchi, H., Iwakura, Y., Morisaka, K., Ohashi, Y., Nakai, Y., Pharm Res. 1991. 8:471-474
83.Kogan, G., Sˇolte´s, L., Stern, R., Gemeiner, P., Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications. Biotechnol Lett. 2007. 29:17–25
84.Platt, V.M., F.C. Szoka, Jr., Anticancer therapeutics: targeting macromolecules and nanocarriers to hyaluronan or CD44, a hyaluronan receptor. Mol Pharm. 2008. 5(4): 474-86
85.Knudson, W., Knudson, C.B., The hyaluronan receptor, CD44. Glycoforum,2004.
86.Laurent, T.C.E., The Chemistry, Biology and Medical Applications of Hyaluronan and its Derivatioves.Wenner-Gren International Series. 1998. 72
87.Perschl, A., Lesley, J., English, N., Trowbridge, I., Hyman, R., Role CD44 cytoplasmic domain in hyaluronan binding. Eur J Immunol. 1995. 25(2):495-501
88.Koh, J. Y., Choi, D. W., Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. J Neurosci Methods. 1987. 20(1):83-90
89.Liu, X., and Schnellmann, R. G. (2003). Calpain mediates progressive plasma membrane permeability and proteolysis of cytoskeleton-associated paxillin, talin, and vinculin during renal cell death. J. Pharmacol. Exp. Ther. 304,63–70.
90.iu, X., Rainey, J.J., Harriman, J.F., Schnellmann, R.G., Calpains mediate acute renal cell death :role of autolysis and translocation. Am J Physiol Renal Physiol. 2001. 81:F728-738
91.Liu, X., Harriman, J.F., Schnellmann, R.G., Cytoprotective properties of novel nonpeptide calpain inhibitors in renal cells. J Pharmacol Exp Ther. 2002. 302:88-94.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top