臺灣博碩士論文加值系統

RAGE (receptor for advanced glycation endproducts) 之活化於臨床上已經證實與心血管疾病、肥胖、糖尿病、神經病變、阿茲海默氏症、癌症及老化等多種疾病之病理進程有密切相關。因此，抑制 RAGE 活化儼然已成為目前新穎藥物設計開發與臨床標靶治療之熱門研究主題。sRAGE (Soluble RAGE) 為 RAGE 之異構物，目前研究將 sRAGE 分為 esRAGE (endogenous secretory RAGE) 與 cRAGE (cleaved RAGE)，其可釋放於血液循環中捕捉多種 RAGE 配體如 AGEs (advanced glycation endproducts)、Aβ (β-amyloid) 等，因此可抑制 RAGE 活化，而具減緩人體疾病之實質生理作用，推測 sRAGE 為未來臨床上治療慢性疾病之主要標靶蛋白。然而 sRAGE 於生理上之調控機轉與促進作用並不十分明確。文獻指出，兒茶素具有降血糖、抗氧化和抗發炎等功效，但是否具有促進 sRAGE 釋放之作用並不明確。故本研究模擬糖尿病患者之高血糖生理環境，將人類單核球細胞 (THP-1) 培養於高糖 (15 mM) 環境中，探討兒茶素EGCG (epigallocatechin gallate) 對 THP-1 細胞中 sRAGE 釋放之影響，同時探討 sRAGE 生成之調控機轉。本研究更進一步分析 sRAGE 對於高糖 (25 mM) 所活化之發炎複合體 (inflammasome) 是否具有抑制效應。
實驗結果顯示，高糖環境誘發過多的胞內活性氧 (ROS)，促進 RAGE 與其配體 (ligands) S100A12 之表現；同時抑制細胞中基因轉錄後修飾作用 (gene splicing)，降低 esRAGE 之生成。高糖亦會阻礙胞內抗氧化系統之轉錄因子 Nrf2 (nuclear factor erythroid 2-related factor 2) 活性以及 Nrf2 與 ADAM10 (a disintegrin and metalloproteinase 10) 基因啟動子 (promoter) 之結合作用，而減少基質金屬蛋白酶 ADAM10 對 RAGE 之截切機制，使 cRAGE 分泌量下降。結果顯示 THP-1 細胞在高糖環境下使細胞中 sRAGE 總分泌量下降。
EGCG 除了可清除 THP-1 細胞胞內活性氧，亦促進 RAGE 基因轉錄合成 esRAGE，降低細胞內 RAGE 蛋白質生成量。EGCG 亦可透過增加 Nrf2 之轉位活性，提升下游基質金屬蛋白酶 ADAM10 之表現，以促進 cRAGE 之釋放量，顯示 EGCG 可透過修飾基因轉錄作用與提升 ADAM10 表現而促進 THP-1 細胞中 sRAGE 之釋放。本研究進一步發現 EGCG 因促進 THP-1 細胞釋放 sRAGE，而可抑制高糖誘導之 TXNIP (thioredoxin interaction protein) 表現與 NLRP3 發炎複合體 (NLRP3 inflammasome) 活化，減少 IL-1β (interleukin-1β) 之釋放。綜合上述，本研究發現，高濃度葡萄糖可誘發胞內活性氧之生成，藉調控 RAGE 與 Nrf2 之表現，使 THP-1 細胞中 sRAGE 之總分泌量顯著下降；而介入 EGCG 具有促進 sRAGE 釋放之調控效應，進而抑制發炎複合體之活化，減少促發炎激素 IL-1β 之表現。顯示 EGCG 為未來臨床上應用於治療與預防糖尿病發炎疾病，具潛力之天然抗氧化物。

In the previous study, activation of receptor for advanced glycation endproduct (RAGE) is associated with many pathological progresses, including cardiovascular disease, obesity, diabetes mellitus (DM), neuropathy, Alzheimer''s disease, cancer and aging. Therefore, inhibition of RAGE activation is regarded as a popular research for novel drug design and clinical therapy. Soluble RAGE (sRAGE) is an isoform of RAGE, which is classified into endogenous secretory RAGE (esRAGE) and cleaved RAGE (cRAGE). Circulating sRAGE may act as a decoy for RAGE ligands, such as glycated protein, S100 protein and amyloid-β (Aβ), and inversely reflect RAGE activation, thus providing a pre-clinical biomarker of RAGE-mediated pathogenesis. However, the regulatory mechanism of sRAGE secretion in human body is still unknown. Many studies indicate that catechins possess anti-hyperglycemia effect, anti-oxidative effect and anti-inflammation. Moreover, effect of EGCG on the secretion of sRAGE remains unclear. Thus, the aim of this study was to investigate the regulatory effect of epigallocatechin-3-gallate (EGCG) on sRAGE secretion in HG-induced THP-1 cells. The inhibitory effect of sRAGE on inflammasome activation induced by high glucose was also investigated.
The results showed that excessive intracellular ROS (reactive oxygen species) induced by high glucose increased the expression of RAGE and its ligand (S100A12). Moreover, ROS decreased the production of esRAGE by inhibiting the alternative splicing process of RAGE gene in THP-1 cells. High glucose also suppressed nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and direct binding of Nrf2 to the ADAM10 (a disintegrin and metalloproteinase) promoter. In addition, ADAM10 was inhibited by reduction of Nrf2 nuclear translocation, leading to the decreased levels of cRAGE in HG-induced THP-1 cells.
EGCG could scavenge ROS to increase esRAGE levels through post-transcriptional regulation of RAGE gene in HG-induced THP-1 cells. EGCG induced ADAM10 expression after increasing Nrf2 translocation and thus promoted the secretion of cRAGE. These results suggest that EGCG stimulates the release of sRAGE through ADAM10-mediated proteolysis of extracellular RAGE in HG-induced THP-1 cells. Furthermore, EGCG-stimulated sRAGE and then blocked the activation of thioredoxin interaction protein (TXNIP) and NOD-like receptor protein 3 (NLRP3) inflammasome, which subsequently decreased the IL-1β secretion in HG-induced THP-1 monocytes. Taken together, high glucose induced intracellular ROS to suppress the sRAGE secretion by up-regulating RAGE and down-regulating Nrf2 nuclear translocation in THP-1 monocytes. Moreover, treatment with EGCG promoted sRAGE release to reduce the secretion of IL-1β by inhibiting the activation of NLRP3 inflammasome. Therefore, EGCG might be a potent agent for the management of diabetes.

全文摘要 1
Abstract 3
前言 5
文獻回顧 7
壹、糖尿病 8
一、背景 8
二、定義 8
三、高血糖誘發生理損傷之機制 9
貳、RAGE (the receptor for advanced glycation endproducts) 15
一、背景 15
二、結構與活化機制 15
三、sRAGE (soluble RAGE) 20
四、RAGE 、sRAGE 與糖尿病之相關研究 22
參、轉錄因子 Nrf2 (Nuclear factor erythroid 2-related factor 2) 23
一、結構與活化機制 23
二、Nrf2 與糖尿病之相關研究 27
肆、發炎複合體 (Inflammasome) 28
一、背景 28
二、NLRP3發炎複合體之活化機制 29
三、發炎複合體與糖尿病之相關研究 32
伍、EGCG (Epigallocatechin gallate) 33
研究目的 35
論文架構 36
第一部分、高糖誘發人類單核球細胞釋放 sRAGE 之分子機制
及介入 EGCG 之調控效應 37
摘要 38
Abstract 40
前言 42
實驗架構 44
材料與方法 45
一、實驗樣品 45
二、實驗材料與試劑 45
三、實驗細胞株 46
四、實驗方法 47
結果 57
(一) 高糖培養環境對人類單核球細胞生理之影響 57
一、高糖培養下對人類單核球細胞 RAGE 基因與蛋白表現之影響 57
二、高糖培養對人類單核球細胞 S100A12 基因表現之影響 57
三、高糖培養對人類單核球細胞胞內活性氧生成之影響 58
四、高糖培養對人類單核球細胞 Nrf2 轉錄蛋白轉位作用之影響 58
五、高糖培養下對人類單核球細胞 sRAGE 分泌之影響 58
六、高糖培養對人類單核球細胞 ADAM10 基因與蛋白表現之影響 59
(二) 高糖調控 sRAGE 釋放之分子機制 60
一、RAGE 對高糖培養人類單核球細胞 sRAGE 分泌之影響 60
二、Nrf2 對高糖培養人類單核球細胞 sRAGE 分泌之
影響 61
三、轉錄因子 Nrf2 與高糖培養之人類單核球細胞中 ADAM10 啟動子結合率之影響 62
四、ROS 對高糖培養對人類單核球細胞 esRAGE 分泌之影響 62
(三) EGCG 於高糖模式中對人類單核球細胞之保護作用 63
一、EGCG於高糖培養對人類單核球細胞 RAGE 蛋白質之影響 63
二、EGCG對高糖培養人類單核球細胞胞內活性氧生成之影響 63
三、EGCG對高糖培養對人類單核球細胞 Nrf2 蛋白轉位作用與其下游抗氧化酵素 HO-1 蛋白質表現之影響 63
四、EGCG於高糖培養對人類單核球細胞之轉錄因子 Nrf2 與 ADAM10 啟動子結合率與 ADAM10 蛋白質表現之影響 64
五、EGCG於高糖培養對人類單核球細胞 sRAGE 分泌之影響 64
討論 66
第二部分、EGCG 促進高糖培養人類單核球細胞釋放 sRAGE
以抑制發炎複合體之效應 94
摘要 95
Abstract 96
前言 97
實驗架構 98
材料與方法 99
一、實驗樣品 99
二、實驗材料與試劑 99
三、實驗細胞株 100
四、實驗方法 100
結果 105
一、高糖環境下對人類單核球細胞 IL-1β 釋放之影響 105
二、EGCG 與 sRAGE 對高糖培養人類單核球細胞 caspase-1 和 IL-1β 之影響 105
三、EGCG 與 sRAGE 對高糖培養人類單核球細胞 NLRP3 發炎複合體之影響 106
四、EGCG 與 sRAGE 對高糖培養人類單核球細胞胞內活性氧生成之影響 106
討論 108
總結論 115
參考文獻 118

行政院衛生署，2010。97 年度死因統計。取自：行政院衛生署，http://www.doh.gov.tw。
卓亭均，2008。抗氧化複方對streptozotocin誘發之糖尿病大鼠致血栓危險性之探討。靜宜大學食品營養研究所碩士論文。
趙雅禪，2010。富含 EGCG 之萃取物對第 2 型糖尿病患慢性發炎及至血栓危險因子影響之探討。靜宜大學食品營養研究所碩士論文。
Aleksunes, L.M., Reisman, S. A., Yeager, R. L., Goedken, M. J. and Klaassen, C. D. 2010. Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice. J. Pharmacol. Exp. Ther. 333: 140-151.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. 2006; 30: S43-48
American Diabetes Association. Diagnosis and classification of diabetes mellitus. 2007; 30: S42-47
American Diabetes Association. Diagnosis and classification of diabetes mellitus. 2010; 33: S62-69
Basta, G., Sironi, A. M., Lazzerini, G., Del Turco, S., Buzzigoli, E., Casolaro, A., Natali, A., Ferrannini, E. and Gastaldelli, A. 2006. Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein. J. Clin. Endocrinol. Metab. 91: 4628-4634.
Bigelow, R.L. and Cardelli, J. A. 2006. The green tea catechins, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG), inhibit HGF/Met signaling in immortalized and tumorigenic breast epithelial cells. Oncogene. 25: 1922-1930.
Bloom, D.A. and Jaiswal, A. K. 2003. Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:Quinone oxidoreductase-1 gene expression. J. Biol. Chem. 278: 44675-44682.
Bloomgarden, Z.T. 2009. The 6th annual world congress on the insulin resistance syndrome. Diabetes Care. 32: e127-33.
Brownlee, M. 2005. The pathobiology of diabetic complications: A unifying mechanism. Diabetes. 54: 1615-1625.
Brownlee, M. 2001. Biochemistry and molecular cell biology of diabetic complications. Nature. 414: 813-820.
Bryant, C. and Fitzgerald, K. A. 2009. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol. 19: 455-464.
Bumrungpert, A., Kalpravidh, R. W., Chitchumroonchokchai, C., Chuang, C. C., West, T., Kennedy, A. and McIntosh, M. 2009. Xanthones from mangosteen prevent lipopolysaccharide-mediated inflammation and insulin resistance in primary cultures of human adipocytes. J. Nutr. 139: 1185-1191.
Cataldegirmen, G., Zeng, S., Feirt, N., Ippagunta, N., Dun, H., Qu, W., Lu, Y., Rong, L. L., Hofmann, M. A., Kislinger, T., Pachydaki, S. I., Jenkins, D. G., Weinberg, A., Lefkowitch, J., Rogiers, X., Yan, S. F., Schmidt, A. M. and Emond, J. C. 2005. RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-alpha and NF-kappaB. J. Exp. Med. 201: 473-484.
Cavet, M.E., Harrington, K. L., Vollmer, T. R., Ward, K. W. and Zhang, J. Z. 2011. Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells. Mol. Vis. 17: 533-542.
Chen, Y., Yan, S. S., Colgan, J., Zhang, H. P., Luban, J., Schmidt, A. M., Stern, D. and Herold, K. C. 2004. Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products. J. Immunol. 173: 1399-1405.
Chow, H.H., Cai, Y., Alberts, D. S., Hakim, I., Dorr, R., Shahi, F., Crowell, J. A., Yang, C. S. and Hara, Y. 2001. Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol. Biomarkers Prev. 10: 53-58.
Coughlan, M.T., Thorburn, D. R., Penfold, S. A., Laskowski, A., Harcourt, B. E., Sourris, K. C., Tan, A. L., Fukami, K., Thallas-Bonke, V., Nawroth, P. P., Brownlee, M., Bierhaus, A., Cooper, M. E. and Forbes, J. M. 2009. RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J. Am. Soc. Nephrol. 20: 742-752.
Cuccurullo, C., Iezzi, A., Fazia, M. L., De Cesare, D., Di Francesco, A., Muraro, R., Bei, R., Ucchino, S., Spigonardo, F., Chiarelli, F., Schmidt, A. M., Cuccurullo, F., Mezzetti, A. and Cipollone, F. 2006. Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes. Arterioscler. Thromb. Vasc. Biol. 26: 2716-2723.
Dandona, P., Aljada, A. and Bandyopadhyay, A. 2004. Inflammation: The link between insulin resistance, obesity and diabetes. Trends Immunol. 25: 4-7.
Dell''Angelica, E.C., Schleicher, C. H. and Santome, J. A. 1994. Primary structure and binding properties of calgranulin C, a novel S100-like calcium-binding protein from pig granulocytes. J. Biol. Chem. 269: 28929-28936.
Devangelio, E., Santilli, F., Formoso, G., Ferroni, P., Bucciarelli, L., Michetti, N., Clissa, C., Ciabattoni, G., Consoli, A. and Davi, G. 2007. Soluble RAGE in type 2 diabetes: Association with oxidative stress. Free Radic. Biol. Med. 43: 511-518.
Dumitriu, I.E., Baruah, P., Valentinis, B., Voll, R. E., Herrmann, M., Nawroth, P. P., Arnold, B., Bianchi, M. E., Manfredi, A. A. and Rovere-Querini, P. 2005. Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J. Immunol. 174: 7506-7515.
Evans, J.L., Goldfine, I. D., Maddux, B. A. and Grodsky, G. M. 2002. Oxidative stress and stress-activated signaling pathways: A unifying hypothesis of type 2 diabetes. Endocr. Rev. 23: 599-622.
Foell, D., Wittkowski, H., Vogl, T. and Roth, J. 2007. S100 proteins expressed in phagocytes: A novel group of damage-associated molecular pattern molecules. J. Leukoc. Biol. 81: 28-37.
Fourquet, S., Guerois, R., Biard, D. and Toledano, M. B. 2010. Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J. Biol. Chem. 285: 8463-8471.
Genco, R.J., Grossi, S. G., Ho, A., Nishimura, F. and Murayama, Y. 2005. A proposed model linking inflammation to obesity, diabetes, and periodontal infections. J. Periodontol. 76: 2075-2084.
Geroldi, D., Falcone, C. and Emanuele, E. 2006. Soluble receptor for advanced glycation end products: From disease marker to potential therapeutic target. Curr. Med. Chem. 13: 1971-1978.
Giacco, F. and Brownlee, M. 2010. Oxidative stress and diabetic complications. Circ. Res. 107: 1058-1070.
Grossin, N., Boulanger, E., Wautier, M. P. and Wautier, J. L. 2010. The different isoforms of the receptor for advanced glycation end products are modulated by pharmacological agents. Clin. Hemorheol. Microcirc. 45: 143-153.
Grzelkowska-Kowalczyk, K. and Wieteska-Skrzeczynska, W. 2006. Exposure to TNF-alpha but not IL-1beta impairs insulin-dependent phosphorylation of protein kinase B and p70S6k in mouse C2C12 myogenic cells. Pol. J. Vet. Sci. 9: 1-10.
Hamada, N., Tanaka, A., Fujita, Y., Itoh, T., Ono, Y., Kitagawa, Y., Tomimori, N., Kiso, Y., Akao, Y., Nozawa, Y. and Ito, M. 2011. Involvement of heme oxygenase-1 induction via Nrf2/ARE activation in protection against H2O2-induced PC12 cell death by a metabolite of sesamin contained in sesame seeds. Bioorg. Med. Chem. 19: 1959-1965.
Hawkins, M., Barzilai, N., Liu, R., Hu, M., Chen, W. and Rossetti, L. 1997. Role of the glucosamine pathway in fat-induced insulin resistance. J. Clin. Invest. 99: 2173-2182.
Hayes, J.D., McMahon, M., Chowdhry, S. and Dinkova-Kostova, A. T. 2010. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid. Redox Signal. 13: 1713-1748.
He, X., Kan, H., Cai, L. and Ma, Q. 2009. Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes. J. Mol. Cell. Cardiol. 46: 47-58.
Hoffman, H.M. and Wanderer, A. A. 2010. Inflammasome and IL-1beta-mediated disorders. Curr. Allergy Asthma Rep. 10: 229-235.
Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., Kono, H., Rock, K. L., Fitzgerald, K. A. and Latz, E. 2008. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9: 847-856.
Houstis, N., Rosen, E. D. and Lander, E. S. 2006. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 440: 944-948.
Hudson, B.I., Kalea, A. Z., Del Mar Arriero, M., Harja, E., Boulanger, E., D''Agati, V. and Schmidt, A. M. 2008. Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J. Biol. Chem. 283: 34457-34468.
Humpert, P.M., Djuric, Z., Kopf, S., Rudofsky, G., Morcos, M., Nawroth, P. P. and Bierhaus, A. 2007. Soluble RAGE but not endogenous secretory RAGE is associated with albuminuria in patients with type 2 diabetes. Cardiovasc. Diabetol. 6: 9.
Jaiswal, A.K. 2004. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic. Biol. Med. 36: 1199-1207.
Jiang, T., Huang, Z., Lin, Y., Zhang, Z., Fang, D. and Zhang, D. D. 2010. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes. 59: 850-860.
Kanneganti, T.D., Lamkanfi, M., Kim, Y. G., Chen, G., Park, J. H., Franchi, L., Vandenabeele, P. and Nunez, G. 2007. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of toll-like receptor signaling. Immunity. 26: 433-443.
Keogh, R.J., Dunlop, M. E. and Larkins, R. G. 1997. Effect of inhibition of aldose reductase on glucose flux, diacylglycerol formation, protein kinase C, and phospholipase A2 activation. Metabolism. 46: 41-47.
Kim, J., Cha, Y. N. and Surh, Y. J. 2010. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat. Res. 690: 12-23.
Koenen, T.B., Stienstra, R., van Tits, L. J., de Graaf, J., Stalenhoef, A. F., Joosten, L. A., Tack, C. J. and Netea, M. G. 2011. Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1beta transcription in human adipose tissue. Diabetes. 60: 517-524.
Kohutek, Z.A., diPierro, C. G., Redpath, G. T. and Hussaini, I. M. 2009. ADAM-10-mediated N-cadherin cleavage is protein kinase C-alpha dependent and promotes glioblastoma cell migration. J. Neurosci. 29: 4605-4615.
Kosaki, A., Hasegawa, T., Kimura, T., Iida, K., Hitomi, J., Matsubara, H., Mori, Y., Okigaki, M., Toyoda, N., Masaki, H., Inoue-Shibata, M., Nishikawa, M. and Iwasaka, T. 2004. Increased plasma S100A12 (EN-RAGE) levels in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 89: 5423-5428.
Koyama, H., Yamamoto, H. and Nishizawa, Y. 2007. RAGE and soluble RAGE: Potential therapeutic targets for cardiovascular diseases. Mol. Med. 13: 625-635.
Krysiak, R. and Okopien, B. 2010. Different effects of simvastatin on ex vivo monocyte cytokine release in patients with hypercholesterolemia and impaired glucose tolerance. J. Physiol. Pharmacol. 61: 725-732.
Lamkanfi, M., Mueller, J. L., Vitari, A. C., Misaghi, S., Fedorova, A., Deshayes, K., Lee, W. P., Hoffman, H. M. and Dixit, V. M. 2009. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J. Cell Biol. 187: 61-70.
Manfredi, A.A., Capobianco, A., Esposito, A., De Cobelli, F., Canu, T., Monno, A., Raucci, A., Sanvito, F., Doglioni, C., Nawroth, P. P., Bierhaus, A., Bianchi, M. E., Rovere-Querini, P. and Del Maschio, A. 2008. Maturing dendritic cells depend on RAGE for in vivo homing to lymph nodes. J. Immunol. 180: 2270-2275.
Marshall, S., Bacote, V. and Traxinger, R. R. 1991. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. role of hexosamine biosynthesis in the induction of insulin resistance. J. Biol. Chem. 266: 4706-4712.
Martinon, F. and Tschopp, J. 2007. Inflammatory caspases and inflammasomes: Master switches of inflammation. Cell Death Differ. 14: 10-22.
Mitroulis, I., Skendros, P. and Ritis, K. 2010. Targeting IL-1beta in disease; the expanding role of NLRP3 inflammasome. Eur. J. Intern. Med. 21: 157-163.
Motohashi, H., Kimura, M., Fujita, R., Inoue, A., Pan, X., Takayama, M., Katsuoka, F., Aburatani, H., Bresnick, E. H. and Yamamoto, M. 2010. NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation. Blood. 115: 677-686.
Mustata, G.T., Rosca, M., Biemel, K. M., Reihl, O., Smith, M. A., Viswanathan, A., Strauch, C., Du, Y., Tang, J., Kern, T. S., Lederer, M. O., Brownlee, M., Weiss, M. F. and Monnier, V. M. 2005. Paradoxical effects of green tea (camellia sinensis) and antioxidant vitamins in diabetic rats: Improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking. Diabetes. 54: 517-526.
Na, H.K., Kim, E. H., Jung, J. H., Lee, H. H., Hyun, J. W. and Surh, Y. J. 2008. (-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Arch. Biochem. Biophys. 476: 171-177.
Nagai, N., Thimmulappa, R. K., Cano, M., Fujihara, M., Izumi-Nagai, K., Kong, X., Sporn, M. B., Kensler, T. W., Biswal, S. and Handa, J. T. 2009. Nrf2 is a critical modulator of the innate immune response in a model of uveitis. Free Radic. Biol. Med. 47: 300-306.
Nakaso, K., Yano, H., Fukuhara, Y., Takeshima, T., Wada-Isoe, K. and Nakashima, K. 2003. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett. 546: 181-184.
Neeper, M., Schmidt, A. M., Brett, J., Yan, S. D., Wang, F., Pan, Y. C., Elliston, K., Stern, D. and Shaw, A. 1992. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J. Biol. Chem. 267: 14998-15004.
Nishikawa, T., Edelstein, D., Du, X. L., Yamagishi, S., Matsumura, T., Kaneda, Y., Yorek, M. A., Beebe, D., Oates, P. J., Hammes, H. P., Giardino, I. and Brownlee, M. 2000. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 404: 787-790.
Nov, O., Kohl, A., Lewis, E. C., Bashan, N., Dvir, I., Ben-Shlomo, S., Fishman, S., Wueest, S., Konrad, D. and Rudich, A. 2010. Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology. 151: 4247-4256.
Oz Gul, O., Tuncel, E., Yilmaz, Y., Ulukaya, E., Gul, C. B., Kiyici, S., Oral, A. Y., Guclu, M., Ersoy, C. and Imamoglu, S. 2010. Comparative effects of pioglitazone and rosiglitazone on plasma levels of soluble receptor for advanced glycation end products in type 2 diabetes mellitus patients. Metabolism. 59: 64-69.
Palsamy, P. and Subramanian, S. 2010. Ameliorative potential of resveratrol on proinflammatory cytokines, hyperglycemia mediated oxidative stress, and pancreatic beta-cell dysfunction in streptozotocin-nicotinamide-induced diabetic rats. J. Cell. Physiol. 224: 423-432.
Park, L., Raman, K. G., Lee, K. J., Lu, Y., Ferran, L. J.,Jr., Chow, W. S., Stern, D. and Schmidt, A. M. 1998. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat. Med. 4: 1025-1031.
Pedra, J.H., Cassel, S. L. and Sutterwala, F. S. 2009. Sensing pathogens and danger signals by the inflammasome. Curr. Opin. Immunol. 21: 10-16.
Peters, C.M., Green, R. J., Janle, E. M. and Ferruzzi, M. G. 2010. Formulation with ascorbic acid and sucrose modulates catechin bioavailability from green tea. Food Res. Int. 43: 95-102.
Portilla, D., Dai, G., Peters, J. M., Gonzalez, F. J., Crew, M. D. and Proia, A. D. 2000. Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure. Am. J. Physiol. Renal Physiol. 278: F667-75.
Ramasamy, R., Yan, S. F. and Schmidt, A. M. 2009. RAGE: Therapeutic target and biomarker of the inflammatory response--the evidence mounts. J. Leukoc. Biol. 86: 505-512.
Raucci, A., Cugusi, S., Antonelli, A., Barabino, S. M., Monti, L., Bierhaus, A., Reiss, K., Saftig, P. and Bianchi, M. E. 2008. A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J. 22: 3716-3727.
Roghani, M. and Baluchnejadmojarad, T. 2010. Hypoglycemic and hypolipidemic effect and antioxidant activity of chronic epigallocatechin-gallate in streptozotocin-diabetic rats. Pathophysiology. 17: 55-59.
Rushworth, S.A., MacEwan, D. J. and O''Connell, M. A. 2008. Lipopolysaccharide-induced expression of NAD(P)H:Quinone oxidoreductase 1 and heme oxygenase-1 protects against excessive inflammatory responses in human monocytes. J. Immunol. 181: 6730-6737.
Santilli, F., Vazzana, N., Bucciarelli, L. G. and Davi, G. 2009. Soluble forms of RAGE in human diseases: Clinical and therapeutical implications. Curr. Med. Chem. 16: 940-952.
Sbai, O., Devi, T. S., Melone, M. A., Feron, F., Khrestchatisky, M., Singh, L. P. and Perrone, L. 2010. RAGE-TXNIP axis is required for S100B-promoted schwann cell migration, fibronectin expression and cytokine secretion. J. Cell. Sci. 123: 4332-4339.
Schlueter, C., Hauke, S., Flohr, A. M., Rogalla, P. and Bullerdiek, J. 2003. Tissue-specific expression patterns of the RAGE receptor and its soluble forms--a result of regulated alternative splicing? Biochim. Biophys. Acta. 1630: 1-6.
Schmidt, A.M., Sahagan, B., Nelson, R. B., Selmer, J., Rothlein, R. and Bell, J. M. 2009. The role of RAGE in amyloid-beta peptide-mediated pathology in alzheimer''s disease. Curr. Opin. Investig Drugs. 10: 672-680.
Schroder, K., Zhou, R. and Tschopp, J. 2010. The NLRP3 inflammasome: A sensor for metabolic danger? Science. 327: 296-300.
Seghrouchni, I., Drai, J., Bannier, E., Riviere, J., Calmard, P., Garcia, I., Orgiazzi, J. and Revol, A. 2002. Oxidative stress parameters in type I, type II and insulin-treated type 2 diabetes mellitus; insulin treatment efficiency. Clin. Chim. Acta. 321: 89-96.
Shi, X. and Zhou, B. 2010. The role of Nrf2 and MAPK pathways in PFOS-induced oxidative stress in zebrafish embryos. Toxicol. Sci. 115: 391-400.
Sparvero, L.J., Asafu-Adjei, D., Kang, R., Tang, D., Amin, N., Im, J., Rutledge, R., Lin, B., Amoscato, A. A., Zeh, H. J. and Lotze, M. T. 2009. RAGE (receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation. J. Transl. Med. 7: 17.
Srikrishna, G., Huttunen, H. J., Johansson, L., Weigle, B., Yamaguchi, Y., Rauvala, H. and Freeze, H. H. 2002. N -glycans on the receptor for advanced glycation end products influence amphoterin binding and neurite outgrowth. J. Neurochem. 80: 998-1008.
Sriram, N., Kalayarasan, S. and Sudhandiran, G. 2008. Enhancement of antioxidant defense system by epigallocatechin-3-gallate during bleomycin induced experimental pulmonary fibrosis. Biol. Pharm. Bull. 31: 1306-1311.
Sun, L., Ishida, T., Yasuda, T., Kojima, Y., Honjo, T., Yamamoto, Y., Yamamoto, H., Ishibashi, S., Hirata, K. and Hayashi, Y. 2009. RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice. Cardiovasc. Res. 82: 371-381.
Surh, Y.J. 2003. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer. 3: 768-780.
Tam, H.L., Shiu, S. W., Wong, Y., Chow, W. S., Betteridge, D. J. and Tan, K. C. 2010. Effects of atorvastatin on serum soluble receptors for advanced glycation end-products in type 2 diabetes. Atherosclerosis. 209: 173-177.
Tan, A.L., Forbes, J. M. and Cooper, M. E. 2007. AGE, RAGE, and ROS in diabetic nephropathy. Semin. Nephrol. 27: 130-143.
Thielecke, F. and Boschmann, M. 2009. The potential role of green tea catechins in the prevention of the metabolic syndrome - a review. Phytochemistry. 70: 11-24.
Tsai, P.Y., Ka, S. M., Chang, J. M., Chen, H. C., Shui, H. A., Li, C. Y., Hua, K. F., Chang, W. L., Huang, J. J., Yang, S. S. and Chen, A. 2011. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic. Biol. Med.
Vazzana, N., Santilli, F., Cuccurullo, C. and Davi, G. 2009. Soluble forms of RAGE in internal medicine. Intern. Emerg. Med. 4: 389-401.
Wang, W. and Lai, M. D. 2006. Alternative splicing of insulin receptor mRNA in cancer and type 2 diabetes mellitus: A review. Yi Chuan. 28: 226-230.
Wang, Y., Wang, H., Piper, M. G., McMaken, S., Mo, X., Opalek, J., Schmidt, A. M. and Marsh, C. B. 2010. sRAGE induces human monocyte survival and differentiation. J. Immunol.
Wautier, M.P., Chappey, O., Corda, S., Stern, D. M., Schmidt, A. M. and Wautier, J. L. 2001. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am. J. Physiol. Endocrinol. Metab. 280: E685-94.
Wei, Y., Chen, K., Whaley-Connell, A. T., Stump, C. S., Ibdah, J. A. and Sowers, J. R. 2008. Skeletal muscle insulin resistance: Role of inflammatory cytokines and reactive oxygen species. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294: R673-80.
Wendt, T., Harja, E., Bucciarelli, L., Qu, W., Lu, Y., Rong, L. L., Jenkins, D. G., Stein, G., Schmidt, A. M. and Yan, S. F. 2006. RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes. Atherosclerosis. 185: 70-77.
Wild, S., Roglic, G., Green, A., Sicree, R. and King, H. 2004. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 27: 1047-1053.
Wolfram, S. 2007. Effects of green tea and EGCG on cardiovascular and metabolic health. J. Am. Coll. Nutr. 26: 373S-388S.
World Health Organization. 2008. World health statistic 2008. Available from: http://www.who.int/whosis/whostat/EN_WHS08_Full.pdf.
Xue, M., Qian, Q., Adaikalakoteswari, A., Rabbani, N., Babaei-Jadidi, R. and Thornalley, P. J. 2008. Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes. 57: 2809-2817.
Yamagishi, S. and Matsui, T. 2010. Soluble form of a receptor for advanced glycation end products (sRAGE) as a biomarker. Front. Biosci. (Elite Ed). 2: 1184-1195.
Yamagishi, S. and Imaizumi, T. 2005. Diabetic vascular complications: Pathophysiology, biochemical basis and potential therapeutic strategy. Curr. Pharm. Des. 11: 2279-2299.
Yamimoto T., Juneja L.R., Djoing-chu C., Kim M. 1997. Chemistry and applications of green tea. Boca. Raton. FL:CRC Press.
Yan, S.F., Ramasamy, R. and Schmidt, A. M. 2010. The RAGE axis: A fundamental mechanism signaling danger to the vulnerable vasculature. Circ. Res. 106: 842-853.
Yan, S.S., Wu, Z. Y., Zhang, H. P., Furtado, G., Chen, X., Yan, S. F., Schmidt, A. M., Brown, C., Stern, A., LaFaille, J., Chess, L., Stern, D. M. and Jiang, H. 2003. Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nat. Med. 9: 287-293.
Yang, C.S., Chen, L., Lee, M. J., Balentine, D., Kuo, M. C. and Schantz, S. P. 1998. Blood and urine levels of tea catechins after ingestion of different amounts of green tea by human volunteers. Cancer Epidemiol. Biomarkers Prev. 7: 351-354.
Yao, D. and Brownlee, M. 2010. Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes. 59: 249-255.
Zhang, H., Tasaka, S., Shiraishi, Y., Fukunaga, K., Yamada, W., Seki, H., Ogawa, Y., Miyamoto, K., Nakano, Y., Hasegawa, N., Miyasho, T., Maruyama, I. and Ishizaka, A. 2008. Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury. Am. J. Respir. Crit. Care Med. 178: 356-362.
Zhou, R., Tardivel, A., Thorens, B., Choi, I. and Tschopp, J. 2010. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11: 136-140.
Zimmet, P., Alberti, K. G. and Shaw, J. 2001. Global and societal implications of the diabetes epidemic. Nature. 414: 782-787.
Zitouni, K., Nourooz-Zadeh, J., Harry, D., Kerry, S. M., Betteridge, D. J., Cappuccio, F. P. and Earle, K. A. 2005. Race-specific differences in antioxidant enzyme activity in patients with type 2 diabetes: A potential association with the risk of developing nephropathy. Diabetes Care. 28: 1698-1703.