臺灣博碩士論文加值系統

動脈粥狀硬化是長期發炎所累積而成的一種病症，其形成的初期過程包含氧化型低密度脂蛋白過度累積並活化血管內皮細胞以及誘發內皮細胞表現黏著分子並吸引血液循環中的白血球黏附到血管內皮細胞。研究指出氧化型低密度脂蛋白會刺激巨噬細胞分泌發炎性細胞激素腫瘤壞死因子 (tumor necrosis factor-α)，因此氧化型低密度脂蛋白被認為是一種促發炎刺激。穿心蓮內酯是一種 diterpene lactone，主要分佈於穿心蓮葉子中，目前證實穿心蓮內酯具有抗癌、保護肝臟與抗發炎等活性。本研究觀察穿心蓮內酯對腫瘤壞死因子誘發單核球黏附至人類臍靜脈內皮細胞的影響，發現穿心蓮內酯可有效抑制 HL-60 細胞株黏附至人類臍靜脈內皮細胞，也可抑制黏著分子 ICAM-1 總蛋白質與細胞表面的表現，以及抑制 ICAM-1 報導基因活性。穿心蓮內酯也可抑制腫瘤壞死因子誘發的 Akt 磷酸化，而且細胞預處理 PI3K 抑制劑 LY294002 也可顯著降低腫瘤壞死因子誘發的 ICAM-1 報導基因活性。此外，穿心蓮內酯也會減少 p65 進入細胞核內以及 NF-κB 與 DNA 的結合。這些結果顯示在人類臍靜脈內皮細胞中，穿心蓮內酯可藉由PI3K/Akt 或 NF-κB負向調控 ICAM-1 表現而具有抗發炎作用，本研究證實穿心蓮內酯在預防發炎反應形成過程扮演重要角色。

Atherosclerosis is an inflammatory disease in which the early stages of atherosclerosis are initiated by accumulation of oxLDL and activation of endothelial cells with subsequent expression of adhesion molecules and increased recruitment of leukocytes to the vascular endothelium. It is reported that stimulation of macrophages with oxLDL leads to enhanced TNF-α secretion. TNF-α is an inflammatory cytokine, and this implicates that oxLDL is an inflammatory stimulus. Andrographolide is a diterpene lactone isolated from the leaves of the Andrographis paniculata, which has been shown to possess anticancer, hepato-protective, and antiinflammatory activities. This study examined the effects of andrographolide on TNF-α-induced monocyte/human endothelial cell interaction. Andrographolide inhibited the adhesion of HL-60 cells to TNF-α-induced human umbilical vein endothelial cells (HUVECs) and suppressed total protein, cell surface expression and the promoter activity of the intracellular adhesion molecules-1 (ICAM-1). Andrographolide also abolished TNF-α-induced phosphorylation of Akt (p-Akt) in a time-dependent manner, and the ICAM-1 promoter activity decreased when cells pretreated with PI3K inhibitor LY294002. Moreover, andrographolide blocked nuclear translocation and DNA binding activity of NF-κB. In summary, these results demonstrated that andrographolide exhibits an anti-inflammatory property by down-regulating the pathway that affects the expression of ICAM-1 and the action of andrographolide may be closely related to the inhibition of PI3K/Akt and NF-κB activation in HUVEC. This indicates that andrographolide may play an important role in the prevention of inflammatory responses such as the atherosclerosis process.

縮寫表 1
Abstract 4
中文摘要 5
第一章 文獻回顧 6
一、穿心蓮 6
(一)穿心蓮簡介 6
(二)穿心蓮與慢性發炎疾病 7
(三)穿心蓮與其他疾病 7
1.癌症 7
2.肝臟疾病 8
二、動脈粥狀硬化 9
(一)動脈粥狀硬化 (atherosclerosis) 9
(二)細胞黏著分子 11
1.選擇素與其配體 (selectins and their ligands) 11
2.類免疫球蛋白分子 (immunoglobulin-like molecules) 12
3.整合素 (integrins) 14
(三)腫瘤壞死因子 (tumor necrosis factor-α，TNF-α) 15
三、Cell signaling 16
(一) NF-κB 16
(二) Mitogen-activated protein kinases (MAPKs) 18
(三) PI3K/Akt pathway 20
第二章 研究目的 24
第三章 實驗材料與方法 25
 實驗材料 25
一、實驗細胞株 25
二、化學試劑 25
(一) 細胞培養 25
(二) 細胞存活率分析 26
(三) 西方墨點法 (Western blotting) 26
(四) 蛋白質定量 27
(五) Electrophoretic mobility shift assay (EMSA) 分析 27
(六) 細胞表面黏附分子表現分析 (Flow cytometry) 28
(七) 單核球黏附分析 (Monocyte adhesion assay) 29
(八) Transient transfection/Luciferase activity assay 29
 實驗方法 29
一、細胞培養 29
(一) 細胞保存 30
(二) 細胞株解凍 30
(三) 細胞處理架構 31
二、細胞存活率分析 (MTT assay) 31
三、細胞蛋白質萃取 32
四、蛋白質定量 32
五、西方墨點法 (Western blotting) 32
六、Electrophoretic Mobility Shift Assay (EMSA) 33
(一) 核蛋白萃取 33
(二) EMSA 33
七、細胞膜 ICAM-1 蛋白分析 (流式細胞儀，Flow cytometry) 34
八、單核球黏著分析 ( Adhesion of HL-60 to HUVEC) 35
九、Transient transfection/Luciferase activity assay 35
(一) Transfection 35
(二) 分析 36
 統計方法 36
第四章 實驗結果與圖表 37
一、穿心蓮內酯減少 TNF-α 誘發單核球細胞株黏附到人類臍靜脈內皮細胞株 37
二、穿心蓮內酯抑制 TNF-α 誘發 HUVECs 之 ICAM-1 蛋白質表現與啟動區活性 37
三、穿心蓮內酯減少 NF-κB nuclear translocation 及其與 DNA 結合之能力 38
四、穿心蓮內酯減少TNF-α 誘發 Akt 磷酸化但不影響 MAPKs 活化 39
五、PI3K 抑制劑 LY294002 減少 TNF-α 誘發 ICAM-1 promoter 活性 40

圖表目次
圖一、人類臍靜脈內皮細胞株預處理穿心蓮內酯 (AP) 對 TNF-α 誘發單核球細胞株黏附到人類臍靜脈內皮細胞株之影響 41
圖二、不同濃度穿心蓮內酯 (AP) 對 HUVECs 存活率之影響 42
圖三、人類臍靜脈內皮細胞株預處理穿心蓮內酯 (AP) 對 TNF-α 誘發人類臍靜脈內皮細胞株 ICAM-1 表現之影響 43
圖四、人類臍靜脈內皮細胞株預處理穿心蓮內酯 (AP) 對 TNF-α 誘發人類臍靜脈內皮細胞株細胞表面 ICAM-1 表現之影響 44
圖五、短暫轉染 pIC-339 HUVECs 預處理穿心蓮內酯 (AP) 對 TNF-α 誘發ICAM-1 luciferase 活性之影響 45
圖六、人類臍靜脈內皮細胞預處理穿心蓮內酯 (AP) 對 TNF-α 誘發 p65 nuclear translocation 之影響 46
圖七、1 ng/ml TNF-α 誘發核內轉錄因子 NF-κB 與 κB site DNA 序列結合之時間效應 47
圖八、人類臍靜脈內皮細胞株預處理穿心蓮內酯 (AP) 對 TNF-α 誘發核內轉錄因子 NF-κB 與 κB site DNA 序列結合之影響 48
圖九、人類臍靜脈內皮細胞株預處理 20 μM 穿心蓮內酯對 TNF-α 誘發Akt 磷酸化之影響 49
圖十、人類臍靜脈內皮細胞株預處理 20 μM 穿心蓮內酯對 TNF-α 誘發JNK 磷酸化之影響 50
圖十一、人類臍靜脈內皮細胞株預處理 20 μM 穿心蓮內酯對 TNF-α 誘發 ERK 磷酸化之影響 51
圖十二、人類臍靜脈內皮細胞株預處理 20 μM 穿心蓮內酯對 TNF-α 誘發 p38 磷酸化之影響 52
圖十三、短暫轉染 pIC-339 HUVECs 預處理 PI3Ks 抑制劑 LY294002對 TNF-α 誘發 ICAM-1 luciferase 活性之影響 53
第五章 討論 54
第六章 結論 59
參考文獻 60

行政院衛生署：死因統計結果分析 (2009)
Baeuerle, P. A. (1991). The inducible transcription activator NF-kappa B: regulation by distinct protein subunits. Biochim Biophys Acta 1072, 63-80.
Ballestas, M. E., and Benveniste, E. N. (1995). Interleukin 1-beta- and tumor necrosis factor-alpha-mediated regulation of ICAM-1 gene expression in astrocytes requires protein kinase C activity. Glia 14, 267-278.
Blankenberg, S., Barbaux, S., and Tiret, L. (2003). Adhesion molecules and atherosclerosis. Atherosclerosis 170, 191-203.
Bonizzi, G., and Karin, M. (2004). The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25, 280-288.
Brand, K., Page, S., Rogler, G., Bartsch, A., Brandl, R., Knuechel, R., Page, M., Kaltschmidt, C., Baeuerle, P. A., and Neumeier, D. (1996). Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest 97, 1715-1722.
Calabrese, C., Berman, S. H., Babish, J. G., Ma, X., Shinto, L., Dorr, M., Wells, K., Wenner, C. A., and Standish, L. J. (2000). A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytother Res 14, 333-338.
Cao, L. H., Lee, Y. J., Kang, D. G., Kim, J. S., and Lee, H. S. (2009) Effect of Zanthoxylum schinifolium on TNF-alpha-induced vascular inflammation in human umbilical vein endothelial cells. Vascul Pharmacol 50, 200-207.
Catron, K. M., Brickwood, J. R., Shang, C., Li, Y., Shannon, M. F., and Parks, T. P. (1998). Cooperative binding and synergistic activation by RelA and C/EBPbeta on the intercellular adhesion molecule-1 promoter. Cell Growth Differ 9, 949-959.
Chang, R. S., Ding, L., Chen, G. Q., Pan, Q. C., Zhao, Z. L., and Smith, K. M. (1991). Dehydroandrographolide succinic acid monoester as an inhibitor against the human immunodeficiency virus. Proc Soc Exp Biol Med 197, 59-66.
Chatterjee, S. (1998). Sphingolipids in atherosclerosis and vascular biology. Arterioscler Thromb Vasc Biol 18, 1523-1533.
Chen, Y. R., Wang, X., Templeton, D., Davis, R. J., and Tan, T. H. (1996). The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem 271, 31929-31936.
Chiou, W. F., Chen, C. F., and Lin, J. J. (2000). Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide. Br J Pharmacol 129, 1553-1560.
Chiou, W. F., Lin, J. J., and Chen, C. F. (1998). Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipopolysaccharide. Br J Pharmacol 125, 327-334.
Choi, J. H., Jeong, T. S., Kim, D. Y., Kim, Y. M., Na, H. J., Nam, K. H., Lee, S. B., Kim, H. C., Oh, S. R., Choi, Y. K., et al. (2003). Hematein inhibits atherosclerosis by inhibition of reactive oxygen generation and NF-kappaB-dependent inflammatory mediators in hyperlipidemic mice. J Cardiovasc Pharmacol 42, 287-295.
Cobb, R. R., Felts, K. A., Parry, G. C., and Mackman, N. (1996). Proteasome inhibitors block VCAM-1 and ICAM-1 gene expression in endothelial cells without affecting nuclear translocation of nuclear factor-kappa B. Eur J Immunol 26, 839-845.
Colletti, L. M., Cortis, A., Lukacs, N., Kunkel, S. L., Green, M., and Strieter, R. M. (1998). Tumor necrosis factor up-regulates intercellular adhesion molecule 1, which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat. Shock 10, 182-191.
Collins, T., Read, M. A., Neish, A. S., Whitley, M. Z., Thanos, D., and Maniatis, T. (1995). Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. Faseb J 9, 899-909.
Coon, J. T., and Ernst, E. (2004). Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med 70, 293-298.
Cuschieri, J., and Maier, R. V. (2005). Mitogen-activated protein kinase (MAPK). Crit Care Med 33, S417-419.
Davies, M. J., Gordon, J. L., Gearing, A. J., Pigott, R., Woolf, N., Katz, D., and Kyriakopoulos, A. (1993). The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol 171, 223-229.
Davis, R. J. (2000). Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252.
de Winther, M. P., Kanters, E., Kraal, G., and Hofker, M. H. (2005). Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol 25, 904-914.
Dean, J. L., Brook, M., Clark, A. R., and Saklatvala, J. (1999). p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem 274, 264-269.
Djordjevic, S., and Driscoll, P. C. (2002). Structural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases. Trends Biochem Sci 27, 426-432.
Fresno Vara, J. A., Casado, E., de Castro, J., Cejas, P., Belda-Iniesta, C., and Gonzalez-Baron, M. (2004). PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30, 193-204.
Friedl, J., Puhlmann, M., Bartlett, D. L., Libutti, S. K., Turner, E. N., Gnant, M. F., and Alexander, H. R. (2002). Induction of permeability across endothelial cell monolayers by tumor necrosis factor (TNF) occurs via a tissue factor-dependent mechanism: relationship between the procoagulant and permeability effects of TNF. Blood 100, 1334-1339.
Fruman, D. A., Meyers, R. E., and Cantley, L. C. (1998). Phosphoinositide kinases. Annu Rev Biochem 67, 481-507.
Gerszten, R. E., Friedrich, E. B., Matsui, T., Hung, R. R., Li, L., Force, T., and Rosenzweig, A. (2001). Role of phosphoinositide 3-kinase in monocyte recruitment under flow conditions. J Biol Chem 276, 26846-26851.
Ghosh, S., May, M. J., and Kopp, E. B. (1998). NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16, 225-260.
Glass, C. K., and Witztum, J. L. (2001). Atherosclerosis. the road ahead. Cell 104, 503-516.
Hajra, L., Evans, A. I., Chen, M., Hyduk, S. J., Collins, T., and Cybulsky, M. I. (2000). The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A 97, 9052-9057.
Hanada, M., Feng, J., and Hemmings, B. A. (2004). Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim Biophys Acta 1697, 3-16.
Handa, S. S., and Sharma, A. (1990a). Hepatoprotective activity of andrographolide against galactosamine & paracetamol intoxication in rats. Indian J Med Res 92, 284-292.
Handa, S. S., and Sharma, A. (1990b). Hepatoprotective activity of andrographolide from Andrographis paniculata against carbontetrachloride. Indian J Med Res 92, 276-283.
Hansson, G. K. (2005). Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352, 1685-1695.
Hernandez-Presa, M., Bustos, C., Ortego, M., Tunon, J., Renedo, G., Ruiz-Ortega, M., and Egido, J. (1997). Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation 95, 1532-1541.
Hidalgo, M. A., Romero, A., Figueroa, J., Cortes, P., Concha, II, Hancke, J. L., and Burgos, R. A. (2005). Andrographolide interferes with binding of nuclear factor-kappaB to DNA in HL-60-derived neutrophilic cells. Br J Pharmacol 144, 680-686.
Ho, A. W., Wong, C. K., and Lam, C. W. (2008). Tumor necrosis factor-alpha up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways. Immunobiology 213, 533-544.
Hosokawa, Y., Hosokawa, I., Ozaki, K., Nakae, H., and Matsuo, T. (2006). Cytokines differentially regulate ICAM-1 and VCAM-1 expression on human gingival fibroblasts. Clin Exp Immunol 144, 494-502.
Huang, W.C., Chan, S.T., Yang, T.L., Tzeng, C.C., and Chen, C.C. (2004). Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel alpha-methylene-gamma-bytyrolactone derivatives. Carcinogenesis 25,1925-1934.
Hughes, P. E., and Pfaff, M. (1998). Integrin affinity modulation. Trends Cell Biol 8, 359-364.
Hunter, T. (2000). Signaling--2000 and beyond. Cell 100, 113-127.
Huo, Y., and Ley, K. (2001). Adhesion molecules and atherogenesis. Acta Physiol Scand 173, 35-43.
Iruretagoyena, M. I., Tobar, J. A., Gonzalez, P. A., Sepulveda, S. E., Figueroa, C. A., Burgos, R. A., Hancke, J. L., and Kalergis, A. M. (2005). Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse. J Pharmacol Exp Ther 312, 366-372.
Jiang, C. G., Li, J. B., Liu, F. R., Wu, T., Yu, M., and Xu, H. M. (2007). Andrographolide inhibits the adhesion of gastric cancer cells to endothelial cells by blocking E-selectin expression. Anticancer Res 27, 2439-2447.
Jobin, C., Hellerbrand, C., Licato, L. L., Brenner, D. A., and Sartor, R. B. (1998). Mediation by NF-kappa B of cytokine induced expression of intercellular adhesion molecule 1 (ICAM-1) in an intestinal epithelial cell line, a process blocked by proteasome inhibitors. Gut 42, 779-787.
Ju, J. W., Kim, S. J., Jun, C. D., and Chun, J. S. (2002). p38 kinase and c-Jun N-terminal kinase oppositely regulates tumor necrosis factor alpha-induced vascular cell adhesion molecule-1 expression and cell adhesion in chondrosarcoma cells. IUBMB Life 54, 293-299.
Kacimi, R., Karliner, J. S., Koudssi, F., and Long, C. S. (1998). Expression and regulation of adhesion molecules in cardiac cells by cytokines: response to acute hypoxia. Circ Res 82, 576-586.
Kaminska, B. (2005). MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta 1754, 253-262.
Kansas, G. S. (1996). Selectins and their ligands: current concepts and controversies. Blood 88, 3259-3287.
Kapil, A., Koul, I. B., Banerjee, S. K., and Gupta, B. D. (1993). Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata. Biochem Pharmacol 46, 182-185.
Karin, M., and Delhase, M. (2000). The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. Semin Immunol 12, 85-98.
Karin, M., and Lin, A. (2002). NF-kappaB at the crossroads of life and death. Nat Immunol 3, 221-227.
Karmann, K., Min, W., Fanslow, W. C., and Pober, J. S. (1996). Activation and homologous desensitization of human endothelial cells by CD40 ligand, tumor necrosis factor, and interleukin 1. J Exp Med 184, 173-182.
Kihara, A., Noda, T., Ishihara, N., and Ohsumi, Y. (2001). Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 152, 519-530.
Kim, T. G., Hwi, K. K., and Hung, C. S. (2005). Morphological and biochemical changes of andrographolide-induced cell death in human prostatic adenocarcinoma PC-3 cells. In Vivo 19, 551-557.
Kim, H. G., Kim, J. Y., Hwang, Yl P., Lee, K. J., Lee, K. Y., Kim, D. H., Kim, D. H., and Jeong, H. G. (2006). The coffee diterpene kahweol innhibits tumor necrosis factor-alpha -induced expression of cell adhesion molecules in human endothelial cells. Toxicol Appl Pharmacol 217, 332-341.
Kobuchi, H., Roy, S., Sen, C. K., Nguyen, H. G., and Packer, L. (1999). Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol 277, C403-411.
Kofler, S., Nickel, T., and Weis, M. (2005). Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation. Clin Sci (Lond) 108, 205-213.
Kucuk, O. (2002). New opportunities in chemoprevention research. Cancer Invest 20, 237-245.
Kutuk, O., and Basaga, H. (2003). Inflammation meets oxidation: NF-kappaB as a mediator of initial lesion development in atherosclerosis. Trends Mol Med 9, 549-557.
Kyriakis, J. M., and Avruch, J. (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81, 807-869.
Lee, J. C., Laydon, J. T., McDonnell, P. C., Gallagher, T. F., Kumar, S., Green, D., McNulty, D., Blumenthal, M. J., Heys, J. R., Landvatter, S. W., and et al. (1994). A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739-746.
Lee, J. C., and Young, P. R. (1996). Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. J Leukoc Biol 59, 152-157.
Lee, G., H. J. Na, H.J., Namkoong, S., Jeong Kwon, H., Han, S., Ha, K.S., Kwin, Y.G.., Lee, H., and Kim, Y.M. (2006). 4-O-methylgallic acid down-regulates endothelial adhesion molecule expression by inhibiting NF-kappaB-DNA-binding activity. European journal of pharmacology 551, 143-151.
Li, Z. W., Chu, W., Hu, Y., Delhase, M., Deerinck, T., Ellisman, M., Johnson, R., and Karin, M. (1999). The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 189, 1839-1845.
Liang, F. P., Lin, C. H., Kuo, C. D., Chao, H. P., and Fu, S. L. (2008). Suppression of v-Src transformation by andrographolide via degradation of the v-Src protein and attenuation of the Erk signaling pathway. J Biol Chem 283, 5023-5033.
Liao, F., Andalibi, A., deBeer, F. C., Fogelman, A. M., and Lusis, A. J. (1993). Genetic control of inflammatory gene induction and NF-kappa B-like transcription factor activation in response to an atherogenic diet in mice. J Clin Invest 91, 2572-2579.
Libby, P. (2002). Inflammation in atherosclerosis. Nature 420, 868-874.
Lopez-Rodriguez, C., Chen, H. M., Tenen, D. G., and Corbi, A. L. (1995). Identification of Sp1-binding sites in the CD11c (p150,95 alpha) and CD11a (LFA-1 alpha) integrin subunit promoters and their involvement in the tissue-specific expression of CD11c. Eur J Immunol 25, 3496-3503.
Luo, J. L., Kamata, H., and Karin, M. (2005). IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy. J Clin Invest 115, 2625-2632.
Madge, L. A., and Pober, J. S. (2000). A phosphatidylinositol 3-kinase/Akt pathway, activated by tumor necrosis factor or interleukin-1, inhibits apoptosis but does not activate NFkappaB in human endothelial cells. J Biol Chem 275, 15458-15465.
Madge, L. A., and Pober, J. S. (2001). TNF signaling in vascular endothelial cells. Exp Mol Pathol 70, 317-325.
Matsuda, T., Kuroyanagi, M., Sugiyama, S., Umehara, K., Ueno, A., and Nishi, K. (1994). Cell differentiation-inducing diterpenes from Andrographis paniculata Nees. Chem Pharm Bull (Tokyo) 42, 1216-1225.
Mbalaviele, G., Anderson, G., Jones, A., De Ciechi, P., Settle, S., Mnich, S., Thiede, M., Abu-Amer, Y., Portanova, J., and Monahan, J. (2006). Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther 317, 1044-1053.
Moiseeva, E. P. (2001). Adhesion receptors of vascular smooth muscle cells and their functions. Cardiovasc Res 52, 372-386.
Molestina, R. E., Miller, R. D., Lentsch, A. B., Ramirez, J. A., and Summersgill, J. T. (2000). Requirement for NF-kappaB in transcriptional activation of monocyte chemotactic protein 1 by Chlamydia pneumoniae in human endothelial cells. Infect Immun 68, 4282-4288.
Morrison, D. K., and Davis, R. J. (2003). Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol 19, 91-118.
Murthy, S. S., Tosolini, A., Taguchi, T., and Testa, J. R. (2000). Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization. Cytogenet Cell Genet 88, 38-40.
Nageh, M. F., Sandberg, E. T., Marotti, K. R., Lin, A. H., Melchior, E. P., Bullard, D. C., and Beaudet, A. L. (1997). Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice. Arterioscler Thromb Vasc Biol 17, 1517-1520.
Negi, A. S., Kumar, J. K., Luqman, S., Shanker, K., Gupta, M. M., and Khanuja, S. P. (2008). Recent advances in plant hepatoprotectives: a chemical and biological profile of some important leads. Med Res Rev 28, 746-772.
Newton, J. P., Buckley, C. D., Jones, E. Y., and Simmons, D. L. (1997). Residues on both faces of the first immunoglobulin fold contribute to homophilic binding sites of PECAM-1/CD31. J Biol Chem 272, 20555-20563.
O''Brien, K. D., Allen, M. D., McDonald, T. O., Chait, A., Harlan, J. M., Fishbein, D., McCarty, J., Ferguson, M., Hudkins, K., Benjamin, C. D., and et al. (1993). Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest 92, 945-951.
Oh, G. T., Choi, J. H., Hong, J. J., Kim, D. Y., Lee, S. B., Kim, J. R., Lee, C. H., Hyun, B. H., Oh, S. R., Bok, S. H., and Jeong, T. S. (2001). Dietary hematein ameliorates fatty streak lesions in the rabbit by the possible mechanism of reducing VCAM-1 and MCP-1 expression. Atherosclerosis 159, 17-26.
Orr, A. W., Sanders, J. M., Bevard, M., Coleman, E., Sarembock, I. J., and Schwartz, M. A. (2005). The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis. J Cell Biol 169, 191-202.
Ozes, O. N., Mayo, L. D., Gustin, J. A., Pfeffer, S. R., Pfeffer, L. M., and Donner, D. B. (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401, 82-85.
Pan, Z. K., Christiansen, S. C., Ptasznik, A., and Zuraw, B. L. (1999). Requirement of phosphatidylinositol 3-kinase activity for bradykinin stimulation of NF-kappaB activation in cultured human epithelial cells. J Biol Chem 274, 9918-9922.
Pankhurst, T., Savage, C. O., and Little, M. A. (2009). Review article: Leukocyte-endothelial dysregulation in systemic small vessel vasculitis. Nephrology (Carlton) 14, 3-10.
Paxton, L. L., Li, L. J., Secor, V., Duff, J. L., Naik, S. M., Shibagaki, N., and Caughman, S. W. (1997). Flanking sequences for the human intercellular adhesion molecule-1 NF-kappaB response element are necessary for tumor necrosis factor alpha-induced gene expression. J Biol Chem 272, 15928-15935.
Poolsup, N., Suthisisang, C., Prathanturarug, S., Asawamekin, A., and Chanchareon, U. (2004). Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials. J Clin Pharm Ther 29, 37-45.
Price, D. T., and Loscalzo, J. (1999). Cellular adhesion molecules and atherogenesis. Am J Med 107, 85-97.
Puri, A., Saxena, R., Saxena, R. P., Saxena, K. C., Srivastava, V., and Tandon, J. S. (1993). Immunostimulant agents from Andrographis paniculata. J Nat Prod 56, 995-999.
Qin, L. H., Kong, L., Shi, G. J., Wang, Z. T., and Ge, B. X. (2006). Andrographolide inhibits the production of TNF-alpha and interleukin-12 in lipopolysaccharide-stimulated macrophages: role of mitogen-activated protein kinases. Biol Pharm Bull 29, 220-224.
Radisavljevic, Z., Avraham, H., and Avraham, S. (2000). Vascular endothelial growth factor up-regulates ICAM-1 expression via the phosphatidylinositol 3 OH-kinase/AKT/Nitric oxide pathway and modulates migration of brain microvascular endothelial cells. J Biol Chem 275, 20770-20774.
Rajagopal, S., Kumar, R. A., Deevi, D. S., Satyanarayana, C., and Rajagopalan, R. (2003). Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. J Exp Ther Oncol 3, 147-158.
Ridley, S. H., Sarsfield, S. J., Lee, J. C., Bigg, H. F., Cawston, T. E., Taylor, D. J., DeWitt, D. L., and Saklatvala, J. (1997). Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol 158, 3165-3173.
Rodriguez-Ayala, E., Anderstam, B., Suliman, M. E., Seeberger, A., Heimburger, O., Lindholm, B., and Stenvinkel, P. (2005). Enhanced RAGE-mediated NFkappaB stimulation in inflamed hemodialysis patients. Atherosclerosis 180, 333-340.
Roebuck, K. A., and Finnegan, A. (1999). Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukoc Biol 66, 876-888.
Roggo, L., Bernard, V., Kovacs, A. L., Rose, A. M., Savoy, F., Zetka, M., Wymann, M. P., and Muller, F. (2002). Membrane transport in Caenorhabditis elegans: an essential role for VPS34 at the nuclear membrane. Embo J 21, 1673-1683.
Ross, R. (1999). Atherosclerosis is an inflammatory disease. Am Heart J 138, S419-420.
Sampath, D., Castro, M., Look, D. C., and Holtzman, M. J. (1999). Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. J Clin Invest 103, 1353-1361.
Schiffrin, E. L. (2002). Beyond blood pressure: the endothelium and atherosclerosis progression. Am J Hypertens 15, 115S-122S.
Schindler, J. F., Monahan, J. B., and Smith, W. G. (2007). p38 pathway kinases as anti-inflammatory drug targets. J Dent Res 86, 800-811.
Schmidt-Supprian, M., Bloch, W., Courtois, G., Addicks, K., Israel, A., Rajewsky, K., and Pasparakis, M. (2000). NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell 5, 981-992.
Schwartz, E. A., Bizios, R., Medow, M. S., and Gerritsen, M. E. (1999). Exposure of human vascular endothelial cells to sustained hydrostatic pressure stimulates proliferation. Involvement of the alphaV integrins. Circ Res 84, 315-322.
See, D., Mason, S., and Roshan, R. (2002). Increased tumor necrosis factor alpha (TNF-alpha) and natural killer cell (NK) function using an integrative approach in late stage cancers. Immunol Invest 31, 137-153.
Senftleben, U., Cao, Y., Xiao, G., Greten, F. R., Krahn, G., Bonizzi, G., Chen, Y., Hu, Y., Fong, A., Sun, S. C., and Karin, M. (2001). Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293, 1495-1499.
Senftleben, U., and Karin, M. (2002). The IKK/NF-kappa B pathway. Crit Care Med 30, S18-26.
Sethi, J. M., Otterbein, L. E., and Choi, A. M. (2002). Differential modulation by exogenous carbon monoxide of TNF-alpha stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells. Antioxid Redox Signal 4, 241-248.
Sheeja, K., Guruvayoorappan, C., and Kuttan, G. (2007). Antiangiogenic activity of Andrographis paniculata extract and andrographolide. Int Immunopharmacol 7, 211-221.
Shen, Y. C., Chen, C. F., and Chiou, W. F. (2002). Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol 135, 399-406.
Sippy, B. D., Hofman, F. M., Wright, A. D., Wang, J. L., Gopalakrishna, R., Gundimeda, U., He, S., Ryan, S. J., and Hinton, D. R. (1996). Induction of intercellular adhesion molecule-1 by tumor necrosis factor-alpha through the 55-kDa receptor is dependent on protein kinase C in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 37, 597-606.
Sluss, H. K., Barrett, T., Derijard, B., and Davis, R. J. (1994). Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol 14, 8376-8384.
Stanimirovic, D. B., Wong, J., Shapiro, A., and Durkin, J. P. (1997). Increase in surface expression of ICAM-1, VCAM-1 and E-selectin in human cerebromicrovascular endothelial cells subjected to ischemia-like insults. Acta Neurochir Suppl 70, 12-16.
Staunton, D. E., Dustin, M. L., Erickson, H. P., and Springer, T. A. (1990). The arrangement of the immunoglobulin-like domains of ICAM-1 and the binding sites for LFA-1 and rhinovirus. Cell 61, 243-254.
Stein, B., Baldwin, A. S., Jr., Ballard, D. W., Greene, W. C., Angel, P., and Herrlich, P. (1993). Cross-coupling of the NF-kappa B p65 and Fos/Jun transcription factors produces potentiated biological function. Embo J 12, 3879-3891.
Tamura, D. Y., Moore, E. E., Johnson, J. L., Zallen, G., Aiboshi, J., and Silliman, C. C. (1998). p38 mitogen-activated protein kinase inhibition attenuates intercellular adhesion molecule-1 up-regulation on human pulmonary microvascular endothelial cells. Surgery 124, 403-407; discussion 408.
Teshima, S., Nakanishi, H., Nishizawa, M., Kitagawa, K., Kaibori, M., Yamada, M., Habara, K., Kwon, A. H., Kamiyama, Y., Ito, S., and Okumura, T. (2004). Up-regulation of IL-1 receptor through PI3K/Akt is essential for the induction of iNOS gene expression in hepatocytes. J Hepatol 40, 616-623.
Tsai, H. R., Yang, L. M., Tsai, W. J., and Chiou, W. F. (2004). Andrographolide acts through inhibition of ERK1/2 and Akt phosphorylation to suppress chemotactic migration. Eur J Pharmacol 498, 45-52.
Underwood, D. C., Osborn, R. R., Bochnowicz, S., Webb, E. F., Rieman, D. J., Lee, J. C., Romanic, A. M., Adams, J. L., Hay, D. W., and Griswold, D. E. (2000). SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol 279, L895-902.
van de Stolpe, A., and van der Saag, P. T. (1996). Intercellular adhesion molecule-1. J Mol Med 74, 13-33.
Vieira, O. V., Botelho, R. J., Rameh, L., Brachmann, S. M., Matsuo, T., Davidson, H. W., Schreiber, A., Backer, J. M., Cantley, L. C., and Grinstein, S. (2001). Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J Cell Biol 155, 19-25.
Visen, P. K., Shukla, B., Patnaik, G. K., and Dhawan, B. N. (1993). Andrographolide protects rat hepatocytes against paracetamol-induced damage. J Ethnopharmacol 40, 131-136.
Vonderheide, R. H., Tedder, T. F., Springer, T. A., and Staunton, D. E. (1994). Residues within a conserved amino acid motif of domains 1 and 4 of VCAM-1 are required for binding to VLA-4. J Cell Biol 125, 215-222.
Voraberger, G., Schafer, R., and Stratowa, C. (1991). Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5''-regulatory region. Induction by cytokines and phorbol ester. J Immunol 147, 2777-2786.
Waldburger, J. M., and Firestein, G. S. (2009). Garden of therapeutic delights: new targets in rheumatic diseases. Arthritis Res Ther 11, 206.
Wang, Y. J., Wang, J. T., Fan, Q. X., and Geng, J. G. (2007). Andrographolide inhibits NF-kappaBeta activation and attenuates neointimal hyperplasia in arterial restenosis. Cell Res 17, 933-941.
Weber, C., Zernecke, A., and Libby, P. (2008). The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 8, 802-815.
Welty, S. E., Rivera, J. L., Elliston, J. F., Smith, C. V., Zeb, T., Ballantyne, C. M., Montgomery, C. A., and Hansen, T. N. (1993). Increases in lung tissue expression of intercellular adhesion molecule-1 are associated with hyperoxic lung injury and inflammation in mice. Am J Respir Cell Mol Biol 9, 393-400.
Widmann, C., Gibson, S., Jarpe, M. B., and Johnson, G. L. (1999). Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79, 143-180.
Wilson, S. H., Best, P. J., Edwards, W. D., Holmes, D. R., Jr., Carlson, P. J., Celermajer, D. S., and Lerman, A. (2002). Nuclear factor-kappaB immunoreactivity is present in human coronary plaque and enhanced in patients with unstable angina pectoris. Atherosclerosis 160, 147-153.
Xia, Y. F., Ye, B. Q., Li, Y. D., Wang, J. G., He, X. J., Lin, X., Yao, X., Ma, D., Slungaard, A., Hebbel, R. P., et al. (2004). Andrographolide attenuates inflammation by inhibition of NF-kappa B activation through covalent modification of reduced cysteine 62 of p50. J Immunol 173, 4207-4217.
Yoshizumi, M., Fujita, Y., Izawa, Y., Suzaki, Y., Kyaw, M., Ali, N., Tsuchiya, K., Kagami, S., Yano, S., Sone, S., and Tamaki, T. (2004). Ebselen inhibits tumor necrosis factor-alpha-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. Exp Cell Res 292, 1-10.
Zhang, C. Y., and Tan, B. K. (1996). Hypotensive activity of aqueous extract of Andrographis paniculata in rats. Clin Exp Pharmacol Physiol 23, 675-678.
Zhang, X. F., and Tan, B. K. (2000). Antihyperglycaemic and anti-oxidant properties of Andrographis paniculata in normal and diabetic rats. Clin Exp Pharmacol Physiol 27, 358-363.
Zhao, H. Y., and Fang, W. Y. (1991). Antithrombotic effects of Andrographis paniculata nees in preventing myocardial infarction. Chin Med J (Engl) 104, 770-775.
Zheng, S., Qian, Z., Tang, F., and Sheng, L. (2005). Suppression of vascular cell adhesion molecule-1 expression by crocetin contributes to attenuation of atherosclerosis in hypercholesterolemic rabbits. Biochem Pharmacol 70, 1192-1199.
Zhou, J., Lu, G. D., Ong, C. S., Ong, C. N., and Shen, H. M. (2008). Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation. Mol Cancer Ther 7, 2170-2180.
Zhou, Z., Connell, M. C., and MacEwan, D. J. (2007). TNFR1-induced NF-kappaB, but not ERK, p38MAPK or JNK activation, mediates TNF-induced ICAM-1 and VCAM-1 expression on endothelial cells. Cell Signal 19, 1238-1248.
Zuckerman, L. A., Pullen, L., and Miller, J. (1998). Functional consequences of costimulation by ICAM-1 on IL-2 gene expression and T cell activation. J Immunol 160, 3259-3268.