發炎是由於外來物質入侵體內或是體內氧化壓力升高所造成，為生物體對抗外來物質的一種保護方式，但長期的發炎會使得體內氧化壓力的升高，並造成許多疾病的發生，例如癌症與心血管疾病皆與發炎相關。發炎反應發生時，會誘發免疫細胞如巨噬細胞內部NF-κB轉錄因子的活化，並促使下游發炎相關蛋白質如iNOS與COX-2的表現，以及各種促發炎激素如NO、TNF-α、PGE2、IL-1β及IL-6等之生成。根據研究，許多植化素 (phytochemical)如類黃酮等物質，已被證實具有抗發炎的功效，且許多皆是透過抑制NF-κB相關路徑以達到抗發炎的效果。
多甲氧基類黃酮 (polymethoxyflavones, PMFs)為黃酮類化合物中的一群，具有超過兩個以上之甲氧取代基，因極性較低而具有較好的生物可利用率，且已有數種PMFs經實驗證實具有抗發炎效果。5,7,3'',4''-tetramethoxyflavone (TMF)是月橘 (Murraya paniculata) 與黑薑 (Kaempferia parviflora)中主要的PMFs之一，這些植物的萃取物已被證實具有抗發炎、抗腫瘤以及抗氧化等活性，然而TMF以及其代謝物之生理活性仍有待進一步的研究。本研究以LPS誘導RAW264.7巨噬細胞作為發炎反應之細胞模式，並以LPS誘導C57BL/6小鼠產生敗血症作為促發炎動物模式，探討TMF以及其生理代謝物3''-hydroxy-5,7,4''-trimethoxyflavone (M1), 4''-hydroxy-5,7,3''-trimethoxyflavone (M4), 5-hydroxy-7,3'',4''-trimethoxyflavone (M5)之抗發炎功效與其可能機制，同時比較不同生理代謝物之間的抗發炎活性。
研究結果顯示TMF及其生理代謝物對於LPS誘導巨噬細胞產生的促發炎激素NO, TNF-α, IL-6, IL-1β皆具有顯著的抑制效果；TMF、M1、M4以及 M5對於抑制NO生成的IC50分別為26.63、47.39、33.17以及30.24 μM。西方墨點法的結果顯示，TMF及所有生理代謝物皆可顯著抑制iNOS的蛋白質表現，並以TMF及M4的抑制效果較佳；而TMF與M5則具有顯著抑制COX-2蛋白質表現的能力。在上游機制方面，則以生理代謝物M1、M4及M5具有抑制iNOS及COX-2 mRNA之能力。綜合比較後發現TMF對於大部分促發炎指標皆具有顯著的抑制效果，因此以TMF作為探討體內抗發炎功效的樣品。動物實驗的結果顯示，腹腔注射20 mg/kg bw TMF可有效降低血清中以LPS誘導促發炎激素TNF-α以及IL-6的生成，同時可有效降低肺臟中的TNF-α與腎臟中的IL-6生成；而腹腔注射50 mg/kg bw之TMF則可分別顯著降低肝臟、脾臟與腎臟中的TNF-α、脾臟與肺臟中的IL-1β以及肺臟中的IL-6含量；若以腹腔注射100 mg/kg bw之TMF則可顯著降低腎臟中的IL-1β含量以及肝臟與脾臟中的IL-6含量，顯示TMF可抑制C57BL/6小鼠因LPS所誘導之發炎現象。

Inflammation is caused by pathogen or elevation of oxidative stress in our body; therefore it is a protective mechanism against external invasions. Inflammation also plays an important role in many degenerative diseases such as cancer and cardiovascular diseases. During inflammation, activation of NF-κB pathway would induce expression of downstream protein such as iNOS and COX-2. Also it would cause the secretion of pro-inflammatory chemokines and cytokines like NO、TNF-α、PGE2、IL-1β and IL-6. Several plant flavonoids have been shown to exhibit anti-inflammatory activities through inhibition of NF-κB pathway.
Polymethoxyflavones (PMFs) are flavonoids that bear two or more methoxy groups on their basic skeleton and therefore have greater bioavailability due to their lower polarity. 5,7,3'',4''-Tetramethoxyflavone (TMF) is one of the major PMFs occurred in Murraya paniculata and Kaempferia parviflora and has been reported to have various bioactivities such as anti-inflammatory, anti-carcinogenic, anti-viral, and antioxidative properties. However, the metabolism of TMF has been scarcely performed. Previous studies in our lab have identified several metabolites of TMF in vivo and developed related methods to synthesize these metabolites, but their bioactivities are still unknown. In this study, TMF and its 3 major metabolites, including 3''-hydroxy-5,7,4''-trime
-thoxyflavone, 4''-hydroxy-5,7,3''-trimethoxyflavone, and 5-hydroxy-7,3'',4''-trime-
thoxyflavone were investigated for their anti-inflammatory effects in lipopolysaccharide (LPS)-induced inflammation in murine macrophage RAW264.7 cells and lipopolysaccharide-induced sepsis in C57BL/6 mice.
Results of western blot analysis revealed that the inhibition of iNOS and COX-2 expressions by TMF and its metabolites in LPS-induced macrophage were different. Our results also showed that induction of NO by LPS in RAW 264.7 cell was suppressed by TMF and its metabolites, with TMF having the lowest IC50. The levels of TNF-α、IL-1β and IL-6 were also decreased differently among the 3 metabolites and TMF. In vivo study revealed that TMF showed anti-inflammatory effects in septic shock mice and exhibited inhibitory effects on serum TNF-α and IL-6 level induced by LPS. The levels of organ pro-inflammatory cytokines, such as TNF-α、IL-1β and IL-6 were also suppressed by TMF. In conclusion, our results suggested that the anti-inflammatory properties of TMF and its metabolites exert through the suppression of NF-κB pathway, and the activities are structure-dependent. We also conclude that TMF has in vivo anti-inflammatory activity in septic shock mice. The detailed mechanism of anti-inflammatory properties of TMF and its metabolites remains to be explored.

中文摘要 i
英文摘要 iii
目錄 v
圖次 viii
表次 x
附錄次 xi
縮寫對照表 xii
壹、 前言 1
貳、 文獻整理 2
第一節、 黃酮類與多甲氧基類黃酮類 2
一、 黃酮類簡介 2
二、 多甲氧基類黃酮簡介 4
三、 5,7,3’,4’-tetramethoxyflavone簡介 4
四、 5,7,3’,4’-tetramethoxyflavone的代謝與吸收 7
五、 5,7,3’,4’-tetramethoxyflavone的代謝產物與途徑 8
第二節、 發炎反應 13
一、 發炎 13
二、 巨噬細胞 (Macrophage) 15
三、 脂多醣體Lipopolysaccharide (LPS) 16
四、 Nuclear factor-κ B (NF-κB) 17
五、 一氧化氮 (NO) 19
六、 環氧化酵素Cyclooxygenase (COX) 21
七、 腫瘤壞死因子α(Tumor necrosis factor α, TNF-α) 22
八、 細胞介白素6 (Interleukin-6, IL-6) 23
九、 細胞介白素1β (Interleukin-1β, IL-1β) 24
第三節、 敗血症與發炎 25
一、 敗血症的定義： 25
二、 敗血症之相關併發症： 26
參、 研究目的與實驗架構 28
第一節、 研究目的 28
第二節、 實驗架構 29
肆、 材料與方法 30
第一節、 實驗材料與儀器設備 30
一、 實驗材料 30
二、 實驗細胞株 30
三、 實驗動物 30
四、 實驗藥品與溶劑 31
五、 細胞培養液 32
六、 西方墨點法材料 33
七、 儀器設備 34
八、 實驗溶液配方 36
第二節、 實驗方法 40
一、 合成樣品之結構鑑定 40
二、 以RAW 264.7細胞株評估樣品之抗發炎功效 40
三、 以螢光素酶報告基因檢測法(Luciferase Assay)評估樣品抗發炎功效 48
四、 以動物敗血症模式探討樣品抗發炎功效 49
五、 統計分析 52
伍、 結果 53
第一節、 以RAW 264.7細胞株評估樣品之抗發炎功效 53
一、 樣品對RAW 264.7巨噬細胞存活能力影響 53
二、 樣品影響LPS誘導RAW 264.7巨噬細胞一氧化氮生成能力 55
三、 樣品影響LPS誘導RAW 264.7巨噬細胞生成促發炎細胞激素之能力 59
四、 樣品影響發炎相關蛋白質之表現能力 70
五、 螢光素酶報告基因檢測法 (Luciferase Assay)評估發炎相關蛋白質之mRNA表現量 75
第二節、 以動物敗血症模式探討樣品抗發炎功效 81
六、 TMF對敗血症模式小鼠血清中促發炎激素濃度的影響 81
七、 TMF對敗血症模式小鼠臟器中促發炎激素濃度的影響 84
陸、 討論 93
第一節、 以RAW 264.7細胞評估樣品抑制一氧化氮功效 93
第二節、 樣品抑制促發炎激素生成之功效 96
第三節、 樣品於細胞模式中抗發炎機制的探討 99
第四節、 以敗血症動物評估TMF之體內抗發炎效果 101
柒、 結論 104
捌、 參考文獻 105
玖、 附錄 117

Ahmad, F., Emrizal, H. M. Sirat, F. Jamaludin, N. M. a. Mustapha, R. M. Ali, D. Arbain and H. Y. Aboul-Enein (2011). "Antimicrobial and anti-inflammatory activities of Piper porphyrophyllum (Fam. Piperaceae)." Arabian Journal of Chemistry Doi:10.1016/j.arabjc.2010.12.032.
Aird, W. C. (2003). "The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome." Blood 101(10): 3765-3777.
Allen, B. W., I. T. Demchenko and C. A. Piantadosi (2009). "Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity." J Appl Physiol 106(2): 662-667.
Ando, H., T. Takamura, T. Ota, Y. Nagai and K. Kobayashi (2000). "Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis." J Pharmacol Exp Ther 294(3): 1043-1046.
Anthony, D. A., D. M. Andrews, M. Chow, S. V. Watt, C. House, S. Akira, P. I. Bird, J. A. Trapani and M. J. Smyth (2010). "A role for granzyme M in TLR4-driven inflammation and endotoxicosis." J Immunol 185(3): 1794-1803.
Arend, W. P. and J. M. Dayer (1995). "Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis." Arthritis Rheum 38(2): 151-160.
Banks, W. A., A. J. Kastin and E. G. Gutierrez (1994). "Penetration of Interleukin-6 across the Murine Blood-Brain-Barrier." Neurosci Lett 179(1-2): 53-56.
Boolbol, S. K., A. J. Dannenberg, A. Chadburn, C. Martucci, X. J. Guo, J. T. Ramonetti, M. Abreu-Goris, H. L. Newmark, M. L. Lipkin, J. J. DeCosse and M. M. Bertagnolli (1996). "Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis." Cancer Res 56(11): 2556-2560.
Brandao, M. G., A. U. Krettli, L. S. Soares, C. G. Nery and H. C. Marinuzzi (1997). "Antimalarial activity of extracts and fractions from Bidens pilosa and other Bidens species (Asteraceae) correlated with the presence of acetylene and flavonoid compounds." J Ethnopharmacol 57(2): 131-138.
Cao, W., W. Zhang, J. Liu, Y. Wang, X. Peng, D. Lu, R. Qi and H. Wang (2011). "Paeoniflorin improves survival in LPS-challenged mice through the suppression of TNF-alpha and IL-1beta release and augmentation of IL-10 production." Int Immunopharmacol 11(2): 172-178.
Celada, A. and C. Nathan (1994). "Macrophage activation revisited." Immunol Today 15(3): 100-102.
Chattopadhyay, D. and M. T. Khan (2008). "Ethnomedicines and ethnomedicinal phytophores against herpesviruses." Biotechnol Annu Rev 14: 297-348.
Chen, K. H., M. S. Weng and J. K. Lin (2007). "Tangeretin suppresses IL-1 beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells." Biochemical Pharmacology 73(2): 215-227.
Choi, S. Y., J. H. Hwang, H. C. Ko, J. G. Park and S. J. Kim (2007). "Nobiletin from citrus fruit peel inhibits the DNA-binding activity of NF-kappaB and ROS production in LPS-activated RAW 264.7 cells." J Ethnopharmacol 113(1): 149-155.
Chow, J. C., D. W. Young, D. T. Golenbock, W. J. Christ and F. Gusovsky (1999). "Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction." J Biol Chem 274(16): 10689-10692.
Cotelle, N., J. L. Bernier, J. P. Catteau, J. Pommery, J. C. Wallet and E. M. Gaydou (1996). "Antioxidant properties of hydroxy-flavones." Free Radic Biol Med 20(1): 35-43.
Cuzzocrea, S., L. Sautebin, G. De Sarro, G. Costantino, L. Rombola, E. Mazzon, A. Ialenti, A. De Sarro, G. Ciliberto, M. Di Rosa, A. P. Caputi and C. Thiemermann (1999). "Role of IL-6 in the pleurisy and lung injury caused by carrageenan." J Immunol 163(9): 5094-5104.
Damas, P., A. Reuter, P. Gysen, J. Demonty, M. Lamy and P. Franchimont (1989). "Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans." Crit Care Med 17(10): 975-978.
Danner, R. L., R. J. Elin, J. M. Hosseini, R. A. Wesley, J. M. Reilly and J. E. Parillo (1991). "Endotoxemia in human septic shock." Chest 99(1): 169-175.
Faubel, S., E. C. Lewis, L. Reznikov, D. Ljubanovic, T. S. Hoke, H. Somerset, D. J. Oh, L. Lu, C. L. Klein, C. A. Dinarello and C. L. Edelstein (2007). "Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1 beta, IL-18, IL-6, and neutrophil infiltration in the kidney." Journal of Pharmacology and Experimental Therapeutics 322(1): 8-15.
Finberg, R. W., F. Re, L. Popova, D. T. Golenbock and E. A. Kurt-Jones (2004). "Cell activation by Toll-like receptors: role of LBP and CD14." J Endotoxin Res 10(6): 413-418.
Gabay, C. (2006). "Interleukin-6 and chronic inflammation." Arthritis Res Ther 8 Suppl 2: S3.
Ghosh, S. and D. Baltimore (1990). "Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B." Nature 344(6267): 678-682.
Gugler, R., M. Leschik and H. J. Dengler (1975). "Disposition of quercetin in man after single oral and intravenous doses." Eur J Clin Pharmacol 9(2-3): 229-234.
Guo, S., P. Qiu, G. Xu, X. Wu, P. Dong, G. Yang, J. Zheng, D. J. McClements and H. Xiao (2012). "Synergistic anti-inflammatory effects of nobiletin and sulforaphane in lipopolysaccharide-stimulated RAW 264.7 cells." J Agric Food Chem 60(9): 2157-2164.
Habtemariam, S. (1997). "Flavonoids as inhibitors or enhancers of the cytotoxicity of tumor necrosis factor-alpha in L-929 tumor cells." Journal of Natural Products 60(8): 775-778.
Harada, S., T. Tominari, C. Matsumoto, M. Hirata, M. Takita, M. Inada and C. Miyaura (2011). "Nobiletin, a polymethoxy flavonoid, suppresses bone resorption by inhibiting NFkappaB-dependent prostaglandin E synthesis in osteoblasts and prevents bone loss due to estrogen deficiency." J Pharmacol Sci 115(1): 89-93.
Harper, J. W., G. R. Adami, N. Wei, K. Keyomarsi and S. J. Elledge (1993). "The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases." Cell 75(4): 805-816.
Kinoshita, T. and K. Firman (1997). "Myricetin 5,7,3′,4′,5′-pentamethyl ether and other methylated flavonoids from Murraya paniculata." Phytochemistry 45(1): 179-181.
Kishimoto, T. (2010). "IL-6: from its discovery to clinical applications." Int Immunol 22(5): 347-352.
Koga, N., C. Ohta, Y. Kato, K. Haraguchi, T. Endo, K. Ogawa, H. Ohta and M. Yano (2011). "In vitro metabolism of nobiletin, a polymethoxy-flavonoid, by human liver microsomes and cytochrome P450." Xenobiotica 41(11): 927-933.
Kolb, M., P. J. Margetts, D. C. Anthony, F. Pitossi and J. Gauldie (2001). "Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis." J Clin Invest 107(12): 1529-1536.
Lai, C. S., S. Li, C. Y. Chai, C. Y. Lo, C. T. Ho, Y. J. Wang and M. H. Pan (2007). "Inhibitory effect of citrus 5-hydroxy-3,6,7,8,3 '',4 ''-hexamethoxyflavone on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mice." Carcinogenesis 28(12): 2581-2588.
Lai, C. S., S. M. Li, C. Y. Chai, C. Y. Lo, S. Dushenkov, C. T. Ho, M. H. Pan and Y. J. Wang (2008). "Anti-inflammatory and antitumor promotional effects of a novel urinary metabolite, 3'',4''-didemethylnobiletin, derived from nobiletin." Carcinogenesis 29(12): 2415-2424.
Li, S., S. Sang, M. H. Pan, C. S. Lai, C. Y. Lo, C. S. Yang and C. T. Ho (2007). "Anti-inflammatory property of the urinary metabolites of nobiletin in mouse." Bioorg Med Chem Lett 17(18): 5177-5181.
Li, S., Y. Wang, S. Dushenkov and C.-T. Ho (2008). "Bioavailability of Polymethoxyflavones." 987: 233-245.
Liaudet, L., F. G. Soriano and C. Szabo (2000). "Biology of nitric oxide signaling." Crit Care Med 28(4 Suppl): N37-52.
Lin, N., T. Sato, Y. Takayama, Y. Mimaki, Y. Sashida, M. Yano and A. Ito (2003). "Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages." Biochemical Pharmacology 65(12): 2065-2071.
Lu, W. C., J. F. Sheen, L. S. Hwang and G. J. Wei (2012). "Identification of 5,7,3'',4''-tetramethoxyflavone metabolites in rat urine by the isotope-labeling method and ultrahigh-performance liquid chromatography-electrospray ionization-mass spectrometry." J Agric Food Chem 60(33): 8123-8128.
Lyons, C. R., G. J. Orloff and J. M. Cunningham (1992). "Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line." J Biol Chem 267(9): 6370-6374.
Mansfield, J. C., H. Holden, J. K. Tarlow, F. S. Di Giovine, T. L. McDowell, A. G. Wilson, C. D. Holdsworth and G. W. Duff (1994). "Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist." Gastroenterology 106(3): 637-642.
Manthey, J. A. and P. Bendele (2008). "Anti-inflammatory activity of an orange peel polymethoxylated flavone, 3'',4'',3,5,6,7,8-heptamethoxyflavone, in the rat carrageenan/paw edema and mouse lipopolysaccharide-challenge assays." J Agric Food Chem 56(20): 9399-9403.
Manthey, J. A., T. B. Cesar, E. Jackson and S. Mertens-Talcott (2011). "Pharmacokinetic study of nobiletin and tangeretin in rat serum by high-performance liquid chromatography-electrospray ionization-mass spectrometry." J Agric Food Chem 59(1): 145-151.
Manthey, J. A. and N. Guthrie (2002). "Antiproliferative activities of citrus flavonoids against six human cancer cell lines." J Agric Food Chem 50(21): 5837-5843.
Marletta, M. A. (1989). "Nitric oxide: biosynthesis and biological significance." Trends Biochem Sci 14(12): 488-492.
Marti-Carvajal, A. J., I. Sola, C. Gluud, D. Lathyris and A. F. Cardona (2012). "Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients." Cochrane Database Syst Rev 12: CD004388.
Matsuda, H., T. Morikawa, S. Ando, I. Toguchida and M. Yoshikawa (2003). "Structural Requirements of Flavonoids for Nitric Oxide Production Inhibitory Activity and Mechanism of Action." Bioorganic & Medicinal Chemistry 11(9): 1995-2000.
Morrissette, N., E. Gold and A. Aderem (1999). "The macrophage--a cell for all seasons." Trends Cell Biol 9(5): 199-201.
Murakami, A., Y. Nakamura, K. Torikai, T. Tanaka, T. Koshiba, K. Koshimizu, S. Kuwahara, Y. Takahashi, K. Ogawa, M. Yano, H. Tokuda, H. Nishino, Y. Mimaki, Y. Sashida, S. Kitanaka and H. Ohigashi (2000). "Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice." Cancer Res 60(18): 5059-5066.
Nicholas, C., S. Batra, M. A. Vargo, O. H. Voss, M. A. Gavrilin, M. D. Wewers, D. C. Guttridge, E. Grotewold and A. I. Doseff (2007). "Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-kappaB through the suppression of p65 phosphorylation." J Immunol 179(10): 7121-7127.
Nielsen, S. E., V. Breinholt, C. Cornett and L. O. Dragsted (2000). "Biotransformation of the citrus flavone tangeretin in rats. Identification of metabolites with intact flavane nucleus." Food and Chemical Toxicology 38(9): 739-746.
Niering, P., G. Michels, W. Watjen, S. Ohler, B. Steffan, Y. Chovolou, A. Kampkotter, P. Proksch and R. Kahl (2005). "Protective and detrimental effects of kaempferol in rat H4IIE cells: implication of oxidative stress and apoptosis." Toxicol Appl Pharmacol 209(2): 114-122.
Noursadeghi, M., M. C. Bickerstaff, J. Herbert, D. Moyes, J. Cohen and M. B. Pepys (2002). "Production of granulocyte colony-stimulating factor in the nonspecific acute phase response enhances host resistance to bacterial infection." J Immunol 169(2): 913-919.
Onozuka, H., A. Nakajima, K. Matsuzaki, R. W. Shin, K. Ogino, D. Saigusa, N. Tetsu, A. Yokosuka, Y. Sashida, Y. Mimaki, T. Yamakuni and Y. Ohizumi (2008). "Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer''s disease." J Pharmacol Exp Ther 326(3): 739-744.
Palladino, M. A., F. R. Bahjat, E. A. Theodorakis and L. L. Moldawer (2003). "Anti-TNF-alpha therapies: The next generation." Nature Reviews Drug Discovery 2(9): 736-746.
Phromnoi, K., S. Prasad, S. C. Gupta, R. Kannappan, S. Reuter, P. Limtrakul and B. B. Aggarwal (2011). "Dihydroxypentamethoxyflavone down-regulates constitutive and inducible signal transducers and activators of transcription-3 through the induction of tyrosine phosphatase SHP-1." Mol Pharmacol 80(5): 889-899.
Pinsky, M. R., J. L. Vincent, J. Deviere, M. Alegre, R. J. Kahn and E. Dupont (1993). "Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality." Chest 103(2): 565-575.
Poltorak, A., X. L. He, I. Smirnova, M. Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton and B. Beutler (1998). "Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene." Science 282(5396): 2085-2088.
Qiu, P., P. Dong, H. Guan, S. Li, C. T. Ho, M. H. Pan, D. J. McClements and H. Xiao (2010). "Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells." Mol Nutr Food Res 54 Suppl 2: S244-252.
Rahman, H. M., U. N. and S. I.Z (2010). "Antidiarrheal and anti-inflammatory activities of Murraya paniculata (L.) Jack." Pharmacologyonline 3: 768-776.
Rajudin, E., F. Ahmad, H. M. Sirat, D. Arbain and H. Y. Aboul-Enein (2010). "Chemical constituents from tiger''s betel, Piper porphyrophyllum N.E.Br. (Fam. Piperaceae)." Nat Prod Res 24(4): 387-390.
Russell, J. A. (2006). "Management of sepsis." N Engl J Med 355(16): 1699-1713.
Sae-Wong, C., H. Matsuda, S. Tewtrakul, P. Tansakul, S. Nakamura, Y. Nomura and M. Yoshikawa (2011). "Suppressive effects of methoxyflavonoids isolated from Kaempferia parviflora on inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells." J Ethnopharmacol 136(3): 488-495.
Sae-wong, C., P. Tansakul and S. Tewtrakul (2009). "Anti-inflammatory mechanism of Kaempferia parviflora in murine macrophage cells (RAW 264.7) and in experimental animals." J Ethnopharmacol 124(3): 576-580.
Schwabe, R. F. and D. A. Brenner (2006). "Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways." Am J Physiol Gastrointest Liver Physiol 290(4): G583-589.
Serban, M., V. Ghiea and D. Pasarica (2002). "Oxidative aggression in atherosclerosis associated to degenerative psychoorganic disturbances." Rom J Intern Med 40(1-4): 117-123.
Shin, H. S., S. I. Kang, S. A. Yoon, H. C. Ko and S. J. Kim (2012). "Sinensetin Attenuates LPS-Induced Inflammation by Regulating the Protein Level of I kappa B-alpha." Bioscience Biotechnology and Biochemistry 76(4): 847-849.
Sundgren-Andersson, A. K., P. Ostlund and T. Bartfai (1998). "IL-6 is essential in TNF-alpha-induced fever." Am J Physiol 275(6 Pt 2): R2028-2034.
Tasdemir, D., M. Kaiser, R. Brun, V. Yardley, T. J. Schmidt, F. Tosun and P. Ruedi (2006). "Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: in vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies." Antimicrob Agents Chemother 50(4): 1352-1364.
Tewtrakul, S. and S. Subhadhirasakul (2007). "Anti-allergic activity of some selected plants in the Zingiberaceae family." J Ethnopharmacol 109(3): 535-538.
Tewtrakul, S. and S. Subhadhirasakul (2008). "Effects of compounds from Kaempferia parviflora on nitric oxide, prostaglandin E2 and tumor necrosis factor-alpha productions in RAW264.7 macrophage cells." J Ethnopharmacol 120(1): 81-84.
Tewtrakul, S. and S. Subhadhirasakul (2008). "Effects of compounds from Kaempferia parviflora on nitric oxide, prostaglandin E-2 and tumor necrosis factor-alpha productions in RAW264.7 macrophage cells." J Ethnopharmacol 120(1): 81-84.
Tewtrakul, S., S. Subhadhirasakul, C. Karalai, C. Ponglimanont and S. Cheenpracha (2009). "Anti-inflammatory effects of compounds from Kaempferia parviflora and Boesenbergia pandurata." Food Chemistry 115(2): 534-538.
Tracey, K. J., B. Beutler, S. F. Lowry, J. Merryweather, S. Wolpe, I. W. Milsark, R. J. Hariri, T. J. Fahey, 3rd, A. Zentella, J. D. Albert and et al. (1986). "Shock and tissue injury induced by recombinant human cachectin." Science 234(4775): 470-474.
Veckenstedt, A., J. Guttner and I. Beladi (1987). "Synergistic action of quercetin and murine alpha/beta interferon in the treatment of Mengo virus infection in mice." Antiviral Res 7(3): 169-178.
Walle, U. K. and T. Walle (2007). "Bioavailable flavonoids: cytochrome P450-mediated metabolism of methoxyflavones." Drug Metab Dispos 35(11): 1985-1989.
Wu, L., P. Li, X. Wang, Z. Zhuang, F. Farzaneh and R. Xu (2010). "Evaluation of anti-inflammatory and antinociceptive activities of Murraya exotica." Pharm Biol 48(12): 1344-1353.
Yenjai, C., K. Prasanphen, S. Daodee, V. Wongpanich and P. Kittakoop (2004). "Bioactive flavonoids from Kaempferia parviflora." Fitoterapia 75(1): 89-92.
Yuasa, K., K. Tada, G. Harita, T. Fujimoto, M. Tsukayama and A. Tsuji (2012). "Sudachitin, a Polymethoxyflavone from Citrus sudachi, Suppresses Lipopolysaccharide-Induced Inflammatory Responses in Mouse Macrophage-Like RAW264 Cells." Bioscience, Biotechnology, and Biochemistry 76(3): 598-600.
Zhang, J. Y., N. Li, Y. Y. Che, Y. Zhang, S. X. Liang, M. B. Zhao, Y. Jiang and P. F. Tu (2011). "Characterization of seventy polymethoxylated flavonoids (PMFs) in the leaves of Murraya paniculata by on-line high-performance liquid chromatography coupled to photodiode array detection and electrospray tandem mass spectrometry." J Pharm Biomed Anal 56(5): 950-961.