胸膜炎及塞来昔布干预的大鼠代谢组学研究
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摘要
炎症是具有血管系统的活体组织对各种损伤因子刺激所发生的以防御反应为主的基本病理过程。它常常表现为红、肿、热、痛和功能障碍。通常情况下,作为机体防御反应的炎症是有益的；但是如果炎症反应没有及时终止而发展成慢性低度状态时,可能导致机体过度应激和组织损伤,从而引发一系列重大疾病。为深入了解炎症疾病机制,本论文采用角叉胶诱导的大鼠胸膜炎模型并给予了塞来昔布治疗,运用基于NMR的代谢组学方法和基于GC-FID的脂肪酸检测方法,动态研究了炎症急性期和恢复期大鼠血浆及各组织器官的代谢应答。主要内容包括以下两个方面。
首先,本论文动态分析了胸膜炎过程中大鼠的胸腺、血、肝脏和附睾脂肪组织的代谢变化。研究发现,胸膜炎急性期时不仅产生大量的胸腔积液等病理改变,而且还引起大鼠全身系统性的代谢变化。此时,脂类变化异常剧烈：附睾脂肪分解增强；肝脏中脂肪p-氧化及酮体生成被激活；血浆中n6/n3脂肪酸比例显著升高且脂蛋白出现扰动。急性期时除脂类代谢变化之外,炎症还引起以下的代谢通路的改变：脂肪组织及血浆中三羧酸循环增强,血浆及肝脏中出现急性期蛋白和氨基酸扰动,肝脏及附睾脂肪组织中核苷酸代谢受到影响。胸膜炎恢复期时,结合炎症的理化指标与大鼠胸腺、血浆的代谢组和脂肪酸数据,我们发现此时炎症大鼠表现出显著的个体差异。恢复不佳的大鼠部分仍含有胸腔积液、胸腺肿大且脾脏重量较轻；而恢复良好的亚组在胸腺脂类代谢、糖代谢、胆碱、牛磺酸及核酸通路上有所缓解。另外此时附睾脂肪组织的脂肪酸含量上升出现逆转,此时机体以脂类合成为主。
其次,本论文研究了塞来昔布干预后,大鼠胸腺、附睾脂肪、血浆和肝脏的代谢组变化。我们发现在炎症恢复期时,塞来昔布能显著改善恢复不佳大鼠的胸腺代谢状况；但对正常大鼠给药塞来昔布会引起胸腺小叶间隔区中性粒细胞聚集,上调氨基酸和胆碱的含量,激活核酸分解通路,塞来昔布可能对胸腺有一定的损伤作用。不论是在炎症基础上给药,还是对正常大鼠给药,塞来昔布都能显著上调附睾脂肪组织中脂肪酸含量。附睾脂肪中上调的脂肪酸不仅包括饱和脂肪酸和单不饱和脂肪酸,也包括n3和n6系列的多不饱和脂肪酸。
综上所述,本论文研究了角叉胶诱导的胸膜炎及塞来昔布给药后体液及多器官的代谢变化。这些结果有助于我们深入理解炎症疾病的机制,为疾病的个体化治疗提供参考；同时这些研究有助于深入了解塞来昔布药物的作用机制及其毒副作用。
Inflammation is a part of the complex biological response of vascular tissues to harmful stimuli. The classical signs of acute inflammation are pain, heat, redness, swelling, and loss of function. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. But in some instances when inflammation occurred in an uncontrolled or inappropriate manner and proceeded to a low grade and chronic state, it always associates with metabolic disorders, cardiovascular disease or even cancer. For these reasons, we employed the NMR based metabonomics approaches and GC-based fatty acid analysis to study rat metabonome responses to pleurisy induced by carrageenan and celecoxib treatment.
First, the dynamic metabolic changes in rat thymus, plasma, epididymal adipose and liver in response to carrageenan induced pleurisy were investigated. The results showed that the inflammation in acute phase not only produced approximately4.6mL pleurisy exudates in local site, but also elicited system metabolic alterations involving dramatically lipid metabolism. The epididymal adipose lipolysis activated drastically while hepatic fatty acid β-oxidation was enhanced. And the ratio of n6/n3also increased in plasma. Besides the change of lipid, many metabolic pathways also altered including disrupted amino acid and the production of acute phase protein in liver and plasma, perturbed TCA cycles in adipose tissure and plasma, disordered nucleotide metabolism in adipose and liver. In inflammatory resolution phase, the great individual differences in thymus and plasma were confirmed by NMR date, GC data and physicochemical index of inflammation. Poor recovered rats had more pleurisy exudates and swollen thymus while well recovered subgroup basically restored in lipid metabolism, carbohydrate metabolism and amino acid metabolism and partly relief in choline metabolism, taurine metabolism and nucleic acid metabolism. In addition, the fatty acids in adipose and plasma shifted into reverse. Compareing with the decoposition in acute phase, in resolution phase the fatty acid in epididymal adipose increased.
Second, the metabolic changes in response to celecoxib treatement were detected. The results showed that wether administrated to inflammatory rats or normal rats, celecoxib could up regulate the fatty acids in epididymal adipose. The up regulated fatty acids not only included saturated fatty acids, but also included monounsaturated fatty acids, n3polyunsaturated fattyacids and n6polyunsaturated fatty acids. What is more, celecoxib might do harm to thymus.On one hand, the histopathology assessments showed the thymus of celecoxib administrated induced polymorphonuclear neutrophil accumulation. On the other hand celecoxib could elicit metabolic disorder including amino acid pathway, nucleotide pathway and choline pathway.
In conclusion, this thesis studies on the matabonomics changes in carrageenan induced pleurity and celecoxib treatement. The results provided metabonimics information to enhance our understanding of the inflammtion mechanism, celecoxib's safty and its work mechanism.
首先,本论文动态分析了胸膜炎过程中大鼠的胸腺、血、肝脏和附睾脂肪组织的代谢变化。研究发现,胸膜炎急性期时不仅产生大量的胸腔积液等病理改变,而且还引起大鼠全身系统性的代谢变化。此时,脂类变化异常剧烈：附睾脂肪分解增强；肝脏中脂肪p-氧化及酮体生成被激活；血浆中n6/n3脂肪酸比例显著升高且脂蛋白出现扰动。急性期时除脂类代谢变化之外,炎症还引起以下的代谢通路的改变：脂肪组织及血浆中三羧酸循环增强,血浆及肝脏中出现急性期蛋白和氨基酸扰动,肝脏及附睾脂肪组织中核苷酸代谢受到影响。胸膜炎恢复期时,结合炎症的理化指标与大鼠胸腺、血浆的代谢组和脂肪酸数据,我们发现此时炎症大鼠表现出显著的个体差异。恢复不佳的大鼠部分仍含有胸腔积液、胸腺肿大且脾脏重量较轻；而恢复良好的亚组在胸腺脂类代谢、糖代谢、胆碱、牛磺酸及核酸通路上有所缓解。另外此时附睾脂肪组织的脂肪酸含量上升出现逆转,此时机体以脂类合成为主。
其次,本论文研究了塞来昔布干预后,大鼠胸腺、附睾脂肪、血浆和肝脏的代谢组变化。我们发现在炎症恢复期时,塞来昔布能显著改善恢复不佳大鼠的胸腺代谢状况；但对正常大鼠给药塞来昔布会引起胸腺小叶间隔区中性粒细胞聚集,上调氨基酸和胆碱的含量,激活核酸分解通路,塞来昔布可能对胸腺有一定的损伤作用。不论是在炎症基础上给药,还是对正常大鼠给药,塞来昔布都能显著上调附睾脂肪组织中脂肪酸含量。附睾脂肪中上调的脂肪酸不仅包括饱和脂肪酸和单不饱和脂肪酸,也包括n3和n6系列的多不饱和脂肪酸。
综上所述,本论文研究了角叉胶诱导的胸膜炎及塞来昔布给药后体液及多器官的代谢变化。这些结果有助于我们深入理解炎症疾病的机制,为疾病的个体化治疗提供参考；同时这些研究有助于深入了解塞来昔布药物的作用机制及其毒副作用。
Inflammation is a part of the complex biological response of vascular tissues to harmful stimuli. The classical signs of acute inflammation are pain, heat, redness, swelling, and loss of function. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. But in some instances when inflammation occurred in an uncontrolled or inappropriate manner and proceeded to a low grade and chronic state, it always associates with metabolic disorders, cardiovascular disease or even cancer. For these reasons, we employed the NMR based metabonomics approaches and GC-based fatty acid analysis to study rat metabonome responses to pleurisy induced by carrageenan and celecoxib treatment.
First, the dynamic metabolic changes in rat thymus, plasma, epididymal adipose and liver in response to carrageenan induced pleurisy were investigated. The results showed that the inflammation in acute phase not only produced approximately4.6mL pleurisy exudates in local site, but also elicited system metabolic alterations involving dramatically lipid metabolism. The epididymal adipose lipolysis activated drastically while hepatic fatty acid β-oxidation was enhanced. And the ratio of n6/n3also increased in plasma. Besides the change of lipid, many metabolic pathways also altered including disrupted amino acid and the production of acute phase protein in liver and plasma, perturbed TCA cycles in adipose tissure and plasma, disordered nucleotide metabolism in adipose and liver. In inflammatory resolution phase, the great individual differences in thymus and plasma were confirmed by NMR date, GC data and physicochemical index of inflammation. Poor recovered rats had more pleurisy exudates and swollen thymus while well recovered subgroup basically restored in lipid metabolism, carbohydrate metabolism and amino acid metabolism and partly relief in choline metabolism, taurine metabolism and nucleic acid metabolism. In addition, the fatty acids in adipose and plasma shifted into reverse. Compareing with the decoposition in acute phase, in resolution phase the fatty acid in epididymal adipose increased.
Second, the metabolic changes in response to celecoxib treatement were detected. The results showed that wether administrated to inflammatory rats or normal rats, celecoxib could up regulate the fatty acids in epididymal adipose. The up regulated fatty acids not only included saturated fatty acids, but also included monounsaturated fatty acids, n3polyunsaturated fattyacids and n6polyunsaturated fatty acids. What is more, celecoxib might do harm to thymus.On one hand, the histopathology assessments showed the thymus of celecoxib administrated induced polymorphonuclear neutrophil accumulation. On the other hand celecoxib could elicit metabolic disorder including amino acid pathway, nucleotide pathway and choline pathway.
In conclusion, this thesis studies on the matabonomics changes in carrageenan induced pleurity and celecoxib treatement. The results provided metabonimics information to enhance our understanding of the inflammtion mechanism, celecoxib's safty and its work mechanism.
引文
[1]李玉林,第六版病理学[M].北京：人民卫生出版社：2004,70-89.
[2]Pickup, J.C. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes[J]. Diabetes Care 2004,27, (3):813-823.
[3]Dandona, P., Aljada, A., Bandyopadhyay, A. Inflammation:the link between insulin resistance, obesity and diabetes[J]. Trends Immunol 2004,25, (1):4-7.
[4]Dandona, P., Aljada, A., Chaudhuri, A., Mohanty, P., Garg, R. Metabolic syndrome-A comprehensive perspective based on interactions between obesity, diabetes, and inflammation[J]. Circulation 2005, 111, (11):1448-1454.
[5]Hotamisligil, GS. Inflammation and metabolic disorders[J]. Nature 2006,444, (7121):860-7.
[6]Libby, P. Inflammation in atherosclerosis[J]. Nature 2002,420, (6917):868-874.
[7]Libby, P., Okamoto, Y., Rocha, V.Z.,Folco, E. Inflammation in Atherosclerosis:Transition From Theory to Practice[J]. Circ J 2010,74, (2):213-220.
[8]Balkwill, F., Mantovani, A. Inflammation and cancer:back to Virchow?[J]. Lancet 2001,357, (9255): 539-45.
[9]Coussens, L.M.,Werb, Z. Inflammation and cancer[J]. Nature 2002,420, (6917):860-7.
[10]Grivennikov, S.I., Greten, F.R., Karin, M. Immunity, inflammation, and cancer[J]. Cell 2010,140, (6): 883-99.
[11]Casserly, I., Topol, E. Convergence of atherosclerosis and Alzheimer's disease:inflammation, cholesterol, and misfolded proteins[J]. Lancet 2004,363, (9415):1139-1146.
[12]Town, T. Inflammation, immunity, and Alzheimer's disease[J]. CNS Neurol Disord Drug Targets 2010, 9, (2):129-31.
[13]Dubois, R.N., Abramson, S.B., Crofford, L., Gupta, R.A., Simon, L.S., Van De Putte, L.B.A., Lipsky, P.E. Cyclooxygenase in biology and disease[J]. Faseb Journal 1998,12, (12):1063-1073.
[14]Needleman, P., Turk, J., Jakschik, B.A., Morrison, A.R., Lefkowith, J.B. Arachidonic-acid metabolism[J]. Annu Rev Biochem 1986,55:69-102.
[15]Simon, L.S. Role and regulation of cyclooxygenase-2 during inflammation[J]. Am J Med 1999,106: 37-42.
[16]Smith, W.L., Dewitt, D.L., Garavito, R.M. Cyclooxygenases:structural, cellular, and molecular biology[J]. Annu Rev Biochem.2000,69:145-182.
[17]Williams, C.S., Mann, M., DuBois, R.N. The role of cyclooxygenases in inflammation, cancer, and development[J]. Oncogene 1999,18, (55):7908-7916.
[18]Moncada, S., Palmer, R.M.J.,Higgs, E.A. Nitric-oxide-physiology, pathophysiology, and pharmacology[J]. Pharmacol Rev 1991,43, (2):109-142.
[19]Bredt, D.S., Snyder, S.H. Nitric oxide:a physiologic messenger molecule[J]. Annu Rev Biochem 1994, 63:175-95.
[20]Hanada, T., Yoshimura, A. Regulation of cytokine signaling and inflammation[J]. Cytokine Growth F R 2002,13, (4-5):413-421.
[21]Lin, W.W., Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer[J]. J Clin Invest 2007,117, (5):1175-1183.
[22]Zu, L.X., He, J.H., Jiang, H.F., Xu, C., Pu, S.S., Xu, G.H. Bacterial endotoxin stimulates adipose lipolysis via Toll-Like Receptor 4 and extracellular signal-regulated kinase pathway[J]. J Biol Chem 2009,284, (9):5915-5926.
[23]Herlaar, E.,Brown, Z. MAPK signalling cascades in inflammatory disease[J]. Mol Med Today 1999,5, (10):439-447.
[24]Bernik, T.R., Friedman, S.G., Ochani, M., DiRaimo, R., Ulloa, L., Yang, H., Sudan, S., Czura, C.J., Ivanova, S.M., Tracey, K.J. Pharmacological stimulation of the cholinergic antiinflammatory pathway[J]. J Exp Med 2002,195, (6):781-788.
[25]Tracey, K.J. Physiology and immunology of the cholinergic antiinflammatory pathway[J]. J Clin Invest 2007,117, (2):289-296.
[26]Salojin, K., Owusu, I.B., Millerchip, K.A., Potter, M., Platt, K.A.,Oravecz, T. Essential role of MAPK phosphatase-1 in the negative control of innate immune responses[J]. J Immunol 2006,176: S177-S177.
[27]Kaminska, B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy-from molecular mechanisms to therapeutic benefits[J]. Bba-Proteins Proteom 2005,1754, (1-2):253-262.
[28]Matsumura, Y, Ananthaswamy, H.N. Toxic effects of ultraviolet radiation on the skin[J]. Toxicol Appl Pharm 2004,195, (3):298-308.
[29]Hruza, L.L., Pentland, A.P. Mechanisms of UV-induced inflammation[J]. J Invest Dermatol 1993,100, (1):S35-S41.
[30]Briganti, S., Picardo, M. Antioxidant activity, lipid peroxidation and skin diseases. What's new[J]. J Eur Acad Dermatol 2003,17, (6):663-669.
[31]Vinegar, R., Truax, J.F., Selph, J.L., Johnston, P.R., Venable, A.L., McKenzie, K.K. Pathway to carrageenan-induced inflammation in the hind limb of the rat[J]. Fed Proc 1987,46, (1):118-26.
[32]Morris, C.J. Carrageenan-induced paw edema in the rat and mouse[J]. Methods Mol Biol 2003,225: 115-21.
[33]Vinegar, R., Truax, J.F., Selph, J.L., Voelker, F.A. Pathway of onset, development, and decay of carrageenan pleurisy in the rat[J]. Fed Proc 1982,41, (9):2588-95.
[34]Murai, N., Nagai, K., Fujisawa, H., Ko, Hatanaka, Michiko Kawamura, Harada, Y. Concurrent evolution and resolution in an acute inflammatory model of rat carrageenin-induced pleurisy[J]. J Leukocyte Biol 2003,73:456-463.
[35]Sedgwick, A.D., Lees, P. A comparison of air pouch, sponge and pleurisy models of acute carrageenan inflammation in the rat[J]. Agents Actions 1986,18, (3-4):439-446.
[36]Martin, S.W., Stevens, A.J., Brennan, B.S., Davies, D., Rowland, M.,Houston, J.B. The six-day-old rat air pouch model of inflammation:characterization of the inflammatory response to carrageenan[J]. J Pharmacol Toxicol Methods 1994,32, (3):139-47.
[37]Saleh, T.S., Calixto, J.B., Medeiros, Y.S. Anti-inflammatory effects of theophylline, cromolyn and salbutamol in a murine model of pleurisy[J]. Br J Pharmacol 1996,118, (3):811-9.
[38]Futaki, N., Arai, I., Hamasaka, Y., Takahashi, S., Higuchi, S., Otomo, S. Selective-inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation[J]. J Pharm Pharmacol 1993,45, (8):753-755.
[39]Ohgami, K., Shiratori, K., Ilieva, I.B., Yazawa, K., Ohno, S. The effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo[J]. Invest Ophth Vis Sci 2004,45: U211-U211.
[40]Ratkay, L.G., Zhang, L., Tonzetich, J., Waterfield, J.D. Complete Freund's adjuvant induces an earlier and more severe arthritis in MRL-lpr mice[J]. J Immunol 1993,151,(9):5081-7.
[41]Cathcart, E.S., Hayes, K.C., Gonnerman, W.A., Lazzari, A.A., Franzblau, C. Experimental arthritis in a nonhuman primate. I. Induction by bovine type II collagen[J]. Lab Invest 1986,54, (1):26-31.
[42]Gaudio, E., Taddei, G., Vetuschi, A., Sferra, R., Frieri, G., Ricciardi, G, Caprilli, R. Dextran sulfate sodium (DSS) colitis in rats:clinical, structural, and ultrastructural aspects[J]. Digest Dis Sci 1999,44, (7):1458-75.
[43]Cooper, H.S., Murthy, S.N., Shah, R.S., Sedergran, D.J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis[J]. Lab Invest 1993,69, (2):238-49.
[44]Dieleman, L.A., Palmen, M.J.H.J., Akol, H., Bloemena, E., Pena, A.S., Meuwissen, S.G.M., van Rees, E.P. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines[J]. Clin Exp Immunol 1998,114, (3):385-391.
[45]Cuzzocrea, S., Mazzon, E., Sautebin, L., Dugo, L., Serraino, L., De Sarro, A.,Caputi, A.P. Protective effects of Celecoxib on lung injury and red blood cells modification induced by carrageenan in the rat[J]. Biochem Pharmacol 2002,63, (4):785-795.
[46]Seibert, K., Zhang, Y, Leahy, K., Hauser, S., Masferrer, J., Perkins, W., Lee, L., Isakson, P. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain[J]. P Natl Acad Sci 1994,91, (25):12013-7.
[47]Hay, C., deBelleroche, J. Carrageenan-induced hyperalgesia is associated with increased cyclo-oxygenase-2 expression in spinal cord[J]. Neuroreport 1997,8, (5):1249-1251.
[48]Salvemini, D., Wang, Z.Q., Wyatt, P.S., Bourdon, D.M., Marino, M.H., Manning, P.T., Currie, M.G Nitric oxide:a key mediator in the early and late phase of carrageenan-induced rat paw inflammation[J]. Br J Pharmacol 1996,118, (4):829-38.
[49]Omote, K., Hazama, K., Kawamata, T., Kawamata, M., Nakayaka, Y., Toriyabe, M., Namiki, A. Peripheral nitric oxide in carrageenan-induced inflammation[J]. Brain Res 2001,912, (2):171-175.
[50]Handy, R.L., Moore, P.K. A comparison of the effects of L-NAME,7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity[J]. Br J Pharmacol 1998,123, (6):1119-26.
[51]Futaki, N., Takahashi, S., Yokoyama, M., Arai, I., Higuchi, S., Otomo, S. NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro[J]. Prostaglandins 1994,47, (1):55-9.
[52]Guay, J., Bateman, K., Gordon, R., Mancini, J., Riendeau, D. Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E2 (PGE2) response in the central nervous system associated with the induction of microsomal PGE2 synthase-1[J]. J Biol Chem 2004,279, (23):24866-72.
[53]Ombrellino, M., Wang, H.C., Yang, H., Zhang, M.H., Vishnubhakat, J., Frazier, A., Scher, L.A., Friedman, S.G,Tracey, K.J. Fetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to carrageenan[J]. Shock 2001,15, (3):181-185.
[54]Cuzzocrea, S., Sautebin, L., De Sarro, G, Costantino, G, Rombola, L., Mazzon, E., Ialenti, A., De Sarro, A., Ciliberto, G., Di Rosa, M., Caputi, A.P. Thiemermann, C., Role of IL-6 in the pleurisy and lung injury caused by carrageenan[J]. J Immunol 1999,163, (9):5094-104.
[55]William L. Smith, David L. DeWitt, Garavito, R.M. Cyclooxygenases:structural, cellular, and molecular biology[J]. Annu Rev Biochem 2000,69:145-182.
[56]Hawkey, C.J. COX-2 inhibitors[J]. Lancet 1999,353, (9149):307-314.
[57]Bensen, W.G, Fiechtner, J.J., McMillen, J.I., Zhao, W.W., Yu, S.S., Woods, E.M., Hubbard, R.C., Isakson, P.C., Verburg, K.M., Geis, GS. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor:a randomized controlled trial[J]. Mayo Clin Proc 1999,74, (11): 1095-1105.
[58]Deeks, J.J., Smith, L.A., Bradley, M.D. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis:systematic review of randomised controlled trials[J]. Bmj 2002,325, (7365):619.
[59]Simon, L.S., Weaver, A. L., Graham, D.Y., Kivitz, A.J., Lipsky, P.E., Hubbard, R.C., Isakson, P.C., Verburg, K.M., Yu, S.S., Zhao, W.W., Geis, S.G Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis:A randomized controlled trial[J]. JAMA 1999,282, (20): 1921-1928.
[60]Dougados, M., Behier, J.M., Jolchine, I., Calin, A., van der Heijde, D., Olivieri, I., Zeidler, H., Herman, H. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis:a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug[J]. Arthritis Rheum 2001,44, (1):180-185.
[61]Gimbel, J.S., Brugger, A., Zhao, W., Verburg, K.M., Geis, GS. Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults[J]. Clin Ther 2001,23, (2):228-241.
[62]Phillips, R.K.S., Wallace, M.H., Lynch, P.M., Hawk, E., Gordon, GB., Saunders, B.P., Wakabayashi, N., Shen, Y., Zimmerman, S., Godio, L., Rodrigues-Bigas, M., Su, L.K., Sherman, J., Kelloff, G., Levin, B., Steinbach, G,Grp, F.S. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis[J]. Gut 2002,50, (6):857-860.
[63]Russell F. Jacoby, Karen Seibert, Carolyn E. Cole, Gary Kelloff, A., Lubet, R.A. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis [J].Cancer Res 2000,60:5040-5044.
[64]Steinbach, G, Lynch, P.M., Phillips, R.K., Wallace, M.H., Hawk, E., Gordon, G.B., Wakabayashi, N., Saunders, B., Shen, Y., Fujimura, T., Su, L.K., Levin, B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis[J]. N Engl J Med 2000,342, (26):1946-1952.
[65]Toshihiko Kawamori, Chinthalapally V. Rao, Karen Seibert, a., Reddy, B.S. Chemopreventive activity of Celecoxib, a specific Cyclooxygenase-2 inhibitor, against colon carcinogenesis1[J]. Cancer Res 1998,58:409-412.
[66]Bandaru S. Reddy, Yoshinobu Hirose, Ronald Lubet, Vernon Steele, Gary Kelloff, Susan Paulson, Karen Seibert, A., Rao, C.V. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis [J]. Cancer Res 2000,60:293-297.
[67]Bertagnolli, M.M., Eagle, C.J., Zauber, A.G, Redston, M., Solomon, S.D., Kim, K., Tang, J., Rosenstein, R.B., Wittes, J., Corle, D., Hess, T.M., Woloj, GM., Boisserie, F., Anderson, W.F., Viner, J.L., Bagheri, D., Burn, J., Chung, D.C., Dewar, T., Foley, T.R., Hoffman, N., Macrae, F., Pruitt, R.E., Saltzman, J.R., Salzberg, B., Sylwestrowicz, T., Gordon, GB., Hawk, E.T. Celecoxib for the prevention of sporadic colorectal adenomas[J]. N Engl J Med 2006,355, (9):873-884.
[68]Gupta, S., Adhami, V.M., Subbarayan, M., MacLennan, GT., Lewin, J.S., Hafeli, U.O., Fu, P., Mukhtar, H. Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model[J]. Cancer Res 2004,64, (9):3334-3343.
[69]Harris, R.E., Alshafie, GA., Abou-Issa, H., Seibert, K. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor[J]. Cancer Res 2000,60, (8):2101-2103.
[70]Fischer, S.M., Lo, H.H., Gordon, GB., Seibert, K., Kelloff, G, Lubet, R.A., Conti, C.J. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis[J]. Mol Carcinog 1999,25, (4):231-240.
[71]Susan K. P., Jeremy D. H., Norman W. K., Liu, J., Elisabeth H., Roy H. B., Karim, A.P. Metabolism and excretion of [14C]celecoxib in healthy male volunteers [J]. Drug Metab Dispos 2000,28, (3):308-314.
[72]Wallace, J.L., McKnight, W., Reuter, B.K., Vergnolle, N. NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2[J]. Gastroenterology 2000,119, (3): 706-714.
[73]Silverstein, F.E., Faich, G, Goldstein, J.L., Simon, L.S., Pincus, t., Whelton, A., Maknch. R., Eisen, G., Agranal, N.M., Stenson, W.F., Burr, A.M., Zhao, W.W., Kent, J.D., Lefkowith, J.B., Verburg, K.M., Geis, GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis:The class study:a randomized controlled trial[J]. JAMA 2000, 284,(10):1247-1255.
[74]Laudanno, O.M., Cesolari, J.A., Esnarriaga, J., Rista, L., Piombo, G., Maglione, C., Aramberry, L. Sambrano, J., Godoy, A., Rocaspana, A. Gastrointestinal damage induced by celecoxib and rofecoxib in rats[J]. Digest Dis Sci 2001,46, (4):779-784.
[75]Um, S.Y., Chung, M.W., Kim, K.-B., Kim, S.H., Oh, J.S., Oh, H.Y., Lee, H.J., Choi, K.H. Pattern Recognition Analysis for the Prediction of Adverse Effects by Nonsteroidal Anti-inflammatory drugs using'H NMR-based metabolomics in rats[J]. Anal Chem 2009,81, (12):4734-4741.
[76]Um, S.Y., Park, J.H., Chung, M.W., Kim, K.B., Kim, S.H., Choi, K.H., Lee, H.J. Nuclear magnetic resonance-based metabolomics for prediction of gastric damage induced by indomethacin in rats[J]. Anal Chim Acta 2012,722:87-94.
[77]Sanchez-Matienzo, D., Arana, A., Castellsague, J., Perez-Gutthann, S. Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs:A case/noncase analysis of spontaneous reports[J]. Clin Ther 2006,28, (8):1123-1132.
[78]Maddrey, W.C., Maurath, C.J., Verburg, K.M., Geis, G.S. The hepatic safety and tolerability of the novel cyclooxygenase-2 inhibitor celecoxib[J]. Am J Ther 2000,7, (3):153-8.
[79]Nachimuthu, S., Volfinzon, L., Gopal, L. Acute hepatocellular and cholestatic injury in a patient taking celecoxib[J]. Postgrad Med J 2001,77, (910):548-50.
[80]Brater, D.C., Harris, C., Redfern, J.S., Gertz, B.J. Renal effects of COX-2-selective inhibitors[J]. Am J Nephrol 2001,21,(1):1-15.
[81]Perazella, M.A. COX-2 selective inhibitors:analysis of the renal effects[J]. Expert Opin Drug Saf 2002, 1,(1):53-64.
[82]Harris, R.C. Cyclooxygenase-2 inhibition and renal physiology [J]. Am J Cardiol 2002,89, (6A): 10d-17d.
[83]Whelton, A., Schulman, G., Wallemark, C., Drower, E.J., Isakson, P.C., Verburg, K.M., Geis, GS. Effects of celecoxib and naproxen on renal function in the elderly[J]. Arch Intern Med 2000,160, (10): 1465-70.
[84]Schwartz, J.I., Vandormael, K., Malice, M.P., Kalyani, R.N., Lasseter, K.C., Holmes, G.B., Gertz, B.J., Gottesdiener, K.M., Laurenzi, M., Redfern, K.J., Brune, K. Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet[J]. Clin Pharmacol Ther 2002,72,(1):50-61.
[85]Akhund, L., Quinet, R.J., Ishaq, S. Celecoxib-related renal papillary necrosis[J]. Arch Intern Med 2003, 163,(1):114-115.
[86]Leese, P.T., Hubbard, R.C., Karim, A., Isakson, P.C., Yu, S.S., Geis, G.S. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults:a randomized, controlled trial[J]. J Clin Pharmacol 2000,40, (2):124-132.
[87]Muscara, M.N., Vergnolle, N., Lovren, F., Triggle, C.R., Elliott, S.N., Asfaha, S.,Wallace, J.L. Selective cyclo-oxygenase-2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence[J]. Br J Pharmacol 2000,129, (7):1423-1430.
[88]Solomon, S.D., McMurray, J.J., Pfeffer, M.A., Wittes, J., Fowler, R., Finn, P., Anderson, W.F., Zauber, A., Hawk, E., Bertagnolli, M. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention[J]. N Engl J Med 2005,352, (11):1071-1080.
[89]Solomon, S.D., Pfeffer, M.A., McMurray, J.J., Fowler, R., Finn, P., Levin, B., Eagle, C., Hawk, E., Lechuga, M., Zauber, A.G, Bertagnolli, M.M., Arber, N.,Wittes, J. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas[J]. Circulation 2006,114, (10):1028-1035.
[90]Solomon, S.D., Wittes, J., Finn, P.V., Fowler, R., Viner, J., Bertagnolli, M.M., Arber, N., Levin, B., Meinert, C.L., Martin, B., Pater, J.L., Goss, P.E., Lance, P., Obara, S., Chew, E.Y., Kim, J., Arndt, G., Hawk, E., Grp, C.T.S.A. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials-The cross trial safety analysis[J]. Circulation 2008,117, (16):2104-2113.
[91]Caldwell, B., Aldington, S., Weatherall, M., Shirtcliffe, P., Beasley, R. Risk of cardiovascular events and celecoxib:a systematic review and meta-analysis[J]. J R Soc Med 2006,99, (3):132-140.
[92]Selmanoglu, G., Kockaya, E.A., Akay, M.T., Kismet, K. Subacute toxicity of celecoxib on thyroid and testis of rats:Hormonal and histopathological changes[J]. Environ Toxicol Pharmacol 2006,22, (1): 85-89.
[93]Kitano, H. Systems biology:A brief overview[J]. Science 2002,295, (5560):1662-1664.
[94]Nicholson, J.K., Lindon, J.C., Holmes, E.'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J]. Xenobiotica 1999,29, (11):1181-1189.
[95]Tang, H.R., Wang, Y.L. Metabonomics:a revolution in progress[J]. Prog Biochem Biophys 2006,33, (5):401-417.
[96]Schmidt, C.W. Metabolomics:What's happening downstream of DNA[J]. Environ Health Persp 2004, 112,(7):A410-A415.
[97]Nicholson, J.K., Connelly, J., Lindon, J.C., Holmes, E. Metabonomics:a platform for studying drug toxicity and gene function[J]. Nat Rev Drug Discov 2002,1, (2):153-161.
[98]Hirai, M.Y., Yano, M., Goodenowe, D.B., Kanaya, S., Kimura, T., Awazuhara, M., Arita, M., Fujiwara, T.,Saito, K. Integration of transcriptomics and metabolomics for understanding of global responses to nutritional stresses in Arabidopsis thaliana[J]. P Natl Acad Sci USA 2004,101, (27):10205-10210.
[99]Bino, R.J., Hall, R.D., Fiehn, O., Kopka, J., Saito, K., Draper, J., Nikolau, B.J., Mendes, P., Roessner-Tunali, U., Beale, M.H., Trethewey, R.N., Lange, B.M., Wurtele, E.S., Sumner, L.W. Potential of metabolomics as a functional genomics tool[J]. Trends Plant Sci 2004,9, (9):418-425.
[100]Grivet, J.P., Delort, A.M., Portais, J.C. NMR and microbiology:from physiology to metabolomics[J]. Biochimie 2003,85, (9):823-840.
[101]Goodenowe, D. Applying comprehensive metabolomics to the understanding of plant physiology[J]. Plant Cell Physiol 2004,45:S8-S8.
[102]Weckwerth, W. Integration of metabolomics and proteomics in molecular plant physiology-coping with the complexity by data-dimensionality reduction[J]. Physiol Plantarum 2008,132, (2):176-189.
[103]Brindle, J. T., Antti, H., Holmes, E., Tranter, G., Nicholson, J. K., Bethell, H. W. L., Clarke, S., Schofield, P. M., Mckilligin, E., Mosedale, D. E., Grainge, D. G Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using:H-NMR-based metabonomics[J]. Nat Med 2002,8:1439-1444.
[104]Dumas, M.E., Barton, R.H., Toye, A., Cloarec, O., Blancher, C., Rothwell, A., Fearnside, J., Tatoud, R., Blanc, V., Lindon, J.C., Mitchell, S.C., Holmes, E., McCarthy, M.I., Scott, J., Gauguier, D., Nicholson, J.K. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice[J]. P Natl Acad Sci USA 2006,103, (33):12511-12516.
[105]Griffiths, J.R., Stubbs, M. Opportunities for studying cancer by metabolomics:preliminary observations on tumors deficient in hypoxia-inducible factor 1[J]. Adv Enzyme Regul 2003,43:67-76.
[106]Blekherman, G., Laubenbacher, R., Cortes, D.F., Mendes, P., Torti, F.M., Akman, S., Torti, S.V.,Shulaev, V. Bioinformatics tools for cancer metabolomics[J]. Metabolomics 2011,7, (3):329-343.
[107]Claudino, W.M., Goncalves, P.H., di Leo, A., Philip, P.A., Sarkar, F.H. Metabolomics in cancer:A bench-to-bedside intersection[J]. Crit Rev Oncol Hemat 2012,84, (1):1-7.
[108]Lindon, J.C., Nicholson, J.K., Holmes, E., Antti, H., Bollard, M.E., Keun, H., Beckonert, O., Ebbels, T.M., Reilly, M.D., Robertson, D., Stevens, G.J., Luke, P., Breau, A.P., Cantor, G.H., Bible, R.H., Niederhauser, U., Senn, H., Schlotterbeck, G., Sidelmann, U.G, Laursen, S.M., Tymiak, A., Car, B.D., Lehman-McKeeman, L., Colet, J.M., Loukaci, A.,Thomas, C. Contemporary issues in toxicology-The role of metabonomics in toxicology and its evaluation by the COMET project[J]. Toxicol Appl Pharm 2003,187, (3):137-146.
[109]夏建飞,梁琼麟,胡坪,王义明,罗国安.代谢组学研究策略与方法的新进展[J].分析化学2009,37,(1)：136-143.
[110]Dai, H., Xiao, C., Liu, H., Hao, F., Tang, H. Combined NMR and LC-DAD-MS Analysis Reveals Comprehensive Metabonomic Variations for Three Phenotypic Cultivars of Salvia Miltiorrhiza Bunge[J]. J Proteome Res2010,9, (3):1565-1578.
[111]Ding, L., Hao, F., Shi, Z., Wang, Y., Zhang, H., Tang, H., Dai, J. Systems Biological Responses to Chronic Perfluorododecanoic Acid Exposure by Integrated Metabonomic and Transcriptomic Studies[J]. J Proteome Res 2009,8, (6):2882-2891.
[112]Beckonert, O., Keun, H.C., Ebbels, T.M.D., Bundy, J.G, Holmes, E., Lindon, J.C., Nicholson, J.K. Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts[J]. Nat Protoc 2007,2, (11):2692-2703.
[113]Han, X.L., Gross, R.W. Global analyses of cellular lipidomes directly from crude extracts of biological samples by ESI mass spectrometry:a bridge to lipidomics[J]. J Lipid Res 2003,44, (6): 1071-1079.
[114]Wenk, M.R. The emerging field of lipidomics[J]. Nat Rev Drug Discov 2005,4, (7):594-610.
[115]Dieterle, F., Ross, A., Schlotterbeck, G, Senn, H. Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in H-1 NMR metabonomics[J]. Anal Chem 2006,78, (13):4281-4290.
[116]Price, W.S. Water signal suppression in NMR spectroscopy[J]. Annu R NMR S 1999,38 1999,38: 289-354.
[117]毛希安.现代核磁共振实用技术及应用[M].1999,201-205.
[118]Neuhaus, D., Ismail, I.M., Chung, C.W. "FLIPSY"-A new solvent-suppression sequence for nonexchanging solutes offering improved integral accuracy relative to 1D NOESY[J]. J Magn Reson Ser A 1996,118, (2):256-263.
[119]Tang, H.R., Wang, Y.L., Nicholson, J.K., Lindon, J.C. Use of relaxation-edited one-dimensional and two dimensional nuclear magnetic resonance spectroscopy to improve detection of small metabolites in blood plasma[J]. Anal Biochem 2004,325, (2):260-272.
[120]Wu, D.H., Chen, A.D., Johnson, C.S. An improved diffusion-ordered spectroscopy experiment incorporating bipolar-gradient pulses[J]. J Magn Reson Ser A,1995,115, (2):260-264.
[121]Hurd, R.E. Gradient-enhanced spectroscopy[J]. J Magn Reson 1990,87, (2):422-428.
[122]Bax, A., Davis, D.G. MLEV-17-based two-dimensional homonuclear magnetization transfer spectroscopy[J]. J Magn Reson 1985,65, (2):355-360.
[123]Aue, W.P. Karhan, J.,Ernst, R.R., Homonuclear broad-band decoupling and 2-dimensional J-resolved NMR spectroscopy[J]. J Chem Phys 1976,64, (10):4226-4227.
[124]Bodenhausen, G., Ruben, D.J. Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopy[J]. Chem Phys Lett 1980,69, (1):185-189.
[125]Bax, A., Summers, M.F.1H and 13C assignments from sensitivity-enhanced detection of heteronuclear multiple-bond connectivity by multiple quantum [J]. J Am Chem. Soc 1986,108, (8):2093-2094.
[126]Cuzzocrea, S., Tan, D.X., Costanitino, G, Mazzon, E., Caputi.A.P., Reiter.R.J. The protective role of endogenous melatonin in carrageenan-induced pleurisy in the rat[J]. FASEB J 1999,13:1930-1938.
[127]Frode, T.S., Buss, Z.S., Reis, GO., Medeiros, Y.S., Fredholm, B.B. Evidence of anti-in fl ammatory effects of Pioglitazone in the murine pleurisy model induced by carrageenan[J]. Int Immunopharmacol 2009,9:1394-1400.
[128]Ianaro, A., Ialenti, A., Maffia, P., Pisano, B., Rosa.M.D. HSFl/hsp72 pathway as an endogenous anti-inmmatory system[J]. FEBS Lett 2001,499:239-244.
[129]Nakano, M., Denda, N., Matsumoto, M., Kawamura, M., Kawakubo, Y., Hatanaka, K., Hiramoto, Y., Sato, Y, Noshiro, M., Harada, Y Interaction between cyclooxygenase (COX)-1-and COX-2-products modulates COX-2 expression in the late phase of acute inflammation[J]. Eur J Pharmacol 2007,559: 210-218.
[130]Zhang, L.M., Ye, Y.F., An, Y.P., Tian, Y, Wang, Y.L., Tang, H.R. Systems responses of rats to Aflatoxin B1 exposure revealed with metabonomic changes in multiple biological matrices[J]. J Proteome Res 2010,10, (2):614-623.
[131]Wu, J.F., Xu, W.X., Ming, Z.P., Dong, H.F., Tang, H.R., Wang, Y.L. Metabolic changes reveal the development of schistosomiasis in mice[J]. PLos Negl Trop Dis 2010,4, (8):e807.
[132]Jiang, L.M., Huang, J., Wang, Y.L., Tang.H.R. Metabonomic analysis reveals the CCl4-Induced systems alterations for multiple rat organs[J]. J Proteome Res 2012,11, (7):3848-3859.
[133]Tian, Y, Zhang, L.M., Wang, Y.L., Tang, H.R. Age-related topographical metabolic signatures for the rat gastrointestinal contents[J]. J. Proteome Res.2011,11, (2):1397-1411.
[134]Lepage, G., Roy, C.C. Direct transesterification of all classes of lipids in a one-step reaction [J]. J. Lipid Res 1986,27:114-120.
[135]Xu, Z.D., Harvey, K., Pavlina, T., Dutot, G, Zaloga, G,Siddiqui, R. An improved method for determining medium-and long-chain FAMEs using Gas Chromatography[J]. Lipids 2010,45: 199-208.
[136]Hotamisligil, G.S. Inflammation and metabolic disorders[J]. Nature 2006,444, (14):860-867.
[137]Libby, P., Ridker, P.M., Maseri, A. Inflammation and atherosclerosis[J]. Circulation 2002,105: 1135-1143.
[138]Pearson, T.A., Mensah, GA., Alexander, R.W., Anderson, J.L., O'Cannon, R., Criqui, M., Fadl, Y.Y., Fortmann, S.P., Hong, Y, Myers, GL., Rifai, N., Smith, S.C., Taubert, J.K., Tracy, R.P.,Vinicor, F. Control and prevention and the American Heart Association Health practice:a statement for healthcare professionals from the centers for disease markers of inflammation and cardiovascular disease: application to clinical and public[J]. Circulation 2003,107:499-511.
[139]Balkwill, F., Mantovani, A. Inflammation and cancer:back to Virchow?[J]. Lancet 2001,357: 539-545.
[140]Coussens, L.M., Werb, Z. Inflammation and cancer[J]. Nature 2002,420:19-26.
[141]Baumann, H., Gauldie, J. The acute phase response.[J]. Immunol. Today 1994,15, (2):74-80.
[142]Schreiber, G, Howlettf, G, Nagashima, M., Millership, A., Martin, H., Urban, J., Kotlerg, L. The acute phase response of plasma protein synthesis during experimental inflammation[J]. J Biol Chem 1982,257, (17):10271-20277.
[143]Gruys.E, Toussaint.M.J.M., Niewnold.T.A., Koopmans.S.J. Acute phase reaction and acute phase proteins[J]. J Zhejiang Univ Sci 2005,11:1045-1056.
[144]Koj, A. Initiation of acute phase response and synthesis of cytokines [J]. Biochim Biophys Acta 1996, 1317:84-94.
[145]Heinrich, P.C., Castelltt, J.V., Andust, T. Interleukin-6 and the acute phase response[J]. J Biochem 1990,265:621-636.
[146]Moshage, H. Cytokines and the hepatic acute phase response[J]. J Pathol 1997,181:257-266.
[147]Vane, J., MIitchell, J., Appleton, I., Tomlinson, A., Bailey, D., Croxtall, J.,Willoughby, D. Inducible isoforms of cyclooxygenase and nitric-oxide synthase ininflammation[J]. Proc Nad Acad Sci 1994,91: 2046-2050.
[148]Salvemini, D., Wang, Z.Q., Wyatt, P.S., Bourdon, D., Marino, M.H., Manning, P.T., Currie, M.G Nitricoxide:a key mediator in the early and late phase of carrageenan-induced rat paw inflammation[J]. Brit J Pharmacol 1996,118:829-838.
[149]Schicho, R., Nazyrova, A., Shaykhutdinov, R., Duggan, G, Vogel, H.J., Storr, M. Quantitative metabolomic profiling of serum and urine in DSS-induced ulcerative colitis of mice by'H NMR spectroscopy[J]. J Proteome Res 2010,9:6265-6273.
[150]Xu, W.X., Wu, J.F., An, Y.P., Xiao, C.N., Hao, F.H., Liu, H.B., Wang, Y.L., Tang, H.R. Streptozotocin-induced dynamic metabonomic changes in rat biofluids[J]. J Proteome Res 2012,11, (6):3423-3435.
[151]Rosa, M.D. Biological properties of carrageenan[J]. J Pharm Pharmac1972,24:89-102.
[152]Catanzaro, P.J., Schwartz, H.J., Graham, R.C. Spectrum and possible mechanism of carrageenan cytotoxicity[J]. Am J Pathol 1971,64:387-404.
[153]Vaugha, M. The metabolism of adipose tissue in vitro [J]. J Lipid Res 1961,2:293-316.
[154]Khovidhunkit, W., Kim, M.S., Memon, R.A., Shigenaga, J.K., Moser, A.H., Feingold, K.R., Grunfeld, C. Effects of infection and inflammation on lipid and lipoprotein metabolism:mechanisms and consequences to the host[J]. J Lipid Res 2004,45:1169-1196.
[155]Raclot, T.,Groscolad, R. Differential mobilization of white adipose tissue fatty acids according to chain length, unsaturation, and positional isomerism[J]. J Lipid Res 1993,34:1513-1519.
[156]Raclot, T., Groscolad, R. Selective mobilization of adipose tissue fatty acids during energy depletion in the rat [J]. J Lipid Res 1995,36:2164-2173.
[157]Suganami, T., Tanimoto-Koyama, K., Nishida, J., Itoh, M., Yuan, X., Mizuarai, S., Kotani, H., Yamaoka, S., Miyake, K., Aoe, S., Kamei, Y., Ogawa, Y. Role of the Toll-like receptor 4/NF-kB Pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages[J]. Arterioscl Throm Vas 2007,27:84-91.
[158]Lee, J.Y., Sohn, K.H., Rhee, S.H.,Wang, D.H. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like Receptor 4[J]. J Biol Chem 2001,276:16683-16689.
[159]Schaffler, A., Schohnerich, J.,Salzberger, B. Adipose tissue as an immunological organ:Toll-like receptors, C1q/TNFs and CTRPs[J]. Trends Immunol 2007,28, (9):393-399.
[160]Juge-Aubry, C.E., Henrichot, E., Meier, C.A. Adipose tissue:a regulator of inflammation[J]. Best Pract Res Cl En 2005,19, (4):547-566.
[161]Shoda, R., Matsueda, K., Yamato, S., Umeda.N. Epidemiologic analysis of crohn disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of crohn disease in Japan [J]. Am J Clin Nutr 1996,63:741-745.
[162]Simopoulos, A.P. The importance of the ratio of omega-6/omega-3 essential fatty acids[J]. Biomed Pharmacother 2002,56:365-379.
[163]Simpoulos, A.P. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases[J]. Exp Biol Med 2008,233:674-688.
[164]Forsythe, C.E., Phinney, S.D., Fernandez, M.L., Quann, E.E., Wood, R.J., Bibus, D.M., Kraemer, W.J., Feinman, R.D.,Volek, J.S. Comparison of low fat and low carbohydrate diets on circulating fatty ccid composition and markers of inflammation[J]. Lipids 2008,43:65-77.
[165]Calder, P.C. n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases[J]. Am J Clin Nutr 2006,83:1505-1519.
[166]Shaikh, S.R., Edidin, M. Polyunsaturated fatty acids, membrane organization, T cells, and antigen presentation[J]. Am J Clin Nutr 2006,84:1277-1289.
[167]Norris, P.C.Dennis, E.A. Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling[J]. Proc Nad Acad Sci 2012,10:1-6.
[168]Ferrucci, L., Cherubini, A., Bartali, B., Corsi, A., Lauretani, F., Martin, A., Andres-Lacueva, C., Senin, U., Guralnik, J.K. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers[J]. J Clin Endocr Metab.2006,91, (2):439-446.
[169]Calder, P.C. Polyunsaturated fatty acids and inflammatory processes:New twists in an old tale[J]. Biochimie 2009,91:791-795.
[170]Kaysen, G.A. Effects of inflammation on plasma composition and endothelial structure and function[J]. J Renal Nutr 2005,15, (1):94-98.
[171]Pussinen, P.J., Malle, E., Metso, J., Sattle, W., Raynes, J.G, Jauhiainen, M., Schaffler, A. Acute-phase HDL in phospholipid transfer protein(PLTP)-mediated HDL conversion[J]. Atherosclerosis 2001,155: 297-305.
[172]Lindhorst, E., Young, D., Bagshaw, W., Hyland, M., Kisilevsky, R. Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse[J]. Biochim Biophys Acta 1997,1339: 143-154.
[173]Esterbauer, H., Dieber-Rotheneder, M., Waeg, G., Striegl, G., Jurgens, G. Biochemical, structural, and functional properties of oxidized Low-Density Lipoprotein [J]. Chem Res Toxicol 1990,3, (2): 77-92.
[174]Memon, R.A., Staprans, I., Noor, M., Holleran, W.M., Uchida, Y., Moser, A.H., Feingold, K.R.,Grunfeld, C. Infection and inflammation Induce LDL oxidation in vivo[J]. Arterioscl Throm Vas 2000,20:1536-1542.
[175]Meijer, A.J., Dubbelhuis, P.F. Amino acid signalling and the integration of metabolism[J]. Biochem Biophys Res Commun 2004,313:397-403.
[176]Hutson, S.M., Sweatt, A.J., LaNoue, K.F. Branched-chain mmino mcid metabolism:Implications for establishing safe intakes[J]. J Nutr 2005,135:1557S-1564S.
[177]Wannemacher, R.W., Klainer, A.S., Dinterman, R.E., Beisel, W.R. The significance and mechanism of an increased serum phenylalanine-tyrosine ratio during infection[J]. Am J Clin Nutr 1976,29: 997-1006.
[178]Phang, J.M., Pandhare, J., Liu, Y.M. The Metabolism of proline as microenvironmental stress substrate[J]. J Nutr 2008,138:2008-2015.
[179]Phang, J.M., Donald, S.P., Pandhare, J., Liu, Y.M. The metabolism of proline, a stress substrate, modulates carcinogenic pathways[J]. Amino Acids 2008,35:681-690.
[180]Shoji, N., Yoshida, A., Yu, Z., Endo, Y., Sasano, T., Klainer, A.S. Lipopoly saccharide stimulates histam ine-forming enzyme (histidine decar boxylase) activ ity in murine dental pulp and gingiva[J]. Arch Oral Biol 2006,51:856-860.
[181]Hirasawa, N., Ohtsu, H., Watanabe, T., Ohuchi, K. Enhancement of neutrophil infiltration in histidine decarboxylase-deficient mice[J]. Immunology 2002,107:217-221.
[182]Masini, E., Fabbroni, V., Giannini, L., Vannacci, A., Messerini, L., Perna, F., Cortesini, C.,Cianchi, F. Histamine and histidine decarboxylase up-regulation in colorectal cancer:correlation with tumor stage[J]. Inflamm Res 2005,54:80-81.
[183]Jutel, M., Watanabe, T., Akdis, M., Blaser, K., Akdis, C.A. Immune regulation by histamine opinion[J]. Curr Opin Immunol 2002,14:735-740.
[184]Glenn, E.M., Bowman, B.J.,Koslowske, T.C. The systemic response to inflammation[J]. Biochim Pharmacol 1968,5:27-49.
[185]Michelis, R., Kristal, B., Snitkovsky, T., Sela, S. Oxidative modifications impair albumin quantification[J]. Biochem Bioph Res Co 2010,401:137-142.
[186]Nassir, F., Zimowska, W., Bayle, D., Gueux, E., Rayssiguier, Y., Mazur, A. Hypoalbuminaemia in acute phase response is not related to depressed albumin synthesis:experimental evidence in magnesium-deficient rat[J]. Nutr Res 2002,22:489-496.
[187]Grootvelda, M., Claxsona, A.W.D., Chandera, C.L., Haycockb, P., Blake, D.R., Hawkesb, GE. High resolution proton NMR investigations of rat blood plasma[J]. FEBS J 1993,322, (3):266-276.
[188]Torri, G.M., Torri, J., Gulian, J.M., Vion-Dury, J., Viout, P., Patrick, J. Magnetic resonance spectroscopy of serum and acute-phase proteins revisited:a multiparametric statistical analysis of metabolite variations in inflammatory, infectious and miscellaneous diseases[J]. Clin Chim Acta 1999, 279:77-96.
[189]Hochepied, T., Berger, F.G., Baumann, H., Libert, C. Acid glycoprotein:an acute phase protein with inflammatoryand immunomodulating properties[J]. Cytokine Growth F R 2003,14:25-34.
[190]Xie, B.G., Waters, M.J., Schirra, H.J. Investigating potential mechanisms of obesity by metabolomics [J]. J Biomed Biotec 2012,2012:1-10.
[191]Vicente Alfaro, Jesus Rodenas, Luis Palacios, Maria T. Mitjavila, Carbonell, T. Blood acid-base changes during acute experimental inflammation in rats[J]. Can J Physiol Pharmacol 1996,74: 313-319.
[192]Trzeciak, S., Dellinger, R.P., Chansky, M.E., Arnold, R.C., Schorr, C., Milcarek, B., Hollenberg, S.M., Parrillo, J.E. Serum lactate as a predictor of mortality in patients with infection[J]. Intensive Care Med 2007,33:970-977.
[193]Finn, A., Oerther, S.C. Can L(+)-lactate be used as a marker of experimentally induced inflammation in rats[J]. Inflamm Res 2010,59:315-321.
[194]Mabley, J.G, Pacher, P., Liaudet, L., Soriano, E.G., Hasko, G., Marton, A., Szabo, C., Salzman, A.L. Inosine reduces inflammation and improves survival in a murine model of colitis[J]. Am J Physiol-Gastr L 2003,284:138-144.
[195]Liaudet, L., Mabley, J., Soriano, F.G, Pacher, P., Marton, A., Hask, G., Szabo, C. Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture[J]. Am J Respir Crit Care 2001,164:1213-1220.
[196]Hasko, G., Sitkovsky, M.V., Szabo, C. Immunomodulatory and neuroprotective effects of inosine[J]. Trends Pharmacol Sci 2004,25, (3):152-157.
[197]Lapa, F.R., Silva, M.D., Cabrini, D.A., Santos, A.R.S. Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy:evidence for the role of adenosine A2 receptors[J]. Puriner Signal 2012,8:693-704.
[198]Wu, W.P., Hao, J.X., Halldner-Henriksson, L., Xu, X.J., Jacobson, A., Wiesenfeld-HallinI, Z., Fredholm, B.B. Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors[J]. Neuroscience 2002,114, (3):523-527.
[199]Al-Awadi, F.M., Khan, I. Studies on purine enzymes in experimental colitis[J]. Mol Cell Biochem 1999,194, (1-2):17-22.
[200]Redmond, H.P., Stapleton, P.P., Neary, P., Bouchier-Hayes, D. Immunonutrition:the role of taurine[J]. Nutrition 1998,14, (7-8):599-604.
[201]Livingston, M., Heaney, L.G., Ennis, M. Adenosine, inflammation and asthma--a review[J]. Inflamm Res 2004,53, (5):171-178.
[202]Nakai, K., Kadiiska, M.B., Jiang, J.J., Stadler, K., Mason, R.P. Free radical production requires both inducible nitric oxide synthase and xanthine oxidase in LPS-treated skin[J]. P Natl Acad Sci 2006,103, (12):4616-4621.
[203]Hassoun, P.M., Yu, F.S., Cote, C.G., Zulueta, J.J., Sawhney, R., Skinner, K.A., Skinner, H.B., Parks, D.A., Lanzillo, J.J. Upregulation of xanthine oxidase by lipopolysaccharide, interleukin-1, and hypoxia role in acute lung injury[J]. Am J Respir Crit Care Med 1998,158, (1):299-305.
[204]Chung, H.Y., Baek, B.S., Song, S.H., Kim, M.S., Huh, J.I., Shim, K.H., Kim, K.W., Lee, K.H. Xanthine dehydrogenase xanthine oxidase and oxidative stress[J]. Age 1997,20, (3):127-140.
[205]Mabley, J.G, Pacher, P., Liaudet, L., Soriano, F.G., Hasko, G., Marton, A., Szabo, C., Salzman, A.L. Inosine reduces inflammation and improves survival in a murine model of colitis[J]. Am J Physiol Gastrointest Liver Physiol 2003,284, (1):G138-144.
[206]Jiang, Q., Blount, B.C., Ames, B.N.5-Chlorouracil, a marker of DNA damage from hypochlorous acid during inflammation. A gas chromatography-mass spectrometry assay[J]. J Biol Chem 2003,278, (35):32834-32840.
[207]Henderson, J.P., Byun, J., Takeshita, J., Heinecke, J.W. Phagocytes produce 5-chlorouracil and 5-bromouracil, two mutagenic products of myeloperoxidase, in human inflammatory tissue[J]. J Biol Chem 2003,278, (26):23522-23528.
[208]Zeisel, S.H., daCosta, K.A. Choline:an essential nutrient for public health[J]. Nutr Rev 2009,67, (11): 615-623.
[209]Gallazzini, M., Burg, M.B. What's new about osmotic regulation of glycerophosphocholine[J]. Physiology (Bethesda) 2009,24:245-249.
[210]Neuhofer, W., Beck, F.X. Survival in hostile environments:strategies of renal medullary cells[J]. Physiology (Bethesda) 2006,21:171-180.
[211]Rosas-Ballina, M., Tracey, K.J. Cholinergic control of inflammation[J]. J Intern Med 2009,265, (6): 663-679.
[212]Lips, K.S., Luhrmann, A., Tschernig, T., Stoeger, T., Alessandrini, F., Grau, V., Haberberger, R.V., Koepsell, H., Pabst, R., Kummer, W. Down-regulation of the non-neuronal acetylcholine synthesis and release machinery in acute allergic airway inflammation of rat and mouse[J]. Life Sci 2007,80, (24-25):2263-2269.
[213]Mehta, A.K., Singh, B.P., Arora, N., Gaur, S.N. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma[J]. Immunobiology 2010,215, (7):527-34.
[214]Mehta, A.K., Gaur, S.N., Arora, N., Singh, B.P. Effect of choline chloride in allergen-induced mouse model of airway inflammation[J]. Eur Respir J 2007,30, (4):662-71.
[215]Mehta, A.K., Arora, N., Gaur, S.N., Singh, B.P. Choline supplementation reduces oxidative stress in mouse model of allergic airway disease[J]. Eur J Clin Invest 2009,39, (10):934-41.
[216]Dong, F., Wang, B., Zhang, L., Tang, H., Li, J., Wang, Y. Metabolic response to Klebsiella pneumoniae infection in an experimental rat model[J]. PLoS One 2012,7, (11):e51060.
[217]Spaeth, D.G., Schneider, D.L. Turnover of taurine in rat tissues[J]. J Nutr 1974,104, (2):179-186.
[218]Kim, C. Accumulation of taurine in tumor and inflammatory lesions[J]. Adv Exp Med Biol 2006,583: 213-217.
[2]Pickup, J.C. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes[J]. Diabetes Care 2004,27, (3):813-823.
[3]Dandona, P., Aljada, A., Bandyopadhyay, A. Inflammation:the link between insulin resistance, obesity and diabetes[J]. Trends Immunol 2004,25, (1):4-7.
[4]Dandona, P., Aljada, A., Chaudhuri, A., Mohanty, P., Garg, R. Metabolic syndrome-A comprehensive perspective based on interactions between obesity, diabetes, and inflammation[J]. Circulation 2005, 111, (11):1448-1454.
[5]Hotamisligil, GS. Inflammation and metabolic disorders[J]. Nature 2006,444, (7121):860-7.
[6]Libby, P. Inflammation in atherosclerosis[J]. Nature 2002,420, (6917):868-874.
[7]Libby, P., Okamoto, Y., Rocha, V.Z.,Folco, E. Inflammation in Atherosclerosis:Transition From Theory to Practice[J]. Circ J 2010,74, (2):213-220.
[8]Balkwill, F., Mantovani, A. Inflammation and cancer:back to Virchow?[J]. Lancet 2001,357, (9255): 539-45.
[9]Coussens, L.M.,Werb, Z. Inflammation and cancer[J]. Nature 2002,420, (6917):860-7.
[10]Grivennikov, S.I., Greten, F.R., Karin, M. Immunity, inflammation, and cancer[J]. Cell 2010,140, (6): 883-99.
[11]Casserly, I., Topol, E. Convergence of atherosclerosis and Alzheimer's disease:inflammation, cholesterol, and misfolded proteins[J]. Lancet 2004,363, (9415):1139-1146.
[12]Town, T. Inflammation, immunity, and Alzheimer's disease[J]. CNS Neurol Disord Drug Targets 2010, 9, (2):129-31.
[13]Dubois, R.N., Abramson, S.B., Crofford, L., Gupta, R.A., Simon, L.S., Van De Putte, L.B.A., Lipsky, P.E. Cyclooxygenase in biology and disease[J]. Faseb Journal 1998,12, (12):1063-1073.
[14]Needleman, P., Turk, J., Jakschik, B.A., Morrison, A.R., Lefkowith, J.B. Arachidonic-acid metabolism[J]. Annu Rev Biochem 1986,55:69-102.
[15]Simon, L.S. Role and regulation of cyclooxygenase-2 during inflammation[J]. Am J Med 1999,106: 37-42.
[16]Smith, W.L., Dewitt, D.L., Garavito, R.M. Cyclooxygenases:structural, cellular, and molecular biology[J]. Annu Rev Biochem.2000,69:145-182.
[17]Williams, C.S., Mann, M., DuBois, R.N. The role of cyclooxygenases in inflammation, cancer, and development[J]. Oncogene 1999,18, (55):7908-7916.
[18]Moncada, S., Palmer, R.M.J.,Higgs, E.A. Nitric-oxide-physiology, pathophysiology, and pharmacology[J]. Pharmacol Rev 1991,43, (2):109-142.
[19]Bredt, D.S., Snyder, S.H. Nitric oxide:a physiologic messenger molecule[J]. Annu Rev Biochem 1994, 63:175-95.
[20]Hanada, T., Yoshimura, A. Regulation of cytokine signaling and inflammation[J]. Cytokine Growth F R 2002,13, (4-5):413-421.
[21]Lin, W.W., Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer[J]. J Clin Invest 2007,117, (5):1175-1183.
[22]Zu, L.X., He, J.H., Jiang, H.F., Xu, C., Pu, S.S., Xu, G.H. Bacterial endotoxin stimulates adipose lipolysis via Toll-Like Receptor 4 and extracellular signal-regulated kinase pathway[J]. J Biol Chem 2009,284, (9):5915-5926.
[23]Herlaar, E.,Brown, Z. MAPK signalling cascades in inflammatory disease[J]. Mol Med Today 1999,5, (10):439-447.
[24]Bernik, T.R., Friedman, S.G., Ochani, M., DiRaimo, R., Ulloa, L., Yang, H., Sudan, S., Czura, C.J., Ivanova, S.M., Tracey, K.J. Pharmacological stimulation of the cholinergic antiinflammatory pathway[J]. J Exp Med 2002,195, (6):781-788.
[25]Tracey, K.J. Physiology and immunology of the cholinergic antiinflammatory pathway[J]. J Clin Invest 2007,117, (2):289-296.
[26]Salojin, K., Owusu, I.B., Millerchip, K.A., Potter, M., Platt, K.A.,Oravecz, T. Essential role of MAPK phosphatase-1 in the negative control of innate immune responses[J]. J Immunol 2006,176: S177-S177.
[27]Kaminska, B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy-from molecular mechanisms to therapeutic benefits[J]. Bba-Proteins Proteom 2005,1754, (1-2):253-262.
[28]Matsumura, Y, Ananthaswamy, H.N. Toxic effects of ultraviolet radiation on the skin[J]. Toxicol Appl Pharm 2004,195, (3):298-308.
[29]Hruza, L.L., Pentland, A.P. Mechanisms of UV-induced inflammation[J]. J Invest Dermatol 1993,100, (1):S35-S41.
[30]Briganti, S., Picardo, M. Antioxidant activity, lipid peroxidation and skin diseases. What's new[J]. J Eur Acad Dermatol 2003,17, (6):663-669.
[31]Vinegar, R., Truax, J.F., Selph, J.L., Johnston, P.R., Venable, A.L., McKenzie, K.K. Pathway to carrageenan-induced inflammation in the hind limb of the rat[J]. Fed Proc 1987,46, (1):118-26.
[32]Morris, C.J. Carrageenan-induced paw edema in the rat and mouse[J]. Methods Mol Biol 2003,225: 115-21.
[33]Vinegar, R., Truax, J.F., Selph, J.L., Voelker, F.A. Pathway of onset, development, and decay of carrageenan pleurisy in the rat[J]. Fed Proc 1982,41, (9):2588-95.
[34]Murai, N., Nagai, K., Fujisawa, H., Ko, Hatanaka, Michiko Kawamura, Harada, Y. Concurrent evolution and resolution in an acute inflammatory model of rat carrageenin-induced pleurisy[J]. J Leukocyte Biol 2003,73:456-463.
[35]Sedgwick, A.D., Lees, P. A comparison of air pouch, sponge and pleurisy models of acute carrageenan inflammation in the rat[J]. Agents Actions 1986,18, (3-4):439-446.
[36]Martin, S.W., Stevens, A.J., Brennan, B.S., Davies, D., Rowland, M.,Houston, J.B. The six-day-old rat air pouch model of inflammation:characterization of the inflammatory response to carrageenan[J]. J Pharmacol Toxicol Methods 1994,32, (3):139-47.
[37]Saleh, T.S., Calixto, J.B., Medeiros, Y.S. Anti-inflammatory effects of theophylline, cromolyn and salbutamol in a murine model of pleurisy[J]. Br J Pharmacol 1996,118, (3):811-9.
[38]Futaki, N., Arai, I., Hamasaka, Y., Takahashi, S., Higuchi, S., Otomo, S. Selective-inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation[J]. J Pharm Pharmacol 1993,45, (8):753-755.
[39]Ohgami, K., Shiratori, K., Ilieva, I.B., Yazawa, K., Ohno, S. The effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo[J]. Invest Ophth Vis Sci 2004,45: U211-U211.
[40]Ratkay, L.G., Zhang, L., Tonzetich, J., Waterfield, J.D. Complete Freund's adjuvant induces an earlier and more severe arthritis in MRL-lpr mice[J]. J Immunol 1993,151,(9):5081-7.
[41]Cathcart, E.S., Hayes, K.C., Gonnerman, W.A., Lazzari, A.A., Franzblau, C. Experimental arthritis in a nonhuman primate. I. Induction by bovine type II collagen[J]. Lab Invest 1986,54, (1):26-31.
[42]Gaudio, E., Taddei, G., Vetuschi, A., Sferra, R., Frieri, G., Ricciardi, G, Caprilli, R. Dextran sulfate sodium (DSS) colitis in rats:clinical, structural, and ultrastructural aspects[J]. Digest Dis Sci 1999,44, (7):1458-75.
[43]Cooper, H.S., Murthy, S.N., Shah, R.S., Sedergran, D.J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis[J]. Lab Invest 1993,69, (2):238-49.
[44]Dieleman, L.A., Palmen, M.J.H.J., Akol, H., Bloemena, E., Pena, A.S., Meuwissen, S.G.M., van Rees, E.P. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines[J]. Clin Exp Immunol 1998,114, (3):385-391.
[45]Cuzzocrea, S., Mazzon, E., Sautebin, L., Dugo, L., Serraino, L., De Sarro, A.,Caputi, A.P. Protective effects of Celecoxib on lung injury and red blood cells modification induced by carrageenan in the rat[J]. Biochem Pharmacol 2002,63, (4):785-795.
[46]Seibert, K., Zhang, Y, Leahy, K., Hauser, S., Masferrer, J., Perkins, W., Lee, L., Isakson, P. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain[J]. P Natl Acad Sci 1994,91, (25):12013-7.
[47]Hay, C., deBelleroche, J. Carrageenan-induced hyperalgesia is associated with increased cyclo-oxygenase-2 expression in spinal cord[J]. Neuroreport 1997,8, (5):1249-1251.
[48]Salvemini, D., Wang, Z.Q., Wyatt, P.S., Bourdon, D.M., Marino, M.H., Manning, P.T., Currie, M.G Nitric oxide:a key mediator in the early and late phase of carrageenan-induced rat paw inflammation[J]. Br J Pharmacol 1996,118, (4):829-38.
[49]Omote, K., Hazama, K., Kawamata, T., Kawamata, M., Nakayaka, Y., Toriyabe, M., Namiki, A. Peripheral nitric oxide in carrageenan-induced inflammation[J]. Brain Res 2001,912, (2):171-175.
[50]Handy, R.L., Moore, P.K. A comparison of the effects of L-NAME,7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity[J]. Br J Pharmacol 1998,123, (6):1119-26.
[51]Futaki, N., Takahashi, S., Yokoyama, M., Arai, I., Higuchi, S., Otomo, S. NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro[J]. Prostaglandins 1994,47, (1):55-9.
[52]Guay, J., Bateman, K., Gordon, R., Mancini, J., Riendeau, D. Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E2 (PGE2) response in the central nervous system associated with the induction of microsomal PGE2 synthase-1[J]. J Biol Chem 2004,279, (23):24866-72.
[53]Ombrellino, M., Wang, H.C., Yang, H., Zhang, M.H., Vishnubhakat, J., Frazier, A., Scher, L.A., Friedman, S.G,Tracey, K.J. Fetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to carrageenan[J]. Shock 2001,15, (3):181-185.
[54]Cuzzocrea, S., Sautebin, L., De Sarro, G, Costantino, G, Rombola, L., Mazzon, E., Ialenti, A., De Sarro, A., Ciliberto, G., Di Rosa, M., Caputi, A.P. Thiemermann, C., Role of IL-6 in the pleurisy and lung injury caused by carrageenan[J]. J Immunol 1999,163, (9):5094-104.
[55]William L. Smith, David L. DeWitt, Garavito, R.M. Cyclooxygenases:structural, cellular, and molecular biology[J]. Annu Rev Biochem 2000,69:145-182.
[56]Hawkey, C.J. COX-2 inhibitors[J]. Lancet 1999,353, (9149):307-314.
[57]Bensen, W.G, Fiechtner, J.J., McMillen, J.I., Zhao, W.W., Yu, S.S., Woods, E.M., Hubbard, R.C., Isakson, P.C., Verburg, K.M., Geis, GS. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor:a randomized controlled trial[J]. Mayo Clin Proc 1999,74, (11): 1095-1105.
[58]Deeks, J.J., Smith, L.A., Bradley, M.D. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis:systematic review of randomised controlled trials[J]. Bmj 2002,325, (7365):619.
[59]Simon, L.S., Weaver, A. L., Graham, D.Y., Kivitz, A.J., Lipsky, P.E., Hubbard, R.C., Isakson, P.C., Verburg, K.M., Yu, S.S., Zhao, W.W., Geis, S.G Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis:A randomized controlled trial[J]. JAMA 1999,282, (20): 1921-1928.
[60]Dougados, M., Behier, J.M., Jolchine, I., Calin, A., van der Heijde, D., Olivieri, I., Zeidler, H., Herman, H. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis:a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug[J]. Arthritis Rheum 2001,44, (1):180-185.
[61]Gimbel, J.S., Brugger, A., Zhao, W., Verburg, K.M., Geis, GS. Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults[J]. Clin Ther 2001,23, (2):228-241.
[62]Phillips, R.K.S., Wallace, M.H., Lynch, P.M., Hawk, E., Gordon, GB., Saunders, B.P., Wakabayashi, N., Shen, Y., Zimmerman, S., Godio, L., Rodrigues-Bigas, M., Su, L.K., Sherman, J., Kelloff, G., Levin, B., Steinbach, G,Grp, F.S. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis[J]. Gut 2002,50, (6):857-860.
[63]Russell F. Jacoby, Karen Seibert, Carolyn E. Cole, Gary Kelloff, A., Lubet, R.A. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis [J].Cancer Res 2000,60:5040-5044.
[64]Steinbach, G, Lynch, P.M., Phillips, R.K., Wallace, M.H., Hawk, E., Gordon, G.B., Wakabayashi, N., Saunders, B., Shen, Y., Fujimura, T., Su, L.K., Levin, B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis[J]. N Engl J Med 2000,342, (26):1946-1952.
[65]Toshihiko Kawamori, Chinthalapally V. Rao, Karen Seibert, a., Reddy, B.S. Chemopreventive activity of Celecoxib, a specific Cyclooxygenase-2 inhibitor, against colon carcinogenesis1[J]. Cancer Res 1998,58:409-412.
[66]Bandaru S. Reddy, Yoshinobu Hirose, Ronald Lubet, Vernon Steele, Gary Kelloff, Susan Paulson, Karen Seibert, A., Rao, C.V. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis [J]. Cancer Res 2000,60:293-297.
[67]Bertagnolli, M.M., Eagle, C.J., Zauber, A.G, Redston, M., Solomon, S.D., Kim, K., Tang, J., Rosenstein, R.B., Wittes, J., Corle, D., Hess, T.M., Woloj, GM., Boisserie, F., Anderson, W.F., Viner, J.L., Bagheri, D., Burn, J., Chung, D.C., Dewar, T., Foley, T.R., Hoffman, N., Macrae, F., Pruitt, R.E., Saltzman, J.R., Salzberg, B., Sylwestrowicz, T., Gordon, GB., Hawk, E.T. Celecoxib for the prevention of sporadic colorectal adenomas[J]. N Engl J Med 2006,355, (9):873-884.
[68]Gupta, S., Adhami, V.M., Subbarayan, M., MacLennan, GT., Lewin, J.S., Hafeli, U.O., Fu, P., Mukhtar, H. Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model[J]. Cancer Res 2004,64, (9):3334-3343.
[69]Harris, R.E., Alshafie, GA., Abou-Issa, H., Seibert, K. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor[J]. Cancer Res 2000,60, (8):2101-2103.
[70]Fischer, S.M., Lo, H.H., Gordon, GB., Seibert, K., Kelloff, G, Lubet, R.A., Conti, C.J. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis[J]. Mol Carcinog 1999,25, (4):231-240.
[71]Susan K. P., Jeremy D. H., Norman W. K., Liu, J., Elisabeth H., Roy H. B., Karim, A.P. Metabolism and excretion of [14C]celecoxib in healthy male volunteers [J]. Drug Metab Dispos 2000,28, (3):308-314.
[72]Wallace, J.L., McKnight, W., Reuter, B.K., Vergnolle, N. NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2[J]. Gastroenterology 2000,119, (3): 706-714.
[73]Silverstein, F.E., Faich, G, Goldstein, J.L., Simon, L.S., Pincus, t., Whelton, A., Maknch. R., Eisen, G., Agranal, N.M., Stenson, W.F., Burr, A.M., Zhao, W.W., Kent, J.D., Lefkowith, J.B., Verburg, K.M., Geis, GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis:The class study:a randomized controlled trial[J]. JAMA 2000, 284,(10):1247-1255.
[74]Laudanno, O.M., Cesolari, J.A., Esnarriaga, J., Rista, L., Piombo, G., Maglione, C., Aramberry, L. Sambrano, J., Godoy, A., Rocaspana, A. Gastrointestinal damage induced by celecoxib and rofecoxib in rats[J]. Digest Dis Sci 2001,46, (4):779-784.
[75]Um, S.Y., Chung, M.W., Kim, K.-B., Kim, S.H., Oh, J.S., Oh, H.Y., Lee, H.J., Choi, K.H. Pattern Recognition Analysis for the Prediction of Adverse Effects by Nonsteroidal Anti-inflammatory drugs using'H NMR-based metabolomics in rats[J]. Anal Chem 2009,81, (12):4734-4741.
[76]Um, S.Y., Park, J.H., Chung, M.W., Kim, K.B., Kim, S.H., Choi, K.H., Lee, H.J. Nuclear magnetic resonance-based metabolomics for prediction of gastric damage induced by indomethacin in rats[J]. Anal Chim Acta 2012,722:87-94.
[77]Sanchez-Matienzo, D., Arana, A., Castellsague, J., Perez-Gutthann, S. Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs:A case/noncase analysis of spontaneous reports[J]. Clin Ther 2006,28, (8):1123-1132.
[78]Maddrey, W.C., Maurath, C.J., Verburg, K.M., Geis, G.S. The hepatic safety and tolerability of the novel cyclooxygenase-2 inhibitor celecoxib[J]. Am J Ther 2000,7, (3):153-8.
[79]Nachimuthu, S., Volfinzon, L., Gopal, L. Acute hepatocellular and cholestatic injury in a patient taking celecoxib[J]. Postgrad Med J 2001,77, (910):548-50.
[80]Brater, D.C., Harris, C., Redfern, J.S., Gertz, B.J. Renal effects of COX-2-selective inhibitors[J]. Am J Nephrol 2001,21,(1):1-15.
[81]Perazella, M.A. COX-2 selective inhibitors:analysis of the renal effects[J]. Expert Opin Drug Saf 2002, 1,(1):53-64.
[82]Harris, R.C. Cyclooxygenase-2 inhibition and renal physiology [J]. Am J Cardiol 2002,89, (6A): 10d-17d.
[83]Whelton, A., Schulman, G., Wallemark, C., Drower, E.J., Isakson, P.C., Verburg, K.M., Geis, GS. Effects of celecoxib and naproxen on renal function in the elderly[J]. Arch Intern Med 2000,160, (10): 1465-70.
[84]Schwartz, J.I., Vandormael, K., Malice, M.P., Kalyani, R.N., Lasseter, K.C., Holmes, G.B., Gertz, B.J., Gottesdiener, K.M., Laurenzi, M., Redfern, K.J., Brune, K. Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet[J]. Clin Pharmacol Ther 2002,72,(1):50-61.
[85]Akhund, L., Quinet, R.J., Ishaq, S. Celecoxib-related renal papillary necrosis[J]. Arch Intern Med 2003, 163,(1):114-115.
[86]Leese, P.T., Hubbard, R.C., Karim, A., Isakson, P.C., Yu, S.S., Geis, G.S. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults:a randomized, controlled trial[J]. J Clin Pharmacol 2000,40, (2):124-132.
[87]Muscara, M.N., Vergnolle, N., Lovren, F., Triggle, C.R., Elliott, S.N., Asfaha, S.,Wallace, J.L. Selective cyclo-oxygenase-2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence[J]. Br J Pharmacol 2000,129, (7):1423-1430.
[88]Solomon, S.D., McMurray, J.J., Pfeffer, M.A., Wittes, J., Fowler, R., Finn, P., Anderson, W.F., Zauber, A., Hawk, E., Bertagnolli, M. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention[J]. N Engl J Med 2005,352, (11):1071-1080.
[89]Solomon, S.D., Pfeffer, M.A., McMurray, J.J., Fowler, R., Finn, P., Levin, B., Eagle, C., Hawk, E., Lechuga, M., Zauber, A.G, Bertagnolli, M.M., Arber, N.,Wittes, J. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas[J]. Circulation 2006,114, (10):1028-1035.
[90]Solomon, S.D., Wittes, J., Finn, P.V., Fowler, R., Viner, J., Bertagnolli, M.M., Arber, N., Levin, B., Meinert, C.L., Martin, B., Pater, J.L., Goss, P.E., Lance, P., Obara, S., Chew, E.Y., Kim, J., Arndt, G., Hawk, E., Grp, C.T.S.A. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials-The cross trial safety analysis[J]. Circulation 2008,117, (16):2104-2113.
[91]Caldwell, B., Aldington, S., Weatherall, M., Shirtcliffe, P., Beasley, R. Risk of cardiovascular events and celecoxib:a systematic review and meta-analysis[J]. J R Soc Med 2006,99, (3):132-140.
[92]Selmanoglu, G., Kockaya, E.A., Akay, M.T., Kismet, K. Subacute toxicity of celecoxib on thyroid and testis of rats:Hormonal and histopathological changes[J]. Environ Toxicol Pharmacol 2006,22, (1): 85-89.
[93]Kitano, H. Systems biology:A brief overview[J]. Science 2002,295, (5560):1662-1664.
[94]Nicholson, J.K., Lindon, J.C., Holmes, E.'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J]. Xenobiotica 1999,29, (11):1181-1189.
[95]Tang, H.R., Wang, Y.L. Metabonomics:a revolution in progress[J]. Prog Biochem Biophys 2006,33, (5):401-417.
[96]Schmidt, C.W. Metabolomics:What's happening downstream of DNA[J]. Environ Health Persp 2004, 112,(7):A410-A415.
[97]Nicholson, J.K., Connelly, J., Lindon, J.C., Holmes, E. Metabonomics:a platform for studying drug toxicity and gene function[J]. Nat Rev Drug Discov 2002,1, (2):153-161.
[98]Hirai, M.Y., Yano, M., Goodenowe, D.B., Kanaya, S., Kimura, T., Awazuhara, M., Arita, M., Fujiwara, T.,Saito, K. Integration of transcriptomics and metabolomics for understanding of global responses to nutritional stresses in Arabidopsis thaliana[J]. P Natl Acad Sci USA 2004,101, (27):10205-10210.
[99]Bino, R.J., Hall, R.D., Fiehn, O., Kopka, J., Saito, K., Draper, J., Nikolau, B.J., Mendes, P., Roessner-Tunali, U., Beale, M.H., Trethewey, R.N., Lange, B.M., Wurtele, E.S., Sumner, L.W. Potential of metabolomics as a functional genomics tool[J]. Trends Plant Sci 2004,9, (9):418-425.
[100]Grivet, J.P., Delort, A.M., Portais, J.C. NMR and microbiology:from physiology to metabolomics[J]. Biochimie 2003,85, (9):823-840.
[101]Goodenowe, D. Applying comprehensive metabolomics to the understanding of plant physiology[J]. Plant Cell Physiol 2004,45:S8-S8.
[102]Weckwerth, W. Integration of metabolomics and proteomics in molecular plant physiology-coping with the complexity by data-dimensionality reduction[J]. Physiol Plantarum 2008,132, (2):176-189.
[103]Brindle, J. T., Antti, H., Holmes, E., Tranter, G., Nicholson, J. K., Bethell, H. W. L., Clarke, S., Schofield, P. M., Mckilligin, E., Mosedale, D. E., Grainge, D. G Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using:H-NMR-based metabonomics[J]. Nat Med 2002,8:1439-1444.
[104]Dumas, M.E., Barton, R.H., Toye, A., Cloarec, O., Blancher, C., Rothwell, A., Fearnside, J., Tatoud, R., Blanc, V., Lindon, J.C., Mitchell, S.C., Holmes, E., McCarthy, M.I., Scott, J., Gauguier, D., Nicholson, J.K. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice[J]. P Natl Acad Sci USA 2006,103, (33):12511-12516.
[105]Griffiths, J.R., Stubbs, M. Opportunities for studying cancer by metabolomics:preliminary observations on tumors deficient in hypoxia-inducible factor 1[J]. Adv Enzyme Regul 2003,43:67-76.
[106]Blekherman, G., Laubenbacher, R., Cortes, D.F., Mendes, P., Torti, F.M., Akman, S., Torti, S.V.,Shulaev, V. Bioinformatics tools for cancer metabolomics[J]. Metabolomics 2011,7, (3):329-343.
[107]Claudino, W.M., Goncalves, P.H., di Leo, A., Philip, P.A., Sarkar, F.H. Metabolomics in cancer:A bench-to-bedside intersection[J]. Crit Rev Oncol Hemat 2012,84, (1):1-7.
[108]Lindon, J.C., Nicholson, J.K., Holmes, E., Antti, H., Bollard, M.E., Keun, H., Beckonert, O., Ebbels, T.M., Reilly, M.D., Robertson, D., Stevens, G.J., Luke, P., Breau, A.P., Cantor, G.H., Bible, R.H., Niederhauser, U., Senn, H., Schlotterbeck, G., Sidelmann, U.G, Laursen, S.M., Tymiak, A., Car, B.D., Lehman-McKeeman, L., Colet, J.M., Loukaci, A.,Thomas, C. Contemporary issues in toxicology-The role of metabonomics in toxicology and its evaluation by the COMET project[J]. Toxicol Appl Pharm 2003,187, (3):137-146.
[109]夏建飞,梁琼麟,胡坪,王义明,罗国安.代谢组学研究策略与方法的新进展[J].分析化学2009,37,(1)：136-143.
[110]Dai, H., Xiao, C., Liu, H., Hao, F., Tang, H. Combined NMR and LC-DAD-MS Analysis Reveals Comprehensive Metabonomic Variations for Three Phenotypic Cultivars of Salvia Miltiorrhiza Bunge[J]. J Proteome Res2010,9, (3):1565-1578.
[111]Ding, L., Hao, F., Shi, Z., Wang, Y., Zhang, H., Tang, H., Dai, J. Systems Biological Responses to Chronic Perfluorododecanoic Acid Exposure by Integrated Metabonomic and Transcriptomic Studies[J]. J Proteome Res 2009,8, (6):2882-2891.
[112]Beckonert, O., Keun, H.C., Ebbels, T.M.D., Bundy, J.G, Holmes, E., Lindon, J.C., Nicholson, J.K. Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts[J]. Nat Protoc 2007,2, (11):2692-2703.
[113]Han, X.L., Gross, R.W. Global analyses of cellular lipidomes directly from crude extracts of biological samples by ESI mass spectrometry:a bridge to lipidomics[J]. J Lipid Res 2003,44, (6): 1071-1079.
[114]Wenk, M.R. The emerging field of lipidomics[J]. Nat Rev Drug Discov 2005,4, (7):594-610.
[115]Dieterle, F., Ross, A., Schlotterbeck, G, Senn, H. Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in H-1 NMR metabonomics[J]. Anal Chem 2006,78, (13):4281-4290.
[116]Price, W.S. Water signal suppression in NMR spectroscopy[J]. Annu R NMR S 1999,38 1999,38: 289-354.
[117]毛希安.现代核磁共振实用技术及应用[M].1999,201-205.
[118]Neuhaus, D., Ismail, I.M., Chung, C.W. "FLIPSY"-A new solvent-suppression sequence for nonexchanging solutes offering improved integral accuracy relative to 1D NOESY[J]. J Magn Reson Ser A 1996,118, (2):256-263.
[119]Tang, H.R., Wang, Y.L., Nicholson, J.K., Lindon, J.C. Use of relaxation-edited one-dimensional and two dimensional nuclear magnetic resonance spectroscopy to improve detection of small metabolites in blood plasma[J]. Anal Biochem 2004,325, (2):260-272.
[120]Wu, D.H., Chen, A.D., Johnson, C.S. An improved diffusion-ordered spectroscopy experiment incorporating bipolar-gradient pulses[J]. J Magn Reson Ser A,1995,115, (2):260-264.
[121]Hurd, R.E. Gradient-enhanced spectroscopy[J]. J Magn Reson 1990,87, (2):422-428.
[122]Bax, A., Davis, D.G. MLEV-17-based two-dimensional homonuclear magnetization transfer spectroscopy[J]. J Magn Reson 1985,65, (2):355-360.
[123]Aue, W.P. Karhan, J.,Ernst, R.R., Homonuclear broad-band decoupling and 2-dimensional J-resolved NMR spectroscopy[J]. J Chem Phys 1976,64, (10):4226-4227.
[124]Bodenhausen, G., Ruben, D.J. Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopy[J]. Chem Phys Lett 1980,69, (1):185-189.
[125]Bax, A., Summers, M.F.1H and 13C assignments from sensitivity-enhanced detection of heteronuclear multiple-bond connectivity by multiple quantum [J]. J Am Chem. Soc 1986,108, (8):2093-2094.
[126]Cuzzocrea, S., Tan, D.X., Costanitino, G, Mazzon, E., Caputi.A.P., Reiter.R.J. The protective role of endogenous melatonin in carrageenan-induced pleurisy in the rat[J]. FASEB J 1999,13:1930-1938.
[127]Frode, T.S., Buss, Z.S., Reis, GO., Medeiros, Y.S., Fredholm, B.B. Evidence of anti-in fl ammatory effects of Pioglitazone in the murine pleurisy model induced by carrageenan[J]. Int Immunopharmacol 2009,9:1394-1400.
[128]Ianaro, A., Ialenti, A., Maffia, P., Pisano, B., Rosa.M.D. HSFl/hsp72 pathway as an endogenous anti-inmmatory system[J]. FEBS Lett 2001,499:239-244.
[129]Nakano, M., Denda, N., Matsumoto, M., Kawamura, M., Kawakubo, Y., Hatanaka, K., Hiramoto, Y., Sato, Y, Noshiro, M., Harada, Y Interaction between cyclooxygenase (COX)-1-and COX-2-products modulates COX-2 expression in the late phase of acute inflammation[J]. Eur J Pharmacol 2007,559: 210-218.
[130]Zhang, L.M., Ye, Y.F., An, Y.P., Tian, Y, Wang, Y.L., Tang, H.R. Systems responses of rats to Aflatoxin B1 exposure revealed with metabonomic changes in multiple biological matrices[J]. J Proteome Res 2010,10, (2):614-623.
[131]Wu, J.F., Xu, W.X., Ming, Z.P., Dong, H.F., Tang, H.R., Wang, Y.L. Metabolic changes reveal the development of schistosomiasis in mice[J]. PLos Negl Trop Dis 2010,4, (8):e807.
[132]Jiang, L.M., Huang, J., Wang, Y.L., Tang.H.R. Metabonomic analysis reveals the CCl4-Induced systems alterations for multiple rat organs[J]. J Proteome Res 2012,11, (7):3848-3859.
[133]Tian, Y, Zhang, L.M., Wang, Y.L., Tang, H.R. Age-related topographical metabolic signatures for the rat gastrointestinal contents[J]. J. Proteome Res.2011,11, (2):1397-1411.
[134]Lepage, G., Roy, C.C. Direct transesterification of all classes of lipids in a one-step reaction [J]. J. Lipid Res 1986,27:114-120.
[135]Xu, Z.D., Harvey, K., Pavlina, T., Dutot, G, Zaloga, G,Siddiqui, R. An improved method for determining medium-and long-chain FAMEs using Gas Chromatography[J]. Lipids 2010,45: 199-208.
[136]Hotamisligil, G.S. Inflammation and metabolic disorders[J]. Nature 2006,444, (14):860-867.
[137]Libby, P., Ridker, P.M., Maseri, A. Inflammation and atherosclerosis[J]. Circulation 2002,105: 1135-1143.
[138]Pearson, T.A., Mensah, GA., Alexander, R.W., Anderson, J.L., O'Cannon, R., Criqui, M., Fadl, Y.Y., Fortmann, S.P., Hong, Y, Myers, GL., Rifai, N., Smith, S.C., Taubert, J.K., Tracy, R.P.,Vinicor, F. Control and prevention and the American Heart Association Health practice:a statement for healthcare professionals from the centers for disease markers of inflammation and cardiovascular disease: application to clinical and public[J]. Circulation 2003,107:499-511.
[139]Balkwill, F., Mantovani, A. Inflammation and cancer:back to Virchow?[J]. Lancet 2001,357: 539-545.
[140]Coussens, L.M., Werb, Z. Inflammation and cancer[J]. Nature 2002,420:19-26.
[141]Baumann, H., Gauldie, J. The acute phase response.[J]. Immunol. Today 1994,15, (2):74-80.
[142]Schreiber, G, Howlettf, G, Nagashima, M., Millership, A., Martin, H., Urban, J., Kotlerg, L. The acute phase response of plasma protein synthesis during experimental inflammation[J]. J Biol Chem 1982,257, (17):10271-20277.
[143]Gruys.E, Toussaint.M.J.M., Niewnold.T.A., Koopmans.S.J. Acute phase reaction and acute phase proteins[J]. J Zhejiang Univ Sci 2005,11:1045-1056.
[144]Koj, A. Initiation of acute phase response and synthesis of cytokines [J]. Biochim Biophys Acta 1996, 1317:84-94.
[145]Heinrich, P.C., Castelltt, J.V., Andust, T. Interleukin-6 and the acute phase response[J]. J Biochem 1990,265:621-636.
[146]Moshage, H. Cytokines and the hepatic acute phase response[J]. J Pathol 1997,181:257-266.
[147]Vane, J., MIitchell, J., Appleton, I., Tomlinson, A., Bailey, D., Croxtall, J.,Willoughby, D. Inducible isoforms of cyclooxygenase and nitric-oxide synthase ininflammation[J]. Proc Nad Acad Sci 1994,91: 2046-2050.
[148]Salvemini, D., Wang, Z.Q., Wyatt, P.S., Bourdon, D., Marino, M.H., Manning, P.T., Currie, M.G Nitricoxide:a key mediator in the early and late phase of carrageenan-induced rat paw inflammation[J]. Brit J Pharmacol 1996,118:829-838.
[149]Schicho, R., Nazyrova, A., Shaykhutdinov, R., Duggan, G, Vogel, H.J., Storr, M. Quantitative metabolomic profiling of serum and urine in DSS-induced ulcerative colitis of mice by'H NMR spectroscopy[J]. J Proteome Res 2010,9:6265-6273.
[150]Xu, W.X., Wu, J.F., An, Y.P., Xiao, C.N., Hao, F.H., Liu, H.B., Wang, Y.L., Tang, H.R. Streptozotocin-induced dynamic metabonomic changes in rat biofluids[J]. J Proteome Res 2012,11, (6):3423-3435.
[151]Rosa, M.D. Biological properties of carrageenan[J]. J Pharm Pharmac1972,24:89-102.
[152]Catanzaro, P.J., Schwartz, H.J., Graham, R.C. Spectrum and possible mechanism of carrageenan cytotoxicity[J]. Am J Pathol 1971,64:387-404.
[153]Vaugha, M. The metabolism of adipose tissue in vitro [J]. J Lipid Res 1961,2:293-316.
[154]Khovidhunkit, W., Kim, M.S., Memon, R.A., Shigenaga, J.K., Moser, A.H., Feingold, K.R., Grunfeld, C. Effects of infection and inflammation on lipid and lipoprotein metabolism:mechanisms and consequences to the host[J]. J Lipid Res 2004,45:1169-1196.
[155]Raclot, T.,Groscolad, R. Differential mobilization of white adipose tissue fatty acids according to chain length, unsaturation, and positional isomerism[J]. J Lipid Res 1993,34:1513-1519.
[156]Raclot, T., Groscolad, R. Selective mobilization of adipose tissue fatty acids during energy depletion in the rat [J]. J Lipid Res 1995,36:2164-2173.
[157]Suganami, T., Tanimoto-Koyama, K., Nishida, J., Itoh, M., Yuan, X., Mizuarai, S., Kotani, H., Yamaoka, S., Miyake, K., Aoe, S., Kamei, Y., Ogawa, Y. Role of the Toll-like receptor 4/NF-kB Pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages[J]. Arterioscl Throm Vas 2007,27:84-91.
[158]Lee, J.Y., Sohn, K.H., Rhee, S.H.,Wang, D.H. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like Receptor 4[J]. J Biol Chem 2001,276:16683-16689.
[159]Schaffler, A., Schohnerich, J.,Salzberger, B. Adipose tissue as an immunological organ:Toll-like receptors, C1q/TNFs and CTRPs[J]. Trends Immunol 2007,28, (9):393-399.
[160]Juge-Aubry, C.E., Henrichot, E., Meier, C.A. Adipose tissue:a regulator of inflammation[J]. Best Pract Res Cl En 2005,19, (4):547-566.
[161]Shoda, R., Matsueda, K., Yamato, S., Umeda.N. Epidemiologic analysis of crohn disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of crohn disease in Japan [J]. Am J Clin Nutr 1996,63:741-745.
[162]Simopoulos, A.P. The importance of the ratio of omega-6/omega-3 essential fatty acids[J]. Biomed Pharmacother 2002,56:365-379.
[163]Simpoulos, A.P. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases[J]. Exp Biol Med 2008,233:674-688.
[164]Forsythe, C.E., Phinney, S.D., Fernandez, M.L., Quann, E.E., Wood, R.J., Bibus, D.M., Kraemer, W.J., Feinman, R.D.,Volek, J.S. Comparison of low fat and low carbohydrate diets on circulating fatty ccid composition and markers of inflammation[J]. Lipids 2008,43:65-77.
[165]Calder, P.C. n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases[J]. Am J Clin Nutr 2006,83:1505-1519.
[166]Shaikh, S.R., Edidin, M. Polyunsaturated fatty acids, membrane organization, T cells, and antigen presentation[J]. Am J Clin Nutr 2006,84:1277-1289.
[167]Norris, P.C.Dennis, E.A. Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling[J]. Proc Nad Acad Sci 2012,10:1-6.
[168]Ferrucci, L., Cherubini, A., Bartali, B., Corsi, A., Lauretani, F., Martin, A., Andres-Lacueva, C., Senin, U., Guralnik, J.K. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers[J]. J Clin Endocr Metab.2006,91, (2):439-446.
[169]Calder, P.C. Polyunsaturated fatty acids and inflammatory processes:New twists in an old tale[J]. Biochimie 2009,91:791-795.
[170]Kaysen, G.A. Effects of inflammation on plasma composition and endothelial structure and function[J]. J Renal Nutr 2005,15, (1):94-98.
[171]Pussinen, P.J., Malle, E., Metso, J., Sattle, W., Raynes, J.G, Jauhiainen, M., Schaffler, A. Acute-phase HDL in phospholipid transfer protein(PLTP)-mediated HDL conversion[J]. Atherosclerosis 2001,155: 297-305.
[172]Lindhorst, E., Young, D., Bagshaw, W., Hyland, M., Kisilevsky, R. Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse[J]. Biochim Biophys Acta 1997,1339: 143-154.
[173]Esterbauer, H., Dieber-Rotheneder, M., Waeg, G., Striegl, G., Jurgens, G. Biochemical, structural, and functional properties of oxidized Low-Density Lipoprotein [J]. Chem Res Toxicol 1990,3, (2): 77-92.
[174]Memon, R.A., Staprans, I., Noor, M., Holleran, W.M., Uchida, Y., Moser, A.H., Feingold, K.R.,Grunfeld, C. Infection and inflammation Induce LDL oxidation in vivo[J]. Arterioscl Throm Vas 2000,20:1536-1542.
[175]Meijer, A.J., Dubbelhuis, P.F. Amino acid signalling and the integration of metabolism[J]. Biochem Biophys Res Commun 2004,313:397-403.
[176]Hutson, S.M., Sweatt, A.J., LaNoue, K.F. Branched-chain mmino mcid metabolism:Implications for establishing safe intakes[J]. J Nutr 2005,135:1557S-1564S.
[177]Wannemacher, R.W., Klainer, A.S., Dinterman, R.E., Beisel, W.R. The significance and mechanism of an increased serum phenylalanine-tyrosine ratio during infection[J]. Am J Clin Nutr 1976,29: 997-1006.
[178]Phang, J.M., Pandhare, J., Liu, Y.M. The Metabolism of proline as microenvironmental stress substrate[J]. J Nutr 2008,138:2008-2015.
[179]Phang, J.M., Donald, S.P., Pandhare, J., Liu, Y.M. The metabolism of proline, a stress substrate, modulates carcinogenic pathways[J]. Amino Acids 2008,35:681-690.
[180]Shoji, N., Yoshida, A., Yu, Z., Endo, Y., Sasano, T., Klainer, A.S. Lipopoly saccharide stimulates histam ine-forming enzyme (histidine decar boxylase) activ ity in murine dental pulp and gingiva[J]. Arch Oral Biol 2006,51:856-860.
[181]Hirasawa, N., Ohtsu, H., Watanabe, T., Ohuchi, K. Enhancement of neutrophil infiltration in histidine decarboxylase-deficient mice[J]. Immunology 2002,107:217-221.
[182]Masini, E., Fabbroni, V., Giannini, L., Vannacci, A., Messerini, L., Perna, F., Cortesini, C.,Cianchi, F. Histamine and histidine decarboxylase up-regulation in colorectal cancer:correlation with tumor stage[J]. Inflamm Res 2005,54:80-81.
[183]Jutel, M., Watanabe, T., Akdis, M., Blaser, K., Akdis, C.A. Immune regulation by histamine opinion[J]. Curr Opin Immunol 2002,14:735-740.
[184]Glenn, E.M., Bowman, B.J.,Koslowske, T.C. The systemic response to inflammation[J]. Biochim Pharmacol 1968,5:27-49.
[185]Michelis, R., Kristal, B., Snitkovsky, T., Sela, S. Oxidative modifications impair albumin quantification[J]. Biochem Bioph Res Co 2010,401:137-142.
[186]Nassir, F., Zimowska, W., Bayle, D., Gueux, E., Rayssiguier, Y., Mazur, A. Hypoalbuminaemia in acute phase response is not related to depressed albumin synthesis:experimental evidence in magnesium-deficient rat[J]. Nutr Res 2002,22:489-496.
[187]Grootvelda, M., Claxsona, A.W.D., Chandera, C.L., Haycockb, P., Blake, D.R., Hawkesb, GE. High resolution proton NMR investigations of rat blood plasma[J]. FEBS J 1993,322, (3):266-276.
[188]Torri, G.M., Torri, J., Gulian, J.M., Vion-Dury, J., Viout, P., Patrick, J. Magnetic resonance spectroscopy of serum and acute-phase proteins revisited:a multiparametric statistical analysis of metabolite variations in inflammatory, infectious and miscellaneous diseases[J]. Clin Chim Acta 1999, 279:77-96.
[189]Hochepied, T., Berger, F.G., Baumann, H., Libert, C. Acid glycoprotein:an acute phase protein with inflammatoryand immunomodulating properties[J]. Cytokine Growth F R 2003,14:25-34.
[190]Xie, B.G., Waters, M.J., Schirra, H.J. Investigating potential mechanisms of obesity by metabolomics [J]. J Biomed Biotec 2012,2012:1-10.
[191]Vicente Alfaro, Jesus Rodenas, Luis Palacios, Maria T. Mitjavila, Carbonell, T. Blood acid-base changes during acute experimental inflammation in rats[J]. Can J Physiol Pharmacol 1996,74: 313-319.
[192]Trzeciak, S., Dellinger, R.P., Chansky, M.E., Arnold, R.C., Schorr, C., Milcarek, B., Hollenberg, S.M., Parrillo, J.E. Serum lactate as a predictor of mortality in patients with infection[J]. Intensive Care Med 2007,33:970-977.
[193]Finn, A., Oerther, S.C. Can L(+)-lactate be used as a marker of experimentally induced inflammation in rats[J]. Inflamm Res 2010,59:315-321.
[194]Mabley, J.G, Pacher, P., Liaudet, L., Soriano, E.G., Hasko, G., Marton, A., Szabo, C., Salzman, A.L. Inosine reduces inflammation and improves survival in a murine model of colitis[J]. Am J Physiol-Gastr L 2003,284:138-144.
[195]Liaudet, L., Mabley, J., Soriano, F.G, Pacher, P., Marton, A., Hask, G., Szabo, C. Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture[J]. Am J Respir Crit Care 2001,164:1213-1220.
[196]Hasko, G., Sitkovsky, M.V., Szabo, C. Immunomodulatory and neuroprotective effects of inosine[J]. Trends Pharmacol Sci 2004,25, (3):152-157.
[197]Lapa, F.R., Silva, M.D., Cabrini, D.A., Santos, A.R.S. Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy:evidence for the role of adenosine A2 receptors[J]. Puriner Signal 2012,8:693-704.
[198]Wu, W.P., Hao, J.X., Halldner-Henriksson, L., Xu, X.J., Jacobson, A., Wiesenfeld-HallinI, Z., Fredholm, B.B. Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors[J]. Neuroscience 2002,114, (3):523-527.
[199]Al-Awadi, F.M., Khan, I. Studies on purine enzymes in experimental colitis[J]. Mol Cell Biochem 1999,194, (1-2):17-22.
[200]Redmond, H.P., Stapleton, P.P., Neary, P., Bouchier-Hayes, D. Immunonutrition:the role of taurine[J]. Nutrition 1998,14, (7-8):599-604.
[201]Livingston, M., Heaney, L.G., Ennis, M. Adenosine, inflammation and asthma--a review[J]. Inflamm Res 2004,53, (5):171-178.
[202]Nakai, K., Kadiiska, M.B., Jiang, J.J., Stadler, K., Mason, R.P. Free radical production requires both inducible nitric oxide synthase and xanthine oxidase in LPS-treated skin[J]. P Natl Acad Sci 2006,103, (12):4616-4621.
[203]Hassoun, P.M., Yu, F.S., Cote, C.G., Zulueta, J.J., Sawhney, R., Skinner, K.A., Skinner, H.B., Parks, D.A., Lanzillo, J.J. Upregulation of xanthine oxidase by lipopolysaccharide, interleukin-1, and hypoxia role in acute lung injury[J]. Am J Respir Crit Care Med 1998,158, (1):299-305.
[204]Chung, H.Y., Baek, B.S., Song, S.H., Kim, M.S., Huh, J.I., Shim, K.H., Kim, K.W., Lee, K.H. Xanthine dehydrogenase xanthine oxidase and oxidative stress[J]. Age 1997,20, (3):127-140.
[205]Mabley, J.G, Pacher, P., Liaudet, L., Soriano, F.G., Hasko, G., Marton, A., Szabo, C., Salzman, A.L. Inosine reduces inflammation and improves survival in a murine model of colitis[J]. Am J Physiol Gastrointest Liver Physiol 2003,284, (1):G138-144.
[206]Jiang, Q., Blount, B.C., Ames, B.N.5-Chlorouracil, a marker of DNA damage from hypochlorous acid during inflammation. A gas chromatography-mass spectrometry assay[J]. J Biol Chem 2003,278, (35):32834-32840.
[207]Henderson, J.P., Byun, J., Takeshita, J., Heinecke, J.W. Phagocytes produce 5-chlorouracil and 5-bromouracil, two mutagenic products of myeloperoxidase, in human inflammatory tissue[J]. J Biol Chem 2003,278, (26):23522-23528.
[208]Zeisel, S.H., daCosta, K.A. Choline:an essential nutrient for public health[J]. Nutr Rev 2009,67, (11): 615-623.
[209]Gallazzini, M., Burg, M.B. What's new about osmotic regulation of glycerophosphocholine[J]. Physiology (Bethesda) 2009,24:245-249.
[210]Neuhofer, W., Beck, F.X. Survival in hostile environments:strategies of renal medullary cells[J]. Physiology (Bethesda) 2006,21:171-180.
[211]Rosas-Ballina, M., Tracey, K.J. Cholinergic control of inflammation[J]. J Intern Med 2009,265, (6): 663-679.
[212]Lips, K.S., Luhrmann, A., Tschernig, T., Stoeger, T., Alessandrini, F., Grau, V., Haberberger, R.V., Koepsell, H., Pabst, R., Kummer, W. Down-regulation of the non-neuronal acetylcholine synthesis and release machinery in acute allergic airway inflammation of rat and mouse[J]. Life Sci 2007,80, (24-25):2263-2269.
[213]Mehta, A.K., Singh, B.P., Arora, N., Gaur, S.N. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma[J]. Immunobiology 2010,215, (7):527-34.
[214]Mehta, A.K., Gaur, S.N., Arora, N., Singh, B.P. Effect of choline chloride in allergen-induced mouse model of airway inflammation[J]. Eur Respir J 2007,30, (4):662-71.
[215]Mehta, A.K., Arora, N., Gaur, S.N., Singh, B.P. Choline supplementation reduces oxidative stress in mouse model of allergic airway disease[J]. Eur J Clin Invest 2009,39, (10):934-41.
[216]Dong, F., Wang, B., Zhang, L., Tang, H., Li, J., Wang, Y. Metabolic response to Klebsiella pneumoniae infection in an experimental rat model[J]. PLoS One 2012,7, (11):e51060.
[217]Spaeth, D.G., Schneider, D.L. Turnover of taurine in rat tissues[J]. J Nutr 1974,104, (2):179-186.
[218]Kim, C. Accumulation of taurine in tumor and inflammatory lesions[J]. Adv Exp Med Biol 2006,583: 213-217.