The Emerging Role of COX-2, 15-LOX and PPARγ in Metabolic Diseases and Cancer: An Introduction to Novel Multi-target Directed Ligands (MTDLs)

doi:10.2174/0929867327999200820173853
摘要

新出现的证据支持一种相互交织的框架，在一个共同的病理背景下不同的炎症途径参与许多疾病。花生四烯酸通过环氧合酶-2 (COX-2)和15-脂氧合酶(15-LOX)代谢的途径是重要的。酶活性及其产物涉及一系列病理生理过程，包括代谢损伤导致脂肪炎症和随后的血管和神经疾病，以及各种促肿瘤和抗肿瘤作用。更复杂的是，COX-2和15-LOX活性和代谢产物相互作用或作用于其他细胞靶点，其中最突出的是过氧化物酶体增殖物激活受体γ (PPARγ)。因此，有效的治疗干预，这类多面障碍需要同时调节多个靶点。在这里，我们描述了COX-2、15-LOX和PPARγ在癌症和代谢紊乱并发症中的作用，强调了设计多靶点定向配体(mtdl)修饰其活性的价值，并对这些配体设计和合成的原理、可行性及其已知的生物学效应进行了综述。我们推测MTDL在这些疾病中的潜在影响，并强调需要结构化的未来努力来转化这些早期结果，促进这些和类似的分子在临床研究中的采用。
关键词: 多靶点定向配体，环氧化酶-2
« Previous
[1] 
Ramsay, R.R.; Popovic-Nikolic, M.R.; Nikolic, K.; Uliassi, E.; Bolognesi, M.L. A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med.,  2018, 7(1), 3.
[http://dx.doi.org/10.1186/s40169-017-0181-2] [PMID:  29340951] 
[2] 
Zhou, J.; Jiang, X.; He, S.; Jiang, H.; Feng, F.; Liu, W.; Qu, W.; Sun, H. Rational design of multitarget-directed ligands: strategies and emerging paradigms. J. Med. Chem.,  2019, 62(20), 8881-8914.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00017] [PMID:  31082225] 
[3] 
Proschak, E.; Stark, H.; Merk, D. Polypharmacology by design: a medicinal chemist’s perspective on multitargeting compounds. J. Med. Chem.,  2019, 62(2), 420-444.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00760] [PMID:  30035545] 
[4] 
Shahid, M.; Hornberg, J.; Superti-Furga, G.; Young, M.; Keiser, M.; Mason, J.; Morphy, J.R.; Lipinski, C.A.; Hopkins, A.; Dancey, J. Clinical need and rationale for multi-target drugs in psychiatry.Designing multi-target drugs; Royal Society of Chemistry, 2012, pp. 14-31.
[5] 
Sánchez-Tejeda, J.F.; Sánchez-Ruiz, J.F.; Salazar, J.R.; Loza-Mejía, M.A. A definition of “multitargeticity”: identifying potential multitarget and selective ligands through a vector analysis. Front Chem.,  2020, 8, 176.
[http://dx.doi.org/10.3389/fchem.2020.00176] [PMID:  32232029] 
[6] 
Hotamisligil, G.S. Inflammation and metabolic disorders. Nature,  2006, 444(7121), 860-867.
[http://dx.doi.org/10.1038/nature05485] [PMID:  17167474] 
[7] 
Todoric, J.; Antonucci, L.; Karin, M. Targeting inflammation in cancer prevention and therapy. Cancer Prev. Res. (Phila.),  2016, 9(12), 895-905.
[http://dx.doi.org/10.1158/1940-6207.CAPR-16-0209] [PMID:  27913448] 
[8] 
Mashima, R.; Okuyama, T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol.,  2015, 6, 297-310.
[http://dx.doi.org/10.1016/j.redox.2015.08.006] [PMID:  26298204] 
[9] 
Schauberger, E.; Peinhaupt, M.; Cazares, T.; Lindsley, A.W. Lipid mediators of allergic disease: pathways, treatments, and emerging therapeutic targets. Curr. Allergy Asthma Rep.,  2016, 16(7), 48.
[http://dx.doi.org/10.1007/s11882-016-0628-3] [PMID:  27333777] 
[10] 
Wang, D.; Dubois, R.N. Eicosanoids and cancer. Nat. Rev. Cancer,  2010, 10(3), 181-193.
[http://dx.doi.org/10.1038/nrc2809] [PMID:  20168319] 
[11] 
Singh, N.K.; Rao, G.N. Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies. Prog. Lipid Res.,  2019, 73, 28-45.
[http://dx.doi.org/10.1016/j.plipres.2018.11.001] [PMID:  30472260] 
[12] 
Sun, L.; Xu, Y-W.; Han, J.; Liang, H.; Wang, N.; Cheng, Y. 12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain. J. Lipid Res.,  2015, 56(3), 502-514.
[http://dx.doi.org/10.1194/jlr.M053058] [PMID:  25605873] 
[13] 
Mateu, A.; Ramudo, L.; Manso, M.A.; De Dios, I. Cross-talk between TLR4 and PPARγ pathways in the arachidonic acid-induced inflammatory response in pancreatic acini. Int. J. Biochem. Cell Biol.,  2015, 69, 132-141.
[http://dx.doi.org/10.1016/j.biocel.2015.10.022] [PMID:  26510582] 
[14] 
Kuhn, H.; Banthiya, S.; van Leyen, K. Mammalian lipoxygenases and their biological relevance. Biochim. Biophys. Acta,  2015, 1851(4), 308-330.
[http://dx.doi.org/10.1016/j.bbalip.2014.10.002] [PMID:  25316652] 
[15] 
Brash, A.R. Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J. Biol. Chem.,  1999, 274(34), 23679-23682.
[http://dx.doi.org/10.1074/jbc.274.34.23679] [PMID:  10446122] 
[16] 
Kuhn, H.; Walther, M.; Kuban, R.J. Mammalian arachidonate 15-lipoxygenases structure, function, and biological implications. Prostaglandins Other Lipid Mediat.,  2002, 68-69, 263-290.
[http://dx.doi.org/10.1016/S0090-6980(02)00035-7] [PMID:  12432923] 
[17] 
Klil-Drori, A.J.; Ariel, A. 15-Lipoxygenases in cancer: a double-edged sword? Prostaglandins Other Lipid Mediat.,  2013, 106, 16-22.
[http://dx.doi.org/10.1016/j.prostaglandins.2013.07.006] [PMID:  23933488] 
[18] 
Schneider, C.; Pozzi, A. Cyclooxygenases and lipoxygenases in cancer. Cancer Metastasis Rev.,  2011, 30(3-4), 277-294.
[http://dx.doi.org/10.1007/s10555-011-9310-3] [PMID:  22002716] 
[19] 
Dobrian, A.D.; Lieb, D.C.; Cole, B.K.; Taylor-Fishwick, D.A.; Chakrabarti, S.K.; Nadler, J.L. Functional and pathological roles of the 12- and 15-lipoxygenases. Prog. Lipid Res.,  2011, 50(1), 115-131.
[http://dx.doi.org/10.1016/j.plipres.2010.10.005] [PMID:  20970452] 
[20] 
Chakrabarti, S.K.; Cole, B.K.; Wen, Y.; Keller, S.R.; Nadler, J.L. 12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes. Obesity (Silver Spring),  2009, 17(9), 1657-1663.
[http://dx.doi.org/10.1038/oby.2009.192] [PMID:  19521344] 
[21] 
Sears, D.D.; Miles, P.D.; Chapman, J.; Ofrecio, J.M.; Almazan, F.; Thapar, D.; Miller, Y.I. 12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice. PLoS One,  2009, 4(9)e7250
[http://dx.doi.org/10.1371/journal.pone.0007250] [PMID:  19787041] 
[22] 
Nunemaker, C.S.; Chen, M.; Pei, H.; Kimble, S.D.; Keller, S.R.; Carter, J.D.; Yang, Z.; Smith, K.M.; Wu, R.; Bevard, M.H.; Garmey, J.C.; Nadler, J.L. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. Am. J. Physiol. Endocrinol. Metab.,  2008, 295(5), E1065-E1075.
[http://dx.doi.org/10.1152/ajpendo.90371.2008] [PMID:  18780776] 
[23] 
Cole, B.K.; Morris, M.A.; Grzesik, W.J.; Leone, K.A.; Nadler, J.L. Adipose tissue-specific deletion of 12/15-lipoxygenase protects mice from the consequences of a high-fat diet. Mediators Inflamm.,  2012, 2012851798
[http://dx.doi.org/10.1155/2012/851798] [PMID:  23326022] 
[24] 
Cole, B.K.; Kuhn, N.S.; Green-Mitchell, S.M.; Leone, K.A.; Raab, R.M.; Nadler, J.L.; Chakrabarti, S.K. 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response. Am. J. Physiol. Endocrinol. Metab.,  2012, 302(6), E654-E665.
[http://dx.doi.org/10.1152/ajpendo.00373.2011] [PMID:  22215650] 
[25] 
Boden, G. Endoplasmic reticulum stress: another link between obesity and insulin resistance/inflammation? Diabetes,  2009, 58(3), 518-519.
[http://dx.doi.org/10.2337/db08-1746] [PMID:  19246600] 
[26] 
Boden, G.; Duan, X.; Homko, C.; Molina, E.J.; Song, W.; Perez, O.; Cheung, P.; Merali, S. Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes,  2008, 57(9), 2438-2444.
[http://dx.doi.org/10.2337/db08-0604] [PMID:  18567819] 
[27] 
Dobrian, A.D.; Huyck, R.W.; Glenn, L.; Gottipati, V.; Haynes, B.A.; Hansson, G.I.; Marley, A.; McPheat, W.L.; Nadler, J.L. Activation of the 12/15 lipoxygenase pathway accompanies metabolic decline in db/db pre-diabetic mice. Prostaglandins Other Lipid Mediat.,  2018, 136, 23-32.
[http://dx.doi.org/10.1016/j.prostaglandins.2018.03.003] [PMID:  29605541] 
[28] 
Song, Y.S.; Lee, D.H.; Yu, J.H.; Oh, D.K.; Hong, J.T.; Yoon, D.Y. Promotion of adipogenesis by 15-(S)-hydroxyeicosatetraenoic acid. Prostaglandins Other Lipid Mediat.,  2016, 123, 1-8.
[http://dx.doi.org/10.1016/j.prostaglandins.2016.02.001] [PMID:  26905195] 
[29] 
Dobrian, A.D.; Lieb, D.C.; Ma, Q.; Lindsay, J.W.; Cole, B.K.; Ma, K.; Chakrabarti, S.K.; Kuhn, N.S.; Wohlgemuth, S.D.; Fontana, M.; Nadler, J.L. Differential expression and localization of 12/15 lipoxygenases in adipose tissue in human obese subjects. Biochem. Biophys. Res. Commun.,  2010, 403(3-4), 485-490.
[http://dx.doi.org/10.1016/j.bbrc.2010.11.065] [PMID:  21094135] 
[30] 
Pober, J.S.; Sessa, W.C. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol.,  2007, 7(10), 803-815.
[http://dx.doi.org/10.1038/nri2171] [PMID:  17893694] 
[31] 
Kundumani-Sridharan, V.; Dyukova, E.; Hansen, D.E., III; Rao, G.N. 12/15-Lipoxygenase mediates high-fat diet-induced endothelial tight junction disruption and monocyte transmigration: a new role for 15(S)-hydroxyeicosatetraenoic acid in endothelial cell dysfunction. J. Biol. Chem.,  2013, 288(22), 15830-15842.
[http://dx.doi.org/10.1074/jbc.M113.453290] [PMID:  23589307] 
[32] 
Chattopadhyay, R.; Dyukova, E.; Singh, N.K.; Ohba, M.; Mobley, J.A.; Rao, G.N. Vascular endothelial tight junctions and barrier function are disrupted by 15(S)-hydroxyeicosatetraenoic acid partly via protein kinase C ε-mediated zona occludens-1 phosphorylation at threonine 770/772. J. Biol. Chem.,  2014, 289(6), 3148-3163.
[http://dx.doi.org/10.1074/jbc.M113.528190] [PMID:  24338688] 
[33] 
Sultana, C.; Shen, Y.; Rattan, V.; Kalra, V.K. Lipoxygenase metabolites induced expression of adhesion molecules and transendothelial migration of monocyte-like HL-60 cells is linked to protein kinase C activation. J. Cell. Physiol.,  1996, 167(3), 477-487.
[http://dx.doi.org/10.1002/(SICI)1097-4652(199606)167: 3<477:AID-JCP12>3.0.CO;2-1] [PMID:  8655602] 
[34] 
Bolick, D.T.; Orr, A.W.; Whetzel, A.; Srinivasan, S.; Hatley, M.E.; Schwartz, M.A.; Hedrick, C.C. 12/15-lipoxygenase regulates intercellular adhesion molecule-1 expression and monocyte adhesion to endothelium through activation of RhoA and nuclear factor-kappaB. Arterioscler. Thromb. Vasc. Biol.,  2005, 25(11), 2301-2307.
[http://dx.doi.org/10.1161/01.ATV.0000186181.19909.a6] [PMID:  16166569] 
[35] 
Bolick, D.T.; Srinivasan, S.; Whetzel, A.; Fuller, L.C.; Hedrick, C.C. 12/15 lipoxygenase mediates monocyte adhesion to aortic endothelium in apolipoprotein E-deficient mice through activation of RhoA and NF-kappaB. Arterioscler. Thromb. Vasc. Biol.,  2006, 26(6), 1260-1266.
[http://dx.doi.org/10.1161/01.ATV.0000217909.09198.d6] [PMID:  16543492] 
[36] 
Hatley, M.E.; Srinivasan, S.; Reilly, K.B.; Bolick, D.T.; Hedrick, C.C. Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice. J. Biol. Chem.,  2003, 278(28), 25369-25375.
[http://dx.doi.org/10.1074/jbc.M301175200] [PMID:  12734208] 
[37] 
Zhang, P.; Xing, X.; Hu, C.; Yu, H.; Dong, Q.; Chang, G.; Qin, S.; Liu, J.; Zhang, D. 15-Lipoxygenase-1 is involved in the effects of atorvastatin on endothelial dysfunction. Mediators Inflamm.,  2016, 20166769032
[http://dx.doi.org/10.1155/2016/6769032] [PMID:  27594770] 
[38] 
Funk, C.D.; Cyrus, T. 12/15-lipoxygenase, oxidative modification of LDL and atherogenesis. Trends Cardiovasc. Med.,  2001, 11(3-4), 116-124.
[http://dx.doi.org/10.1016/S1050-1738(01)00096-2] [PMID:  11686000] 
[39] 
Folcik, V.A.; Nivar-Aristy, R.A.; Krajewski, L.P.; Cathcart, M.K. Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques. J. Clin. Invest.,  1995, 96(1), 504-510.
[http://dx.doi.org/10.1172/JCI118062] [PMID:  7615823] 
[40] 
Cyrus, T.; Witztum, J.L.; Rader, D.J.; Tangirala, R.; Fazio, S.; Linton, M.F.; Funk, C.D. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J. Clin. Invest.,  1999, 103(11), 1597-1604.
[http://dx.doi.org/10.1172/JCI5897] [PMID:  10359569] 
[41] 
Sukhanov, S.; Snarski, P.; Vaughn, C.; Lobelle-Rich, P.; Kim, C.; Higashi, Y.; Shai, S.Y.; Delafontaine, P. Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase. Atherosclerosis,  2015, 238(2), 313-320.
[http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.024] [PMID:  25549319] 
[42] 
Dwarakanath, R.S.; Sahar, S.; Lanting, L.; Wang, N.; Stemerman, M.B.; Natarajan, R.; Reddy, M.A. Viral vector-mediated 12/15-lipoxygenase overexpression in vascular smooth muscle cells enhances inflammatory gene expression and migration. J. Vasc. Res.,  2008, 45(2), 132-142.
[http://dx.doi.org/10.1159/000109966] [PMID:  17943024] 
[43] 
Ylä-Herttuala, S.; Luoma, J.; Viita, H.; Hiltunen, T.; Sisto, T.; Nikkari, T. Transfer of 15-lipoxygenase gene into rabbit iliac arteries results in the appearance of oxidation-specific lipid-protein adducts characteristic of oxidized low density lipoprotein. J. Clin. Invest.,  1995, 95(6), 2692-2698.
[http://dx.doi.org/10.1172/JCI117971] [PMID:  7769108] 
[44] 
Huo, Y.; Zhao, L.; Hyman, M.C.; Shashkin, P.; Harry, B.L.; Burcin, T.; Forlow, S.B.; Stark, M.A.; Smith, D.F.; Clarke, S.; Srinivasan, S.; Hedrick, C.C.; Praticò, D.; Witztum, J.L.; Nadler, J.L.; Funk, C.D.; Ley, K. Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice. Circulation,  2004, 110(14), 2024-2031.
[http://dx.doi.org/10.1161/01.CIR.0000143628.37680.F6] [PMID:  15451785] 
[45] 
Li, C.; Chen, J.W.; Liu, Z.H.; Shen, Y.; Ding, F.H.; Gu, G.; Liu, J.; Qiu, J.P.; Gao, J.; Zhang, R.Y.; Shen, W.F.; Wang, X.Q.; Lu, L. CTRP5 promotes transcytosis and oxidative modification of low-density lipoprotein and the development of atherosclerosis. Atherosclerosis,  2018, 278, 197-209.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.09.037] [PMID:  30300788] 
[46] 
Natarajan, R.; Reddy, M.A.; Malik, K.U.; Fatima, S.; Khan, B.V. Signaling mechanisms of nuclear factor-kappab-mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol.,  2001, 21(9), 1408-1413.
[http://dx.doi.org/10.1161/hq0901.095278] [PMID:  11557664] 
[47] 
Li, W.G.; Stoll, L.L.; Rice, J.B.; Xu, S.P.; Miller, F.J. Jr.; Chatterjee, P.; Hu, L.; Oberley, L.W.; Spector, A.A.; Weintraub, N.L. Activation of NAD(P)H oxidase by lipid hydroperoxides: mechanism of oxidant-mediated smooth muscle cytotoxicity. Free Radic. Biol. Med.,  2003, 34(7), 937-946.
[http://dx.doi.org/10.1016/S0891-5849(03)00032-7] [PMID:  12654483] 
[48] 
Kotla, S.; Singh, N.K.; Heckle, M.R.; Tigyi, G.J.; Rao, G.N. The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis. Sci. Signal.,  2013, 6(293), ra83.
[http://dx.doi.org/10.1126/scisignal.2004214] [PMID:  24045154] 
[49] 
Alaaeddine, R.; Elkhatib, M.A.W.; Mroueh, A.; Fouad, H.; Saad, E.I.; El-Sabban, M.E.; Plane, F.; El-Yazbi, A.F. Impaired endothelium-dependent hyperpolarization underlies endothelial dysfunction during early metabolic challenge: increased ROS generation and possible interference with NO function. J. Pharmacol. Exp. Ther.,  2019, 371(3), 567-582.
[http://dx.doi.org/10.1124/jpet.119.262048] [PMID:  31511364] 
[50] 
Elkhatib, M.A.W.; Mroueh, A.; Rafeh, R.W.; Sleiman, F.; Fouad, H.; Saad, E.I.; Fouda, M.A.; Elgaddar, O.; Issa, K.; Eid, A.H.; Eid, A.A.; Abd-Elrahman, K.S.; El-Yazbi, A.F. Amelioration of perivascular adipose inflammation reverses vascular dysfunction in a model of nonobese prediabetic metabolic challenge: potential role of antidiabetic drugs. Transl. Res.,  2019, 214, 121-143.
[http://dx.doi.org/10.1016/j.trsl.2019.07.009] [PMID:  31408626] 
[51] 
Suzuki, H.; Kayama, Y.; Sakamoto, M.; Iuchi, H.; Shimizu, I.; Yoshino, T.; Katoh, D.; Nagoshi, T.; Tojo, K.; Minamino, T.; Yoshimura, M.; Utsunomiya, K. Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy. Diabetes,  2015, 64(2), 618-630.
[http://dx.doi.org/10.2337/db13-1896] [PMID:  25187369] 
[52] 
Othman, A.; Ahmad, S.; Megyerdi, S.; Mussell, R.; Choksi, K.; Maddipati, K.R.; Elmarakby, A.; Rizk, N.; Al-Shabrawey, M. 12/15-Lipoxygenase-derived lipid metabolites induce retinal endothelial cell barrier dysfunction: contribution of NADPH oxidase. PLoS One,  2013, 8(2)e57254
[http://dx.doi.org/10.1371/journal.pone.0057254] [PMID:  23437353] 
[53] 
Ibrahim, A.S.; Elshafey, S.; Sellak, H.; Hussein, K.A.; El-Sherbiny, M.; Abdelsaid, M.; Rizk, N.; Beasley, S.; Tawfik, A.M.; Smith, S.B.; Al-Shabrawey, M. A lipidomic screen of hyperglycemia-treated HRECs links 12/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase. J. Lipid Res.,  2015, 56(3), 599-611.
[http://dx.doi.org/10.1194/jlr.M056069] [PMID:  25598081] 
[54] 
Elmasry, K.; Ibrahim, A.S.; Saleh, H.; Elsherbiny, N.; Elshafey, S.; Hussein, K.A.; Al-Shabrawey, M. Role of endoplasmic reticulum stress in 12/15-lipoxygenase-induced retinal microvascular dysfunction in a mouse model of diabetic retinopathy. Diabetologia,  2018, 61(5), 1220-1232.
[http://dx.doi.org/10.1007/s00125-018-4560-z] [PMID:  29468369] 
[55] 
Shevalye, H.; Lupachyk, S.; Watcho, P.; Stavniichuk, R.; Khazim, K.; Abboud, H.E.; Obrosova, I.G. Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress. Endocrinology,  2012, 153(3), 1152-1161.
[http://dx.doi.org/10.1210/en.2011-1997] [PMID:  22234462] 
[56] 
Gad, H.I. Effects of pravastatin or 12/15 lipoxygenase pathway inhibitors on indices of diabetic nephropathy in an experimental model of diabetic renal disease. Saudi Med. J.,  2012, 33(6), 608-616.
[57] 
Stavniichuk, R.; Drel, V.R.; Shevalye, H.; Vareniuk, I.; Stevens, M.J.; Nadler, J.L.; Obrosova, I.G. Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies. Free Radic. Biol. Med.,  2010, 49(6), 1036-1045.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.06.016] [PMID:  20599608] 
[58] 
Obrosova, I.G.; Stavniichuk, R.; Drel, V.R.; Shevalye, H.; Vareniuk, I.; Nadler, J.L.; Schmidt, R.E. Different roles of 12/15-lipoxygenase in diabetic large and small fiber peripheral and autonomic neuropathies. Am. J. Pathol.,  2010, 177(3), 1436-1447.
[http://dx.doi.org/10.2353/ajpath.2010.100178] [PMID:  20724598] 
[59] 
Heppner, F.L.; Ransohoff, R.M.; Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci.,  2015, 16(6), 358-372.
[http://dx.doi.org/10.1038/nrn3880] [PMID:  25991443] 
[60] 
Kivipelto, M.; Ngandu, T.; Fratiglioni, L.; Viitanen, M.; Kåreholt, I.; Winblad, B.; Helkala, E.L.; Tuomilehto, J.; Soininen, H.; Nissinen, A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch. Neurol.,  2005, 62(10), 1556-1560.
[http://dx.doi.org/10.1001/archneur.62.10.1556] [PMID:  16216938] 
[61] 
Fakih, W.; Mroueh, A.; Salah, H.; Eid, A.H.; Obeid, M.; Kobeissy, F.; Darwish, H.; El-Yazbi, A.F. Dysfunctional cerebrovascular tone contributes to cognitive impairment in a non-obese rat model of prediabetic challenge: Role of suppression of autophagy and modulation by anti-diabetic drugs. Biochem. Pharmacol.,  2020, •••178114041
[http://dx.doi.org/10.1016/j.bcp.2020.114041] [PMID:  32439335] 
[62] 
Praticò, D.; Zhukareva, V.; Yao, Y.; Uryu, K.; Funk, C.D.; Lawson, J.A.; Trojanowski, J.Q.; Lee, V.M. 12/15-lipoxygenase is increased in Alzheimer’s disease: possible involvement in brain oxidative stress. Am. J. Pathol.,  2004, 164(5), 1655-1662.
[http://dx.doi.org/10.1016/S0002-9440(10)63724-8] [PMID:  15111312] 
[63] 
Yao, Y.; Clark, C.M.; Trojanowski, J.Q.; Lee, V.M.; Praticò, D. Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment. Ann. Neurol.,  2005, 58(4), 623-626.
[http://dx.doi.org/10.1002/ana.20558] [PMID:  16037976] 
[64] 
Querfurth, H.W.; LaFerla, F.M. Alzheimer’s disease. N. Engl. J. Med.,  2010, 362(4), 329-344.
[http://dx.doi.org/10.1056/NEJMra0909142] [PMID:  20107219] 
[65] 
Yang, H.; Zhuo, J.M.; Chu, J.; Chinnici, C.; Praticò, D. Amelioration of the Alzheimer’s disease phenotype by absence of 12/15-lipoxygenase. Biol. Psychiatry,  2010, 68(10), 922-929.
[http://dx.doi.org/10.1016/j.biopsych.2010.04.010] [PMID:  20570249] 
[66] 
Chu, J.; Zhuo, J.M.; Praticò, D. Transcriptional regulation of β-secretase-1 by 12/15-lipoxygenase results in enhanced amyloidogenesis and cognitive impairments. Ann. Neurol.,  2012, 71(1), 57-67.
[http://dx.doi.org/10.1002/ana.22625] [PMID:  22275252] 
[67] 
Giannopoulos, P.F.; Joshi, Y.B.; Chu, J.; Praticò, D. The 12-15-lipoxygenase is a modulator of Alzheimer’s-related tau pathology in vivo. Aging Cell,  2013, 12(6), 1082-1090.
[http://dx.doi.org/10.1111/acel.12136] [PMID:  23862663] 
[68] 
Di Meco, A.; Li, J.G.; Blass, B.E.; Abou-Gharbia, M.; Lauretti, E.; Praticò, D. 12/15-Lipoxygenase inhibition reverses cognitive impairment, brain amyloidosis, and tau pathology by stimulating autophagy in aged triple transgenic mice. Biol. Psychiatry,  2017, 81(2), 92-100.
[http://dx.doi.org/10.1016/j.biopsych.2016.05.023] [PMID:  27499089] 
[69] 
Chu, J.; Li, J.G.; Giannopoulos, P.F.; Blass, B.E.; Childers, W.; Abou-Gharbia, M.; Praticò, D. Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice. Mol. Psychiatry,  2015, 20(11), 1329-1338.
[http://dx.doi.org/10.1038/mp.2014.170] [PMID:  25560760] 
[70] 
Feltenmark, S.; Gautam, N.; Brunnström, A.; Griffiths, W.; Backman, L.; Edenius, C.; Lindbom, L.; Björkholm, M.; Claesson, H.E. Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells. Proc. Natl. Acad. Sci. USA,  2008, 105(2), 680-685.
[http://dx.doi.org/10.1073/pnas.0710127105] [PMID:  18184802] 
[71] 
Janakiram, N.B.; Rao, C.V. Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer. Curr. Mol. Med.,  2009, 9(5), 565-579.
[http://dx.doi.org/10.2174/156652409788488748] [PMID:  19601807] 
[72] 
Serhan, C.N.; Chiang, N.; Van Dyke, T.E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol.,  2008, 8(5), 349-361.
[http://dx.doi.org/10.1038/nri2294] [PMID:  18437155] 
[73] 
Spindler, S.A.; Sarkar, F.H.; Sakr, W.A.; Blackburn, M.L.; Bull, A.W.; LaGattuta, M.; Reddy, R.G. Production of 13-hydroxyoctadecadienoic acid (13-HODE) by prostate tumors and cell lines. Biochem. Biophys. Res. Commun.,  1997, 239(3), 775-781.
[http://dx.doi.org/10.1006/bbrc.1997.7471] [PMID:  9367845] 
[74] 
Brash, A.R.; Boeglin, W.E.; Chang, M.S. Discovery of a second 15S-lipoxygenase in humans. Proc. Natl. Acad. Sci. USA,  1997, 94(12), 6148-6152.
[http://dx.doi.org/10.1073/pnas.94.12.6148] [PMID:  9177185] 
[75] 
Shappell, S.B.; Boeglin, W.E.; Olson, S.J.; Kasper, S.; Brash, A.R. 15-lipoxygenase-2 (15-LOX-2) is expressed in benign prostatic epithelium and reduced in prostate adenocarcinoma. Am. J. Pathol.,  1999, 155(1), 235-245.
[http://dx.doi.org/10.1016/S0002-9440(10)65117-6] [PMID:  10393855] 
[76] 
Jack, G.S.; Brash, A.R.; Olson, S.J.; Manning, S.; Coffey, C.S.; Smith, J.A. Jr.; Shappell, S.B. Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia. Hum. Pathol.,  2000, 31(9), 1146-1154.
[http://dx.doi.org/10.1053/hupa.2000.16670] [PMID:  11014584] 
[77] 
Tang, Y.; Wang, M.T.; Chen, Y.; Yang, D.; Che, M.; Honn, K.V.; Akers, G.D.; Johnson, S.R.; Nie, D. Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15-lipoxygenase-2 in prostate cancer. Int. J. Cancer,  2009, 124(7), 1545-1551.
[http://dx.doi.org/10.1002/ijc.24118] [PMID:  19089921] 
[78] 
Suraneni, M.V.; Schneider-Broussard, R.; Moore, J.R.; Davis, T.C.; Maldonado, C.J.; Li, H.; Newman, R.A.; Kusewitt, D.; Hu, J.; Yang, P.; Tang, D.G. Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence. Oncogene,  2010, 29(30), 4261-4275.
[http://dx.doi.org/10.1038/onc.2010.197] [PMID:  20514017] 
[79] 
Kelavkar, U.P.; Cohen, C.; Kamitani, H.; Eling, T.E.; Badr, K.F. Concordant induction of 15-lipoxygenase-1 and mutant p53 expression in human prostate adenocarcinoma: correlation with Gleason staging. Carcinogenesis,  2000, 21(10), 1777-1787.
[http://dx.doi.org/10.1093/carcin/21.10.1777] [PMID:  11023533] 
[80] 
Kelavkar, U.P.; Nixon, J.B.; Cohen, C.; Dillehay, D.; Eling, T.E.; Badr, K.F. Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis. Carcinogenesis,  2001, 22(11), 1765-1773.
[http://dx.doi.org/10.1093/carcin/22.11.1765] [PMID:  11698337] 
[81] 
Hsi, L.C.; Wilson, L.C.; Eling, T.E. Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma. J. Biol. Chem.,  2002, 277(43), 40549-40556.
[http://dx.doi.org/10.1074/jbc.M203522200] [PMID:  12189136] 
[82] 
Shappell, S.B.; Gupta, R.A.; Manning, S.; Whitehead, R.; Boeglin, W.E.; Schneider, C.; Case, T.; Price, J.; Jack, G.S.; Wheeler, T.M.; Matusik, R.J.; Brash, A.R.; Dubois, R.N. 15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells. Cancer Res.,  2001, 61(2), 497-503.
[83] 
Kelavkar, U.P.; Cohen, C. 15-lipoxygenase-1 expression upregulates and activates insulin-like growth factor-1 receptor in prostate cancer cells. Neoplasia,  2004, 6(1), 41-52.
[http://dx.doi.org/10.1016/S1476-5586(04)80052-6] [PMID:  15068670] 
[84] 
Ikawa, H.; Kamitani, H.; Calvo, B.F.; Foley, J.F.; Eling, T.E. Expression of 15-lipoxygenase-1 in human colorectal cancer. Cancer Res.,  1999, 59(2), 360-366.
[85] 
Hsi, L.C.; Wilson, L.; Nixon, J.; Eling, T.E. 15-lipoxygenase-1 metabolites down-regulate peroxisome proliferator-activated receptor gamma via the MAPK signaling pathway. J. Biol. Chem.,  2001, 276(37), 34545-34552.
[http://dx.doi.org/10.1074/jbc.M100280200] [PMID:  11447213] 
[86] 
Shureiqi, I.; Wojno, K.J.; Poore, J.A.; Reddy, R.G.; Moussalli, M.J.; Spindler, S.A.; Greenson, J.K.; Normolle, D.; Hasan, A.A.; Lawrence, T.S.; Brenner, D.E. Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers. Carcinogenesis,  1999, 20(10), 1985-1995.
[http://dx.doi.org/10.1093/carcin/20.10.1985] [PMID:  10506115] 
[87] 
Mao, F.; Wang, M.; Wang, J.; Xu, W.R. The role of 15-LOX-1 in colitis and colitis-associated colorectal cancer. Inflamm. Res.,  2015, 64(9), 661-669.
[PMID:  26194111] [http://dx.doi.org/10.1007/s00011-015-0852-7]] 
[88] 
Kamitani, H.; Kameda, H.; Kelavkar, U.P.; Eling, T.E. A GATA binding site is involved in the regulation of 15-lipoxygenase-1 expression in human colorectal carcinoma cell line, caco-2. FEBS Lett.,  2000, 467(2-3), 341-347.
[http://dx.doi.org/10.1016/S0014-5793(00)01155-8] [PMID:  10675566] 
[89] 
Mao, F.; Xu, M.; Zuo, X.; Yu, J.; Xu, W.; Moussalli, M.J.; Elias, E.; Li, H.S.; Watowich, S.S.; Shureiqi, I. 15-Lipoxygenase-1 suppression of colitis-associated colon cancer through inhibition of the IL-6/STAT3 signaling pathway. FASEB J.,  2015, 29(6), 2359-2370.
[http://dx.doi.org/10.1096/fj.14-264515] [PMID:  25713055] 
[90] 
Zhu, H.; Glasgow, W.; George, M.D.; Chrysovergis, K.; Olden, K.; Roberts, J.D.; Eling, T. 15-lipoxygenase-1 activates tumor suppressor p53 independent of enzymatic activity. Int. J. Cancer,  2008, 123(12), 2741-2749.
[http://dx.doi.org/10.1002/ijc.23855] [PMID:  18785202] 
[91] 
Wu, Y.; Mao, F.; Zuo, X.; Moussalli, M.J.; Elias, E.; Xu, W.; Shureiqi, I. 15-LOX-1 suppression of hypoxia-induced metastatic phenotype and HIF-1α expression in human colon cancer cells. Cancer Med.,  2014, 3(3), 472-484.
[http://dx.doi.org/10.1002/cam4.222] [PMID:  24634093] 
[92] 
Tunçer, S.; Keşküş, A.G.; Çolakoğlu, M.; Çimen, I.; Yener, C.; Konu, Ö.; Banerjee, S. 15-Lipoxygenase-1 re-expression in colorectal cancer alters endothelial cell features through enhanced expression of TSP-1 and ICAM-1. Cell. Signal.,  2017, 39, 44-54.
[http://dx.doi.org/10.1016/j.cellsig.2017.07.022] [PMID:  28757355] 
[93] 
Cimen, I.; Tunçay, S.; Banerjee, S. 15-Lipoxygenase-1 expression suppresses the invasive properties of colorectal carcinoma cell lines HCT-116 and HT-29. Cancer Sci.,  2009, 100(12), 2283-2291.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01313.x] [PMID:  19775287] 
[94] 
Gonzalez, A.L.; Roberts, R.L.; Massion, P.P.; Olson, S.J.; Shyr, Y.; Shappell, S.B. 15-Lipoxygenase-2 expression in benign and neoplastic lung: an immunohistochemical study and correlation with tumor grade and proliferation. Hum. Pathol.,  2004, 35(7), 840-849.
[http://dx.doi.org/10.1016/j.humpath.2004.04.001] [PMID:  15257547] 
[95] 
Yang, L.; Ma, C.; Zhang, L.; Zhang, M.; Li, F.; Zhang, C.; Yu, X.; Wang, X.; He, S.; Zhu, D.; Song, Y. 15-Lipoxygenase-2/15(S)-hydroxyeicosatetraenoic acid regulates cell proliferation and metastasis via the STAT3 pathway in lung adenocarcinoma. Prostaglandins Other Lipid Mediat.,  2018, 138, 31-40.
[http://dx.doi.org/10.1016/j.prostaglandins.2018.07.003] [PMID:  30110652] 
[96] 
Chen, X.; Ji, N.; Qin, N.; Tang, S.A.; Wang, R.; Qiu, Y.; Duan, H.; Kong, D.; Jin, M. 1,6-O,O-Diacetylbritannilactone inhibits Eotaxin-1 and ALOX15 expression through inactivation of STAT6 in A549 cells. Inflammation,  2017, 40(6), 1967-1974.
[http://dx.doi.org/10.1007/s10753-017-0637-y] [PMID:  28770377] 
[97] 
Yuan, H.; Li, M.Y.; Ma, L.T.; Hsin, M.K.; Mok, T.S.; Underwood, M.J.; Chen, G.G. 15-Lipoxygenases and its metabolites 15(S)-HETE and 13(S)-HODE in the development of non-small cell lung cancer. Thorax,  2010, 65(4), 321-326.
[http://dx.doi.org/10.1136/thx.2009.122747] [PMID:  20388757] 
[98] 
Li, M.Y.; Yuan, H.L.; Ko, F.W.; Wu, B.; Long, X.; Du, J.; Wu, J.; Ng, C.S.; Wan, I.Y.; Mok, T.S.; Hui, D.S.; Underwood, M.J.; Chen, G.G. Antineoplastic effects of 15(S)-hydroxyeicosatetraenoic acid and 13-S-hydroxyoctadecadienoic acid in non-small cell lung cancer. Cancer,  2015, 121(Suppl. 17), 3130-3145.
[http://dx.doi.org/10.1002/cncr.29547] [PMID:  26331820] 
[99] 
Mao, J.T.; Nie, W.X.; Tsu, I.H.; Jin, Y.S.; Rao, J.Y.; Lu, Q.Y.; Zhang, Z.F.; Go, V.L.; Serio, K.J. White tea extract induces apoptosis in non-small cell lung cancer cells: the role of peroxisome proliferator-activated receptor-gamma and 15-lipoxygenases. Cancer Prev. Res. (Phila.),  2010, 3(9), 1132-1140.
[http://dx.doi.org/10.1158/1940-6207.CAPR-09-0264] [PMID:  20668019] 
[100] 
Smith, W.L.; DeWitt, D.L.; Garavito, R.M. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem.,  2000, 69, 145-182.
[http://dx.doi.org/10.1146/annurev.biochem.69.1.145] [PMID:  10966456] 
[101] 
Harris, S.G.; Padilla, J.; Koumas, L.; Ray, D.; Phipps, R.P. Prostaglandins as modulators of immunity. Trends Immunol.,  2002, 23(3), 144-150.
[http://dx.doi.org/10.1016/S1471-4906(01)02154-8] [PMID:  11864843] 
[102] 
Ricciotti, E.; FitzGerald, G.A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol.,  2011, 31(5), 986-1000.
[http://dx.doi.org/10.1161/ATVBAHA.110.207449] [PMID:  21508345] 
[103] 
Chan, P.C.; Liao, M.T.; Hsieh, P.S. The dualistic effect of COX-2-mediated signaling in obesity and insulin resistance. Int. J. Mol. Sci.,  2019, 20(13)E3115
[http://dx.doi.org/10.3390/ijms20133115] [PMID:  31247902] 
[104] 
Hsieh, P.S.; Jin, J.S.; Chiang, C.F.; Chan, P.C.; Chen, C.H.; Shih, K.C. COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver. Obesity (Silver Spring),  2009, 17(6), 1150-1157.
[http://dx.doi.org/10.1038/oby.2008.674] [PMID:  19247274] 
[105] 
Lu, C.H.; Hung, Y.J.; Hsieh, P.S. Additional effect of metformin and celecoxib against lipid dysregulation and adipose tissue inflammation in high-fat fed rats with insulin resistance and fatty liver. Eur. J. Pharmacol.,  2016, 789, 60-67.
[http://dx.doi.org/10.1016/j.ejphar.2016.07.012] [PMID:  27397427] 
[106] 
Chan, P.C.; Hsiao, F.C.; Chang, H.M.; Wabitsch, M.; Hsieh, P.S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance. FASEB J.,  2016, 30(6), 2282-2297.
[http://dx.doi.org/10.1096/fj.201500127] [PMID:  26932930] 
[107] 
García-Alonso, V.; Titos, E.; Alcaraz-Quiles, J.; Rius, B.; Lopategi, A.; López-Vicario, C.; Jakobsson, P.J.; Delgado, S.; Lozano, J.; Clària, J. Prostaglandin E2 exerts multiple regulatory actions on human obese adipose tissue remodeling, inflammation, adaptive thermogenesis and lipolysis. PLoS One,  2016, 11(4)e0153751
[http://dx.doi.org/10.1371/journal.pone.0153751] [PMID:  27124181] 
[108] 
Weisberg, S.P.; McCann, D.; Desai, M.; Rosenbaum, M.; Leibel, R.L.; Ferrante, A.W. Jr. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest.,  2003, 112(12), 1796-1808.
[http://dx.doi.org/10.1172/JCI200319246] [PMID:  14679176] 
[109] 
Lumeng, C.N.; Bodzin, J.L.; Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest.,  2007, 117(1), 175-184.
[http://dx.doi.org/10.1172/JCI29881] [PMID:  17200717] 
[110] 
Chan, P.C.; Wu, T.N.; Chen, Y.C.; Lu, C.H.; Wabitsch, M.; Tian, Y.F.; Hsieh, P.S. Targetted inhibition of CD74 attenuates adipose COX-2-MIF-mediated M1 macrophage polarization and retards obesity-related adipose tissue inflammation and insulin resistance. Clin. Sci. (Lond.),  2018, 132(14), 1581-1596.
[http://dx.doi.org/10.1042/CS20180041] [PMID:  29773671] 
[111] 
Cipollone, F.; Fazia, M.L. COX-2 and atherosclerosis. J. Cardiovasc. Pharmacol.,  2006, 47(Suppl. 1), S26-S36.
[http://dx.doi.org/10.1097/00005344-200605001-00006] [PMID:  16785826] 
[112] 
Metzner, J.; Popp, L.; Marian, C.; Schmidt, R.; Manderscheid, C.; Renne, C.; Fisslthaler, B.; Fleming, I.; Busse, R.; Geisslinger, G.; Niederberger, E. The effects of COX-2 selective and non-selective NSAIDs on the initiation and progression of atherosclerosis in ApoE-/- mice. J. Mol. Med. (Berl.),  2007, 85(6), 623-633.
[http://dx.doi.org/10.1007/s00109-007-0162-9] [PMID:  17318614] 
[113] 
Baldan, A.; Ferronato, S.; Olivato, S.; Malerba, G.; Scuro, A.; Veraldi, G.F.; Gelati, M.; Ferrari, S.; Mariotto, S.; Pignatti, P.F.; Mazzucco, S.; Gomez-Lira, M. Cyclooxygenase 2, toll-like receptor 4 and interleukin 1beta mRNA expression in atherosclerotic plaques of type 2 diabetic patients. Inflamm. Res.,  2014, 63(10), 851-858.
[PMID:  25095741] [http://dx.doi.org/10.1007/s00011-014-0759-8]] 
[114] 
Alarcon, G.; Roco, J.; Medina, M.; Medina, A.; Peral, M.; Jerez, S. High fat diet-induced metabolically obese and normal weight rabbit model shows early vascular dysfunction: mechanisms involved. Int. J. Obes.,  2018, 42(9), 1535-1543.
[http://dx.doi.org/10.1038/s41366-018-0020-6] [PMID:  29445240] 
[115] 
Jacob, S.; Laury-Kleintop, L.; Lanza-Jacoby, S. The select cyclooxygenase-2 inhibitor celecoxib reduced the extent of atherosclerosis in apo E-/- mice. J. Surg. Res.,  2008, 146(1), 135-142.
[http://dx.doi.org/10.1016/j.jss.2007.04.040] [PMID:  17950326] 
[116] 
Raval, M.; Frank, P.G.; Laury-Kleintop, L.; Yan, G.; Lanza-Jacoby, S. Celecoxib combined with atorvastatin prevents progression of atherosclerosis. J. Surg. Res.,  2010, 163(2), e113-e122.
[http://dx.doi.org/10.1016/j.jss.2010.03.011] [PMID:  20538289] 
[117] 
Matesanz, N.; Jewhurst, V.; Trimble, E.R.; McGinty, A.; Owens, D.; Tomkin, G.H.; Powell, L.A. Linoleic acid increases monocyte chemotaxis and adhesion to human aortic endothelial cells through protein kinase C- and cyclooxygenase-2-dependent mechanisms. J. Nutr. Biochem.,  2012, 23(6), 685-690.
[http://dx.doi.org/10.1016/j.jnutbio.2011.03.020] [PMID:  21840193] 
[118] 
Li, L.; Li, J.; Yi, J.; Liu, H.; Lei, H. Dose-effect of irbesartan on cyclooxygenase-2 and matrix metalloproteinase-9 expression in rabbit atherosclerosis. J. Cardiovasc. Pharmacol.,  2018, 71(2), 82-94.
[http://dx.doi.org/10.1097/FJC.0000000000000544] [PMID:  29420356] 
[119] 
Young, W.; Mahboubi, K.; Haider, A.; Li, I.; Ferreri, N.R. Cyclooxygenase-2 is required for tumor necrosis factor-alpha- and angiotensin II-mediated proliferation of vascular smooth muscle cells. Circ. Res.,  2000, 86(8), 906-914.
[http://dx.doi.org/10.1161/01.RES.86.8.906] [PMID:  10785514] 
[120] 
Rival, Y.; Puech, L.; Taillandier, T.; Benéteau, N.; Rouquette, A.; Lestienne, F.; Dupont-Passelaigue, E.; Le Roy, I.; Patoiseau, J.F.; Junquéro, D. PPAR activators and COX inhibitors selectively block cytokine-induced COX-2 expression and activity in human aortic smooth muscle cells. Eur. J. Pharmacol.,  2009, 606(1-3), 121-129.
[http://dx.doi.org/10.1016/j.ejphar.2009.01.010] [PMID:  19374865] 
[121] 
Lee, H.S.; Yun, S.J.; Ha, J.M.; Jin, S.Y.; Ha, H.K.; Song, S.H.; Kim, C.D.; Bae, S.S. Prostaglandin D2 stimulates phenotypic changes in vascular smooth muscle cells. Exp. Mol. Med.,  2019, 51(11), 1-10.
[http://dx.doi.org/10.1038/s12276-019-0330-3] [PMID:  31735914] 
[122] 
Yang, H.M.; Kim, H.S.; Park, K.W.; You, H.J.; Jeon, S.I.; Youn, S.W.; Kim, S.H.; Oh, B.H.; Lee, M.M.; Park, Y.B.; Walsh, K. Celecoxib, a cyclooxygenase-2 inhibitor, reduces neointimal hyperplasia through inhibition of Akt signaling. Circulation,  2004, 110(3), 301-308.
[http://dx.doi.org/10.1161/01.CIR.0000135467.43430.16] [PMID:  15238462] 
[123] 
Beloqui, O.; Páramo, J.A.; Orbe, J.; Benito, A.; Colina, I.; Monasterio, A.; Díez, J. Monocyte cyclooxygenase-2 overactivity: a new marker of subclinical atherosclerosis in asymptomatic subjects with cardiovascular risk factors? Eur. Heart J.,  2005, 26(2), 153-158.
[http://dx.doi.org/10.1093/eurheartj/ehi016] [PMID:  15618071] 
[124] 
Gargiulo, S.; Rossin, D.; Testa, G.; Gamba, P.; Staurenghi, E.; Biasi, F.; Poli, G.; Leonarduzzi, G. Up-regulation of COX-2 and mPGES-1 by 27-hydroxycholesterol and 4-hydroxynonenal: a crucial role in atherosclerotic plaque instability. Free Radic. Biol. Med.,  2018, 129, 354-363.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.09.046] [PMID:  30312760] 
[125] 
Persaud, S.J.; Burns, C.J.; Belin, V.D.; Jones, P.M. Glucose-induced regulation of COX-2 expression in human islets of Langerhans. Diabetes,  2004, 53(Suppl. 1), S190-S192.
[http://dx.doi.org/10.2337/diabetes.53.2007.S190] [PMID:  14749287] 
[126] 
Amior, L.; Srivastava, R.; Nano, R.; Bertuzzi, F.; Melloul, D. The role of Cox-2 and prostaglandin E2 receptor EP3 in pancreatic β-cell death. FASEB J.,  2019, 33(4), 4975-4986.
[http://dx.doi.org/10.1096/fj.201801823R] [PMID:  30629897] 
[127] 
Wang, G.; Liang, R.; Liu, T.; Wang, L.; Zou, J.; Liu, N.; Liu, Y.; Cai, X.; Liu, Y.; Ding, X.; Zhang, B.; Wang, Z.; Wang, S.; Shen, Z. Opposing effects of IL-1β/COX-2/PGE2 pathway loop on islets in type 2 diabetes mellitus. Endocr. J.,  2019, 66(8), 691-699.
[http://dx.doi.org/10.1507/endocrj.EJ19-0015] [PMID:  31105125] 
[128] 
Carboneau, B.A.; Allan, J.A.; Townsend, S.E.; Kimple, M.E.; Breyer, R.M.; Gannon, M. Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human β-cell survival and proliferation. Mol. Metab.,  2017, 6(6), 548-559.
[http://dx.doi.org/10.1016/j.molmet.2017.04.002] [PMID:  28580285] 
[129] 
Parazzoli, S.; Harmon, J.S.; Vallerie, S.N.; Zhang, T.; Zhou, H.; Robertson, R.P. Cyclooxygenase-2, not microsomal prostaglandin E synthase-1, is the mechanism for interleukin-1β-induced prostaglandin E2 production and inhibition of insulin secretion in pancreatic islets. J. Biol. Chem.,  2012, 287(38), 32246-32253.
[http://dx.doi.org/10.1074/jbc.M112.364612] [PMID:  22822059] 
[130] 
Wilkinson-Berka, J.L. Vasoactive factors and diabetic retinopathy: vascular endothelial growth factor, cycoloxygenase-2 and nitric oxide. Curr. Pharm. Des.,  2004, 10(27), 3331-3348.
[http://dx.doi.org/10.2174/1381612043383142] [PMID:  15544519] 
[131] 
Madonna, R.; Giovannelli, G.; Confalone, P.; Renna, F.V.; Geng, Y.J.; De Caterina, R. High glucose-induced hyperosmolarity contributes to COX-2 expression and angiogenesis: implications for diabetic retinopathy. Cardiovasc. Diabetol.,  2016, 15, 18.
[http://dx.doi.org/10.1186/s12933-016-0342-4] [PMID:  26822858] 
[132] 
Du, Y.; Sarthy, V.P.; Kern, T.S. Interaction between NO and COX pathways in retinal cells exposed to elevated glucose and retina of diabetic rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.,  2004, 287(4), R735-R741.
[http://dx.doi.org/10.1152/ajpregu.00080.2003] [PMID:  15371279] 
[133] 
Sennlaub, F.; Valamanesh, F.; Vazquez-Tello, A.; El-Asrar, A.M.; Checchin, D.; Brault, S.; Gobeil, F.; Beauchamp, M.H.; Mwaikambo, B.; Courtois, Y.; Geboes, K.; Varma, D.R.; Lachapelle, P.; Ong, H.; Behar-Cohen, F.; Chemtob, S. Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy. Circulation,  2003, 108(2), 198-204.
[http://dx.doi.org/10.1161/01.CIR.0000080735.93327.00] [PMID:  12821538] 
[134] 
Nassiri, S.; Houshmand, G.; Feghhi, M.; Kheirollah, A.; Bahadoram, M.; Nassiri, N. Effect of periocular injection of celecoxib and propranolol on ocular level of vascular endothelial growth factor in a diabetic mouse model. Int. J. Ophthalmol.,  2016, 9(6), 821-824.
[http://dx.doi.org/10.18240/ijo.2016.06.05] [PMID:  27366681] 
[135] 
Kellogg, A.P.; Pop-Busui, R. Peripheral nerve dysfunction in experimental diabetes is mediated by cyclooxygenase-2 and oxidative stress. Antioxid. Redox Signal.,  2005, 7(11-12), 1521-1529.
[http://dx.doi.org/10.1089/ars.2005.7.1521] [PMID:  16356116] 
[136] 
Kellogg, A.P.; Wiggin, T.D.; Larkin, D.D.; Hayes, J.M.; Stevens, M.J.; Pop-Busui, R. Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes. Diabetes,  2007, 56(12), 2997-3005.
[http://dx.doi.org/10.2337/db07-0740] [PMID:  17720896] 
[137] 
Pop-Busui, R.; Marinescu, V.; Van Huysen, C.; Li, F.; Sullivan, K.; Greene, D.A.; Larkin, D.; Stevens, M.J. Dissection of metabolic, vascular, and nerve conduction interrelationships in experimental diabetic neuropathy by cyclooxygenase inhibition and acetyl-L-carnitine administration. Diabetes,  2002, 51(8), 2619-2628.
[http://dx.doi.org/10.2337/diabetes.51.8.2619] [PMID:  12145179] 
[138] 
Kimura, S.; Kontani, H. Demonstration of antiallodynic effects of the cyclooxygenase-2 inhibitor meloxicam on established diabetic neuropathic pain in mice. J. Pharmacol. Sci.,  2009, 110(2), 213-217.
[http://dx.doi.org/10.1254/jphs.09006SC] [PMID:  19498273] 
[139] 
Matsunaga, A.; Kawamoto, M.; Shiraishi, S.; Yasuda, T.; Kajiyama, S.; Kurita, S.; Yuge, O. Intrathecally administered COX-2 but not COX-1 or COX-3 inhibitors attenuate streptozotocin-induced mechanical hyperalgesia in rats. Eur. J. Pharmacol.,  2007, 554(1), 12-17.
[http://dx.doi.org/10.1016/j.ejphar.2006.09.072] [PMID:  17112505] 
[140] 
Jia, Z.; Sun, Y.; Liu, S.; Liu, Y.; Yang, T. COX-2 but not mPGES-1 contributes to renal PGE2 induction and diabetic proteinuria in mice with type-1 diabetes. PLoS One,  2014, 9(7)e93182
[http://dx.doi.org/10.1371/journal.pone.0093182] [PMID:  24984018] 
[141] 
Khan, K.N.; Stanfield, K.M.; Harris, R.K.; Baron, D.A. Expression of cyclooxygenase-2 in the macula densa of human kidney in hypertension, congestive heart failure, and diabetic nephropathy. Ren. Fail.,  2001, 23(3-4), 321-330.
[http://dx.doi.org/10.1081/JDI-100104716] [PMID:  11499548] 
[142] 
Nguyen, G. Increased cyclooxygenase-2, hyperfiltration, glomerulosclerosis, and diabetic nephropathy: put the blame on the (pro)renin receptor? Kidney Int.,  2006, 70(4), 618-620.
[http://dx.doi.org/10.1038/sj.ki.5001723] [PMID:  16900219] 
[143] 
Cheng, H.; Fan, X.; Moeckel, G.W.; Harris, R.C. Podocyte COX-2 exacerbates diabetic nephropathy by increasing podocyte (pro)renin receptor expression. J. Am. Soc. Nephrol.,  2011, 22(7), 1240-1251.
[http://dx.doi.org/10.1681/ASN.2010111149] [PMID:  21737546] 
[144] 
Quilley, J.; Santos, M.; Pedraza, P. Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats. Am. J. Physiol. Heart Circ. Physiol.,  2011, 300(6), H2316-H2322.
[http://dx.doi.org/10.1152/ajpheart.01259.2010] [PMID:  21441310] 
[145] 
Liu, Z.C.; Zhou, Q.L.; Ouyang, C.; Deng, S-L. Zhong Nan Da Xue Xue Bao Yi Xue Ban,  2004, 29(6), 635-638. [Mechanism and effect of cyclooxygenase-2 inhibitor meloxicam on the protection of diabetic nephropathy in rats
[146] 
Kiritoshi, S.; Nishikawa, T.; Sonoda, K.; Kukidome, D.; Senokuchi, T.; Matsuo, T.; Matsumura, T.; Tokunaga, H.; Brownlee, M.; Araki, E. Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. Diabetes,  2003, 52(10), 2570-2577.
[http://dx.doi.org/10.2337/diabetes.52.10.2570] [PMID:  14514642] 
[147] 
Xu, Z.G.; Li, S.L.; Lanting, L.; Kim, Y.S.; Shanmugam, N.; Reddy, M.A.; Natarajan, R. Relationship between 12/15-lipoxygenase and COX-2 in mesangial cells: potential role in diabetic nephropathy. Kidney Int.,  2006, 69(3), 512-519.
[http://dx.doi.org/10.1038/sj.ki.5000137] [PMID:  16514433] 
[148] 
Guan, P.P.; Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer’s disease. FASEB J.,  2019, 33(1), 13-33.
[http://dx.doi.org/10.1096/fj.201800355RRRR] [PMID:  30020833] 
[149] 
Sil, S.; Ghosh, T. Role of cox-2 mediated neuroinflammation on the neurodegeneration and cognitive impairments in colchicine induced rat model of Alzheimer’s disease. J. Neuroimmunol.,  2016, 291, 115-124.
[http://dx.doi.org/10.1016/j.jneuroim.2015.12.003] [PMID:  26857505] 
[150] 
Mhillaj, E.; Morgese, M.G.; Tucci, P.; Furiano, A.; Luongo, L.; Bove, M.; Maione, S.; Cuomo, V.; Schiavone, S.; Trabace, L. Celecoxib prevents cognitive impairment and neuroinflammation in soluble amyloid β-treated rats. Neuroscience,  2018, 372, 58-73.
[http://dx.doi.org/10.1016/j.neuroscience.2017.12.046] [PMID:  29306052] 
[151] 
Guan, P.P.; Liang, Y.Y.; Cao, L.L.; Yu, X.; Wang, P. Cyclooxygenase-2 induced the β-amyloid protein deposition and neuronal apoptosis via upregulating the synthesis of prostaglandin E2 and 15-Deoxy-Δ12,14-prostaglandin J2. Neurotherapeutics,  2019, 16(4), 1255-1268.
[http://dx.doi.org/10.1007/s13311-019-00770-z] [PMID:  31392591] 
[152] 
Jang, J.H.; Surh, Y.J. Beta-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-kappaB signaling pathway. Free Radic. Biol. Med.,  2005, 38(12), 1604-1613.
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.02.023] [PMID:  15917189] 
[153] 
Ianiski, F.R.; Alves, C.B.; Ferreira, C.F.; Rech, V.C.; Savegnago, L.; Wilhelm, E.A.; Luchese, C. Meloxicam-loaded nanocapsules as an alternative to improve memory decline in an Alzheimer’s disease model in mice: involvement of Na(+), K(+)-ATPase. Metab. Brain Dis.,  2016, 31(4), 793-802.
[http://dx.doi.org/10.1007/s11011-016-9812-3] [PMID:  26922073] 
[154] 
Sooriakumaran, P.; Langley, S.E.; Laing, R.W.; Coley, H.M. COX-2 inhibition: a possible role in the management of prostate cancer? J. Chemother.,  2007, 19(1), 21-32.
[http://dx.doi.org/10.1179/joc.2007.19.1.21] [PMID:  17309847] 
[155] 
Agrawal, A.; Fentiman, I.S. NSAIDs and breast cancer: a possible prevention and treatment strategy. Int. J. Clin. Pract.,  2008, 62(3), 444-449.
[http://dx.doi.org/10.1111/j.1742-1241.2007.01668.x] [PMID:  18194278] 
[156] 
Wang, W.; Wang, J. Toll-like receptor 4 (TLR4)/cyclooxygenase-2 (COX-2) regulates prostate cancer cell proliferation, migration, and invasion by NF-κB activation. Med. Sci. Monit.,  2018, 24, 5588-5597.
[http://dx.doi.org/10.12659/MSM.906857] [PMID:  30098292] 
[157] 
Ko, C.J.; Lan, S.W.; Lu, Y.C.; Cheng, T.S.; Lai, P.F.; Tsai, C.H.; Hsu, T.W.; Lin, H.Y.; Shyu, H.Y.; Wu, S.R.; Lin, H.H.; Hsiao, P.W.; Chen, C.H.; Huang, H.P.; Lee, M.S. Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis. Oncogene,  2017, 36(32), 4597-4609.
[http://dx.doi.org/10.1038/onc.2017.82] [PMID:  28368394] 
[158] 
Herroon, M.K.; Diedrich, J.D.; Rajagurubandara, E.; Martin, C.; Maddipati, K.R.; Kim, S.; Heath, E.I.; Granneman, J.; Podgorski, I. Prostate tumor cell-derived IL1β induces an inflammatory phenotype in bone marrow adipocytes and reduces sensitivity to docetaxel via lipolysis-dependent mechanisms. Mol. Cancer Res.,  2019, 17(12), 2508-2521.
[http://dx.doi.org/10.1158/1541-7786.MCR-19-0540] [PMID:  31562254] 
[159] 
Liu, Y.; Sun, H.; Hu, M.; Zhang, Y.; Chen, S.; Tighe, S.; Zhu, Y. The role of cyclooxygenase-2 in colorectal carcinogenesis. Clin. Colorectal Cancer,  2017, 16(3), 165-172.
[http://dx.doi.org/10.1016/j.clcc.2016.09.012] [PMID:  27810226] 
[160] 
Kargman, S.L.; O’Neill, G.P.; Vickers, P.J.; Evans, J.F.; Mancini, J.A.; Jothy, S. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res.,  1995, 55(12), 2556-2559.
[161] 
Wu, Q.B.; Sun, G.P. Expression of COX-2 and HER-2 in colorectal cancer and their correlation. World J. Gastroenterol.,  2015, 21(20), 6206-6214.
[http://dx.doi.org/10.3748/wjg.v21.i20.6206] [PMID:  26034355] 
[162] 
Albasri, A.M.; Elkablawy, M.A.; Hussainy, A.S.; Yousif, H.M.; Alhujaily, A.S. Impact of cyclooxygenase-2 over-expression on the prognosis of colorectal cancer patients. An experience from western Saudi Arabia. Saudi Med. J.,  2018, 39(8), 773-780.
[http://dx.doi.org/10.15537/smj.2018.8.22837] [PMID:  30106414] 
[163] 
Mima, K.; Nishihara, R.; Yang, J.; Dou, R.; Masugi, Y.; Shi, Y.; da Silva, A.; Cao, Y.; Song, M.; Nowak, J.; Gu, M.; Li, W.; Morikawa, T.; Zhang, X.; Wu, K.; Baba, H.; Giovannucci, E.L.; Meyerhardt, J.A.; Chan, A.T.; Fuchs, C.S.; Qian, Z.R.; Ogino, S. MicroRNA MIR21 (miR-21) and PTGS2 expression in colorectal cancer and patient survival. Clin. Cancer Res.,  2016, 22(15), 3841-3848.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2173 ] [PMID:  26957558] 
[164] 
Ferrández, A.; Prescott, S.; Burt, R.W. COX-2 and colorectal cancer. Curr. Pharm. Des.,  2003, 9(27), 2229-2251.
[http://dx.doi.org/10.2174/1381612033454036] [PMID:  14529404] 
[165] 
Liu, R.; Xu, K.P.; Tan, G.S. Cyclooxygenase-2 inhibitors in lung cancer treatment: Bench to bed. Eur. J. Pharmacol.,  2015, 769, 127-133.
[http://dx.doi.org/10.1016/j.ejphar.2015.11.007] [PMID:  26548623] 
[166] 
Li, W.; Yue, W.; Wang, H.; Lai, B.; Yang, X.; Zhang, C.; Wang, Y.; Gu, M. Cyclooxygenase-2 is associated with malignant phenotypes in human lung cancer. Oncol. Lett.,  2016, 12(5), 3836-3844.
[http://dx.doi.org/10.3892/ol.2016.5207] [PMID:  27895738] 
[167] 
Maeng, H.J.; Lee, W.J.; Jin, Q.R.; Chang, J.E.; Shim, W.S. Upregulation of COX-2 in the lung cancer promotes overexpression of multidrug resistance protein 4 (MRP4) via PGE2-dependent pathway. Eur. J. Pharm. Sci.,  2014, 62, 189-196.
[http://dx.doi.org/10.1016/j.ejps.2014.05.023] [PMID:  24909729] 
[168] 
Li, J.; Lu, X.; Zou, X.; Jiang, Y.; Yao, J.; Liu, H.; Ni, B.; Ma, H. COX-2 rs5275 and rs689466 polymorphism and risk of lung cancer: A PRISMA-compliant meta-analysis. Medicine (Baltimore),  2018, 97(35)e11859
[http://dx.doi.org/10.1097/MD.0000000000011859] [PMID:  30170377] 
[169] 
Zhang, T.; Li, J.; Xia, T.; Zhang, N.; Zhang, Y.; Zhao, J. Association between COX-2 polymorphisms and non-small cell lung cancer susceptibility. Int. J. Clin. Exp. Pathol.,  2015, 8(3), 3168-3173.
[170] 
Bhat, I.A.; Rasool, R.; Qasim, I.; Masoodi, K.Z.; Paul, S.A.; Bhat, B.A.; Ganaie, F.A.; Aziz, S.A.; Shah, Z.A. COX-2 overexpression and -8473 T/C polymorphism in 3′ UTR in non-small cell lung cancer. Tumour Biol.,  2014, 35(11), 11209-11218.
[http://dx.doi.org/10.1007/s13277-014-2420-0] [PMID:  25113252] 
[171] 
Liu, L.; Zhou, F.; Ren, S.; Chen, X.; Li, X.; Li, W.; Zhou, C. Prognostic value of cyclooxygenase-2 gene polymorphisms in advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy. Asia Pac. J. Clin. Oncol.,  2016, 12(2), e339-e346.
[http://dx.doi.org/10.1111/ajco.12258] [PMID:  25131817] 
[172] 
Shimizu, K.; Yukawa, T.; Okita, R.; Saisho, S.; Maeda, A.; Nojima, Y.; Nakata, M. Cyclooxygenase-2 expression is a prognostic biomarker for non-small cell lung cancer patients treated with adjuvant platinum-based chemotherapy. World J. Surg. Oncol.,  2015, 13, 21.
[http://dx.doi.org/10.1186/s12957-014-0426-0] [PMID:  25888998] 
[173] 
Wang, W.; Fan, X.; Zhang, Y.; Yang, Y.; Yang, S.; Li, G. Association between COX-2 polymorphisms and lung cancer risk. Med. Sci. Monit.,  2015, 21, 3740-3747.
[http://dx.doi.org/10.12659/MSM.894839] [PMID:  26624903] 
[174] 
Schellhorn, M.; Haustein, M.; Frank, M.; Linnebacher, M.; Hinz, B. Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1. Oncotarget,  2015, 6(36), 39342-39356.
[http://dx.doi.org/10.18632/oncotarget.5745] [PMID:  26513172] 
[175] 
Kim, B.; Kim, J.; Kim, Y.S. Celecoxib induces cell death on non-small cell lung cancer cells through endoplasmic reticulum stress. Anat. Cell Biol.,  2017, 50(4), 293-300.
[http://dx.doi.org/10.5115/acb.2017.50.4.293] [PMID:  29354301] 
[176] 
Ren, F.; Fan, M.; Mei, J.; Wu, Y.; Liu, C.; Pu, Q.; You, Z.; Liu, L. Interferon-γ and celecoxib inhibit lung-tumor growth through modulating M2/M1 macrophage ratio in the tumor microenvironment. Drug Des. Devel. Ther.,  2014, 8, 1527-1538.
[PMID:  25284985] [http://dx.doi.org/10.2147/DDDT.S66302]] 
[177] 
Ravi Kiran Ammu, V.V.V.; Garikapati, K.K.; Krishnamurthy, P.T.; Chintamaneni, P.K.; Pindiprolu, S.K.S.S. Possible role of PPAR-γ and COX-2 receptor modulators in the treatment of Non-small cell lung carcinoma. Med. Hypotheses,  2019, 124, 98-100.
[http://dx.doi.org/10.1016/j.mehy.2019.02.024] [PMID:  30798928] 
[178] 
Sun, J.; Liu, N.B.; Zhuang, H.Q.; Zhao, L.J.; Yuan, Z.Y.; Wang, P. Celecoxib-erlotinib combination treatment enhances radiosensitivity in A549 human lung cancer cell. Cancer Biomark.,  2017, 19(1), 45-50.
[http://dx.doi.org/10.3233/CBM-160323] [PMID:  28282799] 
[179] 
Zhang, P.; He, D.; Song, E.; Jiang, M.; Song, Y. Celecoxib enhances the sensitivity of non-small-cell lung cancer cells to radiation-induced apoptosis through downregulation of the Akt/mTOR signaling pathway and COX-2 expression. PLoS One,  2019, 14(10)e0223760
[http://dx.doi.org/10.1371/journal.pone.0223760] [PMID:  31613929] 
[180] 
Sun, Y.; Dai, H.; Chen, S.; Zhang, Y.; Wu, T.; Cao, X.; Zhao, G.; Xu, A.; Wang, J.; Wu, L. Disruption of chromosomal architecture of COX2 locus sensitizes lung cancer cells to radiotherapy. Mol. Ther.,  2018, 26(10), 2456-2465.
[http://dx.doi.org/10.1016/j.ymthe.2018.08.002] [PMID:  30131302] 
[181] 
Jiang, G.B.; Fang, H.Y.; Tao, D.Y.; Chen, X.P.; Cao, F.L. COX-2 potentiates cisplatin resistance of non-small cell lung cancer cells by promoting EMT in an AKT signaling pathway-dependent manner. Eur. Rev. Med. Pharmacol. Sci.,  2019, 23(9), 3838-3846.
[http://dx.doi.org/10.26355/eurrev_201905_17811] [PMID:  31115011] 
[182] 
Deng, Q.F.; Fang, Q.Y.; Ji, X.X.; Zhou, S.W. Cyclooxygenase-2 mediates gefitinib resistance in non-small cell lung cancer through the EGFR/PI3K/AKT axis. J. Cancer,  2020, 11(12), 3667-3674.
[http://dx.doi.org/10.7150/jca.42850] [PMID:  32284763] 
[183] 
Hou, L.C.; Huang, F.; Xu, H.B. Does celecoxib improve the efficacy of chemotherapy for advanced non-small cell lung cancer? Br. J. Clin. Pharmacol.,  2016, 81(1), 23-32.
[http://dx.doi.org/10.1111/bcp.12757] [PMID:  26331772] 
[184] 
Lee, M.H.; Kachroo, P.; Pagano, P.C.; Yanagawa, J.; Wang, G.; Walser, T.C.; Krysan, K.; Sharma, S.; John, M.S.; Dubinett, S.M.; Lee, J.M. Combination treatment with apricoxib and IL-27 enhances inhibition of epithelial-mesenchymal transition in human lung cancer cells through a STAT1 dominant pathway. J. Cancer Sci. Ther.,  2014, 6(11), 468-477.
[http://dx.doi.org/10.4172/1948-5956.1000310] [PMID:  26523208] 
[185] 
Marx, N.; Duez, H.; Fruchart, J.C.; Staels, B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ. Res.,  2004, 94(9), 1168-1178.
[http://dx.doi.org/10.1161/01.RES.0000127122.22685.0A] [PMID:  15142970] 
[186] 
Berger, J.P.; Akiyama, T.E.; Meinke, P.T. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol. Sci.,  2005, 26(5), 244-251.
[http://dx.doi.org/10.1016/j.tips.2005.03.003] [PMID:  15860371] 
[187] 
Holm, L.J.; Mønsted, M.Ø.; Haupt-Jorgensen, M.; Buschard, K. PPARs and the development of type 1 diabetes. PPAR Res.,  2020, 20206198628
[http://dx.doi.org/10.1155/2020/6198628] [PMID:  32395123] 
[188] 
Han, L.; Shen, W.J.; Bittner, S.; Kraemer, F.B.; Azhar, S. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-β/δ and PPAR-γ. Future Cardiol.,  2017, 13(3), 279-296.
[http://dx.doi.org/10.2217/fca-2017-0019] [PMID:  28581362] 
[189] 
Rocha, R.M.; Barra, G.B.; Rosa, E.C.; Garcia, E.C.; Amato, A.A.; Azevedo, M.F. Prevalence of the rs1801282 single nucleotide polymorphism of the PPARG gene in patients with metabolic syndrome. Arch. Endocrinol. Metab.,  2015, 59(4), 297-302.
[http://dx.doi.org/10.1590/2359-3997000000086] [PMID:  26331316] 
[190] 
Petrosino, M.; Lori, L.; Pasquo, A.; Lori, C.; Consalvi, V.; Minicozzi, V.; Morante, S.; Laghezza, A.; Giorgi, A.; Capelli, D.; Chiaraluce, R. Single-nucleotide polymorphism of PPARγ, a protein at the crossroads of physiological and pathological processes. Int. J. Mol. Sci.,  2017, 18(2)E361
[http://dx.doi.org/10.3390/ijms18020361] [PMID:  28208577] 
[191] 
Chinetti, G.; Griglio, S.; Antonucci, M.; Torra, I.P.; Delerive, P.; Majd, Z.; Fruchart, J.C.; Chapman, J.; Najib, J.; Staels, B. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem.,  1998, 273(40), 25573-25580.
[http://dx.doi.org/10.1074/jbc.273.40.25573] [PMID:  9748221] 
[192] 
Linares, I.; Farrokhi, K.; Echeverri, J.; Kaths, J.M.; Kollmann, D.; Hamar, M.; Urbanellis, P.; Ganesh, S.; Adeyi, O.A.; Yip, P.; Selzner, M.; Selzner, N. PPAR-gamma activation is associated with reduced liver ischemia-reperfusion injury and altered tissue-resident macrophages polarization in a mouse model. PLoS One,  2018, 13(4)e0195212
[http://dx.doi.org/10.1371/journal.pone.0195212] [PMID:  29617419] 
[193] 
Tokutome, M.; Matoba, T.; Nakano, Y.; Okahara, A.; Fujiwara, M.; Koga, J.I.; Nakano, K.; Tsutsui, H.; Egashira, K. Peroxisome proliferator-activated receptor-gamma targeting nanomedicine promotes cardiac healing after acute myocardial infarction by skewing monocyte/macrophage polarization in preclinical animal models. Cardiovasc. Res.,  2019, 115(2), 419-431.
[http://dx.doi.org/10.1093/cvr/cvy200] [PMID:  30084995] 
[194] 
Wu, H-M.; Ni, X-X.; Xu, Q-Y.; Wang, Q.; Li, X-Y.; Hua, J. Regulation of lipid-induced macrophage polarization through modulating peroxisome proliferator-activated receptor-gamma activity affects hepatic lipid metabolism via a toll-like receptor 4/NF-κB signaling pathway. J. Gastroenterol. Hepatol.,  2020, 35(11), 1998-2008.
[http://dx.doi.org/10.1111/jgh.15025] [PMID:  32128893] 
[195] 
Luo, W.; Xu, Q.; Wang, Q.; Wu, H.; Hua, J. Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci. Rep.,  2017, 7, 44612.
[http://dx.doi.org/10.1038/srep44612] [PMID:  28300213] 
[196] 
Weber, K.J.; Sauer, M.; He, L.; Tycksen, E.; Kalugotla, G.; Razani, B.; Schilling, J.D. PPARγ deficiency suppresses the release of IL-1β and IL-1α in macrophages via a type 1 IFN-dependent mechanism. J. Immunol.,  2018, 201(7), 2054-2069.
[http://dx.doi.org/10.4049/jimmunol.1800224] [PMID:  30143592] 
[197] 
Zhang, T.; Shao, B.; Liu, G-A. Rosuvastatin promotes the differentiation of peripheral blood monocytes into M2 macrophages in patients with atherosclerosis by activating PPAR-γ. Eur. Rev. Med. Pharmacol. Sci.,  2017, 21(19), 4464-4471.
[198] 
Wang, Q.; Su, Y.Y.; Li, Y.Q.; Zhang, Y.F.; Yang, S.; Wang, J.L.; Li, H.Y. Atorvastatin alleviates renal ischemia-reperfusion injury in rats by promoting M1-M2 transition. Mol. Med. Rep.,  2017, 15(2), 798-804.
[http://dx.doi.org/10.3892/mmr.2016.6074] [PMID:  28035383] 
[199] 
Yuan, J.; Ge, H.; Liu, W.; Zhu, H.; Chen, Y.; Zhang, X.; Yang, Y.; Yin, Y.; Chen, W.; Wu, W.; Yang, Y.; Lin, J. M2 microglia promotes neurogenesis and oligodendrogenesis from neural stem/progenitor cells via the PPARγ signaling pathway. Oncotarget,  2017, 8(12), 19855-19865.
[http://dx.doi.org/10.18632/oncotarget.15774] [PMID:  28423639] 
[200] 
Peng, J.; Wang, K.; Xiang, W.; Li, Y.; Hao, Y.; Guan, Y. Rosiglitazone polarizes microglia and protects against pilocarpine-induced status epilepticus. CNS Neurosci. Ther.,  2019, 25(12), 1363-1372.
[http://dx.doi.org/10.1111/cns.13265] [PMID:  31729170] 
[201] 
Meng, Q.Q.; Feng, Z.C.; Zhang, X.L.; Hu, L.Q.; Wang, M.; Zhang, H.F.; Li, S.M. PPAR-γ activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome in spinal cord-derived neurons. Mediators Inflamm.,  2019, 20196386729
[http://dx.doi.org/10.1155/2019/6386729] [PMID:  31015796] 
[202] 
Hussein, H.A.; Moghimi, A.; Roohbakhsh, A. Anticonvulsant and ameliorative effects of pioglitazone on cognitive deficits, inflammation and apoptosis in the hippocampus of rat pups exposed to febrile seizure. Iran. J. Basic Med. Sci.,  2019, 22(3), 267-276.
[http://dx.doi.org/10.22038/IJBMS.2019.35056.8339] [PMID:  31156787] 
[203] 
He, J.; Liu, H.; Zhong, J.; Guo, Z.; Wu, J.; Zhang, H.; Huang, Z.; Jiang, L.; Li, H.; Zhang, Z.; Liu, L.; Wu, Y.; Qi, L.; Sun, X.; Cheng, C. Bexarotene protects against neurotoxicity partially through a PPARγ-dependent mechanism in mice following traumatic brain injury. Neurobiol. Dis.,  2018, 117, 114-124.
[http://dx.doi.org/10.1016/j.nbd.2018.06.003] [PMID:  29886067] 
[204] 
Kinouchi, T.; Kitazato, K.T.; Shimada, K.; Yagi, K.; Tada, Y.; Matsushita, N.; Kurashiki, Y.; Satomi, J.; Sata, M.; Nagahiro, S. Treatment with the PPARγ agonist pioglitazone in the early post-ischemia phase inhibits pro-inflammatory responses and promotes neurogenesis via the activation of innate- and bone marrow-derived stem cells in rats. Transl. Stroke Res.,  2018, 9(3), 306-316.
[http://dx.doi.org/10.1007/s12975-017-0577-8] [PMID:  29110250] 
[205] 
Liu, R.; Diao, J.; He, S.; Li, B.; Fei, Y.; Li, Y.; Fang, W. XQ-1H protects against ischemic stroke by regulating microglia polarization through PPARγ pathway in mice. Int. Immunopharmacol.,  2018, 57, 72-81.
[http://dx.doi.org/10.1016/j.intimp.2018.02.014] [PMID:  29475098] 
[206] 
Bonato, J.M.; Bassani, T.B.; Milani, H.; Vital, M.A.B.F.; de Oliveira, R.M.W. Pioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson’s disease in rats. Exp. Neurol.,  2018, 300, 188-200.
[http://dx.doi.org/10.1016/j.expneurol.2017.11.009] [PMID:  29162435] 
[207] 
Yang, X.; Wang, X.; Liu, D.; Yu, L.; Xue, B.; Shi, H. Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Mol. Endocrinol.,  2014, 28(4), 565-574.
[http://dx.doi.org/10.1210/me.2013-1293] [PMID:  24597547] 
[208] 
Wang, X.; Cao, Q.; Yu, L.; Shi, H.; Xue, B.; Shi, H. Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity. JCI Insight,  2016, 1(19)e87748
[http://dx.doi.org/10.1172/jci.insight.87748] [PMID:  27882346] 
[209] 
Bassaganya-Riera, J.; Misyak, S.; Guri, A.J.; Hontecillas, R. PPAR gamma is highly expressed in F4/80(hi) adipose tissue macrophages and dampens adipose-tissue inflammation. Cell. Immunol.,  2009, 258(2), 138-146.
[http://dx.doi.org/10.1016/j.cellimm.2009.04.003] [PMID:  19423085] 
[210] 
Odegaard, J.I.; Ricardo-Gonzalez, R.R.; Goforth, M.H.; Morel, C.R.; Subramanian, V.; Mukundan, L.; Red Eagle, A.; Vats, D.; Brombacher, F.; Ferrante, A.W.; Chawla, A. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature,  2007, 447(7148), 1116-1120.
[http://dx.doi.org/10.1038/nature05894] [PMID:  17515919] 
[211] 
Dai, L.; Bhargava, P.; Stanya, K.J.; Alexander, R.K.; Liou, Y.H.; Jacobi, D.; Knudsen, N.H.; Hyde, A.; Gangl, M.R.; Liu, S.; Lee, C.H. Macrophage alternative activation confers protection against lipotoxicity-induced cell death. Mol. Metab.,  2017, 6(10), 1186-1197.
[http://dx.doi.org/10.1016/j.molmet.2017.08.001] [PMID:  29031719] 
[212] 
Ruffino, J.S.; Davies, N.A.; Morris, K.; Ludgate, M.; Zhang, L.; Webb, R.; Thomas, A.W. Moderate-intensity exercise alters markers of alternative activation in circulating monocytes in females: a putative role for PPARγ. Eur. J. Appl. Physiol.,  2016, 116(9), 1671-1682.
[http://dx.doi.org/10.1007/s00421-016-3414-y] [PMID:  27339155] 
[213] 
Ricote, M.; Li, A.C.; Willson, T.M.; Kelly, C.J.; Glass, C.K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature,  1998, 391(6662), 79-82.
[http://dx.doi.org/10.1038/34178] [PMID:  9422508] 
[214] 
Kumar, D.; Goand, U.K.; Gupta, S.; Shankar, K.; Varshney, S.; Rajan, S.; Srivastava, A.; Gupta, A.; Vishwakarma, A.L.; Srivastava, A.K.; Gaikwad, A.N. Saroglitazar reduces obesity and associated inflammatory consequences in murine adipose tissue. Eur. J. Pharmacol.,  2018, 822, 32-42.
[http://dx.doi.org/10.1016/j.ejphar.2018.01.002] [PMID:  29331565] 
[215] 
Stienstra, R.; Duval, C.; Keshtkar, S.; van der Laak, J.; Kersten, S.; Müller, M. Peroxisome proliferator-activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue. J. Biol. Chem.,  2008, 283(33), 22620-22627.
[http://dx.doi.org/10.1074/jbc.M710314200] [PMID:  18541527] 
[216] 
Chatterjee, T.K.; Stoll, L.L.; Denning, G.M.; Harrelson, A.; Blomkalns, A.L.; Idelman, G.; Rothenberg, F.G.; Neltner, B.; Romig-Martin, S.A.; Dickson, E.W.; Rudich, S.; Weintraub, N.L. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ. Res.,  2009, 104(4), 541-549.
[http://dx.doi.org/10.1161/CIRCRESAHA.108.182998] [PMID:  19122178] 
[217] 
Rafeh, R.; Viveiros, A.; Oudit, G.Y.; El-Yazbi, A.F. Targeting perivascular and epicardial adipose tissue inflammation: therapeutic opportunities for cardiovascular disease. Clin. Sci. (Lond.),  2020, 134(7), 827-851.
[http://dx.doi.org/10.1042/CS20190227] [PMID:  32271386] 
[218] 
Chang, L.; Zhao, X.; Garcia-Barrio, M.; Zhang, J.; Eugene Chen, Y. MitoNEET in perivascular adipose tissue prevents arterial stiffness in aging mice. Cardiovasc. Drugs Ther.,  2018, 32(5), 531-539.
[http://dx.doi.org/10.1007/s10557-018-6809-7] [PMID:  30022354] 
[219] 
De Silva, T.M.; Li, Y.; Kinzenbaw, D.A.; Sigmund, C.D.; Faraci, F.M. Endothelial PPARγ (peroxisome proliferator-activated receptor-γ) is essential for preventing endothelial dysfunction with aging. Hypertension,  2018, 72(1), 227-234.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10799] [PMID:  29735632] 
[220] 
Zhang, Y.; Zhang, C.; Li, H.; Hou, J. Down-regulation of vascular PPAR-γ contributes to endothelial dysfunction in high-fat diet-induced obese mice exposed to chronic intermittent hypoxia. Biochem. Biophys. Res. Commun.,  2017, 492(2), 243-248.
[http://dx.doi.org/10.1016/j.bbrc.2017.08.058] [PMID:  28822761] 
[221] 
Mukohda, M.; Stump, M.; Ketsawatsomkron, P.; Hu, C.; Quelle, F.W.; Sigmund, C.D. Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress. Am. J. Physiol. Heart Circ. Physiol.,  2016, 310(1), H39-H48.
[http://dx.doi.org/10.1152/ajpheart.00490.2015] [PMID:  26566726] 
[222] 
Martens, F.M.; Rabelink, T.J. op ’t Roodt, J.; de Koning, E.J.; Visseren, F.L. TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone. Eur. Heart J.,  2006, 27(13), 1605-1609.
[http://dx.doi.org/10.1093/eurheartj/ehl079] [PMID:  16762982] 
[223] 
Zhang, Y.; Zhan, R.X.; Chen, J.Q.; Gao, Y.; Chen, L.; Kong, Y.; Zhong, X.J.; Liu, M.Q.; Chu, J.J.; Yan, G.Q.; Li, T.; He, M.; Huang, Q.R. Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway. Eur. J. Pharmacol.,  2015, 754, 41-51.
[http://dx.doi.org/10.1016/j.ejphar.2015.02.004] [PMID:  25687252] 
[224] 
Chen, C.; Peng, S.; Chen, F.; Liu, L.; Li, Z.; Zeng, G.; Huang, Q. Protective effects of pioglitazone on vascular endothelial cell dysfunction induced by high glucose via inhibition of IKKα/β-NFκB signaling mediated by PPARγ in vitro. Can. J. Physiol. Pharmacol.,  2017, 95(12), 1480-1487.
[http://dx.doi.org/10.1139/cjpp-2016-0574] [PMID:  28787583] 
[225] 
Ji, X.X.; Ji, X.J.; Li, Q.Q.; Lu, X.X.; Luo, L. Rosiglitazone reduces apoptosis and inflammation in lipopolysaccharide-induced human umbilical vein endothelial cells. Med. Sci. Monit.,  2018, 24, 6200-6207.
[http://dx.doi.org/10.12659/MSM.910036] [PMID:  30185768] 
[226] 
Rudnicki, M.; Tripodi, G.L.; Ferrer, R.; Boscá, L.; Pitta, M.G.; Pitta, I.R.; Abdalla, D.S. New thiazolidinediones affect endothelial cell activation and angiogenesis. Eur. J. Pharmacol.,  2016, 782, 98-106.
[http://dx.doi.org/10.1016/j.ejphar.2016.04.038] [PMID:  27108791] 
[227] 
D’Souza, A.; Hussain, M.; Howarth, F.C.; Woods, N.M.; Bidasee, K.; Singh, J. Pathogenesis and pathophysiology of accelerated atherosclerosis in the diabetic heart. Mol. Cell. Biochem.,  2009, 331(1-2), 89-116.
[http://dx.doi.org/10.1007/s11010-009-0148-8] [PMID:  19466528] 
[228] 
Kleinhenz, J.M.; Murphy, T.C.; Pokutta-Paskaleva, A.P.; Gleason, R.L.; Lyle, A.N.; Taylor, W.R.; Blount, M.A.; Cheng, J.; Yang, Q.; Sutliff, R.L.; Hart, C.M. Smooth muscle-targeted overexpression of peroxisome proliferator activated receptor-γ disrupts vascular wall structure and function. PLoS One,  2015, 10(10)e0139756
[http://dx.doi.org/10.1371/journal.pone.0139756] [PMID:  26451838] 
[229] 
Law, R.E.; Goetze, S.; Xi, X.P.; Jackson, S.; Kawano, Y.; Demer, L.; Fishbein, M.C.; Meehan, W.P.; Hsueh, W.A. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation,  2000, 101(11), 1311-1318.
[http://dx.doi.org/10.1161/01.CIR.101.11.1311] [PMID:  10725292] 
[230] 
Marx, N.; Schönbeck, U.; Lazar, M.A.; Libby, P.; Plutzky, J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ. Res.,  1998, 83(11), 1097-1103.
[http://dx.doi.org/10.1161/01.RES.83.11.1097] [PMID:  9831704] 
[231] 
Wakino, S.; Kintscher, U.; Kim, S.; Yin, F.; Hsueh, W.A.; Law, R.E. Peroxisome proliferator-activated receptor gamma ligands inhibit retinoblastoma phosphorylation and G1--> S transition in vascular smooth muscle cells. J. Biol. Chem.,  2000, 275(29), 22435-22441.
[http://dx.doi.org/10.1074/jbc.M910452199] [PMID:  10801895] 
[232] 
Goetze, S.; Kintscher, U.; Kim, S.; Meehan, W.P.; Kaneshiro, K.; Collins, A.R.; Fleck, E.; Hsueh, W.A.; Law, R.E. Peroxisome proliferator-activated receptor-gamma ligands inhibit nuclear but not cytosolic extracellular signal-regulated kinase/mitogen-activated protein kinase-regulated steps in vascular smooth muscle cell migration. J. Cardiovasc. Pharmacol.,  2001, 38(6), 909-921.
[http://dx.doi.org/10.1097/00005344-200112000-00013] [PMID:  11707695] 
[233] 
Lim, S.; Lee, K.S.; Lee, J.E.; Park, H.S.; Kim, K.M.; Moon, J.H.; Choi, S.H.; Park, K.S.; Kim, Y.B.; Jang, H.C. Effect of a new PPAR-gamma agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis. Atherosclerosis,  2015, 243(1), 107-119.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.08.037] [PMID:  26363808] 
[234] 
Gao, H.; Li, H.; Li, W.; Shen, X.; Di, B. Pioglitazone attenuates atherosclerosis in diabetic mice by inhibition of receptor for advanced glycation end-product (RAGE) signaling. Med. Sci. Monit.,  2017, 23, 6121-6131.
[http://dx.doi.org/10.12659/MSM.907401] [PMID:  29278639] 
[235] 
Shen, D.; Li, H.; Zhou, R.; Liu, M.J.; Yu, H.; Wu, D.F. Pioglitazone attenuates aging-related disorders in aged apolipoprotein E deficient mice. Exp. Gerontol.,  2018, 102, 101-108.
[http://dx.doi.org/10.1016/j.exger.2017.12.002] [PMID:  29221940] 
[236] 
Yamamoto, S.; Zhong, J.; Yancey, P.G.; Zuo, Y.; Linton, M.F.; Fazio, S.; Yang, H.; Narita, I.; Kon, V. Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype. Atherosclerosis,  2015, 242(1), 56-64.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.06.055] [PMID:  26184694] 
[237] 
Ricote, M.; Huang, J.; Fajas, L.; Li, A.; Welch, J.; Najib, J.; Witztum, J.L.; Auwerx, J.; Palinski, W.; Glass, C.K. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc. Natl. Acad. Sci. USA,  1998, 95(13), 7614-7619.
[http://dx.doi.org/10.1073/pnas.95.13.7614] [PMID:  9636198] 
[238] 
Marx, N.; Sukhova, G.; Murphy, C.; Libby, P.; Plutzky, J. Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am. J. Pathol.,  1998, 153(1), 17-23.
[http://dx.doi.org/10.1016/S0002-9440(10)65540-X] [PMID:  9665460] 
[239] 
Huang, J.V.; Greyson, C.R.; Schwartz, G.G. PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty. J. Lipid Res.,  2012, 53(9), 1738-1754.
[http://dx.doi.org/10.1194/jlr.R024505] [PMID:  22685322] 
[240] 
Zhao, D.; Zhu, Z.; Li, D.; Xu, R.; Wang, T.; Liu, K. Pioglitazone suppresses CXCR7 expression to inhibit human macrophage chemotaxis through peroxisome proliferator-activated receptor γ. Biochemistry,  2015, 54(45), 6806-6814.
[http://dx.doi.org/10.1021/acs.biochem.5b00847] [PMID:  26507929] 
[241] 
Yu, J.; Qiu, Y.; Yang, J.; Bian, S.; Chen, G.; Deng, M.; Kang, H.; Huang, L. DNMT1-PPARγ pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice. Sci. Rep.,  2016, 6, 30053.
[http://dx.doi.org/10.1038/srep30053] [PMID:  27530451] 
[242] 
Tontonoz, P.; Nagy, L.; Alvarez, J.G.; Thomazy, V.A.; Evans, R.M. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell,  1998, 93(2), 241-252.
[http://dx.doi.org/10.1016/S0092-8674(00)81575-5] [PMID:  9568716] 
[243] 
Chawla, A.; Barak, Y.; Nagy, L.; Liao, D.; Tontonoz, P.; Evans, R.M. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat. Med.,  2001, 7(1), 48-52.
[http://dx.doi.org/10.1038/83336] [PMID:  11135615] 
[244] 
Chawla, A.; Boisvert, W.A.; Lee, C.H.; Laffitte, B.A.; Barak, Y.; Joseph, S.B.; Liao, D.; Nagy, L.; Edwards, P.A.; Curtiss, L.K.; Evans, R.M.; Tontonoz, P. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell,  2001, 7(1), 161-171.
[http://dx.doi.org/10.1016/S1097-2765(01)00164-2] [PMID:  11172721] 
[245] 
Chinetti, G.; Lestavel, S.; Bocher, V.; Remaley, A.T.; Neve, B.; Torra, I.P.; Teissier, E.; Minnich, A.; Jaye, M.; Duverger, N.; Brewer, H.B.; Fruchart, J.C.; Clavey, V.; Staels, B. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat. Med.,  2001, 7(1), 53-58.
[http://dx.doi.org/10.1038/83348] [PMID:  11135616] 
[246] 
Leonardini, A.; Laviola, L.; Perrini, S.; Natalicchio, A.; Giorgino, F. Cross-talk between PPARgamma and insulin signaling and modulation of insulin sensitivity. PPAR Res.,  2009, 2009818945
[http://dx.doi.org/10.1155/2009/818945] [PMID:  20182551] 
[247] 
Boughanem, H.; Cabrera-Mulero, A.; Millán-Gómez, M.; Garrido-Sánchez, L.; Cardona, F.; Tinahones, F.J.; Moreno-Santos, I.; Macías-González, M. Transcriptional analysis of FOXO1, C/EBP-α and PPAR-γ2 genes and their association with obesity-related insulin resistance. Genes (Basel),  2019, 10(9)E706
[http://dx.doi.org/10.3390/genes10090706] [PMID:  31547433] 
[248] 
Sugii, S.; Olson, P.; Sears, D.D.; Saberi, M.; Atkins, A.R.; Barish, G.D.; Hong, S.H.; Castro, G.L.; Yin, Y.Q.; Nelson, M.C.; Hsiao, G.; Greaves, D.R.; Downes, M.; Yu, R.T.; Olefsky, J.M.; Evans, R.M. PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization. Proc. Natl. Acad. Sci. USA,  2009, 106(52), 22504-22509.
[http://dx.doi.org/10.1073/pnas.0912487106] [PMID:  20018750] 
[249] 
Xu, L.; Ma, X.; Verma, N.K.; Wang, D.; Gavrilova, O.; Proia, R.L.; Finkel, T.; Mueller, E. Ablation of PPARγ in subcutaneous fat exacerbates age-associated obesity and metabolic decline. Aging Cell,  2018, 17(2)e12721
[http://dx.doi.org/10.1111/acel.12721] [PMID:  29383825] 
[250] 
Soccio, R.E.; Li, Z.; Chen, E.R.; Foong, Y.H.; Benson, K.K.; Dispirito, J.R.; Mullican, S.E.; Emmett, M.J.; Briggs, E.R.; Peed, L.C.; Dzeng, R.K.; Medina, C.J.; Jolivert, J.F.; Kissig, M.; Rajapurkar, S.R.; Damle, M.; Lim, H.W.; Won, K.J.; Seale, P.; Steger, D.J.; Lazar, M.A. Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice. J. Clin. Invest.,  2017, 127(4), 1451-1462.
[http://dx.doi.org/10.1172/JCI91211] [PMID:  28240605] 
[251] 
Mustafa, H.A.; Albkrye, A.M.S. AbdAlla, B.M.; Khair, M.A.M.; Abdelwahid, N.; Elnasri, H.A. Computational determination of human PPARG gene: SNPs and prediction of their effect on protein functions of diabetic patients. Clin. Transl. Med.,  2020, 9(1), 7.
[http://dx.doi.org/10.1186/s40169-020-0258-1] [PMID:  32064572] 
[252] 
Wang, Y.; Wang, X.H.; Li, R-X. Interaction between peroxisome proliferator- activated receptor gamma polymorphism and overweight on diabetic retinopathy in a Chinese case-control study. Int. J. Clin. Exp. Med.,  2015, 8(11), 21647-21652.
[253] 
Ding, J.; Zhu, C.; Mei, X.; Zhou, Y.; Feng, B.; Guo, Z. Peroxisome proliferator-activated receptor γ Pro12Ala polymorphism decrease the risk of diabetic nephropathy in type 2 diabetes: a meta-analysis. Int. J. Clin. Exp. Med.,  2015, 8(5), 7655-7660.
[254] 
Calkin, A.C.; Giunti, S.; Jandeleit-Dahm, K.A.; Allen, T.J.; Cooper, M.E.; Thomas, M.C. PPAR-alpha and -gamma agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse. Nephrol. Dial. Transplant.,  2006, 21(9), 2399-2405.
[http://dx.doi.org/10.1093/ndt/gfl212] [PMID:  16720596] 
[255] 
Pistrosch, F.; Passauer, J.; Herbrig, K.; Schwanebeck, U.; Gross, P.; Bornstein, S.R. Effect of thiazolidinedione treatment on proteinuria and renal hemodynamic in type 2 diabetic patients with overt nephropathy. Horm. Metab. Res.,  2012, 44(12), 914-918.
[http://dx.doi.org/10.1055/s-0032-1314836] [PMID:  22723267] 
[256] 
Miyazaki, Y.; Cersosimo, E.; Triplitt, C.; DeFronzo, R.A. Rosiglitazone decreases albuminuria in type 2 diabetic patients. Kidney Int.,  2007, 72(11), 1367-1373.
[http://dx.doi.org/10.1038/sj.ki.5002516] [PMID:  17805239] 
[257] 
Badeau, R.M.; Honka, M.J.; Lautamäki, R.; Stewart, M.; Kangas, A.J.; Soininen, P.; Ala-Korpela, M.; Nuutila, P. Systemic metabolic markers and myocardial glucose uptake in type 2 diabetic and coronary artery disease patients treated for 16 weeks with rosiglitazone, a PPARγ agonist. Ann. Med.,  2014, 46(1), 18-23.
[http://dx.doi.org/10.3109/07853890.2013.853369] [PMID:  24266715] 
[258] 
Dormandy, J.A.; Charbonnel, B.; Eckland, D.J.; Erdmann, E.; Massi-Benedetti, M.; Moules, I.K.; Skene, A.M.; Tan, M.H.; Lefèbvre, P.J.; Murray, G.D.; Standl, E.; Wilcox, R.G.; Wilhelmsen, L.; Betteridge, J.; Birkeland, K.; Golay, A.; Heine, R.J.; Korányi, L.; Laakso, M.; Mokán, M.; Norkus, A.; Pirags, V.; Podar, T.; Scheen, A.; Scherbaum, W.; Schernthaner, G.; Schmitz, O.; Skrha, J.; Smith, U.; Taton, J.; Investigators, P.R. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitazone clinical trial in macrovascular events): a randomised controlled trial. Lancet,  2005, 366(9493), 1279-1289.
[http://dx.doi.org/10.1016/S0140-6736(05)67528-9] [PMID:  16214598] 
[259] 
Tawfik, A.; Sanders, T.; Kahook, K.; Akeel, S.; Elmarakby, A.; Al-Shabrawey, M. Suppression of retinal peroxisome proliferator-activated receptor gamma in experimental diabetes and oxygen-induced retinopathy: role of NADPH oxidase. Invest. Ophthalmol. Vis. Sci.,  2009, 50(2), 878-884.
[http://dx.doi.org/10.1167/iovs.08-2005] [PMID:  18806296] 
[260] 
Costa, V.; Ciccodicola, A. Is PPARG the key gene in diabetic retinopathy? Br. J. Pharmacol.,  2012, 165(1), 1-3.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01443.x] [PMID:  21501146] 
[261] 
Mirza, R.E.; Fang, M.M.; Novak, M.L.; Urao, N.; Sui, A.; Ennis, W.J.; Koh, T.J. Macrophage PPARγ and impaired wound healing in type 2 diabetes. J. Pathol.,  2015, 236(4), 433-444.
[http://dx.doi.org/10.1002/path.4548] [PMID:  25875529] 
[262] 
Yu, T.; Gao, M.; Yang, P.; Liu, D.; Wang, D.; Song, F.; Zhang, X.; Liu, Y. Insulin promotes macrophage phenotype transition through PI3K/Akt and PPAR-γ signaling during diabetic wound healing. J. Cell. Physiol.,  2019, 234(4), 4217-4231.
[http://dx.doi.org/10.1002/jcp.27185] [PMID:  30132863] 
[263] 
Siebert, A.; Goren, I.; Pfeilschifter, J.; Frank, S. Anti-inflammatory effects of rosiglitazone in obesity-impaired wound healing depend on adipocyte differentiation. PLoS One,  2016, 11(12)e0168562
[http://dx.doi.org/10.1371/journal.pone.0168562] [PMID:  27992530] 
[264] 
Chiang, M.C.; Cheng, Y.C.; Nicol, C.J.; Lin, C.H. The neuroprotective role of rosiglitazone in advanced glycation end product treated human neural stem cells is PPARgamma-dependent. Int. J. Biochem. Cell Biol.,  2017, 92, 121-133.
[http://dx.doi.org/10.1016/j.biocel.2017.09.020] [PMID:  28964868] 
[265] 
Yan, X.L.; Wang, Y.Y.; Yu, Z.F.; Tian, M.M.; Li, H. Peroxisome proliferator-activated receptor-gamma activation attenuates diabetic cardiomyopathy via regulation of the TGF-β/ERK pathway and epithelial-to-mesenchymal transition. Life Sci.,  2018, 213, 269-278.
[http://dx.doi.org/10.1016/j.lfs.2018.09.004] [PMID:  30189217] 
[266] 
Yousefnia, S.; Momenzadeh, S.; Seyed Forootan, F.; Ghaedi, K.; Nasr Esfahani, M.H. The influence of peroxisome proliferator-activated receptor γ (PPARγ) ligands on cancer cell tumorigenicity. Gene,  2018, 649, 14-22.
[http://dx.doi.org/10.1016/j.gene.2018.01.018] [PMID:  29369787] 
[267] 
Fröhlich, E.; Wahl, R. Chemotherapy and chemoprevention by thiazolidinediones. BioMed Res. Int.,  2015, 2015845340
[http://dx.doi.org/10.1155/2015/845340] [PMID:  25866814] 
[268] 
Salgia, M.M.; Elix, C.C.; Pal, S.K.; Jones, J.O. Different roles of peroxisome proliferator-activated receptor gamma isoforms in prostate cancer. Am. J. Clin. Exp. Urol.,  2019, 7(3), 98-109.
[269] 
Olokpa, E.; Moss, P.E.; Stewart, L.V. Crosstalk between the androgen receptor and PPAR gamma signaling pathways in the prostate. PPAR Res.,  2017, 20179456020
[http://dx.doi.org/10.1155/2017/9456020] [PMID:  29181019] 
[270] 
Olokpa, E.; Bolden, A.; Stewart, L.V. The androgen receptor regulates PPARγ expression and activity in human prostate cancer cells. J. Cell. Physiol.,  2016, 231(12), 2664-2672.
[http://dx.doi.org/10.1002/jcp.25368] [PMID:  26945682] 
[271] 
Sikka, S.; Chen, L.; Sethi, G.; Kumar, A.P. Targeting PPARγ signaling cascade for the prevention and treatment of prostate cancer. PPAR Res.,  2012, 2012968040
[http://dx.doi.org/10.1155/2012/968040] [PMID:  23213321] 
[272] 
Ban, J.O.; Oh, J.H.; Son, S.M.; Won, D.; Song, H.S.; Han, S.B.; Moon, D.C.; Kang, K.W.; Song, M.J.; Hong, J.T. Troglitazone, a PPAR agonist, inhibits human prostate cancer cell growth through inactivation of NFκB via suppression of GSK-3β expression. Cancer Biol. Ther.,  2011, 12(4), 288-296.
[http://dx.doi.org/10.4161/cbt.12.4.15961] [PMID:  21613824] 
[273] 
Suzuki, S.; Mori, Y.; Nagano, A.; Naiki-Ito, A.; Kato, H.; Nagayasu, Y.; Kobayashi, M.; Kuno, T.; Takahashi, S. Pioglitazone, a peroxisome proliferator-activated receptor γ agonist, suppresses rat prostate carcinogenesis. Int. J. Mol. Sci.,  2016, 17(12)E2071
[http://dx.doi.org/10.3390/ijms17122071] [PMID:  27973395] 
[274] 
Qin, L.; Gong, C.; Chen, A.M.; Guo, F.J.; Xu, F.; Ren, Y.; Liao, H. Peroxisome proliferator activated receptor γ agonist rosiglitazone inhibits migration and invasion of prostate cancer cells through inhibition of the CXCR4/CXCL12 axis. Mol. Med. Rep.,  2014, 10(2), 695-700.
[http://dx.doi.org/10.3892/mmr.2014.2232] [PMID:  24842333] 
[275] 
Mansour, M.; Schwartz, D.; Judd, R.; Akingbemi, B.; Braden, T.; Morrison, E.; Dennis, J.; Bartol, F.; Hazi, A.; Napier, I.; Abdel-Mageed, A.B. Thiazolidinediones/PPARγ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer. Int. J. Oncol.,  2011, 38(2), 537-546.
[http://dx.doi.org/10.3892/ijo.2010.877] [PMID:  21170507] 
[276] 
Sarraf, P.; Mueller, E.; Smith, W.M.; Wright, H.M.; Kum, J.B.; Aaltonen, L.A.; de la Chapelle, A.; Spiegelman, B.M.; Eng, C. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol. Cell,  1999, 3(6), 799-804.
[http://dx.doi.org/10.1016/S1097-2765(01)80012-5] [PMID:  10394368] 
[277] 
Liang, X.; Fan, X.; Tan, K.; Zhang, L.; Jian, L.; Yu, L. Peroxisome proliferators-activated receptor gamma polymorphisms and colorectal cancer risk. J. Cancer Res. Ther.,  2018, 14(Suppl.), S306-S310.
[http://dx.doi.org/10.4103/0973-1482.235346] [PMID:  29970681] 
[278] 
Motawi, T.K.; Shaker, O.G.; Ismail, M.F.; Sayed, N.H. Peroxisome proliferator-activated receptor gamma in obesity and colorectal cancer: the role of epigenetics. Sci. Rep.,  2017, 7(1), 10714.
[http://dx.doi.org/10.1038/s41598-017-11180-6] [PMID:  28878369] 
[279] 
Dou, X.; Xiao, J.; Jin, Z.; Zheng, P. Peroxisome proliferator-activated receptor-γ is downregulated in ulcerative colitis and is involved in experimental colitis-associated neoplasia. Oncol. Lett.,  2015, 10(3), 1259-1266.
[http://dx.doi.org/10.3892/ol.2015.3397] [PMID:  26622660] 
[280] 
Tsukahara, T.; Haniu, H. Peroxisome proliferator-activated receptor gamma overexpression suppresses proliferation of human colon cancer cells. Biochem. Biophys. Res. Commun.,  2012, 424(3), 524-529.
[http://dx.doi.org/10.1016/j.bbrc.2012.06.149] [PMID:  22771328] 
[281] 
Ban, J.O.; Kwak, D.H.; Oh, J.H.; Park, E.J.; Cho, M.C.; Song, H.S.; Song, M.J.; Han, S.B.; Moon, D.C.; Kang, K.W.; Hong, J.T. Suppression of NF-kappaB and GSK-3beta is involved in colon cancer cell growth inhibition by the PPAR agonist troglitazone. Chem. Biol. Interact.,  2010, 188(1), 75-85.
[http://dx.doi.org/10.1016/j.cbi.2010.06.001] [PMID:  20540935] 
[282] 
Yoon, J.K.; Byeon, H.E.; Ko, S.A.; Park, B.N.; An, Y.S.; Lee, H.Y.; Lee, Y.W.; Lee, S.J. Cell cycle synchronisation using thiazolidinediones affects cellular glucose metabolism and enhances the therapeutic effect of 2-deoxyglucose in colon cancer. Sci. Rep.,  2020, 10(1), 4713.
[http://dx.doi.org/10.1038/s41598-020-61661-4] [PMID:  32170185] 
[283] 
Lau, M.F.; Chua, K-H.; Sabaratnam, V.; Kuppusamy, U.R. Rosiglitazone enhances the apoptotic effect of 5-fluorouracil in colorectal cancer cells with high-glucose-induced glutathione. Sci. Prog.,  2020, 103(1)36850419886448
[http://dx.doi.org/10.1177/0036850419886448] [PMID:  31795844] 
[284] 
Lau, M-F.; Vellasamy, S.; Chua, K-H.; Sabaratnam, V.; Kuppusamy, U.R. Rosiglitazone diminishes the high-glucose-induced modulation of 5-fluorouracil cytotoxicity in colorectal cancer cells. EXCLI J.,  2018, 17, 186-199.
[http://dx.doi.org/10.17179/excli2018-1011] [PMID:  29743857] 
[285] 
Park, H.; Ko, S.H.; Lee, J.M.; Park, J.H.; Choi, Y.H. Troglitazone enhances the apoptotic response of DLD-1 colon cancer cells to photodynamic therapy. Yonsei Med. J.,  2016, 57(6), 1494-1499.
[http://dx.doi.org/10.3349/ymj.2016.57.6.1494] [PMID:  27593880] 
[286] 
Aires, V.; Brassart, B.; Carlier, A.; Scagliarini, A.; Mandard, S.; Limagne, E.; Solary, E.; Martiny, L.; Tarpin, M.; Delmas, D. A role for peroxisome proliferator-activated receptor gamma in resveratrol-induced colon cancer cell apoptosis. Mol. Nutr. Food Res.,  2014, 58(9), 1785-1794.
[http://dx.doi.org/10.1002/mnfr.201300962] [PMID:  24975132] 
[287] 
Sabatino, L.; Pancione, M.; Votino, C.; Colangelo, T.; Lupo, A.; Novellino, E.; Lavecchia, A.; Colantuoni, V. Emerging role of the β-catenin-PPARγ axis in the pathogenesis of colorectal cancer. World J. Gastroenterol.,  2014, 20(23), 7137-7151.
[http://dx.doi.org/10.3748/wjg.v20.i23.7137] [PMID:  24966585] 
[288] 
Lecarpentier, Y.; Claes, V.; Vallée, A.; Hébert, J.L. Interactions between PPAR gamma and the canonical Wnt/Beta-catenin pathway in type 2 diabetes and colon cancer. PPAR Res.,  2017, 20175879090
[http://dx.doi.org/10.1155/2017/5879090] [PMID:  28298922] 
[289] 
Reka, A.K.; Goswami, M.T.; Krishnapuram, R.; Standiford, T.J.; Keshamouni, V.G. Molecular cross-regulation between PPAR-γ and other signaling pathways: implications for lung cancer therapy. Lung Cancer,  2011, 72(2), 154-159.
[http://dx.doi.org/10.1016/j.lungcan.2011.01.019] [PMID:  21354647] 
[290] 
He, X.; Zhang, M.; Chen, Z.; You, Y.; Tian, L.; Zou, P. Zhongguo Fei Ai Za Zhi,  2006, 9(1), 35-39. [Expression of PPAR-γ and its apoptotic significance in lung cancer
[http://dx.doi.org/10.3779/j.issn.1009-3419.2006.01.10] [PMID:  21144279] 
[291] 
Reddy, R.C.; Srirangam, A.; Reddy, K.; Chen, J.; Gangireddy, S.; Kalemkerian, G.P.; Standiford, T.J.; Keshamouni, V.G. Chemotherapeutic drugs induce PPAR-gamma expression and show sequence-specific synergy with PPAR-gamma ligands in inhibition of non-small cell lung cancer. Neoplasia,  2008, 10(6), 597-603.
[http://dx.doi.org/10.1593/neo.08134] [PMID:  18516296] 
[292] 
Khandekar, M.J.; Banks, A.S.; Laznik-Bogoslavski, D.; White, J.P.; Choi, J.H.; Kazak, L.; Lo, J.C.; Cohen, P.; Wong, K.K.; Kamenecka, T.M.; Griffin, P.R.; Spiegelman, B.M. Noncanonical agonist PPARγ ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy. Proc. Natl. Acad. Sci. USA,  2018, 115(3), 561-566.
[http://dx.doi.org/10.1073/pnas.1717776115] [PMID:  29295932] 
[293] 
Yan, K.H.; Yao, C.J.; Chang, H.Y.; Lai, G.M.; Cheng, A.L.; Chuang, S.E. The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells. Mol. Carcinog.,  2010, 49(3), 235-246.
[http://dx.doi.org/10.1002/mc.20593] [PMID:  19908241] 
[294] 
To, K.K.W.; Wu, W.K.K.; Loong, H.H.F. PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors by inducing autophagy. Eur. J. Pharmacol.,  2018, 823, 19-26.
[http://dx.doi.org/10.1016/j.ejphar.2018.01.036] [PMID:  29378193] 
[295] 
Ni, J.; Zhou, L.L.; Ding, L.; Zhao, X.; Cao, H.; Fan, F.; Li, H.; Lou, R.; Du, Y.; Dong, S.; Liu, S.; Wang, Z.; Ma, R.; Wu, J.; Feng, J. PPARγ agonist efatutazone and gefitinib synergistically inhibit the proliferation of EGFR-TKI-resistant lung adenocarcinoma cells via the PPARγ/PTEN/Akt pathway. Exp. Cell Res.,  2017, 361(2), 246-256.
[http://dx.doi.org/10.1016/j.yexcr.2017.10.024] [PMID:  29080795] 
[296] 
Srivastava, N.; Kollipara, R.K.; Singh, D.K.; Sudderth, J.; Hu, Z.; Nguyen, H.; Wang, S.; Humphries, C.G.; Carstens, R.; Huffman, K.E.; DeBerardinis, R.J.; Kittler, R. Inhibition of cancer cell proliferation by PPARγ is mediated by a metabolic switch that increases reactive oxygen species levels. Cell Metab.,  2014, 20(4), 650-661.
[http://dx.doi.org/10.1016/j.cmet.2014.08.003] [PMID:  25264247] 
[297] 
Giaginis, C.; Politi, E.; Alexandrou, P.; Sfiniadakis, J.; Kouraklis, G.; Theocharis, S. Expression of peroxisome proliferator activated receptor-gamma (PPAR-γ) in human non-small cell lung carcinoma: correlation with clinicopathological parameters, proliferation and apoptosis related molecules and patients’ survival. Pathol. Oncol. Res.,  2012, 18(4), 875-883.
[http://dx.doi.org/10.1007/s12253-012-9517-9] [PMID:  22426809] 
[298] 
Nazim, U.M.; Moon, J.H.; Lee, Y.J.; Seol, J.W.; Park, S.Y. PPARγ activation by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux. Oncotarget,  2017, 8(16), 26819-26831.
[http://dx.doi.org/10.18632/oncotarget.15819] [PMID:  28460464] 
[299] 
Bren-Mattison, Y.; Van Putten, V.; Chan, D.; Winn, R.; Geraci, M.W.; Nemenoff, R.A. Peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene,  2005, 24(8), 1412-1422.
[http://dx.doi.org/10.1038/sj.onc.1208333] [PMID:  15608671] 
[300] 
Keshamouni, V.G.; Arenberg, D.A.; Reddy, R.C.; Newstead, M.J.; Anthwal, S.; Standiford, T.J. PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. Neoplasia,  2005, 7(3), 294-301.
[http://dx.doi.org/10.1593/neo.04601] [PMID:  15799829] 
[301] 
Tang, F.; Zhang, Q.; Nie, Z.; Yao, S.; Chen, B. Sample preparation for analyzing traditional Chinese medicines. Trends Analyt. Chem.,  2009, 28(11), 1253-1262.
[http://dx.doi.org/10.1016/j.trac.2009.09.004] 
[302] 
Shao, L. Network systems underlying traditional chinese medicine syndrome and herb formula. Curr. Bioinform.,  2009, 4(3), 188-196.
[http://dx.doi.org/10.2174/157489309789071129] 
[303] 
Zhang, Q-W.; Lin, L-G.; Ye, W-C. Techniques for extraction and isolation of natural products: a comprehensive review. Chin. Med.,  2018, 13(1), 20.
[http://dx.doi.org/10.1186/s13020-018-0177-x] [PMID:  29692864] 
[304] 
Zhang, W.; Huai, Y.; Miao, Z.; Qian, A.; Wang, Y. Systems pharmacology for investigation of the mechanisms of action of traditional Chinese medicine in drug discovery. Front. Pharmacol.,  2019, 10(743), 743.
[http://dx.doi.org/10.3389/fphar.2019.00743] [PMID:  31379563] 
[305] 
Lee, W-Y.; Lee, C-Y.; Kim, Y-S.; Kim, C-E. The methodological trends of traditional herbal medicine employing network pharmacology. Biomolecules,  2019, 9(8), 362.
[http://dx.doi.org/10.3390/biom9080362] [PMID:  31412658] 
[306] 
Reddy, A.S.; Zhang, S. Polypharmacology: drug discovery for the future. Expert Rev. Clin. Pharmacol.,  2013, 6(1), 41-47.
[http://dx.doi.org/10.1586/ecp.12.74] [PMID:  23272792] 
[307] 
Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem.,  2005, 48(21), 6523-6543.
[http://dx.doi.org/10.1021/jm058225d] [PMID:  16220969] 
[308] 
Evans, B.E.; Rittle, K.E.; Bock, M.G.; DiPardo, R.M.; Freidinger, R.M.; Whitter, W.L.; Lundell, G.F.; Veber, D.F.; Anderson, P.S.; Chang, R.S. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem.,  1988, 31(12), 2235-2246.
[http://dx.doi.org/10.1021/jm00120a002] [PMID:  2848124] 
[309] 
Bolognesi, M.L.; Banzi, R.; Bartolini, M.; Cavalli, A.; Tarozzi, A.; Andrisano, V.; Minarini, A.; Rosini, M.; Tumiatti, V.; Bergamini, C.; Fato, R.; Lenaz, G.; Hrelia, P.; Cattaneo, A.; Recanatini, M.; Melchiorre, C. Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer’s disease. J. Med. Chem.,  2007, 50(20), 4882-4897.
[http://dx.doi.org/10.1021/jm070559a] [PMID:  17850125] 
[310] 
Metz, J.T.; Hajduk, P.J. Rational approaches to targeted polypharmacology: creating and navigating protein-ligand interaction networks. Curr. Opin. Chem. Biol.,  2010, 14(4), 498-504.
[http://dx.doi.org/10.1016/j.cbpa.2010.06.166] [PMID:  20609615] 
[311] 
Hopkins, A.L. Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol.,  2008, 4(11), 682-690.
[http://dx.doi.org/10.1038/nchembio.118] [PMID:  18936753] 
[312] 
Rastelli, G.; Pinzi, L. Computational polypharmacology comes of age. Front. Pharmacol.,  2015, 6(157), 157.
[PMID:  26283966] [http://dx.doi.org/10.3389/fphar.2015.00157]] 
[313] 
Abdelall, E.K.; Kamel, G.M. Synthesis of new thiazolo-celecoxib analogues as dual cyclooxygenase-2/15-lipoxygenase inhibitors: Determination of regio-specific different pyrazole cyclization by 2D NMR. Eur. J. Med. Chem.,  2016, 118, 250-258.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.049] [PMID:  27131067] 
[314] 
Abdelall, E.K.A.; Lamie, P.F.; Ali, W.A.M. Cyclooxygenase-2 and 15-lipoxygenase inhibition, synthesis, anti-inflammatory activity and ulcer liability of new celecoxib analogues: determination of region-specific pyrazole ring formation by NOESY. Bioorg. Med. Chem. Lett.,  2016, 26(12), 2893-2899.
[http://dx.doi.org/10.1016/j.bmcl.2016.04.046] [PMID:  27158139] 
[315] 
Rao, P.N.; Chen, Q.H.; Knaus, E.E. Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases. J. Med. Chem.,  2006, 49(5), 1668-1683.
[http://dx.doi.org/10.1021/jm0510474] [PMID:  16509583] 
[316] 
Rao, P.N.; Chen, Q.H.; Knaus, E.E. Synthesis and biological evaluation of 1,3-diphenylprop-2-yn-1-ones as dual inhibitors of cyclooxygenases and lipoxygenases. Bioorg. Med. Chem. Lett.,  2005, 15(21), 4842-4845.
[http://dx.doi.org/10.1016/j.bmcl.2005.07.036] [PMID:  16143531] 
[317] 
Moreau, A.; Rao, P.N.; Knaus, E.E. Synthesis and biological evaluation of acyclic triaryl (Z)-olefins possessing a 3,5-di-tert-butyl-4-hydroxyphenyl pharmacophore: dual inhibitors of cyclooxygenases and lipoxygenases. Bioorg. Med. Chem.,  2006, 14(15), 5340-5350.
[http://dx.doi.org/10.1016/j.bmc.2006.03.054] [PMID:  16677817] 
[318] 
Chen, Q.H.; Rao, P.N.; Knaus, E.E. Synthesis and biological evaluation of a novel class of rofecoxib analogues as dual inhibitors of cyclooxygenases (COXs) and lipoxygenases (LOXs). Bioorg. Med. Chem.,  2006, 14(23), 7898-7909.
[http://dx.doi.org/10.1016/j.bmc.2006.07.047] [PMID:  16904331] 
[319] 
Moreau, A.; Chen, Q.H.; Praveen Rao, P.N.; Knaus, E.E. Design, synthesis, and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl)acrylic acids as dual inhibitors of cyclooxygenases and lipoxygenases. Bioorg. Med. Chem.,  2006, 14(23), 7716-7727.
[http://dx.doi.org/10.1016/j.bmc.2006.08.008] [PMID:  16931030] 
[320] 
Kaur, G.; Silakari, O. Benzimidazole scaffold based hybrid molecules for various inflammatory targets: synthesis and evaluation. Bioorg. Chem.,  2018, 80, 24-35.
[http://dx.doi.org/10.1016/j.bioorg.2018.05.014] [PMID:  29864685] 
[321] 
Moussa, G.; Alaaeddine, R.; Alaeddine, L.M.; Nassra, R.; Belal, A.S.F.; Ismail, A.; El-Yazbi, A.F.; Abdel-Ghany, Y.S.; Hazzaa, A. Novel click modifiable thioquinazolinones as anti-inflammatory agents: design, synthesis, biological evaluation and docking study. Eur. J. Med. Chem.,  2018, 144, 635-650.
[http://dx.doi.org/10.1016/j.ejmech.2017.12.065] [PMID:  29289887] 
[322] 
Omar, Y.M.; Abdu-Allah, H.H.M.; Abdel-Moty, S.G. Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX. Bioorg. Chem.,  2018, 80, 461-471.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.036] [PMID:  29986191] 
[323] 
Omar, Y.M.; Abdel-Moty, S.G.; Abdu-Allah, H.H.M. Further insight into the dual COX-2 and 15-LOX anti-inflammatory activity of 1,3,4-thiadiazole-thiazolidinone hybrids: The contribution of the substituents at 5th positions is size dependent. Bioorg. Chem.,  2020, 97103657
[http://dx.doi.org/10.1016/j.bioorg.2020.103657] [PMID:  32086052] 
[324] 
Boshra, A.N.; Abdu-Allah, H.H.M.; Mohammed, A.F.; Hayallah, A.M. Click chemistry synthesis, biological evaluation and docking study of some novel 2′-hydroxychalcone-triazole hybrids as potent anti-inflammatory agents. Bioorg. Chem.,  2020, 95103505
[http://dx.doi.org/10.1016/j.bioorg.2019.103505] [PMID:  31901755] 
[325] 
Abdu-Allah, H.H.M.; Abdelmoez, A.A.B.; Tarazi, H.; El-Shorbagi, A.A.; El-Awady, R. Conjugation of 4-aminosalicylate with thiazolinones afforded non-cytotoxic potent in vitro and in vivo anti-inflammatory hybrids. Bioorg. Chem.,  2020, 94103378
[http://dx.doi.org/10.1016/j.bioorg.2019.103378] [PMID:  31677858] 
[326] 
Abdelrahman, M.H.; Youssif, B.G.M.; Abdelgawad, M.A.; Abdelazeem, A.H.; Ibrahim, H.M.; Moustafa, A.E.G.A.; Treamblu, L.; Bukhari, S.N.A. Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity. Eur. J. Med. Chem.,  2017, 127, 972-985.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.006] [PMID:  27837994] 
[327] 
Youssif, B.G.M.; Mohamed, M.F.A.; Al-Sanea, M.M.; Moustafa, A.H.; Abdelhamid, A.A.; Gomaa, H.A.M. Novel aryl carboximidamide and 3-aryl-1,2,4-oxadiazole analogues of naproxen as dual selective COX-2/15-LOX inhibitors: design, synthesis and docking studies. Bioorg. Chem.,  2019, 85, 577-584.
[http://dx.doi.org/10.1016/j.bioorg.2019.02.043] [PMID:  30878890] 
[328] 
Maghraby, M.T.; Abou-Ghadir, O.M.F.; Abdel-Moty, S.G.; Ali, A.Y.; Salem, O.I.A. Novel class of benzimidazole-thiazole hybrids: the privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15-lipoxygenase enzymes. Bioorg. Med. Chem.,  2020, 28(7)115403
[http://dx.doi.org/10.1016/j.bmc.2020.115403] [PMID:  32127262] 
[329] 
Elzahhar, P.A.; Alaaeddine, R.; Ibrahim, T.M.; Nassra, R.; Ismail, A.; Chua, B.S.K.; Frkic, R.L.; Bruning, J.B.; Wallner, N.; Knape, T.; von Knethen, A.; Labib, H.; El-Yazbi, A.F.; Belal, A.S.F. Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones. Eur. J. Med. Chem.,  2019, 167, 562-582.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.034] [PMID:  30818268] 
[330] 
Merlo, S.; Spampinato, S.; Canonico, P.L.; Copani, A.; Sortino, M.A. Alzheimer’s disease: brain expression of a metabolic disorder? Trends Endocrinol. Metab.,  2010, 21(9), 537-544.
[http://dx.doi.org/10.1016/j.tem.2010.05.005] [PMID:  20541952] 
[331] 
Kinney, J.W.; Bemiller, S.M.; Murtishaw, A.S.; Leisgang, A.M.; Salazar, A.M.; Lamb, B.T. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement. (N. Y.),  2018, 4, 575-590.
[http://dx.doi.org/10.1016/j.trci.2018.06.014] [PMID:  30406177] 
[332] 
AlFadly, E.D.; Elzahhar, P.A.; Tramarin, A.; Elkazaz, S.; Shaltout, H.; Abu-Serie, M.M.; Janockova, J.; Soukup, O.; Ghareeb, D.A.; El-Yazbi, A.F.; Rafeh, R.W.; Bakkar, N.Z.; Kobeissy, F.; Iriepa, I.; Moraleda, I.; Saudi, M.N.S.; Bartolini, M.; Belal, A.S.F. Tackling neuroinflammation and cholinergic deficit in Alzheimer’s disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase. Eur. J. Med. Chem.,  2019, 167, 161-186.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.012] [PMID:  30771604] 
[333] 
Pirat, C.; Farce, A.; Lebègue, N.; Renault, N.; Furman, C.; Millet, R.; Yous, S.; Speca, S.; Berthelot, P.; Desreumaux, P.; Chavatte, P. Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. J. Med. Chem.,  2012, 55(9), 4027-4061.
[http://dx.doi.org/10.1021/jm101360s] [PMID:  22260081] 
[334] 
Knopfová, L.; Smarda, J. The use of Cox-2 and PPARγ signaling in anti-cancer therapies. Exp. Ther. Med.,  2010, 1(2), 257-264.
[http://dx.doi.org/10.3892/etm_00000040] [PMID:  22993537] 
[335] 
Santin, J.R.; Uchôa, F.D. Lima, Mdo.C.; Rabello, M.M.; Machado, I.D.; Hernandes, M.Z.; Amato, A.A.; Milton, F.A.; Webb, P.; Neves, Fde.A.; Galdino, S.L.; Pitta, I.R.; Farsky, S.H. Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor. Eur. J. Pharm. Sci.,  2013, 48(4-5), 689-697.
[http://dx.doi.org/10.1016/j.ejps.2012.12.029] [PMID:  23305993] 
[336] 
Abdellatif, K.R.A.; Fadaly, W.A.A.; Kamel, G.M.; Elshaier, Y.A.M.M.; El-Magd, M.A. Design, synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors. Bioorg. Chem.,  2019, 82, 86-99.
[http://dx.doi.org/10.1016/j.bioorg.2018.09.034] [PMID:  30278282] 
[337] 
Chen, E.Y.; Blanke, C.D.; Haller, D.G.; Benson, A.B.; Dragovich, T.; Lenz, H.J.; Robles, C.; Li, H.; Mori, M.; Mattek, N.; Sanborn, R.E.; Lopez, C.D. A phase II study of celecoxib with irinotecan, 5-fluorouracil, and leucovorin in patients with previously untreated advanced or metastatic colorectal cancer. Am. J. Clin. Oncol.,  2018, 41(12), 1193-1198.
[http://dx.doi.org/10.1097/COC.0000000000000465] [PMID:  29782360] 
[338] 
Yi, L.; Zhang, W.; Zhang, H.; Shen, J.; Zou, J.; Luo, P.; Zhang, J. Systematic review and meta-analysis of the benefit of celecoxib in treating advanced non-small-cell lung cancer. Drug Des. Devel. Ther.,  2018, 12, 2455-2466.
[http://dx.doi.org/10.2147/DDDT.S169627] [PMID:  30122902] 
[339] 
Kattan, J.; Bachour, M.; Farhat, F.; El Rassy, E.; Assi, T.; Ghosn, M. Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer. Invest. New Drugs,  2016, 34(4), 474-480.
[http://dx.doi.org/10.1007/s10637-016-0357-4] [PMID:  27159981] 
[340] 
James, N.D.; Sydes, M.R.; Mason, M.D.; Clarke, N.W.; Anderson, J.; Dearnaley, D.P.; Dwyer, J.; Jovic, G.; Ritchie, A.W.; Russell, J.M.; Sanders, K.; Thalmann, G.N.; Bertelli, G.; Birtle, A.J.; O’Sullivan, J.M.; Protheroe, A.; Sheehan, D.; Srihari, N.; Parmar, M.K. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol.,  2012, 13(5), 549-558.
[http://dx.doi.org/10.1016/S1470-2045(12)70088-8] [PMID:  22452894] 
[341] 
Firuzi, O.; Praticò, D. Coxibs and Alzheimer’s disease: should they stay or should they go? Ann. Neurol.,  2006, 59(2), 219-228.
[http://dx.doi.org/10.1002/ana.20774] [PMID:  16402383] 
[342] 
Iwama, T.; Akasu, T.; Utsunomiya, J.; Muto, T. Does a selective cyclooxygenase-2 inhibitor (tiracoxib) induce clinically sufficient suppression of adenomas in patients with familial adenomatous polyposis? A randomized double-blind placebo-controlled clinical trial. Int. J. Clin. Oncol.,  2006, 11(2), 133-139.
[http://dx.doi.org/10.1007/s10147-005-0548-z] [PMID:  16622748] 
[343] 
Hudson, L.G.; Cook, L.S.; Grimes, M.M.; Muller, C.Y.; Adams, S.F.; Wandinger-Ness, A. Dual actions of ketorolac in metastatic ovarian cancer. Cancers (Basel),  2019, 11(8)E1049
[http://dx.doi.org/10.3390/cancers11081049] [PMID:  31344967] 
[344] 
Ornelas, A.; Zacharias-Millward, N.; Menter, D.G.; Davis, J.S.; Lichtenberger, L.; Hawke, D.; Hawk, E.; Vilar, E.; Bhattacharya, P.; Millward, S. Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev.,  2017, 36(2), 289-303.
[http://dx.doi.org/10.1007/s10555-017-9675-z] [PMID:  28762014] 
[345] 
Dai, X.; Yan, J.; Fu, X.; Pan, Q.; Sun, D.; Xu, Y.; Wang, J.; Nie, L.; Tong, L.; Shen, A.; Zheng, M.; Huang, M.; Tan, M.; Liu, H.; Huang, X.; Ding, J.; Geng, M. Aspirin inhibits cancer metastasis and angiogenesis via targeting heparanase. Clin. Cancer Res.,  2017, 23(20), 6267-6278.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0242] [PMID:  28710312] 
[346] 
Leone, S.; Ottani, A.; Bertolini, A. Dual acting anti-inflammatory drugs. Curr. Top. Med. Chem.,  2007, 7(3), 265-275.
[http://dx.doi.org/10.2174/156802607779941341] [PMID:  17305569] 
[347] 
Laidlaw, T.M.; Boyce, J.A. Pathogenesis of aspirin-exacerbated respiratory disease and reactions. Immunol. Allergy Clin. North Am.,  2013, 33(2), 195-210.
[http://dx.doi.org/10.1016/j.iac.2012.11.006] [PMID:  23639708] 
[348] 
Berger, J.P.; Petro, A.E.; Macnaul, K.L.; Kelly, L.J.; Zhang, B.B.; Richards, K.; Elbrecht, A.; Johnson, B.A.; Zhou, G.; Doebber, T.W.; Biswas, C.; Parikh, M.; Sharma, N.; Tanen, M.R.; Thompson, G.M.; Ventre, J.; Adams, A.D.; Mosley, R.; Surwit, R.S.; Moller, D.E. Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator. Mol. Endocrinol.,  2003, 17(4), 662-676.
[http://dx.doi.org/10.1210/me.2002-0217] [PMID:  12554792] 
[349] 
Silva, J.C.; César, F.A.; de Oliveira, E.M.; Turato, W.M.; Tripodi, G.L.; Castilho, G.; Machado-Lima, A.; de Las Heras, B.; Boscá, L.; Rabello, M.M.; Hernandes, M.Z.; Pitta, M.G.; Pitta, I.R.; Passarelli, M.; Rudnicki, M.; Abdalla, D.S. New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr(-/-) mice. Pharmacol. Res.,  2016, 104, 49-60.
[http://dx.doi.org/10.1016/j.phrs.2015.12.010] [PMID:  26706782] 
Rights & Permissions Print Cite
Article Metrics
34
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867327999200820173853	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
当代药物化学

COX-2、15-LOX和PPARγ在代代性疾病和癌症中的新作用:介绍新的多靶点定向配体(MTDL)

摘要

当代药物化学

COX-2、15-LOX和PPARγ在代代性疾病和癌症中的新作用:介绍新的多靶点定向配体(MTDL)

摘要 Play Pause

Related Journals

Related Books

摘要
