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

Rana    A.    Alaaeddine; Perihan    A.    Elzahhar; Ibrahim       AlZaim; Wassim       Abou-Kheir; Ahmed    S.F.    Belal; Ahmed    F.    El-Yazbi
Abstract

Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro- and antitumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarizing the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.
Keywords: Multi-target directed ligands, cyclooxygenase-2, 15-lipooxygenase, peroxisome proliferator-activated receptor gamma, adipose inflammation, vascular dysfunction, cancer, neurodegenerative disease.
« 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
47
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
Current Medicinal Chemistry

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

Abstract

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the treatment of chronic inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

Current Medicinal Chemistry

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

Abstract

Call for Papers in Thematic Issues

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the treatment of chronic inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

Related Journals

Related Books
