BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Prostaglandin E Synthase, a Terminal Enzyme for Prostaglandin E2 Biosynthesis

  • Kudo, Ichiro (Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University) ;
  • Murakami, Makoto (Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University)
  • Published : 2005.11.30
Download PDF
⟨ Previous Next ⟩

Abstract

Biosynthesis of prostanoids is regulated by three sequential enzymatic steps, namely phospholipase $A_2$ enzymes, cyclooxygenase (COX) enzymes, and various lineage-specific terminal prostanoid synthases. Prostaglandin E synthase (PGES), which isomerizes COX-derived $PGH_2$ specifically to $PGE_2$, occurs in multiple forms with distinct enzymatic properties, expressions, localizations and functions. Two of them are membrane-bound enzymes and have been designated as mPGES-1 and mPGES-2. mPGES-1 is a perinuclear protein that is markedly induced by proinflammatory stimuli, is down-regulated by anti inflammatory glucocorticoids, and is functionally coupled with COX-2 in marked preference to COX-1. Recent gene targeting studies of mPGES-1 have revealed that this enzyme represents a novel target for anti-inflammatory and anti-cancer drugs. mPGES-2 is synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme. This enzyme is rather constitutively expressed in various cells and tissues and is functionally coupled with both COX-1 and COX-2. Cytosolic PGES (cPGES) is constitutively expressed in a wide variety of cells and is functionally linked to COX-1 to promote immediate $PGE_2$ production. This review highlights the latest understanding of the expression, regulation and functions of these three PGES enzymes.

Keywords

References

  1. Bombardier, C., Laine, L., Reicin, A., Shapiro, D., Burgos-Vargas, R., Davis, B., Day, R., Ferraz, M. B., Hawkey, C. J., Hochberg, M. C., Kvien, T. K. and Schnitzer, T. J. (2000) VIGOR study group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N. Engl. J. Med. 343, 1520-1528 https://doi.org/10.1056/NEJM200011233432103
  2. Boulet, L., Ouellet, M., Bateman, K. P., Ethier, D., Percival, M. D., Riendeau, D., Mancini, J. A. and Methot, N. (2004) Deletion of microsomal prostaglandin $E_2$ synthase-1 reduces both inducible and basal $PGE_2$ production and alters the gastric prostanoid profile. J. Biol. Chem. 279, 23229-23237 https://doi.org/10.1074/jbc.M400443200
  3. Brock, T. G., McNish, R. W. and Peters-Golden, M. (1999) Arachidonic acid is preferentially metabolized by cyclooxygenase- 2 to prostacyclin and prostaglandin $E_2$. J. Biol. Chem. 274, 11660-11666 https://doi.org/10.1074/jbc.274.17.11660
  4. Chen, Q-R., Miyaura, C., Higashi, S., Murakami, M., Kudo, I., Saito, S., Hiraide, T., Shibasaki, Y. and Suda, T. (1997) Activation of cytosolic phospholipase A2 by platelet-derived growth factor is essential for cyclooxygenase-2-dependent prostaglandin $E_2$ synthesis in mouse osteoblasts cultured with interleukin-1. J. Biol. Chem. 272, 5952-5968 https://doi.org/10.1074/jbc.272.9.5952
  5. Crofford, L. J., Lipsky, P. E., Brooks, P., Abramson, S. B., Simon, L. S. and van de Putte, L. B. (2000) Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 43, 4-13 https://doi.org/10.1002/1529-0131(200001)43:1<4::AID-ANR2>3.0.CO;2-V
  6. Crofford, L. J., Oates, J. C., McCune, W. J., Gupta, S., Kaplan, M. J., Catella-Lawson, F., Morrow, J. D., McDonagh, K. T. and Schmaier, A. H. (2000) Thrombosis in patients with conenctive tissue diseases treated with specific COX-2 inhibitors: a report of four cases. Arthritis Rheum. 43, 1891- 1896 https://doi.org/10.1002/1529-0131(200008)43:8<1891::AID-ANR28>3.0.CO;2-R
  7. Engblom, D., Saha, S., Engstrom, L., Westman, M., Audoly, L. P., Jakobsson, P. J. and Blomqvist, A. (2003) Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nat. Neurosci. 6, 1137-1138 https://doi.org/10.1038/nn1137
  8. Harada, Y., Hatanaka, K., Kawamura, M., Saito, M., Ogino, M., Majima, M., Ohno, T., Ogino, K., Yamamoto, K., Taketani, Y., Yamamoto, S. and Katori, M. (1996) Role of prostaglandin H synthase-2 in prostaglandin $E_2$ formation in rat carrageenininduced pleurisy. Prostaglandins 51, 19-33 https://doi.org/10.1016/0090-6980(95)00168-9
  9. Hegen, M., Sun, L., Uozumi, N., Kume, K., Goad, M. E., Nickerson-Nutter, C. L., Shimizu, T. and Clark, J. D. (2003) Cytosolic phospholipase A2-deficient mice are resistant to collagen-induced arthritis. J. Exp. Med. 197, 1297-1302 https://doi.org/10.1084/jem.20030016
  10. Hizaki, H., Segi, E., Sugimoto, Y., Hirose, M., Saji, T., Ushikubi, F., Matsuoka, T., Noda, Y., Tanaka, T., Yoshida, N., Narumiya, S. and Ichikawa, A. (1999) Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP2. Proc. Natl. Acad. Sci. USA 96, 10501- 10596
  11. Jakobsson, P.-J., Thoren, S., Morgenstern, R. and Samuelsson, B. (1999) Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc. Natl. Acad. Sci. USA 96, 7220-7225
  12. Kamei, D., Murakami, M., Nakatani, Y., Ishikawa, Y., Ishii, T. and Kudo, I. (2003) Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis. J. Biol. Chem. 278, 19396-19405 https://doi.org/10.1074/jbc.M213290200
  13. Kamei, D., Yamakawa, K., Takegoshi, Y., Mikami-Nakanishi, M., Nakatani, Y., Oh-Ishi, S., Yasui, H., Azuma, Y., Hirasawa, N., Ohuchi, K., Kawaguchi, H., Ishikawa, Y., Ishii, T., Uematsu, S., Akira, S., Murakami, M., and Kudo, I. (2004) Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E synthase-1. J. Biol. Chem. 279, 33684-33695 https://doi.org/10.1074/jbc.M400199200
  14. Kobayashi, T., Nakatani, Y., Tanioka, T., Tsujimoto, M., Nakajo, S., Nakaya, K., Murakami, M. and Kudo, I. (2004) Regulation of cytosolic prostaglandin E synthase by phosphorylation. Biochem. J. 381, 59-69 https://doi.org/10.1042/BJ20040118
  15. Kulmacz, R. J. and Wang, L.-H. (1995) Comparison of hydroperoxide initiator requirements for the cyclooxygenase activities of prostaglandin H synthase-1 and -2. J. Biol. Chem. 270, 24019-24023 https://doi.org/10.1074/jbc.270.41.24019
  16. Li, S., Wang, Y., Matsumura, K., Ballou, L. R., Morham, S. G. and Blatteis, C. M. (1999) The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2 (-/-), but not in cyclooxygenase-1 (-/-) mice. Brain Res. 825, 86-94 https://doi.org/10.1016/S0006-8993(99)01225-1
  17. Loftin, C. D., Trivedi, D. B., Tiano, H. F., Clark, J. A., Lee, C. A., Epstein, J. A., Morham, S. G., Breyer, M. D., Nguyen, M., Hawkins, B. M., Goulet, J. L., Smithies, O., Koller, B. H. and Langenbach, R. (2001) Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. Proc. Natl. Acad. Sci. USA 98, 1059-1064
  18. Mabuchi, T., Kojima, H., Abe, T., Takagi, K., Sakurai, M., Ohmiya, Y., Uematsu, S., Akira, S., Watanabe, K. and Ito, S. (2004) Membrane-associated prostaglandin E synthase-1 is required for neuropathic pain. Neuroreport 15, 1395-1398 https://doi.org/10.1097/01.wnr.0000129372.89000.31
  19. McAdam, B. F., Catella-Lawson, F., Mardini, I. A., Kapoor, S., Lawson, J. A. and FitzGerald, G. A. (1999) Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc. Natl. Acad. Sci. USA 96, 272-277
  20. Moore, A. H., Olschowka, J. A. and O'Banion, M. K. (2004) Intraparenchymal administration of interleukin-1 induces cyclooxygenase-2-mediated expression of membrane- and cytosolic-associated prostaglandin E synthases in mouse brain. J. Neuroimmunol. 148, 32-40 https://doi.org/10.1016/j.jneuroim.2003.11.001
  21. Morita, I., Schindler, M., Reiger, M. K., Otto, J. C., Hori, T., DeWitt, D. L. and Smith, W. L. (1995) Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2. J. Biol. Chem. 270, 10902-10908 https://doi.org/10.1074/jbc.270.18.10902
  22. Murakami, M., Kambe, T., Shimbara, S. and Kudo, I. (1999) Functional coupling between various phospholipase A2s and cyclooxygenases in immediate and delayed prostanoid biosynthetic pathways. J. Biol. Chem. 274, 3103-3115 https://doi.org/10.1074/jbc.274.5.3103
  23. Murakami, M. and Kudo, I. (2004) Recent advances in molecular biology and physiology of the prostaglandin $E_2$-biosynthetic pathway. Prog. Lipid Res. 43, 3-35 https://doi.org/10.1016/S0163-7827(03)00037-7
  24. Murakami, M., Kuwata, H., Amakasu, Y., Shimbara, S., Nakatani, Y., Atsumi, G. and Kudo, I. (1997) Prostaglandin $E_2$ amplifies cytosolic phospholipase $A_2$ and cyclooxygenase-2- dependent delayed prostaglandin $E_2$ generation in mouse osteoblastic cells: enhancement by secretory phospholipase $A_2$. J. Biol. Chem. 272, 19891-19897 https://doi.org/10.1074/jbc.272.32.19891
  25. Murakami, M., Nakashima, K., Kamei, K., Masuda, S., Ishikawa, Y., Ishii, T., Ohmiya, Y., Watanabe, K., and Kudo, I. (2003) Cellular prostaglandin $E_2$ production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J. Biol. Chem. 278, 37937-37947 https://doi.org/10.1074/jbc.M305108200
  26. Murakami, M., Naraba, H., Tanioka, T., Semmyo, N., Nakatani, Y., Kojima, F., Ikeda, T., Fueki, M., Ueno, A., Oh-Ishi, S. and Kudo, I. (2000) Regulation of prostaglandin $E_2$ biosynthesis by inducible membrane-associated prostaglandin $E_2$ synthase that acts in concert with cyclooxygenase-2. J. Biol. Chem. 275, 32783-32792 https://doi.org/10.1074/jbc.M003505200
  27. Myers, L. K., Higgins, G. C., Finkel, T. H., Reed, A. M., Thompson, J. W., Walton, R. C., Hendrickson, J., Kerr, N. C., Pandya-Lipman, R. K., Shlopov, B. V., Stastny, P., Postlethwaite, A. E. and Kang, A. H. (2001) Juvenile arthritis and autoimmunity to type II collagen. Arthritis Rheum. 44, 1775-1781 https://doi.org/10.1002/1529-0131(200108)44:8<1775::AID-ART313>3.0.CO;2-V
  28. Naraba, H., Murakami, M., Matsumoto, H., Shimbara, S., Ueno, A., Kudo, I. and Oh-ishi, S. (1998) Segregated coupling of phospholipases $A_2$, cyclooxygenases, and terminal prostanoid synthases in different phases of prostanoid biosynthesis in rat peritoneal macrophages. J. Immunol. 160, 2974-2982
  29. Naraba, H., Yokoyama, C., Tago, N., Murakami, M., Kudo, I., Fueki, M., Oh-Ishi, S. and Tanabe, T. (2002) Transcriptional regulation of the membrane-associated prostaglandin $E_2$ synthase gene. Essential role of the transcription factor Egr-1. J. Biol. Chem. 277, 28601-28608 https://doi.org/10.1074/jbc.M203618200
  30. Ni, H., Sun, T., Ma, X. H. and Yang, Z. M. (2003) Expression and regulation of cytosolic prostaglandin E synthase in mouse uterus during the peri-implantation period. Biol. Reprod. 68, 744-750 https://doi.org/10.1095/biolreprod.102.007328
  31. Oshima, H., Oshima, M., Inaba, K. and Taketo, M. M. (2004) Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice. EMBO J. 23, 1669-1678 https://doi.org/10.1038/sj.emboj.7600170
  32. Oshima, M., Dinchuk, J. E., Kargman, S. L., Oshima, H., Hancock, B., Kwong, E., Trzaskos, J. M., Evans, J. F. and Taketo, M. M. (1996) Suppression of intestinal polyposis in $Apc^{716}$ knockout mice by inhibition of cyclooxygenase 2 (COX- 2). Cell 87, 803-809 https://doi.org/10.1016/S0092-8674(00)81988-1
  33. Reddy, S. T. and Herschman, H. R. (1997) Prostaglandin synthase- 1 and prostaglandin synthase-2 are coupled to distinct phospholipases for the generation of prostaglandin D2 in activated mast cells. J. Biol. Chem. 272, 3231-3237 https://doi.org/10.1074/jbc.272.6.3231
  34. Rocca, B., Spain, L. M., Pure, E., Langenbach, R., Patrono, C. and FitzGerald, G. A. (1999) Distinct roles of prostaglandin H synthases 1 and 2 in T-cell development. J. Clin. Invest. 103, 1469-1477 https://doi.org/10.1172/JCI6400
  35. Saha, S., Engstrom, L., Mackerlova, L., Jakobsson, P. J. and Blomqvist, A. (2005) Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288 1100-1107 https://doi.org/10.1152/ajpregu.00872.2004
  36. Segi, E, Sugimoto, Y, Yamasaki, A, Aze, Y, Oida, H, Nishimura, T, Murata, T, Matsuoka, T, Ushikubi, F, Hirose, M, Tanaka, T, Yoshida, N, Narumiya, S, and Ichikawa, A. Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4- deficient mice. Biochem. Biophys. Res. Commun. 246, 7-12 https://doi.org/10.1006/bbrc.1998.8461
  37. Shitashige M, Morita I, Murota S. (1998) Different substrate utilization between prostaglandin endoperoxide H synthase-1 and -2 in NIH3T3 fibroblasts. Biochim. Biophys. Acta 1389, 57-66 https://doi.org/10.1016/S0005-2760(97)00129-X
  38. Sonoshita, M., Takaku, K., Sasaki, N., Sugimoto, Y., Ushikubi, F., Narumiya, S., Oshima, M., and Taketo, M. M. (2001) Acceleration of intestinal polyposis through prostaglandin receptor EP2 in $Apc^{716}$ knockout mice. Nat. Med. 7, 1048-1051 https://doi.org/10.1038/nm0901-1048
  39. Stichtenoth, D. O. and Frolich, J. C. (2000) COX-2 and the kidneys. Curr. Pharm. Des. 6, 1737-1753 https://doi.org/10.2174/1381612003398717
  40. Takaku, K., Sonoshita, M., Sasaki, N., Uozumi, N., Doi, Y., Shimizu, T. and Taketo, M. M. (2002) Suppression of intestinal polyposis in $Apc^{716}$ knockout mice by an additional mutation in the cytosolic phospholipase $A_2$ gene. J. Biol. Chem. 275, 34013-34016
  41. Tanikawa, N., Ohmiya, Y., Ohkubo, H., Hashimoto, K., Kangawa, K., Kojima, M., Ito, S. and Watanabe, K. (2002) Identification and characterization of a novel type of membrane-associated prostaglandin E synthase. Biochem. Biophys. Res. Commun. 291, 884-889 https://doi.org/10.1006/bbrc.2002.6531
  42. Tanioka, T., Nakatani, Y., Semmyo, N., Murakami, M. and Kudo, I. (2000) Molecular identification of cytosolic prostaglandin $E_2$ synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin $E_2$ biosynthesis. J. Biol. Chem. 275, 32775-32782 https://doi.org/10.1074/jbc.M003504200
  43. Thoren, S., Weinander, R., Saha, S., Jegerschold, C., Pettersson, P. L., Samuelsson, B., Hebert, H., Hamberg, M., Morgenstern, R. J. and akobsson, P. J. (2003) Human microsomal prostaglandin E synthase-1: purification, functional characterization, and projection structure determination. J. Biol. Chem. 278, 22199- 22209 https://doi.org/10.1074/jbc.M303227200
  44. Trebino, C. E., Stock, J. L., Gibbons, C. P., Naiman, B. M., Wachtmann, T. S., Umland, J. P., Pandher, K., Lapointe, J. M., Saha, S., Roach, M. L., Carter, D., Thomas, N. A., Durtschi, B. A., McNeish, J. D., Hambor, J. E., Jakobsson, P. J., Carty, T. J., Perez, J. R. and Audoly, L. P. (2003) Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc. Natl. Acad. Sci. USA 100, 9044-9049
  45. Uematsu, S., Matsumoto, M., Takeda, K. and Akira, S. (2002) Lipopolysaccharide-dependent prostaglandin $E_2$ production is regulated by the glutathione-dependent prostaglandin $E_2$ synthase gene induced by the Toll-like receptor 4/MyD88/NFIL6 pathway. J. Immunol. 168, 5811-5816 https://doi.org/10.4049/jimmunol.168.11.5811
  46. Ueno, N., Murakami, M., Tanioka, T., Fujimori, K., Urade, Y. and Kudo, I. (2001) Coupling between cyclooxygenases, terminal prostanoid synthases and phospholipase $A_2$. J. Biol. Chem. 276, 34918-34927 https://doi.org/10.1074/jbc.M100429200
  47. Yamada, T., Komoto, J., Watanabe, K., Ohmiya, Y. and Takusagawa, F. (2005) Crystal structure and possible catalytic mechanism of microsomal prostaglandin E synthase type 2 (mPGES-2). J. Mol. Biol. 348, 1163-1176 https://doi.org/10.1016/j.jmb.2005.03.035
  48. Yamagata, K., Matsumura, K., Inoue, W., Shiraki, T., Suzuki, K., Yasuda, S., Sugiura, H., Cao, C., Watanabe, Y., and Kobayashi, S. (2001) Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever. J. Neurosci. 21, 2669- 2677

Cited by

  1. Expression of genes involved in prostaglandin E2 and progesterone production in bovine cumulus-oocyte complexes during in vitro maturation and fertilization vol.135, pp.5, 2008, https://doi.org/10.1530/REP-07-0453
  2. Immunohistochemical Expressions of Main PGE2 Biosynthesis-related Enzymes and PGE2 Receptor in Rat Nephrogenesis vol.24, pp.4, 2011, https://doi.org/10.1293/tox.24.257
  3. Dimeric and trimeric triazole based molecules as a new class of Hsp90 molecular chaperone inhibitors vol.65, 2013, https://doi.org/10.1016/j.ejmech.2013.05.016
  4. Effects of AF3442 [N-(9-ethyl-9H-carbazol-3-yl)-2-(trifluoromethyl)benzamide], a novel inhibitor of human microsomal prostaglandin E synthase-1, on prostanoid biosynthesis in human monocytes in vitro vol.79, pp.7, 2010, https://doi.org/10.1016/j.bcp.2009.11.011
  5. Immunohistochemical Expression of COX-2, mPGES and EP2 Receptor in Normal and Reactive Canine Bone and in Canine Osteosarcoma vol.147, pp.2-3, 2012, https://doi.org/10.1016/j.jcpa.2012.02.003
  6. Colonic Saturated Fatty Acid Concentrations and Expression of COX-1, but not Diet, Predict Prostaglandin E2 in Normal Human Colon Tissue vol.68, pp.7, 2016, https://doi.org/10.1080/01635581.2016.1213866
  7. Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion vol.2012, 2012, https://doi.org/10.1155/2012/723419
  8. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products vol.164, pp.3, 2011, https://doi.org/10.1111/j.1476-5381.2011.01276.x
  9. Eicosanoids in skin inflammation vol.88, pp.1, 2013, https://doi.org/10.1016/j.plefa.2012.03.009
  10. Prostaglandin E2Enhances Proliferation, Dedifferentiation and Stem-Like Properties of Rat Retinal Müller Glial Cells in vitro vol.49, pp.2, 2013, https://doi.org/10.1159/000345256
  11. Involvement of the constitutive prostaglandin E synthase cPGES/p23 in expression of an initial prostaglandin E2 inactivating enzyme, 15-PGDH vol.94, pp.3-4, 2011, https://doi.org/10.1016/j.prostaglandins.2011.02.001
  12. Anti-inflammatory effects of 5-HT3 receptor antagonists in interleukin-1beta stimulated primary human chondrocytes vol.22, pp.1, 2014, https://doi.org/10.1016/j.intimp.2014.06.003
  13. Bradykinin potentiates cytokine-induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression vol.56, pp.3, 2007, https://doi.org/10.1002/art.22445
  14. Novel membrane-associated prostaglandin E synthase-2 from crustacean arthropods vol.174, 2014, https://doi.org/10.1016/j.cbpb.2014.05.004
  15. Synthesis and pharmacological characterization of benzenesulfonamides as dual species inhibitors of human and murine mPGES-1 vol.21, pp.24, 2013, https://doi.org/10.1016/j.bmc.2013.10.006
  16. 3D-QSAR study of microsomal prostaglandin E2 synthase(mPGES-1) inhibitors vol.13, pp.5, 2007, https://doi.org/10.1007/s00894-007-0172-0
  17. The Endothelium, Part II: EDHF-Mediated Responses "The Classical Pathway" vol.3, pp.4, 2011, https://doi.org/10.4199/C00032ED1V01Y201105ISP020
  18. Expression of microsomal prostaglandin E synthase-1 in human hepatocelluar carcinoma vol.27, pp.7, 2007, https://doi.org/10.1111/j.1478-3231.2007.01530.x
  19. Prostaglandin E2synthase inhibition as a therapeutic target vol.13, pp.7, 2009, https://doi.org/10.1517/14728220903018932
  20. Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum–transfer arthritis vol.58, pp.5, 2008, https://doi.org/10.1002/art.23453
  21. The terminal prostaglandin synthases mPGES-1, mPGES-2, and cPGES are all overexpressed in human gliomas vol.29, pp.2, 2009, https://doi.org/10.1111/j.1440-1789.2008.00963.x
  22. The Endothelium, Part I: Multiple Functions of the Endothelial Cells -- Focus on Endothelium-Derived Vasoactive Mediators vol.3, pp.4, 2011, https://doi.org/10.4199/C00031ED1V01Y201105ISP019
  23. Lipopolysaccharide differently affects prostaglandin E2 levels in fetal and maternal compartments of perfused human term placenta vol.88, pp.1-2, 2009, https://doi.org/10.1016/j.prostaglandins.2008.08.005
  24. Platelets, Cyclooxygenases, and Colon Cancer vol.41, pp.3, 2014, https://doi.org/10.1053/j.seminoncol.2014.04.008
  25. On the mechanism of microsomal prostaglandin E synthase type-2—A theoretical study of endoperoxide reaction with MeS− vol.20, pp.1, 2010, https://doi.org/10.1016/j.bmcl.2009.10.100
  26. Role of PTGS2-generated PGE2 during gonadotrophin-induced bovine oocyte maturation and cumulus cell expansion vol.28, pp.3, 2014, https://doi.org/10.1016/j.rbmo.2013.11.005
  27. Candidate gene association study of type 2 diabetes in a nested case-control study of the EPIC-Potsdam cohort – Role of fat assimilation vol.51, pp.2, 2007, https://doi.org/10.1002/mnfr.200600162
  28. Prostanoids and inflammatory pain vol.104-105, 2013, https://doi.org/10.1016/j.prostaglandins.2012.08.006
  29. Cyclooxygenase and prostaglandin synthases in atherosclerosis: Recent insights and future perspectives vol.118, pp.2, 2008, https://doi.org/10.1016/j.pharmthera.2008.01.002
  30. Enzymes involved in the conversion of arachidonic acid to eicosanoids in the skin of atopic dogs vol.19, pp.8, 2010, https://doi.org/10.1111/j.1600-0625.2009.01037.x
  31. Genetic deletion of microsomal prostaglandin E synthase-1 suppresses mouse mammary tumor growth and angiogenesis vol.106, 2013, https://doi.org/10.1016/j.prostaglandins.2013.04.002
  32. Microsomal prostaglandin E synthase protein levels correlate with prognosis in colorectal cancer patients vol.454, pp.6, 2009, https://doi.org/10.1007/s00428-009-0777-z
  33. Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2activation of EP3and EP4receptors vol.135, pp.5, 2015, https://doi.org/10.1111/jnc.13117
  34. Eugenosedin-A amelioration of lipopolysaccharide-induced up-regulation of p38 MAPK, inducible nitric oxide synthase and cyclooxygenase-2 vol.59, pp.6, 2007, https://doi.org/10.1211/jpp.59.6.0015
  35. NSAIDs and cardiovascular disease: transducing human pharmacology results into clinical read-outs in the general population vol.62, pp.3, 2010, https://doi.org/10.1016/S1734-1140(10)70310-8
  36. Expression Analysis of the Prostaglandin E2 Production Pathway in Human Pancreatic Cancers vol.37, pp.2, 2008, https://doi.org/10.1097/MPA.0b013e31816618ba
  37. Novel human mPGES-1 inhibitors identified through structure-based virtual screening vol.19, pp.20, 2011, https://doi.org/10.1016/j.bmc.2011.08.040
  38. E-type prostanoid receptor 4 (EP4) in disease and therapy vol.138, pp.3, 2013, https://doi.org/10.1016/j.pharmthera.2013.03.006
  39. Identification of novel mPGES-1 inhibitors through screening of a chemical library vol.22, pp.24, 2012, https://doi.org/10.1016/j.bmcl.2012.10.085
  40. Nuclear Factor Kappa B and Cyclo-Oxygenase-2: Two Concordant Players in Psoriasis Pathogenesis vol.39, pp.1, 2015, https://doi.org/10.3109/01913123.2014.952470
  41. Mechanisms of anti-inflammatory property of Anacardium occidentale stem bark: Inhibition of NF-κB and MAPK signalling in the microglia vol.145, pp.1, 2013, https://doi.org/10.1016/j.jep.2012.10.031
  42. Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients’ survival in glioblastoma multiforme vol.26, pp.34, 2007, https://doi.org/10.1038/sj.onc.1210303
  43. Calorie restricted rats do not increase metabolic rate post-LPS, but do seek out warmer ambient temperatures to behaviourally induce a fever vol.107, pp.5, 2012, https://doi.org/10.1016/j.physbeh.2012.06.009
  44. Punicalagin inhibits neuroinflammation in LPS-activated rat primary microglia vol.58, pp.9, 2014, https://doi.org/10.1002/mnfr.201400163
  45. Structural Insights for the Optimization of Dihydropyrimidin-2(1H)-one Based mPGES-1 Inhibitors vol.6, pp.2, 2015, https://doi.org/10.1021/ml500433j
  46. Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions vol.23, pp.1, 2009, https://doi.org/10.1007/s10822-008-9233-4
  47. Prostaglandin E synthases: Understanding their pathophysiological roles through mouse genetic models vol.92, pp.6, 2010, https://doi.org/10.1016/j.biochi.2010.02.007
  48. Regulation of human microsomal prostaglandin E synthase-1 by IL-1β requires a distal enhancer element with a unique role for C/EBPβ vol.443, pp.2, 2012, https://doi.org/10.1042/BJ20111801
  49. Why do a wide variety of animals retain multiple isoforms of cyclooxygenase? vol.109-111, 2014, https://doi.org/10.1016/j.prostaglandins.2014.03.002
  50. Galanin-Like Peptide (GALP) Facilitates Thermogenesis via Synthesis of Prostaglandin E2 by Astrocytes in the Periventricular Zone of the Third Ventricle vol.50, pp.3, 2013, https://doi.org/10.1007/s12031-013-9952-4
  51. Clinical significance of prostaglandin E synthase expression in gastric cancer tissue vol.38, pp.12, 2007, https://doi.org/10.1016/j.humpath.2007.04.020
  52. Cyclooxygenase inhibitors: From pharmacology to clinical read-outs vol.1851, pp.4, 2015, https://doi.org/10.1016/j.bbalip.2014.09.016
  53. Defective endometrial prostaglandin synthesis identified in patients with repeated implantation failure undergoing in vitro fertilization vol.94, pp.4, 2010, https://doi.org/10.1016/j.fertnstert.2009.07.1668
  54. Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice vol.111, pp.18, 2014, https://doi.org/10.1073/pnas.1401797111
  55. Microsomal Prostaglandin E Synthase-1 Inhibits PTEN and Promotes Experimental Cholangiocarcinogenesis and Tumor Progression vol.140, pp.7, 2011, https://doi.org/10.1053/j.gastro.2011.02.056
  56. Fragment-based discovery of novel and selective mPGES-1 inhibitors Part 1: Identification of sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid vol.23, pp.1, 2013, https://doi.org/10.1016/j.bmcl.2012.11.019
  57. Structure-Based Design of Microsomal Prostaglandin E2Synthase-1 (mPGES-1) Inhibitors using a Virtual Fragment Growing Optimization Scheme vol.11, pp.6, 2016, https://doi.org/10.1002/cmdc.201500598
  58. Cyclooxygenase-2-related signaling in the hypothalamus plays differential roles in response to various acute stresses vol.1508, 2013, https://doi.org/10.1016/j.brainres.2013.02.042
  59. Expression of enzymes involved in the synthesis of prostaglandin E2 in bovine in vitro-produced embryos vol.19, pp.03, 2011, https://doi.org/10.1017/S0967199410000596
  60. Prostacyclin production is not controlled by prostacyclin synthase but by cyclooxygenase-2 in a human follicular dendritic cell line, HK vol.44, pp.12, 2007, https://doi.org/10.1016/j.molimm.2007.01.025
  61. Melatonin modulates microsomal PGE synthase 1 and NF-E2-related factor-2-regulated antioxidant enzyme expression in LPS-induced murine peritoneal macrophages vol.171, pp.1, 2014, https://doi.org/10.1111/bph.12428
  62. Effect of propofol on prostaglandin E2 production and prostaglandin synthase-2 and cyclooxygenase-2 expressions in amniotic membrane cells vol.28, pp.6, 2014, https://doi.org/10.1007/s00540-014-1830-x
  63. root bark vol.56, pp.1, 2018, https://doi.org/10.1080/13880209.2018.1447972