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Journal articles on the topic 'Microsomal prostaglandin E2 synthase'

Author: Grafiati

Published: 4 June 2021

Last updated: 5 February 2022

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1

Psarra, Anastasia, Aikaterini Nikolaou, Maroula G. Kokotou, Dimitris Limnios, and George Kokotos. "Microsomal prostaglandin E2 synthase-1 inhibitors: a patent review." Expert Opinion on Therapeutic Patents 27, no. 9 (June 26, 2017): 1047–59. http://dx.doi.org/10.1080/13543776.2017.1344218.

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2

Timmers, L., G. Pasterkamp, and D. P. V. de Kleijn. "Microsomal Prostaglandin E2 Synthase: A Safer Target than Cyclooxygenases?" Molecular Interventions 7, no. 4 (August 1, 2007): 195–99. http://dx.doi.org/10.1124/mi.7.4.5.

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3

Wu, Tom Y. H., Hélène Juteau, Yves Ducharme, Richard W. Friesen, Sébastien Guiral, Lynn Dufresne, Hugo Poirier, et al. "Biarylimidazoles as inhibitors of microsomal prostaglandin E2 synthase-1." Bioorganic & Medicinal Chemistry Letters 20, no. 23 (December 2010): 6978–82. http://dx.doi.org/10.1016/j.bmcl.2010.09.129.

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4

Goedken, Eric R., Andrew I. Gagnon, Gary T. Overmeyer, Junjian Liu, Richard A. Petrillo, Andrew F. Burchat, and Medha J. Tomlinson. "HTRF-Based Assay for Microsomal Prostaglandin E2 Synthase-1 Activity." Journal of Biomolecular Screening 13, no. 7 (July 1, 2008): 619–25. http://dx.doi.org/10.1177/1087057108321145.

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Microsomal prostaglandin E2 synthase-1 (mPGES-1) catalyzes the formation of prostaglandin E2 (PGE2) from the endoperoxide prostaglandin H 2 (PGH2). Expression of this enzyme is induced during the inflammatory response, and mouse knockout experiments suggest it may be an attractive target for antiarthritic therapies. Assaying the activity of this enzyme in vitro is challenging because of the unstable nature of the PGH 2 substrate. Here, the authors present an mPGES-1 activity assay suitable for characterization of enzyme preparations and for determining the potency of inhibitor compounds. This plate-based competition assay uses homogenous time-resolved fluorescence to measure PGE2 produced by the enzyme. The assay is insensitive to DMSO concentration up to 10% and does not require extensive washes after the initial enzyme reaction is concluded, making it a simple and convenient way to assess mPGES-1 inhibition. ( Journal of Biomolecular Screening 2008:619-625)

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5

Koeberle, Andreas, Hinnak Northoff, and Oliver Werz. "Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1." Molecular Cancer Therapeutics 8, no. 8 (August 2009): 2348–55. http://dx.doi.org/10.1158/1535-7163.mct-09-0290.

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6

Koeberle, Andreas, Ulf Siemoneit, Ulrike Bühring, Hinnak Northoff, Stefan Laufer, Wolfgang Albrecht, and Oliver Werz. "Licofelone Suppresses Prostaglandin E2 Formation by Interference with the Inducible Microsomal Prostaglandin E2 Synthase-1." Journal of Pharmacology and Experimental Therapeutics 326, no. 3 (June 11, 2008): 975–82. http://dx.doi.org/10.1124/jpet.108.139444.

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7

Zhou, Jiping, Denise G. Joplin, Janet V. Cross, and Dennis J. Templeton. "Sulforaphane Inhibits Prostaglandin E2 Synthesis by Suppressing Microsomal Prostaglandin E Synthase 1." PLoS ONE 7, no. 11 (November 16, 2012): e49744. http://dx.doi.org/10.1371/journal.pone.0049744.

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8

Koeberle, A., F. Pollastro, H. Northoff, and O. Werz. "Myrtucommulone, a natural acylphloroglucinol, inhibits microsomal prostaglandin E2 synthase-1." British Journal of Pharmacology 156, no. 6 (March 4, 2009): 952–61. http://dx.doi.org/10.1111/j.1476-5381.2009.00070.x.

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9

Ikeda-Matsuo, Yuri, Yuji Ikegaya, Norio Matsuki, Satoshi Uematsu, Shizuo Akira, and Yasuharu Sasaki. "Microglia-specific expression of microsomal prostaglandin E2 synthase-1 contributes to lipopolysaccharide-induced prostaglandin E2 production." Journal of Neurochemistry 94, no. 6 (September 2005): 1546–58. http://dx.doi.org/10.1111/j.1471-4159.2005.03302.x.

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10

Andersson, Susanne, Mattias Norman, Rolf Olsson, Robin Smith, Gang Liu, and Johan Nord. "High-Precision, Room Temperature Screening Assay for Inhibitors of Microsomal Prostaglandin E Synthase-1." Journal of Biomolecular Screening 17, no. 10 (August 15, 2012): 1372–78. http://dx.doi.org/10.1177/1087057112456424.

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Microsomal prostaglandin E synthase-1 (mPGES-1) is the major enzyme catalyzing the isomerization of prostaglandin (PG) H2 to PGE2. Here we report the development of a robust and practical automated assay in a 384-well format for room temperature screening of mPGES-1 inhibitors with high precision and low reagent consumption. The assay should enable precise structure-activity relationship development. It uses acetonitrile as solvent for PGH2, FeCl2/citrate as stop reagent, and a short reaction time. Combined with high-precision liquid transfer and extensive mixing after addition of reactants, these properties let the assay reach Z′ > 0.7 and high reproducibility of inhibitor IC50 values. Thorough investigation of the quality of mixing in all liquid transfer steps proved crucial for reaching high-precision performance. Abbreviations: mPGES-1 (microsomal prostaglandin E synthase-1); FRET (fluorescence resonance energy transfer); HTRF (homogeneous time-resolved fluorescence); PGH2 (prostaglandin H2); PGE2 (prostaglandin E2); SAR (structure-activity relationship); COX-2 (cyclooxygenase-2); GSH (glutathione); ALP (automated labware positioner)

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11

Koeberle, Andreas, Julia Bauer, Moritz Verhoff, Marika Hoffmann, Hinnak Northoff, and Oliver Werz. "Green tea epigallocatechin-3-gallate inhibits microsomal prostaglandin E2 synthase-1." Biochemical and Biophysical Research Communications 388, no. 2 (October 2009): 350–54. http://dx.doi.org/10.1016/j.bbrc.2009.08.005.

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12

San Juan, Amor A., and Seung Joo Cho. "3D-QSAR study of microsomal prostaglandin E2 synthase(mPGES-1) inhibitors." Journal of Molecular Modeling 13, no. 5 (March 28, 2007): 601–10. http://dx.doi.org/10.1007/s00894-007-0172-0.

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13

Jania, Leigh A., Subhashini Chandrasekharan, Michael G. Backlund, Nicholas A. Foley, John Snouwaert, I.-Ming Wang, Patsy Clark, Laurent P. Audoly, and Beverly H. Koller. "Microsomal prostaglandin E synthase-2 is not essential for in vivo prostaglandin E2 biosynthesis." Prostaglandins & Other Lipid Mediators 88, no. 3-4 (April 2009): 73–81. http://dx.doi.org/10.1016/j.prostaglandins.2008.10.003.

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14

Ikeda-Matsuo, Y., H. Tanji, A. Ota, Y. Hirayama, S. Uematsu, S. Akira, and Y. Sasaki. "Microsomal prostaglandin E synthase-1 contributes to ischaemic excitotoxicity through prostaglandin E2 EP3 receptors." British Journal of Pharmacology 160, no. 4 (March 2, 2010): 847–59. http://dx.doi.org/10.1111/j.1476-5381.2010.00711.x.

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15

Vazquez-Tello, Alejandro, Li Fan, Xin Hou, Jean-Sébastien Joyal, Joseph A. Mancini, Christiane Quiniou, Ronald I. Clyman, Fernand Gobeil, Daya R. Varma, and Sylvain Chemtob. "Intracellular-specific colocalization of prostaglandin E2 synthases and cyclooxygenases in the brain." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 287, no. 5 (November 2004): R1155—R1163. http://dx.doi.org/10.1152/ajpregu.00077.2004.

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Prostaglandin E2 (PGE2) is the major primary prostaglandin generated by brain cells. However, the coordination and intracellular localization of the cyclooxygenases (COXs) and prostaglandin E synthases (PGESs) that convert arachidonic acid to PGE2 in brain tissue are not known. We aimed to determine whether microsomal and cytosolic PGES (mPGES-1 and cPGES) colocalize and coordinate activity with either COX-1 or COX-2 in brain tissue, particularly during development. Importantly, we found that cytosolic PGES also associates with microsomes (cPGES-m) from the cerebrum and cerebral vasculature of the pig and rat as well as microsomes from various cell lines; this seemed dependent on the carboxyl terminal 35-amino acid domain and a cysteine residue (C58) of cPGES. In microsomal membranes from the postnatal brain and cerebral microvessels of mature animals, cPGES-m colocalized with both COX-1 and COX-2, whereas mPGES-1 was undetectable in these microsomes. Accordingly, in this cell compartment, cPGES could coordinate its activity with COX-2 and COX-1 (partly inhibited by NS398); albeit in microsomes of the brain microvasculature from newborns, mPGES-1 was also present. In contrast, in nuclei of brain parenchymal and endothelial cells, mPGES-1 and cPGES colocalized exclusively with COX-2 (determined by immunoblotting and immunohistochemistry); these PGESs contributed to conversion of PGH2 into PGE2. Hence, contrary to a previously proposed model of exclusive COX-2/mPGES-1 coordination, COX-2 can coordinate with mPGES-1 and/or cPGES in the brain, depending on the cell compartment and the age group.

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16

Janowski, Tomasz, Wojciech Barański, Karolina Łukasik, Dariusz Skarżyński, Sławomir Zduńczyk, and Katarzyna Malinowska. "Endometrial mRNA expression of prostaglandin synthase enzymes PTGS 2, PTGFS and mPTGES 1 in repeat-breeding cows with cytologically determined endometritis." Acta Veterinaria Hungarica 65, no. 1 (March 2017): 96–104. http://dx.doi.org/10.1556/004.2017.010.

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Little is known about the inflammatory response of the endometrium in repeat-breeding cows with subclinical endometritis (SE). The objective of this study was to evaluate the mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS 2), prostaglandin F2α synthase (PTGFS) and prostaglandin E2 microsomal synthase 1 (mPTGES 1) in the endometrium of repeat-breeding cows with and without SE. SE was diagnosed cytologically using the cytobrush method, with the threshold being set at 5% polymorphonuclear neutrophils. Biopsy samples were obtained from the endometrium of repeat-breeding cows with SE (n = 10) and without SE (n = 10). The mRNA expression of the synthases was evaluated using qRT-PCR. Significantly higher (P < 0.05) expression of the PTGS 2 gene was detected in the repeat breeders with SE, whereas there was no significant difference in the expression of PTGFS and mPTGES 1 mRNAs between repeatbreeding cows with SE and those without it (P > 0.05). Our study confirms that increased endometrial expression of the PTGS 2 gene is involved in the inflammatory response in repeat breeders.

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17

Sanphetchaloemchok, Pitipat, Mohd Fadhlizil Fasihi Mohd Aluwi, Kamal Rullah, and Kok Wai Lam. "Synthesis, In Silico Molecular Docking Modeling and Pharmacophore Mapping of (E)-3-(4-Hydroxy-2,6-Dimethoxyphenyl)-1-Phenylprop-2-en-1-One as Potential New Inhibitor of Microsomal Prostaglandin E₂ Synthase-1." Materials Science Forum 981 (March 2020): 247–52. http://dx.doi.org/10.4028/www.scientific.net/msf.981.247.

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The discovery of potent anti-inflammatory agents through inhibition of prostaglandin E2 (PGE2) via microsomal prostaglandin E2 synthase-1 (mPGES-1) blocking has been proven to be an important game changer in pharmaceutical industry in recent years. In this study, new chalcone derivative has been successfully synthesized via Claisen-Schmidt condensation reaction. The compound was then docked into mPGES-1 active site to predict anti-inflammatory properties through ligand-enzyme interaction investigation. The data collected from in silico molecular docking simulation and pharmacophore modeling studies provide important insight on the molecular conformation and further shed light towards structural modification of the future novel mPGES-1 inhibitor.

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18

Sasaki, Yuka, Yoshihito Nakatani, and Shuntaro Hara. "Role of microsomal prostaglandin E synthase-1 (mPGES-1)-derived prostaglandin E2 in colon carcinogenesis." Prostaglandins & Other Lipid Mediators 121 (September 2015): 42–45. http://dx.doi.org/10.1016/j.prostaglandins.2015.06.006.

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19

Seymour, Michelle L., David G. Binion, Steven J. Compton, Morley D. Hollenberg, and Wallace K. MacNaughton. "Expression of proteinase-activated receptor 2 on human primary gastrointestinal myofibroblasts and stimulation of prostaglandin synthesis." Canadian Journal of Physiology and Pharmacology 83, no. 7 (July 1, 2005): 605–16. http://dx.doi.org/10.1139/y05-046.

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It is known that subepithelial myofibroblast-derived prostaglandin (PG)E2 can regulate intestinal epithelial cell functions, and that proteinase-activated receptor-2 (PAR2) is abundantly expressed in the gastrointestinal tract. Since PAR2 activation has previously been associated with stimulation of PGE2 synthesis, we hypothesized that PAR2 expressed on primary human gastrointestinal myofibroblasts regulates PGE2 synthesis via cyclooxygenase (COX)-1 and (or) COX-2, and associated PGE synthases. Primary human myofibroblasts were isolated from the resection tissue of the esophagus, small intestine, and colon. Expression of functional PAR2 was determined by RT-PCR and by calcium mobilization in Fura-2/AM-loaded cells. Trypsin and the selective PAR2-activating peptide (PAR2-AP) SLIGRL-NH2 stimulated PGE2 synthesis in a concentration-dependent manner, as measured by enzyme immunoassay. Selective COX inhibition showed PAR2-induced PGE2 synthesis to be COX-1 dependent in esophageal myofibroblasts and both COX-1 and COX-2 dependent in colonic cells, consistent with the distribution of COX-1 and COX-2 expression. Although both cytosolic and microsomal PGE synthases were expressed in cells from all tissues, microsomal PGE synthases were expressed at highest levels in the colonic myofibroblasts. Activation of PAR2 on gastrointestinal myofibroblasts stimulates PGE2 synthesis via different pathways in the colon than in the esophagus and small intestine. Key words: Proteinase-activated receptor, myofibroblast, cyclooxygenase, PGE synthase, prostaglandin E2, esophagus, small intestine, colon.

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20

Bouayad, Asmàa, Jean-Claude Fouron, Xin Hou, Martin Beauchamp, Christiane Quiniou, Daniel Abran, Krishna Peri, Ronald I. Clyman, Daya R. Varma, and Sylvain Chemtob. "Developmental regulation of prostaglandin E2 synthase in porcine ductus arteriosus." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 286, no. 5 (May 2004): R903—R909. http://dx.doi.org/10.1152/ajpregu.00437.2003.

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The synthesis of PGE2, the major vasodilator prostanoid of the ductus arteriosus (DA), is catalyzed by PGE2 synthases (PGES). The factors implicated in increased PGE2 synthesis in the perinatal DA are not known. We studied the developmental changes of PGES along with that of cyclooxygenase (COX)-2 and cytosolic phospholipase A2 (cPLA2) in the DA of fetal (75-90% gestation) and immediately postnatal newborn (NB) piglets. Levels of microsomal PGES (mPGES), COX-2, and PGE2 in the DA of NB were ∼7-fold higher than in fetus; activities of cytosolic PGES (cPGES) and cPLA2 in DA of the fetus and NB did not differ. Because platelet-activating factor (PAF) could regulate COX-2 expression, the former was measured and found to be more abundant in the DA of the NB than of fetus. PAF elicited an increase in mPGES, COX-2, and PGE2 in fetal DA to levels approaching those of the NB; cPGES, cPLA2, and COX-1 were unaffected. In perinatal NB DA, PAF receptor antagonists BN-52021 and THG-315 reduced mPGES, COX-2, and PGE2 levels and were associated with increased DA tone. It is concluded that PAF contributes in regulating DA tone by governing mPGES, COX-2, and ensuing PGE2 levels in the perinate.

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21

Rice, G. E., M. H. Wong, and G. D. Thorburn. "Gestational changes in prostaglandin synthase activity of ovine cotyledonary microsomes." Journal of Endocrinology 118, no. 2 (August 1988): 265–70. http://dx.doi.org/10.1677/joe.0.1180265.

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ABSTRACT The capacity of cotyledonary microsomes, prepared from pregnant ewes (20–145 days of gestation), to metabolize exogenous arachidonic acid was quantified using a radiolabel technique. During gestation, the capacity of microsomes to metabolize arachidonic acid increased 25-fold, from 0·36±0·06μmol arachidonic acid/incubation (n = 8) at <100 days of gestation to 9·06±1 ·02μmol arachidonic acid/incubation at 130–145 days of gestation (n = 5; P<0·05). Arachidonic acid was metabolized to prostaglandin E2 and F2α, as determined by thin-layer chromatography and reverse-phase high performance liquid chromatography. The profile of prostaglandins synthesized by cotyledonary microsomes did not change throughout gestation. These data suggest that the increase in cotyledonary prostaglandin synthesis that occurs during late gestation and at term may reflect an increase in the tissue content of prostaglandin H2 synthase. J. Endocr. (1988) 118, 265–270

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22

Mehrotra, Sanjana, Akira Morimiya, Beamon Agarwal, Raymond Konger, and Sunil Badve. "Microsomal prostaglandin E2 synthase-1 in breast cancer: a potential target for therapy." Journal of Pathology 208, no. 3 (2006): 356–63. http://dx.doi.org/10.1002/path.1907.

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23

Singh Bahia, Malkeet, Yogesh Kumar Katare, Om Silakari, Bhawna Vyas, and Pragati Silakari. "Inhibitors of Microsomal Prostaglandin E2 Synthase-1 Enzyme as Emerging Anti-Inflammatory Candidates." Medicinal Research Reviews 34, no. 4 (January 13, 2014): 825–55. http://dx.doi.org/10.1002/med.21306.

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24

Bauer, Julia, Susanne Kuehnl, Judith M. Rollinger, Olga Scherer, Hinnak Northoff, Hermann Stuppner, Oliver Werz, and Andreas Koeberle. "Carnosol and Carnosic Acids from Salvia officinalis Inhibit Microsomal Prostaglandin E2 Synthase-1." Journal of Pharmacology and Experimental Therapeutics 342, no. 1 (April 16, 2012): 169–76. http://dx.doi.org/10.1124/jpet.112.193847.

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25

Ji, Shuang, Rui Guo, Jing Wang, Lei Qian, Min Liu, Hu Xu, Jiayang Zhang, Youfei Guan, Guangrui Yang, and Lihong Chen. "Microsomal Prostaglandin E2 Synthase-1 Deletion Attenuates Isoproterenol-Induced Myocardial Fibrosis in Mice." Journal of Pharmacology and Experimental Therapeutics 375, no. 1 (August 5, 2020): 40–48. http://dx.doi.org/10.1124/jpet.120.000023.

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26

Wiegard, Andrea, Walburga Hanekamp, Klaus Griessbach, Jörg Fabian, and Matthias Lehr. "Pyrrole alkanoic acid derivatives as nuisance inhibitors of microsomal prostaglandin E2 synthase-1." European Journal of Medicinal Chemistry 48 (February 2012): 153–63. http://dx.doi.org/10.1016/j.ejmech.2011.12.009.

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27

Molloy, E. S., M. P. Morgan, G. A. Doherty, B. McDonnell, J. O'Byrne, D. J. Fitzgerald, and G. M. McCarthy. "Microsomal prostaglandin E2 synthase 1 expression in basic calcium phosphate crystal-stimulated fibroblasts: role of prostaglandin E2 and the EP4 receptor." Osteoarthritis and Cartilage 17, no. 5 (May 2009): 686–92. http://dx.doi.org/10.1016/j.joca.2008.09.014.

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28

Myers, S., C. T. Evans, L. Bartula, B. Kalley-Taylor, A. R. Habeeb, and T. Goka. "Increased gall-bladder prostanoid synthesis after bile-duct ligation in the rabbit is secondary to new enzyme formation." Biochemical Journal 288, no. 2 (December 1, 1992): 585–90. http://dx.doi.org/10.1042/bj2880585.

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Ligation of the common bile duct (BDL) in the male rabbit resulted in increased gall-bladder microsomal total cyclo-oxygenase activity with prostaglandin E2 (PGE2) and 6-oxoprostaglandin F1 alpha [6-oxo-PGF1 alpha, stable metabolite of prostaglandin I2 (PGI2; prostacyclin)] as the major prostanoids synthesized after 24 and 72 h. Kinetic analysis of gallbladder microsomal membrane fractions incubated with increasing levels of [14C]arachidonic acid indicated that BDL for 24 and 72 h did not change substrate affinity (apparent Km) but markedly increased the rate of conversion (apparent Vmax.) suggesting the presence of more total enzyme responsible for synthesis of 6-oxo-PGF1 alpha and PGE2. BDL for 24 and 72 h significantly increased gall-bladder tissue slice basal release of 6-oxo-PGF1 alpha, but not PGE2, when compared with the controls. Gall-bladder slice release of PGE2 was 3-fold less than 6-oxo-PGF1 alpha in the control gall-bladder slices. Immunoblot analysis of 72 h BDL gall-bladder microsomal membrane fractions showed a slight increase in cyclo-oxygenase content and a 5-fold increase in the content of prostacyclin synthase as compared with the control. These data suggest that the BDL-stimulated total gall-bladder cyclo-oxygenase activity was the result of an increase in the level of specific prostaglandin-synthetic enzymes, in particular prostacyclin synthase, and not from a change in enzyme affinity.

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29

Brock, Joseph S., Mats Hamberg, Navisraj Balagunaseelan, Michael Goodman, Ralf Morgenstern, Emilia Strandback, Bengt Samuelsson, Agnes Rinaldo-Matthis, and Jesper Z. Haeggström. "A dynamic Asp–Arg interaction is essential for catalysis in microsomal prostaglandin E2 synthase." Proceedings of the National Academy of Sciences 113, no. 4 (January 11, 2016): 972–77. http://dx.doi.org/10.1073/pnas.1522891113.

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Microsomal prostaglandin E2 synthase type 1 (mPGES-1) is responsible for the formation of the potent lipid mediator prostaglandin E2 under proinflammatory conditions, and this enzyme has received considerable attention as a drug target. Recently, a high-resolution crystal structure of human mPGES-1 was presented, with Ser-127 being proposed as the hydrogen-bond donor stabilizing thiolate anion formation within the cofactor, glutathione (GSH). We have combined site-directed mutagenesis and activity assays with a structural dynamics analysis to probe the functional roles of such putative catalytic residues. We found that Ser-127 is not required for activity, whereas an interaction between Arg-126 and Asp-49 is essential for catalysis. We postulate that both residues, in addition to a crystallographic water, serve critical roles within the enzymatic mechanism. After characterizing the size or charge conservative mutations Arg-126–Gln, Asp-49–Asn, and Arg-126–Lys, we inferred that a crystallographic water acts as a general base during GSH thiolate formation, stabilized by interaction with Arg-126, which is itself modulated by its respective interaction with Asp-49. We subsequently found hidden conformational ensembles within the crystal structure that correlate well with our biochemical data. The resulting contact signaling network connects Asp-49 to distal residues involved in GSH binding and is ligand dependent. Our work has broad implications for development of efficient mPGES-1 inhibitors, potential anti-inflammatory and anticancer agents.

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30

Yao, Lu, Weina Chen, Chang Han, and Tong Wu. "Microsomal prostaglandin E synthase-1 protects against Fas-induced liver injury." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 11 (June 1, 2016): G1071—G1080. http://dx.doi.org/10.1152/ajpgi.00327.2015.

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Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme for the synthesis of prostaglandin E2 (PGE2), a proproliferative and antiapoptotic lipid molecule important for tissue regeneration and injury repair. In this study, we developed transgenic (Tg) mice with targeted expression of mPGES-1 in the liver to assess Fas-induced hepatocyte apoptosis and acute liver injury. Compared with wild-type (WT) mice, the mPGES-1 Tg mice showed less liver hemorrhage, lower serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, less hepatic necrosis/apoptosis, and lower level of caspase cascade activation after intraperitoneal injection of the anti-Fas antibody Jo2. Western blotting analysis revealed increased expression and activation of the serine/threonine kinase Akt and associated antiapoptotic molecules in the liver tissues of Jo2-treated mPGES-1 Tg mice. Pretreatment with the mPGES-1 inhibitor (MF63) or the Akt inhibitor (Akt inhibitor V) restored the susceptibility of the mPGES-1 Tg mice to Fas-induced liver injury. Our findings provide novel evidence that mPGES-1 prevents Fas-induced liver injury through activation of Akt and related signaling and suggest that induction of mPGES-1 or treatment with PGE2 may represent important therapeutic strategy for the prevention and treatment of Fas-associated liver injuries.

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31

Budik, Sven, Ingrid Walter, Marie-Christine Leitner, Reinhard Ertl, and Christine Aurich. "Expression of Enzymes Associated with Prostaglandin Synthesis in Equine Conceptuses." Animals 11, no. 4 (April 20, 2021): 1180. http://dx.doi.org/10.3390/ani11041180.

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In the horse, mobility of the conceptus is required for maternal recognition of pregnancy depending on secretion of prostaglandins by the conceptus. The aim of this study was to determine the expression and localization of key enzymes of the different pathways leading to synthesis of prostaglandin E2 and F2α in the equine conceptus during the mobility phase. Enzyme expression was analyzed via quantitative RT-PCR in total RNA samples of equine conceptuses collected on days 10 (n = 5), 12 (n = 12), 14 (n = 5) and 16 (n = 7) from healthy mares. Relative abundance of cyclooxygenase (COX)-2 mRNA was higher (p < 0.05) than of COX-1 irrespective of conceptus age and for phospholipase A2 on day 16 in comparison to all other days (p < 0.01). Abundance of mRNA of cytosolic and microsomal prostaglandin E synthase (PGES) and of carbonyl reductase (CBR) 1 was not influenced by conceptus age. Immunohistochemically, COX-1, COX-2, as well as cytosolic and microsomal PGES were present in both the ectodermal and endodermal layer of the yolk sac wall. CBR-1 was restricted to periembryonic disc area. The localisation of the key enzymes explains the mechanism of embryo mobility. In vitro incubation of primary trophoblast cell cultures with oxytocin had no effect on key enzyme synthesis.

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32

Takemiya, Takako. "Prostaglandin E2 produced by microsomal prostaglandin E synthase-1 regulates the onset and the maintenance of wakefulness." Neurochemistry International 59, no. 6 (November 2011): 922–24. http://dx.doi.org/10.1016/j.neuint.2011.07.001.

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33

Koeberle, Andreas, Stefan A. Laufer, and Oliver Werz. "Design and Development of Microsomal Prostaglandin E2 Synthase-1 Inhibitors: Challenges and Future Directions." Journal of Medicinal Chemistry 59, no. 13 (February 24, 2016): 5970–86. http://dx.doi.org/10.1021/acs.jmedchem.5b01750.

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34

Koeberle, Andreas, and Oliver Werz. "Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders." Biochemical Pharmacology 98, no. 1 (November 2015): 1–15. http://dx.doi.org/10.1016/j.bcp.2015.06.022.

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35

Riendeau, Denis, Renee Aspiotis, Diane Ethier, Yves Gareau, Erich L. Grimm, Jocelyne Guay, Sébastien Guiral, et al. "Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886." Bioorganic & Medicinal Chemistry Letters 15, no. 14 (July 2005): 3352–55. http://dx.doi.org/10.1016/j.bmcl.2005.05.027.

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36

Zang, Shengbing, Mulan Ni, Yuane Lian, Yu Zhang, Jingfeng Liu, and Aimin Huang. "Expression of microsomal prostaglandin E2 synthase-1 and its role in human hepatocellular carcinoma." Human Pathology 44, no. 8 (August 2013): 1681–87. http://dx.doi.org/10.1016/j.humpath.2013.04.007.

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37

Martey, Christine A., Stephen J. Pollock, Chantal K. Turner, Katherine M. A. O'Reilly, Carolyn J. Baglole, Richard P. Phipps, and Patricia J. Sime. "Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 5 (November 2004): L981—L991. http://dx.doi.org/10.1152/ajplung.00239.2003.

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Cigarette smoking can lead to many human pathologies including cardiovascular and respiratory disease. Recent studies have defined a role for fibroblasts in the development of colon cancer. Moreover, fibroblasts are now thought of as key “sentinel” cells that initiate inflammation by releasing proinflammatory mediators including prostaglandins (PGs). Pathological overexpression of cyclooxygenase-2 (COX-2) and excess eicosanoid production are found in the early stages of carcinogenesis. By promoting chronic inflammation, COX-2 and eicosanoid production may actually cause a predisposition to malignancy. Furthermore, the associated inflammation induced by production of these mediators is central to the pathogenesis of chronic obstructive pulmonary disease. Little is known of the responses of normal lung fibroblasts to cigarette smoke, despite their abundance. We report herein that normal human lung fibroblasts, when exposed to cigarette smoke extract, induce COX-2 with concurrent synthesis of prostaglandin E2 (PGE2). The mechanisms by which cigarette-derived toxicants lead to increased COX-2 levels and PGE2 synthesis include increases in steady-state COX-2 mRNA levels (approximately four- to fivefold), phosphorylation of ERK1/2, and nuclear translocation of the p50 and p65 subunits of the transcription factor NF-κB, which are important elements in COX-2 expression. Furthermore, there was a dramatic 25-fold increase in microsomal prostaglandin E synthase, the key enzyme involved in the production of PGE2. We propose that normal human lung fibroblasts, when exposed to cigarette smoke constituents, elicit COX-2 expression with consequent prostaglandin synthesis, thus creating a proinflammatory environment. This chronic inflammatory state may act as one of the first steps towards epithelial transformation.

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Megías, Javier, María Isabel Guillén, Victoria Clérigues, Ana I. Rojo, Antonio Cuadrado, Miguel Angel Castejón, Francisco Gomar, and María José Alcaraz. "Heme oxygenase-1 induction modulates microsomal prostaglandin E synthase-1 expression and prostaglandin E2 production in osteoarthritic chondrocytes." Biochemical Pharmacology 77, no. 12 (June 2009): 1806–13. http://dx.doi.org/10.1016/j.bcp.2009.03.009.

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Jüngel, Astrid, Oliver Distler, Ursula Schulze-Horsel, Lars C. Huber, Huy Riem Ha, Beat Simmen, Joachim R. Kalden, David S. Pisetsky, Steffen Gay, and Jörg H. W. Distler. "Microparticles stimulate the synthesis of prostaglandin E2 via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1." Arthritis & Rheumatism 56, no. 11 (2007): 3564–74. http://dx.doi.org/10.1002/art.22980.

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40

FABIAN, J. "Determination of prostaglandin E2 by on-line solid-phase extraction–liquid chromatography with ultraviolet detection for microsomal prostaglandin E2 synthase-1 inhibitor screening." Journal of Chromatography B 875, no. 2 (November 15, 2008): 557–61. http://dx.doi.org/10.1016/j.jchromb.2008.09.038.

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41

Ivanov, Andrei I., Ralph S. Pero, Adrienne C. Scheck, and Andrej A. Romanovsky. "Prostaglandin E2-synthesizing enzymes in fever: differential transcriptional regulation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 283, no. 5 (November 1, 2002): R1104—R1117. http://dx.doi.org/10.1152/ajpregu.00347.2002.

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The febrile response to lipopolysaccharide (LPS) consists of three phases ( phases I–III), all requiring de novo synthesis of prostaglandin (PG) E2. The major mechanism for activation of PGE2-synthesizing enzymes is transcriptional upregulation. The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS (50 μg/kg) was studied. Using real-time RT-PCR, the expression of seven PGE2-synthesizing enzymes in the LPS-processing organs (liver and lungs) and the brain “febrigenic center” (hypothalamus) was quantified. Phase I involved transcriptional upregulation of the functionally coupled cyclooxygenase (COX)-2 and microsomal (m) PGE synthase (PGES) in the liver and lungs. Phase II entailed robust upregulation of all enzymes of the major inflammatory pathway, i.e., secretory (s) phospholipase (PL) A2-IIA → COX-2 → mPGES, in both the periphery and brain. Phase III was accompanied by the induction of cytosolic (c) PLA2-α in the hypothalamus, further upregulation of sPLA2-IIA and mPGES in the hypothalamus and liver, and a decrease in the expression of COX-1 and COX-2 in all tissues studied. Neither sPLA2-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPLA2-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy.

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Zayed, N., F. El Mansouri, N. Chabane, J. Martel-pelletier, J. P. Pelletier, and H. Fahmi. "230 VALPROIC ACID SUPPRESSES INTERLEUKIN-1β-INDUCED MICROSOMAL PROSTAGLANDIN E2 SYNTHASE-1 EXPRESSION IN CHONDROCYTES." Osteoarthritis and Cartilage 18 (October 2010): S106. http://dx.doi.org/10.1016/s1063-4584(10)60257-9.

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Sjogren, T., J. Nord, M. Ek, P. Johansson, G. Liu, and S. Geschwindner. "Crystal structure of microsomal prostaglandin E2 synthase provides insight into diversity in the MAPEG superfamily." Proceedings of the National Academy of Sciences 110, no. 10 (February 19, 2013): 3806–11. http://dx.doi.org/10.1073/pnas.1218504110.

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Hétu, Pierre-Olivier, and Denis Riendeau. "Down-regulation of Microsomal Prostaglandin E2 Synthase-1 in Adipose Tissue by High-fat Feeding*." Obesity 15, no. 1 (January 2007): 60–68. http://dx.doi.org/10.1038/oby.2007.514.

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Wang, Jane, David Limburg, Jeff Carter, Gabriel Mbalaviele, James Gierse, and Michael Vazquez. "Selective inducible microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from an oxicam template." Bioorganic & Medicinal Chemistry Letters 20, no. 5 (March 2010): 1604–9. http://dx.doi.org/10.1016/j.bmcl.2010.01.060.

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Kim, Jang, Nam, Lee, and Lee. "Inhibition of LPS-Induced PGE2 Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme." Proceedings 22, no. 1 (August 7, 2019): 37. http://dx.doi.org/10.3390/proceedings2019022037.

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Microsomal prostaglandin E synthase-1 (mPGES-1) is responsible for the massive prostaglandin E2 (PGE2) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. Recently, we reported that a novel series of phenylsulfonyl hydrazide derivatives could reduce LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of the mPGES-1 enzyme. However, a few of the phenylsulfonyl hydrazide derivatives showed poor metabolic stability in liver microsomes. In order to identify new mPGES-1 inhibitors with improved metabolic stability, therefore, a series of arylsulfonamide derivatives has been synthesized and biologically evaluated against PGE2 production and the mPGES-1 enzyme. Among them, MPO-0186 inhibits the production of PGE2 (IC50 = 0.20 μM) in A549 cells via inhibition of mPGES-1 (IC50 = 0.49 μM in a cell-free assay) together with high selectivity over both COX-1 and COX-2. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE2 production by blocking the PGH2 binding site of the mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good metabolic stability in human liver microsomes and no significant inhibition observed in clinically relevant CYP isoforms.

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Ha, Jae Won, Hyerim Song, Seong Su Hong, and Yong Chool Boo. "Marine Alga Ecklonia cava Extract and Dieckol Attenuate Prostaglandin E2 Production in HaCaT Keratinocytes Exposed to Airborne Particulate Matter." Antioxidants 8, no. 6 (June 21, 2019): 190. http://dx.doi.org/10.3390/antiox8060190.

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Atmospheric particulate matter (PM) is an important cause of skin damage, and an increasing number of studies have been conducted to discover safe, natural materials that can alleviate the oxidative stress and inflammation caused by PM. It has been previously shown that the extract of Ecklonia cava Kjellman, a perennial brown macroalga, can alleviate oxidative stress in epidermal keratinocytes exposed to PM less than 10 microns in diameter (PM10). The present study was undertaken to further examine the anti-inflammatory effects of E. cava extract and its major polyphenolic constituent, dieckol. HaCaT keratinocytes were exposed to PM10 in the presence or absence of E. cava extract or dieckol and analyzed for their viability, prostaglandin E2 (PGE2) release, and gene expression of cyclooxygenase (COX)-1, COX-2, microsomal prostaglandin E2 synthase (mPGES)-1, mPGES-2, and cytosolic prostaglandin E2 synthase (cPGES). PM10 treatment decreased cell viability and increased the production of PGE2, and these changes were partially abrogated by E. cava extract. E. cava extract also attenuated the expression of COX-1, COX-2, and mPGES-2 stimulated by PM10. Dieckol attenuated PGE2 production and the gene expression of COX-1, COX-2, and mPGES-1 stimulated by PM10. This study demonstrates that E. cava extract and dieckol alleviate airborne PM10-induced PGE2 production in keratinocytes through the inhibition of gene expression of COX-1, COX-2, mPGES-1, and/or mPGES-2. Thus, E. cava extract and dieckol are potentially useful natural cosmetic ingredients for counteracting the pro-inflammatory effects of airborne PM.

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Sweeney, Francis J., Timothy S. Wachtmann, James D. Eskra, Kimberley A. Verdries, Ralph H. Lambalot, Thomas J. Carty, Jose R. Perez, and Laurent P. Audoly. "Inhibition of IL-1β-dependent prostaglandin E2 release by antisense microsomal prostaglandin E synthase 1 oligonucleotides in A549 cells." Molecular and Cellular Endocrinology 205, no. 1-2 (July 2003): 151–57. http://dx.doi.org/10.1016/s0303-7207(03)00091-1.

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Galán, María, Marta Miguel, Amada E. Beltrán, Cristina Rodríguez, Ana B. García-Redondo, Ricardo Rodríguez-Calvo, María J. Alonso, José Martínez-González, and Mercedes Salaices. "Angiotensin II differentially modulates cyclooxygenase-2, microsomal prostaglandin E2 synthase-1 and prostaglandin I2 synthase expression in adventitial fibroblasts exposed to inflammatory stimuli." Journal of Hypertension 29, no. 3 (March 2011): 529–36. http://dx.doi.org/10.1097/hjh.0b013e328342b271.

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Dolan, Jennifer M., Jason B. Weinberg, Edmund O'Brien, Anya Abashian, Megan C. Procario, David M. Aronoff, Leslie J. Crofford, Marc Peters-Golden, Lindsay Ward, and Peter Mancuso. "Increased lethality and defective pulmonary clearance of Streptococcus pneumoniae in microsomal prostaglandin E synthase-1-knockout mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 11 (June 1, 2016): L1111—L1120. http://dx.doi.org/10.1152/ajplung.00220.2015.

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The production of prostaglandin E2 (PGE2) increases dramatically during pneumococcal pneumonia, and this lipid mediator impairs alveolar macrophage (AM)-mediated innate immune responses. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme involved in the synthesis of PGE2, and its expression is enhanced during bacterial infections. Genetic deletion of mPGES-1 in mice results in diminished PGE2 production and elevated levels of other prostaglandins after infection. Since PGE2 plays an important immunoregulatory role during bacterial pneumonia we assessed the impact of mPGES-1 deletion in the host defense against pneumococcal pneumonia in vivo and in AMs in vitro. Wild-type (WT) and mPGES-1 knockout (KO) mice were challenged with Streptococcus pneumoniae via the intratracheal route. Compared with WT animals, we observed reduced survival and increased lung and spleen bacterial burdens in mPGES-1 KO mice 24 and 48 h after S. pneumoniae infection. While we found modest differences between WT and mPGES-1 KO mice in pulmonary cytokines, AMs from mPGES-1 KO mice exhibited defective killing of ingested bacteria in vitro that was associated with diminished inducible nitric oxide synthase expression and reduced nitric oxide (NO) synthesis. Treatment of AMs from mPGES-1 KO mice with an NO donor restored bacterial killing in vitro. These results suggest that mPGES-1 plays a critical role in bacterial pneumonia and that genetic ablation of this enzyme results in diminished pulmonary host defense in vivo and in vitro. These results suggest that specific inhibition of PGE2 synthesis by targeting mPGES-1 may weaken host defense against bacterial infections.

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