scholarly journals Up-regulation of cytosolic prostaglandin E synthase in fetal-membrane and amniotic prostaglandin E2 accumulation in labor

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250638
Author(s):  
Nanase Takahashi ◽  
Toshiaki Okuno ◽  
Hiroki Fujii ◽  
Shintaro Makino ◽  
Masaya Takahashi ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Mrna Level ◽  
Fetal Membrane ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Prostaglandin E Synthase ◽  
Detailed Mechanism ◽  
Human Labor ◽  
Cox 2 ◽  
Cox 1

Prostaglandin E2 (PGE2) is known to have important roles in labor, but the detailed mechanism underlying the spontaneous human labor remains unknown. Here, we examined the involvement of prostaglandin biosynthetic enzymes and transporter in the accumulation of PGE2 in amniotic fluid in human labor. PGE2 and its metabolites were abundant in amniotic fluid in deliveries at term in labor (TLB), but not at term not in labor (TNL). In fetal-membrane Transwell assays, levels of PGE2 production in both maternal and fetal compartments were significantly higher in the TLB group than the TNL group. In fetal-membrane, the mRNA level of PTGES3, which encodes cytosolic prostaglandin E synthase (cPGES), was significantly higher in TLB than in TNL, but the mRNA levels of the other PGE2-synthase genes were not affected by labor. Moreover, the mRNA level of PTGS2, which encodes cyclooxygenase-2 (COX-2) in the amnion was significantly higher in TLB than in TNL. Western blot analyses revealed that the levels of COX-1 and COX-2 were comparable between the two groups, however, the level of cPGES was relatively higher in TLB than in TNL. COXs, cPGES, and prostaglandin transporter (SLCO2A1) proteins were all expressed in both chorionic trophoblasts and amniotic epithelium. These findings suggest that COXs, cPGES and SLCO2A1 contribute to PGE2 production from fetal-membrane in labor.

Sulforaphane, a Chemopreventive Compound, Inhibits Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Expression in Human HT-29 Colon Cancer Cells

2018 ◽  
Vol 206 (1-2) ◽  
pp. 46-53 ◽  
Author(s):  
Maryam Sadat Tafakh ◽  
Massoud Saidijam ◽  
Tayebeh Ranjbarnejad ◽  
Sara Malih ◽  
Solmaz Mirzamohammadi ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Caspase 3 ◽  
Mrna Level ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Ht 29 ◽  
Microsomal Prostaglandin E Synthase

Background: A high expression of prostaglandin E2 (PGE2) is found in colorectal cancer. Therefore, blocking of PGE2 generation has been identified as a promising approach for anticancer therapy. Sulforaphane (SFN), an isothiocyanate derived from glucosinolate, is used as the antioxidant and anticancer agents. Methods: HT-29 cells were treated with various concentrations of SFN and compared to untreated cells for the expression of microsomal prostaglandin E synthase-1 (mPGES-1), cyclooxygenase 2 (COX-2), hypoxia-inducible factor-1 (HIF-1), C-X-C chemokine receptor type 4 (CXCR4), vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP)-2 and MMP-9 at the mRNA level. The PGE2 level was measured by ELISA assay. Apoptosis was evaluated by the proportion of sub-G1 cells. The activity of caspase-3 was determined using an enzymatic assay. HT-29 cell migration was assessed using a scratch test. Results: SFN preconditioning decreased the expression of COX-2, mPGES-1, HIF-1, VEGF, CXCR4, MMP-2, and MMP-9. An apoptotic effect of SFN was preceded by the activation of caspase-3 as well as accumulation of cells in the sub-G1 phase of the cell cycle. SFN decreased PGE2 generation and inhibited the in vitro motility/wound-healing activity of HT-29 cells. Conclusions: SFN anticancer effects are associated with antiproliferative, antiangiogenic, and antimetastatic activities arising from the downregulation of the COX-2/ mPGES-1 axis.

Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys

2006 ◽  
Vol 290 (4) ◽  
pp. F897-F904 ◽  
Author(s):  
Lori Warford-Woolgar ◽  
Claudia Yu-Chen Peng ◽  
Jamie Shuhyta ◽  
Andrew Wakefield ◽  
Deepa Sankaran ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Relative Difference ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Relative Contribution ◽  
Prostanoid Production ◽  
Prostaglandin F ◽  
Cox 2 ◽  
Cox 1

Renal prostanoids are important regulators of normal renal function and maintenance of renal homeostasis. In diseased kidneys, renal cylooxygenase (COX) expression and prostanoid formation are altered. With the use of the Han:Sprague-Dawley- cy rat, the aim of this study was to determine the relative contribution of renal COX isoforms (protein, gene expression, and activity) on renal prostanoid production [thromboxane B2 (TXB2, stable metabolite of TXA2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1α (6-keto-PGF1α, stable metabolite of PGI2)] in normal and diseased kidneys. In diseased kidneys, COX-1-immunoreactive protein and mRNA levels were higher and COX-2 levels were lower compared with normal kidneys. In contrast, COX activities were higher in diseased compared with normal kidneys for both COX-1 [0.05 ± 0.02 vs. 0.45 ± 0.11 ng prostanoids·min−1·mg protein−1 ( P < 0.001)] and COX-2 [0.64 ± 0.10 vs. 2.32 ± 0.22 ng prostanoids·min−1·mg protein−1 ( P < 0.001)]. As the relative difference in activity was greater for COX-1, the ratio of COX-1/COX-2 was higher in diseased compared with normal kidneys, although the predominant activity was still due to the COX-2 isoform in both genotypes. Endogenous and steady-state in vitro levels of prostanoids were ∼2–10 times higher in diseased compared with normal kidneys. The differences between normal and diseased kidney prostanoids were in the order of TXB2 > 6-keto-PGF1α > PGE2, as determined by higher renal prostanoid levels and COX activity ratios of TXB2/6-keto-PGF1α, TXB2/PGE2, and 6-keto-PGF1α/PGE2. This specificity in both the COX isoform type and for the prostanoids produced has implications for normal and diseased kidneys in treatments involving selective inhibition of COX isoforms.

Up-regulation of microsomal prostaglandin E synthase-1 in COX-1 and COX-2 knock-out mouse fibroblast cell lines

2009 ◽  
Vol 88 (3-4) ◽  
pp. 111-116 ◽  
Author(s):  
Duanpen Sandee ◽  
Sasitorn Sivanuntakorn ◽  
Vanicha Vichai ◽  
Jarin Kramyu ◽  
Kanyawim Kirtikara
Keyword(s):  
Cell Lines ◽  
Fibroblast Cell ◽  
Mouse Fibroblast ◽  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Knock Out ◽  
Cox 2 ◽  
Knock Out Mouse ◽  
Cox 1 ◽  
Fibroblast Cell Lines

scholarly journals SAT0315 INHIBITION OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES-1) BY GS-248 REDUCES PROSTAGLANDIN E2 BIOSYNTHESIS WHILE INCREASING PROSTACYCLIN IN HUMAN SUBJECTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1103.2-1103
Author(s):  
C. Edenius ◽  
G. Ekström ◽  
J. Kolmert ◽  
R. Morgenstern ◽  
P. Stenberg ◽  
...  
Keyword(s):  
Whole Blood ◽  
Vascular Tone ◽  
Ex Vivo ◽  
Prostaglandin E ◽  
Maximum Plasma ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Oral Doses ◽  
Microsomal Prostaglandin E Synthase

Background:Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the formation prostaglandin (PG) E2from cyclooxygenase derived PGH2(1, 2). Inhibition of mPGES-1 leads to reduction of pro-inflammatory PGE2, while in vessels there is a concomitant increase of vasoprotective prostacyclin (PGI2) via shunting of PGH2(3,4). Apart from relieving symptoms in experimental animal models of inflammation, inhibitors of mPGES-1 cause relaxation of human medium sized arteries(4)and resistance arteries(5). The prostaglandin profile following mPGES-1 inhibition, explains the anti-inflammatory effects and also opens for the possibility of treating inflammatory diseases with concomitant vasculopathies. GS-248 is a potent and selective inhibitor of mPGES-1 exhibiting sub-nanomolar IC50in human whole bloodex vivo.Objectives:To evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of GS-248.Methods:Healthy males and females (age 18–73 years) were included in the study. Six cohorts were administrated single oral doses of 1-300mg GS-248 (n=36) or placebo (n=12), three cohorts were administered once daily doses of 20-180mg GS-248 (n=18) or placebo (n=12) over ten days. In addition, 8 subjects were treated in a separate cohort with 200mg celecoxib bid for ten days. Blood samples were drawn for measurement of GS-248 exposure and production of PGE2after LPS incubationex vivo. The content of PGE2and PGI2metabolites was measured in urine. All analyses were performed by LC-MS/MS.Results:GS-248 was safe and well tolerated at all tested dose levels. Maximum plasma concentration was achieved 1 - 2.5 hours after dosing, and half-life was about 10 hours. Induced PGE2formationex vivo,catalyzed by mPGES-1, was completely inhibited for 24 hours after a single low dose (40mg) of GS-248. In urine, GS-248 dose-dependently reduced the excretion of PGE2metabolite by more than 50% whereas the excretion of PGI2metabolite increased more than twice the baseline levels. In the celecoxib cohort urinary metabolites of both PGE2and PGI2were reduced with approx 50%.Conclusion:GS-248 at investigated oral doses was safe and well tolerated. There was a sustained inhibition of LPS induced PGE2formation in whole blood. In urine, there was a metabolite shift showing reduced PGE2and increased PGI2, while celecoxib reduced both PGE2and PGI2metabolites. This suggests that selective inhibition of mPGES-1 results in systemic shunting of PGH2to PGI2formation, leading to anti-inflammatory and vasodilatory effects, while preventing platelet activation. The results warrant further evaluation of GS-248 in inflammatory conditions with vasculopathies such as Digital Ulcers and Raynaud’s Phenomenon in Systemic Sclerosis.References:[1]Korotkova M, Jakobsson PJ. Persisting eicosanoid pathways in rheumatic diseases. Nat Rev Rheumatol. 2014;10:229-41[2]Bergqvist F, Morgenstern R, Jakobsson PJ. A review on mPGES-1 inhibitors: From preclinical studies to clinical applications. Prostaglandins Other Lipid Mediat. 2019;147:106383[3]Kirkby NS, et al. Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis. Cardiovasc Res. 2020[4]Ozen G, et al. Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2: a safer alternative to COX-2 inhibition. Br J Pharmacol. 2017;174:4087-98[5]Larsson K, et al. Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone. Br J Pharmacol. 2019;176:4625-38Disclosure of Interests:Charlotte Edenius Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Gunilla Ekström Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Johan Kolmert Consultant of: Gesynta Pharma,, Ralf Morgenstern Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Patric Stenberg Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca,, Göran Tornling Shareholder of: Gesynta Pharma, Vicore Pharma,, Consultant of: Gesynta Pharma, Vicore Pharma, AnaMar

scholarly journals Oleifolioside A, a New Active Compound, Attenuates LPS-Stimulated iNOS and COX-2 Expression through the Downregulation of NF-κB and MAPK Activities in RAW 264.7 Macrophages

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Hai Yang Yu ◽  
Kyoung-Sook Kim ◽  
Young-Choon Lee ◽  
Hyung-In Moon ◽  
Jai-Heon Lee
Keyword(s):  
Nitric Oxide ◽  
Mapk Signaling ◽  
Binding Activity ◽  
Prostaglandin E ◽  
Raw 264.7 ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Raw 264.7 Macrophages ◽  
Dendropanax Morbifera ◽  
Cox 2

Oleifolioside A, a new triterpenoid compound isolated fromDendropanax morbiferaLeveille (D. morbifera), was shown in this study to have potent inhibitory effects on lipopolysaccharide (LPS-)stimulated nitric oxide (NO) and prostaglandin E2(PGE2) production in RAW 264.7 macrophages. Consistent with these findings, oleifolioside A was further shown to suppress the expression of LPS-stimulated inducible nitric oxide synthase (iNOS) and cyclooxigenase-2 (COX-2) in a dose-dependent manner at both the protein and mRNA levels and to significantly inhibit the DNA-binding activity and transcriptional activity of NF-κB in response to LPS. These results were found to be associated with the inhibition of the degradation and phosphorylation of IκB-αand subsequent translocation of the NF-κB p65 subunit to the nucleus. Inhibition of NF-κB activation by oleifolioside A was also shown to be mediated through the prevention of p38 MAPK and ERK1/2 phosphorylation. Taken together, our results suggest that oleifolioside A has the potential to be a novel anti-inflammatory agent capable of targeting both the NF-κB and MAPK signaling pathways.

Ischemia-reperfusion rapidly increases COX-2 expression in piglet cerebral arteries

1999 ◽  
Vol 277 (3) ◽  
pp. H1207-H1214 ◽  
Author(s):  
Ferenc Domoki ◽  
Roland Veltkamp ◽  
Nishadi Thrikawala ◽  
Greg Robins ◽  
Ferenc Bari ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Cerebral Arteries ◽  
Rnase Protection Assay ◽  
Immunoblot Analysis ◽  
Mrna Levels ◽  
Rnase Protection ◽  
Time Control ◽  
Cox 2 ◽  
Cox 1 ◽  
Ischemic Stress

In the newborn, cyclooxygenase (COX)-derived products play an important role in the cerebrovascular dysfunction after ischemia-reperfusion (I/R). We examined effects of I/R on expression of COX-1 and COX-2 isoforms in large cerebral arteries of anesthetized piglets. The circle of Willis, the basilar, and the middle cerebral arteries were collected from piglets at 0.5–12 h after global ischemia (2.5–10 min, n = 50), hypoxia ( n = 3), or hypercapnia ( n = 2) and from time-control ( n = 19) or untreated animals ( n = 7). Tissues were analyzed for COX-1 and COX-2 mRNA and protein using RNase protection assay and immunoblot analysis, respectively. Ischemia increased COX-2 mRNA by 30 min, and maximal levels were reached at 2 h. Hypoxia or hypercapnia had minimal effects on COX-2 mRNA. COX-2 protein levels were also consistently elevated by 8 h after I/R. Increases in COX-2 mRNA or protein were not influenced by pretreatment with either indomethacin (5 mg/kg iv, n = 5) or nitro-l-arginine methyl ester (15 mg/kg iv, n = 7). COX-1 mRNA levels were low in time controls, and ischemic stress had no significant effect on COX-1 expression. Thus ischemic stress leads to relatively rapid, selective induction of COX-2 in cerebral arteries.

IRE1α–XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain

Science ◽  
2019 ◽  
Vol 365 (6450) ◽  
pp. eaau6499 ◽  
Author(s):  
Sahil Chopra ◽  
Paolo Giovanelli ◽  
Perla Abigail Alvarado-Vazquez ◽  
Sara Alonso ◽  
Minkyung Song ◽  
...  
Keyword(s):  
Er Stress ◽  
Myeloid Cells ◽  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Prostaglandin Biosynthesis ◽  
Stress Sensors ◽  
Prostaglandin Endoperoxide Synthase ◽  
Cox 2 ◽  
Control Pain ◽  
Er Homeostasis

Inositol-requiring enzyme 1[α] (IRE1[α])–X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α–XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE2), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human PTGS2 and PTGES genes to enable optimal PGE2 production. Mice that lack IRE1α–XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE2-dependent models of pain. Thus, IRE1α–XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.

Cyclooxygenases and prostaglandin E synthases in preimplantation mouse embryos

Zygote ◽  
2005 ◽  
Vol 13 (2) ◽  
pp. 103-108 ◽  
Author(s):  
Hui-Ning Tan ◽  
Ying Liu ◽  
Hong-Lu Diao ◽  
Zeng-Ming Yang
Keyword(s):  
Blastocyst Stage ◽  
Mouse Embryos ◽  
Prostaglandin E ◽  
Female Reproduction ◽  
Low Level ◽  
Preimplantation Mouse Embryos ◽  
Preimplantation Mouse ◽  
Cox 2 ◽  
High Level ◽  
Cox 1

Prostaglandin E2 (PGE2) is shown to be essential for female reproduction. Cyclooxygenase (COX) is a rate-limiting enzyme in prostaglandin synthesis from arachidonic acid and exists in two isoforms: COX-1 and COX-2. Prostaglandin E synthase (PGES) is a terminal prostanoid synthase and can catalyse the isomerization of the COX product PGH2 to PGE2, including microsomal PGES-1 (mPGES-1), cytosolic PGES (cPGES) and mPGES-2. This study examined the protein expression of COX-1, COX-2, mPGES-1, cPGES and mPGES-2 in preimplantation mouse embryos by immunohistochemistry. Embryos at different stages collected from oviducts or uteri were transferred into a flushed oviduct of non-pregnant mice. The oviducts containing embryos were paraffin-embedded and processed for immunostaining. COX-1 immunostaining was at a basal level in zygotes and a low level at the 2-cell stage, reaching a high level from the 4-cell to blastocyst stage. COX-2 immunostaining was at a low level at the zygote stage and was maintained at a high level from the 2-cell to blastocyst stages. A low level of mPGES-1 immunostaining was observed from the zygote to 8-cell stages. The signal for mPGES-1 immunostaining became stronger at the morula stage and was strongly seen at the blastocyst stage. cPGES immunostaining was strongly observed in zygotes, 2-cell and 8-cell embryos. There was a slight decrease in cPGES immunostaining at the 4-cell, morula and blastocyst stages. mPGES-2 immunostaining was at a low level from the zygote to morula stages and at a high level at the blastocyst stage. We found that the COX-1, COX-2, mPGES-1, cPGES and mPGES-2 protein signals were all at a high level at the blastocyst stage. PGE2 produced during the preimplantation development may play roles during embryo transport and implantation.

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