scholarly journals A representative metalloprotease induces PGE2 synthesis in fibroblast-like synoviocytes via the NF-κB/COX-2 pathway with amplification by IL-1β and the EP4 receptor

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mariana N. Viana ◽  
Elbio Leiguez ◽  
José M. Gutiérrez ◽  
Alexandra Rucavado ◽  
Regina P. Markus ◽  
...  
Keyword(s):  
Pge2 Synthesis ◽  
Ep4 Receptor ◽  
Cox 2 ◽  
Fibroblast Like Synoviocytes

scholarly journals Interleukin 6 stimulates macrophage MMP‐9 expression via COX‐2‐dependent induction of PGE2 synthesis and engagement of the EP4 receptor

2007 ◽  
Vol 21 (5) ◽  
Author(s):  
Domenick J Falcone ◽  
Kazuko Sakamoto ◽  
Michel L Steenport ◽  
KM Faisal Khan ◽  
Baoheng Du ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Pge2 Synthesis ◽  
Ep4 Receptor ◽  
Cox 2

scholarly journals COXIBs and 2,5-dimethylcelecoxib counteract the hyperactivated Wnt/β-catenin pathway and COX-2/PGE2/EP4 signaling in glioblastoma cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Aleksandra Majchrzak-Celińska ◽  
Julia O. Misiorek ◽  
Nastassia Kruhlenia ◽  
Lukasz Przybyl ◽  
Robert Kleszcz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Methylation Status ◽  
Receptor Expression ◽  
Cell Cycle Distribution ◽  
Ep4 Receptor ◽  
Cox 2 ◽  
The Impact

Abstract Background Glioblastoma (GBM) is the deadliest and the most common primary brain tumor in adults. The invasiveness and proliferation of GBM cells can be decreased through the inhibition of Wnt/β-catenin pathway. In this regard, celecoxib is a promising agent, but other COXIBs and 2,5-dimethylcelecoxib (2,5-DMC) await elucidation. Thus, the aim of this study was to analyze the impact of celecoxib, 2,5-DMC, etori-, rofe-, and valdecoxib on GBM cell viability and the activity of Wnt/β-catenin pathway. In addition, the combination of the compounds with temozolomide (TMZ) was also evaluated. Cell cycle distribution and apoptosis, MGMT methylation level, COX-2 and PGE2 EP4 protein levels were also determined in order to better understand the molecular mechanisms exerted by these compounds and to find out which of them can serve best in GBM therapy. Methods Celecoxib, 2,5-DMC, etori-, rofe- and valdecoxib were evaluated using three commercially available and two patient-derived GBM cell lines. Cell viability was analyzed using MTT assay, whereas alterations in MGMT methylation level were determined using MS-HRM method. The impact of COXIBs, in the presence and absence of TMZ, on Wnt pathway was measured on the basis of the expression of β-catenin target genes. Cell cycle distribution and apoptosis analysis were performed using flow cytometry. COX-2 and PGE2 EP4 receptor expression were evaluated using Western blot analysis. Results Wnt/β-catenin pathway was attenuated by COXIBs and 2,5-DMC irrespective of the COX-2 expression profile of the treated cells, their MGMT methylation status, or radio/chemoresistance. Celecoxib and 2,5-DMC were the most cytotoxic. Cell cycle distribution was altered, and apoptosis was induced after the treatment with celecoxib, 2,5-DMC, etori- and valdecoxib in T98G cell line. COXIBs and 2,5-DMC did not influence MGMT methylation status, but inhibited COX-2/PGE2/EP4 pathway. Conclusions Not only celecoxib, but also 2,5-DMC, etori-, rofe- and valdecoxib should be further investigated as potential good anti-GBM therapeutics.

scholarly journals A Representative GIIA Phospholipase A2 Activates Preadipocytes to Produce Inflammatory Mediators Implicated in Obesity Development

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1593
Author(s):  
Elbio Leiguez ◽  
Priscila Motta ◽  
Rodrigo Maia Marques ◽  
Bruno Lomonte ◽  
Suely Vilela Sampaio ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Phospholipase A2 ◽  
Proinflammatory Mediators ◽  
Ep4 Receptor ◽  
Prostaglandin Synthase ◽  
Proinflammatory Responses ◽  
Cox 2 ◽  
Ep3 Receptor ◽  
Cytosolic Pla2 ◽  
Adipose Tissue Cells

Adipose tissue secretes proinflammatory mediators which promote systemic and adipose tissue inflammation seen in obesity. Group IIA (GIIA)-secreted phospholipase A2 (sPLA2) enzymes are found to be elevated in plasma and adipose tissue from obese patients and are active during inflammation, generating proinflammatory mediators, including prostaglandin E2 (PGE2). PGE2 exerts anti-lipolytic actions and increases triacylglycerol levels in adipose tissue. However, the inflammatory actions of GIIA sPLA2s in adipose tissue cells and mechanisms leading to increased PGE2 levels in these cells are unclear. This study investigates the ability of a representative GIIA sPLA2, MT-III, to activate proinflammatory responses in preadipocytes, focusing on the biosynthesis of prostaglandins, adipocytokines and mechanisms involved in these effects. Our results showed that MT-III induced biosynthesis of PGE2, PGI2, MCP-1, IL-6 and gene expression of leptin and adiponectin in preadipocytes. The MT-III-induced PGE2 biosynthesis was dependent on cytosolic PLA2 (cPLA2)-α, cyclooxygenases (COX)-1 and COX-2 pathways and regulated by a positive loop via the EP4 receptor. Moreover, MT-III upregulated COX-2 and microsomal prostaglandin synthase (mPGES)-1 protein expression. MCP-1 biosynthesis induced by MT-III was dependent on the EP4 receptor, while IL-6 biosynthesis was dependent on EP3 receptor engagement by PGE2. These data highlight preadipocytes as targets for GIIA sPLA2s and provide insight into the roles played by this group of sPLA2s in obesity.

p38 MAP kinase mediates mechanically induced COX-2 and PG EP4 receptor expression in podocytes: implications for the actin cytoskeleton

2004 ◽  
Vol 286 (4) ◽  
pp. F693-F701 ◽  
Author(s):  
Louis C. Martineau ◽  
Lyne I. McVeigh ◽  
Bernard J. Jasmin ◽  
Chris R. J. Kennedy
Keyword(s):  
Actin Cytoskeleton ◽  
Map Kinase ◽  
Mechanical Stress ◽  
P38 Map Kinase ◽  
Receptor Expression ◽  
Prostaglandin E ◽  
Glomerular Permeability ◽  
Ep4 Receptor ◽  
Filtration Barrier ◽  
Cox 2

A dynamic cytoskeleton allows podocytes to withstand significant mechanical stress on elevation of intraglomerular capillary pressure (Pgc). However, vasoactive hormones, such as prostaglandin E2 (PGE2), may challenge the integrity of the actin cytoskeleton, alter podocyte morphology, and compromise glomerular permeability. PGE2 synthesis correlates with the onset of proteinuria and increased Pgc following reduced nephron mass. We investigated the interplay among mechanical stress, cyclooxygenase (COX), E-prostanoid (EP) receptor expression, and the actin cytoskeleton, using an in vitro model of cell stretch. Immortalized mouse podocytes grown on flexible silicone membranes were cyclically stretched (5% elongation, 0.5 Hz) for 2 h. EP4 and COX-2 mRNA increased three- and sevenfold above nonstretched controls, whereas EP1 and COX-1 levels were unchanged. Six hours of stretch resulted in a threefold increase in PGE2-stimulated cAMP accumulation, a measure of EP4 receptor function, and an increase in COX-2 protein. The stretch-induced effects on COX-2/EP4 expression and EP4-induced cAMP production were attributable to p38 MAP kinase, as blockade of this pathway, but not of ERK or JNK, abrogated the response. These stretch-induced changes in expression were transcriptionally dependent as they were actinomycin D sensitive. Finally, we investigated the influence of enhanced EP4 signaling on the actin cytoskeleton. Addition of PGE2 resulted in actin filament depolymerization observable only in stretched cells. Our results indicate that key components of the eicosanoid pathway are upregulated by mechanically stimulated p38 MAP kinase in podocytes. Enhanced EP4 receptor signaling may undermine podocyte cytoskeletal dynamics and thereby compromise filtration barrier function under conditions of increased Pgc.

scholarly journals Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia

2015 ◽  
Vol 6 (3) ◽  
pp. e1702-e1702 ◽  
Author(s):  
Q Xia ◽  
Q Hu ◽  
H Wang ◽  
H Yang ◽  
F Gao ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Erk Pathway ◽  
Pge2 Synthesis ◽  
Cox 2

Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves

2004 ◽  
Vol 287 (6) ◽  
pp. F1269-F1282 ◽  
Author(s):  
Ulla C. Kopp ◽  
Michael Z. Cicha ◽  
Kazuhiro Nakamura ◽  
Rolf M. Nüsing ◽  
Lori A. Smith ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Sensory Nerve ◽  
Nerve Fibers ◽  
Prostaglandin E ◽  
Ep4 Receptor ◽  
Pelvic Wall ◽  
Ep4 Receptor Antagonist ◽  
Cox 2 ◽  
Ep3 Receptor ◽  
Stimulation Of

Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E2 (PGE2) leading to stimulation of cAMP production, which results in substance P (SP) release and activation of renal mechanosensory nerves. The subtype of PGE receptors involved, EP2 and/or EP4, was studied by immunohistochemistry and renal pelvic administration of agonists and antagonists of EP2 and EP4 receptors. EP4 receptor-like immunoreactivity (LI) was colocalized with calcitonin gene-related peptide (CGRP)-LI in dorsal root ganglia (DRGs) at Th9-L1 and in nerve terminals in the renal pelvic wall. Th9-L1 DRG neurons also contained EP3 receptor-LI and COX-2-LI, each of which was colocalized with CGRP-LI in some neurons. No renal pelvic nerves contained EP3 receptor-LI and only very few nerves COX-2-LI. The EP1/EP2 receptor antagonist AH-6809 (20 μM) had no effect on SP release produced by PGE2 (0.14 μM) from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982 (10 μM) blocked the SP release produced by the EP2/EP4 receptor agonist butaprost (10 μM) 12 ± 2 vs. 2 ± 1 and PGE2, 9 ± 1 vs. 1 ± 0 pg/min. The SP release by butaprost and PGE2 was similarly blocked by the EP4 receptor antagonist AH-23848 (30 μM). In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost 700 ± 100 and PGE2·780 ± 100%·s (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH-6809. However, 1 μM L-161,982 and 10 μM AH-23848 blocked the ARNA responses to butaprost by 94 ± 5 and 78 ± 10%, respectively, and to PGE2 by 74 ± 16 and 74 ± 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 ± 5%. In conclusion, PGE2 increases renal pelvic release of SP and ARNA by activating EP4 receptors on renal sensory nerve fibers.

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