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Sustained release of prostaglandin E? in fibroblasts expressing ectopically cyclooxygenase 2 impairs P2Y-dependent Ca²?-mobilization.

ABSTRACT: The nucleotide uridine trisphosphate (UTP) released to the extracellular milieu acts as a signaling molecule via activation of specific pyrimidine receptors (P2Y). P2Y receptors are G protein-coupled receptors expressed in many cell types. These receptors mediate several cell responses and they are involved in intracellular calcium mobilization. We investigated the role of the prostanoid PGE2 in P2Y signaling in mouse embryonic fibroblasts (MEFs), since these cells are involved in different ontogenic and physiopathological processes, among them is tissue repair following proinflammatory activation. Interestingly, Ca(2+)-mobilization induced by UTP-dependent P2Y activation was reduced by PGE2 when this prostanoid was produced by MEFs transfected with COX-2 or when PGE2 was added exogenously to the culture medium. This Ca(2+)-mobilization was important for the activation of different metabolic pathways in fibroblasts. Moreover, inhibition of COX-2 with selective coxibs prevented UTP-dependent P2Y activation in these cells. The inhibition of P2Y responses by PGE2 involves the activation of PKCs and PKD, a response that can be suppressed after pharmacological inhibition of these protein kinases. In addition to this, PGE2 reduces the fibroblast migration induced by P2Y-agonists such as UTP. Taken together, these data demonstrate that PGE2 is involved in the regulation of P2Y signaling in these cells.

SUBMITTER: Pimentel-Santillana M

PROVIDER: S-EPMC4151624 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Small-molecule inhibition of prostaglandin E receptor 2 impairs cyclooxygenase-associated malignant glioma growth.

Project description:Background and purposeAn up-regulation of COX-2 in malignant gliomas causes excessive synthesis of PGE2 , which is thought to facilitate brain tumour growth and invasion. However, which downstream PGE2 receptor subtype (i.e., EP1 -EP4 ) directly contributes to COX activity-promoted glioma growth remains largely unknown.Experimental approachUsing a publicly available database from The Cancer Genome Atlas research network, we compared the expression of PGE2 signalling-associated genes in human lower grade glioma and glioblastoma multiforme (GBM) samples. The Kaplan-Meier analysis was performed to determine the relationship between their expression and survival probability. A time-resolved FRET method was used to identify the EP subtype that mediates COX-2/PGE2 -initiated cAMP signalling in human GBM cells. Taking advantage of a recently identified novel selective bioavailable brain-permeable small-molecule antagonist, we studied the effect of pharmacological inhibition of the EP2 receptor on glioma cell growth in vitro and in vivo.Key resultsThe EP2 receptor is a key Gαs -coupled receptor that mediates COX-2/PGE2 -initiated cAMP signalling pathways in human malignant glioma cells. Inhibition of EP2 receptors reduced COX-2 activity-driven GBM cell proliferation, invasion, and migration and caused cell cycle arrest at G0-G1 and apoptosis of GBM cells. Glioma cell growth in vivo was also substantially decreased by post-treatment with an EP2 antagonist in both subcutaneous and intracranial tumour models.Conclusion and implicationsTaken together, our results suggest that PGE2 signalling via the EP2 receptor increases the malignant potential of human glioma cells and might represent a novel therapeutic target for GBM.

| S-EPMC6514294 | biostudies-literature

Evidence for the possible involvement of the P2Y(6) receptor in Ca (2+) mobilization and insulin secretion in mouse pancreatic islets.

Project description:Subtypes of purinergic receptors involved in modulation of cytoplasmic calcium ion concentration ([Ca(2+)](i)) and insulin release in mouse pancreatic beta-cells were examined in two systems, pancreatic islets in primary culture and beta-TC6 insulinoma cells. Both systems exhibited some physiological responses such as acetylcholine-stimulated [Ca(2+)](i) rise via cytoplasmic Ca(2+) mobilization. Addition of ATP, ADP, and 2-MeSADP (each 100 microM) transiently increased [Ca(2+)](i) in single islets cultured in the presence of 5.5 mM (normal) glucose. The potent P2Y(1) receptor agonist 2-MeSADP reduced insulin secretion significantly in islets cultured in the presence of high glucose (16.7 mM), whereas a slight stimulation occurred at 5.5 mM glucose. The selective P2Y(6) receptor agonist UDP (200 microM) transiently increased [Ca(2+)](i) and reduced insulin secretion at high glucose, whereas the P2Y(2/4) receptor agonist UTP and adenosine receptor agonist NECA were inactive. [Ca(2+)](i) transients induced by 2-MeSADP and UDP were antagonized by suramin (100 microM), U73122 (2 microM, PLC inhibitor), and 2-APB (10 or 30 microM, IP(3) receptor antagonist), but neither by staurosporine (1 microM, PKC inhibitor) nor depletion of extracellular Ca(2+). The effect of 2-MeSADP on [Ca(2+)](i) was also significantly inhibited by MRS2500, a P2Y(1) receptor antagonist. These results suggested that P2Y(1) and P2Y(6) receptor subtypes are involved in Ca(2+) mobilization from intracellular stores and insulin release in mouse islets. In beta-TC6 cells, ATP, ADP, 2-MeSADP, and UDP transiently elevated [Ca(2+)](i) and slightly decreased insulin secretion at normal glucose, while UTP and NECA were inactive. RT-PCR analysis detected mRNAs of P2Y(1) and P2Y(6), but not P2Y(2) and P2Y(4) receptors.

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Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin f(2?) impairs endothelial function in renovascular hypertensive rats.

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| S-EPMC3584508 | biostudies-other

Enhanced cardiac reprogramming by Inhibition of cyclooxygenase-2/prostaglandin E2/prostaglandin E receptor 4 signaling

Project description:Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. However, postnatal and adult fibroblasts are less efficient for reprogramming compared with embryonic fibroblasts, and barriers to cardiac reprogramming associated with aging remain undetermined. In this study, we screened 8,400 chemical compounds, and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2. Intriguingly, diclofenac promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs). Mechanistically, diclofenac enhanced cardiac reprogramming by inhibiting cyclooxygenase-2, prostaglandin E2/prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1b pathway, silencing inflammatory and fibroblast programs, which were activated in postnatal and adult TTFs. Thus, anti-inflammation can be a new target for cardiac reprogramming associated with aging.

2019-02-20 | GSE116223 | GEO

Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis.

Project description:Hypoxia-inducible factors (HIFs), in particular HIF-1alpha, have been implicated in tumor biology. However, HIF target genes in the esophageal tumor microenvironment remain elusive. Gene expression profiling was performed upon hypoxia-exposed non-transformed immortalized human esophageal epithelial cells, EPC2-hTERT, and comparing with a gene signature of esophageal squamous cell carcinoma (ESCC). In addition to known HIF-1alpha target genes such as carbonic anhydrase 9, insulin-like growth factor binding protein-3 (IGFBP3) and cyclooxygenase (COX)-2, prostaglandin E synthase (PTGES) was identified as a novel target gene among the commonly upregulated genes in ESCC as well as the cells exposed to hypoxia. The PTGES induction was augmented upon stabilization of HIF-1alpha by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1alpha. Whereas PTGES messenger RNA (mRNA) was negatively regulated by normoxia, PTGES protein remained stable upon reoxygenation. Prostaglandin E(2) (PGE(2)) biosynthesis was documented in transformed human esophageal cells by ectopic expression of PTGES as well as RNA interference directed against PTGES. Moreover, hypoxia stimulated PGE(2) production in a HIF-1alpha-dependent manner. In ESCC, PTGES was overexpressed frequently at the mRNA and protein levels. Finally, COX-2 and PTGES were colocalized in primary tumors along with HIF-1alpha and IGFBP3. Activation of the COX-2-PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1beta and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1alpha target gene, involved in prostaglandin E biosynthesis in the esophageal tumor hypoxic microenvironment, and this has implications in diverse tumors types, especially of squamous origin.

| S-EPMC2832548 | biostudies-literature

Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming.

Project description:Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. However, postnatal and adult fibroblasts are less efficient for reprogramming compared with embryonic fibroblasts, and barriers to cardiac reprogramming associated with aging remain undetermined. In this study, we screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2. Intriguingly, diclofenac promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs). Mechanistically, diclofenac enhanced cardiac reprogramming by inhibiting cyclooxygenase-2, prostaglandin E2/prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1β signaling and by silencing inflammatory and fibroblast programs, which were activated in postnatal and adult TTFs. Thus, anti-inflammation represents a new target for cardiac reprogramming associated with aging.

| S-EPMC6382796 | biostudies-literature

Prostaglandin E<sub>2</sub> inhibits profibrotic function of human pulmonary fibroblasts by disrupting Ca<sup>2+</sup> signaling.

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| S-EPMC6589580 | biostudies-literature

When sustained attention impairs perception.

Project description:Virtually all behavioral and neurophysiological studies have shown that sustained (endogenous, conceptually driven) attention enhances perception. But can this enhancement be held indefinitely? We assessed the time course of attention's effects on contrast sensitivity, reasoning that if attention does indeed boost stimulus strength, the strengthened representation could result in stronger adaptation over time. We found that attention initially enhances contrast sensitivity, but that over time sustained attention can actually impair sensitivity to an attended stimulus.

| S-EPMC1986649 | biostudies-literature

Aspergillus cyclooxygenase-like enzymes are associated with prostaglandin production and virulence.

Project description:Oxylipins comprise a family of oxygenated fatty acid-derived signaling molecules that initiate critical biological activities in animals, plants, and fungi. Mammalian oxylipins, including the prostaglandins (PGs), mediate many immune and inflammation responses in animals. PG production by pathogenic microbes is theorized to play a role in pathogenesis. We have genetically characterized three Aspergillus genes, ppoA, ppoB, and ppoC, encoding fatty acid oxygenases similar in sequence to specific mammalian prostaglandin synthases, the cyclooxygenases. Enzyme-linked immunosorbent assay analysis showed that production of PG species is decreased in both Aspergillus nidulans and A. fumigatus ppo mutants, implicating Ppo activity in generating PGs. The A. fumigatus triple-ppo-silenced mutant was hypervirulent in the invasive pulmonary aspergillosis murine model system and showed increased tolerance to H(2)O(2) stress relative to that of the wild type. We propose that Ppo products, PG, and/or other oxylipins may serve as activators of mammalian immune responses contributing to enhanced resistance to opportunistic fungi and as factors that modulate fungal development contributing to resistance to host defenses.

| S-EPMC1201276 | biostudies-literature

Ellagic acid, a plant phenolic compound, activates cyclooxygenase-mediated prostaglandin production.

Project description:In recent years, ellagic acid (EA), a naturally-occurring phenolic compound richly contained in some of the human food sources such as Longan and Litchi, was reported to have a number of biological effects. Based on our earlier 3D-QSAR/CoMFA models for cyclooxygenase (COX) I and II, we hypothesize that EA may have the potential to modulate the catalytic activity of COX enzymes, and this hypothesis is examined in the present study. The results from both in vitro and in vivo experiments show that EA is an activator of COX enzyme-catalyzed production of prostaglandin E2, a representative prostaglandin tested. Mechanistically, EA can activate the peroxidase active site of COX enzymes by serving as a co-substrate, presumably for the reduction of protoporphorin IX with FeIV inside. The effect of EA is abrogated by the co-presence of galangin, which is known to bind to COX's peroxidase active site and thereby blocks the effect of the reducing co-substrates. In view of the known physiological functions of COX enzymes in the body, it is suggested that some of the pharmacological and/or toxicological effects of EA may result from an increased production of certain prostaglandins and their related derivatives in the body.

| S-EPMC6601391 | biostudies-literature

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