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American Journal of Physiology. Renal... Jan 2013PGE(2) is a natriuretic factor whose production is elevated after water deprivation (WD) but its role in dehydration natriuresis is not well-defined. The goal of the...
PGE(2) is a natriuretic factor whose production is elevated after water deprivation (WD) but its role in dehydration natriuresis is not well-defined. The goal of the present study was to investigate the role of microsomal prostaglandin E synthase-1 (mPGES-1) in dehydration natriuresis. After 24-h WD, wild-type (WT) mice exhibited a significant increase in 24-h urinary Na(+) excretion accompanied with normal plasma Na(+) concentration and osmolality. In contrast, WD-induced elevation of urinary Na(+) excretion was completely abolished in mPGES-1 knockout (KO) mice in parallel with increased plasma Na(+) concentration and a trend increase in plasma osmolality. WD induced a 1.8-fold increase in urinary PGE(2) output and a 1.6-fold increase in PGE(2) content in the renal medulla of WT mice, both of which were completely abolished by mPGES-1 deletion. Similar patterns of changes were observed for urinary nitrate/nitrite and cGMP. The natriuresis in dehydrated WT mice was associated with a significant downregulation of renal medullary epithelial Na channel-α mRNA and protein, contrasting to unaltered expressions in dehydrated KO mice. By quantitative RT-PCR, WD increased the endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS expressions in the renal medulla of WT mice by 3.9-, 1.48-, and 2.6-fold, respectively, all of which were significantly blocked in mPGES-1 KO mice. The regulation of eNOS expression was further confirmed by immunoblotting. Taken together, our results suggest that mPGES-1-derived PGE(2) contributes to dehydration natriuresis likely via NO/cGMP.
Topics: Animals; Dehydration; Dinoprostone; Gene Expression Regulation; Intramolecular Oxidoreductases; Male; Mice; Mice, Knockout; Natriuresis; Plasma; Prostaglandin-E Synthases; Sodium; Water; Water Deprivation; Water-Electrolyte Imbalance
PubMed: 23171554
DOI: 10.1152/ajprenal.00588.2011 -
Frontiers in Immunology 2022, a keystone oral pathogen implicated in development and progression of periodontitis, may also contribute to the pathogenicity of diseases such as arthritis,...
, a keystone oral pathogen implicated in development and progression of periodontitis, may also contribute to the pathogenicity of diseases such as arthritis, atherosclerosis, and Alzheimer's. is a master manipulator of host immune responses due to production of a large variety of virulence factors. Among these, peptidilarginine deiminase (PPAD), an enzyme unique to , converts C-terminal Arg residues in bacterium- and host-derived proteins and peptides into citrulline. PPAD contributes to stimulation of proinflammatory responses in host cells and is essential for activation of the prostaglandin E2 (PGE2) synthesis pathway in gingival fibroblasts. Since is recognized mainly by Toll-like receptor-2 (TLR2), we investigated the effects of PPAD activity on TLR2-dependent host cell responses to , as well as to outer membrane vesicles (OMVs) and fimbriae produced by this organism. Using reporter cell lines, we found that PPAD activity was required for TLR2 activation by cells and OMVs. We also found that fimbriae, an established TLR2 ligand, from wild-type ATCC 33277 (but not from its isogenic PPAD mutant) enhanced the proinflammatory responses of host cells. Furthermore, only fimbriae from wild-type ATCC 33277, but not from the PPAD-deficient strains, induced cytokine production and stimulated expression of genes within the PGE2 synthesis pathway in human gingival fibroblasts activation of the NF-ĸB and MAP kinase-dependent signaling pathways. Analysis of ten clinical isolates revealed that type I FimA is preferable for TLR2 signaling enhancement. In conclusion, the data strongly suggest that both PPAD activity and fimbriae are important for TLR2-dependent cell responses to infection.
Topics: Dinoprostone; Humans; Periodontitis; Porphyromonas gingivalis; Protein-Arginine Deiminases; Toll-Like Receptor 2
PubMed: 35432342
DOI: 10.3389/fimmu.2022.823685 -
Scientific Reports Jan 2023Nephrosclerosis patients are at an exceptionally high cardiovascular (CV) risk. We aimed to determine whether genetic variability represented by 38 tag-SNPs in genes of...
Nephrosclerosis patients are at an exceptionally high cardiovascular (CV) risk. We aimed to determine whether genetic variability represented by 38 tag-SNPs in genes of the cyclooxygenase pathway (PTGS1, PTGS2, PTGES, PTGES2 and PTGES3) leading to prostaglandin E2 (PGE2) synthesis, modified CV traits and events in 493 nephrosclerosis patients. Additionally, we genotyped 716 controls to identify nephrosclerosis risk associations. The addition of three variants, namely PTGS2 rs4648268, PTGES3 rs2958155 and PTGES3 rs11300958, to a predictive model for CV events containing classic risk factors in nephrosclerosis patients, significantly enhanced its statistical power (AUC value increased from 78.6 to 87.4%, p = 0.0003). Such increase remained significant after correcting for multiple testing. In addition, two tag-SNPs (rs11790782 and rs2241270) in PTGES were linked to higher systolic and diastolic pressure [carriers vs. non-carriers = 5.23 (1.87-9.93), p = 0.03 and 5.9 (1.87-9.93), p = 0.004]. PTGS1(COX1) rs10306194 was associated with higher common carotid intima media thickness (ccIMT) progression [OR 1.90 (1.07-3.36), p = 0.029], presence of carotid plaque [OR 1.79 (1.06-3.01), p = 0.026] and atherosclerosis severity (p = 0.041). These associations, however, did not survive Bonferroni correction of the data. Our findings highlight the importance of the route leading to PGE2 synthesis in the CV risk experienced by nephrosclerosis patients and add to the growing body of evidence pointing out the PGE2 synthesis/activity axis as a promising therapeutic target in this field.
Topics: Humans; Dinoprostone; Cyclooxygenase 2; Nephrosclerosis; Carotid Intima-Media Thickness; Prostaglandin-E Synthases; Risk Factors
PubMed: 36690661
DOI: 10.1038/s41598-022-27343-z -
Frontiers in Neural Circuits 2022Inflammation in infants can cause respiratory dysfunction and is potentially life-threatening. Prostaglandin E2 (PGE2) is released during inflammatory events and...
Inflammation in infants can cause respiratory dysfunction and is potentially life-threatening. Prostaglandin E2 (PGE2) is released during inflammatory events and perturbs breathing behavior . Here we study the effects of PGE2 on inspiratory motor rhythm generated by the preBötzinger complex (preBötC). We measured the concentration dependence of PGE2 (1 nM-1 μM) on inspiratory-related motor output in rhythmic medullary slice preparations. Low concentrations (1-10 nM) of PGE2 increased the duration of the inspiratory burst period, while higher concentrations (1 μM) decreased the burst period duration. Using specific pharmacology for prostanoid receptors (EP1-4R, FPR, and DP2R), we determined that coactivation of both EP2R and EP3R is necessary for PGE2 to modulate the inspiratory burst period. Additionally, biased activation of EP3 receptors lengthened the duration of the inspiratory burst period, while biased activation of EP2 receptors shortened the burst period. To help delineate which cell populations are affected by exposure to PGE2, we analyzed single-cell RNA-Seq data derived from preBötC cells. Transcripts encoding for EP2R () were differentially expressed in a cluster of excitatory neurons putatively located in the preBötC. A separate cluster of mixed inhibitory neurons differentially expressed EP3R (). Our data provide evidence that EP2 and EP3 receptors increase the duration of the inspiratory burst period at 1-10 nM PGE2 and decrease the burst period duration at 1 μM. Further, the biphasic dose response likely results from differences in receptor binding affinity among prostanoid receptors.
Topics: Animals; Dinoprostone; Humans; Medulla Oblongata; Neurons; Rats; Rats, Sprague-Dawley; Respiration
PubMed: 35669453
DOI: 10.3389/fncir.2022.826497 -
Mediators of Inflammation 2012The local and systemic production of prostaglandin E(2) (PGE(2)) and its actions in phagocytes lead to immunosuppressive conditions. PGE(2) is produced at high levels... (Review)
Review
The local and systemic production of prostaglandin E(2) (PGE(2)) and its actions in phagocytes lead to immunosuppressive conditions. PGE(2) is produced at high levels during inflammation, and its suppressive effects are caused by the ligation of the E prostanoid receptors EP(2) and EP(4), which results in the production of cyclic AMP. However, PGE(2) also exhibits immunostimulatory properties due to binding to EP(3), which results in decreased cAMP levels. The various guanine nucleotide-binding proteins (G proteins) that are coupled to the different EP receptors account for the pleiotropic roles of PGE(2) in different disease states. Here, we discuss the production of PGE(2) and the actions of this prostanoid in phagocytes from different tissues, the relative contribution of PGE(2) to the modulation of innate immune responses, and the novel therapeutic opportunities that can be used to control inflammatory responses.
Topics: Animals; Central Nervous System; Dinoprostone; Humans; Immunity, Innate; Lung; Macrophages, Peritoneal; Phagocytes; Spleen
PubMed: 23024463
DOI: 10.1155/2012/327568 -
Environmental Science and Pollution... Sep 2022This study evaluated the protective potentials of Moringa oleifera leaf alcoholic extract (MOLE) against bisphenol A (BPA)-induced stomach ulceration and inflammation in...
This study evaluated the protective potentials of Moringa oleifera leaf alcoholic extract (MOLE) against bisphenol A (BPA)-induced stomach ulceration and inflammation in rats. Control rats received olive oil. Second group administered MOLE (200 mg/kg bwt) by oral gavage. Third group was given BPA (50 mg/ kg bwt) for 4 weeks. Fourth group administrated BPA and MOLE simultaneously. Fifth group was given MOLE for 4 weeks then administered BPA and MOLE for another 4 weeks. Bisphenol A induced gastric ulceration and decreased the volume of gastric juice, prostaglandin E2 (PGE2), reduced glutathione (GSH) and interleukin 10 (IL-10) contents, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) protein in stomach tissues, while increased the titratable acidity, malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) contents, and caspase-3 and NF‑κB proteins in stomach tissue. However, MOLE ameliorated BPA-induced gastric ulceration and significantly increased the volume of gastric juice, PGE2, GSH and IL-10 contents, SOD activity, and PCNA protein while significantly decreased titratable acidity, MDA, TNF-α and IL-6 contents, and of NF‑κB and caspase-3 proteins in gastric tissue. This study indicated that MOLE protected stomach against BPA-induced gastric injury via its anti-oxidant, anti-apoptotic, and anti-inflammatory activities.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Benzhydryl Compounds; Caspase 3; Dinoprostone; Glutathione; Interleukin-10; Interleukin-6; Malondialdehyde; Moringa oleifera; NF-kappa B; Olive Oil; Phenols; Plant Extracts; Proliferating Cell Nuclear Antigen; Rats; Stomach Ulcer; Superoxide Dismutase; Tumor Necrosis Factor-alpha
PubMed: 35554805
DOI: 10.1007/s11356-022-20543-0 -
Bioorganic & Medicinal Chemistry Letters May 2023EP2 is a G protein-coupled receptor for prostaglandin E2 (PGE2) derived from cell membrane-released arachidonic acid upon various harmful and injurious stimuli. It is...
EP2 is a G protein-coupled receptor for prostaglandin E2 (PGE2) derived from cell membrane-released arachidonic acid upon various harmful and injurious stimuli. It is commomly upregulated in tumors and injured brain tissues, as its activation by PGE2 is widely believed to be involved in the pathophysiological mechanisms underlying these conditions via promoting pro-inflammatory reactions. Herein, we report the discovery of two novel macrocyclic peptidomimetics based on the screening of a cyclic γ-AApeptides combinatorial library. These two cyclic γ-AApeptides showed excellent binding affinity with the EP2 protein, and they may lead to the development of novel therapeutic agents and/or molecular probes to modulate the PGE2/EP2 signaling.
Topics: Humans; Dinoprostone; Ligands; Signal Transduction; Neoplasms; Receptors, Prostaglandin E, EP2 Subtype
PubMed: 36965536
DOI: 10.1016/j.bmcl.2023.129255 -
Cell Host & Microbe Sep 2018Mucosal healing regenerates the mucosal complex upon injury. Mucosal repair requires sequential biologic steps paradoxically enabled or blocked by prostaglandin E2. In...
Mucosal healing regenerates the mucosal complex upon injury. Mucosal repair requires sequential biologic steps paradoxically enabled or blocked by prostaglandin E2. In this issue of Cell Host & Microbe, Jain et al. (2018) find that the microbial metabolite, deoxycholate, regulates prostaglandin E2 and thus coordinates the steps of mucosal healing.
Topics: Colon; Deoxycholic Acid; Dinoprostone; Mucous Membrane; Regeneration
PubMed: 30212642
DOI: 10.1016/j.chom.2018.08.013 -
Proceedings of the National Academy of... Jul 2003
Review
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Drug Design; Enzyme Inhibitors; Humans; Inflammation Mediators; Intramolecular Oxidoreductases; Isoenzymes; Membrane Proteins; Mice; Prostaglandin-E Synthases; Prostaglandin-Endoperoxide Synthases
PubMed: 12861081
DOI: 10.1073/pnas.1733589100 -
British Journal of Pharmacology Feb 2023Prostaglandin E is considered a major mediator of inflammatory pain, by acting on neuronal G protein-coupled EP2 and EP4 receptors. However, the neuronal EP3 receptor,...
BACKGROUND AND PURPOSE
Prostaglandin E is considered a major mediator of inflammatory pain, by acting on neuronal G protein-coupled EP2 and EP4 receptors. However, the neuronal EP3 receptor, colocalized with EP2 and EP4 receptor, is G protein-coupled and antagonizes the pronociceptive prostaglandin E effect. Here, we investigated the cellular signalling mechanisms by which the EP3 receptor reduces EP2 and EP4 receptor-evoked pronociceptive effects in sensory neurons.
EXPERIMENTAL APPROACH
Experiments were performed on isolated and cultured dorsal root ganglion (DRG) neurons from wild type, phosphoinositide 3-kinase γ (PI3Kγ) , and PI3Kγ mice. For subtype-specific stimulations, we used specific EP2, EP3, and EP4 receptor agonists from ONO Pharmaceuticals. As a functional readout, we recorded TTX-resistant sodium currents in patch-clamp experiments. Western blots were used to investigate the activation of intracellular signalling pathways. EP4 receptor internalization was measured using immunocytochemistry.
KEY RESULTS
Different pathways mediate the inhibition of EP2 and EP4 receptor-dependent pronociceptive effects by EP3 receptor stimulation. Inhibition of EP2 receptor-evoked pronociceptive effect critically depends on the kinase-independent function of the signalling protein PI3Kγ, and adenosine monophosphate activated protein kinase (AMPK) is involved. By contrast, inhibition of EP4 receptor-evoked pronociceptive effect is independent on PI3Kγ and mediated through activation of G protein-coupled receptor kinase 2 (GRK2), which enhances the internalization of the EP4 receptor after ligand binding.
CONCLUSION AND IMPLICATIONS
Activation of neuronal PI3Kγ, AMPK, and GRK2 by EP3 receptor activation limits cAMP-dependent pain generation by prostaglandin E . These new insights hold the potential for a novel approach in pain therapy.
Topics: Animals; Mice; Prostaglandins; AMP-Activated Protein Kinases; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Dinoprostone; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Sensory Receptor Cells; Pain; Analgesics; Receptors, Prostaglandin E, EP3 Subtype
PubMed: 36245399
DOI: 10.1111/bph.15971