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Experimental Biology and Medicine... May 2023The cyclooxygenase (COX)/prostaglandin E2 (PGE) signaling pathway has emerged as a critical target for anti-inflammatory therapeutic development in neurological... (Review)
Review
The cyclooxygenase (COX)/prostaglandin E2 (PGE) signaling pathway has emerged as a critical target for anti-inflammatory therapeutic development in neurological diseases. However, medical use of COX inhibitors in the treatment of various neurological disorders has been limited due to well-documented cardiovascular and cerebrovascular complications. It has been widely proposed that modulation of downstream microsomal prostaglandin E synthase-1 (mPGES-1) enzyme may provide more specificity for inhibiting PGE-elicited neuroinflammation. Heightened levels of mPGES-1 have been detected in a variety of brain diseases such as epilepsy, stroke, glioma, and neurodegenerative diseases. Subsequently, elevated levels of PGE, the enzymatic product of mPGES-1, have been demonstrated to modulate a multitude of deleterious effects. In epilepsy, PGE participates in retrograde signaling to augment glutamate release at the synapse leading to neuronal death. The excitotoxic demise of neurons incites the activation of microglia, which can become overactive upon further stimulation by PGE. A selective mPGES-1 inhibitor was able to reduce gliosis and the expression of proinflammatory cytokines in the hippocampus following status epilepticus. A similar mechanism has also been observed in stroke, where the overactivation of microglia by PGE upregulated the expression and secretion of proinflammatory cytokines. This intense activation of neuroinflammatory processes triggered the secondary injury commonly observed in stroke, and blockade of mPGES-1 reduced infarction size and edema, suppressed induction of proinflammatory cytokines, and improved post-stroke well-being and cognition. Furthermore, elevated levels of PGE have been shown to intensify the proliferation of glioma cells, mediate P-glycoprotein expression at the blood-brain barrier (BBB) and facilitate breakdown of the BBB. For these reasons, targeting mPGES-1, the central and inducible enzyme of the COX cascade, may provide a more specific therapeutic strategy for treating neuroinflammatory diseases.
Topics: Humans; Prostaglandin-E Synthases; Neuroinflammatory Diseases; Cyclooxygenase 2; Dinoprostone; Epilepsy; Stroke; Cytokines; Glioma
PubMed: 37515545
DOI: 10.1177/15353702231179926 -
International Journal of Molecular... Aug 2023The ECM propagates processes in idiopathic pulmonary fibrosis (IPF), leading to progressive lung scarring. We established an IPF-conditioned matrix (IPF-CM) system as a... (Review)
Review
The ECM propagates processes in idiopathic pulmonary fibrosis (IPF), leading to progressive lung scarring. We established an IPF-conditioned matrix (IPF-CM) system as a platform for testing drug candidates. Here, we tested the involvement of a PGE2 and PDE4 inhibitor, Roflumilast, in the IPF-CM system. Primary normal/IPF tissue-derived human lung fibroblasts (N/IPF-HLFs) were cultured on Matrigel and then removed to create the IPF-CM. N-HLFs were exposed to the IPF-CM/N-CM with/without PGE2 (1 nM) and Roflumilast (1 µM) for 24 h. The effect of the IPF-CM on cell phenotype and pro-fibrotic gene expression was tested. In addition, electronic records of 107 patients with up to 15-year follow-up were retrospectively reviewed. Patients were defined as slow/rapid progressors using forced vital capacity (FVC) annual decline. Medication exposure was examined. N-HLFs cultured on IPF-CM were arranged in large aggregates as a result of increased proliferation, migration and differentiation. A PGE2 and Roflumilast combination blocked the large aggregate formation induced by the IPF-CM ( < 0.001) as well as cell migration, proliferation, and pro-fibrotic gene expression. A review of patient records showed that significantly more slow-progressing patients were exposed to NSAIDs ( = 0.003). PGE2/PDE4 signaling may be involved in IPF progression. These findings should be further studied.
Topics: Humans; Dinoprostone; Retrospective Studies; Cells, Cultured; Idiopathic Pulmonary Fibrosis; Lung; Fibroblasts; Fibrosis
PubMed: 37569768
DOI: 10.3390/ijms241512393 -
Folia Medica Cracoviensia 2019Induction of labor is an intervention in the obstetrics, which aim is to achieve cervical ripening and stimulate contractions of uterus before beginning of labor. The...
INTRODUCTION
Induction of labor is an intervention in the obstetrics, which aim is to achieve cervical ripening and stimulate contractions of uterus before beginning of labor. The purpose of our study was to evaluate efficacy of combinations of vaginal misoprostol, intracervical dinoprostone and Foley catheter at term with regard to mode of delivery and rate of emergency C-sections due to birth asphyxia.
MATERIAL AND METHODS
403 singleton pregnant women, who underwent pharmacological labor induction at term, were reviewed. Patients were divided into 2 main cohorts due to beginning of induction algorithm: vaginal misoprostol (66) or intracervical dinoprostone (337) consisting of 3 subgroups - PGE2 alone (184), PGE2+Foley catheter (125), PGE2+Foley catheter+PGE1 (28).
RESULTS
Comparison of maternal age, presence of cervical dilation and parity revealed no major differences between cohorts. Effectiveness of labor induction with misoprostol, dinoprostone and dinoprostone followed by Foley catheter were respectively 90.9%, 51.3%, and 82.8%. Addition of PGE1 was effective in 83% of patients with negative response to PGE2 followed by Foley catheter. ere was no statistically significant difference in rate of C-sections between dinoprostone and misoprostol cohorts, C-section due to birth asphyxia were insignificantly more frequent in PGE1 than in PGE2 cohort. Efficacy in the subgroup administered only dinoprostone was significantly higher in 40th than in 41th (p = 0.016).
CONCLUSIONS
Intracervical dinoprostone seems to be safer, but less effective in labor induction than vaginal misoprostol. Following PGE2 by other methods increased efficacy of induction in this cohort.
Topics: Adult; Case-Control Studies; Catheterization; Cervix Uteri; Cesarean Section; Dinoprostone; Female; Humans; Labor, Induced; Misoprostol; Pregnancy; Pregnancy Outcome; Treatment Outcome; Young Adult
PubMed: 31904752
DOI: 10.24425/fmc.2019.131382 -
Cancer Prevention Research... Jun 2022Chronic inflammation is a well-established risk factor for several diseases, including cancer. It influences tumor cell biology and the type and density of immune cells... (Review)
Review
Chronic inflammation is a well-established risk factor for several diseases, including cancer. It influences tumor cell biology and the type and density of immune cells in the tumor microenvironment (TME), promoting cancer development. While proinflammatory cytokines and chemokines modulate cancer development, emerging evidence has shown that prostaglandin E2 (PGE2) is a known mediator connecting chronic inflammation to cancerization. This review highlights recent advances in our understanding of how the elevation of PGE2 production promotes gastrointestinal cancer initiation, progression, invasion, metastasis, and recurrence, including modulation of immune checkpoint signaling and the type and density of immune cells in the tumor/tissue microenvironment.
Topics: Dinoprostone; Gastrointestinal Neoplasms; Humans; Inflammation; Signal Transduction; Tumor Microenvironment
PubMed: 35288737
DOI: 10.1158/1940-6207.CAPR-22-0038 -
Prostaglandins & Other Lipid Mediators Feb 2022Bone modeling can be modulated by lipid signals such as arachidonic acid (AA) and its cyclooxygenase 2 (COX2) metabolite, prostaglandin E (PGE), which are recognized...
Bone modeling can be modulated by lipid signals such as arachidonic acid (AA) and its cyclooxygenase 2 (COX2) metabolite, prostaglandin E (PGE), which are recognized mediators of optimal bone formation. Hydrolysis of AA from membrane glycerophospholipids is catalyzed by phospholipases A (PLAs). We reported that mice deficient in the Ca- independent PLAbeta (iPLAβ), encoded by Pla2g6, exhibit a low bone phenotype, but the cause for this remains to be identified. Here, we examined the mechanistic and molecular roles of iPLAβ in bone formation using bone marrow stromal cells and calvarial osteoblasts from WT and iPLAβ-deficient mice, and the MC3T3-E1 osteoblast precursor cell line. Our data reveal that transcription of osteogenic factors (Bmp2, Alpl, and Runx2) and osteogenesis are decreased with iPLAβ-deficiency. These outcomes are corroborated and recapitulated in WT cells treated with a selective inhibitor of iPLA β (10 μM S-BEL), and rescued in iPLAβ-deficient cells by additions of 10 μM PGE. Further, under osteogenic conditions we find that PGE production is through iPLAβ activity and that this leads to induction of Runx2 and iPLAβ transcription. These findings reveal a strong link between osteogenesis and iPLAβ-derived lipids and raise the intriguing possibility that iPLAβ-derived PGE participates in osteogenesis and in the regulation of Runx2 and also iPLAβ.
Topics: Animals; Bone and Bones; Dinoprostone; Group VI Phospholipases A2; Insulin-Secreting Cells; Mice; Osteogenesis; Phospholipases A2
PubMed: 34923151
DOI: 10.1016/j.prostaglandins.2021.106605 -
Frontiers in Immunology 2020Asthma represents one of the leading chronic diseases worldwide and causes a high global burden of death and disability. In asthmatic patients, the exacerbation and... (Review)
Review
Asthma represents one of the leading chronic diseases worldwide and causes a high global burden of death and disability. In asthmatic patients, the exacerbation and chronification of the inflammatory response are often related to a failure in the resolution phase of inflammation. We reviewed the role of the main arachidonic acid (AA) specialized pro-resolving mediators (SPMs) in the resolution of chronic lung inflammation of asthmatics. AA is metabolized by two classes of enzymes, cyclooxygenases (COX), which produce prostaglandins (PGs) and thromboxanes, and lypoxygenases (LOX), which form leukotrienes and lipoxins (LXs). In asthma, two primary pro-resolving derived mediators from COXs are PGE and the cyclopentenone prostaglandin15-Deoxy-Delta-12,14-PGJ (15d-PGJ) while from LOXs are the LXA and LXB. In different models of asthma, PGE, 15d-PGJ, and LXs reduced lung inflammation and remodeling. Furthermore, these SPMs inhibited chemotaxis and function of several inflammatory cells involved in asthma pathogenesis, such as eosinophils, and presented an antiremodeling effect in airway epithelial, smooth muscle cells and fibroblasts . In addition, PGE, 15d-PGJ, and LXs are all able to induce macrophage reprogramming to an alternative M2 pro-resolving phenotype and . Although PGE and LXA showed some beneficial effects in asthmatic patients, there are limitations to their clinical use, since PGE caused side effects, while LXA presented low stability. Therefore, despite the strong evidence that these AA-derived SPMs induce resolution of both inflammatory response and tissue remodeling in asthma, safer and more stable analogs must be developed for further clinical investigation of their application in asthma treatment.
Topics: Airway Remodeling; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Asthma; Dinoprostone; Eosinophils; Humans; Inflammation; Inflammation Mediators
PubMed: 33362766
DOI: 10.3389/fimmu.2020.580598 -
Trends in Cancer Feb 2017Elevated cyclooxygenase-2 (COX-2) and the associated inflammation within the brain contribute to glioblastoma development. However, medical use of COX inhibitors in... (Review)
Review
Elevated cyclooxygenase-2 (COX-2) and the associated inflammation within the brain contribute to glioblastoma development. However, medical use of COX inhibitors in glioblastoma treatment has been limited due to their well-documented vascular toxicity and inconsistent outcomes from recent human studies. Prostaglandin E2 (PGE) has emerged as a principal mediator for COX-2 cascade-driven gliomagenesis. Are PGE terminal synthases and receptors feasible therapeutic targets for glioblastoma?
Topics: Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Glioblastoma; Humans; Inflammation; Molecular Targeted Therapy; Signal Transduction
PubMed: 28718447
DOI: 10.1016/j.trecan.2016.12.002 -
Ophthalmic Research 2023Dry eye disease (DED) is a multifactor-induced disease accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Traditional...
INTRODUCTION
Dry eye disease (DED) is a multifactor-induced disease accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Traditional anti-inflammation agent corticosteroids applied in DED treatment could result in high intraocular pressure, especially in long-term treatment. Therefore, we explored a nano drug that aimed to block the formation pathway of DED which had anti-inflammatory, sustained release, and good biocompatibility characteristics in this study.
METHODS
We prepared a novel nanomedicine (Tet-ATS@PLGA) by the thin film dispersion-hydration ultrasonic method and detected its nanostructure, particle size, and zeta potential. Flow cytometry was used to detect the cell survival rate of each group after 24 h of drug treatment on inflammed Statens Seruminstitut Rabbit Corneal (SIRC) cells. Observed and recorded corneal epithelial staining, tear film rupture time, and Schirmer test to detect tear secretion on the ocular surface of rabbits. The corneal epithelial thickness, morphology, and number of bulbar conjunctival goblet cells were recorded by H&E staining. Finally, we detected the expression of VEGF, IL-1β, PGE2, and TNF-α by cellular immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA).
RESULTS
The encapsulation efficiency and drug loading of Tet-ATS@PLGA were 79.85% and 32.47%, respectively. At eye surface temperature, Tet can easily release from Tet-ATS@PLGA while that it was difficult to release at storage temperature and room temperature. After 2 weeks medication, Tet-ATS@PLGA can effectively improve the tear film rupture time and tear secretion time in a DED model (p <0.05). Compared with the normal group (62.34 ± 4.86 mm), the thickness of corneal epithelium in ATS (29.47 ± 3.21 mm), Tet-ATS (46.23 ± 2.87 mm), and Tet-ATS@PLGA (55.76 ± 3.95 mm) gradually increased. Furthermore, the flow cytometry indicated that Tet-ATS@PLGA can effectively promote the apoptosis of inflammatory SIRC cells, and the cellular immunofluorescence and ELISA experiments showed that the expression intensity of inflammatory factors such as VEGF, IL-1β, PGE2, and TNF-α decreased in this process. Interestingly, Tet also had the effect of reducing intraocular pressure.
CONCLUSION
Tet-ATS@PLGA can effectively promote the apoptosis of inflammatory corneal epithelial cells, thus inhibiting the expression of inflammatory factors to block the formation of DED and improve the secretion of tear on the ocular surface.
Topics: Animals; Rabbits; Polyglycolic Acid; Tumor Necrosis Factor-alpha; Dinoprostone; Vascular Endothelial Growth Factor A; Dry Eye Syndromes; Tears; Cornea; Anti-Inflammatory Agents; Nanoparticles
PubMed: 37690450
DOI: 10.1159/000533345 -
Biological & Pharmaceutical Bulletin 2018Prostaglandin (PG) E is a well-established lipid mediator that plays a role in diverse functions and diseases of the brain. Cyclooxygenase and PGE synthase have been... (Review)
Review
Prostaglandin (PG) E is a well-established lipid mediator that plays a role in diverse functions and diseases of the brain. Cyclooxygenase and PGE synthase have been extensively studied as molecular determinants of extracellular concentration of PGE near prostanoid E receptors since the brain has limited capacity of PG metabolism. There is accumulating evidence that several members of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate PGE distribution in brain capillary endothelial cells, choroid plexus (CP) and arachnoid epithelium, and different parenchyma cells such as neuronal and glial cells. These transporters may mediate entry and exit of PGE at blood-brain and blood-cerebrospinal fluid boundaries, resulting in brain distribution of PGE. However, their roles in neuroinflammation and disease progression remain unclear. In this review, current knowledge on transporters involved in brain distribution of PGE is summarized, and especially, potentials of organic anion transporting polypeptide (OATP) and organic anion transporter (OAT) family members are discussed as molecular determinants of PGE concentration in the brain.
Topics: Animals; Brain; Dinoprostone; Humans; Membrane Transport Proteins
PubMed: 30175771
DOI: 10.1248/bpb.b18-00169 -
The FEBS Journal Jan 2023Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in...
Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in mediating ferroptosis during acute kidney injury. When renal tubular epithelial cells stimulated by H O , the contents of glutathione (GSH) and glutathione peroxidase 4 (GPX4) decreased, whereas the level of lipid peroxide increased. Ferrostatin-1 can effectively attenuate these changes. In this process, the expression levels of cyclooxygenase (COX)-1 and COX-2 were up-regulated. Meanwhile, the expression of microsomal prostaglandin E synthase-2 was elevated, whereas the expression of microsomal prostaglandin E synthase-1 and cytosolic prostaglandin E synthase were down-regulated. Furthermore, the expression of 15-hydroxyprostaglandin dehydrogenase decreased. An excessive accumulation of PGE2 promoted ferroptosis, whereas the PGE2 inhibitor pranoprofen minimized the changes for COX-2, GSH, GPX4 and lipid peroxides. A decrease in the levels of the PGE2 receptor E-series of prostaglandin 1/3 partially restored the decline of GSH and GPX4 levels and inhibited the aggravation of lipid peroxide. Consistent with the in vitro results, increased PGE2 levels led to increased levels of 3,4-methylenedioxyamphetamine, Fe accumulation and decreased GSH and GPX4 levels during renal ischaemia/reperfusion injury injury in mice. Our results indicate that the PGE2 pathway mediated oxidative stress-induced ferroptosis in renal tubular epithelial cells.
Topics: Mice; Animals; Dinoprostone; Ferroptosis; Cyclooxygenase 2; Prostaglandin-E Synthases; Lipid Peroxides; Oxidative Stress; Epithelial Cells
PubMed: 36031392
DOI: 10.1111/febs.16609