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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 -
Natural Product Research Oct 2022Two new chemical constituents, japopenoid D (), and japopenoid E (), were isolated and identified from the flower buds of Thunb. The structures of these compounds were...
Two new chemical constituents, japopenoid D (), and japopenoid E (), were isolated and identified from the flower buds of Thunb. The structures of these compounds were elucidated based on spectroscopic analysis (HR-ESI-MS, NMR), and the absolute configurations of and were determined by comparison of their electronic circular dichroism (ECD) spectra with literature and theoretical calculation. The anti-inflammatory activities of the isolates were evaluated by measuring their inhibitory effects on PGE and IL-6 production in LPS stimulated RAW 264.7 macrophages. As a result, compound could reduce PGE and IL-6 levels in LPS-activated RAW 264.7 macrophages with IC values of 6.78 and 42.07 , respectively.[Formula: see text].
Topics: Anti-Inflammatory Agents; Flowers; Interleukin-6; Lipopolysaccharides; Lonicera; Prostaglandins E
PubMed: 33960222
DOI: 10.1080/14786419.2021.1921769 -
PloS One 2021Prostaglandins are thought to be important mediators in the initiation of human labour, however the evidence supporting this is not entirely clear. Determining how, and...
Prostaglandins are thought to be important mediators in the initiation of human labour, however the evidence supporting this is not entirely clear. Determining how, and which, prostaglandins change during pregnancy and labour may provide insight into mechanisms governing labour initiation and the potential to predict timing of labour onset. The current study systematically searched the existing scientific literature to determine how biofluid levels of prostaglandins change throughout pregnancy before and during labour, and whether prostaglandins and/or their metabolites may be useful for prediction of labour. The databases EMBASE and MEDLINE were searched for English-language articles on prostaglandins measured in plasma, serum, amniotic fluid, or urine during pregnancy and/or spontaneous labour. Studies were assessed for quality and risk of bias and a qualitative summary of included studies was generated. Our review identified 83 studies published between 1968-2021 that met the inclusion criteria. As measured in amniotic fluid, levels of PGE2, along with PGF2α and its metabolite 13,14-dihydro-15-keto-PGF2α were reported higher in labour compared to non-labour. In blood, only 13,14-dihydro-15-keto-PGF2α was reported higher in labour. Additionally, PGF2α, PGF1α, and PGE2 were reported to increase in amniotic fluid as pregnancy progressed, though this pattern was not consistent in plasma. Overall, the evidence supporting changes in prostaglandin levels in these biofluids remains unclear. An important limitation is the lack of data on the complexity of the prostaglandin pathway outside of the PGE and PGF families. Future studies using new methodologies capable of co-assessing multiple prostaglandins and metabolites, in large, well-defined populations, will help provide more insight as to the identification of exactly which prostaglandins and/or metabolites consistently change with labour. Revisiting and revising our understanding of the prostaglandins may provide better targets for clinical monitoring of pregnancies. This study was supported by the Canadian Institutes of Health Research.
Topics: Amniotic Fluid; Body Fluids; Databases, Factual; Dinoprost; Female; Humans; Labor Onset; Labor, Obstetric; Oxytocics; Plasma; Pregnancy; Prostaglandins; Prostaglandins E; Prostaglandins F; Serum; Urine
PubMed: 34793529
DOI: 10.1371/journal.pone.0260115 -
Pharmacology & Therapeutics May 2018The body is exposed to foreign pathogens every day, but remarkably, most pathogens are effectively cleared by the innate immune system without the need to invoke the... (Review)
Review
The body is exposed to foreign pathogens every day, but remarkably, most pathogens are effectively cleared by the innate immune system without the need to invoke the adaptive immune response. Key cellular components of the innate immune system include macrophages and neutrophils and the recruitment and function of these cells are tightly regulated by chemokines and cytokines in the tissue space. Innate immune responses are also known to regulate development of adaptive immune responses often via the secretion of various cytokines. In addition to these protein regulators, numerous lipid mediators can also influence innate and adaptive immune functions. In this review, we cover one particular lipid regulator, prostaglandin E (PGE) and describe its synthesis and signaling and what is known about the ability of this lipid to regulate immunity and host defense against viral, fungal and bacterial pathogens.
Topics: Adaptive Immunity; Animals; Autophagy; Dinoprostone; Extracellular Traps; Humans; Immunity, Innate; Infections; Interleukin-1beta; Toll-Like Receptors
PubMed: 29274705
DOI: 10.1016/j.pharmthera.2017.12.008 -
Translational Neurodegeneration Jun 2023Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E (PGE) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.
Topics: Mice; Animals; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Motor Neurons; Mice, Transgenic; Dinoprostone
PubMed: 37337289
DOI: 10.1186/s40035-023-00366-w -
Journal of Medicinal Chemistry Jul 2023Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E (PGE) triggers several physiological and pathological conditions. It mediates signaling... (Review)
Review
Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E (PGE) triggers several physiological and pathological conditions. It mediates signaling through four G-protein coupled receptors, EP1, EP2, EP3, and EP4. Among these, EP2 is expressed throughout the body including the brain and uterus. The functional role of EP2 has been extensively studied using EP2 gene knockout mice, cellular models, and selective small molecule agonists and antagonists for this receptor. The efficacy data from in vitro and in vivo animal models indicate that EP2 receptor is a major proinflammatory mediator with deleterious functions in a variety of diseases suggesting a path forward for EP2 inhibitors as the next generation of selective anti-inflammatory and antiproliferative agents. Interestingly in certain diseases, EP2 action is beneficial; therefore, EP2 agonists seem to be clinically useful. Here, we highlight the strengths, weaknesses, opportunities, and potential threats (SWOT analysis) for targeting EP2 receptor for therapeutic development for a variety of unmet clinical needs.
Topics: Animals; Mice; Receptors, Prostaglandin E; Dinoprostone; Cyclooxygenase 2; Drug Discovery; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 37458373
DOI: 10.1021/acs.jmedchem.3c00655 -
Frontiers in Bioscience (Landmark... Oct 2023Ischemic stroke is one of the major causes of death and disability. Since the currently used treatment option of reperfusion therapy has several limitations, ongoing... (Review)
Review
Ischemic stroke is one of the major causes of death and disability. Since the currently used treatment option of reperfusion therapy has several limitations, ongoing research is focusing on the neuroprotective effects of microglia and stem cells. By exerting the bystander effect, secreting exosomes and forming biobridges, mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and multilineage-differentiating stress-enduring cells (Muse cells) have been shown to stimulate neurogenesis, angiogenesis, cell migration, and reduce neuroinflammation. Exosome-based therapy is now being extensively researched due to its many advantageous properties over cell therapy, such as lower immunogenicity, no risk of blood vessel occlusion, and ease of storage and modification. However, although preclinical studies have shown promising therapeutic outcomes, clinical trials have been associated with several translational challenges. This review explores the therapeutic effects of preconditioned microglia as well as various factors secreted in stem cell-derived extracellular vesicles with their mechanisms of action explained. Furthermore, an overview of preclinical and clinical studies is presented, explaining the main challenges of microglia and stem cell therapies, and providing potential solutions. In particular, a highlight is the use of novel stem cell therapy of Muse cells, which bypasses many of the conventional stem cell limitations. The paper concludes with suggestions for directions in future neuroprotective research.
Topics: Humans; Microglia; Ischemic Stroke; Stroke; Alprostadil; Mesenchymal Stem Cells
PubMed: 37919085
DOI: 10.31083/j.fbl2810269 -
Nature Communications Jan 2024Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8 T cells to the intestinal microenvironment...
Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8 T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8 T cell pool. CD8 T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8 T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E (PGE), which drives mitochondrial depolarization in CD8 T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE sensing promotes CD8 T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE-autophagy-glutathione axis defines the metabolic adaptation of CD8 T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; Autophagy; Dinoprostone; Genes, Mitochondrial; Glutathione
PubMed: 38200005
DOI: 10.1038/s41467-024-44689-2 -
The Journal of Allergy and Clinical... Nov 2019
Topics: Animals; Cytokines; Dermatitis, Atopic; Dinoprostone; Eczema; Inflammation; Lipids; Mice; Thymic Stromal Lymphopoietin
PubMed: 31560874
DOI: 10.1016/j.jaci.2019.09.008 -
Nature Metabolism Feb 2022β-cell dysfunction is a hallmark of type 1 and type 2 diabetes. Type 2 diabetes is strongly associated with ageing-related β-cell abnormalities that arise through...
β-cell dysfunction is a hallmark of type 1 and type 2 diabetes. Type 2 diabetes is strongly associated with ageing-related β-cell abnormalities that arise through unknown mechanisms. Here we show better β-cell identity, less β-cell senescence, enhanced glucose-stimulated insulin secretion and improved glucose homeostasis in global microsomal prostaglandin E synthase-2 (mPGES-2)-deficient mice challenged with a high-fat diet or bred with a genetic model of type 2 diabetes (db/db mice). Furthermore, the function of mPGES-2 in β-cells is validated using mice with β-cell-specific mPGES-2 deficiency or overexpression. Mechanistically, the protective role of mPGES-2 deletion is induced by antagonizing β-cell senescence via interference of the PGE-EP3-NR4A1 signalling axis. We also discover an inhibitor of mPGES-2, SZ0232, which protects against β-cell dysfunction and diabetes, similar to mPGES-2 deletion. We conclude that mPGES-2 contributes to ageing-associated β-cell senescence and dysfunction via the PGE-EP3-NR4A1 signalling axis. Pharmacologic blockade of mPGES-2 might be effective for treating ageing-associated β-cell dysfunction and diabetes.
Topics: Animals; Cellular Senescence; Diabetes Mellitus, Type 2; Dinoprostone; Glucose; Mice; Mice, Knockout; Nuclear Receptor Subfamily 4, Group A, Member 1; Prostaglandin-E Synthases
PubMed: 35228744
DOI: 10.1038/s42255-022-00536-6