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Advanced Science (Weinheim,... Dec 2023Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little...
Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs downstream of a reduced prostaglandin E2 (PGE2)-mediated ascending interoceptive signaling of the skeletal interoception. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes rescue bone loss in the unloading model. Moreover, depletion of TH sympathetic nerves or inhibition of norepinephrine release ameliorated bone resorption. Stereotactic inhibition of NPY expression in the hypothalamic neurons reduces the food intake with altered energy expenditure with a limited effect on bone, indicating hypothalamic neuroendocrine factor NPY in the facilitation of bone formation by sympathetic TH activity. These findings suggest that reduced PGE2-mediated interoceptive signaling in response to microgravity or unloading has impacts on the skeletal and central nervous systems that are reciprocally regulated.
Topics: Humans; Mice; Animals; Dinoprostone; Interoception; Neuropeptide Y; Hypothalamus; Neurons
PubMed: 37880864
DOI: 10.1002/advs.202305042 -
European Journal of Obstetrics,... Jul 2023To compare the effectiveness and safety of Dinoprostone Gel (DG), Misoprostol Vaginal Insert (MVI) and Dinoprostone Vaginal Insert (DVI) for induction of labour (IOL) in...
OBJECTIVES
To compare the effectiveness and safety of Dinoprostone Gel (DG), Misoprostol Vaginal Insert (MVI) and Dinoprostone Vaginal Insert (DVI) for induction of labour (IOL) in twin pregnancies.
STUDY DESIGN
Retrospective cohort study of twin pregnancies > 34 + 0 weeks gestation that underwent induction of labour (IOL) with DG, MVI or DVI between December 2016 and November 2019 in a Tertiary NHS hospital, North West England, UK. Delivery characteristics, maternal complications and neonatal outcomes were compared between the three groups.
RESULTS
A total of 87 twin pregnancies were included for analysis. 27 women received DG, 34 received MVI and 26 DVI. The MVI cohort had a higher proportion of nulliparous women (55.9%) compared to the DG and DVI cohorts, 29.6% and 38.5% respectively. No other differences amongst demographic characteristics were considered clinically significant. DG demonstrated a significantly quicker time to delivery (minutes) compared to DVI (1021 ± 556 versus 1649 ± 852; P = 0.0026). Significantly fewer women required terbutaline for hyperstimulation/tachysystole in the DG group compared to MVI (0% vs 32%; RR 0.05; 95% CI 0.003-0.88). Both DG and MVI groups required significantly less oxytocin following artificial rupture of membranes compared to DVI (33% vs 65%; RR 0.51; 95% CI 0.28-0.93) and (29% vs 65%; RR 0.45; 95% CI 0.25-0.81). There were no significant differences in mode of delivery, maternal complications and neonatal outcomes.
CONCLUSION
Our data suggests that for women with a twin pregnancy considering a planned labour that induction with DG, MVI and DVI appear to be equally safe and effective IOL methods. These results should be interpreted with caution due to the study being underpowered to detect significant adverse outcomes. In order to determine the optimal method of IOL in twins, direct randomised comparison is needed.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Administration, Intravaginal; Dinoprostone; Labor, Induced; Misoprostol; Oxytocics; Pregnancy, Twin; Retrospective Studies
PubMed: 37167810
DOI: 10.1016/j.ejogrb.2023.04.024 -
Molecular Human Reproduction Apr 2023Uterine glands and, by inference, their secretions impact uterine receptivity, blastocyst implantation, stromal cell decidualization, and placental development. Changes...
Uterine glands and, by inference, their secretions impact uterine receptivity, blastocyst implantation, stromal cell decidualization, and placental development. Changes in gland function across the menstrual cycle are primarily governed by the steroid hormones estrogen (E2) and progesterone (P4) but can also be influenced by extrinsic factors from the stroma. Using a human endometrial epithelial organoid system, transcriptome and proteome analyses identified distinct responses of the organoids to steroid hormones and prostaglandin E2 (PGE2). Notably, P4 and PGE2 modulated the basolateral secretion of organoid proteins, particularly cystatin C (CST3), serpin family A member 3 (SERPINA3), and stanniocalcin 1 (STC1). CST3, but not SERPINA3 or STC1, attenuated the in vitro stromal decidualization response to steroid hormones and PGE2. These findings provide evidence that uterine gland-derived factors impact stromal cell decidualization, which has implications for pregnancy establishment and fertility in women.
Topics: Humans; Pregnancy; Female; Dinoprostone; Placenta; Endometrium; Embryo Implantation; Progesterone; Stromal Cells; Decidua
PubMed: 36821428
DOI: 10.1093/molehr/gaad007 -
Expert Opinion on Therapeutic Targets 2023Prostaglandin E (PGE) is produced by cyclooxygenases (COX-1/2) and the microsomal prostaglandin E synthase 1 (mPGES-1). PGE is pro-inflammatory in diseases such as... (Review)
Review
INTRODUCTION
Prostaglandin E (PGE) is produced by cyclooxygenases (COX-1/2) and the microsomal prostaglandin E synthase 1 (mPGES-1). PGE is pro-inflammatory in diseases such as rheumatoid arthritis, cardiovascular disorders, and cancer. While Nonsteroidal anti-inflammatory drugs (NSAIDs) targeting COX can effectively reduce inflammation, their use is limited by gastrointestinal and cardiovascular side effects resulting from the blockade of all prostanoids. To overcome this limitation, selective inhibition of mPGES-1 is being explored as an alternative therapeutic strategy to inhibit PGE production while sparing or even upregulating other prostaglandins. However, the exact timing and location of PGH conversion to PGD, PGI, TXB or PGF, and whether it hinders or supports the therapeutic effect of mPGES-1 inhibition, is not fully understood.
AREAS COVERED
The article briefly describes prostanoid history and metabolism with a strong focus on the vascular effects of prostanoids. Recent advances in mPGES-1 inhibitor development and results from pre-clinical and clinical studies are presented. Prostanoid shunting after mPGES-1 inhibition is highlighted and particularly discussed in the context of cardiovascular diseases.
EXPERT OPINION
The newest research demonstrates that inhibition of mPGES-1 is a potent anti-inflammatory treatment strategy and beneficial and safer regarding cardiovascular side effects compared to NSAIDs. Inhibitors of mPGES-1 hold great potential to advance to the clinic and there are ongoing phase-II trials in endometriosis.
Topics: Female; Humans; Prostaglandin-E Synthases; Prostaglandins; Anti-Inflammatory Agents; Dinoprostone; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2
PubMed: 38015194
DOI: 10.1080/14728222.2023.2285785 -
British Journal of Pharmacology Oct 2023Glioblastoma (GBM) is the most aggressive brain tumour in the central nervous system, but the current treatment is very limited and unsatisfactory. PGE -initiated cAMP...
BACKGROUND AND PURPOSE
Glioblastoma (GBM) is the most aggressive brain tumour in the central nervous system, but the current treatment is very limited and unsatisfactory. PGE -initiated cAMP signalling via EP and EP receptors is involved in the tumourigenesis of multiple cancer types. However, whether or how EP and EP receptors contribute to GBM growth largely remains elusive.
EXPERIMENTAL APPROACH
We performed comprehensive data analysis of gene expression in human GBM samples and determined their expression correlations through multiple bioinformatics approaches. A time-resolved fluorescence energy transfer (TR-FRET) assay was utilized to characterize PGE -mediated cAMP signalling via EP and EP receptors in human glioblastoma cells. Using recently reported potent and selective small-molecule antagonists, we determined the effects of inhibition of EP and EP receptors on GBM growth in subcutaneous and intracranial tumour models.
KEY RESULTS
The expression of both EP and EP receptors was upregulated and highly correlated with a variety of tumour-promoting cytokines, chemokines, and growth factors in human gliomas. Further, they were heterogeneously expressed in human GBM cells, where they compensated for each other to mediate PGE -initiated cAMP signalling and to promote colony formation, cell invasion and migration. Inhibition of EP and EP receptors revealed that these receptors might mediate GBM growth, angiogenesis, and immune evasion in a compensatory manner.
CONCLUSION AND IMPLICATIONS
The compensatory roles of EP and EP receptors in GBM development and growth suggest that concurrently targeting these two PGE receptors might represent a more effective strategy than inhibiting either alone for GBM treatment.
Topics: Humans; Dinoprostone; Glioblastoma; Glioma; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 37232020
DOI: 10.1111/bph.16148 -
Safety of misoprostol vs dinoprostone for induction of labor: A systematic review and meta-analysis.European Journal of Obstetrics,... Oct 2023Pharmacological agents such as prostaglandins (dinoprostone and misoprostol) are commonly used to reduce the duration of labor and promote vaginal delivery. However, key... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Pharmacological agents such as prostaglandins (dinoprostone and misoprostol) are commonly used to reduce the duration of labor and promote vaginal delivery. However, key safety considerations with its use include an increased risk of uterine rupture, tachysystole and hyperstimulation of pregnant women, which could potentially lead to a non-reassuring fetal heart rate and to fetal hypoxemia. The aim of this systematic review was to assess maternal and fetal outcomes between misoprostol group (PGE1) and dinoprostone group (PGE2) STUDY DESIGN: We search on MEDLINE (PubMed), CINHAL (EBSCOhost), EMBASE, Scopus (Ovid), CENTRAL (January 1, 1998, to December 31, 2022). Patients were eligible if they presented at greater than 36 weeks gestation with an indication for induction of labor and a single live cephalic fetus. We conducted a meta-analysis of data for both primary (cesarean section rate, instrumental deliveries rate, tachysystole, uterine rupture, post-partum haemorrage; chorionamiositis) and secondary outcomes (Apgar at 5 min <7, meconium-stained liquor, NICU admission, infant death) using odds-ratio (OR) as a measure of effect-size. Risk of bias assessment was performed with RoB-I. We performed statistical analyses using Cochrane RevMan version 5.4 software.
RESULTS
We found 39 RCTs comparing the outcomes of interest between misoprostol and dinoprostone. The pooled effect showed no statistically significant difference between the two groups in terms of cesarean section rate [OR: 0.94; 95% CI 0.84-1.05], instrumental deliveries rate [OR: 1.04; 95% CI: 0.90-1.19; p = 0.62], tachysystole [OR: 1.21; 95% CI: 0.91-1.60; p = 0.19], post-partum hemorrhage [OR: 0.85; 95% CI: 0.62-1.15p = 0.30], chorioamnionitis [OR: 0.94; 95% CI: 0.76-1.17p = 0.59], Apgar at 5 min < 7 [OR: 0.83; 95% CI: 0.61-1.12, p = 0.21], meconium-stained liquor [OR: 1.11; 95% CI: 0.97-1.27p = 0.59], NICU admission group [OR: 0.91; 95% CI: 0.77-1.09], infant death [OR: 0.57; 95% CI: 0.22-1.44]. After performing a sub-group analysis based on the type of prostaglandins administrations (oral, vaginal gel, vaginal pessary), results did not change substantially.
CONCLUSIONS
This systematic review and meta-analysis demonstrate that misoprostol and dinoprostone appear to have a similar safety profile.
Topics: Infant; Humans; Female; Pregnancy; Dinoprostone; Misoprostol; Cesarean Section; Uterine Rupture; Prostaglandins; Oxytocics; Abortifacient Agents, Nonsteroidal; Infant Death; Labor, Induced
PubMed: 37660506
DOI: 10.1016/j.ejogrb.2023.08.382 -
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 -
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 -
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 -
Trends in Immunology Mar 2023The etiology of most autoimmune diseases remains unknown; however, shared among them is a disruption of immunoregulation. Prostaglandin lipid signaling molecules possess... (Review)
Review
The etiology of most autoimmune diseases remains unknown; however, shared among them is a disruption of immunoregulation. Prostaglandin lipid signaling molecules possess context-dependent immunoregulatory properties, making their role in autoimmunity difficult to decipher. For example, prostaglandin E (PGE) can function as an immunosuppressive molecule as well as a proinflammatory mediator in different circumstances, contributing to the expansion and activation of T cell subsets associated with autoimmunity. Recently, PGE was shown to play important roles in the resolution and post-resolution phases of inflammation, promoting return to tissue homeostasis. We propose that PGE plays both proinflammatory and pro-resolutory roles in the etiology of autoimmunity, and that harnessing this signaling pathway during the resolution phase might help prevent autoimmune attack.
Topics: Humans; Autoimmunity; Dinoprostone; Signal Transduction; Autoimmune Diseases; T-Lymphocyte Subsets
PubMed: 36707339
DOI: 10.1016/j.it.2023.01.004