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Molecular Therapy : the Journal of the... Dec 2023In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying...
In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying process but also death-independent functions that may shape the immunogenicity of apoptotic cells. Therefore, a better characterization of the immunological profile of apoptotic MSCs (ApoMSCs) could shed light on their mechanistic action and therapeutic applications. We analyzed the transcriptomes of MSCs undergoing apoptosis and identified several immunomodulatory factors and chemokines dependent on caspase activation following Fas stimulation. The ApoMSC secretome inhibited human T cell proliferation and activation, and chemoattracted monocytes in vitro. Both immunomodulatory activities were dependent on the cyclooxygenase2 (COX2)/prostaglandin E2 (PGE2) axis. To assess the clinical relevance of ApoMSC signature, we used the peripheral blood mononuclear cells (PBMCs) from a cohort of fistulizing Crohn's disease (CD) patients who had undergone MSC treatment (ADMIRE-CD). Compared with healthy donors, MSCs exposed to patients' PBMCs underwent apoptosis and released PGE2 in a caspase-dependent manner. Both PGE2 and apoptosis were significantly associated with clinical responses to MSCs. Our findings identify a new mechanism whereby caspase activation delivers ApoMSC immunosuppression. Remarkably, such molecular signatures could implicate translational tools for predicting patients' clinical responses to MSC therapy in CD.
Topics: Humans; Crohn Disease; Dinoprostone; Leukocytes, Mononuclear; Secretome; Mesenchymal Stem Cells; Immunomodulation; Apoptosis; Caspases
PubMed: 37805713
DOI: 10.1016/j.ymthe.2023.10.004 -
Nature Communications Nov 2022Aging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the factors within the aged...
Aging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the factors within the aged lung that compromise host defense to IAV remain unknown. Using a murine model and human samples, we identified prostaglandin E (PGE), as such a factor. Senescent type II alveolar epithelial cells (AECs) are overproducers of PGE within the aged lung. PGE impairs the proliferation of alveolar macrophages (AMs), critical cells for defense against respiratory pathogens, via reduction of oxidative phosphorylation and mitophagy. Importantly, blockade of the PGE receptor EP2 in aged mice improves AM mitochondrial function, increases AM numbers and enhances survival to IAV infection. In conclusion, our study reveals a key mechanism that compromises host defense to IAV, and possibly other respiratory infections, with aging and suggests potential new therapeutic or preventative avenues to protect against viral respiratory disease in older adults.
Topics: Mice; Humans; Animals; Aged; Influenza, Human; Influenza A virus; Macrophages, Alveolar; Dinoprostone; Mitochondria; Orthomyxoviridae Infections
PubMed: 36351902
DOI: 10.1038/s41467-022-34593-y -
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 -
Molecular Pharmacology May 2021Prostaglandin E (PGE) is a key lipid mediator in health and disease and serves as a crucial link between the immune response and cancer. With the advent of cancer... (Review)
Review
Prostaglandin E (PGE) is a key lipid mediator in health and disease and serves as a crucial link between the immune response and cancer. With the advent of cancer therapies targeting PGE signaling pathways at different levels, there has been increased interest in mapping and understanding the complex and interconnected signaling pathways arising from the four distinct PGE receptors. Here, we review phosphoproteomics studies that have investigated different aspects of PGE signaling in T cells. These studies have elucidated PGE's regulatory effect on T cell receptor signaling and T cell function, the key role of protein kinase A in many PGE signaling pathways, the temporal regulation of PGE signaling, differences in PGE signaling between different T cell subtypes, and finally, the crosstalk between PGE signaling pathways elicited by the four distinct PGE2 receptors present in T cells. SIGNIFICANCE STATEMENT: Through the reviewed studies, we now have a much better understanding of PGE's signaling mechanisms and functional roles in T cells, as well as a solid platform for targeted and functional studies of specific PGE-triggered pathways in T cells.
Topics: Dinoprostone; Humans; Phosphorylation; Proteome; Proteomics; Signal Transduction; T-Lymphocytes
PubMed: 33674363
DOI: 10.1124/molpharm.120.000170 -
Biochemical Pharmacology Nov 2023This review article summarizes the role of prostaglandin E (PGE) and its receptors (EP1-EP4) as it relates to the inflammatory cardiomyopathy, myocarditis. During the... (Review)
Review
This review article summarizes the role of prostaglandin E (PGE) and its receptors (EP1-EP4) as it relates to the inflammatory cardiomyopathy, myocarditis. During the COVID-19 pandemic, the onset of myocarditis in a subset of patients prompted a debate on the use of nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, which act to inhibit the actions of prostaglandins. This review aims to further understanding of the role of PGE in the pathogenesis or protection of the myocardium in myocarditis. Inflammatory cardiomyopathies encompass a broad spectrum of disorders, all characterized by cardiac inflammation. Therefore, for the purpose of this review, the authors have placed particular emphasis on etiologies of myocarditis where effects of PGE have been documented.
Topics: Humans; Myocarditis; Pandemics; Receptors, Prostaglandin E, EP4 Subtype; Dinoprostone; Prostaglandins
PubMed: 37722627
DOI: 10.1016/j.bcp.2023.115813 -
Obstetrics and Gynecology Jun 2021To assess the comparative effectiveness and potential harms of cervical ripening in the outpatient compared with the inpatient setting, or different methods of ripening... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To assess the comparative effectiveness and potential harms of cervical ripening in the outpatient compared with the inpatient setting, or different methods of ripening in the outpatient setting alone.
DATA SOURCES
Searches for articles in English included MEDLINE, EMBASE, CINAHL, Cochrane Library, ClinicalTrials.gov, and reference lists (up to August 2020).
METHODS OF STUDY SELECTION
Using predefined criteria and DistillerSR software, 10,853 citations were dual-reviewed for randomized controlled trials (RCTs) and cohort studies of outpatient cervical ripening using prostaglandins and mechanical methods in pregnant women at or beyond 37 weeks of gestation.
TABULATION, INTEGRATION, AND RESULTS
Using prespecified criteria, study data abstraction and risk of bias assessment were conducted by two reviewers, random-effects meta-analyses were conducted and strength of evidence was assessed. We included 30 RCTs and 10 cohort studies (N=9,618) most generalizable to women aged 25-30 years with low-risk pregnancies. All findings were low or insufficient strength of evidence and not statistically significant. Incidence of cesarean delivery was not different for any comparison of inpatient and outpatient settings, or comparisons of different methods in the outpatient setting (most evidence available for single-balloon catheters and dinoprostone). Harms were inconsistently reported or inadequately defined. Differences were not found for neonatal infection (eg, sepsis) with outpatient compared with inpatient dinoprostone, birth trauma (eg, cephalohematoma) with outpatient compared with inpatient single-balloon catheter, shoulder dystocia with outpatient dinoprostone compared with placebo, maternal infection (eg, chorioamnionitis) with outpatient compared with inpatient single-balloon catheters or outpatient prostaglandins compared with placebo, and postpartum hemorrhage with outpatient catheter compared with inpatient dinoprostone. Evidence on misoprostol, hygroscopic dilators, and other outcomes (eg, perinatal mortality and time to vaginal birth) was insufficient.
CONCLUSION
In women with low-risk pregnancies, outpatient cervical ripening with dinoprostone or single-balloon catheters did not increase cesarean deliveries. Although there were no clear differences in harms when comparing outpatient with inpatient cervical ripening, the certainty of evidence is low or insufficient to draw definitive conclusions.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, CRD42020167406.
Topics: Ambulatory Care; Catheters; Cervical Ripening; Cesarean Section; Dilatation; Dinoprostone; Female; Hospitalization; Humans; Labor, Induced; Obstetric Labor Complications; Oxytocics; Pregnancy
PubMed: 33752219
DOI: 10.1097/AOG.0000000000004382 -
Ceska Gynekologie 2021Comparison of dinoprostone, misoprostol and amniotomy in labor induction.
OBJECTIVE
Comparison of dinoprostone, misoprostol and amniotomy in labor induction.
METHODS
The study group included a total of 437 women who underwent consecutive induction of labor after evaluation of the indication and Bishops score. The most common indications were: postmaturity, hypertensive disease, diabetes mellitus and fetal growth restriction. In 327 cases we chose to induce labor using vaginal tablets of dinoprostone at a dose of 0.75mg, in 36 cases dinoprostone at a dose of 3mg, in 16 cases we used a vaginal insert of misoprostol (200 µg), and in 58 cases amniotomy was performed.
RESULTS
In the subgroup of dinoprostone (0.75mg) the rate of vaginal delivery (including extraction delivery) was 90.2%, in the subgroup of dinoprostone (3mg) it was 91.6%, in the subgroup of misoprostol it was 100% and in the subgroup of amniotomy it was 93.1%. The time period between onset of labor induction and delivery was an average of 15.75 hours in the dinoprostone (0.75mg) subgroup, 21.41 hours in the dinoprostone (3mg) subgroup, 17.41 hours in the misoprostol subgroup and 7.49 hours in the amniotomy subgroup.
CONCLUSION
Subgroup of patients with misoprostol showed the highest rate of vaginal delivery after labor induction. In the subgroup with amniotomy, the shortest time period between onset of induction and delivery was reached.
Topics: Administration, Intravaginal; Amniotomy; Dinoprostone; Female; Humans; Labor, Induced; Misoprostol; Oxytocics; Pregnancy
PubMed: 35038873
DOI: 10.48095/cccg2021368 -
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