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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 -
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 -
International Journal of Molecular... Aug 2022The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new... (Review)
Review
The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new therapeutic strategies. Prostaglandin E2 is a membrane-derived lipid molecule that contributes to developing ASD associated with canonical Wnt signaling. Cyclooxygenase-2 plays a key role in neuroinflammation and is implicated in the pathogenesis of neurodevelopmental diseases, such as ASD. The endocannabinoid system maintains a balance between inflammatory and redox status and synaptic plasticity and is a potential target for ASD pathophysiology. Redox signaling refers to specific and usually reversible oxidation-reduction reactions, some of which are also involved in pathways accounting for the abnormal behavior observed in ASD. Redox signaling and redox status-sensitive transcription factors contribute to the pathophysiology of ASD. Cannabinoids regulate the redox balance by altering the levels and activity of antioxidant molecules via ROS-producing NADPH oxidase (NOX) and ROS-scavenging superoxide dismutase enzymes. These signaling cascades integrate a broad range of neurodevelopmental processes that may be involved in the pathophysiology of ASD. Based on these pathways, we highlight putative targets that may be used for devising novel therapeutic interventions for ASD.
Topics: Autism Spectrum Disorder; Dinoprostone; Humans; NADPH Oxidases; Reactive Oxygen Species; Wnt Signaling Pathway
PubMed: 36077195
DOI: 10.3390/ijms23179803 -
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 -
International Journal of Molecular... Jan 2022Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However,... (Review)
Review
Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin's potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Signal Transduction
PubMed: 35163356
DOI: 10.3390/ijms23031432 -
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 -
PloS One 2024The Maternal and Perinatal Death Surveillance and Response (MPDSR) was introduced in Kenya in 2016 and implemented at Kiambu Level 5 Hospital (KL5H) three years later in... (Comparative Study)
Comparative Study
BACKGROUND
The Maternal and Perinatal Death Surveillance and Response (MPDSR) was introduced in Kenya in 2016 and implemented at Kiambu Level 5 Hospital (KL5H) three years later in 2019. During a routine MPDSR meeting at KL5H, committee members identified a possible link between the off-label use of 200mcg misoprostol tablets divided eight times to achieve the necessary dose for labour induction (25mcg) and maternal deaths. Following this, an administrative decision was made to switch from misoprostol to dinoprostone for the induction of labour in June of 2019. This study aimed to assess the overall impact of MPDSR as well as the effect of replacing misoprostol with dinoprostone on uterine rupture, maternal and neonatal deaths at KL5H.
METHODS
We conducted a retrospective cohort study of women who gave birth at KL5H between January 2018 and December 2020. We defined the pre-intervention period as January 2018-June 2019, and the intervention period as July 2019-December 2020. We randomly selected the records of 411 mothers, 167 from the pre-intervention period and 208 from the intervention period, all of whom were induced. We used Bayes-Poisson Generalised Linear Models to fit the risk of uterine rupture, maternal and perinatal death. 12 semi-structured key person questionnaires was used to describe staff perspectives regarding the switch from misoprostol to dinoprostone. Inductive and deductive data analysis was done to capture the salient emerging themes.
RESULTS
We reviewed 411 patient records and carried out 12 key informant interviews. Mothers induced with misoprostol (IRR = 3.89; CI = 0.21-71.6) had an increased risk of death while mothers were less likely to die if they were induced with dinoprostone (IRR = 0.23; CI = 0.01-7.12) or had uterine rupture (IRR = 0.56; CI = 0.02-18.2). The risk of dying during childbearing increased during Jul 2019-Dec 2020 (IRR = 5.43, CI = 0.68-43.2) when the MPDSR activities were strengthened. Induction of labour (IRR = 1.01; CI = 0.06-17.1) had no effect on the risk of dying from childbirth in our setting. The qualitative results exposed that maternity unit staff preferred dinoprostone to misoprostol as it was thought to be more effective (fewer failed inductions) and safer, regardless of being more expensive compared to misoprostol.
CONCLUSION
While the period immediately following the implementation of MPDSR at KL5H was associated with an increased risk of death, the switch to dinoprostone for labour induction was associated with a lower risk of maternal and perinatal death. The use of dinoprostone, however, was linked to an increased risk of uterine rupture, possibly attributed to reduced labour monitoring given that staff held the belief that it is inherently safer than misoprostol. Consequently, even though the changeover was warranted, further investigation is needed to determine the reasons behind the rise in maternal mortalities, even though the MPDSR framework appeared to have been put in place to quell such an increase.
Topics: Humans; Misoprostol; Female; Labor, Induced; Pregnancy; Retrospective Studies; Adult; Dinoprostone; Oxytocics; Uterine Rupture; Infant, Newborn; Young Adult; Perinatal Death; Maternal Mortality
PubMed: 38820427
DOI: 10.1371/journal.pone.0304631 -
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 -
The Journal of Neuroscience : the... Aug 2020We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated...
We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. In male rats, HMWH also signals via Toll-like receptor 4 (TLR4), and AS-ODN for TLR4 mRNA administered intrathecally, attenuated HMWH-induced antihyperalgesia. Since HMWH signaling is dependent on CD44 clustering in lipid rafts, we pretreated animals with methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts. MβCD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, including phospholipase C and phosphoinositide 3-kinase (PI3K), also attenuated HMWH-induced antihyperalgesia. Furthermore, application of HMWH attenuated PGE-induced sensitization of tetrodotoxin-resistant sodium current, in small-diameter dorsal root ganglion neurons, an effect that was attenuated by a PI3K inhibitor. Our results indicate a central role of CD44 signaling in HMWH-induced antihyperalgesia and suggest novel therapeutic targets, downstream of CD44, for the treatment of pain generated by nociceptor sensitization. High-molecular-weight-hyaluronan (HMWH) is used to treat osteoarthritis and other pain syndromes. In this study we demonstrate that attenuation of inflammatory hyperalgesia by HMWH is mediated by its action at cluster of differentiation 44 (CD44) and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1), phospholipases (phospholipases Cε and Cγ1), and phosphoinositide 3-kinase, in nociceptors. These findings contribute to our understanding of the antihyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.
Topics: Animals; Cells, Cultured; Dinoprostone; Female; Ganglia, Spinal; Hyaluronan Receptors; Hyaluronic Acid; Hyperalgesia; Male; Nociception; Rats, Sprague-Dawley; Signal Transduction; Toll-Like Receptor 4
PubMed: 32665406
DOI: 10.1523/JNEUROSCI.0166-20.2020