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Reproduction (Cambridge, England) Aug 2023Inappropriate uterine contractions are a matter of concern during pregnancy or menses. We identified the transient receptor potential melastatin 4 (TRPM4) ion channel as...
IN BRIEF
Inappropriate uterine contractions are a matter of concern during pregnancy or menses. We identified the transient receptor potential melastatin 4 (TRPM4) ion channel as a new actor in mouse uterine contractions highlighting this protein as a potential pharmacological target for a better control of myometrial activity.
ABSTRACT
Control of uterine contractions is of interest in the context of inappropriate myometrial activity during pregnancy and at time of delivery, but it is also a matter for menstrual pain. While several molecular determinants of myometrial contractions have been described, the complete distribution of roles to the various actors is far from understood. A key phenomenon is a variation in cytoplasmic Ca2+ which leads to the activation of calmodulin in smooth muscle and also in the phosphorylation of myosin allowing contraction. The Ca2+ - TRPM4 channel which is known to modulate Ca2+- fluxes in several cell types was shown to participate in vascular as well as detrusor muscle contraction. We thus designed a study to determine whether it also participates in myometrial contraction. Uterine rings were isolated from Trpm4+/+ and Trpm4-/- non-pregnant adult mice and contractions were recorded using an isometric force transducer. In basal conditions, spontaneous contractions were similar in both groups. Application of 9-phenanthrol, a pharmacological TRPM4 inhibitor, dose-dependently reduced contraction parameters in Trpm4+/+ rings with an IC50 around 2.10-6 mol/L. The effect of 9-phenanthrol was significantly reduced in Trpm4-/- rings. The effect of oxytocin was tested and was found to be stronger in Trpm4+/+ rings compared to Trpm4-/-. Under a constant stimulation by oxytocin, 9-phenanthrol still reduced contraction parameters in Trpm4+/+ rings with a smaller effect on Trpm4-/-. Altogether it indicates that TRPM4 participates in uterine contractions in mice and may thus be evaluated as a new target to control such contractions.
Topics: Female; Pregnancy; Mice; Animals; Uterine Contraction; Calcium; Oxytocin; TRPM Cation Channels; Myometrium
PubMed: 37204208
DOI: 10.1530/REP-22-0484 -
Reproduction in Domestic Animals =... Sep 2023Canine pregnancy relies on luteal steroidogenesis for progesterone (P4) production. The canine placenta responds to P4, depending on the nuclear P4 receptor (PGR). This... (Review)
Review
Canine pregnancy relies on luteal steroidogenesis for progesterone (P4) production. The canine placenta responds to P4, depending on the nuclear P4 receptor (PGR). This has sparked interest in investigating the interaction between ovarian luteal steroids and the placenta in dogs. Canine placentation is characterized by restricted (shallow) trophoblast invasion, making the dog an interesting model for studying decidua-derived modulation of trophoblast invasion, compared with the more invasive (hemochorial) placentation. The PGR is expressed in maternally derived decidual cells and plays a crucial role in feto-maternal communication during pregnancy maintenance. Understanding PGR-mediated signalling has clinical implications for improving reproductive performance control in dogs. Altering the PGR signalling induces the release of PGF2α from the foetal trophoblast, hindering placental homeostasis, which can also be achieved with antigestagens like aglepristone. Consequently, luteolysis, both natural and antigestagen-induced, involves apoptosis, vascular lesion, and immune cell infiltration in the placenta, resulting in placentolysis and foetal membranes expulsion. Our laboratory developed the immortalized dog uterine stromal (DUS) cell line to study canine-specific decidualization. We study canine reproduction by observing physiological processes and investigating evidence-based mechanisms of decidualization and feto-maternal interaction. Our focus on morphology, function and molecular aspects enhances understanding and enables targeted and translational studies.
Topics: Female; Pregnancy; Dogs; Animals; Placenta; Ovary; Apoptosis; Corpus Luteum; Dinoprost
PubMed: 37724655
DOI: 10.1111/rda.14443 -
Obstetrical & Gynecological Survey Jan 2024Several medications have been used to achieve medical abortion in the first trimester of pregnancy. The most commonly used is the combination of mifepristone and... (Review)
Review
IMPORTANCE
Several medications have been used to achieve medical abortion in the first trimester of pregnancy. The most commonly used is the combination of mifepristone and misoprostol; however, different doses and routes of administration have been proposed.
OBJECTIVE
The aim of this study was to summarize published data on the effectiveness, adverse effects, and acceptability of the various combinations of mifepristone and misoprostol in medical abortion protocols in the first trimester of pregnancy.
EVIDENCE ACQUISITION
This was a comprehensive review, synthesizing the findings of the literature on the current use of mifepristone and misoprostol for first-trimester abortion.
RESULTS
The combination of mifepristone and misoprostol seems to be more effective than misoprostol alone. Regarding the dosages and routes, mifepristone is administered orally, and the optimal dose is 200 mg. The route of administration of misoprostol varies; the sublingual and buccal routes are more effective; however, the vaginal route (800 μg) is associated with fewer adverse effects. Finally, the acceptability rates did not differ significantly.
CONCLUSIONS
Different schemes for first-trimester medical abortion have been described so far. Future research needs to focus on identifying the method that offers the best trade-off between efficacy and safety in first-trimester medical abortion.
Topics: Pregnancy; Female; Humans; Mifepristone; Misoprostol; Pregnancy Trimester, First; Abortion, Induced; Abortifacient Agents, Nonsteroidal
PubMed: 38306292
DOI: 10.1097/OGX.0000000000001222 -
European Journal of Obstetrics,... Apr 20241. (Meta-Analysis)
Meta-Analysis Review
UNLABELLED
1.
OBJECTIVE
To perform a network meta-analysis to specify the route of administration that maximises the effectiveness of each of the available prophylactic uterotonics without increasing the risk for side effects. 2.
DATA SOURCES
Literature searches on 12th September 2022 included: CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. The reference lists of the retrieved study records were also searched. 3.
STUDY ELIGIBILITY CRITERIA
Population: Randomized controlled trials involving women in the third stage of labour after a vaginal or caesarean delivery in hospital or community settings.
INTERVENTIONS
Systemically administered prophylactic uterotonics of any route and dose for primary postpartum hemorrhage prevention. Comparison: Any other prophylactic uterotonic, or a different route or dose of a given uterotonic, or placebo, or no treatment. Outcomes (primary): postpartum hemorrhage ≥ 500 mL and ≥ 1000 mL. 4.
STUDY APPRAISAL AND SYNTHESIS METHODS
Risk of bias and trustworthiness assessments were performed, according to Cochrane's guidance. Direct, indirect and network meta-analyses were conducted, and results were summarized either as risk ratio or mean difference with 95% confidence intervals for dichotomous and continuous outcomes, respectively. The certainty of generated evidence was assessed according to the GRADE approach. Cumulative probabilities were calculated and the surface under the cumulative ranking curve was used to create a ranking of the available drugs. 5.
RESULTS
One hundred eighty-one studies involving 122,867 randomised women were included. Most studies were conducted in hospital settings in lower-middle income countries and involved women delivering vaginally. When compared with intramuscular oxytocin, carbetocin (RR 0.58, 95 % CI 0.40-0.84) and oxytocin (RR 0.75, 95 % CI 0.59-0.97) by an intravenous bolus, and intramuscular ergometrine plus oxytocin combination (RR 0.71, 95 % CI 0.56-0.91) are probably more effective in preventing primary postpartum hemorrhage. Intramuscularly administered oxytocin and carbetocin by an intravenous bolus have a favourable side effects profile. 6.
CONCLUSIONS
Generated evidence was generally moderate and global inconsistency was low. Carbetocin and oxytocin by an intravenous bolus, and intramuscular ergometrine plus oxytocin combination are probably the top uterotonics for primary postpartum hemorrhage prevention. Large scale studies exploring different routes of administration for available prophylactic uterotonics, and women's views should be conducted.
Topics: Pregnancy; Female; Humans; Postpartum Hemorrhage; Oxytocin; Oxytocics; Ergonovine; Network Meta-Analysis; Labor Stage, Third; Randomized Controlled Trials as Topic
PubMed: 38367391
DOI: 10.1016/j.ejogrb.2024.02.021 -
PloS One 2023Shiso (Perilla frutescens var crispa f. purprea) is a traditional medicinal herb that exerts anti-inflammatory effects and alleviates lower urinary tract symptoms. In...
Shiso (Perilla frutescens var crispa f. purprea) is a traditional medicinal herb that exerts anti-inflammatory effects and alleviates lower urinary tract symptoms. In this study, we examined the effects of rosmarinic acid, a major polyphenol in shiso, on urinary function and the bladder in a rat hydrochloric acid-induced cystitis model. Sprague-Dawley rats were administered intravesically with hydrochloric acid or saline solution (control) to induce cystitis. Afterwards, the rats were administered orally with distilled water or rosmarinic acid for three days and then the intravesical pressure was measured, a stretch stimulation test was performed using the harvested bladder, and histological and biochemical analyses were performed. In addition, we investigated the effects of rosmarinic acid on the expression of inflammation-related molecules in normal human bladder epithelial cells. Rosmarinic acid ameliorated hydrochloric acid-induced shortening of micturition interval by 49%. In hydrochloric acid-treated bladders, significantly more prostaglandin E2 was released after stretching; however, rosmarinic acid suppressed its release to control levels. Rosmarinic acid also reduced hydrochloric acid-induced epithelial thickening and the levels of inflammatory molecules in the bladder. Furthermore, rosmarinic acid suppressed interleukin 1β-induced increases in Cox2 and Il6 expression in bladder epithelial cells. These findings indicate that rosmarinic acid can ameliorate hydrochloric acid-induced cystitis in rats and that these effects are due, at least in part, to its anti-inflammatory effects on the bladder and inhibition of stretch-induced prostaglandin E2 release.
Topics: Humans; Rats; Animals; Rats, Sprague-Dawley; Hydrochloric Acid; Dinoprostone; Cystitis; Anti-Inflammatory Agents; Rosmarinic Acid
PubMed: 37463180
DOI: 10.1371/journal.pone.0288813 -
The Journal of Maternal-fetal &... Dec 2023With the development of precision medicine and artificial intelligence, the infusion of many drugs has been intelligently controlled according to patients' conditions.... (Review)
Review
With the development of precision medicine and artificial intelligence, the infusion of many drugs has been intelligently controlled according to patients' conditions. However, the infusion of oxytocin (OT) still relies on medical staff responsible for implementing artificial regulation based on observation of fetal electronic monitoring and other maternal and fetal conditions. In this review, we discussed recent trends in intelligent infusion systems, the development status and dilemma of intelligent control of OT infusion, the drug intelligent feedback control system principle, and current risks and challenges to further promote obstetric informatization.
Topics: Pregnancy; Female; Humans; Oxytocin; Artificial Intelligence; Fetal Monitoring; Fetus; Fetal Diseases
PubMed: 37403363
DOI: 10.1080/14767058.2023.2230512 -
American Family Physician Nov 2023
Topics: Pregnancy; Female; Humans; Self-Management; Abortion, Induced; Misoprostol; Abortion, Spontaneous
PubMed: 37983709
DOI: No ID Found -
Journal of Advanced Research Apr 2024Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone...
INTRODUCTION
Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B × N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis.
OBJECTIVES
To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis.
METHODS
The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B × N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments.
RESULTS
We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation.
CONCLUSION
Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory diseases.
Topics: Humans; Animals; Mice; Extracellular Traps; Dinoprostone; Extracellular Signal-Regulated MAP Kinases; Cyclic AMP-Dependent Protein Kinases; Arthritis, Rheumatoid; Inflammation
PubMed: 37169220
DOI: 10.1016/j.jare.2023.05.001 -
Journal of Physiological Investigation Jan 2024Oxytocin (OXT), a neuropeptide originating from the hypothalamus and traditionally associated with peripheral functions in parturition and lactation, has emerged as a... (Review)
Review
Oxytocin (OXT), a neuropeptide originating from the hypothalamus and traditionally associated with peripheral functions in parturition and lactation, has emerged as a pivotal player in the central regulation of the autonomic nervous system (ANS). This comprehensive ANS, comprising sympathetic, parasympathetic, and enteric components, intricately combines sympathetic and parasympathetic influences to provide unified control. The central oversight of sympathetic and parasympathetic outputs involves a network of interconnected regions spanning the neuroaxis, playing a pivotal role in the real-time regulation of visceral function, homeostasis, and adaptation to challenges. This review unveils the significant involvement of the central OXT system in modulating autonomic functions, shedding light on diverse subpopulations of OXT neurons within the paraventricular nucleus of the hypothalamus and their intricate projections. The narrative progresses from the basics of central ANS regulation to a detailed discussion of the central controls of sympathetic and parasympathetic outflows. The subsequent segment focuses specifically on the central OXT system, providing a foundation for exploring the central role of OXT in ANS regulation. This review synthesizes current knowledge, paving the way for future research endeavors to unravel the full scope of autonomic control and understand multifaceted impact of OXT on physiological outcomes.
Topics: Oxytocin; Humans; Autonomic Nervous System; Animals
PubMed: 38780268
DOI: 10.4103/EJPI.EJPI-D-23-00037 -
Neuron Jun 2024A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different neuromodulators compete or cooperate at various temporal...
A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different neuromodulators compete or cooperate at various temporal scales remain an open question. We investigated the interaction of acetylcholine (ACh) and oxytocin (OXT) at slow and fast timescales during various brain states. Although these neuromodulators fluctuated in parallel during NREM packets, transitions from NREM to REM were characterized by a surge of ACh but a continued decrease of OXT. OXT signaling lagged behind ACh. High ACh was correlated with population synchrony and gamma oscillations during active waking, whereas minimum ACh predicts sharp-wave ripples (SPW-Rs). Optogenetic control of ACh and OXT neurons confirmed the active role of these neuromodulators in the observed correlations. Synchronous hippocampal activity consistently reduced OXT activity, whereas inactivation of the lateral septum-hypothalamus path attenuated this effect. Our findings demonstrate how cooperative actions of these neuromodulators allow target circuits to perform specific functions.
Topics: Oxytocin; Acetylcholine; Hippocampus; Animals; Male; Optogenetics; Neurons; Gamma Rhythm; Neurotransmitter Agents; Mice; Rats; Wakefulness
PubMed: 38537642
DOI: 10.1016/j.neuron.2024.02.021