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Methods in Enzymology 2024Peptide drugs are a promising alternative to classical small molecule therapeutics with diverse applications, ranging from antibiotic resistant infection to prostate...
Peptide drugs are a promising alternative to classical small molecule therapeutics with diverse applications, ranging from antibiotic resistant infection to prostate cancer. Oxytocin (OT) is a highly evolutionarily conserved peptide neurohormone and has been of interest for pharmaceutical use since 1909. Despite their increased safety profile relative to most small molecule drugs, peptides are poor candidates based on the pharmacokinetic (PK) properties from their peptide nature. Broad application of OT as a drug has been limited by these same PK issues. Several strategies have been proposed to overcome these limitations, among them glycosylation, which was used in combination with other sequence modifications to produce robust antinociception in mouse models, increased selectivity and potency at the OT receptor, and improved stability in rats.
Topics: Oxytocin; Animals; Rats; Mice; Pain; Drug Design; Glycosides; Substance-Related Disorders; Humans; Analgesics; Glycosylation; Receptors, Oxytocin
PubMed: 38886038
DOI: 10.1016/bs.mie.2024.04.016 -
Journal of Pharmacological Sciences Aug 2024We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions...
We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions elicited by U46619 and prostaglandin F without affecting those elicited by 80 mM KCl, histamine, acetylcholine, and serotonin. ALA rightward shifted the concentration-response curve of U46619, and Schild plot analysis revealed that ALA competitively antagonized U46619. Furthermore, ALA inhibited the increase in intracellular Ca concentration caused by TP receptor stimulation but not that caused by FP receptor stimulation. These results suggest that ALA behaves as a selective antagonist of TP receptors in coronary arteries.
Topics: Animals; Coronary Vessels; alpha-Linolenic Acid; Swine; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Calcium; Receptors, Thromboxane; Dose-Response Relationship, Drug; Male; Dinoprost; Muscle Contraction
PubMed: 38880549
DOI: 10.1016/j.jphs.2024.06.001 -
Immunity Jun 2024Mast cells (MCs) are effectors in type 2 immunity, well known for their detrimental roles in allergy. In this issue of Immunity, Alhallak et al. now identify a...
Mast cells (MCs) are effectors in type 2 immunity, well known for their detrimental roles in allergy. In this issue of Immunity, Alhallak et al. now identify a protective role of MCs against exacerbated immune responses mediated by prostaglandin E (PGE)-driven soluble ST2.
Topics: Mast Cells; Animals; Humans; Inflammation; Dinoprostone; Interleukin-1 Receptor-Like 1 Protein; Mice; Receptors, Cell Surface
PubMed: 38865961
DOI: 10.1016/j.immuni.2024.05.011 -
Frontiers in Endocrinology 2024Given its putative roles in mediating prosocial behavior, attachment bonds, and stress physiology, oxytocin modulation has been hypothesized to be a biological correlate...
BACKGROUND
Given its putative roles in mediating prosocial behavior, attachment bonds, and stress physiology, oxytocin modulation has been hypothesized to be a biological correlate of the salubrious effects of meditation practice. Here we investigated the effects of a month-long silent meditation retreat on changes in oxytocin, and the related hormone and vasopressin, in relation to psychosocial changes in attachment style, anxiety, personality measures, and feelings of social connectedness with fellow meditators.
METHODS
Plasma oxytocin and vasopressin and self-report questionnaires were measured in retreat participants ( = 28) at the beginning of, and 3 weeks into, a residential meditation retreat. Control participants ( = 34), who were similar in age, gender, and meditation experience, were also assessed across a 3-week interval. Linear mixed effects models were used to assess outcomes.
RESULTS
The retreat group showed a small but significant decrease in oxytocin compared to controls who showed no change. In the retreat group, higher openness to experience at Time 1 predicted greater reductions in oxytocin during the retreat, and lower oxytocin at Time 2 was related to stronger feelings of personal connection with fellow meditators. The changes in oxytocin were not related to attachment style or anxiety. Vasopressin decreased over time across both groups, suggesting no specific effect of retreat.
CONCLUSION
These preliminary findings suggest that meditation training in the context of a silent residential retreat may reduce circulating levels of oxytocin. We interpret this finding from multiple theoretical perspectives, discussing key measurement limitations and proposing future study designs that may help to differentiate the effects of different meditation practices and contexts on oxytocin signaling.
Topics: Humans; Oxytocin; Meditation; Female; Male; Adult; Middle Aged; Vasopressins; Anxiety
PubMed: 38863930
DOI: 10.3389/fendo.2024.1345527 -
Actas Espanolas de Psiquiatria Jun 2024Postpartum depression (PPD) is a common mental disorder in postpartum women, negatively impacting physical and mental health. Correlation analysis can predict the...
BACKGROUND
Postpartum depression (PPD) is a common mental disorder in postpartum women, negatively impacting physical and mental health. Correlation analysis can predict the relationship between variables. By detecting the abnormal level of oxytocin, clinicians can timely know the emotional states of parturients to guide clinical practice. This study aimed to investigate the relationship between emotional states and oxytocin (OT) levels in patients with PPD.
MATERIALS AND METHODS
The medical records of 166 PPD patients admitted to Cangzhou Central Hospital from May 2020 to March 2023 were retrospectively analyzed. After excluding 9 patients who did not meet the inclusion criteria, the remaining 157 patients were included in this study. The 7-item Generalized Anxiety Disorder Scale and Patient Health Questionaire-9 items were used to evaluate the emotional states of 157 patients, and the included subjects were grouped according to the results of the scale. The serum OT levels of patients was measured, and the relationship between the OT levels and emotional states was analyzed.
RESULTS
In this study, 75 patients were included in the mild anxiety group, and 82 patients were included in the moderate and severe anxiety group. Seventy-nine patients were selected as the mild depression group, and 78 patients were included in the moderate and severe depression group. The mild anxiety group had a higher OT level than the moderate and severe anxiety group (Z = -10.121, p < 0.001). The mild depression group had a higher OT level than the moderate and severe depression group (Z = -9.758, p < 0.001). OT level was negatively correlated with anxiety and depression scores (r = -0.676, r = -0.665, p < 0.001).
CONCLUSION
There is a specific relationship between the emotional states of PPD patients and the OT levels in the body, and active clinical management strategies need to be implemented.
Topics: Humans; Oxytocin; Female; Depression, Postpartum; Adult; Retrospective Studies; Emotions; Anxiety; Severity of Illness Index
PubMed: 38863049
DOI: 10.62641/aep.v52i3.1627 -
BMC Pregnancy and Childbirth Jun 2024However, misoprostol is often used to terminate a pregnancy, but it can also cause side effects. Isosorbide mononitrate (ISMN) can help the cervix mature by increasing... (Meta-Analysis)
Meta-Analysis Comparative Study
Efficacy and safety of isosorbide mononitrate plus misoprostol compared to misoprostol alone in the management of the first and second trimester abortion: a systematic review and meta-analysis.
BACKGROUND
However, misoprostol is often used to terminate a pregnancy, but it can also cause side effects. Isosorbide mononitrate (ISMN) can help the cervix mature by increasing the production of prostaglandin E2 and vasodilation. Considering that the results of studies in this field are contradictory, it is the purpose of this study to evaluate the efficacy and safety of vaginal ISMN plus misoprostol compared to misoprostol alone in the management of first- and second-trimester abortions.
METHOD
The search process was conducted for MEDLINE through the PubMed interface, Scopus, Web-of-Science, Science Direct, the Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform until November 10, 2023. Our assessment of bias was based on version 2 of the risk-of-bias tool (RoB2) for randomized trials and our level of evidence quality was determined by GRADE. Meta-analysis of all data was carried out using Review Manager (RevMan) version 5.1.
RESULT
Seven randomized clinical trials were included in the systematic review and three in the meta-analysis, with mixed quality. The results of the meta-analysis revealed that in the second-trimester abortion, the inclusion of ISMN in conjunction with vaginal misoprostol results in a noteworthy reduction in the induction abortion interval, specifically by 4.21 h (95% CI: -7.45 to -0.97, P = 0.01). The addition of vaginal ISMN to misoprostol, compared to vaginal misoprostol alone, increased the odds of a completed abortion by 3.76 times. (95% CI: 1.08 to 13.15, P = 0.04).
CONCLUSION
The findings of this study can offer valuable insights aimed at enhancing counseling and support for non-surgical methods of medication abortion within professional settings. Moreover, it improves the effectiveness of clinical treatment and reduces the occurrence of unnecessary surgical interventions in the abortion management protocol.
Topics: Humans; Misoprostol; Female; Pregnancy; Pregnancy Trimester, Second; Isosorbide Dinitrate; Abortion, Induced; Abortifacient Agents, Nonsteroidal; Pregnancy Trimester, First; Drug Therapy, Combination; Administration, Intravaginal; Treatment Outcome
PubMed: 38858628
DOI: 10.1186/s12884-024-06614-9 -
BMC Urology Jun 2024This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development.
BACKGROUND
This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development.
METHODS
By using immunofluorescence and Western blot, we were able to locate EP receptors in the ureter. In vitro experiments assessed the impact of PGE2, receptor antagonists, and agonists on ureteral relaxation rate. We constructed a model of ureteral calculi with flowable resin and collected ureteral tissue from postoperative side of the ureter after obstruction surgery. Western blot analysis was used to determine the protein expression levels of EP receptors and the PGE2 terminal synthase mPGES-1. Additionally, PGE2 was added to smooth muscle cells to observe downstream cAMP and PKA changes.
RESULTS
The expression of EP2 and EP4 proteins in ureteral smooth muscle was verified by Western blot analysis. According to immunofluorescence, EP2 was primarily found on the cell membrane, while EP4 was found in the nucleus. In vitro, PGE2 induced concentration-dependent ureteral relaxation. Maximum diastolic rate was 70.94 ± 4.57% at a concentration of 30µM. EP2 antagonists hindered this effect, while EP4 antagonists did not. Obstructed ureters exhibited elevated mPGES-1 and EP2 protein expression (P < 0.01). Smooth muscle cells treated with PGE2 displayed increased cAMP and phosphorylated PKA.
CONCLUSIONS
PGE2 binding to EP2 induces ureteral relaxation through the cAMP-PKA pathway. This will provide a new theoretical basis for the development of new therapeutic approaches for the use of PGE2 in the treatment of ureteral stones.
Topics: Receptors, Prostaglandin E, EP2 Subtype; Cyclic AMP; Dinoprostone; Cyclic AMP-Dependent Protein Kinases; Ureteral Calculi; Animals; Ureter; Signal Transduction; Male; Muscle Relaxation
PubMed: 38851678
DOI: 10.1186/s12894-024-01504-w -
JAMA Jul 2024
Topics: Humans; Female; Pregnancy; Abortion, Induced; Postal Service; Abortifacient Agents; United States; Misoprostol
PubMed: 38848095
DOI: 10.1001/jama.2024.10330 -
Nature Medicine Jun 2024Timely detection and treatment of postpartum hemorrhage (PPH) are crucial to prevent complications or death. A calibrated blood-collection drape can help provide...
Timely detection and treatment of postpartum hemorrhage (PPH) are crucial to prevent complications or death. A calibrated blood-collection drape can help provide objective, accurate and early diagnosis of PPH, and a treatment bundle can address delays or inconsistencies in the use of effective interventions. Here we conducted an economic evaluation alongside the E-MOTIVE trial, an international, parallel cluster-randomized trial with a baseline control phase involving 210,132 women undergoing vaginal delivery across 78 secondary-level hospitals in Kenya, Nigeria, South Africa and Tanzania. We aimed to assess the cost-effectiveness of the E-MOTIVE intervention, which included a calibrated blood-collection drape for early detection of PPH and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination and escalation), compared with usual care. We used multilevel modeling to estimate incremental cost-effectiveness ratios from the perspective of the public healthcare system for outcomes of cost per severe PPH (blood loss ≥1,000 ml) avoided and cost per disability-adjusted life-year averted. Our findings suggest that the use of a calibrated blood-collection drape for early detection of PPH and bundled first-response treatment is cost-effective and should be perceived by decision-makers as a worthwhile use of healthcare budgets. ClinicalTrials.gov identifier: NCT04341662 .
PubMed: 38844798
DOI: 10.1038/s41591-024-03069-5 -
BMJ Open Gastroenterology Jun 2024The management of non-alcoholic steatohepatitis (NASH) is an unmet clinical need. Misoprostol, a structural analogue of naturally occurring prostaglandin E1, has been... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The management of non-alcoholic steatohepatitis (NASH) is an unmet clinical need. Misoprostol, a structural analogue of naturally occurring prostaglandin E1, has been reported to decrease proinflammatory cytokine production and may have a potential role in treating NASH. We aimed to evaluate the efficacy and safety of misoprostol in treating patients with NASH.
METHODS
In this phase 2, double-blind, randomised, placebo-controlled trial, patients with NASH were randomly assigned in a 1:1 ratio to receive 200 µg of misoprostol or placebo thrice daily for 2 months. The primary endpoint was an improvement in liver function tests (LFTs), interleukin-6 (IL-6) and endotoxin levels. The secondary endpoint was improvement in insulin resistance, dyslipidaemia, hepatic fibrosis and hepatic steatosis.
RESULTS
A total of 50 patients underwent randomisation, of whom 44 (88%) were males. The age range was 25-64 years (mean±SE of mean (SEM) 38.1±1.4). 19 (38%) patients had concomitant type 2 diabetes mellitus. 32 (64%) patients were either overweight or obese. At the end of 2 months' treatment, a reduction in total leucocyte count (TLC) (p=0.005), alanine aminotransferase (ALT) (p<0.001), aspartate aminotransferase (AST) (p=0.002) and controlled attenuation parameter (CAP) (p=0.003) was observed in the misoprostol group, whereas placebo ensued a decline in ALT (p<0.001), AST (p=0.018), gamma-glutamyl transferase (GGT) (p=0.003), CAP (p=0.010) and triglycerides (p=0.048). There was no diminution in insulin resistance, hepatic fibrosis (elastography) and dyslipidaemia in both groups. However, misoprostol resulted in a significant reduction in CAP as compared with the placebo group (p=0.039). Moreover, in the misoprostol group, pretreatment and post-treatment IL-6 and endotoxin levels remained stable, while in the placebo group, an increase in the IL-6 levels was noted (p=0.049). Six (12%) patients had at least one adverse event in the misoprostol group, as did five (10%) in the placebo group. The most common adverse event in the misoprostol group was diarrhoea. No life-threatening events or treatment-related deaths occurred in each group.
CONCLUSION
Improvement in the biochemical profile was seen in both misoprostol and placebo groups without any statistically significant difference. However, there was more improvement in steatosis, as depicted by CAP, in the misoprostol group and worsening of IL-6 levels in the placebo group.
TRIAL REGISTRATION NUMBER
NCT05804305.
Topics: Humans; Male; Female; Non-alcoholic Fatty Liver Disease; Middle Aged; Double-Blind Method; Adult; Misoprostol; Interleukin-6; Treatment Outcome; Insulin Resistance; Liver Cirrhosis; Liver Function Tests; Liver
PubMed: 38844374
DOI: 10.1136/bmjgast-2023-001342