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We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.

Gliotoxin (GT), a secondary metabolite and virulence factor of the fungal pathogen Aspergillus fumigatus, suppresses innate immunity and supports the suppression of host immune responses. Recently, we revealed that GT blocks the formation of the chemotactic lipid mediator leukotriene (LT)B4 in activated human neutrophils and monocytes, and in rodents in vivo, by directly inhibiting LTA4 hydrolase. Here, we elucidated the impact of GT on LTB4 biosynthesis and the entire lipid mediator networks in human M1‐ and M2‐like monocyte‐derived macrophages (MDMs) and in human tissue‐resident alveolar macrophages. In activated M1‐MDMs with high capacities to generate LTs, the formation of LTB4 was effectively suppressed by GT, connected to attenuated macrophage phagocytic activity as well as human neutrophil movement and migration. In resting macrophages, especially in M1‐MDMs, GT elicited strong formation of prostaglandins, while bacterial exotoxins from Staphylococcus aureus evoked a broad spectrum of lipid mediator biosynthesis in both MDM phenotypes. We conclude that GT impairs functions of activated innate immune cells through selective suppression of LTB4 biosynthesis, while GT may also prime the immune system by provoking prostaglandin formation in macrophages. [ABSTRACT FROM AUTHOR]

Purpose: Fetal heart diseases significantly contribute to neonatal mortality. Improved prenatal diagnostics enable defect detection before delivery, emphasizing the need for a personalized approach to address anomalies and predict outcomes. Categorizing diseases into risk classes aids obstetricians in counseling and delivery decisions. This study classifies fetal heart diseases by severity, examining factors related to maternal, fetal, and delivery that affect neonatal mortality. The aim is to identify key determinants of neonatal mortality and create an individual approach to assess and manage risks in the first days of a newborn's life. Methods: A prospective study from 2019 to 2023 at a tertiary care institute involved pregnant women diagnosed with fetal heart disease. 382 women were categorized into three groups based on potential risk for hemodynamic instability at birth: Group-1 (no or low risk, n = 114), Group-2 (moderate risk, n = 201), and Group-3 (high risk, n = 67). Antenatal follow-up used fetal echocardiography. The study explored the association between maternal–fetal-delivery-related factors and neonatal mortality, with statistical significance set at p < 0.05. Results: Significant associations with neonatal mortality were found in cases with birth weight < 2500 g (p = 0.002), presence of genitourinary system anomaly (p = 0.001), group-2 and 3 heart disease (p < 0.001), and induction of labor (p = 0.01). Conclusion: Factors influencing neonatal mortality in fetal heart disease cases include heart disease severity (group-3 heart disease), low birth weight, and extracardiac anomalies. While labor induction with prostaglandin ± oxytocin appears to elevate neonatal mortality, this observation requires further validation with larger sample sizes. Obstetricians should consider selective use of prostaglandin for labor induction. [ABSTRACT FROM AUTHOR]

Cilia are hair-like structures found on the surface of nearly all vertebrate cell types where they have central roles in regulating development and orchestrating physiological events. There is growing interest in understanding the mechanisms of ciliogenesis due to the profound consequences that follow from the absence of proper ciliary function, which include diseases that affect the renal, respiratory, reproductive, nervous, visual, and digestive systems, among others. Now, a recent report has discerned new roles for the transcription factor estrogen-related receptor gamma a (esrrγa) in ciliated cell ontogeny within the embryonic zebrafish kidney and other tissues. Further, the team of researchers discovered that genetic ablation of murine homolog ERRγ in adult kidney epithelial cells led to shortened cilia, which precedes cystogenesis. These intriguing findings expand our fundamental understanding of the pathological basis of cilia defects, which is relevant for identifying future therapeutic targets for ciliopathies. [ABSTRACT FROM AUTHOR]

Novel benzophenone–thiazole hybrids with different substituents were synthesized and evaluated for anti‐inflammatory activity using an ex vivo human whole‐blood assay. All hybrids (3c and 5a–h) showed significant anti‐inflammatory activity via prostaglandin E2 (PGE2) release inhibition. Moreover, 5c (82.8% of PGE2 inhibition), 5e (83.1% of PGE2 inhibition), and 5h (82.1% of PGE2 inhibition) were comparable to the reference drugs. Molecular docking revealed potential preferable binding to the active sites of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase‐1 (mPGES‐1) enzymes. This study provides the first evidence that benzophenone–thiazole hybrids may also dock in mPGES‐1, a new attractive anti‐inflammatory drug target, besides providing promising ex vivo anti‐inflammatory activity. Thus, the novel hybrids are promising anti‐inflammatory lead compounds and highlight the significance of optimal substituent selection in the design of potent PGE2 inhibitors. [ABSTRACT FROM AUTHOR]

Multiciliated cells (MCCS) form bundles of cilia and their activities are essential for the proper development and physiology of many organ systems. Not surprisingly, defects in MCCs have profound consequences and are associated with numerous disease states. Here, we discuss the current understanding of MCC formation, with a special focus on the genetic and molecular mechanisms of MCC fate choice and differentiation. Furthermore, we cast a spotlight on the use of zebrafish to study MCC ontogeny and several recent advances made in understanding MCCs using this vertebrate model to delineate mechanisms of MCC emergence in the developing kidney. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the effect of intranasal (IN) flunixin meglumine (FM) and intra-inguinal (IG) lidocaine on castration inflammation using prostaglandin E2 (PGE2) concentration as a biomarker. METHODS This randomized controlled trial was conducted in March 2022. Blood was collected at -24, 1, and 24 hours postcastration for PGE2 quantification from 195 piglets that received 1 of 8 treatments: (1) saline (1.5 mL) applied IG and IN (0.2 mL) followed by surgical castration (n = 24); (2) saline (1.5 mL) IG and IN (0.2 mL) followed by sham castration (25); (3) lidocaine (20 mg/kg or 1.5 mL) IG followed by surgical castration (24); (4) lidocaine (20 mg/ kg or 1.5 mL) IG followed by sham castration (25); (5) FM (2.2 mg/kg) IN followed by surgical castration (25); (6) FM (2.2 mg/kg) IN followed by sham castration (24); (7) lidocaine (20 mg/kg or 1.5 mL) IG and FM (2.2 mg/kg) IN followed by surgical castration (24); and (8) lidocaine (20 mg/kg or 1.5 mL) IG and FM (2.2 mg/kg) IN followed by sham castration (24). RESULTS Prostaglandin E2 concentrations did not increase following the castration procedure and were not an effective biomarker of castration inflammation. Piglets that received lidocaine demonstrated no difference in PGE2 levels across all time points. Piglets administered FM had lower PGE2 concentrations at 1 hour and 20 minutes postdrug administration in both the sham and castrated piglets. CONCLUSIONS Prostaglandin E2 was not an effective biomarker to quantify castration inflammation. Flunixin meglumine was able to reduce PGE2 concentration in piglets regardless of castration procedure, but lidocaine had no impact. Decreased PGE2 levels in FM-treated pigs are likely associated with the drug's ability to mitigate a noncastration-associated inflammatory process occurring independent of the castration procedure. CLINICAL RELEVANCE Flunixin meglumine reduced circulating PGE2 concentration in the blood, regardless of the castration procedure, indicating a potential for the drug to mitigate an inflammatory process unrelated to castration. [ABSTRACT FROM AUTHOR]

Enteral feeds are often withheld from neonates with ductal dependent cardiac lesions who are receiving prostaglandins. This is despite positive benefits of enteral feeding. We describe a multicenter cohort of these neonates who were fed pre-operatively. We also give a granular description of vital sign measurements and other risk factors prior to feeding. A retrospective chart review was performed at seven centers. Inclusion criteria were full-term neonates under one month of age with ductal dependent lesions receiving prostaglandins. These neonates were fed for at least 24 h during the pre-operative period. Premature neonates were excluded. Using the inclusion criteria, 127 neonates were identified. While being fed, 20.5% of the neonates were intubated, 10.2% were on inotropes, and 55.9% had an umbilical arterial catheter in place. Median oxygen saturations in the six hours prior to feeding were 92.5% in patients with cyanotic lesions, median diastolic blood pressure was 38 mmHg and median somatic NIRS were 66.5%. The median peak daily feeding volume reached was 29 ml/kg/day (IQ range 15.5–96.8 ml/kg/day). One patient developed suspected necrotizing enterocolitis (NEC) in this cohort. Only one adverse event occurred, which was an aspiration thought to be related to feeding, but did not result in intubation or cessation of feeds. NEC was rare among neonates with ductal dependent lesions while receiving enteral nutrition pre-operatively. Umbilical arterial catheters were in place in the majority of these patients. Hemodynamic measures demonstrated a high median oxygen saturation prior to initiation of feeds. [ABSTRACT FROM AUTHOR]

The lipid prostaglandin E2 (PGE2) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.

Asman Sadino,1,2,&ast; Nyi Mekar Saptarini,3 Jutti Levita,4,&ast; Dwi Syah Fitra Ramadhan,5 Adryan Fristiohady,6 Supat Jiranusornkul7 1Doctoral Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia; 2Department of Pharmacology and Clinical Pharmacy, Faculty of Mathematics and Natural Sciences, Garut University, Garut, West Java, 44151, Indonesia; 3Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia; 4Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, West Java, Indonesia; 5Department of Pharmacy, Poltekkes Kemenkes Makassar, Makassar, South Sulawesi, 90222, Indonesia; 6Faculty of Pharmacy, Halu Oleo University, Kendari, Southeast Sulawesi, 93132, Indonesia; 7Department of Pharmaceutical Science, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand&ast;These authors contributed equally to this workCorrespondence: Jutti Levita, Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 46363, Indonesia, Email jutti.levita@unpad.ac.idBackground: Human monoacylglycerol lipase (MGL) is accountable for the hydrolysis of 2-arachidonoylglycerol (2-AG), thus contributing pivotally to neuroprotection because 2-AG is the main source of arachidonic acid, the precursor of prostaglandins production. Inhibiting MGL reduces inflammatory damage in the ischemic brain and enhances cerebral blood flow. Plants have been reported for their neuroprotective effect, such as Morinda citrifolia on pentylenetetrazol (PTZ)-induced kindling seizures in mice, by reducing the seizures and restoring behavioral and biochemical changes, although the mechanism is not described.Purpose: To evaluate the binding affinity and stability of phytoconstituents in M. citrifolia fruits toward human MGL (PDB ID 3PE6), compared to the known MGL inhibitors (JZL195 and ZYH). The in silico pharmacology study was validated by an in vitro study of the phytosterols and the ethanol extract of M. citrifolia fruits (EEMC) towards MGL.Methods: Initially, nine phytoconstituents of M. citrifolia fruits were docked to the catalytic pocket of human MGL (PDB ID: 3PE6), and compounds with the best affinity were subjected to a molecular dynamic (MD) simulation. The in vitro study was performed using the MGL inhibitor screening assay kit.Results: The best binding affinity and stability toward human MGL were shown by stigmasterol and beta-sitosterol, and the MM-PBSA total binding energy of stigmasterol and beta-sitosterol to MGL is stronger than that of JZL195 and ZYH. Moreover, beta-sitosterol and EEMC inhibit MGL with an IC50 value of, respectively, 8.10 μg/mL and 196.20 μg/mL, while JZL195 shows an IC50 of 0.028 μg/mL.Conclusion: Beta-sitosterol of Morinda citrifolia fruits may have the potential to protect human neurons by occupying the catalytic site of human MGL, thus competitively inhibiting the substrate of the enzyme. However, the inhibitory activity towards human MGL is lower than JZL195.Keywords: 2-arachidonoylglycerol, beta-sitosterol, phytosterols, prostaglandin, serine hydrolase, stigmasterol

Prostaglandin E2 (PGE2) has been reported to be involved in reproduction as one of the most abundant and widely distributed prostaglandins in invertebrates. Regulating gonad development and gamete production in mollusks can greatly assist artificial breeding, which is believed to promote the commercial benefits of various mollusk species. In the present study, the contents of PGE2 in the gonads of abalone at different developmental stages (maturing stage, ripe stage, and spawning stage) and reproduction states (before and after spawning) were measured. A higher PGE2 level was found in the gonads of abalones at the ripe stage than other stages, and the highest PGE2 level was detected in the ovaries of female H. diversicolor in the UV-stimulated group. Then the effects of PGE2 injection on the spawning efficiency were explored, and the gamete emission rates of female and male abalone were significantly increased after PGE2 injection. Through qRT-PCR and in situ hybridization assay, higher expression levels and wide distribution of phospholipase A2 (PLA2), cyclooxygenase 2 (COX2), prostaglandin E synthases (PGES2), and prostaglandin E2 receptor 4 (EP4) in the gonads of H. diversicolor were observed after spawning. It is speculated that PGE2 may promote the reproductive cycle in both male and female H. diversicolor, although the regulation mechanism of PGE2 in female and male abalone might be different. The results will be useful for the application of PGE2 in the abalone aquaculture practices to increase the reproduction efficiency in future.

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by restricted and repetitive behaviors as well as difficulties with social interaction. Numerous studies have revealed aberrant lipid mediators and autoimmunity as a recognized etiological cause of ASD that is amenable to therapeutic intervention. In this study, the relationship between the relative cyclooxygenase-2/prostaglandin E2 ratio (COX-2/PGE2) as a lipid mediator marker and anti-nucleosome autoantibodies as an autoimmunity marker of ASD was investigated using multiple regression and combined receiver operating characteristic (ROC) curve analyses. The study also sought to identify the linear combination of these variables that optimizes the partial area under the ROC curves. There were forty ASD children and forty-two age- and gender-matched controls included in the current study. Using combined ROC curve analysis, a notable increase in the area under the curve was seen in the patient group, using the control group as a reference group. Additionally, it was reported that the combined markers had improved specificity and sensitivity. This study demonstrates how the predictive value of particular biomarkers associated with lipid metabolism and autoimmunity in children with ASD can be measured using a ROC curve analysis. This technique should help us better understand the etiological mechanism of ASD and how it may adversely affect cellular homeostasis, which is essential to maintaining healthy metabolic pathways. Early diagnosis and intervention may be facilitated by this knowledge.

Elayna Kirsch,1 Sadiq Rahman,2 Katrina Kerolus,2 Rabale Hasan,1 Dorota B Kowalska,1 Amruta Desai,2 Sergio D Bergese2 1Department of Obstetrics and Gynecology, Stony Brook University Hospital, Stony Brook, NY, USA; 2Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY, USACorrespondence: Sergio D Bergese, School of Medicine, Stony Brook University, Health Science Center, Level 4, Room 060, Stony Brook, NY, 11794, USA, Tel +631444-2979, Fax +631444-2907, Email sergio.bergese@stonybrookmedicine.eduAbstract: Dysmenorrhea is the most common pathology women of childbearing age face. It is defined as painful uterine cramping associated with menstruation. Primary dysmenorrhea occurs in the absence of an organic cause, whereas secondary dysmenorrhea is pelvic pain associated with an underlying pelvic pathology. The purpose of this review is to discuss the pathophysiology of dysmenorrhea and provide a discussion of pharmacologic and non-pharmacologic treatment options. Prostaglandins play a large role in the pathophysiology of dysmenorrhea by causing myometrial contraction and vasoconstriction. The first-line treatment for dysmenorrhea is with nonsteroidal anti-inflammatory drugs due to the inhibition of cyclooxygenase enzymes, thereby blocking prostaglandin formation, as well as hormonal contraception. Other pharmacologic treatment options include Paracetamol, as well as Gonadotrophic Release Hormone Analogs, which are typically used in the treatment for endometriosis. Non-pharmacologic treatments with strong evidence include heat therapy and physical exercise. There are less evidence-based data behind other modalities for treating dysmenorrhea, such as dietary supplements, acupuncture, and transcutaneous nerve stimulation, and these methods should be used in conjunction with first-line therapy after a discussion of risks and benefits. Lastly, for women who fail medical management, surgical options include endometrial ablation, presacral neurectomy, and laparoscopic uterosacral nerve ablation. Further research is needed to measure the socioeconomic burden of dysmenorrhea on the healthcare system and to evaluate the efficacy of treatment combinations, as a multi-modal approach likely provides the most benefit for women who suffer from this condition.Keywords: dysmenorrhea, prostaglandin, NSAIDs, hormonal contraception, pelvic pain, pharmacologic management, behavioral interventions, surgical intervention

ABSTRACT Uterine vascular alterations take place in pyometra bitches speculatively influenced by prostaglandin and nitric oxide pathways. However, no causative effect of nitric oxide on endometrial vascularization was proved elsewhere for medically treated pyometra bitches. This study aimed to identify the main in situ uterine artery vasodilation pathway in pyometra bitches medically treated with antigestagen solely or coupled with prostaglandin. Pyometra bitches were enrolled into groups: Ovariohysterectomy at diagnosis (Control‐OHE; n = 7), Antigestagen (10 mg/kg aglepristone on Days 1, 2, and 8 after diagnosis; n = 5), and Antigestagen + luteolytic (aglepristone plus 1 μg/kg of cloprostenol from Days 1–7; n = 5). Treated bitches were ovariohysterectomized after 8 days of treatment. Uterine artery fragments from all bitches were collected for tissue nitric oxide and prostaglandin E2 assays. Control‐OHE group had lower uterine artery concentration of nitric oxide compared to treated bitches (Antigestagen and Antigestagen + luteolytic groups). No significant difference was verified between the medical treated groups. Uterine artery concentration of prostaglandin E2 was not different between control and treated bitches, as well as between both treated groups. In conclusion, nitric oxide and prostaglandin E2 are not directly involved in vascular modulation of the uterine artery, albeit pyometra medical treatment influences nitric oxide concentration in the uterine artery. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionsTo identify and evaluate the risk factors for ptosis repair failure.Retrospective, case-controlled study evaluating adult patients with ptosis who underwent ptosis surgery by external levator advancement/resection (ELR) or Müller muscle conjunctival resection (MMCR) with at least 3 months postoperative follow-up. Regression analyses were performed of ptosis repair outcomes comparing preoperative and perioperative risk factors for failure.A total of 240 patients (404 eyelids) met the inclusion criteria for the study. Surgical outcomes were measured categorically by success rate and measured quantitively over time using Kaplan–Meier survival analysis. Success was categorically achieved in 101/112 (90%) eyelids after MMCR and 231/292 (79%) eyelids after ELR (p = .0088). Success as measured over 5 years of follow-up was significantly better in eyelids following MMCR compared to ELR (p = .0469). In terms of surgical failure, the following variables were found to be predictive in order of decreasing risk: chronic topical prostaglandin use, chronic topical corticosteroid use, surgical approach, lower preoperative margin reflex distance 1, prior intraocular surgery, age, lower preoperative levator function, concomitant blepharoplasty, presence of a glaucoma filtering bleb, and female gender.Ptosis repair surgery is a complex and challenging procedure. This study provides the largest comparative analysis of ELR versus MMCR to date with findings suggesting MMCR to be more a successful surgery than ELR. Topical prostaglandin analogue use appears to be the highest known risk factor for MMCR and ELR ptosis repair failure. [ABSTRACT FROM AUTHOR]

Prostaglandin E2 (PGE2) has been reported to be involved in reproduction as one of the most abundant and widely distributed prostaglandins in invertebrates. Regulating gonad development and gamete production in mollusks can greatly assist artificial breeding, which is believed to promote the commercial benefits of various mollusk species. In the present study, the contents of PGE2 in the gonads of abalone at different developmental stages (maturing stage, ripe stage, and spawning stage) and reproduction states (before and after spawning) were measured. A higher PGE2 level was found in the gonads of abalones at the ripe stage than other stages, and the highest PGE2 level was detected in the ovaries of female H. diversicolor in the UV-stimulated group. Then the effects of PGE2 injection on the spawning efficiency were explored, and the gamete emission rates of female and male abalone were significantly increased after PGE2 injection. Through qRT-PCR and in situ hybridization assay, higher expression levels and wide distribution of phospholipase A2 (PLA2), cyclooxygenase 2 (COX2), prostaglandin E synthases (PGES2), and prostaglandin E2 receptor 4 (EP4) in the gonads of H. diversicolor were observed after spawning. It is speculated that PGE2 may promote the reproductive cycle in both male and female H. diversicolor, although the regulation mechanism of PGE2 in female and male abalone might be different. The results will be useful for the application of PGE2 in the abalone aquaculture practices to increase the reproduction efficiency in future. [ABSTRACT FROM AUTHOR]

Viruses, bacteria, fungus, protozoans, and different metazoan parasites and parasitoids present a constant threat to insects. Insect immunity has two components: humoral and cell mediated. Humoral immunity can be achieved by various antimicrobial proteins, namely, cecropins, sarcotoxin, defensin, attacin, etc. The cell‐mediated immunity comprises various cells having immune functions fostering nodulation, phagocytosis, microaggregation, encapsulation etc. Eicosanoids play a crucial role in insect immunity comparable to other animals. The above‐mentioned are signaling molecules derived from polyunsaturated fatty acids and they exert numerous physiological effects, namely, inflammation, immune modulation, and regulation of cellular processes. The review article elucidates various roles of eicosanoids, namely, nodulation reaction, Toll signaling pathway, nitric oxide (NO) generation, Ca2+ mobilization, production of reactive oxygen species (ROS), actin polymerization and aquaporin activation. Eicosanoids can function in immune priming in insects drawing hemocytes. An agent named Duox was also identified serving as ROS generator in insect gut. Moreover, role of Repat gene in insect immunity was also studied. However, recently the role of prostacyclin (PGI2) was found to be negative as it inhibits platelet aggregation. In this brief review, we have tried to shed light on the various functions of eicosanoids in immunity of insect those have been discovered recently. This concise study will allow to decipher eicosanoids’ function in insect immunity in a nutshell, and it will pave the way for more researches to understand the key players of insect immunity which may eventually help to develop novel vector and pest control strategies in near future. [ABSTRACT FROM AUTHOR]

Objective: Acute intranasal (IN) instillation of lupus-prone NZBWF1 mice with crystalline silica (cSiO2) triggers robust lung inflammation that drives autoimmunity. Prior studies in other preclinical models show that soluble epoxide hydrolase (sEH) inhibition upregulates pro-resolving lipid metabolites that are protective against pulmonary inflammation. Herein, we assessed in NZBWF1 mice how acute IN cSiO2 exposure with or without the selective sEH inhibitor TPPU influences lipidomic, transcriptomic, proteomic, and histopathological biomarkers of inflammation, fibrosis, and autoimmunity. Methods: Female 6-week-old NZBWF1 mice were fed control or TPPU-supplemented diets for 2 weeks then IN instilled with 2.5 mg cSiO2 or saline vehicle. Cohorts were terminated at 7 or 28 days post-cSiO2 instillation (PI) and lungs analyzed for prostaglandins, cytokines/chemokines, gene expression, differential cell counts, histopathology, and autoantibodies. Results: cSiO2-treatment induced prostaglandins, cytokines/chemokine, proinflammatory gene expression, CD206+ monocytes, Ly6B.2+ neutrophils, CD3+ T cells, CD45R+ B cells, centriacinar inflammation, collagen deposition, ectopic lymphoid structure neogenesis, and autoantibodies. While TPPU effectively inhibited sEH as reflected by skewed lipidomic profile in lung and decreased cSiO2-induced monocytes, neutrophils, and lymphocytes in lung lavage fluid, it did not significantly impact other biomarkers. Discussion: cSiO2 evoked robust pulmonary inflammation and fibrosis in NZBWF1 mice that was evident at 7 days PI and progressed to ELS development and autoimmunity by 28 days PI. sEH inhibition by TPPU modestly suppressed cSiO2-induced cellularity changes and pulmonary fibrosis. However, TPPU did not affect ELS formation or autoantibody responses, suggesting sEH minimally impacts cSiO2-triggered lung inflammation, fibrosis, and early autoimmunity in our model. [ABSTRACT FROM AUTHOR]

Fever represents one of the most frequent causes of demand for attention in traditional medicine, its presence is an unequivocal warning sign of disease and when it is very high it becomes a cause of greater concern. Based on a bibliographic review, fever is described from the traditional medicine of various medical cultures in Mexico: how it is conceived, what causes it, what are the signs and symptoms that accompany it and what are the information gaps. In a special way, the herbalits resources and procedures used for their treatment (pharmacological and physical) are described and analyzed. Twenty-eight frequently reported species were selected, highlighting sauco (Sambucus mexicana), palo mulato (Bursera simaruba) and higuerilla (Ricinus communis). The pharmacological background suggests that 17 species possess antipyretic action by inhibiting prostaglandins that act as endopyrogens; of other seven species there are already preclinical studies that prove this property. Likewise, the possible effects of heat loss by conduction, convection, evaporation and radiation through the external application of traditional remedies are briefly analyzed. [ABSTRACT FROM AUTHOR]

Background: Induction of labour (IOL) is common practice and different methods carry different effectiveness and safety profiles. Objectives: To compare the effectiveness, and maternal and perinatal safety outcomes of IOL with vaginal misoprostol versus vaginal dinoprostone using individual participant data from randomised clinical trials. Search strategy: The following databases were searched from inception to March 2023: CINAHL Plus, ClinicalTrials.gov, Cochrane Pregnancy and Childbirth Group Trial Register, Ovid Embase, Ovid Emcare, Ovid MEDLINE, Scopus and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Selection criteria: Randomised controlled trials (RCTs), with viable singleton gestation, no language restrictions, and all published and unpublished data. Data collection and analysis: An individual participant data meta‐analysis was carried out. Main results: Ten of 52 eligible trials provided individual participant data, of which two were excluded after checking data integrity. The remaining eight trials compared low‐dose vaginal misoprostol versus dinoprostone, including 4180 women undergoing IOL, which represents 32.8% of all participants in the published RCTs. Of these, 2077 were assigned to low‐dose vaginal misoprostol and 2103 were assigned to vaginal dinoprostone. Compared with vaginal dinoprostone, low‐dose vaginal misoprostol had a comparable rate of vaginal birth. Composite adverse perinatal outcomes did not differ between the groups. Compared with vaginal dinoprostone, composite adverse maternal outcomes were significantly lower with low‐dose vaginal misoprostol (aOR 0.80, 95% CI 0.65–0.98, P = 0.03, I2 = 0%). Conclusions: Low‐dose vaginal misoprostol and vaginal dinoprostone for IOL are comparable in terms of effectiveness and perinatal safety. However, low‐dose vaginal misoprostol is likely to lead to a lower rate of composite adverse maternal outcomes than vaginal dinoprostone. This article includes Author Insights, a video abstract available at: https://vimeo.com/915799731. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects. Methods: Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression. Results: Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression. Conclusions: Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic epilepsy (IE) and meningoencephalomyelitis of unknown origin (MUO) are common causes of brain diseases leading to seizures in dogs. In this study, the concentrations of 196 lipid metabolites and nitrogen oxide (NO) production in the cerebrospinal fluid (CSF) and plasma of dogs with MUO or IE were measured using a LC-MS/MS and a NOx analyzer, respectively. Methods: Nine clinically healthy dogs and 11 and 12 dogs with IE and MUO, respectively, were included in the study. Results: Lipid analysis revealed variations in the levels of four and six lipid metabolites in CSF and plasma, respectively, between the groups. The levels of 6-keto-prostaglandin (PG) F1a (PGF1a), 20-carboxy arachidonic acid (20-carboxy-AA), 9-hydroxyoctadecadienoic acid, and lyso-platelet-activating factor were high in the CSF of dogs with MUO. In addition, the plasma levels of 11,12-dihydroxyeicosatrienoic acid, 20-carboxy-AA, and oleoylethanolamide were high in dogs with IE, and those of PGF1a were high in dogs with MUO. NO production levels were high in CSF but not in plasma in dogs with MUO or IE. Discussion: It remains unknown whether these changes represent the cause or effect of diseases of the central nervous system; however, lipid metabolites and NO production in CSF and plasma may be used as diagnostic biomarkers and could be exploited for treating idiopathic or inflammatory epilepsy in dogs. [ABSTRACT FROM AUTHOR]

The protocols PreSynch/OvSynch, OvSynch and OvSynch+PRID were applied in breeding season (IBS) and out of it (OBS) in 133 buffalo cows and OBS in 75 heifers. Gestation was diagnosed sonographically 45 days after timed artificial insemination (TAI). Dispersion analysis was conducted, including the factors: protocol; clinical signs of estrus (without CSE; patency of cervix; mucous discharge); age. Another 3-factor analysis solely on buffalo cows included the effect of season. The results show that the factor protocol has the most pronounced effect on TAI success (P= 0.01), significantly lowest being the pregnancy rate (pi values) under PreSynch/OvSynch protocol - only 23.9%, compared to 40.7 and 47.4% under OvSynch and OvSynch+PRID, respectively. Although the effect of age is non-significant, in the heifers OvSynch+PRID and OvSynch show markedly higher results (50.0 and 52.9% respectively), while in the buffalo cows the differences are smaller, the OvSynch protocol having a relatively low pregnancy rate (38.3%), OvSynch+PRID - highest (45.0%), and PreSynch/OvSynch - lowest (30.4%). Season has non-significant effect, but the conception rate from OvSynch+PRID applied OBS is higher than IBS, so it can be used for overcoming the problematic seasonal anestrus. CSE is a significant source of variance of conception rates (P= 0.05), predictably the highest pi value belonging to the cases with mucus. The superiority of the OvSynch+PRID protocol finds expression in the highest incidence of full estrus (with mucus) in the lactating buffaloes (70%) and even more in the heifers (82%), as compared to PreSynch/OvSynch (56.5 and 52.2% respectively) and OvSynch (51.1 and 50.0%). [ABSTRACT FROM AUTHOR]

The transitional epithelial cells (urothelium) that line the lumen of the urinary bladder form a barrier between potentially harmful pathogens, toxins, and other bladder contents and the inner layers of the bladder wall. The urothelium, however, is not simply a passive barrier, as it can produce signaling factors, such as ATP, nitric oxide, prostaglandins, and other prostanoids, that can modulate bladder function. We investigated whether substances produced by the urothelium could directly modulate the contractility of the underlying urinary bladder smooth muscle. Force was measured in isolated strips of mouse urinary bladder with the urothelium intact or denuded. Bladder strips developed spontaneous tone and phasic contractions. In urothelium-intact strips, basal tone, as well as the frequency and amplitude of phasic contractions, were 25%, 32%, and 338% higher than in urothelium-denuded strips, respectively. Basal tone and phasic contractility in urothelium-intact bladder strips were abolished by the cyclooxygenase (COX) inhibitor indomethacin (10 µM) or the voltage-dependent Ca2+ channel blocker diltiazem (50 µM), whereas blocking neuronal sodium channels with tetrodotoxin (1 µM) had no effect. These results suggest that prostanoids produced in the urothelium enhance smooth muscle tone and phasic contractions by activating voltage-dependent Ca2+ channels in the underlying bladder smooth muscle. We went on to demonstrate that blocking COX inhibits the generation of transient pressure events in isolated pressurized bladders and greatly attenuates the afferent nerve activity during bladder filling, suggesting that urothelial prostanoids may also play a role in sensory nerve signaling. NEW & NOTEWORTHY: This paper provides evidence for the role of urothelial-derived prostanoids in maintaining tone in the urinary bladder during bladder filling, not only underscoring the role of the urothelium as more than a barrier but also contributing to active regulation of the urinary bladder. Furthermore, cyclooxygenase products greatly augment sensory nerve activity generated by bladder afferents during bladder filling and thus may play a role in perception of bladder fullness. [ABSTRACT FROM AUTHOR]

Introduction: One of the most common obstetrical interventions is the induction of labour. Cervical ripening drugs are typically used before conventional methods of induction since they are linked to an increased risk of protracted labour, chorioamnionitis, and Caesarean Sections (CS) during labour induction when an unfavourable cervix is present. The two major techniques for cervical ripening are mechanical interventions, such as the insertion of balloon catheters, and the application of pharmacologic agents, such as prostaglandins. It is widely accepted that the induction of labour, which ultimately leads to vaginal delivery, is largely dependent on the condition of the uterus’ cervix. Aim: To compare the efficacy of a combination of Foley bulb catheter and intracervical Dinoprostone and intracervical Dinoprostone alone for the induction of labour. Materials and Methods: A prospective observational study was performed over 150 pregnant mothers from May 2018 to April 2019. in the labour room of North Bengal Medical College and Hospital, a tertiary care institution in Darjeeling, West Bengal, India. The pregnant women were divided into two groups: intracervical Dinoprostone gel alone (Group-1) and a combination of intracervical Foley catheter and intracervical Dinoprostone gel (Group-2) with n=75 patients in each group. Group-1 received intracervical Dinoprostone gel 0.5 mg, which was repeated every 6 hours, a maximum of three doses, or until she went into active labour, whichever occurred earlier. In Group-2, a 16 F Foley catheter was inserted into the cervix, inflated, and a single dose of intracervical Dinoprostone gel 0.5 mg was given alongside it. Participant demographic characteristics, medical and pregnancy history, indication for labour induction, labour course, and outcomes were collected. The collected data were analysed with the mean and standard deviation for numerical variables and counts and percentages for categorical variables. Odds ratio was calculated where deemed relevant. Results: The induction to delivery time was considered the primary outcome and was shorter in Group-2 by 28 minutes (p=0.342). Among the secondary outcomes, the duration of the latent phase of labour was shorter in Group-2 by 57 minutes, and the proportion of patients delivering within 12 hours was also higher (28%) but statistically insignificant (p>0.05). The rates of CS were unaffected by the mode of induction. None of the two methods were found to be inferior to the other in respect to neonatal outcomes or complications of labour like chorioamnionitis and postpartum haemorrhage. Conclusion: The combination of Foley catheter with intracervical Dinoprostone gel did not prove to be more efficient than intracervical Dinoprostone alone for labour induction in the current study.

The main neuroendocrine pathways of induction of reproductive behavior in fish are elucidated. 17α, 20β-dihydroxy-4-pregnen-3-one (17,20β-DHP), an oocyte maturation-inducing hormone, was found to act as a pheromone to induce male reproductive behavior. 17α, 20β-DHP-sulfate (17,20β-DHP-S), a derivative of 17,20β-DHP, was also identified as a later-acting pheromone. In addition, prostaglandin F2 alpha (PGF2α), which is synthesized during female ovulation, has been shown to also act as a pheromone, inducing the final oviposition-inducing behavior to make fertilization successful. It appears that these molecular events are initiated by stimuli from the brain. Numerous neuropeptides have been discovered that promote the initiation of reproductive behavior. Recently, with the proliferation of genome editing technology, a detailed analysis of the molecules involved in these pathways is underway. Analysis of gene knockout in zebrafish and medaka is actively underway. On the other hand, many research reports have shown that the induction pathways of male reproductive behavior are adversely affected by chemical substances. Knowledge of the adverse effects of chemical substances is not only useful as information to prevent their mixing from the viewpoint of protecting the natural environment and as a point of caution in fish farming, but also provides clues for elucidating the pathways of reproductive behavior induction. The elucidation of the pathways of reproductive behavior induction is also important from the point of view of breeding technology for fish farming and biodiversity conservation. In this review, we summarize recent research on the pathways of male reproductive behavior induction in fish and the possibility of developing new aquaculture techniques depending on the results.

The aim of this study was to evaluate the effects of two different methods of controlling ovine reproduction (ram effect and a combination of eco-friendly substances) in three Greek indigenous sheep breeds, namely Florina, Karagouniko, and Chios. 180 ewes, aged 2–3 years old, were used, equally divided between the three Greek sheep breeds. Each breed was divided in two equal experimental groups: In group ECO (combination of eco-friendly substances), a dose of Gonadotropin-releasing hormone (GnRH) was administered at day 0, followed by an intramuscular injection of prostaglandin seven days later and another dose of GnRH at day 9. In group ME, sexually active males were introduced to the females that have been isolated for 3 months. The experiment was conducted in three consecutive years: 2020, 2021, and 2022. Average estrus expression and fecundity in all three examined breeds was comparable, with the exemption of Florina ewes treated with the eco-friendly substances in the first year, a result that could be attributed to the strong seasonal pattern in estrus expression of the Florina breed. The average length to estrus expression in days was significantly lower in the eco-friendly method than the procedure using male effect and the prolificacy was higher for the Chios sheep than the Florina and the Karagouniko breeds. Overall, both methods for the induction and synchronization of estrus (male effect and PGF2a administration) could be used in sheep reproduction with promising results. Nevertheless, the male effect seems to be more efficient in indigenous breeds with long anestrus periods.

Background/purpose: Bacterial infection was the major etiology for pulpal/root canal infection. This study aimed to investigate the activation of toll-like receptor-3 (TLR) on cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) and PGF2α production of human dental pulp cells (HDPCs) and associated signaling. Materials and methods: HDPCs were exposed to different concentrations of Poly (I:C) (a TLR3 activator). Cell viability was determined by 3- (4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and alkaline phosphatase (ALP) activity was evaluated by ALP staining. Activation of extracellular signal-regulated kinase (ERK) and p38 by Poly (I:C) was determined by immunofluorescent staining. The COX-2 protein expression was analyzed by Western blot. PGE2 and PGF2α production was measured by enzyme-linked immunosorbent assay. The mRNA expression was studied by real-time polymerase-chain reaction. Moreover, HDPCs were exposed to Poly(I:C) with/without U0126 or SB203580 treatment and analysis of COX-2 expression and prostanoid production were conducted. Results: Poly (I:C) showed little effect on ALP activity, but decreased viability of HDPCs. It stimulated COX-2 mRNA and protein expression. Poly (I:C) induced PGE2 and PGF2α production of HDPCs. Poly (I:C) activated p-ERK, and p-p38 protein expression. Treatment by U0126 (a mitogen-activated protein kinase kinase (MEK)/ERK inhibitor) and SB203580 (a p38 inhibitor) attenuated Poly (I:C)-induced COX-2 mRNA and protein expression as well as PGE2 and PGF2α production. Conclusion: TLR3 activation is involved in the infection and inflammatory responses of pulp tissues, via MEK/ERK, and p38 signaling to mediate COX-2 expression as well as PGE2 and PGF2α production, contributing to the pathogenesis and progression of pulpal/periapical diseases.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of analgesics that inhibit the activity of cyclooxygenase isoenzymes, which drive tissue inflammation pathways. Caution should be exercised when taking these drugs during pregnancy as they increase the risk of developmental defects. Due to the high rates of NSAID use by individuals, possibilities for in utero exposure to NSAIDs are high, and it is vital that we define the potential risks these drugs pose during embryonic development. In this review, we characterize the identified roles of the cyclooxygenase signaling pathway components throughout pregnancy and discuss the effects of cyclooxygenase pathway perturbation on developmental outcomes.

Objective Saline vaginal douching prior to intravaginal prostaglandin application might increase the vaginal pH, leading to improvement of prostaglandin bioavailability, by which the outcomes of labor induction can be greatly improved. Thus, we aimed to evaluate the effect of vaginal washing with normal saline before insertion of vaginal prostaglandin for labor induction. Study Design A systematic search was done in PubMed, Cochrane Library, Scopus, and ISI Web of Science from inception to March 2022. We selected randomized controlled trials (RCTs) that compared vaginal washing using normal saline versus no vaginal washing in the control group before intravaginal prostaglandin insertion during labor induction. We used RevMan software for our meta-analysis. Our main outcomes were the duration of intravaginal prostaglandin application, duration from intravaginal prostaglandin insertion to active phase of labor, duration from intravaginal prostaglandin insertion till total cervical dilatation, labor induction failure rate, incidence of cesarean section (CS), and rates of neonatal intensive care unit (NICU) admission and fetal infection postdelivery. Results Five RCTs were retrieved with a total number of 842 patients. Duration of prostaglandin application, duration from prostaglandin insertion to active phase of labor, and time interval from prostaglandin insertion to total cervical dilatation were significantly shorter among vaginal washing group (p < 0.05). Vaginal douching prior to prostaglandin insertion significantly decreased the incidence of failed labor induction (p < 0.001). After the removal of reported heterogeneity, vaginal washing was linked to a significant decline in CS incidence (p = 0.04). In addition, the rates of NICU admission and fetal infection were significantly lower in the vaginal washing group (p < 0.001). Conclusion Vaginal washing with normal saline before intravaginal prostaglandin insertion is a useful and easily applicable method for labor induction with good outcomes. Key Points Induction of labor is frequently used in the obstetrics field. We assessed vaginal washing impact before prostaglandin insertion for labor induction. Vaginal washing is an easily applicable method for labor induction with good outcomes. [ABSTRACT FROM AUTHOR]

Sub‐estrus buffaloes do not exhibit estrus signs despite being cyclic contributing to extended service periods and inter‐calving intervals causing significant economic loss. The present study described the effect of synthetic prostaglandin (PGF2α) on estrus behaviour, follicular and luteal morphometry, and serum estradiol (E2) and progesterone (P4) profile in sub‐estrus buffaloes during the non‐breeding season. The incidence of sub‐estrus was 38.4% during the non‐breeding season. The sub‐estrus buffaloes (n = 33) were divided into two groups, viz., Control (n = 16) and PGF2α treatment (Inj. Cloprostenol 500 μg, i.m., n = 17). Estrus induction response was significantly greater in the treatment (100 vs. 18.75%, p <.001), and a relatively greater proportion of animals conceived in the treatment group (29.41 vs. 6.25%, p =.08). The time elapsed to induction of estrus and insemination following treatment was significantly lower in the treatment group than control. A significant increment in the follicle diameter (9.72 ± 0.45 vs. 13.00 ± 0.45 mm, P <.0001) and serum estradiol (E2) concentration (66.01 ± 11.92 vs. 104.9 ± 13.21 pg/mL, p =.003) observed at the post‐treatment period in the PGF2α treatment group. At the same time, CL diameter was reduced significantly at a higher regression rate in the PGF2α treated buffaloes than those of control. Of the responded buffaloes, only 30% showed high‐intensity estrus attributed to the expulsion of cervico‐vaginal mucus (CVM), uterine tonicity, micturition, and mounting response by a teaser bull. From this study, it can be concluded that the administration of PGF2α could induce estrus in the sub‐estrus buffaloes during the non‐breeding season. Behavioural changes, along with sonographic observation of POF, regressing CL, and serum E2 and P4 concentration would be useful to determine the right time of insemination in sub‐estrus buffaloes during non‐breeding season. [ABSTRACT FROM AUTHOR]

A novel series of dihydropyrimidine/sulphonamide hybrids 3a-j with antiinflammatory properties have been developed and tested as dual mPGES-1/5- LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound 3j was the most potent dual inhibitor with IC50 values of 0.92 ^M and 1.98 ^M, respectively. In vivo, anti-inflammatory studies demonstrated that compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-a, and IL-6) with gastrointestinal safety profiles. Molecular docking simulations explored the most potent derivatives' binding affinities and interaction patterns within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation. [ABSTRACT FROM AUTHOR]

The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) influences neurotransmission in the central nervous system mainly by activating type 1 cannabinoid receptor (CB1). Following its release, 2-AG is broken down by hydrolases to yield arachidonic acid, which may subsequently be metabolized by cyclooxygenase-2 (COX-2). COX-2 converts arachidonic acid and also 2-AG into prostanoids, well-known inflammatory and pro-nociceptive mediators. Here, using immunohistochemical and biochemical methods and pharmacological manipulations, we found that reactive spinal astrocytes and microglia increase the expression of COX-2 and the production of prostaglandin E2 when exposed to 2-AG. Both 2-AG and PGE2 evoke calcium transients in spinal astrocytes, but PGE2 showed 30% more efficacy and 55 times more potency than 2-AG. Unstimulated spinal dorsal horn astrocytes responded to 2-AG with calcium transients mainly through the activation of CB1. 2-AG induced exaggerated calcium transients in reactive astrocytes, but this increase in the frequency and area under the curve of calcium signals was only partially dependent on CB1. Instead, aberrant calcium transients were almost completely abolished by COX-2 inhibition. Our results suggest that both reactive spinal astrocytes and microglia perform an endocannabinoid-prostanoid switch to produce PGE2 at the expense of 2-AG. PGE2 in turn is responsible for the induction of aberrant astroglial calcium signals which, together with PGE2 production may play role in the development and maintenance of spinal neuroinflammation-associated disturbances such as central sensitization. [ABSTRACT FROM AUTHOR]

C-C motif chemokine ligand 2 (CCL2) has been reported to be expressed in the bovine endometrium during pregnancy. However, the details of its functions involved in the implantation mechanism are still not clear. The purpose of this study is to analyze the functional properties of CCL2 in the bovine endometrium and embryos. The expression of CCR2 was not different between the luteal phase and implantation phase of their endometrial tissues, but was significantly high in IFNa treated bovine endometrial stromal (BES) cells in vitro. The expressions of PGES1, PGES2, AKR1C4, and AKR1C4 were high at the implantation stage compared with the luteal stage. On the other hand, PGES2 and AKR1B1 in BEE and PGES3 and AKR1A1 in BES were significantly increased by CCL2 treatment, respectively. The expressions of PCNA and IFNt were found significantly high in the bovine trophoblastic cells (BT) treated with CCL2 compared to the control. CCL2 significantly increased the attachment rate of BT vesicles to BEE in in vitro co-culture system. The expression of OPN and ICAM-1 increased in BEE, and ICAM-1 increased in BT by CCL2 treatment, respectively. The present results indicate that CCL2 has the potential to regulate the synthesis of PGs in the endometrium and the embryo growth. In addition, CCL2 has the possibility to regulate the process of bovine embryo attachment to the endometrium by modulation of binding molecules expression. [ABSTRACT FROM AUTHOR]

Signaling through prostaglandin E2 EP3 receptor (EP3) actively contributes to the β-cell dysfunction of type 2 diabetes (T2D). In T2D models, full-body EP3 knockout mice have a significantly worse metabolic phenotype than wild-type controls due to hyperphagia and severe insulin resistance resulting from loss of EP3 in extra-pancreatic tissues, masking any potential beneficial effects of EP3 loss in the β cell. We hypothesized β-cell-specific EP3 knockout (EP3 βKO) mice would be protected from high-fat diet (HFD)-induced glucose intolerance, phenocopying mice lacking the EP3 effector, Gαz, which is much more limited in its tissue distribution. When fed a HFD for 16 wk, though, EP3 βKO mice were partially, but not fully, protected from glucose intolerance. In addition, exendin-4, an analog of the incretin hormone, glucagon-like peptide 1, more strongly potentiated glucose-stimulated insulin secretion in islets from both control diet- and HFD-fed EP3 βKO mice as compared with wild-type controls, with no effect of β-cell-specific EP3 loss on islet insulin content or markers of replication and survival. However, after 26 wk of diet feeding, islets from both control diet- and HFD-fed EP3 βKO mice secreted significantly less insulin as a percent of content in response to stimulatory glucose, with or without exendin-4, with elevated total insulin content unrelated to markers of β-cell replication and survival, revealing severe β-cell dysfunction. Our results suggest that EP3 serves a critical role in temporally regulating β-cell function along the progression to T2D and that there exist Gαz-independent mechanisms behind its effects. NEW & NOTEWORTHY: The EP3 receptor is a strong inhibitor of β-cell function and replication, suggesting it as a potential therapeutic target for the disease. Yet, EP3 has protective roles in extrapancreatic tissues. To address this, we designed β-cell-specific EP3 knockout mice and subjected them to high-fat diet feeding to induce glucose intolerance. The negative metabolic phenotype of full-body knockout mice was ablated, and EP3 loss improved glucose tolerance, with converse effects on islet insulin secretion and content. [ABSTRACT FROM AUTHOR]

Aim: Even though the number of inductions is still rising, limited information is available about the results of subsequent pregnancies following induction. The current study was aimed at comparing the effectiveness of dinoprostone and low-dose oxytocin with dinoprostone in the induction of laborlabor for term pregnancies to assess the need for additional uterotonic agents. Materials and Methods: In this retrospective case-control study, 99 patients with fullterm pregnancies (completed 37 weeks or more of pregnancy) who had unripe cervixes underwent laborlabor induction for different reasons were evaluated. BISHOP score was performed to predict the patient who required laborlabor induction. All participants were given either only a sustained-release dinoprostone vaginal insert or low-dose administration of oxytocin to the dinoprostone. Two patient groups' clinical characteristics were compared. Results: No statistically significant differences were found between the two groups based on age, gravity, parity, and gestation weeks. However, there was a significant difference between the two groups in terms of the duration of the active phase of laborlabor and time from admission until the end of the second stage of laborlabor (p=0.04). Labor and birth occurred in a significantly shorter time in the dinoprostone + oxytocin group. Common indications for induction of laborlabor were post-term pregnancy (77.14%). The cesarean section ratio was found to be similar in both groups (p=0.084). There was no statistically significant difference between the two groups in terms of adverse events such as tachysystole and hyperstimulation of the uterus and infant outcomes (p>0.05). Conclusion: Sustained-release dinoprostone and dinoprostone with low-dose oxytocin were both found to be effective augmentations in the management of delay in labor. Our results supported that administration of oxytocin with dinoprostone vaginal insert dramatically shortened induction to delivery times, and no significant increase of cesarean section rate had been found. [ABSTRACT FROM AUTHOR]

Introduction: One of the most common obstetrical interventions is the induction of labour. Cervical ripening drugs are typically used before conventional methods of induction since they are linked to an increased risk of protracted labour, chorioamnionitis, and Caesarean Sections (CS) during labour induction when an unfavourable cervix is present. The two major techniques for cervical ripening are mechanical interventions, such as the insertion of balloon catheters, and the application of pharmacologic agents, such as prostaglandins. It is widely accepted that the induction of labour, which ultimately leads to vaginal delivery, is largely dependent on the condition of the uterus' cervix. Aim: To compare the efficacy of a combination of Foley bulb catheter and intracervical Dinoprostone and intracervical Dinoprostone alone for the induction of labour. Materials and Methods: A prospective observational study was performed over 150 pregnant mothers from May 2018 to April 2019. in the labour room of North Bengal Medical College and Hospital, a tertiary care institution in Darjeeling, West Bengal, India. The pregnant women were divided into two groups: intracervical Dinoprostone gel alone (Group-1) and a combination of intracervical Foley catheter and intracervical Dinoprostone gel (Group-2) with n=75 patients in each group. Group-1 received intracervical Dinoprostone gel 0.5 mg, which was repeated every 6 hours, a maximum of three doses, or until she went into active labour, whichever occurred earlier. In Group-2, a 16 F Foley catheter was inserted into the cervix, inflated, and a single dose of intracervical Dinoprostone gel 0.5 mg was given alongside it. Participant demographic characteristics, medical and pregnancy history, indication for labour induction, labour course, and outcomes were collected. The collected data were analysed with the mean and standard deviation for numerical variables and counts and percentages for categorical variables. Odds ratio was calculated where deemed relevant. Results: The induction to delivery time was considered the primary outcome and was shorter in Group-2 by 28 minutes (p=0.342). Among the secondary outcomes, the duration of the latent phase of labour was shorter in Group-2 by 57 minutes, and the proportion of patients delivering within 12 hours was also higher (28%) but statistically insignificant (p>0.05). The rates of CS were unaffected by the mode of induction. None of the two methods were found to be inferior to the other in respect to neonatal outcomes or complications of labour like chorioamnionitis and postpartum haemorrhage. Conclusion: The combination of Foley catheter with intracervical Dinoprostone gel did not prove to be more efficient than intracervical Dinoprostone alone for labour induction in the current study. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is a common disease in the elderly, with an increasing incidence rate, easy rupture, high mortality, and no effective drugs to slow down the development of AAA. The pathogenesis of AAA is closely related to extracellular matrix degradation, apoptosis of vascular smooth muscle cells and inflammation. It has been found that arachidonic acid derivatives, especially prostaglandins such as prostaglandin E2 (PGE2), prostaglandin D2 (PGD2) and thromboxane A2(TXA2), play important roles in the development of AAA. Therefore, this review discusses the mechanism of arachidonic acid derivatives in the development of AAA, as well as the latest research progress of the drugs, to provide ideas for the treatment of AAA and the discovery of new drug targets. [ABSTRACT FROM AUTHOR]

The main neuroendocrine pathways of induction of reproductive behavior in fish are elucidated. 17α, 20β-dihydroxy-4-pregnen-3-one (17,20β-DHP), an oocyte maturation-inducing hormone, was found to act as a pheromone to induce male reproductive behavior. 17α, 20β-DHP-sulfate (17,20β-DHP-S), a derivative of 17,20β-DHP, was also identified as a later-acting pheromone. In addition, prostaglandin F2 alpha (PGF2α), which is synthesized during female ovulation, has been shown to also act as a pheromone, inducing the final ovipositioninducing behavior to make fertilization successful. It appears that these molecular events are initiated by stimuli from the brain. Numerous neuropeptides have been discovered that promote the initiation of reproductive behavior. Recently, with the proliferation of genome editing technology, a detailed analysis of the molecules involved in these pathways is underway. Analysis of gene knockout in zebrafish and medaka is actively underway. On the other hand, many research reports have shown that the induction pathways of male reproductive behavior are adversely affected by chemical substances. Knowledge of the adverse effects of chemical substances is not only useful as information to prevent their mixing from the viewpoint of protecting the natural environment and as a point of caution in fish farming, but also provides clues for elucidating the pathways of reproductive behavior induction. The elucidation of the pathways of reproductive behavior induction is also important from the point of view of breeding technology for fish farming and biodiversity conservation. In this review, we summarize recent research on the pathways of male reproductive behavior induction in fish and the possibility of developing new aquaculture techniques depending on the results. [ABSTRACT FROM AUTHOR]

Objective: Docosahexaenoic acid (DHA) is recommended routinely in pregnancy to promote fetal development. DHA has anti‐inflammatory activity, but its effects on the fetal heart and circulation are unknown. This study aimed to investigate whether maternal DHA supplementation in the third trimester affects maternal prostaglandin levels and fetal ductus arteriosus flow dynamics. Methods: This was a double‐blind randomized controlled trial with parallel groups conducted between 2018 and 2021. Pregnant women aged over 18 years with a normal fetus at 27–28 weeks' gestation showing no cardiac/extracardiac anomalies or ductal constriction were eligible for the trial. Women consuming substances with a known inhibitory effect on prostaglandin metabolism, such as non‐steroidal anti‐inflammatory drugs and polyphenol‐rich foods, were excluded. The intervention group received oral supplementation of omega‐3 with 450 mg/day of DHA for 8 weeks and the placebo group received capsules of soy lecithin for 8 weeks. Anthropometric measurements, assessment of polyphenol and omega‐3 consumption, fetal morphological ultrasound examination, fetal Doppler echocardiographic examination and blood sample collection were performed at the start of the study and the latter two were repeated at follow‐up. Prostaglandin E2 (PGE2) level and echocardiographic parameters were compared between the intervention and placebo groups and between baseline and follow‐up. Results: A total of 24 participants were included in each group. After 8 weeks, there were no significant differences between the intervention and placebo groups in maternal serum PGE2 level or Doppler echocardiographic parameters of ductal flow. No case of ductus arteriosus constriction was observed. The expected intragroup changes in cardiac morphology, as a result of advancing gestation, were present. Conclusions: Maternal DHA supplementation in the third trimester at a clinically recommended dose did not result in inhibition of PGE2 or constriction of the ductus arteriosus. These findings should be confirmed in postmarket surveillance studies with larger patient numbers in order to test the full safety profile of DHA and provide robust clinical reassurance. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Sigma-class glutathione transferase (GST) proteins with dual GST and prostaglandin synthase (PGS) activities play a crucial role in the establishment of Clonorchis sinensis infection. Herein, we analyzed the structural and enzymatic properties of sigma-class GST (CsGST-σ) proteins to obtain insight into their antioxidant and immunomodulatory functions in comparison with mu-class GST (CsGST-μ) proteins. CsGST-σ proteins conserved characteristic structures, which had been described in mammalian hematopoietic prostaglandin D2 synthases. Recombinant forms of these CsGST-σ and CsGST-μ proteins expressed in Escherichia coli exhibited considerable degrees of GST and PGS activities with substantially different specific activities. All recombinant proteins displayed higher affinities toward prostaglandin H2 (PGS substrate; average Km of 30.7 and 3.0 μm for prostaglandin D2 [PGDS] and E2 synthase [PGES], respectively) than those toward CDNB (GST substrate; average Km of 1,205.1 μm). Furthermore, the catalytic efficiency (Kcat/Km) of the PGDS/PGES activity was higher than that of GST activity (average Kcat/Km of 3.1, 0.7, and 7.0×10-3 s-1μm-1 for PGDS, PGES, and GST, respectively). Our data strongly suggest that the C. sinensis sigma- and mu-class GST proteins are deeply involved in regulating host immune responses by generating PGD2 and PGE2 in addition to their roles in general detoxification. [ABSTRACT FROM AUTHOR]

Eight new amide‐based carboxylate derivatives were synthesized and evaluated for anti‐inflammatory potentials using in‐vitro, in‐vivo and in silico studies. In cyclooxygenase‐2 assay, maximum percent antagonist potential was exhibited by sodium 4‐((4‐fluorophenyl) amino)‐4‐oxobutanoate (93.91 %), bis ((4‐((4‐methoxy‐2‐nitrophenyl)amino)‐4‐oxobutanoyl)oxy) zinc (93.04 %), and bis ((4‐((4‐bromo‐2‐fluorophenyl) amino)‐4‐oxobutanoyl)oxy)zincio (2‐bromopyridine) (92.64 %) with IC50 values of 1.65, 2.08, and 0.288 μM/ml respectively. Celecoxib demonstrated 98.60 % effect with an IC50 value of 0.041 μM/ml. In LOX assay, 4‐((4‐methoxy‐2‐nitrophenyl)amino)‐4‐oxobutanoic acid (97.03 %), bis ((4‐((4‐methoxy‐2‐nitrophenyl)amino)‐4‐oxobutanoyl)oxy)zinc (95.45 %), and (92.53 %) demonstrated maximum percent effect with IC50 values 3.48, 0.45, and 0.83 μM/ml respectively. The standard 5‐lipoxygenase inhibitor (montelukast) resulted from a 98.39 % inhibitory effect with an IC50 value of 0.194 μM/ml. In in‐vivo analysis, the potent tested compounds (5, 10, and, 20 mg/kg) significantly (p<0.001) reversed the induced edema by carrageenan. The standard drug aspirin displayed significant results (74–83 %). The standard drugs in these phlogestic agents displayed excellent results like cetirizine (67.9 %), celecoxib (81.61 %), icatibant (82.22 %) and nemesulide (87.17 %) at 5th h. The compounds displayed the inhibitory potential against targeted proteins. 4‐((4‐methoxy‐2‐nitrophenyl)amino)‐4‐oxobutanoic acid, 4‐((4‐fluorophenyl)amino)‐4‐oxobutanoic acid and sodium 4‐((4‐bromo‐2‐fluorophenyl)amino)‐4‐oxobutanoate shown excellent behavior by giving negative binding energies close of standard drugs montelukast (5F1A: −7.9 kcal/mol) and diclofenac (3O8Y: −8.5 Kcal/mol). The tested compounds were proven significant anti‐inflammatory potentials. [ABSTRACT FROM AUTHOR]

Objective: To assess whether, after induction of labor with prostaglandin, multiparous (≥2 para) women have an increased risk of uterine rupture compared with nulliparous or uniparous women. Methods: This was a retrospective population‐based cohort study including women who underwent induction with prostaglandin in all maternity wards in Sweden between May 1996 and December 2019 (n = 56 784). The study cohort was obtained by using data from the Swedish Medical Birth Register, which contains information from maternity and delivery records. The main outcome measure was uterine rupture. Results: Overall, multiparous women induced with prostaglandin had an increased risk of uterine rupture compared with nulliparous women (adjusted odds ratio [OR], 3.33 [95% confidence interval (CI), 1.38–8.04]; P < 0.007). Multiparous women with no previous cesarean section (CS) induced with prostaglandin had more than three times higher risk of uterine rupture (crude OR, 3.55 [95% Cl, 1.48–8.53]; P = 0.005) compared with nulliparous women and four times higher risk compared with uniparous women (OR, 4.10 [95% CI, 1.12–15.00]; P < 0.033). Multiparous women with previous CS had a decreased risk of uterine rupture compared with uniparous women with one previous CS (crude OR, 0.41 [95% Cl, 0.21–0.78]; P = 0.007). Conclusion: Our study implies that multiparity in women with no previous CS is a risk factor for uterine rupture when induced with prostaglandin. This should be taken into consideration when deciding on the appropriate method of induction. Synopsis: Induction of labor with prostaglandin increases the risk of uterine rupture among multiparous women with no previous cesarean section. [ABSTRACT FROM AUTHOR]

Bacterial infection was the major etiology for pulpal/root canal infection. This study aimed to investigate the activation of toll-like receptor-3 (TLR) on cyclooxygenase-2 (COX-2) expression and prostaglandin E 2 (PGE 2) and PGF 2α production of human dental pulp cells (HDPCs) and associated signaling. HDPCs were exposed to different concentrations of Poly (I:C) (a TLR3 activator). Cell viability was determined by 3- (4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and alkaline phosphatase (ALP) activity was evaluated by ALP staining. Activation of extracellular signal-regulated kinase (ERK) and p38 by Poly (I:C) was determined by immunofluorescent staining. The COX-2 protein expression was analyzed by Western blot. PGE 2 and PGF 2α production was measured by enzyme-linked immunosorbent assay. The mRNA expression was studied by real-time polymerase-chain reaction. Moreover, HDPCs were exposed to Poly(I:C) with/without U0126 or SB203580 treatment and analysis of COX-2 expression and prostanoid production were conducted. Poly (I:C) showed little effect on ALP activity, but decreased viability of HDPCs. It stimulated COX-2 mRNA and protein expression. Poly (I:C) induced PGE 2 and PGF 2α production of HDPCs. Poly (I:C) activated p -ERK, and p-p38 protein expression. Treatment by U0126 (a mitogen-activated protein kinase kinase (MEK)/ERK inhibitor) and SB203580 (a p38 inhibitor) attenuated Poly (I:C)-induced COX-2 mRNA and protein expression as well as PGE 2 and PGF 2α production. TLR3 activation is involved in the infection and inflammatory responses of pulp tissues, via MEK/ERK , and p38 signaling to mediate COX-2 expression as well as PGE 2 and PGF 2α production, contributing to the pathogenesis and progression of pulpal/periapical diseases. [ABSTRACT FROM AUTHOR]

An experiment was conducted from June 2022 to April 2023 at Debrezeit Agricultural Research Center to evaluate the effectiveness of single shot prostaglandin based estrus synchronization protocol in Boran, Boran*Holstein-Friesian crosses, and Holstein-Friesian cattle upon manual detection of mature corpus luteum (CL). A total of 120 animals (80 cows and 40 heifers) with detected CL from different age, body condition (BC), parity, days in milk, and lactation status were included in the experiment. A single injection of 5 ml LUTALYSE® Injection (dinoprost tromethamine, a prostaglandin F2a analog) was used to synchronize the animals. The observed estrus response and conception rate were 83.3% and 73.0%, respectively. Among the predictor factors considered, BC score significantly influenced both estrus response and conception rates, while days in milk (DIM) had significant effect on conception (p <0.05). Estrus response and pregnancy rates were higher in animals with better BC, and cattle with >60 DIM had significantly higher conception rate compared to those with less DIM. Both estrus response and pregnancy rates were not significantly different between cows and heifers, as parity had no significant association (p >0.05) with both outcomes. The result showed that manual per rectal detection of CL and injection of a prostaglandin analog were effective in inducing heat. Therefore, synchronization with a single injection of LUTALYSE in heifers and cows after manual detection of mature CL could minimize drug cost and can achieve optimal results. [ABSTRACT FROM AUTHOR]