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Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules derived from unsaturated fatty acids. To better understand the basis of the substrate selectivity of MRP4, we used cryogenic-electron microscopy to determine six structures of nanodisc-reconstituted MRP4 at various stages throughout its transport cycle. Substrate-bound structures of MRP4 in complex with PGE1, PGE2 and the sulfonated-sterol DHEA-S reveal a common binding site that accommodates a diverse set of organic anions and suggest an allosteric mechanism for substrate-induced enhancement of MRP4 ATPase activity. Our structure of a catalytically compromised MRP4 mutant bound to ATP-Mg2+ is outward-occluded, a conformation previously unobserved in the MRP subfamily and consistent with an alternating-access transport mechanism. Our study provides insights into the endogenous function of this versatile efflux transporter and establishes a basis for MRP4-targeted drug design.

The aim of this study was to compare radiographic and clinical status and peri-implant sulcular fluid (PISF) prostaglandin E2 (PGE2) levels among patients with and without peri-implant disease. Patients with peri-implant mucositis (PiM) (Group 1) and peri-implantitis (Group 2) and individuals without peri-implant disease (Group 3) were included. Demographic information was collected, and peri-implant modified plaque and bleeding indices (mPI and mBI), probing depth (PD), and crestal bone loss (CBL) were recorded. PISF samples were collected and PGE2 levels measured. Statistical significance was set at P < .01. A total of 22 patients with PiM, 22 with peri-implantitis, and 23 without peri-implant disease (controls) were included. Scores of mPI (P < .01), mBI (P < .01), and PD (P < .01) were higher in patients with PiM and peri-implantitis than the controls. The volumes of collected PISF were significantly higher in patients with peri-implantitis (P < .01) compared to patients with PiM and the controls. The PISF volume was significantly higher in PiM patients (P < .01) than in the controls. There was a significant correlation between peri-implant PD and PISF PGE2 levels in patients with peri-implantitis (P < .001). Raised PISF PGE2 levels indicate poor peri-implant health; therefore, PGE2 is a potential biomarker for the assessment of peri-implant health status. [ABSTRACT FROM AUTHOR]

Hepatic inflammation is commonly identified in Wilson disease (WD), a genetic disease of hepatic and brain copper accumulation. Copper accumulation is associated with increased oxidative stress and reactive oxygen species generation which may result in non-enzymatic oxidation of membrane-bound polyunsaturated fatty acids (PUFA). PUFA can be oxidized enzymatically via lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). Products of PUFA oxidation are collectively known as oxylipins (OXL) and are bioactive lipids that modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models, the toxic milk mouse from The Jackson Laboratory (tx-j) and the Atp7b knockout on a C57Bl/6 background (Atp7b-/-B6). Targeted lipidomic analysis performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry showed that in both tx-j and Atp7b-/-B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The levels of oxidative stress marker, 9-HETE were increased more markedly in tx-j mice. However, both genotypes showed upregulated transcript levels of many genes related to oxidative stress and inflammation. Both genotypes showed higher prostaglandins, thromboxin along with higher PUFA-derived alcohols, diols, and ketones with altered epoxides; the expression of Alox5 was upregulated and many CYP-related genes were dysregulated. Pathway analyses show dysregulation in arachidonic acid and linoleic acid metabolism characterizes mice with WD. Our findings indicate alterations in hepatic PUFA metabolism in early-stage WD and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation, which could have implications for hepatic manifestations in WD and represent potential targets for future therapies.

Prokineticin 1 (PROK1) is an important factor in pregnancy establishment in pigs, acting at the embryo–maternal interface and the corpus luteum (CL). Estradiol-17β (E2) is the primary pregnancy recognition signal in pigs, and its effects are augmented by luteotropic prostaglandin E2 (PGE2). On the contrary, prostaglandin F2α (PGF2α) exerts mainly a luteolytic effect. The present study aimed to elucidate whether E2, PGE2, and PGF2α regulate the expression of PROK1 and its receptors in the porcine CL and to determine the PROK1 effect on luteal endothelial cells and pathways that may be involved in this regulation. The effects of E2, PGE2, and PGF2α on the expressions of PROK1 and its receptors in the CL were studied using an in vitro model of ultrathin luteal tissue explants model. Additionally, the effects of E2 and PGE2 on the PROK1 system were determined using an in vivo approach, in which the hormones were administered into the uterine lumen to imitate their secretion by embryos. Endothelial cell proliferation was measured using the colorimetric method. E2 acting via estrogen receptors simulated the mRNA and protein expressions of PROK1 and PROKR1 in CL explants in vitro (p < 0.05). The simultaneous action of E2 with PGE2 enhanced the expression of luteal PROK1 mRNA in vitro (p < 0.05). Estradiol-17β acting alone significantly increased PROK1 mRNA levels in vivo, whereas E2 simultaneously administered with PGE2 significantly elevated the PROK1 mRNA expression and PROKR1 mRNA and protein contents in CLs adjacent to uterine horns receiving hormonal infusion compared with CLs adjacent to placebo-treated uterine horns (p < 0.01). The PROK1 protein expression was significantly higher in the CLs of pigs treated with E2, PGE2, and E2 together with PGE2 than in the control group. PGF2α increased the PROK1 mRNA content in CLs on days 12 and 14 of the estrous cycle (p < 0.05). The expression of PROKR2 at the mRNA and protein levels remained unchanged in response to in vitro and in vivo treatments. PROK1 stimulated the proliferation of luteal endothelial cells by activating the MAPK, AKT, and mTOR pathways (p < 0.05). In summary, the luteal expressions of PROK1 and PROKR1 in early pregnancy are regulated by E2 and PGE2. PROK1 stimulates luteal angiogenesis by activating the MAPK, AKT, and mTOR pathways. The regulation of luteal PROK1 expression by PGF2α indicates PROK1's putative role during luteolysis. We conclude that PROK1-PROKR1 signaling supports luteal function during CL rescue in pregnancy in pigs. [Display omitted] • Luteal expressions of prokineticin 1 and PROKR1 are regulated by primary embryonic signal (estradiol) and prostaglandin E2. • Luteolytic factor (prostaglandin F2α) is a putative regulator of luteal gene PROK1 expression during luteolysis. • Prokineticin 1 contributes to angiogenesis in the porcine CL by activation of MAPK, AKT and mTOR intracellular pathways. [ABSTRACT FROM AUTHOR]

This Perspectives article reflects on findings from our systematic review about adolescent dysmenorrhoea Q, drawing on sociology of diagnosis theory. We consider tensions and uncertainties between presentation with symptoms of dysmenorrhoea and processes of symptom categorisation and diagnosis in adolescents, tracing these through research and clinical guidance, considering possible implications for clinical practice. We argue that challenges in distinguishing between primary and secondary dysmenorrhoea in research translate into challenges in differentiation in clinical practice. We argue that framing this distinction as clear cut and straightforward belies the well-documented challenges in diagnosis of endometriosis, and that not recognising uncertainty and complexity inherent in this task may benefit neither clinicians nor patients. [ABSTRACT FROM AUTHOR]

Peptic ulcers, recognized for their erosive impact on the gastrointestinal mucosa, present a considerable challenge in gastroenterology. Epidemiological insights underscore the global prevalence of peptic ulcers, affecting 5–10+% of individuals, with a yearly incidence of 0.3 to 1.9 cases per thousand. Recent decades have witnessed a decline in complications, attributed to improved diagnostics and therapeutic advancements. The review deepens into H. pylori -associated and NSAID-induced ulcers, emphasizing their distinct prevalence in developing and industrialized nations, respectively. Despite advancements, managing peptic ulcers remains challenging, notably in H. pylori -infected individuals facing recurrence and the rise of antibiotic resistance. The pathophysiology unravels the delicate balance between protective and destructive factors, including the intricate molecular mechanisms involving inflammatory mediators such as TNF-α, ILs, and prostaglandins. Genetic and ethnic factors, rare contributors, and recent molecular insights further enhance our understanding of peptic ulcer development. Diagnostic approaches are pivotal, with upper gastrointestinal endoscopy standing as the gold standard. Current treatment strategies focus on H. pylori eradication, NSAID discontinuation, and proton pump inhibitors. Surgical options become imperative for refractory cases, emphasizing a comprehensive approach. Advances include tailored H. pylori regimens, the emergence of vonoprazan, and ongoing vaccine development. Challenges persist, primarily in antibiotic resistance, side effects of acid suppressants, and translating natural compounds into standardized therapies. Promising avenues include the potential H. pylori vaccine and the exploration of natural compounds, with monoterpenes showing therapeutic promise. This review serves as a compass, guiding healthcare professionals, researchers, and policymakers through the intricate landscape of peptic ulcer management. [ABSTRACT FROM AUTHOR]

Objective: Oxylipins are bioactive lipids derived from polyunsaturated fatty acids (PUFAs) that modulate inflammation and may remain overexpressed in refractory synovitis. In plasma, they could also be biomarkers of synovial pathology. The aim of this study is to determine if synovial oxylipins in inflamed joints correlate with plasma oxylipins and with synovial histologic patterns. Methods: Patients with established rheumatoid or psoriatic arthritis with active disease despite treatment were recruited, and paired synovial tissue (ST) and plasma were collected. Oxylipins were determined by liquid chromatography with tandem mass spectrometry and were classified into groups according to their PUFA precursor and enzyme. The expression of CD20, CD68, CD3, and CD138 was obtained to describe synovial histology. Cell‐specific expression of oxylipin‐related genes was identified by examining available synovial single‐cell RNA sequencing data. Results: We included a total of 32 ST and 26 paired‐plasma samples. A total of 71 oxylipins were identified in ST, but only 24 were identified in plasma. Only levels of 9,10‐dihydroxyoctadecenoic acid and tetranor‐Prostaglandin FM had a significant positive correlation between plasma and ST. Several oxylipins and oxylipin‐related genes were differentially expressed among synovial phenotypes. Specifically, several 5‐lipoxygenase (LOX)–derived oxylipins were statistically elevated in the lympho‐myeloid phenotype and associated with B cell expression in rheumatoid arthritis samples. Conclusion: The lack of correlation between ST and plasma oxylipins suggests that ST lipid profiling better characterizes active pathways in treated joints. Synovial 5‐LOX–derived oxylipins were highly expressed in lympho‐myeloid–enriched synovium. Combination therapy with 5‐LOX inhibitors to improve refractory inflammation may be needed in patients with this histologic group. [ABSTRACT FROM AUTHOR]

Objective: Recently, two randomized controlled trials compared removal of cervical ripening balloon (CRB) after 6 versus 12 h. Their results showed similar Bishop score changes in both groups and a shorter time to delivery in the 6‐h group. Neither of the studies was powered to show difference in mode of delivery. The aim of this study was to compare mode of delivery when the CRB was removed after 6 versus 12 h. Methods: A historical control study comparing induction of labor with a CRB between two time periods, one in which the CRB was removed after 12 h (12‐h group), and the other in which it was removed after 6 h (6‐h group). We included term pregnancies with a singleton fetus in vertex presentation. We excluded patients with a previous cesarean delivery, failed ripening with prostaglandins prior to CRB insertion, and any contraindication for vaginal delivery. The primary outcome was mode of delivery. Secondary outcomes included delivery within 24 h and other maternal and neonatal outcomes. Results: We included 1704 patients, 914 in the 12‐h group, and 717 in the 6‐h group. Removal after 6 h was associated with a lower rate of cesarean and instrumental deliveries (28.6% vs 22.5%, and 12% vs 6.2%, respectively) and a higher rate of vaginal delivery within 24 h. All differences were statistically significant. Conclusion: Removing a cervical ripening balloon after 6 rather than 12 h is associated with reduced cesarean and instrumental delivery rates, and should be considered as a reasonable, and potentially superior alternative in labor induction protocols with intracervical ripening balloon. Synopsis: Removal of cervical ripening balloon after 6 versus 12 h was associated with lower cesarean delivery rates and higher vaginal delivery rates within 24 h. [ABSTRACT FROM AUTHOR]

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The aim was to compare reproductive outcomes of Nelore heifers submitted to timed AI (TAI) protocols, with 7 or 9 d of permanence of the intravaginal progesterone (P4) device and different times of prostaglandin F2α (PGF) administration, for first (n = 935) and second (n = 530) services. On Day −24, heifers without corpus luteum (CL) underwent a protocol for induction of ovulation. On Day 0, heifers received a P4 device (0.5 g) and 1.5 mg estradiol (E2) benzoate. In order for the TAI to be carried out on the same day, these treatments were performed 2 d later on the heifers treated with the 7-d protocol. Additionally, heifers received 0.5 mg PGF at different times, resulting in four experimental groups: 9dP4-PGFd9 (n = 365); 9dP4-PGFd7 (n = 369); 9dP4-PGFd0&9 (n = 364); 7dP4-PGFd0&7 (n = 367). These nomenclatures indicate for how many d the P4 device was kept and the specific day on which PGF was given. At P4 removal, all heifers received 0.5 mg E2 cypionate and 200 IU eCG, and TAI was performed 2 d later. Effects were considered significant when P ≤ 0.05 (superscript letters a,b) whereas a tendency was assumed when 0.05 < P ≤ 0.10. Groups 9dP4-PGFd0&9 and 7dP4-PGFd0&7 had lower percentage of heifers with CL at P4 removal. The diameter (mm) of the dominant follicle (DF) was affected by treatment at P4 removal (9dP4-PGFd9: 11.3 ± 0.3b; 9dP4-PGFd7: 11.8 ± 0.2ab; 9dP4-PGFd0&9: 12.6 ± 0.2a; 7dP4-PGFd0&7: 10.8 ± 0.2c) and at TAI (9dP4-PGFd9: 12.7 ± 0.3ab; 9dP4-PGFd7: 13.2 ± 0.2a; 9dP4-PGFd0&9: 13.4 ± 0.2a; 7dP4-PGFd0&7: 12.4 ± 0.3b). Expression of estrus (%) was affected by treatment (9dP4-PGFd9: 89.6a; 9dP4-PGFd7: 93.5a; 9dP4-PGFd0&9: 88.2ab; 7dP4-PGFd0&7: 85.6b). There were no differences among treatments for P/AI on Day 40 (30–35 d post AI), final P/AI (between Day 70 and parturition) and pregnancy loss (between Day 40 and final P/AI). When the permanence of the P4 device was compared, regardless of PGF treatments, 9-d protocols resulted in greater DF diameter at P4 removal and at TAI, and greater expression of estrus (90.4 vs. 85.6%) than the 7-d protocol. Despite that, the 7-d protocol resulted in greater P/AI on Day 40 (55.3 vs. 49.1%). In addition, there was an interaction between protocol duration and body weight, in which heavier heifers (≥ 307 kg) had greater P/AI when treated with the 7-d protocol, in comparison to 9-d. In conclusion, longer TAI protocols (9 d of P4 device duration) resulted in greater DF diameter and expression of estrus. However, the shorter TAI protocol (7 d of P4 device duration) produced greater P/AI on Day 40, particularly in heavier heifers. Within 9-d protocols, the additional dose of PGF on Day 0 or the anticipation of the PGF to Day 7 did not influence fertility. • 7 or 9 d of permanence of the P4 intravaginal device were evaluated in heifers. • PGF2α was administered at different times in E2/P4-based TAI protocols. • 9-d protocols resulted in larger DF and greater expression of estrus. • P/AI 30–35 d post AI was greater in heifers treated with 7-d protocol. • Heavier heifers had greater fertility when treated with the 7-d protocol. [ABSTRACT FROM AUTHOR]

Background: The implications of SARS‐CoV‐2 infection on male fertility remain largely unknown. Besides their well‐known pro‐ and anti‐inflammatory actions, prostaglandins and polyamines are present in semen, where they play key roles in sperm quality. Objectives: To analyze semen parameters, oxidative profile and the seminal fluid prostaglandin and polyamine systems in samples collected from individuals without coronavirus disease 2019 diagnosis and men who recovered from coronavirus disease 2019. Materials and methods: This study compared semen collected from men without positive coronavirus disease 2019 diagnosis with samples obtained from individuals 1–6 months and 7–30 months post SARS‐CoV‐2 infection. Semen parameters, thiobarbituric acid reactive substances, cyclooxygenase 2 expression by fluorescence immunocytochemistry and immunoblotting, prostaglandin levels by enzyme immunoassay, ornithine decarboxylase activity by a radioactive assay, and polyamine and acetylated polyamine levels by thin‐layer chromatography were assessed. Results: In both groups of semen samples from coronavirus disease 2019 recovered men, sperm vitality, total and progressive sperm motility, and putrescine levels were significantly decreased when compared with samples from the uninfected group. In contrast, lipid peroxidation, leukocyte‐associated cyclooxygenase 2 expression, and prostaglandin D2 levels were higher in semen from coronavirus disease 2019 recovered men than in samples from uninfected individuals. While sperm concentration and morphology, ornithine decarboxylase activity, and N‐acetylputrescine levels were statistically diminished in semen obtained up to 6 months after coronavirus disease 2019 recovery, these parameters remained unchanged when samples were collected 7–30 months after coronavirus disease 2019 recovery. Coronavirus disease 2019 vaccination did not show negative effects on any of the parameters evaluated. Discussion and conclusion: Our work provides insights into the detrimental impact of coronavirus disease 2019 on several sperm parameters, in some cases, even more than a year after SARS‐CoV‐2 infection, which would be accompanied by alterations in the seminal fluid prostaglandin and polyamine profiles. Therefore, future treatments targeting the prostaglandin and polyamine pathways in coronavirus disease 2019 recovered men could lead to a successful reinstatement of semen parameters. [ABSTRACT FROM AUTHOR]

Summary: The red alga Gracilaria vermiculophylla is a prostaglandin (PG)‐producing macroalga. The alga is rich in polyunsaturated fatty acids with 20 carbon atoms, mainly arachidonic acid (AA), which is a precursor of PGs. The purpose of the present study was to analyze the ability of the red alga to produce PGs using acetone powder as the crude enzyme prepared from the alga. The acetone powder (250 mg) was incubated with different amounts of exogenous AA (0.1–4 mg). For the determination of PG contents, 5 μL of a sample solution (5 mL in water) consisting of acetone powder and AA was injected into the HPLC column. For PG analysis, an HPLC system connected with a mass spectrometer was used. Results of the study showed that the released PGs from incubation of acetone powder and AA consisted of PGE2, 15‐keto‐PGE2, 15‐hydroperoxy‐PGE2, PGA2, and PGF2α. The capability of the crude enzyme prepared from the red alga to produce PGs was affected by available oxygen and AA concentrations. The crude enzyme (250 mg) was capable of producing 164 and 141 μg of PGE2 and 15‐keto‐PGE2, respectively, from incubation with 250 μg of AA. This in vitro method could be a simple way to provide PGs in the laboratory. [ABSTRACT FROM AUTHOR]

The travoprost intracameral implant was recently approved by the US Food and Drug Administration for sustained release medical treatment of open-angle glaucoma in the USA. The approval represents a substantial and progressive step forward in the area of sustained-release glaucoma therapy. Topical intraocular pressure-lowering medications for the treatment of glaucoma are faced with a host of challenges for long-term and usually lifelong care. A changing paradigm in glaucoma management involves first-line interventions with laser modalities, micro-invasive surgeries, and sustained-release treatment platforms. Future needs in the area of sustained-release therapy include a non-prostaglandin drug delivery platform and longer-term treatments that do not require surgical reintervention. [ABSTRACT FROM AUTHOR]

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D2, and low levels of prostaglandin E2. Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown. OBJECTIVE: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD. METHODS: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis. RESULTS: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081). CONCLUSION: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis.

Dysmenorrhea is defined as “painful menstruation”. Two types of dysmenorrhea are known: primary, which occurs in the absence of any gynecological disease, and secondary, which is associated with an underlying pathology. Primary dysmenorrhea typically occurs approximately 6 months after menarche. Approximately 16% to 81% of women of childbearing age experience primary dysmenorrhea, with 2% to 29% reporting moderate to severe intensity. The treatment of primary dysmenorrhea focuses on pain relief. However, supplements such as Vitamin D3 and Zinc should be considered. Vitamin D3 inhibits prostaglandin synthesis, while zinc also inhibits its synthesis, thereby improving uterine microcirculation and reducing the intensity of uterine contractions. It is important to note that not only pharmacological treatment should be considered, but also lifestyle changes that promote maximum physical and emotional well-being to reduce the consumption of analgesics and achieve control or remission of the underlying pathology.

SARS-CoV-2 is an obligatory intracellular pathogen that requires a lipid bilayer membrane for its transport to build its nucleocapsid envelope and fuse with the host cell. The biological membranes are constituted by phospholipids (PLs), and vitamin E (Vit E) protects them from oxidative stress (OS). The aim of this study was to demonstrate if treatment with Vit E restores the modified profile of the FA in PLs in serum from patients with coronavirus disease-19 (COVID-19). We evaluated Vit E, total fatty acids (TFAs), fatty acids of the phospholipids (FAPLs), total phospholipids (TPLs), 8-isoprostane, thromboxane B2 (TXB2), prostaglandins (PGE2 and 6-keto-PGF1α), interleukin-6 (IL-6), and C-reactive protein (CRP) in serum from 22 COVID-19 patients before and after treatment with Vit E and compared the values with those from 23 healthy subjects (HSs). COVID-19 patients showed a decrease in Vit E, TPLs, FAPLs, and TFAs in serum in comparison to HSs (p ≤ 0.01), and Vit E treatment restored their levels (p ≤ 0.04). Likewise, there was an increase in IL-6 and CRP in COVID-19 patients in comparison with HSs (p ≤ 0.001), and treatment with Vit E decreased their levels (p ≤ 0.001). Treatment with Vit E as monotherapy can contribute to restoring the modified FA profile of the PLs in the SARS-CoV-2 infection, and this leads to a decrease in lipid peroxidation, OS, and the inflammatory process.

Prostaglandins have many roles in the equine reproductive tract, including but not limited to luteolysis, luteal support, ovulation, transport through the uterine tube, uterine contraction, embryonic mobility, inflammation, and fibrosis. Altered secretion of inflammatory proteins are likely to disrupt the balance of endometrial function and could impair fertility. Our overall goal was to measure the expression of several prostaglandin- and inflammation-related genes in mares with different degrees of endometrial histological changes. Our hypothesis was that mares with neutrophilic and lymphocytic plasmocytic inflammation, fibrosis, or different biopsy grades would have altered concentrations of prostaglandin E2 (PGE2) and F2α (PGF2α), as well as altered expression of inflammation- and prostaglandin-related genes, compared to mares with minimal to no histological changes on biopsy evaluation. Forty-five endometrial biopsies from estrous mares were assessed by a reproductive pathologist for the degree of neutrophilic inflammation, lymphocytic and plasmocytic inflammation, and fibrosis, and a biopsy grade was assigned based on the Kenney-Doig system. A low-volume uterine lavage was collected from a subset of twenty-six mares prior to biopsy collection and was used to measure PGE2 and PGF2α concentrations via ELISA. Total RNA was extracted from biopsies and mRNA expression was evaluated for twenty-five genes of interest. A restricted maximum likelihood linear model was used to compare differences of mRNA expression, with a statistical significance set at P < 0.05. There was no difference in the abundance of PGE2 or PGF2α between any of the variables tested. Mares with endometrial biopsy grade I had lower expression of NF-kB, PTGS1 and HPGD compared to grade IIA or IIB (P < 0.05). Mares with neutrophilic inflammation had decreased expression of NF-kB, PTGS1, PTGER4, CBR1, mPGES2 and PTGIS compared to mares without inflammation. Mares with mild or minimal endometrial fibrosis had increased expression of mPGES2 and PTGIS , compared to mares with moderate endometrial fibrosis. In conclusion, several genes were identified to be differentially expressed in mares with histological changes compared to mares with no to minimal histological changes. The presence of inflammation and fibrosis may alter the concentration of prostaglandins in endometrial tissue, which could impair many of the uterine reproductive and immune functions during estrus, affecting early embryo survival. • Prostaglandins were differentially expressed based on histological assessment. • Prostaglandin expression was increased in IIA and IIB endometrial biopsies. • mPGES2 and PTGIS relative expression were decreased with moderate fibrosis. • Endometrial biopsies with inflammation had decreased prostaglandin expression. [ABSTRACT FROM AUTHOR]

Francesco Oddone,1 Lucia Tanga,1 Sara Giammaria,1 Lorenzo Sabbatini,2 Alfonso Strianese,2 Manuela Ferrazza,1 Luca Mario Rossetti2 1IRCCS - Fondazione Bietti, Rome, Italy; 2Eye Clinic, ASST Santi Paolo E Carlo, University of Milan, Milan, ItalyCorrespondence: Francesco Oddone, Glaucoma Unit IRCCS Fondazione Bietti, Via Livenza 3, Roma, 00198, RM, Italy, Tel +39-06-85356727 ; +39-3291921575, Email odd1fr@gmail.comPurpose: The effectiveness, safety and tolerability of the preservative-free fixed combination of tafluprost and timolol (PF-TTFC) were evaluated over the 24-h in patients with open-angle glaucoma or ocular hypertension showing signs and symptoms of Ocular Surface Disease (OSD) and uncontrolled intraocular pressure (IOP) on prior benzalkonium chloride (BAK) – Latanoprost monotherapy.Methods: In this multi-center, prospective, interventional, non-comparative clinical trial, patients treated with BAK-Latanoprost underwent 24-h IOP measurements (8 am, 11 am, 2 pm, 5 pm, 8 pm, 11 pm, 2 am, 5 am) at baseline and after 3 months from switch to PF-TTFC. Mean 24-h IOP and daytime (8 am– 8 pm) vs nighttime (11 pm – 5 am) IOP were compared. Changes in OSD signs and symptoms, quality of life (QoL) and in-vivo corneal confocal microscopy (IVCM) were also evaluated.Results: Thirty-eight patients were analyzed. The mean 24-h IOP significantly decreased after 3 months from 17.8 mmHg (95% CI: 17.1– 18.6) to 15.3 mmHg (95% CI: 14.6– 16.1, p < 0.001). IOP was significantly reduced both at daytime (p < 0.001) and nighttime (p < 0.001), with better IOP control at night [− 2.9 (95% CI: − 3.5 to − 2.1) mmHg vs − 2.3 (95% CI: − 2.9 to − 1.6) mmHg]. In 20 patients (52.6%), corneal fluorescein staining improved, whereas in 4 patients (10.5%) it worsened. Hyperemia has improved in 24 (63.3%) patients and worsened in 2 (5.3%). Breakup time, Schirmer test and QoL scores showed no changes. At IVCM, the mean corneal wing-cell size was found significantly decreased (p < 0.005).Conclusion: The switch from BAK-Latanoprost to PF-TTFC significantly reduced IOP over the 24-h and improved OSD signs and symptoms.Keywords: glaucoma, tafluprost-timolol fixed combination, preservative free, BAK, prostaglandins, 24-h effectiveness, ocular surface disease

Fever is an adaptive host-defense response to infection and nowadays is rightly considered to be an expression of a healthy body and a well-functioning immune system. The condition is that it must be tightly regulated. Therefore, in individual cases, fever may be detrimental and should be treated. Specific excessive febrile reaction to pathogens which occurs after aseptic injuries is one among such cases. We previously found that among necrotic products, high mobility group box protein 1 (HMGB1) released from the site of aseptic injury affects immune effectors (cells) to mediate higher fever in response to further contact with bacterial lipopolysaccharide (LPS). Here we observed that intraperitoneal (i.p.) pre-injection of recombinant HMGB1 (5 µg/rat i.p.) provoked an increase in plasma levels of prostaglandin E2 (PGE2) in rats and augmented release of interleukin (IL)-1β and IL-6 after LPS administration at a dose of 50 µg/kg i.p. compared to rats pre-injected with saline or heat-denatured HMGB1. Furthermore, peripheral blood mononuclear cells (PBMCs) isolated from rats injected with HMGB1 were more sensitized to produce enhanced levels of IL-1β and PGE2 when stimulated with LPS in vitro (1 µg/ml/10 6 cells for 4 h) compared to control animals injected with saline or heat-denatured HMGB1. We also noted a significant increase in activation of nuclear factor κB (NF-κB) in cells isolated from rats injected with HMGB1. Altogether, the obtained results suggest that HMGB1 participates in priming of immune cells to further contact with pathogens.

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF. The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12. [ABSTRACT FROM AUTHOR]

Endometritis is a common disease in animals, leading to disruption of reproductive processes and economic losses. Noradrenergic control of prostaglandin (PG)I2 formation by inflamed endometrium is unknown. We determined the involvement of α1-, α2- and β-adrenoreceptors (ARs) in noradrenaline-influenced PGI synthase (PGIS) protein abundance and PGI2 release from porcine (1) endometrial explants with Escherichia coli (E. coli)-induced inflammation in vivo, and (2) E. coli lipopolysaccharide (LPS)-treated endometrial epithelial cells. Experiment 1. E. coli suspension (E. coli group) or saline (CON group) was injected into the uterine horns. In both groups, noradrenaline increased endometrial PGIS abundance and PGI2 release versus the control values, and it was higher in the E. coli group than in the CON group. In the CON group, a noradrenaline stimulating effect on both parameters takes place through α1D-, α2C- and β2-ARs. In the E. coli group, noradrenaline increased PGIS abundance and PGI2 release via α1A-, α2(B,C)- and β(1,2)-ARs, and PGI2 release also by α2A-ARs. Experiment 2. LPS and noradrenaline augmented the examined parameters in endometrial epithelial cells versus the control value. In LPS-treated cells, β(1,2)-ARs mediate in noradrenaline excitatory action on PGIS protein abundance and PGI2 release. β3-ARs also contribute to PGI2 release. Under inflammatory conditions, noradrenaline via ARs increases PGI2 synthesis and release from the porcine endometrium, including epithelial cells. Our findings suggest that noradrenaline may indirectly affect processes regulated by PGI2 in the inflamed uterus. [ABSTRACT FROM AUTHOR]

In an effort to improve the spawning success rate in hypophysed pacu (Piaractus mesopotamicus) females, we investigated the effects of the time of administration and the concentration of Ciosin® (i.e., an analogue of prostaglandin F2α (PGF2α)) on ovulation. To that end, in Experiment 1, hypophysed females received 2 mL/fish of ciosin either at the time of the resolving dose (0H) or at five (5H) or seven hours (7H) postresolving dose. Then, in Experiment 2, hypophysed females were induced at the time of resolving the dose with five ciosin doses ranging from 1.0 to 7.0 mL/kg. Reproductive parameters and plasma levels of 17α-20β-dihydroxy-4-pregnen-3-one (DHP) and PGF2α were evaluated at the time of spawning for both experiments. Neither the timing of ciosin application closer to spawning nor its higher concentrations resulted in increased reproductive parameters or elevated PGF2α and DHP levels. The absence of the PGF2α peak at the time of ovulation in both experiments can be attributed to the rapid increase and subsequent decrease in exogenous PGF2α levels shortly after application. In Experiment 2 two main clusters were observed: one characterized by spawning failure, poor-quality spawn and low DHP levels and the other characterized by successful spawning, high fecundity and elevated DHP levels. Although positive correlations were observed between DHP and good reproductive performance, the reasons behind the substantial variation in DHP among females subjected to the same treatments remain unknown. An emerging focus is to elucidate the pattern of expression of PGF2α receptors and their relationship with DHP in pacu. [ABSTRACT FROM AUTHOR]

Introduction: Electroacupuncture (EA) has been applied in dysmenorrhea and has shown good efficacy. The mechanisms of EA are associated with autonomic nervous system adjustments and neuroendocrine regulation. Laser acupuncture (LA), however, has been widely investigated for its noninvasiveness. However, it remains uncertain whether LA is as effective as EA. This study aimed to compare EA and LA head to head in dysmenorrhea. Methods: A crossover, randomized clinical trial was conducted. EA or LA was applied to selected acupuncture points. Participants were randomized into two sequence treatment groups who received either EA or LA twice per week in luteal phase for 3 months followed by 2-month washout, then shifted to other groups (sequence 1: EA > LA; sequence 2: LA > EA). Outcome measures were heart rate variability (HRV), prostaglandins (PGs), pain, and quality-of-life (QoL) assessment (QoL-SF12). We also compared the effect of EA and LA in low and high LF/HF (low frequency/high frequency) status. Results: Totally, 43 participants completed all treatments. Both EA and LA significantly improved HRV activity and were effective in reducing pain (Visual Analog Scale [VAS]; EA: p < 0.001 and LA: p = 0.010) and improving QoL (SF12: EA: p < 0.001, LA, p = 0.017); although without intergroup difference. EA reduced PGs significantly (p < 0.001; δ p = 0.068). In low LF/HF, EA had stronger effects than LA in increasing parasympathetic tone in respect of percentage of successive RR intervals that differ by more than 50 ms (pNN50; p = 0.053) and very low-frequency band (VLF; p = 0.035). Conclusion: There is no significant difference between EA and LA in improving autonomic nervous system dysfunction, pain, and QoL in dysmenorrhea. EA is prominent in PGs changing and preserving vagus tone in low LF/HF; yet LA is noninvasive for those who have needle phobia. Whether LA is equivalent with EA and the mechanism warrants further study. Clinical trial identification number: NCT04178226. [ABSTRACT FROM AUTHOR]

This article, published in the Indian Journal of Medical & Paediatric Oncology, explores the role of prostaglandins secreted by senescent cells in inhibiting myoblast differentiation. The study found that senescent myoblasts secrete 15 deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2), which inhibits myoblast differentiation through the activation of the HRas-MAPK pathway. The researchers also discovered that 15d-PGJ 2 covalently modifies HRas at Cysteine 184, altering its intracellular distribution and activity, which is necessary for the inhibition of myoblast differentiation. This study suggests that the accumulation of senescent cells and the secretion of prostaglandins may contribute to chemotherapy-induced cachexia. [Extracted from the article]

Purpose: To analyze the medical management of primary open‑angle glaucoma (POAG) and ocular hypertension (OHT) and the placement of fixed‑drug combination drugs (FDC) in the treatment paradigm at a tertiary eye care center in South India. Methods: Retrospective study (January 2011–December 2015) of newly diagnosed POAG and OHT patients (≥18 years) with ≥5 years follow‑up. Primary outcome included percentage use of different antiglaucoma drugs (at initiation) and FDCs at the first, second, and third progression (sequencing). Secondary outcomes: Percentage discontinuation for different FDCs, efficacy parameters (decrease in intraocular pressure (IOP)/visual field), adverse events, and the median number of antiglaucoma medications (AGMs) after 5 years. Results: Three hundred and seventy eyes (198 patients) were analyzed; 84% of them had POAG. Prostaglandin analogs (PGAs) were the most common (66.2%). FDCs were started in 48 eyes (12.9%), with brimonidine + timolol combination being the most common. FDC usage at subsequent modifications was 10.1%, 24.04%, and 30.0%. Beta‑blockers and PGAs were the most frequently prescribed AGMs in our practice pattern, with β‑blockers being the most consistent one. Conclusion: This study is a fairly large study with a minimum of a 5‑year follow‑up of patients with POAG and OHT and gives insights into the treatment patterns, use of FDCs, and the need for multiple medications over time. [ABSTRACT FROM AUTHOR]

This study aimed to examine the changes in lower eyelid position after blepharoptosis surgery and the factors that influence the outcome. We conducted a retrospective study of 155 eyes of 89 patients who underwent blepharoptosis surgery between June 2019 and October 2022. The margin reflex distance (MRD)-1 and MRD-2 were examined preoperatively and 3 months postoperatively in two groups: one with lower scleral show (LSS) (n = 37) and one without LSS (n = 118). The clinical characteristics of the two groups were compared. Both the LSS and non-LSS groups showed significant postoperative improvement in MRD-1 scores (p <.01, p <.01, respectively). MRD-2 was significantly reduced in the LSS group, while it remained unchanged in the non-LSS group (p <.01, p =.27, respectively). There were no significant differences between the two groups in age, sex, history of hard contact lens use, preoperative levator function, use of topical steroids, history of endophthalmic surgery, or history of filtration surgery; however, the LSS group significantly used prostaglandin analogs (PGAs) (p =.03). Postoperatively, MRD-2 decreased in 13 eyes (35.1%) and was maintained in 24 eyes (64.9%) in the LSS group and was maintained in all eyes in the non-LSS group. In the LSS group, we also examined the association between postoperative MRD-2 reduction and the use of PGAs and found that more patients with MRD-2 reduction used PGAs (p =.02). Lower scleral show in PGAs-associated blepharoptosis is expected to improve after blepharoptosis surgery. [ABSTRACT FROM AUTHOR]

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]

Introduction: Even though the local tolerance of prostaglandin (PG) analogues has improved drastically since the introduction of preservative-free (PF) eye drops, prescription patterns still vary widely among practitioners and between countries and could have an impact on the ocular surface of treated patients and, in consequence, their adherence. The aim of this study is to explore the prescribing patterns of PG analogues monotherapy in France and to evaluate their impact on ocular surface status. Methods: This was a national multicenter cross-sectional observational study that was conducted by 18 glaucoma experts in France. Patients over 18 years of age and receiving monotherapy with topical PG analogues for the treatment of ocular hypertension and/or glaucoma, with no history of prior glaucoma surgery, were consecutively selected from the glaucoma outpatient clinics of participating physicians and underwent an ocular surface examination. Results: A total of 344 eyes of 344 patients were enrolled between November 2022 and November 2023. Prescribed PG monotherapy was PF in 271 (78.7%) patients. Clinical history and ocular surface evaluation indicated that 79.4% of the study population (n = 273) presented with at least one symptom or clinical sign of dry eye and that three patients out of four had an unstable tear film. Subgroup analysis comparing preserved and PF PG analogues showed a higher prevalence of conjunctival hyperemia and corneal staining in the preserved group. Multivariate analysis identified conjunctival hyperemia as consistently associated with preservative use (odds ratio = 7.654; p = 0.003 for moderate conjunctival hyperemia). Conclusions: This study highlights the growing trend toward PF PG analogue prescriptions by specialists in France. However, ocular surface issues remain prevalent, impacting patient adherence and treatment efficacy. Comprehensive ocular surface examinations are crucial in glaucoma management to enhance long-term tolerance, compliance, and overall treatment success. [ABSTRACT FROM AUTHOR]

The efficiency of combining oestrous induction via a light program (16 h of light and 8 h of darkness for 60 days, ending on Day 0 – D0) with cloprostenol administration, followed by the male effect or not, was tested in acyclic Saanen goats during the non‐breeding season (June/2019 to January/2020). Initially, all animals (males and females) were submitted to the described light program; 60 days after its ending (D60), the females were divided into two groups, with (G1; n = 67) or without (G2; n = 61) a male effect from D60 to D75 after the light program. At D75, both groups received two cloprostenol doses (120 μg; intramuscular) 7.5 days apart (D75 and D82.5). Artificial insemination was performed at a specific time according to the oestrous onset (approximately 68.4 ± 1.2 h between the second cloprostenol dose and IA). Ultrasound scans were performed at different intervals to evaluate follicular dynamics and confirm pregnancy. At the first cloprostenol dose (D75), the proportion of does with at least a corpus luteum (CL), which indicates resumed cyclicity, was greater in G1 than in G2 (85.2% vs. 48.8%; p <.05), although no difference was found at the second dose (p >.05). The adjusted pregnancy rates (number of pregnant goats/oestrous goats) differed between G1 and G2 (21.7% vs. 42.0%; p <.05). G1 also showed a higher frequency of functional CL (based on blood flow and morphology) compared to G2 (96.9% vs. 66.7%; p <.05) at D116. A male effect using photo‐stimulated bucks after the first cloprostenol dose increased the number of does presenting CL after buck removal, and no impairment in the pregnancy rates of multiparous does was found. [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]

Prostaglandin E2 (PGE2) is a recognized inhibitor of granulocyte functions. However, most of the data supporting this was obtained when available pharmacological tools mainly targeted the EP2 receptor. Herein, we revisited the inhibitory effect of PGE2 on reactive oxygen species production, leukotriene biosynthesis, and migration in human neutrophils. Our data confirm the inhibitory effect of PGE2 on these functions and unravel that the effect of PGE2 on human neutrophils is obtained by the combined action of EP2 and EP4 agonism. Accordingly, we also demonstrate that the inhibitory effect of PGE2 is fully prevented only by the combination of EP2 and EP4 receptor antagonists, underscoring the importance of targeting both receptors in the effect of PGE2. Conversely, we also show that the inhibition of ROS production by human eosinophils only involves the EP4 receptor, despite the fact that they also express the EP2 receptor. [ABSTRACT FROM AUTHOR]

The endocannabinoid system and prostaglandins are important modulators in the genitourinary system. This study aimed to investigate the possible interactions between the endocannabinoid system and the cyclooxygenase (COX) pathway on rat vas deferens. For this purpose, the concentration responses of the endocannabinoid anandamide, prostaglandin F2α analog latanoprost, and prostaglandin E1 analog misoprostol on the electrical field stimulation (EFS)-induced contractile responses were obtained. The concentration responses to anandamide were obtained again in the presence of nonselective COX inhibitor flurbiprofen and prostaglandin analogs, while the concentration responses of latanoprost and misoprostol were obtained in the presence of cannabinoid receptor antagonists and fatty acid amide hydrolase (FAAH) enzyme inhibitor URB597. FAAH, COX-1, and COX-2 enzyme levels in vas deferens tissue samples were also determined. The cumulative addition of anandamide was not different from the vehicle; however, the EFS-induced contractile responses were significantly increased with the incubation of latanoprost or flurbiprofen in the prostatic portion. Flurbiprofen and misoprostol decreased FAAH enzyme levels in both portions of the vas deferens, while latanoprost induced the inhibition in the prostatic portion. The cumulative administration of latanoprost and misoprostol significantly enhanced the contractile responses in the prostatic portion. This effect of latanoprost was significantly antagonized by URB597 and AM251. The enhancing effect of misoprostol was antagonized by anandamide, URB597, AM251, and AM630. Anandamide, AM251, AM630, and URB597 decreased enzyme levels of COX-1 and COX-2 in both portions of the vas deferens. These results demonstrate an intricate crosstalk between endocannabinoids and prostaglandins in modulation of the vas deferens contractility. [ABSTRACT FROM AUTHOR]

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Background: The restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke. An-Gong-Niu-Huang-Wan (AGNHW) is a famous traditional compound Chinese medicine that has been used for over 220 years to treat acute ischaemic stroke; however, its role in the regulation of cerebral blood flow is still unclear. The aim of the present study was to investigate the regulatory effect of AGNHW on cerebral blood flow and microcirculation after ischaemic stroke and to elucidate the underlying mechanisms involved. Methods: Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (dMCAO) and randomly assigned to the sham, MCAO, or AGNHW groups. AGNHW was administered intragastrically 1 h after dMCAO. The rotarod test was utilized to evaluate behavioural function; TTC was used to determine the infarct volume; and ischaemic injury was assessed by detecting brain levels of SOD, MDA and NO. Then, cortical perfusion and acetazolamide-induced cerebrovascular reactivity were assessed using laser speckle contrast imaging, and the velocity and flux of red blood cells in cortical capillaries were detected using two-photon laser scanning microscopy. In addition, we employed RNA-Seq to identify variations in gene expression profiles and assessed endothelium-dependent changes in microcirculatory dysfunction by measuring vasoactive mediator levels. Results: AGNHW significantly increased cerebral blood flow, reduced the infarct volume, and promoted functional recovery after cerebral ischaemia. AGNHW increased the velocity and flux of red blood cells in capillaries and improved cerebrovascular reactivity in the ischaemic cortex. Furthermore, AGNHW regulated endothelium-dependent microcirculation, as evidenced by decreases in the expression of endothelins (Edn1, Edn3 and Ednrb) and the ratios of brain and serum TXB2/6-keto-PGF1α and ET-1/CGRP. Conclusions: AGNHW improved cerebral hypoperfusion, regulated cerebrovascular reactivity and attenuated microcirculatory dysfunction within the ischaemic cortex after stroke. This outstanding effect was achieved by modulating the expression of genes related to vascular endothelial cell function and regulating endothelium-dependent vasoactive mediators. [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]

The prostaglandin transporter (PGT, SLCO2A1) mediates transport of prostanoids (a.o. prostaglandin E2 (PGE2)) into cells and thereby promotes their degradation. Overexpression of PGT leads to low extracellular PGE2 levels and has been linked to impaired wound healing of diabetic foot ulcers. Inhibition of PGT could thus be beneficial, however, no PGT inhibitors are currently on the market and drug discovery efforts are hampered by lack of high-through screening assays for this transporter. Here we report on a label-free impedance-based assay for PGT that measures transport activity through receptor activation (TRACT) utilizing prostaglandin E2 receptor subtype EP3 and EP4 that are activated by PGE2. We found that induction of PGT expression on HEK293-JumpIn-SLCO2A1 cells that also express EP3 and EP4 leads to an over 10-fold reduction in agonistic potency of PGE2. PGE2 potency could be recovered upon inhibition of PGT-mediated PGE2 uptake with PGT inhibitors olmesartan and T26A, the potency of which could be established as well. Moreover, the TRACT assay enabled the assessment of transport function of PGT natural variants. Lastly, HUVEC cells endogenously expressing prostanoid receptors and PGT were exploited to study wound healing properties of PGE2 and T26A in real-time using a novel impedance-based scratch-induced wound healing assay. These novel impedance-based assays will advance PGT drug discovery efforts and pave the way for the development of PGT-based therapies. [ABSTRACT FROM AUTHOR]

The aim of the study was to compare the effect of three substances with ecbolic activity, Oxytocin, Prostaglandin F2α (PGF2α) and Scopolamine, on the uterine involution process in dairy cows and on the resumption of ovarian activity. Eighty bovine were randomly divided in four groups: GROUP C: 20 cows treated, within 24 h of calving, with 5 mL/head of saline solution; GROUP PG: 20 cows treated, within 24 h of calving, with 150 µg/head of d-cloprostenol; GROUP OX: 20 cows treated, within 24 h of calving, with 50 IU/head of oxytocin acetate; GROUP S: 20 cows treated, within 24 h of calving, with 40 mg/q Scopolamine Butylbromide. Each cow was subjected to blood samples to evaluate the Hydroxyproline (HYP) levels, at T0, within 24 h after calving, and T7, T14, T28, 7, 14, and 28 days after calving, respectively. At T14 and T28, an ultrasound examination was performed to measure the diameter of expregnant horn. In all cows, the reproductive indices (days to first service and number of artificial insemination for conception) were evaluated. In all groups, the HYP concentrations have been rising from T0 to T28, with the maximum levels obtained at T28 in the groups PG and S. As regard the diameter of uterine horn, the comparison among the groups showed significant differences only at T28, with lower values in the group PG and S. In group S and PG, the days to first service were less than other groups. Treatment with Scopolamine and PGF2α resulted in better outcomes, evidenced clinically by more efficient uterine involution and faster ovarian recovery. [ABSTRACT FROM AUTHOR]

Prostaglandin analogs (PGAs) are commonly used to treat ocular hypertension and glaucoma patients. Nowadays, the use of PGAs enhances eyelashes in cosmetics, particularly in the condition of hypotrichosis. A method was developed in which surface molecularly imprinted polymers were synthesized for selective extraction of PGAs (bimatoprost, latanoprost, and travoprost) by using bimatoprost as template molecules which were coupled with liquid chromatography‐mass spectrometry (LC‐MS) system. Scanning electron microscopy and Fourier‐transform infrared spectroscopy techniques were used to study the morphological and physical characterization. The adsorption selectivity studies showed the high selectivity of PGAs. The adsorption capacities of bimatoprost, latanoprost, and travoprost were 93.8, 92.3, and 91.5 μg/g, respectively. The recoveries and precision of samples at three concentration levels (10–30 ng/mL) of bimatoprost, latanoprost, and travoprost were tested (98.5%–102.5%, 1.2%–4.5%, n = 3). The % relative standard deviation for repeatability of the method for bimatoprost, latanoprost, and travoprost ranged from 1.8 to 5.6, 1.5 to 4.8, and 1.6 to 5.2, respectively. While the limit of detection for bimatoprost, latanoprost, and travoprost was 0.20, 0.25, and 0.45 ng/mL, respectively. The method of surface molecularly imprinted polymer coupled with LC‐MS was successfully applied to cosmetic products for selective extraction of PGAs. [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]

Background: Acetaminophen and ibuprofen are widely administered to babies due to their presumed safety as over‐the‐counter drugs. However, no reports exist on the effects of cyclooxygenase inhibitors on undifferentiated spermatogonia and spermatogonial stem cells. Infancy represents a critical period for spermatogonial stem cell formation and disrupting spermatogonial stem cells or their precursors may be associated with infertility and testicular cancer formation. Objectives: The goal of this study was to examine the molecular and functional impact of cyclooxygenase inhibition and silencing on early steps of undifferentiated spermatogonia (u spg) and spermatogonial stem cell development, to assess the potential reproductive risk of pharmaceutical cyclooxygenase inhibitors. Methods: The effects of cyclooxygenase inhibition were assessed using the mouse C18‐4 undifferentiated juvenile spermatogonial cell line model, previously shown to include cells with spermatogonial stem cell features, by measuring prostaglandins, cell proliferation, and differentiation, using cyclooxygenase 1‐ and cyclooxygenase 2‐selective inhibitors NS398, celecoxib, and FR122047, acetaminophen, and ibuprofen. Cyclooxygenase 1 gene silencing was achieved using a stable short‐hairpin RNA approach and clone selection, then assessing gene and protein expression in RNA sequencing, quantitative real‐time polymerase chain reaction, and immunofluorescence studies. Results: Cyclooxygenase 2 inhibitors NS398 and celecoxib, as well as acetaminophen, but not ibuprofen, dose‐dependently decreased retinoic acid‐induced expression of the spg differentiation gene Stra8, while NS398 decreased the spg differentiation marker Kit, suggesting that cyclooxygenase 2 is positively associated with spg differentiation. In contrast, short‐hairpin RNA‐based cyclooxygenase 1 silencing in C18‐4 cells altered cellular morphology and upregulated Stra8 and Kit, implying that cyclooxygenase 1 prevented spg differentiation. Furthermore, RNA sequencing analysis of cyclooxygenase 1 knockdown cells indicated the activation of several signaling pathways including the TGFb, Wnt, and Notch pathways, compared to control C18‐4 cells. Notch pathway genes were upregulated by selective cyclooxygenase inhibitors, acetaminophen and ibuprofen. Conclusion: We report that cyclooxygenase 1 and 2 differentially regulate undifferentiated spermatogonia/spermatogonial stem cell differentiation. Cyclooxygenases regulate Notch3 expression, with the Notch pathway targeted by PGD2. These data suggest an interaction between the eicosanoid and Notch signaling pathways that may be critical for the development of spermatogonial stem cells and subsequent spermatogenesis, cautioning about using cyclooxygenase inhibitors in infants. [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]

Background/aim: Our recent study revealed that the expression of lipoxygenase (LOX) and cyclooxygenase (COX) enzymes in the hypothalamus is activated by nesfatin-1, leading to the liberation of leukotrienes and prostaglandins (PG), respectively. Moreover, our prior report explained that intracerebroventricular (ICV) nesfatin-1 treatment triggers cardiovascular responses mediated by central LOX and COX enzymes. Building upon our prior reports, the present investigation sought to clarify the role of cardiovascularly active central COX products, such as thromboxane (TX) A2, PGF2α, PGE, and PGD, in orchestrating nesfatin-1-evoked reactions in mean arterial pressure (MAP) and heart rate (HR). Materials and methods: The Sprague Dawley rats, which had guide cannula in the lateral ventricle for intracerebroventricular (ICV) injections and catheter in arteria femoralis for monitoring MAP and HR, were underwent central pretreatment with furegrelate (the TXA2 synthase inhibitor), PGF2α-dimethylamine (PGF2α-DA, the PGF2α receptor antagonist), or AH6809 (the PGE and PGD receptor antagonist), 5 min prior to ICV nesfatin-1 administration. The cardiovascular parameters were observed and recorded for 60 min posttreatment Results: Nesfatin-1 induced cardiovascular responses in rats leading to pressor effect in MAP, and tachycardia following bradycardia in HR. Interestingly, ICV furegrelate, PGF2α-DA, or AH6809 pretreatment partially mitigated the cardiovascular effects revealed by nesfatin-1. Conclusion: The findings illuminate the role of nesfatin-1 in modulating MAP and HR through the central activation of specifically TXA2, PGF2α, PGE, and PGD from COX metabolites. Additionally, the study may also suggest the potential involvement of other central COX or LOX metabolites beyond these COX metabolites in mediating the cardiovascular effects produced by nesfatin-1. [ABSTRACT FROM AUTHOR]

The article describes various forms of hair loss, including androgenetic alopecia (AGA) and diffuse alopecia. AGA is a hereditary form of hair loss that leads to receding hairline in men. The causes of AGA include increased androgen receptor density, increased expression of prostaglandin D2, and a shortened anagen phase of the hair cycle. On the other hand, diffuse alopecia results in a diffuse hair loss on the entire scalp and can be caused by various factors such as stress, medication, or chronic illnesses. Other forms of hair loss are also described, as well as factors that can influence hair loss. It is emphasized that early diagnosis and treatment are important. [Extracted from the article]

Objective: This study aims to investigate the effect of physical activity, body mass index (BMI), and levels of prostaglandins (PGF2α) urine on the occurrence of dysmenorrhea in adolescents. Methods: A total of 128 female students included in the study. The study was conducted from January to March 2023 using a cross‐sectional design. This study utilized the Menstrual Symptom Questionnaire (MSQ) and gynecological examination with ultrasonography. The urinary prostaglandin (PGF2α) was measured using the enzyme linked immuno sorbent assay (ELISA). Data were analyzed using the chi‐square test and logistic regression test. Results: The age range of the participants included in the study was 14–17, with a mean age of 15.85 ± 0.65. There was an correlation between physical activity, BMI, and urinary prostaglandin (PGF2α) levels with the incidence of dysmenorrhea in adolescents (p < 0.001). In multivariate analysis, it revealed that underweight, and had a high urinary prostaglandin significant correlated to primary dysmenorrhea with odds ratio 4.78 (95% confidence interval [CI] 1.98–11.54) and 4.88 (95% CI 1.98–12.08), respectively. High physical activity and overweight was not associated with incidence of dysmenorrhea in adolescents. Conclusion: This study provides valuable insights into the correlation between physical activity, BMI, and levels of prostaglandins (PGF2α) in urine. A high level of urinary prostaglandin was found to be the most influential factor in the incidence of primary dysmenorrhea in adolescents. By addressing factors associated with dysmenorrhea in adolescents, healthcare professionals can potentially enhance well‐being by reducing menstrual pain and encouraging a healthy lifestyle to prevent dysmenorrhea. [ABSTRACT FROM AUTHOR]

The study of neurogenesis is essential to understanding fundamental developmental processes and for the development of cell replacement therapies for central nervous system disorders. Here, we designed an in vivo drug screening protocol in developing zebrafish to find new molecules and signalling pathways regulating neurogenesis in the ventral spinal cord. This unbiased drug screen revealed that 4 cyclooxygenase (COX) inhibitors reduced the generation of serotonergic interneurons in the developing spinal cord. These results fitted very nicely with available single‐cell RNAseq data revealing that floor plate cells show differential expression of 1 of the 2 COX2 zebrafish genes (ptgs2a). Indeed, several selective COX2 inhibitors and two different morpholinos against ptgs2a reduced the number of serotonergic neurons in the ventral spinal cord and led to locomotor deficits. Single‐cell RNAseq data and different pharmacological manipulations further revealed that COX2‐floor plate‐derived prostaglandin D2 promotes neurogenesis in the developing spinal cord by promoting mitotic activity in progenitor cells. Rescue experiments using a phosphodiesterase‐4 inhibitor suggest that intracellular changes in cAMP levels underlie the effects of COX inhibitors on neurogenesis and locomotion. Our study provides compelling in vivo evidence showing that prostaglandin signalling promotes neurogenesis in the ventral spinal cord. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the impact of Pulmonary Arterial Hypertension (PAH) therapies on the incidence of pericardial effusion and its prognostic implications for patient survival. Methods: This retrospective cohort study included 60 patients diagnosed with PAH at a high-volume tertiary care center, treated with intravenous or subcutaneous prostanoids. Data were collected from 2015 to 2019, including echocardiographic assessments, right heart catheterization, World Health Organization functional class evaluations, six-minute walk distance tests, and biomarkers such as brain natriuretic peptide and N-terminal prohormone of brain natriuretic peptide. Follow-up was conducted at least 90 days post-treatment initiation. Results: Pericardial effusion was observed in 31.7% of patients before therapy. Patients with moderate to large effusions had a significantly higher mortality risk (HR = 1.92; 95% CI 1.1-44.78; p = 0.0044), while small effusions appeared protective (HR = 0.27; 95% CI 0.15-0.48; p = 0.006). Survival rates declined from 89% at one year to 71% at three years post-therapy, with effusion presence correlating with more severe PAH manifestations. Conclusions: Initial pericardial effusion severity is a critical predictor of mortality in PAH patients. Early assessment and stratified management of pericardial effusion are essential for optimizing therapeutic outcomes in PAH management. Future research should explore targeted interventions for managing pericardial effusion to improve patient prognosis. [ABSTRACT FROM AUTHOR]

Blood stasis syndrome (BSS) has persistent health risks; however, its pathogenesis remains elusive. This obscurity may result in missed opportunities for early intervention, increased susceptibility to chronic diseases, and reduced accuracy and efficacy of treatments. Metabolomics, employing the matrix-assisted laser desorption/ionization (MALDI) strategy, presents distinct advantages in biomarker discovery and unraveling molecular mechanisms. Nonetheless, the challenge is to develop efficient matrices for high-sensitivity and high-throughput analysis of diverse potential biomarkers in complex biosamples. This work utilized nitrogen-doped porous transition metal carbides and nitrides (NP-MXene) as a MALDI matrix to delve into the molecular mechanisms underlying BSS pathogenesis. Structural optimization yielded heightened peak sensitivity (by 1.49-fold) and increased peak numbers (by 1.16-fold) in clinical biosamples. Validation with animal models and clinical serum biosamples revealed significant differences in metabolic fingerprints between BSS and control groups, achieving an overall diagnostic efficacy of 0.905 (95% CI, 0.76–0.979). Prostaglandin F2α was identified as a potential biomarker (diagnostics efficiency of 0.711, specificity = 0.7, sensitivity = 0.6), and pathway enrichment analysis disclosed disruptions in arachidonic acid metabolism in BSS. This innovative approach not only advances comprehension of BSS pathogenesis, but also provides valuable insights for personalized treatment and diagnostic precision. [ABSTRACT FROM AUTHOR]