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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]

Capsaicin induces the reversible opening of tight junctions (TJs) and enhances the delivery of hydrophilic macromolecules through a paracellular route. We previously revealed that TRPA1 is involved in the capsaicin-induced Ca2+ influx and TJ permeability increase, although there are no reports that capsaicin directly activates TRPA1. In this study, we investigated the upstream factors of TRPA1 using RNA-seq analysis, and found that the cyclooxygenase 2 (COX2) gene was upregulated by capsaicin. Cyclooxygenase 2 converts arachidonic acid (AA), a metabolite by phospholipase A2 (PLA2), to prostaglandins. Prostaglandin E2 (PGE2) production was stimulated by capsaicin, and capsaicin-induced Ca2+ influx was effectively inhibited by PLA2 and COX2 inhibitors. The AA-induced TJ permeability increase was inhibited by a TRPA1 antagonist, but the capsaicin- and AA-induced TJ permeability increases were hardly inhibited by a COX2 inhibitor. These results suggest that capsaicin-induced PLA2 activation and AA production are the important steps for the TJ permeability increase. [ABSTRACT FROM AUTHOR]

Aim: Differentiating alcoholic hepatitis (AH) from acute decompensation of alcoholic cirrhosis (DC) is challenging, as the presentation and biochemistry are similar. We aimed to identify potential metabolomic biomarkers to differentiate between AH and DC, and to predict short-term mortality. Methods: We included consecutive biopsy proven AH and DC patients, which were managed according to current guidelines and followed up until the end of the study. Untargeted metabolomics was assessed in all patients at baseline. Specific analyses were successively performed to identify potential biomarkers, which were further semi-quantitatively analysed against relevant clinical endpoints. Results: Thirty-four patients with AH and 37 with DC were included. UHPLC-MS analysis identified 83 molecules potentially differentiating between AH and DC. C16-Sphinganine-1P (S1P) was the most increased, whereas Prostaglandin E2 (PGE2) was the most decreased. The PGE2/S1P ratio < 1.03 excellently discriminates between AH and DC: AUC 0.965 (p < 0.001), Se 90%, Sp 100%, PPV 0.91, NPV 1, and diagnostic accuracy 95%. This ratio is not influenced by the presence of infection (AUC 0.967 vs. 0.962), correlates with the Lille score at 7 days (r  = −0.60; P  = 0.022) and tends to be lower in corticosteroid non-responders as compared with patients who responded [0.85(±0.02) vs. 0.89(±0.05), P  = 0.069]. Additionally, decreased ursodeoxycholic acid levels are correlated with MELD and Maddrey scores and predict mortality with a 77.27% accuracy (NPV = 100%). Conclusion: This study suggests the PGE2 (decreased)/S1P (increased) ratio as a biomarker to differentiate AH from DC. The study also finds that low levels of ursodeoxycholic acid could predict increased mortality in AH. [ABSTRACT FROM AUTHOR]

12(S)-hydroxyheptadecatrienoic acid (12-HHT) is a bioactive fatty acid synthesized from arachidonic acid via the cyclooxygenase pathway and serves as an endogenous ligand for the low-affinity leukotriene B4 receptor 2 (BLT2). Although the 12-HHT/BLT2 axis contributes to the maintenance of epithelial homeostasis, 12-HHT metabolism under physiological conditions is unclear. In this study, 12-keto-heptadecatrienoic acid (12-KHT) and 10,11-dihydro-12-KHT (10,11dh-12-KHT) were detected as 12-HHT metabolites in the human megakaryocytic cell line MEG01s. We found that 12-KHT and 10,11dh-12-KHT are produced from 12-HHT by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin reductase 1 (PTGR1), key enzymes in the degradation of prostaglandins, respectively. The 15-PGDH inhibitor SW033291 completely suppressed the production of 12-KHT and 10,11dh-12-KHT in MEG01s cells, resulting in a 9-fold accumulation of 12-HHT. 12-KHT and 10,11dh-12-KHT were produced in mouse skin wounds, and the levels were significantly suppressed by SW033291. Surprisingly, the agonistic activities of 12-KHT and 10,11dh-12-KHT on BLT2 were comparable to that of 12-HHT. Taken together, 12-HHT is metabolized into 12-KHT by 15-PGDH, and then 10,11dh-12-KHT by PTGR1 without losing the agonistic activity. [ABSTRACT FROM AUTHOR]

Background: Obesity has now been recognized as a high-risk factor for reproductive health. Although remarkable advancements have been made in ART, a considerable number of infertile obese women still suffer from serial implantation failure, despite the high quality of embryos transferred. Although obesity has long been known to exert various deleterious effects on female fertility, the underlying mechanisms, especially the roles of lipid metabolism in endometrial receptivity, remain largely elusive.Objective and Rationale: This review summarizes current evidence on the impacts of several major lipids and lipid-derived mediators on the embryonic implantation process. Emerging methods for evaluating endometrial receptivity, for example transcriptomic and lipidomic analysis, are also discussed.Search Methods: The PubMed and Embase databases were searched using the following keywords: (lipid or fatty acid or prostaglandin or phospholipid or sphingolipid or endocannabinoid or lysophosphatidic acid or cholesterol or progesterone or estrogen or transcriptomic or lipidomic or obesity or dyslipidemia or polycystic ovary syndrome) AND (endometrial receptivity or uterine receptivity or embryo implantation or assisted reproductive technology or in vitro fertilization or embryo transfer). A comprehensive literature search was performed on the roles of lipid-related metabolic pathways in embryo implantation published between January 1970 and March 2022. Only studies with original data and reviews published in English were included in this review. Additional information was obtained from references cited in the articles resulting from the literature search.Outcomes: Recent studies have shown that a fatty acids-related pro-inflammatory response in the embryo-endometrium boundary facilitates pregnancy via mediation of prostaglandin signaling. Phospholipid-derived mediators, for example endocannabinoids, lysophosphatidic acid and sphingosine-1-phosphate, are associated with endometrial receptivity, embryo spacing and decidualization based on evidence from both animal and human studies. Progesterone and estrogen are two cholesterol-derived steroid hormones that synergistically mediate the structural and functional alterations in the uterus ready for blastocyst implantation. Variations in serum cholesterol profiles throughout the menstrual cycle imply a demand for steroidogenesis at the time of window of implantation (WOI). Since 2002, endometrial transcriptomic analysis has been serving as a diagnostic tool for WOI dating. Numerous genes that govern lipid homeostasis have been identified and, based on specific alterations of lipidomic signatures differentially expressed in WOI, lipidomic analysis of endometrial fluid provides a possibility for non-invasive diagnosis of lipids alterations during the WOI.Wider Implications: Given that lipid metabolic dysregulation potentially plays a role in infertility, a better understanding of lipid metabolism could have significant clinical implications for the diagnosis and treatment of female reproductive disorders. [ABSTRACT FROM AUTHOR]

This document is a correction to an article titled "The Effect of Thiazide Diuretics on Urinary Prostaglandin Estradiol Excretion and Serum Sodium in the General Population." The correction addresses an error in the title and in Table 1 of the article. The corrected title now reads "The Effect of Thiazide Diuretics on Urinary Prostaglandin E2 Excretion and Serum Sodium in the General Population." Additionally, the abbreviation "prostaglandin estradiol" in Table 1 has been corrected to "prostaglandin E2." The publisher acknowledges the error and the corrected article is available online. [Extracted from the article]

The physiological mechanisms underlying late embryonic/early fetal mortality in beef cows are largely unknown. Our lab, as well as others, have documented that cows undergoing late embryonic mortality have significantly decreased circulating concentrations of prostaglandin F2a metabolite (PGFM) and increased concentrations of prostaglandin E2 metabolite (PGEM) during gestational d 30 to 38, coinciding with the time of active placentation. Thus, the overall objective of this study was to analyze the physiological effect of inhibiting local prostaglandin synthesis during late embryonic development in beef cows. To determine the appropriate dosage and drug required for the sufficient knockdown of uterine-derived prostaglandins, three pilot studies were conducted. In pilot study one and two, indomethacin was administered intravenously or intrauterine into cyclic cows at a dose of 80 mg/d (n = 4) or, 160 mg/d (n = 4), directly into the jugular of pregnant cows at a dose of 270 mg/d (n = 1) or directly into the uterine artery of pregnant cows at a dose 360 mg/d (n = 2). Administration of indomethacin did not significantly knockdown PGFM or PGEM (P > 0.05). However, in pilot study three, a 720 mg/d dose of flunixin meglumine (FM; Banamine, Merck Animal Health, NJ) infused intrauterine into cyclic beef cows (n = 5) resulted in a treatment by day interaction (P < 0.001) in which luteolysis in treatment cows was inhibited as well as the synthesis of both prostaglandin F2a and prostaglandin E2. Following this validation, the next study was performed using multiparous beef cows that were subjected to a 7-d CO-Synch + CIDR synchronization protocol with insemination occurring on d 0. Pregnancy was confirmed by the presence of a fetal heartbeat on d 28 via ultrasonography and subsequent blood collections every 8 h via venipuncture (n = 9). Intrauterine infusions began on d 29 and occurred every 8 h via infusette catheter consisting of either 240 mg of FM diluted in 10 mL of flush media (ABT; FMTrt; n = 6), or 10 mL of flush media (CON; n = 3). Both infusion solutions were corrected to a pH of 7.4. Serum concentrations of PGFM were measured with a validated commercial ELISA (Cayman Chemical, MI). Though all cows were confirmed pregnant on d 28, concentrations of PGFM were significantly greater on d 28 (P < 0.01) and d 29 (P < 0.05) in the FMTrt cows than the CON cows. There was a significant decline in circulating PGFM within the FMTrt cows (P < 0.05) post infusion on d 29. After two infusions, CON cows had significantly greater PGFM concentrations compared with the FMTrt group (P < 0.01). By d 30, after three infusions, all FMTrt cows had terminated their pregnancies; however, CON cows maintained their pregnancies. Perhaps, these data indicate the importance of prostaglandins during this critical period of pregnancy. Further research is required to fully understand the physiological contribution that prostaglandins elicit in regard to pregnancy. [ABSTRACT FROM AUTHOR]

Microsomal prostaglandin E synthase-1 (mPGES-1) synthesizes PGE2 from prostaglandin H2 (PGH2) following an ischaemic insult and favors Treg-dependent activation of post-ischaemic revascularization. This editorial refers to 'The microsomal prostaglandin E synthase-1/prostaglandin E SB 2 sb axis induces recovery from ischaemia via recruitment of regulatory T cells', by H. Amano I et al. i , https://doi.org/10.1093/cvr/cvac137. [Extracted from the article]

We previously reported that prostaglandin (PG)D2 and its isosteric analog, 11-deoxy-11-methylene-PGD2 (11d-11m-PGD2), promote adipogenesis in 3T3-L1 cells during the maturation phase. Focusing on the differentiation phase, although both PGs inhibited adipogenesis, this effect was canceled out by PGI2 and PGJ2 derivatives. Thus, PGD2 and 11d-11m-PGD2 play different roles during the phases, but do not affect PGI2 - and PGJ2-derivative-induced adipogenesis. [ABSTRACT FROM AUTHOR]

Objectives The current study evaluates survival rates among SSc-associated pulmonary arterial hypertension (SSc-PAH) patients on i.v. prostanoids, and short-term impact of i.v. prostanoids on clinical and haemodynamic parameters. Methods Baseline demographics, invasive and non-invasive data, European Society of Cardiology (ESC) score and REVEAL score of 81 SSc-PAH patients (median age 61 years, interquartile range 54–67 years, 84% females) were prospectively recorded, from November 2006 till November 2020, before initiation of i.v. prostanoids, and at first formal reassessment. Survival data were retrieved from National Health Service Spine and hospital databases. Results Significant improvements in clinical and haemodynamic parameters in response to i.v. prostanoid therapy were documented. Functional class (FC) (16.6% improved by 1FC, P =0.041), mean pulmonary arterial pressure (−6.5 mmHg, P =0.036), pulmonary vascular resistance (−2.6 WU, P =0.012), cardiac index (Q/m2) (+0.7 l/min/m2, P =0.003) and mixed venous oxygen saturation (SvO2) (+3%, P =0.036) improved. Estimated survival for CTD-PAH patients on i.v. prostanoids was 64%, 31% and 18%, at 1 year, 3 years and 5 years, respectively. Independent baseline predictors of mortality were older age (HR: 1.043, 95% CI: 1.011–1.075, P =0.007), higher N-terminal pro-brain natriuretic peptide levels (HR: 2.191, 95% CI: 1.131–4.243, P =0.020), and lower SvO2 levels (HR: 0.962, 95% CI: 0.926–0.998, P =0.039). High ESC risk or high and very high REVEAL score was associated with significantly worse survival compared with patients with lower risk scores, both at baseline and when reassessed after a median of 6.5 months. Conclusions Survival among SSc-PAH patients on i.v. prostanoids remains poor, risk scoring at baseline and after 6.5 months of therapy improves prognostication. [ABSTRACT FROM AUTHOR]

Background: Symptom intensity during a common cold is highly variable, particularly after the illness peaks, contributing to delay in recovery. Rhinoviruses frequently cause colds and, during acute infections, generate leukotriene B4 and prostaglandin E2 (PGE2). PGE2 is known to initiate oxylipin class switching and resolution of acute inflammation. Thus, we hypothesized that during acute rhinovirus colds, oxylipins with pro-resolving capabilities reduce symptom severity and speed recovery.Methods: Four groups of healthy volunteers were inoculated with placebo or 3 different doses of rhinovirus A16. Participants kept daily records of symptoms and contributed serial nasal lavage fluid samples. We collected semi-quantitative mass spectrometry data for 71 oxylipins in these acute samples from all participants. An ensemble analysis approach was used to further reduce this dataset.Results: Levels of 15-keto-PGE2 at day 3 of the cold were consistently among the top candidates in these models of recovery symptoms. 15-keto-PGE2 was the only oxylipin with an interaction between inoculum dose and time. Acute 15-keto-PGE2 levels were inversely associated with symptoms during cold recovery in a multivariable analysis (P = .0043).Conclusions: These findings show that high 15-keto-PGE2 levels during the acute cold are associated with fewer symptoms during recovery. [ABSTRACT FROM AUTHOR]

Although hormonally-derived female sex pheromones have been well described in approximately a dozen species of teleost fish, only a few male sex pheromones have been characterized and the neuroendocrine underpinnings of behavioral responsiveness to them is not understood. Herein, we describe a study that addresses this question using the goldfish, Carassius auratus , an important model species of how hormones drive behavior in egg-laying teleost fishes. Our study had four components. First, we examined behavioral responsiveness of female goldfish and found that when injected with prostaglandin F2α (PGF2α), a treatment that drives female sexual receptivity, and found that they became strongly and uniquely attracted to the odor of conspecific mature males, while non-PGF2α-treated goldfish did not discern males from females. Next, we characterized the complexity and specificity of the male pheromone by examining the responsiveness of PGF2α-treated females to the odor of either mature male conspecifics or male common carp odor, as well as their nonpolar and polar fractions. We found that the odor of male goldfish was more attractive than that of male common carp, and that its activity was attributable to both its nonpolar and polar fractions with the later conveying information on species-identity. Third, we hypothesized that androstenedione (AD), a 19-carbon sex steroid produced by all male fish might be the nonpolar fraction and tested whether PGF2α-treated goldfish were attracted to either AD alone or as part of a mixture in conspecific water. We found that while AD was inactive on its own, it became highly attractive when added to previously unattractive female conspecific water. Lastly, in a test of whether nonhormonal conspecific odor might determine species-specificity, we added AD to water of three species of fish and found that while AD made goldfish water strongly attractive, its effects on other species holding water were small. We conclude that circulating PGF2α produced at the time of ovulation induces behavioral sensitivity to a male sex pheromone in female goldfish and that this male pheromone is comprised of AD and a mixture of body metabolites. Because PGF2α commonly mediates ovulation and female sexual behavior in egg-laying fishes, and AD is universally produced by male fishes as a precursor to testosterone, we suggest that these two hormones may have similar roles mediating male–female behavior and communication in many species of fish. [ABSTRACT FROM AUTHOR]

Male, 41 years old (yo) had been complaining of severe arthralgia. Past History indicated obstruction of intestinal tract at 12 yo and gastric ulcer at 13 yo. He had been suffered from polyarthralgia especially at PIP and MP joints of both hands from 38 yo. Finally, he complained severe arthralgia at PIP and MP joints with clubbed fingers without swelling. Biochemical finding indicated negative rheumatoid factor and anti-CCP antibody and normal MMP-3 level, but slightly increased CRP and ESR levels. Radiological finding indicated periostosis of long bone without bone erosion and osteoporosis. His facial appearance was acromegalic with cutaneous manifestation of pachydermia and cutis vertices gyrate without abnormal growth hormone response. Histological findings of skin indicated oedema and hyperplasia of sebaceous glands with infiltration of lymphocytes around small blood vessels compatible with pachydermoperiostosis. In this case mutation of SLCO2A1 gene, which coded prostaglandin transport protein, was identified. The mutation c.940 + 1G > A of SLCO2A1 gene results in deletion of exon 7 and truncation of PG transporter (p.Arg288Glyfs*7). We suggest that severe arthralgia was originated from over production of prostaglandin E2. Further studies will be required. [ABSTRACT FROM AUTHOR]

To determine effects of delaying the injection of prostaglandin F2α (PGF) and fixed-time artificial insemination (TAI) in the 14-d CIDR-PG protocol, 1,049 Angus heifers at six locations were enrolled in a completely randomized design. Within location heifers were randomly assigned to one of two treatment groups: 1) PG16 (n = 518), heifers received a controlled internal drug release (CIDR) insert on d 0 for 14 d, a 25-mg injection of PGF 16 d after CIDR removal (d 30), and a 100-µg injection of gonadotropin-releasing hormone concurrent with TAI 66 ± 2 h later; or 2) PG17 (n = 531), heifers were treated the same as PG16, however, PGF was administered 17 d after CIDR removal (d 31), and heifers were TAI 66 ± 2 h later. Estrus detection patches were applied to a subset (n = 482) of heifers at the time of PGF administration and were examined for activation at TAI. Dominant follicle diameter was determined via transrectal ultrasonography at PGF administration and TAI in a subset of heifers (n = 116). Transrectal ultrasonography was performed to determine pregnancy rates to TAI (PR/AI) between 30 and 45 d after TAI. Estrus expression prior to TAI differed by treatment where PG17 heifers had greater (P < 0.01) expression of estrus than PG16 heifers (57.8 ± 6.1% vs. 43.4 ± 6.1%, respectively). Nevertheless, dominant follicle diameters at PGF and at TAI were similar (P ≥ 0.59) between PG16 and PG17 heifers. In addition, PR/AI did not differ (P = 0.29) between PG16 and PG17 treatments (50.5 ± 3.2% vs. 45.7 ± 3.1%, respectively). Results of this experiment indicate that delaying the injection of PGF and TAI in the 14-d CIDR-PG protocol increased estrus expression prior to TAI yet did not improve fertility in beef heifers. [ABSTRACT FROM AUTHOR]

Historically, sows have been induced to farrow using prostaglandin followed by an injection of oxytocin 24 h later. Benefits of induction can include decreased rate of stillbirths, dystocia, and postnatal mortality along with increasing the likelihood of farrowings being attended. Several studies have indicated that oxytocin administration may negatively impact fetal oxygen supply during parturition, potentially from umbilical cords breaking prior to birth, resulting in increased preweaning mortality. Therefore, the objective of this study was to determine if various induction protocols impact umbilical cord breakage and fetal blood parameters at birth. Fifty-eight primiparous and multiparous sows were assigned to one of three treatments: no induction (NO; n = 24) or 2 cc prostaglandin administered on day 114 of gestation followed by either 1 cc of oxytocin 24 h later (OXY24; n = 13) or 0.5 cc of oxytocin at 6 and 12 h after prostaglandin (OXY6; n = 21). Details of the farrowing process were recorded, and umbilical cord blood was collected from piglets at birth and evaluated on an iSTAT machine using an Abbott EC8+ test cartridge. There were no differences in total born, number born alive, stillborns, mummies, or assistance needed during farrowing. Induced sows were more likely to farrow by day 115 compared to naturally farrowing sows (P = 0.02). Sows in the OXY24 treatment tended to have longer farrowings when compared to both NO and OXY6 (4.8 vs. 3.6 vs. 3.9 h; P = 0.09). Colostrum from OXY6 sows tended to have a greater amount of lactose present than NO and OXY24 (P = 0.05). Colostrum from sows with longer gestation lengths had a higher percentage of fat (P = 0.03). Piglets born from NO sows had higher base excess, total carbon dioxide, and glucose, which suggests that these piglets had prolonged moments of asphyxiation (P < 0.01). OXY24 piglets had the lowest blood pH which is indicative of hypoxic birthing conditions (P < 0.01). Preweaning mortality was driven largely by a low birth weight coupled with low colostrum intake (P = 0.03). All piglets, regardless of treatment, displayed signs of stress during farrowing. Induction did not influence preweaning mortality but has the potential to decrease the incidence by increasing attended farrowings. [ABSTRACT FROM AUTHOR]

The mammalian oviduct is a dynamic organ where important events such as final maturation of oocytes, transport of gametes, sperm capacitation, fertilization, embryo development, and transport take place. Prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase 2 (COX-2), is the rate-limiting enzyme in the production of prostaglandins (PGs) and plays an essential role during early pregnancy, including ovulation, fertilization, implantation, and decidualization. Even though the maternal-embryo communication originates in the oviduct, not many studies have systemically investigated PTGS2 signaling during early development. Most of the studies investigating implantation and decidualization processes in Ptgs2 -/- mice employed embryo transfer into the uterus, thereby bypassing the mammalian oviduct. Consequently, an understanding of the mechanistic action as well as the regulation of PTGS2 and derived PGs in oviductal functions is far from complete. In this review, we aim to focus on the importance of PTGS2 and associated PGs signaling in the oviduct particularly in humans, farm animals, and laboratory rodents to provide a broad perspective to guide further research in this field. Specifically, we review the role of PTGS2-derived PGs in fertilization, embryo development, and transport. We focus on the actions of ovarian steroid hormones on PTGS2 regulation in the oviduct. Understanding of cellular PTGS2 function during early embryo development and transport in the oviduct will be an important step toward a better understanding of reproduction and may have potential implication in the assisted reproductive technology. [ABSTRACT FROM AUTHOR]

Summary: Prostaglandin D2 (PGD2) plays an important role in atopic dermatitis (AD), and 11,15‐dioxo‐9α‐hydroxy‐2,3,4,5‐tetranorprostan‐1,20‐dioicacid (PGDM) is a major metabolite of PGD2. We investigated the relationship between urinary PGDM levels and severity of paediatric AD. In total, 31 patients with AD and 21 healthy controls (HCs) without AD were recruited, and urinary PGDM levels were measured. Of the 31 patients with AD, 14 were reassessed for urinary PGDM after topical steroid therapy. There was no difference in urinary PGDM levels between patients with AD and HCs. Although there was a significant positive correlation between the SCORing Atopic Dermatitis (SCORAD) index and the serum level of thymus and activation‐regulated chemokine (TARC), the urinary PGDM levels did not correlate with either SCORAD or serum TARC. Moreover, both SCORAD and serum TARC were significantly improved by topical steroid therapy; however, urinary PGDM levels were not changed. In conclusion, the level of urinary PGD2 metabolites in children with AD is substantially the same as that in HCs even if the disease is severe. [ABSTRACT FROM AUTHOR]

The excreta of Trogopterus xanthipes (also called Wulingzhi in Chinese, WLZ) is a well-known traditional Chinese medicine used for the treatment of irregular menstruation in clinic. Few reports are available on the chemical profiling of WLZ. In this work, qualitative and quantitative analyses of endogenous prostaglandin and hormones in WLZ were performed using UHPLC-orbitrap-MSn. In total, 48 compounds were identified in urine of T. xanthipes. Furthermore, the contents of four target compounds were simultaneously quantitated in 20 batches of samples by UPLC-MS/MS. The quantitative method showed a good linear correlation (R  > 0.995) in a wide range for each compound. The method had a high sensitivity with LOD (0.5–1.0 ng/mL) and LOQ (1.0–2.5 ng/mL). The intra- and inter-day precisions were < 9.17 (RSD %), and repeatability and stability were < 6.14 (RSD %). The recovery of the analytes varied between 85.8% and 97.3% at three different concentrations. The present integrated qualitative and quantitative assessment of WLZ provides an evaluation strategy to assess the constituent in traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

The excreta of Trogopterus xanthipes (also called Wulingzhi in Chinese, WLZ) is a well-known traditional Chinese medicine used for the treatment of irregular menstruation in clinic. Few reports are available on the chemical profiling of WLZ. In this work, qualitative and quantitative analyses of endogenous prostaglandin and hormones in WLZ were performed using UHPLC-orbitrap-MSn. In total, 48 compounds were identified in urine of T. xanthipes. Furthermore, the contents of four target compounds were simultaneously quantitated in 20 batches of samples by UPLC-MS/MS. The quantitative method showed a good linear correlation (R > 0.995) in a wide range for each compound. The method had a high sensitivity with LOD (0.5–1.0 ng/mL) and LOQ (1.0–2.5 ng/mL). The intra- and inter-day precisions were < 9.17 (RSD %), and repeatability and stability were < 6.14 (RSD %). The recovery of the analytes varied between 85.8% and 97.3% at three different concentrations. The present integrated qualitative and quantitative assessment of WLZ provides an evaluation strategy to assess the constituent in traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

Introduction Tobacco Heating System (THS) 2.2, a candidate modified-risk tobacco product, aims at offering an alternative to cigarettes for smokers while substantially reducing the exposure to harmful and potentially harmful constituents found in cigarette smoke. Methods One hundred and sixty healthy adult US smokers participated in this randomized, three-arm parallel group, controlled clinical study. Subjects were randomized in a 2:1:1 ratio to menthol Tobacco Heating System 2.2 (mTHS), menthol cigarette, or smoking abstinence for 5 days in confinement and 86 subsequent ambulatory days. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents (reported in our co-publication, Part 1) and biomarkers of potential harm (BOPH). Results Compliance (protocol and allocated product exposure) was 51% and 18% in the mTHS and smoking abstinence arms, respectively, on day 90. Nonetheless, favorable changes in BOPHs of lipid metabolism (total cholesterol and high- and low-density cholesterol), endothelial dysfunction (soluble intercellular adhesion molecule-1), oxidative stress (8-epi-prostaglandin F2α), and cardiovascular risk factors (eg, high-sensitivity C-reactive protein) were observed in the mTHS group. Favorable effects in other BOPHs, including ones related to platelet activation (11-dehydrothromboxane B2) and metabolic syndrome (glucose), were more pronounced in normal weight subjects. Conclusions The results suggest that the reduced exposure demonstrated when switching to mTHS is associated with overall improvements in BOPHs, which are indicative of pathomechanistic pathways underlying the development of smoking-related diseases, with some stronger effects in normal weight subjects. Implications Switching to mTHS was associated with favorable changes for some BOPHs indicative of biological pathway alterations (eg, oxidative stress and endothelial dysfunction). The results suggest that switching to mTHS has the potential to reduce the adverse health effects of smoking and ultimately the risk of smoking-related diseases. Switching to mTHS for 90 days led to reductions in a number of biomarkers of exposure in smokers, relative to those who continued smoking cigarettes, which were close to those observed when stopping smoking (reported in our co-publication, Part 1). Initial findings suggest reduced levels of 8-epi-prostaglandin F2α and intercellular adhesion molecule 1, when switching to mTHS for 90 days. These changes are comparable to what is observed upon smoking cessation. In normal weight subjects, additional favorable changes were seen in 11-dehydrothromboxane B2, fibrinogen, homocysteine, hs-CRP, percentage of predicted forced expiratory volume in 1 second, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, apolipoprotein A1, and triglycerides. Trial registration NCT01989156. [ABSTRACT FROM AUTHOR]

Introduction: In recent years, therapeutic approaches for treating vasculogenic Erectile Dysfunction (ED) have evolved, with Low Intensity Shock Wave Therapy (LISWT) emerging as a promising modality. Objective: To objectively evaluate the efficacy of LISWT for ED patients and to predict the required number of sessions, we examined the effects of administering up to 10 mcg of intracavernous alprostadil injections both before and after treatment Methods: 85 vasculogenic ED patients (Average age: 57); 33 with mild to moderate ED and 52 with moderate or severe ED. Intracavernous injection (ICI) of ≤10 mcg of alprostadil was given before LISWT and one month post-treatment. Depending on ICI response, patients underwent either six (Erection Hardness Score (EHS) ≤3) or four (EHS=4) weekly LISWT sessions using PiezoWave2 from Richard WOLF. LISWT Parameters: 0.16mj/mm2 energy flux density, 8 Hz frequency, 10mm wave focus penetration depth, and 6000 shocks per session distributed among the two crura of the penis (2000 shocks), dorsum penis (2000 shocks), and lateral penis (2000 shocks). Results: 33 patients showed a robust response to the 10mcg ICI and were treated with four LISWT sessions. 52 patients exhibited a partial response to the 10mcg ICI, necessitating six LISWT sessions. 78.6% (26 out of 33) of the patients who initially responded well to 10 mcg ICI had a consistent response to 8 mcg ICI; 63.6% (33 out of 52) of those with a partial initial response to 10 mcg ICI demonstrated an improved reaction to the same dosage post-treatment (table 1) (fig. 1). No complications were reported from the ICI. Conclusions: Intracavernous prostaglandin injection can serve as a predictor for the required number of LISWT sessions and can objectively gauge the treatment's effectiveness in ED patients. Further randomized studies, incorporating parameters such as EHS, IIEF, and the ICI dosage, are recommended to validate this method's feasibility Disclosure: No. [ABSTRACT FROM AUTHOR]

An experiment was designed to evaluate modifications to the 7 & 7 synch protocol with the hypothesis that tandem administration of prostaglandin F2a (PG) and gonadotropin-releasing hormone (GnRH) during the presynchronization portion of the protocol would generate a convergent ovarian response among anestrous and estrous cycling females. Nulliparous (n = 153), primiparous (n = 92), and multiparous (n = 413) Angus-cross females across four locations were blocked based on parity and pre-treatment cyclicity status (presence or absence of a corpus luteum) as assessed via transrectal ovarian ultrasonography. Within block, females were randomly assigned to one of three treatments. Females assigned to the 7 & 7 Synch treatment received an intravaginal progesterone-releasing insert (CIDR) and administration of PG on day 0, administration of GnRH on day 7, and administration of PG coincident with CIDR removal on day 14. Females assigned to 7 & 7 Synch + G received the same treatment schedule with the modification that GnRH was administered in tandem with the PG on day 0. Females assigned to 7 & 7 Synch + G + P received GnRH in tandem with PG on both day 0 and day 7 of the treatment schedule. Fixed-time artificial insemination (FTAI) was performed at 54 h after CIDR removal for nulliparous females and at 66 h for primiparous and multiparous females. Transrectal ovarian ultrasonography was performed on day 7 and day 14 to characterize the largest follicle diameter (LFD) as well as the presence/absence and number of corpora lutea (CL). Expression of estrus before FTAI was characterized in three locations using estrus detection patches (Estrotect. Approximately 75 to 90 days after FTAI, pregnancy status was determined via transrectal ultrasonography. Day 7 CL status was affected by treatment (P = 0.002), with a greater proportion of females presenting with CL on Day 7 when treated with the modified treatments (64%) as compared with the 7 & 7 Synch treatment (31%). Day 14 LFD was affected by treatment (P = 0.002), with a larger average LFD among females treated with 7 & 7 Synch + G + P (12.0 mm) as compared with 7 & 7 Synch (11.4 mm) or 7 & 7 + G (10.7 mm). Pregnancy rate to FTAI was affected by pre-treatment cyclicity status (P < 0.0001) and semen type (P = 0.0003) and tended to be affected by treatment (P = 0.09) with 7 & 7 Synch + G + P tending to result in a greater proportion pregnant (58.86%) as compared with 7 & 7 Synch (49.17%) and 7 & 7 Synch + G (48.79%). Tandem administration of GnRH and PG on days 0 and 7 of the 7 & 7 Synch protocol effectively generated a convergent ovarian response among anestrous and estrous cycling beef females and tended to result in increased pregnancy rates to FTAI. [ABSTRACT FROM AUTHOR]

Objectives: The colloquial terms "grower" and "shower" refer to those men whose penis change significantly without or with erection, and those whose penis don't. We aim to analyze the morphometric changes in the penis after prostaglandin injection, detect if there are different patterns and which factors might be related to those patterns. Methods: The retrospectively review a total of 225 patients from February 2021 to October 2022 who underwent penile ultrasonography with prostaglandin injection (10 mcg). Demographic, vascular and other relevant variables were recorded for analysis. A history of Peyronie disease or penile surgery (excluding postectomy and frenuloplasty) were exclusion criteria. We measured penile length (in cm) and tunica albuginea thickness (in mm) in flaccid and erect state. Only grade 3 of Erection Hardness Score (EHS) and EHS 4 were included. Results: Mean age 48 (range 17-98). Mean penis size (flaccid) 10.07cm (range 4-17). Mean SFLP (stretch flaccid penile length) 15.32 cm (range 10.4-19.7). Mean EPL (erect penile length) 14.37 cm (range 9-19.5) Median penile growth (PG) 42.6 % (range 3.57-264.1). PG has a normal distribution, based on 1 SD: PG<30.94% can be considered "shower". PG >55.73% can be considered "grower". Intermediate results would be the "grey area". "Growers" have a thinner albuginea (0,9 mm; p < 0,05) and a greater albuginea reduction (28%; p < 0,05) in erection compared to "showers" (1,2 mm and 16,2%) respectively. Conclusions: We have established growth ranges from which we can consider a penis grower, shower or grey zone. The size of the albuginea and its reduction during erection is related to the growth of the erect penis. Conflicts of Interest: Authors have no potential conflict of interest to report. [ABSTRACT FROM AUTHOR]

Background The clinical relevance of arachidonic acid (AA) metabolites in chronic kidney disease (CKD) progression is poorly understood. We aimed to compare the concentrations of 85 enzymatic pathway products of AA metabolism in patients with CKD who progressed to end-stage kidney disease (ESKD) versus patients who did not in a subcohort of Chronic Renal Insufficiency Cohort (CRIC) and to estimate the risk of CKD progression and major cardiovascular events by levels of AA metabolites and their link to enzymatic metabolic pathways. Methods A total 123 patients in the CRIC study who progressed to ESKD were frequency matched with 177 nonprogressors and serum eicosanoids were quantified by mass spectrometry. We applied serum collected at patients' Year 1 visit and outcome of progression to ESKD was ascertained over the next 10 years. We used logistic regression models for risk estimation. Results Baseline 15-hydroxyeicosatetraenoate (HETE) and 20-HETE levels were significantly elevated in progressors (false discovery rate Q  ≤ 0.026). The median 20-HETE level was 7.6 pmol/mL [interquartile range (IQR) 4.2–14.5] in progressors and 5.4 pmol/mL (IQR 2.8–9.4) in nonprogressors (P < 0.001). In an adjusted model, only 20-HETE independently predicted CKD progression. Each 1 standard deviation increase in 20-HETE was independently associated with 1.45-fold higher odds of progression (95% confidence interval 1.07–1.95; P = 0.017). Principal components of lipoxygenase (LOX) and cytochrome P450 (CYP450) pathways were independently associated with CKD progression. Conclusions We found higher odds of CKD progression associated with higher 20-HETE, LOX and CYP450 metabolic pathways. These alterations precede CKD progression and may serve as targets for interventions aimed at halting progression. [ABSTRACT FROM AUTHOR]

The article presents a study evaluating the effects of a high-concentration dose of prostaglandin F2α in a 5-d CO-Synch + controlled internal drug release protocol on fertility in beef cows. Topics discussed include ways in which Estrous synchronization is a useful management tool to facilitate the use of fixed-time artificial insemination (AI) and improve fertility in beef herds; and addition of progesterone (P4) in the form of a controlled internal drug release (CIDR) device.

Prostaglandins (PGs) are lipid signaling molecules with numerous physiologic functions, including pain/inflammation, fertility, and cancer. PGs are produced downstream of cyclooxygenase (COX) enzymes, the targets of non-steroidal anti-inflammatory drugs (NSAIDs). In numerous systems, PGs regulate actin cytoskeletal remodeling, however, their mechanisms of action remain largely unknown. To address this deficiency, we undertook a pharmaco-genetic interaction screen during late-stage Drosophila oogenesis. Drosophila oogenesis is as an established model for studying both actin dynamics and PGs. Indeed, during Stage 10B, cage-like arrays of actin bundles surround each nurse cell nucleus, and during Stage 11, the cortical actin contracts, squeezing the cytoplasmic contents into the oocyte. Both of these cytoskeletal properties are required for follicle development and fertility, and are regulated by PGs. Here we describe a pharmaco-genetic interaction screen that takes advantage of the fact that Stage 10B follicles will mature in culture and COX inhibitors, such as aspirin, block this in vitro follicle maturation. In the screen, aspirin was used at a concentration that blocks 50% of the wild-type follicles from maturing in culture. By combining this aspirin treatment with heterozygosity for mutations in actin regulators, we quantitatively identified enhancers and suppressors of COX inhibition. Here we present the screen results and initial follow-up studies on three strong enhancers - Enabled, Capping protein, and non-muscle Myosin II Regulatory Light Chain. Overall, these studies provide new insight into how PGs regulate both actin bundle formation and cellular contraction, properties that are not only essential for development, but are misregulated in disease. [ABSTRACT FROM AUTHOR]

Chronic inflammation and oxidative stress play pivotal roles in the pathogenesis of hepatocellular carcinoma (HCC). We conducted a nested case–control study of 347 HCC cases and 691 matched controls within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8- epi -prostaglandin F2α (8- epi -PGF2α), a biomarker of oxidative stress, and prostaglandin E2 (PGE2) metabolite (PGE-M), a biomarker of the inflammation mediator PGE2, were determined in baseline urine samples using validated mass spectrometry assays. 8- epi- PGF2α levels were significantly higher in HCC cases than control subjects (geometric means 0.92 versus 0.80 pmol/mg creatinine, P < 0.001). The relative risks of developing HCC for the highest relative to the lowest quartile of 8- epi- PGF2α were 2.55 (95% confidence interval = 1.62–4.01, P trend < 0.001). This positive 8- epi -PGF2α–HCC risk association was independent of smoking status, alcohol consumption and hepatitis B or liver cirrhosis and was present 10 years before the clinical manifestation of HCC. This study did not find any significant association between urinary PEG-M and HCC risk. This study provides direct evidence in support of the critical role of oxidative stress in the development of HCC regardless of its underlying causes. [ABSTRACT FROM AUTHOR]

Background: Cancer cells from different origins exhibit various basal redox statuses and thus respond differently to intrinsic or extrinsic oxidative stress. These intricate characteristics condition the success of redox-based anticancer therapies that capitalize on the ability of reactive oxygen species to achieve selective and efficient cancer cell killing.Methods: Redox biology methods, stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics, and bioinformatics pattern comparisons were used to decipher the underlying mechanisms for differential response of lung and breast cancer cell models to redox-modulating molecule auranofin (AUF) and to combinations of AUF and vitamin C (VC). The in vivo effect of AUF, VC, and two AUF/VC combinations on mice bearing MDA-MB-231 xenografts (n = 5 mice per group) was also evaluated. All statistical tests were two-sided.Results: AUF targeted simultaneously the thioredoxin and glutathione antioxidant systems. AUF/VC combinations exerted a synergistic and hydrogen peroxide (H2O2)-mediated cytotoxicity toward MDA-MB-231 cells and other breast cancer cell lines. The anticancer potential of AUF/VC combinations was validated in vivo on MDA-MB-231 xenografts in mice without notable side effects. On day 14 of treatments, mean (SD) tumor volumes for the vehicle-treated control group and the two AUF/VC combination-treated groups (A/V1 and A/V2) were 197.67 (24.28) mm3, 15.66 (10.90) mm3, and 10.23 (7.30)mm3, respectively; adjusted P values of the differences between mean tumor volumes of vehicle vs A/V1 groups and vehicle vs A/V2 groups were both less than .001. SILAC proteomics, bioinformatics analysis, and functional experiments linked prostaglandin reductase 1 (PTGR1) expression levels with breast cancer cell sensitivity to AUF/VC combinations.Conclusion: The combination of AUF and VC, two commonly available drugs, could be efficient against triple-negative breast cancer and potentially other cancers with similar redox properties and PTGR1 expression levels. The redox-based anticancer activity of this combination and the discriminatory potential of PTGR1 expression are worth further assessment in preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

Study Question: Does the uterine vasculature play a localized role in promoting stromal cell decidualization in the human endometrium?Summary Answer: Our study demonstrated that hemodynamic forces induced secretion of specific endothelial cell-derived prostanoids that enhanced endometrial perivascular decidualization via a paracrine mechanism.What Is Known Already: Differentiation of stromal cell fibroblasts into the specialized decidua of the placenta is a progesterone-dependent process; however, histologically, it has long been noted that the first morphological signs of decidualization appear in the perivascular stroma. These observations suggest that the human endometrial vasculature plays an active role in promoting stromal differentiation.Study Design, Size, Duration: Primary human endometrial stromal cells were co-cultured for 14 days with primary uterine microvascular endothelial cells within a microfluidic Organ-on-Chip model of the endometrium.Participants/materials, Setting, Methods: Cultures were maintained with estradiol and a progestin, with or without continuous laminar perfusion to mimic hemodynamic forces derived from the blood flow. Some cultures additionally received exogenous agonist-mediated challenges. Decidualization in the microfluidic model was assessed morphologically and biochemically. ELISA was used to examine the culture effluent for expression of decidualization markers and prostaglandins. Immunofluorescence was used to monitor cyclooxygenase-2 expression in association with decidualization.Main Results and the Role Of Chance: A significantly enhanced stromal decidualization response was observed in the co-cultures when the endothelial cells were stimulated with hemodynamic forces (e.g. laminar shear stress) derived from controlled microfluidic perfusion (<0.001). Furthermore, the enhanced progestin-driven stromal differentiation was mediated via cyclooxygenase-2 and the paracrine action of prostaglandin E2 and prostacyclin. Altogether, these translational findings indicate that the vascular endothelium plays a key physiologic role during the early events of perivascular decidualization in the human endometrium.Large Scale Data: N/A.Limitations, Reasons For Caution: This report is largely an in vitro study. Although we were able to experimentally mimic hemodynamic forces in our microfluidic model, we have not yet determined the contribution of additional cell types to the decidualization process or determined the precise physiological rates of shear stress that the microvasculature of the endometrium undergoes in vivo.Wider Implications Of the Findings: Identification of specific endothelial-derived prostaglandins and their role during endometrial reproductive processes may have clinical utility as therapeutic targets for reproductive disorders such as infertility, endometriosis, adenomyosis, pre-eclampsia and poor pregnancy outcomes.Study Funding/competing Interest(s): This work was supported by the Veterans Affairs (I01 BX002853), the Bill and Melinda Gates Foundation Grand Challenges Exploration (OPP1159411), the Environmental Toxicology Training Grant (NIH T32 ES007028) and the Environmental Protection Agency STAR Center Grant (83573601).Conflict Of Interest: The authors report no conflicts of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Cyclooxygenases are responsible for the production of prostaglandin H2 (PGH2) from arachidonic acid. PGH2 can be converted into some bioactive prostaglandins, including prostaglandin F2α (PGF2α), a potent chemical messenger used as a biological regulator in the fields of obstetrics and gynecology. The chemical messenger PGF2α has been industrially produced by chemical synthesis. To develop a biotechnological process, in which PGF2α can be produced by a microorganism, we transformed an oleaginous fungus, Mortierella alpina 1S-4, rich in triacylglycerol consisting of arachidonic acid using a cyclooxygenase gene from a red alga, Gracilaria vermiculophylla. PGF2α was accumulated not only in the mycelia of the transformants but also in the extracellular medium. After 12 days of cultivation approximately 860 ng/g and 6421 µg/L of PGF2α were accumulated in mycelia and the extracellular medium, respectively. The results could facilitate the development of novel fermentative methods for the production of prostanoids using an oleaginous fungus. [ABSTRACT FROM AUTHOR]

Background Obesity is associated with increased severity of influenza infection. However, the underlying mechanism is largely unknown. Methods We employed a mouse model with diet-induced obesity (DIO) to study the innate immune responses induced by influenza virus. Results The lungs of DIO mice were heavily affected by obesity-associated chronic systemic inflammation with a significant increase in inflammatory cytokines/chemokines. Concurrently, lipid immune mediator prostaglandin E2 (PGE2) was also significantly elevated in DIO mice. However, the DIO mice mounted a blunted and delayed upregulation of mRNA and protein concentrations of interferon-β and inflammatory cytokines/chemokines upon A(H1N1)pdm09 virus (H1N1/415742Md) challenge compared with those of lean mice. PGE2 concentrations were significantly higher in the lungs of DIO mice compared to that of lean mice postchallenge. Treatment with paracetamol in challenged DIO mice significantly enhanced the expression of interferon-α/β and cytokine genes at days 1 and 3 postinfection compared with that of untreated DIO mice. Furthermore, paracetamol treatment alone started 3 days before virus challenge and continued until 6 days postchallenge ameliorated the severity of a lethal H1N1/415742Md infection in DIO mice with improved survival. Conclusions Impaired innate response to influenza in DIO mice is associated with elevated PGE2, which could be restored to some degree by paracetamol treatment. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) may cause lipid peroxidation via reactive oxygen species generation. 15-F2t-isoprostane (IsoP), an oxidative stress marker, is formed from arachidonic acid (AA) by a free-radical induced oxidation. AA may also be converted to prostaglandins (PG) by prostaglandin-endoperoxide synthase (PTGS) induced by NF-κB. We treated human embryonic lung fibroblasts (HEL12469) with benzo[a]pyrene (B[a]P), 3-nitrobenzanthrone (3-NBA) and extractable organic matter (EOM) from ambient air particulate matter <2.5 µm for 4 and 24 h. B[a]P and 3-NBA induced expression of PAH metabolising, but not antioxidant enzymes. The concentrations of IsoP decreased, whereas the levels of AA tended to increase. Although the activity of NF-κB was not detected, the tested compounds affected the expression of prostaglandin-endoperoxide synthase 2 (PTGS2). The levels of prostaglandin E2 (PGE2) decreased following exposure to B[a]P, whereas 3-NBA exposure tended to increase PGE2 concentration. A distinct response was observed after EOM exposure: expression of PAH-metabolising enzymes was induced, IsoP levels increased after 24-h treatment but AA concentration was not affected. The activity of NF-κB increased after both exposure periods, and a significant induction of PTGS2 expression was found following 4-h treatment. Similarly to PAHs, the EOM exposure was associated with a decrease of PGE2 levels. In summary, exposure to PAHs with low pro-oxidant potential results in a decrease of IsoP levels implying 'antioxidant' properties. For such compounds, IsoP may not be a suitable marker of lipid peroxidation. [ABSTRACT FROM AUTHOR]

The objective of this experiment was to assess the effects of eprinomectin, an extended-release injectable parasiticide, on fescue toxicosis and its impacts on beef heifer performance and reproduction. Fall-born Angus × Simmental heifers (age = 246.3 ± 22.4 d; 264.8 ± 21.1 kg body weight [BW]) were randomly assigned to one of two treatments: extended-release eprinomectin injection (ERE; n = 100) or control (CON; saline; n = 99). Treatments were administered at a rate of 1 mL/50 kg BW. Prior to experiment, heifers were dosed with oral fenbendazole to minimize parasite load. All heifers grazed endophyte-infected tall fescue as a single group and were offered a 50:50 supplement mix of corn gluten feed and soybean hulls (2.7 kg as fed per heifer per day). Body condition scores (BCS), BW, hair coat score (HCS), blood, and fecal samples were collected throughout the experiment. A subset of 40 heifers were randomly selected (20 per treatment) to assess respiration rate (RR). On d 138, heifers began a 14-d controlled internal drug release + prostaglandin synchronization protocol. Following artificial insemination (AI), heifers were exposed to five bulls for 71 d. On d 214 and 291, AI and overall pregnancy rates, respectively, were determined. There was a treatment × time interaction (P < 0.01) for BW, BCS, and average daily gain (ADG). The ERE heifers had greater (P < 0.04) BW and BCS compared to CON heifers from d 55 and 112, respectively. In addition, ERE heifers had greater (P ≤ 0.04) ADG from d 0 to 56, 56 to 112, 112 to 171, and 171 to 214; however CON heifers had greater (P < 0.01) ADG from d 214 to 291. There was no treatment × time interaction or treatment difference (P ≥ 0.27) for HCS, RR, and serum prolactin concentrations. However, serum prolactin decreased (P < 0.01) in all heifers over time. There was a treatment × time interaction (P< 0.01) for fecal egg counts (FEC). The FEC did not differ (P ≥ 0.32) on d −1 or 55; however, ERE heifers had decreased (P < 0.01) FEC compared with CON heifers on d 111 (1.52 vs. 13.56 eggs per gram). The ERE heifers tended (P = 0.10) to have greater AI pregnancy rates (69% vs. 58%) and had greater (P = 0.01) overall pregnancy rates (84% vs. 68%) than CON heifers. Spring administration of extended-release eprinomectin improved BW, ADG, BCS, and AI and overall pregnancy rates in fall-born beef heifers. However, the underlying mechanism is still unclear, as there were minimal to no differences in HCS, RR, serum prolactin, and FEC. [ABSTRACT FROM AUTHOR]

Forty years ago, 12-oxophytodienoic acid (12-OPDA) was reported as a prostaglandin (PG)-like metabolite of linolenic acid found in extracts of flaxseed. Since then, numerous studies have determined the role of 12-OPDA in regulating plant immunity, seed dormancy, and germination. This review summarizes our current knowledge of the regulation of 12-OPDA synthesis in the chloroplast and 12-OPDA-dependent signaling in gene expression and targeting protein functions. We describe the properties of OPDA that are linked to the activities of PGs, which are derived from arachidonic acid and act as tissue hormones in animals, including humans. The similarity of OPDA with bioactive PGs is particularly evident for the most-studied cyclopentenone, PG 15-dPGJ2. In addition to chemical approaches towards 12-OPDA synthesis, bio-organic synthesis strategies for 12-OPDA and analogous substances have recently been established. The resulting availability of OPDA will aid the identification of additional effector proteins, help in elucidating the mechanisms of OPDA sensing and transmission, and will foster the analysis of the physiological responses to OPDA in plants. There is a need to determine the compartmentation and transport of 12-OPDA and its conjugates, over long distances as well as short. It will be important to further study OPDA in animal and human cells, for example with respect to beneficial anti-inflammatory and anti-cancer activities. [ABSTRACT FROM AUTHOR]

Study Question: Does the chemosensory activation of CatSper Ca2+ channels in human sperm give rise to additive, sub-additive or even synergistic actions among agonists?Summary Answer: We show that oviductal ligands and endocrine disrupting chemicals (EDCs) activate human CatSper highly synergistically.What Is Known Already: In human sperm, the sperm-specific CatSper channel controls the intracellular Ca2+ concentration and, thereby, several crucial stages toward fertilization. CatSper is activated by oviductal ligands and structurally diverse EDCs. The chemicals mimic the action of the physiological ligands, which might interfere with the precisely coordinated sequence of events underlying fertilization.Study Design, Size, Duration: For both oviductal ligands and EDCs, we examined in quantitative terms whether stimulation of human sperm in vitro with mixtures results in additive, sub-additive or synergistic actions.Participants/materials, Setting, Methods: We studied activation of CatSper in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. The combined action of progesterone and prostaglandins and of the EDCs benzylidene camphor sulfonic acid (BCSA) and α-Zearalenol was evaluated by curve-shift analysis, curvilinear isobolographic analysis and the combination-index method.Main Results and the Role Of Chance: Analysis of the action of progesterone/prostaglandin and BCSA/α-Zearalenol mixtures in human sperm by fluorimetry revealed that the oviductal ligands and EDCs both evoke Ca2+ influx via CatSper in a highly synergistic fashion. Patch-clamp recordings of CatSper currents in human sperm corroborated the synergistic ligand-activation of the channel.Limitations, Reasons For Caution: This is an in vitro study. Future studies have to assess the physiological relevance in vivo.Wider Implications Of the Findings: These findings indicate that the fertilization process is orchestrated by multiple oviductal CatSper agonists that act in concert to control the behavior of sperm. Moreover, our results substantiate the concerns regarding the negative impact of EDCs on male reproductive health. So far, safety thresholds like the "No Observed Adverse Effect Level (NOAEL)" or "No Observed Effect Concentration (NOEC)" are set for individual EDCs. Our finding that EDCs act synergistically in human sperm challenges the validity of this procedure.Study Funding/competing Interest(s): This work was supported by the German Research Foundation (SFB 645; CRU326), the Cells-in-Motion (CiM) Cluster of Excellence, Münster, (FF-2016-17), the 'Innovative Medical Research' of the University of Münster Medical School (BR121507), an EDMaRC research grant from the Kirsten and Freddy Johansen's Foundation, and the Innovation Fund Denmark (InnovationsFonden; 14-2013-4). The authors have no competing financial interests. [ABSTRACT FROM AUTHOR]

It has been hypothesized that the pathogenesis of lung cancer induced by cigarette smoking involves oxidative damage by free radicals. Epidemiological data on biomarkers of oxidative damage and risk of lung cancer development are sparse. A nested case-control study of 610 lung cancer cases and 610 matched controls was conducted within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8-epi-prostaglandin F2 (8-epiPGF2), a biomarker of oxidative stress, were determined in baseline urine samples using a validated mass-spectrometry assay. Current smokers had significantly higher level of 8-epiPGF2 than former smokers or never smokers (P < 0.001). 8-epiPGF2 levels were significantly higher in lung cancer cases than their smoking-matched controls in former and current smokers, but not different in never smokers (P for interaction = 0.019). The relative risks of developing lung cancer for former and current smokers in the highest relative to the lowest quartile of 8-epiPGF2 were 5.25 (P trend = 0.035) and 1.99 (P trend =0.007), respectively. The effect of 8-epiPGF2 and biomarkers of cigarette smoke exposure on lung cancer risk was additive; the relative risk was 5.33 (95% confidence interval = 2.65-7.51) for current smokers with the highest thirds of 8-epiPGF2 and total cotinine compared with their lowest thirds. Smokers with a heightened state of oxidative stress in response to the insults of cigarette smoking may be more susceptible to smoking-induced lung carcinogenesis. [ABSTRACT FROM AUTHOR]

The antitumor effect of prostaglandin D2 (PGD2) on gastric cancer (GC) has been known for decades. However, the mechanism of PGD2's control of GC growth is unclear. Cancer stem cells (CSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. Herein, we discovered that signaling between PGD2 and its receptor (PTGDR2) has the ability to restrict the self‐renewal of GC cells in vitro and suppress tumor growth and metastasis in vivo. To obtain these findings, we first determined that PGD2 synthase (L‐PTGDS) and PTGDR2 expression were lower in GC tissues than adjacent tissues and was associated with the patients' prognosis. Moreover, the expression of L‐PTGDS and PTGDR2 was negatively correlated with the GC‐CSC markers Sall4 and Lgr5 in GC tissues. Second, L‐PTGDS and PTGDR2 expression were knocked down in CSC‐like cells, resulting in enhanced expression of CSC markers and self‐renewal ability. Direct PGD2 stimulation and L‐PTGDS overexpression produced the opposite effect. Thirdly, PGD2 inhibited tumor growth and incidence rate in a subcutaneous tumor model and suppressed liver and mesenteric metastasis in a peritoneal metastasis model. Interfering with the expression of PTGDR2 reversed these effects in vivo. Last, a mechanistic study found that PGD2 inhibited STAT3 phosphorylation and nuclear expression. Further experiments revealed that the inhibitory effect of PGD2 on the expression of CSC markers disappeared after mutations were introduced into STAT3 phosphorylation (Thr705) site. In short, this study reveals a novel function of PGD2/PTGDR2 signaling on CSC regulation and provides a new way to control the development of GC. Stem Cells2018;36:990–1003 [ABSTRACT FROM AUTHOR]

In Mycobacterium tuberculosis-infected macrophages, cyclooxygenase-2 (COX-2) expression considerably increases to defend the body against mycobacteria by regulating adaptive immunity and restoring the mitochondrial inner membrane. Moreover, in cancer cells, COX-2 enhances the autophagy machinery, an important bactericidal mechanism. However, the association between M. tuberculosis-induced COX-2 and autophagy-mediated antimycobacterial response has not been explored. Here, COX-2 expression silencing reduced the autophagy and bactericidal activity against intracellular M. tuberculosis, while COX-2 overexpression reversed the above effects. In addition, enhancement of bactericidal activity was suppressed by inhibiting autophagy in COX-2-overexpressing cells, indicating that COX-2 accelerated mycobacterial elimination by promoting autophagy. Furthermore, the regulatory effects of COX-2 on autophagy were mediated by its catalytic products, which functioned through inhibiting the protein kinase B/mammalian target of rapamycin pathway. Thus, COX-2 contributes to host defense against mycobacterial infection by promoting autophagy, establishing the basis for development of novel therapeutic agents against tuberculosis by targeting COX-2. [ABSTRACT FROM AUTHOR]

A series of experiments was designed to evaluate treatment schedules for control of the estrous cycle in which luteolysis is induced before atresia of the first follicular wave following a long-term progestin presynchronization treatment in beef heifers. The central hypothesis was that the proportion of heifers undergoing luteolysis and expressing estrus following PG administration would be affected by the duration of treatment with an intravaginal progesteronereleasing insert (CIDR; 1.38 g progesterone) and/or by the interval from CIDR removal to prostaglandin F2α (PG; 500 μg cloprostenol) administration. In each experiment, heifers were blocked by reproductive tract score and body weight and assigned randomly within block to treatment. In Experiment 1, heifers (n = 91) were assigned to one of four treatments in a 2 x 2 factorial design: presynchronization via CIDR treatment for either 14 d or 18 d with administration of PG either 8 d or 9 d following CIDR removal. In Experiment 2, heifers (n = 63) were assigned to receive administration of PG either 9 d or 10 d following a 14 d CIDR presynchronization. In Experiment 3, heifers (n = 83) were assigned to receive administration of PG either 9 d or 16 d following a 14 d CIDR presynchronization. In Experiments 1 and 2, heifers were artificially insemination (AI) 8 to 12 h after expressing estrus, with timed AI performed 96 h after PG administration for heifers failing to express estrus. In Experiment 3, heifers expressing estrus by 66 h after PG administration were inseminated at that time and all remaining heifers were inseminated at 90 h. In Experiment 1, there was a tendency for a greater proportion of heifers to express estrus by 96 h after PG administration when PG administration occurred 9 d versus 8 d after CIDR removal (P = 0.07). Additionally, serum estradiol concentrations were greater at the time of PG administration when PG was administered 9 d versus 8 d after CIDR removal following an 18 d CIDR treatment (P = 0.006). In Experiment 2, pregnancy rate to AI (P/AI) was greater among heifers receiving PG administration 9 d versus 10 d after CIDR removal (P = 0.03). There was a tendency for largest follicle diameter measured at timed AI to be greater among non-estrous heifers receiving PG administration 10 d versus 9 d after CIDR removal (P < 0.08). In Experiment 3, there was a tendency for serum progesterone concentrations at the time of PG administration to be greater among heifers receiving PG administration 16 d versus 9 d after CIDR removal (P = 0.07). These results provide a preliminary evaluation of the feasibility of inducing luteolysis before atresia of the first follicular wave following long-term progestin presynchronization. [ABSTRACT FROM AUTHOR]

Administration of a single injection of prostaglandin after ram introduction has previously been reported as an effective method to synchronize estrus in ewes housed in a dry lot setting. The objective of this study was to investigate the effectiveness of a single injection of prostaglandin administered at the beginning of the breeding season after ram introduction, on estrus synchronization in range ewes. Western Whiteface cross ewes, of which thirty-six were ½ blood South African Meat Merino (SAMM) and seventeen ¼ blood SAMM (total n=53) were assigned to one of two treatments: control (CON; n=26) or one injection of prostaglandin (PG; n=27). Ewes were utilized in a complete randomized block design and were stratified by SAMM percentage, body condition score (BCS) and age. Ewes assigned to PG treatment were administered 3 mL of prostaglandin IM (Lutalyse, Zoetis Animal Health) approximately 60 h after rams were introduced with ewes. Rams (n=4) were applied with marking paint and placed with ewes on (d 0: December 21) and remained for the duration of the 56 d breeding season for natural service. Ewes were observed for estrus twice daily at 0730 h and 1700 h for d 0-10 and d 16-21 of the breeding season, by an experienced evaluator. At lambing, birth weight, sex, and type of birth was recorded. The MIXED and GLIMMIX procedures of SAS were used to analyze estrus response, ewes bred in the first 5 d of the breeding season, days to lambing, lambing date, number of lambs born, and lamb weight. South African Meat Merino percentage was included as an independent variable but was found to be nonsignificant and was removed from the statistical model. The proportion of ewes bred during the first 5 d of the breeding season was not different among the two treatments (P ≥ 0.60). There was no difference between the PG ewes and the CON ewes for the date of estrus (P ≥ 0.82). There was no difference between the PG ewes and the CON ewes for the lambing date (P = 0.60). Treatment did not influence days to lambing (P ≥ 0.25). The number of lambs born per ewe tended to be influenced by treatment (P < 0.08), with PG ewes tending to have more lambs than CON ewes. Lamb weights were not different among treatments (P ≥ 0.50). In conclusion, the administration of a single PG injection after ram exposure did not influence estrus expression, days to lambing, or lambing date, however, PG ewes did tend to have more lambs. [ABSTRACT FROM AUTHOR]

Introduction: Modified-risk tobacco products are expected to reduce exposure to harmful and potentially harmful constituents of cigarette smoke, and ultimately reduce the health burden of smoking-related diseases. Clinically relevant risk markers of smoking-related diseases inform about the risk profile of new tobacco products in the absence of in-market epidemiological data. The menthol Tobacco Heating System 2.2 (mTHS) is a modified-risk tobacco product in development as an alternative to cigarettes (conventional cigarettes [CCs]).Methods: In this parallel-group study, Japanese adult smokers (23-65 years; ≥10 mCCs/day) were randomized to mTHS, menthol CCs (mCC), or smoking abstinence (SA) for 5 days in confinement and 85 days in ambulatory settings. Endpoints included biomarkers of exposure to harmful and potentially harmful constituents and clinically relevant risk markers of smoking-related diseases.Results: One-hundred and sixty participants were randomized to the mTHS (n = 78), mCC (n = 42), and SA (n = 40) groups. Switching to the mTHS was associated with reductions in biomarkers of exposure compared with continuing mCCs. Reductions in 8-epi-prostaglandin F2α (biomarker of oxidative stress), 11-dehydro-thromboxane B2 (biomarker of platelet activation), soluble intracellular adhesion molecule-1 (biomarker of endothelial function), and an increase in high-density lipoprotein cholesterol (biomarker of lipid metabolism) and forced expiratory volume in 1 second (biomarker of lung function) occurred in the mTHS group compared with the mCC group. The changes in the mTHS group approached those in the SA group.Conclusions: Switching from mCCs to mTHS was associated with improvements in clinically relevant risk markers linked to mechanistic pathways involved in smoking-related diseases.Implications: In this three-way randomized study, switching from menthol cigarettes to mTHS for 5 days in confinement and 85 days in ambulatory settings was associated with reductions in biomarkers of exposure to cigarette smoke, and changes were observed in clinically relevant biomarkers of oxidative stress (8-epi-prostaglandin F2α), platelet activity (11-dehydro-thromboxane B2), endothelial function (soluble intracellular adhesion molecule-1), lipid metabolism (high-density lipoprotein cholesterol) and lung function (forced expiratory volume in 1 second), similar to the SA group. The results suggest that switching to the mTHS has the potential to reduce the adverse health effects of conventional cigarettes. [ABSTRACT FROM AUTHOR]

Background: Prostaglandin (PG) D2 is the most abundant prostaglandin in the mammalian brain. The physiological and pharmacological actions of PGD2 in the central nervous system seem to be associated with some of the symptoms exhibited by patients with major depressive disorder. Previous studies have found that PGD2 synthase was decreased in the cerebrospinal fluid of major depressive disorder patients. We speculated that there may be a dysregulation of PGD2 levels in major depressive disorder. Methods: Ultra-performance liquid chromatography-tandem mass spectrometry coupled with a stable isotopic-labeled internal standard was used to determine PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice. A total of 32 drug-free major depressive disorder patients and 30 healthy controls were recruited. An animal model of depression was constructed by exposing mice to 5 weeks of chronic unpredictable mild stress. To explore the role of PGD2 in major depressive disorder, selenium tetrachloride was administered to simulate the change in PGD2 levels in mice. Results: Mice exposed to chronic unpredictable mild stress exhibited depression-like behaviors, as indicated by reduced sucrose preference and increased immobility time in the forced swimming test. PGD2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice were both decreased compared with their corresponding controls. Further inhibiting PGD2 production in mice resulted in an increased immobility time in the forced swimming test that could be reversed by imipramine. Conclusion: Decreased PGD2 levels in major depressive disorder are associated with depression-like behaviors. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Acute pulmonary hypertension following cardiac surgery can have a significant effect on postoperative morbidity and mortality. However, limited data are available on the efficacy and potency of clinically used systemic vasopressors on the pulmonary vasculature. The aim of this study was to use human pulmonary artery to characterize the pharmacological effects of clinically used vasopressors on the human pulmonary vasculature. METHODS: Fifty-seven pulmonary artery rings of internal diameter 2–4mm and 2mm long, mounted in a multiwire myograph system, were used to measure changes in isometric tension. We constructed concentration response curves by cumulative addition to the myograph chambers of KCl, noradrenaline (NA), adrenaline (AD), vasopressin, endothelin-1 (ET-1) and prostaglandin F2a (PGF2a). RESULTS: AD, NA, ET-1, PGF2a and KCl caused dose-dependent vasoconstriction in the pulmonary artery samples (EC50 246nM [95% confidence interval, CI, 153–394 nM], 150nM [95% CI 51–447 nM], 1.46nM [95% CI 0.69–3.1 nM], 6.35 μM [95% CI 3.58–11.2 μM] and 17.24mM [95% CI 12.43–24.07 mM], respectively), whereas vasopressin had no significant effect. The order of efficacy was KCl = PGF2a > AD> NA> ET-1 and the order of potency was ET-1 T-AD =NA > PGF2a > KCl. CONCLUSIONS: This study demonstrated the efficacy and potency of clinically used vasopressors and endogenous vasopressors on human pulmonary vascular tone. PGF2a and KCl equally caused maximal amounts of constriction, whereas ET-1 had less effect and vasopressin had no effect. These effects may need to be taken into account in the clinical setting because they might result in the development of pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Cyclooxygenase (COX) inhibitors are ubiquitous in aquatic systems and have been detected in fish tissues. The exposure of fish to these pharmaceuticals is concerning because COX inhibitors disrupt the synthesis of prostaglandins (PGs), which modulate a variety of essential biological functions, including reproduction. In this study, we investigated the effects of wellcharacterizedmammalian COX inhibitors on female fatheadminnow reproductive health. Fish (n=8) were exposed for 96h to water containing indomethacin (IN; 100 μg/l), ibuprofen (IB; 200 mg/l) or celecoxib (CX; 20 μg/l), and evaluated for effects on livermetabolome and ovarian gene expression. Metabolomic profiles of IN, IB and CX were not significantly different from control or one another. Exposure to IB and CX resulted in differential expression of comparable numbers of genes (IB=433, CX=545). In contrast, 2558 genes were differentially expressed in IN-treated fish. Functional analyses (canonical pathway and gene set enrichment) indicated extensive effects of IN on PG synthesis pathway, oocyte meiosis, and several other processes consistent with physiological roles of PGs. Transcriptomic data were congruent with PG data; IN-reduced plasma PG F2a concentration, whereas IB and CX did not. Five putative AOPs were developed linking the assumedmolecular initiating event of COX inhibition, with PG reduction and the adverse outcome of reproductive failure via reduction of: (1) ovulation, (2) reproductive behaviorsmediated by exogenous or endogenous PGs, and (3) oocytematuration in fish. These pathways were developed using, in part, empirical data fromthe present study and other publicly available data. [ABSTRACT FROM AUTHOR]

Objectives: EHS 3 is defined like: "Penis is hard enough for penetration, but not completely hard" and EHS 4 is defined like: "Penis is completely hard and fully rigid". In both cases we speak of penile hardness but not of penile size. We aim to analyze if there are significant differences between penile growth in ESH 3 and EHS 4 Methods: We retrospectively review a total of 225 patients from February 2021 to October 2022 who underwent penile ultrasonography with prostaglandin injection (10 mcg). Demographic, vascular and other relevant variables were recorded for analysis. A history of Peyronie disease or penile surgery (excluding postectomy and frenuloplasty) were exclusion criteria. We measured the penile length (in cm) in the flaccid state. After injecting prostaglandin, penile measures were taken only EHS 3 and EHS 4 were included. Results: Mean age 48 (range 17-98). Mean penis size (flaccid) 10.07cm (range 4-17). Mean erect penile length (EPL) 14.37 (range 9.0-19.5). Mean EPL (EHS 3) 14.05 (range 9.0-19.5). Mean EPL (EHS 4) 14.76 (range 11.0-19.0). Mean penile growth (EHS 3) 42.3 % (range 1.8-279.5) Mean penile growth (EHS 4) 48.5% (range 1.5-107.2). The Mann-Whitney U test indicates that the difference between penile growth in EHS 3 compared to EHS 4 is statistically significant (p < 0.05). However, difference in growth between EHS3 and EHS 4 is only 6.2%. Conclusions: Differences in growth between EHS 3 and 4, although statistically significant, are not clinically relevant. Penile growth evaluation could be done together in EHS 3 and 4. Conflicts of Interest: Authors have no potential conflict of interest to report. [ABSTRACT FROM AUTHOR]

Common cyclooxygenase (COX)-inhibiting drugs enhance resistance exercise induced muscle mass and strength gains in older individuals. The purpose of this investigation was to determine whether the underlying mechanism regulating this effect was specific to Type I or Type II muscle fibers, which have different contractile and metabolic profiles. Muscle biopsies (vastus lateralis) were obtained before and after 12 weeks of knee-extensor resistance exercise (3 days/week) from healthy older men who consumed either a placebo (n = 8; 64±2 years) or COX inhibitor (acetaminophen, 4 gram/day; n = 7; 64±1 years) in double-blind fashion. Muscle samples were examined for Type I and II fiber cross-sectional area, capillarization, and metabolic enzyme activities (glycogen phosphorylase, citrate synthase, β-hydroxyacyl-CoA-dehydrogenase). Type I fiber size did not change with training in the placebo group (304±590 μm(2)) but increased 28% in the COX inhibitor group (1,388±760 μm(2), p < .1). Type II fiber size increased 26% in the placebo group (1,432±499 μm(2), p < .05) and 37% in the COX inhibitor group (1,825±400 μm(2), p < .05). Muscle capillarization and enzyme activity were generally maintained in the placebo group. However, capillary to fiber ratio increased 24% (p < .1) and citrate synthase activity increased 18% (p < .05) in the COX inhibitor group. COX inhibitor consumption during resistance exercise in older individuals enhances myocellular growth, and this effect is more pronounced in Type I muscle fibers. [ABSTRACT FROM AUTHOR]

A novel, simple, sensitive and stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the quantitative determination of the geometric isomer (Trans) and other related substances in the active pharmaceutical ingredient (API) of Tafluprost (TFL), with their determination by an assay. A chromatographic separation of TFL and its impurities was achieved with a C18 analytical column, using gradient elution with mobile phase A consisting of a mixture of water, methanol and orthophosphoric acid (900:100:1, v/v) and mobile phase B consisting of a mixture of acetonitrile and water (900:100, v/v). The instrumental settings included a flow rate of 1.0 mL/min for related substances and 1.2 mL/min for the assay, a column temperature of 50°C and a detector wavelength of 210 nm, using a photodiode array detector. TFL was exposed to thermal, photolytic, hydrolytic and oxidative stress conditions and the stressed samples were analyzed by the proposed method. Peak homogeneity data of TFL were obtained by using a photodiode array detector in the stressed sample chromatograms, which demonstrated the specificity of the method for estimation in the presence of degradants. The developed method was validated for parameters such as precision, accuracy, linearity, limit of detection, limit of quantification, ruggedness and robustness as per ICH guidelines. [ABSTRACT FROM AUTHOR]

Palytoxin (PLTX) is one of the most harmful marine toxins known so far. Although the ingestion of contaminated seafood is the most dangerous exposure route for humans, cutaneous and inhalational exposures are far more frequent, and can cause strong inflammatory reactions. However, little is known about the inflammatory events that follow the cutaneous exposure to the toxin. In this study, we investigated (1) the effects of both short (2 h) and long (24 h) term exposures of HaCaT keratinocytes to a sub-cytotoxic PLTX concentration on pro-inflammatory mediator gene expression and release and (2) the effect of PLTX-conditioned HaCaT cell media on undifferentiated (monocytes) and differentiated (macrophages; immature dendritic cells, iDCs; mature dendritic cells, mDCs) THP-1 cells. At 10−11 M, PLTX induced interleukin (IL)-6 and IL-8 release from HaCaT keratinocytes after 24 h of continuous exposure to the toxin, as well as after 23 h in toxin-free medium preceded by 1 h exposure to PLTX. Under the same experimental conditions, release of the inflammatory mediators prostaglandin-E2 and histamine was also found after both short and long exposures to the toxin. The conditioned media collected from HaCaT cells treated with PLTX increased the migration of the differentiated and undifferentiated THP-1 cells (potency rank order: monocytes ≥ iDCs > mDCs > macrophages) but did not induce cell differentiation. These results indicate that keratinocytes can be actively involved in the recruitment of inflammatory cells in response to cutaneous contact with PLTX. The lack of a significant effect on monocyte differentiation towards mature immune cells suggests that PLTX is endowed with irritant rather than sensitizing properties. [ABSTRACT FROM AUTHOR]

Unfettered inflammation is thought to play critical role in the development of different clinical forms of tegumentary leishmaniasis. Eicosanoids are potent mediators of inflammation and tightly associated with modulation of immune responses. In this cross-sectional exploratory study, we addressed whether targets from the eicosanoid biosynthetic pathway, assessed by multiplexed expression assays in lesion biopsy and plasma specimens, could highlight a distinct biosignature in patients with mucocutaneous leishmaniasis (MCL) or localized cutaneous leishmaniasis (LCL). Differences in immunopathogenesis between MCL and LCL may result from an imbalance between prostaglandins and leukotrienes, which may serve as targets for future host-directed therapies. [ABSTRACT FROM AUTHOR]