Comparing the tolerability of preservative-free tafluprost versus preserved latanoprost in the management of glaucoma and ocular hypertension - an observer blinded active-control trial.

BACKGROUND: Dry eye is a condition related to long-term topical eye therapy. We wish to evaluate the effectiveness and tolerability of preservative free prostaglandin drops versus benzalkonium chloride containing prostaglandin drops in the treatment of glaucoma. METHODS: Patients undergoing prostaglandin monotherapy underwent a washout period of at least 1 month after which baseline measurements of dry eye severity were taken. Patients were randomised to receive either 0.0015% tafluprost drops or 0.005% latanoprost preserved with 0.02% benzalkonium chloride. Repeat measurements were taken after a 2-month interval. RESULTS: Thirty-five patients completed randomised treatment. No significant difference between groups was found in objective and subjective measurements of dry eye severity. No significant difference was found in measurement of treatment effectiveness. CONCLUSION: Preservative-free and benzalkonium chloride-containing drops were found to be equally effective in lowering IOP with no significant difference in either subjective or objective measurements of dry eye severity.

Preservative-Free Fixed Combination of Tafluprost 0.0015% and Timolol 0.5% for Treatment-Naive Patients with Open-Angle Glaucoma.

PURPOSE: To assess efficacy, safety, and tolerability of the preservative-free (PF) fixed-dose combination (FC) of tafluprost 0.0015%/timolol 0.5% (PF tafluprost/timolol FC) in treatments-naive patients with primary open-angle glaucoma (POAG). METHODS: This was a retrospective, real-world clinical practice setting study that included 107 eyes of 107 subjects with POAG who had never been treated for glaucoma. All subjects were received PF tafluprost/timolol FC once daily. Intraocular pressure (IOP) levels were documented for each eye at the untreated baseline and up to 6 months after the initiation of medical treatment. All adverse events, including ocular and systemic adverse reactions, were recorded. Additionally, the reasons for medication discontinuations were thoroughly documented. RESULTS: A total of 32 POAG patients with high-baseline IOP (>21 mmHg) and 75 with normal-baseline IOP were included in the study. The subjects' baseline mean age was 62.4 ± 8.7 years (range, 26.0-85.0 years); among them, 42 were female (39.3%). Mean IOP at baseline for all patients was 18.6 ± 4.3 mmHg. The mean IOP at 6 months was 12.6 ± 4.7 mmHg, representing a significant decrease compared to the baseline (-32%, p < 0.001). In POAG patients with high-baseline IOP, mean IOP was significantly lowered from 28.0 ± 5.7 mmHg at baseline to 18.0 ± 5.5 mmHg (-35%, p < 0.001); in patients with normal-baseline IOP, from 14.6 ± 3.4 mmHg at baseline to 10.3 ± 4.1 mmHg (-29%, p < 0.001). PF tafluprost/timolol FC was well-tolerated and safe. After 6 months, 97.2% of all patients remained on therapy. CONCLUSIONS: In this real-world observational study, once-daily treatment with PF tafluprost/timolol FC demonstrated clinically relevant and statistically significant efficacy, as well as safety and good tolerability, in treatment-naive patients diagnosed with POAG.

Effect of very long-term storage and multiple freeze and thaw cycles on 11-dehydro-thromboxane-B2 and 8-iso-prostaglandin F2α, levels in human urine samples by validated enzyme immunoassays.

Biological samples are often frozen and stored for years and/or thawed multiple times, thus assessing their stability on long-term storage and repeated freeze-thaw cycles is crucial. The study aims were to assess:-the long-term stability of two major enzymatic and non-enzymatic metabolites of arachidonic acid, i.e. urinary 11-dehydro-thromboxane-(Tx) B2, 8-iso-prostaglandin (PG)F2α, and creatinine in frozen urine samples;-the effect of multiple freeze-thaw cycles. Seven-hundred and three urine samples measured in previously-published studies, stored at -40 °C, and measured for a second time for 11-dehydro-TxB2 (n = 677) and/or 8-iso-PGF2α (n = 114) and/or creatinine (n = 610) were stable over 10 years and the 2 measurements were highly correlated (all rho = 0.99, P < 0.0001). Urine samples underwent 10 sequential freeze-thaw cycles, with and without the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (10 mM); urinary 11-dehydro-TxB2 and creatinine were stable across all cycles (11-dehydro-TxB2: 100.4 ± 21%; creatinine: 101 ± 7% of baseline at cycle ten; n = 17), while 8-iso-PGF2α significantly increased by cycle 6 (151 ± 22% of baseline at cycle ten, n = 17, P < 0.05) together with hydrogen peroxide only in the absence of antioxidant. Arachidonic acid metabolites and creatinine appear stable in human urines stored at -40 °C over 10 years. Multiple freeze-thaw cycles increase urinary 8-iso-PGF2α in urine samples without antioxidants. These data are relevant for studies using urine samples stored over long-term and/or undergoing multiple freezing-thawing.

Intrauterine devices influence prostaglandin secretion by equine uterus: in vitro and in vivo studies.

BACKGROUND: Intrauterine devices (IUD) are used in the veterinary practice as the non-pharmacological method of oestrus suppression in mares. When placed in the uterus, IUD create a physical contact with the endometrium that mimics the presence of an equine embryo. However, the mechanism of their action has not been fully elucidated. The objective of the present study was to examine the effect of mechanical stimulation of IUD on mare`s endometrium in both in vitro and in vivo study. For this purpose, we demonstrated the effect of IUD on prostaglandin (PG) F2α and PGE2 secretion, and mRNA transcription of genes involved in PG synthesis pathway in equine endometrial cells in vitro. In the in vivo study, we aimed to compare short-term effect of IUD inserted on day 0 (oestrus) with day 5-6 post-ovulation (the specific time when embryo reaches uterus after fertilization) on PG secretion from equine endometrium. To determine the long-term effect on PG synthase mRNA transcription, a single endometrial biopsy was taken only once within each group of mares at certain time points of the estrous cycle from mares placement with IUD on days 0 or 5-6 post-ovualtion. RESULTS: We showed for the first time that the incubation of the endometrial cells with the presence of IUD altered the pattern of PG synthase mRNA transcription in equine epithelial and stromal endometrial cells. In vivo, in mares placement with IUD on day 0, PGE2 concentrations in blood plasma were upregulated between 1 and 6, and at 10 h after the IUD insertion, compared with the control mares (P < 0.05). Moreover, the decrease of PTGFS mRNA transcription on day 16- 18, associated with an elevation in PTGES mRNA transcription on day 20 -21 of the estrous cycle in endometrial biopsies collected from mares placement with IUD on days 5-6 suggest an antiluteolytic action of IUD during the estrous cycle. CONCLUSION: We conclude that the application of IUD may mimic the equine conceptus presence through the physical contact with the endometrium altering PG synthase transcription, and act as a potent modulator of endometrial PG secretion both in vitro and in vivo.

GnRH analogs induce a LH peak and increase pregnancy per timed-AI in ewes.

To date, there have been no studies testing the capacity of GnRH analogs and respective doses to induce a LH peak in sheep. In this sense, the present study aimed to evaluate the capacity of different synthetic forms and doses of GnRH in inducing LH release in sheep, and the effect of GnRH administration at timed artificial insemination (TAI) on pregnancy per timed-AI. In experiment 1, ewes (n = 40) received an intravaginal device (IVD) of medroxyprogesterone acetate (MPA; 60 mg) for 7 d and prostaglandin F2α analog on Day 5. On Day 7, the ewes were allocated randomly into one of eight groups (n = 5/group), which received a GnRH analog at a specific dose, as follows: lecirelin (12.5 or 25 µg), gonadorelin (50 or 100 µg), buserelin acetate (4.2 or 8.4 µg), or deslorelin (375 or 750 µg). Blood samples for LH determination were obtained at 0, 2, 4, and 6 h after GnRH and the IVDs were removed after the last blood collection. The maximal LH concentration induced by gonadorelin at doses of 50 µg and 100 µg (12.0 ± 2.4 ng/mL and 28.6 ± 7.1 ng/mL, respectively) was lower (P < 0.05) than serum LH induced by 8.4 µg of buserelin (78.9 ± 12.9 ng/mL), 375 µg and 750 µg of deslorelin (75.6 ± 7.4 ng/mL and 72.1 ± 10.6 ng/mL, respectively) and 12.5 µg and 25 µg of lecirelin (73.3 ± 17.8 ng/mL and 61.6 ± 5.9 ng/mL, respectively). However, the maximal LH concentration induced by 4.2 µg of buserelin (49.4 ± 5.9 ng/mL) was similar (P > 0.05) to the 100 µg of gonadorelin. The total release of LH (area under the curve - AUC) after treatment with 50 µg of gonadorelin (31.7 ± 5.9 ng h/mL) was lower (P < 0.05) than after other agonists. In a second experiment, 330 ewes were treated with IVD containing MPA for 7 d. Simultaneously with IVD removal, 250 µg of cloprostenol and 200 IU of eCG were administered. Then, ewes were assigned randomly to either no further treatment (control); or to receive 4.2 µg of buserelin acetate (GnRH group) at cervical TAI, which was performed with fresh semen 54 h after IVD withdrawal in all the animals. Higher pregnancy per timed-AI was observed for GnRH (50.3 %) compared to control (40.7 %). We conclude that buserelin acetate (8.4 µg), lecirelin (12.5 and 25 µg) and deslorelin (375 and 750 µg) induced a greater stimulatory effect on LH secretion than gonadorelin treatment. Furthermore, buserelin acetate treatment at TAI increased pregnancy per timed-AI in ewes previously treated with MPA and eCG.

Effects of intravaginal administration of prostaglandin F2α on luteolysis and subsequent estrus in Shiba goats (Capra hircus).

This study examined the effects of intravaginal administration of prostaglandin F2α (PGF2α ) on luteolysis and subsequent estrus in cycling goats. Goats with functional corpus lutea received one of five treatments: 2 mg of PG intramuscularly (IM2 × 1; n = 6), 2 mg of PGF2α intravaginally (IVG2 × 1; n = 7), 4 mg of PGF2α intravaginally (IVG4 × 1; n = 7), and 1 or 2 mg of PGF2α intravaginally 8 h apart (IVG1 × 2 group; n = 6 and IVG2 × 2; n = 8). Blood samples were collected at 24-h intervals from 0 to 7 days after PGF2α administration. Estrus was checked twice daily during the experiment. The proportion of goats with complete luteolysis (reduction of progesterone concentrations to <1 ng/mL until 48 h after treatment) in the IVG2 × 1 group (28.6%) was significantly lower than in the other groups (IM2 × 1; 100%, IVG4 × 1; 57.1%, IVG1 × 2; 87.5%, IVG2 × 2; 100%, respectively). For goats completing luteolysis, there was no significant difference in the onset and duration of estrus among the groups. These results suggest that intravaginal administration of PGF2α can be applied as an alternative to intramuscular administration.

Efficacy of preserved Tafluprost 0.0015% in lowering intraocular pressure.

OBJECTIVE: To investigate the intraocular pressure (IOP) lowering effect of topical preserved tafluprost 0.0015% in a tertiary hospital setting in India. METHODS: This is a retrospective chart review of patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) attending regular outpatient visits in December 2019 and January 2021, and treated with topical preserved tafluprost 0.0015%. Based on their medication history, patients were divided into two groups, the "treatment naïve" group and the "switched" group, which included patients switched to tafluprost monotherapy after treatment with at least one prior drug. RESULTS: The mean IOP of the study population reduced significantly from baseline level by 20.6% and 25.5% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). The mean IOP in patients with only OHT reduced significantly from baseline level by 21% and 26% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). The mean IOP in patients with POAG reduced significantly from baseline level by 19% and 24% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). The baseline IOP ± SD in POAG treatment naïve patients was 25.3 ± 0.3 mmHg, which reduced significantly by 24% and 28% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). The baseline IOP ± SD in POAG switched patients was 24.3 ± 0.1 mmHg, which reduced significantly by 18% and 22% at 1 month and 3 months after preserved tafluprost 0.0015% treatment (P < 0.001 for both). In the POAG switch group, the percent reduction in IOP at 3 months after preserved tafluprost 0.0015% treatment was 23% with timolol as first line, 22% with bimatoprost as first line, 20% with latanoprost as first line, and 19% with travoprost as first line (P < 0.001 for all). CONCLUSIONS: We show significant IOP reduction with preserved tafluprost 0.0015% in a real-world setting. As first-line monotherapy in patients with OHT and in POAG-naïve patients, preserved tafluprost 0.0015% significantly reduced IOP at 3 months. Even as second-line therapy in nonresponders (POAG-Switched) to various drugs (same class [PGAs] versus different class), treatment with preserved tafluprost 0.0015% resulted in significant IOP reduction at 3 months.

Low progesterone concentration in early pregnancy is detrimental to conceptus development and pregnancy outcome in horses.

High progesterone concentrations in the early luteal phase support pregnancy, whereas subphysiological progesterone concentrations delay embryonic development at least until placentation. In this study, fetal growth and development of pregnancy was investigated in pregnancies with prostaglandin F2α-induced low progesterone concentrations (PGF) in the early luteal phase and control pregnancies (CON) in the same mares (n = 12). Mares were inseminated and in PGF pregnancies received the prostaglandin F2α analogue cloprostenol (62.5 µg) on days 0-3 after ovulation to induce subphysiological progesterone concentrations; CON pregnancies remained untreated. Mares were assigned to PGF or CON treatments in alternating order and received the opposite treatment in the following year. Blood was collected and conceptus size determined repeatedly by transrectal (≤day 101) and transabdominal (>day 101) ultrasonography. After birth, foals were weighed, measured and submitted to a clinical examination. Treatment PGF resulted in fewer pregnancies than CON treatment. All foals born from CON pregnancies were healthy and mature, whereas 4/7 PGF pregnancies were either lost (one embryonic death, one abortion) or resulted in the birth of compromised foals (P = 0.018). Size of the conceptus (e.g., diameter day 49: PGF 6.6 ± 0.7, CON 7.7 ± 0.7 cm, P = 0.006) and embryo proper (e.g., crown rump length day 54; PGF 4.4 ± 0.8, CON 5.8 ± 0.6 cm, P = 0.015) differed between treatments. These size differences decreased over time and at birth PGF foals did not differ significantly from CON foals. In conclusion, reduced progesterone concentration in the early luteal phase leads to delayed conceptus growth beyond placentation and increased pregnancy loss.

Effect of pseudopregnancy duration in nonpregnant sows on induced lactation.

This study was conducted to examine the effects of different pseudopregnancy periods in nonpregnant sows on artificial lactation induction efficiency and milk composition. Sixteen pseudopregnant sows (n = 4 per group) were treated with 5 mg of estradiol dipropionate at 28 (Group D38), 35 (Group D45), 42 (Group D52), and 49 (Group D59) days after the end of estrus, followed by prostaglandin F2α as 0.175-mg cloprostenol twice at 12 h intervals 10 days later. The overall success rate of lactation induction was 81.3%. The lactation rates were significantly higher in Groups D38, D45, and D59 (100.0%) than in Group D52 (25.0%). The milk immunoglobulin (Ig) G concentration was significantly higher in Group D38 than in Group D59. However, IgA levels and milk compositions (protein, ash, and lactose) did not differ among the groups. Lactation induction was successful between 38 and 59 days of pseudopregnancy. Apart from IgG, pseudopregnancy length did not affect milk components from 38 to 59 days of pseudopregnancy.

The evaluation of the effect of tafluprost on the intraocular pressure of healthy male guinea pigs under different light-and-darkness regimes.

BACKGROUND: Ocular hypertension is one of the most underdiagnosed ocular abnormalities among guinea pigs around the world. OBJECTIVES: The current study investigates the effect of 0.0015% preservative-free tafluprost ophthalmic solution (Zioptan) on the intraocular pressure of 16 healthy male guinea pigs (Cavia porcellus) under different light/darkness regimes. METHODS: All guinea pigs received a single drop of tafluprost at 5:30 in the right eye, whereas the contralateral eyes served as control to receive a placebo. Then, the animals were randomly divided into two groups; group A was exposed to light, whereas group B was placed in darkness from 5:30 to 18:00. Rebound tonometry (TonoVet) was instrumented to measure IOP values at 5:30 (baseline), 6:00, 7:00, 8:00, 9:00 and then every 3 h until 18:00. RESULTS: The maximum IOP reduction associated with tafluprost was observed at 6:00 by -1.4 ± 1.1 mmHg (p-value = 0.026) and -2.5 ± 1.2 mmHg (p-value = 0.011) in group A and B, respectively (repeated measure ANOVA test). There was a significant difference between the mean right and left eye IOP values in both groups at 5:30, 6:00, 7:00 and 8:00 (p-value <0.05), which was greater in amount in group B compared to group A due to the effect of darkness on IOP reduction. CONCLUSIONS: It is suggested that the variations of IOP in different light/dark conditions be taken into consideration when applying ocular hypotensive agents on guinea pigs' eyes.

Single-Cell Transcriptomics of Endothelial Cells in Upper and Lower Human Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a type of progressive and distant metastatic tumor. Targeting anti-angiogenic genes could effectively hinder ESCC development and metastasis, whereas ESCC locating on the upper or the lower esophagus showed different response to the same clinical treatment, suggesting ESCC location should be taken into account when exploring new therapeutic targets. In the current study, to find novel anti-angiogenic therapeutic targets, we identified endothelial cell subsets in upper and lower human ESCC using single-cell RNA sequencing (scRNA-seq), screened differentially expressed genes (DEGs), and performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The results showed that common DEGs shared in the upper and the lower endothelial cells mainly are involved in vessel development, angiogenesis, and cell motility of endothelial cells by regulating PI3K-AKT, Rap1, Ras, TGF-beta, and Apelin signaling pathways. The critical regulatory genes were identified as ITGB1, Col4A1, Col4A2, ITGA6, LAMA4, LAMB1, LAMC1, VWF, ITGA5, THBS1, PDGFB, PGF, RHOC, and CTNNB1. Cell metabolism-relevant genes, e.g., MGST3, PNP, UPP1, and HYAL2 might be the prospective therapeutic targets. Furthermore, we found that DEGs only in the upper endothelial cells, such as MAPK3, STAT3, RHOA, MAPK11, HIF1A, FGFR1, GNG5, GNB1, and ARHGEF12, mainly regulated cell adhesion, structure morphogenesis, and motility through Phospholipase D, Apelin, and VEGF signaling pathways. Moreover, DEGs only in the lower endothelial cells, for instance PLCG2, EFNA1, CALM1, and RALA, mainly regulated cell apoptosis and survival by targeting calcium ion transport through Rap1, Ras, cAMP, Phospholipase D, and Phosphatidylinositol signaling pathways. In addition, the upper endothelial cells showed significant functional diversity such as cytokine-responsive, migratory, and proliferative capacity, presenting a better angiogenic capacity and making it more sensitive to anti-angiogenic therapy compared with the lower endothelial cells. Our study has identified the potential targeted genes for anti-angiogenic therapy for both upper and lower ESCC, and further indicated that anti-angiogenic therapy might be more effective for upper ESCC, which still need to be further examined in the future.

The mechanism of ginger and its processed products in the treatment of estradiol valerate coupled with oxytocin-induced dysmenorrhea in mice via regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway.

Ginger (Rhizoma zingiberis, RZ) has been used as a food, spice, supplement, flavoring agent, and as an edible herbal medicine. It is characterized by its pungency and aroma, and is rich in nutrients with remarkable pharmacological effects. It is used in traditional medicine clinics to treat diseases and symptoms, such as colds, headache, and primary dysmenorrhea (PD). In China, a variety of processed products of RZ are used as herbal medicines, such as baked ginger (BG) or ginger charcoal (GC) to treat different diseases and symptoms. However, the molecular mechanism of the therapeutic effect of RZ and its processed products (RZPPs, including BG or GC) against PD has not been well characterized. Moreover, whether the transient receptor potential (TRP) ion channels are involved in this process is not clear. In the present study, UHPLC-Q-TOF MS was adopted to analyse the differential quality markers (DQMs) between RZ and RZPPs. In addition, differential metabolomics (DMs) was acquired between RZ- and RZPPs-treated estradiol valerate coupled with an oxytocin-induced PD mouse uterus using untargeted metabolomics (UM). A correlation analysis between DQMs and DMs was also conducted. Benzenoids, lipids, and lipid-like molecules were the main DQMs between RZ and RZPPs. RZ and RZPPs were found to improve the pathological status of the uterus of a PD mouse, with significantly decreased serum levels of E2, PGF2α, TXB2 and remarkably increased levels of PROG and 6-keto-PGF1α. Moreover, RZ and RZPPs alleviated PD in mice via regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway. Our results indicate that the therapeutic effect of RZ and RZPPs against PD may be mediated by regulating the TRP ion channel-mediated ERK1/2/NF-κB signaling pathway, and provide a reference for the development of new dietary supplements or medicines.

Direct action of leptin, obestatin and ginkgo on hormone release by luteinised human ovarian granulosa cells.

CONTEXT: The role of metabolic hormones, medicinal plants and their interrelationships in the control of human reproductive processes are poorly understood. AIMS: To examine how leptin, obestatin and ginkgo (Ginkgo biloba L.) affect human ovarian hormone release. METHODS: We analysed the influence of leptin and obestatin alone and in combination with ginkgo extract on cultured human ovarian granulosa cells. The release of progesterone (P), insulin-like growth factor I (IGF-I), oxytocin (OT) and prostaglandin F (PGF) were analysed by enzyme immunoassay and enzyme-linked immunosorbent assay. KEY RESULTS: Leptin addition promoted the release of all the measured hormones. Obestatin stimulated the release of P, IGF-I and OT and inhibited PGF output. Ginkgo suppressed P, IGF-I and OT and promoted PGF release. Furthermore, ginkgo changed the stimulatory action of leptin on PGF to an inhibitory one. CONCLUSIONS: Leptin and obestatin are involved in the control of human ovarian hormone release and ginkgo influences their function. IMPLICATIONS: Leptin and obestatin could be useful as stimulators of human ovarian cell functions. The suppressive influence of ginkgo on ovarian function should lead to the development of ginkgo-containing drugs.

Placental DAAM2 is unaltered in preeclampsia, but upregulated by treatment with proton pump inhibitors.

BACKGROUND: Dishevelled Associated Activator Of Morphogenesis 2 (DAAM2) levels are elevated in the maternal circulation and placenta in pregnancies complicated by fetal growth restriction. However, placental DAAM2 levels in cases of preeclampsia have not previously been explored. Here, we examined placental DAAM2 in pregnancies complicated by preterm preeclampsia, and whether candidate preeclampsia therapeutics altered its expression. METHODS: DAAM2 mRNA and protein levels were assessed in placental tissue from cases of preterm preeclampsia and gestation-matched controls (delivering ≤ 34 weeks; qPCR and western blot respectively). Short interfering RNAs were used to silence DAAM2 in isolated primary cytotrophoblast under normoxic (8 % O2) and hypoxic (1 % O2) conditions, and expression of anti-angiogenic sFLT-1, angiogenic PGF, antioxidant, fetal growth, and inflammatory genes assessed. DAAM2 expression was measured in placental explant tissue from pregnancies complicated by preeclampsia, treated with three proton pump inhibitors (100 µM esomeprazole, lansoprazole, and rabeprazole). RESULTS: DAAM2 expression was significantly reduced in preeclamptic placental tissue compared to controls, but protein production was unchanged. Silencing DAAM2 in hypoxic cytotrophoblast increased sFLT-i13 isoform expression, but did not alter sFLT-e15a or PGF expression, or sFLT-1 secretion. DAAM2 knockdown did not alter expression of antioxidant (NQO-1, TXN, GCLC), fetal growth (SPINT1), or inflammasome (NLRP3) genes. Esomeprazole and lansoprazole, but not rabeprazole, increased DAAM2 expression in placental explant tissue from cases of preeclampsia. CONCLUSION: Placental DAAM2 protein is not significantly altered in placental tissue in cases of preeclampsia, and its suppression does not alter sFLT-1 secretion. Hence, placental DAAM2 is unlikely to drive the pathogenesis associated with preeclampsia.

Mediators of inflammation resolution and vasoactive eicosanoids in gestational diabetes and preeclampsia.

OBJECTIVE: Women with gestational diabetes (GDM) have an increased risk of preeclampsia and postpartum diabetes. Inflammation associates with both GDM and preeclampsia. This study examined specialized proresolving mediators (SPM) that direct inflammation resolution and eicosanoids that are involved in inflammation, in relation to the development of preeclampsia and ongoing postpartum glucose intolerance in GDM. METHODS: Participants were selected from a prospective study examining the development of preeclampsia in women with GDM. Four groups of age-matched women were studied: GDM ( n  = 20), GDM who developed preeclampsia (GDM+PE, n  = 21), GDM who remained glucose-intolerant postpartum (GDM+PPIGT, n  = 20), or pregnancies with glucose tolerance within the normal range (NGT, n  = 21). Measurement of SPM (E-series resolvins and D-series resolvins), SPM pathway intermediates (14-HDHA, 18-HEPE and 17-HDHA), 20-hydroxyeicosatetraenoic acid (20-HETE), and the urinary metabolite of the vasodilator prostacyclin 2,3-dinor-6-Keto-PGF 1α , were made at 28, 32 and 36 weeks gestation and at 6 months postpartum. RESULTS: Compared with GDM, GDM+PE had elevated levels of 20-HETE and the SPM pathway intermediates 14-HDHA, 18-HEPE, 17-HDHA, at 32 weeks, and the SPM RvE1 at 32 and 36 weeks gestation. Compared with NGT and regardless of whether they developed preeclampsia or PPIGT, GDM had lower levels of 2,3-dinor-6-Keto-PGF 1α during pregnancy. CONCLUSION: Reduced levels of the prostacyclin metabolite 2,3-dinor-6-Keto-PGF 1α may contribute to the increased risk of preeclampsia in women with GDM. The increase in 20-HETE, a vasoconstrictor and mediator of inflammation, and SPM that contribute to inflammation resolution, prior to the onset of preeclampsia require further investigation to clarify their clinical significance.

Changes in the C-reactive protein and 13,14-dihydro-15-keto-prostaglandin F2α concentrations of uterine lavage samples after the administration of povidone-iodine in cows.

Changes in the C-reactive protein (CRP) and 13,14-dihydro-15-keto-prostaglandin F2α (PGFM) concentrations of uterine lavage fluid were examined in cows given an intrauterine povidone-iodine (PI) infusion. The mean polymorphonuclear leukocyte (PMN) ratios (the ratio of PMN to total cells) and CRP concentration of uterine lavage fluid on the day after the treatment were significantly (P<0.05) greater in the PI infusion group (PMN: 53.0 ± 32.7%, CRP: 50.2 ± 32.3 ng/mL) than in the non-treatment control group (PMN: 7.9 ± 21.9%, CRP: 17.2 ± 5.9 ng/mL), whereas there was no significant difference in the mean PGFM concentration between the two groups. The present findings suggest that the uterine CRP level is a useful biomarker of local uterine inflammation in cows.

Effectiveness and safety of tafluprost in primary open-angle glaucoma and ocular hypertension: a post-marketing phase IV study in China.

BACKGROUND: Prostaglandin analogs (PGAs) are the first-line treatment for primary open-angle glaucoma (POAG) and ocular hypertension (OH). This study aimed to confirm the effectiveness and safety of Tapros® (0.0015% tafluprost eye drops) in Chinese patients with POAG and OH. METHODS: This phase IV, multicenter, non-comparative, prospective study enrolled patients with POAG and OH in China between 12/27/2017 and 04/15/2020. Patients who were treatment-naïve or untreated within one month (group A) or with unreached intraocular pressure (IOP) target after previous monotherapy of other PGAs (group B) or non-PGA IOP-lowering drugs (group C) were treated with 0.0015% tafluprost for three months. The IOP reduction, response rate, and safety were observed. RESULTS: There were 165, 89, and 31 patients in groups A, B, and C, with baseline IOPs of 22.4 ± 4.7, 21.0 ± 3.5, and 22.5 ± 3.2 mmHg, respectively. The least-square means and percentages of IOP reduction at 3 months for groups A, B, and C were 4.7 (19.8%), 1.6 (6.1%), and 4.6 mmHg (20.3%), respectively. A significant reduction in IOP was observed at each visit compared with baseline (all P < 0.05). At the final visit, 57.0% of the participants in group A achieved an IOP reduction of ≥ 20%, while 40.4% and 77.4% in groups B and C achieved an IOP reduction of ≥ 10%. Fifty-eight treatment-related adverse events occurred in 46 participants (15.7%), of which the most common one was conjunctival hyperemia (34/293, 11.6%). CONCLUSIONS: Tafluprost showed a sustained and significant effect with tolerable adverse events in Chinese patients with POAG and OH who were treatment-naïve or untreated within one month or received prior treatments with unsatisfying outcomes.

Effect of a targeted reproductive management program designed to prioritize insemination at detected estrus and optimize time to insemination on the reproductive performance of lactating dairy cows.

The primary objective of this randomized controlled experiment was to evaluate the insemination dynamic and reproductive performance of cows managed with a targeted reproductive management (TRM) program designed to prioritize artificial insemination (AI) at detected estrus (AIE) and optimize timing of AI by grouping cows based on detection of estrus during the voluntary waiting period (VWP). Our secondary objective was to evaluate reproductive outcomes for cows with or without estrus during the VWP. Lactating Holstein cows fitted with an ear-attached sensor for detection of estrus were randomly assigned to a TRM treatment that prioritized AIE based on detection of estrus during the VWP (TP-AIE; n = 488), a non-TRM treatment that prioritized AIE (P-AIE; n = 489), or an all timed AI (TAI) treatment with extended VWP (ALL-TAI; n = 491). In TP-AIE, cows with or without automated estrus alerts (AEA) recorded during the VWP received AIE if detected in estrus for at least 31 ± 3 or 17 ± 3 d after a 49 d VWP, respectively. Cows not AIE with or without AEA during the VWP received TAI after Ovsynch with progesterone supplementation and 2 PGF2α treatments (P4-Ov) at 90 ± 3 or 74 ± 3 d in milk (DIM), respectively. In P-AIE, cows received AIE if detected in estrus for 24 ± 3 d after a 49 d VWP, and if not AIE received TAI at 83 ± 3 DIM after P4-Ov. In ALL-TAI, cows received TAI at 83 ± 3 DIM after a Double-Ovsynch protocol. Data were analyzed by logistic and Cox's proportional hazard regression. The proportion of cows AIE did not differ for TP-AIE (71.0%) and P-AIE (74.6%). Overall P/AI at 39 d after first service was greater for the ALL-TAI (47.6%) than for the P-AIE (40.2%) and TP-AIE (39.5%) treatments. The hazard of pregnancy up to 150 DIM was greater for cows in TP-AIE (hazard ratio = 1.2; 95% confidence interval: 1.1-1.4) and P-AIE (hazard ratio = 1.2; 95% confidence interval: 1.1-1.4) than for cows in the ALL-TAI treatment which resulted in median time to pregnancy of 89, 89, and 107 d. Conversely, the proportion of cows pregnant at 150 DIM did not differ (ALL-TAI 78.5%, P-AIE 76.3%, TP-AIE 76.0%). Except for a few outcomes for which no difference was observed, cows detected in estrus during the VWP had better performance than cows not detected in estrus. Cows with AEA during the VWP were more likely to receive AIE, had greater P/AI, and greater pregnancy rate up to 150 DIM regardless of first service management. We conclude that a TRM program designed to prioritize AIE by grouping cows based on detection of estrus during the VWP was an effective strategy to submit cows for first service resulting in similar or improved performance than a non-TRM program that prioritized AIE or an all-TAI program with extended VWP. Also, AEA recorded during the VWP might be used as a strategy for identifying subgroups of cows with different reproductive performance.

Prostaglandin D2 and F2α as Regulators of Adipogenesis and Obesity.

Prostaglandins (PGs) are lipid-derived autacoids that are synthesized from arachidonic acid by the action of cyclooxygenases and PG terminal synthases. PGs consist of PGD2, PGE2, PGF2α, prostacyclin (PGI2), and thromboxane A2, which act through G protein-coupled receptors. PGs sustain homeostatic functions and exert a variety of pathophysiological roles to regulate the development of various diseases such as obesity and dyslipidemia. Adipocytes (fat cells) have the unique capacity to accumulate large amounts of lipids as energy source in lipid droplets. Adipogenesis is the process of differentiation from preadipocytes to mature adipocytes, which is regulated by various adipogenic transcription factors. Obesity is defined as an abnormal increase in adipose tissue mass and is considered to be a risk factor for the development of lifestyle-related diseases including cardiovascular disease, hyperlipidemia, and type 2 diabetes mellitus. This review summarizes insights into the roles of PGD2, PGF2α, and their synthases in the regulation of adipogenesis and obesity.

Pharmacokinetics-derived absorbed components responsible for Guizhi-Fuling capsule target PI3K/Akt-Erk to exert an anti-dysmenorrhea effect.

ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi-Fuling capsule (GZFL), a well-known herbal remedy, has been widely used to treat primary dysmenorrhea (PD). Hence, systematic identifying multiple active ingredients and the involved mechanism is essential and urgently needed for GZFL. AIM OF THE STUDY: This study was planned to assess the pharmacokinetics of GZFL in rats, and identify whether these GZFL-derived absorbed components (ACs) contribute to the efficacy of source herbs and relevant mechanism. MATERIALS AND METHODS: The in vivo pharmacokinetic profile of 11 phytochemicals and 13 metabolites in healthy and PD rats were evaluated using liquid chromatography with mass spectrometry (LC-MS/MS). Whereafter, the introduced contribution strategy assessed ACs' effect (doses = their contents in GZFL) in PD rats with the mechanism. RESULT: The pharmacokinetic profiles of prototypes and metabolites differed in healthy and PD rats. As a main proxy of GZFL, 11ACs exerted an anti-PD effect (improvement of indexes for writhing latency, writhing time, PGF2α/PGE2, TXB2/6-keto-PGF1α and ß-EP) by regulating PI3K-Akt/ERK pathway. CONCLUSION: As a paradigmatic example, 11ACs contributed an average of 113.55% to GZFL in terms of anti-PD efficacy, providing an approach to rapidly, accurately and consistently identify the bioactive components and their pathway from herbs.