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Nature Communications Dec 2023Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F and an agonist for the prostaglandin F2-alpha...
Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH). However, off-target activation of closely related receptors such as the prostaglandin E receptor subtype EP3 (EP3 receptor) by carboprost results in side effects and limits the clinical application. Meanwhile, the FP receptor selective agonist latanoprost is not suitable to treat PPH due to its poor solubility and fast clearance. Here, we present two cryo-EM structures of the FP receptor bound to carboprost and latanoprost-FA (the free acid form of latanoprost) at 2.7 Å and 3.2 Å resolution, respectively. The structures reveal the molecular mechanism of FP receptor selectivity for both endogenous prostaglandins and clinical drugs, as well as the molecular mechanism of G protein coupling preference by the prostaglandin receptors. The structural information may guide the development of better prostaglandin drugs.
Topics: Female; Humans; Carboprost; Dinoprost; Latanoprost; Ligands; Receptors, Prostaglandin; Cryoelectron Microscopy
PubMed: 38065938
DOI: 10.1038/s41467-023-43922-8 -
BMC Veterinary Research Nov 2023Heat stress negatively impacts the reproductive performance of sheep including the efficiency of estrous synchronization regimens. This study aimed to investigate the...
Incorporation of L-Carnitine in the OvSynch protocol enhances the morphometrical and hemodynamic parameters of the ovarian structures and uterus in ewes under summer climatic conditions.
Heat stress negatively impacts the reproductive performance of sheep including the efficiency of estrous synchronization regimens. This study aimed to investigate the potential effects of L-Carnitine (LC) administration on the efficacy of the OvSynch protocol in ewes under summer climatic conditions. Ewes were synchronized for estrus using the OvSynch protocol and a dose of LC (20 mg/kg body weight) was intravenously (IV) administered on the same day of PGF injection to one group (n = 8; LC group), while other ewes (n = 8; control group) received the same protocol without LC. Ultrasonographic evaluation (including B-mode, color, and pulsed Doppler) was used to assess the morphometrical and hemodynamic parameters of ovarian structures [number, size, and blood flow of follicles (GFs) and corpora lutea (CLs)] and uterus during the estrous phase (Day 0), and on Day 8 post ovulation (luteal phase). Uterine artery blood flow (MUA) was assessed by measuring the resistive index (RI) and pulsatility index (PI) at both stages. The serum samples were collected to measure the concentrations of estradiol (E2), progesterone (P4), and total antioxidant capacity (TAC) using commercial kits. Results revealed a significant (P<0.05) increase in the colored pixel area of GFs and uterus in the LC group (392.84 ± 31.86 and 712.50 ± 46.88, respectively) compared to the control one (226.25 ± 17.74 and 322 ± 18.78, respectively) during Day 0. Circulating E2 and TAC levels were significantly (P<0.05) higher in the LC-treated ewes (31.45 ± 1.53 pg/ml and 1.80 ± 0.13 mM/L, respectively) compared to those in the control ewes (21.20 ± 1.30 pg/ml and 0.98 ± 0.09 mM/L, respectively) during Day 0. Moreover, LC improved the colored pixel area of CLs (2038.14 ± 102.94 versus 1098 ± 82.39) and uterus (256.38 ± 39.28 versus 121.75 ± 11.36) and circulating P4 (2.99 ± 0.26 ng/ml versus1.67 ± 0.15 ng/ml) on Day 8. Values of RI of MUA were significantly lower in the LC group compared to the control one on Day 0 and Day 8 (0.48 ± 0.03 versus 0.72 ± 0.03 and 0.58 ± 0.03 versus 0.78 ± 0.02, respectively). In conclusion, LC incorporation in the OvSynch protocol enhanced the morphometrical and hemodynamic parameters of the ovarian structures and the uterus concomitantly with improvements in the TAC, E2, and P4 concentrations in ewes under hot summer conditions.
Topics: Animals; Female; Sheep; Ovarian Follicle; Carnitine; Estrus Synchronization; Dinoprost; Corpus Luteum; Progesterone; Ovulation; Uterus; Hemodynamics
PubMed: 37996926
DOI: 10.1186/s12917-023-03814-x -
Indian Journal of Ophthalmology Dec 2023To investigate the intraocular pressure (IOP) lowering effect of topical preserved tafluprost 0.0015% in a tertiary hospital setting in India.
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.
Topics: Humans; Intraocular Pressure; Glaucoma, Open-Angle; Retrospective Studies; Prostaglandins F; Ocular Hypertension; Glaucoma; Timolol; Antihypertensive Agents; Treatment Outcome
PubMed: 37991299
DOI: 10.4103/IJO.IJO_3312_22 -
JCI Insight Dec 2023Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive...
Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptgfr) are implicated as a TGF-β1-independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen-treated IER-SftpcI73T mice developed an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr-null (FPr-/-) line showed attenuated weight loss and gene dosage-dependent rescue of mortality compared with FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single-cell RNA-Seq, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts, which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α /FPr-dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.
Topics: Mice; Animals; Dinoprost; Fibroblasts; Idiopathic Pulmonary Fibrosis; Fibrosis; Population Dynamics
PubMed: 37934604
DOI: 10.1172/jci.insight.172977 -
Journal of Dairy Science Apr 2024Our objective was to compare insemination rate and pregnancies per artificial insemination (P/AI) of lactating Jersey cows inseminated at first service with sexed Jersey...
Effect of postpartum body condition score change on the pregnancy outcomes of lactating Jersey cows inseminated at first service with sexed Jersey or conventional beef semen after a synchronized estrus versus a synchronized ovulation.
Our objective was to compare insemination rate and pregnancies per artificial insemination (P/AI) of lactating Jersey cows inseminated at first service with sexed Jersey or conventional beef semen after submission to a Double-Ovsynch protocol for timed artificial insemination (TAI) versus a protocol to synchronize estrus at similar days in milk (DIM). Secondary objectives were to determine the effect of protocol synchrony and postpartum body condition score (BCS) change on P/AI. Lactating Jersey cows (n = 1,272) were allocated by odd versus even ear tag number, which was randomly allocated within the herd, within parity and semen type for submission to a Double-Ovsynch protocol (DO; n = 707) or a protocol to synchronize estrus (ED; n = 565). All ED cows detected in estrus were inseminated (EDAI; n = 424), with undetected cows receiving TAI after an Ovsynch protocol (EDTAI; n = 141). There was a treatment by parity interaction on insemination rate with 100% of DO cows receiving TAI, but a tendency for fewer primiparous ED cows to be detected in estrus and AI than multiparous cows (69.5% ± 0.04% vs. 77.1% ± 0.02%, respectively). For cows inseminated with sexed Jersey or conventional beef semen, DO cows tended to have and had more P/AI than EDAI cows (sexed, 49.2% ± 0.03% vs. 43.6% ± 0.03%; beef, 64.2% ± 0.04% vs. 56.3% ± 0.05%, respectively) and had more P/AI than EDAI+EDTAI cows (sexed, 49.1% ± 0.03% vs. 40.6% ± 0.03%; beef, 65.5% ± 0.04% vs. 56.2% ± 0.04%, respectively). Overall, 29.1% of DO cows expressed estrus with 5.0% and 24.2% of cows detected in estrus ≥24 h before and at TAI, respectively, and there was no difference in P/AI 61 ± 4 d after AI based on expression of estrus at TAI. The synchronization rate was greater for DO than EDAI cows (92.1% ± 0.01% vs. 79.2% ± 0.02%, respectively); however, synchronized DO cows had more P/AI than synchronized EDAI cows (55.0% ± 0.02% vs. 49.2% ± 0.03%, respectively). There was an interaction between BCS change from 7 to 39 ± 2 DIM and treatment on P/AI 61 ± 4 d after AI with no difference between DO and EDAI cows that lost = 0.25 (49.8% ± 0.04% vs. 51.0% ± 0.05%, respectively) or maintained or gained (55.6% ± 0.04% vs. 50.8% ± 0.05%, respectively) BCS, but within cows that lost ≥0.5 BCS, DO cows had more P/AI than EDAI cows (54.1% ± 0.04% vs. 36.1% ± 0.04%, respectively). In conclusion, submission of lactating Jersey cows to a Double-Ovsynch protocol for first insemination increased insemination rate and fertility to first insemination compared with AI after a detected estrus regardless of semen type and expression of estrus, particularly for cows with excessive postpartum BCS loss.
Topics: Pregnancy; Female; Cattle; Animals; Pregnancy Outcome; Lactation; Semen; Estrus Synchronization; Dinoprost; Estrus; Ovulation; Postpartum Period; Insemination, Artificial; Gonadotropin-Releasing Hormone; Progesterone
PubMed: 37923205
DOI: 10.3168/jds.2023-23892 -
Biomedicine & Pharmacotherapy =... Dec 2023Colistin (polymyxin E) is an antibiotic that is effective against multidrug-resistant gram-negative bacteria. However, the high incidence of nephrotoxicity caused by...
Colistin (polymyxin E) is an antibiotic that is effective against multidrug-resistant gram-negative bacteria. However, the high incidence of nephrotoxicity caused by colistin limits its clinical use. To identify compounds that might ameliorate colistin-induced nephrotoxicity, we obtained 1707 compounds from the Korea Chemical Bank and used a high-content screening (HCS) imaging-based assay. In this way, we found that bimatoprost (one of prostaglandin F2α analogue) ameliorated colistin-induced nephrotoxicity. To further assess the effects of bimatoprost on colistin-induced nephrotoxicity, we used in vitro and in vivo models. In cultured human proximal tubular cells (HK-2), colistin induced dose-dependent cytotoxicity. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, indicative of apoptosis, was higher in colistin-treated cells, but this effect of colistin was ameliorated by cotreatment with bimatoprost. The generation of reactive oxygen species, assessed using 2,7-dichlorodihydrofluorescein diacetate, was less marked in cells treated with both colistin and bimatoprost than in those treated with colistin alone. Female C57BL/6 mice (n = 10 per group) that were intraperitoneally injected with colistin (10 mg/kg/12 hr) for 14 days showed high blood urea nitrogen and serum creatinine concentrations that were reduced by the coadministration of bimatoprost (0.5 mg/kg/12 hr). In addition, kidney injury molecule-1 (KIM1) and Neutrophil gelatinase-associated lipocalin (NGAL) expression also reduced by bimatoprost administration. Further investigation in tubuloid and kidney organoids also showed that bimatoprost attenuated the nephrotoxicity by colistin, showing dose-dependent reducing effect of KIM1 expression. In this study, we have identified bimatoprost, prostaglandin F2α analogue as a drug that ameliorates colistin-induced nephrotoxicity.
Topics: Mice; Animals; Female; Humans; Colistin; Bimatoprost; Dinoprost; Mice, Inbred C57BL; Anti-Bacterial Agents; Kidney; Prostaglandins
PubMed: 37918255
DOI: 10.1016/j.biopha.2023.115446 -
Journal of Optometry 2024To investigate the effect of benzalkonium chloride (BAK)-preserved latanoprost and bimatoprost, polyquad (PQ)-preserved travoprost, and preservative-free (PF)...
Comparing the effect of benzalkonium chloride-preserved, polyquad-preserved, and preservative-free prostaglandin analogue eye drops on cultured human conjunctival goblet cells.
PURPOSE
To investigate the effect of benzalkonium chloride (BAK)-preserved latanoprost and bimatoprost, polyquad (PQ)-preserved travoprost, and preservative-free (PF) latanoprost and tafluprost, all prostaglandin analogues (PGAs), on human conjunctival goblet cell (GC) survival. Furthermore, to investigate the effect of BAK-preserved and PF latanoprost on the cytokine secretion from GC.
METHODS
Primary human conjunctival GCs were cultivated from donor tissue. Lactate dehydrogenase (LDH) and tetrazolium dye colorimetric (MTT) assays were used for the assessment of GC survival. A cytometric bead array was employed for measuring secretion of interleukin (IL)-6 and IL-8 from GC.
RESULTS
BAK-preserved latanoprost and bimatoprost reduced cell survival by 28% (p = 0.0133) and 20% (p = 0.0208), respectively, in the LDH assay compared to a negative control. BAK-preserved latanoprost reduced cell proliferation by 54% (p = 0.003), BAK-preserved bimatoprost by 45% (p = 0.006), PQ-preserved travoprost by 16% (p = 0.0041), and PF latanoprost by 19% (p = 0.0001), in the MTT assay compared to a negative control. Only PF tafluprost did not affect the GCs in either assay. BAK-preserved latanoprost caused an increase in the secretion of pro-inflammatory IL-6 and IL-8 (p = 0.0001 and p = 0.0019, respectively) compared to a negative control, which PF latanoprost did not.
CONCLUSION
BAK-preserved PGA eye drops were more cytotoxic to GCs than PQ-preserved and PF PGA eye drops. BAK-preserved latanoprost induced an inflammatory response in GC. Treatment with PF and PQ-preserved PGA eye drops could mean better tolerability and adherence in glaucoma patients compared to treatment with BAK-preserved PGA eye drops.
Topics: Humans; Benzalkonium Compounds; Travoprost; Latanoprost; Ophthalmic Solutions; Goblet Cells; Bimatoprost; Cloprostenol; Interleukin-8; Prostaglandins F, Synthetic; Antihypertensive Agents; Preservatives, Pharmaceutical; Prostaglandins, Synthetic
PubMed: 37788596
DOI: 10.1016/j.optom.2023.100481 -
Animal Reproduction Science Oct 2023High progesterone concentrations in the early luteal phase support pregnancy, whereas subphysiological progesterone concentrations delay embryonic development at least...
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 F-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 F 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.
Topics: Pregnancy; Horses; Animals; Female; Progesterone; Pregnancy Outcome; Ovulation; Prostaglandins F; Cloprostenol
PubMed: 37725863
DOI: 10.1016/j.anireprosci.2023.107334 -
European Journal of Drug Metabolism and... Nov 2023All latanoprost formulations currently available for the treatment of glaucoma or ocular hypertension contain the same concentration of latanoprost (0.005%) but differ...
BACKGROUND AND OBJECTIVE
All latanoprost formulations currently available for the treatment of glaucoma or ocular hypertension contain the same concentration of latanoprost (0.005%) but differ in excipients, which may affect corneal drug permeability or stability. This study aimed at comparing corneal penetration of three marketed latanoprost solutions with different excipient formulations in in vitro and in vivo drug permeability studies.
METHODS
Three latanoprost formulations were tested under good laboratory practice conditions: a formulation containing benzalkonium chloride (BAK) but no surfactant (Preserved latanoprost); the same formulation except preservative-free (PF) without BAK or surfactant (SF) (PF SF latanoprost); and a different formulation without BAK but containing a non-ionic surfactant (MGHS 40 at 5%) combined with thickening agents (Carbomer 974P, Macrogol 4000) (PF latanoprost). Corneal permeation of latanoprost acid (LAT) was first determined in vitro using a reconstructed human corneal epithelium tissue. Then, in vivo pharmacokinetic studies were performed on pigmented rabbits, for which LAT concentration was measured in the aqueous humour (AH) and iris-ciliary body (ICB).
RESULTS
In vitro, the cumulative transport of LAT was linear between 1 h and 4 h for preserved latanoprost and PF SF latanoprost, and LAT concentrations matched exactly at each timepoint. By contrast, the permeation of PF latanoprost was linear between 2 h and 12 h and was significantly lower than that of preserved latanoprost and PF SF latanoprost at 4 and 8 h (p < 0.001). In rabbits, the concentrations of LAT in AH and ICB were not statistically different between preserved latanoprost and PF SF latanoprost at each timepoint, except at 1 h in ICB (p = 0.005). By comparison, the LAT concentration of PF latanoprost was statistically (p < 0.05) lower than that of preserved latanoprost and PF SF latanoprost in AH and ICB from 0.5 to 3 h.
CONCLUSION
BAK did not influence the corneal penetration of latanoprost in in vitro and in vivo studies. The formulation containing a non-ionic surfactant resulted in lower and slower ocular penetration compared with preserved or PF SF formulations. This raises questions about the relevance of BAK and some surfactants in enhancing corneal penetration of ocular formulations.
Topics: Humans; Animals; Rabbits; Latanoprost; Biological Availability; Prostaglandins F, Synthetic; Ophthalmic Solutions; Antihypertensive Agents; Preservatives, Pharmaceutical; Surface-Active Agents
PubMed: 37682463
DOI: 10.1007/s13318-023-00853-5 -
Journal of Dairy Science Dec 2023The aim of this study was to evaluate the effect of different progesterone (P4) concentrations during the follicular growth on the intensity of estrous expression,...
The aim of this study was to evaluate the effect of different progesterone (P4) concentrations during the follicular growth on the intensity of estrous expression, ovarian response to the superovulatory treatment, and embryo production and quality in superovulated heifers. A total of 63 Holstein heifers were randomly assigned into 2 experimental groups: Low P4 (n = 31) and High P4 (n = 32). Animals received a pre-synchronization protocol followed by a protocol of superovulation that included the allocated P4 treatment. Activity was monitored continuously by an automated activity monitor, and estrus characteristics (maximum intensity and duration) were recorded. Embryo collection was performed 7 d post artificial insemination (AI). Embryos were counted and graded from good or excellent (1) to degenerated (4). The outcomes of interest were: number and diameter of follicles at the time of AI, ovulation success (confirmed 7 d post-AI), time to estrus event, maximum intensity and duration of estrus, number and quality of embryos. Data were analyzed according to the type of outcome variable using logistic, linear, or Poisson regression models. A total of 105 embryos (High P4: n = 42; Low P4: n = 63) were graded for quality. Different P4 levels did not affect the maximum intensity (High P4 = 497.8 ± 23.9%; Low P4 = 542.2 ± 23.5%) or the duration (High P4 = 13.5 ± 1.5 h; Low P4 = 14.3 ± 1.4 h) of estrus. Heifers in the High P4 treatment had greater number of follicles at time of AI (High P4 = 16.6 ± 1.6 follicles; Low P4 = 13.9 ± 1.2 follicles), but with smaller diameter (High P4 = 11.3 ± 0.1 mm; Low P4 = 12.0 ± 0.1 mm) compared with Low P4. High P4 heifers tended to have better embryo quality compared with Low P4 heifers (odds ratio = 1.98; 95% CI = 0.90-4.35). High P4 heifers had less embryos than Low P4 heifers, but this was modified by the CIDR (intravaginal implant of P4) removal to estrus interval (interval 0-21 h: mean ratio = 1.15, 95% CI = 0.42-1.87; interval 22-46 h: mean ratio = 0.58, 95% CI = 0.27-0.96). Although estrous expression was not associated with embryo quality, as the duration and the maximum intensity of estrous expression increased, the number of embryos recovered 7 d post-AI increased (duration: mean ratio = 1.04; 95% CI = 1.03-1.05; maximum intensity: mean ratio = 1.50; 95% CI = 1.42-1.58). In conclusion, P4 during the follicular growth, and intensity of estrus, are playing a role in regulating the quality and the number of embryos produced by superovulated heifers. This study was supported by contributions from Resilient Dairy Genome Project and the Natural Sciences and Engineering Research Council.
Topics: Female; Cattle; Animals; Progesterone; Superovulation; Estrus Synchronization; Estrus; Ovary; Insemination, Artificial; Dinoprost; Gonadotropin-Releasing Hormone
PubMed: 37641352
DOI: 10.3168/jds.2022-23065