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Background and Objectives: Topically administered antiglaucoma medications, especially those containing benzalkonium chloride (BAC), may cause local adverse effects and compromise ocular surface. The aim of the study was to assess the effect of topical prostaglandin F2α analogs (PGAs): preservative-free latanoprost, BAC-preserved latanoprost, preservative-free tafluprost, and BAC-preserved bimatoprost, on selected oxidative stress parameters in the tear film. Materials and Methods: The patients were divided into five groups: group C (n = 25) control group—subjects who did not use topical antiglaucoma medications, group L (n = 22)—patients using topical preservative-free latanoprost, group L+BAC (n = 25)—patients using topical BAC-preserved latanoprost, group T (n = 19)—patients using topical preservative-free tafluprost, and group B+BAC (n = 17)—patients using topical BAC-preserved bimatoprost. The oxidative stress markers in the tear film samples were evaluated: total protein (TP) concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl (-SH) groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response (TAR), and Oxidative Stress Index (OSI). Results: The TP concentrations in the groups L, L+BAC, and B+BAC were statistically significantly higher in comparison with group C. The SOD and CAT activities in the groups L+BAC and B+BAC were statistically significantly higher when compared to group C. As compared to group C, AOPP and TOS were statistically significantly higher in all the study groups. OSI was found to be statistically significantly higher in the groups L+BAC, T, and B+BAC in comparison with group C. Conclusion: Use of topical PGAs by the patients with ocular hypertension or primary open-angle glaucoma is associated with increased oxidative stress in the tear film which is additionally exacerbated by the presence of BAC in the formulation.

Background Measuring the effects of the acute intake of natural products on human biomarker concentrations, such as those related to oxidation and inflammation, can be an advantageous strategy for early clinical research on an ingredient or product. Methods 31 total healthy subjects were randomized in a double-blinded, placebo-controlled, acute pilot study with post-hoc subgroup analysis on 20 of the subjects. The study examined the effects of a single dose of a polyphenol-rich beverage (PRB), commercially marketed as \"SoZo ® \", on serum anti-inflammatory and antioxidant markers. In addition, phytochemical analyses of PRB, and in vitro antioxidant capacity were also performed. Results At 1 hour post-intake, serum values for 8-iso-PGF2-alpha and advanced oxidation protein products decreased significantly by 40% and 39%, respectively. Additionally, there was a trend toward decreased C-reactive protein, and increased nitric oxide levels. Both placebo and PRB treatment resulted in statistically significant increases in hydroxyl radical antioxidant capacity (HORAC) compared to baseline; PRB showed a higher percent change (55-75% versus 23-74% in placebo group), but the two groups did not differ significantly from each other. Conclusions PRB produced statistically significant changes in several blood biomarkers related to antioxidant/anti-inflammatory effects. Future studies are justified to verify results and test for cumulative effects of repeated intakes of PRB. The study demonstrates the potential utility of acute biomarker measurements for evaluating antioxidant/anti-inflammatory effects of natural products.

This experiment evaluated the impacts of estrus expression and intensity, estimated by physical activity during a timed-AI protocol, on reproductive performance of Bos indicus-influenced beef cows. A total of 290 lactating, primiparous, and multiparous nonpregnant Nelore × Angus cows received a 2 mg injection of estradiol benzoate and an intravaginal progesterone (P4) releasing device (CIDR) on d −11, a 12.5 mg injection of PGF2α on d −4, CIDR removal in addition to 0.6 mg injection of estradiol cypionate and 300 IU injection of eCG on d −2, and timed-AI on d 0. Cows were fitted with a pedometer behind their left shoulder on d −4. An estrus detection patch was attached to the tail-head of each cow on d −2. Pedometer results were recorded on d −2 and 0. Estrus expression was defined as removal of >50% of the rub-off coating from the patch on d 0. Net physical activity during estrus was calculated by subtracting total steps from d −4 to −2 (nonestrus basal activity) from total steps from d −2 to 0 (proestrus + estrus period) of each cow. Cows that did not express estrus were classified as NOESTR. Cows that expressed estrus were ranked by net physical activity; those above the median were classified as HIESTR and the remaining cows as LWESTR. Ovarian ultrasonography was performed on d 0 and 7. Blood was collected on d 0, 7, 20, and 30. Pregnancy status was verified by ultrasonography on d 30. Only data from cows responsive to the estrus synchronization protocol were utilized (NOESTR, n = 59; LWESTR, n = 100; HIESTR, n = 98). Diameter of dominant follicle on d 0, corpus luteum volume on d 7, and plasma P4 concentrations on d 7 were greater (P ≤ 0.05) in HIESTR vs. LWESTR and NOESTR and also greater (P ≤ 0.05) for LWESTR vs. NOESTR. Plasma P4 concentrations on d 0 were greater (P < 0.01) in NOESTR vs. HIESTR and LWESTR and similar (P = 0.93) between HIESTR and LWESTR. Whole blood mRNA expression of myxovirus resistance 2 on d 20 was greater (P ≤ 0.05) in HIESTR vs. LWESTR and NOESTR, and similar (P = 0.72) between LWESTR and NOESTR. Pregnancy rates were less (P ≤ 0.04) in NOESTR vs. HIESTR and LWESTR (52.4%, 68.9%, and 73.5%, SEM = 7.2), and similar (P = 0.57) between HIESTR and LWESTR. Hence, expression of estrus during a timed-AI protocol improved ovarian dynamics and pregnancy success, whereas estrus intensity modulated key biological markers associated with fertility but not pregnancy rates in B. indicus-influenced cows beef cows.

Oxytocin receptor antagonists (OTR-A) have been developed as tocolytics for the management of preterm labour due to the significant role of oxytocin (OT) in the onset of both term and preterm labour. Similar to OT, prostaglandins (PGs) play key roles in myometrial contractility and cervical ripening. Inhibition of PG synthesis/activity is used to delay preterm birth. Thus, targeting the PG pathway in combination with an OTR-A may be an effective strategy for delaying preterm delivery. In this study, we examined the effects of atosiban and nolasiban on PGF -induced contractions and pro-inflammatory responses in human pregnant myometrium. Both OTR-As, atosiban and nolasiban, inhibited PGF -induced contractions in a dose-dependent manner (p < 0.001 and p < 0.01, respectively). These inhibitory effects involved the suppression of PGF -mediated increase in intracellular calcium levels. In addition, the OTR-As significantly suppressed PGF -induced activation of pro-inflammatory pathways such as NF-κB and mitogen activated protein kinases (MAPKs), and the subsequent expression of contraction-associated-protein, COX-2. We have demonstrated that atosiban and nolasiban not only inhibit contractions elicited by OT, but also inhibit contractions and inflammation induced by PGF . This suggests a possible crosstalk between OTR and PG receptor signalling and highlights the importance of understanding G protein-coupled receptor interactions/crosstalk in the development of future tocolytics.

2D and 3D cultures of 3T3-L1 cells were employed in a study of the effects of Omidenepag (OMD), interacting with a non-prostanoid EP2 receptor, on adipogenesis. Upon adipogenesis, the effects on lipid staining, the mRNA expression of adipogenesis-related genes ( Pparγ, CEBPa , Ap2, and Glut4 ) and the extracellular matrix (ECM) including collagen type 1, 4 and 6, and fibronectin, and the size and physical property of 3D organoids were compared between groups that had been treated with EP2 agonists (butaprost and OMD) and PGF2α. Upon adipogenesis, these significantly suppressed lipid staining and the mRNA expression of related genes. EP2 agonists and PGF2α influenced the mRNA expression of ECM in different manners, and these effects were also different between 2 and 3D cultures. Examining the physical properties by a microsqueezer indicated that the solidity of the 3D organoids became significantly lowered upon adipogenesis and these effects were not affected by EP2 agonists. In contrast, 3D organoid stiffness was markedly enhanced by the presence of PGF2α. These observations indicate that EP2 agonists affect the adipogenesis of 3T3-L1 cells in different manners, as compared to PGF2α, suggesting that OMD may not induce PGF2α related orbital fat atrophy, called the deepening of the upper eyelid sulcus (DUES).

Purpose: This study aimed to compare the effects of the phytoestrogens resveratrol (RES) and genistein (GEN) on the contractility of isolated uterine smooth muscle from rats, focusing on both spontaneous and stimulated contractions, and to investigate the underlying mechanisms. Methods: Uterine strips were suspended vertically in perfusion chambers containing Kreb’s solution, various concentrations of RES and GEN were added to the ex vivo uterine strips, and contractions were measured before and after incubation with RES or GEN. Results: (1) Both RES and GEN inhibited K+-induced contractions in a dose-dependent manner; the β/β2-adrenoceptor antagonist propranolol (PRO), ICI118551, the ATP-dependent K+ channel blocker glibenclamide (HB-419) and the NO synthase inhibitor N-nitro-L-arginine (L-NNA) diminished the inhibitory effects of RES and GEN on K+-induced contractions. (2) RES and GEN also dose-dependently inhibited PGF2α-induced uterine contractions. (3) The inhibitory effects of RES and GEN were observed in spontaneous contractile activities as well; PRO, ICI118551, HB-419 and L-NNA attenuated the inhibitory effects of RES and GEN on the spontaneous contractions of isolated uterine muscle strips. (4) RES and GEN significantly decreased the cumulative concentration response of Ca2+ and shifted the Ca2+ cumulative concentration–response curves to the right in high-K+ Ca2+-free Kreb’s solution. (5) RES and GEN markedly reduced the first phasic contraction induced by oxytocin, acetylcholine, and prostaglandin F2α but did not alter the second phasic contraction caused by CaCl2 in Ca2+-free Kreb’s solution. Conclusions: RES and GEN can directly inhibit both spontaneous and activated contractions of isolated uterine smooth muscle. The mechanisms underlying the inhibitory effects of RES and GEN likely involve β adrenergic receptor activation, reduced Ca2+ influx and release, the activation of ATP-dependent K+ channels and increased NO production.

Optimal oxygen saturation as measured by pulse oximetry (SpO2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the SpO2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO2) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance and oxidative stress. Meconium was instilled into endotracheal tubes in 25 near-term gestation lambs, and the umbilical cord was occluded to induce asphyxia and gasping, causing MAS and PPHN. Lambs were randomized into four groups and ventilated for 6 hours with fixed fraction of inspired oxygen (FiO2) = 1.0 irrespective of SpO2, and three groups had FiO2 titrated to keep preductal SpO2 between 85% and 89%, 90% and 94%, and 95% and 99%, respectively. Tissues were collected to measure nitric oxide synthase activity, 3-nitrotyrosine, and 8-isoprostanes. Throughout the 6-hour exposure period, lambs in the 95–99% SpO2 target group had the highest Qp, lowest pulmonary vascular resistance, and highest bDO2 but were exposed to higher FiO2 (0.5 ± 0.21 vs. 0.29 ± 0.17) with higher lung 3-nitrotyrosine (0.67 [interquartile range (IQR), 0.43–0.73] ng/mcg protein vs. 0.1 [IQR, 0.09–0.2] ng/mcg protein) and lower lung nitric oxide synthase activity (196 [IQR, 192–201] mMol nitrite/mg protein vs. 270 [IQR, 227–280] mMol nitrite/mg protein) compared with the 90–94% target group. Brain 3-nitrotyrosine was lower in the 85–89% target group, and brain/lung 8-isoprostane levels were not significantly different. In term lambs with MAS and PPHN, Qp and bDO2 through the first 6 hours are higher with target SpO2 in the 95–99% range. However, the 90–94% target range is associated with significantly lower FiO2 and lung oxidative stress. Clinical trials comparing the 90–94% versus the 95–99% SpO2 target range in term infants with PPHN are warranted.

Prostaglandin F2 alpha (PGF2α) analogues such as latanoprost are common first-line intraocular pressure (IOP) lowering medications. However, their clinical use is limited in some patient populations due to minimal or no IOP lowering response or side effects. In searching for a more targeted approach for IOP reduction, our lab recently identified Stanniocalcin-1 (STC-1) as a molecule that was required for latanoprost-mediated IOP reduction and also acted as a stand-alone IOP lowering agent. In order to determine whether latanoprost and STC-1 were equivalent and/or additive for IOP reduction, we treated C57BL/6J mice with one or a combination of these agents and measured IOP. Importance of the FP receptor for latanoprost- and STC-1-mediated IOP reduction was examined in C57BL/6J mice utilizing the pharmacologic FP receptor inhibitor AL-8810 as well as FP receptor knockout mice generated in our laboratory. Latanoprost-free acid (LFA) and STC-1 reduced IOP to a similar degree and were non-additive in C57BL/6J mice. As expected, the IOP lowering effects of LFA were abrogated by pharmacologic inhibition of the FP receptor with AL-8810 and in FP receptor knockout mice. In contrast, STC-1 maintained IOP-lowering effects in the presence of AL-8810 and also in FP receptor knockout mice. These results suggest that LFA and STC-1 show equivalent and non-additive IOP reduction in C57BL/6J mice and that unlike LFA, STC-1-mediated IOP reduction occurs independent of the FP receptor.

Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy.

Partial budget analysis was used to determine the economic outcome of estrus synchronization (ES) and timed artificial insemination (TAI) in commercial cow-calf production. Suckled beef cows (n = 1,197) from 8 locations were assigned randomly within each location to 1 of 2 treatment groups: 1) cows were inseminated artificially after synchronization of ovulation using the CO-Synch + CIDR protocol, which includes a 100-μg injection of GnRH (OvaCyst; TevaAnimal Health, St. Joseph, MO) when a controlled internal drug-releasing device (CIDR; Pfizer Animal Health, New York, NY) containing 1.38 g of progesterone was inserted. The CIDR was removed 7 d later, and cows received a 25-mg injection of PGF(2α) (PGF; Lutalyse; Pfizer Animal Health), followed in 66 h with TAI and a second 100-μg injection of GnRH (TAI; n = 582), and 2) cows were exposed to natural service (NS) without estrous synchronization (Control; n = 615). Within each herd, cows from both treatments were maintained together in similar pastures and were exposed to bulls 12 h after the last cow in the TAI treatment was inseminated. Overall, the percentage of cows exposed to treatments that subsequently weaned a calf was greater (P < 0.05) for TAI (84%) than Control (78%) cows. In addition, survival analysis demonstrated that cumulative calving distribution differed (P < 0.05) between the TAI and Control treatments. Weaning weights per cow exposed to treatments were greater (P < 0.01) for cows in the TAI treatment (193.4 ± 4.3 kg) than those cows in the Control treatment (175.9 ± 4.3 kg). Overall, increased returns plus decreased costs ($82.32) minus decreased returns plus increased costs ($33.18) resulted in a $49.14 advantage per exposed cow in the TAI treatment compared with the Control treatment. Location greatly influenced weaned calf weights, which may have been a result of differing management, nutrition, genetic selection, production goals, and environments. We concluded that ES and TAI had a positive economic impact on subsequent weaning weights of exposed cows.