Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors

A high throughput screening (HTS) hit, 1 (Plk1 K_i = 2.2 μM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor–acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K_i = 5 nM; EC₅₀ = 1.05 μM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.     

Design,synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors

A novel series of formoterol–phthalazinone hybrids were synthesised and evaluated as dual pharmacology β₂-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β₂-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC₅₀ = 1.05 nM, pEC₅₀ = 9.0) and potent PDE4B2 inhibitory activities (IC₅₀ = 0.092 μM).     

A comparison of a moderately hypofractionated IMRT planning technique used in a randomised UK external beam radiotherapy trial with an in-house technique for localised prostate cancer

AimTo compare the radiotherapy technique used in a randomised trial with VMAT and an in-house technique for prostate cancer.BackgroundTechniques are evolving with volumetric modulated arc therapy (VMAT) commonly used. The CHHiP trial used a 3 PTV forward planned IMRT technique (FP_CH). Our centre has adopted a simpler two PTV technique with locally calculated margins.Materials and methods25 patients treated with FP_CH to 60 Gy in 20 fractions were re-planned with VMAT (VMAT_CH) and a two PTV protocol (VMAT_60/52 and VMAT_60/48). Target coverage, conformity index (CI), homogeneity index (HI), monitor units (MU) and dose to the rectum, bladder, hips and penile bulb were compared.ResultsPTV coverage was high for all techniques. VMAT_CH plans had better CI than FP_CH (p ≤  0.05). VMAT_60/52/48 plans had better CI than VMAT_CH. FP_CH had better HI and fewer MU than VMAT (p ≤  0.05). More favourable rectum doses were found for VMAT _CH than FP_CH (V_48.6, V_52.8, V₅₇, p ≤  0.05) with less difference for bladder (p ≥  0.05). Comparing VMAT_CH to VMAT_60/52/48 showed little differences for the bladder and rectum but VMAT_CH had larger penile bulb doses (V_40.8, V_48.6, mean, D_2, p ≤  0.05). Femoral head doses (V_40.8) were similarly low for all techniques (p = ≥ 0.05).ConclusionVMAT produced more conformal plans with smaller rectum doses compared to FP_CH albeit worse HI and more MU. VMAT_60/52 and VMAT_60/48 plans had similar rectal and bladder doses to VMAT_CH but better CI and penile bulb doses which may reduce toxicity.     

Monitoring of acaricide resistance of Tetranychus urticae (Acari: Tetranychidae) from Korean apple orchards

Tetranychus urticae populations were collected from ten commercial apple orchards and their susceptibilities to 12 acaricides were tested using a leaf disc bioassay. The resistance of each T. urticae population was reported as the LC₅₀ value, the resistance ratio (RR) and the slope of the probit–concentration regression. Cross resistances of T. urticae populations were estimated using the Spearman's rank correlation coefficient. Most local populations showed low resistance levels (RR ≤ 10). Development of resistance to METI and pyrethroid acaricides differed among local populations. The highest RR value (154.6) was found in the Uiseong population to tebufenpyrad. The Geochang population was highly resistant, especially to METI and pyrethroid acaricides. T. urticae populations collected from Suwon, Chungju, Yeongju and Geochang showed moderate resistance (10 < RR ≤ 40) to more than two acaricides. Resistance ratios to abamectin, chlorfenapyr, fenbutatin-oxide and milbemectin were low (RR ≤ 10) in all populations. The LC₅₀ values of abamectin, chlorfenapyr, fenbutatin-oxide and milbemectin ranged from 0.06 to 0.2 mg/l, from 0.67 to 3.38 mg/l, from 10.12 to 40.85 mg/l and from 0.47 to 3.01 mg/l, respectively. We discuss possible cross-resistance to acaricides using Spearman's rank correlation coefficient.     

In vitro cytotoxicity and genotoxicity of five Ochna species (Ochnaceae) with excellent antibacterial activity

Extracts and fractions of some Ochna species had excellent antibacterial activity. Before considering the potential therapeutic use of these extracts it is important to determine the safety of extracts. The cytotoxicity of Ochna natalitia, Ochna pretoriensis, Ochna pulchra, Ochna gamostigmata, and Ochna serrulata (Ochnaceae) was determined in monkey kidney (Vero) cells, human hepatocellular carcinoma (C3A) cells and bovine dermis cells using the mitochondrial viability MTT assay. Their potential mutagenic effects were also determined using the Ames test with strains Salmonella typhimurium TA98 and TA100 with and without metabolic activation. The LC₅₀ values (the lethal concentration at which 50% of the cells are killed) of the extracts on the various cell lines ranged from 26 to 99 μg/ml. None of the plant species was mutagenic (mutagenic index values ≤ 1.59 for TA98 and ≤ 0.92 for TA100). In a previous study, we determined the antibacterial activity of the five extracts against Staphylococcus aureus, Escherichia coli, Enterococcus faecalis and Pseudomonas aeruginosa. From this we calculated the selectivity index (SI) values by dividing the LC₅₀ value by the minimum inhibitory concentration (MIC) to obtain the ratio of toxicity to bioactivity of each extract. The plant extracts had low SI values ≤ 1.307. This is a clear indication of non-selective toxicity, i.e. extracts are almost equally toxic to the bacteria and mammalian cell lines used in the assays. As a result, the extracts may have limited application as ingestible or intravenous therapeutic agents based on the in vitro findings. However, it may be necessary to also evaluate in vivo toxicity of the extracts in animal models as in vitro toxicity does not always equate to in vivo toxicity because of the difference in physiological microenvironment in live animals and tissue culture. Additionally, if it is the case that the toxic compounds are not the same as the active compounds, it may be possible to potentiate the extracts by the removal of toxic compounds and concentration of active compounds. The extracts may then be useful for development into treatments for topical bacterial infections.     

Esculentin-2CHa: A host-defense peptide with differential cytotoxicity against bacteria,erythrocytes and tumor cells

The host-defense peptide, esculentin-2CHa (GFSSIFRGVA¹⁰KFASKGLGK D²⁰LAKLGVDLVA³⁰ CKISKQC) shows potent (MIC ≤ 6 μM) growth inhibitory activity against clinical isolates of multidrug-resistant strains of Staphylococcus aureus, Acinetobacter baumannii, and Stenotrophomonas maltophilia and differential cytotoxic activity against human erythrocytes (LC₅₀ = 150 μM) and human non-small cell lung adenocarcinoma A549 cells (LC₅₀ = 10 μM). Esculentin-2CHa significantly (P < 0.01) stimulates the release of the anti-inflammatory cytokine IL-10 by mouse lymphoid cells and elevates its production after stimulation with concanavalin A and significantly (P < 0.05) stimulates TNF-α production by peritoneal macrophages. Effects on IL-6 and IL-1β production were not significant. Removal of the hydrophobic N-terminal hexapeptide (GFSSIF) from esculentin-2CHa results in abolition of growth inhibitory activity against S. aureus and cytotoxic activity against erythrocytes and A549 cells as well as a marked (≥16-fold) reduction in potency against A. baumannii and S. maltophilia. The primary structure of esculentin-2 has been poorly conserved between frog species but evolutionary pressure has acted to maintain the hydrophobic character of this N-terminal hexapeptide sequence. Removal of the cyclic C-terminal domain (CKISKQC) and replacement of the Cys³¹ and Cys³⁷ residues by serine resulted in appreciable decreases in cytotoxicity against all microorganisms and against mammalian cells. The more cationic [D20K, D27K] analog showed a modest increase in potency against all microorganisms (up to 4-fold) but a marked increase in cytotoxicity against erythrocytes (LC₅₀ = 11 μM) and A549 cells (LC₅₀ = 3 μM).     

Release of ferulic acid from corn cobs by alkaline hydrolysis

The process of corn cobs alkaline hydrolysis to produce solutions with high hydroxy-cinnamic acids content was investigated. In particular the attention was focused on the solubilisation of ferulic acid (FA) and related compounds, mainly p-coumaric acid (p-CA). Although these compounds have applications as antioxidants, the purpose of this work was to obtain FA solutions that can be used as feedstock for the biotechnological production of vanillin in future studies. The effects of different concentrations of NaOH (0.2 ≤ C_a ≤ 2.0N) and solid/liquid ratios (0.028 ≤ S/L ≤ 0.168 g/g) on the solubilisation of FA versus time have been investigated at room temperature. Optimal hydrolysis conditions (C_a = 0.5N, S/L = 0.084 g/g after 6 h) ensured the production of hydrolysates with relatively high contents of both FA (1171 ± 34 mg/L) and p-coumaric acid (2156 ± 64 mg/L), which can be used in future studies for the microbial transformation into vanillin.     

Synthesis and anti-parasitic activity of a novel quinolinone–chalcone series

A series of novel quinolinone–chalcone hybrids and analogues were designed, synthesized and their biological activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum evaluated. Promising molecular scaffolds with significant microbicidal activity and low cytotoxicity were identified. Quinolinone–chalcone 10 exhibited anti-parasitic properties against both organisms, being the most potent anti-L. infantum agent of the entire series (IC₅₀ value of 1.3 ± 0.1 μM). Compounds 4 and 11 showed potency toward the intracellular, amastigote stage of L. infantum (IC₅₀ values of 2.1 ± 0.6 and 3.1 ± 1.05 μM, respectively). Promising trypanocidal compounds include 5 and 10 (IC₅₀ values of 2.6 ± 0.1 and 3.3 ± 0.1 μM, respectively) as well as 6 and 9 (both having IC₅₀ values of <5 μM). Chemical modifications on the quinolinone–chalcone scaffold were performed on selected compounds in order to investigate the influence of these structural features on antiparasitic activity.     

Mixing of oxidized and bilayer phospholipids

Composition and phase dependence of the mixing of 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), with the oxidized phospholipid, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC) were investigated by characterizing the aggregation states of DPPC/PGPC and DOPC/PGPC using a fluorescence quenching assay, dynamic light scattering, and time-resolved fluorescence quenching in the temperature range 5–60 °C. PGPC forms 3.5 nm radii micelles of aggregation number 33. In the gel phase, DPPC and PGPC fuse to form mixed vesicles for PGPC molar fraction, X_PGPC ≤ 0.3 and coexisting vesicles and micelles at higher X_PGPC. Data suggest that liquid phase DPPC at 50 °C forms mixed vesicles with segregated or hemi fused DPPC and PGPC for X_PGPC ≤ 0.3. At 60 °C, DPPC and PGPC do not mix, but form coexisting vesicles and micelles. DOPC and PGPC do not mix in any proportion in the liquid phase. Two dissimilar aggregates of the sizes of vesicles and PGPC micelles were observed for all X_PGPC for T ≥ 22 °C. DOPC–PGPC and DPPC–PGPC mixing is non-ideal for X_PGPC > 0.3 in both gel and fluid phases resulting in exclusion of PGPC from the bilayer. Formation of mixed vesicles is favored in the gel phase but not in the liquid phase for X_PGPC ≤ 0.3. For X_PGPC ≤ 0.3, aggregation states change progressively from mixed vesicles in the gel phase to component segregated mixed vesicles in the liquid phase close to the chain melting transition temperature to separated coexisting vesicles and micelles at higher temperatures.     

Directional selection by termites at a branching node created by a ballpoint pen

Subterranean termites excavate complex underground tunnels for foraging. Most tunnels comprise primary and secondary tunnels. Tunnels originating from the nest are called primary and those branching from the primary tunnels are named secondary tunnels; tertiary and quaternary tunnels are rarely observed. During foraging, termites may thus encounter a considerable number of tunnel-branching nodes. Directional selection at such a node is likely correlated to tunnel-growth activity because tunnels containing more termites have a higher probability of growth. In this study, we investigated how termites select the direction of movement at an artificially-designed branching node, by making chemical trails on filter paper, drawing lines using a ballpoint pen which contained the chemical substance that induces the termite to follow trails. The trails consisted of two lines: straight and branching. The branching line was drawn from the center of the straight line at an angle θ (10°, 20°,…, 90°). We then calculated the ratio of the directional selection as r = N_s/N_b, where N_s and N_b represent the number of straight and branching tunnels selected, respectively. The values of r were statistically classified into three groups based on the angle of the branching trail, as follows: 10° ≤ θ ≤ 20°, 30° ≤ θ ≤ 60°, and 70° ≤ θ ≤ 90°. Our paper briefly discusses the underlying mechanisms of the experimental results.     

5,6-Dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase

5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC₅₀ (1b) < 10 nM; IC₅₀ (1a) < 25 nM, EC₅₀ (1b) = 16 nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F = 24%).     

STK15 rs2273535 polymorphism and cancer risk: A meta-analysis of 74,896 subjects

Background: It has been suggested that the serine/threonine kinase 15 (STK15) T91A rs2273535 polymorphism is associated with susceptibility to cancer. However, the results are conflicting. We performed this meta-analysis to derive a more precise estimation of the relationship. Methods: PubMed was searched to select studies. Case–control studies containing available genotype frequencies of the STK15 rs2273535 polymorphism were chosen, and the odds ratio (OR) with its 95% confidence interval (CI) was utilized to assess the strength of association. Results: 52 studies – including 34,057 cases and 40,839 controls – were identified. A significant effect of the STK15 rs2273535 polymorphism on cancer risk was found (AA vs. TT: OR = 1.13, 95%CI = 1.01–1.26, P_{heterogeneity} < 0.001; AA vs. TA/TT: OR = 1.12, 95%CI = 1.02–1.22, P_{heterogeneity} < 0.001; TA/AA vs. TT: OR = 1.06, 95%CI = 1.01–1.12, P_{heterogeneity} < 0.001). Stratified analysis by cancer type revealed that the STK rs2273535 polymorphism may contribute to the risk of breast cancer (AA vs. TT: OR = 1.21, 95%CI = 1.01–1.44, P_{heterogeneity} = 0.002), colorectal cancer (AA vs. TA/TT: OR = 1.24, 95%CI = 1.05–1.47, P_{heterogeneity} = 0.124), and esophageal cancer (AA vs. TA/TT: OR = 1.19, 95%CI = 1.02–1.39, P_{heterogeneity} = 0.148). Further subgroup analysis by ethnicity indicated that there was a statistically increased cancer risk in Asians (AA vs. TA/TT: OR = 1.20, 95%CI = 1.05–1.37, P_{heterogeneity} = 0.004). Conclusion: This meta-analysis suggests that the STK15 rs2273535 polymorphism is a candidate gene polymorphism for cancer susceptibility, especially in Asian populations.     

Quantitative analysis of RU38486 (mifepristone) by HPLC triple quadrupole mass spectrometry

A sensitive liquid chromatography–mass spectrometric method was validated for the quantification of RU38486 (mifepristone) in human and murine plasma. The analyte and internal standard (alfaxolone) were extracted by liquid–liquid extraction with diethyl ether, resolved on a C18 column using gradient elution with methanol and ammonium acetate and detected after positive electrospray ionization (m/z 430 → 372; m/z 333 → 297, respectively). Quantification was linear over the range 0.5–500 ng (r² > 0.997), precise and accurate (intra-assay RSD ≤ 7.2%, RME ≤ 8.2%; inter-assay RSD ≤ 15.7% RME ≤ 10.2%). The limit of quantification (LOQ) was 50 pg injected on column, permitting reproducible analysis of RU38486 in small volumes of plasma.     

Stimuli responsive polymorphism of C12NO/DOPE/DNA complexes: Effect of pH,temperature and composition

N,N-dimethyldodecylamine-N-oxide (C₁₂NO) is a surfactant that may exist either in a neutral or cationic protonated form depending on the pH of aqueous solutions. Using small angle X-ray diffraction (SAXD) we observe the rich structural polymorphism of pH responsive complexes prepared due to DNA interaction with C₁₂NO/dioleoylphosphatidylethanolamine (DOPE) vesicles and discuss it in view of utilizing the surfactant for the gene delivery vector of a pH sensitive system. In neutral solutions, the DNA uptake is low, and a lamellar L_α phase formed by C₁₂NO/DOPE is prevailing in the complexes at 0.2 ≤ C₁₂NO/DOPE < 0.6 mol/mol. A maximum of ~ 30% of the total DNA volume in the sample is bound in a condensed lamellar phase L_α^C at C₁₂NO/DOPE = 1 mol/mol and pH 7.2. In acidic conditions, a condensed inverted hexagonal phase H_II^C was observed at C₁₂NO/DOPE = 0.2 mol/mol. Commensurate lattice parameters, a_HC ≈ d_LC, were detected at 0.3 ≤ C₁₂NO/DOPE ≤ 0.4 mol/mol and pH = 4.9–6.4 suggesting that L_α^C and H_II^C phases were epitaxially related. While at the same composition but pH ~ 7, the mixture forms a cubic phase (Pn3m) when the complexes were heated to 80 °C and cooled down to 20 °C. Finally, a large portion of the surfactant (C₁₂NO/DOPE > 0.5) stabilizes the L_α^C phase in C₁₂NO/DOPE/DNA complexes and the distance between DNA strands (d_DNA) is modulated by the pH value. Both the composition and pH affect the DNA binding in the complexes reaching up to ~ 95% of the DNA total amount at acidic conditions.     

Evaluation of insecticidal activity of the essential oil of Allium chinense G. Don and its major constituents against Liposcelis bostrychophila Badonnel

Water-distilled essential oil from the dried bulbs of Allium chinense (Liliaceae) was analyzed by gas chromatography–mass spectrometry (GC–MS). Eighteen compounds, accounting for 98.4% of the total oil, were identified and the main components of the essential oil of A. chinense were methyl allyl trisulfide (30.7%), dimethyl trisulfide (24.1%), methyl propyl disulfide (12.8%) and dimethyl disulfide (9.6%) followed by methyl allyl disulfide (3.4%) and methyl propyl trisulfide (3.6%). The essential oil exhibited contact toxicity against the booklice (Liposcelis bostrychophila) with an LC₅₀ value of 441.8 μg/cm² while the two major constituents, dimethyl trisulfide and methyl propyl disulfide had LC₅₀ values of 153.0 μg/cm² and 738.0 μg/cm² against the booklice, respectively. The essential oil of A. chinense possessed strong fumigant toxicity against the booklice with an LC₅₀ value of 186.5 μg/l while methyl allyl trisulfide (LC₅₀ = 90.4 μg/l) and dimethyl trisulfide (LC₅₀ = 114.2 μg/l) exhibited stronger fumigant toxicity than methyl propyl disulfide (LC₅₀ = 243.4 μg/l) and dimethyl disulfide (LC₅₀ = 340.8 μg/l) against the booklice. The results indicated that the essential oil and its major constituents have potential for development into natural insecticides or fumigants for control of insects in stored grains.     

Local control rates in stereotactic body radiotherapy (SBRT) of lung metastases associated with the biologically effective dose

AimTo evaluate dose differences in lung metastases treated with stereotactic body radiotherapy (SBRT), and the correlation with local control, regarding the dose algorithm, target volume and tissue density.BackgroundSeveral studies showed excellent local control rates in SBRT for lung metastases, with different fractionation schemes depending on the tumour location or size. These results depend on the dose distributions received by the lesions in terms of the tissue heterogeneity corrections performed by the dose algorithms.Materials and methodsForty-seven lung metastases treated with SBRT, using intrafraction control and respiratory gating with internal fiducial markers as surrogates (ExacTrac, BrainLAB AG), were calculated using Pencil Beam (PB) and Monte Carlo (MC) (iPlan, BrainLAB AG).Dose differences between both algorithms were obtained for the dose received by 99% (D_99%) and 50% (D_50%) of the planning treatment volume (PTV). The biologically effective dose delivered to 99% (BED_99%) and 50% (BED_50%) of the PTV were estimated from the MC results. Local control was evaluated after 24 months of median follow-up (range: 3–52 months).ResultsThe greatest variations (40.0% in ΔD_99% and 38.4% in ΔD_50%) were found for the lower volume and density cases. The BED_99% and BED_50% were strongly correlated with observed local control rates: 100% and 61.5% for BED_99% > 85 Gy and <85 Gy (p < 0.0001), respectively, and 100% and 58.3% for BED_50% > 100 Gy and <100 Gy (p < 0.0001), respectively.ConclusionsLung metastases treated with SBRT, with delivered BED_99% > 85 Gy and BED_50% > 100 Gy, present better local control rates than those treated with lower BED values (p = 0.001).     

Effect of mercury and gold on growth,nutrient uptake,and anatomical changes in Chilopsis linearis

Plants of Chilopsis linearis were grown with 0, 50, 100, and 200 μM Hg [as Hg(CH₃COO)₂] and 0 and 50 μM Au (as KAuCl₄) in hydroponics. The results showed that seedling grown with 50 μM Au + 50 μM Hg and 50 μM Au + 100 μM Hg had roots 25 and 55% shorter than control roots, respectively. The element uptake determination using ICP/OES demonstrated that Hg at 50 and 100 μM (with and without Au) significantly increased (p < 0.05) the S concentration in leaves. On the other hand, the concentration of Fe significantly increased in roots of plants treated with Au–Hg. In addition, the stems of plants treated with Hg at 100 μM, with and without Au, had 239 and 876 mg Hg/kg dry biomass (d wt), respectively. Also, at 50 μM Hg, with and without Au, stems accumulated 375 and 475 mg Hg/kg d wt. The Hg concentration in leaves (287 mg Hg/kg d wt) was higher (p < 0.05) for the treatment containing 50 μM Au + 100 μM Hg. Without Au, the Hg concentration in leaves decreased to 75 mg Hg/kg d wt. Toxicity symptoms induced by Hg in cortex cells and the vascular system were lower in plants exposed to 50 μM Au + 50 μM Hg compared to plants exposed to 50 μM Hg only. Further, the SEM micrographs revealed deposition of Au–Hg particles inside the root. Although the concentrations of Hg used in this study showed different degree of toxicity, the plants displayed good agronomic value.     

Prostaglandin E1 (PGE1), but not prostaglandin E2 (PGE2), alters luteal and endometrial luteinizing hormone (LH) occupied and unoccupied LH receptors and mRNA for LH receptors in ovine luteal tissue to prevent luteolysis

Loss of luteal progesterone secretion at the end of the ovine estrous cycle is via uterine PGF₂α secretion. However, uterine PGF₂α secretion is not decreased during early pregnancy in ewes. Instead, the embryo imparts a resistance to PGF₂α. Prostaglandins E (PGE; PGE₁ + PGE₂) are increased in endometrium and uterine venous blood during early pregnancy in ewes to prevent luteolysis. Chronic intrauterine infusion of PGE₁ or PGE₂ prevents spontaneous or IUD, estradiol-17β, or PGF₂α-induced premature luteolysis in nonbred ewes. The objective was to determine whether chronic intrauterine infusion of PGE₁ or PGE₂ affected mRNA for LH receptors, occupied and unoccupied receptors for LH in luteal and caruncular endometrium, and luteal function. Ewes received Vehicle, PGE₁, or PGE₂ every 4 h from days 10 to 16 of the estrous cycle via a cathether installed in the uterine lumen ipsilateral to the luteal-containing ovary.Jugular venous blood was collected daily for analysis of progesterone and uterine venous blood was collected on day-16 for analysis of PGF₂α and PGE. Corpora lutea and caruncular endometrium were collected from day-10 preluteolytic control ewes and day-16 ewes treated with Vehicle, PGE₁ or PGE₂ for analysis of the mRNA for LH receptors and occupied and unoccupied receptors for LH. Luteal weights on day-16 in ewes treated with PGE₁ or PGE₂ and day-10 control ewes were similar (P ≥ 0.05), but were greater (P ≤ 0.05) than in day-16 Vehicle-treated ewes. Progesterone profiles on days 10–16 differed (P ≤ 0.05) among treatment groups: PGE₁ > PGE₂ > Vehicle-treated ewes. Concentrations of PGF₂α and PGE in uterine venous plasma on day-16 were similar (P ≥ 0.05) in the three treatment groups. Luteal mRNA for LH receptors and unoccupied and occupied LH receptors were similar (P ≥ 0.05) in day-10 control ewes and day-16 ewes treated with PGE₂ and were lower (P ≤ 0.05) in day-16 Vehicle-treated ewes. PGE₂ prevented loss (P ≤ 0.05) of day-16 luteal mRNA for LH receptors and occupied and unoccupied LH receptors. Luteal and caruncular tissue mRNA for LH receptors and occupied and unoccupied LH receptors were greater (P ≤ 0.05) on day-16 of PGE₁-treated ewes than any treatment group. mRNA for LH receptors and occupied and unoccupied receptors for LH in caruncules were greater (P ≤ 0.05) in day-16 Vehicle or PGE₂-treated ewes than in day-10 control ewes. It is concluded that PGE₁ and PGE₂ share some common mechanisms to prevent luteolysis; however, only PGE₁ increased luteal and endometrial mRNA for LH receptors and occupied and unoccupied LH receptors. PGE₂ prevents a decrease in luteal mRNA for LH receptors and occupied and unoccupied receptors for LH without altering endometrial mRNA for LH receptors or occupied and unoccupied receptors for LH.     

Symmetric adamantyl-diureas as soluble epoxide hydrolase inhibitors

A series of inhibitors of the soluble epoxide hydrolase (sEH) containing two urea groups has been developed. Inhibition potency of the described compounds ranges from 2.0 μM to 0.4 nM. 1,6-(Hexamethylene)bis[(adamant-1-yl)urea] (3b) was found to be a potent slow tight binding inhibitor (IC₅₀ = 0.5 nM) with a strong binding to sEH (K_i = 3.1 nM) and a moderately long residence time on the enzyme (k_off = 1.05 × 10⁻³ s⁻¹; t_1/2 = 11 min).