Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides

The soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of epoxy-fatty acids, signaling molecules involved in numerous biologies. Toward finding novel inhibitors of sEH, a library of known drugs was tested for inhibition of sEH. We found that fulvestrant, an anticancer agent, is a potent (KI = 26 nM) competitive inhibitor of sEH. From this observation, we found that alkyl-sulfoxides represent a new kind of pharmacophore for the inhibition of sEH. © 2013 Elsevier Ltd. All rights reserved

Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase

© 2018 Elsevier Ltd Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These inhibitors are selective for FAAH over other serine hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH inhibitors have improved cross-species potency. These dual inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition

Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure-activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development. © 2012 Elsevier Ltd. All rights reserved

The development of a toxicity database using freshwater macroinvertebrates, and its application to the protection of South African water resources

There is a growing international trend towards the protection of freshwater resources from pollution by imposing instream guidelines and specified waste-discharge conditions. Current methods for devising freshwater quality guidelines are based on species sensitivity distributions (SSDs) that are used to identify pollutant concentrations, ensuring the protection of a modelled percentage of species (95% protection is a common goal). SSDs are derived from the toxicity test results of as many taxa as possible for each polluting substance. Waste-discharge licences can be for single substances, specified in terms of chemical concentrations, and derived in conjunction with instream guidelines; or for complex mixtures, specified in terms of toxic units. In both cases toxicity test results are the core data used. The emphasis on SSDs calls into question the species constituting the test populations. It is likely that SSDs based in part on the responses of local organisms will achieve superior site-specific ecological protection. Until the early 1990s, there were very few data on the tolerances of South African freshwater organisms. In the intervening decade, the Unilever Centre for Environmental Water Quality at Rhodes University has developed a toxicity database that, to date, records the responses of 21 South African freshwater taxa to 26 single-substance pollutants or mixtures. This is the most comprehensive database of South African toxicity responses available and has been used in the drawing up of methods and guidelines to protect water resources. This paper aims to make these data available and to describe applications of the data using selected case studies

Two-particle decays of B_c meson into charmonium states

The factorization of hard and soft contributions into the hadronic decays of B_c meson at large recoils is explored in order to evaluate the decay rates into the S, P and D-wave charmonia associated with rho and pi. The constraints of approach applicability and uncertainties of numerical estimates are discussed. The mode with the J/psi in the final state is evaluated taking into account the cascade radiative electromagnetic decays of excited P-wave states, that enlarges the branching ratio by 20-25%.Comment: 13 pages, LaTeX axodraw-style, 1 figure, 2 table

Prospects for the Bc Studies at LHCb

We discuss the motivations and perspectives for the studies of the mesons of the (bc) family at LHCb. The description of production and decays at LHC energies is given in details. The event yields, detection efficiencies, and background conditions for several Bc decay modes at LHCb are estimated.Comment: 20 pages, 5 eps-figure

Hygienic assessment of educational load in school children

The article describes the analysis of the weekly lesson schedule of students in the 5th grade of one of the schools in the region, the purpose of which is a hygienic assessment of the lesson schedule and the study of the level of performance of students. As a result of the hygienic assessment, violations in the schedule were revealed (optional classes are scheduled for the busiest day of the week, irrational distribution of lessons in accordance with the scale of difficulty of subjects).В статье описан анализ недельного расписания уроков учеников 5-го класса одной из школ, целью которого являются гигиеническая оценка расписания уроков и исследование уровня работоспособности школьников. В результате гигиенической оценки были выявлены нарушения в составлении расписания (факультативное занятие запланировано на самый загруженный день недели, нерациональное распределение уроков в соответствии со шкалой трудности предметов)

Gender differences in the pharmacological actions of pegylated glucagon-Like peptide-1 on endothelial progenitor cells and angiogenic precursor cells in a combination of metabolic disorders and lung emphysema

In clinical practice, the metabolic syndrome (MetS) is often associated with chronic obstructive pulmonary disease (COPD). Although gender differences in MetS are well documented, little is known about sex-specific differences in the pathogenesis of COPD, especially when combined with MetS. Consequently, it is not clear whether the same treatment regime has comparable efficacy in men and women diagnosed with MetS and COPD. In the present study, using sodium glutamate, lipopolysaccharide, and cigarette smoke extract, we simulated lipid metabolism disorders, obesity, hyperglycemia, and pulmonary emphysema (comorbidity) in male and female C57BL/6 mice. We assessed the gender-specific impact of lipid metabolism disorders and pulmonary emphysema on angiogenic precursor cells (endothelial progenitor cells (EPC), pericytes, vascular smooth muscle cells, cells of the lumen of the nascent vessel), as well as the biological effects of pegylated glucagon-like peptide 1 (pegGLP-1) in this experimental paradigm. Simulation of MetS/COPD comorbidity caused an accumulation of EPC (CD45−CD31+CD34+), pericytes, and vascular smooth muscle cells in the lungs of female mice. In contrast, the number of cells involved in the angiogenesis decreased in the lungs of male animals. PegGLP-1 had a positive effect on lipids and area under the curve (AUC), obesity, and prevented the development of pulmonary emphysema. The severity of these effects was stronger in males than in females. Furthermore, PegGLP-1 stimulated regeneration of pulmonary endothelium. At the same time, PegGLP-1 administration caused a mobilization of EPC (CD45−CD31+CD34+) into the bloodstream in females and migration of precursors of angiogenesis and vascular smooth muscle cells to the lungs in male animals. Gender differences in stimulatory action of pegGLP-1 on CD31+ endothelial lung cells in vitro were not observed. Based on these findings, we postulated that the cellular mechanism of in vivo regeneration of lung epithelium was at least partly gender-specific. Thus, we concluded that a pegGLP-1-based treatment regime for metabolic disorder and COPD should be further developed primarily for male patients

Leptonic constants of heavy quarkonia in potential approach of NRQCD

We consider a general scheme for calculating the leptonic constant of heavy quarkonium QQ-bar in the framework of nonrelativistic quantum chromodynamics, NRQCD, operating as the effective theory of nonrelativistic heavy quarks. We explore the approach of static potential in QCD, which takes into account both the evolution of effective charge in the three-loop approximation and the linearly raising potential term, which provides the quark confinement. The leptonic constants of bb-bar and cc-bar systems are evaluated by making use of two-loop anomalous dimension for the current of nonrelativistic quarks, where the factor for the normalization of matrix element is introduced in order to preserve the renormalization group invariance of estimates.Comment: 18 pages, 6 eps-figures, discussion and references added, vNRQCD analysis considere

Effects of reprogrammed splenic CD8+ T-cells in vitro and in mice with spontaneous metastatic Lewis lung carcinoma

Abstract Background Metastatic disease is a major and difficult-to-treat complication of lung cancer. Considering insufficient effectiveness of existing therapies and taking into account the current problem of lung cancer chemoresistance, it is necessary to continue the development of new treatments. Methods Previously, we have demonstrated the antitumor effects of reprogrammed CD8+ T-cells (rCD8+ T-cells) from the spleen in mice with orthotopic lung carcinoma. Reprogramming was conducted by inhibiting the MAPK/ERK signalling pathway through MEKi and the immune checkpoint PD-1/PD-L1. Concurrently, CD8+ T-cells were trained in Lewis lung carcinoma (LLC) cells. We suggested that rCD8+ T-cells isolated from the spleen might impede the development of metastatic disease. Results The present study has indicated that the reprogramming procedure enhances the survival and cytotoxicity of splenic CD8+ T-cells in LLC culture. In an LLC model of spontaneous metastasis, splenic rCD8 + T-cell therapy augmented the numbers of CD8+ T-cells and CD4+ T-cells in the lungs of mice. These changes can account for the partial reduction of tumors in the lungs and the mitigation of metastatic activity. Conclusions Our proposed reprogramming method enhances the antitumor activity of CD8+ T-cells isolated from the spleen and could be valuable in formulating an approach to treating metastatic disease in patients with lung cancer. Keywords Metastatic disease, Lung cancer, Lewis lung carcinoma, Reprogrammed spleen CD8+ T-cells, Cell therap