New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1

Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the TOP1 inhibitor topotecan, which is a clinically used anticancer drug. This article reports the synthesis and study of usnic acid thioether and sulfoxide derivatives that efficiently suppress TDP1 activity, with IC₅₀ values in the 1.4–25.2 μM range. The structure of the heterocyclic substituent introduced into the dibenzofuran core affects the TDP1 inhibitory efficiency of the compounds. A five-membered heterocyclic fragment was shown to be most pharmacophoric among the others. Sulfoxide derivatives were less cytotoxic than their thioester analogs. We observed an uncompetitive type of inhibition for the four most effective inhibitors of TDP1. The anticancer effect of TOP1 inhibitors can be enhanced by the simultaneous inhibition of PARP1, TDP1, and TDP2. Some of the compounds inhibited not only TDP1 but also TDP2 and/or PARP1, but at significantly higher concentration ranges than TDP1. Leader compound 10a showed promising synergy on HeLa cells in conjunction with the TOP1 inhibitor topotecan.     

Impairments of Long-Term Synaptic Plasticity in the Hippocampus of Young Rats during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

Status epilepticus (SE) causes persistent abnormalities in the functioning of neuronal networks, often resulting in worsening epileptic seizures. Many details of cellular and molecular mechanisms of seizure-induced changes are still unknown. The lithium–pilocarpine model of epilepsy in rats reproduces many features of human temporal lobe epilepsy. In this work, using the lithium–pilocarpine model in three-week-old rats, we examined the morphological and electrophysiological changes in the hippocampus within a week following pilocarpine-induced seizures. We found that almost a third of the neurons in the hippocampus and dentate gyrus died on the first day, but this was not accompanied by impaired synaptic plasticity at that time. A diminished long-term potentiation (LTP) was observed following three days, and the negative effect of SE on plasticity increased one week later, being accompanied by astrogliosis. The attenuation of LTP was caused by the weakening of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling. NMDAR-current was more than two-fold weaker during high-frequency stimulation in the post-SE rats than in the control group. Application of glial transmitter D-serine, a coagonist of NMDARs, allows the enhancement of the NMDAR-dependent current and the restoration of LTP. These results suggest that the disorder of neuron–astrocyte interactions plays a critical role in the impairment of synaptic plasticity.     

Involvement of Reactive Oxygen Species in ABA-Induced Increase in Hydraulic Conductivity and Aquaporin Abundance

The role of reactive oxygen species (ROS) in ABA-induced increase in hydraulic conductivity was hypothesized to be dependent on an increase in aquaporin water channel (AQP) abundance. Single ABA application or its combination with ROS manipulators (ROS scavenger ascorbic acid and NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI)) were studied on detached roots of barley plants. We measured the osmotically driven flow rate of xylem sap and calculated root hydraulic conductivity. In parallel, immunolocalization of ABA and HvPIP2;2 AQPs was performed with corresponding specific antibodies. ABA treatment increased the flow rate of xylem, root hydraulic conductivity and immunostaining for ABA and HvPIP2;2, while the addition of antioxidants prevented the effects of this hormone. The obtained results confirmed the involvement of ROS in ABA effect on hydraulic conductivity, in particular, the importance of H₂O₂ production by ABA-treated plants for the effect of this hormone on AQP abundance.     

Nucleation of methane hydrate and ice in emulsions of water in crude oils and decane under non-isothermal conditions

Achievable supercooling for the formation of methane hydrate from water emulsions was studied in seven different crude oils and in decane. The experiments were performed under constant rate cooling from + 20 to-15 °C and a pressure of methane of 12 MPa. It was demonstrated that the shapes and positions of the resulting survival curves depend on the density, viscosity and dispersive power of oil samples used in the experiments, as well as on the degree of oil oxidation. In addition, results of the experiments on ice freezing under the same emulsions are presented. The results obtained in the work allowed us to discuss the possibility and features of primary and secondary nucleation of the hydrate and ice in the systems under consideration.     

Fluorescence spectroelectrochemical sensor for 1-hydroxypyrene

A spectroelectrochemical sensor was demonstrated for an organic compound whose oxidation proceeds through an electron transfer-chemical reaction-electron transfer (ECE) mechanism to generate new chemical species that are used for detection by fluorescence. The polycyclic aromatic hydrocarbon 1-hydroxypyrene (1-PyOH) served as a representative model analyte. The spectroelectrochemical properties of 1-PyOH in solution were explored with an optically transparent thin layer electrode. Electrochemical oxidation of 1-PyOH under acidic conditions proceeds via the ECE mechanism to a diquinonepyrene, which shows reversible electrochemistry and fluoresces at 425 nm in its reduced form, dihydroxypyrene. The sensor consisted of a tin-doped indium optically transparent electrode coated with a Nafion thin-film (20 nm) that rapidly preconcentrated the analyte at the sensor surface. Fluorescence in the film was excited by the evanescent wave from attenuated total reflection spectroscopy. Electrochemical modulation of dihydroxypyrene fluorescence at 425 nm in the 500 to -200 mV (vs Ag/AgCl) potential range was used for indirect detection of 1-PyOH. The spectroelectrochemical sensor calibration curve had a range of 5 × 10(-9) to 1 × 10(-6) M with a calculated detection limit of 1 × 10(-9) M.     

Specificity of soybean lipoxygenase-1 in hydrated reverse micelles of sodiumbis(2-ethylhexyl)sulfosuccinate (aerosol OT)

Soybean lipoxygenase-1 (EC 1.13.11.33) was purified by fast protein liquid chromatography on a MONO Q column and studied with respect to the conversion of linoleic and arachidonic acids in reverse micelles of sodiumbis(2-ethylhexyl)sulfosuccinate inn-octane. In this system the specific activities were lower by one order of magnitude than those in the corresponding aqueous system. High-performance liquid chromatography analyses indicated the predominant formation of 13S-hydroperoxy-9Z,11E-octadecadienoic acid (13-HpODE) from linoleic acid and of 15S-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15) from arachidonic acid both in the aqueous system and in the reverse micelles. After sedimentation of the hydrated reverse micelles by ultracentrifugation, both linoleic acid and 13-HpODE were found to be enriched in the micelles with only small amounts of these compounds present inn-octane. It is proposed that substrates and products of the lipoxygenase reaction are located mainly in the surfactant shell of the hydrated reverse micelles and reach the micelle-entrapped enzyme by diffusion into the aqueous interior space.     

The study of bitumen by differential scanning calorimetry: The interpretation of thermal effects

By the method of temperature-modulated differential scanning calorimetry it`s carried out the study of the microstructure of petroleum bitumen and its fractions (macro- and microcrystalline paraffins, mono-, bi-, poly cycloaromatic hydrocarbons, asphaltenes, nonpolar and polar resins). The method makes it possible to separate “order-disorder” transition from glass transition and to identify phase transitions invisible or overlapping on the curves of conventional DSC. The thermal effects of glass transition, cold crystallization and recrystallization, melting of crystalline structures, isotropization and disordering of mesophases were identified on the thermograms of bitumen and its fractions.     

On the Stochastic Sensitivity and Noise-Induced Transitions of a Kaldor-Type Business Cycle Model

In the paper, we consider a Kaldor-type model of the business cycle with external additive and internal parametric disturbances. We study analytically and numerically the probability properties of stochastically forced equilibria and limit cycles via stochastic sensitivity function technique. In particular, we discuss the effects of additive and parametric noises on the economic variables and we detect some stochastic bifurcations such as a P-bifurcation, i.e a phenomenon of noise-induced transition from monostability to bistability. This stochastic bistability causes a new trigger regime in economic dynamics.     

Studying the surface of UHMWPE films modified with graphene nanoplatelets using a Raman mapping method

Abstract

This article discusses the nature of the distribution of intact polyaniline-functionalized graphene nanoplatelets (GNPs) in the surface layer of nanomodified films of ultra-high molecular weight polyethylene (UHMWPE) using a Raman mapping method. On the Raman maps, D, G, and 2D peaks can be observed for the 0.1?wt.% GNPs content in the UHMWPE. In the surface layer of the films containing 1.0?wt.% GNPs, these signals are not detected, thereby indicating the displacement of the nanomodifier into the polymer bulk. In contrast, the polyaniline-functionalized GNPs tend to migrate to the surface of the UHMWPE nanocomposite film and evenly distribute in the surface layer as the concentration increases from 0.1 to 2.0?wt.%.