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In Russia today, more than ever, various social welfare institutions (Centers for social services, Social assistance centers for families and children, Rehabilitation centers for disabled children and their families, Centers for work with refugees and IDPs, Centers of medico-social rehabilitation of military men, etc.) require legal profile specialists, who are characterized by high professional culture and capable of effective advocacy. The article considers peculiarities of the lawyer's professional activity in social welfare institutions. It describes structural components, levels of formedness of the lawyer's professional readiness to work in social service. Didactic characteristics of the process of forming future lawyers' professional readiness to work in various types of social welfare institutions is given, and conditions providing efficiency of this process are experimentally proven.

The aerosol inhalation delivery of composite particles consisting of Ag nanoparticles enveloped by polyvinylpyrrolidone was investigated in experiments with mice. An ultrasonic nebulizing system was created for the generation of aerosols with a mean diameter and mass concentration of 700 ± 50 nm and 65 ± 5 mg/m3, respectively. The mass fraction of Ag in the composite particles was α = 0.061. The aerosol delivery was performed in a whole-body chamber with an exposition time of 20 min. Pharmacokinetic measurements were taken and the silver concentrations in the blood and lungs of the mice were measured as a function of time after exposition by means of electrothermal (graphite furnace) atomic absorption spectrometry. The inhalation dose and other pharmacokinetic parameters were determined. The antibacterial effect of aerosolized silver was assessed for mice infected with Klebsiella pneumoniae 82 and Staphylococcus aureus ATCC 25953. The survival rate of the infected mice after the aerosol exposure demonstrated the high antibacterial efficiency of Ag nanoparticles after inhalation delivery.

One of the little-studied ways that climate warming or temperature increases in aquaculture could affect aquatic animals is through accelerated aging. This study is dedicated to understanding the principles of molecular and cellular aging in the target tissues of juvenile whitefishes (Yenisei hump-snout whitefish and its hybrid) under the influence of acute heat stress (up to 26 °C), and the effects of thermal preconditioning as pre-adaptation. Non-adapted stressed hump-snout whitefish showed a higher induction threshold for functionally active mitochondria in the blood and a decrease in telomerase activity in the liver after heat shock exposure as a long-term compensatory response to prevent telomere shortening. However, we observed heat-induced telomere shortening in non-adapted hybrids, which can be explained by a decrease in mitochondrial membrane stability and a gradual increase in energy demand, leading to a decrease in protective telomerase activity. The pre-adapted groups of hump-snout whitefish and hybrids showed a long-term or delayed response of telomerase activity to heat shock, which served as a therapeutic mechanism against telomere shortening. We concluded that the telomerase and telomere responses to thermal stress demonstrate plasticity of tolerance limits and greater stability in hump-snout whitefish compared with hybrids.

Ayan et al. report two structures of the protein streptavidin - one at ambient temperature determined using serial femtosecond crystallography and a second one determined at cryogenic temperature. These results provide insights into the structural dynamics of apo streptavidin and reveal a cooperative allostery between monomers for binding to biotin, and the findings are supported by GNM analysis.

The article presents the results of a longitudinal study of young people belonging to the category of generation Z. The study was conducted over a period of 3 years, starting in 2019, and was devoted to studying the formation of social characteristics of generation Z under the influence of socialization in the digital environment. The study also included a comparative analysis of the younger and older age groups in Generation Z, who are now high school students and students. The results of the study showed that the younger representatives of generation Z have a more pronounced desire for individualism and self-organization on the Internet. The social characteristics of generation Z must be taken into account when organizing online learning.

Berberine is a phytogenic isoquinoline alkaloid which demonstrates several pharmacological effects, including a hypoglycemic effect. Its medical use is limited by its very low bioavailability. Synthesizing new berberine derivatives might help in overcoming this problem. In this work, we report on the synthesis and biological evaluation of a novel berberine 9-O-derivative. At an oral dose of 25 mg/kg, the compound demonstrated hypoglycemic activity in an oral glucose tolerance test performed using C57BL/6 mice.

Derivatives of dihydropyridines are promising agents for research, as they have high biological activity. Their low toxicity and polytargeted properties make it possible to create new derivatives and identify new biological activity. As part of this work, we have obtained six new fluorinated derivatives of 4-phenyl-1,4-dihydropyridines. These compounds were synthesized by a modified Hantzsch reaction, the interaction of polyfluorinated sulfur-containing benzaldehydes with ethyl acetoacetate and ethyl 3-aminobut-2-enoate. Studies on the isolated atrium have shown that the possible mechanism of action of the dihydropyridine derivatives lies in the blockade of beta-adrenergic receptors. At the same time, it is not a blocker of potassium and calcium channels. The fluorinated 4-phenyl-1,4-dihydropyridine derivatives, with SCF2H (decrease pressure) and SO2CH3 (increase pressure) groups showed pronounced activity in the study of these derivatives on the blood pressure of rats.

Еhe anabolic properties of a new composition of leuzea and cranberry meal extracts in a ratio of 7:50, containing ecdisten and ursolic acid, respectively, have been investigates on a model of isolated overload of the skeletal muscle of the rats leg by the method of excision. Material and methods. The experiment was conducted on Wistar stock rats of both sexes weighing 220–250 g. At the beginning of the experiment, all animals underwent musculus gastrocnemius tenotomy (m.gastrocnemius), and then the composition has been intragastrically administered for 14 days. At the end of the experiment, the rats were decapitated, blood was taken to determine biochemical parameters (creatine phosphokinase activity, glucose and lactate level) and muscles from both legs were separated to determine the difference between the mass of the musculus soleus (m. soleus) operated on and the mass m.soleus of a non-operated paw. Results and discussion. A dose-dependent anabolic effect was established for the composition of leuzea and cranberry meal extracts. A gender difference was found, which was confirmed by the obtained values of creatine phosphokinase activity and glucose/lactate ratio. Conclusions. The composition of leuzea and cranberry meal extracts exhibits a dose-dependent anabolic effect in males and increase physical endurance in female rats on the model of isolated overload of the skeletal muscle of the leg of rats with tenotomy operation.

With advances in X-ray free-electron lasers (XFELs), serial femtosecond crystallography (SFX) has enabled the static and dynamic structure determination for challenging proteins such as membrane protein complexes. In SFX with XFELs, the crystals are typically destroyed after interacting with a single XFEL pulse. Therefore, thousands of new crystals must be sequentially introduced into the X-ray beam to collect full data sets. Because of the serial nature of any SFX experiment, up to 99% of the sample delivered to the X-ray beam during its “off-time” between X-ray pulses is wasted due to the intrinsic pulsed nature of all current XFELs. To solve this major problem of large and often limiting sample consumption, we report on improvements of a revolutionary sample-saving method that is compatible with all current XFELs. We previously reported 3D-printed injection devices coupled with gas dynamic virtual nozzles (GDVNs) capable of generating samples containing droplets segmented by an immiscible oil phase for jetting crystal-laden droplets into the path of an XFEL. Here, we have further improved the device design by including metal electrodes inducing electrowetting effects for improved control over droplet generation frequency to stimulate the droplet release to matching the XFEL repetition rate by employing an electrical feedback mechanism. We report the improvements in this electrically triggered segmented flow approach for sample conservation in comparison with a continuous GDVN injection using the microcrystals of lysozyme and 3-deoxy-D-manno-octulosonate 8-phosphate synthase and report the segmented flow approach for sample injection applied at the Macromolecular Femtosecond Crystallography instrument at the Linear Coherent Light Source for the first time.

Serial femtosecond crystallography (SFX) at X-ray free-electron lasers (XFELs) enables essentially radiation-damage-free macromolecular structure determination using microcrystals that are too small for synchrotron studies. However, SFX experiments often require large amounts of sample in order to collect highly redundant data where some of the many stochastic errors can be averaged out to determine accurate structure-factor amplitudes. In this work, the capability of the Swiss X-ray free-electron laser (SwissFEL) was used to generate large-bandwidth X-ray pulses [Δλ/λ = 2.2% full width at half-maximum (FWHM)], which were applied in SFX with the aim of improving the partiality of Bragg spots and thus decreasing sample consumption while maintaining the data quality. Sensitive data-quality indicators such as anomalous signal from native thaumatin micro-crystals and de novo phasing results were used to quantify the benefits of using pink X-ray pulses to obtain accurate structure-factor amplitudes. Compared with data measured using the same setup but using X-ray pulses with typical quasi-monochromatic XFEL bandwidth (Δλ/λ = 0.17% FWHM), up to fourfold reduction in the number of indexed diffraction patterns required to obtain similar data quality was achieved. This novel approach, pink-beam SFX, facilitates the yet underutilized de novo structure determination of challenging proteins at XFELs, thereby opening the door to more scientific breakthroughs.

Here, we illustrate what happens inside the catalytic cleft of an enzyme when substrate or ligand binds on single-millisecond timescales. The initial phase of the enzymatic cycle is observed with near-atomic resolution using the most advanced X-ray source currently available: the European XFEL (EuXFEL). The high repetition rate of the EuXFEL combined with our mix-and-inject technology enables the initial phase of ceftriaxone binding to the Mycobacterium tuberculosis β-lactamase to be followed using time-resolved crystallography in real time. It is shown how a diffusion coefficient in enzyme crystals can be derived directly from the X-ray data, enabling the determination of ligand and enzyme–ligand concentrations at any position in the crystal volume as a function of time. In addition, the structure of the irreversible inhibitor sulbactam bound to the enzyme at a 66 ms time delay after mixing is described. This demonstrates that the EuXFEL can be used as an important tool for biomedically relevant research.

Usnic acid is produced by lichens and exhibits different biological properties, including hypoglycemic ones. However, this effect becomes noticeable only at relatively high doses, something that may lead to some adverse effects. The chemical modification of the molecule is able to enhance its safety profile and its hypoglycemic properties. We synthesized six enamine derivatives of (+)-usnic acid, and two of them are novel. All compounds were evaluated for the hypoglycemic effect after oral introduction in mice with alloxan-induced diabetes mellitus at a dose of 50 mg/kg. The derivative containing a 4-trifluoromethylphenyl fragment showed the most pronounced hypoglycemic effect, which was detected starting from sixth day of the experiment. Also, OGTT was performed in mice without alteration of glucose metabolism (C57BL/6), which showed no hypoglycemic effect after oral introduction of all studied compounds.

Opisthorchiosis is a parasitic liver disease found in mammals that is widespread throughout the world and causes systemic inflammation. Praziquantel remains the drug of choice for the treatment of opisthorchiosis, despite its many adverse effects. An anthelmintic effect is attributed to the main curcuminoid of Curcuma longa L. roots—curcumin (Cur)—along with many other therapeutic properties. To overcome the poor solubility of curcumin in water, a micellar complex of curcumin with the disodium salt of glycyrrhizic acid (Cur:Na2GA, molar ratio 1:1) was prepared via solid-phase mechanical processing. In vitro experiments revealed a noticeable immobilizing effect of curcumin and of Cur:Na2GA on mature and juvenile Opisthorchis felineus individuals. In vivo experiments showed that curcumin (50 mg/kg) had an anthelmintic effect after 30 days of administration to O. felineus-infected hamsters, but the effect was weaker than that of a single administration of praziquantel (400 mg/kg). Cur:Na2GA (50 mg/kg, 30 days), which contains less free curcumin, did not exert this action. The complex, just as free curcumin or better, activated the expression of bile acid synthesis genes (Cyp7A1, Fxr, and Rxra), which was suppressed by O. felineus infection and by praziquantel. Curcumin reduced the rate of inflammatory infiltration, whereas Cur:Na2GA reduced periductal fibrosis. Immunohistochemically, a decrease in liver inflammation markers was found, which is determined by calculating the numbers of tumor-necrosis-factor-positive cells during the curcumin treatment and of kynurenine-3-monooxygenase-positive cells during the Cur:Na2GA treatment. A biochemical blood test revealed a normalizing effect of Cur:Na2GA (comparable to that of curcumin) on lipid metabolism. We believe that the further development and investigation of therapeutics based on curcuminoids in relation Opisthorchis felineus and other trematode infections will be useful for clinical practice and veterinary medicine.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. Several classes of hypoglycemic drugs are used to treat it, but various side effects limit their clinical use. Consequently, the search for new anti-diabetic agents remains an urgent task for modern pharmacology. In this investigation, we examined the hypoglycemic effects of bornyl-containing benzyloxyphenylpropanoic acid derivatives (QS-528 and QS-619) in a diet-induced model of T2DM. Animals were given the tested compounds per os at a dose of 30 mg/kg for 4 weeks. At the end of the experiment, compound QS-619 demonstrated a hypoglycemic effect, while QS-528 showed hepatoprotection. In addition, we performed a number of in vitro and in vivo experiments to study the presumed mechanism of action of the tested agents. Compound QS-619 was determined to activate the free fatty acid receptor-1 (FFAR1) similarly to the reference agonist GW9508 and its structural analogue QS-528. Both agents also increased insulin and glucose-dependent insulinotropic polypeptide concentrations in CD-1 mice. Our results indicate that QS-619 and QS-528 are probably full FFAR1 agonists.

Mix-and-inject serial crystallography (MISC) is a technique designed to image enzyme catalyzed reactions in which small protein crystals are mixed with a substrate just prior to being probed by an X-ray pulse. This approach offers several advantages over flow cell studies. It provides (i) room temperature structures at near atomic resolution, (ii) time resolution ranging from microseconds to seconds, and (iii) convenient reaction initiation. It outruns radiation damage by using femtosecond X-ray pulses allowing damage and chemistry to be separated. Here, we demonstrate that MISC is feasible at an X-ray free electron laser by studying the reaction of M. tuberculosis ß-lactamase microcrystals with ceftriaxone antibiotic solution. Electron density maps of the apo-ß-lactamase and of the ceftriaxone bound form were obtained at 2.8 Å and 2.4 Å resolution, respectively. These results pave the way to study cyclic and non-cyclic reactions and represent a new field of time-resolved structural dynamics for numerous substrate-triggered biological reactions.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5′-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5′-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

This study was conducted to evaluate the effects of long-term administration of a new herbal composition of leuzea and cranberry meal extracts at a dose of 70:500 mg/kg in healthy and pathological mice. After 4 weeks of daily composition administration to healthy CD-1 mice and C57BL/6 mice with diet-induced metabolic syndrome, oral glucose tolerance test (OGTT), serum biochemical examination and histology of internal organs were performed. Additionally, histological examination of white and brown adipose tissue was performed to evaluate the ability of the composition to prevent abdominal obesity in C57BL/6Ay (agouti yellow) mice. The results showed that the composition increased tissue sensitivity to glucose in healthy CD-1 mice; at the same time, it did not worsen the course of pathological processes in pathological mice. In both cases, the application of the developed composition was safe and contributed to the restoration of metabolic parameters.

Free fatty acid receptor-1 (FFAR1) agonists are promising candidates for therapy of type 2 diabetes because of their ability to normalize blood sugar levels during hyperglycemia without the risk of hypoglycemia. Previously, we synthesized compound QS-528, a FFA1 receptor agonist with a hypoglycemic effect in C57BL/6NCrl mice. In the present work, structural analogs of QS-528 based on (hydroxyphenyl)propanoic acid bearing a bornyl fragment in its structure were synthesized. The seven novel compounds synthesized were structural isomers of compound QS-528, varying the positions of the substituents in the aromatic fragments as well as the configuration of the asymmetric center in the bornyl moiety. The studied compounds were shown to have the ability to activate FFAR1 at a concentration of 10 μM. The cytotoxicity of the compounds as well as their effect on glucose uptake in HepG2 cells were studied. The synthesized compounds were found to increase glucose uptake by cells and have no cytotoxic effect. Two compounds, based on the meta-substituted phenylpropanoic acid, 3-(3-(4-(((1R,2R,4R)-1,7,7-trimethylbicyclo-[2.2.1]heptan-2-ylamino)methyl)benzyloxy)phenyl)propanoic acid and 3-(3-(3-(((1R,2R,4R)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-ylamino)methyl)benzyloxy)phenyl)propanoic acid, were shown to have a pronounced hypoglycemic effect in the oral glucose tolerance test with CD-1 mice.

The composition of an ethanol extract from the roots of Rumex tianschanicus Losinsk of the Trans-Ili Alatau wild flora was studied in order to determine its antiulcer activity. The phytochemical composition of the anthraquinone–flavonoid complex from (AFC) R. tianschanicus revealed the presence of numerous polyphenolic compounds, the most abundant of which are anthraquinones (1.77%), flavonoids (6.95%), and tannins (13.39%). The use of column chromatography (CC) and thin-layer chromatography (TLC) in conjunction with UV, IR, NMR spectroscopy, and mass spectrometry data allowed the researchers to isolate and identify the major components of the anthraquinone–flavonoid complex’s polyphenol fraction: physcion, chrysophanol, emodin, isorhamnetin, quercetin, and myricetin. The gastroprotective effect of the polyphenolic fraction of the anthraquinone–flavonoid complex (AFC) of R. tianschanicus roots was examined in an experimental model of rat gastric ulcer induced by indomethacin. The preventive and therapeutic effect of the anthraquinone–flavonoid complex at a dose of 100 mg/kg was analyzed using intragastric administration per day for 1 to 10 days, followed by a histological examination of stomach tissues. It has been demonstrated that prophylactic and prolonged use of the AFC R. tianschanicus in laboratory animals resulted in significantly less pronounced hemodynamic and desquamative changes in the epithelium of gastric tissues. The acquired results thus offer fresh insight into the anthraquinone and flavonoid metabolite component composition of R. tianschanicus roots, and they imply that the examined extract can be used to develop herbal medicines with antiulcer activity.

A method for targeted structural modification of the methyl ester of phlomisoic acid was developed by introduction of an additional C-16 ketopyrazole moiety via cyclocondensation of diterpenoid alkyne-1,2- diones with arylhydrazines. The conditions for regioselective formation of labdanoid 1,3-diarylpyrazol-5- ylmethanones were found. The possibility of a sequential four-component reaction in a single pot was demonstrated. Significant analgesic activity of labdanoid-substituted diarylpyrazoles in thermal and chemical irritation models was established. [ABSTRACT FROM AUTHOR]

Introduction. In order to perform endovasal vein lining, the American Rodney D.Raabe developed a system for varicose veins obliteration, consisting of a glue gun and two catheters, called “VenaSeal”. As an occlusant for varicose veins in this system, “Medtronic” company today proposes to use an adhesive compound synthesized on the basis of butyl ether of α-cyanacrylic acid.Materials and methods. Endovasal catheter obliteration of tributaries and main trunks of the great saphenous vein on the tibia was performed in 15 patients with varicose disease (C2 to CEAR) in order to substantiate the possibility of using the adhesive compound Sulfacrylate. Severity of pain, presence or absence of phlebitis and thrombophlebitis, hyper pigmentation, neurological disorders, allergic reaction were clinically evaluated.Results and discussion. All patients after the introduction of the glue Sulfakrilat had a clinic of moderate phlebitis, without the formation of blood clots in the lumen of the vein. No local or general allergic reaction was observed. From day 7 occluded venous segments were palpated in the form of moderate density bands, without infiltration to surrounding tissues. In the absence of blood flow ultrasound examination showed gradual biodegradation of the adhesive strip inside the vein with the development of complete obliteration of the lumen starting from the 4th month. Starting with the 7th day gradually stopped aseptic inflammation in the wall of the vein was observed on histological examination. Monocytic infiltration of the venous wall with the formation of multinucleated cells of foreign bodies was present until the time of complete biodegradation of the glue. The process of diffuse growth of connective tissue with the presence of fibroblasts from the subendothelium and in the middle shell was most actively observed in histological material from 90 to 120 days after occlusion. Within 180 days, the lumen of the veins occluded by “Sulfacrylate” was completely obliterated by mature connective tissue, in the absence of glue particles, which indicated its complete biodegradation.Conclusion. The experimental studies conducted with the assessment of clinical symptoms, ultrasound examination and histological study of morphogenesis in the lumen of blood vessels in different periods up to 6 months allow us to conclude the potential use of the adhesive compound “Sulfacrylate” (produced in Russia) for endovasal obliteration of varicose veins in humans.

Free fatty acid receptor-1 (FFAR1) is one of the possible therapeutic targets in the search for new hepatoprotective drugs. FFAR1 agonists were found to have hypolipidemic, antifibrotic, anti-inflammatory, antiproliferative and antioxidant effects in addition to hypoglycemic action. In this work, we conducted a study of the hepatoprotective effect of the compound QS-528 (previously discovered as an agonist of FFAR1) at doses of 60, 90, 120 and 150 mg/kg on carbon tetrachloride (CCl4)-induced liver injury. At the end of the experiment, a biochemical blood assay demonstrated that the introduction of QS-528 dose-dependently reduces the levels of liver enzymes (AST, ALT and ALKP). Histological and morphometric studies of animals’ livers treated with QS-528 at doses of 120 and 150 mg/kg showed a decrease in degenerative/necrotic changes in hepatocytes and an increase in the regenerative activity of the liver. In addition, no toxicity at a single oral dose of 1000 mg/kg and an increase in HepG2 cell viability in vitro were found. Thus, the compound QS-528 was found to exhibit a hepatoprotective effect against CCl4-induced toxic liver damage.

Natural and synthetic coumarins are often considered privileged scaffolds for obtaining pharmacological agents with hypoglycemic activity. Chemical modification of coumarins often leads to antidiabetic agents with greater efficacy. In the present work, twenty monoterpene-substituted 7-hydroxycoumarins were synthesized. A new approach using the Mitsunobu reaction was shown to be effective for the synthesis of target compounds. All of the synthesized compounds were evaluated in an oral glucose tolerance test, and two of them containing geranyl and (-)-myrtenyl substituents showed in vivo hypoglycemic action. A possible mechanism of action of these compounds may include inhibition of DPP IV, which was proved in an in vitro test.

Xanthine derivatives have been a great area of interest for the development of potent bioactive agents. Thirty-eight methylxanthine derivatives as acetylcholinesterase inhibitors (AChE) were designed and synthesized. Suzuki–Miyaura cross-coupling reactions of 8-chlorocaffeine with aryl(hetaryl)boronic acids, the CuAAC reaction of 8-ethynylcaffeine with several azides, and the copper(I) catalyzed one-pot three-component reaction (A3-coupling) of 8-ethynylcaffeine, 1-(prop-2-ynyl)-, or 7-(prop-2-ynyl)-dimethylxanthines with formaldehyde and secondary amines were the main approaches for the synthesis of substituted methylxanthine derivatives (yield 53–96%). The bioactivity of all new compounds was evaluated by Ellman’s method, and the results showed that most of the synthesized compounds displayed good and moderate acetylcholinesterase (AChE) inhibitory activities in vitro. The structure-activity relationships were also discussed. The data revealed that compounds 53, 59, 65, 66, and 69 exhibited the most potent inhibitory activity against AChE with IC50 of 0.25, 0.552, 0.089, 0.746, and 0.121 μM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies.