Current Approaches to the Preclinical Assessment of Endocrine Toxicity

Scientific relevance. Endocrine disruptors affect the functioning of endocrine organs, which leads to adverse drug reactions. Endocrine toxicity requires special attention in preclinical studies of candidate medicinal products.Aim. The study aimed to review international guidelines and approaches to assessing the risk of endocrine toxicity associated with medicinal products.Discussion. This review covers documents that provide a methodological framework for identifying and classifying a chemical compound as an endocrine disruptor. These documents include the following: Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption (Organisation for Economic Cooperation and Development, 2018), Nonclinical Evaluation of Endocrine-Related Drug Toxicity (Food and Drug Administration, 2015), and Guidance for the Identification of Endocrine Disruptors in the Context of Regulations (EU) No. 528/2012 and (EC) No. 1107/2009. The proposed algorithm for endocrine toxicity assessment involves collecting all available data on the test compound, such as the literature and previously obtained experimental data, including acute and subchronic toxicity data, and in silico predictions. Particular attention should be paid to the standard battery of preclinical chronic toxicity studies, which can identify most side effects associated with the endocrine system. The main endpoints for endocrine toxicity include changes in the mass and histopathology of the major endocrine organs (adrenal glands, testes, epididymides, ovaries, and the thyroid gland), oestrous cycle effects, reproductive toxicity, and transplacental action. A thorough assessment of the data obtained provides for the determination of unfavourable endocrine activity that requires further studies.Conclusions. The OECD guidelines offer a set of validated in vivo and in vitro tests that characterise the most important mechanisms of endocrine toxicity (oestrogen, androgen, thyroid, and steroidogenic endocrine pathways) by identified toxic effects. This approach allows researchers to identify potential endocrine disorders early in the drug development process and to optimise the scope of the required studies accordingly

THE NATURAL BETAINE INFLUENCE ON FINISHING PIGS SLAUGHTER CHARACTERISTICS

Вивчали вплив кормової добавки бетаїн на забійні показники гібридних кабанців F1. Оцінювали передзабійну масу, забійну масу, забійний вихід та масу внутрішніх органів.Встановлено, що кормова добавка бетаїн у кількості 1 кг на 1 т комбікорму сприяє збільшенню  передзабійної маси у третій дослідній групі на 4,7 кг, забійної маси на 7,4 кг та забійного виходу на 3,5 %,  порівняно з контролем.Використання бетаїну у годівлі гібридних кабанців сприяє зниженню маси селезінки у другій і четвертій дослідних групах на 21,5 % та 21,7 %.Встановлено оптимальну дозу бетаїну для згодовування гібридним кабанцям на відгодівлі.Изучали влияние кормовой добавки бетаин на убойные показатели гибридных кабанов F1. Оценивали предубойный вес, убойный вес, убойный выход и вес внутренних органов.Установлено, что кормовая добавка бетаин в количестве 1 кг на 1 т комбикорма способствует увеличению предубойного веса в третьей опытной группе на 4,7 кг, убойного веса на 7,4 кг и убойного выхода на 3,5% по сравнению с контролем.Использование бетаина в кормлении гибридных кабанов способствует снижению веса селезенки во второй и четвертой опытных группах на 21,5 % и 21,7%.Установлено оптимальную дозу бетаина для скармливания гибридным кабанам на откорме.The influence of the feed additive betaine on the slaughter characteristics of  the crossbred F1 castrated male pigs were researched. The preslaughter weight, slaughter weight, slaughter yield and viscera weight were studied.It is proved that the feed additive betaine at a dose of 1 kilogram per 1 ton of mixed feed  influences on   preslaughter weight  in the third experimental group by 4,7 kg, slaughter weight by 7,4 kg  and slaughter yield  by 3,5%  compared to control group.Using the betaine in castrated male pigs feeding  reduces the weight of the spleen in the second and fourth experimental group by 21,5 and 21,7%.The optimal dose of betaine for feeding hybrid castrated male pigs of finishing pigs has been established

Azoloazines as Perspective Antiglycating Agents for Therapy of Diabetes Complications

This work was supported by Russian Federation Ministry of education and science (grant № 4.6351.2017/8.9) and Russian Foundation for Basic Research (grant № 18-03-00787)

Совершенствование инфраструктуры аэропортов гражданской авиации с учетом проектирования организаций по техническому обслуживанию воздушных судов

Air transport is of the essence in providing conditions for the effective performance of modern economic paradigm. Operating airlines, the subjects of the Russian Federation and the State as a whole, are equally interested in the development of air transportation system infrastructure. Civil aviation ensures the transport system integrated safety and stability, the relationship of regions and human settlements, especially Siberia, the North and the Far East regions. Over the post-Soviet period in the Russian Federation, the volume of passenger and cargo operations has decreased significantly, air transport linkages between regions have been lost. Such a passenger and cargo operations-related situation has occurred with heavy traffic congestion in the country’s hubs and does not allow the Russian Federation air transportation system to develop comprehensively and harmoniously. A detailed assessment of the country's civil aviation infrastructure will enable experts to put forward proposals for the air transport system modernization and development. Working space of aircraft maintenance organizations is an integral part among air transport infrastructure facilities. In order to conduct aeronautical equipment maintenance, it is necessary to have engineering and manufacturing objects, hangars and areas to accommodate and store maintenance facilities, equipment (general, individual, specialpurpose), consumables, premises for planning and dispatching departments, space to accommodate served aircraft, their components, etc. In addition, depending on the number of served aircraft types, the air transportation volume and regular pattern, the calculation of workforce and means of engineering and aviation support is essential. These issues require in-depth development on the basis of a scientific approach using the simulation modeling methods.Воздушный транспорт играет существенную роль в обеспечении условий для эффективного функционирования современной экономики. В развитии инфраструктуры авиационно-транспортной системы одинаково заинтересованы авиаперевозчики, субъекты Российской Федерации и государство в целом. Гражданская авиация обеспечивает комплексную безопасность и устойчивость транспортной системы, взаимосвязь регионов и населенных пунктов, особенно районов Сибири, Севера и Дальнего Востока. За постсоветское время в Российской Федерации существенно сократился объем пассажирских и грузовых перевозок, были утрачены авиатранспортные связи между регионами. Такое положение с пассажирскими и грузовыми перевозками создалось при значительной концентрации транспортных потоков в узловых аэропортах страны и не позволяет авиатранспортной системе Российской Федерации развиваться всесторонне и гармонично. Комплексная оценка инфраструктуры гражданской авиации страны позволит разработать предложения по модернизации и развитию авиационно-транспортной системы. Важное место среди объектов инфраструктуры воздушного транспорта занимают производственные помещения организаций по техническому обслуживанию воздушных судов. Для выполнения технического обслуживания авиационной техники необходимы производственно-технологические сооружения, ангары и площадки для размещения и хранения средств технического обслуживания, инструмент (общий, индивидуальный, специальный), расходные материалы; помещения планово-диспетчерских отделов; площади для размещения обслуживаемых воздушных судов, их компонентов и др. Кроме того, в зависимости от количества типов обслуживаемых летательных аппаратов, интенсивности и регулярности авиаперевозок необходим расчет сил и средств инженерно-авиационного обеспечения. Эти вопросы требуют детальной проработки на основе научного подхода, в том числе с использованием методов имитационного моделирования

Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury

Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion. We identified lead compound 9g that inhibits IL-6 secretion with IC50 of 3.72 µM without apparent cytotoxicity and with minimal suppression of macrophage phagocytosis in contrast to dexamethasone. In a mouse model of LPS-induced acute lung injury, 30 mg/kg i.p. 9g ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of 9g. Treatment with compound 9g prevented the migration of CD68+ macrophages and the incidence of hemorrhage. Hence, we have identified a promising pharmacological approach for the treatment of acute lung injury that may hold promise for the development of novel drugs against cytokine-mediated complications of bacterial and viral infections. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Ministry of Education and Science of the Russian Federation, Minobrnauka: 075-15-2020-777Funding: This research was funded by the Ministry of Science and Higher Education of the Russian Federation (Agreement on the provision of grants from the federal budget in the form of subsidies under paragraph 4 of Article 78.1 of the Budget Code of the Russian Federation, Moscow, 1 October 2020 No. 075-15-2020-777)

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

© 2017 The Author(s). Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD 50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity

New antiglycating agents for diabetes therapy

It was shown that azoloazines (1) demonstrated higher antiglycation activity than reference compound, aminoguanidine, and have some potential as dipeptidylpeptidase-4 inhibitors. By given results this class of heterocycles can be considered as candidate for extended studies to develop drugs against complications of T2DM [1-4].The work was supported by the Ministry of Education and Science of Russia (grant №0836-2020-0058)

БИОЛОГИЧЕСКИЕ РЕСУРСЫ ОЗЕРА ГУСИНОЕ СЕЛЕНГИНСКОГО РАЙОНА РЕСПУБЛИКИ БУРЯТИЯ

The research is conducted on Gusinoe lake in Selenginskiy district of theRepublicofByryatiya. The lake is one of the biggest in the Gusino-Ubukinskaya system and it suffers from anthropogenic impact. The wastewaters of Hydro Power Plant and wastewaters of the settlement flow into the lake where the water is used for drinking. The authors explored thelakebioresourcesand registered 4 main cropping. The main part of biomass contains perch – Perca fluviatilis (L.), roach – Rutillus rutilus L.) and pike – Esoxlucius (L.). The authors explored the dimensionally species variation based on the analysis of research skinning and application of heterobrochate nets. The research explores the data on the age distribution in the population. The authors observed perch, roach and pike in the fish fauna of Gusinoe lake where perch dominated 93.1% on the number and 77.1% on biomass. The roach can be referred to the species of common occurrence when its share in controlling yields was 6.4% on the number and 16.4% on the mass. The proportion of pike in the biomass was 6.3%. The perch population is characterized by dominating species aged 2+ to 4+. The researchers observed insufficient number of the fish aged 6+ to 11+ in the population. The roach is characterized by the fish aged 1+ to 12+ where the species aged 3+, 8+ and 10+ dominate. The linear growth of perch is steady during 20 years. The perch growth indicator was 11% higher than average in Gusinoe lake that that in the basins of Baikal region.Исследования проведены на оз. Гусиное, расположенном вСеленгинском районе Республики Бурятия. Озеро является одним из крупнейших в Гусино-Убукунской системе озер и в настоящее время подвергается сильнейшему антропогенному воздействию. В озеро поступают сточные воды ГРЭС и непосредственно стоки самого населенного пункта, воду используют для питьевых целей. Нами были проведены исследования по изучению биоресурсов озера. В ихтиофауне зарегистрированы четыре основных промысловых вида. Основу численности биомассы составляли окунь – Perca fluviatilis (L.), плотва – Rutillus rutilus (L.), щука – Esoxlucius (L.). Нами была изучена размерно-видовая изменчивость на основе анализов научных съемок с использованием разноячеистых сетей. Были получены также данные по возрастному распределению в популяции. В период 2013–2016 гг. в ихтиофауне оз. Гусиное отмечены окунь, плотва, щука. Доминировал в уловах окунь – 93,1% по численности и 77,1% по массе. Плотву сибирскую можно отнести к обычно встречающимся видам, ее доля в контрольных уловах по численности составила 6,4, по массе – 16,4%. Удельный вес щуки по биомассе – 6,3%. У окуня в популяции преобладают особи от 2+ до 4+. Рыбы в возрасте от 6+ до 11+ составляют незначительное количество популяции. Плотва представлена рыбами в возрасте от 1+ до 12+, преобладают особи 3+, 8+ и 10+. Линейный рост окуня остается стабильным в течение 20 лет. Показатель роста окуня в оз. Гусиное был на 11% выше средних для водоемов Забайкалья значений и находился на уровне предыдущих лет

CK2 Inhibition and Antitumor Activity of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines

Today, cancer is one of the most widespread and dangerous human diseases with a high mortality rate. Nevertheless, the search and application of new low-toxic and effective drugs, combined with the timely diagnosis of diseases, makes it possible to cure most types of tumors at an early stage. In this work, the range of new polysubstituted 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines was extended. The structure of all the obtained compounds was confirmed by the data of 1H, 13C NMR spectroscopy, IR spectroscopy, and elemental analysis. These compounds were evaluated against human recombinant CK2 using the ADP-GloTM assay. In addition, the IC50 parameters were calculated based on the results of the MTT test against glioblastoma (A-172), embryonic rhabdomyosarcoma (Rd), osteosarcoma (Hos), and human embryonic kidney (Hek-293) cells. Compounds 5f, 5h, and 5k showed a CK2 inhibitory activity close to the reference molecule (staurosporine). The most potential compound in the MTT test was 5m with an IC50 from 13 to 27 µM. Thus, our results demonstrate that 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines are promising for further investigation of their antitumor properties. © 2022 by the authors.Ministry of Education and Science of the Russian Federation, Minobrnauka: FEUZ-2020–0058, H687.42B.223/20This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation, State Contract № FEUZ-2020–0058 (H687.42B.223/20)