Losartan effects on liver cytochromes CYP3A, CYP2C and CYP2E1 functioning at metabolic syndrome in young and adult rats

CYP450-dependent interactions and toxicological consequences of hypoglycemic and antihypertensivedrugs used in treatment of children with metabolic syndrome (MS) remained unclear. Our aim was to carryout a complex estimation of metabolic syndrome and losartan mediated changes in CYP3A, CYP2C, CYP2E1mRNA expression, corresponding marker enzymes activities, liver antioxidant system and lipid peroxidationparameters of adult and pubertal rats. Wistar albino male rats of two age categories (young animals of 21days age (50–70 g) and adults (160–180 g) were divided into 6 groups (6 animals in each): 1 – Control 1(intact young rats); 2 – Control 2 (intact adult rats); 3 –young rats with MS; 4 – adult rats with MS; 5 – youngrats with MS+losartan; 6 – adult rats with MS+ losartan. The metabolic syndrome model was inducedby full replacement of drinking water with 20% fructose solution (200 g/l). After 60 days of MS modeling,investigation of rat liver CYP3A, CYP2C, CYP2E1 mRNA expression, their marker enzymes activities, lipidperoxidation parameters were carried out. Losartan administration caused increase of CYP3A, CYP2Cand CYP2E1 mRNA expression rates in both age groups. Marker enzymes, glutathione transferase andreductase rates were normalized only in adult rats. In group of pubertal animals losartan administration ledto CYP3A and CYP2C marker enzymes activities normalization. Liver reduced glutathione contents remaineddecreased in both age groups. Thus, losartan demonstrates some age-dependent effectiveness towardsnormalization of CYP450 isoforms expression rates, p-nitrophenol hydroxylase, erythromycin-N-demethylaseand diclofenac hydroxylase activities, but not glutathione system and lipid peroxidation rates

Study of analgesic and myotropic spasmolytic activity of alkylcarb

The work is devoted to the search for new biologically active substances in a series of alkylamides of dihydroquinoline-3-carboxylic acid. Analgesic properties of 30 newly synthesized substances were studied, which made it possible to identify the leader compound (provisional name alkylcarb) and recommend its effectiveness for further research as an antispasmodic agent for pain relief. It has been established experimentally, that the substance alkylcarb exhibits concentration-dependent vasodilatory properties in vitro on segments of the thoracic aorta of rats. The data, obtained in the work, justify the prospect of using the leader substance as a new analgesic and antispasmodic drug. The research expands and deepens knowledge about the pharmacological properties of alkylamide derivatives of dihydroquinoline-3-carboxylic acid. The aim of the work was to conduct screening studies to establish the analgesic activity of a newly synthesized series of chemical compounds among alkylamides of dihydroquinoline-3-carboxylic acid and to study the myotropic spasmolytic activity of the leader substance. Materials and methods. Analgesic properties of alkylamides of dihydroquinoline-3-carboxylic acid were studied on outbred white mice in the "acetic acid convulsions" test. During the experiment, the animals were treated in accordance with the International Principles of the European Convention for the Protection of Vertebrate Animals Used for Experiments and Other Scientific Purposes (Strasbourg, March 18, 1986). The studied substances were administered intragastrically to experimental animals at a dose of 10 mg/kg in the form of a finely dispersed aqueous suspension, stabilized with Tween-80. Voltaren at a dose of 8 mg/kg, recommended for preclinical studies, and analgin at a dose of 50 mg/kg were chosen as reference drugs. The studies of the contractile activity of smooth muscle vessels were carried out on segments of the thoracic aorta of rats of both sexes weighing 180-200 g. The studies of dilator reactions were carried out against the background of preliminary contraction with phenylephrine at a concentration of 10-6 mol/l. The antispasmodic efficiency of the new compound was determined in comparison with the classic antispasmodic drotaverine. The statistical processing of the results was carried out using the package of statistical analysis of electronic spreadsheets Exel, with the help of the program "Statgraphics Plus v. 3.0.” and the standard package of statistical programs "Statistica, V. 6.0". We used the Student's test, a non-parametric analog of univariate variance analysis - the Kruskal-Wallis test, and the Mann-Whitney test. Differences were considered statistically significant at p<0.05. Results. The study of the analgesic activity of substances АO1-АO30 in the "acetic acid convulsion" test in mice showed that a compound АO26 (provisional name alkylcarb) has the most pronounced analgesic activity when administered intragastrically. In the "acetic acid convulsion" test, alkylcarb (10 mg/kg, per os) probably reduces the number of convulsions, caused by acetic acid. The level of activity of this compound is comparable to the activity of diclofenac (8 mg/kg, per os) and exceeds analgin (50 mg/kg, per os). The substance alkylcarb relieved vasospasm at the level of the comparison drug drotaverine in in vitro experiments on a model of an isolated fragment of the thoracic aorta of rats against the background of previous constriction with phenylephrine. Conclusion. Today, the search for new highly effective non-opioid analgesics is an urgent problem of modern pharmacology, since painkillers used in clinical practice do not meet the requirements of efficiency and safety. In this regard, in recent years, scientists of the National Pharmaceutical University have been intensively searching for new, highly effective substances with antinociceptive, anti-inflammatory and antipyretic effects among alkylamides of dihydroquinoline-3-carboxylic acid

Design, synthesis, computational and biological evaluation of new anxiolytics

Abstract New anxiolytics have been discovered by prediction of biological activity with computer programs PASS and DE DEREK for a heterogeneous set of 5494 highly chemically diverse heterocyclic compounds (thiazoles, pyrazoles, isatins, a fused imidazoles and others). The majority of tested compounds exhibit the predicted anxiolytic effect. The most potent activity was found in 2 (4 nitro phenyl) 3 (4 phenylpiperazinomethyl)imidazo[1,2 a]pyridine 8, 1 [(4 bromophenyl) 2 oxoethyl] 3 (1,3 dioxolano) 2 indolinone 3, 5 hydroxy 3 methoxycarbonyl 1 phenylpyrazole 5 and 2 (4 fluorophenyl) 3 (4 methylpiperazinomethyl)imidazo[1,2 a]pyridine 7. The application of the computer assisted approach significantly reduced the number of synthesized and tested compounds and increased the chance of finding new chemical entities (NCEs)

Digitalization of Modern Education: Problems and Solutions

The relevance of the research topic is due to modern global digital transformations and the transition to the digital economy and digital society. Social digitalization is caused by qualitative technological changes. All over the world, digitalization in education is closely related to a new way of life in a digital environment and the emergence of generations who were born and study in the specific environment. The study was based on a survey assessing the quality of digitalization in education, which involved 475 students and 118 teachers of the Russian State Vocational Pedagogical University (Yekateringburg). Based on the analysis of modern research on digital education, the most important components of digitalization have been identified and assessed in the survey. The survey was based on a Likert scale; the importance of each significant aspect of digitalization was assessed from 0 to 10. Unanimously, the research participants rated the level of penetration of digital technologies into Russian higher education as low: 3.15 (students) and 3.43 (teachers). The contribution of digitalization to academic performance was rated above average (7.25 and 5.21, respectively). There were some differences in the assessment of the role of the teacher in the digital environment (4.65 and 7.14), the convenience of the digital environment (7.11 and 2.53) and its positive impact on student motivation (8.09 and 3.61, respectively). The increase in the cognitive capabilities of students due to digitalization was also differently assessed by the students and teachers (6.88 and 3.11, respectively). Thus, digitalization in Russian universities generally reflects the expectation of its future development and a positive student attitude to the available opportunities. The novelty of the research is an attempt to objectively assess the internal process of digitalization and determine further research directions. In practice, the study can reform the education system, accelerate and improve the process of higher education digitalization

Influence of chronic intrauterine hypoxia on development of testicles of newborns

Аim ― to assess the effect of chronic hypoxia on the development of the reproductive glands of the fetus of rats in experiment. Material and Methods ― In the work, 10 white outbred female rats aged 4 to 10 months with a weight of 200 ± 30 g were used. Laboratory animals were divided into 2 experimental groups, 5 rats in each. The first (experimental) group underwent hypoxia throughout the entire pregnancy (21 days). Modeling of hypoxia was carried out in accordance with the technique of N.N. Karkischenko (2010). The second (control) group was not exposed to any treatment throughout the entire pregnancy. Results ― There was a decrease in body weight in the offspring of the experimental group as compared to the control group.Histological examination of testicular tissue showed a significant decrease in the number of tubules in the field of vision, a decrease in the diameter and area of the tubules, with a simultaneous increase in the stroma area, a decrease in the proliferative potential, and an increase in the apoptosis of gonocytes, Leydig and Sertoli cells in the experimental group. Conclusion ― as a result of the conducted studies it was found that hypoxia in the antenatal period adversely affects the number and somatometric parameters of newborn rats in the offspring. Histological examination of testicular tissue showed a significant decrease in the number of tubules in the field of vision, a decrease in the diameter and area of the tubules, with a simultaneous increase in the stromal area, a decrease in the proliferative potential, and an increase in the apoptosis of gonocytes, Leydig and Sertoli cells in the test group rats. This indicates a delay and impaired tissue development testicles in conditions of hypoxia already in the antenatal period