Behavioral Neuroscience, Drug Discovery, Physiology
22
Scopus Publications
Scopus Publications
Microbial Synthesis and Biological Activity of 20β-Hydroxylated Progestins: Ovarian and Neural Action of 17α,20β,21α-Trihydroxy-4-Pregnen-3-One in Danio rerio Vyacheslav V. Kollerov, Vsevolod V. Pavshintsev, Alexey V. Kazantsev, Andrei A. Shutov, Aleksey A. Vatlin, et al. Biomolecules, 2026 In this study, the biocatalytic activity of four steroid-transforming strains isolated from the African frog Xenopus laevis and identified as Streptomyces rochei towards pregnane steroids has been investigated. All the isolated strains facilitated the reduction of the C20-carbonyl group and the structures of the metabolites were confirmed by mass spectrometric (MS) and 1H NMR spectroscopic analyses. Hydrocortisone and progesterone were poorly transformed by the streptomycete strains, whereas cortexolone (Reichstein’s substance S) was effectively biotransformed, yielding more than 90% of 17α,20β,21α-trihydroxy-4-pregnen-3-one (20β-S). Primarily, 20α-reduction was detected when the microbial isolates were incubated with 17α-hydroxyprogesterone with the yield of 17α,20α-dihydroxy-4-pregnen-3-one (17,20α-P) reaching 70%. The biological activity of 20β-S was evaluated in Danio rerio. The results demonstrated that 20β-S modulated stress- and anxiety-related behavioral responses and activated Pgr-dependent transcriptional pathways in the brain and ovarian tissues. These observations support the potential relevance of the synthesized progestin as a functional regulator in teleost physiology. The findings enhance our understanding of the biodiversity of steroid-transforming actinomycetes inhabiting amphibians and can be successfully employed for the effective microbiological synthesis of biologically active 20-hydroxylated progestins that serve as bioregulators in teleosts.
Kidney-Related Function of Mitochondrial Protein Mitoregulin Olga A. Averina, Oleg A. Permyakov, Mariia A. Emelianova, Ekaterina A. Guseva, Olga O. Grigoryeva, et al. International Journal of Molecular Sciences, 2023 A small protein, Mitoregulin (Mtln), localizes in mitochondria and contributes to oxidative phosphorylation and fatty acid metabolism. Mtln knockout mice develop obesity on a high-fat diet, demonstrating elevated cardiolipin damage and suboptimal creatine kinase oligomerization in muscle tissue. Kidneys heavily depend on the oxidative phosphorylation in mitochondria. Here we report kidney-related phenotypes in aged Mtln knockout mice. Similar to Mtln knockout mice muscle mitochondria, those of the kidney demonstrate a decreased respiratory complex I activity and excessive cardiolipin damage. Aged male mice carrying Mtln knockout demonstrated an increased frequency of renal proximal tubules’ degeneration. At the same time, a decreased glomerular filtration rate has been more frequently detected in aged female mice devoid of Mtln. An amount of Mtln partner protein, Cyb5r3, is drastically decreased in the kidneys of Mtln knockout mice.
Mitoregulin Contributes to Creatine Shuttling and Cardiolipin Protection in Mice Muscle Olga A. Averina, Oleg A. Permyakov, Mariia A. Emelianova, Olga O. Grigoryeva, Maxim L. Lovat, et al. International Journal of Molecular Sciences, 2023 Small peptides compose a large share of the mitochondrial proteome. Mitoregulin (Mtln) is a mitochondrial peptide known to contribute to the respiratory complex I functioning and other processes in mitochondria. In our previous studies, we demonstrated that Mtln knockout mice develop obesity and accumulate triglycerides and other oxidation substrates in serum, concomitant with an exhaustion of tricarboxylic acids cycle intermediates. Here we examined the functional role of Mtln in skeletal muscles, one of the major energy consuming tissues. We observed reduced muscle strength for Mtln knockout mice. Decrease of the mitochondrial cardiolipin and concomitant increase in monolysocardiolipin concentration upon Mtln inactivation is likely to be a consequence of imbalance between oxidative damage and remodeling of cardiolipin. It is accompanied by the mitochondrial creatine kinase octamer dissociation and suboptimal respiratory chain performance in Mtln knockout mice.
In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties Anton V. Malyshev, Iuliia A. Sukhanova, Alexander S. Zlobin, Vasilina R. Gedzun, Vsevolod V. Pavshintsev, et al. Frontiers in Neuroscience, 2021 The aim of the study was to develop better anxiolytics and antidepressants. We focused on GABAAreceptors and the α2δ auxiliary subunit of V-gated Ca2+channels as putative targets because they are established as mediators of efficacious anxiolytics, antidepressants, and anticonvulsants. We further focused on short peptides as candidate ligands because of their high safety and tolerability profiles. We employed a structural bioinformatics approach to develop novel tetrapeptides with predicted affinity to GABAAreceptors and α2δ.In silicodocking studies of one of these peptides, LCGA-17, showed a high binding score for both GABAAreceptors and α2δ, combined with anxiolytic-like properties in aDanio reriobehavioral screen. LCGA-17 showed anxiolytic-like effects in the novel tank test, the light–dark box, and the social preference test, with efficacy comparable to fluvoxamine and diazepam. In binding assays using rat brain membranes, [3H]-LCGA-17 was competed more effectively by gabapentinoid ligands of α2δ than ligands of GABAAreceptors, suggesting that α2δ represents a likely target for LCGA-17. [3H]-LCGA-17 binding to brain lysates was unaffected by competition with ligands for GABAB, glutamate, dopamine, serotonin, and other receptors, suggesting specific interaction with α2δ. Dose-finding studies in mice using acute administration of LCGA-17 (i.p.) demonstrated anxiolytic-like effects in the open field test, elevated plus maze, and marble burying tests, as well as antidepressant-like properties in the forced swim test. The anxiolytic effects were effectively blocked by bicuculline. Therefore, LCGA-17 is a novel candidate anxiolytic and antidepressant that may act through α2δ, with possible synergism by GABAAreceptors.
The influence of the Semax nootropic agent on the behavioral signs of the withdrawal syndrome and on the craving for alcohol in white rats and the determination of its clinical efficacy and safety in patients with alcohol dependence Neurochemical Journal, 2008
Administration of the omega-3 polyunsaturated fatty acid drug eiferol decreases alcohol motivation in albino rats by elevating the level of antibodies to alcohol dehydrogenase Patologicheskaia Fiziologiia I Eksperimental Naia Terapiia, 2003
Mechanisms of suppression of alcohol motivation after immunization of albino rats against alcohol dehydrogenase I: The role of ADH epitopes and ADH activity in the adrenal glands Izvestiia Akademii Nauk Seriia Biologicheskaia Rossiiskaia Akademiia Nauk, 2001
