Vol 13, No 4 (2021)


The Hydrodynamics of a Swirling Blood Flow in the Left Heart and Aorta

Agafonov A.V., Talygin E.A., Bockeria L.A., Gorodkov A.Y.


This paper proposes a new approach to the quantitative analysis of the hydrodynamic structure of a blood flow in the flow channel running from the left atrium to the end of the aorta. This approach is based on the concept of the structural organization of tornado-like swirling jets in channels with a given geometric configuration. Considering the large amount of experimental data in our possession, it was shown that along the entire length of the flow channel, conditions exist for the generation and maintenance of a swirling structure of the jet throughout the entire cardiac cycle. This study has given rise to a new direction in research in fundamental physiology and medicine, which is of great practical importance for diagnosing and treating circulatory disorders accompanied by changes in the geometric configuration and biomechanical characteristics of the heart and great vessels.

Acta Naturae. 2021;13(4):4-16
pages 4-16 views

Molecular Tools for Targeted Control of Nerve Cell Electrical Activity. Part II

Kolesov D.V., Sokolinskaya E.L., Lukyanov K.A., Bogdanov A.M.


In modern life sciences, the issue of a specific, exogenously directed manipulation of a cell’s biochemistry is a highly topical one. In the case of electrically excitable cells, the aim of the manipulation is to control the cells’ electrical activity, with the result being either excitation with subsequent generation of an action potential or inhibition and suppression of the excitatory currents. The techniques of electrical activity stimulation are of particular significance in tackling the most challenging basic problem: figuring out how the nervous system of higher multicellular organisms functions. At this juncture, when neuroscience is gradually abandoning the reductionist approach in favor of the direct investigation of complex neuronal systems, minimally invasive methods for brain tissue stimulation are becoming the basic element in the toolbox of those involved in the field. In this review, we describe three approaches that are based on the delivery of exogenous, genetically encoded molecules sensitive to external stimuli into the nervous tissue. These approaches include optogenetics (overviewed in Part I), as well as chemogenetics and thermogenetics (described here, in Part II), which is significantly different not only in the nature of the stimuli and structure of the appropriate effector proteins, but also in the details of experimental applications. The latter circumstance is an indication that these are rather complementary than competing techniques.

Acta Naturae. 2021;13(4):17-32
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Research Articles

Development of Neutralizing Nanobodies to the Hemagglutinin Stem Domain of Influenza A Viruses

Voronina D.V., Shcheblyakov D.V., Esmagambetov I.B., Derkaev A.A., Popova O., Shcherbinin D.N.


The influenza virus infection claims ~650,000 lives annually. Taking into account the evolving resistance of the pathogen to antiviral drugs and the waning effectiveness of vaccination among certain populations, new approaches to the treatment of influenza are needed. The current study is aimed at obtaining single-domain antibodies (Nanobodies®) to the highly conserved stem domain of influenza A virus hemagglutinin by phage display. Two high-affinity neutralizing clones of Nanobodies® with a particular specificity were selected; they ensured 100% neutralization of the H1N1 and H5N2 influenza viruses in vivo. The obtained data demonstrate that it is possible to develop highly effective VHH-based drugs for the treatment of influenza.

Acta Naturae. 2021;13(4):33-41
pages 33-41 views

The rs1800470 Polymorphism of the TGFB1 Gene Is Associated with Myocardial Fibrosis in Heart Transplant Recipients

Gichkun O.E., Shevchenko O.P., Kurabekova R.M., Mozheiko N.Р., Shevchenko A.O.


The transforming growth factor β1 (TGFβ1), whose level may depend on the polymorphism of the TGFB1 gene, is involved in the formation of myocardial fibrosis. Myocardial fibrosis in a cardiac allograft may lead to a heart’s structural and functional remodeling and subsequent dysfunction. The frequency of occurrence of alleles and genotypes of the TGFB1 gene polymorphic regions rs1800469, rs1800470, and rs1800471 in heart transplant recipients and their association with graft myocardial fibrosis were analyzed. Carriers of the CC genotype (p = 0.023, OR = 0.12, 95% CI: 0.017–1.0), and more often the G allele of rs1800471 (p = 0.023, OR = 7.76, 95% CI: 1.0–60.20), were found among heart transplant recipients less frequently than among healthy individuals. In patients with ischemic heart disease (IHD), the GG genotype was less common (p = 0.035, OR = 2.68, 95% CI: 1.061–6.793), while the A allele of rs1800469 was found more frequently (p = 0.035, OR = 0.37 95% CI: 0.148–0.942) than in patients with dilated cardiomyopathy (DCM). In heart transplant recipients with the AA genotype of rs1800470, myocardial fibrosis, verified by endomyocardial biopsy, was detected more often than in carriers of the G allele (OR = 10.4, 95% CI: 1.152–94.538, p = 0.013). The revealed differences suggest a relationship between TGFB1 gene polymorphism and graft myocardial fibrosis. Studies on a larger group of patients would make it possible to characterize the influence of genetic factors on the formation of myocardial fibrosis in heart transplant recipients.

Acta Naturae. 2021;13(4):42-46
pages 42-46 views

A Sorbent with Synthetic Ligand for Removing Pro-atherogenic and Pro-inflammatory Components from Human Blood Plasma

Dmitrieva O.A., Ovchinnikova E.D., Utkina E.A., Levashov P.A., Afanasieva O.I., Adamova I.Y., Pokrovsky S.N.


Elevated levels of apoB-100 containing lipoproteins and markers of systemic inflammation are often observed in patients with cardiovascular diseases. The concentrations can be reduced by pharmacotherapy or extracorporeal treatment. The sorbent, which removes CRP and atherogenic lipoproteins, simultaneously reduces the bloodstream concentration of these components. The efficacy and selectivity of the designed sorbent were studied, desorption constants of CRP (Kd = 4.2 × 10-8 M) and LDL (Kd = 7.7 × 10-7 M) were distribution coefficients of CRP (Kc = 101) and Lp(a) (Kc = 38) were calculated, and the ability to bind large amounts of atherogenic lipoproteins (up to 32 mg of TC per mL of the sorbent gel) was demonstrated. Our sorbent can be recommended for performing complex removal of CRP and atherogenic lipoproteins from the blood plasma in patients with refractory hyperlipidemia and CVD that are accompanied by elevated levels of CRP.

Acta Naturae. 2021;13(4):47-52
pages 47-52 views

Nanobodies Are Potential Therapeutic Agents for the Ebola Virus Infection

Esmagambetov I.B., Shcheblyakov D.V., Egorova D.A., Voronina O.L., Derkaev A.A., Voronina D.V., Popova O., Ryabova E.I., Shcherbinin D.N., Aksenova E.I., Semenov A.N., Kunda M.S., Ryzhova N.N., Zubkova O.V., Tukhvatulin A.I., Logunov D.Y., Naroditsky B.S., Borisevich S.V., Gintsburg A.L.


Ebola fever is an acute, highly contagious viral disease with a mortality rate that can reach 90%. There are currently no licensed therapeutic agents specific to Ebola in the world. Monoclonal antibodies (MAbs) with viral-neutralizing activity and high specificity to the Ebola virus glycoprotein (EBOV GP) are considered as highly effective potential antiviral drugs. Over the past decade, nanobodies (single-domain antibodies, non-canonical camelid antibodies) have found wide use in the diagnosis and treatment of various infectious and non-infectious diseases. In this study, a panel of nanobodies specifically binding to EBOV GP was obtained using recombinant human adenovirus 5, expressing GP (Ad5-GP) for alpaca (Vicugna pacos) immunization, for the first time. Based on specific activity assay results, affinity constants, and the virus-neutralizing activity against the recombinant vesicular stomatitis virus pseudotyped with EBOV GP (rVSV-GP), the most promising clone (aEv6) was selected. The aEv6 clone was then modified with the human IgG1 Fc fragment to improve its pharmacokinetic and immunologic properties. To assess the protective activity of the chimeric molecule aEv6–Fc, a lethal model of murine rVSV-GP infection was developed by using immunosuppression. The results obtained in lethal model mice have demonstrated the protective effect of aEv6–Fc. Thus, the nanobody and its modified derivative obtained in this study have shown potential protective value against Ebola virus.

Acta Naturae. 2021;13(4):53-63
pages 53-63 views

Circulating Actin-Binding Proteins in Laryngeal Cancer: Its Relationship with Circulating Tumor Cells and Cells of the Immune System

Kakurina G.V., Stakheeva M.N., Bakhronov I.A., Sereda E.E., Cheremisina O.V., Choynzonov E.L., Kondakova I.V.


We previously exposed the role of actin-binding proteins (ABPs) in cancer development and progression. In this paper, we studied the relationship between circulating ABPs and the number of ABP-expressing leukocytes and circulating tumor cells (CTCs) in patients with highly aggressive laryngeal squamous cell carcinoma (LSCC). The levels of cofilin (CFL1), profilin (PFN1), ezrin (EZR), fascin (FSCN1), and adenylate cyclase-associated protein 1 (CAP1) were determined using enzyme immunoassay. The ABP expression by the cellular pools was analyzed by flow cytometry. The highest levels of FSCN1 and EZR were found in the blood serum of LSCC patients. There was a difference in ABP expression between the pools of leukocytes and CTCs. Leukocytes were mainly represented by CAP1+ and FSCN1+ pools, and CTCs contained CAP1+, FSCN1+, and EZR+ cells. The serum FSCN1 level correlated with the number of FSCN1-containing and CFL1-containing leukocytes. Thus, the level of circulating EZR is likely related to its expression in CTCs. The levels of CFL1 and PFN1 are likely to be supported by the expression of these proteins by leukocytes. Both CTCs and leukocytes can be a source of FSCN1 and CAP1 in blood serum. The results suggest that serum proteins can be produced by various cells, thus indicating both cancer development and the response of the immune system to this process.

Acta Naturae. 2021;13(4):64-68
pages 64-68 views

The Different Impact of ERK Inhibition on Neuroblastoma, Astrocytoma, and Rhabdomyosarcoma Cell Differentiation

Lebedev T.D., Vagapova E.R., Prassolov V.S.


Aberrant ERK activity can lead to uncontrolled cell proliferation, immortalization, and impaired cell differentiation. Impairment of normal cell differentiation is one of the critical stages in malignant cell transformation. In this study, we investigated a relationship between ERK tyrosine kinase activity and the main differentiation features (changes in cell morphology and expression of genes encoding differentiation markers and growth factor receptors) in SH-SY5Y neuroblastoma, U-251 astrocytoma, and TE-671 rhabdomyosarcoma cells. ERK activity was assessed using a reporter system that enabled live measurements of ERK activity in single cells. We demonstrated that suppression of ERK activity by selective ERK inhibitors, in contrast to a commonly used differentiation inducer, retinoic acid, leads to significant changes in TE-671 cell morphology and expression of the myogenic differentiation marker genes PROM1, MYOG, and PAX7. There was a relationship between ERK activity and morphological changes at an individual cell level. In this case, SH-SY5Y cell differentiation induced by retinoic acid was ERK-independent. We showed that ERK inhibition increases the sensitivity of TE-671 cells to the EGF, IGF-1, and NGF growth factors, presumably by reducing basal ERK activity, and to the BDNF growth factor, by increasing expression of the TrkB receptor.

Acta Naturae. 2021;13(4):69-77
pages 69-77 views

Evaluation of the Antiviral Potential of Modified Heterocyclic Base and 5’-Norcarbocyclic Nucleoside Analogs Against SARS-CoV-2

Matyugina E.S., Novikov M.S., Kozlovskaya L.I., Volok V.P., Shustova E.Y., Ishmukhametov A.A., Kochetkov S.N., Khandazhinskaya A.L.


The pandemic caused by the novel betacoronavirus SARS-CoV-2 has already claimed more than 3.5 million lives. Despite the development and use of anti-COVID-19 vaccines, the disease remains a major public health challenge throughout the world. Large-scale screening of the drugs already approved for the treatment of other viral, bacterial, and parasitic infections, as well as autoimmune, oncological, and other diseases is currently underway as part of their repurposing for development of effective therapeutic agents against SARS-CoV-2. In this work, we present the results of a phenotypic screening of libraries of modified heterocyclic bases and 5’-norcarbocyclic nucleoside analogs previously synthesized by us. We identified two leading compounds with apparent potential to inhibit SARS-CoV-2 replication and EC50 values in a range of 20–70 μM. The structures of these compounds can be further optimized to develop an antiviral drug.

Acta Naturae. 2021;13(4):78-81
pages 78-81 views

Extracellular Vesicles from Mycoplasmas Can Penetrate Eukaryotic Cells In Vitro and Modulate the Cellular Proteome

Mouzykantov A.A., Rozhina E.V., Fakhrullin R.F., Gomzikova M.O., Zolotykh M.A., Chernova O.A., Chernov V.M.


The extracellular vesicles (EVs) produced by bacteria transport a wide range of compounds, including proteins, DNA and RNA, mediate intercellular interactions, and may be important participants in the mechanisms underlying the persistence of infectious agents. This study focuses on testing the hypothesis that the EVs of mycoplasmas, the smallest prokaryotes capable of independent reproduction, combined in the class referred to as Mollicutes, can penetrate into eukaryotic cells and modulate their immunoreactivity. To verify this hypothesis, for the first time, studies of in vitro interaction between human skin fibroblasts and vesicles isolated from Acholeplasma laidlawii (the ubiquitous mycoplasma that infects higher eukaryotes and is the main contaminant of cell cultures and vaccines) were conducted using confocal laser scanning microscopy and proteome profiling, employing a combination of 2D-DIGE and MALDI-TOF/TOF, the Mascot mass-spectrum analysis software and the DAVID functional annotation tool. These studies have revealed for the first time that the extracellular vesicles of A. laidlawii can penetrate into eukaryotic cells in vitro and modulate the expression of cellular proteins. The molecular mechanisms behind the interaction of mycoplasma vesicles with eukaryotic cells and the contribution of the respective nanostructures to the molecular machinery of cellular permissiveness still remain to be elucidated. The study of these aspects is relevant both for fundamental research into the “logic of life” of the simplest prokaryotes, and the practical development of efficient control over hypermutable bacteria infecting humans, animals and plants, as well as contaminating cell cultures and vaccines.

Acta Naturae. 2021;13(4):82-88
pages 82-88 views

A Comparative Analysis of CSF and the Blood Levels of Monoamines As Neurohormones in Rats during Ontogenesis

Murtazina A.R., Bondarenko N.S., Pronina T.S., Chandran K.I., Bogdanov V.V., Dilmukhametova L.K., Ugrumov M.V.


According to the literature, the cerebrospinal fluid (CSF) in the cerebral ventricles contains numerous neuron-derived physiologically active substances that can function as neurohormones and contribute to volume neurotransmission in the periventricular region of the brain. This study was aimed at carrying out a comparative analysis of CSF and the blood levels of monoamines in rats during ontogenesis as an indicator of age-related characteristics of monoamine transport to body fluids and their function as neurohormones in volume neurotransmission in the periventricular region of the brain. We have shown that CSF in the perinatal period and adulthood contains the most functionally significant monoamines: dopamine, noradrenaline, and serotonin. A comparison of the monoamine levels in the CSF and blood of animals of different age groups revealed that CSF contains monoamines of predominantly neuronal (cerebral) origin and almost no monoamines derived from the general circulation. We also established that monoamines are found in the CSF at physiologically active levels that allow them to act as neurohormones in both reversible volume neurotransmission in the adult brain and irreversible regulation of brain development in the perinatal period.

Acta Naturae. 2021;13(4):89-97
pages 89-97 views

Mechanism of Action of Monoclonal Antibodies That Block the Activity of the Lethal Toxin of Bacillus Anthracis

Romanenko Y.O., Riabko A.K., Marin M.A., Kartseva A.S., Silkina M.V., Shemyakin I.G., Firstova V.V.


Neutralization of the lethal toxin of Bacillus anthracis is an important topic of both fundamental medicine and practical health care, regarding the fight against highly dangerous infections. We have generated a neutralizing monoclonal antibody 1E10 against the lethal toxin of Bacillus anthracis and described the stages of receptor interaction between the protective antigen (PA) and the surface of eukaryotic cells, the formation of PA oligomers, assembly of the lethal toxin (LT), and its translocation by endocytosis into the eukaryotic cell, followed by the formation of a true pore and the release of LT into the cell cytosol. The antibody was shown to act selectively at the stage of interaction between Bacillus anthracis and the eukaryotic cell, and the mechanism of toxin-neutralizing activity of the 1E10 antibody was revealed. The interaction between the 1E10 monoclonal antibody and PA was found to lead to inhibition of the enzymatic activity of the lethal factor (LF), most likely due to a disruption of true pore formation by PA, which blocks the release of LF into the cytosol.

Acta Naturae. 2021;13(4):98-104
pages 98-104 views

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