Vol 11, No 2 (2019)


Application of Polyhydroxyalkanoates in Medicine and the Biological Activity of Natural Poly(3-Hydroxybutyrate)

Bonartsev A.P., Bonartseva G.A., Reshetov I.V., Shaitan K.V., Kirpichnikov M.P.


Biodegradable and biocompatible polymers, polyhydroxyalkanoates (PHAs), are actively used in medicine to produce a wide range of medical devices and dosage formulations. The medical industry mainly utilizes PHAs obtained by chemical synthesis, but interest in the medical application of natural PHAs obtained biotechnologically is also growing. Synthetic PHAs are the biomimetic analogs of bacterial poly(3-hydroxybutyrate) (PHB) and other natural PHAs. This paper addresses the issue of the presence of biological activity in synthetic and natural PHAs (stimulation of cell proliferation and differentiation, tissue regeneration) and their possible association with various biological functions of PHB in bacteria and eukaryotes, including humans.

Acta Naturae. 2019;11(2):4-16
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Molecular Biomarkers of Brain and Spinal Cord Astrocytomas

Konovalov N.A., Asyutin D.S., Shayhaev E.G., Kaprovoy S.V., Timonin S.Y.


Spinal cord astrocytomas are rare diseases of the central nervous system. The localization of these tumors and their infiltrative growth complicate their surgical resection, increase the risk of postoperative complications, and require more careful use of radio- and chemotherapy. The information on the genetic mutations associated with the onset and development of astrocytomas provides a more accurate neoplasm diagnosis and classification. In some cases, it also allows one to determine the optimal methods for treating the neoplasm, as well as to predict the treatment outcomes and the risks of relapse. To date, a number of molecular markers that are associated with brain astrocytomas and possess prognostic value have been identified and described. Due to the significantly lower incidence of spinal cord astrocytomas, the data on similar markers are much more sparse and are presented with a lesser degree of systematization. However, due to the retrospective studies of clinical material that have been actively conducted abroad in recent years, the formation of statistically significant genetic landscapes for various types of tumors, including intradural spinal cord tumors, has begun. In this regard, the purpose of this review is to analyze and systematize the information on the most significant genetic mutations associated with various types of astrocytomas, as well as discuss the prospects for using the corresponding molecular markers for diagnostic and prognostic purposes.

Acta Naturae. 2019;11(2):17-27
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Targeted Drug Delivery in Lipid-like Nanocages and Extracellular Vesicles

Sokolov A.V., Kostin N.N., Ovchinnikova L.A., Lomakin Y.A., Kudriaeva A.A.


The possibility of targeted drug delivery to a specific tissue, organ, or cell has opened new promising avenues in treatment development. The technology of targeted delivery aims to create multifunctional carriers that are capable of long circulation in the patient’s organism and possess low toxicity at the same time. The surface of modern synthetic carriers has high structural similarity to the cell membrane, which, when combined with additional modifications, also promotes the transfer of biological properties in order to penetrate physiological barriers effectively. Along with artificial nanocages, further efforts have recently been devoted to research into extracellular vesicles that could serve as natural drug delivery vehicles. This review provides a detailed description of targeted delivery systems that employ lipid and lipid-like nanocages, as well as extracellular vesicles with a high level of biocompatibility, highlighting genetically encoded drug delivery vehicles.

Acta Naturae. 2019;11(2):28-41
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Research Articles

Assessment of the Phenylketonuria (PKU)-Associated Mutation p.R155H Biochemical Manifestations by Mass Spectrometry-Based Blood Metabolite Profiling

Baturina O.A., Chernonosov A.A., Koval V.V., Morozov I.V.


Homozygous siblings with different treatment histories represent an excellent model to study both the phenotypic manifestation of mutations and the efficacy of therapy. We compared phenylketonuria (PKU) manifestations in two different gender siblings who were homozygous carriers of a rare phenylalanine hydroxylase (PAH) mutation, p.R155H, subjected to different treatments. PKU caused by mild mutations may be easily underdiagnosed if the diagnosis is based solely on the phenylalanine (Phe) blood concentration. One of the described patients is an example of this diagnostic error. For reducing diagnostic errors, we suggest the use of more elaborate methods in screening practice, in particular mass spectrometric analysis of blood metabolites, the efficiency of which is demonstrated in the present study.

Acta Naturae. 2019;11(2):42-46
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“Green” Synthesis of Cytotoxic Silver Nanoparticles Based on Secondary Metabolites of Lavandula Angustifolia Mill.

Belova M.M., Shipunova V.O., Kotelnikova P.A., Babenyshev A.V., Rogozhin E.A., Cherednichenko M.Y., Deyev S.M.


In this study, we used “green” synthesis to prepare silver nanoparticles (NPs) from aqueous plant and callus extracts of the narrow-leaved lavender Lavandula angustifolia Mill. 35.4 ± 1.6 nm and 56.4 ± 2.4 nm nanoparticles, colloidally stable in phosphate-buffered saline, were synthesized using the plant extract and the callus extract, respectively. NPs were characterized by spectrophotometry, dynamic light scattering, and scanning electron microscopy. We studied the dynamics of the nanoparticle synthesis and evaluated the cytotoxic properties of the plant extract-based NPs. Modification of NPs with bovine serum albumin demonstrated that blockage of the nanoparticle surface completely suppressed NP cytotoxic activity in vitro. The synthesized NPs possess localized surface plasmon resonance properties and are of small sizes, and their surface can be modified with protein molecules, which makes them promising agents for cancer theranostics.

Acta Naturae. 2019;11(2):47-53
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Septin Polymerization Slows Synaptic Vesicle Recycling in Motor Nerve Endings

Grigoryev P.N., Khisamieva G.A., Zefirov A.L.


Septins are GTP-binding proteins recognized as a component of the cytoskeleton. Despite the fact that septins are highly expressed by neurons and can interact with the proteins that participate in synaptic vesicle exocytosis and endocytosis, the role of septins in synaptic transmission and the synaptic vesicle recycling mechanisms is poorly understood. In this study, neurotransmitter release and synaptic vesicle exocytosis and endocytosis were investigated by microelectrode intracellular recording of end-plate potentials and fluorescent confocal microscopy in mouse diaphragm motor nerve endings during septin polymerization induced by forchlorfenuron application. It was shown that forchlorfenuron application reduces neurotransmission during prolonged high-frequency (20 and 50 pulses/s) stimulation. Application of pairs of short high-frequency stimulation trains showed that forchlorfenuron slows the replenishment of the readily releasable pool. Forchlorfenuron enhanced FM 1-43 fluorescent dye loading by synaptic vesicle endocytosis but decreased dye unloading from the preliminarily stained nerve endings by synaptic vesicle exocytosis. It was concluded that the septin polymerization induced by forchlorfenuron application slows the rate of synaptic vesicle recycling in motor nerve endings due to the impairment of synaptic vesicle transport.

Acta Naturae. 2019;11(2):54-62
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The Role of Recombinant Human Cyclophilin A in the Antitumor Immune Response

Kalinina A.A., Silaeva Y.Y., Kazansky D.B., Khromykh L.M.


Cyclophilin A (CypA) is a multifunctional protein that exhibits an isomerase activity and exists in the intracellular and secretory forms. Secretory CypA promotes regeneration of the hematopoietic and the immune systems of an organism by stimulating stem cell migration from the bone marrow. New approaches based on CypA are currently being developed for the treatment of limb ischemia, neutralization of the side effects of Cyclosporine A (CsA) therapy, etc. However, the role of CypA in the antitumor immune response is still unexplored. In this work, we used the model experimental system of lymphoma EL-4 rejection in B10.D2(R101) mice and showed that recombinant human CypA (rhCypA) stimulates the antitumor immune response via early recruitment of granulocytes to the tumor cell localization site and rapid accumulation of effector T-killers

Acta Naturae. 2019;11(2):63-67
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The Differential Anti-HIV Effect of a New Humic Substance-Derived Preparation in Diverse Cells of the Immune System

Kornilaeva G.V., Siniavin A.E., Schultz A., Germann A., Moog C., von Briesen H., Turgiev A.S., Karamov E.V.


The anti-HIV activity of a new humic substance-derived preparation has been studied in individual pools of immune cells (CD4+ T lymphocytes, macrophages, dendritic cells).steve mcqueen monaco replica Near-complete inhibition of the HIV infection (by more than 90%) was achieved by treating each of the abovementioned cell types with non-toxic concentrations of the preparation. The inhibitory effect demonstrates the possibility of preventing the depletion of a significant portion of functionally important immune cells. A comparative study of infection inhibition in individual cell pools has allowed us 1965 corvette grand sport replica for sale to reveal the differences in the preparation’s effectiveness in each of the cell populations. A R5-tropic HIV-1 infection in macrophages exhibited maximum sensitivity to the preparation: 90% and 50% inhibition of the infection were observed in the presence of concentrations as low as 1.4 and 0.35 μg/ml, respectively. titan black rolex replica for sale A 15- and 19-fold higher concentration was required to achieve the same repair rolex replica extent of inhibition in dendritic cells infected with the same strain. The effectiveness of the drug in CD4 + T lymphocytes is quite rolex replica deep sea comparable to its effectiveness in macrophages. The drug is universally effective for rolex datejust real or fake both the T- and M-tropic variants of HIV-1.

Acta Naturae. 2019;11(2):68-76
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Studying the Possibilities of Using 2-Halogen-Substituted Acetamides As Acyl Donors in Penicillin Acylase-Catalyzed Reactions

Panin N.V., Nikulin M.V., Tiurin E.S., Drobot V.V., Morozova I.A., Švedas V.K.


The possibility of using amides of halogen-substituted acetic acids as acyl donors in penicillin acylase-catalyzed reactions has been investigated, and the ability of this group of compounds to inactivate enzymes in the course of the catalytic conversion has been established. The strongest inactivating effect was demonstrated by iodoacetamide and bromoacetamide. However, the negative contribution of this side activity can be minimized by decreasing the temperature, when the rate of acyl donor conversion by penicillin acylases is still high enough, but the impact of enzyme inactivation becomes less significant. The catalytic activity of penicillin acylase from Alcaligenes faecalis in the conversion of 2-haloacetamides was significantly (5-8 times) higher than that of penicillin acylase from Escherichia coli.

Acta Naturae. 2019;11(2):77-81
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The Profile of Post-translational Modifications of Histone H1 in Chromatin of Mouse Embryonic Stem Cells

Starkova T.Y., Artamonova T.O., Ermakova V.V., Chikhirzhina E.V., Khodorkovskii M.A., Tomilin A.N.


Linker histone H1 is one of the main chromatin proteins which plays an important role in organizing eukaryotic DNA into a compact structure. There is data indicating that cell type-specific post-translational modifications of H1 modulate chromatin activity. Here, we compared histone H1 variants from NIH/3T3, mouse embryonic fibroblasts (MEFs), and mouse embryonic stem (ES) cells using matrix-assisted laser desorption/ ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FT-ICR-MS). We found significant differences in the nature and positions of the post-translational modifications (PTMs) of H1.3-H1.5 variants in ES cells compared to differentiated cells. For instance, methylation of K75 in the H1.2-1.4 variants; methylation of K108, K148, K151, K152 K154, K155, K160, K161, K179, and K185 in H1.1, as well as of K168 in H1.2; phosphorylation of S129, T146, T149, S159, S163, and S180 in H1.1, T180 in H1.2, and T155 in H1.3 were identified exclusively in ES cells. The H1.0 and H1.2 variants in ES cells were characterized by an enhanced acetylation and overall reduced expression levels. Most of the acetylation sites of the H1.0 and H1.2 variants from ES cells were located within their C-terminal tails known to be involved in the stabilization of the condensed chromatin. These data may be used for further studies aimed at analyzing the functional role played by the revealed histone H1 PTMs in the self-renewal and differentiation of pluripotent stem cells.

Acta Naturae. 2019;11(2):82-91
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A New MicroRNA Cluster Involved in the Reprogramming to a Pluripotent State

Sherstyuk V.V., Davletshina G.I., Vyatkin Y.V., Shtokalo D.N., Vlasov V.V., Zakian S.M.


Reprogramming of somatic cells to a pluripotent state is a complex, multistage process that is regulated by many factors. Among these factors, non-coding RNAs and microRNAs (miRNAs) have been intensively studied in recent years. MiRNAs play an important role in many processes, particularly in cell reprogramming. In this study, we investigated the reprogramming of rat fibroblasts with a deleted locus encoding a cluster comprising 14 miRNAs (from miR-743a to miR-465). The deletion of this locus was demonstrated to decrease significantly the efficiency of the cell reprogramming. In addition, the cells produced by the reprogramming differed from rat embryonic and induced pluripotent stem cells, which was an indication that reprogramming in these cells had not been completed. We suggest that this miRNA cluster or some of its members are involved in regulating the reprogramming of rat cells to a pluripotent state.

Acta Naturae. 2019;11(2):92-97
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Short communications

Bacteriophage MS2 As a Tool for Targeted Delivery in Solid Tumor Chemotherapy

Kolesanova E.F., Melnikova M.V., Bolshakova T.N., Rybalkina E.Y., Sivov I.G.


Bacteriophage MS2 was employed for targeted delivery of an apoptosis-inducing agent, Tl+, into a tumor tissue. The targeted delivery was ensured by iRGD peptide, a ligand of integrins presumably located on the surface of endotheliocytes of the tumor tissue neovasculature and certain tumor cells. The synthesized peptide was conjugated to MS2 capsid proteins. Tl+ ions from TlNO3 penetrated the phage particles and tightly bound to phage RNA. Peptide-modified MS2 preparations filled with Tl+ caused cell death in two types of cultivated human breast cancer cells and effected necrosis of these tumor xenografts in mice. Neither peptide-conjugated bacteriophage MS2 without Tl+ nor the phage filled with Tl+ but without the peptide or the same phage with the non-conjugated peptide in solution produced such effects. The preparation exhibited no acute toxicity at a therapeutic dose.

Acta Naturae. 2019;11(2):98-101
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