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1.  Microbiota, Intestinal Immunity, and Mouse Bustle 
Acta Naturae  2014;6(1):6-8.
The composition of the intestinal microbiota is regulated by the immune system. This paper discusses the role of cytokines and innate immunity lymphoid cells in the intestinal immune regulation by means of IgA.
PMCID: PMC3999461  PMID: 24772322
2.  Williams Syndrome As a Model for Elucidation of the Pathway Genes – the Brain – Cognitive Functions: Genetics and Epigenetics 
Acta Naturae  2014;6(1):9-22.
Genomic diseases or syndromes with multiple manifestations arise spontaneously and unpredictably as a result of contiguous deletions and duplications generated by unequal recombination in chromosomal regions with a specific architecture. The Williams syndrome is believed to be one of the most attractive models for linking genes, the brain, behavior and cognitive functions. It is a neurogenetic disorder resulting from a 1.5 Mb deletion at 7q11.23 which covers more than 20 genes; the hemizigosity of these genes leads to multiple manifestations, with the behavioral ones comprising three distinct domains: 1) visuo-spatial orientation; 2) verbal and linguistic defect; and 3) hypersocialisation. The shortest observed deletion leads to hemizigosity in only two genes: eln and limk1. Therefore, the first gene is supposed to be responsible for cardiovascular pathology; and the second one, for cognitive pathology. Since cognitive pathology diminishes with a patient’s age, the original idea of the crucial role of genes straightforwardly determining the brain’s morphology and behavior was substituted by ideas of the brain’s plasticity and the necessity of finding epigenetic factors that affect brain development and the functions manifested as behavioral changes. Recently, non-coding microRNAs (miRs) began to be considered as the main players in these epigenetic events. This review tackles the following problems: is it possible to develop relatively simple model systems to analyze the contribution of both a single gene and the consequences of its epigenetic regulation in the formation of the Williams syndrome’s cognitive phenotype? Is it possible to use Drosophila as a simple model system?
PMCID: PMC3999462  PMID: 24772323
Williams syndrome; LIMK1; non-coding RNAs; Drosophila
3.  Molecular Mechanism of Global Genome Nucleotide Excision Repair 
Acta Naturae  2014;6(1):23-34.
Nucleotide excision repair (NER) is a multistep process that recognizes and eliminates a wide spectrum of damage causing significant distortions in the DNA structure, such as UV-induced damage and bulky chemical adducts. The consequences of defective NER are apparent in the clinical symptoms of individuals affected by three disorders associated with reduced NER capacities: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). These disorders have in common increased sensitivity to UV irradiation, greatly elevated cancer incidence (XP), and multi-system immunological and neurological disorders. The eucaryotic NER system eliminates DNA damage by the excision of 24–32 nt single-strand oligonucleotides from a damaged strand, followed by restoration of an intact double helix by DNA repair synthesis and DNA ligation. About 30 core polypeptides are involved in the entire repair process. NER consists of two pathways distinct in initial damage sensor proteins: transcription-coupled repair (TC-NER) and global genome repair (GG-NER). The article reviews current knowledge on the molecular mechanisms underlying damage recognition and its elimination from mammalian DNA.
PMCID: PMC3999463  PMID: 24772324
nucleotide excision repair; repair factors; molecular mechanisms of damage recognition and elimination
4.  “Green” Nanotechnologies: Synthesis of Metal Nanoparticles Using Plants 
Acta Naturae  2014;6(1):35-44.
While metal nanoparticles are being increasingly used in many sectors of the economy, there is growing interest in the biological and environmental safety of their production. The main methods for nanoparticle production are chemical and physical approaches that are often costly and potentially harmful to the environment. The present review is devoted to the possibility of metal nanoparticle synthesis using plant extracts. This approach has been actively pursued in recent years as an alternative, efficient, inexpensive, and environmentally safe method for producing nanoparticles with specified properties. This review provides a detailed analysis of the various factors affecting the morphology, size, and yield of metal nanoparticles. The main focus is on the role of the natural plant biomolecules involved in the bioreduction of metal salts during the nanoparticle synthesis. Examples of effective use of exogenous biomatrices (peptides, proteins, and viral particles) to obtain nanoparticles in plant extracts are discussed.
PMCID: PMC3999464  PMID: 24772325
biomatrices; bioreduction; metal nanoparticles; plant metabolites; plant extracts
5.  Generation of iPS Cells from Human Hair Follice Dermal Papilla Cells 
Acta Naturae  2014;6(1):45-53.
Dermal papilla (DP) cells are unique regional stem cells of the skin that induce formation of a hair follicle and its regeneration cycle. DP are multipotent stem cells; therefore we supposed that the efficiency of DPC reprogramming could exceed that of dermal fibroblasts reprogramming. We generated induced pluripotent stem cells from human DP cells using lentiviral transfection with Oct4, Sox2, Klf4, and c-Myc, and cultivation of cells both in a medium supplemented with valproic acid and at a physiological level of oxygen (5%). The efficiency of DP cells reprogramming was ~0.03%, while the efficiency of dermal fibroblast reprogramming under the same conditions was ~0.01%. Therefore, we demonstrated the suitability of DP cells as an alternative source of iPS cells.
PMCID: PMC3999465  PMID: 24772326
Hair follicle dermal papilla (DP) cells; induced pluripotent stem (iPS) cells; reprogramming
6.  Patient-Specific Induced Pluripotent Stem Cells for SOD1-Associated Amyotrophic Lateral Sclerosis Pathogenesis Studies 
Acta Naturae  2014;6(1):54-60.
The genetic reprogramming technology allows one to generate pluripotent stem cells for individual patients. These cells, called induced pluripotent stem cells (iPSCs), can be an unlimited source of specialized cell types for the body. Thus, autologous somatic cell replacement therapy becomes possible, as well as the generation of in vitro cell models for studying the mechanisms of disease pathogenesis and drug discovery. Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that leads to a loss of upper and lower motor neurons. About 10% of cases are genetically inherited, and the most common familial form of ALS is associated with mutations in the SOD1 gene. We used the reprogramming technology to generate induced pluripotent stem cells with patients with familial ALS. Patient-specific iPS cells were obtained by both integration and transgene-free delivery methods of reprogramming transcription factors. These iPS cells have the properties of pluripotent cells and are capable of direct differentiation into motor neurons.
PMCID: PMC3999466  PMID: 24772327
induced pluripotent stem cells; amyotrophic lateral sclerosis; differentiation; motor neurons
7.  Fusion to the Lysosome Targeting Signal of the Invariant Chain Alters the Processing and Enhances the Immunogenicity of HIV-1 Reverse Transcriptase 
Acta Naturae  2014;6(1):61-68.
Intracellular processing of the antigen encoded by a DNA vaccine is one of the key steps in generating an immune response. Immunization with DNA constructs targeted to the endosomal-lysosomal compartments and to the MHC class II pathway can elicit a strong immune response. Herein, the weakly immunogenic reverse transcriptase of HIV-1 was fused to the minimal lysosomal targeting motif of the human MHC class II invariant chain. The motif fused to the N-terminus shifted the enzyme intracellular localization and accelerated its degradation. Degradation of the chimeric protein occurred predominantly in the lysosomal compartment. BALB/c mice immunized with the plasmid encoding the chimeric protein demonstrated an enhanced immune response, in the form of an increased antigen-specific production of Th1 cytokines, INF-γ and IL-2, by mouse splenocytes. Moreover, the majority of the splenocytes secreted both cytokines; i.e., were polyfunctional. These findings suggest that retargeting of the antigen to the lysosomes enhances the immune response to DNA vaccine candidates with low intrinsic immunogenicity.
PMCID: PMC3999467  PMID: 24772328
reverse transcriptase; invariant chain; antigen processing; DNA immunization; T-helper immune response
8.  The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III 
Acta Naturae  2014;6(1):69-75.
A mechanism for the induction of programmed cell death (apoptosis) upon dysfunction of the mitochondrial respiratory chain has been studied. Previously, we had found that inhibition of mitochondrial cytochrome bc1, a component of the electron transport chain complex III, leads to activation of tumor suppressor p53, followed by apoptosis induction. The mitochondrial respiratory chain is coupled to the de novo pyrimidine biosynthesis pathway via the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The p53 activation induced in response to the inhibition of the electron transport chain complex III has been shown to be triggered by the impairment of the de novo pyrimidine biosynthesis due to the suppression of DHODH. However, it remained unclear whether the suppression of the DHODH function is the main cause of the observed apoptotic cell death. Here, we show that apoptosis in human colon carcinoma cells induced by the mitochondrial respiratory chain complex III inhibition can be prevented by supplementation with uridine or orotate (products of the reaction catalyzed by DHODH) rather than with dihydroorotate (a DHODH substrate). We conclude that apoptosis is induced in response to the impairment of the de novo pyrimidine biosynthesis caused by the inhibition of DHODH. The conclusion is supported by the experiment showing that downregulation of DHODH by RNA interference leads to accumulation of the p53 tumor suppressor and to apoptotic cell death.
PMCID: PMC3999468  PMID: 24772329
apoptosis; p53 tumor suppressor; mitochondrial respiratory chain; dihydroorotate dehydrogenase; de novo pyrimidine biosynthesis
9.  Protective Immune Response against Bacillus anthracis Induced by Intranasal Introduction of a Recombinant Adenovirus Expressing the Protective Antigen Fused to the Fc-fragment of IgG2a 
Acta Naturae  2014;6(1):76-84.
Anthrax is a particularly dangerous infectious disease that affects humans and livestock. It is characterized by intoxication, serosanguineous skin lesions, development of lymph nodes and internal organs, and may manifest itsself in either a cutaneous or septic form. The pathogenic agent is Bacillus anthracis, a grampositive, endospore-forming, rod-shaped aerobic bacterium. Efficacious vaccines that can rapidly induce a long-term immune response are required to prevent anthrax infection in humans. In this study, we designed three recombinant human adenovirus serotype-5-based vectors containing various modifications of the fourth domain of the B. anthracis protective antigen (PA). Three PA modifications were constructed: a secretable form (Ad-sPA), a non-secretable form (Ad-cPA), and a form with the protective antigen fused to the Fc fragment of immunoglobulin G2a (Ad-PA-Fc). All these forms exhibited protective properties against Bacillus anthracis. The highest level of protection was induced by the Ad-PA-Fc recombinant adenovirus. Our findings indicate that the introduction of the Fc antibody fragment into the protective antigen significantly improves the protective properties of the Ad-PA-Fc adenovirus against B. anthracis.
PMCID: PMC3999469  PMID: 24772330
Bacillus anthracis; immunization; protective antigen; recombinant adenovirus
10.  Development of Immunoassays Using Interferometric Real-Time Registration of Their Kinetics 
Acta Naturae  2014;6(1):85-95.
A method for effective development of solid-phase immunoassays on a glass surface and for optimization of related protocols by highly sensitive quantitative monitoring of each assay step has been proposed and experimentally implemented. The method is based on the spectral correlation interferometry (SCI) that allows real-time measuring of the thickness of a biomolecular layer bound to the recognition molecular receptors on the sensor chip surface. The method is realized with compact 3-channel SCI-biosensors that employ as the sensor chips standard cover glass slips without deposition of any additional films. Different schemes for antibody immobilization on a glass surface have been experimentally compared and optimized toward a higher sorption capacity of the sensor chips. Comparative characterization of the kinetics of each immunoassay stage has been implemented with the optimized protocols: i) covalent immobilization of antibody on an epoxylated surface and ii) biotinylated antibody sorption on a biotinylated surface via a high-affinity biotin-streptavidin bond. We have shown that magnetic nanoparticles employed as labels with model detection of cardiac troponin I further amplify the SCI signal, resulting in 100-fold improvement of the detection limit. The developed protocols can also be used with the alternative immunoassay platforms, including the label methods based on registration of only the final assay result, which is the quantity of bound labels.
PMCID: PMC3999470  PMID: 24772331
Label-free biosensors; interferometry; sensor chips; surface functionalization; surface epoxylation; surface biotinylation; efficiency of biomolecular immobilization; immunoassay; magnetic nanoparticles; cardiac troponin I
11.  Composite Scaffolds Containing Silk Fibroin, Gelatin, and Hydroxyapatite for Bone Tissue Regeneration and 3D Cell Culturing 
Acta Naturae  2014;6(1):96-101.
Three-dimensional (3D) silk fibroin scaffolds were modified with one of the major bone tissue derivatives (nano-hydroxyapatite) and/or a collagen derivative (gelatin). Adhesion and proliferation of mouse embryonic fibroblasts (MEF) within the scaffold were increased after modification with either nano-hydroxyapatite or gelatin. However, a significant increase in MEF adhesion and proliferation was observed when both additives were introduced into the scaffold. Such modified composite scaffolds provide a new and better platform to study wound healing, bone and other tissue regeneration, as well as artificial organ bioengineering. This system can further be applied to establish experimental models to study cell-substrate interactions, cell migration and other complex processes, which may be difficult to address using the conventional two-dimensional culture systems.
PMCID: PMC3999471  PMID: 24772332
adhesion; hydroxyapatite; gelatin; composite biodegradable scaffolds; proliferation; silk fibroin
12.  Impact of Surface Modification with Gold Nanoparticles on the Bioelectrocatalytic Parameters of Immobilized Bilirubin Oxidase 
Acta Naturae  2014;6(1):102-106.
We unveil experimental evidence that put into question the widely held notion concerning the impact of nanoparticles on the bioelectrocatalytic parameters of enzymatic electrodes. Comparative studies of the bioelectrocatalytic properties of fungal bilirubin oxidase from Myrothecium verrucaria adsorbed on gold electrodes, modified with gold nanoparticles of different diameters, clearly indicate that neither the direct electron transfer rate (standard heterogeneous electron transfer rate constants were calculated to be 31±9 s-1) nor the biocatalytic activity of the adsorbed enzyme (bioelectrocatalytic constants were calculated to be 34±11 s-1) depends on the size of the nanoparticles, which had diameters close to or larger than those of the enzyme molecules.
PMCID: PMC3999472  PMID: 24772333
gold nanoparticle; bilirubin oxidase; direct electron transfer; bioelectrocatalysis
13.  “Epigenetic Memory” Phenomenon in Induced Pluripotent Stem Cells 
Acta Naturae  2013;5(4):15-21.
To date biomedicine and pharmacology have required generating new and more consummate models. One of the most perspective trends in this field is using induced pluripotent stem cells (iPSCs). iPSC application requires careful high-throughput analysis at the molecular, epigenetic, and functional levels. The methods used have revealed that the expression pattern of genes and microRNA, DNA methylation, as well as the set and pattern of covalent histone modifications in iPSCs, are very similar to those in embryonic stem cells. Nevertheless, iPSCs have been shown to possess some specific features that can be acquired during the reprogramming process or are remnants of epigenomes and transcriptomes of the donor tissue. These residual signatures of epigenomes and transcriptomes of the somatic tissue of origin were termed “epigenetic memory.” In this review, we discuss the “epigenetic memory” phenomenon in the context of the reprogramming process, its influence on iPSC properties, and the possibilities of its application in cell technologies.
PMCID: PMC3890985  PMID: 24455179
pluripotency; reprogramming; epigenetics
14.  The Role of Integrins in the Development and Homeostasis of the Epidermis and Skin Appendages 
Acta Naturae  2013;5(4):22-33.
Integrins play a critical role in the regulation of adhesion, migration, proliferation, and differentiation of cells. Because of the variety of the functions they play in the cell, they are necessary for the formation and maintenance of tissue structure integrity. The trove of data accumulated by researchers suggests that integrins participate in the morphogenesis of the epidermis and its appendages. The development of mice with tissue-specific integrin genes knockout and determination of the genetic basis for a number of skin diseases in humans showed the significance of integrins in the biology, physiology, and morphogenesis of the epidermis and hair follicles. This review discusses the data on the role of different classes of integrin receptors in the biology of epidermal cells, as well as the development of the epidermis and hair follicles.
PMCID: PMC3890986  PMID: 24455180
basement membrane; hair follicle; differentiation; integrins; keratinocytes; migration; morphogenesis; proliferation; stem cells
15.  Aptamers: Problems, Solutions and Prospects 
Acta Naturae  2013;5(4):34-43.
Aptamers are short single-stranded oligonucleotides that are capable of binding various molecules with high affinity and specificity. When the technology of aptamer selection was developed almost a quarter of a century ago, a suggestion was immediately put forward that it might be a revolutionary start into solving many problems associated with diagnostics and the therapy of diseases. However, multiple attempts to use aptamers in practice, although sometimes successful, have been generally much less efficient than had been expected initially. This review is mostly devoted not to the successful use of aptamers but to the problems impeding the widespread application of aptamers in diagnostics and therapy, as well as to approaches that could considerably expand the range of aptamer application.
PMCID: PMC3890987  PMID: 24455181
SELEX; aptamer; diagnostics; therapeutics; problems
16.  Antiviral Activity of Binase against the Pandemic Influenza A (H1N1) Virus 
Acta Naturae  2013;5(4):44-51.
The lack of effective antiviral drugs restricts the control of the dangerous RNA-containing influenza A (H1N1) virus. Extracellular ribonuclease of Bacilli (binase) was shown to manifest antiviral activity during single- and multi-cycle viral replication in the range of concentrations non-toxic to epithelial cells and 0.01-0.1 multiplicity of infection. During antiviral treatment for 15-30 min, the concentration of 1 μg/ml binase reduced the amount of focus-forming units of viruses by a factor of 3-10 and suppressed the virus-induced cytopathic effect in A549 human lung cells. The possible mechanisms of interaction between the virus and enzyme are discussed. Positive charges in both binase and viral hemagglutinin cause electrostatic interaction with negatively charged sialic acid on the host cell’s surface followed by its penetration into the cell. Capsid elimination and release of viral RNA from endosome to the cytoplasm allows catalytic RNA cleavage by internalized binase. The data obtained confirm that binase is an effective antiviral agent against the pandemic influenza A (H1N1) virus. Certain progress in this field is associated with clarifying the detailed mechanism underlying the antiviral action of binase and development of the most effective way for its practical use.
PMCID: PMC3890988  PMID: 24455182
Bacillus intermedius ribonuclease; influenza A (H1N1) virus; A549 epithelial cell; cytotoxicity; antiviral activity
17.  Competition within Introns: Splicing Wins over Polyadenylation via a General Mechanism 
Acta Naturae  2013;5(4):52-61.
Most eukaryotic messenger RNAs are capped, spliced, and polyadenylated via co-transcriptional processes that are coupled to each other and to the transcription machinery. Coordination of these processes ensures correct RNA maturation and provides for the diversity of the transcribed isoforms. Thus, RNA processing is a chain of events in which the completion of one event is coupled to the initiation of the next one. In this context, the relationship between splicing and polyadenylation is an important aspect of gene regulation. We have found that cryptic polyadenylation signals are widely distributed over the intron sequences of Drosophila melanogaster. As shown by analyzing the distribution of genes arranged in a nested pattern, where one gene is fully located within an intron of another gene, overlapping of putative polyadenylation signals is a fairly common event affecting about 17% of all genes. Here we show that polyadenylation signals are silenced within introns: the poly(A) signal is utilized in the exonic but not in the intronic regions of the transcript. The transcription does not end within the introns, either in a transient reporter system or in the genomic context, while deletion of the 5'-splice site restores their functionality. According to a full Drosophila transcriptome analysis, utilization of intronic polyadenylation signals occurs very rarely and such events are likely to be inducible. These results confirm that the transcription apparatus ignores premature polyadenylation signals for as long as they are intronic.
PMCID: PMC3890989  PMID: 24455183
transcription termination; splicing; polyadenylation signals; exon; intron
18.  3D Structure Modeling of Alpha-Amino Acid Ester Hydrolase from Xanthomonas rubrilineans 
Acta Naturae  2013;5(4):62-70.
Alpha-amino acid ester hydrolase (EC 3.1.1.43, AEH) is a promising biocatalyst for the production of semi-synthetic β-lactam antibiotics, penicillins and cephalosporins. The AEH gene from Xanthomonas rubrilineans (XrAEH) was recently cloned in this laboratory. The three-dimensional structure of XrAEH was simulated using the homology modeling method for rational design experiments. The analysis of the active site was performed, and its structure was specified. The key amino acid residues in the active site - the catalytic triad (Ser175, His341 and Asp308), oxyanion hole (Tyr83 and Tyr176), and carboxylate cluster (carboxylate groups of Asp209, Glu310 and Asp311) - were identified. It was shown that the optimal configuration of residues in the active site occurs with a negative net charge -1 in the carboxylate cluster. Docking of different substrates in the AEH active site was carried out, which allowed us to obtain structures of XrAEH complexes with the ampicillin, amoxicillin, cephalexin, D-phenylglycine, and 4-hydroxy-D-phenylglycine methyl ester. Modeling of XrAEH enzyme complexes with various substrates was used to show the structures for whose synthesis this enzyme will show the highest efficiency.
PMCID: PMC3890990  PMID: 24455184
alpha-amino acid ester hydrolase; Xanthomonas ; rubrilineans; computer simulation; docking; enzymatic synthesis of antibiotics; protein engineering
19.  Neolactoferrin As a Stimulator of Innate and Adaptive Immunity 
Acta Naturae  2013;5(4):71-77.
The effect of the innovative product Neolactoferrin, a natural combination of recombinant human lactoferrin (90%) and goat lactoferrin (10%) isolated from the milk of transgenic goats carrying the full-length human lactoferrin gene, on human immune system cells was studied. Neolactoferrin enhanced the production of IL-1β. Neolactoferrin saturated with iron ions increased the synthesis of pro-inflammatory cytokine TNFα. It determined the direction of the differentiation of precursor dendrite cells. Under the action of T cells, Neolactoferrin amplified the expression of the transcription factors responsible for the differentiation of Th- and Treg-cells and stimulated the production of both IFNγ and IL-4. The results suggest that Neolactoferrin exhibits an immunotropic activity and hinders the development of immune inflammatory processes. Iron saturation of Neolactoferrin increases its pro-inflammatory activity.
PMCID: PMC3890991  PMID: 24455185
Recombinant human lactoferrin; Neolactoferrin; immunity; inflammation; cytokines; transcription factors
20.  Depolarization-Induced Calcium-Independent Synaptic Vesicle Exo- and Endocytosis at Frog Motor Nerve Terminals 
Acta Naturae  2013;5(4):77-82.
The transmitter release and synaptic vesicle exo- and endocytosis induced by constant current depolarization of nerve terminals were studied by microelectode extracellular recording of miniature endplate currents and fluorescent microscopy (FM 1-43 styryl dye). Depolarization of the plasma membrane of nerve terminals in the control specimen was shown to significantly increase the MEPC frequency (quantal transmitter release) and exocytotic rate (FM 1-43 unloading from the synaptic vesicles preliminarily stained with the dye), which was caused by a rise in the intracellular Ca2+ concentration due to opening of voltage-gated Ca channels. A slight increase in the MEPC frequency and in the rate of synaptic vesicle exocytosis was observed under depolarization in case of blockade of Ca channels and chelating of intracellular Ca2+ ions (cooperative action of Cd2+ and EGTA-AM). The processes of synaptic vesicle endocytosis (FM 1-43 loading) were proportional to the number of synaptic vesicles that had undergone exocytosis both in the control and in case of cooperative action of Cd2+ and EGTA-AM. A hypothesis has been put forward that Ca-independent synaptic vesicle exo- and endocytosis that can be induced directly by depolarization of the membrane exists in the frog motor terminal in addition to the conventional Ca-dependent process.
PMCID: PMC3890992  PMID: 24455186
motor nerve terminals; exocytosis; endocytosis; calcium; constant depolarization current; cadmium
21.  Alu- and 7SL RNA Analogues Suppress MCF-7 Cell Viability through Modulating the Transcription of Endoplasmic Reticulum Stress Response Genes 
Acta Naturae  2013;5(4):83-93.
11% of the human genome is composed of Alu-retrotransposons, whose transcription by RNA polymerase III (Pol III) leads to the accumulation of several hundreds to thousands of Alu-RNA copies in the cytoplasm. Expression of Alu-RNA Pol III is significantly increased at various levels of stress, and the increase in the Alu-RNA level is accompanied by a suppression of proliferation, a decrease in viability, and induction of apoptotic processes in human cells. However, the question about the biological functions of Pol III Alu-transcripts, as well as their mechanism of action, remains open. In this work, analogues of Alu-RNA and its evolutionary ancestor, 7SL RNA, were synthesized. Transfection of human breast adenocarcinoma MCF-7 cells with the Alu-RNA and 7SL RNA analogues is accompanied by a decrease in viability and by induction of proapoptotic changes in these cells. The analysis of the combined action of these analogues and actinomycin D or tamoxifen revealed that the decreased viability of MCF-7 cells transfected with Alu-RNA and 7SL RNA was due to the modulation of transcription. A whole transcriptome analysis of gene expression revealed that increased gene expression of the transcription regulator NUPR1 (p8), as well as the transcription factor DDIT3 (CHOP), occurs under the action of both the Alu- and 7SL RNA analogues on MCF-7 cells. It has been concluded that induction of proapoptotic changes in human cells under the influence of the Alu-RNA and 7SL RNA analogues is related to the transcriptional activation of the genes of cellular stress factors, including the endoplasmic reticulum stress response factors.
PMCID: PMC3890993  PMID: 24455187
Alu-repeats; Alu-RNA; 7SL RNA; MCF-7 human breast adenocarcinoma cells
22.  Polyreactive Monoclonal Autoantibodies in Multiple Sclerosis: Functional Selection from Phage Display Library and Characterization by Deep Sequencing Analysis 
Acta Naturae  2013;5(4):94-104.
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that primarily affects young and middle-aged people. It is widely accepted that B lymphocyte activation is required for MS progression. Despite the fact that the exact triggering mechanisms of MS remain enigmatic, one may suggest that MS can be induced by viral or bacterial infection in combination with specific genetic and environmental factors. Using deep sequencing and functional selection methodologies we characterized clones of poly- and cross-reactive antibodies that are capable of simultaneous recognition of viral proteins and autoantigens. The latter, in turn, possibly may trigger MS progression through molecular mimicry. It was identified that two cross-reactive antigens are probably recognized by light or heavy chains individually. According to the high structural homology between selected autoantibodies and a number of various antiviral IgGs, we suggest that a wide range of pathogens, instead of a single virus, be regarded as possible triggers of MS.
PMCID: PMC3890994  PMID: 24455188
Multiple sclerosis; deep sequencing; cross-reactivity; autoreactive B cells; myelin basic protein; viral triggers
23.  Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF 
Acta Naturae  2013;5(4):105-109.
A large amount of clinical and experimental data suggest the involvement of neurotrophins, in particular the brain-derived neurotrophic factor (BDNF), in depression pathogenesis. However, the therapeutic use of BDNF is limited because of its instability in biological fluids, poor blood-brain barrier (BBB) permeability, and the presence of side effects. A low-molecular-weight mimetic GSB-106, which is a substituted dimeric dipeptide bis(N-monosuccinyl-L-seryl-L-lysine)hexamethylenediamide, was designed and synthesized based on the BDNF fourth loop structure at the V.V. Zakusov Institute of Pharmacology (RAMS). GSB-106 was found to exhibit an antidepressant activity in various models of depressive-like state when administered intraperitoneally to outbred mice and rats. An effect for the substance, when administered daily for 4–5 days, was detected in the Porsolt forced swimming test (0.1 and 1.0 mg/kg) and in the tail suspension test in mice (1.0 and 1.5 mg/ kg). An effect for GSB-106 at doses of 0.1 and 0.5 mg/kg was observed after a single application in experiments on rats in the Nomura water wheel test. The obtained evidence supports the hypothesis on the involvement of BDNF in the pathogenesis of various depression conditions, thus opening prospects for searching for new original antidepressants.
PMCID: PMC3890995  PMID: 24455189
BDNF; mimetic; GSB-106; antidepressant activity; forced swimming test; tail suspension test
24.  Three-Dimensional Model of Mouse Epidermis for Experimental Studies of Psoriasis 
Acta Naturae  2013;5(4):110-117.
Three-dimensional models of skin and epidermis imitate the structure of real tissues and provide accurate information about certain skin conditions, such as psoriasis. A three-dimensional model of mouse epidermis was generated from the epidermal keratinocytes of newborn mice and treated with cytokines. The aim of this study was to evaluate this model as an experimental model of psoriasis and to assess the changes occurring in its structure and gene expression after the exposure to proinflammatory cytokines. Treatment of the three-dimensional model with either interleukin 17 or a combination of tumor necrosis factor and interferon γ was shown to produce morphological changes, which were similar to acanthosis in psoriatic skin. The observed changes in gene expression of metalloproteinases and certain psoriasis biomarkers, such as mki67, krt16 and fosl1, were similar to the changes in patients’ skin. Notably, changes caused by interleukin 17 were less evident than those caused by the combination of interferon γ and tumor necrosis factor. On the contrary, HaCaT cells exhibited no significant changes in the expression of fosl1 and had decreased levels of mki67 after being treated with a combination of TNF and IFNG. Moreover, treatment with IL17 had no significant effect on krt16 and mki67 expression and even reduced the fosl1 levels. The findings suggest that artificially generated three-dimensional models of murine skin can be used to study psoriasis.
PMCID: PMC3890996  PMID: 24455190
acanthosis; cell culturing; psoriasis; cornification; qPCR; three-dimensional modeling
25.  Intensity of Free Radical Processes in Rat Liver under Type 2 Diabetes and Introduction of Epifamin 
Acta Naturae  2013;5(4):118-122.
The effect of epifamin on free radical processes, the activity of caspase-1 and -3, aconitate hydratase and citrate content in rat’s liver at experimentally induced type 2 diabetes mellitus (T2DM) was studied. The action of epifamin at T2DM leads to a decrease in biochemiluminescence parameters, characterizing the intensity of free radical processes, and changes in aconitase activity and citrate level towards the control. Activities of caspase-1 and caspase-3 in the tissue decreased by a factor of 2.4 and 1.6 in comparison with the levels at the disease. Apparently, epifamin-mediated correction of the level of melatonin, providing a significant antioxidant effect, promotes positive action on the free radical homeostasis.
PMCID: PMC3890997  PMID: 24455191
type 2 diabetes mellitusXXXX; biochemiluminescence; aconitate hydratase; citrate, caspase; epifamin

Results 1-25 (216)