Vol 5, No 3 (2013)


Modern Aspects of the Structural and Functional Organization of the DNA Mismatch Repair System

Perevoztchikova S.A., Romanova E.A., Oretskaya T.S., Friedhoff P., Kubareva E.A.


This review is focused on the general aspects of the DNA mismatch repair (MMR) process. The key proteins of the DNA mismatch repair system are MutS and MutL. To date, their main structural and functional characteristics have been thoroughly studied. However, different opinions exist about the initial stages of the mismatch repair process with the participation of these proteins. This review aims to summarize the data on the relationship between the two MutS functions, ATPase and DNA-binding, and to systematize various models of coordination between the mismatch site and the strand discrimination site in DNA. To test these models, novel techniques for the trapping of short-living complexes that appear at different MMR stages are to be developed.

Acta Naturae. 2013;5(3):17-34
pages 17-34 views

Non-Viral Delivery and Therapeutic Application of Small Interfering RNAs

Nikitenko N.A., Prassolov V.S.


RNA interference (RNAi) is a powerful method used for gene expression regulation. The increasing knowledge about the molecular mechanism of this phenomenon creates new avenues for the application of the RNAi technology in the treatment of various human diseases. However, delivery of RNA interference mediators, small interfering RNAs (siRNAs), to target cells is a major hurdle. Effective and safe pharmacological use of siRNAs requires carriers that can deliver siRNA to its target site and the development of methods for protection of these fragile molecules from in vivo degradation. This review summarizes various strategies for siRNA delivery, including chemical modification and non-viral approaches, such as the polymer-based, peptide-based, lipid-based techniques, and inorganic nanosystems. The advantages, disadvantages, and prospects for the therapeutic application of these methods are also examined in this paper.

Acta Naturae. 2013;5(3):35-53
pages 35-53 views

AZT 5’-Phosphonates: Achievements and Trends in the Treatment and Prevention of HIV Infection

Khandazhinskaya А.L., Shirokova E.A.


Despite the numerous drawbacks, 3’-azido-3’-deoxythymidine (AZT, Zidovudine, Retrovir) remains one of the key drugs used in the treatment and prevention of HIV infection in both monotherapy and HAART. A strategy in searching for new effective and safe AZT agents among latent (depot) forms of AZT has yielded its first positive results. In particular, the sodium salt of AZT 5’-H-phosphonate (Nikavir, phosphazide) has demonstrated clinical advantages over parent AZT: first and foremost, lower toxicity and better tolerability. It can be effectively used for the prevention of vertical transmission from mothers to babies and as an alternative drug for HIV-infected patients with low tolerance to Zidovudine. Preclinical studies of another phosphonate, AZT 5’-aminocarbonylphosphonate, have demonstrated that it releases AZT when taken orally. Pharmacokinetic studies have shown a prolonged action potential. Based on the analysis of both toxicological and pharmacological data, AZT 5’-aminocarbonylphosphonate has been recommended for clinical trials.

Acta Naturae. 2013;5(3):54-61
pages 54-61 views

Clathrin-Mediated Endocytosis and Adaptor Proteins

Popova N.V., Deyev I.E., Petrenko A.G.


Macromolecules gain access to the cytoplasm of eukaryotic cells using one of several ways of which clathrin-dependent endocytosis is the most researched. Although the mechanism of clathrin-mediated endocytosis is well understood in general, novel adaptor proteins that play various roles in ensuring specific regulation of the mentioned process are being discovered all the time. This review provides a detailed account of the mechanism of clathrin-mediated internalization of activated G protein-coupled receptors, as well as a description of the major proteins involved in this process.

Acta Naturae. 2013;5(3):62-73
pages 62-73 views

Research Articles

Acadesine Triggers Non-apoptotic Death in Tumor Cells

Glazunova V.A., Lobanov K.V., Shakulov R.S., Mironov A.S., Shtil A.A.


We studied the cytotoxicity of acadesine (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) for tumor and normal cells of various species and tissue origin. In tumor cells, acadesine triggered non-apoptotic death; the potency of the compound to normal cells was substantially lower. Acadesine was toxic for tumor cells with multidrug resistant phenotypes caused by the transmembrane transporter Р-glycoprotein or lack of proapoptotic p53. Activity of adenosine receptors was required for acadesine-induced cell death, whereas functioning of АМР-dependent protein kinase was not required. A more pronounced cytotoxicity for tumor cells, as well as the non-canonical death mechanism(s), makes acadesine a promising candidate for antitumor therapy.

Acta Naturae. 2013;5(3):74-78
pages 74-78 views

Cancer Specificity of Promoters of the Genes Involved in Cell Proliferation Control

Kashkin K.N., Chernov I.P., Stukacheva E.A., Kopantzev E.P., Monastyrskaya G.S., Uspenskaya N.Y., Sverdlov E.D.


Core promoters with adjacent regions of the human genes CDC6, POLD1, CKS1B, MCM2, and PLK1 were cloned into a pGL3 vector in front of the Photinus pyrails gene Luc in order to study the tumor specificity of the promoters. The cloned promoters were compared in their ability to direct luciferase expression in different human cancer cells and in normal fibroblasts. The cancer-specific promoter BIRC5 and non-specific CMV immediately early gene promoter were used for comparison. All cloned promoters were shown to be substantially more active in cancer cells than in fibroblasts, while the PLK1 promoter was the most cancer-specific and promising one. The specificity of the promoters to cancer cells descended in the series PLK1, CKS1B, POLD1, MCM2, and CDC6. The bidirectional activity of the cloned CKS1B promoter was demonstrated. It apparently directs the expression of the SHC1 gene, which is located in a “head-to-head” position to the CKS1B gene in the human genome. This feature should be taken into account in future use of the CKS1B promoter. The cloned promoters may be used in artificial genetic constructions for cancer gene therapy.

Acta Naturae. 2013;5(3):79-83
pages 79-83 views

Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease

Povarnina P.Y., Vorontsova O.N., Gudasheva T.A., Ostrovskaya R.U., Seredenin S.B.


Dipeptide mimetic of the nerve growth factor (NGF) loop 4, hexamethylenediamide bis-(N-monosuccinyl-glutamyl-lysine) (GK-2), was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology of the Russian Academy of Medical Sciences. GK-2 exhibited in vitro neuroprotective activity at nanomolar concentrations, was efficient in animal models of the Parkinson’s disease, ischemic and hemorrhagic stroke, and global cerebral ischemia at doses of 0.01–5 mg/kg (intraperitoneally) and 10 mg/kg (per os). The mnemotropic effects of subchronic intraperitoneal administration of GK-2 on rat models of the Alzheimer’s disease are described in this paper. Dipeptide GK-2 at a dose of 1 mg/kg is found to decrease the habituation deficit induced by the septo-hippocampal pathway transsection and, at a dose of 0.5 mg/kg, to significantly prevent spatial memory impairment in Morris water maze induced by intracerebral injection of streptozotocin. Thus, GK-2, an original dipeptide mimetic of NGF, acts on models of the Alzheimer’s disease upon systemic administration.

Acta Naturae. 2013;5(3):84-91
pages 84-91 views

Kinetic Parameters and Cytotoxic Activity of Recombinant Methionine γ-Lyase from Clostridium tetani, Clostridium sporogenes, Porphyromonas gingivalis and Citrobacter freundii

Morozova E.A., Kulikova V.V., Yashin D.V., Anufrieva N.V., Anisimova N.Y., Revtovich S.V., Kotlov M.I., Belyi Y.F., Pokrovsky V.S., Demidkina T.V.


The steady-state kinetic parameters of pyridoxal 5’-phosphate-dependent recombinant methionine γ-lyase from three pathogenic bacteria, Clostridium tetani, Clostridium sporogenes, and Porphyromonas gingivalis, were determined in β- and γ-elimination reactions. The enzyme from C. sporogenes is characterized by the highest catalytic efficiency in the γ-elimination reaction of L-methionine. It was demonstrated that the enzyme from these three sources exists as a tetramer. The N-terminal poly-histidine fragment of three recombinant enzymes influences their catalytic activity and facilitates the aggregation of monomers to yield dimeric forms under denaturing conditions. The cytotoxicity of methionine γ-lyase from C. sporogenes and C. tetani in comparison with Citrobacter freundii was evaluated using K562, PC-3, LnCap, MCF7, SKOV-3, and L5178y tumor cell lines. K562 (IC50=0.4-1.3 U/ml), PC-3 (IC50=0.1-0.4 U/ml), and MCF7 (IC50=0.04-3.2 U/ml) turned out to be the most sensitive cell lines.

Acta Naturae. 2013;5(3):92-98
pages 92-98 views

The Impact of ADH1B Alleles and Educational Status on Levels and Modes of Alcohol Consumption in Russian Male Individuals

Borinskaya S.A., Kim A.A., Rubanovich A.V., Yankovsky N.K.


Alcohol abuse is one of the main reasons behind the low life span in Russia. Both social and genetic factors affect the alcohol consumption level. The genetic factors are alleles of the alcohol dehydrogenase ADH1B and aldehyde dehydrogenaseALDH2 genes. We have typed and found frequencies for the alleles in a cohort of 642 men, ethnic Russians. The individuals of the cohort were asked to complete a questionnaire in the framework of the Izhevsk Family Study (Leon et al., 2007, 2009) regarding the amount of alcohol consumed and on the type of hazardous alcohol consumption (nonbeverage alcohol consumption and the so-called “zapoï” which is a Russian term for a heavy drinking bout lasting for at least 2 days, when an individual is withdrawn from the normal social life). The ADH1B*48His allele was found among heterozygous individuals only (N=68, 10.6% of the cohort). The ALDH2*504Lys allele was also found among heterozygous individuals only (N=2, 0.3%) The effect of ADH1B alleles and the influence of the education level on the amount and type of alcohol consumed had not previously been studied in Russians. We have found that the amount of consumed alcohol is 21.6% lower (1733 g of ethanol per year) for ADH1B*48His allele carriers in the cohort of Russian men. The amount of consumed alcohol was found to be 9.8% lower (793 g of ethanol per year) in the case when individuals had a higher education as compared to those who had a secondary- or elementary school education level in the same cohort. Hence, the protective effect of the genetic factor (ADH1B*48His allele carriage) has proven to be more pronounced than the influence of the social factor (education level) at the individual level in the cohort of Russian men. Both factors have also proven to have a protective effect against hazardous types of alcohol consumption. Zapoï was not scored among individuals of the cohort with ADH1B*48His allele carriage (OR=12.6, P=0.006), as compared to 8.4% of “zapoï” individuals who did not carry the ADH1B*48His allele (genotype Arg/Arg).The percentage of individuals who consume non-beverage alcohol is lower (0.6%) in the subcohort of people with a higher education degree. This percentage is higher (6.0%, OR=10.0, P=0.004) in the subcohort of people without a higher education degree.

Acta Naturae. 2013;5(3):99-106
pages 99-106 views

Transfer of Silver Nanoparticles through the Placenta and Breast Milk during in vivo Experiments on Rats

Melnik E.A., Buzulukov Y.P., Demin V.F., Demin V.A., Gmoshinski I.V., Tyshko N.V., Tutelyan V.A.


Silver nanoparticles (NPs), widely used in the manufacture of various types of consumer products and for medical applications, belong to novel types of materials that pose potential risks to human health. The potential negative effects of the influence of these NPs on reproduction are insufficiently researched. A quantitative assessment of the transfer of metallic silver nanoparticles through the placenta and breast milk was carried out during an in vivo experiment. We used 34.9 ± 14.8 nm in size silver NPs that were stabilized by low-molecularweight polyvinylpyrrolidone and labeled with the 110mAg radioactive isotope using thermal neutron irradiation in a nuclear reactor. [110mAg]-labeled NPs preparations were administered intragastrically via a gavage needle to pregnant (20th day of gestation) or lactating (14-16th day of lactation) female rats at a dose of 1.69-2.21 mg/kg of body weight upon conversion into silver. The accumulation of NPs in rat fetuses and infant rats consuming their mother’s breast milk was evaluated using a low-background semiconductor gamma-ray spectrometer 24 and 48 hours following labeling, respectively. In all cases, we observed a penetration of the [110mAg]-labeled NPs through the placenta and ther entry into the mother’s milk in amounts exceeding by 100-1,000 times the sensitivity of the utilized analytical method. The average level of accumulation of NPs in fetuses was 0.085-0.147% of the administered dose, which was comparable to the accumulation of the label in the liver, blood, and muscle carcass of adult animals and exceeded the penetration of NPs across the hematoencephalic barrier into the brain of females by a factor of 10-100. In lactating females, the total accumulation of [110mAg]-labeled NPs into the milk exceeded 1.94 ± 0.29% of the administered dose over a 48 h period of lactation; not less than 25% of this amount was absorbed into the gastrointestinal tract of infant rats. Thus, this was the first time experimental evidence of the transfer of NPs from mother to offspring through the placenta and breast milk was obtained.

Acta Naturae. 2013;5(3):107-115
pages 107-115 views

Metagenomic Analysis of the Dynamic Changes in the Gut Microbiome of the Participants of the MARS-500 Experiment, Simulating Long Term Space Flight

Mardanov A.V., Babykin M.M., Beletsky A.V., Grigoriev A.I., Zinchenko V.V., Kadnikov V.V., Kirpichnikov M.P., Mazur A.M., Nedoluzhko A.V., Novikova N.D., Prokhortchouk E.B., Ravin N.V., Skryabin K.G., Shestakov S.V.


A metagenomic analysis of the dynamic changes of the composition of the intestinal microbiome of five participants of the MARS-500 experiment was performed. DNA samples were isolated from the feces of the participants taken just before the experiment, upon 14, 30, 210, 363 and 510 days of isolation in the experimental module, and two weeks upon completion of the experiment. The taxonomic composition of the microbiome was analyzed by pyrosequencing of 16S rRNA gene fragments. Both the taxonomic and functional gene content of the microbiome of one participant were analyzed by whole metagenome sequencing using the SOLiD technique. Each participant had a specific microbiome that could be assigned to one of three recognized enterotypes. Two participants had enterotype I microbiomes characterized by the prevalence of Bacteroides, while the microbiomes of two others, assigned to type II, were dominated by Prevotella. One participant had a microbiome of mixed type. It was found that (1) changes in the taxonimic composition of the microbiomes occurred in the course of the experiment, but the enterotypes remained the same; (2) significant changes in the compositions of the microbiomes occurred just 14-30 days after the beginning of the experiment, presumably indicating the influence of stress factors in the first stage of the experiment; (3) a tendency toward a reversion of the microbiomes to their initial composition was observed two weeks after the end of the experiment, but complete recovery was not achieved. The metagenomic analysis of the microbiome of one of the participants showed that in spite of variations in the taxonomic compositions of microbiomes, the “functional” genetic composition was much more stable for most of the functional gene categories. Probably in the course of the experiment the taxonomic composition of the gut microbiome was adaptively changed to reflect the individual response to the experimental conditions. A new, balanced taxonomic composition of the microbiome was formed to ensure a stable gene content of the community as a whole without negative consequences for the health of the participants.

Acta Naturae. 2013;5(3):116-125
pages 116-125 views

Short communications

Stabilization of the Central Part of Tropomyosin Molecule Alters the Ca 2+-sensitivity of Actin-Myosin Interaction

Shchepkin D.V., Matyushenko A.M., Kopylova G.V., Artemova N.V., Bershitsky S.Y., Tsaturyan A.K., Levitsky D.I.


We show that the mutations D137L and G126R, which stabilize the central part of the tropomyosin (Tm) molecule, increase both the maximal sliding velocity of the regulated actin filaments in the in vitro motility assay at high Са 2+ concentrations and the Са 2+-sensitivity of the actin-myosin interaction underlying this sliding. Based on an analysis of the recently published data on the structure of the actin-Tm–myosin complex, we suppose that the physiological effects of these mutations in Tm can be accounted for by their influence on the interactions between the central part of Tm and certain sites of the myosin head.

Acta Naturae. 2013;5(3):126-129
pages 126-129 views


Bibliometric Indicators of Russian Journals by JCR-Science Edition, 1995-2010

Libkind A.N., Markusova V.A., Mindeli L.E.


A representative empirical bibliometric analysis of Russian journals included in the Journal Citation Reports-Science Edition (JCR-SE) for the time period 1995–2010 was conducted at the macro level (excluding the subject categories). It was found that the growth in the number of articles covered by JCR (a 1.8-fold increase compared to 1995) is ahead of the growth rates of Russian publications (1.2-fold increase). Hence, the share of Russian articles covered by JCR-SE was down from 2.5% in 1995 to 1.7% in 2010. It was determined that the number of articles published in an average Russian journal reduced by 20% as compared to the number of articles in an average journal of the full data set. These facts could partly shed light on the question why Russian research performance is staggering (approximately 30,000 articles per year), although the coverage of Russian journals has expanded to 150 titles. Over the past 15 years, a twofold increase in the impact factor of the Russian journals has been observed, which is higher than that for the full data set of journals (a 1.4-fold increase). Measures to improve the quality of Russian journals are proposed.

Acta Naturae. 2013;5(3):6-12
pages 6-12 views

Big Data in Biology and Medicine

Trifonova O.P., Il’in V.A., Kolker E.V., Lisitsa A.V.



Acta Naturae. 2013;5(3):13-16
pages 13-16 views

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