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Kostyuk V.A.,Laboratory of Tissue Engineering and Cutaneous Pathophysiology | Kostyuk V.A.,Belarusian State University | Potapovich A.I.,Laboratory of Tissue Engineering and Cutaneous Pathophysiology | Potapovich A.I.,Belarusian State University | And 12 more authors.
Antioxidants and Redox Signaling | Year: 2010

Oxidative stress due to increased epidermal levels of H2O 2 with consequent inhibition of catalase activity is generally accepted as a leading cytotoxic mechanism of melanocyte loss in vitiligo. Keratinocyte-derived cytokines are considered key factors in the maintenance of melanocyte structure and functions. We hypothesized that abnormal redox control may lead to impaired cytokine production by keratinocytes, thus causing noncytotoxic defects in melanocyte proliferation and melanogenesis. We found significantly suppressed mRNA and protein expression of glutathione-S- transferase (GST) M1 isoform, and higher-than-normal levels of both 4-hydroxy-2-nonenal (HNE)-protein adducts and H2O2 in the cultures of keratinocytes derived from unaffected and affected skin of vitiligo patients, and in their co-cultures with allogeneic melanocytes. GST and catalase activities, as well as glutathione levels, were dramatically low in erythrocytes, whilst HNE-protein adducts were high in the plasma of vitiligo patients. The broad spectrum of major cytokines, chemokines, and growth factors was dysregulated in both blood plasma and cultured keratinocytes of vitiligo patients, when compared to normal subjects. Exogenous HNE added to normal keratinocytes induced a vitiligo-like cytokine pattern, and H2O 2 overproduction accompanied by adaptive upregulation of catalase and GSTM1 genes, and transient inhibition of Erk1/2 and Akt phosphorylation. Based on these results, we suggest a novel GST-HNE-H2O2-based mechanism of dysregulation of cytokine-mediated keratinocyte-melanocyte interaction in vitiligo. © 2010 Mary Ann Liebert, Inc.

Shevchenko O.V.,Smolensk State Medical Academy | Mudrak D.Y.,Moscow Medical Academy | Skleenova E.Y.,Smolensk State Medical Academy | Kozyreva V.K.,Smolensk State Medical Academy | And 5 more authors.
Clinical Microbiology and Infection | Year: 2012

An Escherichia coli isolate co-producing VIM-4 metallo-β-lactamase and CTX-M-15 extended spectrum β-lactamase was recovered from the urine of a patient with head trauma in Moscow, Russia. The bla VIM-4 and bla CTX-M-15 genes were carried, respectively, by transmissible plasmids of IncW and IncI1 groups. The nucleotide sequence of the VIM-4-encoding integron was nearly identical to that of In416, which represent a large group of structurally related integrons previously found in Enterobacteriaceae all around the Mediterranean basin. This is the first report of a metallo-β-lactamase-producing E. coli in Russia. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.

Varizhuk A.,RAS Engelhardt Institute of Molecular Biology | Chizhov A.,RAS N. D. Zelinsky Institute of Organic Chemistry | Smirnov I.,Institute for Physical Chemical Medicine | Kaluzhny D.,RAS Engelhardt Institute of Molecular Biology | Florentiev V.,RAS Engelhardt Institute of Molecular Biology
European Journal of Organic Chemistry | Year: 2012

A new class of backbone-modified oligonucleotide analogs has emerged since the discovery of the Cu I-catalyzed [3+2] azide/alkyne cycloaddition reaction. These are oligonucleotide analogs with 1,4-disubstituted 1,2,3-triazoles as the internucleotide linkages. Of all such analogs known, only the triazole-linked deoxythymidine decamer [(dT) 10] has been reported to show enhanced binding affinity to complementary DNA. Importantly, it is a fully modified (dT) 10 analog. To date, sequentially heterogeneous oligonucleotides bearing the same backbone modification have not been described. With the goal of investigating sequence and regularity dependence of the effect of this modification on duplex stability, we have designed partially modified mixed-base oligonucleotides, which can be prepared by using a modified dinucleoside block. In this paper we report the synthesis of a dithymidine phosphoramidite analog with a triazole linker, its use in oligonucleotide synthesis and hybridization data of the resulting oligonucleotide analogs. The effect of single and multiple modifications on stability of mixed-base duplexes is assessed and compared with published data for the oligo(T)/oligo(A) duplex. We also compared the effect of the linker concerned with that of a shorter triazole linker. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tatarinova O.,Institute for Physical Chemical Medicine | Tsvetkov V.,RAS Topchiev Institute of Petrochemical Synthesis | Basmanov D.,Institute for Physical Chemical Medicine | Barinov N.,Institute for Physical Chemical Medicine | And 7 more authors.
PLoS ONE | Year: 2014

Noncanonically structured DNA aptamers to thrombin were examined. Two different approaches were used to improve stability, binding affinity and biological activity of a known thrombin-binding aptamer. These approaches are chemical modification and the addition of a duplex module to the aptamer core structure. Several chemically modified aptamers and the duplex-bearing ones were all studied under the same conditions by a set of widely known and some relatively new methods. A number of the thrombin-binding aptamer analogs have demonstrated improved characteristics. Most importantly, the study allowed us to compare directly the two approaches to aptamer optimization and to analyze their relative advantages and disadvantages as well as their potential in drug design and fundamental studies. © 2014 Tatarinova et al.

Varizhuk A.M.,RAS Engelhardt Institute of Molecular Biology | Tsvetkov V.B.,RAS Topchiev Institute of Petrochemical Synthesis | Tatarinova O.N.,Institute for Physical Chemical Medicine | Kaluzhny D.N.,RAS Engelhardt Institute of Molecular Biology | And 8 more authors.
European Journal of Medicinal Chemistry | Year: 2013

A series of DNA aptamers bearing triazole internucleotide linkages that bind to thrombin was synthesized. The novel aptamers are structurally analogous to the well-known thrombin-inhibiting G-quadruplexes TBA15 and TBA31. The secondary structure stability, binding af finity for thrombin and anticoagulant effects of the triazole-modifi ed aptamers were measured. A modification in the central loop of the aptamer quadruplex resulted in increased nuclease resistance and an inhibition efficiency similar to that of TBA15. The likely aptamer-thrombin binding mode was determined by molecular dynamics simulations. Due to their relatively high activity and the increased resistance to nuclease digestion imparted by the triazole internucleotide linkages, the novel aptamers are a promising alternative to known DNA-based anticoagulant agents. © 2013 Elsevier Masson SAS. All rights reserved.

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