Original research Aminopyridine- and aminopyrimidine-based serine/threonine protein kinase inhibitors are drug candidates for treating drug-resistant tuberculosis
Maslov DA, Bekker OB, Alekseeva MG, Kniazeva LM, Mavletova DA, Afanasyev II, Vasilevich NI, Danilenko VN
Tuberculosis (TB) is the world’s deadliest bacterial infection. Its causative agent Mycobacterium tuberculosis evolves into rapidly spreading multidrug-resistant and extensively drug-resistant (MDR and XDR) strains, which complicates the treatment. Therefore, the use of novel target-specific chemical compounds is crucial for the development of effective antituberculosis agents. Serine/threonine protein kinases (STPKs) of M. tuberculosis are currently considered as attractive drug targets. In turn, aminopyridines and aminopyrimidines that have not been used for TB treatment so far exhibit inhibitory activity towards STPKs. In this study we screened 192 aminopyridine- and aminopyrimidine-based compounds using the Mycobacterium smegmatis aphVIII+ test system designed to screen for active STPKs inhibitors. First, we selected 53 compounds with subinhibiting concentrations of up to 100 nmol/disk. Of them, 22 showed STPKs-inhibiting activity in the test system, which was confirmed in vitro on the M. tuberculosis PknA protein with a maximum of 26.9 ± 6.1 %. Toxicity testing was performed in vitro on human embryo fibroblasts using the MTT-assay. Ultimately, 3 relatively active and relatively non-toxic STPKs inhibitors were selected for further research as drug candidates for MDR-TB treatment.
Received: 2017-01-30
Published online: 2017-03-13
DOI: 10.24075/brsmu.2017-01-04
Comments 0
VIEWS 6981
Original research Polymorphism of the dtxR gene in the currently existing strains of Сorynebacterium diphtheriae
Chagina IA, Perevarova YuS, Perevarov VV, Chaplin AV, Borisova OYu, Kafarskaya LI, Afanas'ev SS, Aleshkin VA
The pathogenic mechanism used by Corynebacterium diphtheriae is attributed to the ability of the diphtheria toxin to disrupt protein synthesis in human cells. Diphtheria toxin production is regulated by the DtxR protein. The latter is involved in the iron-mediated repression of the toxin gene and coordinates activities of other genes essential for the survival of C. diphtheriae. The DtxR-encoding gene occurs in both toxigenic and non-toxigenic strains; therefore it can be used to analyze the population structure of the species. In our work we have studied 45 strains of C. diphtheriae isolated in the Russian Federation in 2010–2015. These strains were analyzed to reveal that gene dtxR is a highly conservative region of С. diphtheriae genome that can be found in all members of the studied species. The majority of the discovered polymorphisms were synonymous (16 of 18 single nucleotide polymorphisms identified). In spite of the low phylogenetic signal, the allelic variant of dtxR was associated with the strain’s phenotype (biovar, toxigenicity). The obtained data indicate the presence of aggressive negative selection aimed to maintain the existing protein sequence in the population. Based on the results, we recommend dtxR polymerase chain reaction as an additional technique for pathogen identification, which is especially relevant considering the increasing prevalence of the disease associated with non-toxigenic C. diphtheriae strains.
Received: 2017-02-02
Published online: 2017-03-11
DOI: 10.24075/brsmu.2017-01-03
Comments 0
VIEWS 6298
Original research Genetic polymorphism of Staphylococcus epidermidis strains in patients of the Neonatal Intensive Care Unit
Gordeev AB, Lyubasovskaya LA, Rodchenko JV, Dubodelov DV, Mukosey IS, Kochetkova TO, Nikitina IV, Ionov OV, Zubkov VV, Trofimov DYu, Priputnevich TV
Staphylococcus epidermidis is a member of the normal bacterial flora of humans capable of causing potentially dangerous diseases in neonates with very or extremely low birth weight. The number of genes responsible for virulence and antibiotic resistance may vary in different S. <i>epidermidis</i> strains. We sequenced isolates of S. <i>epidermidis</i> to explore genetic diversity of 14 strains circulating in the Neonatal Intensive Care Unit of Kulakov Research Center for Obstetrics, Gynecology and Perinatology. Among the studied strains, 8 sequence types were identified, the most frequent being ST2 and ST59, both of which belong to the clonal complex CC2. Of 14 studied strains, 10 were of CC2 type. The studied strains revealed a variety of genes responsible for antibiotic resistance. We found 15 genes that provided resistance to aminoglycosides, beta-lactam antibiotics, fusidic acid, macrolides, lincosamides, streptogramin B, tetracycline, and trimethoprim. We identified a number of genes associated with virulence (<i>aae, atlE, aap, embp</i>), whose frequency in the studied isolates was varied. The insertion element IS256 was detected in 9 strains, and 7 strains revealed the presence of the <i>ica</i>-operon responsible for the biosynthesis of the biofilm matrix proteins.
Received: 2017-02-02
Published online: 2017-03-11
DOI: 10.24075/brsmu.2017-01-02
Comments 0
VIEWS 6300
Review Emergence of new infections in the 21st century and identification of pathogens using next generation sequencing
Makarov VV, Khromov AV, Gushchin VA, Tkachuk AP
Each new emerging infection may become a big challenge to the medical community. Changing environment, tropical deforestation, melting of the Antarctic ice, growing population density and uncontrolled use of antibiotics provoke emergence and evolution of pathogens. Epidemics caused by new strains of the influenza virus, respiratory syndromes associated with coronaviruses, outbreaks of hemolytic Escherichia coli infections and antibiotic-resistant superbacteria are hazards to humans. Among high-priority measures for pathogen control that are yet to be taken is development of fast and accurate techniques for pathogen identification. Our review looks at the cases of new infections registered in the 21st century and explores feasibility of next generation sequencing for the detection and identification of new pathogens.
Received: 2017-02-03
Published online: 2017-03-11
DOI: 10.24075/brsmu.2017-01-01
Comments 0
VIEWS 6709
Original research Nuclear medicine in the diagnosis of renal and coronary angiopathies in patients with type 2 diabetes and impaired glucose tolerance
Kharina DS, Poletaeva TA, Kondakov AK, Mosin DYu, Znamensky IA
The number of patients suffering from diabetes mellitus (DM) is increasing necessitating the development of new strategies for early detection of the disease. Here, radionuclide imaging may be a promising diagnostic technique. We have conducted a retrospective analysis of medical records and scintigrams of patients with type 2 diabetes (n = 83) and impaired glucose tolerance (n = 52) to evaluate the effectiveness of dynamic renal scintigraphy and myocardial perfusion scintigraphy at rest (single-photon emission computed tomography, SPECT) in detecting coronary and renal angiopathies. The control group consisted of patients with normal levels of blood sugar. To evaluate the functional state of the renal parenchyma, we conducted a qualitative analysis of patients’ scintigrams and renographic curves; the glomerular filtration rate (GFR) was evaluated using Gates and Cockroft-Gault methods; myocardial scarring was evaluated using perfusion SPECT images synchronized with ECG. The functional activity of the renal parenchyma was shown to decrease significantly in patients with type 2 DM (Pearson’s chi- squared test was applied, p-value was 0.03). With Gates method applied, GFR in both experimental groups was significantly lower than in the controls (Mann-Whitney U was calculated; p-value was 0.0004 and 0.0002, respectively). In patients with type 2 DM, GFR was lower than in patients with impaired glucose tolerance (p = 0.0004). With Cockroft–Gault method applied, we observed the same GFR pattern; however, the difference between patients with impaired glucose tolerance and the controls was insignificant (p = 0.08). The correlation between GFR values obtained using different methods was moderate in all groups (Spearman’s rank correlation coefficient rs = 0.53, with p = 0.038).
Received: 2016-11-25
Published online: 2017-01-19
DOI: 10.24075/brsmu.2016-06-06
Comments 0
VIEWS 6036
Editorial Stolen science: why plagiarism and self-plagiarism are unacceptable
Kulikova EYu
Plagiarism is appropriation of someone else’s ideas, texts, images and other materials without acknowledging their author. It is a serious violation of publication ethics that once detected results in the retraction of the submitted article. It has a disastrous impact on the author’s reputation, because the publication is not removed from online databases, but stored there with a retracted publication tag. Plagiarism comes in different forms many of which still cannot be detected even by a special software; Plagiarism comes in different forms; the originality of an article is still assessed by peer reviewers and readers in the first place. Plagiarism can be unintentional. Most often, poor citation and reference style is typical of young researchers. To avoid unpleasant situations, authors are advised to use paraphrasing instead of merely copying and pasting fragments of texts. A verbatim use of a source requires quotation marks, references are expected to come right after the fragment borrowed from the original source; with multiple references (from 5 to 10) pointing to a single idea are bad style. Authors are advised to always double check basic information about the publication they specify in a reference. The first author and a corresponding author are expected to monitor the quality of their co-authors’ work. Full or partial copying of a previously published article by the same author is considered self-plagiarism and does not comply with the guidelines of the majority of academic journals.
Received: 2016-12-28
Published online: 2017-01-19
DOI: 10.24075/brsmu.2016-06-09
Comments 0
VIEWS 6449
Original research Clinical and laboratory features of hemostatic disorders in patients with retinal vein occlusion
Shelkovnikova TV, Takhchidi KhP, Volkov AN, Shishlyannikova NYu
The number of patients with retinal venous occlusions is increasing, especially among young people. Often, they have revealed a genetic predisposition to thrombosis. Risk factors for thrombosis are genetic resistance to activated protein C (RAPC), genetic defect in factor V (FV Leiden) and the presence of lupus anticoagulant (LA). In this study we analyze the dependence of the various parameters of hemostasis in patients with retinal vein occlusion (RVO) on the background of FV Leiden mutation and LA. A total of 150 patients (150 eyes) with RVO (mean age — 42 ± 10 years) were examined and divided into three groups. Group 1: patients with RVO, FV Leiden and LA (n = 12); group 2: patients with RVO and FV Leiden (n = 11) without LA; group 3: patients with RVO without FV Leiden and LA, selected from remaining 107 people for a comparable number of groups (n = 30). The control group was 50 people without RVO, but with hypertension. It was shown that RAPC index in patients with FV Leiden mutation and the LA has the less value (0,6 ± 0,01) on comparison to patients with RVO (1,50 ± 0,18) (p < 0,05). They also have enhanced V, VIII and von Willebrand factors and intravascular platelet activity. LA exacerbates endotheliosis in the microvasculature of the retina and in combination with FV Leiden mutation increases the thrombogenesis, participating in the pathogenesis of ischemic thrombosis of central retinal vein and its branches, which clinically manifested as retinal thrombo-hemorrhagic syndrome. The hemostasis regulation genes polymorphisms detection (as well as lupus anticoagulant detection) is recommended to clarify the diagnosis and selection of adequate therapy.
Received: 2016-11-28
Published online: 2017-01-19
DOI: 10.24075/brsmu.2016-06-08
Comments 0
VIEWS 6045
Original research Dynamics of functional activity of thyrocytes in the setting of changing morphofunctional activity of mast cells of the thyroid gland upon infrared laser therapy
Smelova IV, Golovneva ES
Exposure to laser radiation is an interesting method of treating hypothyroidism and autoimmune thyroiditis. Its effect depends on the applied radiation dose. Degranulation of stromal mast cells of the thyroid gland (mastocytes) is dose dependent; release of granular contents into the surrounding tissues may affect microcirculation, result in the increased activity of the thyroid epithelium or stimulate the thyroid. Our study aimed to investigate the effect of moderate-intensity infrared laser radiation at total surface doses of 112 and 450 J/cm<sup>2</sup> on the functional state of mast cells and blood serum levels of thyroid gland hormones in healthy and hypothyroid subjects. The experiment was carried out in 78 random-bred mature male rats. Hypothyroidism was modeled by per os administration of 25 mg/kg Mercazolil (Akrikhin, Russia) for 21 days. Radiation therapy was performed using a IRE-Polus laser with a wavelength of 970 nm (NTO IRE-Polus, Russia). The animals received radiation therapy for 5 days and were sacrificed 1, 7, and 30 days after the experiment. Subsequently, we calculated the total number of mast cells, degranulated mastocytes, mastocytes with degree 1, 2 and 3 degranulation, degranulation coefficient, and levels of TSH in blood serum. Mast cells of the intact thyroid gland demonstrated low sensitivity to laser radiation, but hormone levels changed soon after radiation was discontinued. In the animals with hypothyroidism induced by thiamazole (the active component of Mercazolil), activation of mast cells was observed in the recovery period after the drug was discontinued. Hypothyroidism was accompanied by changes in TSH, Т<sub>4</sub> and Т<sub>3</sub> levels in blood serum. Comparison of the effects of two laser therapy modes in the animals with induced hypothyroidism revealed increased functional activity of mastocytes and normalized levels of secreted hormones at a total dose of 112 J/cm<sup>2</sup> and reduced mast cell activity at a total dose of 450 J/cm<sup>2</sup>.
Received: 2016-11-28
Published online: 2017-01-19
DOI: 10.24075/brsmu.2016-06-07
Comments 0
VIEWS 6242