Vol 73, No 5 (2018)


The Role of Redox Proteins in Arresting Proliferation of Breast Epithelial Cells Under Oxidative Stress

Shakhristova E.V., Stepovaya E.A., Rudikov E.V., Sushitskaya O.S., Rodionova D.O., Novitsky V.V.


Background: Redox status imbalance against the backdrop of oxidative stress development underlies the pathogenesis of a whole range of diseases. Many intracellular proteins contain free thiol groups and undergo redox regulation which is one of the key processes in controlling cell proliferation. Thioredoxin and glutaredoxin are involved in maintaining intracellular redox homeostasis and act as candidates in regulating proliferation. This provides prospects for future development of methods for diagnosis and targeted therapy of socially sensitive diseases accompanied by oxidative stress. The aim of the study is to reveal the role of redox proteins in molecular mechanisms of regulating HBL-100 breast epithelial cell proliferation under the effect of roscovitine, a cell cycle inhibitor. Materials and methods: Two research groups were formed. They included HBL-100 human breast epithelial cells incubated in the presence and absence of 20 mcM roscovitine for 18 hours. The intracellular thioredoxin levels were determined using Western blot analysis with specific monoclonal antibodies. Distribution of the cells among cell cycle phases were evaluated by flow cytometry. The activity of glutathione reductase, glutathione peroxidase, and thioredoxin reductase were measured by spectrophotometry. Results: Under the effect of roscovitine in the HBL-100 cells, cell cycle arrest in the G2/М phases occurred and oxidative stress developed. In the meantime, the decrease in the thioredoxin and glutaredoxin concentrations was registered along with the change in the functional activity of glutathione-dependent enzymes. Conclusions: Application of roscovitine, a cell cycle inhibitor, allowed creating a model of oxidative stress in the breast epithelial cells against the backdrop of inhibited cell proliferation. We identified that thioredoxin and glutaredoxin contributed to impairment of cell cycle progression. It points at a possibility to regulate cell proliferation by modulating the functional features of cellular redox-dependent proteins in different pathologies accompanied by oxidative stress.

Annals of the Russian academy of medical sciences. 2018;73(5):289-293
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Ursodeoxycholic Acid: Efficacy and Safety in the Treatment of Nonalcoholic Fatty Liver Disease (Meta-Analysis)

Pavlov С.S., Varganova D.L., Semenistaia M.C., Kuznetsova E.A., Usanova A.A., Svistunov A.A.


Вackground: Non-alcoholic liver disease (NAFLD) is a widely spread disease that needs an effective and safe treatment strategy. One of pharmacological treatments for people with NAFLD is ursodeoxycholic acid (UDCA). The use of UDCA is pathogenetically justified because of its cytoprotective, antiapoptotic, antioxidant, and hypoglycemic properties. Aim: Our meta-analysis (M-A) aimed to assess the benefits and harms of UDCA in people with NAFLD. Material and methods: We identified trials through electronic searches in the Cochrane Hepato-Biliary (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, SCI, LILACS, eLibrary (May 2018). We considered for inclusion randomised clinical trials (RCTs) assessing URSO versus placebo/no intervention in adult participants with NAFLD. We allowed co-interventions in the trial groups if they were similar. We followed Cochrane methodology, CHB Group methodology using Review Manager 5 and Trial Sequential Analysis to perform meta-analysis (M-A), assessed bias risk of the trials, quality of evidence using GRADE. Results: Four RCT, at high bias risk, low quality of evidence, provided data for analysis: 254 participants at different stages of NAFLD received oral UDCA (median of 18 months), 256 ― placebo/no intervention; age 18 to 75 years. We found no evidence of effect on mortality (there were no deaths) and on histological parameters such as steatosis (MD -0.13; CI -0.40−0.13; participants 323; trials 3; I2=43%), fibrosis (MD 0.00; CI -0.00−0.22; participants 323; trials 3; I2=0%), and inflammation (MD -0.05; CI -0.20−0.10; participants 325; trials 3; I2=0%). Also we found no evidence for significant influence of UDCA on occurrence of serious adverse events (RR 1.45, 95% CI 0.65−3.21; participants 292; trials 2; I2=0%), adverse events (RR 1.52, 95% CI 0.73−3.16; participants 510; trials 4; I2=36%) neither with traditional M-A (random-effects), nor with TSA SAE (CI 0.56−2.91; participants 292; trials 2; I2=0%, D2=0%), AE (CI 0.77–2.21; participants 510; trials 4; I2=0%, D2=0%). There was no evidence of effect on cytolysis, but beneficial effect of UDCA on cholestasis (GGTP) (data from two trials only) (р<0.0001). We found no data on quality of life. All the trials were funded by the industry. Conclusion: Based on the small number of trials at high risk of bias, low quality, despite the safety profile observed with our M-A, we can neither recommend nor reject the use of UDCA for people with NAFLD. Further trials with low risk of bias and high quality are required to assess the benefits and harms of UDCA. 

Annals of the Russian academy of medical sciences. 2018;73(5):294-305
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UV-radiation as a Risk Factor for Non-melanoma Skin Cancer. Genetic Determinants of Carcinogenesis

Zhilova M.B., Butareva M.M.


The review presents modern data on the role of ultraviolet (UV) radiation in the pathogenesis of non-melanoma skin cancer (NMSC), the problem of THE risk of developing NMSC, in particular, squamous cell and basal cell skin cancer both in the population and in long-term repeated irradiation of phototherapy (PUVA therapy, UVB therapy, UVB-311 therapy) in patients with psoriasis. The paper considers the mechanisms of UV-induced cell damage by different spectral ranges (UVA, UVB) including the formation of photoproducts, damage to genomic DNA and other cellular structures, violation of the regulation of signaling pathways, the development of chronic inflammation, secondary immunosuppression. The review summarizes the results of large epidemiological studies discussing the role of gene polymorphisms in the homologous DNA repair XRCC3, gene telomerase TERT-CLPTMI, cytokine IL10 gene, MTHFR gene, encoding the folate synthesis, genes involved in pigmentirovanie MC1R, EXOC2, UBAC2 in the modulation of risk of carcinogenic effect of UV radiation. According to the authors’ opinion, the most vital and significant is data on the role of vitamin D receptor (VDR) gene polymorphisms as possible predictors of the risk of NMSC development. The further prospects of academic research on the cumulative role of the genome and environmental factors in the risk assessment of NMSC are revealed.

Annals of the Russian academy of medical sciences. 2018;73(5):306-313
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Clinical Trials: What, Where, When?

Kobyakova O.S., Deev I.A., Kulikov E.S., Shtykh R.I., Pimenov I.D., Zvonareva O.I., Mareev I.V.


Currently randomized clinical trials (RCTs) are a key stage in the development of new drugs. Despite the huge scale of the CT market, general awareness of the issue remains low and the society has formed a number of stereotypes and misconceptions about CTs. The presented review of Russian and foreign studies provides the information on the level of general awareness of clinical research in different countries, as well as among patients and practitioners. The conducted literature analysis demonstrates that awareness of clinical trials remains low both in society at large and among patients or in the professional community of practitioners. According to foreign studies, only 20–30% of respondents have heard anything about medical research while a relatively small percentage of respondents have more complete knowledge of RCTs. Among practitioners, only one in five is sufficiently informed about CTs while, according to different data, only about half fully realize what evidence-based medicine is and understand the importance of CTs as a source of reliable knowledge in everyday practice.

Annals of the Russian academy of medical sciences. 2018;73(5):314-320
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Cytokine Profile and Expression of FYN, ZAP-70 and LAT During Concanavalin A Stimulation in Patients with Resistant Bronchial Asthma

Petrov V.A., Saltykova I.V., Nevskaya K.V., Dorofeeva J.B., Lezhava S.P., Kirillova N.A., Kulikov E.S., Sazonov A.E., Ogorodova L.M.


Background: Bronchial asthma (BA) is one of the most spreading chronic lung pathology in the world. The disease is characterized by high heterogeneity of clinical phenotypes including resistant forms which provoke significant clinical problem. Immune shift from Th2 to alternative immunological response is considered to be a mechanism of drug-resistance in BA treatment but this issue is not considerably studied yet. Aims: Detection of distinctive patterns in cytokine secretion and genetic expression (ZAP-70, FYN and LAT) of naïve and concanavalin A stimulated lymphocytes in patients with resistant BA. Materials and methods: The study enrolled ten patients in each group: subjects with treatment resistant BA, severe BA, and controls (30 in total). During the experiment, all patients with BA received treatment according to the condition. For each participant lymphocytes isolation from venous blood was performed. Cells were cultured with concanavalin A and without stimulation. Concentrations of cytokines IL-2, IL-12, TNF-α, IL-4, IL-5, and IL-6 in supernatants were measured with ELISA. Reverse transcription polymerase chain reaction was used to detect the mRNA expression of LAT, ZAP-70, and FYN genes. Results: Significant disease contribution to the lymphocyte secretion profile was established without concanavalin A stimulation: increased levels of IL-2 and IL-4 was observed in lymphocytes of patients with resistant BA if compared to the results of gorup with severe BA. Patients with resistant BA were characterized by weak cytokine response to the stimulation: only TNF-α and IL-5 levels were significantly increased whereas in group with severe BA all cytokines concentrations increased except IL-12, in controls — except IL-12 and IL-2. Significant FYN upregulation was identified in resistant BA group if compared with other groups, and in severe BA patients if compared with controls. The concanavalin A-stimulated cells showed increased expression of ZAP-70 in cells of patients with resistant BA compared to control group. Conclusions: Lymphocytes from patients with resistant BA are characterized by lack of cytokine response to concanavalin A stimulation, alteration of cytokine secretion, and genetic expression profile similar to cells with low sensitivity to apoptosis. The FYN gene is a perspective target for finding approaches to overcome resistance to steroid drugs in bronchial asthma.

Annals of the Russian academy of medical sciences. 2018;73(5):321-329
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Tuberculosis in the Russian Federation: Situation, Challenges and Perspectives

Ergeshov A.Е.


Tuberculosis (TB) is a significant problem of public health both in Russia and abroad. About one third of the world’s population is infected with Mycobacterium tuberculosis. Every year more than 10 million new TB cases are registered in the world, and about 1.7 million people die from TB. In the Russian Federation, due to the measures taken by the Government and health authorities the epidemic TB situation has been noticeably improved since the sharp deterioration in the 90s of the last century. At the same time, the spread of drug-resistant TB and its low treatment effectiveness, the spread of combined HIV and TB infection reduces the effectiveness of anti-tuberculosis interventions. The research conducted by CTRI, the WHO Collaborating Center for TB in the Russian Federation, is aimed at solving such urgent problems as studying latent infection mechanisms, developing new test systems for accelerated diagnostics of drug resistance, clinical approbation and introduction of short effective regimens of chemotherapy, developing new antituberculosis agents. The achieved successes in the study of tuberculosis in the 21st century creates preconditions for eliminating its epidemic both in Russia and the world, though suggesting imminent breakthrough for tuberculosis is a hasty conclusion. 

Annals of the Russian academy of medical sciences. 2018;73(5):330-337
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Environmental Exposure to Endocrine Disruptor of Bisphenol A and Semen Quality of Men

Chigrinets S.V., Brukhin G.V.


Background: The reproductive health disorders in men are one of the urgent problems of international medicine. The prevalence of idiopathic male infertility has the highest rate. Oxidative stress, genetic factor, and endocrine disruptors are considered to be the most probable causes for the idiopathic male infertility. In this regard, studying the effect of endocrine disruptors, in particular bisphenol A on male reproductive health, becomes actual and relevant. Aims: The aim of the study was to reveal the relationship between the concentration level of bisphenol A (BPA) in seminal fluid and semen quality in men with normo- or pathozoospermia, as well as between the concentration level of bisphenol A and the level of total testosterone and estradiol in plasma. Materials and methods: 53 samples of seminal fluid of men with normo- or pathoospermia were studied. In seminal fluid the concentration of bisphenol A was determined by gas chromatography with mass spectrometry (GC-MS). The spermiological analysis was performed according to the WHO recommendations (2010) including the evaluation of sperm count/concentration, motility and morphology, and DNA fragmentation index. In addition, the concentration of total testosterone and estradiol in plasma was determined. The results were statistically processed using the Mann–Whitney U test, the correlation analysis, the paired regression method, and the ROC curves to determine the cut-off point for BPA in the seminal fluid. The results were considered statistically significant at p<0.05. Results: In 100% of the ejaculate samples BPA with a median concentration of 0.15 (0.06–0.31) ng/ml was detected. Using the Spearman rank correlation coefficient, statistically significant correlations between the concentration of BPA and the total count (r=-0.330, p=0.016), concentration (r=-0.309; p=0.024), the proportion of progressively motile spermatozoa (r=-0.575; p=0.001), the proportion of spermatozoa with normal morphology (r=-0.397, p=0.003), the degree of sperm DNA fragmentation (r=0.349, p=0.025), and the concentration of total testosterone (r =-0.616; p<0.001) were registered. A statistically significant inverse linear relationship (r=-0.406, p=0.003) and (r =-0.364, p=0.048) was determined by a paired linear regression between the BPA concentration in the seminal fluid and the proportion of progressively motile spermatozoa, and the total testosterone level respectively. To assess the risk of pathozoospermia, the threshold value of seminal BPA concentration was determined using the analysis of ROC-curves; the cut-off point was 0.1025 ng/ml. Conclusions: BPA in the seminal fluid influences negatively on the quality of the sperm and suppress the level of total testosterone in plasma.

Annals of the Russian academy of medical sciences. 2018;73(5):338-343
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Is Absence of Carbohydrate Metabolism Disorders in Patients with Prolonged History of Obesity due to Low Insulin Resistance or Preserved Insulin Secretion?

Shestakova E.A., Sklyanik I.A., Panevina A.S., Shestakova M.V.


Background: At present a lot of attention is paid to the so-called “metabolically healthy obesity”. More than a half of patients with prolonged history of obesity lack any carbohydrate metabolism disorders. Unfortunately, physiological factors forming the foundation of a favorable metabolic profile in such patients are not sufficiently defined. Aims: Evaluation of insulin resistance (IR) degree, the level of insulin secretion by pancreatic β-cells, and the contribution of both these mechanisms to the maintenance of normal carbohydrate metabolism in patients with prolonged history of obesity. Methods: An observational cross-sectional non-blinded selective comparative case-control study was performed. Patients with prolonged history of obesity without carbohydrate metabolism disorders and with type 2 diabetes mellitus (DM2) were included into the study. The following parameters were analyzed: IR parameters (М-index, HOMA-IR); insulin secretion parameters (НОМА-%β and insulinogenic index, glucose disposition index, GDI); body composition indices (total body fat and visceral fat area). Results: 68 patients participated in the study: 34 patients with obesity and normal carbohydrate metabolism («Obesity and NCM» group), and 34 patients with obesity and DM2 («Obesity and DM2» group); both groups were matched by body mass index, known obesity duration, and sex ratio (males/females) in each group. «Obesity and NCM» groups significantly differed from «Obesity and DM2» group by the following parameters: lower IR level (М-index median 4.13 vs 1.52 mg/kg/min, p<0.001; HOMA-IR median 4.84 vs 9.94, p<0.001); better insulin secretion (insulinogenic index median 28.15 vs 15.24, p<0.002; HOMA-%β median 115.63 vs 25.94, p<0.001); higher GDI (median 115.63 vs 25.94, p<0.001); lower visceral fat area (median 170.00 vs 230.00 cm2, p<0.001). Differences in total body fat (%) were not statistically significant. Conclusions: Patients with obesity and NCM compared to patients with DM2 have a less significant IR and a more preserved basal & stimulated insulin secretion, which allows to maintain normal carbohydrate metabolism. Low visceral fat grade also contributes to this. Most likely, the most important factor contributing to the “maintenance” of normal carbohydrate metabolism in patients with obesity is preserved insulin secretion, which is confirmed by the high glucose disposal index (almost 4.5-fold higher than that in patients with DM2) characterizing the ability of β-cells to secrete the amount of insulin required to overcome IR.

Annals of the Russian academy of medical sciences. 2018;73(5):344-353
pages 344-353 views

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