Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review.publishersversionPeer reviewe

Outpatient Practice of Lipid-Lowering Therapy Prescription (According to the ARGO-3 Study)

Aim. To study the frequency of prescriptions of various types of lipid-lowering therapy and their effectiveness in outpatient clinical practice based on the results of a questionnaire of primary care physicians.Material and methods. The study was performed in 2022 in 75 constituent entities of the Russian Federation with the participation of 1117 doctors working in outpatient clinics. Most of the doctors had work experience of 10-20 years or more. Doctors of polyclinics (therapists and cardiologists, etc.) before the start of the study received instructions, questionnaires for filling out, developed by the National Atherosclerosis Society. The frequency of prescriptions by primary care physicians of various types of lipid-lowering therapy and their effectiveness in terms of the frequency of achieving target levels of low-density lipoprotein cholesterol (LDL-C) was studied based on the results of a questionnaire.Results. Monotherapy with statins was prescribed in 55.2% of cases, free combination of rosuvastatin with ezetimibe – in 17.2%, single pill combination of rosuvastatin with ezetimibe – in 23.2%, combination therapy with PCSK9 inhibitors – in 4.1% of cases. Target levels of LDL-C ˂ 1.8 mmol/l and ˂ 1.4 mmol/l were achieved with statin monotherapy in 42.6% and 28.2% of cases, respectively, free combination of rosuvastatin with ezetimibe – in 61.7% and 39 .5%, a fixed combination of rosuvastatin with ezetimibe – in 67.8% and 48.5%, combination therapy with PCSK9 inhibitors – in 96.8% and 92.8% of cases.Conclusion. The single pill combination of rosuvastatin with ezetimibe is more effective in achieving target levels of LDL-C compared with statin monotherapy and therapy with free combination of statin with ezetimibe. Despite the fact that the target values of LDL-C when prescribing a combination with PCSK9 inhibitors were achieved in 96.8% and 92.8% of cases, they were used quite rarely at the outpatient stage of treatment in the Russian Federation

ASSOCIATION OF MATRIX METALLOPROTEINASES GENE POLYMORPHISM WITH CLINICAL MANIFESTATIONS OF BRONCHIAL ASTHMA IN CHILDREN

In the present study, we have examined association between different polymorphic variants of metalloproteinases genes and clinical manifestations of bronchial asthma in children. We observed 103 patients including 42 children with an established diagnosis of asthma. Moreover, 61 persons were examined in the control group. All patients underwent genetic testing by allele-specific polymerase chain reaction. In particular, 320A>C polymorphic locus of ММР20 gene; Val275Ala ММР20, and -8202A>G gene ММР9 were analyzed.We have found that 30 patients (71.4% of total) had bronchial asthma of mild severity, 9 children (21.4%) exhibited moderate degree, and 3 patients (7%) had severe-grade disease. Homozygous C/C variant of the polymorphic ММР20 gene, 320A>C heterozygous variant of the ММР20 Val275Ala polymorphism, and heterozygous locus of -8202A>G ММР9 gene were found to be most frequent among the children with asthma. Generally, we have observed that the frequencies of the studied alleles and genotypes did not significantly differ berween the asthma patients and children from the control group (p < 0.05). However, in patients with GGgenotype of -8202A>G ММР9 polymorphism combined with homozygosity for the C allele of ММР20 320A>C, a more severe disease was observed, being combined with polyvalent sensitization and high total IgE levels in blood serum.In conclusion, frequencies of alleles and genotypes among patients with asthma did not show any statistically significant differences from the group of healthy children. The patients homozygous for G allele of ММР9 -8202A>G polymorphism gene and for the C allele ММР20 gene (320A>C) seem to be predisposed for a more severe clinical course of the disease

E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia

Acute lung injury (ALI) is linked to mitochondrial injury, resulting in impaired cellular oxygen utilization; however, it is unknown how these events are linked on the molecular level. Cardiolipin, a mitochondrial-specific lipid, is generated by cardiolipin synthase (CLS1). Here, we show that S.aureus activates a ubiquitin E3 ligase component, Fbxo15, that is sufficient to mediate proteasomal degradation of CLS1 in epithelia, resulting in decreased cardiolipin availability and disrupted mitochondrial function. CLS1 is destabilized by the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), which binds CLS1 to phosphorylate and regulates CLS1 disposal. Like Fbxo15, PINK1 interacts with and regulates levels of CLS1 through a mechanism dependent upon Thr219. S.aureus infection upregulates this Fbxo15-PINK1 pathway to impair mitochondrial integrity, and Pink1 knockout mice are less prone to S.aureus-induced ALI. Thus, ALI-associated disruption of cellular bioenergetics involves bioeffectors that utilize a phosphodegron to elicit ubiquitin-mediated disposal of a key mitochondrial enzyme. © 2014 The Authors

Prokaryotic expression, purification and immunogenicity in rabbits of the small antigen of hepatitis delta virus

Funding Information: Expression and purification of HDV antigen was supported by Russian Foundation for Basic Research (grant 16-04-01490a). Evaluation of serum by Western blot and confocal microscopy was supported by Russian Science Foundation (grant 14-14-01021). Experiments in rabbits were supported by the Swedish Institute grants 09272_2013 and 19806_2016. Cross-border collaboration of the partners, exchange of the materials and standard operation procedures used in the study, and dissemination of the data were supported by the EU Twinning project VACTRAIN, contract nr 692293. Publisher Copyright: © 2016 by the authors; licensee MDPI, Basel, Switzerland.Hepatitis delta virus (HDV) is a viroid-like blood-borne human pathogen that accompanies hepatitis B virus infection in 5% patients. HDV has been studied for four decades; however, the knowledge on its life-cycle and pathogenesis is still sparse. The studies are hampered by the absence of the commercially-available HDV-specific antibodies. Here, we describe a set of reproducible methods for the expression in E. coli of His-tagged small antigen of HDV (S-HDAg), its purification, and production of polyclonal anti-S-HDAg antibodies in rabbits. S-HDAg was cloned into a commercial vector guiding expression of the recombinant proteins with the C-terminal His-tag. We optimized S-HDAg protein purification procedure circumventing a low affinity of the His-tagged S-HDAg to the Ni-nitrilotriacetyl agarose (Ni-NTA-agarose) resin. Optimization allowed us to obtain S-HDAg with >90% purity. S-HDAg was used to immunize Shinchilla grey rabbits which received 80 µg of S-HDAg in two subcutaneous primes in the complete, followed by four 40 µg boosts in incomplete Freunds adjuvant. Rabbits were bled two weeks post each boost. Antibody titers determined by indirect ELISA exceeded 107. Anti-S-HDAg antibodies detected the antigen on Western blots in the amounts of up-to 100 pg. They were also successfully used to characterize the expression of S-HDAg in the eukaryotic cells by immunofluorescent staining/confocal microscopy.publishersversionPeer reviewe

Relation Between the Thickness of Stellar Disks and the Relative Mass of Dark Halo in Galaxies

We consider a thickness of stellar disks of late-type galaxies by analyzing the R and K_s band photometric profiles for two independent samples of edge-on galaxies. The main goal is to verify a hypotesis that a thickness of old stellar disks is related to the relative masses of the spherical and disk components of galaxies. We confirm that the radial-to-vertical scale length ratio for galactic disks increases (the disks become thinner) with the increasing of total mass-to-light ratio of the galaxies, which characterize the contribution of dark halo to the total mass, and with the decreasing of central deprojected disk brightness (surface density). Our results are in good agreement with numerical models of collisionless disks evolved from subcritical velocity dispersion state to a marginally stable equilibrium state. This suggests that in most galaxies the vertical stellar velocity dispersion, which determine the equilibrium disk thickness, is close to the minimum value, that ensures disk stability. The thinnest edge-on disks appear to be low brightness galaxies (after deprojection) in which a dark halo mass far exceeds a mass of the stellar disk.Comment: 13 pages. To be Published in Astronomy Letters, v.28(2002

Specificity of Growth and Synthesis of Secondary Metabolites in Cultures in vitro Digitalis lanata Ehrh.

Abstract: Rhizogenic, callus, and suspension cultures in vitro were obtained for Digitalis lanata and their growth, cytophysiological and biochemical characteristics were investigated. The obtained cultures were characterized by good growth characteristics (growth indexes I in the range of 5–13). Suspension cell culture had a specific growth rate μ within 0.2–0.3 days–1 and it was characterized by a two-phase growth curve (growth retardation during the exponential phase). In the obtained cultures, a study of the qualitative and quantitative composition of secondary metabolites by UPLC-ESI-MS and HPLC-ESI-MS showed the absence of cardiac glycosides. At the same time, phenylethanoids and steroidal glycosides of the furostanol type were found in all studied cultures. The total content of phenylethanoids in callus and suspension cultures was approximately 0.5% of the dry biomass. Based on the results of mass spectrometry, ten phenylethanoid structures, including digiciliside A, digiciliside B, maxoside, purpureaside E, and their methyl derivatives and isomers, and also seven furostanol glycosides with aglycones tigogenin and gitogenin were identified. It has been shown that the composition of secondary metabolites depends on the degree of cell differentiation: furostanol glycosides were prevalent in a rhizogenic culture consisting mainly of differentiated cells, while the diversity of phenylethanoids significantly increases in callus and suspension cell cultures consisting of dedifferentiated cells. The results of the study confirm the hypothesis put forward in our previous works about the specificity of secondary metabolism and its high intensity in plant cell cultures. © 2022, The Author(s).Government Council on Grants, Russian Federation: 075-15-2019-1882The work was carried out on the basis of the “Scientific and Production Biotechnological Complex for the Study, Preservation, and Practical Application of Cultured Cells and Organs of Higher Plants and Microalgae” with the financial support of the Megagrant of the Government of the Russian Federation (Agreement no. 075-15-2019-1882)

Lipoprotein(a) concentration and the blood content of INFγ-producing T-helpers 17 (Th17/1) in males with premature coronary artery disease

Aim. To analyze the relationship of blood lipid profile parameters, including the level of lipoprotein(a) (Lp(a)), and the content of circulating CD4+ T-lymphocytes with premature coronary artery disease (CAD).Material and methods. This retrospective cross-sectional study included 76 men aged 40 to 79 years. Patients were divided into following groups: main group — patients with CAD (58 [54;64] years, n=56) onset before the age of 55; control group — patients (62 [57;66] years, n=20) without CAD and obstructive CAD and peripheral arterial disease. Statins were taken by 51 (91%) and 9 (45%) patients in the main and control groups, respectively. In serum and plasma samples, lipid spectrum parameters and Lp(a) concentration were determined. Cellular phenotyping was performed by direct immunofluorescence in a culture of mononuclear leukocytes isolated from blood. To determine cytokines, cells were in vitro activated with inhibitor of intracellular transport of secretory proteins. Cell fluorescence was determined using flow cytometry.Results. Patients of both groups were comparable in age, body mass index, prevalence of hypertension and diabetes. Blood Lp(a) concentrations were higher in the CAD group than in the control group (49 [10;102] mg/dL vs 12 [4,3;32] mg/ dL, p<0,05). The content of INFγ-producing T-helpers 17 (Th17/1) was also higher in the CAD group (19 [15;24] vs 13 [11;22], % of Th17, p=0,05). Logistic regression revealed that elevated Lp(a) levels (≥30 mg/dL) and relative amounts of Th17/1 (>14% of Th17) independently of each other, atherogenic lipoprotein cholesterol levels, classical risk factors, and statin use were associated with premature CAD in the general group of patients with odds ratio (OR) of 4,6 (95% confidence interval (CI), 1,1-20,2) and 10,9 (2,1-56,7), p<0,05, respectively. The combination of Lp(a) >30 mg/dl and Th17/1 over 14% significantly increased the risk of premature CAD (OR, 28,0, 95% CI, 4,31-181,75, p=0,0005).Conclusion. We have shown for the first time that an increased Lp(a) concentration with an increased Th17/1 content is associated with the premature CAD in men

The optical identifcation of events with poorly defined locations: The case of the Fermi GBM GRB140801A

We report the early discovery of the optical afterglow of gamma-ray burst (GRB) 140801A in the 137 deg$^2$ 3-$\sigma$ error-box of the Fermi Gamma-ray Burst Monitor (GBM). MASTER is the only observatory that automatically react to all Fermi alerts. GRB 140801A is one of the few GRBs whose optical counterpart was discovered solely from its GBM localization. The optical afterglow of GRB 140801A was found by MASTER Global Robotic Net 53 sec after receiving the alert, making it the fastest optical detection of a GRB from a GBM error-box. Spectroscopy obtained with the 10.4-m Gran Telescopio Canarias and the 6-m BTA of SAO RAS reveals a redshift of $z=1.32$. We performed optical and near-infrared photometry of GRB 140801A using different telescopes with apertures ranging from 0.4-m to 10.4-m. GRB 140801A is a typical burst in many ways. The rest-frame bolometric isotropic energy release and peak energy of the burst is $E_\mathrm{iso} = 5.54_{-0.24}^{+0.26} \times 10^{52}$ erg and $E_\mathrm{p, rest}\simeq280$ keV, respectively, which is consistent with the Amati relation. The absence of a jet break in the optical light curve provides a lower limit on the half-opening angle of the jet $\theta=6.1$ deg. The observed $E_\mathrm{peak}$ is consistent with the limit derived from the Ghirlanda relation. The joint Fermi GBM and Konus-Wind analysis shows that GRB 140801A could belong to the class of intermediate duration. The rapid detection of the optical counterpart of GRB 140801A is especially important regarding the upcoming experiments with large coordinate error-box areas.Comment: in press MNRAS, 201

Historical, theoretical and methodological issues of special pedagogy

The purpose of the article is to present the scientific views of one of the leading special pedagogues of our country, whose work over the past decades has been devoted to the history of special pedagogy and its theoretical and methodological foundations - N. M. Na¬zarova. Her work is characterized by a wealth of ideas, diversity and wide cov-erage of the problems of teaching and raising children with special educational needs, so the article does not purport to be comprehensively complete while describing the theoretical positions of the scholar.В статье представлены научные взгляды Н. М. Назаровой, одного из ведущих специальных педагогов нашей страны