Polymorphisms of Genes Involved in Endothelial Dysfunction in the Yakuts with COPD and Metabolic Syndrome

The aim of our research was to study the association of the -675 4G/5G (rs1799889) SNP of the SERPINE1 (PAI-1) gene and the Arg353Gln G>A (rs6046) SNP of the F7 gene with metabolic syndrome (MetS) in the Yakuts with COPD. Methods and Results: A molecular-genetic examination was conducted in 200 COPD patients of Yakut ethnicity. The main group (MG) consisted of 100 COPD patients with MetS, the comparison group (CG) included 100 COPD patients without MetS. The distribution of genotypes of studied SNPs was in Hardy-Weinberg equilibrium in all cases. Studying the SERPINE1 -675 4G/5G SNP, we found the prevalence of a 4G allele in MG, compared to CG (OR=1.84, 95% CI 1.23–2.74; χ2=9.06, P=0.003). Incidence of the homozygous 4G/4G mutation was rather high in MG, compared to CG (OR=2.35, 95%CI 1.24–4.44; χ2=9.31, P=0.002). According to our data, the presence of MetS in Yakut patients with COPD has been associated with the carrier of the 4G/4G genotype. Studying the F7 Arg353Gln SNP, we found the prevalence of an Arg253 allele in both groups (0.72 in MG and 0.71 in CG; χ2=0.01, P=0.91). The homozygous Gln353/Gln353 mutant genotype was rare in both groups (0.12 in MG and 0.10 in CG; OR=1.23, 95%CI 0.50–2.99; χ2=0.01, P=0.92). In our study, the F7 Arg353Gln SNP was not associated with protection against MetS in COPD patients

Creative activity approach in teaching English language for medical students

The paper addresses the creative activity approach in teaching English language for medical students of the first and second years. Activation of the cognitive, design-research and practical activities of students is based on authentic material and material with an ethnocultural component. The study involved first and second year students of the Medical Institute of Northeastern University named after M.K. Ammosov 36% of students defending creative projects rated their skills at 3 points out of 5. Creative projects on the topics My Dream Trip and My Native District and my Village received the greatest response in students (43%). A total of 36% of students assessed their knowledge of special terminology (medical) at 3 and 4 on a five-point scale. Improvement in pronunciation and the ability to extract basic information from a text/article (medical) were noted by 43% of students. Students report difficulties in writing of the main part of annotation and rated their skills at 3 points (36%), 4 points (21%), and 2 points (28%). A total of 64% of students improved their knowledge on the Republic of Sakha Yakutia due to the geographical lotto used in English lessons. The creative activity approach is implemented by enhancing the cognitive, design-research and practical activities of students based on authentic material and material with an ethnocultural component

Synthesis of Novel Lipophilic Polyamines via Ugi Reaction and Evaluation of Their Anticancer Activity

Natural polyamines (PAs) are involved in the processes of proliferation and differentiation of cancer cells. Lipophilic synthetic polyamines (LPAs) induce the cell death of various cancer cell lines. In the current paper, we have demonstrated a new method for synthesis of LPAs via the multicomponent Ugi reaction and subsequent reduction of amide groups by PhSiH3. The anticancer activity of the obtained compounds was evaluated in the A-549, MCF7, and HCT116 cancer cell lines. For the first time, it was shown that the anticancer activity of LPAs with piperazine fragments is comparable with that of aliphatic LPAs. The presence of a diglyceride fragment in the structure of LPAs appears to be a key factor for the manifestation of high anticancer activity. The findings of the study strongly support further research in the field of LPAs and their derivatives

Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins

The development of malignant tumors is caused by a complex combination of genetic mutations and epigenetic alterations, the latter of which are induced by either external environmental factors or signaling disruption following genetic mutations. Some types of cancer demonstrate a significant increase in epigenetic enzymes, and targeting these epigenetic alterations represents a compelling strategy to reverse cell transcriptome to the normal state, improving chemotherapy response. Curaxin CBL0137 is a new potent anticancer drug that has been shown to activate epigenetically silenced genes. However, its detailed effects on the enzymes of the epigenetic system of transcription regulation have not been studied. Here, we report that CBL0137 inhibits the expression of DNA methyltransferase DNMT3a in HeLa TI cells, both at the level of mRNA and protein, and it decreases the level of integral DNA methylation in Ca Ski cells. For the first time, it is shown that CBL0137 decreases the level of BET family proteins, BRD2, BRD3, and BRD4, the key participants in transcription elongation, followed by the corresponding gene expression enhancement. Furthermore, we demonstrate that CBL0137 does not affect the mechanisms of histone acetylation and methylation. The ability of CBL0137 to suppress DNMT3A and BET family proteins should be taken into consideration when combined chemotherapy is applied. Our data demonstrate the potential of CBL0137 to be used in the therapy of tumors with corresponding aberrant epigenetic profiles

HeLa TI cell-based assay as a new approach to screen for chemicals able to reactivate the expression of epigenetically silenced genes.

Chemicals reactivating epigenetically silenced genes target diverse classes of enzymes, including DNMTs, HDACs, HMTs and BET protein family members. They can strongly influence the expression of genes and endogenous retroviral elements with concomitant dsRNA synthesis and massive transcription of LTRs. Chemicals reactivating gene expression may cause both beneficial effects in cancer cells and may be hazardous by promoting carcinogenesis. Among chemicals used in medicine and commerce, only a small fraction has been studied with respect to their influence on epigenetic silencing. Screening of chemicals reactivating silent genes requires adequate systems mimicking whole-genome processes. We used a HeLa TSA-inducible cell population (HeLa TI cells) obtained by retroviral infection of a GFP-containing vector followed by several rounds of cell sorting for screening purposes. Previously, the details of GFP epigenetic silencing in HeLa TI cells were thoroughly described. Herein, we show that the epigenetically repressed gene GFP is reactivated by 15 agents, including HDAC inhibitors-vorinostat, sodium butyrate, valproic acid, depsipeptide, pomiferin, and entinostat; DNMT inhibitors-decitabine, 5-azacytidine, RG108; HMT inhibitors-UNC0638, BIX01294, DZNep; a chromatin remodeler-curaxin CBL0137; and BET inhibitors-JQ-1 and JQ-35. We demonstrate that combinations of epigenetic modulators caused a significant increase in cell number with reactivated GFP compared to the individual effects of each agent. HeLa TI cells are competent to metabolize xenobiotics and possess constitutively expressed and inducible cytochrome P450 mono-oxygenases involved in xenobiotic biotransformation. Thus, HeLa TI cells may be used as an adequate test system for the extensive screening of chemicals, including those that must be metabolically activated. Studying the additional metabolic activation of xenobiotics, we surprisingly found that the rat liver S9 fraction, which has been widely used for xenobiotic activation in genotoxicity tests, reactivated epigenetically silenced genes. Applying the HeLa TI system, we show that N-nitrosodiphenylamine and N-nitrosodimethylamine reactivate epigenetically silenced genes, probably by affecting DNA methylation

Molecular Mechanisms of Anticancer Activity of N-Glycosides of Indolocarbazoles LCS-1208 and LCS-1269

Novel indolocarbazole derivatives named LCS were synthesized by our research group. Two of them were selected as the most active anticancer agents in vivo. We studied the mechanisms of anticancer activity in accordance with the previously described effects of indolocarbazoles. Cytotoxicity was estimated by MTT assay. We analyzed LCS-DNA interactions by circular dichroism in cholesteric liquid crystals and fluorescent indicator displacement assay. The effect on the activity of topoisomerases I and II was studied by DNA relaxation assay. Expression of interferon signaling target genes was estimated by RT-PCR. Chromatin remodeling was analyzed–the effect on histone H1 localization and reactivation of epigenetically silenced genes. LCS-induced change in the expression of a wide gene set was counted by means of PCR array. Our study revealed the cytotoxic activity of the compounds against 11 cancer cell lines and it was higher than in immortalized cells. Both compounds bind DNA; binding constants were estimated—LCS-1208 demonstrated higher affinity than LCS-1269; it was shown that LCS-1208 intercalates into DNA that is typical for rebeccamycin derivatives. LCS-1208 also inhibits topoisomerases I and IIα. Being a strong intercalator and topoisomerase inhibitor, LCS-1208 upregulates the expression of interferon-induced genes. In view of LCSs binding to DNA we analyzed their influence on chromatin stability and revealed that LCS-1269 displaces histone H1. Our analysis of chromatin remodeling also included a wide set of epigenetic experiments in which LCS-1269 demonstrated complex epigenetic activity. Finally, we revealed that the antitumor effect of the compounds is based not only on binding to DNA and chromatin remodeling but also on alternative mechanisms. Both compounds induce expression changes in genes involved in neoplastic transformation and target genes of the signaling pathways in cancer cells. Despite of being structurally similar, each compound has unique biological activities. The effects of LCS-1208 are associated with intercalation. The mechanisms of LCS-1269 include influence on higher levels such as chromatin remodeling and epigenetic effects