Том 90, № 8 (2025)

Autophagy is not just a way to get rid of damaged, mutated, or genetically unstable cells, but it also increases the chances that tumor cells can overcome the effects of chemotherapy-induced damage. Anthracyclines have a cytoprotective effect of autophagy in most cancer cell lines. The blocking of autophagy in this case makes tumor cells more sensitive to therapy. Cytoprotective autophagy activation can cause chemoresistance, and if it is overstimulated, it can cause energy depletion and autophagic death. In some cases, cytotoxic autophagy develops under the action of anthracyclines and blocking it increases cell survival. On the contrary, activation of cytotoxic autophagy triggers the process of "self-eating". Modulating autophagy can be a dual-edged sword for tumor cells, leading to both death and survival.

Aging biomarkers enable the assessment of aging rate, prediction of age-associated diseases, and monitoring of preventive intervention efficacy, such as diet, physical activity, and geroprotectors. This article examines key criteria for aging biomarkers, including their association with age, prognostic value regarding mortality, ability to identify early stages of age-related pathologies, and minimal invasiveness. A comprehensive classification of markers (clinical, functional, molecular, omics, digital) and the evolution of aging clocks - from epigenetic models to causal systems based on Mendelian randomization - is presented. Special emphasis is placed on explainable artificial intelligence (XAI) technologies that allow algorithm interpretation, as well as practical application of biomarkers in clinical research. The prospects for developing comprehensive biomarker panels and personalized approaches to aging assessment are discussed.

The expression levels of genes involved in high-density lipoprotein metabolism and atherogenesis and underlying metabolic pathways were aimed to relate to the number of stenotic coronary arteries. The expression of 65 preselected genes in the peripheral blood mononuclear cells of control patients (n = 63) and coronary artery disease (CAD) patients with one or two (low stenosis group, n = 35) or three or four (high stenosis group, n = 41) stenotic vessels, confirmed by coronary angiography, was measured with real-time PCR. Functional enrichment analysis was applied for annotation of differentially expressed genes. Differentially expressed genes in CAD patients compared to controls were characterized by metabolic pathways connected to plasma lipoprotein assembly, remodeling, and clearance and signaling and regulation of gene expression linked to cholesterol transport and efflux. However, specific expression profiles and metabolic pathways existed for high versus low stenosis comparisons. The expression of the CETP, PLTP, CD36, IL18, ITGB3, S100A8, S100A12, and VEGFA genes increased with the increase in the number of stenotic vessels, which suggests the involvement of these genes in stenosis expansion via lipoprotein metabolism, inflammation, angiogenesis, and innate immunity. The ITGB3, VEGFA, and CETP hub genes were selected as new signature of the expansion of coronary artery stenosis, which was validated with the GSE12288 dataset, with a combined OR value of 7.49 (95% CI, 2.21 to 25.43). The expression levels of the ITGB3, VEGFA, and CETP genes may be used for the diagnosis, prognosis estimation, and treatment of coronary stenosis with strong predictive power.

One of the hallmark features of malignant neoplasms is their ability to sustain growth under hypoxic conditions resulting from insufficient oxygenation of tumor tissues. Prolonged hypoxia is associated with the gradual adaptation of tumor cells to low oxygen levels, leading to enhanced survival, increased metastatic potential, and the development of resistance to anticancer therapies. The aim of this study was to investigate the mechanisms underlying breast cancer cell adaptation to prolonged hypoxia and the maintenance of the hypoxia-tolerant phenotype. Using long-term cultivation under low oxygen conditions (1% O2), we established hypoxia-adapted sublines of luminal (MCF-7/H) and triple-negative (MDA-MB-231/H) breast cancer cells, characterized by stable growth in a hypoxic environment. We demonstrated that the acquisition of hypoxia tolerance is accompanied by the activation of the HIF-1α-dependent transcription factor STAT3 and persistent overexpression of Snail, a key downstream effector of STAT3. The maintenance and stabilization of this phenotype are mediated by miR-181a-2, which targets the STAT3/Snail signaling axis in resistant cells. Analysis of DNA methylation status revealed no significant changes in the expression or activity of DNA methyltransferases (DNMTs) in the hypoxia-adapted cells. However, pharmacological inhibition of DNMTs using decitabine, or DNMT knockdown, increased cellular sensitivity to hypoxia and partially reversed the resistant phenotype, which was accompanied by the activation of pro-apoptotic p53 signaling. In conclusion, our findings suggest that acquired hypoxia tolerance in breast cancer cells is, at least in part, mediated by the activation of the miR-181a-2/STAT3/Snail signaling pathway. Furthermore, demethylating agents may represent a promising therapeutic approach to target hypoxia-tolerant cancer cell populations.

Melting of promoter DNA around the transcription start site (TSS) is a critical step of transcription required for initiation of RNA synthesis. In bacteria, promoter melting is achieved by the holoenzyme of RNA polymerase (RNAP) consisting of the catalytic core enzyme and a promoter recognition subunit, the σ factor. Previously, we showed that RNAPs from thermophilic Thermus aquaticus and mesophilic Deinococcus radiodurans are unable to open promoters at ambient temperatures and require heating for DNA melting. These properties depend on their σ factors and are recapitulated in hybrid holoenzymes including these σ factors and the core enzyme of Escherichia coli. Here, we show that DNA supercoiling alleviates the observed cold-sensitivity of promoter opening by Deinococcus-Thermus RNAPs and by hybrid holoenzymes and allows melting of the transcription start site at the same temperatures as in the case of E. coli RNAP. Supercoiling also suppresses salt sensitivity of promoter complexes formed by these RNAPs. The results demonstrate that RNAPs from Deinococcus-Thermus species are sensitive to DNA supercoiling and suggest that they can be rapidly switched-off or activated by the supercoiling state of the host genomes.

DNA damage results in distortion of the B-form structure of the double DNA helix. Recognition of such distortion by DNA repair proteins is an important stage in the process initiation. The nucleosome structure imposes restrictions on the mobility and plasticity of the DNA geometry. Under interaction of repair proteins with nucleosomal DNA, the main issue is the implementation of the DNA structure that characterize the damage itself in a specific context. In addition, the DNA duplex in the nucleosome has a regular profile of contacts with histones corresponding to the turn of the DNA helix. By changing this profile, one can judge about changes in the DNA structure. This profile correlates with the availability of the corresponding nucleotides for interaction with DNA-binding proteins. In our work, using the footprinting assay, it was shown that the presence of an AP site within the second-third turn from the 5'-end of the nucleosomal DNA does not significantly affect the profile of DNA contacts with histones.