Structural and functional disruptions of the epigenome are hallmarks of breast and ovarian carcinogenesis. This review dissects the reciprocal regulatory networks co-operated by DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and key non-coding RNAs (microRNAs and lncRNAs). We map the precise molecular mechanisms through which these epigenetic modulators alter chromatin accessibility, drive transcriptional reprogramming, and promote phenotypic plasticity in hormone-dependent malignancies. By systematically contrasting the distinct yet overlapping epigenetic profiles of breast and ovarian tumors, we elucidate how these aberrations dictate clinical outcomes. This comprehensive synthesis offers critical insights into the dual utility of these epigenetic elements as dual-purpose diagnostic biomarkers and druggable therapeutic targets, laying the groundwork for next-generation targeted epigenetical therapies.

Despite the brain’s use of adenosine triphosphate (ATP) to perform various intracellular processes, its major energy consumption occurs during neuronal communication. It is estimated that the majority of energy expenditure occurs at excitatory synapses via the activity of energy-dependent pumps (ATPases), which are involved in maintaining and restoring ion gradients after receptor activity. Inhibitory synapses are believed to contribute insignificantly to energy consumption because of their indirect energy consumption via cation-coupled chloride cotransporters (CCCs) and the subsequent function of Na+, K+ ATPase. Recent findings concerning the properties of inhibitory receptors suggest that they directly contribute to energy consumption. Fast synaptic inhibition in the brain is mediated by type A GABAA receptors (GABAARs), which are ligand-gated, anion-selective channels that are open upon the binding of the neurotransmitter and that play a key role in regulating neuronal excitation. Impairment of their function during network/seizure activity is accompanied by changes in the ionic and energy levels in neurons, the mechanisms of which remain largely unclear. Clarification of these processes is crucial for the treatment of neurodegenerative disorders that are linked with dysregulation of the inhibition/excitation (I/E) balance and energy deficiency. Recent evidence has shown the presence of an ATP-hydrolyzing site in the structure of GABAARs, which is involved in network activity. We hypothesized that this ATPase activity can directly contribute to energy use. This hypothesis is supported by data indicating that γ-phosphate analogs targeting distinct ATP binding and hydrolysis stages can reduce the receptor function under certain conditions. Moreover, some GABAARs assemblies have the capacity to participate in both the passive and active transport of Cl– against the electrochemical gradient. Finally, under conditions of brain hypoxia or glucose deficiency syndrome, the function of inhibitory neurons is primarily impaired. Here, we explore the ATPase hypothesis that some GABAAR subtypes may be directly involved in reducing the energy budget, and we present arguments for and against this theory while highlighting gaps in our knowledge of this neurobiological process.

The content of cancer stem cells and CD3+CD8+ T cells in the blood of a patient with small cell lung cancer (SCLC) and chronic obstructive pulmonary disease (COPD) was evaluated. In vitro analysis of tumorospheres allowed us to characterize circulating tumor stem cells in the blood of patients at risk. The fundamental possibility of reprogramming exhausted CD3+CD8+ T cells (rCD3CD8T) of a patient with SCLC and COPD using a mitogen-activated protein kinase inhibitor (iMEK) and human monoclonal antibody nivolumab was demonstrated. Target cell elimination by rCD3CD8T was achieved by treatment with autologous cancer cell and stem cancer cell lysate in vitro. Thus, blockade of the MAPK/ERK signaling pathway and the PD-1/PD-L1 checkpoints may be used to overcome exhaustion and enhance cytotoxicity of CD3+CD8+ T cells in patients with SCLC and COPD.

We studied the effect of reprogrammed CD8+ T cells (rT cells) from the bone marrow of intact mice on tumor cells and neovasculogenesis in mice with orthotopic Lewis lung carcinoma (LLC). Reprogramming of T cells was carried out using a MEK inhibitor and a PD-1 blocker; the targeting of rT cells to tumor cells was achieved by preincubation with LLC cell lysate. It was shown that the antitumor effect of rT cells was based on apoptosis of tumor cells. In addition, cell therapy reduced the number of endothelial cells (CD45—CD309+) and angiogenic cell precursors (CD45—CD117+CD309+), mesenchymal stem cells (CD45—CD31—CD34—CD44+), myeloid (CD45+CD34+CD31—) and non-myeloid (CD45+CD34—CD31—) fibrocytes, and leukocytes (CD45+) in the lungs and increased their number in the blood. Thus, rT cells impaired the recruitment of neovasculogenic cells to the lung. The antitumor effects of rT cells are superior to those of naive CD8+ T cells. The proposed reprogramming method can be useful in developing effective approaches to the therapy of lung cancer, as it allows obtaining cytotoxic rT cells capable of reducing the activity of neovasculogenesis.

We propose a model of combination treatment of Lewis lung carcinoma (LLC) in C57BL/6 mice that includes tumor resection and chemotherapy. A single injection of 5×106 LLC cells into the right lateral subcostal region caused the growth of the primary tumor and its metastasis to the lung. For reducing metastasis and mortality after resection, the primary tumor should be removed with subcutaneous fat on day 8 after inoculation. Antitumor and antimetastatic effects and reduced mortality were achieved by intraperitoneal injection of carboplatin (63.3 mg/kg) and paclitaxel (13.3 mg/kg); chemotherapy was administered twice. The combination of the two approaches increased the survival: the antitumor and antimetastatic effects were observed in 60

The GABAA receptors, through a short-term interaction with a mediator, induce hyperpolarization of the membrane potential (Vm) via the passive influx of chloride ions (Cl−) into neurons. The massive (or intense) activation of the GABAARs by the agonist could potentially lead to depolarization/excitation of the Vm. Although the ionic mechanisms of GABAA-mediated depolarization remain incompletely understood, a combination of the outward chloride current and the inward bicarbonate current and the resulting pH shift are the main reasons for this event. The GABAA responses are determined by the ionic gradients—neuronal pH/bicarbonate homeostasis is maintained by carbonic anhydrase and electroneutral/electrogenic bicarbonate transporters and the chloride level is maintained by secondary active cation–chloride cotransporters. Massive activation can also induce the rundown effect of the receptor function. This rundown effect partly involves phosphorylation, Ca2+ and the processes of receptor desensitization. In addition, by various methods (including fluorescence and optical genetic methods), it has been shown that massive activation of GABAARs during pathophysiological activity is also associated with an increase in [Cl−]i and a decline in the pH and ATP levels in neurons. Although the relationship between the neuronal changes induced by massive activation of GABAergic signaling and the risk of developing neurodegenerative disease has been extensively studied, the molecular determinants of this process remain somewhat mysterious. The aim of this review is to summarize the data on the relationship between the massive activation of inhibitory signaling and the ionic changes in neurons. The potential role of receptor dysfunction during massive activation and the resulting ionic and metabolic disruption in neurons during the manifestation of network/seizure activity will be considered.

Although some GABAA receptor subtypes are involved in both the passive permeability of anions and the ATP-dependent recovery of neuronal anion concentrations, the molecular mechanisms that ensure the coordination of passive and active transport processes remain unclear. Here we used fluorescence measurements to investigate the role of genistein (tyrosine kinase inhibitor) and vanadate (tyrosine phosphatase and ATPase inhibitor) in modulating GABAAR-mediated [Cl-]i/[HCO3-]i changes and ATPase activity in rat cortical neurons and HEK 293FT cells expressing the heteropentameric α2β3γ2 GABAAR isoform. We found that genistein plays an important role in the inhibition of passive GABAAR-mediated Cl- influx and Cl-ATPase activity, whereas vanadate plays an important role in the inhibition of Cl-, HCO3-ATPase activity and ATP-dependent recovery of [HCO3-]i via changes in the formation of the phosphorylated intermediate. The effect of blockers was significantly restored in the presence of phenol. In behavioral experiments, the administration of phenol has been established to induce tremors and head twitching in rats, with the involvement of GABAAR/ATPase in these behavioral responses. Genistein can reduce the adverse effects of phenol, thereby confirming the interaction of these chemicals when binding to binding receptor sites. While our data demonstrate the opposing roles of genistein and vanadate in modulating GABAAR/ATPase function in a bicarbonate-dependent manner. Such multidirectional systems are considered to be bistable elements involved in the regulatory mechanisms of synaptic plasticity.

Integral indicators of systemic endotoxemia (SEE): the level of endotoxin (ET) and the concentration of antibodies against the hydrophobic (AB-LPS-PHOB) and hydrophilic (AB-LPS-PHIL) forms of the lipopolysaccharide molecule (LPS) in the general circulation, can be used to determine the risk category of the development and progression of atherosclerosis whose dynamics is an objective marker of aging rate. The comparison of images of the structure of the brachiocephalic artery wall in dynamics with changes in blood parameters is one of the most successful models for monitoring the atherosclerotic process in the clinical setting. In total, 42 subjects without recognized risk factors for the progression of atherosclerosis were examined at baseline and after 1.5–2 years. It was found that lipid profile indicators, such as the concentration of total cholesterol, low- and high-density lipoproteins, triglycerides, and the atherogenic index were of no prognostic value. While in the group with progression of damage to the arterial wall, an increase in the ET concentration and a decrease in the AB-LPS-PHOB and AB-LPS-PHIL concentrations were noted. In the group with regression of atherosclerotic changes, on the contrary, there was an AB increase against the background of a decrease in the ET concentration. A prospective study revealed an extremely important fact of a decrease in the LPS concentration in the blood of patients with positive dynamics of morphological manifestations of atherosclerosis, indicating both the reversibility of the atherosclerotic process and the involvement of ET in atherogenesis. This is a real way of extending the life span of an individual, which shows the perspective of how to achieve this goal, which is antiendotoxin therapy.

Background Awareness of age-related features of carcinogenesis and the importance of cellular immunity is crucial for developing effective antitumor therapies for specific patient groups. Methods In this study, we examined different populations of cancer stem cells (CSCs) and circulating tumor cells (CTCs) in "young" (8-10 weeks) and "aged" (80-82 weeks) C57BL/6 male mice. We used an orthotopic model of Lewis lung carcinoma (LLC) to evaluate the effectiveness of cell therapy targeting lung cancer through reprogrammed CD8-positive T cells (rCD8+ T cells) in mice from two different ages. Results The findings revealed that tumor progression with age is primarily caused by impaired recruitment of T cells to the lungs. Additionally, a lower number of CTCs and CSCs were observed in younger mice compared to the older mice. The antitumor effect of rCD8+ T cells in aged mice was found to be inferior to that in young mice, which can be attributed to the reduced impact of therapy on specific CSCs populations. Conclusions These results offer new insights into the treatment of lung cancer using rCD8+ T cells. Considering the age-related characteristics influencing disease progression, this therapy has the potential to significantly enhance the effectiveness of treatment methods.

The study of the physiological and pathophysiological processes under extreme conditions facilitates a better understanding of the state of a healthy organism and can also shed light on the pathogenesis of diseases. In recent years, it has become evident that gravitational stress affects both the whole organism and individual cells. We have previously demonstrated that simulated microgravity inhibits proliferation, induces apoptosis, changes morphology, and alters the surface marker expression of megakaryoblast cell line MEG-01. In the present work, we investigate the expression of cell cycle cyclins in MEG-01 cells. We performed several experiments for 24 h, 72 h, 96 h and 168 h. Flow cytometry and Western blot analysis demonstrated that the main change in the levels of cyclins expression occurs under conditions of simulated microgravity after 96 h. Thus, the level of cyclin A expression showed an increase in the RPM group during the first 4 days, followed by a decrease, which, together with the peak of cyclin D, may indicate inhibition of the cell cycle in the G2 phase, before mitosis. In addition, based on the data obtained by PCR analysis, we were also able to see that both cyclin A and cyclin B expression showed a peak at 72 h, followed by a gradual decrease at 96 h. STED microscopy data also confirmed that the main change in cyclin expression of MEG-01 cells occurs at 96 h, under simulated microgravity conditions, compared to static control. These results suggested that the cell cycle disruption induced by RPM-simulated microgravity in MEG-01 cells may be associated with the altered expression of the main regulators of the cell cycle. Thus, these data implicate the development of cellular stress in MEG-01 cells, which may be important for proliferating human cells exposed to microgravity in real space.

The intestinal microbiota is a vital organ – a participant in the processes of adaptation and evolution, an inducer of inflammation and the progression of aging. The key element of the interaction of intestinal microbiota with the body is lipopolysaccharides, the level of which in the general bloodstream increases significantly in so-called “microbiota-associated diseases”, which indicates the participation of endotoxin aggression in their pathogenesis, and most likely their initiation. One of the most common reasons for the development of endotoxin aggression may be quantitative and qualitative changes in the structure of the intestinal microbiota, leading to an increase in intestinal permeability, which are largely determined by nutritional factors. The antiendotoxin component in the treatment regimen for patients with various nosological forms of the diseases significantly increases the effectiveness of the treatment and prophylactic process, which can become one of the most promising areas of anti-aging measures.

γ-Aminobutyric acid type A receptors (GABAARs) are members of the pentameric ligand-gated ion channel (pLGIC) family, which are widespread throughout the invertebrate and vertebrate central nervous system. GABAARs are engaged in short-term changes of the neuronal concentrations of chloride (Cl−) and bicarbonate (HCO3−) ions by their passive permeability through the ion channel pore. GABAARs are regulated by various structurally diverse phenolic substances ranging from simple phenols to complex polyphenols. The wide chemical and structural variability of phenols suggest similar and different binding sites on GABAARs, allowing them to manifest themselves as activators, inhibitors, or allosteric ligands of GABAAR function. Interest in phenols is associated with their great potential for GABAAR modulation, but also with their subsequent negative or positive role in neurological and psychiatric disorders. This review focuses on the GABAergic deficit hypotheses during neurological and psychiatric disorders induced by various phenols. We summarize the structure–activity relationship of general phenol groups concerning their differential roles in the manifestation of neuropsychiatric symptoms. We describe and analyze the role of GABAAR subunits in manifesting various neuropathologies and the molecular mechanisms underlying their modulation by phenols. Finally, we discuss how phenol drugs can modulate GABAAR activity via desensitization and resensitization. We also demonstrate a novel pharmacological approach to treat neuropsychiatric disorders via regulation of receptor phosphorylation/dephosphorylation.

Regenerative processes in the liver were studied in 3-month-old (young) and 9-month-old (aged) male Wistar rats on day 1 after 30 and 70% hepatectomy. Regardless of the resected liver volume, shifts in the biochemical parameters of the serum in aged rats were more pronounced than in young animals. After 30% hepatectomy, no age differences in the rate of hepatic regeneration were found, while after 70% liver resection this parameter was higher in young rats. Hepatectomy in young rats led to recruitment of MSC, hepatocyte precursors, endothelial and epithelial progenitor cells into the liver parenchyma and increased fluidity of the plasma and mitochondrial membranes of hepatocytes. In aged rats, the recruitment of MSC, hepatocyte precursors, and endothelial progenitor cells into the injured liver was impaired and the rigidity of the mitochondrial membranes of hepatocytes increased.

The enhancement of early diagnosis of lung cancer is mandatory to improve prognosis. We observed the increase cancer stem cells (CSC) and circulating tumor cells (CTC) in blood of mice on d3 after Lewis lung carcinoma (LLC) cell implantation before disease symptom. Besides we have developed an approach to reprogramming immune cells by inhibiting the MAPK/ERK pathway through MEKi and the PD-1/PD-L1 immune checkpoint signaling pathway. We hypothesized that reprogramming of spleen CD8+ T-cells could also create a population of immune cells with high antitumor activity. We reprogrammed CD8+ T-cells derived from the spleen of C57BL/6 mice (rsCD8+T-cells). The rsCD8+T-cells were able to migrate to lung and were more resistant after the exhaustion in vitro in comparison with naïve sCD8+T-cells. In the orthotopic LLC model, the rsCD8+T-cells therapy increased the amount of proliferating CD8+ and CD4+ T-cells in blood and lung from mice. The amount of CSC decreased in the blood and lung of mice treated with rsCD8+ T-cells. A morphological study revealed a decrease in the number of metastases in lung tissue. The antitumor effects of rsCD8+T-cells are based on the activation of the host immune response by increasing the populations of CD8+ and CD4+ T-cells and apoptosis of CSCs.

The antitumor and antimetastatic activity of dopamine D2 receptor antagonists spiperone was studied in C57BL/6 mice in a model of combined pathology (emphysema and lung cancer). Emphysema was induced by administration of LPS and cigarette smoke extract. Lung cancer was induced by injection of Lewis lung carcinoma cells into the lung. It has been shown that under conditions of combined lung pathology, spiperone prevents inflammatory infiltration and emphysematous expansion of the lungs and reduces the size of the primary tumor node, the number of metastases, and the area of the lungs affected by metastases. Spiperone reduces the number of cancer stem cells (CSCs) in the lungs and blood of mice with combined pathology. CSCs isolated from the lungs and blood of mice with combined pathology treated with spiperone had a significantly lower potential to form a tumorosphere in vitro than CSCs from untreated mice with emphysema and lung carcinoma. Thus, blockade of dopamine D2 receptors is a promising approach for correcting combined lung pathology and can be used in the development of a method for treating lung cancer in patients with emphysema.

Intestinal microbiota is a kind of satellite organ that performs digestive and protective functions, a supplier of molecules vital for homeostasis processes, involved in metabolic processes and determining the activity level of adaptive systems, including immunity. Immunity works both for and against the host, which is predetermined by the very nature of adaptive immunity and its interaction with the innate link of the immune system. The key element of this interaction is endotoxin molecules, or lipopolysaccharides, the concentration of which in the general bloodstream determines the activity level of adaptive (mediated by innate) immunity, which operates in a stochastic mode. This provides both antitumor protection and self-destruction of the body based on autoimmune damage. Over the past 35 years, there has been a powerful breakthrough in the field of understanding the mechanisms of interaction between the intestinal microbiota and the host organism. Interesting data have been obtained and published that have not yet been fully systematized and understood. The methodology for studying the biological role of lipopolysaccharides in clinical settings developed by Russian scientists was based on the ability of agents for reducing their blood levels to increase the effectiveness of the treatment and preventive process. In particular, it made it possible to establish the involvement of the lipopolysaccharide factor in the pathogenesis of a number of diseases. The phenomenon of systemic endotoxinemia discovered by Russian researchers is a process of controlling the activity of adaptive systems (including the immune system) with the participation of the hypothalamic-pituitary-adrenal system by means of intestinal endotoxins. We see the following issues for wide discussion in the clinical community: (1) determining the directions for finding agents for normalizing systemic endotoxinemia indicators as the basis of preventive medicine, including pro- and prebiotics, entero- and hemosorbents, hepatoprotectors, immunopreparations, chaotropic effects (plasmapheresis, blood irradiation); (2) clinical and experimental models for studying diseases associated with intestinal microbiota; (3) creation of a research protocol to establish the age range of integral indicators of systemic endotoxinemia (the level of lipopolysaccharides and the activity of antiendotoxin immunity that resists endotoxin aggression); (4) ways to understand the mechanisms of development of endotoxin tolerance accompanying aging and its overcoming.

Introduction: Depression is increasingly diagnosed in adolescence, necessitating specific prevention and treatment methods. However, there is a lack of animal models mimicking juvenile depression. This study explores a novel model using ultrasound (US) stress in juvenile mice. Methods: We employed the US stress model in one -month -old C57/BL6 mice, exposing them to alternating ultrasound frequencies (20 -25 kHz and 25 -45 kHz) for three weeks. These frequencies correspond to negative and neutral emotional states in rodents and can induce a depressive -like syndrome. Concurrently, mice received either an omega -3 food supplement (FS) containing eicosapentaenoic acid (EPA; 0.55 mg/kg/day) and docosahexaenoic acid (DHA; 0.55 mg/kg/day) or a vehicle. Post -stress, we evaluated anxiety- and depressive -like behaviors, blood corticosterone levels, brain expression of pro -inflammatory cytokines, and conducted metabolome analysis of brain, liver and blood plasma. Results: US -exposed mice treated with vehicle exhibited decreased sucrose preference, a sign of anhedonia, a key feature of depression, increased anxiety -like behavior, elevated corticosterone levels, and enhanced TNF and IL1 beta gene expression in the brain. In contrast, US -FS mice did not display these changes. Omega -3 supplementation also reduced anxiety -like behavior in non -stressed mice. Metabolomic analysis revealed US -induced changes in brain energy metabolism, with FS increasing brain sphingomyelin. Liver metabolism was affected by both US and FS, while plasma metabolome changes were exclusive to FS. Brain glucose levels correlated positively with activity in anxiety tests. Conclusion: Chronic omega -3 intake counteracted depressive- and anxiety -like behaviors in a US model of juvenile depression in mice. These effects likely stem from the anti-inflammatory properties of the supplement, suggesting potential therapeutic applications in juvenile depression.

The role of altered brain mitochondrial regulation in psychiatric pathologies, including Major Depressive Disorder (MDD), has attracted increasing attention. Aberrant mitochondrial functions were suggested to underlie distinct inter-individual vulnerability to stress-related MDD syndrome. In this context, insulin receptor sensitizers (IRSs) that regulate brain metabolism have become a focus of recent research, as their use in pre-clinical studies can help to elucidate the role of mitochondrial dynamics in this disorder and contribute to the development of new antidepressant treatment. Here, following 2-week chronic mild stress (CMS) using predation, social defeat, and restraint, MDD-related behaviour and brain molecular markers have been investigated along with the hippocampus-dependent performance and emotionality in mice that received the IRS dicholine succinate (DS). In a sucrose test, mice were studied for the key feature of MDD, a decreased sensitivity to reward, called anhedonia. Based on this test, animals were assigned to anhedonic and resilient-to-stress-induced-anhedonia groups, using a previously established criterion of a decrease in sucrose preference below 65%. Such assignment was based on the fact that none of control, non-stressed animals displayed sucrose preference that would be smaller than this value. DS-treated stressed mice displayed ameliorated behaviours in a battery of assays: sucrose preference, coat state, the Y-maze, the marble test, tail suspension, and nest building. CMS-vulnerable mice exhibited overexpression of the inflammatory markers Il-1β, tnf, and Cox-1, as well as 5-htt and 5-ht2a-R, in various brain regions. The alterations in hippocampal gene expression were the closest to clinical findings and were studied further. DS-treated, stressed mice showed normalised hippocampal expression of the plasticity markers Camk4, Camk2, Pka, Adcy1, Creb-ar, Nmda-2r-ar, and Nmda-2r-s. DS-treated and non-treated stressed mice who were resilient or vulnerable to anhedonia were compared for hippocampal mitochondrial pathway regulation using Illumina profiling. Resilient mice revealed overexpression of the mitochondrial complexes NADH dehydrogenase, succinate dehydrogenase, cytochrome bc1, cytochrome c oxidase, F-type and V-type ATPases, and inorganic pyrophosphatase, which were decreased in anhedonic mice. DS partially normalised the expression of both ATPases. We conclude that hippocampal reduction in ATP synthesis is associated with anhedonia and pro-inflammatory brain changes that are ameliorated by DS.