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Vol 23, No 5 (2025)
Original research
Sirtuin expression in skin fibroblasts: pharmacomodulatory effect of quercetin
Abstract
Introduction. Sirtuins (SIRTs) are NAD+-dependent histone deacetylases involved in the intracellular regulation of multiple biological processes including DNA repair, autophagy, inflammation, oxidative stress defence and metabolism associated with age-associated diseases, including dermal ageing. Reduced levels of these proteins in tissues correlate with the progression of endothelial dysfunction and cellular aging, which makes sirtuins promising targets for the prevention and therapy of age-related pathologies. The development of strategies to activate the expression of SIRT -1, -3, -6 in cells to inhibit the aging process is relevant. The natural flavonoid quercetin, a natural flavonoid with proven geroprotective efficacy, is capable of influencing sirtuin gene expression.
Purpose. To study the modulatory effect of quercetin in the hyaluronan gel on the content of endogenous geroprotective proteins SIRT -1, -3, -6 in human skin fibroblast culture during the development of inflammaging.
Material and methods. The study was carried out on cell cultures of human skin fibroblasts with modelling of genotoxic stress inflammaging by UV-irradiation. 1 ml of hydrogel preparation with quercetin was injected into growth cultures, obtaining 3 groups of cells under study. Methods of immunocytochemistry and immunofluorescence confocal microscopy were applied to visualise the content of sirtuins in them. The obtained images were analysed using ImageJ software. Relative area of expression was calculated as the area of marker expression to the total area of the field of view. Statistical processing was performed in Origin.
Results. Revitalisant containing hyaluronan and quercetin showed effective enhancement of SIRT-1, -3, -6 levels in senescent skin cells.
Conclusion. Quercetin, an activator of SIRT-1, -3, -6 dermal anti-aging biomarkers, has therapeutic potential in the treatment of age-related pathologies. Selective pharmacological modulation of sirtuin activity in skin fibroblasts by quercetin appears to be an effective and promising way to slow down dermal aging.
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Biochemical markers of inflammation in drug-resistant tuberculous meningitis (experimental study)
Abstract
Introduction. The determination of inflammatory markers used to monitor the course of the disease and monitor the effectiveness of treatment.
Goal. To evaluate biochemical markers of inflammation in cerebrospinal fluid (CSF) and blood serum in experimental meningitis caused by a multidrug-resistant strain of M. tuberculosis.
Material and methods. Three groups of rabbits studied: infection control (IC) – infected, untreated; treatment control (TC) – those who received anti-tuberculosis drugs (ATD) in accordance with the spectrum of drug sensitivity; the main group (MG) – infected who received roncoleukin (12.5 mcg/kg, 5 injections, 1 time every 3 days) against the background of ATD. The glucose, total protein, albumin, ceruloplasmin, elastase, adenosine deaminase (ADA), its isoenzymes evaluated in CSF and serum.
Results. After 4 months of treatment, the number of neutrophils in the CSF decreased in the TC and MG, and lymphocytes increased in the TC and a decrease in MG. The total protein level decreased in the MG. There was a tendency to decrease glucose in the MG compared to the TC. ADA decreased in the TC and MG. The serum levels of albumin, ceruloplasmin, glucose, total protein in these groups remained within the baseline values. ADA in the TC increased, while ADA-1 only tended to increase. In the MG, an increase in elastase detected.
Conclusion. A decrease in the activity of the inflammatory process was revealed in both the TC and MG groups, and more significant with the administration of roncoleukin along with ATD. Assessment of the activity of ADA and its isoenzymes in CSF is important in assessing the regression of a specific inflammatory process during the treatment of experimental TBM.
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Immunohistochemical study of somatostatin and dopamine receptors (SSTR2, SSTR5, DR2) in pituitary adenomas to justify targeted therapy
Abstract
Introduction. Adenomas are the most common disease affecting the pituitary gland. Most of these tumors can be successfully treated. The main method is transsphenoidal resection. The exception is prolactinomas, which are treated with dopamine agonists.
Objective. Analysis of DR2, SSTR2, SSTR5 expression in various adenomas and normal adenohypophysis to justify targeted therapy.
Material and methods. Histological and immunohistochemical examination of surgical material from 42 pituitary adenomas and 6 pituitary glands without pathology (autopsy) with SSTR2, SSTR5, DR2 markers, ACTH, PRL, GH, FSH, LH, TSH hormones. Of these, 22 prolactinomas of patients undergoing preoperative treatment with cabergoline, 10 corticotropin, 10 zero-cell adenomas; 6 pituitary glands without pathology (control group). Receptor expression was assessed in points from 1 to 4.
Results. DR2 were expressed in 39 of 42 adenomas and in all 6 normal adenohypophysis; SSTR2 – in 12 adenomas and all normal adenohypophysis, SSTR5 – in 29 and 6, respectively. Statistical analysis did not reveal a significant difference in DR2 expression in different types of adenomas; in prolactinomas and normal adenohypophysis; in the level of SSTR2 and SSTR5 expression in corticotropinomas and normal adenohypophysis; SSTR5 and DR2 in a group with 19 prolactinomas, 2 mammosomatropinomas, 1 plurihormonal adenoma (the last 3 were considered by clinicians as prolactinomas).
Conclusion. There is no significant difference in DR2 expression in patients with prolactinomas, zero-cell adenomas, and corticotropinomas, which raises questions about the feasibility of dopamine agonist therapy only in patients with hyperprolactinemia.
There is no significant difference in DR2 and SSTR5 expression in prolactinomas, which indicates the possibility of alternative therapy with somatostatin receptor analogs.
The pronounced expression of DR2, SSTR2, and SSTR5 not only in pituitary adenomas but also in the normal adenohypophysis raises questions about the adverse effects on unchanged adenomeres and also requires larger-scale studies.
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The effect of a high-fat diet and phytocomposition based on B. vulgaris, C. bergamia, D. villosa and L. meyenii on the expression of genes for carbohydrate and lipid metabolism enzymes in the liver of rats
Abstract
Introduction. The liver serves as a buffer for the accumulation and utilization of excess intake of nutritional fats, the intake of plant compounds can improve metabolic processes in the liver, but the molecular mechanisms of this phenomenon have been little studied.
The purpose of the study. To study the effect of oral administration of a phytocomposition based on B. vulgaris, C. bergamia, D. villosa and L. meyenii (PC) on the expression levels of carbohydrate and lipid metabolism genes in the liver of rats on a standard diet (SD) or a high-fat diet (HFD).
Material and methods. 48 male Wistar rats were divided into groups (G) of equal numbers. During 4 and 7 weeks, animals G1 and G5, respectively, received SD (the proportion of fat in total calories was 11%), G2 and G6 – SD+PC, G3 and G7 – HFD (the proportion of fat in total calories was 36% due to the addition of lard to the diet), G4 and G8 – HFD+PC. After the animals were removed from the experiment, the liver was fixed in 1 ml of «Riti» reagent (Diem, Russia) and stored at -20 °C until the study. The expression of the genes acetyl-CoA carboxylase A (Acaca), acetyl-CoA carboxylase B (Acacb), fatty acid synthase (Fasn), stearyl-CoA desaturase (Scd), glucokinase (Gck) and pyruvate kinase (Pklr) was determined in the liver by reverse transcription polymerase chain reaction.
Results and discussion. It has been shown that HFD causes phase changes in the expression of lipid and carbohydrate metabolism genes in the rat liver: at week 4, there is an increase in Fasn expression, a decrease in Acaca and Pklr, indicating activation of lipogenesis; at week 7, a decrease in Fasn and Acacb expression, indicating activation of β-oxidation of fatty acids, an increase in the expression of Gck and Acaca indicates an increase in glycogenogenesis. The administration of PC potentiates these compensatory shifts, significantly enhancing the expression of Acaca and Gck. Correlation analysis showed that taking PC in SD conditions increased the number of correlations from 2 to 6 (new connections: Acacb and Pklr with Fasn and Scd), and in HFD conditions it transformed the feedback Acaca with Acacb into direct Acaca with Gck and Pklr.
Conclusion. The data obtained indicate that biologically active compounds of the studied PC contribute to the enhancement of the conjugation of carbohydrate and lipid metabolism and the activation of glycogenogenesis in the liver due to their direct or indirect action as inducers of lipid and carbohydrate metabolism gene expression, thereby leading to a restructuring of metabolic pathways aimed at compensating for HFD.
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Indicators of oxidative stress in adolescents with migraines
Abstract
Introduction. To date, there are a number of relevant studies devoted to changes in the LPO-AOP system indicators in adolescents and young adults with migraine. However, specific quantitative data and relationships between LPO-AOP indicators and migraine require further study.
The aim of the study was to evaluate migraine-specific LPO-AOZ indices in adolescents and their associations with age and gender of patients.
Material and methods. The study included 104 adolescents aged 12–17 years (boys and girls), comprising 66 participants with migraine (index group) and 38 without migraine (comparison group). The diagnosis was verified using a standardized screening questionnaire in accordance with the International Classification of Headache Disorders, 3rd edition (ICHD-3), which allowed confirmation of migraine and exclusion of other primary headache disorders. Components of the lipid peroxidation–antioxidant defense (LPO–AOD) system were quantified by spectrophotometric methods. Data were processed in Statistica 12 (TIBCO/StatSoft).
Results. Adolescents with migraine showed higher malondialdehyde (MDA) levels in both plasma and erythrocytes, alongside reduced erythrocyte superoxide dismutase (SOD) activity. Compared with controls, the migraine group contained a larger proportion of participants with elevated plasma and erythrocyte MDA and with diminished erythrocyte antioxidant enzyme activities, particularly SOD and catalase (CAT).
Conclusion. Migraine in adolescents is associated with a higher concentration in plasma and red blood cells of the pro–oxidant component of oxidative stress – MDA and lower activity of the enzymatic link of antioxidant protection – SOD and CAT, which indicates a more pronounced intensity of oxidative stress in this contingent. Given the significant role of the imbalance of the POL-AOР system in the development of oxidative stress, the increase in MDA and decrease in SOD and CAT activity that we have identified can probably be regarded as metabolic markers of the presence and/or risk of migraine. This assumption can be confirmed by further research.
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Polypragmasy in elderly and senile patients with chronic kidney disease: START/STOP criteria in elderly and senile patients taking DOAC
Abstract
Introduction. Thanks to the achievements of modern medicine, it was possible to significantly increase the life expectancy of the population. Molecular mechanisms of aging include telomere shortening, DNA damage accumulation, mitochondrial dysfunction, leading to decreased functional reserves of organs and systems. The cohort of geriatric patients is at risk of polypragmasy and has features of drug pharmacokinetics.
Objective: To evaluate factors that increase the risk of taking direct oral anticoagulants in elderly patients with polypragmasy and chronic kidney disease taking into account molecular mechanisms of drug action and individual pharmacogenetic features.
Material and methods. For this study, a database of 503 patients seen in «GVH No.2 DZM» from April to September 2023 was collected. The method of questionnaire was used, as well as the collection of clinical and laboratory data allowing to evaluate DOAC-dependent complications – cases of bleeding, duration of DOAC administration. Additionally, renal function biomarkers (cystatin C, NGAL), coagulation parameters and CYP3A4/CYP2C19 activity by indirect markers were analyzed.
Results. DOAC administration increases bleeding risks when creatinine clearance is significantly decreased, especially when dabigatran is administered. Administration of apixaban and rivaroxaban have no statistically significant increase in the incidence of hemorrhagic complications as renal impairment progresses. Concomitant DOAC and heparins significantly increase the risk of bleeding during 1 year of therapy. Co-administration of dabigatran and verapamil increases the risk of bleeding, which is not seen with other DOACs.
Conclusion. Investigation of drug interactions and the association of DOAC intake with various endpoints in larger samples will help to identify predictors of adverse outcomes and adjust therapy. Personalized approach considering pharmacogenetic features and molecular biomarkers can significantly improve the safety of anticoagulant therapy in elderly patients.
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Reviews
Artificial intelligence in early diagnosis: integration of pre-nosological screening and personalized prevention of chronic non-communicable diseases
Abstract
Introduction. Chronic non-communicable diseases (NCDs) account for 75% of global mortality, while traditional treatment paradigm demonstrates inability to contain epidemiological burden. Artificial intelligence (AI) technologies combined with telemedicine enable healthcare transformation: from reactive treatment to proactive health management through personalized prevention. Russian school of pre-nosological diagnostics, focused on identifying pre-pathological states through assessment of body’s functional reserves, creates methodological foundation for personalized approach that can be significantly enhanced by modern machine learning methods.
Objective: to develop methodology for remote questionnaire-based screening of NCDs using AI with integration of holistic approach to pre-nosological diagnostics, providing generation of personalized prevention recommendations, and evaluate its effectiveness in young adults.
Material and methods. Study included 3,155 university students from St. Petersburg (mean age 19.6±1.5 years) from 83 regions of Russian Federation. AI-based technology for remote screening was developed using holistic approach. System verifies risk factors by five pathology profiles (cardiology, gastroenterology, pulmonology, endocrinology, oncology). Questionnaire contains 198 information requests. Decision rules system (1,098 rules) was applied. Systematic literature review in PubMed, Scopus, Web of Science, eLibrary for 2020–2025 was conducted; RCTs, systematic reviews, WHO and Food and Drug Administration regulatory documents, methodological guidelines were analyzed.
Results. Low NCD risk detected in 57.4%, moderate in 30.9%, high in 11.7% of examined individuals. Most frequent complaints related to endocrine (28.9%), digestive (21.8%), respiratory (21.1%), and cardiovascular systems (20.1%). More than 75% showed signs of polymorbidity. Statistical analysis confirmed significant consistency between system and physician assessments (p < 0.001). Cohen’s kappa showed substantial agreement for cardiology and pulmonology profiles, moderate for gastroenterology and endocrinology. System generates personalized recommendations considering age, gender, anthropometric data, harmful habits, and psychological state. Physician time savings reached 20%. User satisfaction – 96.6%, healthcare workers – 91.7%.
Conclusion. Developed methodology for remote questionnaire-based AI screening with holistic approach showed high effectiveness for early risk factor detection in young adults. Integration of Russian pre-nosological diagnostics experience through pathology profiles with modern machine learning technologies creates conditions for transition to personalized prevention focused on correction of body’s functional reserves. System demonstrates significant social and economic effectiveness.
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Novel strategies for post-exposure rabies prophylaxis: the role of immunomodulatory and targeted molecular technologies in personalized medicine
Abstract
Introduction. Rabies is currently a rare but deadly viral disease transmitted through animal bites, mainly dogs. There is no standardized effective therapy for clinically manifest rabies. Patients with developed symptoms are mainly provided with palliative care and intensive therapy. In this regard, the search for new therapeutic solutions for rabies is urgent.
Objective. To analyze current advances in rabies post-exposure prophylaxis (PEP) with emphasis on molecular technologies and their integration into personalized medicine.
Material and methods. Systematic search in PubMed and Scopus databases for 2018–2025 using key terms: rabies, post-exposure prophylaxis, monoclonal antibodies, mRNA vaccine, favipiravir, siRNA, aptamer. Original studies, meta-analyses, systematic reviews, and WHO/CDC guidelines were analyzed.
Results. Rabies maintains nearly 100% fatality rate upon symptom manifestation, causing approximately 59 000 deaths annually, predominantly in Africa and Asia. Standard PEP remains highly effective but is limited by immunoglobulin availability in resource-limited regions. Recent advances include: monoclonal antibodies against rabies virus G-protein (docaravimab/miromavimab) demonstrating favorable safety profile as alternative to human rabies immunoglobulin; mRNA vaccines encoding full-length RABV-G providing complete protection in preclinical studies; nucleoside analogs effective when applied early before CNS penetration; RNA therapeutics (aptamers/siRNA) showing convincing in vitro viral suppression results.
Conclusion. Molecular technologies expand personalized PEP capabilities. Monoclonal antibodies are already entering clinical practice, mRNA vaccines are approaching clinical trials, while RNA therapeutics require solving CNS delivery challenges. Key challenges include proving equivalence to standard therapy, ensuring accessibility in endemic regions, and standardizing combined approaches considering individual risk factors.
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Glutathione: a key molecule of redox homeostasis and its potential for nutritional and metabolic regulation. a review of the literature
Abstract
Introduction. Glutathione (GSH) is a key intracellular antioxidant involved in maintaining redox homeostasis, detoxifying xenobiotics, regulating immune and neurotransmitter systems, and supporting protein folding and degradation. Depletion of GSH is associated with numerous chronic conditions, including neurodegenerative and metabolic disorders, cancer, liver diseases, HIV infection, and cardiovascular pathologies.
Objective. To summarize and systematize modern scientific data on the role of glutathione (GSH) as a key molecule in maintaining redox homeostasis in the body, and to study the existing possibilities of nutrient and metabolic regulation of its synthesis and metabolism.
Results. This review summarizes the molecular mechanisms of GSH synthesis and recycling, focusing on the role of enzymatic systems (e.g., GST, GGT, GCL), genetic polymorphisms, nutritional status, and amino acid availability (notably cysteine, glutamine, glycine, serine, and taurine). Special attention is given to nutrient-based interventions to restore GSH levels using precursors such as N-acetylcysteine (NAC), S-adenosylmethionine (SAMe), and oxothiazolidine derivatives (OTC). The bioavailability and effectiveness of different GSH delivery forms–oral, sublingual, liposomal, and intravenous–are discussed in the context of oxidative stress and disease. The review highlights the importance of integrating genetic profiling, nutrient intake, and redox biomarkers to personalize GSH-targeted therapeutic strategies.
Conclusion. Glutathione is a key molecule in antioxidant, metabolic, and immune defense. Disturbances in its metabolism, caused by external and internal factors, are associated with the development of chronic diseases. The use of glutathione and its precursors (NAC, glycine, etc.) holds promise for nutritional support in GSH deficiency, but requires further clinical study. Nutrigenetics and redox status assessment allow for personalized correction of glutathione metabolism and increased effectiveness of antioxidant therapy.
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The Impact of Genetic Polymorphisms in Toll-like Receptor Genes on Interaction with Helicobacter pylori
Abstract
The aim of the study. To describe the interaction between Helicobacter pylori and Toll-like receptors, and to outline the role of TLRs gene polymorphisms in the pathogenesis of this infection.
Material and methods. An analysis of publications from 2000 to 2025 in PubMed, Scopus, and Elsevier databases was conducted.
In the present review the structure and classification of Toll-like receptors (TLRs), mechanisms of TLRs interaction with Helicobacter pylori, and the role of TLRs gene polymorphisms in infection pathogenesis were observed. Current evidence indicates that single nucleotide polymorphisms (SNPs) in TLRs genes causing receptor dysfunction can significantly influence an individual’s susceptibility to Helicobacter pylori infection and determine the nature of inflammatory response, affecting complication risks. An important aspect of individual susceptibility to H. pylori-associated diseases are TLRs gene polymorphisms which regulate the intensity and nature of immune response. The most studied variants are: TLR4 Asp299Gly (rs4986790) and Thr399Ile (rs4986791), associated with lipopolysaccharide hyporesponsiveness and increased risk of atrophic gastritis; TLR5 (rs5744174) increasing gastric cancer risk in combination with H. pylori infection; and TLR9 (rs5743836) -1237T/C enhancing gene expression and predisposing to precancerous mucosal changes.
Conclusion. These data emphasize that infection outcomes depend not only on strain virulence but also on host genetic factors determining immune response efficacy. Genetic variations in TLRs genes may influence individual risks of severe complications, including gastric cancer. Further research in this field could facilitate the development of personalized approaches for diagnosis, prognosis, and treatment of H. pylori-associated diseases, as well as identify new targets for immunotherapy.
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Serotonin as a modulator of neurogenesis processes in post-traumatic stress disorder
Abstract
The purpose of this review is to discuss the role of serotonin in the processes of neurogenesis in the hippocampus in post-traumatic stress disorder. Full-text materials were searched in Medline (PubMed) and Scopus databases over the past 15 years.
Results. Cognitive impairment that occurs in post-traumatic stress disorder (PTSD) is associated with a decrease in the level of neurogenesis in the dentate gyrus of the hippocampus and disruption of the monoaminergic brain systems: catecholamines and serotonin. Animal studies using the Single Prolonged Stress (SPS) protocol confirm PTSD-like symptoms, decreased levels of neurogenesis and serotonin in the hippocampus, and the use of Tph1-/-, Tph2-/-, Tph1/Tph2-/-, TetO-shTph2 models allow us to suggest that serotonin does not play a major role in maintaining the basal level of neural stem cell (NSC) proliferation, but is required to modulate neurogenesis in response to changed conditions (physical activity, enriched environment). Modulation of neurogenesis probably occurs through activation of serotonin receptors located on both NSCs and glial cells, of which 5-HTR1 and 5-HTR2 are of greatest interest.
Conclusion: Serotonin modulates the processes of neurogenesis in the hippocampus in response to changing environmental conditions through activation of receptors 5-HTR1 and 5-HTR2.
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