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Renalase (RNLS) is a protein that plays an important role in the regulation of blood pressure in humans and animals. Previously, we found higher levels of RNLS mRNA in the hearts of spontaneously hypertensive rats (SHR rats) compared to normotensive controls (WKY - Wistar Kyoto rats) (Fedchenko et al., 2013; Med. Sci. Monit. Basic Res., 19, 267-270). In this study, we assessed the RNLS protein level in the hearts of these animals by means of available poly- and monoclonal antibodies to human and rat RNLS. Western blot analysis revealed an increase in several protein bands within the molecular mass range of RNLS from various sources (35-40 kDa). However, mass spectrometry analysis did not detect the presence of RNLS, and other rat heart proteins were detected in the protein bands of varying intensity: lactate dehydrogenase (LDHB; P42123) and mitochondrial malate dehydrogenase (MDHM; P04636). The interaction of highly purified LDH with anti-RNLS antibodies was confirmed in direct experiments using Western blot analysis. These results indicate that some cardiac proteins can (non-specifically?) interact with anti-RNLS antibodies. This significantly limits their use and requires detailed verification of the obtained results using more specific (alternative) molecular tools.

Recurrent vulvovaginal candidiasis (RVVC) is one of the most complex forms of urogenital infection in terms of its clinical burden, impact on quality of life, and difficulty in preventing relapses. The aim of this study was to comprehensively characterize the taxonomic composition and functional potential of the vaginal microbiome associated with RVVC. This case-control study included patients with RVVC and conditionally healthy women. Vaginal samples were analyzed using shotgun metagenomic sequencing, followed by taxonomic and functional annotation of the microbiome using data quality control, taxonomic classification (Kraken2, MetaPhlAn4), and functional annotation (HUMAnN 3.9). At the community structure level, the RVVC microbiome exhibited pronounced interindividual variability and did not represent a uniform microbiota configuration. The taxonomic profile of the microbiome in RVVC was characterized by an increased relative abundance of Lactobacillus iners and anaerobic taxa (Prevotella bivia, Dialister microaerophilus), forming a compact "core" of intergroup differences. Functional analysis revealed a limited but reproducible set of metabolic pathways associated with RVVC; these included pathways of purine metabolism, central carbohydrate metabolism, and biosynthesis of cofactors and cell wall components. RVVC is associated not only with changes in the taxonomic composition of the microbiota but also with a stable reconfiguration of its functional potential. The identified shifts in metabolic pathway patterns reflect a transition of the vaginal microbial community to an alternative functional state, thus highlighting the need to develop new therapeutic strategies alternative to traditional antifungal-based approaches.

The aim of this study was to investigate the effects of Gloydius blomhoffii and Gloydius halys venoms and their fractions on platelet and plasma hemostasis, and to evaluate the ability of the sPLA2 inhibitor Varespladib to neutralize the coagulopathic activity mediated by secretory phospholipase A2 (sPLA2) present in these venoms. The proaggregatory effect of whole G. halys and G. blomhoffii venoms on platelet hemostasis was associated with multidirectional effects of their multiple protein components, while sPLA2-containing fractions exhibited an antiaggregatory effect. Whole G. halys and G. blomhoffii venoms and Varespladib added to them did not affect the extrinsic pathway of hemocoagulation, but inhibited the intrinsic pathway of human blood coagulation. The paradoxical effect of further enhancing the anticoagulant activity of G. halys and G. blomhoffii venoms with the sPLA2 inhibitor Varespladib could be determined by a stronger sPLA2 interaction with blood coagulation factor Xa after formation of the enzyme-inhibitor complex.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder, which is commonly related to reduced insulin responsiveness and altered appetite-related hormones. In this study, we have evaluated how combined metformin and sulfonylurea therapy affects glycemic indicators and appetite hormones, with special focus on hormone ratios. Sixty participants were involved in the study: 30 diabetic patients receiving combined metformin-sulfonylurea therapy and 30 conditionally healthy individuals serving as controls. Fasting blood samples were collected to assess indicators of glycemic control, lipid profiles, and hormone levels using standard biochemical assays and ELISA. The patient group showed clear increases in fasting glucose, HbA1c, insulin, insulin resistance indices, lipid profile measurements, and leptin levels, whereas the levels of HDL, ghrelin, and adiponectin were markedly decreased compared with the control group (p < 0.001). The results of the study show that T2DM patients continue to have both insulin resistance and poor blood glucose control despite combined metformin-sulfonylurea therapy. Alterations in appetite hormones also reflect underlying metabolic dysregulation, and hormonal ratios, especially the leptin/adiponectin ratio, are more accurate indicators of this imbalance than individual hormone measurements.

Physical inactivity triggers several metabolic syndromes and influences cognitive function, including the development of dementia. Exercise can help to prevent these negative effects. However, there is currently limited research examining how exercise affects cognitive function through brain-derived neurotrophic factor (BDNF) levels, and the underlying mechanisms remain unclear. The aim of this study was to analyze existing literature on the effect of physical exercise on brain-derived neurotrophic factor (BDNF) levels as a biomarker of cognitive function. Several journal databases, including Scopus, Web of Science, PubMed, and Science Direct, were searched for this study. The study considered several variables, including studies on BDNF, high-intensity exercise, and moderate-intensity exercise published within the last ten years. Articles that did not meet the inclusion criteria (e.g. animal studies) were excluded from this systematic review. Using databases from PubMed, Science Direct, Web of Science, and Scopus, a total of 152 publications were identified. Ten carefully selected, peer-reviewed articles addressed the need for this systemic change. Standard operating procedures for this study were established using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Based on the results of this comprehensive study, it is evident that exercise increases BDNF levels in humans. Although high-intensity exercise is more effective in increasing BDNF levels in humans than moderate-intensity exercise, further research is needed for selection of the optimal physical load required for BDNF expression. Physical exercise is recommended to improve brain development and memory ability.

In this study we have reanalyzed the original proteomic data from studies of hippocampal [DOI: 10.1172/jci.insight.188612] and temporal cortex [DOI: 10.1016/j.expneurol.2025.115361] tissues of patients with temporal lobe epilepsy. The goal was to identify proteins whose levels of post-translational modifications (PTMs) could be altered in this disease. Three datasets (PXD064519, ZMP8KU, and PXD010154) deposited at PRIDE and Texas Data Repository were used. Phosphorylation and N-terminal acetylation were considered as target PTMs. During re-identification of peptides we considered only peptides, for which both variants (with and without PTMs) were identified. A data comparison algorithm independent of experimental data alignment between individual samples was used. As a result, 35 proteins were selected that showed significant changes in phosphorylation levels. For 12 of these proteins, significant changes were recorded in both data sets. Twenty-nine proteins from this list have been linked to epilepsy pathogenesis in the literature.

The natural antioxidant astaxanthin (AST) demonstrates the cardioprotective effect on cardiac mitochondria in rats subjected to chronic alcohol intoxication. Particularly, AST restored cardiac mitochondrial respiratory activity and Ca2+ capacity of rats exposed to chronic alcohol intoxication; it also had a positive impact on the balance of functionally important processes of mitochondrial fission/fusion, as well as mitophagy. In addition, AST prevented alcohol-induced morphological damage to cardiac tissue. Overall, the results demonstrate that AST promotes normalization of cardiac mitochondrial function, protecting these organelles from degenerative changes caused by alcohol intoxication and improving cardiac energy metabolism. Thus, AST helps to compensate the cardiac mitochondrial damage caused by chronic alcohol intake by restoring their functional activity and stress resistance.

MicroRNAs are small non-coding RNA molecules of 20-24 nucleotides in length. They play a key role in regulation of gene expression by influencing stability and translation of mRNA in a wide range of biological processes. Since their discovery, a large number of microRNAs have been described, and significant progress has been made in elucidating their functions. Convincing evidence now exists that microRNAs are powerful genetic regulators. The discovery of a link between microRNAs and numerous human diseases, particularly various types of cancer, stimulated a significant interest in exploring their therapeutic potential. They represent a new class of therapeutics capable of restoring impaired cellular functions, especially in various malignancies. Despite significant progress in preclinical research, microRNA-based therapy is still in the beginning stages; only a few microRNAs have been taken into further clinical trials. This is due to their off-target effects, primarily toxicity and immunogenicity, which significantly limit the use of microRNAs as therapeutic agents. One way to overcome off-target effects is to develop new systems for targeted delivery of microRNAs to the target tissue (disease site). Managing the off-target effects of microRNAs is a serious problem that requires solutions.

Age-related cerebral microangiopathy (CMA) also known as cerebral small vessel disease (CSVD), is a leading cause of cognitive impairment and stroke. Difficulties in studying CSVD are associated with limitations in visualizing small vessels and diagnostics based on MRI signs of brain damage (white matter hyperintensity, lacunae, microbleeds, etc.). Our previous assessment of each CSVD MRI feature using a four-point severity scale and distribution among brain region using cluster analysis revealed the existence of two MRI types. They do not differ in the severity of vascular risk factors but do differ in the severity of clinical manifestations and levels of circulating plasma biomarkers. Here we present results of a pilot panoramic study of the proteome of peripheral blood mononuclear cells from patients with CSVD MRI types I and II, as well as healthy volunteers. CSVD patients showed a tendency toward downregulation of proteins associated with vesicular trafficking and extracellular matrix (ECM) remodeling relative to control values. Patients with CSVD MRI type 1 showed trends toward insufficient activation of protective proteins (arginase-1, thioredoxin, autophagy and protein stress regulators) and excessive activation of platelet proteins and vascular wall remodeling regulators (such as profilin-1), compared to patients with CSVD MRI type 2. These results indicate the need to study the microstructure of the basement membrane, vascular ECM, and perivascular spaces in cerebral small vessels.

The VPS35 is an essential protein that plays multifunctional roles in various biological processes. It is a core component of the retromer complex, involved in protein recycling from endosomes to the trans-Golgi network (TGN) and the plasma membrane. Besides its role as the retromer complex component, VPS35 interacts with many proteins and regulates mitochondrial homeostasis, mitochondrial dynamics (fusion and fission), and other important processes in various cell compartments. In the context of Parkinson's disease (PD) convincing evidence exists that VPS35 mutations, particularly [D620N], have a significant impact on normal retromer functioning, mitochondrial dysfunction, and impairment of neuronal health and survival. In this review we briefly consider structure and functions of the retromer complex, the role of VPS35 in mitochondria, and finally analyze physical and functional interactions of this protein with PD-important proteins associated with mitochondria.

Modern diagnostics in oncohematology is based on highly informative "gold standards" such as bone marrow biopsy, immunophenotyping, and cytogenetic analysis. The need to monitor the progression of the disease and the effectiveness of therapy requires the development of additional noninvasive approaches. One such approach is nuclear magnetic resonance spectroscopy (&#xb9;H NMR spectroscopy); its key advantage is the ability to quickly and simultaneously identify many metabolites in biological body fluids to construct clinically relevant metabolomic profiles and provide an integrated picture of metabolic processes. The aim of the study was to identify key plasma metabolites altered due to carboplatin toxicity in the bone marrow of CBA mice and to evaluate the possibility of correcting these changes by oral administration of poloxamer P188. The animals were divided into 6 groups: intact control (CTR), a group with a pathology model without treatment (MYS), and 4 experimental groups receiving poloxamer P188 at doses from 10 mg/kg to 1000 mg/kg for 7 or 21 days. The plasma metabolic profile was analyzed by &#xb9;H NMR spectroscopy on days 8 and 22. A total of 36 metabolites were identified in plasma by &#xb9;H NMR spectroscopy, with statistically significant differences between groups found only for 15 compounds. A single intraperitoneal administration of carboplatin at a dose of 100 mg/kg caused significant metabolic shifts in the plasma of CBA mice associated with the development of myelosuppression: an increase in the concentrations of D-glucose-1-phosphate and lysine and a decrease in dimethylglycine, &#x3b2;-hydroxybutyrate, isobutyrate, and trimethylamine. Daily oral administration of P188 for 7 and 21 days in the myelosuppression model significantly affected the concentrations of key metabolites, resulting in increased isobutyrate and trimethylamine levels and decreased lysine levels. Thus, &#xb9;H NMR spectroscopy enabled us to identify characteristic metabolic disturbances in carboplatin-induced myelosuppression in CBA mice and demonstrate the efficacy of P188, which normalized key metabolites: isobutyrate, trimethylamine, and lysine. These data confirm the potential of using NMR metabolomics for noninvasive and personalized monitoring of therapy efficacy.

The combined effects of two inhibitors, Torin 1, acting on mTOR, a key regulator of autophagy, and H-151, inhibiting STING, a key regulator of inflammation, on the autophagolysosomal system, have been studied in a primary culture of peripheral blood macrophages from healthy donors and the SH-SY5Y neuroblastoma cell line. Combined use of these drugs resulted in a decrease in the levels of lysosphingolipids, triggering alpha-synuclein oligomerization, as well as a decrease in the levels of monomeric and neurotoxic phosphorylated (Ser129) alpha-synuclein and an increase in tyrosine hydroxylase. These results open new prospects for the use of combination therapy with these proposed drugs in the treatment of both diseases associated with lysosomal dysfunction and neurodegenerative pathologies.

Using atomic force microscopy (AFM), the heights of individual horseradish peroxidase (HRP) molecules were determined at different stages of the catalytic cycle of this enzyme (I-IV). The HRP heights were determined in two buffer systems: Dulbecco's phosphate-buffered saline (PBSD) (pH 7.2) and citrate-phosphate buffer (CPB) (pH 5.0). Spectrophotometric analysis showed that the enzyme was more active in CPB. AFM data processing under these conditions revealed a tendency toward a decrease in the HRP molecule height after addition of the ABTS substrate (stage (II)). After the addition of H2O2 (stage (III)), an increase in the height was observed followed by a further decrease after the addition of the NaN3 inhibitor (stage (IV)). No such trend was observed in PBSD. The increase in the molecular height at stage (III) (in the presence of all enzyme system components) was interpreted as an evidence of the HRP activity. The proportion of molecules with the increased height at stage (III) reached 50.5% in CPB and did not exceed 14.8% in PBSD. These data support the existence of "active" and "non-active" HRP molecules in the studied sample, thus confirming the need to move from traditional biochemical "enzyme activity" to identifying "active" and "non-active" enzyme molecules using a fundamentally new approach of analysis of the properties of individual molecules.

Glucocorticosteroids (GCS) are often the medication of choice for chronic inflammation. Since not all patients are equally sensitive to GCS, certain efforts are undertaken to increase sensitivity and complement glucocorticosteroid therapy with other nonsteroidal medications that can enhance the anti-inflammatory effect of GCS. The tricyclic antidepressant nortriptyline has demonstrated anti-inflammatory properties in several experimental studies, as well as the ability to complement the action of GCS. The aim of this study was to investigate the effects of nortriptyline, as well as its combination with mometasone, on blood mononuclear cells (MNCs) under conditions of stimulated immune responses (IR) of types 1, 2, and 17. In isolated MNCs from six healthy donors, IR type I, type 2, or type 17 were stimulated in the presence of nortriptyline, mometasone, or their combination by adding recombinant activator proteins (IL-2, IL-25, IL-33, thymic stromal lymphopoietin (TSLP), IL-12, IL-1&#x3b2;, IL-23). After three days, the concentration of IL-6 and IL-8 was determined in the supernatants by enzyme-linked immunosorbent assay. In the presence of nortriptyline at a final concentration of 10-5 M, IR type 2 and type 17 were accompanied by a decrease in IL-6 concentration. Addition of a combination of mometasone and nortriptyline to the MNC culture medium under conditions of IR type II activation had a potentiating effect. This was evidenced by a decrease in IL-6 and IL-8 secretion compared to the use of mometasone alone. The study demonstrates the ability of nortriptyline to suppress the secretion of proinflammatory cytokines by blood cells, which is selective and dependent on the type of immune response.

This literature review examines the biological properties of hyaluronic acid (HA), its various chemical modifications with carboxyl, hydroxyl, and acetamide groups, applicable in drug and genetic material delivery systems. Special attention is paid to the use of HA in complexes with metal nanoparticles, other biopolymers, and biomolecules. HA molecules of different molar masses exhibit different effects on cellular processes. Therefore, HA fractions with strictly defined molecular masses are used to achieve various goals. Unique properties of HAsuch as high bioavailability, biocompatibility, antioxidant properties, and high affinity for a number of cellular receptors make HA a promising means for use in targeted therapy. The use of HA in regenerative medicine has been also discussed.

Renalase (RNLS) is a protein exhibiting various functions inside and outside cells. A series of synthetic peptides, corresponding to the fragments of the RNLS amino acid sequence, may reproduce the effects of the full-length RNLS. In this study we have investigated the interaction of proteins in the mitochondrial brain fraction of rats with the full-length RNLS and its peptides RP211-223 (peptide 1) and RP224-232 (peptide 2) immobilized on CNBr-activated Sepharose. Proteomic profiles of proteins bound to the full-length RNLS and its peptide RP211-223 were significantly different, whereas RP224-232 bound a small number of proteins (6), similar to those bound to the full-length RNLS. However, most proteins bound to RNLS and its peptides were multifunctional and associated with neurodegenerative pathology (Alzheimer's and Parkinson's diseases, etc.).

Neuroinflammation is a process implicated in the development of many neurodegenerative diseases. It involves microglia, astrocytes, and cytokines. The aim of this study was to investigate the effects of neuroprotectors on morphology of microglial cell during lipopolysaccharide (LPS)-induced neuroinflammation. Immunocytochemical detection of microglia using the IBA1 marker in glial cell cultures obtained from rat cerebral cortex revealed the presence of a significant number of microglial cells in the studied culture. In the control, microglial cells possessed a large number of processes typical of nonactivated cells. In cultures treated with LPS (10 &#x3bc;g/ml, 24 h), microglia had a flattened amoeboid morphology, characteristic of activated cells. Furthermore, LPS treatment also resulted in an increase in the profile field area of the cell body, while the perimeter did not increase significantly, indicating a more rounded cell body shape compared to the control. In cultures treated with methylene blue (1 &#x3bc;M, 24 h) in the presence of LPS, microglial cells had a larger number of processes and a smaller body profile area than microglia treated with LPS alone, and their perimeter did not differ significantly from that of control cells. In the case of menadione (1 &#x3bc;M, 24 h) in the presence of LPS, the cells retained an amoeboid shape, and their size did not change significantly compared to the LPS group. Microglia treated with methylene blue alone did not differ from control microglia in morphology, body profile area, or perimeter, whereas menadione caused a significant increase in the cell's body profile area and a shift in their morphology toward an activated phenotype. Methylene blue, a substance whose anti-inflammatory action is associated with Nrf2 activation, is capable of not only reducing the production of proinflammatory cytokines but also preventing the transition of microglia to the activated phenotype.

The study of saliva composition attracts much attention and the number of publications in this area is constantly growing. However, the impact individual factors on saliva composition still needs better understanding. The limited use of saliva as a biological fluid for clinical laboratory diagnostics is determined by the lack of standardized preanalytical methods and the absence of reference values for biochemical parameters that take into account a number of factors affecting saliva composition and properties. In this review we have analyzed some factors influencing saliva composition. The impact of these factors on saliva composition is associated with dysfunction of the salivary glands, changes in salivation rate, salivary viscosity, dry mouth, pH balance, and electrolyte composition, leading to impaired homeostasis of the oral cavity.

Immune thrombocytopenia (ITP) is one of the most common causes of decreased platelet count. Bleeding is the main clinical symptom of ITP; although its severity correlates with the depth of thrombocytopenia, it may also depend on changes in the functional activity of platelets. In this study we have compared platelet functional activity in healthy volunteers (HV) and in ITP patients, as well as in groups of ITP patients with different levels of bleeding. The study included 65 HV and 84 ITP patients. Platelet activity was assessed by flow cytometry. Platelets were activated with thrombin receptor activating peptide (TRAP) or ADP, and the exposure of activation markers, activated form of glycoprotein (GP) IIb-IIIa and alpha-granule membrane protein P-selectin, was determined on their surface by measuring the binding of PAC-1 and CD62P antibodies, respectively. Platelet-associated IgG (PA-IgG, an indicator of the level of antiplatelet autoantibodies), the percentage of "young" reticular platelets (RP, %) and platelet light scatter (an indicator of their size) were also assessed using flow cytofluorimetry. Platelet binding of PAC-1 (and, to a lesser extent, CD62P binding) was lower in ITP patients than in HV. In ITP patients, PAC-1 binding inversely correlated with the PA-IgG content. In contrast to HV, in ITP patients, PAC-1 and CD62P binding did not directly correlate with the platelet size and RP, %. In ITP patients with severe bleeding, the platelet count was lower, PAC-1 and CD62P binding was reduced and PA-IgG and RP, % levels were increased. Thus, a decrease in the content of activation markers on the platelet surface was registered in ITP patients; it was more pronounced in patients with severe bleeding. It is suggested that the cause of this decrease may be due to the effect of autoantibodies (PA-IgG) on platelets, and in particular on GP IIb-IIIa.