The blood serum antioxidant status and the blood plasma metabolomic profile have been analyzed in Parkinson's disease (PD) patients, both pharmacologically naive and taking levodopa (treatment duration 7.4±5.4 years) at...The blood serum antioxidant status and the blood plasma metabolomic profile have been analyzed in Parkinson's disease (PD) patients, both pharmacologically naive and taking levodopa (treatment duration 7.4±5.4 years) at low (< 300 mg/day) and high (> 300 mg/day) doses. High-dose levodopa therapy caused changes in both the antioxidant status and metabolome of patients. High-dose levodopa treatment also activated lipid peroxidation, manifested by an increase in the level of lipid hydroperoxides. High-resolution mass spectrometry revealed accumulation of levodopa and dopamine metabolic products in the metabolome, particularly the neurotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), and associated changes in related metabolic pathways. Low-dose levodopa treatment did not cause significant changes in the antioxidant status and metabolome of patients, thus suggesting that maintaining a low-dose regimen as long as possible could potentially reduce neurotoxic metabolite accumulation and also maintain normal antioxidant functions in PD patients.
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 visua...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.
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...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.
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 r...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.
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...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.
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 system...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.
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 glucocort...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-1β, 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.
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...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 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 primar...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.
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 a...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.
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...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.
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...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.
The use of in silico approaches to assess potential adverse reactions of new pharmaceutical substances reduces the risks, financial and time costs, associated with drug development. Using our previously developed method...The use of in silico approaches to assess potential adverse reactions of new pharmaceutical substances reduces the risks, financial and time costs, associated with drug development. Using our previously developed method for identifying chemical motifs associated with certain types of undesirable biological activity, we have evaluated the off-target toxicity of clinically investigated pharmaceutical substances that would help to evaluate the potential risks of further research and use in clinical practice. For this purpose, we have created highly specific structural fragments for epidermal growth factor receptor and dipeptidyl peptidase 4 inhibitors, which are two molecular targets associated with a wide range of adverse reactions. A search for compounds containing these fragments was performed among 12,070 entries with information on clinical trials in the PubChem database. We have shown that five compounds entering phase I and II trials may have an unfavorable benefit-risk ratio due to the potential inhibition of at least one of the analyzed enzymes. Incorporating such analytical frameworks into early drug discovery and preclinical assessment could substantially reduce overall development costs and timelines, facilitating the introduction of safer and more cost-effective therapeutic agents.
Sepsis-associated encephalopathy (SAE) is a condition characterized by acute brain dysfunction developed in the absence of a primary infection in the central nervous system. The aim of this study was to perform a pilot,...Sepsis-associated encephalopathy (SAE) is a condition characterized by acute brain dysfunction developed in the absence of a primary infection in the central nervous system. The aim of this study was to perform a pilot, untargeted metabolomic profiling of the blood plasma of SAE patients to identify metabolic changes potentially associated with the pathological condition and to generate hypotheses for further studies of its pathogenesis, as well as to the search for promising biomarkers, and the assessment of the severity of the patient's condition. Metabolomic profiling was performed using HPLC-HR-MS, followed by statistical analysis of the obtained data. This blinded, randomized, controlled clinical trial revealed significant differences in the metabolic profiles of the study and control groups. Functional analysis showed the metabolic pathways most affected by pathological processes in SAE patients. These included metabolism of acylcarnitines, lysophosphatidylcholines, and taurine, folate biosynthesis, and the drug metabolism involving the cytochrome P450 pathway. In SAE patients with impaired consciousness, including delirium and coma, decreased levels of long-chain acylcarnitines and lysophosphatidylcholines were observed. The metabolomic profiles of SAE patients differed significantly between the groups of deceased and surviving patients: concentrations of sulfur-containing amino acids were significantly lower in the group of deceased than in the group of survivors. Our study identified 64 candidate biomarkers that could potentially be used to predict sepsis outcomes. However, further study is needed using an expanded and independent cohort of patients.
Prodrugs based on pyridoxine and ketorolac (the most potent analgesic NSAIDs) exhibit analgesic activity comparable to ketorolac in vivo and significantly higher safety and prolonged action. In this study the antioxidant...Prodrugs based on pyridoxine and ketorolac (the most potent analgesic NSAIDs) exhibit analgesic activity comparable to ketorolac in vivo and significantly higher safety and prolonged action. In this study the antioxidant and protective properties, inhibitory activity against cyclooxygenase (COX) and intracellular permeability for two prodrug bipharmacophoric conjugates based on pyridoxine and ketorolac have been investigated in vitro. Their inhibitory activity towards the COX-1 and COX-2 enzymes was comparable to that of ketorolac (the IC50 values ranged from 12.0 μM to 34.7 μM). These compounds markedly protected albumin against thermal and chemical (urea and citric acid) treatments and demonstrated the cell-penetrating ability through passive diffusion.
Copper ions (Cu2+) at concentrations of 25-50 μM stimulate lipopolysaccharide (LPS)-induced nitric oxide (NO) production in glial cell cultures derived from rat cerebral cortex and containing both astrocytes and microgli...Copper ions (Cu2+) at concentrations of 25-50 μM stimulate lipopolysaccharide (LPS)-induced nitric oxide (NO) production in glial cell cultures derived from rat cerebral cortex and containing both astrocytes and microglia. Addition of a higher Cu2+ concentration (100 μM) during LPS stimulation did not significantly increase NO in the incubation medium, while 200 μM Cu2+ decreased this parameter compared to LPS. Cu2+ ions at these concentrations decreased viability of cultured cells. Apparently, the decrease in cell viability is not associated with nitrite accumulation, because the addition of even 100 μM sodium nitrite to the culture medium did not reduce cell viability or affect the cytotoxicity of Cu2+. The study of microglial cells (using the IBA1 marker) revealed that in LPS-treated cultures, microglia had a predominantly flattened amoeboid morphology, characteristic of activated microglia. The LPS treatment also increased the cell body profile area and perimeter. At a concentration of 25 μM, Cu2+ ions did not affect the morphological changes in microglia associated with the inflammatory phenotype. It is possible that the copper-induced increase in LPS-induced NO production is mediated by astrocytes.
Tumor necrosis factor-α (TNFα) is a key proinflammatory cytokine; its level increased in inflammatory diseases of the upper respiratory tract. In this study, the dose- and time-dependent effects of TNFα (1-100 ng/ml, 6-4...Tumor necrosis factor-α (TNFα) is a key proinflammatory cytokine; its level increased in inflammatory diseases of the upper respiratory tract. In this study, the dose- and time-dependent effects of TNFα (1-100 ng/ml, 6-48 h) on the RPMI 2650 cell line, a model of nasal epithelium, have been investigated. Short-term exposure (6 h) caused activation of NF-κB and an increase in the levels of the intercellular contact proteins E-cadherin and ZO-1, without a significant effect on cell viability. Long-term exposure (24-48 h) led to an increase in the level of pro-IL-1β, activation of apoptosis, and a decrease in cell viability. At the same time, a decrease in the level of intercellular contact proteins was noted. Thus, short-term exposure to TNFα can exert a protective effect by increasing the density of intercellular contacts, while during prolonged exposure it triggers apoptosis and reduces the density of intercellular contacts, which can contribute to increased permeability of the cell layer.
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, characterized by an extremely poor prognosis. Difficulties in diagnostics and monitoring this disease stimulate the search for minimally invasive...Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, characterized by an extremely poor prognosis. Difficulties in diagnostics and monitoring this disease stimulate the search for minimally invasive approaches. In this context liquid biopsy is considered as a promising approach. This review analyzes results of recent studies aimed at identifying circulating protein biomarkers of GBM in plasma and serum. These biomarkers include cell-free circulating plasma proteins and proteins of extracellular vesicles (EVs). Special attention is paid to the results obtained using both immunochemical methods and mass spectrometric approaches for identification of protein biomarkers, which have been summarized here as a list of identified potential diagnostic and prognostic biomarkers. Analysis of the literature demonstrates that proteomic analysis focused on the plasma EV fraction significantly expands the possibilities for identifying biomarkers for noninvasive GBM diagnostics and monitoring.
Epidemiological studies indicate a consistent global increase, including in the Russian Federation, in the number of patients with cognitive impairments associated with neurodegenerative diseases and various affective di...Epidemiological studies indicate a consistent global increase, including in the Russian Federation, in the number of patients with cognitive impairments associated with neurodegenerative diseases and various affective disorders. In this context there is a clear need in the development of more effective therapeutic approaches for their corrections. Good evidence exists that regular physical activity improves cognitive functions and alleviates depression. Working muscles secrete biologically active substances known as myokines, which regulate muscle recovery and functions of internal organs, endocrine glands, the immune system, and the brain. This results in a coordinated response of organs and systems aimed at restoring functional activity of the body after physical exercises and improves memory and learning ability. Patients with cognitive impairments or depression are often unable to engage in regular physical activity due to physical limitations or decreased motivation. Therefore, pharmaceuticals that mimic the effects of muscle activity are a promising therapeutic option. One potential direction in this field could be the development of drugs based on the myokine irisin, which is produced during physical exercise and exerts a range of beneficial effects on cognitive function and mood. This review summarizes existing data on the effects of physical exercise on cognitive function in health and disease; it describes the physiological effects of irisin, and presents the proposed mechanisms of irisin action on cognitive function and symptoms of depression.
Vitaphospholip®, a water-soluble form of phosphatidylcholine, has been evaluated in a clinical trial aimed at reducing non-HDL-cholesterol (non-HDL-C) and triglyceride (TG) levels in patients with combined hyperlipidemia...Vitaphospholip®, a water-soluble form of phosphatidylcholine, has been evaluated in a clinical trial aimed at reducing non-HDL-cholesterol (non-HDL-C) and triglyceride (TG) levels in patients with combined hyperlipidemia. The randomized, double-blind, placebo-controlled study included 100 patients. Vitaphospholip® or placebo was administered orally 500 mg twice a day for 12 weeks.Treatment with Vitaphospholip® resulted in a 13.2% decrease in non-HDL-C compared to 4.3% in the placebo group (p = 0.001). The absolute decrease of non-HDL-C was 0.6 mmol/l compared to -0.2 mmol/l in the placebo group (p = 0.001). The target non-HDL-C level of less than 3.4 mmol/L was achieved in 15 of 39 patients (38.5%) in the Vitaphospholip® group versus 2 of 41 patients (4.9%) in the placebo group (p = 0.000). The absolute decrease of TG in the group of patients treated with Vitaphospholip® was -0.7 mmol/l versus -0.1 mmol/L in the placebo group (p = 0.001). During therapy with Vitaphospholip®, a significant decrease in the levels of apolipoprotein B, total cholesterol, and very low-density lipoprotein cholesterol was observed. No changes in liver or kidney function, vital signs, or ECG were registered. No serious adverse events were identified. Thus, Vitaphospholip® significantly reduced the levels of non-HDL-C, TG, and atherogenic lipoprotein in patients with combined hyperlipidemia and moderate cardiovascular risk.