Biomeditsinskaya khimiya最新文献

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.

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.

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.

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.

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.

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.

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.

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.

Fucoidan, an anionic polysaccharide from brown algae, demonstrates anticoagulant, antioxidant, anti-inflammatory, antitumor, and antiviral activities. It can form polyelectrolyte complexes with various proteins, including the therapeutically important protein lactoferrin. The aim of this study was to investigate the physicochemical and functional properties of a fucoidan-lactoferrin complex formed by mixing their solutions at physiological pH. The complex, detected using atomic force microscopy, had a negative charge and a hydrodynamic diameter of 382 nm. Interaction with lactoferrin changed the IR spectrum of fucoidan in the absorption band in the range of 1220-1260 cm-1, corresponding to vibrations of the sulfate group. It increased the total antioxidant activity of biopolymers in the Fenton reaction and reduced the anticoagulant activity of fucoidan, assessed by determining the activated partial thromboplastin time. Fucoidan reduced luciferase activity in a luciferin-luciferase model system, and complex formation with lactoferrin attenuated the inhibitory capacity of fucoidan. These results demonstrate the possibility of targeted influence on the functional activity of biopolymers during complex formation and prospects for using fucoidan and lactoferrin as a complex in the development of new drugs and drug delivery systems.

Comparative mass spectrometry analysis of hippocampal tissue samples from patients with sclerotic and non-sclerotic temporal lobe epilepsy and nonepileptic patients was undertaken to identify differences in the levels of protein post-translational modifications (PTMs). The original proteomic data obtained by Mathoux et al. [DOI: 10.1172/jci.insight.188612] and deposited in the PRIDE repository (PXD064519) were used in this work. Our reanalysis of the comparative proteomic data identified 53 proteins with PTMs (phosphorylation, methylation, acetylation, and citrullination) that exhibited significant changes in the levels of individual modified peptides. According to the published original data, all 53 proteins are involved in processes associated with neurological diseases in general and epileptogenesis in particular. The analysis identified PTMs of proteins that could play an important role in the pathogenesis of neurological diseases.