Biomeditsinskaya khimiya最新文献

Chemotherapeutic agents containing targeted systems are a promising pathway to increase the effectiveness of glioblastoma treatment. Specific proteins characterized by increased expression on the surface of tumor cells are considered as possible targets. Integrin αvβ3 is one of such proteins on the cell surface. It effectively binds the cyclic Arg-Gly-Asp (cRGD) peptide. In this study, the cRGD peptide-modified doxorubicin (Dox) phospholipid composition was investigated. The particle size of this composition was 43.76±2.09 nm, the ζ-potential was 4.33±0.54 mV. Dox was almost completely incorporated into the nanoparticles (99.7±0.58%). The drug release increased in an acidic medium (at pH 5.0 of about 35±3.2%). The total accumulation and internalization of Dox used the composition of phospholipid nanoparticles with the targeted vector was 1.4-fold higher as compared to the free form. In the HeLa cell line (not expressing αvβ3 integrin) this effect was not observed. These results suggest the prospects of using the cyclic RGD peptide in the delivery of Dox to glioblastoma cells and the feasibility of further investigation of the mechanism of action of the entire composition as a whole.

Glioblastoma is a primary brain tumor and one of the most aggressive malignant neoplasms. The prognosis remains poor with a short survival period after diagnosis even in the case of timely detection and early treatment with the use of advanced chemotherapy, radiation therapy and surgical treatment. In this regard, the research of the main pathogenetic links in the glioblastoma development continues. The current focus is on studying the molecular characteristics of tumours, including the analysis of extracellular vesicles, which play an essential role in intercellular communication processes. In this review, in order to provide up-to-date information on the role of extracellular vesicles in the diagnosis and therapy of gliomas, the analysis of the achieved results of Russian and foreign research related to this area has been carried out. The main goal of this review is to describe the features of extracellular vesicles as the containers and glioma marker transporters, as well as nucleic acids used in diagnosis and therapy.

Functional disorders in obesity are largely due to a decrease in tissue sensitivity to insulin and leptin. One of the ways to restore it is inhibition of protein phosphotyrosine phosphatase 1B (PTP1B) and T-cell protein phosphotyrosine phosphatase (TCPTP), negative regulators of the insulin and leptin signaling. Despite progress in the development of inhibitors of these phosphatases, commercial preparations based on them have not been developed yet, and the mechanisms of action are poorly understood. The aim of the work was to study the effect of new derivatives of 4-oxo-1,4-dihydrocinnoline (PI04, PI06, PI07) on the activity of PTP1B and TCPTP, as well as to study the effect of their five-day administration (i.p., 10 mg/kg/day) to Wistar rats with diet-induced obesity on body weight and fat, metabolic and hormonal parameters, and gene expression of phosphatase and insulin and leptin receptors in the liver. It has been shown that PI04 is a mild, low selective inhibitor of both phosphatases (PTP1B, IC50=3.42(2.60-4.51) μM; TCPTP, IC50=4.16(3.49-4.95) μM), while PI06 and PI07 preferentially inhibit PTP1B (IC50=3.55 (2.63-4.78) μM) and TCPTP (IC50=1.45(1.18-1.78) μM), respectively. PI04 significantly reduced food intake, body weight and fat, attenuated hyperglycemia, normalized glucose tolerance, basal and glucose-stimulated levels of insulin and leptin, and insulin resistance index. Despite the anorexigenic effect, PI06 and PI07 were less effective, having little effect on glucose homeostasis and insulin sensitivity. PI04 significantly increased the expression of the PTP1B and TCPTP genes and decreased the expression of the insulin and leptin receptor genes. PI06 and PI07 had little effect on these indicators. Thus, PI04, the inhibitor of PTP1B and TCPTP phosphatases, restored metabolic and hormonal parameters in obese rats with greater efficiency than inhibitors of PTP1B (PI06) and TCPTP (PI07). This indicates the prospect of creating mixed PTP1B/TCPTP inhibitors for correction of metabolic disorders.

The review considers the main molecular biological features of the COVID-19 causative agent, the SARS-CoV-2 virus: life cycle, viral cell penetration strategies, interactions of viral proteins with human proteins, cytopathic effects. We also analyze pathological conditions that occur both during the course of the COVID-19 disease and after virus elimination. A brief review of the biological activities of polysaccharides isolated from various sources is given, and possible molecular biological mechanisms of these activities are considered. Data analysis shows that polysaccharides are a class of biological molecules with wide potential for use in the treatment of both acute conditions in COVID-19 and post-COVID syndrome.

The experimental results available in the ProteomeXchange database (accession code PXD016538) (Simats et al. (2020) Molecular and Cellular Proteomics, 19(12), 1921-1936) obtained using a comprehensive multi-omics approach were analyzed in mouse blood to identify potential biomarkers of ischemic stroke. Acetylation, methylation, and ubiquitination were considered as post-translational modifications. The analysis of the significance of changes in the level of protein modification was evaluated for ischemic tissue in comparison with tissue undamaged by stroke and control taken from mice after sham operation. At the level of statistically significant differences according to the Mann-Whitney test (p < 0.05), 2 proteins were found (Q02248 and Q8BL66); for additional 7 proteins, the differences were at the level of a statistical trend (p < 0.1). For 7 of 9 selected proteins there are reports in the literature, for their association with cerebral ischemia.

It was shown, that genotoxic stress can trigger endothelial disfunction and atherosclerosis, but the molecular genetic mechanisms of this process are poorly investigated. At the same time, inflammation also plays the important role in atherogenesis. This study aimed access of inflammatory marker expression in the endothelial cells exposed to alkylating mutagen mitomycin C (MMC). Primary human coronary (HCAEC) and internal thoracic artery endothelial cells (HITAEC) exposed to 500 ng/ml MMC (experimental group) and 0.9% NaCl (control) were used in this research. A gene expression profile was evaluated by quantitative reverse transcription PCR after 6 h exposure of endothelial cells to MMC (or 0.9% NaCl) followed by subsequent 24 h incubation in the mutagen-free cell growth media. The cytokine profile of endotheliocytes was studied by dot blotting. We found that MIF, IL-8, MCP-1, IP-10 and PDGFB were upregulated both in HCAEC and HITAEC, while MIP-1β release remained unchanged. TIMP-2 was upregulated in HCAEC but not in HITAEC. sTNF RI was expressed only in HCAEC. According to gene expression analysis, HCAEC exposed to MMC are characterized by the increased mRNA level of IL-8, MCP-1 and IP-10; decreased expression of TIMP-2 and no differences in the expression of MIF, MIP-1β and PDGFB compared to the control. In HITAEC, increased mRNA level of IL-8 and IP-10; decreased expression of MIF and TIMP-2, no differences in the expression of MCP-1, MIP-1β and PDGFB was shown. TNF-RI expression was not detected in both cell lines. Thus, genotoxic stress in endothelial cells induced by MMC leads to differential inflammatory response that can trigger endothelial dysfunction.

In recent years, the interrelationship between the brain and the gut has become an area of high scientific interest. The intestine is responsible not only for digestion, as it contains millions of neurons, its own immune system, and affects the emotional and cognitive processes. The relationship between the gut and the brain suggests that the processes carried out by the gut microbiota play a significant role in the regulation of brain function, and vice versa. A special role here is played by intercellular tight junctions (TJ), where the zonulin protein holds an important place. Zonulin, an unprocessed precursor of mature haptoglobin, is the only physiological modulator of intercellular TJ that can reversibly regulate the permeability of the intestinal (IB) and blood-brain (BBB) barriers in the human body. BBB disruption and altered microbiota composition are associated with many diseases, including neurological disorders and neuroinflammation. That is, there is a gut-brain axis (GBA) - a communication system through which the brain modulates the functions of the gastrointestinal tract (GIT) and vice versa. GBA is based on neuronal, endocrine, and immunological mechanisms that are interconnected at the organismal, organ, cellular, and molecular levels.

Regulation of gene expression is an extremely complex and multicomponent biological phenomenon. Proteins containing the CXXC-domain "zinc fingers" (CXXC-proteins) are master regulators of expression of many genes and have conserved functions of methylation of DNA bases and histone proteins. CXXC proteins function as a part of multiprotein complexes, which indicates the fundamental importance of studying post-translational regulation through modulation of the protein-protein interaction spectrum (PPI) in both normal and pathological conditions. In this paper we discuss general aspects of the involvement of CXXC proteins and their protein partners in neoplastic processes, both from the literature data and our own studies. Special attention is paid to recent data on the particular interactomics of the CFP1 protein encoded by the CXXC1 gene located on the human chromosome 18. CFP1 is devoid of enzymatic activity and implements epigenetic regulation of expression through binding to chromatin and a certain spectrum of PPIs.

Trace elements are important factors in human health. Zinc, an essential trace element, is necessary for normal functioning of many body systems where it plays an important role in metabolism. Obesity is accompanied by various metabolic pathologies provoking the development of dyslipidaemia, metabolic syndrome, type 2 diabetes mellitus, arterial hypertension, cardiovascular diseases and cancer. Many studies demonstrate changes in zinc homeostasis in obese men, but the data are conflicting, and a relationship between serum zinc and anthropometric and metabolic indicators remains controversial. In this study we have investigate the relationship between serum zinc level and body mass index (BMI), waist circumference (WC), and some metabolic parameters in Russian men. In 260 young men from the general population (n=268, median age 22 years), serum zinc, triglycerides (TG), total cholesterol (TC), high and low density lipoprotein cholesterol (HDL and LDL), glucose and uric acid levels were determined, as well as body weight, height, waist circumference (WC), and BMI were evaluated. According to BMI, men were divided into four groups: deficient and normal body weight, overweight, obesity. According to WC men were subdivided into two groups: normal and abdominal-visceral type of obesity. The median serum zinc concentration in men of the entire studied population was 20.3 μmol/l, and in men with obesity (BMI≥30) the median serum zinc concentration was higher than in the corresponding value in men with normal weight (30.9 and 20.8 μmol/l, respectively, p<0.01). Serum levels of TG, TC and LDL in obese men were also significantly higher (p<0.01) as compared to men with normal weight. In men with abdominal-visceral obesity, the median serum zinc concentration was significantly higher in comparison with control (26.3 and 19.9 μmol/l, respectively, p<0.01). It is suggested that elevated serum zinc level in obese young men can counter chronic inflammation and oxidative stress caused by increased body fat.

Aging of a living organism is closely related to systemic metabolic changes. But due to the multilevel and network nature of metabolic pathways, it is difficult to understand these connections. Today, this problem is solved using one of the main approaches of metabolomics - untargeted metabolome profiling. The purpose of this publication is to systematize the results of metabolomic studies based on such profiling, both in animal models and in humans.