Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry最新文献

Chemotherapy is one of the promising areas for the treatment of cancer. Platinum-based drugs are widely used in clinical practice. However, due to their high cost and a number of limitations related to their toxicity and resistance to a number of tumors, other effective drugs based on metals, in particular organotin compounds and their complexes with various ligands, are under study. The review provides data on the toxicity of Sn(IV) compounds, their effect on the human body and also analyzes the pharmacotherapeutic potential at various levels both in vitro and in vivo in animals of chemically modified organotin candidates for therapeutic agents over the past 10 years. Special attention is paid to the study of the antiproliferative activity of organotins with protective, antioxidant, and steroid fragments. Antitumor and antimetastatic activity has been detected for a number of Sn(IV) complexes in experiments on a number of tumor models in vivo. The analysis of the obtained results sets the vector of development in conducting preclinical studies of such compounds from the selection of candidates, the search for animal models with tumor processes, methods of introduction into the body, etc. The proposed approach can be used to achieve a rational activity to toxicity ratio and reduce side effects during the course use of organotin complexes as chemotherapeutic agents.

A comparative analysis of the quantitative composition of phospholipids and fatty acids of blood erythrocyte membranes and their dimensional characteristics and hemolytic resistance to hemolysis in indigenous and nonindigenous populations of the North of the Russian Federation was carried out. The data on ethnic peculiarities of metabolic reactions in representatives of two ethnic groups (the indigenous population of Mongoloids and the nonindigenous population of Caucasians) were obtained. A notable alteration in the ratio of phospholipid fractions within the erythrocyte membrane was observed in the indigenous Chukchi population. This involved a decline in phosphatidylcholine and its replacement by sphingomyelin and an increase in the values of phosphatidylethanolamine and metabolically active fractions, including phosphatidylserine, phosphatidylinositol, and phosphatidic acid. These findings contrast with those observed in the newly arrived population. Additionally, notable discrepancies were observed in the fatty acid profiles of erythrocyte membrane lipids. The predominant presence of n-3 polyunsaturated fatty acids in the overall lipid composition and in the primary structural phospholipids, namely phosphatidylcholine (PC) and phosphatidylethanolamine (PE), substantiates the ethnic distinctions observed in both indigenous and immigrant populations. These differences in the composition of polyunsaturated fatty acids in the structures of PC and PE indicate the emergence of modified molecular species of these fractions in the indigenous population. The aforementioned ethnic peculiarities in the phospholipid component of erythrocyte membranes result in differences in the dimensional characteristics of erythrocytes and an increase in the resistance of cells to hemolysis in individuals of the indigenous population. In the authors’ opinion, this is not evidence of any deviation from the norm but is more likely to be associated with one of the variants of human metabolism.

The expression of selenoproteins, which in turn depends on the provision of tissues with exogenous selenium supplied with food, is important in the functioning of the antioxidant system. There is data on an increase in the intensity of free radical processes with a deficiency of selenium in the organism. The aim of this study is to establish the effect of sodium selenite on lipid peroxidation processes and concentration of sex hormones during intensive physical exercise. The study was carried out on 60 male rats that were divided into four groups (n = 15). The first group included the control animals. The second and third groups were experimental (animals of these groups swam with the same load (10% of the body weight) but differed in the intensity of training). Animals of the fourth group swam with the load of 10% and received sodium selenite (Na₂SeO₃) at a dose of 30 μg/day/kg of body weight. After completing the experiment, the blood was taken from animals to study biochemical indices (total testosterone, free testosterone, thyroxine, triiodothyronine, malondialdehyde, glutathione, activity of glutathione peroxidase and glutathione reductase). During the experiment, it was established that intensive physical exercise causes a decrease in concentration of the studied hormones in the blood serum and contribute to the intensification of free radical oxidation and processes of lipid peroxidation, which is evidenced by an increase in the content of malonic dialdehyde in erythrocytes and a change in the parameters of the glutathione antioxidant system. The administration of sodium selenite at a dose of 30 μg/day/kg of body weight contributes to the restoration of the level of sex steroids, without affecting the level of thyroid hormones and contributes to a decrease in the level of malonic dialdehyde and an increase in the concentration of glutathione as compared with the third group. The activity of glutathione-dependent enzymes under the effect of sodium selenite also increases. Thus, high intensity physical exercise contributes to an increase in the content of lipid peroxidation products in the blood, inhibition of antioxidant function, and a decrease in the level of thyroid and sex hormones. The administration of sodium selenite contributes to a decrease in free radical processes and an increase in the concentration of sex hormones but has no effect on the content of thyroid hormones as compared with the group of rats experiencing intensive physical exercise.

Neuroinflammation plays the key role in progression of Parkinson’s disease (PD), the neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons of the substantia nigra, which results in the motor impairment. The major pathogenetic mechanisms of PD are metabolic dysfunctions, mitochondrial impairments and inflammatory response determined by the activation of microglia. Understanding the molecular pathways underlying these processes is an important stage in the development of target therapeutic strategies. Recent studies have emphasized the significance of lactate metabolism and the related signaling pathways in modulation of both neuroinflammation and energy homeostasis. GPR81, also known as HCAR1, is a lactate receptor involved in the regulation of metabolism and inflammatory processes. In spite of the well-studied role of this receptor in peripheral tissues, its involvement in the pathogenesis of neurodegenerative diseases such as PD yet remains insufficiently studied. In the present study, the expression of GPR81 in the substantia nigra of the rat brain is studied under the conditions of LPS-induced PD model with the accent on its potential role in the regulation of inflammatory and metabolic processes. The analysis of dynamic changes in the expression of GPR81 will reveal its contribution to neuroprotection and metabolic plasticity of the brain, opening up new prospects for slowing down neurodegeneration in PD.

The 2019–2022 coronavirus pandemic has brought vaccination to the forefront in recent years. As a result, various approaches to vaccine development and their efficacy and safety assessment have emerged. Methods for assessing recombinant vector vaccines using the specific safety criteria (SSC) have been developed in accordance with the FDA requirements. This resulted in the discovery of a link between the ratio of viral particles to cell suspension density and the characteristics of plaques (shape, size, absence of confluent plaques). A vaccine sample was added to a suspension of trypsinized adherent cells. The optimal density for this analysis is 0.6 million/mL for a T-175 culture flask. The study found that Neutral Red was the best dye for intravital cell staining. It enabled the differentiation of dead cells from living cells via cytoplasmic inclusions. The study produced a method with a lower limit of quantification (LLOQ) of 3 PFU/dose that satisfies international regulatory requirements, including those of the Food and Drug Administration (FDA).

Multiple myeloma (MM) is a malignant lymphoproliferative disorder associated with accumulation of terminally differentiated B lymphocytes (plasma cells) in the bone marrow, monoclonal expression of pathologic immunoglobulin, anemia, renal damage, hypercalcemia, and bone lesions. Despite considerable attention to the study of ММ pathogenesis and the development of new drugs, this disease remains incurable. Omics technologies are contributing significantly to the understanding of the molecular mechanisms of plasma cell neoplastic transformation in MM and may lead to the identification of novel therapeutic targets. In this work, the authors performed comparative gene expression analysis in CD138+ cell samples obtained from bone marrow aspirates of 46 MM patients and seven healthy donors using high-throughput RNA sequencing technology. Differential expression analysis identified 1230 genes with statistically significant expression changes in MM patient samples compared to donor samples. Functional analysis of the transcriptome revealed that pathogenetic changes in MM were associated with groups related to growth factors and intracellular signaling (DKK1, BMP4, HGF, TGFB2, FGF), extracellular matrix modification and regulation of cell adhesion (VCAM1, MMP16, LAMP5), ion channel activity (GRIA3, CLCNKA, GABRB2), regulation of immune functions, chromatin organization, cytoskeleton, and Ca²⁺ signaling. A significant proportion of genes from the ion channel category were associated with the regulation of neuronal transmission. The last category is poorly characterized, which could provide a new direction for MM therapy. The presented functional analysis of differentially expressed genes helps to elucidate the molecular mechanisms of MM, which will contribute to the development of new treatment approaches.

The issues of potential applicability of synthetic framework aluminosilicates (zeolites) as components of medical materials are considered. The physicochemical characteristics, moisture capacity and sorption capacity in relation to model toxins of protein nature of synthetic zeolites of several structural types (Beta, Rho, Y, and paulingite) differing in their chemical composition, porosity, and methods of production were studied. The hemolytic activity and cytotoxicity in relation to human Ea.hy926 line endothelial cells were studied. It was established that synthetic zeolites have a high moisture capacity and selective sorption capacity in relation to model protein preparations in the medium of a synthetic biological fluid. Zeolites exhibit the largest sorption capacity in relation to low molecular weight proteins that are a basis of intoxication of the organism during wound, burn, and other lesions. A toxicity of zeolites is determined by their chemical composition and the conditions for their production. Among the studied zeolites, the zeolite Y can be recommended for the use as a component of wound coverings and other medical materials as a nontoxic, highly efficient selective sorbent.

The results of the study on isolation, purification, and study of the cytotoxicity of α-alectoronic and α-collatolic acids isolated from lichens are presented in the article. The methods of extraction and purification allowing to obtain these acids with a high yield and degree of purity are described. The conducted experiments on studying cytotoxicity revealed that both acids have significant activity in relation to the cell lines HeLa, A549. Data obtained demonstrate a potential of alectoronic and collatolic acids as new antitumor agents.

Therapeutic peptides are an interesting class of pharmaceutical compounds that are structurally intermediate between small molecules and proteins but biochemically and therapeutically distinct from both. Currently, peptide-based drugs are used to treat immunological diseases, infections, and endocrinological and oncological diseases. The expression of therapeutic peptides in bacterial systems, for example, in E. coli, has a large number of advantages, such as high specific productivity, low production costs, great optimization potential, and good knowledge of the process. However, the creation of bacterial producer strains expressing therapeutic peptides with a molecular weight of less than 5 kDa is an extremely complex and time-consuming task due to the rapid degradation of the product by cell proteolytic enzymes or the high cytotoxicity of the target product. To solve such problems, the peptide is expressed in the form of tandem repeats or as a hybrid protein fused with another large protein, for example, SUMO. In this work, four peptide antigens differing in physicochemical properties were purified. The peptides were synthesized in soluble form as precursor proteins consisting of an N-terminal polyhistidine tag (His 6 tag), a SUMO fragment, and the amino acid sequence of the peptide. Hybrids were isolated from bacterial cells by disintegrating biomass under high pressure. The proteins were then purified by metal affinity chromatography using Ni-NTA agarose and enzymatically hydrolyzed with a highly specific SUMO protease. The resulting peptides were purified using metal affinity chromatography and final high-performance reverse phase chromatography on an SP-100-C8-PK sorbent. Next, the peptides were freeze-dried. As a result of work using the general technology, four peptides with different physicochemical properties were obtained. The purity by RP-HPLC was greater than 95%, and the mass of all peptides and fusion proteins was confirmed by HPLC-MS. The authenticity of the peptides was additionally confirmed by the ELISA method.

Malignant tumors represent a serious problem for humanity due to their widespread distribution and severe posttherapeutic consequences. The formation of metastases is the main criterion for tumor malignancy. A search for new compounds with antimetastatic activity remains an urgent problem. In this work, the antitumor activity of a cytolytic toxin Hct-S3 оf the sea anemone Heteractis magnifica was studied in an in vivo model of solid Ehrlich adenocarcinoma. It was established that intraperitoneal administration of Hct-S3 at doses of 0.01 and 0.02 mg/kg has hardly any effect on the tumor growth rate but prevents its metastasis from the primary tumor localization to other tissues. A significant decrease in the proliferative capacity of tumor cells was observed in the groups of mice treated with 0.01 and 0.02 mg/kg Hct-S3: the area of the tumor fluorescence zone decreased by 40 and 48%, and the index of integrated fluorescence density increased by 134 and 146%, respectively, as compared with animals without therapy. The obtained results confirm a high antiproliferative and antimetastatic potential of Hct-S3, which allows it to be considered as a promising compound for creating antitumor drugs.