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

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.

The review presents an analysis of literary data on the role of microRNAs in the pathogenesis of type 2 diabetes mellitus and use in diagnostics as potential biomarkers and existing modern molecular genetic methods for the detection of microRNAs. The main functions of microRNAs in glucose metabolism are regulation of key enzymes of glucose catabolism, inhibition of activators/repressors of insulin transcription and genes that should not be expressed in β-cells, reduction of fusion and release of insulin granules, and influence on enzymatic reactions in peripheral tissues. The methods for determining microRNA expression levels were analyzed: Northern blotting, microarrays, NGS sequencing, RT-PCR, and ligation-mediated PCR. The results of the review will be useful for the development of microRNA-based diagnostic strategies for type 2 diabetes mellitus.

As a result of application of hydrogels with 0.05 and 0.005% HCRG21 calcipotriol-induced inflammatory swelling and flaking of the auricle were significantly reduced. As a result of application of hydrogels with 0.05 and 0.005% HCRG21 calcipotriol-induced inflammatory swelling and flaking of the auricle were significantly reduced. Treatment with HCRG21 normalized peripheral blood parameters in mice, including total white blood cell count and basophil percentage. In addition, treatment with gels containing HCRG21 resulted in a decrease in the level of proinflammatory cytokines: interleukin-23 (IL-23) and macrophage-derived chemokine (MDC) by 1.5 and 2 times, respectively, compared to the control group of animals. According to the results of histological analysis of the auricle of mice, treatment with peptide-containing gels enhanced the regeneration of the affected skin area, reducing hyperkeratosis, hyperplasia of the epidermis and dermis, and tissue hypervascularization. Thus, the discovered anti-inflammatory and regenerative effect of HCRG21 in the calcipotriol-induced allergic dermatitis model determines the potential of the peptide as a dermatotropic drug.

The unregulated and inappropriate use of antibiotics triggered the rapid spread of antimicrobial resistance in pathogenic microorganisms such as Pseudomonas aeruginosa. Antimicrobial peptides (AMPs) require investigations of their remarkable bioactivities and unique microbicidal mechanisms as potential replacement treatments for conventional antibiotics. Specifically, a naturally occurring antimicrobial dodecapeptide named Histatin 8 (HS8), from the Histatin family, has weak to moderate antimicrobial activities but is a promising bioactive molecule. In this study, three well-represented HS8-derived peptides with potential in silico bioactive propensities namely HS8-1 (Tyr12Phe), HS8-2 (Ser8Phe and Tyr12Phe), and HS8-3 (Gly11Phe) were explored. Results showed that HS8-1 was a significantly more active AMP than HS8-2 and HS8-3, displaying 3.0-fold and 3.56-fold decrease in minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values, respectively, against wild-type P. aeruginosa. Furthermore, HS8-1 and HS8-2 displayed the lowest MIC and MBC values against the antibiotic-resistant P. aeruginosa. Both HS8-2 and HS8-1 are the more active peptides showing inhibitory activities against wild-type and antibiotic-resistant P. aeruginosa biofilms in vitro, respectively. HS8-1 and HS8-2, at their MICs, can both primarily induce surface roughening and corrugation suggesting possible disruptive effects on the P. aeruginosa membrane reflecting antimicrobial action. HS8-1 lyses human red blood cells (RBCs) in vitro at concentrations 250 µg/mL and below, suggesting it to be the least hemolytic peptide compared to HS8-2 and HS8-3 which strongly lyse RBCs at relatively lower concentrations. Overall, the results imply that the HS8-derived peptide bioactivities can be enhanced by site-specific phenylalanine (Phe) substitutions against P. aeruginosa.

Atranorin is one of the main secondary metabolites of lichens of the group of depsides, which are of considerable interest due to their biological properties. Recently, its antioxidant and antiglycating properties, which may be important in the fight against the aging process and the development of age-related diseases, such as diabetes and neurodegenerative disorders, have attracted the active attention of researchers. The antioxidant action of atranorin is due to the neutralization of free radicals, which prevents oxidative damage to cells. Atranorin also exhibits antiglycation properties suppressing protein glycation, which can reduce the risk of complications in metabolic disorders.