Biomeditsinskaya khimiya最新文献

The review summarizes existing knowledge on the relationship between certain diseases and alteration (degeneration) of the intestinal microbiome. We consider major microbial metabolites firmly recognized as signaling molecules acting in communication between the microbiome and the host organism. These include short-chain fatty acids, bile acids, amines, amino acids, and their metabolites. Special attention is paid to metabolomic studies of the microbiome in chronic kidney diseases, in particular, immunoglobulin A nephropathy. The arguments supporting a concept of the microbiome of blood, previously considered an exclusively sterile environment in healthy humans, are considered. Metagenomic methods plays a key role in characterization of both the composition and potential physiological effects of microbial communities. The advantages and limitations of metabolomic analysis of blood serum/plasma and feces have been analyzed. Since the potential of clinical studies of the mutual impact of the microbiome-metabolome is limited by genetic and external factors, preclinical studies still employ both germ-free models and models based on the effects of antibiotics. The review considers the problems and prospects of metabolomics in studying the nature and mechanisms of the mutual impact of the microbiome and metabolome.

Gut microbiota is one of the key suppliers of tryptophan metabolites, which perform various functions in the host organism, including their role as signaling molecules. Fecal microbiota transplantation (FMT) is widely used as a method for determining the contribution of microorganisms to the content of various metabolites in the holoorganism. In this regard, the aim of our study was to investigate the effect of FMT on the level of tryptophan metabolites in feces and blood in gnotobiotic mice. It was found that both before and after FMT, indole-3-lactate, and quinolinic acid were the dominant tryptophan metabolites in the intestine. FMT increased the content of both indoles (indole-3-acetate, indole-3-acrylate, indole-3-butyrate, indole-3-lactate) and kynurenines (anthranilic and xanthurenic acids) in the intestine. In serum of mice after FMT, indole metabolites (indole-3-butyrate, indole-3-carboxaldehyde, indole-3-lactate, indole-3-propionate) predominantly increased; however, tryptamine and xanthurenic acid also demonstrated a clear increase. The use of FMT demonstrates that the intestinal microbiota is a source of not only indole derivatives of tryptophan, but also metabolites of the kynurenine pathway.

Fabomotizole is an original anxiolytic agent developed at the Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies that acts on a number of important receptor systems of the brain. In a model of Parkinson's disease induced in rats by a course of rotenone administration, fabomotizole attenuated manifestations of behavioral impairments and influenced the profile and relative content of brain proteins. Five days after the last administration of rotenone, the fabomotizole effect on the behavioral reactions of rats persisted. According to the proteomic study, the profile of brain proteins and changes in their relative content differed significantly from the results obtained immediately after the last administration of rotenone, as well as rotenone in combination with fabomotizole. Changes in the relative content of almost all proteins detected immediately after the last administration of rotenone or rotenone with fabomotizole were not detectable five days later. However, at this time point, there were changes in the relative content of other proteins associated with neurodegeneration in Parkinson's and Alzheimer's diseases. Such dynamics suggests a wave-like change in the content of pathogenetically important brain proteins involved in the mechanisms of neurodegeneration and neuroprotection.

Currently, various potential tumor markers have been proposed for clinical practice. Although some of them are successfully used in diagnostics, and treatment, none of them fully meets the needs of oncology. Therefore, the search for new markers continues. In this context much attention is paid to multiomics technologies such as genomics, transcriptomics, and metabolomics. However, since tumor biomarkers are mainly proteins, proteomics plays a central role in the search of tumor markers. Blood is the most popular source of information about a patient's health and therefore the search is focused on plasma/serum proteins In order to increase the sensitivity and specificity of the analysis, a very promising approach is to assess the levels of certain sets of relevant proteins rather than individual proteins and this review is devoted to analysis of this problem.

The brain's nucleus accumbens (NAc) is a key link in the internal reinforcement system, which mediates manifestations of various components of addiction, including ethanol. The neuroinflammatory theory of alcoholism development suggests that changes in the molecular mechanisms of the innate immune system may be involved in the development of this pathology. The aim of our study was to investigate the effect of azithromycin (AZM) on expression of toll-like receptor system genes in the NAc during experimental alcoholization of rats. The objectives of the study also included an in silico search for possible molecular targets for AZM that could be associated with the toll-like receptor system. AZM corrected the changes observed in the expression of toll-like receptor system genes under conditions of alcohol withdrawal after long-term ethanol exposure in the NAc of the brain. The in silico analysis revealed the most probable proteins which could be involved in the interaction with AZM. Based on results of these predictions a number of assumptions about possible ways of implementing the observed pharmacological effect of AZM in the experiment have been made.

Currently, the search for new slow-binding inhibitors of enzymes (SBI) and their identification primary in vitro studies still attracts much attention in the context of their potential role as putative pharmacological agents for the treatment of various diseases. In contrast to their classical reversible analogues, SBI exhibit a slow enzyme binding kinetics, where the equilibrium steady-state is reached not in microseconds, but after longer time intervals. Such compounds could be promising drugs, because regardless of their pharmacokinetics in the bloodstream, they have such advantages as high affinity for the target enzyme, long residence time on the target, and therefore, prolonged action. These pharmacological properties ensure optimized dosage of drugs required to achieve high activity with less side effects. In this review we have considered mechanisms of SBI interaction with enzyme targets, the principles of their recognition at the level of in vitro studies and analysis of binding and kinetic parameters.

N6-methyladenosine (m6A) is a common RNA modification, which plays a critical role in RNA fate and regulating such aspects as splicing, stability, nuclear export, and translation efficiency. The introduction, removal, and recognition of m6A modifications in RNA are regulated by a number of factors, known as writer, eraser, and reader proteins. It is known that the m6A modification can play an important role in the life cycle of viruses, including hepatitis B virus. The m6A methylation system has a significant impact on the hepatitis B viral cycle (HBV), particularly, on stability of mRNA transcripts, encapsidation efficiency, and reverse transcription of HBV pgRNA. In this study, we assessed the effect of knockout and activation of expression of several factors of the m6A methylation system on the HBV viral cycle, including pregenomic RNA (pgRNA) and circular covalently closed DNA (cccDNA). The study was carried out using the StCas9 nuclease system for knockout and the dCas9-p300 system for activation of gene expression. The levels of pgRNA and cccDNA were estimated by real-time PCR. The data obtained show the restriction of the viral cycle at the basal level by the factors METTL3, METTL14, METTL16, FTO, JMJD6, and hnRNPA2B1, as well as suppression of the viral cycle with overexpression of all of the above factors, except for hnRNPA2B1.

A comparative analysis of HaCaT keratinocyte proteins has been performed after cell exposure to subtoxic doses (5 J/cm² and 25 J/cm²) of ultraviolet A (UVA) radiation. 930 proteins were identified by two or more unique peptides. More than half of all identified proteins (54.5%) demonstrated at least 2-fold increase in their relative content after HaCaT keratinocyte irradiation with a cumulative dose of 5 J/cm², while a decrease in the relative content was found only for 4 proteins. Irradiation of keratinocytes with a cumulative dose of 25 J/cm² resulted in a decrease in the proportion of up-regulated proteins (43.0%) and an increase in the number of down-regulated proteins (84). Among the proteins with increased relative content in HaCaT keratinocytes the most proteins were associated with "cell motility" (GO: 0048870), as well as regulation of cell shape and size, cell morphogenesis, and skin remodeling.

Ischemia-reperfusion injury (IRI) is a complex process accompanying cessation of blood supply to an organ or tissue followed by subsequent restoration of blood circulation. The IRI is especially prominent in surgery and organ transplantation. One of the strategies for reducing organ and tissue damage during transplantation is regulation of intracellular ion concentrations. Maintenance of ion concentrations in the cell during damage development can be controlled by influencing voltage-dependent ion channels with certain types of compounds. We propose the peptide toxins tropic to calcium (omega-hexatoxin-Hv1a) and sodium (mu-agatoxin-Aa1a) voltage-dependent ion channels as potential agents reducing IRI. The toxins were obtained using solid-phase peptide synthesis. The IRI modeling for evaluation of the action of toxins was carried out on a culture of epithelial cells CHO-K1 during their incubation under conditions of hypoxia and nutrient deprivation followed by subsequent replenishment of the nutrient medium. The level of cell death, concentrations of calcium, sodium, potassium ions, and pH were recorded using a multimodal plate reader and fluorescent dyes. Experiments have shown that regardless of different mechanisms of action, both toxins reduced the development of CHO-K1 cell death by changing ion concentrations and maintaining the pH level.

Renalase (RNLS) is a protein involved in the regulation of blood pressure; it has various functions inside and outside cells. The twenty-membered peptide RP220, corresponding to the amino acid sequence of human RNLS 220-239, reproduces a number of effects of extracellular RNLS and can bind to many intracellular proteins in the kidney. The RP220 sequence contains several cleavage sites for extracellular proteases, which could potentially produce RP224-232 and RP233-239 peptides. The aim of this work was to perform proteomic profiling of kidney tissue from normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) derived from WKY, using potential proteolytic fragments (RP224-232 and RP233-239) of the RP220 peptide as affinity ligands, and to compare these proteomic profiles with the profiles obtained using the parent RP220 peptide. The obtained results indicate that the relative content of proteins bound to the RNLS peptides in SHR, compared to that in WKY rats, changes most significantly in the case of the RP224-232 peptide. Almost all of these proteins, with a few exceptions, are associated with cardiovascular pathology, many with hypertension. The results of our work indicate that proteolytic processing of RP220 does not lead to the inactivation of this peptide, but to a change in its ligand/regulatory properties, as well as the repertoire of potential protein partners and, consequently, protein-protein interactions that may have possible pharmacological application.