Biomeditsinskaya khimiya最新文献

{"title":"Repositioning of drugs for the treatment of major depressive disorder based on prediction of drug-induced gene expression changes.","authors":"S M Ivanov, A A Lagunin, V V Poroikov","doi":"10.18097/PBMC20247006403","DOIUrl":"https://doi.org/10.18097/PBMC20247006403","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is one of the most common diseases affecting millions of people worldwide. The use of existing antidepressants in many cases does not allow achieving stable remission, probably due to insufficient understanding of pathological mechanisms. This indicates the need for the development of more effective drugs based on in-depth understanding of MDD's pathophysiology. Since the high costs and long duration of the development of new drugs, the drug repositions may be the promising alternative. In this study we have applied the recently developed DIGEP-Pred approach to identify drugs that induce changes in expression of genes associated with the etiopathogenesis of MDD, followed by identification of their potential MDD-related targets and molecular mechanisms of the antidepressive effects. The applied approach included the following steps. First, using structure-activity relationships (SARs) we predicted drug-induced gene expression changes for 3690 worldwide approved drugs. Disease enrichment analysis applied to the predicted genes allowed to identify drugs that significantly altered expression of known MDD-related genes. Second, potential drug targets, which are probable master regulators responsible for drug-induced gene expression changes, have been identified through the SAR-based prediction and network analysis. Only those drugs whose potential targets were clearly associated with MDD according to the published data, were selected for further analysis. Third, since potential new antidepressants must distribute into brain tissues, drugs with an oral route of administration were selected and their blood-brain barrier permeability was estimated using available experimental data and in silico predictions. As a result, we identified 19 drugs, which can be potentially repurposed for the MDD treatment. These drugs belong to various therapeutic categories, including adrenergic/dopaminergic agents, antiemetics, antihistamines, antitussives, and muscle relaxants. Many of these drugs have experimentally confirmed or predicted interactions with well-known MDD-related protein targets such as monoamine (serotonin, adrenaline, dopamine) and acetylcholine receptors and transporters as well as with less trivial targets including galanin receptor type 3 (GALR3), G-protein coupled estrogen receptor 1 (GPER1), tyrosine-protein kinase JAK3, serine/threonine-protein kinase ULK1. Importantly, that the most of 19 drugs act on two or more MDD-related targets, which may produce the stronger action on gene expression changes and achieve a potent therapeutic effect. Thus, the revealed 19 drugs may represent the promising candidates for the treatment of MDD.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 6","pages":"403-412"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of bitter honey against cerebral malaria-induced inflammasome cell death: network pharmacology-based in silico evaluation.","authors":"M O Daniyan, O B Adeoye, E Osirim, I D Asiyanbola","doi":"10.18097/PBMC20247006442","DOIUrl":"https://doi.org/10.18097/PBMC20247006442","url":null,"abstract":"<p><p>Cerebral malaria (CM) is a fatal complication of Plasmodium falciparum infection. The biological and physiological links between CM, inflammation, and inflammasome, point to the complexity of its pathology. Resistance to available and affordable drugs, worsening economic crisis, and urgent need for integration of orthodox with traditional/alternative medicine, actualized the search for sustainable pharmacotherapy. Previous works from our team on the medicinal properties of bitter honey have established botanical and bioactive markers, inhibitory effects on pancreatic alpha-amylase activity, and anti-dyslipidemia, cardio-protective, and ameliorative effects on hepatorenal damage in streptozotocin-induced diabetic rats. In this study, we have identified bitter honey (BH) derived phytochemicals using gas chromatography coupled with mass spectrometry (GC-MS), and 9 targets from genes associated with CM, inflammation, inflammasome, and BH phytochemicals. Network analysis revealed significant functional and physical interactions among these targets and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3). Molecular docking of bitter honey-derived phytochemicals against these targets identified 3 most promising phytochemical candidates for further experimental validation. Based on these results, we predict that bitter honey may aid in the suppression of CM-mediated inflammasome cell death via its interactions with these targets.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 6","pages":"442-455"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of mouse brain proteoforms: comparison of 2D-electrophoresis data and independent experiment with mass spectrometric identification.","authors":"A V Rybina","doi":"10.18097/PBMC20247006475","DOIUrl":"https://doi.org/10.18097/PBMC20247006475","url":null,"abstract":"<p><p>A previously developed algorithm for the preliminary identification of protein proteoforms associated with post-translational modifications (PTMs) based on 2D electrophoresis data (DOI: 10.18097/BMCRM00191) has been used in this study for analysis of experimental data obtained using mice and reported in two papers by different authors. The authors of the first paper identified 8 groups of spots on 2D electrophoretic maps corresponding to 8 proteins with at least two unconcretised proteoforms. The authors of the second paper analyzed brain samples by means of the LC-MS/MS. In this study identification of peptides with PTMs was repeated using the raw data from the second paper. Among the 8 target proteins, 7 were identified in most of the biological samples. For 4 of them, 17 possible peptides with modifications were found. The 5 proteoform variants with identified PTMs matched the spots on the 2D electrophoresis maps. Thus, the prediction of pI values for proteins with hypothetical PTMs allows to form a set of hypotheses about the presence of particular proteoforms on the 2D electrophoretic maps.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 6","pages":"475-480"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homology modeling of the orthoflavivirus NS1 protein for virtual screening of potential ligands.","authors":"A D Fomina, V A Palyulin, D I Osolodkin","doi":"10.18097/PBMC20247006456","DOIUrl":"https://doi.org/10.18097/PBMC20247006456","url":null,"abstract":"<p><p>The orthoflavivirus NS1 protein is a relatively understudied target for the design of broad-spectrum anti-orthoflaviviral drugs. Currently, the NS1 protein structures of tick-borne orthoflaviviruses have not been published yet, but these structures can be modelled by homology, thus generating a large amount of structural data. We performed homology modelling of the NS1 protein structures of epidemiologically significant orthoflaviviruses and analysed the possibility of using these models in ensemble docking-based virtual screening. The limitations of the method and the importance of separating the models based on the vector organism when selecting an ensemble have been demonstrated.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 6","pages":"456-468"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Registration of activity of a single molecule of horseradish peroxidase using a detector based on a solid-state nanopore.","authors":"Yu D Ivanov, A N Ableev, A V Vinogradova, E D Nevedrova, I D Shumov, V S Ziborov, A F Kozlov, I A Ivanova, N V Vaulin, D V Lebedev, A S Bukatin, I S Mukhin, E A Ponomarenko, A I Archakov","doi":"10.18097/PBMC20247005349","DOIUrl":"https://doi.org/10.18097/PBMC20247005349","url":null,"abstract":"<p><p>This work demonstrates the use of a solid-state nanopore detector to monitor the activity of a single molecule of a model enzyme, horseradish peroxidase (HRP). This detector includes a measuring cell, which is divided into cis- and trans- chambers by a silicon nitride chip (SiN structure) with a nanopore of 5 nm in diameter. To entrap a single HRP molecule into the nanopore, an electrode had been placed into the cis-chamber; HRP solution was added into this chamber after application of a negative voltage. The reaction of the HRP substrate, 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS), oxidation by the enzyme molecule was performed in the presence of hydrogen peroxide. During this reaction, the functioning of a single HRP molecule, entrapped in the nanopore, was monitored by recording the time dependence of the ion current flowing through the nanopore. The approach proposed in our work is applicable for further studies of functioning of various enzymes at the level of single molecules, and this is an important step in the development of single-molecule enzymology.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 5","pages":"349-355"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The human proteome size as a technological development function.","authors":"E V Sarygina, A S Kozlova, E A Ponomarenko, E V Ilgisonis","doi":"10.18097/PBMC20247005364","DOIUrl":"https://doi.org/10.18097/PBMC20247005364","url":null,"abstract":"<p><p>Changes in information on the number of human proteoforms, post-translational modification (PTM) events, alternative splicing (AS), single-amino acid polymorphisms (SAP) associated with protein-coding genes in the neXtProt database have been retrospectively analyzed. In 2016, our group proposed three mathematical models for predicting the number of different proteins (proteoforms) in the human proteome. Eight years later, we compared the original data of the information resources and their contribution to the prediction results, correlating the differences with new approaches to experimental and bioinformatic analysis of protein modifications. The aim of this work is to update information on the status of records in the databases of identified proteoforms since 2016, as well as to identify trends in changes in the quantities of these records. According to various information models, modern experimental methods may identify from 5 to 125 million different proteoforms: the proteins formed due to alternative splicing, the implementation of single nucleotide polymorphisms at the proteomic level, and post-translational modifications in various combinations. This result reflects an increase in the size of the human proteome by 20 or more times over the past 8 years.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 5","pages":"364-373"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of low-copy proteins in proteomic studies: issues and solutions.","authors":"A I Archakov, N E Vavilov, V G Zgoda","doi":"10.18097/PBMC20247005342","DOIUrl":"https://doi.org/10.18097/PBMC20247005342","url":null,"abstract":"<p><p>Detection of low-copy proteins in complex biological samples is one of the most important issues of modern proteomics. The main reason for inefficient detection of low protein concentrations is the insufficient sensitivity of mass spectrometric detectors and the high dynamic range of protein concentrations. In this study we have investigated the possibilities and limitations of a targeted mass spectrometric analysis using the reconstructed system of standard proteins UPS1 (Universal Proteomic Standard 1) as an example. The study has shown that the sensitivity of the method is affected by the concentration of target proteins of the UPS1 system, as well as by a high level of biological noise modelled by proteins of whole E. coli cell lysate. The limitations of the method have been overcome by concentrating and pre-fractionating the sample peptides in a reversed phase chromatographic system under alkaline elution conditions. Proteomic analysis of the biological sample (proteins of the human hepatocellular carcinoma cell line HepG2 encoded by genes of human chromosome 18) showed an increase in the sensitivity of the method as compared to the standard targeted mass spectrometric analysis. This culminated in registration of 94 proteins encoded by genes located on human chromosome18.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 5","pages":"342-348"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanowire-based biosensors for solving biomedical problems.","authors":"K V Goldaeva, T O Pleshakova, Yu D Ivanov","doi":"10.18097/PBMC20247005304","DOIUrl":"https://doi.org/10.18097/PBMC20247005304","url":null,"abstract":"<p><p>The review considers modern achievements and prospects of using nanowire biosensors, principles of their operation, methods of fabrication, and the influence of the Debye effect, which plays a key role in improving the biosensor characteristics. Special attention is paid to the practical application of such biosensors for the detection of a variety of biomolecules, demonstrating their capabilities and potential in the detection of a wide range of biomarkers of various diseases. Nanowire biosensors also show excellent results in such areas as early disease diagnostics, patient health monitoring, and personalized medicine due to their high sensitivity and specificity. Taking into consideration their high efficiency and diverse applications, nanowire-based biosensors demonstrate significant promise for commercialization and widespread application in medicine and related fields, making them an important area for future research and development.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 5","pages":"304-314"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biosensing platforms for DNA diagnostics based on CRISPR/Cas nucleases: towards the detection of nucleic acids at the level of single molecules in non-laboratory settings.","authors":"S A Khmeleva, K G Ptitsyn, L K Kurbatov, O S Timoshenko, E V Suprun, S P Radko, A V Lisitsa","doi":"10.18097/PBMC20247005287","DOIUrl":"https://doi.org/10.18097/PBMC20247005287","url":null,"abstract":"<p><p>The use of CRISPR/Cas nucleases for the development of DNA diagnostic systems in out-of-laboratory conditions (point-of-need testing, PONT) has demonstrated rapid growth in the last few years, starting with the appearance in 2017-2018 of the first diagnostic platforms known as DETECTR and SHERLOCK. The platforms are based on a combination of methods of nucleic acid isothermal amplification with selective CRISPR/Cas detection of target amplicons. This significantly improves the sensitivity and specificity of PONT, making them comparable with or even superior to the sensitivity and specificity of polymerase chain reaction, considered as the \"gold standard\" of DNA diagnostics. The review considers modern approaches to the coupling of CRISPR/Cas detection using Cas9, Cas12a, Cas12b, Cas13a, Cas14, and Cas3 nucleases to various methods of nucleic acid isothermal amplification, with an emphasis on works in which sensitivity at the level of single molecules (attomolar and subattomolar concentrations of the target) is achieved. The properties of CRISPR/Cas nucleases used for targeted DNA diagnostics and the features of methods of nucleic acid isothermal amplification are briefly considered in the context of the development of diagnostic biosensing platforms. Special attention is paid to the most promising directions for the development of DNA diagnostics using CRISPR/Cas nuclease.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 5","pages":"287-303"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico and in cellulo approaches for functional annotation of human protein splice variants.","authors":"O I Kiseleva, V A Arzumanian, I Yu Kurbatov, E V Poverennaya","doi":"10.18097/PBMC20247005315","DOIUrl":"https://doi.org/10.18097/PBMC20247005315","url":null,"abstract":"<p><p>The elegance of pre-mRNA splicing mechanisms continues to interest scientists even after over a half century, since the discovery of the fact that coding regions in genes are interrupted by non-coding sequences. The vast majority of human genes have several mRNA variants, coding structurally and functionally different protein isoforms in a tissue-specific manner and with a linkage to specific developmental stages of the organism. Alteration of splicing patterns shifts the balance of functionally distinct proteins in living systems, distorts normal molecular pathways, and may trigger the onset and progression of various pathologies. Over the past two decades, numerous studies have been conducted in various life sciences disciplines to deepen our understanding of splicing mechanisms and the extent of their impact on the functioning of living systems. This review aims to summarize experimental and computational approaches used to elucidate the functions of splice variants of a single gene based on our experience accumulated in the laboratory of interactomics of proteoforms at the Institute of Biomedical Chemistry (IBMC) and best global practices.</p>","PeriodicalId":8889,"journal":{"name":"Biomeditsinskaya khimiya","volume":"70 5","pages":"315-328"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}