Acta Naturae最新文献

The widespread fungus Fusarium proliferatum can infect numerous plant species and produce a range of mycotoxins, the amount of which can vary significantly. Twelve F. proliferatum sensu lato strains isolated from six wheat, four oat, and two maize grain samples were analyzed. The strains were identified through a phylogenetic analysis of nucleotide sequences derived from gene fragments of the translation elongation factor EF-1α, β-tubulin, and RNA polymerase II second subunit. The mating types of the strain were determined by allele-specific PCR. Secondary toxic metabolite production by the strains was quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). All twelve Fusarium strains formed a distinct clade alongside the F. proliferatum reference strains, thereby confirming the taxonomic identification. Only one idiomorph at the MAT locus in each F. proliferatum strain was found, indicative of heterothallic mating. The frequency of the MAT1-1 idiomorph was double that of the MAT1-2 idiomorph. The active biosynthesis of fumonisins B1 (71-6175 mg/kg), B2 (12-2661 mg/kg), and B3 (6-588 mg/kg), significant beauvericin (64-455 mg/kg), and trace amounts of moniliformin (12-6565 μg/kg) were identified across all examined F. proliferatum strains.

Ferroptosis, iron-dependent regulated cell death, is induced by the polyunsaturated fatty acid peroxidation of membrane phospholipids and is controlled by glutathione peroxidase 4. In recent years, convincing evidence has emerged, demonstrating a close relationship between chemo-, radio-, immuno-, and targeted therapy resistance and ferroptosis resistance. In this review, we discuss the basic principles of ferroptosis in cancer. Considerable attention is paid to the formation of an immunosuppressive tumor microenvironment. The main focus is centered on the involvement of the excessive, chronic production of pro-inflammatory cytokines in ferroptosis resistance development in tumors.

Although the immunogenicity of clinically approved COVID-19 vaccines remains under intensive investigation, little is still known about the parameters of long-term immune responses. In this paper, we present for the first time the parameters of humoral immunity studied in the phase 1-2 open-label clinical trial of the Sputnik Light vaccine, with a special focus on late follow-up time points (90 and 180 days). For the most accurate assessment of the parameters of humoral post-vaccination immunity (titer and avidity index of antigen-specific antibodies against the RBD domain of SARS-CoV-2), we conducted an additional analysis that allowed us to triage volunteers with immunity formed only in response to vaccination, as well as those with hybrid immunity (infected with SARS-CoV-2 before and after vaccination). The findings indicate that single-shot vaccination with the Sputnik Light vaccine induces a durable (seroconversion 73% on day 180) and mature humoral immunity. Natural immunization as a result of the SARS-CoV-2 infection leads to significant changes in the studied parameters of post-vaccination immunity.

Immunoregulatory enzymes, which function both as biological catalysts and regulatory elements, play a crucial role in controlling immune responses. Dysfunction of these proteins can contribute to various pathological conditions, such as the suppression of antitumor immunity or impairment of anti-infectious immune responses. This review discusses the most extensively studied immunoregulatory enzymes, including indoleamine 2,3-dioxygenase 1, arginase 1, inducible nitric oxide synthase, glyceraldehyde-3-phosphate dehydrogenase, and ectonucleoside triphosphate diphosphohydrolase 1. Their classification is provided, along with an analysis of the distinctive characteristics inherent to this group of enzymes. Additionally, new directions for the medical application of immunoregulatory enzymes are explored.

Neutralizing antibodies are capable of specifically binding to the HBsAg virus, thereby preventing HBV infection and subsequently reducing viral antigen load in both the liver and systemic circulation. This has significant implications for restoring the postnatal immune function. By utilizing the phage antibody library technology, we successfully screened a fully humanized neutralizing antibody targeting the hepatitis B surface antigen. The antiviral activity was assessed in primary human hepatocytes (PHHs) by determining the EC₅₀ values for HBeAg and HBsAg biomarkers in HBV types B, C, and D; no cytotoxicity was observed within the tested concentration range. Furthermore, HT-102 exhibited no ADCC effect but displayed a weak CDC effect along with a dose-dependent response. We established an AAV/HBV mouse model and observed significant dose-dependent reduction in HBsAg and HBV DNA levels for both the medium-dose and highdose groups. The immunohistochemical staining data showed dose-dependent reduction in HBsAg expression in the liver, with high-dose group exhibiting minimal positive expression. Finally, a mild immune response was induced, while reducing the burden of antigen-antibody complexes circulating within the system. Consequently, strain on the patient's immune system was alleviated by effectively slowing down CD8⁺T lymphocyte depletion, and functional cure was ultimately achieved as intended.

Over the past decades, number of evidences has accumulated that demonstrates the importance of genomic introgression between relatively distant eukaryote species, including the introgression of teleost fish species; the three-spined stickleback (Gasterosteus aculeatus) and the nine-spined stickleback (Pungitius pungitius). The whole-genome datasets of both teleost species give reasons for suggesting that the marine population of nine-spined stickleback increases its adaptive potential to the marine environment through introgression with the anadromous three-spined stickleback. These findings demand a reinterpreting of the mechanisms of evolution towards a process in which organisms acquire new traits not only through longterm accumulation and selection of spontaneous mutations, but also via introgression from other species and ecological forms.

TLR2 and TLR4 play a key role in the development of an inflammation in response to a bacterial infection. We studied the effect of Rhodobacter capsulatus PG lipopolysaccharide (LPS) on proinflammatory cytokine synthesis activation by the TLR2 and TLR4 agonists E. coli LPS, Streptococcus pyogenes lipoteichoic acid (LTA), and Pam3CSK4 (a synthetic bacterial lipopeptide) in human whole blood cells. Rhodobacter capsulatus PG LPS was shown to exhibit antagonistic properties against the studied TLR4 and TLR2 agonists, blocking the synthesis of the cytokines TNF-α, IL-6, and IL-8. Possible mechanisms behind the suppressing effect of Rhodobacter capsulatus PG LPS are proposed. Rhodobacter capsulatus PG LPS can serve as a prototype for drugs against both gram-negative and gram-positive bacteria.

Mitogen-activated protein kinases, ERK1/2 (MAPK3/1), play a key role in the regulation of cell growth, differentiation, and apoptosis. We have previously presented evidence proving that activation of the ERK1/2 axis in cancer cells following the administration of therapeutics leads to the overexpression of growth factor receptors and drug resistance. Recently, we have proposed a new bioinformatic technique that enables direct construction of interactome network-based molecular pathways for gene products of interest, as well as quantitation of their activation levels using high-throughput gene expression data. In this study, we, for the first time, algorithmically constructed ERK1/2 molecular pathways and investigated how their activation levels (PALs) affect survival and responsiveness to targeted drugs at the pan-cancer level based on transcriptomic data. We examined a total of 11 287 human tumor profiles from 31 types of cancer, drawn from 53 of our previously published and other literature datasets, looking at patient survival and clinical response to 29 chemo- and targeted therapy regimens. We found that activation of the ERK1/2 pathways has different prognostic significance depending on cancer type. In glioblastoma, sarcoma, lung, kidney, bladder, gastric, colon, and several other cancer types, ERK pathway activation was associated with worse survival. In contrast, the same phenomenon was associated with a better chance of survival in HER2+, luminal A and luminal B breast cancer, and uterine corpus cancer. These trends were consistent with treatment response analysis. At the same time, we found significantly worse associations with the expression levels of individual MAPK1 and MAPK3 genes: hence, ERK1/2 pathway activation levels can be considered putative biomarkers for predicting clinical outcomes and selecting new personalized treatment strategies, such as the use of MAPK inhibitors.

Antibiotic resistance threatens global healthcare. In clinical practice, conventional antibiotics are becoming gradually less effective. Moreover, the introduction of new antimicrobial agents into clinical practice leads to the emergence of resistant pathogenic strains within just a few years. Hence, the development of platforms for massive creation and screening of new antimicrobial agents is of particular importance. Massive parallel screening will greatly reduce the time required to identify the most promising drug candidates. Meanwhile, DNA-encoded antimicrobial agents offer unique opportunities for the high-throughput development of new antibiotics. Here, the yeast Pichia pastoris was engineered to produce a panel of antimicrobial peptides (AMPs), followed by high-throughput screening of AMP producers that inhibit bacterial growth in situ. Yeast clones producing thanatin and protegrin-1 exhibited the highest level of antimicrobial activity among the panel of AMPs under investigation. The production level of recombinant thanatin was significantly higher than that of protegrin-1, which correlates with its low toxicity. The designed technique of massive assessment of the activity of DNA-encoded antimicrobial agents enables the identification of drug candidates with an increased therapeutic index. Further development of methods for a rational design of artificial diversity in AMPs, followed by deep functional profiling of antimicrobial activity, will yield new AMPs with improved therapeutic characteristics.

Despite the achievements brought about by high-throughput screening technologies, there is still a lack of effective platforms to be used to search for new antimicrobial drugs. The antimicrobial activity of compounds continues, for the most part, to be assessed mainly using in vitro pathogen cultures, a situation which does not make easy a detailed investigation of the molecular mechanisms underlying host-pathogen interactions. In vivo testing of promising compounds using chordate models is labor-intensive and expensive and, therefore, is used in preclinical studies of selected drug candidates but not in primary screening. This approach does not facilitate the selection of compounds with low organ toxicity and is not suitable for the identification of therapeutic compounds that affect virulence factors. The use of microscopic nematode C. elegans to model human infections is a promising approach that enables one to investigate the host-pathogen interaction and identify anti-infective compounds with new mechanisms of action.