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.

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.

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.

Most clinical studies confirm the negative impact diabetes mellitus (DM) has on the course and outcome of cardiovascular complications caused by a myocardial ischemia-reperfusion injury (IRI). In this regard, the search for new approaches to IRI treatment in diabetic myocardium is of undeniable value. The aim of this work was to study the effect of galanin (G) on the size of myocardial infarct (MI), on mitochondrial functions, and on the energy state in the area at risk (AAR) in rats with type 1 diabetes mellitus (DM1) subjected to regional myocardial ischemia and reperfusion. Rat G was obtained by solid-phase synthesis using the Fmoc strategy and purified by HPLC. DM1 was induced by streptozotocin administration. Myocardial IRI was modeled by occlusion of the left anterior descending coronary artery and subsequent reperfusion. G at a dose of 1 mg/kg was administered intravenously before reperfusion. G decreased MI size and plasma creatine kinase MB (CK-MB) activity in DM rats by 40 and 28%, respectively. G injection improved mitochondrial respiration in saponin-skinned fibers in the AAR: namely, the maximal ADP-stimulated state 3, respiratory control, and the functional relationship between the mitochondrial CK-MB and oxidative phosphorylation. G provided significantly higher ATP levels, total adenine nucleotide pool, and adenylate energy charge of cardiomyocytes. It also reduced total creatine loss in myocardial AAR in DM rats. The results suggest there is a possibility of therapeutic use of G in myocardial IRI complicated by DM1.

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.

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.

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.

Skin cancers such as squamous cell carcinoma (SCC) are among the most aggressive types of tumors. They come with a high rate of growth, metastasis, and frequently occurring chemoresistance. Smoking is one of the risk factors for SCC progression, and the α7 nicotinic acetylcholine receptor (α7-nAChR) is a promising target for SCC therapy. Human secreted protein SLURP-1 is an auto/paracrine regulator of epithelial homeostasis and a selective negative allosteric modulator of α7-nAChR. Recently, we demonstrated the high efficiency of the therapy based on the recombinant SLURP-1 in controlling SCC cell growth and metastasis in vivo. The anti-tumor effect of SLURP-1 was mediated through interaction with both α7-nAChR and the epidermal growth factor receptor (EGFR). Cytotoxic antibiotic doxorubicin has been proposed for the SCC therapy; however, its use is limited due to the high toxicity. In this study we investigated the use of an enhanced SLURP-1 dose and of a combination of SLURP-1 with low-dozen doxorubicin for SCC treatment of mice xenografted with squamous cell carcinoma A431 cells. An increased SLURP-1 dose didn't significantly enhance the efficiency of the therapy. However, the combination with doxorubicin further enhanced the anti- tumor activity of SLURP-1 and dramatically suppressed metastasis. The effect from the combined therapy was accompanied by down-regulation of EGFR expression in tumors. Direct inhibition of EGFR activation by SLURP-1 was shown. No toxicity of the combined therapy was encountered. Our data indicate that the combination of SLURP-1 with chemotherapy in lower doses is a promising approach in SCC treatment and should be further studied.

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.

Proprotein convertases (PCs) constitute an enzyme family that includes nine highly specific human subtilisin-like serine proteases. It is known that the PCs mRNA levels vary in tumors, and that these proteases are involved in carcinogenesis. Thus, PCs may be considered as potential markers for typing and predicting the course of the disease, as well as potential targets for therapy. We used quantitative real-time PCR to evaluate the expression levels of PC genes in the paired samples of tumor and adjacent normal tissues derived from 19 patients with esophageal squamous cell carcinomas. We observed a significant enrichment of PCSK6, PCSK9, MBTPS1, and FURIN mRNAs in the tumor tissue, which may be indication of the involvement of these PCs in the development and progression of esophageal cancers. Additionally, cluster analysis of PC expression alteration patterns in tumor compared to normal adjacent tissues (esophageal and previously analyzed lung tissue samples) revealed a limited set of scenarios for the changes in PC expression. These scenarios are implemented during malignant transformation of lung and esophagus cells, as well as, probably, the cells of other organs. These findings indicate that PC genes may be important markers of human cancers.