Acta Naturae

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.

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.

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.

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.

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.

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 high-dose 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.

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.