Significant advancements have been achieved over recent decades in deciphering the molecular mechanisms driving malignant tumor development. Despite this progress, the precise roles of individual genes, their interactions, and the associated signaling pathways involved in tumor proliferation remain insufficiently characterized. Among these pathways, the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK)1/2 and p38, which regulate essential cellular functions such as growth, differentiation, and apoptosis, have garnered considerable research attention. Building on recent insights into MAPK signaling, we identified components closely linked to ERK1/2 and p38 activity and examined changes in their behavior during tumorigenesis. Furthermore, we developed quantifiable metrics to assess ERK1/2 and p38 activity, including the ERK/p38 ratio, a key indicator of tumor cell proliferative or quiescent states, along with activation levels of these signaling pathways. Our findings underscore the potential of ERK and p38-related gene expression and pathway dynamics as biomarkers for predicting clinical outcomes and informing tailored therapeutic approaches.

The evolution of protein-coding genes has both structural and regulatory components. The first can be assessed by measuring the ratio of non-synonymous to synonymous nucleotide substitutions. The second component can be measured as the normalized proportion of transposable elements that are used as regulatory elements. For the first time, we characterized in parallel the regulatory and structural evolutionary profiles for 10,890 human genes and 2972 molecular pathways. We observed a ~0.1 correlation between the structural and regulatory metrics at the gene level, which appeared much higher (~0.4) at the pathway level. We deposited the data in the publicly available database RetroSpect. We also analyzed the evolutionary dynamics of six cancer pathways of two major axes: Notch/WNT/Hedgehog and AKT/mTOR/EGFR. The Hedgehog pathway had both components slower, whereas the Akt pathway had clearly accelerated structural evolution. In particular, the major hub nodes Akt and beta-catenin showed both components strongly decreased, whereas two major regulators of Akt TCL1 and CTMP had outstandingly high evolutionary rates. We also noticed structural conservation of serine/threonine kinases and the genes related to guanosine metabolism in cancer signaling: GPCRs, G proteins, and small regulatory GTPases (Src, Rac, Ras); however, this was compensated by the accelerated regulatory evolution.

Background: pathogen heterogeneity and complexity are the main obstacles for schizophrenia and autism spectrum disorders (ASD) differential diagnosis in children. The role of oxidative stress in the molecular mechanisms of schizophrenia and autism pathogenesis is beyond doubt. Free radicals that accumulate during stress can cause oxidative modifications and the formation of breaks in the сell-free DNA (cfDNA) and nuclear DNA of blood cells. To date, it has been proven that 8-hydroxy-2’- deoxyguanosine (8-OHdG) can be considered as an oxidative stress biomarker. However, it is still unclear how pronounced the genotoxic consequences of oxidative stress are in ASD of varying severity and in childhood onset schizophrenia (COS). Objective: to study the relationship between the oxidative DNA damage level in peripheral blood cells and the circulating cell-free DNA characteristics with the severity of COS and the course of ASD in children. Patients and methods: blood samples of 96 patients with childhood autism (CA — F84.0 according to ICD-10), atypical autism (AA — F84.1 according to ICD-10) and with childhood onset schizophrenia (COS — F20.8 according to ICD-10) were obtained from the Child Psychiatry Department of the Mental health research center. Blood samples of the control group (34 people) — from the collection of samples of the Research Centre for medical Genetics. The selection of patients was carried out using the clinical and psychopathological method. Cell-free DNA was isolated by extraction with organic solvents. The concentration of cfDNA was determined fluorimetrically. The level of 8-OHdG in cell-free DNA was determined by binding of the corresponding antibodies on membrane filters, endonuclease activity was determined by radial diffusion in a gel. G0-peripheral blood lymphocytes were isolated by gradient centrifugation. The level of 8-OHdG and the level of the phosphorylated form of histone H2AX (yH2AX) in G0-peripheral blood lymphocytes were analyzed in fixed cells by flow cytofluorometry using appropriate antibodies. Statistical processing was carried out using Microsoft Office Excel, Statistica 6.0, StatGraph. Results and conclusions: oxidative stress has different severity in ASD, occurring in severe form (AA) and mild/moderate form (CA). In CA, the level of oxidative damage to the DNA of lymphocytes tends to increase, but does not reach statistically significant level; the level of oxidative damage to cfDNA does not differ from the control. In AA and, to an even stronger extent, in COS, the level of oxidative damage to the DNA of cells and cfDNA is significantly increased, which indicates the development of systemic oxidative stress, which is not compensated by the body’s antioxidant system. The level of 8-OHdG in the composition of the cfDNA and DNA of the nuclei of peripheral blood cells can be a marker of oxidative stress, which is important not only for diagnosing the severity of the pathological process, but also for treatment regimens development for COS and ASD in children.

The metabolism of zinc and manganese plays a pivotal role in cancer progression by mediating cancer cell growth and metastasis. The SLC30A family proteins SLC30A3 and SLC30A10 mediate the efflux of zinc, manganese, and probably other transition element ions outside the cytoplasm to the extracellular space or into intracellular membrane compartments. The SLC39A family members SLC39A8 and SLC39A14 are their functional antagonists that transfer these ions into the cytoplasm. Recently, the SLC30A10 gene was suggested as a promising methylation biomarker of colorectal cancer. Here, we investigated whether forced overexpression or inactivation of SLC30A and SLC39A family genes has an impact on the phenotype of cancer cells and their sensitivity to cancer therapeutics. In the human colon adenocarcinoma HCT-15 and duodenal adenocarcinoma HuTu80 cell lines, we generated clones with knockouts of the SLC39A8 and SLC39A14 genes and forced overexpression of the SLC30A3, SLC30A10, and SLC39A8 genes. Gene expression in the mutant and control cells was assessed by RNA sequencing. The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of SLC30A10 resulted in an ~2.7–4 times increased IC50 of cisplatin, and overexpression of SLC30A3 resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets.

Activation of the p38 mitogen-activated protein kinase (MAPK) pathways is vital in regulating cell growth, differentiation, apoptosis, and stress response, significantly affecting tumorigenesis and cancer progression. We developed a bioinformatic technique to construct an interactome network-based molecular pathways for genes of interest and quantify their activation levels using high-throughput gene expression data. This study is focused on the p38α, p38β, p38γ, and p38δ kinases, examining their activation levels (PALs) based on transcriptomic data and their associations with survival and drug responsiveness across various cancer types. We analyzed 11,287 human tumor profiles from 31 cancer types and 53 datasets to assess patient survival and clinical response to 29 therapies. Activation of p38 pathways showed varying prognostic significance depending on the cancer type. In astrocytoma, glioblastoma, thymoma, renal, bladder, esophageal, colorectal, stomach cancers, and lung squamous cell carcinoma, p38 pathway activation correlated with poor survival. Conversely, it indicated better survival in the gender-associated tumors (HER2+, luminal A and B subtypes of breast cancer, prostate carcinoma), sarcomas, lung adenocarcinoma, and others. These trends are aligned with the response-to-therapy analysis. For instance, higher activation of the p38β and p38γ pathways was linked to positive responses to taxane and anthracycline therapies in breast cancer, while lower activation of the p38α and p38β pathways correlated with better responses to 5-fluorouracil-based treatments in colorectal cancer. However, associations with individual MAPK14, MAPK11, MAPK12, and MAPK13 gene expression levels were less robust. Hence, the p38 pathway activation levels could serve as potential biomarkers for predicting clinical outcomes and personalizing treatment strategies, including use of the selective p38 MAPK inhibitors.