Anatoly Viktorovich Skalny

Oxidative stress plays a critical role in the methylmercury (MeHg) neurotoxicity, as MeHg induces reactive oxygen species (ROS) generation and impairs antioxidant defense systems. However, the precise molecular mechanisms underlying MeHg-induced neurotoxicity remain elusive. The nuclear factor erythroid 2-related factor 2 (Nrf2) activates antioxidant defense genes in response to acute MeHg exposure. Similarly, the signal transducer and activator of transcription 3 (STAT3), a transcription factor involved in cell growth and anti-apoptotic genes, also contributes to maintaining redox homeostasis. Here, we sought to investigate the roles of Nrf2 and STAT3 in mouse hypothalamic neuronal GT1-7 cells exposed to MeHg. We inhibited STAT3 either pharmacologically with AG490 (a JAK2 inhibitor) or C188-9 (a small-molecule STAT3 SH2 domain inhibitor) or genetically using a lentivirus carrying STAT3 shRNA (vs. scramble control), in GT1-7 cells exposed to 5 µM MeHg. To further dissect the role of Nrf2, the pathway was pharmacologically inhibited using brusatol or activated with sulforaphane (SFN) in GT1-7 cells co-exposed to 5 µM MeHg. Changes in cell viability, reactive species production, and protein and gene expression were analyzed. Our findings reveal that deficits of either the Nrf2 or STAT3 pathways exacerbated MeHg-induced toxicity. Moreover, in MeHg-exposed cells, Nrf2 ablation led to increased STAT3 activity, suggesting a reciprocal and potentially compensatory responses between these two pathways in protecting against MeHg-induced oxidative stress. Our novel findings provide crucial understanding of the molecular mechanisms underlying MeHg neurotoxicity and offer insights into potential therapeutic strategies for mitigating acute MeHg-induced neurotoxicity. Graphical Abstract

Introduction: Zinc is an essential trace element with well-known physiological functions. Although various zinc salts are available, novel zinc complexes with organic ligands remain of pharmacological interest. Pharmacokinetic studies are essential to clarify the contribution of the zinc ion and organic ligand to their biological activity. Materials and Methods: The pharmacokinetics of bis(N-allylimidazole) zinc diacetate (ALL) components were studied in 66 BALB/c mice. The compound was administered once intraperitoneally at 25 mg/kg. Blood, brain, liver, pancreas, kidneys, and spleen were collected at 0, 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 24 h, with 6 animals per time point. N-allylimidazole was quantified using a validated HPLC-MS/MS method, while zinc was determined by atomic absorption spectrometry. Results and Discussion: ALL likely dissociates into N-allylimidazole and zinc under physiological conditions, resulting in distinct pharmacokinetic profiles. N-allylimidazole was detected in all tissues, including the brain. The Tmax for most tissues was 0.25 h, indicating rapid systemic distribution. The highest concentration was observed in the kidneys (Cmax 7907.58 µg/g), suggesting their involvement in ligand excretion. In the liver, N-allylimidazoleshowed prolonged retention, with a T1/2 of 14.5 h and AUC(0–24) of 11168.41 µg·h/mL. After correction for endogenous zinc, the highest zinc concentrations were detected in the liver (60.21 µg/g), pancreas (57.52 µg/g), and spleen (54.80 µg/g). Conclusion: ALL administration resulted in rapid systemic distribution of both components. N-allylimidazole penetrated highly perfused tissues, including the brain and kidneys, whereas zincaccumulated in the liver, pancreas, and spleen. Distinct tissue distribution and elimination profiles, together with equilibrium calculations, support complete in vivo dissociation of the complex.

The aim of the study was to synthesize nanocomposites based on cerium orthophosphate stabilized with citrate at different ratios for biomedical applications, and to evaluate its safety in different animal species. Nanocomposites were synthesized using four different initial mass ratios of Ce(NO₃)₃ × 6H₂O to citric acid: 1:5 (Ce:5CA), 1:3 (Ce:3CA), 1:1 (Ce:1CA), and 1:0.5 (Ce:0.5CA). The obtained products were characterized by a series of physicochemical methods including X-ray diffraction, transmission electron microscopy, and IR spectroscopy. Biomedical studies of the sols were performed to evaluate redox activity and their effects on the metabolism and proliferation of human fibroblasts. Safety studies were carried out in different animal species, including determination of the acute toxicity of the selected nanocomposite following application to intact skin and intragastric administration, as well as determination of subchronic toxicity using a model of acute experimental full-thickness skin wounds. According to the physicochemical studies, all synthesized nanocomposites contained nanocrystals with bimodal dimensions (width 3–10 nm, length 15–40 nm) and diffraction peaks characteristic of CePO₄. IR spectroscopy demonstrated the formation of new chemical bonds. Antioxidant activity was observed for the Ce:3CA, Ce:1CA, and Ce:0.5CA samples, being most pronounced for Ce:1–0.5CA, whose antioxidant capacity exceeded that of ascorbic acid. In contrast, Ce:5CA exhibited pro-oxidant activity at all tested concentrations. Biocompatibility with human cells was demonstrated. Ce:0.5CA was identified as the most promising candidate for biomedical applications owing to its highest regenerative and antioxidant potential and its demonstrated safety in animals following topical and intragastric administration, as well as in wound models. Histomorphological examination of the internal organs supported the safety and potential of the developed nanocomposites for skin regeneration and wound healing.

The use of manganese oxide nanoparticles (MnOxNPs) in biomedicine increases the risk of their accumulation in the body, potentially leading to toxicity in various organs and tissues. In addition, occupational exposure to MnOxNPs-containing aerosols may also occur. MnOxNPs have been shown to accumulate in the brain and induce neurobehavioral alterations. However, the specific mechanisms of MnOxNPs toxicity in the brain and other tissues remain incompletely understood. Therefore, the objective of this review is to summarize existing data on the toxicity of MnOxNPs in the brain and other tissues, and to discuss the molecular mechanisms underlying their neurotoxic effects. It has been shown that MnOxNPs induce neuronal death through induction of mitochondrial dysfunction and subsequent apoptosis, and overaccumulation of tau protein and amyloid-β. Neurotoxic effects of MnOxNPs may also be mediated by blood–brain barrier disruption, and dysregulation of dopaminergic and glutaminergic signaling. Exposure to MnOxNPs induces neuroinflammation through activation of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK) pathways in a reactive oxygen species-dependent manner. In vitro studies further demonstrate that MnOxNPs exhibit a dose-dependent cytotoxic effects in alveolar macrophages, as well as in respiratory, colonic, and other epithelial cells, through the promotion of oxidative stress and an inflammatory response. Overexposure to MnOxNPs has significant nephrotoxic, hepatotoxic, and immunotoxic effects, as well as affecting the reproductive system. Smaller particles exhibit more pronounced toxic effects in the brain and other tissues than larger nanoparticles or microparticles. However, the mechanisms underlying the different toxicities of MnOxNPs of different sizes, shapes, and surface modifications remain unclear. These observations highlight the potential of MnOxNP exposure to contribute to neurological disorders and dysfunction of other systems, underscoring the need for further mechanistic studies to ensure their safe application in biomedicine.

The objective of the study was to assess the level of selenium (Se) in biosamples, serum selenoprotein P (SELENOP) concentration, and blood gluta-thione peroxidase (GPX) activity in patients with rheumatoid, psoriatic, and gouty arthritis, as well as to estimate their association with the level of car-tilage oligomeric matrix protein (COMP), being a marker of cartilage damage. Material and Methods. The study enrolled patients with rheumatoid arthritis (RA) (n = 101), psoriatic arthritis (PA) (n = 105), gout (n = 105), and 131 healthy subjects. Assessment of circulating SELENOP and COMP levels was performed using enzyme-linked immunosorbent assay. Blood GPX activity was estimated spectrophotometrically. Analysis of Se levels in blood serum, urine, and hair was performed using inductively-coupled plasma mass-spectrometry. Results. The obtained data demonstrate that serum COMP levels in patients with inflammatory arthropathies exceeded the control values by a factor of more than 9. SELENOP levels in RA, PA, and gout was 4.9, 3.9, and 2.7–fold lower than in healthy controls, respectively. Serum Se levels in RA and PA patients were 11% and 10% lower compared to the respective control values. Hair and urinary Se levels were less variable. Multiple linear regres-sion analysis showed that serum SELENOP level and urinary Se concentration were significant negative predictors of COMP levels in the examinees even after adjustment for case status. Conclusion. Therefore, the results of the study showed that patients with inflammatory arthropathies are characterized by lower serum Se and SELENOP levels. Furthermore, SELENOP concentration is characterized by a significant inverse association with cartilage damage intensity, indicative of the modulatory effect of Se on cartilage damage in arthritis.

Relevance. As medical research develops, more and more attention is being paid to the study of elemental changes in cancer patients not only as a marker of the disease, but also as a possible complication of the disease. The aim was to study changes in the level of essential and toxic trace elements in patients who have undergone antitumor therapy (AT) for malignant neoplasms (MN). Materials and Methods. As part of a retrospective monocenter study, a group of 214 patients from the Russian Field Medical and Rehabilitation Research Center aged 4 to 17 years was formed. All patients were in remission after the completion of antitumor treatment: 107 patients with hemoblastosis and 107 with solid tumors. The age of the participants ranged from 4.2 to 17.6 years, with an average age of 11.4 years. For a comprehensive assessment of the elemental status in children, hair and blood serum were used, measurements were carried out by mass spectrometry after mineralization of the samples. Results and Discussion. The results of the study of hair samples and blood serum showed that the elemental profile of patients after AT has both similar patterns and distinctive features depending on the histological type of tumor. Conclusions. Patients with solid tumors had a higher accumulation of toxic metals compared to samples taken from patients with tumors of the hematopoiesis organs. Nevertheless, no serious specific changes in elemental homeostasis were observed depending on the histological structure. The results obtained emphasize the importance of careful monitoring of homeostasis parameters to prevent the development of complications of antitumor therapy associated with elemental homeostasis.

The objective of the present study was to evaluate serum trace element and mineral levels in female patients with knee osteoarthritis (kOA) and concomitant knee and hip osteoarthritis (khOA). The study enrolled 61 healthy women without OA or any other pathology of joints (OA-free group), 180 subjects with bilateral kOA, and 99 patients with khOA. Age, anthropometric parameters, and the prevalence of concomitant diseases were registered. Serum trace element and mineral levels were assessed using inductively-coupled plasma mass-spectrometry. The obtained data demonstrate that patients with kOA and especially khOA are characterized by higher age, body mass index, and the prevalence of hypertension and certain other comorbidities. Serum analysis demonstrated that Zn and Fe levels in kOA and khOA patients were lower than those in OA-free patients by 7% and 9%, and 14% and 18%, respectively. In turn, circulating Se concentrations in patients with kOA and khOA were 9% and 7% lower compared to OA-free group values. Serum Cu and Mo levels in khOA patients exceeded the respective values in kOA subjects. Factorial analysis demonstrated that OA case status had a significant impact on serum Ca, Cr, Fe, Mn, Se, V, and Zn. At the same time, multiple regression analysis revealed a significant association with OA only for serum Zn, Se, V after adjustment for age, BMI, and the prevalence of concomitant diseases. Therefore, the obtained data indicate that involvement of multiple joints in OA patients is associated with more severe alterations in trace element levels.

The objective of the present study was to assess the patterns of trace element and mineral accumulation in 21 medicinal plants collected in the Altai Mountains foothills. The levels of trace elements and minerals in Hippophae rhamnoides, Aronia melanocarpa, Sorbus aucuparia, Viburnum opulus, Rosa canina, Crataegus sanguinea (fruits), Chamaenerion angustifolium, Echinacea purpurea, Fagopyrum esculentum, Trifolium pratense, Origanum vulgare, Achillea millefolium, Mentha piperita (herbs), Plantago major, Salvia officinalis, Urtica dioica (leaves), Panax ginseng, Rhaponticum carthamoides, Eleuterococcus senticosus, and Taraxacum officinale (roots), and Matricaria recutita flowers were assessed using inductively-coupled plasma mass-spectrometry. Comparative analysis revealed that R. carthamoides roots accumulated the highest level of toxic trace elements (Al, Cd, Ni, Pb). C. angustifolium herbs and V. opulus fruits are characterized by the highest As and Sn levels, respectively. The highest content of essential trace elements and minerals was observed in H. rhamnoides fruits (Zn), V. opulus fruits (Cu), E. purpurea herbs (I, Mg), R. carthamoides roots (Fe), O. vulgare herbs (Mn), and M. recutita herbs (Se). In turn, R. canina fruits are characterized by the lowest levels of certain essential and toxic trace elements. Significant differences in B, Cr, Li, Si, and Sr content were also revealed. Discriminant analysis revealed complete discrimination of certain medicinal plants based on their trace element and mineral content. The obtained data indicate the potential usefulness of medicinal plants as sources of certain essential trace elements and minerals, as well as provides data for risk assessment of toxic trace element intake following administration of medicinal plants.

Introduction. In previous years, RUDN University conducted a comparative analysis of the ionomic profiles of first-year students from Africa, Central Asia, Latin America, the Middle East, China and others, but a comparison of the elemental status of first-year RUDN University students from the Middle East and the Moscow region has not been described in the literature. The purpose of the study is to study the relationship between the ionomic profile of hair of first-year RUDN University students from the Middle East and the Moscow region with the natural and climatic conditions of the living environment. Material and methods. In the period from September 1, 2022 to January 1, 2023, a study of the elemental composition of hair was carried out using inductively coupled plasma mass spectrometry in 180 first-year RUDN University students who previously lived in the ME countries (60 people) and in the MR (120 people) aged 18–26 years. The average age of the subjects was 22.7 ± 4 years. Gender differences in the comparison groups were not taken into account. Results. It was found that in the ionic profile of the hair of students who arrived from the Moscow region, the predominant macroelements are calci-um, magnesium, essential microelements manganese, cobalt, iron, toxic microelement mercury, and potentially toxic microelement tin. In the ionic profile of the hair of students who arrived from the Middle East, the predominant elements are sodium, essential microelements molybdenum, silicon, toxic microelements thallium, cesium, antimony, tungsten, beryllium, conditionally essential and potentially toxic microelements arsenic, rubidium, nickel. Conclusions. The article presents the results of a comparative analysis of the content of 22 elements in the hair of first-year RUDN students from the Middle East and the Moscow region during the adaptation period to study in 2023. The features of the elemental profiles of students were established, it was shown that the hair of the subjects reflects the territorial climatic and geographical features of the region of residence of the subject.