The aging of the immune system is accompanied by a significant increase in the risk of developing age-related pathologies, including inflammatory, autoimmune diseases and oncology. Age-dependent decline in immune function is accompanied by a gradual accumulation of senescent (aged) cells that are the source of chronic inflammation. The main producers of proinflammatory cytokines in the body are activated effector T cells. With age, along with an increase in chronic inflammation (InflamAging), the ability of the immune system to suppress and/or remove activated and senescent effector cells decreases. With age, there is also a decrease in the function of CD3⁺CD4⁺CD25^hiCD127^lo/- T-regulatory cells (Treg), which unbalances the immune system and increases the risk of autoimmune pathologies. In ex vivo analysis, senescence and effector function in CD4⁺ and CD8⁺, activated (CD25⁺ and HLA-DR+) and non-activated (CD25^- and HLA-DR^-) T cells, as well as the suppressor activity of senescent Tregs were assessed by functional tests and using SA-β-galactosidase assay. Additional analysis, p16^INK4A, p21^WAF1/CIP1, phospho-histone H2A.X and HMGB1 was applied to confirm the senescent status of these cells. PBMCs irradiated with UV or reaching the replication limit were used as a positive control of senescent cells. UV radiation increased SA-β-Gal activity and correlated with an increase in the level of phospho-histone H2A.X, confirming their senescent status and the relevance of SA-β-Gal as a marker of senescence. In middle-aged donors in activated (CD25⁺ and HLA-DR⁺) both CD4⁺ and CD8⁺ lymphocytes, SA-β-Gal activity was higher compared to non-activated lymphocytes. Whereas, SA-β-Gal activity was lowest in Tregs, suggesting their specific metabolic patterns. Among middle-aged donors, there were no significant differences between the populations of CD3⁺CD4⁺ and CD3⁺CD8⁺ lymphocytes in SA-β-Gal activity. Thus, the activity of SA-β-Gal marker of senescent and activated effector T cells can be used to analyze the aging of the immune system in further functional tests. Using this approach, the phenotypic features and functional activity of senescent T cells among young (<30 years old) and older (>60 years old) donors will be studied in detail. The development of this model in non-human primates of different age groups will facilitate future preclinical trials for senolytic and senomorphic drugs, and substances that enhance the repair of double-strand breaks.

This work was supported by the Russian Science Foundation, No. 23-15-00443.

Sida linifolia L. is a weed ubiquitously found in Africa with several folkloric applications. Traditional healers in the Southeastern part of Nigeria employ the alcoholic concoction of S. linifolia leaves as antidepressants, anti-malaria, antihypertensive, anti-abortifacients, and for managing painful whitlow; however, these claims lack scientific validation. The present study was aimed to explore the phytochemical profile of the plant, S. linifolia with special emphasis to its antioxidant and inhibitory actions on enzymes linked to inflammation, diabetes, and neurological disorders. Phytochemical profiling and in vitro antioxidant and enzyme inhibition assays were employed to assess the pharmacological profile of S. linifolia ethanolic leaf fraction (SLELF). Preliminary phytochemical screening of SLELF revealed appreciable amounts of total phenolics (91.64 ± 7.61 mg GAE/g), total tannins (62.44 ± 3.86 mg TAE/g), and total flavonoids (27.35 ± 1.48 mg QE/g) present in SLELF. Results of HPLC analysis of SLELF revealed rich composition in bioactive compounds such as ellagic acid, quercetin, ferulic acid, 3,4-dimethoxy benzoic acid, gallic acid, 4-methoxy cinnamic acid, sinapic acid, vanillic acid, and chlorogenic acid. Enzymatic antioxidants (catalase and superoxide dismutase), non-enzymatic antioxidants (reduced glutathione (GSH), Vit A, C, and E), elemental minerals (Cu, Mn, Zn, Cr, Fe, and Ca), and γ-aminobutyric acid (GABA) were present in SLELF in appreciable levels. At various concentrations (0.2 – 1.0 mg/ml), SLELF exhibited potent and concentration-dependent hydrogen peroxide (H₂O₂) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS) radical scavenging activities and exerted moderate inhibitory actions on enzymes associated with inflammation (cyclooxogenase-2 (COX-2) and lipoxygenases (LOXs), diabetes (α-amylase, α-glucosidase), and neurological disorders (butyrylcholinesterase (BChE) and γ-aminobutyric acid transaminase (GABA-T), compared to respective standards (ascorbic acid, acarbose, indomethacin, galanthamine, and vigabatrin). Perhaps, the observed potent pharmacological activities of SLELF could be anchored to its phytoconstituents. Furthermore, the slightly higher ranges of IC₅₀ values (0.57 – 0.87 mg/ml) of SLELF compared to standards (0.44 – 0.68 mg/ml) suggest moderation in enzyme inhibition that may preclude adverse side effects. This study lends credence to the folklore claims of S. linifolia leaves and revealed its potential as possible source of bioactive compounds for medicinal and pharmaceutical exploration.

Lung cancer is the second most common type of cancer, affecting more than two million people. The available treatments show limited effectiveness and undesirable side effects, thus, there is a huge demand for more effective treatments. The use of drugs already on the market has been proposed as a potential valuable approach. The aim of this study was to test the potential use of β-blockers, atenolol and metoprolol, and the peroxisome proliferator-activated receptor alpha (PPAR-α) receptor agonists, fenofibrate and gemfibrozil as coadjuvant in the treatment of this pathology. Thus, non-small cell lung cancer cell lines, A549 and H460, were exposed to different concentrations of β-blockers (500, 250, 125, 62.5, 31.25, 15.625 and 7.8125 µM) and PPAR-α receptor agonists (25, 12.5, 6.25, 3.125, 1.563, 0.781 and 0.391 µM). Metabolic viability was assessed by Resazurin and MTT viability assay at three different time points, 24, 48 and 72 hours. Atenolol and metoprolol did not demonstrate toxicity towards both cell lines in the tested concentrations and time-points. Gemfibrozil demonstrated limited toxicity towards both cell lines, with decreases of 20% of cellular viability at the maximum concentration tested at 24 hours and Fenofibrate showed toxicity only towards H460 with a calculated LC₅₀ of 20.6 µM. Therefore, Fenofibrate is a strong candidate to act as coadjuvant in the treatment of non-small cell lung cancer. Further studies are necessary to understand the impact of lipid regulators in the treatment of lung cancer.

The low cost and free sale of some medicines are two of the main factors behind the considerable increase in the consumption of non-steroidal anti-inflammatory drugs around the world, particularly ketoprofen (Kp). Despite its widespread use, the ecotoxicological profile of Kp remains poorly explored and therefore, to date, the intra- and interspecific effects of Kp have yet to be explored. Therefore, this study aimed to provide a classification of the environmental hazard of Kp, firstly by determining the intraspecific tolerance of a laboratory-simulated cladoceran population comprising five different clonal lineages selected accordingly to their previous tolerance to copper contamination; and secondly, by providing the lethal and sublethal concentrations for effect (LC_x and EC_x, respectively) of Kp for freshwater species representative of the different trophic levels. The LC_x were later assembled into Species Sensitivity Distribution (SSD) curves to derive hazard concentrations that affect 5% of the population (HC₅, probabilistic approach) and compared with the deterministic approach (lowest L(E)_x divided by an assessment factor of 1000). Risk quotient for Kp was determined based on the most conservative value. In relation to the results with the simulated population in the laboratory with clones of Daphnia longispina, the results showed significant correlation (0.97) between their baseline tolerance to copper and their tolerance to a compound they had never been exposed to before, such as ketoprofen. This type of approach, which is generally neglected in ecological risk assessment, can help to outline more realistic environmental protection targets, since genetic diversity is the cornerstone of population resilience in the face of environmental change. Regarding interspecific variability, the results showed that the embryos of the fish Danio rerio were the most sensitive ecological receptors, while the green microalga Raphidocelis subcapitata was the most tolerant to Kp. The estimated LC₅₀ values (95% confidence limits) were 6.16 (5.17 - 7.43) mg Kp/L and 47.2 (28.3 - 66.7) mg Kp/L for D. rerio and R. subcapitata, respectively. The estimated HC₅ of the SSD was 4.91 mg Kp/L. Determination of the risk quotient [based on the lowest and most conservative L(E)C₅₀/1000] indicated a quotient >1, meaning that Kp poses a risk to aquatic biota. Given that ketoprofen is an increasingly used drug and has the potential to have long-lasting effects, its ecotoxicity deserves to be further explored considering various exposure scenarios.

Equine Metabolic Syndrome (EMS) is a prevalent condition that primarily affects horses and ponies. It is characterized by a cluster of metabolic disturbances, including insulin resistance, obesity or abnormal fat distribution, and a heightened risk of laminitis (a painful hoof condition). Sex hormone binding globulin (SHBG) is a glycoprotein produced by the liver and released into the bloodstream. It plays a crucial role in the regulation of sex hormones in the body, primarily testosterone and estrogen. Recent findings have shown that SHBG is also produced by adipocytes and their precursors, thus playing an important role in the balance of adipose tissue metabolism. On the other hand, peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that promotes adipogenesis, lipid absorption and storage, insulin sensitivity, and glucose metabolism. Therefore, PPARγ defects are associated with the development of metabolic disorders, and as with SHBG, reduced PPARγ levels are associated with insulin resistance and related endocrine abnormalities.

The aim of our study was to evaluate for the first time the impact of SHBG protein on mitochondrial changes in ASCs isolated from horses and to verify whether SHBG can restore impaired PPARγ functions and therefore represents a new candidate PPARγ agonist for the treatment of EMS.

Our obtained data showed that PPARγ knockdown resulted in significant changes in mitochondrial membrane potential as well as the expression of metabolic and dynamics related markers. Interestingly, SHBG treatment improved the transmembrane potential, normalized the expression levels of key mitochondrial dynamics mediators as well as such as mitochondrial recycling machinery effectors including PINK protein.

The outcomes of this study suggest that SHBG can exert PPARγ-like effects and improve the mitochondrial function of ASC, and thus highlights the possible interaction between PPARγ and SHBG in the regulation of cellular metabolic processes.

The research focused on elucidating potential targets for breast cancer therapy through the empirical approach to biological networks involved in disease progression. The study was initiated by collecting targets of FDA-approved small-molecule drugs for breast cancer, specifically focusing on those belonging to the kinase inhibitor class. The Swiss Target database was employed to select the kinase inhibitor targets. These targets are then merged and used to construct a network using the String database, which is visualized in Cytoscape. The network analysis is performed using the Cytohubba plugin to identify the top 10 hubgenes in the network. The analysis revealed several high-ranking hub genes, including well-known regulators of breast cancer like EGFR, ERBB2, AKT1, MAPK1, and biomarkers such as JAK1, JAK3, and PRKCD thereby validating the network's reliability. Furthermore, a drug-target analysis was conducted to identify candidate inhibitors for the identified hubgenes. Selection criteria include kinase-specificity, as well as safety and efficacy profiles. Molecular docking was employed to evaluate the binding affinity of MAPK1 with Tucatinib, a protein kinase inhibitor, revealing a strong interaction having a binding affinity of -9.6 kcal/mol. Molecular dynamics (MD) simulations are then performed to assess the stability and dynamics of the MAPK1-Tucatinib complex. The results provide insights into the initial binding conformation and interactions between the protein and ligand. The constructed protein-protein interaction networks offer valuable information on the crosstalk and network interactions of Protein Kinase (PK) within breast oncosystems, while hub genes offer significant targets for interventions in personalized medicine in breast cancer treatment.

Pollution stands as a major factor affecting wildlife populations, with amphibians being an exceptionally vulnerable group. Plastic pollution, particularly nanoplastics (NPs) stemming from primary and secondary sources, garners traction owing to its distinctive characteristics, including its minute size, large surface area, and heightened surface reactivity. As the demand for more sustainable alternatives to conventional plastics intensifies, the emergence of Polyhydroxybutyrate (PHB) as a novel bio-based and biodegradable plastic stands out. However, the understanding of its environmental impact, particularly regarding its nanosized particles, remains limited. These particles possess the potential to exert pernicious effects and act as carriers for environmental contaminants into biota. Sertraline, one of the most consumed antidepressants, is expected to be present in the aquatic environment due to patient excretion, inefficient wastewater treatment, and improper disposal. Given its bioactive nature, even low concentrations of sertraline may pose undesirable effects on biota. The objectives of this work were to assess the hazards of PHB nanoplastics and sertraline, in single and combined exposure, towards two aquatic early life stages of the model organism Xenopus laevis. Additionally, in vitro assays were conducted to understand the suitability of two cell lines as non-animal alternatives to be used in first tiers of environmental risk assessment for this type of contamination. Our results suggested high tadpole sensitivity to sertraline (96-h LC₅₀: 449.81 µg L^-1), when compared to embryos (96-h LC₅₀: 2.58 mg L^-1), while PHB-NPs did not show statistically differences in the monitored parameters, however NPs may exert modulatory effects in mixture with sertraline.

When it comes to creating new carbon-carbon bonds during the hydrocyanation of α, β-unsaturated ketones, catalytic Michael addition reactions are extremely effective tools. A simple method for converting α, β-unsaturated ketone to its hydrocyanic form involves using cyanohydrin acetone with a mild base and a phase transfer catalyst. This reaction stoichiometry produced a high-quality product with a high yield on the gram scale. Density functional theory (DFT) calculations have been used in a comprehensive theoretical investigation to elucidate the mechanism of base-catalyzed hydrocyanation reaction of enolizable α, β-unsaturated ketone. B3LYP-D3(BJ)/6-311+G**//B3LYP-D3(BJ)/6-311G** was used to study the genesis and reaction mechanism of asymmetric induction for conjugate addition of cyanide to the C=C bond of α, β-unsaturated ketone. Additionally taken into account are the relative stability of the investigated compounds as well as their atomic charges, electron densities, energetic characteristics, chemical thermodynamics, dipole moments, etc. The final charge transfer interaction within the investigated molecule is suggested by the narrow frontier orbital gap, which also demonstrated significant chemical reactivity. Lastly, to visualise the charge transfer between the localised bonds and lone pairs, natural bond orbital analysis is done. The current study's mechanistic insights should be helpful in the logical design of efficient catalysts with high selectivity and yield for this type of reaction.

Background and objectives: This study compares the effect of aspartame consumption alone and combined with vitamin C and E over biochemical parameters related to liver and kidney function and oxidative stress biomarkers. Methodology: 5 groups of rats - Control I: treated with drinking water. Control II: 0.2 ml of olive oil (vehicle for vitamin E). Experimental Groups - Group I: aspartame (40 mg/Kg). Group II: aspartame (40 mg/Kg) plus vitamin C (150 mg/Kg). Group III: aspartame (40 mg/Kg) plus vitamin E (100 mg/Kg). All the treatments were administered by gavage once a day during 60 days. Results: Aspartame combined with vitamin C or E led to a decrease on body weight of 7% and 10%, respectively. Total cholesterol concentration was decreased when aspartame was combined with vitamin C (7%) or E (20%). AST activity was increased by aspartame which was prevented when its consumption was combined with vitamins C or E. ALT activity was decreased in presence of vitamin C (40%) or E (36%). Aspartame with vitamin C or E decreases level of creatinine 31% and 30%, respectively. Vitamin E decreased catalase activity (31%). Inclusion of vital C and E reduced the concentration of oxidative stress biomarkers, brain 8-OHdG and urinary isoprostane, when compared with the group just receiving aspartame. Conclusion: The results obtained in the present study suggest that combining vitamin C or E with the administration of aspartame has a protective effect over liver and kidney functions as well as protective effect agains oxidative stress.

Usnea barbata L. (Parmeliaceae Zenker.) is used in folk medicine as an antimicrobial agent in various diseases of bacterial genesis. The antimicrobial activity is associated with the presence of the lichen acids, especially usnic acid (UA). Aim of the study is isolation, identification and assay of UA by HPLC-UV. The lichen Usnea barbata was collected from tree branches in the Altai Krai during the growing season (June-July 2022). The sum of lichen acids was isolated in the form of sodium salts by re-extraction with 20% sodium hydroxide solution from chloroform extract. The re-extract was acidified with 10% hydrochloric acid until a precipitate formed, which was filtered off, dried, dissolved in acetonitrile and analyzed. The HPLC analysis was conducted using a MiliChrom A-02 HPLC System equipped with UV-spectrophotometric detector. The chromatographic conditions: column - reverse-phase, ProntoSIL 120-5 C18 (75×2.0 mm, 5 µm); column oven temperature - 40°С; mobile phase (MP) - 0.1% trifluoroacetic acid aqueous solution (solvent A), 100% acetonitrile (solvent B); MP flow rate - 150 µL/min with gradient elution - from 10 to 50% of solvent B in 5 minutes, gradually increased to 100% up to 20 minutes; sample injection volume - 4 µL; detection at 230 and 280 nm. By comparing the retention times (τ = 15.0±0.1 min) and spectral characteristics (λmax) with those of the 0.05% UA reference sample solution, the presence of UA in the studied thallus was established. Quantitative content, calculated from the peak area, compared with the peak area of the reference sample -1.45±0.07%.