Background. Oxaliplatin (OXP), a third-generation chemotherapeutic platinum compound, is widely used in treating metastatic colorectal cancer. However, its clinical utility is limited by oxaliplatin-induced peripheral neuropathy (OIPN), a dose-dependent and often persistent adverse effect characterized by sensory dysfunction such as cold allodynia. Current pharmacological options for OIPN management are limited, with duloxetine being the only drug recommended with moderate confidence by clinical guidelines. Novel analgesics with alternative mechanisms of action are urgently needed. Objective. This study aimed to evaluate the antihyperalgesic (analgesic) effect of propoxazepam, a novel benzo­diazepine derivative with known GABAergic and glycinergic activity, in a rat model of OXP-induced peripheral neuropathy. Methods. Chronic peripheral neuropathy was induced in male Sprague–Dawley rats via repeated intraperitoneal injections of OXP (4 mg/kg, twice weekly for 3 weeks). Cold allodynia was assessed using the paw immersion test at 10 °C. Rats received a single oral dose of propoxazepam (0.5–8 mg/kg) or duloxetine (100 mg/kg) on days 4, 11, and 18, with paw withdrawal latency (PWL) measured at 60, 120, and 180 minutes post-administration. Data were analyzed using Student's t-test with p £ 0.05 as the threshold for statistical significance. Results. OXP administration significantly reduced PWL, indicating development of cold allodynia. Propoxazepam demonstrated a dose-dependent analgesic effect starting as early as Day 4. Significant increases in PWL were observed at doses of 4 and 8 mg/kg, with maximal effects on Day 11 (up to 62% relative to the control). While duloxetine induced a stronger initial effect (~70–75%), it diminished rapidly to 19% by 180 minutes. Lower doses (0.5–2 mg/kg) of propoxazepam did not show statistically significant effects. The analgesic effect of propoxazepam peaked at 120 minutes post-administration and declined by 180 minutes. Conclusions. Propoxazepam effectively reduces cold allodynia in a rat model of OIPN in a dose- and time-dependent manner. Its analgesic efficacy, mediated through GABAergic and glycinergic modulation and supported by anti-inflammatory properties, positions it as a promising candidate for treating chemotherapy-induced neuropathic pain. Given its favorable safety profile and novel mechanism, propoxazepam warrants further investigation in clinical trials. Objective. This study aimed to evaluate the antihyperalgesic (analgesic) effect of propoxazepam, a novel benzodiazepine derivative with known GABAergic and glycinergic activity, in a rat model of OXP-induced peripheral neuropathy. Methods: Chronic peripheral neuropathy was induced in male Sprague-Dawley rats via repeated intraperitoneal injections of OXP (4 mg/kg, twice weekly for 3 weeks). Cold allodynia was assessed using the paw immersion test at 10°C. Rats received a single oral dose of propoxazepam (0.5–8 mg/kg) or duloxetine (100 mg/kg) on days 4, 11, and 18, with paw withdrawal latency (PWL) measured at 60, 120, and 180 minutes post-administration. Data were analyzed using Student's t-test with p ≤ 0.05 as the threshold for statistical significance. Results. OXP administration significantly reduced PWL, indicating development of cold allodynia. Propoxazepam demonstrated a dose-dependent analgesic effect starting as early as Day 4. Significant increases in PWL were observed at doses of 4 and 8 mg/kg, with maximal effects on Day 11 (up to 62% relative to the control). While duloxetine induced a stronger initial effect (~70–75%), it diminished rapidly to 19% by 180 minutes. Lower doses (0.5–2 mg/kg) of propoxazepam did not show statistically significant effects. The analgesic effect of propoxazepam peaked at 120 minutes post-administration and declined by 180 minutes. Conclusion. Propoxazepam effectively reduces cold allodynia in a rat model of OIPN in a dose- and time-dependent manner. Its analgesic efficacy, mediated through GABAergic and glycinergic modulation and supported by anti-inflammatory properties, positions it as a promising candidate for treating chemotherapy-induced neuropathic pain. Given its favorable safety profile and novel mechanism, propoxazepam warrants further investigation in clinical trials.

Background. The spread of infectious diseases caused by drug-resistant bacteria and fungi, especially nosoco­mial strains, is currently considered a serious medical problem. It is known that the fungus Candida albicans is the most common causative agent of candidal infection, including the severe type. The emergence and rapid formation of drug resistance, as a risk factor in the treatment of oncological diseases burdened by candidal infection, requires new therapeutic approaches, including the study of synthetic bioregulators with antifungal and anticancer efficacy. Objective. To synthesize and to determine the antifungal activity and cytotoxicity of imidazole- and morpholine-based lysosomotropic detergents (LDs) comprising both dodecyl radicals and ester-functionalized long alkyl chains. Methods. To develop the QSAR models by the OCHEM platform, machine learning methods such as Transfor­mer Convolutional Neural Network (Trans-CNN), Transformer Convolutional Neural Fingerprint (Trans-CNF), and Random Forest (RF) were used. Imidazole- and morpholine-based lysosomotropic detergents comprising both dodecyl radicals and ester-functionalized long alkyl chains were synthesized and characterized by 1H Nuclear Magnetic Resonance spectroscopy. The antifungal properties of studied compounds were estimated by the disc diffusion method against the C. albicans ATCC 10231, C. albicans, C. glabrata and C. krusei clinical isolates. The in vitro cytotoxic activity of LDs was evaluated by IC50 value against the throat cancer HEp-2 cell lines. AutoDock Vina software was used for the evaluation of the synthesis compounds as ligands of several antifungal targets. Results. The identified and synthesized imidazole- and morpholine-based LDs showed high antifungal potential against all Candida spp., specifically against the fluconazole-resistant C. albicans, C. glabrata, and C. krusei clinical isolates. Imidazole-based LD 1 (IM-C12) and morpholine-based LD 4 (Mor-C12) were the most active against tested fungal strains. Molecular docking results suggest that the antifungal mechanisms of the compounds may be related to the inhibition of fungal lanosterol 14a-demethylase. The cytotoxic results of the synthesized compounds against the HEp-2 cell line demonstrated that morpholine-based LDs are less cytotoxic compared to imidazole-based Conclusions. It was found that LD IM-C12 (1) is the most promising cytostatic and antifungal agent based on the obtained results. LDs IM-CH2COOC10 (2) and Mor-C12 (4), which, under conditions of chemical modifi­cation, including through the carbon chain, may also be interesting for developing potential anticancer agents.

Background. Propoxazepam is a new anelgetic agent of the benzodiazepine group, chemically known as 7-bromo-5-(o-chlorophenyl)-3-propyloxy-1,2-dihydro-3H-1,4-benzodiazepine-2-one. Propoxazepam is considered a possible substrate of the CYP system, so its effect of on the CYP3A4 enzyme activity was investigated in vitro using human liver microsomes. Objective. To evaluate the effects of propoxazepam on CYP3A4 activity in vitro using testosterone and midazolam as markers of metabolic activity for CYP3A4 in human liver microsomes. Methods. Midazolam (1′-hydroxylation reaction) and testosterone (6β-hydroxylation reaction) were used as markers for CYP3A4-mediated activity. Ketoconazole (0.2 μM) was used as a positive control for reversible inhibition, and troleandomycin (50 μM) for metabolism-dependent inhibition. For reversible inhibition, propoxazepam was added together with the corresponding substrate and cofactor (NADPH), while for metabolism-dependent inhibition, it was incubated with microsomes and cofactor for 30 minutes prior to substrate addition. Results. Propoxazepam at various concentrations (0 to 100 μM) consistently inhibited CYP3A4 activities for both substrates, showing a similar "concentration–activity inhibition" dependence, with IC50 values of 52.3 ± 4.9 μM for midazolam and 46.1 ± 9.2 μM for testosterone. For metabolism-dependent inhibition, IC50 values were 36.6 ± 8.6 μM for midazolam and 28.3 ± 7.4 μM for testosterone. Given that the binding of propoxazepam to microsomal protein under the experimental conditions, which reflected those in the IC50 experiments, was low, no microsomal binding correction factor was applied to the reported IC50 values. Conclusions. The highest predicted unbound Cmax plasma concentration of propoxazepam, above which interactions can occur, is between 0.462 and 0.524 μM, or 462 and 524 nM. This corresponds to concentrations of 188 to 214 ng/mL (based on the molecular weight of propoxazepam, 414.73 g/mol). According to pharmacokinetic data, these concentrations are not achievable after a single oral administration. Further studies are required for multiple-dose administration.

Background. Obtaining biologically active natural compounds involved in the regulation of metabolism is an important goal in biotechnology. Colostrum is a unique natural source of various biologically active compounds. However, the extremely high natural variability of colostrum composition does not meet the existing requirements for standardization in pharmaceutical preparations. Objective. To develop a method for separating colostrum into its basic components (lipids, casein, and protein fractions), thereby reducing the variability of whole colostrum composition, obtaining several target products, and demonstrating the possibility of acquiring new protein substances from different sources. Methods. Colostrum separation was carried out through centrifugation and membrane filtration. Plant proteins (sunflower) and milk proteins were used to obtain protein substances from different sources. The composition of proteins, carbohydrates, and nucleic acids was determined using mass spectrometry, centrifugation, and membrane filtration. Results. The proposed method for obtaining basic substances from colostrum significantly reduced the vari­ability in composition compared to whole colostrum. The efficiency of protein sedimentation in concentrated protein solutions by centrifugation and ultrafiltration was shown to depend on protein concentration. Additionally, the formation of non-specific protein aggregates in the centrifugal field allowed the extraction of protein substances from various natural sources, which is relevant for functional nutrition. Conclusions. The proposed selective-integrative technology for obtaining different substances from colostrum significantly reduces the high variability of whole colostrum composition. It increases the efficiency of component separation into lipid, casein fractions, low molecular weight protein fractions, and ultrafiltrate, while also enabling the acquisition of protein substances from diverse sources.

Background. Endothelial cells as participants in angiogenesis choose their phenotype as tip cells (leading, migratory) or stalk cells (following). It has been experimentally found and theoretically modeled that rapid oscillations in intracellular calcium concentration play a key role in controlling phenotype selection and possible vessel architecture. In addition, the intracellular calcium concentration in endothelial cells is known to be regulated by mechanical wall shear stress induced by blood flow, which controls mechanosensitive calcium ion channel gating. Experimental methods of controlling mechanosensitive ion channel gating in external magnetic fields with application of magnetic nanoparticles are developed that affect magnetic nanoparticles artificially attached to cell membranes. Objective. A key question is raised about the possibility of controlled selection of endothelial cell phenotype in external magnetic fields due to the presence of artificial or biogenic magnetic nanoparticles embedded in the cell membrane. Methods. The magnetic wall shear stress is calculated due to the influence of the external magnetic field on the magnetic nanoparticles embedded in the cell membrane, which controls the mechanosensitive calcium ion pathways. Numerical modeling of oscillations in intracellular calcium concentration in endothelial cells and determination of their final phenotype was carried out taking into account intercellular communication. The python programming language and scipy, py-pde, matplotlib packages of the python programming language were used for numerical modeling. Results. The magnetic field flux density and frequency ranges of a uniform rotating magnetic field, as well as the magnitude of the gradient and the frequency of a non-uniform oscillating magnetic field were calculated for controlling the amplitude and frequency of intracellular calcium concentration oscillations in endothelial cells, as well as the selection of their phenotype. It opens the perspective of controlling angiogenesis and vessel architecture. Conclusions. Phenotype selection by endothelial cells can be controlled in a uniform rotating external magnetic field, as well as in a non-homogeneous oscillating magnetic field.

Background. With the increase in soybean cultivation areas, inoculants are becoming increasingly sought after. They are not only compatible with the original preparations for seed treatment of soybean but also offer the possibility of applying them for several days or even months before sowing into the soil. Objective. The viability of new strains of nodule bacteria Bradyrhizobium japonicum (strain PC07 and strain B78) was investigated on the surface of soybean seeds treated with fungicides Fever and Maxim XL during the extended storage of inoculated seeds. Additionally, their ability for nitrogen fixation under symbiotic conditions was evaluated. Methods. Сultivation, serial dilution method, determination of bacterial titer of inoculants, quantification of colony forming units (CFU), gas chromatography. Results. In laboratory conditions, on the soybean seeds of Almaz and Vasylkivska varieties, the viability of the nodule bacteria B. japonicum PC07 and B78, which are more resistant to the active substances of these fungicides in pure culture, decreased. This reduction was dependent on the storage period, the fungicide used, and the strain of inoculant. One day after inoculation on the seeds without the use of fungicide, 68.6–75.4% CFU of the initial number was retained. Seeds treated with the fungicide Fever contained 36.5–38.3% CFU, and those treated with Maxim XL contained 26.2–27.0% CFU. The use of inoculants based on fungicide-resistant strains of B. japonicum PC07 and B78 also provided high cell viability – 2.41–2.8×106 (on the seeds without treatment), 1.40–1.70×106 (with Fever) and 0.8–1.17×106 (with Maxim XL) CFU/seed after 5 days of storage. The nitrogen-fixing activity of root nodules in soybean plants of Almaz and Vasylkivska varieties, whose seeds were treated with Fever, decreased on both varieties by 18.4–22.4% and 32.1–39.5%, respectively and for treatment with Maxim XL, the reduction was 24.5–33.7% and 47.7–75.2%, respectively, during the storage of seeds for 5 and 7 days before sowing, compared to control variants (seeds without fungicide treatment). Conclusions. The utilization of fungicide-resistant strains of B. japonicum PC07 and B78 for bacterization of soybean seeds treated with fungicides Fever and Maxim XL provides a high inoculation titer during 5 days of storage. Viability of microbial cells on seeds treated with fungicides significantly diminishes during storage for more than 7–14 days. Insufficient titer of CFU of B. japonicum strains PC07 and B78 on the seed surface after 14 days of storage can considerably impede the efficacy of biopreparations. Therefore, it is crucial to seek substances that can enhance the resistance of rhizobia on seeds to the adverse effects of fungicide seed treatment, ensuring a longer period of their viability.

Background. Atopic dermatitis (AD) is an inflammatory skin disease caused by a shift in the interaction between cells of the immune system and the skin. Steroid anti-inflammatory drugs used to treat AD often lead to numerous side effects. Therefore, the development of new natural multifunctional preparations with immunomodulatory activity is of great importance. Objective. To determine the changes in indices of the leukocytes cluster of peripheral blood and determine the peculiarities of cytomorphological changes in the spleen and lymph nodes (LN) of rats with induced AD before and after administration of cryopreserved (cHCBL) and lyophilized (lHCBL) forms of human cord blood leukoconcentrate. Methods. The experiments were conducted using 6-month-old Wistar rats. AD was induced by topically applying a 5% alcohol-acetone solution of dinitrochlorobenzene (DNCB) to the skin of the rats' back for 21 days. Each form of the preparation (cHCBL and lHCBL) was administered intraperitoneally in a 0.5 ml dose containing 5´106 cells, one day after the final DNCB treatment. The following parameters were assessed in the blood: leukocyte count and the neutrophil-to-lymphocyte ratio (N/L index). Сytomorphological characteristics were determined in the spleen and inguinal LN. Results. In AD, specific changes in the cytomorphological characteristics of the lymphohematopoietic complex (LHС) structures, namely the spleen and LN, were observed alongside alterations in the leukocyte cluster indices. The most notable changes in the spleen included the dominance of the white pulp over the red pulp and the prevalence of follicles of stages II and III of development in the LN. Animals with AD displayed pronounced leukocytosis and an increased N/L index in their blood. The study demonstrates the positive corrective effects of cHCBL and lHCBL on the morphological characteristics of LHC and the specified blood parameters. Conclusions. The effectiveness of the cHCBL and lHCBL use for correcting indices of leukocytes cluster of peripheral blood and the structural organization of lymphohemopoietic organs in the development of AD have been proven.

Background. Metabolic syndrome (MS) is a complex of disorders characterized by abdominal obesity, insulin resistance and glucose tolerance, arterial hypertension, and all types of metabolic disorders. Taking into account the wide range of symptoms accompanying MS, the use of preparations with pleiotropic effects on metabolic processes in the body could be promising for its treatment.
 Objective. The aim of this study is comparative estimation of metformin or its combination with vitamins' complex or liposomal preparation treatment effects on DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes in testes of rats with MS induced in juvenile age.
 Methods. MS model was induced by full replacement of drinking water with 10% fructose solution in Wistar male rats of 21–23 days age (50–70 g). DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes investigations were carried out after 60 days of MS modeling and metformin or its combination with vitamins' complex or liposomal preparation treatment.
 Results. In experiments with pubertal rats with MS and metformin or its combination vitamins' complex or liposomal preparation treatment, we established partially corrective effects of these medications for DNA, RNA, histones, ATP, ADP, AMP contents, and DNA fragmentation processes changes caused by MS development.
 Conclusions. A comparative analysis of the studied preparations' effects under MS simulation in the juvenile age showed that none of these drugs was able to completely normalize the disorders in studied indicators caused by MS. However, both combinations of metformin with vitamins' complex or liposomal preparation were still more effective in these negative changes' correction then metformin itself. Metformin with vitamins' complex caused a more pronounced influence on the processes of DNA fragmentation, the levels of adenyl nucleotides, and the energy charge of rat testicular cells, while the corrective effect of metformin with liposomal preparation was more noticeable with respect to the content of chromatin components.

Background. Peptic ulcer is a prevalent gastrointestinal tract disease worldwide. One of the treatment methods for the indicated pathology is trunk gastric cryodenervation (TGC), the feature of which is the preservation of the regenerative potential of n. vagus. Cryopreserved placenta extract (CPE) caught our attention among modern means capable of stimulating regeneration processes. Objective. We are aimed to characterize the state of gastric secretion after TGC and the application of СPE. Methods. TGC was performed by cryoinfusion on the front and back trunks of the abdominal part of n. vagus. Gastric secretion was studied using the H.A. Shay method. Results. On the 30th day after TGC, a statistically significant (p < 0.001) decrease in the total acidity of gastric juice by 33.7% and a decrease (p < 0.01) in the level of free acidity were observed compared to intact animals. Administration of СPE after TGC resulted in a statistically significant (p < 0.001) decrease in total acidity by 24.2 % and a statistically significant (p < 0.001) decrease in free acidity by 48.7% compared to the parameters of intact rats. This led to a statistically significant (p < 0.001) decrease in the "free/bound acidity" ratio compared to the indicator of intact animals (1.4 ± 0.03 RU) which was higher than the similar ratio observed after esomeprazole usage or TGC. Conclusions. Administration of СPE contributed to the partial regeneration of n. vagus, as indicated by an increase in the level of total acidity to 104.1 ± 4.7 RU and a statistically significant (p < 0.001) decrease in the "free/bound acidity" ratio compared to the indicator of intact animals.

Background. Macromycete cultivation methods development will contribute to the production of biotechnological products based on fungus. Determination of the main factors affecting medicinal macromycetes’ life processes allows to control biosynthetic activity of a fungal organism and obtain biotechnological products based on it. Objective. Screening of Fomitopsis officinalis strains promising for biotechnological use, and determining of physico-chemical factors that affect the cultures life processes. Methods. The objects of the study were three pure cultures of F. officinalis (IBK-2497, IBK-2498, IBK-5004). The influence of the acidity of the environment on the growth of mycelium, the needs of the cultures in the sources of carbon and nitrogen nutrition were determined. The following carbon sources were used: monosaccharides (glucose, xylose), disaccharides (sucrose, lactose) and trisaccharides (raffinose), polysaccharides (starch); nitrogen sources: KNO3, (NH4)2HPO4, asparagine, peptone. Dynamics of the culture growth were determined under the conditions of deep cultivation, on a liquid nutrient medium of glucose-peptone-yeast extract (GPA), g/l: glucose – 30.0; peptone – 3.5; yeast extract – 2.0; KH2PO4 – 1.0; K2HPO4 – 1.0; MgSO4×7H2O – 0.25. Results. The pH range between 5.5 and 6.0 was the most favorable for active growth of all studied strains of F. officinalis. The best carbon sources for growth were glucose and starch; peptone and asparagine were the best source of nitrogen. Nutrient media with xylose, lactose and nitrate nitrogen were least suitable for growth. Analysis of the strains growth dynamics on the GPA medium showed that the largest mass of mycelium (up to 11.54 ± 0.2 g/l) was produced by culture F. officinalis IBK-5004 on the 10-th day of cultivation. Cultures F. officinalis IBK-2497, IBK-2498 grew slower, and the mycelial mass was 10.33 ± 0.2 and 9.68 ± 0.3 g/l on the 14-th day of cultivation. Conclusions. Based on the obtained data, the F. officinalis IBK-5004 strain was selected. It can be considered a promising mycelial mass producer based on the set of characteristics.