Background:Chronic intrauterine hypoxia (IUH) is a cause not only of early postnatal mortality but also of delayed central nervous system (CNS) impairments in offspring, including increased risks of acute cerebrovascular disorders, epilepsy, and neurodegenerative diseases. The above necessitates the urgent development of targeted neuroprotective strategies for newborns following IUH. The aim of the present study was to evaluate the neuroprotective effects of the 70 kDa heat shock protein (HSP70) modulators (angiolin, thiotriazolin, cerebrocurin, tamoxifen, glutaredoxin, and heat shock factor 1 (HSF-1)), as well as reference drugs, based on their impact on molecular markers of endothelial dysfunction (vascular endothelial growth factor A (VEGF-A), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and caspase-8 in the brains of offspring after IUH at 1 and 2 months of age.Methods:Chronic hemic IUH was modeled in pregnant rats by daily administration of sodium nitrite (50 mg/kg, intraperitoneally) on days 16–21 of pregnancy. The male offspring were treated with the study drugs for 30 days starting on P1. Brain homogenates of offspring at P30 and P60 were analyzed using enzyme-linked immunosorbent assay (ELISA) for VEGF-A, eNOS, iNOS, nitrotyrosine, BDNF, NGF, and caspase-8.Results:IUH caused persistent endothelial dysfunction, characterized by decreased VEGF and eNOS levels, and nitrosative stress, associated with increased iNOS and nitrotyrosine levels. These changes were accompanied by decreased neurotrophin levels, including BDNF and NGF, and increased caspase-8 levels. Course administration of angiolin, cerebrocurin, HSF-1, thiotriazolin, and glutaredoxin improved the eNOS/iNOS balance, increased VEGF levels, and decreased nitrotyrosine levels, with the effect persisting until P60. Cerebrocurin and angiolin demonstrated the strongest recovery of neurotrophic factors (normalization or exceeding normal BDNF/NGF levels by P60) and effectively suppressed caspase-8 to near-normal levels. A positive correlation was established between BDNF, NGF, and HSP70 levels.Conclusions:Pharmacological modulators of HSP70 provide effective multimodal neuroprotection due to endothelioprotective and neurotrophic effects. Angiolin and Cerebrocurin demonstrate significant therapeutic potential, offering a promising strategy for mitigating the long-term neurological sequelae of IUH.

Periodontitis (P) is one of the most common human dental diseases, with significant medical and social implications. According to the World Health Organization, more than 45% of the adult population worldwide exhibits clinical signs of periodontitis, with 10%–15% of cases becoming generalized with destruction of the alveolar bone. This review presents the results of modern research demonstrating that the etiopathogenesis of periodontitis is not limited to local microbial factors; systemic, social, and behavioral factors can play a significant role, determining the body's susceptibility to chronic inflammation. In this study, we focus on the role of cytokines in the athogenesis of periodontitis. Based on modern research, we demonstratethe general biological significance of cytokines and their role in initiating periodontal inflammation and systemic diseases associated with periodontitis. The molecular and biochemical cytokine-dependent mechanisms of initiation and progression of oxidative stress in periodontitis are covered in detail. The role of individual cytokines in the pathogenesis of periodontitis is shown: interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF-α), interferon-gamma, IL-10, IL-23, IL-17, and Th17 cells. The review presents a modern approach to complex drug therapy of periodontitis. The arsenal of antiseptics, antibiotics, and synthetic antimicrobial agents available to dentists is presented. A new approach is demonstrated in the use of probiotics—live microorganisms (probiotics, symbiotics, and bacteriophages) that maintain the balance of the oral microbiome. Beyond standard antimicrobial and anti-inflammatory therapies, host modulators, antioxidants, and bioregulatory agents play a vital role in treating P. They effectively suppress proinflammatory cytokines, mitigate oxidative stress, and improve metabolic activity in affected tissues. We present data on the development of individual regenerative structures using bioactive polymers and 3D printing for the future treatment of chronic periodontitis, as well as the potential use of biomaterials with nanostructured components, collagen matrices with nanoparticles, hydrogels with functional peptides, synthetic polymers with a modest antibacterial effect, and transplantation of mesenchymal stem cells, as well as bioactive scaffolds with stem cells. The most important section of the review is devoted to the clinical and pharmacological properties of cytokine modulators—TNF-α blockers, IL-6 blockers, and IL-1 blockers. Using current research results, including our own, we demonstrate the potential of using an IL-1 receptor antagonist and its new dosage form, such as a dental gel.

This study describes the rational design, synthesis, and evaluation of forty 2'-R-6'H-spiro(cycloalkyl/heterocyclyl)[1,2,4]triazolo[1,5-c]quinazolines as potential neuroprotective agents targeting multiple receptor systems implicated in cognitive dysfunction. The molecular design integrated structural features from established nootropic and anxiolytic pharmacophores to create compounds with putative multi-target activity. In silico ADMET analyses assessed drug-likeness parameters, while molecular docking studies evaluated binding interactions with nine neuroreceptor targets: glutamate GluA3, GABA(A)R, dopamine D2, serotonin 5-HT1A and 5-HT7, cannabinoid CB2, muscarinic M2 acetylcholine, corticotropin-releasing factor receptor 1 (CRF1R), and metabotropic glutamate receptor 5 (mGluR5). Based on computational predictions, selected compounds underwent preliminary in vivo screening using a ketamine-induced cognitive impairment model in rats. Behavioral assessments examined anxiety-related responses and cognitive performance relative to piracetam and fabomotizole controls. Biochemical analyses measured inflammatory markers (IL-1β, caspase-1), cell survival indicators (Bcl-2), and hypoxic adaptation responses (HIF-1 mRNA). Docking studies indicated favorable binding profiles across tested receptor targets compared to reference ligands, with calculated affinities suggesting potential modulatory interactions. The experiments showed that compounds 25, 26, and 32 attenuated ketamine-induced behavioral alterations, demonstrating effects in anxiety reduction and cognitive performance that appeared numerically greater than piracetam and fabomotizole, though the magnitude and statistical robustness of these differences require further characterization. Compound 31 reduced IL-1β expression by 72% and caspase-1 by 80% relative to ketamine-treated controls. Compound 26 increased Bcl-2 expression by 96% and HIF-1 mRNA levels by 3.5-fold compared to control conditions. These findings suggest that spirotriazoloquinazolines may function as positive modulators at cognitive-enhancing receptors, potentially exerting neuroprotective effects through anti-inflammatory and anti-apoptotic mechanisms. Further investigation is necessary to validate the observed effects, establish dose-response relationships, and elucidate the molecular mechanisms underlying the apparent neuroprotective properties of these compounds.

Chronic heart failure (CHF) remains a leading cause of global mortality, characterized by profound molecular and biochemical disturbances, including nitric oxide (NO) system dysfunction, mitochondrial impairment, and oxidative stress. While standard therapies such as ACE inhibitors, SGLT2 inhibitors, and beta-blockers address clinical symptoms, their capacity to interrupt the underlying biochemical mechanisms of cardiomyopathy is often limited. This review examines the pathophysiological role of impaired NO production and reactive oxygen species (ROS) accumulation in exacerbating myocardial contractile dysfunction and disease progression. Special focus is directed toward the development of next-generation β1-blockers with multifunctional properties, including antioxidant, NO-mimetic, and antiapoptotic effects. Evidence suggests that the novel compound Hypertril (1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide) exhibits significant cardioprotective potential. Experimental data indicate that Hypertril improves eNOS/iNOS expression and enhances NO bioavailability more effectively than conventional β-blockers, leading to stabilized ECG parameters and restored energy metabolism. These findings underscore the clinical relevance of developing NO-mimetic agents to optimize the pharmacological management of CHF.

BackgroundThe management of pharmacotherapy in patients with multimorbidity and polypharmacy is a difficult task in routine clinical practice. Clinicians must consider diagnoses, prescribed drugs, contraindications, drug-drug interactions, renal and hepatic function, laboratory values, dose limits and individual risk factors. Clinical decision support systems in traditional settings are based on static rules, and hard to update. Standalone large language models are capable of processing clinical language but their outputs may be unsupported by evidence, incomplete or out of date. In this study, we developed and evaluated a hybrid multi-agent GraphRAG framework for personalised pharmacotherapy safety verification.MethodsWe developed a system that integrates graph based retrieval with large language models. The framework was composed of three parts: (1) a schema for a pharmacotherapy knowledge graph that encoded indications, contraindications, interactions, laboratory thresholds, dose limitations and relevant patient conditions; (2) an Extractor–Critic workflow that transformed unstructured medical text into graph elements with quality checks prior to their incorporation; and (3) a retrieval and re-ranking module that leveraged semantic search, graph traversal and safety-directed scoring. The system was evaluated on 12 benchmark cases extraction and 30 clinical safety questions answering. Comparison of conventional RAG and GraphRAG was done using linear mixed effects models, permutation testing, and paired case-level analysis.ResultsThe multi-agent extraction workflow beat the zero-shot baseline. Strict F1 improved by 0.156 points (p < 0.01), mainly due to higher ecall (+0.172, p < 0.001). For clinical question answering, we found that GraphRAG outperformed conventional RAG in terms of medical accuracy (0.545 vs. 0.443, absolute difference of 0.102, p = 0.04). GraphRAG provided the better answer 66.7% of the time. The advantage was greatest where safety was dependent on contra-indications, laboratory cut-offs or patient specific factors. Smaller models performed as well as the larger models with the same GraphRAG configuration.ConclusionThe evaluation revealed that the integration of LLM-based extraction with a pharmacotherapy knowledge graph enhanced safety-oriented clinical decision support. GraphRAG provided more accurate and traceable answers than traditional RAG. Routine adoption will require validation on larger graphs, a wider range of datasets and real clinical populations, but this approach may be appropriate for cost sensitive and privacy conscious workflows.

Prenatal hypoxia (PH) is a key factor in the development of long-term cardiovascular disorders, which are caused by various mechanisms of endothelial dysfunction (ED), including those associated with NO deficiency. This emphasizes the potential of therapeutic agents with NO modulator properties, such as Thiotriazoline, Angiolin, Mildronate, and L-arginine, in the treatment of PH. Methods: Pregnant female rats were given a daily intraperitoneal dose of 50 mg/kg of sodium nitrite starting on the 16th day of pregnancy. A control group of pregnant rats received saline instead. The resulting offspring were divided into the following groups: Group 1—intact rats; Group 2—rat pups subjected to prenatal hypoxia (PH) and treated daily with physiological saline; and Groups 3 to 6—rat pups exposed to prenatal hypoxia and treated daily from the 1st to the 30th day after birth. Levels of sEPCR, Tie2 tyrosine kinase, VEGF-B, SOD1/Cu-Zn SOD, GPX4, and GPX1 in the heart’s cytosolic homogenate were assessed using ELISA. The expression of VEGF and VEGF-B mRNA was analyzed via real-time polymerase chain reaction, and the nuclear area of myocardial microvessel endothelial cells was evaluated morphometrically. Results: We have shown that only two representatives of this group—Angiolin and Thiotriazoline—are able to exert full effect on the indices of endothelial dysfunction after PH to decrease sEPCR, increase Tie-2, VEGF-B and VEGF-B mRNA, Cu/ZnSOD, and GPX in myocardial cytosol, and increase the area of endotheliocyte nuclei in 1- and 2-month-old rats in comparison with the control. Conclusions: Our results experimentally substantiate the necessity of early postnatal cardio- and endothelioprotection using NO modulators, taking into account the role of NO-dependent mechanisms in the pathogenesis of cardiovascular system disorders in neonates after PH.

Prenatal hypoxia (PH) significantly impacts the central nervous system (CNS) development, often resulting in long-term cognitive, behavioral, and neurological deficits due to oxidative stress, mitochondrial dysfunction, and neuroapoptosis. The brain’s endogenous protective mechanisms are often insufficient under prolonged hypoxia, necessitating the development of novel neuroprotective strategies. This study aimed to evaluate the neuroprotective efficacy of nasal administration of Angiolin gel—a novel pharmacological agent—in experimental model of PH. Chronic intrauterine hypoxia was induced in pregnant rats via sodium nitrite administration. Newborn rats were divided into groups receiving either Angiolin gel intranasally, Piracetam intraperitoneally, or saline (control) for 30 days. Biochemical, morphometric, histoimmunochemical, and neurophysiological methods were employed to assess outcomes. The results demonstrated that PH induced mitochondrial dysfunction, oxidative and nitrosative stress, GABAergic system impairment, and neuroapoptosis, leading to increased neonatal mortality and deficits in cognitive and motor functions. Angiolin gel administration significantly enhanced energy metabolism by restoring mitochondrial enzyme activities (SDH, MDH, and CPK), increasing ATP production, and reducing lactate accumulation. It also normalized GABAergic parameters, increased the activity of antioxidant enzymes (Cu/Zn-SOD, GPX1/4) and decreased nitrosative stress markers (iNOS, nitrotyrosine). Histomorphometric analysis revealed preserved neuronal density and reduced apoptosis in the hippocampus, alongside enhanced Fos/Bcl-2 expression. Behavioral tests demonstrated improved motor activity, memory retention, and exploratory behavior, with a 47% reduction in early mortality. Comparative analysis showed superior efficacy of Angiolin over Piracetam, which exacerbated lactate acidosis. These findings suggest that intranasal administration of Angiolin gel effectively targets multiple pathophysiological pathways triggered by PH, providing robust neuroprotection and promoting functional recovery. Given its favorable safety profile and the non-invasive nature of intranasal delivery, Angiolin gel represents a promising therapeutic approach for mitigating the long-term neurological consequences of prenatal hypoxia and warrants further clinical investigation in neonatal and pediatric neurology.

Prenatal hypoxia (PH) adversely affects the development of the fetal heart, contributing to persistent cardiovascular impairments in postnatal life. A key component in regulating cardiac physiology is the nitric oxide (NO) system, which influences vascular tone, myocardial contractility, and endothelial integrity during development. Exposure to PH disrupts NO-related signaling pathways, leading to endothelial dysfunction, mitochondrial damage, and an escalation of oxidative stress—all of which exacerbate cardiac injury and trigger cardiomyocyte apoptosis. The excessive generation of reactive nitrogen species drives nitrosative stress, thereby intensifying inflammatory processes and cellular injury. In addition, the interplay between NO and hypoxia-inducible factor (HIF) shapes adaptive responses to PH. NO also modulates the synthesis of heat shock protein 70 (HSP70), a critical factor in cellular defense against stress. This review emphasizes the involvement of NO in cardiovascular injury caused by PH and examines the cardioprotective potential of NO modulators—Angiolin, Thiotriazoline, Mildronate, and L-arginine—as prospective therapeutic agents. These agents reduce oxidative stress, enhance endothelial performance, and alleviate the detrimental effects of PH on the heart, offering potential new strategies to prevent cardiovascular disorders in offspring subjected to prenatal hypoxia.

The study of mitochondrial dysfunction has become increasingly pivotal in elucidating the pathophysiology of various cerebral pathologies, particularly neurodegenerative disorders. Mitochondria are essential for cellular energy metabolism, regulation of reactive oxygen species (ROS), calcium homeostasis, and the execution of apoptotic processes. Disruptions in mitochondrial function, driven by factors such as oxidative stress, excitotoxicity, and altered ion balance, lead to neuronal death and contribute to cognitive impairments in several brain diseases. Mitochondrial dysfunction can arise from genetic mutations, ischemic events, hypoxia, and other environmental factors. This article highlights the critical role of mitochondrial dysfunction in the progression of neurodegenerative diseases and discusses the need for targeted therapeutic strategies to attenuate cellular damage, restore mitochondrial function, and enhance neuroprotection.

The study of mitochondrial dysfunction has become increasingly pivotal in elucidating the pathophysiology of various cerebral pathologies, particularly neurodegenerative disorders. Mitochondria are essential for cellular energy metabolism, regulation of reactive oxygen species (ROS), calcium homeostasis, and the execution of apoptotic processes. Disruptions in mitochondrial function, driven by factors such as oxidative stress, excitotoxicity, and altered ion balance, lead to neuronal death and contribute to cognitive impairments in several brain diseases. Mitochondrial dysfunction can arise from genetic mutations, ischemic events, hypoxia, and other environmental factors. This article highlights the critical role of mitochondrial dysfunction in the progression of neurodegenerative diseases and discusses the need for targeted therapeutic strategies to attenuate cellular damage, restore mitochondrial function, and enhance neuroprotection.

Beta-blockers are first-line drugs in the treatment of chronic heart failure (CHF). However, there is no consensus on the specific effects of the beta-blockers of the I-III generation on energy metabolism in CHF. The aim of this study is to conduct a study of beta-blockers of different generations on myocardial energy metabolism in experimental CHF. CHF was modeled in white outbred rats by administering doxorubicin. The study drugs were administered intragastrically—new drug Hypertril (1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide)-3.5 mg/kg, Metoprolol—15 mg/kg, Nebivolol −10 mg/kg, Carvedilol 50 mg/kg, and Bisoprolol, 10 mg/kg. In the myocardium, the main indices of energy metabolism were determined—ATP, ADP, AMP, malate, lactate, pyruvate, succinate dehydrogenase (SDH) activity, and NAD-dependent malate dehydrogenase (NAD-MDH) activity. Traditional second-generation beta-blockers (Metoprolol and Bisoprolol) did not affect the studied indices of energy metabolism, and third-generation beta-blockers with additional properties—Carvedilol and, especially, Nebivalol and Hypertril—improved myocardial energy metabolism. The obtained results will help to expand our understanding of the effect of beta-blockers of various generations used to treat cardiovascular diseases on energy metabolism, and are also an experimental justification for the practical choice of these drugs in the complex therapy of CHF.

Background: beta blockers of three generations are first-line drugs in the treatment of chronic heart failure (CHF). However, to date there is no clear understanding of the effect of beta blockers on myocardial energy metabolism disorders in CHF. The aim of the study: to conduct a study of beta-blockers of different generations on myocardial energy metabolism in the experimental CHF. Methods: CHF was modeled in white outbred rats by administering doxorubicin. The study drugs were administered intragastrically – new drug Hypertril (1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide)-3.5 mg/kg, metoprolol - 15 mg/kg, Nebivolol -10 mg/kg, Carvedilol 50 mg/kg, Bisoprolol, 10 mg/kg. In the myocardium, the main indices of energy metabolism were determined - ATP, ADP, AMP, malate, lactate, pyruvate, succinate dehydrogenase (SDH) activity, NAD-dependent malate dehydrogenase (NAD-MDH) activity. Results: traditional second-generation beta-blockers (Metoprolol and Bisoprolol) did not affect the studied indices of energy metabolism, and third-generation beta-blockers with additional properties - Carvedilol and, especially, Nebivalol and Hypertril improved myocardial energy metabolism. Conclusions: obtained results will help to expand our understanding of the effect of beta-blockers of various generations used to treat cardiovascular diseases on energy metabolism, and are also an experimental justification for the practical choice of these drugs in the complex therapy of CHF.

The authors propose a novel approach to a comprehensive evaluation of neuroprotective effects using both in vitro and in vivo methods. This approach allows for the initial screening of numerous newly synthesized chemical compounds and substances from plant and animal sources while saving animal life by reducing the number of animals used in research. In vitro techniques, including mitochondrial suspensions and neuronal cell cultures, enable the assessment of neuroprotective activity, which can be challenging in intact organisms. The preliminary methods help outline the neuroprotection mechanism depending on the neurodestruction agent. The authors have validated a model of acute cerebrovascular accident, which simulates key cerebrovascular phenomena such as reduced cerebral blood flow, energy deficit, glutamate–calcium excitotoxicity, oxidative stress, and early gene expression. A significant advantage of this model is its ability to reproduce the clinical picture of cerebral ischemia: impaired motor activity; signs of neurological deficits (paresis, paralysis, etc.); as well as disturbances in attention, learning, and memory. Crucial to this approach is the selection of biochemical, molecular, and cellular markers to evaluate nerve tissue damage and characterize potential neuroprotective agents. Additionally, a comprehensive set of molecular, biochemical, histological, and immunohistochemical methods is proposed for evaluating neuroprotective effects and underlying mechanisms of potential pharmaceutical compounds.

Objectives: Periodontal diseases are a rather complex problem of modern dentistry and do not have only medical but also social significance. : The objective of this study is to weigh the effect of a mixture of Thiotriazoline and L-arginine (1:4) on the parameters of the system of endogenous cytoprotection of blood and periodontal illness in rats with experimental chronic generalized periodontitis and substantiate further study of this blend. Materials and Methods: The study aimed to evaluate the impact of a combination of Thiotriazoline and L-arginine (in a ratio of 1:4) on the parameters of the endogenous blood cytoprotection system and periodontium in rats with experimental chronic generalized periodontitis. A group of outbred rats weighing 190-220 g and sourced from the vivarium of the Institute of Pharmacology and Toxicology of the Academy of Medical Sciences of Ukraine were divided into four groups, each consisting of 10 animals. : (1) Intact group, animals that were injected intragastrically with a solution of sodium chloride to chloride 0.9% for 30 days. (2) control, animals with experimental CGP who intragastrically sodium chloride solution 0.9% for 30 days. (3) animals with experimental CGP were injected intramuscularly with Thiotriazoline + L-arginine (1:4) in a dosage of 200 mg/kg (30 days). (4) animals with experimental CGP, for which daily intragastric reference drug Mexidol, in dosage 250 mg/kg (30 days). : In this study, we utilized two substances: Thiotriazoline and L-arginine hydrochloride. The combination of Thiotriazoline and L-arginine (in a ratio of 1:4) was prepared at the Department of Pharmaceutical Chemistry of ZSMU. At the conclusion of the experiment, the rats were carefully removed from the study while under thiopental-sodium anesthesia, and administered at a dosage of 40 mg/kg. Results: We have found that the administration of a combined preparation of Thiotriazoline with L-arginine to rats with CGP leads to a significant decrease in the blood concentration of pro-inflammatory cytokines IL-1b and TNF-a by 56.1% and 71%, respectively. Conclusion: The administration of Mexidol at a dosage of 250 mg/kg, as well as the combination of Thiotriazoline and Larginine in a ratio of 1:4 at a dosage of 200 mg/kg, resulted in a significant reduction in gingival pocket depth in animals with CGP. Specifically, the gingival pocket depth was reduced to 6 mm (p < 0.05) with Mexidol and further reduced to 4 mm (p < 0.05) with the combination of Thiotriazoline and L-arginine. Additionally, the animals exhibited minimal bleeding, swelling, and tooth mobility when treated with the combination of Thiotriazoline and L-arginine. : The administration of a combination of Thiotriazoline and L-arginine (in a ratio of 1:4) at a dosage of 200 mg/kg to animals with CGP resulted in a noteworthy reduction in the blood concentration of pro-inflammatory cytokines IL-1b and TNF-a. Specifically, there was a significant decrease of 56.1% (p < 0.05) in IL-1b and 71% (p < 0.05) in TNF-a levels. The course administration of a combination of Thiotriazoline and L-arginine (1:4) (200 mg/kg) to animals with CGP led to an increased expression of HSP70 mRNA (p < 0.05) in the periodontium by 8.2 times and HIF-1a mRNA by 8.2 times. 2.8 times (p < 0.05) against the background of an increase in the blood concentration of HSP70 by 95% (p < 0.05). Also, in the periodontium of animals in this group, a decrease in the expression of c-Fos mRNA by 36.7% (p < 0.05) was found compared to the control group.

Prenatal hypoxia plays a crucial role in programming long-term cardiovascular dysfunction through mechanisms like endothelial dysfunction and nitric oxide system impairment, highlighting the potential of therapeutic agents, such as thiotriazoline, angiolin, mildronate, and L-arginine, for mitigating these adverse effects. Methods. Levels of sEPCR, Tie2 tyrosine kinase, VEGF-B, SOD1/Cu-Zn SOD, GPX4, and GPX1 were measured in the heart's cytosolic homogenate using ELISA. Results. Modeling prenatal hypoxia (PH) resulted in significant alterations in the concentrations of proteins linked to endothelial function and oxidative stress in the heart cytosol of experimental animals, including an increase in sEPCR and reductions in Tie-2, VEGF-B, Cu/ZnSOD, GPX4, and GPX1 levels. Postnatal administration of nitric oxide modulators (L-arginine, thiotriazoline, angiolin, and mildronate) demonstrated differential efficacy in normalizing these proteins. Notably, angiolin produced the most substantial therapeutic effect, restoring Tie2, VEGF-B, and antioxidant enzyme levels to near-normal levels. Our results highlight the efficacy of Angiolin and Thiotriazoline in restoring endothelial function and antioxidant enzyme levels in the car-diovascular system following prenatal hypoxia, supporting their potential as early postnatal in-terventions to prevent long-term cardiovascular dysfunction.

Endothelial dysfunction is characterized by a decrease in the bioavailability of the vasodilator – nitric oxide (NO), and an increase in the level of vasoconstrictor substances. This imbalance leads to vasoconstriction, leukocyte attachment and inflammatory reactions in the vascular wall, atherosclerosis and thrombosis. The aim: to evaluate the role of adipose tissue elements in the regulation of parameters of the nitroxidergic system under hypoxia conditions. Materials and methods. The studies were carried out on 30 adult white male Wistar rats. All animals were randomly assigned and divided into groups: a control group (15 rats), type 2 diabetes mellitus (T2DM) was induced in the animals of the second group (15 rats). Isolated fragments of the popliteal arteries (PA) and intrapulmonary artery (IPA) were cleared of perivascular adipose tissue (PVAT-) or left uncleaned (PVAT+) and cut into rings. The simulation of acute hypoxia with further study of medical agents were performed. Results. The PA and IPA with PVAT responded to acute hypoxia with vasoconstriction – an increase in the amplitude of contraction in the first and second phases, and after removing PVAT, they responded with a decrease in the maximum amplitude of contraction by 3.4 times in the 1st phase and an increase in amplitude by 1.8 times in the 2nd phase. Perfusion with Angiolin reduced 2nd phase of HV of the PA and IPA. Adding a combination of Thiotriazoline and L-arginine (1:4) to a solution for perfusion of fragments of arteries of animals with T2DM, causes a significant increase in constrictor reactions in both the 1st and 2nd phases of HV, regardless of presence of perivascular adipose tissue. Conclusions. The presence of PVAT affects the HV of arteries, both in normal and in T2DM. The possibilities of ways of pharmacological modulation of the nitroxidergic system depending on the state of PVAT were determined.

In this study, a 1-(beta-phenylethyl)-4-amino-1,2,4-triazolium bromide (Hypertril) with beta-blocker and NO-mimetic properties, which is of interest for the treatment of chronic heart failure (CHF) was examined. The purpose was to study the effect of various beta-blockers on the indicators of the NO system in a CHF model. CHF was induced with doxorubicin at a cumulative dose of 14 mg/kg in 85 Wistar rats, which were intragastrically administered metoprolol succinate (15 mg/kg), carvedilol (50 mg/kg), bisoprolol (10 mg/kg), nebivolol (10 mg/kg) and Hypertril (3.5 mg/kg). In the heart, the expression of eNOS and iNOS and the concentration of stable metabolites NO, nitrotyrosine and SH groups were determined. Modelling of CHF leads to a decrease in the expression of eNOS and an increase in iNOS and nitrotyrosine, as well as a deficiency of NO and the SH group. Nebivolol, especially Hypertril, had the most pronounced normalising effect on the NO system. The advantage of Hypertril over basic beta-blockers was revealed.

For the first time, to optimize the creation of new neuroprotective agents based on bioflavonoids, we applied information technologies; these include docking analysis to calculate the binding of candidate molecules to the pharmacological target protein transthyretin as well as a program of virtual screening of NO scavengers. As a result of this approach, the substance catechin was isolated from candidate molecules—quercetin, catechin, Epicatechin gallate, Epicatechin, Procyanidin B1, Procyanidin B2, Procyanidin B3, and Catechin-3-gallate—according to docking analysis. As a result of virtual screening, catechin was identified as a potential NO scavenger (55.15% prediction). The results of the prediction were confirmed by in vitro experiments. Course administration of catechin to animals with experimental multiple sclerosis (MS) against the background of methylprednisolone administration completely eliminated lethal cases, reduced the number of diseased animals by 20% as well as prevented the development of severe neurological symptoms by 20% (compared to the methylprednisolone group) and by 60% compared to the control group. Course administration of catechin with methylprednisolone leads to a decrease in the neurodegradation markers in the cytosol of rats, with EAE: NSE by 37% and S-100 by 54.8%. The combined administration of methylprednisolone significantly exceeds the combination of methylprednisolone with the reference drug mexidol by the degree of NSE reduction. The obtained results indicate a significant neuroprotective effect of ocular combinations of methylprednisolone and catechin. The above-mentioned confirms the correctness of the bioflavonoid selection with the help of a virtual screening program.

Background: Designing novel biologically active compounds with anti-inflammatory properties based on condensed quinazolines is a significant area of interest in modern medicinal chemistry. In the present study, we describe the development of promising new bioactive molecules through the bioisosteric replacement of a carbon atom with a sulfur atom in anti-inflammatory agents, specifically 3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)butanoate. Methods: Design and synthetic studies have led to the series of previously unknown substituted 2-[((3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)methyl)thio]carboxylic acids and their esters. These compounds were synthesized by reacting 6-chloroalkyl-3-R-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones with sulfanylalkyl carboxylic acids and their functional derivatives. The purity and structure of the obtained compounds were confirmed using a set of physicochemical methods, including elemental analysis, HPLC-MS, and 1H NMR spectroscopy. Molecular modeling, predicted toxicity, drug-likeness, and pharmacokinetics data were used to select compounds for evaluation of their effects on acute aseptic inflammation (carrageenan-induced paw edema test) and on markers of the inflammatory process. Results: The compound 2-((1-(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)ethyl)thio)acetic acid (compound 2e) was identified as the most active anti-inflammatory agent (AA = 53.41%), demonstrating significant inhibition of both paw edema development and the generation of pro-inflammatory cytokines and mediators. Conclusions: Results from docking studies and analysis of “structure-affinity” correlations revealed that these compounds are promising candidates for further modification and detailed investigation of their anti-inflammatory activity

β-adrenergic blockers have been actively used in the treatment of heart failure, which relieve excessive sympathetic stimulation of the myocardium, reduce calcium overload of cardiomyocytes, reduce the heart's oxygen demand, inhibit lipid peroxidation and stabilize cell membranes, have an antiarrhythmic effect. The aim: to compare efficiency of various drugs with new potential "Hypertril" in the conditions of modeling doxorubicin chronic heart failure (CHF) to improve parameters. Objective: CHF was modeled on 85 white outbred rats weighing 190–220g by administering doxorubicin at a cumulative dose of 15 mg/kg. Material and metods: Nebivalol, Carvedilol, Bisoprolol, Metoprolol and Hypertril were administered intragastrically once a day in the form of a suspension of 1% starch mucus for 30 days after a 14-day administration of doxorubicin. To determine damage, we used the solid-phase immunosorbent sandwich ELISA method, enzyme immunoassay and the immunoturbodimetric method. Result and discussion: Administration of Hypertril to rats with CHF led to a decrease in the blood of the main molecular markers of CHF to the values of intact animals, which indicated its significant cardioprotective effect in comparison with other drugs. Hypertril reduces manifestations of mitochondrial dysfunction, protects the myocardium and positively affects the morphological and functional parameters of cardiomyocytes, inhibits apoptosis