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Objective: to determine the molecular mechanisms of action of 7-hydroxymatairesinol (7(OH)MR), the main lignan of spruce extracts, characterized by oncoprotective and anti-inflammatory properties.Material and methods. The analysis of 7(OH)MR was carried out by chemoinformatic approach using the combinatorial theory of solvability and the topological theory of recognition. The postgenomic approach makes it possible to assess the effect of drugs on genome transcription (transcriptome) and on the proteome as a whole.Results. 7(OH)MP has anti-inflammatory (inhibition of 5-lipoxygenase, matrix metalloproteinase 2, mitogen-activated kinase p38-alpha, leukotriene В4 receptor, prostacyclin receptor), and oncoprotective (antioxidant effect due to inhibition of heme oxygenase-2, inhibition of cyclin-dependent kinases 3 and 4, epidermal growth factor, mTOR protein) pharmacological effects.Conclusion. By reducing the expression of proliferative genes and genes involved in chronic inflammation, the 7(OH)MP molecule inhibits the proliferation of tumor cells. Pharmacoinformatic modeling showed that the anti-inflammatory effects of 7(OH)MR may contribute to increased lifespan in animal models.

Objective: to study the antitumor effects of organic lithium salt (lithium ascorbate) in different doses in comparison with inorganic lithium salt (carbonate).Material and methods. Two series of experiments were carried out on the effect of lithium preparations on the dynamics of transplantable Lewis lung carcinoma (LLC) growth and metastasis in F1 mice (CBA × C57Bl/6j). In the first series, a comparative study of the effects of different lithium ascorbate doses (1 and 10 mg/kg/day based on elemental lithium) was performed, and in the second series, a comparison was made of the effects of lithium ascorbate and carbonate when used at the same dose (5 mg/kg/day).Results. Significant antitumor effects were found for lithium ascorbate lower doses (1 and 5 mg/kg/day). A statistically significant antitumor effect of lithium ascorbate was observed from Day 10 throughout the entire observation period (tumor growth inhibition index (TGII) 30–40%). The antitumor effect of lithium carbonate in this experiment was less pronounced and stable (TGII 20–30%). No antimetastatic effect was observed with both preparations.Conclusion. Subchronic intragastric administration of lithium ascorbate and carbonate to tumor-bearing animals at a daily dose of 5 mg/kg, an antitumor effect is observed, manifested by LLC growth inhibition. Effective and safe antitumor doses of lithium ascorbate are in the range of 1–5 mg/kg.

Objective: to conduct chemoreactomic, pharmacoinformatic and chemoneurocytological analyzes of the properties of racetams (piracetam, aniracetam, pramiracetam, levetiracetam, fonturacetam).Material and methods. Chemoreactomic, pharmacoinformatic and chemoneurocytological methods of molecule properties analyzis are based on chemoreactomic methodology – the latest direction in the application of machine learning systems in the field of postgenomic pharmacology. Analysis of pharmacological capabilities of molecules within the framework of chemoreactomic methodology is carried out by comparing the chemical structure of racetam molecules with the structures of molecules for which pharmacological properties were studied using training artificial intelligence algorithms based on big data information presented in PubChem, HMDB, STRING, PharmGKB databases. Based on the entire complex of differences between molecules in interactions with receptor proteins, an “anti-obesity” score was calculated for each one as a serial number of this molecule in descending order by corresponding IC50, EC50 chemoreactomic constants values.Results. The lipolytic effect is predicted specifically for fonturacetam as a result of activation by this molecule of β3-adrenoceptors, adenosine receptors, glucagon-like peptide, sphingosine phosphate and peroxisome proliferators, as well as specific inhibition of cannabinoid, opioid, histamine, glutamate, nociceptin, orexin and neuropeptide Y receptors. Due to these mechanisms fonturacetam will contribute to normalizing appetite and improving adipose tissue metabolism. The total lipolytic effect score was calculated for all established interactions with receptors and amounted to 4.3±0.9 for fonturacetam, 3.0±1.4 for pramiracetam, and 2.5±1.5 for all other molecules.Conclusion. The results of the analysis suggest that the lipolytic effects of fonturacetam (Actitropil – Pharmstandard, Russia) will be much stronger than for other racetams (piracetam, aniracetam, pramiracetam, levetiracetam). Chemoreactomic analysis of fonturacetam indicated new mechanisms of pharmacological action of the molecule, providing a decrease in excess appetite and body weight normalization. Fonturacetam is the only nootropic drug indicated for the treatment of obesity.

Background. Lithium salts are used in psychiatry and may exhibit neuroprotective effects due to anion constituents.Objective: to study a dose-dependent effect of oral lithium ascorbate (LiAsc) and lithium carbonate on manifestation and severity of primary generalized seizures caused by thiosemicarbazide in rats in vivo.Material and methods. The study was conducted on 30 Wistar white male rats weighing 200–300 g in five groups: control, lithium carbonate 5 mg/kg, LiAsc 5, 10, 15 mg/kg/day, administered by probing for 14 days. The model of primary generalized seizures was reproduced by intraperitoneally administered 28 mg/kg thiosemicarbazide. The degree of neurological deficit was assessed based on seizure indicators (latency period before seizures, number of seizures and startles, clonic seizures, etc.). Histopathological studies of brain tissue were carried out using morphometry of histological sections on BioVision image analyzer (Austria).Results. A course of carbonate and LiAsc significantly reduced seizure duration. The use of LiAsc at doses of 10–15 mg/kg/day not only significantly shortened seizure duration (p=0.01), but also increased the latent period before seizures (p=0.03), reduced the number of seizures (р

The article presents an analysis of publications on myoinositol in order to clarify the possibilities of prescribing drugs based on it. Myoinositol is one of the endogenous human metabolites that has a significant effect on the functioning of cells and tissues of the whole body. The main function of myoinositol and its derivatives is to participate in intracellular signal transmission and ensure the functioning of such important receptors as insulin receptors, catecholamines, metabotropic receptors of various neurotransmitters, growth factors, etc. (Myoinositol is the basis for the synthesis of an important group of signaling molecules, inositol phosphates, which mediate signal transmission from growth factor receptors and neurotransmitters). Most inositol-dependent proteins with known functions are necessary for the vital functions of the cardiovascular, immune system, and connective tissue structure. Equally important is the role of myoinositol in maintaining the functioning of the central nervous system (including neurotrophic and neuroprotective roles), sugar metabolism (primarily the signaling cascade of insulin) and the functioning of the kidneys and liver. Myoinositol subsidies contribute to the prevention of folate-resistant malformations and neuroprotection of the brain under stress.

7-hydroxymatairesinol (7(OH)MR) is the main lignan of spruce extracts, characterized by oncoprotective and anti-inflammatory properties. The results of chemoreactome modeling made it possible to formulate the molecular mechanisms of the pharmacological effects of 7(OH)MR for anti-inflammatory (inhibition of 5-lipoxygenase, matrix metalloproteinase MMP2, mitogen-activated kinase p38-alpha, leukotriene b4 receptor, prostacyclin receptor), oncoprotective (antioxidant effect due to inhibition heme oxygenase-2, inhibition of cyclin-dependent kinases 3 and 4, epidermal growth factor, mTOR protein). An assessment of the transcriptomic effects of 7(OH)MR in breast cancer cells showed significant dose-dependent effects on the transcription of 3468 of 12700 genes. The 7(OH)MR molecule, reducing the expression of proliferative genes (401 genes) and chronic inflammation (148 genes), while simultaneously increasing the transcription of oncoprotective immunity genes (100 genes), inhibits the proliferation of tumor cells. Experiments on solid Ehrlich carcinoma showed a significant oncoprotective effect of 7(OH)MR at doses of 60, 120 mg/day, even while taking estrogen (p = 0.007). A clinical study showed that 7(OH)MR (60 mg/day, 1 month) helps normalize estrogen metabolism and improve the clinical symptoms of mastopathy.

Background. Nonsteroidal anti-inflammatory drugs (NSAIDs) are characterized by ulcerogenic effects and used for effective and safe pharmacotherapy of inflammation and pain. The zinc-containing drug acyzole is a promising anti-inflammatory drug that potentially does not have this drawback. Objective: to conduct chemoreactomic modeling of the pharmacological effects of acyzole and zinc derivatives of well-known NSAIDs (diclofenac, nimesulide, ketorolac).Material and methods. The analysis of the pharmacological capabilities of NSAIDs was based on a chemoinformatic approach, i.e. comparing the chemical structure of the studied molecules with the structures of millions of other molecules with established molecular pharmacological properties. The analysis procedure was based on the latest machine learning technologies developed in the theory of topological and metric analysis of feature descriptions.Results. It was shown that acyzole might have an anti-inflammatory effect due to its impact on the activity of cytokines and, partly, on the metabolism of prostaglandins and leuktrienes. The central effects of acyzole are comparable to those of zinc-NSAIDs. The analgesic effect of acyzole may be associated with kinin receptors inhibition, and weak antihistamine and antinociceptin effects. Acizol may also exhibit a gastroprotective effect. It was established that acyzole, to a lesser extent than the reference molecules, negatively affected the metabolism of vitamins and microelements.Conclusion. Chemoreactomic profiling of acyzole indicates prospects for its use as an anti-inflammatory drug.

Background. The search for an effective and safe pharmacotherapy for tumor diseases includes the evaluation of the action of candidate molecules on various types of tumor cells. Vitamin B12 and its derivatives are promising molecules whose properties can be controlled through chemical modifications.Objective: conducting in silico chemoreactom screening and in vitro experimental study of aquacobalamin and heptamethyl ester of cyanoaquacobyrinic acid (HECСA).Material and methods. Chemoreactome screening was carried out on the basis of a problem-oriented theory of chemograph isomorphism analysis, which is an extension of the algebraic approach to machine learning and recognition problems. Trainable algorithms for calculating chemical distances between molecules were used, on the basis of which the values of half-maximal inhibitory concentration (IC50) were calculated. Screening was carried out for 470 cultures of human tumor cells, including SNB19 (astrocytoma), HCT116 (colon cancer), HeLa (cervical carcinoma), BT-474 (breast duct carcinoma), and A549 (lung carcinoma) cell lines. Dicyanocobyric acid heptamethyl ester ((CN)2Cby(OCH3)7) was obtained by boiling a solution of vitamin B12 in methanol with sulfuric acid (1.0 M) for 4 days. HECСA ((CN)(H2O)Cby(OCH3)7) was obtained by vacuum drying an aqueous solution of (CN)2Cby(OCH3)7 (pH 4.0 and 25 °С). The ester structure and purity were confirmed by 1H nuclear magnetic resonance data, elemental analysis, and MALDI-ToF (matrix-assisted laser desorption/ionization time of flight) mass spectroscopy. Experimental studies of tumor cell cultures were carried out using the MTT testwith aquacobalamin and HECСA on cell lines of immortalized (telomerized) fibroblasts (Fb-hTERT), lung carcinoma (A549), and breast duct cancer (BT-474).Results. Chemoreactome screening of the effects of molecules on tumor cells made it possible to obtain estimates of cell growth IC50 for 470 tumor cell lines. Depending on cell line and vitamin B12 derivative molecule, IC50 values varied in a fairly wide range: from 15 to 2000 nM. In vitro studies on cultures of two human tumor cell lines (BT-474 and A549) and telomerized Fb-hTERT fibroblasts confirmed the cytotoxic effect of aquacobalamin and its hydrophobic derivative HECСA. It was shown that aquacobalamin had weak cytotoxic properties in the concentration range of 3.125–200 µg/l (IC50 > 200 nM), and HECСA significantly reduces the survival of BT-474 and A549 tumor cell lines at high concentrations (100–200 µg/l, IC50 about 100 nM).Conclusion. Correspondence was shown between the results of in silico chemoreactome screening and in vitro cell culture studies: IC50 values for HECСA were significantly lower than for aquacobalamin, and the conversion factor from chemoreactome estimates to experimental ones was almost the same (2.64 for BT-474, and 2.63 for A549). The results of chemoreactome screening for other tumor cell lines can be used to plan further cell experiments with vitamin B12 derivatives.

Background. Renal-hepatic dysfunction, which often occurs in liver dysfunction, requires the use of effective and safe nephroprotective agents. Human placenta hydrolysates (HPH) are hepatoprotectors, but little is known about HPH nephroprotective properties and the molecular mechanisms of their implementation.Objective: identification of potential molecular mechanisms of Laennec® HPH neuroprotective action based on bioinformatic analysis of collected mass spectrometric data.Material and methods. Methods of proteomic analysis of peptide preparations were used. The analysis of Laennec® HPH peptide composition included four stages: drug purification, chromatographic separation of peptides, determination of the multidimensional mass spectrum of peptide fraction and de novo sequencing of the isolated peptides.Results. The study of Laennec® HPH peptide composition allowed to identify 48 peptides that can exhibit nephroprotective effects. It was shown that HPH contains biologically active fragments of nephroprotective adrenomedullins, inhibitor peptides of a number of kinases (FYN, SHH, WNK1/4, SGK1, IRAK4, ROCK1/2) and fibrogenic receptors (PDGFR, TGFB1I1).Conclusion. By inhibiting the listed target proteins, HPH peptides provide nephroprotection through reducing inflammation, anti-stress effects and preventing fibrotic changes in kidney tissue

Objective: comprehensive analysis of the spectrum of antibacterial action of bactеriocins.Material and methods. Chemomicrobiome analysis of bacteriocins A/B, C, S, 28b, RS-2020 was performed to assess the minimum inhibitory concentration (MIC) values for 152 strains of pathogenic bacteria and the area under the growth curve (AUC) values for a representative sample of normobiota (38 human commensal bacteria).Results. Compared to other molecules, bacteriocin C was characterized by lower MIC constants for a wide range of pathogenic bacterial strains. Thus, it more effectively inhibited strains of pathogens of bacterial pneumonia (H. influenzae, S. mutans, S. pneumoniae, S. pyogenes), nosocomial infections (K. pneumoniae, P. aeruginosa, S. aureus, S. epidermidis, S. pneumoniae), skin diseases (M. audouinii, T. mentagrophytes, etc.), urinary tract infections (E. cloacae, P. mirabilis and P. vulgaris), Fusobacterium necrophorum and Candida fungi. At the same time, bacteriocin C to a lesser extent than the reference molecules inhibited the growth of the normophysiological microbiota of the Bacteroides, Enterococcus genera, non-pathogenic Escherichia, yeast S. cerevisiae and others. By stimulating butyrate (butyric anion) producing microorganisms, bacteriocin C can exhibit prebiotic properties.Conclusion. The main structural features of the bacteriocin C molecule associated with the antibacterial effect on pathogenic microbiota were identified and described.

Objective: to systematize fundamental, clinical, and epidemiological data on the oncoprotective effects of chondroprotectors: chondroitin sulfate (CS), glucosamine (including glucosamine sulfate, GS), and undenatured type II collagen (UC-II).Material and methods. A systematic computer analysis of 6176 publications on the relationship between CS/GS/UC-II and tumor diseases found by the query “(glucosamine OR chondroitin OR ((“Collagen Type II” OR “type II collagen”) AND pharmacology)) AND (Cancer OR cancers OR tumor OR tumors OR tumors OR tumour*) NOT tumor necrosis)” in PubMed and Embase databases was performed. All articles of any format from 1900 to the present day with full available abstracts were taken. A topological approach to data analysis was used.Results. Large-scale clinical and epidemiological studies and meta-analyses showed that regular consumption of CS/GS reduced the risk of colorectal cancer and lung cancer, as well as mortality from tumor diseases. The mechanisms of oncoprotective action of CS/GS are through inhibition of the pro-inflammatory cascade of tumor necrosis factor alpha, CD44 receptor and nuclear factor kappa B, and initiation of tumor cell apoptosis. By modulating the CD44 receptor and specific O-glycosylation of intracellular proteins, GS inhibits the pro-inflammatory effects of arachidonic acid cascade, interleukins IL-6, IL-8, the PI3K/Akt proliferative pathway, and cyclin-dependent kinases. The first postgenomic studies of CS/GS oncoprotective effects, including microbiome studies, was performed. Additionally, CS contributes to the inhibition of the effects of vascular endothelial growth factor and matrix metalloproteinases involved in tumor metastasis and invasion. Potentially, CS/GS oncoprotective effects may be enhanced by the anti-inflammatory effect of UC-II: the addition of NC-II substance to CS/GS complex makes it possible to reduce the autoimmune branch of pathogenesis not only in primary, but also in secondary OA and rheumatoid arthritis.Conclusion. The CS and glucosamine (including GS) chondroprotectors exhibit oncoprotective effects. The use of CS and GS together with UС-II standardized pharmaceutical forms can enhance their anti-inflammatory and immunomodulatory effects.

In periodicals, vitamins and vitamin-mineral complexes (VMCs) are “accused” of having allegedly carcinogenic effects. The results of a systematic review of the literature on B vitamins presented in this paper clearly show that vitamins have at least no influence on tumour risk. When analysing experimental and clinical data on this topic, particular attention should be paid to the dosage of vitamins in monotherapy and when used as part of a VMCs.

Mass spectrometric sequencing of peptides in Laennec indicated the presence of 5 peptides in the drug, the biological activity of which may determine the antibacterial properties of the drug. The most significant result of this study is the presence in Laennec of a fragment of the antibacterial peptide cathelicidin (LL-37), an important vitamin D-dependent factor of innate immunity. Other Laennec peptides help reduce excess inflammation by inhibiting the activity of the NF-kB protein, which mediates the effects of TNF-α.

Currently, the study of promising “biogenic stimulants” that exhibit pathogenetic effects in relation to various diseases continues. The first results of studies of peptide “biogenic stimulants” based on human placenta extracts (HPE) were obtained by Prof. Filatov VP in the thirties of the 20th century. Currently, through modern methods of postgenomic pharmacology (including high-precision mass spectrometry, enzyme-linked immunosorbent assay and sequencing), it becomes possible to obtain new data on the structure and functions of peptide extracts, which indicates the molecular pharmacological mechanisms of their action. Analysis of peptide fractions of individual standardized ENPs and the results of clinical studies of these ENPs indicate a wide range of clinical applications of ENPs: (1) liver diseases; (2) viral diseases — COVID-19, etc.; (3) diseases accompanied by iron overload and hyperferritinemia; (4) chronic fatigue syndrome; (5) skin diseases; (6) joint pathologies; (7) acceleration of wound healing; (8) diseases associated with the female reproductive system.

Palm oil is a component of most food products, characterized by a high content of palmitic and oleic acids, an excess of which leads to the formation of tripalmitins, practically do not respond to enzymatic hydrolysis by lipoprotein lipase and predetermine the development of obesity, type 2 diabetes mellitus and atherosclerosis. This paper presents the results of a study of the drug Laennek, produced on the basis of standardized hydrolysates of the human placenta (HRP). The use of HRP under the influence of excessive consumption of palm oil in the diet led to a significant decrease in markers of liver dysfunction (ALT), which increase with an enriched diet of refined palm oil (bilirubin, total protein, ALT, AST). The hepatoprotective effect of Laennek was confirmed by the results of histological and biochemical studies indicating a decrease in the severity and prevalence of fatty liver dystrophy.

Background. The enzymatic cofactor coenzyme Q10 (CoQ10) is involved in the synthesis of adenosine triphosphate in mitochondria. The CoQ10 biosynthesis declines when using statin drugs.Objective: systematization of the impact of coenzyme Q10 on chronic, sluggish systemic inflammation leading to the development of atherosclerosis, liver and pancreas pathologies, and neurodegeneration.Material and methods. Systematic computer analysis of 16,788 publications on CoQ10 found by the query “coenzyme Q10 OR ubiquinone” in PubMed/MEDLINE database of biomedical publications was carried out. Current methods of topological and metric data analysis developed at the scientific school of Academician of the Russian Academy of Sciences Yu.I. Zhuravlev were used.Results. CoQ10 is involved in the regulation of inflammation and exhibits lipid-lowering, hepatoprotective, nephroprotective, anti-asthenic, cardioprotective, and neuroprotective effects. CoQ10 favorably affects carbohydrate metabolism and a wide range of neurological diseases.Conclusion. CoQ10 supplementation improves glycemic control in insulin resistance, kidney function, and is useful in the treatment of migraine and neurodegenerative pathologies (Parkinson’s disease, etc.).

Background. The structure of corrin tetrapyrrole macrocycles (compounds similar in structure to vitamin B12) is a kind of universal chemical template for targeted drug delivery, and the development of chemical sensors and antidotes.Objective: systematization of information on targeted modulation of certain corrins’ properties through chemical modifications.Material and methods. Literature analysis using modern methods of topological and metric data analysis was carried out. All relevant publications (n=863) were extracted from the PubMed/MEDLINE database on request “(cobalamin OR Cobyrinic OR vitamin B12) AND (Molecular Conformation [MeSH Terms] OR Vitamin B 12/*analogs & derivatives/*chemistry [MeSH Terms] OR Vitamin B 12/*chemistry [MeSH Terms] OR Structure-Activity Relationship [MeSH Terms])”.Results. Information was systematized on how it is possible to regulate the properties of vitamin B12 (cobalamin) derivatives by introducing specific substitutions of groups in the corrin ring, on chemical modifications of cobalamin derivatives, biosynthetic approaches to the synthesis of cobalamin derivatives, and the effects of interactions of these modified corrins with “small” inorganic and organic molecules.Conclusion. The results obtained by systematic computer analysis of publications on corrins make it possible to reasonably form samples of candidate molecules for corrin studies in silico, in vitro, and in vivo.

Objective: to evaluate the efficacy and safety of human placenta hydrolysate (HPH) Laennec® in the treatment of nonalcoholic fatty liver disease (NAFLD) in a clinical trial.Material and methods. The study involved hospitalized NAFLD patients (with non-alcoholic steatohepatitis, cirrhosis) (n=34, mean age 53±14 years). In the therapy group (n=17), patients received Laennec® HPH (4 ml intravenous drip infusion in a solution of 5% glucose 5 times a week for 2 weeks). In the control group (n=17), patients hospitalized in other departments of the clinic did not receive any therapy for NAFLD. The effectiveness of therapy was assessed after 2 and 3 weeks by subjective NAFLD symptoms (fatigue, anorexia, bloating, constipation, nausea, and pain in hypochondrium) and biochemical indicators of liver function: levels of blood serum aspartate aminotrans-ferase (AST), alanine notransferase (ALT), gamma-glutamyltransferase (GGT).Results. At the start of the study, there were no significant differences between the groups in the values of the studied indicators of liver function: blood levels of AST, ALT, GGT, etc. By the end of Week 1, a significant decrease in AST levels was registered in the group receiving Laennec® (–35 U/l; control: –8 U/l; p

Introduction. Establishing the effects of anticancer drugs on the transcriptome is an important procedure in postgenomic pharmacology necessary to comprehensively assess the desired and undesirable effects of candidate drugs. Aim: to assess the effects of lignan 7-hydroxymatairesinol (7HMR) on breast tumor cells.Materials and Methods. Chemotranscriptome profiling was carried out in MCF7 cells (breast cancer cell line) after 24-hour incubation with 7HMR. The GEO (Gene Expression Omnibus) database contains samples of data from transcriptomic studies allowing to model dose-dependent compound-related effects on gene expression based on the chemograph-derived combinatorial analysis algorithms. As a result, a panel of genes with altered expression is generated, which are analyzed by the functional linkage method using the international nomenclature of Gene Ontology (GO) linked to biological roles of genes/proteins.Results. Dose-dependent effects of 7HMR on gene transcription (change in transcription by 5 % or more per 1 μmol 7HMR) were established for 3,468 out of 12,700 genes studied. 7HMR significantly reduced the expression of genes involved in maintaining cell proliferation (401 genes including those involved in telomere maintenance), protein synthesis (194 genes) and proteasomal protein degradation (70 genes), energy metabolism in tumor cells (91 genes) and chronic inflammation (148 genes). A decline in the expression of such gene groups retards the processes of proliferation and vital activity along with protecting host body from excessive inflammation. 7HMR contributed to a predominant increase in the transcription of gene groups involved in antitumor activity (more than 100 genes), including the genes involved in maintaining antitumor immunity as well as those mediating the antitumor effects of vitamin D, retinoids, and vitamin C.Conclusion. The revealed changes in gene transcription enhance 7HMR-related effects on proteome proteins and suggest the prospects for using 7HMR for effective and safe prevention and treatment of nodular mastopathy and breast cancer.

Antibiotics are most often used to combat urinary tract infections (UTIs). Taking into account the side effects related to antibiotic therapy, existing antibiotic-resistant strains of uropathogens, as well as the low effectiveness of the vast majority of antibiotics against bacterial agglomerations (biofilms), a search for alternative approaches to treat UTIs is highly relevant. One of the important in such search is presented by use of nutraceuticals – D-mannose (prevents interaction between pathogenic E. coli strains and the urothelium, destroys bacterial biofilms), Lactobacilli (prevents formation of bacterial pathogen biofilms, normalizes human microbiome, alleviates inflammation) and standardized cranberry extracts (inhibits uropathogen adhesion, exerts anti-inflammatory action). The results from basic and clinical studies suggest not only about high safety of such pharmaconutraceutical support of UTIs therapy, but also the effectiveness of separate and combined use of such nutraceuticals comparable to that of antibiotics, especially in treatment of uncomplicated UTIs forms

Osteoarthritis (OA) is a painful and disabling disease that affects millions of people around the world. OA is the most common form of arthritis and is characterized by joint pain and stiffness, leading to a decrease in functional activity and loss of quality of life. Approaches to OA therapy are constantly being revised, as new molecules appear, data on drugs/molecules already in use, including data on adverse events, new randomized controlled trials results, new methods of adjunctive therapy become available. OA therapy and prevention, drugs with chondroprotective properties are prescribed according to the opinion of European experts (2019): chondroitin sulfate (CS), glucosamine sulfate (GS), diacerein, avocado soybean unsaponifiables, hyaluronic acid (HA) for intra-articular administering. Only CS and GS have proven effectiveness and the level of recommendations A1, they are included in clinical recommendations and standards of the Ministry of Health of the Russian Federation (MHRF), and international recommendations according to which CS and GS should be used for a long time (up to 6 months). The article focuses on the analysis of erroneous statements regarding the classification, composition and mechanisms of action of different drugs of this group. Differences in terminology of drug groups are given, such as: chondroprotectors, symptomatic slow acting drugs for osteoarthritis (SYSADOAs), disease-modifying osteoarthritis drugs, between which an equal sign cannot be placed. Based on the analysis, a conclusion was made about erroneous attitudes towards some SYSADOAs: 1) according to the Anatomical Therapeutic Chemical Classification, the active substances CS, GS, diacerein and HA are classified as nonsteroidal anti-inflammatory drugs due to their antiinflammatory activity; 2) quite often, drugs based on bioactive concentrate of small sea fish and glycoaminoglycan-peptide complex do not belong to SYSADOAs according to any of the existing generally recognized classifications, they do not contain a sufficient amount of active substances (CS or peptides), there is no proper level of evidence, they are not included in the recommendations of international medical communities and MHRF clinical recommendations and standards. In Russia, physicians must follow MHRF clinical guidelines and standards for OA therapy.

Background. Therapy of hyperlipidemia with synthetic statin drugs is characterized by a number of side effects. In particular, statin-dependent myopathy occurs as a result of statin inhibition of biosynthesis of cofactor coenzyme Q10 (CoQ10), which plays a central role in the electron transport chains during adenosine triphosphate (ATP) synthesis in mitochondria.Objective: systematic analysis of scientific publications on CoQ10 pharmacology with an emphasis on its effect on the lipid profile.Material and methods. The analysis included 16,788 articles found by “coenzyme Q10 OR ubiquinone" query in the PubMed/MEDLINE biomedical publications database. Topological and metric big data analysis methods were used developed in the scientific school of Academician of the Russian Academy of Sciences Yu.I. Zhuravlev.Results. A much wider range of CoQ10 pharmacological effects was established than simply supporting ATP biosynthesis. Coenzyme Q10 exhibits pronounced lipid-lowering, anti-asthenic, and anti-inflammatory effects and can be successfully used in the treatment of asthenic conditions, cardiovascular pathology (including hyperlipidemia and statin-induced myopathy), carbohydrate metabolism disorders (insulin resistance), and diverse neurological diseases. CoQ10 supplements reduce mortality by 50% in patients with cardiovascular diseases, improve glycemic control in insulin resistance, kidney function, and are useful in the treatment of migraine and neurodegenerative pathologies (Parkinson's disease, etc.).Conclusion. Experimental data and evidence base indicate the potential of using CoQ10 in patients with hyperlipidemia and other cardiovascular system diseases.

We present the results of a systemic biological analysis of human proteome proteins, biological functions of which are somehow related to the metabolism of B group vitamins and the molecular implementation of nociceptive processes. Among 983 proteins involved in the homeostasis of B vitamins, 21 proteins were involved in the molecular mechanisms of nociception, 91 proteins were involved in the regulation of inflammation processes, and 17 proteins were involved in the neuroprotective and neurotrophic effects of B vitamins. All these groups of proteins are important for the treatment of neuropathic pain associated with the degeneration of nervous tissue.

Background. The rapidly developing resistance of viruses to synthetic antiviral drugs indicates the need to use substances with multitarget action (to avoid polypharmacy and to improve the safety of treatment).Objective: systematic analysis of the scientific literature on the pharmacology of bioflavonoids with an emphasis on their antiviral action.Material and methods. More than 150,000 references of primary sources were found in the PubMed/MEDLINE database of biomedical publications, including 3282 references on the antiviral effects of bioflavonoids. A systematic computerized analysis of this array of publications was carried out in order to identify the main directions in the pharmacology of bioflavonoids with an emphasis on their antiviral, antibacterial and immunomodulatory effects. The literature analysis was carried out using modern methods of topological and metric analysis of big data.Results. The molecular mechanisms of action of baicalin, hesperidin, rutin, quercetin, leukodelphinidin bioflavonoids and epigallocatechin-3-gallate, curcumin polyphenols, their anti-inflammatory, antioxidant, antiviral, bactericidal, angioprotective, regenerative effects, and their prospects in therapy, prevention and rehabilitation of patients with COVID-19 and other respiratory viral infections were described in detail.Conclusion. Bioflavonoids and synergistic polyphenols exhibit not only multitarget antiviral effects by inhibiting the main protease, spike proteins, and other target proteins, but also pronounced anti-inflammatory, hepatoprotective, and immunomodulatory effects.

Background. To plan effective and safe pharmacotherapy for inflammation and pain, it is important to evaluate the mechanisms and spectrum of action of nonsteroidal anti-inflammatory drugs (NSAIDs), including their effects on human proteome.Objective: to identify and evaluate the most significant specific differences of candidate molecule RRS-1 (N-{(Z)-2-(1-methyl-1H-indol-3-yl)-1-[(propylamino)carbonyl]vinyl}benzamide) from other NSAIDs through differential chemoreactome analysis.Materials and methods. Chemoproteomic modeling of pharmacological effects of RRS-1 molecule and a number of well-known NSAIDs (diclofenac, nimesulide, ketorolac) on human proteome was carried out on the basis of numerical prediction algorithms over the space of heterogeneous feature descriptions, developed in the topological approach to recognition by Yu.I. Zhuravlev and K.V. Rudakov scientific school.Results. Significant differences in the effects of the studied molecules were found for 1232 proteins of human proteome. The features of assessing interactions of the studied molecules with 47 target proteins, which most distinguished the effects of RRS-1 molecule from all others were identified. RRS-1 could activate adenosine and dopamine receptors, cannabinoid receptor 2 and GABAA receptor to a greater extent than other molecules. Activation of these receptors corresponded to anti-inflammatory, anti-nociceptive and neuroprotective effects. RRS-1 could preferably inhibit a number of pro-inflammatory proteins, receptor bradykinin 1, metabotropic glutamate receptor 5, matrix metalloproteinases 8, 9, 12, and blood coagulation factor X. Additionally, RRS-1 molecule showed preferable inhibition of a number of kinases targeted in antitumor and anti-inflammatory therapy. RRS-1, less than other studied molecules, interacted with the receptors of vitamin D3, thyroid hormone, acetylcholine, cannabinoids and opioids, orexin, and various metabolic enzymes, which is important in assessment of the safety of using drugs based on this molecule. RRS-1 characteristically exhibited a moderate profile of antivitamin action: the total score of vitamin and mineral loss (7.4±3.7) was significantly less in comparison to diclofenac (11.7±4.5) and was actually on the same level as nimesulide (6.9±3.7) and ketorolac (6.7±3.6).Conclusion. Chemoreactomic and chemoproteomic profiling of RRS-1 candidate molecule provided pre-experimental assessments of its efficacy and safety through modeling interactions with the human proteome.

Background. Synthetic derivatives of vitamin B12 exhibit various physical, chemical and pharmacological properties. The development of methods for predicting the properties of these molecules based on their chemical structure is important for the targeted organic synthesis of corrins with the desired properties and range of applications in pharmacology.Objective: chemoreactomic assessment of the antioxidant effects of vitamin B12 and its derivatives: aquacobalamin, diaquacobinamide, aquacyano-forms of heptaethanolamine-, heptaethylenediamine-, heptamethyl- and heptabutylcobyrinates.Material and methods. The study was conducted using the method of chemoreactomic analysis, implemented within the framework of the algebraic theory of recognition and topological data analysis and based on the theory of isomorphism of labeled graphs and modern methods for predicting numerical target variables. To carry out chemoinformatic chemoreactome analysis, a special problem-oriented theory was developed within the boundaries of the combinatorial theory of solvability and the antioxidant properties of vitamin B12 derivatives were assessed (140 activities in total).Results. Significant differences were found in the properties of the studied substances in relation to oxidative stress. In test systems based on the oxidant 1,1-diphenyl-2-picrylhydrazyl, at different exposure times to molecules (15–60 min) in different concentrations (10–125 μM, 50–3000 μg/ml), aquacobalamin exhibited the most pronounced antioxidant properties at lower concentrations (up to 100 µM). At higher concentrations of substances (125 μM), the antioxidant activity of other vitamin B12 derivatives was higher. All studied molecules had a moderate antimicronutrient effect (total score of about 3.0; for most synthetic drugs, this score is higher than 3.6). Aquacobalamin was characterized by еhe least pronounced antimicronutrient effect (total score less than 0.8), which indicates an almost complete absence of antivitamin and antimineral action, corresponding to an average increase in the risk of a particular micronutrient excretion by no more than 5%.Conclusion. All the studied compounds exert antioxidant properties to one degree or another. Regardless of the choice of simulated test systems for assessing oxidative stress, aquacobalamin demonstrated antioxidant effects to the greatest extent and practically did not stimulate the loss of other micronutrients.

Background. Chemical derivatives of vitamin B12 are characterized by a wide range of pharmacological effects. It is important to learn how to establish relationships between changes of the corrin ring structure in vitamin B12 derivatives and changes in pharmacological properties.Objective: to evaluate the interaction of six vitamin B12 derivatives (aquacobalamin, diaquacobinamide, aquacyano-forms of heptaethanolamine, heptaethylenediamine, heptamethyl and heptabutyl cobyrinates) with human proteome proteins.Material and methods. Using the method of chemoinformational (chemoproteomic) analysis, implemented within the framework of algebraic recognition theory and topological data analysis, the constants of half maximal inhibitory concentration (IC50) and half maximal effective concentration (EC50) of human proteome proteins were assessed.Results. Significant differences were found in the interactions of the studied molecules with 1200 proteins. It was shown that the chemoproteomic profiles of each of the compounds form three groups of molecules with similar proteomic properties: (1) aquacobalamin, (2) diaquacobinamide, aquacyano-forms of heptaethanolamine and heptaethylenediamine cobyrinates, (3) aquacyano-forms of heptamethyl and heptabutyl cobyrinates. A more detailed analysis of the chemoproteomic profiles of the studied compounds using the GO (Gene Ontology) nomenclature of biological functions of proteins made it possible to identify functional GO categories indicating differences in the biological effects of the studied compounds: neuroprotective regulation of neurotransmitter activity (serotonin receptor activity, cholinergic synapses, regulation of dopamine secretion, receptor thyroid hormones), reduction of inflammation (inhibition of cytokine biosynthesis, including tumor necrosis factor alpha and interleukin 1 beta, I-kappa-B kinases / nuclear factor kappa В, leukocyte migration), etc.Conclusion. Based on the obtained data conclusions were drawn about the potential effects and safety of the studied substances.

Background. Phenol and parabens exert bactericidal properties, are relatively low-toxic (in acute toxicity tests) and are used in pharmaceutical, cosmetic and food industries as stabilizers/preservatives for the final product. Despite their widespread use, the long-term toxicological effects of phenol and parabens remain largely unexplored.Objective: to conduct an analysis of the results of basic and clinical studies on chronic toxicity of phenol and parabens.Material and methods. The study included 544 articles found using the query “Preservatives, Pharmaceutical [MeSH Terms] AND Phenol [MeSH Terms]” in the PubMed/MEDLINE biomedical publications database. Methods of topological and metric analysis of big data were applied, developed in the scientific school of Academician of the Russian Academy of Sciences Yu.I. Zhuravlev. Keywords were sorted by empirical Rudakov–Torshin informativeness functionals in the context of combinatorial theory of solvability, followed by combinatorial testing of solvability to find terms with the greatest informativeness.Results. Despite the existence of individual studies on the acute toxicity of phenol and its derivatives (including parabens), the chronic toxicity of phenol and parabens remains poorly understood. This fact is indicated not only by a lack of carefully performed research, but also by the information in safety data sheets supplied by manufacturers of the relevant substances. The associations of phenol and paraben blood levels with certain chronic pathologies in humans have been insufficiently studied. At the same time, the authors of fundamental research, if not “sound the alarm,” then strongly underline the need to conduct large-scale clinical trials on the long-term toxic effects of phenol and parabens. Firstly, this is due to complex estrogen-like effect of phenol and parabens, including (1) effects on estrogen sulfotransferases, (2) direct interactions with estrogen receptors, (3) influence on the expression of steroid receptor genes. Secondly, the available data from fundamental research indicate that phenol/parabens obviously stimulate the the molecular mechanisms of oncogenesis pathophysiology (systematic disturbances in gene expression and corresponding changes in the structure of organ tissues). Thirdly, teratogenic and other toxic effects on the embryo and pregnancy were demonstrated not only in experimental studies (neurotoxicity and teratogenesis in animal models), but also in clinical observations (metabolic disorders in a pregnant woman, including the metabolism of purines and fatty acids beta-oxidation, hyperactivity and/or excess body weight in children, asthma, thyroid dysfunction, etc.).Conclusion. Findings from basic research and selected clinical studies dictate an urgent need to examine the association of phenol/paraben blood levels with chronic pathologies in large-scale clinical trials with cross-sectional and longitudinal design. The lack of indication on toxic effects of parabens and phenols in certain clinical studies may just be an artifact of incorrect data analysis.

Objective: to investigate the antitumor effects of various forms of vitamin B12 in combination with various synergistic vitamins and evaluate the prospects for clinical applications.Material and methods. Cell lines BT-474 (breast ductal carcinoma) and A549 (lung carcinoma) were used as an in vitro cell model, and transplantable epidermoid Lewis lung carcinoma (LLC) was used as an in vivo animal tumor model. Animal studies of LLC were carried out on 25 male F1 hybrid mice (age 2.5–3 months, body weight 23–26 g). In silico research was conducted as a systematic computer analysis of 9,326 scientific sources.Results. In vitro studies on cultures of two human tumor cell lines (BT-474 and A549) confirmed the cytotoxic effect of vitamin B12 (aquacobalamin). It has been shown that vitamin B12 has weak cytotoxic properties in the concentration range of 3.125–200 μg/L (IC50>200 nM), and its hydrophobic derivative (heptamethyl cyanoquacobyric acid ester) significantly reduces the survival of tumor lines. BT-474 and A549 cells at high concentrations (100–200 µg/l, IC50~100 nM). Experimental animals with an in vivo LLС model easily tolerated a drug based on vitamin B12. Exposure to the drug up to the 21st day of LLС development was accompanied by an increasing tendency to inhibit tumor growth by 10–20% (р=0.059). The results of a systematic in silico review of the literature show that clinical data confirmed the significant antitumor effect of vitamin B12.Conclusion. The cellular model indicated the antitumor properties of vitamin B12 and its hydrophobic derivative. With subchronic intragastric administration of B12 to tumor-bearing animals, a steady tendency to inhibit the LLС growth was observed. Analysis of clinical data confirmed the feasibility of the antitumor use of vitamin B12 individually and in combination with synergistic vitamins.

Background. Osteoarthritis (OA) is one of the leading causes of chronic pain in adults, wherein half of the cases is coupled to a neuropathic component. Agents with chondroprotective properties such as chondroitin sulfate (CS) and glucosamine sulfate (GS) have been successfully used in the treatment of OA-related pain. CS/GS exhibit diverse analgesic, anti-inflammatory, antioxidant and chondroregenerative effects that contribute to the restoration of cartilage tissue.Objective: to analyze the misconceptions associated with the medical terminology used for CS/HS in the treatment of OA-related pain, approaches to standardize the quantitative and qualitative composition of CS/HS extracts.Material and methods. Expert analysis was performed along with computational linguistics methods (sentiment analysis, i.e. analysis of text-related emotional modality). Sentiment analysis was carried out using the topological theory of data analysis and algorithms, with 90% accuracy allowing to classify texts into 16 classes of sentiment (manipulative constructs, research without positive results, propaganda, data falsification, etc.). This technique was tested earlier on 20 million publications retrieved from PubMed/MEDLINE database.Results. In recent years, the use of highly dubious terms such as “symptomatic slow acting drug for osteoarthritis, SYSADOA”, etc., has been extensively promoted at certain international conferences. The introduction of such barely scientific terms is not justified neither by the results of basic research nor clinical practice. Using the methods of computational linguistics and data mining of the biomedical literature, we have shown that some misconceptions actively promoted at the so-called "grand conferences" and "international congresses" virtually lack in real-world published scientific literature. Such misconceptions, logically contradicting the entire system of other medical terms, confuse scientific terminology. Moreover, texts promoting this misconceptions are easily recognized as manipulative not only by experts in the analysis of medical literature, but also by artificial intelligence algorithms.Conclusion. A number of misconceptions associated with inadequate interpretation of data obtained during basic and clinical studies of CS/GS has been explored. Specific examples show how practitioners can distinguish between manipulative propaganda and a balanced presentation of research data.

Background. Prediction of breast cancer (BC) progression is important for the timely correction of patient therapy.Objective: to assess a relationship between BC progression and degree of vitamin D deficiency.Material and methods. A retrospective controlled study was performed. The results of examining 67 women aged 29–48 years with histologically verified BC and vitamin D deficiency are presented. All patients were divided into two groups: the main group – 34 women administered with vitamin D, comparison group – 33 patients not taking vitamin D.Results. It was shown that 25(OH)D3 level less than 18.9 ng/ml was significantly associated with prominent disease progression, regardless of the tumor molecular subtype. Additional criteria were developed allowing to predict BC progression.Conclusion. In order to detect secondary changes (distant metastases in ВС patients) and improve patient monitoring, it is recommended to use additional diagnostic methods and determine the intermediate metabolite of vitamin D – 25(OH)D3 in peripheral blood.

The relationship between the pathophysiology of osteoarthritis (OA) and metabolic disorders (metabolic syndrome, obesity) is provided not only by mechanical causes (increased body weight pressure on the joints). A complex of molecular mechanisms, which mediates OA effect on the development of obesity, was established. Excessive activity of toll receptors, the NF-κB cascade, and metabolic disorders of endogenous chondroitin sulfates (CS) lead to chronic inflammation and the development of a complex of comorbid pathologies, including OA, atherosclerosis, and obesity. The relationship between insulin resistance and CS metabolism is also mediated by impaired genomic DNA methylation. Exogenous CS and glucosamine sulfate (GS) used in the long-term treatment of OA also contribute to the inhibition of the pathophysiology of obesity. By inhibiting O-glucosamination of intranuclear proteins (i.e., p53), GS can accelerate lipolysis of visceral fat. Anti-inflammatory effects of CS and GS is associated with inhibition of toll receptors and NF-κB, increased levels of antioxidant enzymes, regulation of expression of fibroblast growth factor 21, activation of adenosine monophosphate-activated protein kinase, and inhibition of secretion of chemoattractant protein MCP-1 and pancreatic lipase. Positive effect of CS and its oligosaccharides exposure on the pathophysiology of metabolic disorders is associated not only with a decrease in inflammation and normalization of fat metabolism but also with an improvement in the state of the intestinal microbiota. Experimental and clinical studies confirm the effects of CS and GS on body mass control. CS and GS are effective and safe when used in patients with OA associated with metabolic syndrome and/or obesity.

In the treatment of joint diseases, including osteoarthritis (OA), the use of standardized extracts of undenatured type II collagen (UDC-II) is promising. It is known that UDC-II is involved in the regulation of innate and adaptive immunity (reduction of autoimmune reactions that stimulate cartilage degradation) and in the reduction of chronic inflammation activity (modulation of cytokines and prostaglandins). The effect of UDC-II on discoidin receptors of chondrocytes helps to prevent structural disorders of the cartilage connective tissue. Experimental and clinical studies have shown that under the influence of standardized UDC-II, there is an increase in the proportion of regulatory CD4+ T cells, a decrease in the levels of pro-inflammatory cytokines, such as interleukin (IL) 1β, IL6, tumor necrosis factor α, CRP, prostaglandins in the blood, as well as matrix metalloproteinase 3 and NF-κB expression in cartilage. The use of UDC-II in OA leads to a significant reduction in pain, an increase in the range of joint motion, an improvement in joint function according to WOMAC and quality of life.

It is well known that a complex of nervous and hormonal signals during stress stimulates adrenal glands to secrete adrenaline, norepinephrine and cortisol. Much less attention has been paid to the roles of intermediate signaling proteins mediating the effects of “stress hormones”, neurotransmitters, and other signaling molecules. This paper presents the results of a systematization of studies of glycogen synthase kinases GSK-3α and GSK-3β, whose excessive activity aggravates the course of chronic stress, has a negative effect on neuronal survival and adaptation processes. Lithium ions are a natural inhibitor of the excessive activity of both GSK-3, which partly determines the normothymic and antidepressant effects of lithium drugs. Taking lithium salts based on organic anions is the safest and most effective way to replenish lithium deficiency in the body. The prospects for the use of lithium ascorbate to increase the body's adaptive reserves are considered.

Standardized extracts of undenatured type II collagen (UC-II) are used as alternative approaches to the treatment of osteoarthritis (OA). The effect of UC-II extracts is associated with the modulation of the mechanisms of innate and acquired immunity, a decrease in the activity of proinflammatory cytokines and prostaglandins. Epitopes of native collagen in the structure of UC-II contribute to a decrease in the activity of autoimmune reactions that stimulate cartilage degradation. Interacting with discoidin receptors, UC-II accelerates the reconstruction of cartilage connective tissue and inhibits the pro-inflammatory effects of endogenous collagens. Experimental and clinical studies confirm the effectiveness of the use of standardized substances UC-II for acceleration of cartilage regeneration and reduce pain in OA and subclinical joint dysfunction.

Background. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are widely used in modern cardiology. The anti-inflammatory effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is realized, in particular, by modulating the activity of the arachidonic acid (ARA) cascade.Objective: to conduct biophysical analysis of the interactions of various forms of PUFAs (ARA, EPA, DHA, EPA and DHA ethyl esters) with three target proteins-enzymes of the ARA cascade (cyclooxygenase-1 (COX-1), COX-2, 5-lipoxygenase (5-LPOG)).Material and methods. The minimization of the energy of the ligand-receptor complexes at various initial positions of the molecule relative to the receptor pocket and the molecular energy profiles of the protein (the energy of side chain transfer from solvent to protein) were calculated using the ECMMS package.Results. EPA and DHA ethyl esters were characterized by significantly higher absolute values of specific binding energies of target proteins than ARA or simply EPA/DHA. For example, in the case of COX-2, EPA, DHA and EPA ethyl ester had similar ∆∆G values (–3.0...–3.1 kcal/mol), while the COX-2 complex with DHA ethyl ester was somewhat more stable (∆∆G = –3.4 kcal/mol). In the case of the 5-LPOG enzyme, the complex with EPA ethyl ester was the most stable (∆∆G = –1.62 kcal/mol). Higher absolute binding energies indicate a higher affinity of EPA and DHA ethyl esters to enzymes of the ARA cascade.Conclusion. The results suggest that the high affinity of EPA and DHA ethyl esters to the enzymes of the ARA cascade is one of the molecular bases of therapeutic efficacy of ω-3 PUFAs with high degree of standardization.

Objective: the development and verification of a scale for identifying patients at high risk of osteoarthritis (OA).Material and methods. The results of the analysis of a sample of patients aged 35–90 years from the database of the Institute of Trace Elements (n=3440), which included information on clinical and anamnestic, diagnostic parameters and pharmacotherapy of patients, including patients with OA (n=107), are presented. To analyze information about patients, modern methods of data analysis proposed within the topological theory of pattern recognition were used.Results. Based on the analysis of the sample, a 100-point scale of 27 points was developed which allows to identify patients at high risk of OA (sensitivity 88%, specificity 100%). For patients with high scores on the scale, a kind of “preemptive” prescription of symptomatic slowacting drugs for osteoarthritis (SySADOA) based on highly purified substances of chondroitin sulfate (CS) and glucosamine sulfate (GS) is promising. The evidence for CS/GS is extensive and has been reviewed previously.Conclusion. Early adoption of preventive measures (including the usage of SySADOA – CS/GS) in patients with a high score on the developed scale may reduce the risk of OA.

We present the review of clinical and experimental studies on the pathogenesis of neurorheumatological complications (NRC) in COVID-19. The influence of systemic hyperinflammation caused by impaired innate immunity on the functioning of the neurovascular endothelium and the bloodbrain barrier, activation of signaling pathways of innate immunity and parainfectious autoimmunity in the central nervous system were analyzed.Hyperinflammation has been shown to contribute to the development of NRC in COVID-19. The potential therapeutic efficacy of drugs, including those based on chondroitin sulfate, which can be used for the prevention and treatment of NRC in COVID-19, is considered.

Objective: comparative pharmacoeconomic analysis of iron preparations for intravenous infusion in the treatment of iron deficiency anemia (IDA) within the concept of patient blood management program.Material and methods. A retrospective pharmacoeconomic study was carried out using methods of analysis of efficiency, costs and costeffectiveness. Comparison of preparations of oligoisomaltose iron [III] (Monofer) and carboxymaltose iron [III] (Ferinject®) was carried out.Results. In general, Monofer and Ferinject® are characterized by comparable efficacy in terms of hematological response. Using a dosiological model of an increase in hemoglobin blood levels over time in treatment with the drugs under consideration the frequencies of the hematological response were calculated (Monofer – 79%, Ferinject® – 70%). The cost of treating one patient with an average body weight of 88.3 kg and an initial hemoglobin level of 100 g/l was 13,097 rubles for Monofer and 15,681 rubles for Ferinject®. The values of the cost-effectiveness indicator calculated in accordance with the criterion of the effectiveness of the hematological response amounted to 16,578 rubles (Monofer) and 22,402 rubles (Ferinject®), which allows to consider Monofer as strictly preferred. With the colorectal surgery as an example, it has been shown that the use of this drug in patients blood management can reduce the total cost of treatment (in particular, by reducing the required number of portions of red blood cells).Conclusion. The wider use of iron preparations for intravenous infusion in IDA has reasonable economic advantages. The preparation of oligoisomaltose iron Monofer is strictly preferred in relation to the preparation of carboxymaltose iron.

Joint endoprosthetics is a treatment of choice for patients with decompensated osteoarthritis (OA), who have exhausted the possibilities of pharmacotherapy and other methods of conservative treatment. Preparation for endoprosthetics and rehabilitation after surgery usually includes measures to improve the muscle condition and local blood circulation in the joint area, and if necessary, pain management. The unique spectrum of anti-inflammatory effect of chondroprotectors based on chondroitin sulfate and glucosamine sulfate includes inhibition of NF-κB cascade, toll-like receptors, pro-inflammatory cytokines, metalloproteinases, and significantly alleviates the course of OA. Reducing the severity of OA is important for preparing for surgery, subsequent rehabilitation, and preventing the revision surgery.

Background. Osteoarthritis (OA) is associated with an activation of local inflammation and involves subchondral tissue of the joint.Objective: to conduct a systemic analysis of the publications on the association between OA and metabolic disorders in bones.Material and methods. The authors analyzed 3,926 publications on the studies of OA and metabolic disorders in bones tissue by the method of a topologic theory of recognition selected by the request “osteoarthritis AND (bone resorption OR osteopenia OR osteoporosis)” in the database of biomedical publications PubMed/MEDLINE. The control sampling included 4,000 articles randomly selected out of 97,331 found by the request “osteoarthritis NOT bone NOT resorption NOT osteopenia NOT osteoporosis” (i.e. publications on OA that do not cover issues of bone metabolism).Results. The associations between cartilaginous pathology and bone tissue destruction are mediated by anti-inflammatory cytokines, osteoblast and osteoclast balance impairments, steroid hormone imbalance, and carbohydrate metabolism. Bone metabolism disorders are associated with an intensification of OA-associated pain syndrome. Chondroprotective agents (chondroitin sulfate (CS), glucosamine sulfate (GS), and undenaturated collagen) block the activity of anti-inflammatory cytokines (NF-κB and toll-receptors), stimulate the activity of osteoblasts (bone tissue synthesizing cells), and decrease the excessive activity of osteoclasts (cells that degrade bone tissue).Conclusion. Pharmaceutically standardized forms of CS and GS can be used for the normalization of bone metabolism along with safe osteoptotective means (vitamin D, calcium, etc.) in patients with OA.

Chronic systemic inflammation, which is significantly exacerbated by COVID-19 or in conditions of induced physical inactivity, has a great negative effect on the condition of patients with osteoarthritis (OA). Conversely, diseases associated with chronic inflammation (OA, obesity, hypercholesterolemia, bronchial asthma, diabetes mellitus, chronic kidney disease, deficiency of essential micronutrients, etc.) are the background for a more severe course of coronavirus infection. In patients with this comorbid background, infection with SARS-CoV-2 exacerbates chronic systemic inflammation through activation of the NLRP3 inflammasome with the involvement of toll receptors (TLRs). Inflammasome activation is the central mechanism for the formation of the so-called cytokine storm, which leads to pyroptosis of various cell types and the development of multiple organ pathologies characteristic of COVID-19. In addition, induced physical inactivity (immobilization stress) contributes to the development of sarcopenia and increased pain in OA. The chondroprotectors chondroitin sulfate, glucosamine sulfate, undenatured collagen inhibit TLR and inflammasome activation, inhibit muscle mass loss, and may exhibit a direct antiviral effect (inhibit the replication of the SARS-CoV-2 virus).

Purpose of the study. The pharmacological effects of ornithine are primarily due to its participation in the neutralization of ammonia and in the metabolism of amino acids. To clarify the mechanisms of action of ornithine, a chemoreactom analysis of ornithine aspartate was performed in comparison with S-ademetionine (S-AM) and ursodeoxycholic acid (UDCA). Methods. The effects of the investigated substances on the metabolism of urates (derivatives of uric acid), vasoactivity, vascular structure and cytoprotection were assessed by the method of chemoreactome analysis. Results. It was found that a decrease in blood urate levels is associated with inhibition by ornithine of the urate transporter URAT1 (ornithine – IC50 = 65 nM, S-AM – 1060 nM, UDCA – 94 nM) and xanthine oxidase (ornithine – IC50 = 910 nM, other molecules IC50 = 9655-11040 nM). Among the studied molecules, ornithine was distinguished by the most pronounced vasodilatory properties (probably associated with inhibition of adrenergic receptors: Kd = 35 nM, other molecules – 1108-1428 nM). The highest antidyslipidemic activity was also shown for ornithine (9.4 %) and S-AM (10.2 %), the lowest for UDCA (4.6 %). The antidyslipidemic effect of ornithine is associated with inhibition of endothelial lipase (IC50 = 258 nM for ornithine). The cytoprotective effects of ornithine are associated with an increase in glutathione synthesis, a decrease in the glutamatergic activity of neurons under conditions of glutamate stress, inhibition of prostaglandin D-synthase, and a decrease in the intensity of acute lymphocytic inflammation without immunosuppression. Conclusion. Thus, the results of the ornithine chemoreactom analysis indicate a significant expansion of the spectrum of the pharmacological effects of ornithine, including not only hepatoprotection, but also cardioprotection and nephroprotection.

Background. The complex mechanisms of action of chondroitin sulfate (CS) and glucosamine sulfate (GS) at the molecular level make it possible to assert the applicability of the corresponding drugs far beyond chondroprotection. Inhibition of proinflammatory mechanisms (NF-κB, activation of toll-receptors, increased levels of cytokines, degranulation of mast cells, etc.) by CS and GS provide the prospects for their use to inhibit inflammation in the respiratory tracts, allergic processes and to enhance the effects of glucocorticoids.Objective: to systemize data on the effects of chondroitin sulfate and glucosamine sulfate on pathophysiological processes in pulmonary pathology.Material and methods. Using the methods of the theory of text topological analysis an intellectual analysis of 1273 publications on fundamental and clinical studies of the relationship of CS and GS with lung function was carried out. The search was performed by a key query “(glucosamine OR chondroitin) AND (lung OR lungs OR pulmonary OR pulmonology)” in the Pubmed/MEDLINE database. As a result, 59 informative biomedical terms were identified.Results. The chemoproteomic study of CS and GS showed that their intake promoted an increase in the expression of 19 antitumor proteins and a decrease in the expression of 25 pro-inflammatory proteins involved in lung function. CS and GS can be used in the complex therapy of infectious diseases of the lungs, with fibrotic changes in the respiratory tracts and, as well, help to reduce the risk of neoplastic diseases of the lungs.Conclusion. The results of this analysis allow us to assert the promising nature of the use of CS and GS in several neoplastic diseases of the lungs, as well as the high safety of drugs based on pharmaceutical standardized forms of CS and GS in terms of lung function.

Objective: identification of peptides in the composition of Laennec®, which can inhibit the development of endotheliopathy (endothelial dysfunction).Material and methods. Hybrid mass spectrometry followed by data analysis based on topological recognition theory was performed. The analysis of the peptide composition of Laennec® included four stages: purification of the drug, chromatographic separation of peptides, determination of the multidimensional mass spectrum of the peptide fraction, and de novo sequencing of the isolated peptides.Results. The preparation contains peptides-inhibitors of specific target proteins (PRKCZ, PKB, PKD1, MAPK14, IKKB, PDPK1) involved in the activation of the pro-inflammatory transcription factor NF-κB. Inhibition of CDK5 and SHC1 kinases helps to reduce endothelial cell apoptosis. The peptides of the drug also block enzymes involved in the synthesis and maturation of the tumor necrosis factor alpha (MAPKAPK2/3, ADAM17).Conclusion. In the composition of Laennec®, peptides have been found that contribute to a complex pathogenetic action against endotheliopathy. Endothelial regeneration is especially important in the rehabilitation of patients who have recovered from COVID-19.

Background. Long-term use of chondroprotective agents – chondroitin sulfate (CS) and glucosamine sulfate (GS) in the treatment of osteoarthritis puts forward increased requirements for the safety of drugs, primarily in terms of effects on the liver and kidneys.Objective: systematization of data on the effect of chondroprotectors on liver structure and functions.Material and methods. Using the methods of the theory of topological text analysis, an intellectual analysis of 2319 publications on fundamental and clinical studies of the relationship of CS and GS with liver function was carried out. The search was performed by a key query “(chondroitine OR glucosamine) AND (liver OR hepatic OR hepatocy*)” in the PubMed/MEDLINE database.Results. The systematic analysis indicated a pronounced hepatoprotective effect of CS and GS pharmaceutical substances with a high degree of purification from inorganic and organic impurities. By regulating inflammation processes, lymphocyte function, fat and carbohydrate metabolism in the liver, standardized forms of CS and GS have a beneficial effect on fat metabolism, reduce chronic inflammation in the liver, exhibit antitumor and pronounced hepatoprotective effects on various models of liver intoxication.Conclusion. The results of this analysis allow us to assert the high safety of drugs based on pharmaceutical standardized forms of CS and GS in terms of liver function.

The pharmacoinformation approach to the assessment and modeling of drugs involves the use of modern methods of data mining. These methods include: 1) analysis of big data (selection of texts of scientific publications, search for new biomarkers); 2) computer analysis of texts (automatic classification of texts by content, identification of pseudoscientific texts); 3) analysis of metric maps (visualization and analysis of complex patterns, including clustering) and 4) chemoinformation analysis, including the assessment of the effect of drugs on the transcriptome, proteome and microbiome of a person. The article provides examples of the application of these methods of pharmacoinformatics to chondroprotectors containing standardized forms of chondroitin sulfate and glucosamine sulfate.

The negative effects of hypovitaminosis D3 and vitamin D3 deficiency in 80% of Russians make eliminating vitamin D deficiency an issue of state concern. Hundreds of effective clinical studies showed realistic opportunities of vitamin D3 to help patients with disorders of carbohydrate and lipid metabolism, high levels of nonspecific inflammation, tuberculosis, and women with a higher risk of complications and pregnancy losses. Vitamin D3 supplements are essential for the prevention and treatment of a wide range of “bone” and “extraosseous” diseases. One of the most important aspects of the clinical uses of vitamin D3 is the dosage and dosage regimen of the vitamin. This paper presents the results of a “mega-analysis” of 3965 clinical studies of vitamin D3 in terms of the effectiveness of different dosages in achieving different clinical outcomes. It was shown that dosages of 2000 IU/day and 4000 IU/day correspond to the peak values of the effectiveness index, regardless of the diagnoses studied (mega-analysis of 420 randomized trials). Some effectiveness in the treatment of rickets, gestational diabetes, calcium metabolism disorders, disorders of bone density and structure, diseases of the musculoskeletal system and connective tissue can be achieved using weekly dosages of 50,000 IU/week (mega-analysis of 196 studies). It has been shown that dosages of 100,000-1,000,000 IU, intended for a single dose once a month, are almost always found only among studies with a negative result (mega-analysis of 368 studies).

Toll-like receptors (TLRs) act as receptors for bacterial lipopolysaccharides (LPS) and participate in innate immunity. Excessive TLRs activity leads to chronic inflammation and the development of several comorbid pathologies, including osteoarthritis (OA). Computer analysis of 52,312 publications devoted to TLRs was made to systematically describe the mechanisms of biological action of TLRs and their influence on the OA pathophysiology. In addition, we identified the mechanisms by which slow-acting drugs based on standardized forms of chondroitin sulfate (CS), which have symptom-modifying and structural-modifying effects, can decrease TLRs activity and be used in the treatment of OA. Our conclusions are supported by the results of TLRs chemoreactom analysis, as well as by clinical and experimental data.

The search for original publications on fundamental and clinical medicine that would produce results of the highest scientific quality represents an urgent need for every medical researcher. Such publications are essential, in particular, for the development of reliable treatment standards. The Englishlanguage resources PUBMED and EMBASE are essential to help in solving this problem. However, there is an obvious problem in assessing the quality of the studies found. The paper formulates a method for analyzing the texts of biomedical publications, which is based on an algorithmic assessment of the emotional modality of medical texts (so-called sentiment analysis). The use of the topological theory of data analysis made it possible to develop a set of high-precision algorithms for identifying 16 types of sentiments (manipulative turns of speech, research without positive results, propaganda, falsification of results, negative personal attitude, aggressiveness of the text, negative emotional background, etc.). On the basis of the developed algorithms, a point scale for assessing the sentiment quality of research was obtained, which we called the "β-score": the higher the β-score, the less the evaluated text contains manipulative language constructions. As a result, the ANTIFAKE system (http://antifake-news.ru) was developed to analyze the sentiment-quality of Englishlanguage scientific texts. An analysis of ~ 20 million abstracts from PUBMED showed that publications with low sentiment quality (β-score