[Prevention and treatment of COVID-19 based on post-genomic pharmacological analysis: Systematic computer analysis of 290,000 scientific articles on COVID-19].

The COVID-19 pandemic has highlighted pressing challenges in biomedical research methodology. It has become obvious that the rapid and effective development of treatments for "new" viral infections is impossible without the coordination of interdisciplinary research and in-depth analysis of data obtained within the framework of the post-genomic paradigm. Presents the results of a systematic computer analysis of 290,000 scientific articles on COVID-19, with an emphasis on the results of post-genomic studies of SARS-CoV-2. The futility of the overly simplified approach, which considers only one "most important receptor protein", only one "key virus gene", etc., is shown. It is shown how post-genomic technologies will make it possible to find informative biomarkers of severe coronavirus infection, including those based on complex immune disorders associated with COVID-19.

[Study of antitumor effects of human placenta hydrolysate on PC-3, OAW-42, BT-474 cell cultures].

AIM: To investigate the antitumor effects of human placenta hydrolysate (HPH) peptides on three hormone-dependent human cell lines: prostate adenocarcinoma, breast carcinoma, and ovarian cancer by metabolic analysis of cell cultures. MATERIALS AND METHODS: The effect of HPH on tumor and control tumor cell lines was evaluated. Study stages: (A) de novo peptide sequencing by collision-induced dissociation mass spectrometry; (B) detection of peptides with anti-tumor properties; (C) expert analysis of the obtained lists of peptides. RESULTS: Dose-dependent cytotoxic effects of HPH on three tumor cell lines are shown: PC-3 (human prostate adenocarcinomas), OAW-42 (human ovarian cancer), BT-474 (human breast carcinomas), and IC50 constants (1.3-2.8 mg/ml) were obtained. The analysis of the HPH peptide fraction showed more than 70 peptides with antitumor properties in the composition of this HPH, including kinase inhibitors: mitogen-activated protein kinases, kappa-bi nuclear factor inhibitor kinase, AKT serine/threonine kinase 1, protein kinase C zeta, interleukin-1 receptor-associated kinase 4 and cyclin-dependent kinase 1. CONCLUSION: The results of the study indicate not only the oncological safety of the HPH used in therapy but also the mild antitumor effects of this HPH at high concentrations.

[Influence of chronic pain in osteoarthritis on the risk of cardiovascular diseases and modern methods of drug prevention]. / Vliyanie khronicheskoi boli pri osteoartrite na risk razvitiya serdechno-sosudistykh zabolevanii i sovremennye sposoby ikh lekarstvennoi profilaktiki.

The purpose of the review of scientific medical literature was to evaluate the data of the epidemiology of osteoarthritis (OA) and cardiovascular diseases (CVD) with the analysis of risk factors, pathophysiological and pathobiochemical mechanisms of the relationship between OA and the risk of developing CVD in the presence of chronic pain, modern strategies for screening and management of this cohort of patients, the mechanism of action and pharmacological effects of chondroitin sulfate (CS). Conclusions were drawn about the need for additional clinical and observational studies of the efficacy and safety of the parenteral form of CS (Chondroguard) in patients with chronic pain in OA and CVD, improvement of clinical recommendations for the treatment of chronic pain in patients with OA and cardiovascular risk, with special attention to interventions that eliminate mobility restrictions in patients and the inclusion of basic and adjuvant therapy with DMOADs to achieve the goals of multipurpose monotherapy in patients with contraindications to standard therapy drugs.

[Systematic analysis of the results of fundamental and clinical studies of ethifoxin]. / Sistematizirovannyi analiz rezul'tatov fundamental'nykh i klinicheskikh issledovanii etifoksina.

The main pharmacological use of etifoxine is the treatment of psychosomatic manifestations of anxiety. The purpose of this work is a systematic analysis of fundamental and clinical studies of etifoxine. In addition to the anxiolytic effect, which partially persists even after discontinuation of therapy, etifoxine is characterized by analgesic, neurotrophic and neuroprotective properties. Such a pharmacological profile of etifoxine is due not only to the activation of GABA receptors, but also to the effect on the levels of neurosteroids in the blood and in the brain. Modulation by etifoxine of neurosteroids' metabolism contributes to the manifestation of anxiolytic, anti-inflammatory, neuroprotective and other properties of etifoxine.

[Cardiovascular effects of omega-3 polyunsaturated fatty acids: position of omega-3 polyunsaturated fatty acids in Russian and international guidelines. Council of Experts].

This Expert Council focuses on the meta-analysis of studies on the risk of atrial fibrillation (AF) in patients taking omega-3 polyunsaturated fatty acids (PUFA) and of data on the omega-3 PUFA treatment in patients with cardiovascular and kidney diseases.The major statements of the Expert Council: the meta-analysis of AF risk in patients taking omega-3 PUFA showed an increased risk of this arrhythmia. However, it should be taken into account that the risk of complications was low, and there was no significant increase in the risk of AF when omega-3 PUFA was used at a dose of ≤1 g and a standard dose of the only omega-3 PUFA drug registered in the Russian Federation, considering all AF episodes in the ASCEND study.At the present time, according to Russian and international clinical guidelines, the use of omega-3 PUFA can be considered in the following cases: • for patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction as a supplement to the basic therapy (2B class of recommendations according to the 2020 Russian Society of Cardiology guidelines (RSC) and the 2022 AHA / ACC / HFSA guidelines); • for patients with hypertriglyceridemia (>1.5 mmol/l) as a part of combination therapy (IIb class of recommendations and B level of evidence according to the 2021 European guidelines on cardiovascular disease prevention, etc.); • for adult patients with stage 3-4 chronic kidney disease (CKD), long-chain omega-3 PUFA 2 g/day is recommended for reducing the level of triglycerides (2C class of recommendations). Data on the use of omega-3 PUFA for other indications are heterogenous, which can be partially explained by using different form and doses of the drugs.

[A systematic analysis of neurobiological roles of lithium]. / Neirobiologicheskaya rol' solei litiya.

Lithium salts have been the mainstay of treatment for bipolar disorder for more than 50 years, since the FDA approved the treatment in 1970. Molecular mechanisms of lithium's action include inhibition of glycogen synthase kinase 3 beta and inositol monophosphatase, resulting in induction of brain-derived neurotrophic factor, antiapoptotic proteins, deprivation of calcium-induced apoptosis. Recent findings suggest autophagy regulation as a possible mechanism of lithium neuroprotective action. Moreover, lithium treatment has been reported to decrease accumulation of various pathological proteins including phosphorylated tau and amyloid-B. Also, telomeres length and telomerase activity are suggested to be upregulated by lithium. Clinical applications of lithium treatment include various neurodegenerative diseases, primarily Alzheimer disease, with increasing importance given to the use of lithium microdoses. Chemoreactome screening is used to find more safe and effective lithium compounds.

[Points of undenatured type II collagen application in musculoskeletal pain syndromes treatment]. / Tochki prilozheniya nedenaturirovannogo kollagena II tipa v terapii skeletno-myshechnykh bolevykh sindromov.

The dominant collagen of the cartilaginous matrix in adults is type II collagen. The amount of type II collagen in the intercellular matrix of cartilage is significantly reduced against the background of musculoskeletal system diseases. The basis of articular cartilage is hyaline cartilage tissue consisting of chondrocytes with tissue-specific antigens that induce the production of antibodies in patients with osteoarthritis (OA). Today, new approaches are being considered in the treatment of OA with the use of udenatured type II collagen (UC-II). Such molecular mechanisms of action of UC-II as the formation of a systemic response through oral tolerance are discussed, since the induction of tolerance is the immune pathway, by default, in the intestine. A number of experimental, preclinical (on volunteers) and clinical studies have shown the effectiveness and safety of the use of UC-II in OA. Standardized extracts of UC-II exhibit anti-inflammatory, immunoregulatory, chondroprotective effects, contributing to the reduction of pain symptoms of OA. Against the background of taking UC-II with induced OA, there is a statistically significant decrease in the level of proinflammatory cytokines, such as interleukin (IL-1ß, IL-6), tumor necrosis factor alpha (TNF), C-reactive protein (CRP) in serum and the level of max proteinases (MMP-3), nucleated factor «kappa-bi¼ (NF-κB) in the knee joint. UC-II significantly inhibits the production of prostaglandin E2 (by 20%) and the expression of genes encoding proinflammatory proteins. In experimental models and in OA patients, a decrease in the severity of pain syndrome, an increase in endurance, mobility and an improvement in the functional state of the joints were noted. Clinically, no changes in the structure of the muscle fiber were detected with increased physical exertion. With OA on the background of UC-II (10-40 mg/s), there was a statistically significant decrease in joint pain according to WOMAC. A promising direction of OA therapy is the combination of UC-II with chondroitin sulfate and glucosamine sulfate.

[Human placenta hydrolysates: from V.P. Filatov to the present day: Review].

Works of V.P. Filatov and his school laid the foundation for the study and clinical use of human placenta hydrolysates (HPH). To date, the PubMed database contains more than 5,000 publications on basic and clinical research on HPH. Studies of the peptide composition of HPH, carried out using the methods of modern proteomics, have made it possible to propose a complex of molecular mechanisms of the action of HPH in various pathologies. The article discusses the effects of HPH on the treatment of liver diseases, atopic dermatitis, viral infections (herpes, COVID-19, viral hepatitis), iron overload and chronic fatigue syndrome. Stimulation of HPH regenerative capabilities of the body is important for accelerating and improving the quality of wound healing, treatment of diseases of the joints and the reproductive system.

Direct and Indirect Neurological Signs of COVID-19.

Objective. To systematize the neurological manifestations of COVID-19. Materials and methods. A systematic computerized analysis of all currently available publications on the neurological manifestations of COVID-19 was undertaken (2374 reports in PubMed) by topological data analysis. Results. A set of interactions between infection with SARS-CoV-2, metabolic impairments affecting neurotransmitters (acetylcholine, dopamine, serotonin, and GABA), enkephalins, and neurotrophins, micronutrients, chronic and acute inflammation, encephalopathy, cerebral ischemia, and neurodegeneration (including demyelination) was described. The most typical neurological manifestations of COVID-19 were anosmia/ageusia due to ischemia, neurodegeneration, and/or systematic increases in proinflammatory cytokine levels. COVID-19 provoked ischemic stroke, Guillain-Barré syndrome, polyneuropathy, encephalitis, meningitis, and parkinsonism. Coronavirus infection increased the severity of multiple sclerosis and myopathies. The possible roles of the human virome in the pathophysiology of COVID-19 are considered. A clinical case of a patient with neurological complications of COVID-19 is described. Conclusions. In the long-term perspective, COVID-19 promotes increases in neurodegenerative changes, which requires special neurological rehabilitation programs. Use of cholinergic drugs and antihypoxic agents compatible with COVID-19 therapy is advised.

[Molecular and clinical aspects of the effect of cytidyndiphosphocholine on cognitive functions]. / Molekulyarnye i klinicheskie aspekty deistviya tsitidindifosfokholina na kognitivnye funktsii.

OBJECTIVE: Systematization of the array of publications on cytidyldiphosphocholine (CDP-choline). MATERIAL AND METHODS: Systematic computer analysis of all currently available publications on CDP-choline (1750 publications in PUBMED) using the topological theory of big data analysis. RESULTS: CDP-choline is essential for acetylcholine biosynthesis, phospholipid metabolism, and DNA methylation. The article describes the effects of CDP-choline on acetylcholinergic and other types of neurotransmission, anti-inflammatory, neuroprotective and neurotrophic effects of CDP-choline. Also, the paper presents the effects of the molecule on lipid metabolism and gene expression within the post-genomic paradigm (in particular, an increase in the expression of nicotinic and muscarinic acetylcholine receptors). The results of fundamental and clinical studies of CDP-choline in the treatment of cognitive impairments associated with cerebral ischemia and neurodegeneration are presented. CONCLUSION: The pharmacological effects of CDP-choline are mediated through multiple molecular mechanisms that contribute to the nootropic action of this molecule.

[Comparative chemoreactome analysis of the synergism of vinpocetine, piracetam, and cinnarizine molecules]. / Sravnitel'nyi khemoreaktomnyi analiz sinergizma molekul vinpotsetina, piratsetama i tsinnarizina.

OBJECTIVE: Neuroprotective and nootropic drugs often exhibit complementary, «synergistic¼ effects, the consideration of which is important for choosing the most effective and safe drug combinations. MATERIAL AND METHODS: Chemoinformatic analysis of vinpocetine, piracetam and cinnarizine on neuron cultures, on model organisms (mice, rats) based on modern data mining and machine learning methods. RESULTS: The paper presents the results of the chemoreactom analysis of vinpocetine, piracetam, and cinnarizine. Estimates of various biological activities of molecules on neuronal cultures, on model organisms (mice, rats) and estimates of modulation of the activity of target proteins in rats and humans were obtained. The data obtained made it possible to quantify the value of the synergism score for the combination «vinpocetine + piracetam¼ (54 points) compared with the combination «piracetam + cinnarizine¼ (25 points). CONCLUSIONS: The combination of «vinpocetine + piracetam¼ in the fixed combination (Vinpotropil) is thus more preferable for combined use than for the combination of «piracetam + cinnarizine¼.

[Roles of active forms of vitamin D in supporting innate immune systems and in reducing excess inflammation in COVID-19].

A reduced supply of micronutrient vitamin D leads to a more severe course of coronavirus infection (COVID-19). Vitamin D deficiency is combined with a decrease in innate antiviral immunity and excess of inflammation. Vitamin D supplementation stimulates the synthesis of antibacterial peptides and is important for weakening the cytokine storm, reducing excessive acute and chronic inflammation, and also for compensating for chronic comorbid pathologies. Active forms of vitamin D (alfacalcidol, etc.) are of particular importance for compensating for vitamin D deficiency in elderly patients, endocrine-immune dysfunction, sarcopenia, chronic renal failure (in which the metabolism of vitamin D in the kidneys is disturbed).

[Direct and indirect neurological manifestations of COVID-19]. / O pryamykh i kosvennykh nevrologicheskikh proyavleniyakh COVID-19.

OBJECTIVE: To systemize the neurological manifestations of COVID-19. MATERIALS AND METHODS: A systematic computer analysis of all currently available publications on the neurological manifestations of COVID-19 (2374 publications in PUBMED) using algorithms of topological data analysis was performed. RESULTS: A complex of interactions between SARS-CoV-2 infection, metabolic disorders of neurotransmitters (acetylcholine, dopamine, serotonin and GABA), enkephalins and neurotrophins, micronutrients, chronic and acute inflammation, encephalopathy, cerebral ischemia and neurodegeneration, including demyelination, was described. The most common neurological manifestation of COVID-19 is anosmia/ageusia arising as a result of ischemia, neurodegeneration, and/or systemic elevation of proinflammatory cytokine levels. COVID-19 provokes ischemic stroke, Guillain-Barré syndrome, polyneuropathy, encephalitis, meningitis and parkinsonism. Coronavirus infection significantly aggravates the course of multiple sclerosis and myopathies. Possible roles of the human virome in the neuropathophysiology of COVID-19 are considered. A case of clinical management of a patient with neurological complications of COVID-19 is described. CONCLUSION: In the long term, COVID-19 stimulates neurodegenerative changes, which require specific programs of neurological rehabilitation. It is advisable to use choline drugs and antihypoxants that are compatible with COVID-19 therapy.

[Choice of neuroprotective therapy regimens in patients with chronic cerebral ischemia, taking into account the synergy of drug interactions]. / Vybor neiroprotektivnoi terapii u patsientov s khronicheskoi ishemiei golovnogo mozga s uchetom sinergizma lekarstvennykh vzaimodeistvii.

OBJECTIVE: Optimization of the choice of neuroprotective treatment regimens in patients with chronic cerebral ischemia that takes into account the synergy of drug interactions gives the doctor an opportunity for personalized approach that increases the effectiveness of treatment. MATERIAL AND METHODS: Differential chemoreactomic analysis of the synergism of ethyl methyl hydroxypyridine succinate (EMHPS) and a number of monocomponent neuroprotective agents (piracetam, vinpocetine, citicoline, choline alfoscerate); proteomic analysis of polypeptide neuroprotectors (cerebrolysin, etc.); an expert analysis of multicomponent neuroprotector Cytoflavin. RESULTS: Piracetam, citicoline (Neupilept) and choline alfoscerate (Cereton) effectively enhance the pharmacological properties of EMHPS and vice versa. Expert assessments of the synergism between the properties of EMHPS, polypeptide neuroprotectors (cerebrolysin) and other multicomponent drugs (cytoflavin), which are also used in adjuvant therapy with EMHPS, are presented. CONCLUSION: In real clinical practice, of particular interest is the objectification of the appointment of combined therapy regimens. This study indicates that EMHPS can provide a favorable background for maximizing the effectiveness of therapy when used with other drugs.

[Comprehensive study of the composition of fish fat extracts and quantitative criteria for distinguishing standardized omega-3 polyunsaturated fatty acids extracts].

Background Effects of drugs and biologically active supplements based on omega-3 polyunsaturated fatty acids (ω3 PUFA) considerably depend on the standardized content of eicosatetraenoic acid (EPA), docosahexaenoic acid (DHA), and other fatty acids in the extracts.Material and methods In this study, we comprehensively examined the composition of 10 ω3 PUFA samples with chromatographic measurement of more than 40 metabolites of fatty acids and other compounds. The data on extract composition were analyzed with current methods of intelligent data analysis (metric condensation method; multidimensional scaling; principal component analysis with axis identification; topology-metrical approach to recognition).Results Quantitative markers were obtained, which allowed separating the standardized ω3 PUFA-based samples (Omacor, Solgar omega-3 700, Femibion Natalker-2, Omega-3 concentrate, Omegamama) from less standardized ones (Fish oil-Teva, Omegatrin, Omeganol, etc.) based on results of a chromatographic analysis of fatty acid composition in the studied samples (EPA+DHA marker, ω6+ω11 marker, and standardization coefficient showing conformity of measured ω3 PUFA levels with the content stated by the manufacturer).Conclusions Among the studied samples, the pharmaceutical product Omacor showed the best values of standardization indexes.

[The chemoreactomic analysis of the central mechanisms of action of non-steroidal anti-inflammatory drugs]. / Khemoreaktomnyi analiz tsentral'nykh mekhanizmov nesteroidnykh protivovospalitel'nykh preparatov.

AIM: To perform a chemoreactome modeling of the pharmacological central effects of 4 non-steroidal anti-inflammatory drugs (NSAIDs): dexketoprofen, ketoprofen, aceclofenac, lornoxicam. MATERIAL AND METHODS: An analysis of the pharmacological spectrum of the central action of dexketoprofen, ketoprofen, aceclofenac and lornoxicam was based on the chemoinformatic approach, which compared drug-likeness properties with public and commercial software. RESULTS: The effectiveness of NSAIDs is related to the inhibition of cannabinoid receptors CB-1, the vanilloid receptor TRPV1, NMDA and AMPA receptors and of the GABA reuptake transporter, with dexketoprofen being the most effective inhibitor. The safety of the central effects of NSAID is due to weak interactions of the NSAIDs studied with opioid, adrenergic, serotonin and dopamine receptors. Chemoreactome modeling made it possible to compare the particulars of the effects of the studied NSAIDs on experimental pain and cramps. CONCLUSION: Inhibition of CB-1, TRPV1, NMDA, AMPA, GABA transporter by the NSAID molecules corresponds to a decrease in the intensity of nociceptive signals. A weak intervention of the studied NSAIDs in opioid, adrenergic, serotonin and dopaminergic neurotransmission corresponds to a decrease in the central side-effects of NSAIDs and to a lessened antagonism of these NSAIDs towards exogenous and endogenous opioids.

[Comparative studies of neurotrophic drugs based on brain hydrolysates]. / O sravnitel'nykh éksperimental'nykh issledovaniiakh neirotroficheskikh preparatov na osnove gidrolizatov golovnogo mozga.

The results of the analysis of comparative studies of neurotrophic drugs based on brain hydrolysates (BH) are presented. The most comprehensive comparative study of the BH drugs carried out by Zhang, et al. 2019 investigated the effects of four drugs (cognistar, cerebrolysate, cortexin, cerebrolysin) on a model of ischemic stroke in rats. The study showed that a significant improvement in the neurological outcome compared with placebo was observed only with cerebrolysin. Higher standardization in elemental composition, higher antioxidant activity, and presence of active peptide fragments of neuropeptides of nerve growth factor, enkephalins, orexin and galanin in cerebrolysin explains neurotrophic and neuroprotective effects of the drug.

[An analysis of the peptide composition of a 'light' peptide fraction of cerebrolysin]. / Kompleksnyi proteomnyi analiz 'legkoi' peptidnoi fraktsii preparata Tserebrolizin.

AIM: To analyze the peptide composition of a light peptide fraction of cerebrolysin. MATERIAL AND METHODS: Mass spectrometry (MS) with orbital ion traps and modern de novo MS-sequencing algorithms was performed. RESULTS: The amino acid sequences of 14 635 peptides corresponding to the 1643 porcine proteome neuronal proteins are identified. An analysis of the human proteome annotation shows that these peptides can mimic the corresponding human peptides. In particular, 405 peptide fragments correspond to 300 known biologically active peptides, including fragments of antibacterial peptides (defensins, histatins), immunomodulatory (granulin, manserin) and vasoactive (endothelin, VIP) peptides. At the same time, 8953 of 14 635 peptides can modulate the activity of 275 human signaling proteins, including kinases CDK1, CDK2, TGFBR2, GSK3, MTOR, pro-apoptotic caspases CASP1, CASP3 and CASP6 etc. The results confirm the presence of Leu- and Met-enkephalins, fragments of neuropeptide orexin, neuropeptide VF, galanin and nerve growth factor that have a neurotrophic effect. CONCLUSION: The results of a proteomic study of the peptide composition of cerebrolysin indicate the widest range of molecular mechanisms responsible for the clinical efficacy of this drug.

[Systematic Analysis of the Roles of Trace Elements in the Prevention and Treatment of Chronic Heart Failure].

Systematic analysis of 3 728 publications on the relationship between microelement status and chronic heart failure (CHF) was carried out. Three main areas of research have been identified: 1) magnesium, electrolytes and CHF; 2) the transcriptional and antioxidant effects of zinc, selenium, copper; 3) iron-deficiency anemia and CHF. In this paper, we consider a complex of relationships between the magnesium insufficiency and CHF, the effect of magnesium on vascular tone, mitochondria, heart rhythm and the susceptibility of cardiomyocytes to adrenergic stimulation. Using magnesium orotate for the treatment of CHF is a feasible approach to compensate magnesium insufficiency in patients with CHF.

[Cerebrolysin peptides as mood stabilizers]. / O peptidakh Tserebrolizina, sposobstvuiushchikh normotimii.

AIM: To establish the molecular mechanisms of the mood stabilizing (normothymic) action of the neuroprotector Cerebrolysin. MATERIAL AND METHODS: Mass-spectrometric analysis of the peptide composition of cerebrolysin followed by a complex bioinformatics analysis was utilized. RESULTS: Cerebrolysin contains considerable amounts of Leu- and Met-enkephalins, partial analogues of enkephalins, peptide fragments of beta-lipotropin. These peptides stimulate the endorphinergic system thus contributing to normothymic action and an increase in the levels of the brain-derived neurotrophic factor (BDNF). Specific inhibition of kinases ABL1, PINK1, CDK5 and arginine N-methyltransferase PRMT5 by the peptides of cerebrolysin has a multidirectional effect on the dopaminergic system, also helping to stabilize mood. Cerebrolysin peptides do not directly affect neither the serotonergic, adrenergic, nor GABAergic systems. CONCLUSION: The normothymic effect of Cerebrolysin is due to the stabilization of endorphinergic and dopaminergic neurotransmission.