[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.

[Molecular mechanisms of the effect of standardized placental hydrolysate peptides on mitochondria functioning].

BACKGROUND: Human placenta hydrolysates (HPH), the study of which was initiated by the scientific school of Vladimir P. Filatov, are currently being investigated using modern proteomic technologies. HPH is a promising tool for maintaining the function of mitochondria and regenerating tissues and organs with a high content of mitochondria (liver, heart muscle, skeletal muscles, etc.). The molecular mechanisms of action of HPH are practically not studied. AIM: Identification of mitochondrial support mitochondrial function-supporting peptides in HPH (Laennec, produced by Japan Bioproducts). MATERIALS AND METHODS: Data on the chemical structure of the peptides were collected through a mass spectrometric experiment. Then, to establish the amino acid sequences of the peptides, de novo peptide sequencing algorithms based on the mathematical theory of topological and metric analysis of chemographs were applied. Bioinformatic analysis of the peptide composition of HPH was carried out using the integral protein annotation method. RESULTS: The biological functions of 41 peptides in the composition of HPH have been identified and described. Among the target proteins, the activity of which is regulated by the identified peptides and significantly affects the function of mitochondria, are caspases (CASP1, CASP3, CASP4) and other proteins regulating apoptosis (BCL2, CANPL1, PPARA), MAP kinases (MAPK1, MAPK3, MAPK4, MAPK8, MAPK9 , MAPK10, MAPK14), AKT1/GSK3B/MTOR cascade kinases, and a number of other target proteins (ADGRG6 receptor, inhibitor of NF-êB kinase IKKE, pyruvate dehydrogenase 2/3/4, SIRT1 sirtuin deacetylase, ULK1 kinase). CONCLUSION: HPH peptides have been identified that promote inhibition of mitochondrial pore formation, apoptosis, and excessive mitochondrial autophagy under conditions of oxidative/toxic stress, chronic inflammation, and/or hyperinsulinemia.

[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.

[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.

[Deficit of Magnesium and States of Hypercoagulation: Intellectual Analysis of Data Obtained From a Sample of Patients Aged 18-50 years From Medical and Preventive Facilities in Russia].

The states characterized by pronounced hypercoagulable components (deep vein thrombosis, cardio- and cerebro-vascular pathologies) are caused by multiple pathophysiological factors, including insufficient supply of magnesium (Mg) and other micronutrients. AIM: to present results of analysis of the Institute of Microelements Data Base (IMDB) performed from point of view of interrelationships of Mg deficit and hypercoagulable states in adults treated in medico-preventive facilities of Central, Northwestern, Northern, and Siberian federal districts of Russia. METHODS: The analysis was realized as analysis of data obtained in a cross-sectional study. In the cohort of patients (n=1453) formed from the IMBD adequacy of Mg supply was assessed by magnesium levels in blood plasma (Mg BP) (0.69±0.15 mmol/L) and estimates of daily Mg consumption according to dietary diaries (Mg D) (185±90 mg/day). RESULTS: Mg supply was adequate (Mg BP >0.80 mmol/L, Mg D >300 mg/day) in not more than 6 % of patients. Presence of "Hypercoagulation" label in data base was associated with greater number of chronic diseases (2.3±2.1 and 0.83±0.8 with and without this label, respectively, р=0.0006) and elevated risk of the presence on 4 comorbid pathologies (odds ratio [OR] 18, 95 % confidence interval [CI] 10-25, р=0.0006). Mg deficit (Mg BP.

[An experimental study of anticonvulsant effects of myo-inositol and folic acid]. / Protivosudorozhnye effekty mio-inozitola v sochetanii s folievoi kislotoi v eksperimente.

AIM: To study the micronutrients that potentiate the action of anticonvulsant drugs, and in particular, of myo-inositol (vitamin B8). MATERIAL AND METHODS: An experimental study of neurotrophic and anticonvulsant effects of a preparation based on myo-inositol (inofert) on thiosemicarbazide models of seizures was carried out. RESULTS: Inofert significantly increased the latent time before the first convulsive seizure, reduced the severity of seizures (p<0.05) and reduced mortality in the models of thiosemicarbazide seizures. Myo-inositol enhanced anticonvulsant action of gabapentin and sodium valproate; neuroprotective effect of myo-inositol was also confirmed. CONCLUSION: The Inofert preparation, containing myo-inositol and folic acid, modulates the effects of drugs with both convulsive and anticonvulsive action, reduces the severity and duration of seizures caused by thiosemicarbazide and increases the survival rate of animals.

Identification of serovar-specific single-nucleotide polymorphisms of C. Trachomatis omp1 gene.

Complete sequences of omp1 gene encoding chlamydial main outer membrane protein were analyzed in 76 clinical strains of C. trachomatis. Thirty-four serovar-specific single-nucleotide polymorphisms were identified, 20 of them meet two criteria: unique position of the nucleotide and unique nucleotide substitution. Evaluation of serovar-specific single-nucleotide polymorphisms of omp1 gene can appreciably simplify and accelerate genetic diagnosis of C. trachomatis serovars.

Structure of murine Tcl1 at 2.5 A resolution and implications for the TCL oncogene family.

Tcl1 and Mtcp1, members of the Tcl1 family, are implicated in T-cell prolymphocytic leukemia. The crystal structure of a dimer of murine Tcl1 has been determined at 2.5 A resolution with an R factor of 0.225. Murine Tcl1, human Tcl1 and Mtcp1 share very similar subunit structures, with RMS differences of 0.6 and 1.4 A for C(alpha) atoms, respectively, while the sequences share 50 and 36% identity, respectively. These structures fold into an eight-stranded beta-barrel of unique topology and high internal symmetry of 1.1-1.3 A for the two halves of human and murine Tcl1 and 1.7 A for Mtcp1, despite the low 12-13% sequence identity. The molecular surfaces of all three structures showed a common planar region which is likely to be involved in protein-protein interactions.

Charge centers and formation of the protein folding core.

Electrostatic interactions are important for protein folding. At low resolution, the electrostatic field of the whole molecule can be described in terms of charge center(s). To study electrostatic effects, the centers of positive and negative charge were calculated for 20 small proteins of known structure, for which hydrogen exchange cores had been determined experimentally. Two observations seem to be important. First, in all 20 proteins studied 30-100% of the residues forming hydrogen exchange core(s) were clustered around the charge centers. Moreover, in each protein more than half of the core sequences are located near the centers of charge. Second, the general architecture of all-alpha proteins from the set seems to be stabilized by interactions of residues surrounding the charge centers. In most of the alpha-beta proteins, either or both of the centers are located near a pair of consecutive strands, and this is even more characteristic for alpha/Beta and all-beta structures. Consecutive strands are very probable sites of early folding events. These two points lead to the conclusion that charge centers, defined solely from the structure of the folded protein may indicate the location of a protein's hydrogen exchange/folding core. In addition, almost all the proteins contain well-conserved continuous hydrophobic sequences of three or more residues located in the vicinity of the charge centers. These hydrophobic sequences may be primary nucleation sites for protein folding. The results suggest the following scheme for the order of events in folding: local hydrophobic nucleation, electrostatic collapse of the core, global hydrophobic collapse, and slow annealing to the native state. This analysis emphasizes the importance of treating electrostatics during protein-folding simulations.

Clustering amino acid contents of protein domains: biochemical functions of proteins and implications for origin of biological macromolecules.

Structural classes of protein domains correlate with their amino acid compositions. Several successful algorithms (that use only amino acid composition) have been elaborated for the prediction of structural class or potential biochemical significance. This work deals with dynamic classification (clustering) of the domains on the basis of their amino acid composition. Amino acid contents of domains from a non-redundant PDB set were clustered in 20-dimensional space of amino acid contents. Despite the variations of an empirical parameter and non-redundancy of the set, only one large cluster (tens-hundreds of proteins) surrounded by hundreds of small clusters (1-5 proteins), was identified. The core of the largest cluster contains at least 64% DNA (nucleotide)-interacting protein domains from various sources. About 90% of the proteins of the core are intracellular proteins. 83% of the DNA/nucleotide interacting domains in the core belong to the mixed alpha-beta folds (a+b, a/b), 14% are all-alpha (mostly helices) and all-beta (mostly beta-strands) proteins. At the same time, when core domains that belong to one organism (E.coli) are considered, over 80% of them prove to be DNA/nucleotide interacting proteins. The core is compact: amino acid contents of domains from the core lie in relatively narrow and specific ranges. The core also contains several Fe-S cluster-binding domains, amino acid contents of the core overlap with ferredoxin and CO-dehydrogenase clusters, the oldest known proteins. As Fe-S clusters are thought to be the first biocatalysts, the results are discussed in relation to contemporary experiments and models dealing with the origin of biological macromolecules. The origin of most primordial proteins is considered here to be a result of co-adsorption of nucleotides and amino acids on specific clays, followed by en-block polymerization of the adsorbed mixtures of amino acids.

Dissociative thermal inactivation, stability, and activity of oligomeric enzymes.

Results of kinetic studies on dissociative thermal inactivation of oligomeric enzymes are discussed. Dissociative thermal inactivation is the process in which the kinetically irreversible protein change is preceded by a reversible stage of oligomer dissociation. In experiments, this is demonstrated by the dependence of inactivation rate on total protein concentration. This paper gives the relations which allow the calculation from experimental data the following physicochemical constants which characterize the stability of oligomeric enzymes: the constant for the rate of irreversible change of monomeric protein, the equilibrium constant for dimer dissociation, and the rate constant for dimer dissociation. The problem of a "conformational lock", the contact between protein globules that admits a multistep destruction of active oligomer and explains the induction period occurring in kinetic thermal inactivation curves, is discussed. The X-ray structural analyses for several dimeric enzymes, i.e., alkaline phosphatase (EC 3.1.3.1) from E. coli, alcohol dehydrogenase (EC 1.1.1.1) from horse liver, and baker's yeast enolase (EC 4.2.1.11), explain why they lose catalytic activity during the dissociation of the protein into monomers and also provide a physically reasonable picture of the structure of their conformational lock. Also, these data support the kinetic scheme used to describe the dissociative inactivation of dimeric enzymes.