[Disallowed conformations of polypeptide chain exemplified by the ß-bend of the ß-hairpin in the α-spectrin CH3-domain].

The work presents the results of an exhaustive conformational analysis of ß-turns involving amino acid residues with disallowed backbone conformation of the polypeptide chain. It is known that the first residue of the ß-turn (Asn47) of the distal ß-hairpin in the α-spectrin SH3-domain is characterized by sterically disallowed main chain conformation (values of the dihedral angles (φ and ψ are in the right bottom quadrant of the Ramachandran plot). All α-spectrin structures with the anomalous elements deposited in the PDB were analysed. We hypothesized that the formation of disallowed conformation may occur through the fixation (due to the SH3 domain structure) of the adjacent to the ß-turn amino acid residues with the ß-structure. These residues are disposed in such a manner that ß-turn conformation of the residues contributes just to the disallowed local conformation of this residue whereas any other ß-turn conformations (with allowed local conformation) are impossible. To test this hypothesis an exhaustive conformational analysis of the ß-bend has been performed by altering internal coordinates (two pairs of φ and ψ angles and two Ω angles). The conformations were selected as a result of grid search procedure with. 1 degrees step that corresponded to stereochemically allowed local deformations of the polypeptide chain segment forming the ß-turn. In all conformations obtained the local conformation of Asn47 rests in the disallowed region. The conformations found include conformations coinciding with experimentally determined structures from the PDB as well as an additional variant that differs from X-ray structure in values of a pair of φ and ψ angles of the second residue belonging to the ß-bend. Values of these angles fall in the region of the Ramachandran plot near the line φ = 0 (and negative values of ψ) i.e. in strongly disallowed region without experimental points. Therefore the additional variants of the ß-turn local deformation are impossible to observe in experiment. Thus, the idea that disallowed conformation is intruded to the ß-bend by fixation of adjacent residues receives confirmation in this work. The topological limitations in a context of the structure in such kind of ß-hairpins exclude the allowed local conformations.

[Magnesium deficiency and dysregulation of vascular tone].

Magnesium deficiency is associated with impaired vascular tone bidirectionally and can lead to both an abnormal increase and abnormal lowering of blood pressure. This article analyzes studies on the relationship between blood pressure parameters and the level of magnesium in the blood. Evidence base for the use of magnesium for correction of vascular tone is presented.

[Mechanisms of neurotrophic and neuroprotective effects of cerebrolysin in cerebral ischemia]. / Mekhanizmy neirotroficheskogo i neiroprotektornogo deistviia preparata tserebrolizin pri ishemii golovnogo mozga.

Cerebrolysin is the drug which contains peptides derived from the brain of a pig. It is used in neurological practice for recovery of stroke patients and treatment of dementia. Despite the evidence-basis and some experimental studies, the distinct mechanisms of pharmacological action of this drug remain unclear for most neurologists. In this paper, we present results of a molecular-biological analysis of peptide content of cerebrolysin. We have demonstrated the presence of active peptide fragments of nerve growth factor, enkephalins, orexin, halanin. The results of current clinical and experimental studies of cerebrolysin have been compared. The activity of above-mentioned neuropeptides explain experimental and clinical details of all known effects (neurotrophic, neuroprotective and immunomodulating) of cerebrolysin in ischemic and neurodegenerative CNS injuries. The analysis allowed to make conclusions about mechanisms of cerebrolysin action that were important for increasing the efficacy of this drug in clinical practice.

[Diagnostics of magnesium deficiency and measurements of magnesium concentrations in biosubstrates in norm and in various pathologies].

In accordance with the evidence from large-scale studies magnesium deficiency has a significant negative impact on the cardiovascular system, carbohydrate and fat metabolism. Diagnosis of magnesium deficiency should be based on clinical symptoms of magnesium deficit and confirmed by additional diagnostic methods--ECG myography, bone densitometry, and quantitative determination of magnesium in various biosubstrates (whole blood, red blood cells, plasma, serum, saliva, urine, nails, hair). It is also desirable to estimate dietary intake of magnesium according to food frequency questionnaires verified by measurements of magnesium in blood. Analysis of magnesium content in blood and other biosubstrates allows to establish those perturbations of compartmentalization of magnesium in tissues that are typical for a particular pathology. It is important to emphasize that one should not confuse values of magnesium levels measured in serum and in plasma as it leads to serious errors in the diagnosis of magnesium deficiency and results in underdiagnosis of magnesium deficiency (code E61.2 of ICD-10).

[Systematic analysis of magnesium dependent mitochondrial proteins].

Magnesium is principally important for maintenance of function of cardiomyocytes. Magnesium deficit provokes asthenia of cardiomyocytes accompanying cardiovascularpathology. In this paper we present results of conducted for the first time bioinformatic analysis of magnesium dependent mitochondrial proteins. The results have principal significance for understanding pharmacodynamics effects of action of magnesium on function of mitochondria.

[System analysis of the relationship between the metabolism of vitamins by micro-biota and the survival of the positive microflora of the digestive tract].

A perspective direction of the treatment of dysbacteriosis is the use of so-called metabolic prebiotics--products of metabolism of positive flora (for example, water substrate of the products of metabolism of E. coli, S. faecalis, L. acidophilus, L. helveticus (strains of DSM), out of which, as known, drug Hylak Forte is made. Our earlier systematic analysis of metabolomics, representatives of positive microflora, pointed to the fact that the latter contain specific biochemical mechanisms for biosynthesis and processing of a number of vitamins. In the present paper the results of a systematic analysis of the effects of vitamins B2, B6 and K on the survival of the representatives of the positive microflora on the basis of the substrate of metabolic products of positive flora have been presented. The results of the analysis allow us clarify the molecular mechanisms of the therapeutic effects of this drug with a very complex structure and confirm the available clinical data and are an important foundation for subsequent microbiological research. Metabolites in the preparation composition contribute to the normalization of metabolism of pyridoxalphosphate (vitamin B6), flavin adenin dinucleotide (FAD, a derivative of vitamin B2) and nicotinamide dinucleotide (NAD, a derivative of vitamin B3)--cofactors of enzymes that have a significant impact on the survival of microbiota. The proposed molecular mechanisms also indicate on a possible synergies between certain vitamins and micro elements, on the one hand, and molecular components of the preparations on the basis of waste products of microbiota on the other.

[Trace elements in the nervous tissue and ischemic stroke].

Disbalance of the trace elements increases the risk of cerebrovascular disease and, first of all, of ischemic stroke (IS). This is due to the fact that certain trace elements are necessary for maintaining various aspects of the metabolism of neurons and glia. Energetic and plastic processes in the nervous tissue have an extremely active dynamics and their dependence on the availability of brain macro-and micronutrients makes it necessary to take into account the trace element status of patients with IS. This paper presents the results of clinical and basic research which revealed the association between the content of certain trace elements in different biological substrates and the course of stroke. The importance of magnesium, zinc, manganese, copper and selenium for the support of the function of the nervous tissue was shown. The study of the trace element profile in various regions of the brain in patients with IS is a very promising area of modern neurological research.

[Potassium-preserving properties of magnesium].

Current fundamental research indicates importance of conducting clinical studies of the influence of magnesium content of the body on the potassium homeostasis. In this work we systematically analyze molecular mechanisms through which magnesium regulates potassium homeostasis: ATP-sensitive inward rectifier K-channels, Na+/K(+)-ATPases and their regulatory protein SIK1, transporter SLC12A3 and WNK-kinases. Hyperkalemia as well as hypokalemia require safe and effective prevention and therapy, including restoration of magnesium homeostasis.

[Analysis of a disturbance of trace element balance in patients with ischemic stroke with arterial hypertension].

Disturbance of trace element balance increases the risk of cerebrovascular disease and, above all, ischemic stroke (IS). A comparative analysis of clinical and demographic parameters and trace element composition of hair was performed in the group of 30 ischemic stroke patients with arterial hypertension (AH) and 30 stroke patients without hypertension (mean age 55±7 years). The stroke patients with hypertension were characterized by the elevated body mass index (28.5±4.1 kg/m2, AI, 26.0±2.9 kg/m2, p=0.006), higher incidence of coronary heart disease (p=0.04). Alcohol consumption more than 3 drinks a week was associated with a 5-fold increase of the risk of stroke with hypertension (95% CI 1.0-27, p=0.035). The results revealed a number of statistically significant differences in trace element profile in the studied groups of patients: deficits of essential magnesium, manganese, cobalt, copper, zinc, a statistically significant increase in sodium levels, toxic and conditionally toxic trace elements (cadmium, mercury, bismuth, barium, etc.). One of the probable factors that lead to the accumulation of toxic trace elements in stroke patients is the increased consumption of alcohol including that of substandard quality. The data obtained also show the feasibility of implementing screening programs to assess micronutrient status (including trace elements) for early detection of pathological abnormalities in the elemental homeostasis that might lead to an increased risk of ischemic stroke and hypertension.

[Systematic analysis of molecular mechanisms of action of omega-3 polyunsaturated fatty acids on arrhythmia].

Safe pharmacotherapy and prevention of arrhythmia is an urgent problem of modern cardiology. Essential micronutrients such as omega-3 polyunsaturated fatty acids (-3 PUF-) significantly contribute to the metabolic processes in cardiomyocytes and cardiac conduction system. This article presents a systematic analysis of anti-arrhythmic effects of omega-3 PUFA and of standardized ethyl esters of omega-3 PUFA. The currently available data indicate two fundamentally different molecular mechanisms of anti-arrhythmic effects: "slow" and "fast" types. Formulation of fundamental prospects of bioinformatic studies of molecular effects of anti-arrhythmic action of omega-3 PUF-s is presented.

[Cerebrolysin alleviates perinatal CNS disorders through the autoimmune modulation and antioxidant protection].

We investigated the effects of the neuroprotective drug cerebrolysin on the autoimmune parameters (FasL, Fas and metallotionein-1) in 20 newborns with perinatal ischemic CNS damage and 20 healthy newborns. The treatment with cerebrolysin in dosage of 0,1 ml per 1 kg of body mass, 10 injections every other day, resulted in the normalization (p<0,001) of the T-lymphocyte apoptosis (the increase of Fas and decrease of FasL) and activation of antioxidant protection through the increase of metallotionein-1 expression. The normalization of the autoimmunity was found to reduce edema and improve the circulation of the brain sites affected with ischemia.

[Connective tissue dysplasia, magnesium, and nucleotide polymorphisms].

Undifferentiated connective tissue dysplasia (UCTD) is one of most common diseases of the connective tissue. High frequency of UCTD in population along with the fact that it can provoke a number of other diseases make UCTD an important object of the modern biomedical research in the areas of cardiology, neurology, rheumatology and pulmonology. Modern diagnostics and determination of the predisposition to UCTD allow elaboration of personalized therapy. In particular, Mg-containing supplements and medications can be effectively used in the therapy of UCTD. In one of our previous works we have analyzed possible molecular mechanisms of UCTD etiology as well as therapeutic action of magnesium. The use of data on nucleotide polymorphisms as complementation of standard medical diagnostics is one of perspective trends of the post-genomic medical research. The present work suggest a number of nucleotide polymorphisms that can be used in genetic association analyses of the UCTD as of well as therapeutic efficiency of magnesium treatment. Selection and analysis of the polymorphisms was done on the base of molecular mechanisms we had proposed earlier, comprehensive analysis of published data and also with the use of an integral approach to analysis of the functional effects of the nucleotide polymorphisms and corresponding amino acid substitutions.