Today, cardio- and cerebrovascular diseases pose a severe threat to human health and life quality, leading to reduced working capacity, disability and, often, death. The most common cardiovascular diseases are arterial hypertension, chronic cerebral ischemia and ischemic heart disease. Metabolic disorders that cause oxidative stress growth, vessel wall damage, and injury of body cells and tissues, as well as affect energy formation processes are the key aspects of their formation. Glutathione is a powerful antioxidant that protects cell structures from damage by free radicals, helping to reduce oxidative stress. Eltacin has a corrective effect on these pathological processes, rising the antioxidant protection of the body by increasing the efficiency of glutathione-dependent mechanisms of cell redox regulation. As a result of the complex impact on metabolic processes in the tissue, Eltacin has not only antioxidant, but also neuro- and cytoprotective and vegetotropic effects. The drug has a positive effect on the hemodynamic performance of patients with cardiovascular diseases, which is expressed in blood flow normalization in the heart as well as in the brain. The inclusion of Eltacin in traditional therapy for cardiovascular diseases patients leads to an increase in the antianginal and hypotensive effects. Its use in combined treatment regimens contributes to structural and functional state improvement of the myocardium of the left ventricle, which is a key factor for maintaining normal heart functioning. Increased physical activity tolerance allows patients to lead a more active lifestyle, which has a beneficial effect on their overall condition and life quality. In addition, the vegetotropic effectiveness of Eltacin has been proven. It results in meteoprotective effect, which reduces weather factors influence on the hemodynamics of weather-dependent patients with arterial hypertension and ischemic heart disease. Thus, Eltacin not only improves the condition of patients and increases traditional therapy effectiveness, but also provides additional protection from adverse environmental influence.

Glutathione (γ-glutamyl-cysteinyl-glycine) is one of the main intracellular antioxidants that play an important role in cellular metabolism. In mammalian cells, glutathione is synthesized in two stages, the first of which is catalyzed by glutamate–cysteine ligase and is limiting. In this study, a stochastic algorithm based on Markov chains with continuous time was used to simulate glutamate-cysteine ligase functioning. Several catalytic mechanisms were considered, taking the reverse inhibition of glutathione into account, as well as ATP binding order. Based on the physiological concentrations of the metabolites involved in the reaction, the rate of work of glutamate–cysteine ligase of human erythrocytes was calculated. Among the possible options for the substrate binding to the active site of the enzyme under study, only the mechanism involving primary ATP binding allows obtaining a value for the reaction rate corresponding to the experimentally measured glutamate-cysteine ligase activity at physiological substrate levels. In the case of other substrate binding schemes, the difference in rates was more than an order of magnitude. The analysis performed allows to conclude that when modeling glutathione biosynthesis under in vivo conditions, it is necessary to take into account both the ATP concentration and the reverse inhibition by glutathione.

The article discusses the metabolism of niacin, also known as vitamin B3 or PP, and the mechanisms of its receptor-induced functions in the human body. Niacin exists as a several molecular compounds that act as the nicotinamide coenzymes precursors. These coenzymes being electron donors or acceptors in redox reactions catalyzed by various enzymes play a crucial role in metabolism. Maintenance of the intracellular niacin pool is vital not only for redox metabolism, but also for the NAD-dependent pathways functioning. At the same time, pathophysiological situations and changes in enzyme activity can affect the necessity for various niacin forms. In addition to indirect effects via nicotinamide coenzymes, it also has a number of direct effects, including anti-lipolytic, vasodilatory, and neuroprotective functions, the exact mechanism of which has not been studied fully up to date. Overall, niacin plays a vital role in maintaining the efficient cell functioning, and further study of its influence on various physiological aspects, including the gut microbiome and epigenetic regulation, could lead to new discoveries and treatments for various diseases.

Glucose and oxygen concentration gradients are the key indicators that form the trophic tissue supply in mammalian brain. To describe them in detail it is essential to combine the solution of both hemodynamics and the convection-diffusion-reaction problems in the tissue. Visualization of spatio-temporal distributions of the metabolites noted above can be carried out both using the gradients themselves and the corresponding probability density functions. In the case of considering large parts of the brain, as well as the entire organ as a whole, the second method for metabolite heterogeneity description is of greater interest for practical purposes. This paper presents an approach to obtain a probability density functions based on structural segmentation of the diffusion region using Delaunay triangulation and the spherical source diffusion field method. It is shown that the average values of the estimated distributions deviate by 8 % from the experimentally obtained results and it corresponds to the best match during the validation by the finite element method in the triangulation simplices of basic topology. Given the relatively low computational complexity of both the segmentation process and the estimation of concentration in a single segment, the proposed method to obtain integral distributions of various compounds, in particular glucose and oxygen, can be used as an affordable alternative to precise calculation of the concentration gradients in the whole brain and its distinct anatomical structures.

Vascular networks possess properties of self-similarity, which allows one to consider them as stochastic fractals. The box-counting method based on calculations along the vessel centerlines is traditionally used to evaluate the parameters of the fractal structure. Such an algorithm does not allow one to consider structural differences between different bifurcation levels of the system, characterized by the natural property of changing the blood vessel caliber. In this case, the discrepancy between the values of the fractal dimension may exceed 20%. In this paper, an approach that allows one to avoid underestimating the complexity of the system for low bifurcation orders and large vessels is proposed. Based on the constructed arterial tree of the rat brain, it was shown that the fractal dimension increases with an increase in the values of both bifurcation exponent and length coefficient. The obtained values most fully reflect the properties of the arterial tree considering the real geometry of the vessels; they are proposed for use in estimating three-dimensional vascular networks.

All metabolic processes in living tissues are provided by the vascular system, whose functionality largely depends on its structure and topology. The paper proposes an algorithm for constructing the circulatory system based on a combination of stochastic and deterministic approaches. Analyses of the topological characteristics of arterial tree models with different values of the bifurcation exponent ([Formula: see text]) and length coefficient ([Formula: see text]) show that the maximum agreement with experimental data can be achieved only with the optimal values of both parameters (3.0 and 0.90, respectively). Application of the multiparametric optimization in conjunction with topological analysis makes it possible to quantify the biological division of the distributing and delivering vessels of a tree with a high degree of branching. The proposed approach allows both the correct spatial localization of the main arteries and the complex topology of the complete arterial system down to the capillaries to be reproduced.

The studies of mammalian vasculature are an essential part of biomedical research, enabling the development of physiological understanding and forming the background of medical techniques and therapy. Despite the fact that the basic principles of vessel network description were established in the first quarter of the twentieth century, a digital model describing the vasculature in full accordance with experimental data has not yet been created. In the present study, we combine the determined structure design of basic arterial vessels with the stochastic creation of small vessel networks. By the example of rat brain arterial network model it was shown that the arterial blood volume and the magnitude of the blood flow impose a limitation on the network architecture. In particular, the bifurcation exponent (γ) should not be less than 2.7, and the optimal value of this parameter lies in the range of 2.9-3.0. Although the networks with a low γ appear as branched and complex, they do not fill out the phantom properly. Thus, the architecture of the vasculature is fundamentally determined by topological geometrical parameters.

This work presents computer modeling of the activity of glutamine synthetase, which is a key component of nitrogen metabolism that catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-depending reaction. An algorithm based on the stochastic approach was applied to simulate the processes of substrate binding and activation. An evaluation of the effects of free Mg2+ ions on the activity of glutamine synthetase was performed and the optimal activation mechanism was determined. The major conclusion is that activation of bacterial glutamine synthetase in vivo is due to a consecutive mechanism with sequential Mg2+ ions binding first to the substrate-free form.

Mammalian glutamate transporters are essential for the most aspects of normal brain functioning including cognition, memory and learning. Its structure and functional properties are vigorously investigated now. However, there is no compliance amongst researchers with the elementary events sequence of glutamate transporter cycle. The sequence of elementary events was analysed using stochastic simulation of the processes. It was shown that in the case of invariant equilibrium constants of reactions of substrate and co-transported ions associations transposition in binding events sequence leads to alteration of protein affinity to substrate, but has insufficient impact on maximal transport velocity. Moreover, it was indicated that glutamate should be bound to the protonated form of transporter after the second sodium ion association.

Metabolism of glutamate and glutamine in brain is highly dependent on regional distribution and proper regulation of the phosphate activated glutaminase. Being predominantly a mitochondrial enzyme, glutaminase has a catalytically active form on the inner mitochondrial membrane, but to date, the exact localization of its active center remains a controversial and unresolved issue. In this paper, we used a multi-compartment kinetic modeling to simulate metabolism of glutamate and glutamine in astrocytes. The simulation results confirmed the experimental hypothesis, in which the active site of glutaminase faces the outer surface of the inner mitochondrial membrane.

The optimal network topology and spatial arrangement of the vessels providing a large surface area are necessary for the efficient functioning of the vasculature. In the present study we have developed the algorithm for construction of the arterial system model with physiologically significant geometric properties. The analysis of the effect of the bifurcation exponent on the topology of the arterial network was made using the proposed approach.

Localization times of Na+ corresponding to the pore-lining amino acid residues of the 5-HT3 receptor are obtained using Langevin dynamics with respect to hydrodynamic and dielectric friction. The transmembrane potential is modelled by the external uniform electric field. The simulation shows that the ion localization times for T257 and E250 are similar, even though threonine has an uncharged side chain. Moreover, the time values obtained for T257 exceed more than twice the appropriate results for S253. Despite of the non-polar nature of I267 and I268, these residues are noticed to have the highest time values. This result may confirm the suggestion of the hydrophobic gating existence.

The influence of pH on the activity of cytochrome c oxidase is investigated using the stochastic modelling based on Markov processes. The functioning of the K-channel is considered on four different schemes. A change of channel modes can be observed under high values of pH: the fraction of K-protons transferred through the membrane increases significantly while D-proton flow disappears. Moreover, the pumping efficiency at high pH values rises more than twice under the circumstances when at the beginning of the pumping there are three or four protons in the binuclear center under pumping both D- and K-protons.

The process of proton transport in cytochrome c oxidase is studied in the framework of stochastic modeling. The activation energies are calculated using Marcus theory. This model allows to define the key amino acid residues and water molecules which form the main H+ transduction pathway. According to the simulation results, Asn-207 and Asn-121 are not involved in direct proton translocation. The estimated rate of the proton transfer through the D-channel of cytochrome c oxidase is (1.43±0.18)·104 s-1.

The model presented in this work allows simulation of isotopic exchange reactions at chemical equilibrium catalyzed by a glutamine synthetase. To simulate the functioning of the enzyme the algorithm based on the stochastic approach was applied. The dependence of exchange rates for C-14 and P-32 on metabolite concentration was estimated. The simulation results confirmed the hypothesis of the ascertained validity for preferred order random binding mechanism. Corresponding values of K-0.5 were also obtained.