Autoregulation and Autoinhibition of the Main NO Synthase Isoforms (Brief Review).

Nitric oxide (II) (NO) is the most important mediator of a wide range of physiological and pathophysiological processes. It is synthesized by NO synthases (NOSs), which have three main isoforms differing from each other in terms of activation and inhibition features, levels of NO production, subcellular localization, etc. At the same time, all isoforms are structurally very similar, and these differences are determined by NOS autoregulatory elements. The article presents an analysis of the autoregulatory and autoinhibitory mechanisms of the NOS reductase domain that determine differences in the productivity of isoforms, as well as their dependence on the concentration of Ca2+ ions. The main regulatory elements in NOS that modulate the electron transfer from flavin to heme include calmodulin (CaM), an autoinhibitory insert (AI), and the C-terminal tail (C-tail). Hydrophobic interactions of CaM with the surface of the NOS oxidase domain are assumed to facilitate electron transfer from flavin mononucleotide (FMN). CaM binding causes a change in the inter-domain distances, a shift of AI and the C-tail, and, as a result, a decrease in their inhibitory effect. CaM also shifts the conformational equilibrium of the reductase domain towards more open conformations, reduces the lifetime of conformations, their stereometric distribution, and accelerates the flow of electrons through the reductase domain. The AI element, apparently, induces a conformational change that hinders electron transfer within the reductase domain, similar to the hinge domain in cytochrome P450. Together with CaM, the C-tail regulates the electron flow between flavins, the distance and relative orientation of isoalloxane rings, and also modulates the electron flow from FMN to the terminal acceptor. Together with the C-tail, AI also predetermines the dependence of neuronal and endothelial forms of NOS on the concentration of Ca2+ ions, and the C-tail length affects differences in the productivity of NO synthesis. The inhibitory effect of the C-tail is likely to be reduced by CaM binding due to the C-tail shift due to the electrostatic repulsive forces of the negatively charged phosphate and aspartate residues. The autoregulatory elements of NOS require further study, since the mechanisms of their interaction are complex and multidirectional, and hence provide a wide range of characteristics of the observed isoforms.

[Oxidative stress in pathogenesis of bronchial asthma: a method of correction by inhalation of phospholipid nanoparticles].

The authors present the results of a prospective simple blind randomized placebo-controlled study for the evaluation of dynamics of biomarkers of oxidative stress (total concentration of nitrate- and nitrite-anions in condensed exhaled breath and plasma, pH of exhaled breath, total antioxidative activity of plasma in patients with bronchial asthma inhaling phospholipid nanoparticles. The results suggest significant positive effect of proposed therapy on dynamics of the main parameters of oxidative stress including reduced concentration of nitric oxide metabolites and increased total antioxidative activity of plasma. No clinically significant reactions were documented.

[Experience with the use of phospholipid preparations in the combined treatment of bronchial asthma].

The authors report the results of a single-blind randomized placebo-controlled study of the efficacy and safety of inhalation of phospholipid nanoparticles in patients with bronchial asthma. They give evidence of the statistically significant positive effect of the proposed therapeutic modality on the clinical status of the patients and lung functional tests. No clinically significant adverse events were documented during the study.