[Cellular and molecular mechanisms of inflammation of esophageal mucosa under different clinical course of gastroesophageal reflux disease and its complications].

The review presents modern data on the cellular and molecular mechanisms of inflammatory changes of esophageal mucosa exposed to different types of reluctate (gastric, biliary or duodenal/mixed). The authors describe data on key mediators of inflammation in gastroesophageal reflux disease (GERD) and their major cellular sources, changes of the immune profile of patients. Discusses the possible impact of changes in the cellular and molecular components in the development of the inflammatory response in the esophagus on the clinical features of GERD and its therapy-refractory forms.

[The role of cellular mediators in the development of the phenomenon of inhibition induced by barium sulfate luminol-dependent chemiluminescence of blood under the influence of non-steroidal anti-inflammatory drugs in patients with intolerance to these drugs].

We investigated contribution mediator mechanism in the development of the phenomenon of inhibition induced by barium sulfate luminol-dependent chemiluminescence (SLCHL) of blood under the influence of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with intolerance to these drugs. It was found that the phenomenon of suppression SLCHL blood under the influence of NSAIDs in patients with intolerance is mediated by the participation of mediators, and the contribution of H1--and H2--histamine receptors, 5-HT2 serotonin receptors and Cys-leukotriene receptors in the development of that phenomenon depends on the chemical nature of NSAIDs and the clinical manifestations of intolerance.

[Epigenetic, post-transcriptional and metabolic mechanisms of macrophage reprogramming].

A key role in the ability of immunity to adequately respond to pathogenic factors play macrophages. Depending on the type of infection and the microenvironment macrophages can rapidly change their phenotype towards the proinflammatory M1 or antiinflammatory M2 one. The process of changing the cell phenotype is termed "reprogramming". This process plays a central role in the immune response and therefore its disturbance triggers the development of disease. Reprogramming of macrophages is provided by intracellular signaling pathways. These paths can also control epigenetic, post-transcriptional and metabolic mechanisms of phenotypic activity of macrophages. Epigenetic mechanisms can be divided into the reprogramming mechanisms towards M1 and M2 phenotype. A key component of post-transcriptional regulation is micro-mRNA (miR). On M1- and M2-stimuli macrophages express different sets of miRs. MiRs may form a positive feedback mechanism for quick reprogramming of macrophages and negative feedback mechanisms, to limit excessive inflammation in the case of M1 phenotype and to restrict fall bactericidal activity in the case of M2 phenotype. Reprogramming of macrophages leads to a change in the metabolism of these cells. Formation of M1 phenotype accompanied by a shift of the arginine metabolism towards NO-synthase activation and increased production of NO, an increase in the contribution of glycolysis to ATP production, increased deposition of bacteriostatic iron. Formation of the M2 phenotype is accompanied by a shift of the arginine metabolism towards arginase 1 activation and increasing production of urea, increased ATP synthesis in mitochondria and increased capture of fatty acids, increased the capture of heme iron. Metabolic control of macrophage phenotype also involves the positive and negative feedback. In general, macrophage reprogramming involves very good coordinated and adapted to each other changes in the activity of signaling, epigenetic, post-translational and metabolic mechanisms. A detailed understanding of the mechanisms of reprogramming will assist in selecting the correct effective therapeutic targets to develop new ways for correction of impaired immunity. Keywords: immunity; macrophages; reprogramming

[Possibility of diagnostics of the non-steroidal anti-inflammatory drugs intolerance with a change in the chemiluminescent glow of the polymorphonuclear leukocytes of the peripheral blood].

We investigated the intensity of barium sulfate stimulated luminol-dependent chemiluminescence (SLCL) of pre-incubated blood with various concentrations of sodium salicylate, sodium metamizol or sodium diclofenac. Blood was received from healthy donors and patients with intolerance to aspirin and/or sodium metamizol and/or sodium diclofenac. Revealed valid differences in SLCL of blood received from healthy donors and patients with intolerance to these drugs allows us to use chemiluminescence method for the diagnosis of intolerance to non-steroidal anti-inflammatory drugs.

HSP70 stress proteins, nitric oxide, and resistance of August and Wistar rats to myocardial infarction.

Accumulation of HSP70 stress proteins in the myocardium and blood content of nitrite/nitrate in August rats with modeled myocardial infarction surpassed these parameters in Wistar rats less resistant to cardiovascular disorders by 2-2.5 and 1.8 times, respectively. Our results suggest that various resistance of August and Wistar rats to myocardial infarction is related to genetically determined differences in the activity of HSP70 and nitric oxide systems.

Nitric oxide increases gene expression of Ca(2+)-ATPase in myocardial and skeletal muscle sarcoplasmic reticulum: physiological implications.

The aim of the study was to verify the hypothesis that NO-dependent regulation of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) gene expression can play an important role in prevention of calcium overload under the influence of detrimental factors. It was shown that 2 hours after the administration of the NO donor dinitrosyl iron complex (DNIC), the gene expression of myocardial SERCA was increased by 20% as compared to the control. In skeletal muscles, the maximum increase in SERCA expression was observed in 6 hours and amounted to 156% as compared with the initial value. Simultaneously DNIC enhanced the resistance of isolated heart and the organism as a whole to damaging effects of intracellular calcium overload induced by post-ischemic reperfusion or vigorous exercise, respectively. The results obtained confirm the existence of NO-dependent activation of SERCA expression and the important role of this mechanism in restriction of calcium overload.

The function of endogenous protective systems in patients with insulin-dependent diabetes mellitus and polyneuropathy: effect of antioxidant therapy.

alpha-Lipoic acid is a very efficient antioxidants for the treatment and prevention of diabetic neuropathy. The aim of the present study was to evaluate the function of nitric oxide (NO) and stress proteins (HSP72) in insulin-dependent diabetes complicated by polyneuropathy and possible contribution of these systems to the therapeutic effects of alpha-lipoic acid. Plasma content of nitrites and nitrates in diabetic patients was almost 2-fold below the normal. The treatment with alpha-lipoic acid completely normalized the plasma content of these stable NO metabolites. The majority of patients had also low level of HSP72. Positive clinical effects of alpha-lipoic acid were accompanied by normalization of HSP72 synthesis. Thus, activation of the NO and HSP protective systems is involved in the therapeutic effect of alpha-lipoic acid in diabetic patients (type 1 diabetes mellitus) with polyneuropathy.

Role of thyroid hormones in stress-induced synthesis of heat-shock proteins in the myocardium.

Thyroxine in near-physiological doses increased the content of heat-shock proteins in the myocardium and stimulated their accumulation during immobilization stress. Blockade of thyroid functions with methimazole decreased the content of heat-shock proteins in rat myocardium during stress and heat shock and prevented their accumulation during adaptation to short-term immobilizations.

Production and storage of nitric oxide in adaptation to hypoxia.

Adaptation to hypobaric hypoxia is known to exert multiple protective effects related with nitric oxide (NO). However the effect of adaptation to hypoxia on NO metabolism has remained unclear in many respects. In the present work we studied the interrelation between NO production and storage in the process of adaptation to hypoxia. The NO production was determined by the total nitrite/nitrate concentration in rats plasma. The volume of NO store was evaluated in vitro by the magnitude of isolated aorta relaxation to diethyldithiocarbamate. It was shown that both the nitrite/nitrate level and the NO store increased as adaptation to hypoxia developed. Furthermore, the NO store volume significantly correlated with plasma nitrite/nitrate. Therefore, adaptation to hypoxia stimulates NO production and storage and these effects can potentially underlie NO-dependent beneficial effects of adaptation.

Dinitrosyl iron complexes with thiol-containing ligands and S-nitroso-D,L-penicillamine as inductors of heat shock protein synthesis in H35 hepatoma cells.

The concentration-dependent effect of various nitric oxide donors on synthesis of different heat shock proteins was evaluated in Reuber H35 hepatoma cells and their heat shock protein-inducing ability was compared with the effect of a heat shock. A 6 h incubation of H35 cells with the dimeric (diamagnetic) form of dinitrosyl iron complex with glutathione or N-acetyl-L-cysteine activated synthesis of various heat shock proteins, heat shock protein 28, 32, 60, 70, 90 and 100. Synthesis of these proteins was evaluated by [35S]methionine and [35S]cysteine labelling with subsequent separation of proteins by polyacrylamide gel electrophoresis. The dinitrosyl iron complex with glutathione appeared to be the most efficient inductor of heat shock protein synthesis and initiated the synthesis of heat shock protein 28 even more efficiently than a 30 min heating of cells. In the same experiments, S-nitroso-D,L-penicillamine exerted a considerably lesser effect on the synthesis of heat shock proteins. It was suggested that the active moiety of dinitrosyl iron complexes as inductors of heat shock protein synthesis is represented by their Fe+(NO+)2 groups which move to thiol groups of the proteins participating in the initiation of heat shock protein synthesis.

NO-dependent mechanisms of adaptation to hypoxia.

In studying NO-dependent mechanisms of resistance to hypoxia, it was shown that (1) acute hypoxia induces NO overproduction in brain and leaves unaffected NO production in liver of rats; (2) adaptation to hypoxia decreases NO production in liver and brain; and (3) adaptation to hypoxia prevents NO overproduction in brain and potentiates NO synthesis in liver in acute hypoxia. Dinitrosyl iron complex (DNIC, 200 microg/kg, single dose, iv), a NO donor, decreases the resistance of animals to acute hypoxia by 30%. Nomega-nitro-L-arginine (L-NNA, 50 mg/kg, single dose, ip), a NO synthase inhibitor, and diethyl dithiocarbamate (DETC, 200 mg/kg, single dose, iv), a NO trap, increases this parameter 1.3 and 2 times, respectively. Adaptation to hypoxia developed against a background of accumulation of heat shock protein HSP70 in liver and brain. A course of DNIC reproduced the antihypoxic effect of adaptation. A course of L-NNA during adaptation hampered both accumulation of HSP70 and development of the antihypoxic effect. Therefore, NO and the NO-dependent activation of HSP70 synthesis play important roles in adaptation to hypoxia.

Stress, adaptation, and nitric oxide.

The biological role of nitric oxide (NO) has been studied for more than ten years. Nevertheless, the number of investigations in this field continues to increase. It is now suggested that NO is a previously unrecognized, very important regulator of physiological functions and cell metabolism in the body. Through the application of the methods of molecular biology, more and more data are being accumulated on the regulatory role of NO in the mechanism of gene expression and protein biosynthesis. The data presented in this review show an important role of NO in stress and adaptive responses of organisms and thereby expand existing notions on the biological role of this unique molecule. This review substantiates the idea that the system of NO generation is a newly discovered stress-limiting system. The action of this NO-ergic system is based on the capability of NO to limit key links of the stress reaction and to enhance the potency of endogenous defense systems of the organism. The role of NO is considered at the major stages of adaptation: 1) at the urgent stage related with the stress reaction; 2) at the stage of the transition from urgent to long-term adaptation; and 3) at the stage of long-term adaptation characterized by the formation of stable protective effects. It is demonstrated that pharmacological "imitation" of the activated NO-ergic system by administration of NO donors to the organism provides in many instances an efficient protection against stress damage and enhances the adaptive capacity of the organism.

The role of hsp70 and IP3-DAG mechanism in the adaptive stabilization of structures and heart protection.

This study has shown that the maximal activation of the IP3-DAG regulatory circuit is observed on the 14th day of adaptation to repeated stresses. This activation is characterized by increased activity of phospholipase C and of the positive inotropic response of isolated heart to an alpha-agonist. Simultaneously, this activation is accompanied by the accumulation of five heat shock protein 70 (hsp70) isoforms. The IP3-DAG circuit activation and the hsp70 accumulation are accompanied by a significant increase in the cardiac resistance to post-ischemic reperfusion, as evidenced by a considerable decrease in the contracture, arrhythmias and the creatine kinase release into the perfusate. Continuation of the adaptation to repeated stresses for 28 days leads to complete reversal of the observed shifts.