Anti-inflammatory action of new hybrid N-acyl-[1,2]dithiolo-[3,4-c]quinoline-1-thione.

Most of pharmaceutical agents display a number of biological activities. It is obvious that testing even one compound for thousands of biological activities is not practically possible. A computer-aided prediction is therefore the method of choice in this case to select the most promising bioassays for particular compounds. Using the PASS Online software, we determined the probable anti-inflammatory action of the 12 new hybrid dithioloquinolinethiones derivatives. Chemical similarity search in the World-Wide Approved Drugs (WWAD) and DrugBank databases did not reveal close structural analogues with the anti-inflammatory action. Experimental testing of anti-inflammatory activity of the synthesized compounds in the carrageenan-induced inflammation mouse model confirmed the computational predictions. The anti-inflammatory activity of the studied compounds (2a, 3a-3k except for 3j) varied between 52.97% and 68.74%, being higher than the reference drug indomethacin (47%). The most active compounds appeared to be 3h (68.74%), 3k (66.91%) and 3b (63.74%) followed by 3e (61.50%). Thus, based on the in silico predictions a novel class of anti-inflammatory agents was discovered.

[Neuropathic pain in dry eye syndrome. Part 1. Pathophysiological mechanisms of pain formation]. / Nevropaticheskaya bol' pri sindrome «sukhogo glaza¼. Chast' 1. Patofiziologicheskie mekhanizmy formirovaniya boli.

The review details the features and mechanisms of the formation of various types of pain. The emphasis is placed on the occurrence of pain syndrome in various ophthalmological diseases, particularly in dry eye syndrome. The article also presents literature data on the role of cytokines in the formation of a neuroinflammatory cascade affecting damage to corneal nerve fibers and the development of pain syndrome, which is a characteristic feature of a subtype of dry eye disease - burning eye syndrome.

[Neuropathic pain in dry eye syndrome. Part 2. Clinical picture, diagnosis and treatment]. / Nevropaticheskaya bol' pri sindrome «sukhogo glaza¼. Chast' 2. Klinicheskaya kartina, diagnostika i lechenie.

Burning eye syndrome is a chronic neuropathic pain syndrome, which is characterized by dysesthesia, spontaneous pain, allodynia and hyperalgesia. The review describes clinical features and presents available data on possible methods of diagnosis and therapy of this condition.

Computer-aided discovery of pleiotropic effects: Anti-inflammatory action of dithioloquinolinethiones as a case study.

Most of pharmaceutical agents exhibit several or even many biological activities. It is clear that testing even one compound for thousands of biological activities is a practically not feasible task. Therefore, computer-aided prediction is the method-of-the-choice to select the most promising bioassays for particular compounds. Using PASS Online software, we determined the likely anti-inflammatory action of the 13 dithioloquinolinethione derivatives with antimicrobial activities. Chemical similarity search in the Cortellis Drug Discovery Intelligence database did not reveal close structural analogues with anti-inflammatory action. Experimental testing of anti-inflammatory activity of the synthesized compounds in carrageenan-induced inflammation mouse model confirmed the computational predictions. The anti-inflammatory activity of the studied compounds was comparable with or higher than the reference drug Indomethacin. Thus, based on the in silico predictions, novel class of the anti-inflammatory agents was discovered.

1-benzoyl-6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline exerts a neuroprotective effect and normalises redox homeostasis in a rat model of cerebral ischemia/reperfusion.

Ischemia is one of the main etiological factors of stroke and is associated with the development of energy deficiency, oxidative stress, and inflammation. An abrupt restoration of blood flow, called reperfusion, can worsen the effects of ischemia. In our study, we assessed the neuroprotective potential of 1-benzoyl-6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline (BHDQ) in cerebral ischemia/reperfusion (CIR) in rats. Wistar rats, divided into 4 groups were used in the study: sham-operated animals; animals with CIR caused by occlusion of the common carotid arteries and subsequent removal of the occlusions; rats treated with BHDQ at a dose of 50 mg/kg in the presence of pathology; sham-operated animals treated with BHDQ. The analysis of the state of energy metabolism in the brain, the level of the S100B protein and the histological assessment of the brain tissue were carried out. The antioxidant potential of BHDQ was assessed by measuring biochemiluminescence parameters, analysing the level of 8-isoprostane, products of lipid and protein oxidation, concentration of α-tocopherol and citrate, and aconitate hydratase activity during CIR in rats. A study of the effect of BHDQ on the regulation of the enzymatic antioxidant system and the inflammatory processes was performed. We demonstrated that BHDQ has a neuroprotective effect in CIR, reducing histopathological changes in the brain, normalizing pyruvate and lactate concentrations, and the transcripts level of Hif-1α gene. The positive effect of BHDQ was probably due to its antioxidant and anti-inflammatory activity, manifested in a decrease in the parameters of the oxidative stress, decreased mRNA of proinflammatory cytokines and NF-κB factor genes. In addition, BHDQ reduced the load on antioxidant protection enzymes, contributing to a change in their activities, decreased the level of antioxidant gene transcripts and expression of Nrf2 and Foxo1 factors toward control. Thus, BHDQ exhibited a neuroprotective effect due to a decrease in the level of oxidative stress and inflammation and the normalization of redox homeostasis on CIR in rats.

Detection of Hispidin by a Luminescent System from Basidiomycete Armillaria borealis.

In in vitro experiments, the possibility of using a luminescent system extracted from the luminous fungus Armillaria borealis has been shown to detect and determine the concentration of hispidin. A linear dependence of the luminescent response on the content of hispidin in solutions in the concentration range of 5.4 × 10-5-1.4 × 10-2 µM was detected. The stability of the enzyme system and the high sensitivity of the bioluminescent reaction allows carrying out multiple measurements with the analyte detection limit of 1.3 × 10-11 g. The obtained results show the prospects of creating a rapid bioluminescent method for the analysis of medical substances or extracts from various biological objects for the presence of hispidin.

Devil's staircase and the absence of chaos in the dc- and ac-driven overdamped Frenkel-Kontorova model.

The devil's staircase structure arising from the complete mode locking of an entirely nonchaotic system, the overdamped dc+ac driven Frenkel-Kontorova model with deformable substrate potential, was observed. Even though no chaos was found, a hierarchical ordering of the Shapiro steps was made possible through the use of a previously introduced continued fraction formula. The absence of chaos, deduced here from Lyapunov exponent analyses, can be attributed to the overdamped character and the Middleton no-passing rule. A comparative analysis of a one-dimensional stack of Josephson junctions confirmed the disappearance of chaos with increasing dissipation. Other common dynamic features were also identified through this comparison. A detailed analysis of the amplitude dependence of the Shapiro steps revealed that only for the case of a purely sinusoidal substrate potential did the relative sizes of the steps follow a Farey sequence. For nonsinusoidal (deformed) potentials, the symmetry of the Stern-Brocot tree, depicting all members of particular Farey sequence, was seen to be increasingly broken, with certain steps being more prominent and their relative sizes not following the Farey rule.

Reaction of Lymphoid Organs to Injection of Iron-Carbon Nanoparticles.

The distribution of iron-carbon nanoparticles in FeC-DSPE-PEG-2000 modification (micellar particles with structure (Fe) core-carbon shell; PEG-based coating) is studied. The greater part of the nanoparticles accumulated in the spleen and liver, a small amount in the lungs, and the minimum amount in the thymus. The structural changes in the lymphoid organs were minor and involved only the microcirculatory bed. Analysis of the peripheral blood showed manifest anemia, thrombocytopenia, and leukocytosis.

[The influence of low-frequency pulsed electric and magnetic signals or their combination on the normal and modified fibroblasts (an experimental study)]. / Vliyanie nizkochastotnykh impul'snykh elektricheskogo, magnitnogo signalov i ikh sochetaniya na normal'nye i transformirovannye fibroblasty (eksperimental'noe issledovanie).

The results of clinical studies give evidence of the beneficial preventive and therapeutic effects of the «Tiline-EM¼ physiotherapeutic device designed for the combined specific treatment of the skin regions onto which both discomfort and pain sensations are directly projected, reflectively active sites and zones, as well as trigger zones with the use of low-frequency pulsed electric current and magnetic field. The efficient application of the device requires the understanding of the general mechanisms underlying such action on the living systems including those operating at the cellular and subcellular levels. The objective of the present study was the investigation of the specific and complex effects produced by the low-frequency pulses of electric current and magnetic field generated in the physiotherapeutic device «Tiline-EM¼ on the viability, proliferative activity, and morphofunctional characteristics of normal skin fibroblasts and the transformed fibroblast line K-22. It has been demonstrated that the biological effects of the electric and magnetic signals vary depending on the type of the cell culture and the mode of impact. The transformed fibroblasts proved to be more sensitive to the specific and complex effects of electric and magnetic pulses than the normal skin fibroblasts. The combined action of the electric and magnetic signals was shown to have the greatest influence on both varieties of fibroblasts. It manifests itself in the form of enhanced viability, elevated proliferative and synthetic activity in the cultures of transformed fibroblasts and as the acceleration of cell differentiation in the cultures of normal fibroblasts. The effect of stimulation of dermal fibroblast differentiation in response to the combined treatment by the electric and magnetic signals is of interest from the standpoint of the physiotherapeutic use of the «Tiline-EM¼ device for the purpose of obtaining fibroblasts cultures to be employed in regenerative therapy and the treatment of skin injuries in cosmetology, aesthetic and regenerative medicine.

[Feasibility of using connective tissue prosthesis for autoplastic repair of urinary bladder wall defects (an experimental study)].

Experiments on laboratory rats have shown the feasibility of autoplastic repair of urinary bladder wall defects using a connective-tissue capsule formed as the result of an inflammatory response to the presence of a foreign body. The formation of connective tissue prosthesis is characterized by developing fibrous connective tissue, ordering of collagen fibers, reducing the number of cells per unit area with a predominance of more mature cells - fibroblasts. With increasing time of observation, connective tissue prostheses were found to acquire a morphological structure similar to that of the urinary bladder wall. By month 12, the mucosa, the longitudinal and circular muscle layers were formed. The proposed method of partial autoplastic repair of urinary bladder wall is promising, has good long-term results, but requires further experimental studies.

[Severity of anxiety and depressive disorders and their relationship with cerebral and hemodynamic impairment in patients with arterial hypertension in the practice of general practitioner]. / Vyrazhennost' trevozhno-depressivnykh rasstroistv i ikh sootnoshenie s tserebral'nymi i gemodinamicheskimi narusheniyami u bol'nykh arterial'noi gipertoniei v praktike vracha obshchego profilya.

AIM: To determine the relationship of anxiety and depressive disorders with cerebral and hemodynamic impairment in arterial hypertension (AH). MATERIAL AND METHODS: The study involved 97 patients with AH, stage II, who were followed up by a general practitioner. The severity of anxiety and depression assessed with the HADS, severity of cerebral disorders and a set of hemodynamic parameters were evaluated. RESULTS AND CONCLUSION: It was found that psycho-emotional disorders were combined with an increase in the frequency of modifying risk factors (smoking, high salt intake, overweight and obesity), severe cerebral disorders and significant changes in the elastic-tonic properties of a vascular wall. Significant correlations between depression and vascular age were found.

[The First Russian Consensus on the Multilevel Abobotulinumtoxin A Injections in Spastic Forms of Cerebral Palsy]. / Pervyi Rossiiskii konsensus po primeneniyu mnogourovnevykh in''ektsii abobotulinumtoxin A pri lechenii spasticheskikh form detskogo tserebral'nogo paralicha.

Spasticity treatment is one of the key aspects of the contemporary cerebral palsy (CP) rehabilitation that influences on the effectiveness of other methods. The paper presents the first Russian document that unites the recommendations for the BTA treatment of CP and could be used as the guideline for the multilevel injections. The Russian consensus on the multilevel botulinum toxin A (BTA) treatment of spastic CP is based on the international data and the results of national studies. The authors describe typical CP spasticity patterns in the upper and lower extremities, give recommended intervals for the BTA (Abobotulinum toxin A) dosages for the whole injection procedure and for the separate muscles. The method of dosage calculation for functional segments is also described. Attention is paid to the frequency, optimal intervals between the repeated injections and the whole duration of BTA treatment. The authors discuss effectiveness and safety of BTA, factors that potentially influence the results of the injections, including ultrasound and electromyography control, and indications for the continuation and termination of treatment.

[Total Peroxidase and Catalase Activity of Luminous Basidiomycetes Armillaria borealis and Neonothopanus nambi in Comparison with the Level of Light Emission].

The peroxidase and catalase activities in the mycelium of luminous basidiomycetes Armillaria borealis and Neonothopanus nambi in normal conditions and under stress were compared. An increase in the luminescence level was observed under stress, as well as an increase in peroxidase and catalase activities. Moreover, the peroxidase activity in extracts of A. borealis mycelium was found to be almost one and a half orders of magnitude higher, and the catalase activity more than two orders of magnitude higher in comparison with the N. nambi mycelium. It can be suggested that the difference between the brightly luminescent and dimly luminescent mycelium of N. nambi is due to the content of H2O2 or other peroxide compounds.

Evaluation of Biodistribution of Functionalized Magnetic Core/Carbon-Shell Nanoparticles in Systemic Method of Administration.

We studied new magnetic nanocomposites consisting of a core(Fe) and carbon-shell inert to biological media. Iron-carbon nanoparticles circulate in the bloodstream for several minutes and are primarily accumulated in the liver; less intensive accumulation was found in the spleen and minimum in the lungs, kidneys, and heart. Accumulation of nanoparticles in the liver leads to the development of destructive processes and is accompanied by activation of compensatory-adaptive mechanisms. In the liver and spleen, structural changes are mild and mainly relate to changes in the microvasculature. In 6 months, the total content of nanoparticles in all tissues decreased due to their elimination from the body and the structure of the organs returned to normal.

The impact of immunomodulator compound from the group of substituted thiadiazines on the course of stress reaction.

A significant role of the stress response to many different diseases prompted a search for new specialized and non-specialized anti-stress agents. This study examines the effect of the compound L17 from the group of 5-phenyl substituted-6H-1,3,4-thiadiazine-2-amines, on the manifestations of the stress response. The authors used a standard model of immobilization stress, in which an animal was immobilized on its back for 6h a day. Parameters of the morphological and functional states of the organs studied were measured and biochemical and enzyme-immunoassays were carried out on the first and second days. This study reveals that the main mechanism by which the L17 compound mediates of its anti-stress was by activation of macrophages on the second day of the experiments and the inhibition of apoptosis in the thymus. The results enable us to suggest that the compound L17 does not improve resistance to stress; however, it does lower the reaction to stress.

Morphological restructuring of myocardium during the early phase of experimental diabetes mellitus.

The purpose of this study was to determine the specific features of the morphological restructuring of the myocardium in the early stage of experimental diabetes mellitus (DM). Experimental type 1 DM rat model was developed by intraperitoneal injection of alloxan solution at a dose of 30 mg per 100 g body mass. After 1 month, 3 mL of blood was drawn by heart puncture and the plasma separated by centrifugation for biochemical analysis. Plasma glucose, insulin, and glycosylated haemoglobin in whole blood were determined. Light microscopy and morphometric studies were conducted of histological slices of the hearts of experimental animals. The investigation of heart morphology showed a statistically significant alteration in chamber wall thickness in the right auricle in rats with alloxan-induced DM. A change in cardiomyocyte diameter in myocardium slices was observed in all chambers of DM rats except for the left ventricle. Average cardiomyocyte diameter in rats with experimental DM increased by 26.6% and 15.5% in the right auricle and right ventricle, respectively, while average cardiomyocyte diameter in the left auricle decreased by 20.8%. Histological investigation of the heart following alloxan injection demonstrated, under the epicardium, distended vessels of the venous collecting microcirculatory system. Aggregation and agglutination of red blood cells and endothelial cell destruction were found in some vessels. In the early stage of DM development, structural alterations in the microcirculatory channels and myocardiocytes can be observed in the heart. These structural alterations were most evident in the right chambers of the heart.

Structured chaos in a devil's staircase of the Josephson junction.

The phase dynamics of Josephson junctions (JJs) under external electromagnetic radiation is studied through numerical simulations. Current-voltage characteristics, Lyapunov exponents, and Poincaré sections are analyzed in detail. It is found that the subharmonic Shapiro steps at certain parameters are separated by structured chaotic windows. By performing a linear regression on the linear part of the data, a fractal dimension of D = 0.868 is obtained, with an uncertainty of ±0.012. The chaotic regions exhibit scaling similarity, and it is shown that the devil's staircase of the system can form a backbone that unifies and explains the highly correlated and structured chaotic behavior. These features suggest a system possessing multiple complete devil's staircases. The onset of chaos for subharmonic steps occurs through the Feigenbaum period doubling scenario. Universality in the sequence of periodic windows is also demonstrated. Finally, the influence of the radiation and JJ parameters on the structured chaos is investigated, and it is concluded that the structured chaos is a stable formation over a wide range of parameter values.