Role of Hematopoietic Stem Cells in Inflammation of the Pancreas during Diabetes Mellitus.

The model of streptozotocin-induced diabetes mellitus in C57Bl/6 mice was employed to study the role of precursors of insulin-producing ß-cells, hematopoietic stem cells, and progenitor hematopoietic cells in inflammation. In addition to provoking hyperglycemia, streptozotocin elevated serum levels of IL-1ß and hyaluronic acid, induced edema in the pancreatic insular tissue and its infiltration by inflammatory cells (neutrophils, lymphocytes, and macrophages) and fibroblasts. Inflammation in pancreatic islets was accompanied by necrotic processes and decreasing counts of multipotent progenitor ß-cells (CD45(-), TER119(-), c-kit-1(-), and Flk-1(-)), oligopotent progenitor ß-cells (CD45(-), TER119(-), CD133(+), and CD49f(low)), and insulinproducing ß-cells (Pdx1(+)). Pancreatic infl ammation was preceded by elevation of the number of short-term hematopoietic stem cells (Lin-Sca-1(+)c-kit(+)CD34(+)) relative to long-term cells (Lin(-)Sca-1(+)c-kit(+)CD34(-)) in the bone marrow as well as recruitment of hematopoietic stem and progenitor cells into circulation. Transplantation of bone marrow hematopoietic stem and progenitor cells from diabetic C57Bl/6 donor mice to recipient CBA mice with 5-fluorouracilinduced leukopenia accelerated regeneration of granulocytopoiesis in recipient mice.

Role of PI3K, ERK, and p38 Signaling Pathways in the Production of Humoral Erythropoiesis Regulators under Normal Conditions.

PI3- and MAP-kinase signaling pathways duplicate and interchange each other in production of agents that determine total erythropoietic activity under conditions of balanced erythropoiesis. The alternative p38-dependent MAP-kinase pathway is the major regulator of erythropoietic activity of adherent bone marrow cells. Blockade of PI3K and p38 signaling pathways stimulated production of erythropoietin by cells that do not produce it constitutively.

Response of hemopoietic, progenitor, and multipotent mesenchymal stromal cells to administration of ketanserin during pulmonary fibrosis.

We studied the effect of ketanserin on hemopoietic progenitor cells (Lin(-)Sca-1(+)c-Kit(+)CD34- and Lin(-)Sca-1(+)c-Kit(+)CD34(+)), progenitor hemopoietic cells (Lin(-)Sca-1(+)c-kit(+)), and multipotent mesenchymal stromal cells (CD45(-)CD73(+)CD106(+)) in C57Bl/6 mice during pulmonary fibrosis. It was shown that the blocker of 5-HT2A receptors lowers the activity of bleomycin-induced inflammation in the lungs and prevents the infiltration of alveolar interstitium and alveolar ducts by hemopoietic stem and hemopoietic progenitor cells; in this case, they are more numerous in the bone marrow of sick animals. Ketanserin reduces the capacity for self-renewal of lung multipotent mesenchymal stromal cells in the fibrotic phase of the disease and inhibits their differentiation into stromal cell lines (adipocytes, chondrocytes, and fibroblasts) simultaneously with the decrease in the percentage of connective tissue in the lung parenchyma.

Effect of spiperone on mesenchymal multipotent stromal and hemopoietic stem cells under conditions of pulmonary fibrosis.

The antifibrotic properties of spiperone and its effect on stem and progenitor cells were studied on the model of reversible bleomycin-induced pulmonary fibrosis in C57Bl/6 mice. Spiperone reduced infiltration of the alveolar interstitium and alveolar ducts with inflammatory cells and prevented the growth of the connective tissue in the parenchyma of bleomycin lungs. Apart from anti-inflammatory effect, spiperone suppressed bone marrow hemopoietic cells (CD3, CD45R (B220), Ly6C, Ly6G (Gr1), CD11b (Mac1), TER-119)-, Sca-1+, c-Kit+, CD34- and progenitor hemopoietic cells (granulocyte-erythroid-macrophage-megakaryocytic and granulocyte CFU). Spiperone-induced disturbances of fi brogenesis were paralleled by restoration of endothelial cells in the lung parenchyma, reduction of the number of circulating bone marrow cells and lung mesenchymopoietic cells (mesenchymal multipotent stromal cells (CD31-, CD34-, CD45-, CD44+, CD73+, CD90+, CD106+) and progenitor fi broblast cells), and suppression of multilineage differentiation of multipotent mesenchymal stromal cells (including fi broblast-lineage cells).

[The primary screening of patients with autonomic disorders in outpatient clinics in Russia (START1) using the Russian version of The Four-Dimensional Symptom Questionnaire (4DSQ)].

OBJECTIVE: To develop an effective diagnostic algorithm for detection of a mental component in the state of patients diagnosed with autonomic nervous system disorder. MATERIAL AND METHODS: In the frames of START1 epidemiological study, we examined 6633 patients with autonomic nervous system disorders (ICD-10 G.90.8 and G90.9) and somatoform disorders (F45) including 18,8% patients who got a referral to a psychiatrist. A linguistically validated Russian version of The Dutch Four-Dimensional Symptoms Questionnaire (4DSQ) was tested in domain subpopulations. RESULTS: In subpopulations of anxiety and depression, more than 26% of the patients got a referral to a psychiatrist that indirectly supported the assumption on the conformity of 4DSQ to the purposes of primary screening of four-dimensional disorders in the general population of patients with autonomic nervous system disorders. CONCLUSION: The linguistically validated Russian version of 4DSQ enabled to formalize the description of clinical profile of these patients. Cluster analysis of the results allowed to single out two superdomains by the pairwise combination somatization with distress (SDis) and anxiety with depression (ADep). The detection of superdomain SDis appears to be a population specific characteristic of autonomic nervous system disorders in the Russian Federation.

[Effect of Ingavirin on the ultrastructure of the morphogenesis of adenovirus infection in vivo].

The goal of this study was to evaluate the effect of Ingavirin on the morphological features of the foci of adenovirus hepatitis in Syrian hamsters by electron microscopy. The use of the drug was shown to cause a substantial reduction in the rate of destructive processes and inflammatory reactions in the liver, by normalizing its structure at the levels of both tissue and individual hepatocytes. After administration of Ingavirin, the morphogenesis of adenovirus infection in the infected hepatocytes did not differ from that in the controls; however, the infected cells were fewer. The proportion of morphologically inadequate virions in the presence of Ingavirin increased from 35 to 46%. The findings suggest that Ingavirin is an effective drug that has antiviral, anti-inflammatory, and cytoprotective activities in the focus of adenovirus tissue involvement.

[Ingavirin treatment of experimental parainfluenza pneumonia in Syrian hamsters].

Parainfluenza viruses affect the upper respiratory tract in all age group patients, in children aged 6 months to 3 years in particular. The most urgent task is to design drugs to treat parainfluenza. This investigation studied the antiviral activity of Ingavirin (2-(imidazole-4-yl) ethanamide of pentandioic-1,5 acid) on a model of parainfluenza infection in Syrian hamsters. The drug was shown to restrict the infectious process in animal lung tissue. This restriction manifested itself as reductions in the infectious titer of parainfluenza virus in the lung tissue, in the degree of pulmonary edema and tissue cell infiltration, and in virus-specific lesion of bronchial epithelial cells. The in vitro experiments demonstrated the ability of Ingavirin to diminish the infective activity of viral descendants. The finding allows one to consider Ingavirin to be a promising antiviral agent that is active against parainfluenza infection in vivo.

[Effects of granulocyte colony-stimulating factor on experimental bleomycin-induced pulmonary fibrosis].

The influence of granulocyte colony-stimulating factor (G-CSF) has been studied on a model of bleomycin-induced pulmonary fibrosis. It is established that G-CSF significantly increases infiltration of alveolar and alveolar duct interstitium by inflammation cells (lymphocytes, neutrophils, plasmocytes) and increases collagen deposition in lung under conditions of bleomycin introduction. Simultaneously with profibrotic and anti-inflammation effects, G-CSF increased the content of granulocyte cells in the bone marrow and peripheral blood, which was related to the stimulation of committed granulocyte precursors in the bone marrow.

[In vitro and in vivo effects of ingavirin on the ultrastructure and infectivity of influenza virus].

The aim of this investigation was to study the effect of ingavirin on the structure and properties of influenza virions forming in its presence. The infectious activity of the virus and the morphology of the virions were analyzed by titration in cell culture and electron microscopy, respectively. The use of ingavirin was shown to reduce the proportion of morphologically intact virions and to increase that of filamentous and giant particles. No defects of surface glycoproteins were observed. The effect of the drug did not depend on the chosen model of virus replication and it was similarly shown in both cultured human cells and laboratory animals. In MDCK and A549 cells and in the mouse lungs, viral infectious activity was decreased by 1-2 orders of magnitude in relation to a model. The findings suggest that Ingavirin is able to impair the processes of viral morphogenesis, which in turn leads to a reduction in the infectivity of progeny virions.

[Antiviral activity of Ingavirin on an animal model for experimental disseminated adenovirus infection].

Adenoviruses constitute a clinically important family of human pathogens. Due to their wide tissue tropism, adenoviruses are able to induce different diseases from moderate respiratory disorders to fatal outcomes in patients with immunodeficiencies. The authors present the results of a trial of the antiviral activity of the new drug Ingavirin [2-(imidazole-4-yl-ethanamide) pentandioic-1,5 acid] against human adenovirus type 5 on an animal model. Ingavirin is shown to decrease an adenoviral infectious titer in the liver and lung of neonatal Syrian hamsters (by approximately 1 log10 TCID50 as compared to the control) and to reduce the sizes of liver inflammation foci by 2-fold. Furthermore, it also decreases the count of virus-infected cells detectable by morphological analysis. Hepatocytes from Ingavirin-treated animals appear intact unlike strongly vacuolized cells from the animals given placebo. The findings make it possible to regard Ingavirin as a promising agent of the combination therapy of human adenovirus disease.

Study of anti-inflammatory action of aurothiomalate, an inhibitor of NF-κB.

We compared the effects of NF-κB inhibitor aurothiomalate and voltaren on NO production by mouse macrophages in vitro, their ability to cause local edema at the site of injection, and their effect on carrageenan-induced inflammation. High concentrations of aurothiomalate reduced NO production, while in low concentrations both aurothiomalate and voltaren stimulated this process. When injected into mouse footpad, aurothiomalate in a dose >1 mM and voltaren in a dose >1.6 µM induce paw edema. Both compounds suppressed carrageenan-induced inflammation, but the efficacy of aurothiomalate 2-fold exceeded that of voltaren.

Effects of extracts from medicinal plants on the development of metastatic process.

The possibility of inhibiting metastases by preparations from plants growing in Siberia and Far East after removal of the tumor node was proven in experiments on animals with transplanted tumors. Plant preparations stimulated the antitumor resistance of the organism.