Role of JAK/STAT3 Signaling in Functional Stimulation of Mesenchymal Progenitor Cells by Fibroblast Growth Factor.

JAK/STAT signaling pathway was examined during functional stimulation of mesenchymal progenitor cells with fibroblast growth factor. The differences were observed in the realizations of the proliferation-differentiation potential of CFU-fibroblasts under blockade of JAKs or during selective inactivation of STAT3. The study revealed stimulating influences of JAKs and STAT3 on mitotic activity of progenitor cells and individual roles of these proteins in the control of their maturation. Blockade of JAKs diminished the level of fibroblast colony formation and the score of actively proliferating CFU-fibroblasts at the background increase of the differentiation rate of progenitor cells. In contrast, STAT3 inhibitor resulted in a coordinated decrease of all examined parameters.

[Distribution of 4-methyl-2,6-diisobornylphenol in rat tissues].

We have studied the distribution of the new compound 4-methyl-2,6-diisobornylphenol in rats after a single oral administration in a dose of 20 mg/kg. The pharmacokinetic parameters have been estimated by the noncompartmental method. It is established that the drug is nonuniformly distributed in the body and has a high affinity for liver and heart. A low penetration of 4-methyl-2,6-diisobornilphenol has been found in brain tissue. The accumulation of 4-methyl-2,6-diisobornilphenol in adipose tissues has not been found. It been showed that the drug is slowly eliminated from the body, especially from the heart tissues for which the mean retention time is MRT = 45 h.

[Evaluation of the linearity of pharmacokinetics of the phenolic antioxidant 4-methyl-2,6-diisobornylphenol upon intragastric administration].

The linearity of pharmacokinetics of 4-methyl-2,6-diisobornylphenol after single intragastric administration in doses within 10 - 200 mg/kg has been studied in rats. It has been established that pharmacokinetics of 4-methyl-2,6-diisobornilphenol in the indicated dose range is not linear due to a limited absorption of the drug from the intestine.

Effect of pegylated hyaluronate-endo-ß-N-acetylhexosaminidase on humoral mechanisms regulating the functions of progenitor cells during chronic hepatitis.

We studied the effect of hyaluronate-endo-ß-N-acetylhexosaminidase on the secretory function of the liver and bone marrow microenvironment cells in chronic hepatitis. Enhanced production of substances stimulating parenchymal tissue-specific precursors and stem cell homing factors by liver cells was revealed. At the same time, production of SDF-1 and other chemoattractants and adhesion factors of progenitor cells by bone marrow elements was reduced.

Mechanisms underlying modulation of the pharmacological properties of pegylated erythropoietin by pegylated hyaluronate-endo-ß-N-acetylhexosaminidase.

Pegylated hyaluronate-endo-ß-N-acetylhexosaminidase was shown to potentiate significantly the hemostimulatory effect of pegylated erythropoietin. It was found that enhanced production of hemopoietin by adherent and non-adherent cells of the hemopoiesis-inducing microenvironment and elevated serum content of endogenous erythropoietin along with increased susceptibility of erythroid precursors to pegylated erythropoietin underlay this phenomenon.

Humoral mechanisms regulating the functions of progenitor cells in chronic hepatitis.

We studied the secretory function of the liver and bone marrow microenvironment cells under conditions of chronic CCl4-induced hepatitis. Enhanced production of substances stimulating parenchymal tissue-specific precursors and stem cell homing factors by liver cells was observed. In situ binding of stem cells by bone marrow elements increased due to production of various cooperation and adhesion factors against the background of reduced SDF-1 secretion.

Potentiation of hemostimulating effects of erythropoietin with pegylated hyaluronate-endo-ß-N-acetylhexosaminidase.

Pegylated hyaluronate-endo-ß-N-acetylhexosaminidase considerably potentiates the hemostimulating effects of erythropoietin due to intensification of proliferation and differentiation of erythroid precursors against the background of enhanced secretion of hemopoietins by nonadherent hemopoiesis-inducing environment cells and elevation of serum erythropoietin concentration. The use of the enzyme allows 10-fold reduction of the maximum effective erythropoietin dose.

Hypoglycemic effects of hyaluronate-endo-ß-N-acetylhexosaminidase immobilized by electron beam synthesis nanotechnology.

Hypoglycemic effect of hyaluronate-endo-ß-N-acetylhexosaminidase immobilized by electron-beam synthesis nanotechnology (imHEA-HA) was studied in experimental insulin-dependent and insulin-independent diabetes mellitus. The drug exhibited a hypoglycemic effect of its own and potentiated the pharmacological effect of exogenous insulin injected in vivo. Studies on liver cell culture demonstrated an increase of cell sensitivity to insulin after treatment with imHEA-HA.

Hepatoprotective effects of immobilized granulocyte colony-stimulating factor and hyaluronidase preparation and their mechanisms.

High hepatoprotective activity of granulocytic CSF and hyaluronidase immobilized using electron-beam immobilization technology was demonstrated on the model of CCl(4)-induced hepatitis: the preparations produced anticholestatic, anti-inflammatory, and antisclerotic effects. These effects developed against the background of stimulation of bone marrow multipotent precursor cells and their mobilization into circulation accompanied by an increase in the content of parenchymatous progenitor cells in the liver. The most pronounced positive effect was observed in combined treatment with the test preparations.

Effect of hyaluronate-endo-ß-N-acetylhexosaminidase pegylated by electron beam synthesis nanotechnology on the formation of hematological shifts in chronic hepatitis.

We studied the effect of mobilization of bone marrow multipotent stem cells induced by intragastric administration of pegylated hyaluronate-endo-ß-N-acetylhexosaminidase (Peg-HEAHA) on hemopoiesis under conditions of experimental chronic hepatitis. Peg-HEAHA increased the counts of hemopoietic precursors in the hemopoietic tissue against the background of their decelerated maturation. This was paralleled by a short-term decrease in the count of neutrophilic granulocyte in the bone marrow and a slight increase of neutrophil count in the peripheral blood.

[Pharmacokinetics of phenolic antioxidant 4-methyl-2,6-diisobornylphenol upon intravenous injection].

The pharmacokinetics of 4-methyl-2,6-diisobornylphenol (MDIBP) in rat blood plasma has been studied after intravenous injection. The drug concentration in the plasma was determined using a reverse-phase HPLC procedure. It is shown that MDIBP rapidly penetrates into intensively perfused organs, but is slowly eliminated from the organism (MRT value amounting to 9 h).

Pharmacological correction of the negative effects of acetylsalicylic acid on the energy production system.

Experiments of outbred rats with modeled xenobiotic load with acetylsalicylic acid (250 mg/kg for 7 days) revealed inhibition of mitochondrial respiration rate in states of rest and active phosphorylation, inhibition of succinate-dependent oxidation pathway, and a decrease in energization of organelles in the heart. For correction of the observed changes in energy production, succinic acid was preventively administered in a dose of 50 mg/kg for 7 days, which abolished the negative metabolic shifts in myocardial mitochondria. Comparison of pharmacokinetics of acetylsalicylic acid and acetylsalicylic acid against the background of succinate treatment performed on rabbits revealed complete coincidence of the studied parameters, which attests to the possibility of prevention of mitochondrial dysregulations with this Krebs cycle intermediate.

Pharmacological properties of granulocytic colony-stimulating factor pegylated using electron beam synthesis nanotechnologies.

Granulocytic CSF pegylated using electron-beam synthesis nanotechnology exhibits pronounced granulomonocytopoiesis-stimulating and SC-mobilizing activity. More potent stimulation of committed precursors against the background of less pronounced activation of polypotent hemopoietic cells is a peculiarity of hemostimulating action of pegylated using electron-beam synthesis nanotechnology granulocytic CSF in comparison with its non-modified analog. The mobilizing effect of pegylated using electron-beam synthesis nanotechnology granulocytic CSF on early progenitor elements surpasses that of non-conjugated cytokine.

Mechanisms for hepatoprotective effects of hyaluronidase immobilized by the nanotechnology method of electron-beam synthesis.

Immobilized hyaluronidase (nanotechnology method of electron-beam synthesis) exhibited high hepatoprotective activity on the model of Cl4-induced hepatitis. This agent produced anticholestatic, anti-inflammatory, and antisclerotic effects. These effects were shown to accompany stimulation of multipotent bone marrow precursors, mobilization of these cells into the peripheral blood, and cell migration to the target organ increasing the number of parenchymal progenitor cells in the liver. The mechanisms for targeted migration of progenitor cells suggest a decrease in SDF-1 production by bone marrow stromal cells and increase in the synthesis of this factor by microenvironmental cells of the liver tissue.

Effect of hyaluronidase immobilized using electron-beam synthesis nanotechnology on sensitivity of progenitor cells to regulatory factors.

In vitro experiments demonstrated increased colony-forming capacity of erythroid, granulomonocytic, and mesenchymal progenitors of the bone marrow and parenchymal progenitor elements of the liver after treatment with immobilized hyaluronidase. Increased sensitivity of these progenitor cells to erythropoietin, granulocyte colony-stimulating factor, fibroblast growth factor, and stem cell factor, respectively, was demonstrated. Immobilized hyaluronidase enhanced the formation of tissue-specific hepatic CFU against the background of reduced yield of stromal precursors in liver tissue culture containing insulin.

Modulation of the blood-stimulating effect of immobilized granulocyte colony-stimulating factor by immobilized hyaluronidase.

We evaluated whether immobilized hyaluronidase can modify the hematotropic effect of immobilized granulocyte CSF (G-CSF). The preparation of immobilized hyaluronidase (50 arb. units per mouse) potentiated the specific effect of immobilized G-CSF on granulomonocytopoiesis. The preparation was shown to facilitate the indirect effect of immobilized G-CSF on hemopoiesis (stimulation of the erythroid and lymphoid hemopoietic stems). These changes were accompanied by an increase in functional activity of hemopoietic precursor cells, secretion of humoral factors by bone marrow myelokaryocytes, and concentration of hemopoietins in the serum.

Anxiolytic and antidepressant effects of aqueous tincture of the aerial part of Myosotis arvensis.

Experiments on outbred albino mice showed a significant anxiolytic effect of aqueous tincture of the aerial part of Myosotis arvensis (L.) (Boraginaceae) in a single daily dose of 0.5 ml/kg. In a dose of 2 ml/kg, the tincture of M. arvensis aerial part exhibited an anxiolytic and antidepressant effect. In contrast to phenazepam, aqueous tincture of M. arvensis did not inhibit exploratory and motor activities.

Hemopoiesis-stimulating activity of immobilized oligonucleotides and hyaluronidase during cytostatic-induced myelosuppression.

The hemopoiesis-stimulating effect of combined treatment with immobilized oligonucleotides and hyaluronidase preparations was studied during cytostatic-induced myelosuppression caused by cyclophosphamide administration. Immobilized hyaluronidase was shown to increase the efficiency of correction of changes in the erythroid and granulocytic hemopoietic stems with immobilized oligonucleotides. This potentiation of the effect of immobilized oligonucleotides by immobilized hyaluronidase was related to an increase in functional activity of committed hemopoietic precursors.

[Dependence of the pharmacokinetics of captopril on the type of adaptation reactions in the organism].

The dependence of the pharmacokinetic profiles (PhP) of captopril in the phase of adaptation reactions in the organism has been studied within the framework of randomized, comparative, double cross research of bioeqivalency of captopril (Aspharma Co, Anzhero-Sudzhensk) and capoten (Bristol Myers Squibb Co.; official Russian producer, Akrikhin KhimFarmKombinat). It is established that the maximum bioaccessibility and high concentration of captopril in the blood plasma is determined on the background of physiologically optimum reactions of training and in the zone of quiet activation. These characteristics decrease during the reactions of general adaptation syndrome according to the type of increased activation and reactivation.