ABSTRACT
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.
Subject(s)
Fibroblast Growth Factors/pharmacology , Janus Kinases/metabolism , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , STAT3 Transcription Factor/metabolism , Animals , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Mice, Inbred C57BL , Phosphorylation/drug effects , Regenerative Medicine , Signal Transduction/drug effectsABSTRACT
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.
Subject(s)
Camphanes/pharmacokinetics , Cresols/pharmacokinetics , Fibrinolytic Agents/pharmacokinetics , Adipose Tissue/metabolism , Administration, Oral , Animals , Brain/metabolism , Camphanes/blood , Cresols/blood , Female , Fibrinolytic Agents/blood , Kidney/metabolism , Liver/metabolism , Male , Muscles/metabolism , Myocardium/metabolism , Rats , Rats, Wistar , Tissue DistributionABSTRACT
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.
Subject(s)
Antioxidants/pharmacokinetics , Camphanes/pharmacokinetics , Cresols/pharmacokinetics , Intestinal Mucosa/metabolism , Animals , Antioxidants/administration & dosage , Antioxidants/metabolism , Area Under Curve , Camphanes/administration & dosage , Camphanes/blood , Cresols/administration & dosage , Cresols/blood , Drug Administration Schedule , Intestinal Absorption/physiology , Male , Rats , Rats, Wistar , StomachABSTRACT
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.
Subject(s)
Bone Marrow Cells/metabolism , Chemokine CXCL12/biosynthesis , Hepatitis, Chronic/metabolism , Liver/metabolism , Polyethylene Glycols/pharmacology , Stem Cells/drug effects , beta-N-Acetylhexosaminidases/pharmacology , Animals , Bone Marrow Cells/drug effects , Cell Movement/drug effects , Cellular Microenvironment/drug effects , Hyaluronoglucosaminidase , Liver/cytology , Liver/drug effects , Male , Mice , Mice, Inbred C57BL , Stem Cells/metabolismABSTRACT
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.
Subject(s)
Anemia/drug therapy , Erythropoietin/pharmacology , Hematinics/pharmacology , Polyethylene Glycols/pharmacology , beta-N-Acetylhexosaminidases/pharmacology , Anemia/chemically induced , Animals , Bone Marrow Cells/drug effects , Carboplatin , Cell Differentiation , Cell Proliferation , Cells, Cultured , Drug Synergism , Drug Therapy, Combination , Erythroid Cells/drug effects , Erythropoietin/administration & dosage , Hematinics/administration & dosage , Mice , Mice, Inbred CBA , Polyethylene Glycols/administration & dosage , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Stem Cells/drug effects , Stem Cells/physiology , beta-N-Acetylhexosaminidases/administration & dosageABSTRACT
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.
Subject(s)
Bone Marrow Cells/metabolism , Chemical and Drug Induced Liver Injury, Chronic/pathology , Hepatitis, Chronic/pathology , Liver/cytology , Liver/metabolism , Stem Cells/physiology , Animals , Carbon Tetrachloride , Cell Movement , Cellular Microenvironment , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Chemokine CXCL12/metabolism , Culture Media, Conditioned/chemistry , Hepatitis, Chronic/metabolism , Male , Mice , Mice, Inbred C57BL , Stem Cell NicheABSTRACT
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.
Subject(s)
Anemia/drug therapy , Erythropoietin/metabolism , Erythropoietin/pharmacology , Polyethylene Glycols/metabolism , beta-N-Acetylhexosaminidases/metabolism , Animals , Carboplatin , Dose-Response Relationship, Drug , Drug Synergism , Enzyme-Linked Immunosorbent Assay , Erythrocyte Count , Erythropoietin/blood , Female , Hemoglobins/metabolism , Male , Mice , Mice, Inbred CBA , Nanotechnology/methods , Recombinant Proteins , Statistics, NonparametricABSTRACT
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.
Subject(s)
Enzymes, Immobilized/therapeutic use , Glycosaminoglycans/chemistry , Hypoglycemic Agents/therapeutic use , Nanotechnology/methods , beta-N-Acetylhexosaminidases/chemistry , beta-N-Acetylhexosaminidases/therapeutic use , Animals , Diabetes Mellitus/drug therapy , Hyaluronoglucosaminidase/metabolism , Hypoglycemic Agents/chemistry , MiceABSTRACT
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.
Subject(s)
Enzymes, Immobilized/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Hepatitis, Chronic/drug therapy , Hyaluronoglucosaminidase/therapeutic use , Animals , Male , Mice , Nanotechnology , Rats , Rats, Wistar , Regenerative MedicineABSTRACT
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.
Subject(s)
Electrons , Hematopoiesis/drug effects , Hepatitis, Chronic/drug therapy , Hyaluronic Acid/chemistry , Nanoparticles/therapeutic use , beta-N-Acetylhexosaminidases/chemistry , Animals , Hepatitis, Chronic/metabolism , Male , Mice , Mice, Inbred C57BL , Nanoparticles/chemistry , Nanotechnology/methods , Regenerative Medicine/methodsABSTRACT
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).
Subject(s)
Antioxidants/pharmacokinetics , Camphanes/pharmacokinetics , Cresols/pharmacokinetics , Models, Biological , Animals , Antioxidants/administration & dosage , Antioxidants/chemistry , Camphanes/administration & dosage , Camphanes/blood , Camphanes/chemistry , Cresols/administration & dosage , Cresols/blood , Cresols/chemistry , Injections, Intravenous , Male , Organ Specificity , Rats , Rats, Wistar , Tissue DistributionABSTRACT
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.
Subject(s)
Aspirin/pharmacology , Cell Respiration/drug effects , Energy Metabolism/drug effects , Heart/physiology , Mitochondria/drug effects , Succinic Acid/pharmacology , Animals , Area Under Curve , Aspirin/pharmacokinetics , Energy Metabolism/physiology , Polarography , Rabbits , RatsABSTRACT
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.
Subject(s)
Granulocyte Colony-Stimulating Factor/pharmacology , Hematinics/pharmacology , Polyethylene Glycols/pharmacology , Animals , Bone Marrow/drug effects , Bone Marrow Cells/drug effects , Cell Count , Cyclophosphamide/pharmacology , Granulocyte Colony-Stimulating Factor/chemical synthesis , Granulocytes/cytology , Granulocytes/drug effects , Hematinics/chemical synthesis , Hematopoiesis/drug effects , Humans , Immunosuppressive Agents/pharmacology , Male , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/physiology , Mice , Mice, Inbred CBA , Nanotechnology , Neutrophils/cytology , Neutrophils/drug effects , Poisson Distribution , Polyethylene Glycols/chemical synthesis , Statistics, NonparametricABSTRACT
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.
Subject(s)
Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacology , Boraginaceae/chemistry , Plant Components, Aerial/chemistry , Plant Extracts/pharmacology , Animals , Animals, Outbred Strains , Behavior, Animal/drug effects , Benzodiazepines/pharmacology , Drug Evaluation, Preclinical , Male , Mice , Movement/drug effects , Restraint, Physical , Solvents/chemistry , Statistics, Nonparametric , Water/chemistryABSTRACT
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.
Subject(s)
Cytoprotection , Enzymes, Immobilized/therapeutic use , Hepatitis, Animal/drug therapy , Hyaluronoglucosaminidase/therapeutic use , Liver/drug effects , Multipotent Stem Cells/drug effects , Animals , Biomarkers/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Carbon Tetrachloride , Cell Movement/drug effects , Cellular Microenvironment/drug effects , Chemokine CXCL12/metabolism , Enzymes, Immobilized/administration & dosage , Enzymes, Immobilized/chemistry , Hepatitis, Animal/metabolism , Hepatitis, Animal/pathology , Hyaluronoglucosaminidase/administration & dosage , Hyaluronoglucosaminidase/chemistry , Liver/metabolism , Liver/pathology , Mice , Multipotent Stem Cells/cytology , Nanotechnology , Rats , Stromal Cells/cytology , Stromal Cells/drug effectsABSTRACT
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.
Subject(s)
Enzymes, Immobilized/pharmacology , Hematopoietic Stem Cells/drug effects , Hyaluronoglucosaminidase/pharmacology , Mesenchymal Stem Cells/drug effects , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Colony-Forming Units Assay , Enzymes, Immobilized/chemistry , Erythropoietin/pharmacology , Fibroblast Growth Factors/pharmacology , Granulocyte Colony-Stimulating Factor/pharmacology , Hematopoietic Stem Cells/cytology , Hyaluronoglucosaminidase/chemistry , Insulin/metabolism , Insulin/pharmacology , Liver/cytology , Liver/drug effects , Male , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred CBA , Nanotechnology , Stem Cell Factor/pharmacology , Tissue Culture TechniquesABSTRACT
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.
Subject(s)
Granulocyte Colony-Stimulating Factor/pharmacology , Granulocytes/drug effects , Hematopoiesis/drug effects , Hyaluronoglucosaminidase/metabolism , Animals , Bone Marrow/drug effects , Bone Marrow Cells/drug effects , Cyclophosphamide/pharmacology , Enzymes, Immobilized , Hematopoietic Cell Growth Factors/blood , Hematopoietic Stem Cells/drug effects , MiceABSTRACT
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.
Subject(s)
Cell Differentiation/drug effects , Hematopoiesis/drug effects , Hematopoietic Stem Cells/metabolism , Hyaluronoglucosaminidase/pharmacology , Oligonucleotides/pharmacology , Animals , Bone Marrow/drug effects , Cyclophosphamide/adverse effects , Cyclophosphamide/pharmacology , Cytostatic Agents/pharmacology , Enzymes, Immobilized/pharmacology , Erythroid Cells/drug effects , Erythroid Cells/metabolism , Granulocyte Colony-Stimulating Factor , Granulocytes/drug effects , Granulocytes/metabolism , Hematopoietic Stem Cells/drug effects , Mice , Mice, Inbred CBAABSTRACT
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.
