The Role of Intracellular Signaling Molecules in the Production of Granulocytic CSF Mononuclear Phagocytes in Stress and Cytostatic Influence.

Under conditions of steady-state hemopoiesis, nuclear factor NF-κB, in contrast to MAP kinase p38, plays an important role in the maintenance of the initial level of secretory activity of monocytes. The increase in the production of G-CSF under stress conditions (10-h immobilization) is mainly regulated by the alternative p38MARK signaling pathway via activation of p38 synthesis. It was shown that under conditions of cytostatic-induced myelosuppression, the production of protein kinase p38 in cells decreases, and it, like NF-κB, is not the main one in the production of hemopoietin by mononuclear phagocytes.

Role of PI3K, MAPK/ERK 1/2, and p38 in Production of Erythropoietic Activity by Bone Marrow Cells after Blood Loss.

The leading role in the regulation of erythropoietic activity of adherent bone marrow cells under conditions of post-hemorrhagic anemia is played by classical MAP kinase pathway (ERK pathway). Erythropoietin is not the decisive factor in the formation of erythropoietic activity of adherent cells. PI3K, MAPK/ERK 1/2, and p38-signaling proteins are not the main regulators of local production of erythropoietin after 30% loss of circulating blood volume.

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.

Role of JNK and Contribution of p53 to the Realization of the Growth Potential of Mesenchymal Precursor Cells under the Effect of Fibroblast Growth Factor.

The role of JNK-mediated signal pathway and participation of p53 transcription factor in stimulation of mesenchymal precursor cell function by the fibroblast growth factor was studied. The levels of fibroblast colony- and cluster formation and proliferative activity of mesenchymal precursors increased in response to JNK and p53 specific inhibitors. JNK and p53 blockers did not change the rate of fibroblast growth factor-induced progenitor element differentiation.

Role of PI3K, MAPK/ERK1/2, and p38 in implementation of the proliferative and differentiation potential of erythroid progenitors after blood loss.

The involvement of PI3K, ERK and p38-dependent signaling system in the regulation of functional activity of erythroid precursors after blood loss (30% of circulating volume) was studied. We demonstrated the important role of PI3K and p38 in the suppression of differentiation of erythroid precursors the contribution of p38 to stimulation of mitotic activity of erythroid CFU, which maintains the growth potential of the precursors at the optimal physiological level. The classical MAPK/ERK-kinase pathway does not determine the proliferative and differentiation status of erythroid CFU.

Involvement of NF-κB-dependent signaling and p38 MAPK signaling pathway in the regulation of hemopoiesis during restrain stress.

Protein kinase p38 was shown to contribute to the increase in production of granulocyte CSF by microenvironmental cells under conditions of restraint stress. Stimulation of colony-forming activity was not accompanied by the increase in maturation of clonogenic structures in the bone marrow granulocytic stem. This process was realized with the involvement of NF-κB-dependent signaling and p38 MAPK signaling pathway. Our study showed that the p38 MAPK signaling pathway plays an important role in the regulation of granulocytopoiesis, but not of erythropoiesis.

Mechanisms of stimulating effect of glycyram and D-glucuronic acid on granulocytopoiesis suppression by 5-fluorouracil.

We compared hemostimulating activity of glycyram and a preparation of D-glucuronic acid on the model of granulocytic hemopoiesis suppressed by 5-fluorouracil. Different mechanisms were shown to underlie activation of hemopoiesis by the above preparations: D-glucuronic acid directly affects hemopoietic cells, while glycyram modulates local mechanisms regulating hemopoiesis.

Specific activity of electron-beam synthesis immobilized hyaluronidase on G-CSF induced mobilization of bone marrow progenitor cells.

The effects of nanotechnology (electron-beam) -PEGylated (or immobilized; Im) hyaluronidase (HD) on the state of the pool of bone marrow progenitor cells and their mobilization induced by granulocyte colony stimulating factor (G-CSF) were studied. A high specific activity of the drug Im-HD on progenitor cells of different classes was demonstrated using parenteral and enteral administration. An increase in the content of erythroid (E), granulomonocytic (GM), fibroblast (F) colony-forming units (CFU) and mesenchymal stem cells (MSC) in bone marrow was shown, as well as G-CSF-induced stimulation of mobilization of precursors into the peripheral blood under the influence of Im-HD. The detected activity of this novel drug on progenitor cells indicates the potential for a safe and highly effective treatment for hematology practice and regenerative medicine.

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.

Mechanisms of protective effect of Dicarbamin on the blood system in cytostatic treatment.

The effect of Dicarbamin preparation on hemopoiesis suppressed with cyclophosphamide was studied in animal experiments. It was shown that Dicarbamin produced a protective effect on granulocytic hemopoietic steam. This property of the preparation is determined by both protection of immature granulocytic cells at early terms after cytostatic treatment and more active maturation of neutrophils in the bone marrow due to enhanced secretion of humoral factors by elements of hemopoietic environment at late terms of the experiment.

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.

Hemostimulating effects of erythropoietin immobilized by the nanotechnology method of electron-beam synthesis.

The hemostimulating effect of erythropoietin immobilized by the nanotechnology method of electron-beam synthesis was studied on the model of carboplatin-induced myelosuppression. Subcutaneous injection or oral administration of immobilized erythropoietin was followed by stimulation of erythropoiesis. The effect was most pronounced after parenteral treatment with this agent. The increase in proliferative activity and maturation of erythroid precursor cells serve as a factor determining acceleration of reparative processes in the hemopoietic tissue.

Mechanisms of hepatoprotective effect of immobilized granulocyte colony-stimulating factor.

The effect of immobilized granulocyte CSF on morphological characteristics and functional state of the liver was studied during chronic toxic hepatitis. The mechanisms of the therapeutic action of this agent were evaluated. The product had a strong hepatoprotective effect and exhibited the antiinflammatory and antisclerotic properties. The mechanism of activation of reserve systems for cell renewal (involved in restoration of the liver tissue) is probably related to an increase in proliferative activity of early precursor cells in the bone marrow, mobilization of these cells into the peripheral circulation, and directed homing into the liver tissue where they activate local regenerative mechanisms and prevent hepatocyte destruction. It should be emphasized that the concentration of SDF-1 increases in the liver tissue, but decreases in the bone marrow. These changes create the concentration gradient, which determines the migration of undifferentiated precursor cells to the liver.

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.

Mechanisms of hemostimulating effects of granulocytic CSF and pantohematogen under conditions of cytostatic myelosuppression.

We compared hemostimulating activity of pantohematogen and granulocytic CSF under conditions of 5-fluorouracil-induced cytostatic myelosuppression. It was found that activation of hemopoiesis regeneration under the effect of the test preparations was accompanied by the development of hyperplasia of the granulocytic and monocytic hemopoietic bone marrow lineages and more rapid recovery of the count of pholymorphonuclear leukocytes and monocytes in the peripheral blood (more marked under the effect of pantohematogen) followed by neutrophilia and monocytosis.

Reactions of granulocytic lineage of hemopoiesis and mechanisms of their development in combined treatment with adriablastin and taxotere.

We studied myelotoxic effects of adriablastin and taxotere combination on granulocytic lineage cells and processes of their recovery in patients with stage III-IV breast cancer. Intensive maturation of granulocytic CFU provided regeneration of the hemopoiesis even under conditions of reduced proliferative activity of these cells, which, in turn, led to accumulation of mature and immature neutrophilic granulocytes in the bone marrow and improved reserve capacities of the neutrophil pool in the bone marrow.

Hemostimulating effects of immobilized hyaluronidase and their mechanisms during cytostatic-induced myelosuppression.

We studied the effect of immobilized hyaluronidase on hemopoiesis under conditions of cyclophosphamide-induced suppression. The preparation was shown to possess high hemostimulating activity. The stimulatory effect of hyaluronidase on the erithron was more pronounced than its effect on the granulocytic hemopoietic stem due to increase in functional activity of hemopoietic precursors and hemopoiesis-inducing microenvironment.

Mechanisms of granulocytopoiesis-stimulating activity of immobilized granulocytic colony-stimulating factor in cytostatic myelosuppression.

The hemostimulatory effects of granulocytic CSF, immobilized on polyethyleneglycol using radiation synthesis nanotechnology, were studied on the model of cyclophosphamide-induced myelosuppression. Immobilization of granulocytic CSF led to stimulation of granulomonocytopoiesis by increasing functional activity of granulomonocytic precursors and secretion of humoral factors by elements of hemopoiesis-inducing microenvironment, and due to more intensive formation of hemopoietic islets. The granulocytopoiesis-stimulating effect of immobilized granulocytic CSF was comparable to the effect of standard nonconjugated granulocytic CSF. Specific activity of immobilized granulocytic CSF in oral treatment was demonstrated.