L. A. Miroshnichenko

Mechanisms of Regeneratory Effects of Baikal Aconite Diterpene Alkaloids

Regeneratory activities of Baikal aconite alkaloids were studied on the excision skin wound model. Manifest wound healing effects of songorine, napelline, and hypaconitine were detected. The therapeutic efficiency was based on activation of residual mesenchymal progenitor elements. The development of this phenomenon was explained by the direct effects of alkaloids on precursors and by higher production of growth factors by the skin stromal cells. Songorine exhibited the most pronounced specific activity due to more significant stimulation of progenitor cell differentiation associated with maximum activation of the secretory function of the microenvironment cells.

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.

Role of NF-κB-Dependent Signaling in the Realization of Growth Potential of Mesenchymal Progenitor Cells in Vitro

Signal pathways of realization of growth potential of mesenchymal progenitor cells related to transcription factor NF-κB were studied in vitro. NF-κB was found to participate in the proliferation and differentiation of progenitor elements that can be blocked by its specific inhibitor oridonin. NF-κB inhibitor aurothiomalate had no effect on the functions of fibroblastic CFU.

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.

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.

Role of Receptors to Fibroblast Growth Factor (FGF) on Mesenchymal Precursor Cells in the Realization of Regenerative Effects of Alkaloid Songorine

We studied the mechanisms of regenerative (wound healing) effects of songorine associated with functional activation of mesenchymal progenitor cells. The key role of FGF receptors on these progenitor cells in the stimulation of realization of their growth potential under the effect of the alkaloid was demonstrated. Under in vitro conditions, the antibodies to FGF receptor abolished the songorine-induced increase in the number of fibroblast colony-forming units in bone marrow cell culture. The intensity of differentiation of mesenchymal precursors remained unchanged.

PI3K, MAPK EPK1/2 and p38 are Involved in the Realization of Growth Potential of Mesenchymal Progenitor Cells under the Infl uence of Basic Fibroblast Growth Factor

We studied PI3K, MAPK/EPK1/2 and p38-dependent signaling cascade under stimulation of the functions of mesenchymal progenitor cells by fibroblast growth factor. The important role of PI3K and EPK1/2 in the realization of their growth potential has been revealed. Experiments have demonstrated a blocking effect of PI3K inhibitor on proliferation and differentiation of progenitor cells and EPK1/2 inhibitor on mitotic activity of the progenitor cells. The p38-mediated MAPK pathway did not play a role in determining the proliferative and differentiation status of fibroblast CFU.

Involvement of PI3K, MAPK ERK1/2 and p38 in Functional Stimulation of Mesenchymal Progenitor Cells by Alkaloid Songorine

We studied the role of intracellular signaling molecules PI3K, МАРK ERK1/2, and р38 in stimulation of realization of the growth potential of mesenchymal progenitor cells by alkaloid songorine in vitro. Inhibitors of PI3K, ERK1/2 and р38 canceled the increase in proliferative activity of progenitor cells, the blockers of ERK1/2 and р38 reduced the intensity of progenitor cell differentiation.

Cerebroprotective and Regenerative Effects of Alkaloid Z77 under Conditions of Brain Ischemia

We studied the psychopharmacological effects of atisine-type diterpene alkaloid Z77 in a rat model of cerebral ischemia. Pronounced cerebroprotective effect was found consisting in normalization of the orienting and exploratory activity and conditioned behavior associated with significant correction of morphological changes in the brain. The direct stimulatory effect of Z77 on neural stem cells was shown in vitro.

Role of cAMP- and IKK-2-Dependent Signaling Pathways in Functional Stimulation of Mesenchymal Progenitor Cells with Alkaloid Songorine

The role of cAMP- and IKK-2-dependent pathways in stimulation of the growth capacity of mesenchymal progenitor cells with alkaloid songorine was studied in vitro. Inhibitors of adenylate cyclase and IKK-2 were shown to abolish the increase in proliferative activity of progenitor cells. Moreover, blockade of the inhibitory kinase complex was accompanied by a decrease in the intensity of progenitor cell differentiation.