Mechanisms of stimulation of granulocytopoiesis with neupogen in patients with breast cancer during chemotherapy

The mechanisms of granulocytopoiesis stimulation with granulocytic CSF (neupogen), added to chemotherapy protocol (adriablastine+taxotere) in patients with stages III–IV breast cancer, were studied. The hemostimulatory effect of granulocytic CSF preparation is based on stimulation of proliferation and differentiation of granulomonocytopoisis precursor cell in the hemopoietic tissue, due to neupogen effects on hemopoietic elements and on the hemopoiesis-inducing microenvironment cells. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 449–454, April, 2008     

Mechanisms of mobilization of mesenchymal precursor cell under the effect of granulocytic colony-stimulating factor and hyaluronidase

Binding of mesenchymal precursor cells to intact extracellular matrix and stroma increased under the effect of hyaluronidase and decreased after treatment of adhesion substrates with the enzyme. The stimulation of the release of progenitor elements into the blood by granulocytic CSF depended on the interaction of mesenchymal precursors with the feeder stimulating bone marrow microenvironment. Additional in vivo treatment with hyaluronidase potentiated mobilization of precursor cells by granulocytic CSF against the background of increased affinity of precursor to the stroma. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 12, pp. 652–656, December, 2007     

Role of central adrenergic structures in the regulation of granulocytopoiesis during cytostatic treatment

We studied the role of central adrenergic structures in the regulation of granulocytic hemopoietic stem during cytostatic treatment. It was found that brain norepinephrine promoted the decrease in functional activity of adherent mononuclears of the hemopoiesis-inducing environment, cytokine-dependent and α-adrenergic mechanisms of regulation of division and maturation of granulomonocytic precursors under conditions of cyclophosphamide treatment. Under conditions of 5-fluorouracil treatment, the effect of the adrenergic system was aimed at the formation of granulocytic and fibroblast-type cell complexes, activation of the production of colony-forming activity by microenvironmental cells, and acceleration of maturation of neutrophilic granulocytes associated with the system of granulocytic CSF and peripheral α-adrenergic structures. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 4, pp. 383–388, April, 2008     

Role of cytokines in the regulation of reproductive function

The levels of 17 cytokines in the follicular fluid were measured by multiplex proteome analysis at the peak of stimulated ovulation during the in vitro fertilization cycle. In patients with ineffective folliculogenesis, the concentrations of IL-2, IL-4, IL-7, and granulocytic CSF in the follicular fluid were significantly lower than in women with greater mean number of collected oocytes. It was shown that multicomponent cytokine deficit was associated with lower production of high quality oocytes and lower efficiency of fertilization of the resultant oocytes in vitro. The absence of pregnancy after in vitro fertilization cycle is associated with lower levels of IL-2, IL-4, IL-7, granulocytic CSF, and macrophagic inflammatory protein 1b in combination with elevated contents of IL-8 and IL-13. The results attest to an important role of cytokines in the regulation of oogenesis and in preparation of the endometrium to implantation of the embryo. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 1, pp. 81–85, January, 2007     

Thymodepressin inhibits migration of CD34<Superscript>+</Superscript> cells from bone marrow in normal and granulocyte CSF-stimulated hemopoiesis

We studied the effect of thymodepressin on migration and adhesion of mouse hemopoietic CD34⁺ cells under normal conditions and under the effect of granulocytic CSF. It was found that the peptide reduced the absolute number of CD34⁺ hemopoietic cells in the peripheral blood, increased the percent of cells bound to fibronectin and expressing receptor for integrin β₁ (CD29⁺) in the bone marrow of mice under normal conditions and after stimulation with granulocytic CSF, and reduced the relative number of cells carrying CXCR4 receptor for stromal factor-1 (CD184⁺) in the bone marrow (CD34⁺CD184⁺) and blood (CD184⁺) of mice stimulated with granulocytic CSF. The results suggest that thymodepressin can inhibit migration of CD34⁺ cells from bone marrow into peripheral blood under conditions of normal and granulocytic CSF-stimulated hemopoiesis. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 12, pp. 682–685, December, 2007     

Effects of Molecular Liposomal Hybrid Compositions with Oxidized Dextrans and Isonicotinic Acid Hydrazide on Production of Granulocytic Macrophage Colony-Stimulating Factor by Macrophages

The effects of molecular liposomal hybrid compositions consisting of liposomes (200–450 nm) containing oxidized dextrans (dextranals; 35–60 kDa) conjugated with isonicotinic acid hydrazide (dextrazides), their components, and native dextrans on the production of granulocytic macrophage CSF by peritoneal macrophages were studied in vitro. Dextranals proved to be more potent inductors of granulocytic macrophage CSF than native dextrans. Conjugation of nicotinic acid hydrazide with dextranals did not modify their capacity to stimulate the production of granulocytic macrophage CSF. Liposomes in the molecular liposomal hybrid compositions did not attenuate the dextrazide capacity to stimulate the production of granulocytic macrophage CSF. Molecular liposomal compositions containing 60 kDa dextrazide exhibited the most potent stimulatory effect on macrophage production of granulocytic macrophage CSF.     

Effects of granulocyte colony-stimulating factor and hyaluronidase on the formation of blood system reactions

We studied the possibility of modification of hematotropic effects of granulocytic CSF and hyaluronidase. It was found that hyaluronidase in a dose of 20 U/mouse potentiates the specific effect of granulocytic CSF on granulocytopoiesis, while granulocytic CSF potentiates the stimulating effect of the enzyme on the erythroid stem. Functional activity of hemopoiesis precursors, secretion of humoral factors by adherent myelokaryocytes, and serum content of hemopoietins increased under these conditions. Hyaluronidase (100 U/mouse) against the background of treatment with granulocytic CSF leads to uncoupling of proliferation and differentiation of hemopoietic cells and abolishes the mutually activating hematotropic effect of preparations. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 145, No. 6, pp. 628–633, June, 2008     

Pharmacological Regulation of Functional Activity of Stem Cells in Restoration of the Myocardium during the Postinfarction Period

The effect of granulocytic CSF on myocardial tissue recovery after acute myocardial infarction was studied on rats. A course of granulocytic CSF after ligation of the left coronary artery normalized ECG parameters and morphological picture of the myocardium 1 month after treatment. It was shown on mouse model of myocardial infarction that this process was associated with more intensive mobilization and homing of mesenchymal stem cells in the heart. __________ Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 4, pp. 190–194, November, 2005     

Mechanisms of the Effects of Granulocytic CSF on Tissue Reparation during Chronic CCl4-Induced Damage to the Liver

Hepatoprotective effects of granulocytic CSF were studied using experimental model of CCl₄-induced hepatitis. It was found that treatment with granulocytic CSF increased the content of stromal precursors and mesenchymal stem cells in the bone marrow and peripheral blood with subsequent increase in the number of hepatic precursor cells in the liver. These findings attest to mobilization of progenitor mesenchymal cells and their migration into damages liver tissue, which accelerates its regeneration related to changes in the parenchyma, but not connective tissue development. __________ Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 4, pp. 243–246, November, 2005     

Evaluation of the Efficacy of Granulocytic Colony-Stimulating Factor for the Treatment of Experimental Myocardial Destruction in Mice

We studied the effects of recombinant granulocytic CSF on heart remodeling in BALB/c mice after cryodestruction. Administration of granulocytic CSF was started 1 day after cryodestruction (subcutaneously, 10 μg/kg/day, for 4 days). As early as after the first injection, leukocytosis in the peripheral blood started to develop, leukocyte count peaked on days 4-6 and returned to normal on day 14. Treatment with granulocytic CSF significantly increased the content of progenitor cells in the bone marrow and led to rapid development of the inflammatory reaction and myocardium infiltration with mononuclear cells. Injections of granulocytic CSF did not reduce scar area, but provided significantly less pronounced heart hypertrophy, which attests to its better functional properties. By day 30 after cryodestruction, control animals and animals receiving granulocytic CSF exhibited similar morphological picture at the site of damage. Thus, our regimen of granulocytic CSF administration produced a mobilizing effect on bone marrow progenitor cells and postinfarction heart remodeling. Direct effects of granulocytic CSF on the heart have to be established for its use in the treatment of myocardial infarction.     

Role of serotonin in the regulation of granulocytopoiesis during cytostatic-induced myelosuppressions

We studied the role of the serotoninergic system in the regulation of the granulocytic hemopoietic stem during cytostatic myelosuppressions caused by administration of cyclophosphamide or 5-fluorouracil. After cytostatic treatment, the state of granulocytopoietic precursors and functional activity of cells in the hemopoiesis-inducing microenvironment were regulated by serotoninergic structures of the brain. The regulatory influence of CNS was realized via serotonin receptors on precursors and microenvironment cells. The response of the granulocytic stem was determined by specific interaction between distant and local regulatory structures and inhibitory effect of cyclophosphamide and 5-fluorouracil on granulocytic cells and regulatory systems. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 5, pp. 501–507, May, 2007     

Active control and its stress effects

The effects of 5-fold injections of normal saline were studied in Wistar rats in two conditioned reflex situations: defense and alimentary. Intact animals developed conditioned pain avoidance reflex in repeated tail-flick test after 60 presentations over 3 days. Two injections of normal saline were sufficient for the formation of a stable negative stress status in experimental rats, which manifested by a drastic increase in tactile sensitivity persisting for 5 days after discontinuation of injections. Only 15% experimental ratsvs. 40% intact animals developed the food-procuring response in a multialternative maze. Presumably, repeated injections of normal saline should be regarded as a potent negative stress factor modulating animals behavior, and these signs should be taken into consideration, when interpreting the effects observed in pharmacological investigations. Translated fromByulleten’ Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 8, pp. 235–237, August, 2004     

Fine-needle aspiration cytology of extramedullary hematopoiesis (myeloid metaplasia)

Myeloproliferative disease may be associated with extramedullary hematopoiesis (EH). Clinically, however, the differential diagnosis of solid masses in these patients includes not only EH but also inflammatory lesions and malignant neoplasms, including granulocytic sarcoma. We report the fine-needle aspiration (FNA) cytology of extramedullary hematopoiesis in five patients with a history of myeloproliferative disease. All of the masses developed subsequent to the diagnosis of myeloproliferative disease. Two of the patients had chronic myelogenous leukemia, one had essential thrombocythemia, and two had an unspecified chronic myeloproliferative disorder. The patients ranged in age from 50 to 88 years, and all presented with solid masses involving the kidney (two aspirates), liver (one aspirate), and lymph nodes (three aspirates). One of the lymph node aspirates was from a paratracheal lymph node. Cytologically, the lesions were composed of varying numbers of hematopoietic cells from all three hematologic cell lines. The Diff-Quik stain was especially helpful in the recognition of the hematopoietic cells such as granulocytic precursors, eosinophils, and megakaryocytes. In several cases, the megakaryocytic component was particularly prominent. In one case, the Factor VIII immunoperoxidase stain was used to confirm the megakaryocytic lineage of the multinucleated cells. The cytologic differential diagnosis, which includes granulocytic sarcoma, inflammatory disorders, and other lesions containing multinucleated giant cells, is discussed.     

Experimental Study of Ultralow-Dose Antibodies to Cyclophosphamide on Cyclophosphamide Myelotoxicity

The possibility of using ultralow-dose cyclophosphamide for reducing the myelotoxicity of cyclophosphamide, injected in the maximum permissible dose, was studied in mice. Combined treatment by the cytostatic and its ultralow-dose preparation led to a lesser suppression of the erythroid, lymphocytic, and particularly granulocytic hemopoiesis stems. This effect is explained by stimulation of the secretory activity of hemopoiesisinducing microenvironment and hence, of the functional activity of granulocytopoiesis under the effect of ultralow-dose cyclophosphamide. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 147, No. 3, pp. 295–299, March, 2009     

Sister chromatid exchanges at different times after repeated injections of thiophosphamidein vivo

The frequency of sister chromatid exchanges in rabbit peripheral blood lymphocytes was estimated after three intravenous injections of thiophosphamide in doses of 0.5 and 2 mg/kg body weight at 2-week intervals. It is demonstrated that 24 h after the first injection the frequency is significantly higher than after subsequent injections. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 1, pp. 73–74, January, 1997     

Role of Nitric Oxide in Prevention of Cognitive Disorders in Neurodegenerative Brain Injuries in Rats

NO synthesis disturbances play an important role in the development of neurodegenerative damage in Alzheimer disease. We previously showed that adaptation to intermittent hypobaric hypoxia prevents cognitive disturbances in rats with experimental Alzheimer disease [6]. Here we evaluated the role of NO in cognitive disorders and development of adaptive protection during experimental Alzheimer disease. Adaptation to hypoxia in rats was performed in a hypobaric pressure chamber at a simulated altitude of 4000 m (4 h per day for 14 days). Alzheimer disease was simulated by bilateral injections of a toxic fragment of β-amyloid (25–35) into n. basalis magnocellularis. For evaluation of the role of NO in the development and prevention of memory disorders, the rats received intraperitoneally either NO-synthase inhibitor N^ω-nitro-L-arginin (L-NNA, 20 mg/kg, every other day for 14 days) or NO-donor dinitrosyl iron complex (200 μg/kg daily for 14 days). NO-synthase inhibitor potentiated the damaging effect of β-amyloid, abolished the protective effect of adaptation to hypoxia, and produced memory disorders in rats similar to those observed during experimental Alzheimer disease. In contrast, the increase in NO level in the body provided by injections of the NO-donor produced a protective effect against memory disorders caused by β-amyloid similar to that induced by adaptation to hypoxia. We concluded that reduced NO production in the organism plays an important role in the development of cognitive disorders produced by injections of β-amyloid, while prevention of NO deficit by administration of NO-donors or nonpharmacological stimulation of NO synthesis can provide a protective effect in experimental Alzheimer disease. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 146, No. 10, pp. 371–375, October, 2008     

Reaction of bone marrow hematopoiesis to the toxic effect of paclitaxel

Intraperitoneal injection of paclitaxel (Mitotax) in a single dose of 40 mg/kg was followed by an increase in the number of mitotic granulocytic and erythroid cells, hypoplasia, and pancytopenia of the bone marrow in CBA/CaLac mice. The test preparation decreased the number of hematopoietic precursor cells for erythropoiesis and granulocytopoiesis, but increased the count of polyploid cells and incidence of structural and genomic abnormalities in bone marrow cells. These changes were reversible. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 2, pp. 173–177, February, 2008     

Effect of liposomall-Dopa on the Parkinson’s syndrome in mice

The effects of freel-Dopa andl-Dopa enclosed in small monolamellar liposomes consisting of egg phosphatidylcholine and cholesterol (molar ratio 7:3) on the severity of Parkinson’s syndrome are studied. The syndrome is modeled in C57B1/6 mice by repeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A single injection of liposomes withl-Dopa on day 7 after the start of MPTP administration has no effect on this syndrome. Repeated injections (for 14 days) ofl-Dopa solution (50 mg/kg) into MPTP-treated mice with oligokinesia and muscle rigidity increase their locomotor activity and the number of upright postures 7-fold and decrease muscle rigidity for 1 h after the last injection. The inhibitory effect of a 10-fold lower dose of liposomes withl-Dopa on oligokinesia and muscle rigidity is 2- to 3-fold stronger and 5207 h longer compared with that of freel-Dopa. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 1, pp. 29–33, January, 1997     

Peripheral erythrophagocytosis in two reptiles

Two cases of peripheral erythrophagocytosis in reptiles are presented. The first case was from an anorectic and depressed adult bearded dragon (Pogona vitticeps) that had a massively elevated white blood cell count (158×10⁹/l) due to an increase in circulating azurophils with approximately 12% of these cells exhibiting erythrophagia. The second case was from an adult Children’s python (Liasis childreni) with a protracted history of anorexia after an episode of respiratory tract disease. Blood from the snake demonstrated a moderate basophilia (2.3×10⁹/l) and a normal azurophil count (4.1×10⁹/l) but with approximately 66% of the azurophils containing phagocytosed erythrocytes. While the cause of the erythrophagocytosis could not be definitively identified in these cases, a leukemoid-type monocyte population in the bearded dragon resulted in a differential of myeloproliferative disease, while the Children’s python exhibited cytological features suggestive of acquired haemophagocytic syndrome.     

Immunomodulation of reparative processes in the skin with ribomunyl

A stimulatory effect of intradermal injections of ribomunyl on healing of a skin wound was shown in rats. The effect is based on activation of glycosaminoglycan synthesis and stimulation of neoangiogenesis in newly formed granulation tissue. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 6, pp. 660–662, June, 2007