The title of the article should read:"Role of β Cell Precursors in the Regeneration of Insulin-Producing Pancreatic β Cells under the Influence of the Pegylated Form of Glucagon-Like Peptide 1".

We studied the effects of elastase, cigarette smoke extract, D-galactosamine hydrochloride, and tyrosine kinase inhibitor SU5416 on endothelial progenitor cells and angiogenesis precursors, as well as on Notch-1 expression by immature endothelial cells. Simultaneously with pulmonary emphysema, different damaging factors with diverse mechanisms of action caused pathological changes in the microvascular network of the lungs and destroyed the alveolar endothelium in female C57Bl/6 mice. D-galactosamine hydrochloride disturbed mobilization of endothelial progenitor cells expressing VEGFR (CD45—CD309 + ) and angiogenesis progenitors (CD45 — CD309 + CD117 + ) and their migration into emphysema expanded lungs. Elastase inhibited VEGFR-expressing endothelial progenitor cells, while cigarette smoke extract inhibited cells with CD45 — CD31 + CD34 + phenotype. In pulmonary emphysema provoked by elastase or D-galactosamine hydrochloride, angiogenesis was provided by endothelial cells with CD45 — CD31 + CD34 + phenotype, whereas in emphysema modeled with SU5416 or cigarette smoke extract, it was provided by the endothelial VEGFR-expressing cells and mature CD31 + endothelial cells, respectively. Replenishment of immature endothelial cells damaged by elastase and SU5416 involved Notch-1 + angiogenesis precursors and Notch-1 + endothelial progenitor cells with VEGFR.

The effects of the pegylated form of glucagon-like peptide 1 (pegGLP-1) on oligopotent β cell precursors (CD45 — TER119 — CD133 + CD49f low ) in the pancreas were studied in C57Bl/6 mice. Under conditions of streptozotocin-induced type 1 diabetes mellitus, intraperitoneal injection of pegGLP1 increased the content of β cell precursors and dithizone-stained cells in the pancreas. β Cell precursors of mice with diabetes demonstrated high self-maintenance potential. In contrast to pegGLP-1, native GLP-1 did not affect β cell precursors in diabetic animals. Treatment of a culture of β cell precursors from mice with diabetes induced the yield of dithizone-stained mononuclears. In conditioned mediums of dithizone-positive cells obtained as a result of differentiation of β cell precursors from mice with diabetes, insulin was detected after administration of pegGLP-1 (10 —7 M) and glucose (3 mmol/liter); the level of insulin increased with increasing glucose concentration (to 20 mmol/liter). The in vitro effect of pegGLP-1 did not differ from the effect of GLP-1 (10 —7 M).

The aim of this research was to investigate the regenerative potential of stem and progenitor cells derived from the pancreas and testes in metabolic disorders.Materials and methods. The experiments were performing on C57Bl/6 mice. Metabolic disorders (MD) were modeling by streptozotocin and fat diet. Morphological methods were used to assess morphopathological changes in the pancreas and testicular tissue and fertility. We investigated the insulin expression in the islets of Langerhans, CD16 in testes by immunohistochemical methods. We evaluated the blood lipids, level of glucose, inflammatory mediators, testosterone and a glucose-dependent insulinotropic polypeptide levels in biological samples by biochemical methods and ELISA. We used cytometric methods to study the surface markers of stem and progenitor cells, culture methods and transplantation test to investigate the regenerative potential of stem and progenitor cells.Results. After streptozotocin injection and fatty diet we observed the metabolic imbalance of lipids, testosterone, glucose and insulin resistance in C57BL/6 male mice. The inflammation, type 2 diabetes, asthenoand oligozoospermia were developed and the fertility index was decreased after the metabolic disorders. We observed the increase of oligopotent β-cell precursors (CD45- TER119- CD133+CD49flow) and precursors of hemangiogenesis (CD45- TER119- cKit-1+Flk-1+) count in the pancreas, spermatogonial stem cells (CD117- CD90+ and CD117+CD90+) and precursors of hemangiogenesis (CD45- TER119- cKit-1+Flk-1+) in the testes in MD. Stem and progenitor cells had a high clonal activity and self-renewal capacity, the ability to differentiate into mature cells in vitro, the effective engrafment in injured tissue.Conclusions. In experiments in vitro and in vivo we detected a high regenerative potential of precursors of hemangiogenesis and insulin-producing β-cells, spermatogonial stem cells of C57BL/6 male mice with metabolic disorders. Low rates of regeneration of the microvasculature, insulin-producing β-cells and germ cells in metabolic disorders are associated with the inhibitory effect of diabetic factors and inflammation on stem and progenitor cells.

The properties of spermatogonial stem cells, endothelial progenitor cells, and the epithelial progenitors of C57Bl/6 mice under conditions of metabolic disorders were studied using the model of busulfan-induced suppression of spermatogenesis and in vitro culture technique. Spermatogonial stem cells CD117—CD90+ and epithelial progenitors CD45—CD31—Sca-1+CD49f+ derived from the testes of mice with metabolic disturbances demonstrated 17- and 28-fold increase in the respective cell mass and generated cell colonies in vitro. In contrast, spermatogonial stem cells with immune phenotype CD51—CD24+CD52+ had reduced selfrenewal capacity. Spermatogonial stem cells CD117—CD90+ and CD117+CD90+ as well as endothelial progenitors CD45—CD31+ derived from the testes of donor mice with metabolic disorders demonstrated high transplantation capacity in C57Bl/6 mouse testes damaged by cytostatic busulfan.

Course administration streptozotocin to male C57Bl/6 mice induces a complex of symptoms typical of type 1 diabetes mellitus: hyperglycemia and insulin deficiency, focal inflammatory infiltration of the pancreas, destructive changes in the Langerhans islets, damage to the insular apparatus (reduced number of PDX1+ cells and insulin expression by the secreting cells). Male reproductive disorder are serious complications of type 1 diabetes mellitus. In “diabetic” mice, interstitial edema with inflammatory infiltration and microvascular disorders in the testicular tissue are observed, the number of endothelial precursors (CD45—/CD31+) and the total number and percentage of motile spermatozoa decreased, immature spermatogenic epithelium cells are desquamated of into the lumen of the tubules. Disturbances in the proliferation and differentiation of various spermatogonial stem cell populations (c-kit—/CD90+, c-kit+/CD90+, and CD51—/CD24+/CD52+) in diabetes can be explained by the inhibitory influence of inflammatory factors on testosterone-producing Leydig cells.

The regenerative potential of stem and progenitor cells from ischemic testes of C57Bl/6 mice was studied in vitro (cell culture) and in vivo (mouse model of busulfan-induced suppression of spermatogenesis). Spermatogonial stem cells with phenotypes CD117-CD90+ and CD51-CD24+CD52+ from ischemic testes demonstrated 33-fold and 7-fold increments of cell mass and generated colonies in vitro. Epithelial (CD45-CD31-Sca-1+CD49f+) and endothelial (CD45-CD31+) precursors exhibited lower self-renewal capacity. On day 30 after injection of stem and progenitor cells from ischemic testes to the rete testis zone of the testes of busulfantreated animals, an increase in the count of CD117-CD90+ spermatogonial stem cells, total count, and mobile sperm count in the testes of recipient mice was observed. In addition, we observed an increase in Sca-1+ cell count, recovery of the spermatogenic epithelium in the seminiferous tubules, and appearance of immature Leydig cells in "busulfan" testes; the level of tissue testosterone and fertility index also increased.

The gene protection effects of the hairy transgenic root extract, obtained as a result of the transformation of Scutellaria baicalensis into Agrobacterium rhizogenes, were revealed on a model of paclitaxel induced genotoxicity in mouse bone marrow and the Drosophila melanogaster somatic cells both under acute and chronic administration at the early and late periods of the study. The stimulation of granylocyto- and erythrocytopoiesis was demonstrated for the hairy roots extract of Scutellaria baicalensis on a rat model of paclitaxel- induced myelosuppression.

Inflammation, extracellular matrix proteins (hydroxyproline, connective tissue growth factor, collagen, and fibronectin), stem and progenitor cells (multipotent mesenchymal stromal cells, Clara cells, angiogenesis, precursors, endothelial and epithelial cells) were studied in female C57Bl/6 mice with experimental elastase-induced emphysema. Diffuse emphysema reduced the number of endothelial (CD45 – CD31 + CD34 + ) and epithelial (CD45 – CD117 + CD49f + ) cells, induced microcirculation disturbances, and decreased the area occupied by the connective tissue. Emphysematous changes in the lungs were accompanied by infiltration of the alveolar septa with macrophages and lymphocytes, increase in the serum and lung concentrations of transforming growth factor-β, IL-1β, IL-2, IL-5, IL-10, and IL-13, and lung concentration of IL-17. In the lungs, inflammation was associated with marked increase in the number of multipotent mesenchymal stromal cells CD90 + CD73 + CD106 + CD44 + ) and Clara cells (CD45 – CD34 – CD31 – Sca1 + ) and overexpression of extracellular matrix proteins (hydroxyproline, connective tissue growth factor, collagen, fibronectin) and Clara cells protein. On the other hand, elastase reduced the number of angiogenic precursor cells (CD45 – CD117 + Flk1 + ).

Polysaccharides from Tussilago farfara L., Acorus calamus L., and Echinacea purpurea (L.) Moench attenuated the toxic effect of fl uorouracil on the small intestinal epithelium of mice with Lewis lung carcinoma. Addition of polysaccharides to chemotherapy protocols stimulated reparative regeneration processes in the small intestine damaged by the cytostatic treatment. No stimulating effects of the polysaccharides on tumor growth and metastasizing were revealed.

Stem and progenitor cells were studied on mouse model of testicular ischemia. Testicular ischemia led to a decrease in free testosterone concentration. Hemodynamic changes, interstitial edema, and destruction of spermatogenic epithelium, Leydig, and Sertoli cells were observed in the testicular tissue. Accumulation of degenerative germ cells was accompanied by reduction in the count of spermatogonial stem cells with immunophenotype CD117–CD29+CD90+ and CD117+CD29+CD90+. Simultaneously with pathomorphological changes in the testes and suppression of spermatogenesis, ischemia reduced the count of hematopoietic progenitor cells, hematopoietic stem cells with immunophenotype Lin–CD117+Sca-1+c-kit+CD34+ and Lin–CD117+Sca-1+c-kit+CD34–, and multipotent mesenchymal stromal cells (CD45–CD31– CD90+CD106+) in the testicular tissue. The population of CD45–CD31+-endothelial cells in ischemic testicular tissue increased.

The model of streptozotocin-induced diabetes mellitus in C57Bl/6 mice was employed to study the role of precursors of insulin-producing β-cells, hematopoietic stem cells, and progenitor hematopoietic cells in inflammation. In addition to provoking hyperglycemia, streptozotocin elevated serum levels of IL-1β and hyaluronic acid, induced edema in the pancreatic insular tissue and its infiltration by inflammatory cells (neutrophils, lymphocytes, and macrophages) and fibroblasts. Inflammation in pancreatic islets was accompanied by necrotic processes and decreasing counts of multipotent progenitor β-cells (CD45 – , TER119 – , c-kit-1 – , and Flk-1 – ), oligopotent progenitor β-cells (CD45 – , TER119 – , CD133 + , and CD49f low ), and insulinproducing β-cells (Pdx1 + ). Pancreatic infl ammation was preceded by elevation of the number of short-term hematopoietic stem cells (Lin–Sca-1 + c-kit + CD34 + ) relative to long-term cells (Lin – Sca-1 + c-kit + CD34 – ) in the bone marrow as well as recruitment of hematopoietic stem and progenitor cells into circulation. Transplantation of bone marrow hematopoietic stem and progenitor cells from diabetic C57Bl/6 donor mice to recipient CBA mice with 5 - fluorouracilinduced leukopenia accelerated regeneration of granulocytopoiesis in recipient mice.

We studied toxicity of a new Russian radiopharmaceutical Nanocolloid, 99mTc-Al2O3. Tests for acute toxicity showed that this agent belongs to a class of moderate-toxicity substances and does not have cumulative properties. The evaluation of subchronic toxicity after subcutaneous injection of this product to rats (0.04, 0.2, and 0.4 ml/kg) and rabbits (0.02 and 0.2 ml/kg) for 7 days did not reveal changes in the general state, temperature, body weight, indices of the peripheral blood and bone marrow, functions of the heart, liver, kidneys, and nervous system, and morphological characteristics of the internal organs in animals. The drug does not produce a local irritant effect.

Using the model of hypogonadism in C57Bl/6 male mice, we showed that injection of streptozotocin to newborn animals and high-fat diet induced serum IFN-γ and IL-17 elevation, glucose metabolism disturbances, insulin resistance, destructive changes of the Langerhans islets (deficit of PDX1+β cells), while the number of oligopotent β cell precursors (CD45—TER119—CD133+CD49flow) increased. Diabetes played the role of an inducer of testicular tissue inflammation (pan-hemopoietic cell infiltration, increase of IL-2, IL-17, and IL-23 content) and reproductive system disturbances in mice (decrease in free testosterone concentration, suppression of spermatogenesis, and infertility). The development of hypogonadism was paralleled by an increase in the count of spermatogonial stem cells (CD117+CD29+CD90+), multipotent mesenchymal stromal cells (CD45—CD31—CD90+CD106+), hemangiogenesis precursors (CD45—CD117+Flk1+), and epithelial cells (CD45—CD31—CD49f+CD326+).

Intramuscular injections of Relatox in therapeutic and toxic doses to young outbred laboratory rats for 14 days caused no changes in the peripheral blood and bone marrow parameters, serum biochemical parameters, and morphology of the major viscera. In the toxic dose, the drug caused local irritation (inflammation, atrophy, and sclerosis in muscle tissue). Regeneration processes started in muscle tissue 7 days after Relatox withdrawal.

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.

We studied in vitro differentiation of pancreatic stem and progenitor cells into insulin secreting cells in the model of streptozotocin-induced diabetes in C57Bl/6 mice. Streptozotocin was shown to increase the population of pancreatic oligopotent β-cell precursors (CD45 – , TER119 – , CD133 + , and CD49f low ) and did not affect multipotent (stem) progenitor cells (CD45 – , TER119 – , CD17 – , CD309 – ). During long-term culturing, diabetic multipotent progenitor cells showed high capacity for self-renewal. A population of dithizone-positive (insulin secreting cells) mononuclear cells was obtained releasing insulin after prolonged culturing in suspension enriched with diabetic CD45 – , TER119 – , CD17 – , and CD309 – cells. The rate of generation of “new” insulin-producing cells and insulin release in the samples of experimental group considerably exceeded activity of the corresponding processes in the control group.

Experimental evaluation of efficiency of a new prostatotropic medication tertapeptide lysil-glutamyl-aspartyl-proline (Lys-Glu-Asp-Pro) in treatment of benign prostatic hyperplasia was performed in Wistar rats.The efficiency of the medication was compared with that one of injections of the Serenoa repens extract.The investigation showed the statistically significant decrease in the square of the epithelium of acini.The same effect of similar severity was obtained when the Serenoa repens extract was applied.Tertapeptide Lys-Glu-Asp-Pro, in difference from Serenoa repens extract, also resulted in weight loss and volume decrease of the prostate gland.