Chausheva A.I.,Research Center for Medical Genetics |
Nikitina V.A.,Research Center for Medical Genetics |
Zhanataev A.K.,Vv Zakusov Institute Of Pharmacology |
Durnev A.D.,Vv Zakusov Institute Of Pharmacology |
Bochkov N.P.,Research Center for Medical Genetics
Cellular Transplantation and Tissue Engineering | Year: 2011
The levels of DNA-damage and 8-oxiguanine were estimated using the comet assay in multipotent mesenchymal stromal cells (MSC) on different passages. Twenty eight cultures MSC from bone marrow of healthy donors have been analyzed. The level of DNA-damages in MSC, estimated as percent of DNA in comet tail (%DNA in comet tail), didn't change in the process of cultivation (3,9±0,4 % on 3-4 passages and 3,8±0,6 % on 10-12 passages). No significant differences in the content of 8-oxiguanine in the DNA of cells at different stages of cultivation (1,9±0,24 p.u. 3-4 passages and 2,1±0,22 p.u. on 10-12 passages) haven't been revealed. The higher levels of DNA damage and apoptotic comets observed in two cultures of MSC.
Gudasheva T.A.,Vv Zakusov Institute Of Pharmacology |
Povarnina P.Y.,Vv Zakusov Institute Of Pharmacology |
Antipova T.A.,Vv Zakusov Institute Of Pharmacology |
Firsova Y.N.,Vv Zakusov Institute Of Pharmacology |
And 2 more authors.
Journal of Biomedical Science | Year: 2015
Background: This study aimed at developing nerve growth factor (NGF) mimetics that selectively activate specific biological signals and, as a result, lack the side effects of the full-length protein. Two dimeric dipeptides, bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide (GK-6) and bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), were designed based on the most exposed outside fragments of NGF, namely, the loop 1 and loop 4 β-turn sequences, respectively. These dipeptides exhibited neuroprotective activity in vitro at micro-nanomolar concentrations. Results: Studies on the mechanism of action revealed that both compounds elevate the level of tyrosine kinase A (TrkA) receptor phosphorylation and that they each have different postreceptor signaling patterns. GK-6 increases the levels of extracellular signal-regulated kinase (ERK) and AKT kinase phosphorylation, whereas GK-2 only increases the level of AKT phosphorylation. Apart from the neuroprotective activity, GK-6 promoted differentiation in PC12 cells, whereas GK-2 did not. Furthermore, it was established that the neuroprotective activity of GK-2 was completely abolished by a selective inhibitor of phosphatidylinositol 3-kinase (LY294002) but not by a specific inhibitor of mitogen-activated protein kinases MEK1 and MEK2 (PD98059). In vivo experiments demonstrated that GK-2 did not induce hyperalgesia, which is one of the primary adverse effects of NGF. By contrast, GK-6 produced a significant decrease in the pain threshold of rats as determined by the tail flick test. Conclusion: The data obtained suggest that dimeric dipeptide NGF mimetics are promising candidates in the development of pharmacological agents with NGF-like activity that are free of the main side effect of NGF. © 2015 Gudasheva et al.