ABSTRACT
In order to obtain models of gliomas of varying degrees of malignancy, we performed morphological and molecular genetic study of a tissue strain of glioma 10-17-2 (Astrid-17) obtained by intracranial passaging of tumor fragments of chemically induced rat brain tumor, and a cell strain isolated from it. More or less pronounced changes in the expression levels of Mki67, Trp53, Vegfa, and Gfap genes in the tissue and cell strain of glioma 10-17-2 (Astrid-17) compared with intact brain tissue were shown. The tissue model of glioma 10-17-2 (Astrid-17) according to the studied characteristics shows features of grade 3-4 astrocytoma and the cellular model - grade 2-3 astrocytoma.
ABSTRACT
One of the key problems of glioblastoma treatment is the low effectiveness of chemotherapeutic drugs. Incorporation of doxorubicin into PLGA nanoparticles allows increasing the antitumor effect of the cytostatics against experimental rat glioblastoma 101.8. Animal survival, tumor volume, and oncogene expression in tumor cells were compared after early (days 2, 5, and 8 after tumor implantation) and late (days 8, 11, and 14) start of the therapy. At late start, a significant increase in the expression of oncogenes Gdnf, Pdgfra, and Melk and genes determining the development of multidrug resistance Abcb1b and Mgmt was revealed. At early start of therapy, only the expression of oncogenes Gdnf, Pdgfra, and Melk was enhanced. Early start of treatment prolonged the survival time and increased tumor growth inhibition by 141.4 and 95.7%, respectively, in comparison with the untreated group; these differences were not observed in the group with late start of therapy. The results indicate that the time of initiation of therapy is a critical parameter affecting the antitumor efficacy of DOX-PLGA.
Subject(s)
Doxorubicin , Glioblastoma , Nanoparticles , Animals , Glioblastoma/drug therapy , Glioblastoma/pathology , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Rats , Nanoparticles/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Antibiotics, Antineoplastic/pharmacology , Antibiotics, Antineoplastic/therapeutic use , Male , Cell Line, Tumor , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Polyglycolic Acid/chemistry , Gene Expression Regulation, Neoplastic/drug effectsABSTRACT
The dynamics of morphofunctional changes in the thymus during the LPS-induced systemic inflammatory response was assessed in prepubertal male Wistar rats in relationship with the resistance to hypoxia. The systemic inflammatory response was modeled by intraperitoneal administration of E. coli O26:B6 LPS. In histological sections of the thymus, the relative number of thymic bodies and proliferative activity of cells were evaluated. The relative number of CD3+CD4+, CD3+CD8+, and CD4+CD8+ cells in the thymus was determined by flow cytometry. The content of HIF-1α and endotoxin was determined in the blood serum. The expression level of Nfkb mRNA was assessed in the liver. The most pronounced changes in the indicators of the functional state of the thymus were detected 3 and 6 h after LPS administration following the increase in the content of HIF-1α and endotoxin in blood serum and Nfkb mRNA expression in the liver. In the thymus, a decrease in the number of thymic bodies consisting of 3-5 epithelial cells and an increase in the number of bodies consisting of 5 or more cells was observed. In 24 h after LPS administration, the relative number of CD3+CD4+ and CD3+CD8+ cells in the thymus decreased. At the same time, the number of Ki-67+ cells in the subcapsular zone of the thymus increased 6 and 24 h after LPS administration. These data should be taken into account in the development of approaches to the treatment of infectious and inflammatory diseases in prepubertal children.
Subject(s)
Escherichia coli , Lipopolysaccharides , Rats , Animals , Male , Rats, Wistar , Lipopolysaccharides/pharmacology , Lipopolysaccharides/metabolism , Thymus Gland , Endotoxins , Hypoxia/metabolism , NF-kappa B/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Systemic Inflammatory Response SyndromeABSTRACT
A comprehensive morphofunctional study of the lungs and alveolar macrophages was carried out in Sprague-Dawley rats with acute respiratory distress syndrome (n=10) induced by intratracheal administration of E. coli LPS 0111:B4 in a dose of 15 mg/kg. On the first day after LPS administration, bronchopneumonia was observed in the lungs, the number of macrophages of the bone marrow origin and the number of M1 macrophages with the proinflammatory phenotype in the bronchoalveolar lavage increased, the expression of proinflammatory cytokines increased and the expression of anti-inflammatory cytokines decreased, which was accompanied by an increase in LPS and C-reactive protein in the blood serum. The revealed changes correspond to the development of acute respiratory distress syndrome in humans, and the decrease in the number of macrophages in the lungs and their predominant polarization to the M1-proinflammatory phenotype substantiate the use of cell therapy with reprogrammed M2 macrophages.