We studied the structures of the cerebellar cortex of young adult and old cats for age-related changes, which were statistically analysed. Nissl staining was used to visualize the cortical neurons. The immunohistochemical method was used to display glial fibrillary acidic protein (GFAP)-immunoreactive (IR) astrocytes and neurofilament-immunoreactive (NF-IR) neurons. Under the microscope, the thickness of the cerebellar cortex was measured; and the density of neurons in all the layers as well as that of GFAP-IR cells in the granular layer was analysed. Compared with young adult cats, the thickness of the molecular layer and total cerebellar cortex was significantly decreased in old cats, and that of the granular layer increased. The density of neurons in each layer was significantly lower in old cats than in young adult ones. Astrocytes in old cats were significantly denser than in young adult ones, and accom-panied by evident hypertrophy of the cell bodies and enhanced immunoreaction of GFAP substance. Purkinje cells (PCs) in old cats showed much fewer NF-IR dendrites than those in young adults. The above findings indicate a loss of neurons and decrease in the number of dendrites of the PCs in the aged cerebellar cortex, which might underlie the functional decline of afferent efficacy and information integration in the senescent cerebellum. An age-dependent enhancement of activity of the astrocytes may exert a protective effect on neurons in the aged cerebellum.
Introduction:The delivery of biomolecules by tumor cell-secreted extracellular vesicles (EVs) is linked to the development of glioma. Here, the present study was implemented to explore the functional significance of hypoxic glioma cell-derived EVs carrying microRNA-10b-5 (miR-10b-5p) on glioma with the involvement of polarization of M2 macrophages.
Methods: EVs were isolated from hypoxia-stimulated glioma cells, and their role in polarization of M2 macrophages was studied by co-culturing with macrophages. miR-10b-5p expression in glioma tissues, glioma-derived EVs, and macrophages cocultured with EVs was characterized. Interaction among miR-10b-5p, NEDD4L, and PIK3CA was analyzed. The macrophages or glioma cells were transfected with overexpressing plasmid or shRNA to study the effects of miR-10b-5p/NEDD4L/PIK3CA on M2 macrophage polarization, and glioma cell proliferation, migration, and invasion in vitro and in vivo. Results: Promotive role of hypoxia-stimulated glioma-derived EVs in macrophage M2 polarization was confirmed. Elevation of miR-10b-5p occurred in glioma tissues, glioma-derived EVs and macrophages co-cultured with EVs, and stimulated M2 polarization of macrophages. NEDD4L was a target gene of miR-10b-5p. Overexpression of NEDD4L could inhibit PI3K/AKT pathway through increase in ubiquitination and degradation of PIK3CA. Hypoxic glioma-derived EVs harboring upregulated miR-10b-5p triggered an M2 phenotype in macrophages as well as enhanced aggressive tumor biology of glioma cells via inhibition of PIK3CA/PI3K/AKT pathway by targeting NEDD4L. Conclusions: In summary, miR-10b-5p delivered by hypoxic glioma-derived EVs accelerated macrophages M2 polarization to promote the progression of glioma via NEDD4L/PIK3CA/PI3K/AKT axis.
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