ABSTRACT
Glioblastoma (GBM) is a neoplasm characterized by an extensive blood vessel network. Hypoxic niches of GBM can induce tumorigenic properties of a small cell subpopulation called Glioblastoma stem-like cells (GSCs) and can also increase extracellular adenosine generation which activates the A3 adenosine receptor (A3AR). Moreover, GSCs potentiates the persistent neovascularization in GBM. The aim of this study was to determine if A3AR blockade can reduce the vasculogenesis mediated by the differentiation of GSCs to Endothelial Cells (ECs) under hypoxia. We evaluated the expression of endothelial cell markers (CD31, CD34, CD144, and vWF) by fluorescence-activated cell sorting (FACS), and vascular endothelial growth factor (VEGF) secretion by ELISA using MRS1220 (A3AR antagonist) under hypoxia. We validate our results using U87MG-GSCs A3AR knockout (GSCsA3-KO). The effect of MRS1220 on blood vessel formation was evaluated in vivo using a subcutaneous GSCs-tumor model. GSCs increased extracellular adenosine production and A3AR expression under hypoxia. Hypoxia also increased the percentage of GSCs positive for endothelial cell markers and VEGF secretion, which was in turn prevented when using MRS1220 and in GSCsA3-KO. Finally, in vivo treatment with MRS1220 reduced tumor size and blood vessel formation. Blockade of A3AR decreases the differentiation of GSCs to ECs under hypoxia and in vivo blood vessel formation.
Subject(s)
Cell Differentiation , Endothelial Cells/metabolism , Endothelial Cells/pathology , Glioblastoma/metabolism , Glioblastoma/pathology , Receptor, Adenosine A3/metabolism , Adenosine/pharmacology , Adenosine A3 Receptor Antagonists/pharmacology , Animals , Biomarkers, Tumor/metabolism , Cell Differentiation/drug effects , Cell Hypoxia/drug effects , Cell Line, Tumor , Endothelial Cells/drug effects , Humans , Male , Models, Biological , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Neovascularization, Physiologic/drug effects , Rats, Sprague-DawleyABSTRACT
Fluoride is an important element for humans. It inhibits initiation and progression of dental caries and stimulates bone formation. However, excessive intake may lead to the appearance of dental and/or skeletal fluorosis and a decrease in intellectual coefficient in child populations. This study evaluates exposure to fluoride in the child population of Chaco province (Argentina) by analysis of drinking water, food and its bioaccessible fraction (quantity of fluoride solubilised by gastrointestinal digestion and available for intestinal absorption) and urine as a biomarker of internal dose. The concentration of fluoride in drinking water varied between 0.050 and 4.6 mg L-1, and 80% of the samples exceeded the WHO drinking-water guideline value (1.5 mg L-1). Fluoride concentrations in food ranged between 0.80 and 3.0 mg kg-1 fresh weight (fw), being lower in bioaccessible fraction (0.43-1.9 mg kg-1, fw). On the basis of the consumption data declared for the young child population, fluoride intake varies between 4.1 and 6.5 mg day-1, greater than the level recommended for this age group. Moreover, in some cases, concentrations of fluoride found in urine (0.62-8.9 mg L-1) exceeded those reported in areas with declared fluorosis. All data obtained show the worrying situation of child population in this area of Argentina.
Subject(s)
Drinking Water/analysis , Environmental Exposure , Fluorides/urine , Food Analysis , Groundwater/analysis , Adolescent , Argentina , Biological Availability , Biomarkers/urine , Child , Fluorides/analysis , Humans , Rural PopulationABSTRACT
The most aggressive type of brain tumor is glioblastoma multiforme, which to date remains incurable. Thuja occidentalis is used in homeopathy for the treatment of cancer, however, its mechanism of action remains unknown. We set out to study the effects of thujone fractions of Thuja on glioblastoma using in vitro and in vivo models. We found that the α/ ß-thujone fraction decrease the cell viability and exhibit a potent anti-proliferative, pro-apoptotic and anti-angiogenic effects in vitro. In vivo assays showed that α /ß-thujone promotes the regression of neoplasia and inhibits the angiogenic markers VEGF, Ang-4 and CD31 into the tumor.
Subject(s)
Antineoplastic Agents/pharmacology , Glioblastoma/drug therapy , Monoterpenes/pharmacology , Phytotherapy , Plant Extracts/pharmacology , Thuja , Angiogenesis Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Bicyclic Monoterpenes , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Glioblastoma/blood supply , Glioblastoma/pathology , Glioblastoma/physiopathology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/physiology , Humans , Male , Neoplasm Transplantation , Rats, Sprague-DawleyABSTRACT
Glutathione S-tranferases (GST) are multigenic enzymes that have been associated with arsenic metabolism. The objective of this study was to evaluate the relationship between polymorphic variants of GST and urinary concentration of arsenic species in people exposed to low levels of arsenic. A cross-sectional study among 66 nonoccupationally exposed subjects, living in the city of Antofagasta, Chile. Polymorphic variants were analyzed by polymerase chain reaction (PCR) and arsenic species was determined by atomic absorption spectrometry. The effect of GST variants on arsenic concentration was evaluated using univariate and covariate-adjusted regressions. For both GSTT1 and GSTM1 there were no significant differences in detected arsenic relative species between carriers of the active and null polymorphic variants. There was nondefinitive evidence that polymorphic variants of GST play a role in arsenic metabolism in sample of the Chilean subjects studied.