Glioblastoma is the most aggressive cancer among primary brain tumours. As with other cancers, the incidence of glioblastoma is increasing; despite modern therapies, the overall mean survival of patients post-diagnosis averages around 16 months, a figure that has not changed in many years. Cannabigerol (CBG) has only recently been reported to prevent the progression of certain carcinomas and has not yet been studied in glioblastoma. Here, we have compared the cytotoxic, apoptotic, and anti-invasive effects of the purified natural cannabinoid CBG together with CBD and THC on established differentiated glioblastoma tumour cells and glioblastoma stem cells. CBG and THC reduced the viability of both types of cells to a similar extent, whereas combining CBD with CBG was more efficient than with THC. CBD and CBG, both alone and in combination, induced caspase-dependent cell apoptosis, and there was no additive THC effect. Of note, CBG inhibited glioblastoma invasion in a similar manner to CBD and the chemotherapeutic temozolomide. We have demonstrated that THC has little added value in combined-cannabinoid glioblastoma treatment, suggesting that this psychotropic cannabinoid should be replaced with CBG in future clinical studies of glioblastoma therapy.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractDespite the importance of the tumor microenvironment in regulating tumor progression, few in vitro models have been developed to understand the effects of nonneoplastic cells and extracellular matrix (ECM) on drug resistance in glioblastoma (GBM) cells. Using CellTrace-labeled human GBM and microglial (MG) cells, we established a 2D co-culture including various ratios of the two cell types. Viability, proliferation, migration, and drug response assays were carried out to assess the role of MG. A 3D model was then established using a hyaluronic acid-gelatin hydrogel to culture a mixture of GBM and MG and evaluate drug resistance. A contact coculture of fluorescently labeled GBM and MG demonstrated that MG cells modestly promoted tumor cell proliferation (17%-30% increase) and greater migration of GBM cells (>1.5-fold increase). Notably, the presence of MG elicited drug resistance even when in a low ratio (10%-20%) relative to co-cultured tumor cells. The protective effect of MG on GBM was greater in the 3D model (>100% survival of GBM when challenged with cytotoxics). This new 3D human model demonstrated the influence of non-neoplastic cells and matrix on chemoresistance of GBM cells to three agents with different mechanisms of action suggesting that such sophisticated in vitro approaches may facilitate improved preclinical testing. K E Y W O R D S3D co-culture, drug resistance, human serum, hyaluronic acid hydrogel | 1711 LEITE ET aL.
Autism spectrum disorder (ASD) is a complex developmental disorder in which communication and behavior are affected. A number of studies have investigated potential biomarkers, including uremic toxins. The aim of our study was to determine uremic toxins in the urine of children with ASD (143) and compare the results with healthy children (48). Uremic toxins were determined with a validated high-performance liquid chromatography coupled to mass spectrometry (LC-MS/MS) method. We observed higher levels of p-cresyl sulphate (pCS) and indoxyl sulphate (IS) in the ASD group compared to the controls. Moreover, the toxin levels of trimethylamine N-oxide (TMAO), symmetric dimethylarginine (SDMA), and asymmetric dimethylarginine (ADMA) were lower in ASD patients. Similarly, for pCS and IS in children classified, according to the intensity of their symptoms, into mild, moderate, and severe, elevated levels of these compounds were observed. For mild severity of the disorder, elevated levels of TMAO and comparable levels of SDMA and ADMA for ASD children as compared to the controls were observed in the urine. For moderate severity of ASD, significantly elevated levels of TMAO but reduced levels of SDMA and ADMA were observed in the urine of ASD children as compared to the controls. When the results obtained for severe ASD severity were considered, reduced levels of TMAO and comparable levels of SDMA and ADMA were observed in ASD children.
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