National Institutes of Science and Technology Translational Medicine INCT TM

Porto Alegre, Brazil

National Institutes of Science and Technology Translational Medicine INCT TM

Porto Alegre, Brazil
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Schonhofen P.,Federal University of Rio Grande do Sul | Schonhofen P.,National Institutes of Science and Technology Translational Medicine INCT TM | de Medeiros L.M.,Federal University of Rio Grande do Sul | de Medeiros L.M.,National Institutes of Science and Technology Translational Medicine INCT TM | And 14 more authors.
Molecular Neurobiology | Year: 2015

Cannabidiol (CBD), one of the most abundant Cannabis sativa-derived compounds, has been implicated with neuroprotective effect in several human pathologies. Until now, no undesired side effects have been associated with CBD. In this study, we evaluated CBD’s neuroprotective effect in terminal differentiation (mature) and during neuronal differentiation (neuronal developmental toxicity model) of the human neuroblastoma SH-SY5Y cell line. A dose-response curve was performed to establish a sublethal dose of CBD with antioxidant activity (2.5 μM). In terminally differentiated SH-SY5Y cells, incubation with 2.5 μM CBD was unable to protect cells against the neurotoxic effect of glycolaldehyde, methylglyoxal, 6-hydroxydopamine, and hydrogen peroxide (H2O2). Moreover, no difference in antioxidant potential and neurite density was observed. When SH-SY5Y cells undergoing neuronal differentiation were exposed to CBD, no differences in antioxidant potential and neurite density were observed. However, CBD potentiated the neurotoxicity induced by all redox-active drugs tested. Our data indicate that 2.5 μM of CBD, the higher dose tolerated by differentiated SH-SY5Y neuronal cells, does not provide neuroprotection for terminally differentiated cells and shows, for the first time, that exposure of CBD during neuronal differentiation could sensitize immature cells to future challenges with neurotoxins. © 2014, Springer Science+Business Media New York.


Lisboa Da Motta L.,Federal University of Rio Grande do Sul | Lisboa Da Motta L.,National Institutes of Science and Technology Translational Medicine INCT TM | Muller C.B.,Federal University of Rio Grande do Sul | Muller C.B.,National Institutes of Science and Technology Translational Medicine INCT TM | And 17 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2014

Purpose: The expression levels of human antioxidant genes (HAGs) and oxidative markers were investigated in light of lung adenocarcinoma aggressiveness and patient outcome. Methods: We assayed in vitro the tumoral invasiveness and multidrug resistance in human lung adenocarcinoma (AdC) cell lines (EKVX and A549). Data were associated with several redox parameters and differential expression levels of HAG network. The clinicopathological significance of these findings was investigated using microarray analysis of tumor tissue and by immunohistochemistry in archival collection of biopsies. Results: An overall increased activity (expression) of selected HAG components in the most aggressive cell line (EKVX cells) was observed by bootstrap and gene set enrichment analysis (GSEA). In vitro validation of oxidative markers revealed that EKVX cells had high levels of oxidative stress markers. In AdC cohorts, GSEA of microarray datasets showed significantly high levels of HAG components in lung AdC samples in comparison with normal tissue, in advanced stage compared with early stage and in patients with poor outcome. Cox multivariate regression analysis in a cohort of early pathologic (p)-stage of AdC cases showed that patients with moderate levels of 4-hydroxynonenal, a specific and stable end product of lipid peroxidation, had a significantly less survival rate (hazard ratio of 8.87) (P < 0.05). Conclusions: High levels of oxidative markers are related to tumor aggressiveness and can predict poor outcome of early-stage lung adenocarcinoma patients. © 2014 Springer-Verlag Berlin Heidelberg.


da Motta L.L.,Federal University of Rio Grande do Sul | da Motta L.L.,National Institutes of Science and Technology Translational Medicine INCT TM | De Bastiani M.A.,Federal University of Rio Grande do Sul | De Bastiani M.A.,National Institutes of Science and Technology Translational Medicine INCT TM | And 4 more authors.
Tumor Biology | Year: 2015

Oxidative stress is involved in many cancer-related processes; however, current therapeutics are unable to benefit from this approach. The lungs have a very exquisite redox environment that may contribute to the frequent and deadly nature of lung cancer. Very few studies specifically address lung large-cell carcinoma (LCC), even though this is one of the major subtypes. Using bioinformatic (in silico) tools, we demonstrated that a more aggressive lung LCC cell line (HOP-92) has an overall increase activity of the human antioxidant gene (HAG) network (P = 0.0046) when compared to the less aggressive cell line H-460. Gene set enrichment analysis (GSEA) showed that the expression of metallothioneins (MT), glutathione peroxidase 1 (GPx-1), and catalase (CAT) are responsible for this difference in gene signature. This was validated in vitro, where HOP-92 showed a pro-oxidative imbalance, presenting higher antioxidant enzymes (superoxide dismutase (SOD), CAT, and GPx) activities, lower reduced sulfhydryl groups and antioxidant potential, and higher lipoperoxidation and reactive species production. Also, HAG network is upregulated in lung LCC patients with worst outcome. Finally, the prognostic value of genes enriched in the most aggressive cell line was assessed in this cohort. Isoforms of metallothioneins are associated with bad prognosis, while the thioredoxin-interacting protein (TXNIP) is associated with good prognosis. Thus, redox metabolism can be an important aspect in lung LCC aggressiveness and a possible therapeutic target. © 2015, International Society of Oncology and BioMarkers (ISOBM).


Schonhofen P.,Federal University of Rio Grande do Sul | Schonhofen P.,National Institutes of Science and Technology Translational Medicine INCT TM | de Medeiros L.M.,Federal University of Rio Grande do Sul | de Medeiros L.M.,National Institutes of Science and Technology Translational Medicine INCT TM | And 6 more authors.
Mini-Reviews in Medicinal Chemistry | Year: 2014

Cofilin-1 protein, which main function is to regulate actin cytoskeleton dynamics, appears to be involved with many steps in the neurotoxicity processes found in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the dynamics of actin filaments play a major role in several cellular processes, the primary involvement of cofilin-1 dysfunctions in the pathophysiology of these disorders may be related to a cytoskeleton stress. However, recently cofilin-1 has also been related to other biological processes such as cell death by apoptosis. In both cases, ATP depletion associated with the presence of reactive species and other stressors regulate cofilin-1 by inducing the formation of aggregates composed primarily by actin and cofilin-1, known as cofilin/actin rods. These structures seem to be formed initially as a neuroprotective response to mitochondrial damage; but once the stressor persists they are thought to act as inducers of further impairments and loss of neuronal functions. Therefore, here we provide a brief overview of the current knowledge about the central role of cofilin/actin rods formation, where its dysregulation and malfunction might be the trigger to neurodegeneration. © 2014 Bentham Science Publishers.

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