Resveratrol (RSV) is known for its antioxidant properties; however, this compound has been proposed to have cytotoxic and pro-oxidant effects depending on its concentration and time of exposure. We previously reported the cell cycle arrest effect of low doses of RSV in GRX cells, an activated hepatic stellate cell model. Here, we evaluated the effects of RSV treatment (0.1-50 μM) for 24 and 120 h on GRX viability and oxidative status. Only treatment with 50 μM of RSV reduced the amount of live cells. However, even low doses of RSV induced an increased reactive species production at both treatment times. While being diminished within 24 h, RSV induced an increase in the SOD activity in 120 h. The cellular damage was substantially increased at 24 h in the 50 μM RSV-treated group, as indicated by the high lipoperoxidation, which may be related to the significant cell death and low proliferation. Paradoxically, this cellular damage and lipoperoxidation were considerably reduced in this group after 120 h of treatment while the surviving cells proliferated. In conclusion, RSV induced a dose-dependent pro-oxidant effect in GRX cells. The highest RSV dose induced oxidative-related damage, drastically reducing cell viability; but this cytotoxicity seems to be attenuated during 120 h of treatment.

Resveratrol (RSV) exerts anti-proliferative and pro-apoptotic actions in different cell lines. Hepatic stellate cells (HSCs) are major fibrogenic cell types that contribute to collagen accumulation during chronic liver disease. In the present study, the inhibitory effects of RSV on cell proliferation, cell cycle, and apoptosis were evaluated in the mouse hepatic stellate cell line GRX. Cells treated with 1 nM-1 muM of RSV demonstrated a decrease in cell growth of about 35% after 5 days. GRX cells, treated with RSV (100 nM or 1 muM), were analyzed by flow cytometry; RSV induced an increase in the number of GRX cells in the S- and sub-G1 phases. The increase in sub-G1 phase cells and the nuclear condensation and fragmentation shown by DAPI staining identified a possible pro-apoptotic effect of RSV on GRX cells. Furthermore, the RSV anti-proliferative effects could be explained by an S-phase accumulation caused by a decrease in the progression through the cell cycle or an inhibition of S or G2 phase transition. It is notable that these RSV actions are mediated at nanomolar levels, compatible with the concentrations of free RSV in biological fluids after ingestion of polyphenol-rich foods, suggesting a possible effect of these foods as an adjuvant treatment in chronic liver diseases.

Heat shock proteins (HSPs) are evolutionary conserved proteins that work as molecular chaperones and perform broad and crucial roles in proteostasis, an important process to preserve the integrity of proteins in different cell types, in health and disease. Their function in cancer is an important aspect to be considered for a better understanding of disease development and progression. Glioblastoma (GBM) is the most frequent and lethal brain cancer, with no effective therapies. In recent years, HSPs have been considered as possible targets for GBM therapy due their importance in different mechanisms that govern GBM malignance. In this review, we address current evidence on the role of several HSPs in the biology of GBMs, and how these molecules have been considered in different treatments in the context of this disease, including their activities in glioblastoma stem-like cells (GSCs), a small subpopulation able to drive GBM growth. Additionally, we highlight recent works that approach other classes of chaperones, such as histone and mitochondrial chaperones, as important molecules for GBM aggressiveness. Herein, we provide new insights into how HSPs and their partners play pivotal roles in GBM biology and may open new therapeutic avenues for GBM based on proteostasis machinery.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Hypoxia is a distinct feature in GBM and plays a significant role in tumor progression, resistance to treatment, and poor outcome. However, there is lack of studies relating type of cell death, status of Akt phosphorylation on Ser473, mitochondrial membrane potential, and morphological changes of tumor cells after hypoxia and reoxygenation. The rat glioma C6 cell line was exposed to oxygen deprivation (OD) in 5 % fetal bovine serum (FBS) or serum-free media followed by reoxygenation (RO). OD induced apoptosis on both 5 % FBS and serum-free groups. Overall, cells on serum-free media showed more profound morphological changes than cells on 5 % FBS. Moreover, our results suggest that OD combined with absence of serum provided a favorable environment for glioblastoma dedifferentiation to cancer stem cells, since nestin, and CD133 levels increased. Reoxygenation is present in hypoxic tumors through microvessel formation and cell migration to oxygenated areas. However, few studies approach these phenomena when analyzing hypoxia. We show that RO caused morphological alterations characteristic of cells undergoing a differentiation process due to increased GFAP. In the present study, we characterized an in vitro hypoxic microenvironment associated with GBM tumors, therefore contributing with new insights for the development of therapeutics for resistant glioblastoma.

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Alzheimer's disease is a neurodegenerative disorder characterized by extracellular deposition of amyloid‐β (Aβ) peptide and hyperphosphorylation of Tau protein, which ultimately leads to the formation of intracellular neurofibrillary tangles and cell death. Increasing evidence indicates that genistein, a soy isoflavone, has neuroprotective effects against Aβ‐induced toxicity. However, the molecular mechanisms involved in its neuroprotection are not well understood. In this study, we have established a neuronal damage model using retinoic‐acid differentiated SH‐SY5Y cells treated with different concentrations of Aβ25–35 to investigate the effect of genistein against Aβ‐induced cell death and the possible involvement of protein kinase B (PKB, also termed Akt), glycogen synthase kinase 3β (GSK‐3β), and Tau as an underlying mechanism to this neuroprotection. Differentiated SH‐SY5Y cells were pre‐treated for 24 hr with genistein (1 and 10 nM) and exposed to Aβ25–35 (25 μM), and we found that genistein partially inhibited Aβ induced cell death, primarily apoptosis. Furthermore, the protective effect of genistein was associated with the inhibition of Aβ‐induced Akt inactivation and Tau hyperphosphorylation. These findings reinforce the neuroprotective effects of genistein against Aβ toxicity and provide evidence that its mechanism may involve regulation of Akt and Tau proteins.

Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazosin’s (an antihypertensive drug) activity against glioblastoma cells (C6 and U138-MG) and its neurotoxicity on primary astrocytes and organoptypic hippocampal cultures. For this study, the following methods were used: citotoxicity assays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosin induces cell death on C6 and U138-MG cells. We observed that doxazosin’s effects on the PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor). In glioblastoma cells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activities of proteins downstream of Akt we observed upregulation of GSK-3β and p53. This led to cell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrest at G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinase inhibitor, as a comparison with doxazosin because they present similar chemical structure. We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic cultures and observed that doxazosin induced cell death on a small percentage of non-tumor cells. Aggressiveness of glioblastoma tumors and dismal prognosis require development of new treatment agents. This includes less toxic drugs, more selective towards tumor cells, causing less damage to the patient. Therefore, our results confirm the potential of doxazosin as an attractive therapeutic antiglioma agent.