Glioblastoma is a devastating primary brain tumor resistant to conventional therapies. In this study, we tested the efficacy of combining temozolomide with curcumin, a phytochemical known to inhibit glioblastoma growth, and investigated the mechanisms involved. The data showed that synergy between curcumin and temozolomide was not achieved due to redundant mechanisms that lead to activating protective autophagy both in vitro and in vivo. Autophagy preceded apoptosis, and blocking this response with autophagy inhibitors (3-methyl-adenine, ATG7 siRNA and chloroquine) rendered cells susceptible to temozolomide and curcumin alone or combinations by increasing apoptosis. While curcumin inhibited STAT3, NFκB and PI3K/Akt to affect survival, temozolomide-induced autophagy relied on the DNA damage response and repair components ATM and MSH6, as well as p38 and JNK1/2. However, the most interesting observation was that both temozolomide and curcumin required ERK1/2 to induce autophagy. Blocking this ERK1/2-mediated temozolomide and curcumin induced autophagy with resveratrol, a blood-brain barrier permeable drug, improved temozolomide/curcumin efficacy in brain-implanted tumors. Overall, the data presented demonstrate that autophagy impairs the efficacy of temozolomide/curcumin, and inhibiting this phenomenon could provide novel opportunities to improve brain tumor treatment.

No abstract

All AS used gave satisfactory results during the first 21 days of storage based on the degree of hemolysis, and on ATP and 2,3-DPG concentrations. When compared with day 1 values, significant changes were seen in these variables by day 31 with all AS.

Scope. To elucidate the morphological and biochemical in vitro effects exerted by caffeine, taurine, and guarana, alone or in combination, since they are major components in energy drinks (EDs). Methods and Results. On human neuronal SH-SY5Y cells, caffeine (0.125–2 mg/mL), taurine (1–16 mg/mL), and guarana (3.125–50 mg/mL) showed concentration-dependent nonenzymatic antioxidant potential, decreased the basal levels of free radical generation, and reduced both superoxide dismutase (SOD) and catalase (CAT) activities, especially when combined together. However, guarana-treated cells developed signs of neurite degeneration in the form of swellings at various segments in a beaded or pearl chain-like appearance and fragmentation of such neurites at concentrations ranging from 12.5 to 50 mg/mL. Swellings, but not neuritic fragmentation, were detected when cells were treated with 0.5 mg/mL (or higher doses) of caffeine, concentrations that are present in EDs. Cells treated with guarana also showed qualitative signs of apoptosis, including membrane blebbing, cell shrinkage, and cleaved caspase-3 positivity. Flow cytometric analysis confirmed that cells treated with 12.5–50 mg/mL of guarana and its combinations with caffeine and/or taurine underwent apoptosis. Conclusion. Excessive removal of intracellular reactive oxygen species, to nonphysiological levels (or “antioxidative stress”), could be a cause of in vitro toxicity induced by these drugs.

No abstract

A adaptação metabólica é um processo importante para a produção de leite em vacas de alta produção leiteira. A fisiologia das mudanças hematológicas e endócrinas durante o pós-parto é complexa e muitas respostas homeostáticas são importantes para obter o máximo da produção de leite. O perfil hematológico é uma ferramenta diagnóstica útil nos diferentes estágios do ciclo produtivo de vacas leiteiras. O objetivo deste estudo foi avaliar alguns parâmetros hematológicos em diferentes estágios do ciclo produtivo de vacas leiteiras e correlacioná-los com o cortisol. Foram selecionadas 210 vacas multíparas, distribuídas por semanas: -3, -1 (antes do parto) e 2, 5, 8 e 11 (após o parto). Os parâmetros hematológicos avaliados foram hematócrito, concentração de hemoglobina, contagem total e diferencial de leucócitos. O estresse durante o periparto foi avaliado pela concentração de cortisol analisado através do método de radioinmunoensaio de fase sólida. Todos os parâmetros determinados (hematológicos e cortisol) estavam dentro do intervalo de referência para a espécie. Os maiores valores de cortisol foram observados na segunda semana após o parto. Alterações hematológicas associadas a sinais de alto estresse não foram observadas no presente estudo e isto provavelmente se deve ao estado de saúde satisfatório dos animais durante o período de experimento e às condições adequadas de manejo e nutrição.

No abstract

Mitochondria perform crucial roles in many biochemical processes, and mitochondrial depolarization is an early sign of platelet apoptosis. The mitochondrial membrane potential is usually evaluated through JC-1 probe, but it can also be assessed with MitoTracker probes. Our aim was to evaluate mitochondrial viability in stored canine platelet concentrates (PCs) with the fluorescent probes JC-1 and MitoTracker. Platelets from 22 canine PCs were stained with JC-1 and MitoTracker probes on days 1, 3, and 5 of storage. Data on metabolic parameters were also collected for correlation studies. Results of JC-1 and MitoTracker revealed a decrease in mitochondrial membrane potential in day 5 of storage compared to days 1 and 3, providing evidence of mitochondrial depolarization, a finding that was confirmed by the data on metabolic parameters. MitoTracker probes also added information regarding platelet swelling. In conclusion, MitoTracker probes offered a more complete mitochondrial analysis in the evaluation of stored canine PCs.