The mesoionic compound MI-D changes energy metabolism and induces apoptosis in T98G glioma cells.

The mesoionic compound 4-phenyl-5-(4-nitro-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride (MI-D) impairs mitochondrial oxidative phosphorylation and has a significant antitumour effect against hepatocarcinoma and melanoma. This study evaluated the cytotoxic effect of MI-D on T98G glioblastoma cells and investigated whether the impairment of oxidative phosphorylation promoted by MI-D is relevant to its cytotoxic effect. The effects of MI-D on T98G cells cultured in high glucose Dulbecco's modified Eagle's medium (DMEM) HG (glycolysis-dependent) and galactose plus glutamine-supplemented Dulbecco's modified Eagle's medium (DMEM) GAL (oxidative phosphorylation-dependent) were compared. T98G cells grown in DMEM GAL medium exhibited higher respiration rates and citrate synthase activity and lower lactate levels, confirming the metabolic shift to oxidative phosphorylation in these cells. MI-D significantly decreased the cell viability in a dose-dependent manner in both media; however, T98G cells cultured in DMEM GAL medium were more susceptible. The mesoionic significantly inhibited mitochondrial oxidative phosphorylation of glioma cells in both media. At the same time, lactate levels were not altered, indicating an absence of compensatory glycolysis activation. Additionally, MI-D increased the citrate synthase activity of cells in both media, which in DMEM HG-cultivated cells was followed by citrate accumulation. Apoptosis dependent on caspase-3 mediated the toxicity of MI-D on T98G cells. The higher susceptibility of glioma cells cultured in DMEM GAL medium to MI-D indicates that the impairment of mitochondrial functions is involved in mesoionic cytotoxicity. The results of this study indicate the potential use of MI-D for glioblastoma treatment.

Effects of the Crotalus durissus terrificus snake venom on hepatic metabolism and oxidative stress.

Snake venoms present different action mechanisms because of their complex composition, represented mainly by toxins and enzymes. This work aimed to investigate the effects of the Crotalus durissus terrificus(Cdt) venom in the liver. Wistar rats were inoculated intraperitoneally with saline (control) or Cdt venom. After 3, 4, or 6 h, the following parameters were analyzed: (a) hepatic function, (b) oxidative stress parameters, and (c) the metabolism of alanine in the isolated perfused liver. Plasma activities of alanine aminotransferase and aspartate aminotransferase and hepatic glutathione S-transferase and catalase presented significant elevation in rats inoculated with 300 µg ⋅ kg(-1) Cdt venom. Liver lipoperoxidation was enormously increased by venom doses of 100, 200, and 300 µg ⋅kg(-1) , whereas glutathione S-transferase was not changed. Perfused livers from rats inoculated with 1500 µg ⋅kg(-1) venom showed increased production of lactate, pyruvate, and ammonia when alanine was the metabolic substrate. These results demonstrate that the Cdt venom can produce several changes in hepatocytes. The causes of the changes are possibly related to the disequilibrium in the redox homeostasis but also to specific needs of the poisoned organism, for example, an increased supply of lactate and pyruvate in response to an increased activity of the Cori cycle.