Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 fluxes and cy...

Previous work demonstrated that a brief, sublethal excitotoxic insult strikingly increased the sensitivity of cortical neurons to the cytotoxic effects of the terminal pathway of complement, a process termed "excitotoxic sensitization." Here, we sought to elucidate the cellular mechanism of excitotoxic sensitization in embryonic rat cortical neurons in vitro. Excitotoxic sensitization did not i...

BACKGROUND Low-level endotoxemia (ie, >or=50 pg/mL) in apparently healthy subjects was recently identified as a powerful, independent risk factor for atherosclerosis. METHODS AND RESULTS We treated human saphenous veins (HSVs) with low levels of endotoxin. Release of the proinflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) was measured by ELISA. Super...

Reactive oxygen species (ROS) have been implicated as the cause of cumulative damage to DNA, proteins and lipids that can ultimately result in cell death. A common problem when measuring oxidative DNA damage has been the introduction of modifications in the native state of the molecule by many DNA isolation methods. We circumvented this problem by employing direct PCR (DPCR) of whole cell lysat...

We previously showed that membrane-depolarizing agents such as K+ and ATP-sensitive potassium (KATP) channel inhibitors potentiate tumor necrosis factor-related apoptosis‑inducing ligand (TRAIL)-induced apoptosis in human melanoma cells, but not in normal melanocytes. In this study, we investigated whether the tumor-selective effect of depolarization was observed among different tumor cell type...

PURPOSE Increased superoxide levels are implicated in the pathogenesis of diabetic retinopathy. We have shown that functional activation of a small molecular weight G-protein, H-Ras, is one of the signaling steps involved in glucose-induced apoptosis of retinal capillary cells. The goal of this study was to elucidate the mechanism(s) by which oxidative stress could result in the activation of H...

OBJECTIVE The objective of this study was to determine the effects and potential mechanisms of C-reactive protein (CRP) on cholesterol efflux from human macrophage foam cells, which may play a critical role in atherogenesis. METHODS AND RESULTS Human THP-1 monocytes and peripheral blood mononuclear cells (PBMCs) were preincubated with acetylated LDL and [3H]-cholesterol to form foam cells, wh...

Inorganic phosphate (Pi) plays an important role in cell signaling and energy metabolism. In insulin-releasing cells, Pi transport into mitochondria is essential for the generation of ATP, a signaling factor in metabolism-secretion coupling. Elevated Pi concentrations, however, can have toxic effects in various cell types. The underlying molecular mechanisms are poorly understood. Here, we have...

Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor activation results in production of reactive oxygen species (ROS) and activation of extracellular signal-regulated kinase (ERK) in hippocampal area CA1. In addition, application of ROS to hippocampal slices has been shown to result in activation of ERK in area CA1. To determine whether these events were linked causally, we in...

Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, suggesting that ROS might be involved in the development of these cells. However, recent studies suggest that inducing an excess of ROS in cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumors frequently exhibit multiple genetic alter...