The tumor suppressor protein p53 is a redox-active transcription factor that organizes and directs cellular responses in the face of a variety of stresses that lead to genomic instability. One of the most important questions in the study of p53 is how selective transactivation of certain p53 target genes is achieved. Reactive oxygen species (ROS), generated by cells as products or by-products, can function either as signaling molecules or as cellular toxicants. Cellular generation of ROS is central to redox signaling. Recent studies have revealed that each cellular concentration and distribution of p53 has a distinct cellular function and that ROS act as both an upstream signal that triggers p53 activation and a downstream factor that mediates apoptosis. Here, we examine the newly discovered role of p53 in regulating cellular ROS generation and how ROS modulate selective transactivation of p53 target genes. The focus is on interlinks between ROS and p53.

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Injury to nontargeted tissues in chemotherapy often complicates cancer treatment by limiting therapeutic dosages of anticancer drugs and by impairing the quality of life of patients during and after treatment. Oxidative stress, directly or indirectly caused by chemotherapeutics as exemplified by doxorubicin, is one of the underlying mechanisms of the toxicity of anticancer drugs in noncancerous tissues, including the heart and brain. A comprehensive understanding of the mechanisms of oxidative injury to normal tissue will be essential for the improvement of strategies to prevent or attenuate the toxicity of chemotherapeutic agents without compromising their chemotherapeutic value.

The gas-phase reaction of SO3 with H2O and the heterogeneous reaction of SO3 with H2O−H2SO4 surfaces have been studied in a fast flow reactor coupled to a chemical ionization mass spectrometer (CIMS) for species detection. The gas-phase reaction was studied under turbulent flow conditions over the pressure range from 100 to 760 Torr N2 and the temperature range from 283 to 370 K. The loss rate of SO3 was measured under pseudo-first-order conditions; it exhibits a second-order dependence on water vapor concentration and has a strong negative temperature dependence. The first-order rate coefficient for the SO3 loss by gas-phase reaction shows no significant pressure dependence and can be expressed as k I(s-1) = 3.90 × 10-41 exp(6830.6/T)[H2O]2 where [H2O] is in units of molecule cm-3 and T is in Kelvin. The overall uncertainty of our experimentally determined rate coefficients is estimated to be ±20%. At sufficiently low SO3 concentrations (<1012 molecule cm-3) the rate coefficient is independent of the initial SO3 level, as expected for a gas-phase reaction mechanism involving one SO3 and two H2O molecules. However, at higher concentrations and lower temperatures, increased rate coefficients were observed, indicating a fast heterogeneous reaction after the onset of binary homogeneous nucleation of acid hydrate clusters leading to particle formation, which was verified by light-scattering experiments. The heterogeneous loss of SO3 to the reactor walls has also been investigated under low pressure (1.1−12.5 Torr) laminar flow conditions. The loss rate is highly dependent on the humidity of the surface. In the presence of excess water the reactive sticking coefficient approaches unity and the wall loss rate is gas diffusion limited; under dry conditions it approaches zero, as expected. The atmospheric implications of the homogeneous and heterogeneous SO3−water reaction are discussed.

Cu-based nanocatalysts have been widely used for CO2 hydrogenation, but their poor stability is the bottleneck for further industrial applications. A high-performance and long-lived Cu/SiO2 nanocatalyst was synthesized by an ammonia-evaporation method for CO2 hydrogenation. The conversion of CO2 reaches up to 28%, which is close to the equilibrium conversion of CO2 (30%), and the selectivity to methanol is 21.3%, which is much higher than the equilibrium selectivity (6.6%) at 320 °C and 3.0 MPa. Furthermore, after 120 h of evaluation, the conversion can be still maintained at a high value (27%), which is much better than a Cu/SiO2 catalyst prepared by traditional impregnation. The Cu+ species has been demonstrated to be the active component for the activation and conversion of CO2. The higher ratio of Cu+/(Cu0 + Cu+) and interaction between the metal and support deriving from copper phyllosilicate are mainly responsible for the high catalytic activity and excellent stability, respectively.

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The Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnIIITE-2-PyP5+ (AEOL-10113) has proven effective in treating oxidative stress-induced conditions including cancer, radiation damage, diabetes, and central nervous system trauma. The ortho cationic pyridyl nitrogens of MnTE-2-PyP5+ are essential for its high antioxidant potency. The exceptional ability of MnIIITE-2-PyP5+ to dismute O2.- parallels its ability to reduce ONOO- and CO3-. Decreasing levels of these species are considered its predominant mode of action, which may also involve redox regulation of signaling pathways. Recently, Ferrer-Sueta at al. (Free Radic. Biol. Med. 41:503-512; 2006) showed, with submitochondrial particles, that>or=3 microM MnIIITE-2-PyP5+ was able to protect components of the mitochondrial electron transport chain from peroxynitrite-mediated damage. Our study complements their data in showing, for the first time that micromolar mitochondrial concentrations of MnIIITE-2-PyP5+ are obtainable in vivo. For this study we have developed a new and sensitive method for MnIIITE-2-PyP5+ determination in tissues. The method is based on the exchange of porphyrin Mn2+ with Zn2+, followed by the HPLC/fluorescence detection of ZnIITE-2-PyP4+. At 4 and 7 h after a single 10 mg/kg intraperitoneal administration of MnIIITE-2-PyP5+, the mice (8 in total) were anesthetized and perfused with saline. Mitochondria were then isolated by the method of Mela and Seitz (Methods Enzymol.55:39-46; 1979). We found MnIIITE-2-PyP5+ localized in heart mitochondria to 2.95 ng/mg protein. Given the average value of mitochondrial volume of 0.6 microL/mg protein, the calculated MnIIITE-2-PyP5+ concentration is 5.1 microM, which is sufficient to protect mitochondria from oxidative damage. This study establishes, for the first time, that MnIIITE-2-PyP5+, a highly charged metalloporphyrin, is capable of entering mitochondria in vivo at levels sufficient to exert there its antioxidant action; such a result encourages its development as a prospective therapeutic agent.

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