The p53-transcriptional target TP53INP1 is a potent stress-response protein promoting p53 activity. We previously showed that ectopic overexpression of TP53INP1 facilitates cell cycle arrest as well as cell death. Here we report a study investigating cell death in mice deficient for TP53INP1. Surprisingly, we found enhanced stress-induced apoptosis in TP53INP1-deficient cells. This observation is underpinned in different cell types in vivo (thymocytes) and in vitro (thymocytes and MEFs), following different types of injury inducing either p53-dependent or -independent cell death. Nevertheless, absence of TP53INP1 is unable to overcome impaired cell death of p53-deficient thymocytes. Stress-induced ROS production is enhanced in the absence of TP53INP1, and antioxidant NAC complementation abolishes increased sensitivity to apoptosis of TP53INP1-deficient cells. Furthermore, antioxidant defenses are defective in TP53INP1-deficient mice in correlation with ROS dysregulation. Finally, we show that autophagy is reduced in TP53INP1-deficient cells both at the basal level and upon stress. Altogether, these data show that impaired ROS regulation in TP53INP1-deficient cells is responsible for their sensitivity to induced apoptosis. In addition, they suggest that this sensitivity could rely on a defect of autophagy. Therefore, these data emphasize the role of TP53INP1 in protection against cell injury.

No abstract

There is increasing attraction of measuring pH in biological studies using nitroxides having pHdependent electron paramagnetic resonance (EPR) spectra. Aiming to improve the spectral sensitivity, a X , of these probes (i.e. the difference between limiting EPR hyperfine splittings (hfs) in their protonated and unprotonated forms), we present here a series of novel linear -carboxy, '-diethoxyphosphoryl nitroxides constructed on an amino acid core and featuring a ( or ')-C−H bond.In buffers the three main hfs (a N , a H and a P ) of their X-band EPR spectra vary reversibly with pH and, when it is inferred from a P or a H titration curves, a 2−4-fold increase in sensitivity is achieved vs reference imidazoline or imidazolidine nitroxides. Lead crystallized carboxylate 10b (pK a ≈ 3.6), which demonstrated low cytotoxicity and good resistance to bioreduction, was applied to probe the stomach acidity in rats. The results pave the way to a novel generation of highly sensitive EPR pH markers.

Dry sesamol emulsions were synthesized from several combinations of saccharose with hydroxypropylmethylcellulose (HPMC) or sodium caseinate (SC) using spray-drying techniques at 1201 to 1801C, or freeze-drying. On the basis of physical characteristics such as droplet size distribution, residual moisture, and microscopic structure, the best material was obtained when spray-drying was applied at either 1501 or 1801C with SC or HPMC as excipients, respectively. The extent to which the antioxidant properties of free sesamol towards a set of free radicals (galvinoxyl, diphenylpicrylhydrazyl, superoxide, and hydroxyl) were altered in the starting and reconstituted liquid emulsions submitted to normal storage or pre-exposed to a flux hydroxyl radicals was investigated. Emulsions were further evaluated for their antioxidant properties in cultured 3T3 murine fibroblasts and in an ex vivo model of ultraviolet irradiated rat skin. It was found that, in the material having the best physical properties, encapsulation was decisive in: (1) improving the overall antioxidant behavior of reconstituted versus starting liquid emulsions: (2) sparing sesamol consumption due to free radical attack; and (3) significantly protecting cells and skin against free radical-or irradiation-induced enzymatic release and/or lipid peroxidation. Demonstrating a high activity at high dilutions where interactions of excipient become negligible, the new emulsions could be of great interest in sesamol-based pharmacology or topical applications. Drug Dev Res 69: 251-266, 2008.

No abstract