Targeting tissue oxidative damage by means of cell signaling modulators: The antioxidant concept revisited. Pharmacol Ther.

The complex system of molecular communications underlying cell biochemistry and function includes numerous components, kinases, phosphatases and transcription factors, that have been conclusively proven to be sensitive to cellular and tissue redox changes. Reactive oxygen species (ROS), whose constitutive generation in cells and tissues is amplified under pro-oxidant conditions, are now unanimously recognized to be important triggers and modulators of cell signaling, and consequently of cell behavior. This review considers the major signaling pathways that mediate gene regulation in response to ROS, and analyzes their modulation by the most important non-enzymatic molecules having an antioxidant effect. Because of the primary role played by ROS-mediated signaling and gene expression in pathophysiology, the so-called “antioxidant compounds” may significantly interfere with cell signal transduction, not simply by quenching ROS generation and propagation but also by intercepting reactive species at the level of critical signaling pathways. Notably, a third mechanism of action has recently emerged that is independent of antioxidant properties, i.e. direct chemical interaction of the “antioxidant” with signaling enzymes and transcription factors. However, severe inhibition of ROS production might interfere with certain physiological cellular and organ functions, and would thus eventually be detrimental rather than beneficial. To address the need for appropriate administration of non-enzymatic antioxidants, the most advanced technologies for their targeted delivery are analyzed and reported.