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From: ironjustice on 10 Aug 2008 20:20 Radical-free biology of oxidative stress Dean P. Jones1* 1 Emory University * To whom correspondence should be addressed. E-mail: dpjones(a)emory.edu. Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease which can occur without free radicals. This hypothesis, which is termed the "redox hypothesis", is that oxidative stress occurs as a consequence of disruption of thiol redox circuits which normally function in cell signaling and physiologic regulation. The redox states of thiol systems are sensitive to 2-electron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH) and cysteine (Cys). Trx and GSH systems are maintained under stable but non-equilibrium conditions due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H- Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, NF-B), receptor activation (e.g., IIb3 integrin in platelet activation) and other processes. Non-radical oxidants, including peroxides, aldehydes, quinones and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the non-equilibrium conditions in the thiol pathways, aberrant generation of non-radical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease. Who loves ya. Tom Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh Man Is A Herbivore! http://tinyurl.com/4rq595 DEAD PEOPLE WALKING http://tinyurl.com/zk9fk
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