Reactive oxygen species (ROS), which include superoxide, nitric oxide, hydroxyl radicals, nitrogen dioxide and peroxynitrite, play a crucial role in vital processes such as blood pressure regulation, cell migration, neurotransmission, immune regulation, microorganism defense and smooth muscle relaxation . Under normal conditions in healthy systems, ROS are regulated by enzymes including superoxide dismutase (SOD) and catalase, as well as by small molecule natural antioxidants such as glutathione, ascorbic acid, coenzyme Q10, vitamin A and vitamin E. The overproduction of ROS leads to a condition known as oxidative stress, and at elevated concentrations, ROS readily cause oxidative damage to biomolecules including DNA, lipids, proteins and enzymes. Extreme levels of oxidative stress lead to extensive cellular damage, and these elevated levels of ROS often accompany acute injuries such as traumatic brain injury, inflammatory response and stroke as well as chronic diseases including cancer, cardiovascular dysfunction, rheumatoid arthritis, Parkinson’s disease and Alzheimer’s disease . While natural antioxidants can regulate and alleviate oxidative stress to some degree, they have little effect on extremely elevated ROS levels, and this is due to their specific mechanisms of action. Many naturally occurring antioxidants and antioxidant enzymes act through chain reactions of radical transfers, often requiring cofactors, or need to act in concert with other antioxidants to be effective. For example, SOD converts two molecules of superoxide into oxygen and hydrogen peroxide, but it requires the presence of another enzyme, catalase, to complete the catalytic cycle. Additionally, as with SOD, many natural antioxidants can only quench one or two reactive species per molecule before requiring regeneration. Thus, these natural antioxidants can be easily overwhelmed by the highly elevated levels of ROS during disease or traumatic injury, and the effects are exacerbated when the trauma is accompanied by hemorrhagic shock. Overall, these limitations of natural antioxidants explain why most studies of antioxidant therapies in a clinical setting show little to no benefit in disease or injury treatment . The benefit there is from antioxidant therapy is mostly apparent in models where the antioxidant is administered before the injury takes place, and few have been shown to have any significant affect postinjury. There is therefore a distinct need to develop synthetic antioxidant treatments that renormalize elevated levels of oxidative stress, and especially therapies that can be administered after an injury has taken place.
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