Antioxidant activity and the role of gene and protein expression in oxidative stress

At the level of cellular signaling pathways that regulate homeostasis and a healthy phenotype, antioxidants function in maintaining normal cell physiology. Perturbation of these pathways involving antioxidants also leads to pathological states. Normal cell physiology and pathophysiological states can manifest through antioxidant activity affecting gene and protein expression. Reactive oxygen species have both primary metabolic functions and also act as secondary messengers in critical cellular pathways that react to and modulate oxidative stress and invoke antioxidant defense mechanisms. Activation of key transcription factors, notably nuclear factor-E2-related factor 2 (Nrf2), invokes activation of antioxidant response elements leading to changes in gene expression across a range of functions. Multiple kinases (key regulators at the protein level) including mitogen-activated protein kinases (MAPK), protein kinase B (Akt), and phosphoinositol-3-kinase (PI3K) are involved in multiple pathways regulating the cellular redox state. Thioredoxins, peroxiredoxins and glutaredoxins are also key regulators in these pathways. Disease states generated through dysregulation of redox homeostasis particularly impact the central nervous system, the cardiovascular system, the respiratory system, bone and integument and are implicated in some cancers and in diabetes mellitus. Novel drugs across a range of molecular classes with high efficacy in correcting imbalances in gene expression and protein regulation have recently been developed. Both natural and synthetic compounds feature as novel and potential therapeutics. Better understanding of the regulation of key gene and protein expression pathways is contributing to strategies for treatment of pathologies resulting from dysregulation of antioxidants at cellular and molecular levels.