Oxidative Stress and Its Role in Human Disease: Molecular Mechanisms, Biochemical Biomarkers, and Therapeutic Perspectives; as Review Article

Abstract

Oxidative stress is a dynamic imbalance in cellular redox homeostasis caused by an excess production, accumulation and/or localization of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) relative to the ability of antioxidant, repair and adaptive systems. At low to moderate concentrations, ROS and RNS are not themselves toxic; they play a role in several signaling, host defense, metabolic, vascular regulatory, and adaptation processes. However, pathological redox imbalance can lead to lipid peroxidation, protein oxidation, damage of nucleic acids, mitochondrial dysfunction, inflammation, changes in cell signaling, senescence and regulated cell death. This review summarizes the most recent research regarding biochemical sources of ROS/RNS, antioxidant defense, glutathione and thiol redox regulation, KEAP1-NRF2 signaling, oxidation of lipids, proteins and DNA, mitochondrial dysfunction, ferroptosis and how redox imbalance contributes to diabetes, cardiovascular, neurodegenerative, hepatic, renal, inflammatory and malignant diseases. Special attention is paid to oxidative stress biomarkers and their analytical shortcomings, and the fact that none of the biomarkers is sufficient to reflect the multidimensional redox state. Current therapeutic strategies such as dietary and pharmacological antioxidants, NRF2 modulation, glutathione directed therapies, mitochondria targeted antioxidants and selective modulation of ROS producing enzymes are critically discussed. The review concludes that future redox medicine should focus on restoration of redox homeostasis in a compartment specific fashion, as opposed to the elimination of reactive species in a non-specific manner, using biomolecules as indicators.