Biochemical basis and metabolic interplay of redox regulation

Abstract

Accumulated evidence strongly indicates that oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidants in favor of oxidants, plays an important role in disease pathogenesis. However, ROS can act as signaling molecules and fulfill essential physiological functions at basal levels. Each ROS would be different in the extent to stimulate and contribute to different pathophysiological effects. Importantly, multiple ROS generators can be activated either concomitantly or sequentially by relevant signaling molecules for redox biological functions. Here, we summarized the current knowledge related to chemical and biochemical features of primary ROS species and corresponding antioxidants. Metabolic pathways of five major ROS generators and five ROS clearance systems were described, including their ROS products, specific ROS enriched tissue, cell and organelle, and relevant functional implications. We provided an overview of ROS generation and induction at different levels of metabolism. We classified 11 ROS species into three types based on their reactivity and target selectivity and presented ROS homeostasis and functional implications in pathological and physiological status. This article intensively reviewed and refined biochemical basis, metabolic signaling and regulation, functional insights, and provided guidance for the identification of novel therapeutic targets.

Role of Oxidative Stress in Hepatic and Extrahepatic Dysfunctions during Nonalcoholic Fatty Liver Disease (NAFLD)

“…In the organism, cells regularly and continuously produce reactive species, such as ROS and reactive nitrogen species (RNS). ROS and RNS are closely related to each other; so typically, the term ROS is used to represent both oxidant species [ 16 ]. ROS is fundamental for the normal function of the immune response, metabolism, and cellular proliferation and differentiation at a low amount.…”

“…ROS is fundamental for the normal function of the immune response, metabolism, and cellular proliferation and differentiation at a low amount. ROS act as signaling molecules to modulate several cell functions in diverse cell types [ 16 , 17 ]. ROS production involves enzymatic and nonenzymatic reactions in the cytoplasm, cell membrane, ER, mitochondria, and peroxisome or through enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), xanthine oxidase (XO), cytochrome P450 2E1, cyclooxygenases, and lipoxygenases [ 16 , 18 ].…”

“…Among free radicals are superoxide anion (O 2 · − ), hydroxyl radical, nitric oxide (NO)-, nitrogen dioxide radical, carbonate radical anion, and alkoxyl/alkyl peroxyl. Among the main nonradical species are hydrogen peroxide, hypochlorous acid, and peroxynitrite/peroxynitrous acid [ 16 , 19 , 20 ].…”

“…A balance between ROS and antioxidant systems is critical to ensure proper cell function [ 16 , 20 , 21 ]. There are enzymatic and nonenzymatic antioxidant systems.…”

“…Among the enzymatic systems are superoxide dismutase 1-3 (SOD), catalase (CAT), glutathione peroxidase 1-8 (GPX), and peroxiredoxin 1-6. Among the nonenzymatic molecules are glutathione (GSH), thioredoxin (TRX), uric acid, vitamins E and C, and bilirubin [ 16 ]. In normal conditions, antioxidant systems avoid cellular damage by neutralizing oxidative species [ 22 , 23 ].…”