Oxidative Stress in Health and Disease

Abstract

Oxidative stress, resulting from the excessive intracellular accumulation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other free radical species, contributes to the onset and progression of various diseases, including diabetes, obesity, diabetic nephropathy, diabetic neuropathy, and neurological diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Oxidative stress is also implicated in cardiovascular disease and cancer. Exacerbated oxidative stress leads to the accelerated formation of advanced glycation end products (AGEs), a complex mixture of crosslinked proteins and protein modifications. Relatively high levels of AGEs are generated in diabetes, obesity, AD, and other I neurological diseases. AGEs such as N^e-carboxymethyllysine (CML) serve as markers for disease progression. AGEs, through interaction with receptors for advanced glycation end products (RAGE), initiate a cascade of deleterious signaling events to form inflammatory cytokines, and thereby further exacerbate oxidative stress in a vicious cycle. AGE inhibitors, AGE breakers, and RAGE inhibitors are therefore potential therapeutic agents for multiple diseases, including diabetes and AD. The complexity of the AGEs and the lack of well-established mechanisms for AGE formation are largely responsible for the lack of effective therapeutics targeting oxidative stress and AGE-related diseases. This review addresses the role of oxidative stress in the pathogenesis of AGE-related chronic diseases, including diabetes and neurological disorders, and recent progress in the development of therapeutics based on antioxidants, AGE breakers and RAGE inhibitors. Furthermore, this review outlines therapeutic strategies based on single-atom nanozymes that attenuate oxidative stress through the sequestering of reactive oxygen species (ROS) and reactive nitrogen species (RNS).

Keywords: 4-hydroxy-trans-2-nonenal (HNE); Alzheimer’s disease; diabetes; lipid peroxidation; nanozymes; oxidative stress; reactive nitrogen species; reactive oxygen species; receptors for advanced glycation end products (RAGE).

Figure 1

Single-atom Mn catalyst embedded in a Ag₂Te near-infrared probe for the sequestration of intracellular ROS; the redox-active Mn^2+/3+, through a single-electron transfer to a hydroxyl radical and superoxide radical anion, forms the non-harmful hydroxide anion and dioxygen, respectively.

Figure 2

Lipoic-acid-based polymer and proposed mechanism for the sequestration of ROS and lipid peroxidation products; such multi-target-based therapeutics candidates, when conjugated to imaging agents, could serve as theranostics for treating TBI.

Figure 3

Intracellular formation of ROS (superoxide radical anion and hydroxyl radical); a superoxide radical anion (O₂·⁻) is formed from molecular oxygen either through an Fe(II)-catalyzed Fenton reaction or through an enzyme-catalyzed single electron transfer from NADPH (or NADH). The Fenton reaction of O₂·⁻ forms the highly reactive hydroxyl radial (HO·) through the intermediate formation of H₂O₂, which is also classified as a ROS.

Figure 4

Formation of an MDA adduct from deoxyguanosine; MDA is used as a marker of oxidative stress and lipid peroxidation.

Figure 5

Sequestration of HNE by phloretin, a polyphenolic antioxidant found in apples; other naturally occurring polyphenolic compounds, such as resveratrol, also sequester HNE and other lipid peroxidation products, such as acrolein and MDA.

Figure 6

Cellular toxicity of HNE through protein and DNA modifications and sequestration of HNE by glutathione and N-acetylcysteine; HNE and its DNA-based adducts are also used as biomarkers for monitoring the progression of human cancers.

Figure 7

Structure of 8-hydroxy-2′deoxyguanosine (8-oxo-dG); 8-oxo-dG serves as a marker for oxidative stress and DNA damage.

Figure 8

Reactive nitrogen species and their effect on protein modifications; nitric oxide exists as a radical species and acts as a signaling molecule in various physiological processes.

Figure 9

Schematic representation of AGE formation through nonenzymatic glycation and glycoxidation; oxidative stress contributes to the glycoxidation reactions of the Schiff base adducts of reducing sugars and protein amino groups, forming AGE-crosslinked proteins and AGE-protein modifications.

Figure 10

Structure of alagebrium (ALT-711), an AGE-crosslink breaker; clinical trials of this drug candidate were terminated due to its adverse effects.

Figure 11

Structure of the RAGE inhibitors FPS-ZM 1 and azeliragon; clinical trials of such RAGE inhibitors are ongoing to treat various diseases, including cancers.