What is oxidative stress?

Understanding Oxidative Stress

Oxidative stress is defined as an imbalance between reactive oxygen species (ROS) production and the body's ability to neutralize these reactive intermediates, leading to potential cellular and tissue damage. 1

Fundamental Concepts of Oxidative Stress

Definition and Mechanism

• Oxidative stress represents a deviation from redox homeostasis due to an imbalance between production and metabolism of reactive species 1
• This imbalance can lead to two main outcomes:
  • Oxidative macromolecule damage (lipids, proteins, DNA)
  • Altered redox signaling pathways 1

Sources of Reactive Oxygen Species

• Primary sources of ROS include:

  • Mitochondria (major source of intracellular ROS) 1
  • NADPH oxidase system in phagocytes 1
  • 5-lipoxygenase 1
  • Pro-oxidant enzymic systems 1

• During normal metabolism, free electrons in the mitochondrial electron transport chain may leak and react with molecular oxygen, generating superoxide anion (O₂⁻) 1

Key Reactive Species

• Superoxide anion (O₂⁻) - primary ROS produced by mitochondria
• Hydrogen peroxide (H₂O₂) - generated by superoxide dismutase (SOD)
• Hydroxyl radical - highly reactive species
• Peroxynitrite (ONOO⁻) - formed from nitric oxide and superoxide 1
• Nitric oxide (NO) - can act as both pro-oxidant and antioxidant depending on context 1

Physiological and Pathological Implications

Normal Physiological Roles

• ROS serve as important signaling molecules in various cellular processes 2
• They play roles in:
  • Cell signaling pathways
  • Inflammation and tissue repair
  • Defense mechanisms against pathogens 1

Pathological Effects

• When excessive, oxidative stress contributes to:
  • Cardiovascular diseases (atherosclerosis, hypertension)
  • Neurodegenerative disorders (Alzheimer's, Parkinson's)
  • Cancer
  • Diabetes
  • Inflammatory diseases 3, 4
  • Ischemic injury (stroke) 1

Molecular Damage

• Oxidative stress can cause:
  • Lipid peroxidation
  • Protein oxidation and misfolding
  • DNA damage
  • Mitochondrial dysfunction 1, 5
  • S-Nitrosylation of proteins, affecting their function 1

Antioxidant Defense Systems

Endogenous Antioxidants

• Enzymatic systems:

  • Superoxide dismutase (SOD)
  • Catalase
  • Glutathione peroxidase (GPX)
  • Thioredoxin system 1

• Non-enzymatic molecules:

  • Glutathione
  • Coenzyme Q
  • Bilirubin
  • Uric acid 6

Exogenous Antioxidants

• Dietary sources:
  • Vitamin C (ascorbic acid)
  • Vitamin E (tocopherols)
  • Polyphenols
  • Flavonoids 2

Clinical Relevance and Assessment

Measuring Oxidative Stress

• Direct measurement of ROS is challenging due to their short half-life
• Clinical assessment relies on biomarkers including:
  • Oxidized lipids (malondialdehyde, F2-isoprostanes)
  • Oxidized proteins (advanced oxidation protein products)
  • DNA oxidation products (8-hydroxy-2'-deoxyguanosine)
  • Antioxidant enzyme levels 1

Therapeutic Approaches

• Enhancing endogenous antioxidant systems may be more effective than direct ROS scavengers 3
• Targeted antioxidant therapies show promise for specific conditions 3
• Anti-inflammatory strategies may help reduce oxidative stress 3

Important Considerations

Balance is Critical

• Both excessive oxidative stress AND excessive antioxidant activity ("antioxidative stress") can be harmful 7
• Moderate levels of ROS are necessary for normal physiological functions 7

Therapeutic Challenges

• Despite theoretical benefits, many antioxidant interventions have shown limited clinical success 4, 5
• Context-specific approaches are needed rather than general antioxidant supplementation 3

Special Populations

• Dialysis patients may benefit from antioxidant supplementation to reduce oxidative stress markers 1, 3
• Patients with ischemic conditions experience increased oxidative stress during reperfusion 1

Understanding oxidative stress requires recognizing its dual nature—both as a normal physiological process necessary for cellular function and as a potential driver of pathology when dysregulated.