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Targeting oxidative stress in disease: promise and limitations of antioxidant therapy.
Literature Information
| DOI | 10.1038/s41573-021-00233-1 |
|---|---|
| PMID | 34194012 |
| Journal | Nature reviews. Drug discovery |
| Impact Factor | 101.8 |
| JCR Quartile | Q1 |
| Publication Year | 2021 |
| Times Cited | 1004 |
| Keywords | oxidative stress, antioxidant therapy, disease mechanisms, pharmacological success |
| Literature Type | Journal Article, Research Support, N.I.H., Extramural, Review |
| ISSN | 1474-1776 |
| Pages | 689-709 |
| Issue | 20(9) |
| Authors | Henry Jay Forman, Hongqiao Zhang |
TL;DR
This review explores the complex interplay between oxidative stress, redox signaling, and various diseases, highlighting the mechanisms by which oxidative stress contributes to pathology and the limitations of current antioxidant therapies. By understanding these relationships and how to enhance antioxidant defenses through physiological signaling and dietary or pharmaceutical interventions, the study aims to inform more effective therapeutic strategies for diseases linked to oxidative stress.
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oxidative stress · antioxidant therapy · disease mechanisms · pharmacological success
Abstract
Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success. Here, we review the relationships between oxidative stress, redox signalling and disease, the mechanisms through which oxidative stress can contribute to pathology, how antioxidant defences work, what limits their effectiveness and how antioxidant defences can be increased through physiological signalling, dietary components and potential pharmaceutical intervention.
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Primary Questions Addressed
- What specific mechanisms of oxidative stress contribute to the pathology of diseases like Alzheimer’s and cancer?
- How do dietary components influence the effectiveness of antioxidant therapy in managing oxidative stress?
- What are the potential pharmaceutical interventions that could enhance antioxidant defenses beyond current therapies?
- In what ways can redox signaling pathways be manipulated to improve therapeutic outcomes in oxidative stress-related diseases?
- What lessons can be learned from the disappointing clinical trial results of antioxidant therapies that could inform future research?
Key Findings
Research Background and Purpose
Oxidative stress is implicated in various diseases, including atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer's disease, and cancer. Despite the promising results of antioxidant therapies in preclinical studies, clinical trials have often yielded disappointing outcomes. This review aims to elucidate the mechanisms by which oxidative stress contributes to disease pathology, the functioning of antioxidant defenses, and the limitations of current antioxidant therapies, while proposing rational approaches for future interventions.
Main Methods/Materials/Experimental Design
The review employs a comprehensive literature analysis of oxidative stress, redox signaling, and antioxidant defenses. It discusses the biochemical mechanisms of oxidative stress and how antioxidants function, as well as the physiological signaling pathways that can enhance antioxidant defenses.
Key Results and Findings
Oxidative Stress and Disease: The review highlights two primary mechanisms of oxidative stress:
- Direct oxidation of macromolecules (e.g., lipids, proteins, DNA) by reactive species such as hydroxyl radicals and peroxynitrite.
- Aberrant redox signaling, where excessive ROS disrupts normal signaling pathways, leading to inflammation and cell death.
Antioxidant Defense Mechanisms: The body employs various strategies to combat oxidative stress, primarily through enzymatic actions (e.g., SOD, GPX) and non-enzymatic antioxidants (e.g., vitamins C and E). However, many small molecule antioxidants have limited effectiveness in vivo due to their inability to effectively scavenge ROS within cells.
Clinical Trials and Antioxidant Therapies: Several clinical trials are currently investigating novel antioxidant therapies, including ebselen (a GPX mimic) and GC4419 (an SOD mimic), showing varying degrees of success.
Main Conclusions/Significance/Innovation
The review emphasizes the complexity of oxidative stress and its dual role in physiology and pathology. It advocates for a shift in the approach to antioxidant therapy, focusing on enhancing the body's endogenous antioxidant defenses rather than relying solely on exogenous antioxidants. The authors suggest that understanding the timing and location of oxidative stress can improve therapeutic outcomes.
Research Limitations and Future Directions
- Limitations: The review notes that many antioxidant therapies have failed due to misconceptions about how antioxidants work, particularly the assumption that scavenging ROS is a viable strategy.
- Future Directions: There is a need for targeted therapies that enhance the body's own antioxidant defenses, such as through the activation of NRF2 signaling pathways, which regulate the expression of various antioxidant genes. The potential of dietary antioxidants and pharmacological agents that induce NRF2 should be further explored.
| Aspect | Current Understanding | Future Directions |
|---|---|---|
| Mechanisms of Oxidative Stress | Involves direct damage to macromolecules and aberrant signaling | Targeting specific pathways to enhance antioxidant defenses |
| Antioxidant Therapies | Limited effectiveness of small molecules in clinical trials | Focus on enhancing endogenous defenses and NRF2 activation |
| Clinical Trial Outcomes | Mixed results, often disappointing | Investigate novel compounds and combinations for efficacy |
In summary, the review underscores the importance of a nuanced understanding of oxidative stress and advocates for innovative approaches in antioxidant therapy to address the challenges faced in clinical settings.
References
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- Serum Bilirubin Levels and Extent of Symptomatic Intracranial Atherosclerotic Stenosis in Acute Ischemic Stroke: A Cross-Sectional Study. - Fang Yu;Lin Zhang;Di Liao;Yunfang Luo;Xianjing Feng;Zeyu Liu;Jian Xia - Frontiers in neurology (2021)
- Mitochondria: Endosymbiont bacteria DNA sequence as a target against cancer. - Hiroki Nagase;Takayoshi Watanabe;Nobuko Koshikawa;Seigi Yamamoto;Keizo Takenaga;Jason Lin - Cancer science (2021)
- Neurotherapeutic Potential of Cervus elaphus Sibericus on Axon Regeneration and Growth Cone Reformation after H2O2-Induced Injury in Rat Primary Cortical Neurons. - Jin Young Hong;Junseon Lee;Hyunseong Kim;Wan-Jin Jeon;Changhwan Yeo;Bo Ram Choi;Jee Eun Yoon;Ji Yun Shin;Jeom-Yong Kim;In-Hyuk Ha - Biology (2021)
- Antioxidants Threaten Multikinase Inhibitor Efficacy against Liver Cancer by Blocking Mitochondrial Reactive Oxygen Species. - Blanca Cucarull;Anna Tutusaus;Tania Hernáez-Alsina;Pablo García de Frutos;María Reig;Anna Colell;Montserrat Marí;Albert Morales - Antioxidants (Basel, Switzerland) (2021)
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- Current Status and Future Perspectives on Therapeutic Potential of Apigenin: Focus on Metabolic-Syndrome-Dependent Organ Dysfunction. - Waqas Alam;Carmine Rocca;Haroon Khan;Yaseen Hussain;Michael Aschner;Anna De Bartolo;Nicola Amodio;Tommaso Angelone;Wai San Cheang - Antioxidants (Basel, Switzerland) (2021)
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- Cytotoxicity and Mitochondrial Effects of Phenolic and Quinone-Based Mitochondria-Targeted and Untargeted Antioxidants on Human Neuronal and Hepatic Cell Lines: A Comparative Analysis. - Carlos Fernandes;Afonso J C Videira;Caroline D Veloso;Sofia Benfeito;Pedro Soares;João D Martins;Beatriz Gonçalves;José F S Duarte;António M S Santos;Paulo J Oliveira;Fernanda Borges;José Teixeira;Filomena S G Silva - Biomolecules (2021)
... (994 more literatures)
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