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Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases
Ana I Rojo1, Brigitta Buttari2, Susana Cadenas3
1Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain.
Abstract:
Non-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE). The products of these genes participate in numerous functions including biotransformation and redox homeostasis, lipid and iron metabolism, inflammation, proteostasis, as well as mitochondrial dynamics and energetics. Thus, it is possible that a single pharmacological NRF2 modulator might mitigate the effect of the main hallmarks of NCDs, including oxidative, proteostatic, inflammatory and/or metabolic stress. Research on model organisms has provided tremendous knowledge of the molecular mechanisms by which NRF2 affects NCDs pathogenesis. This review is a comprehensive summary of the most commonly used model organisms of NCDs in which NRF2 has been genetically or pharmacologically modulated, paving the way for drug development to combat NCDs. We discuss the validity and use of these models and identify future challenges.
Insights
Nuclear factor erythroid 2-like 2 (NRF2) is a key regulator of cellular defense against non-communicable chronic diseases (NCDs). Modulating NRF2 in model organisms offers a promising therapeutic strategy for combating NCDs by targeting oxidative and inflammatory stress.
Area of Science:
- Molecular Biology
- Genetics
- Pharmacology
Background:
- Non-communicable chronic diseases (NCDs) involve age-related decline in homeostasis and environmental factors causing oxidative stress, inflammation, and metabolic imbalance.
- Nuclear factor erythroid 2-like 2 (NRF2) is a transcription factor critical for maintaining cellular redox homeostasis.
- NRF2 regulates over 250 genes involved in detoxification, metabolism, inflammation, and mitochondrial function via the antioxidant response element (ARE).
Purpose of the Study:
- To review model organisms used to study the role of NRF2 in NCD pathogenesis.
- To explore the potential of NRF2 modulators as a unified therapeutic approach for NCDs.
- To discuss the utility and challenges of NRF2-focused NCD models in drug development.
Main Methods:
- Comprehensive literature review of studies involving genetic or pharmacological modulation of NRF2 in NCD model organisms.
- Analysis of NRF2's impact on key NCD hallmarks: oxidative stress, inflammation, proteostasis, and metabolic imbalance.
- Evaluation of the translational relevance of findings from model organisms to human NCDs.
Main Results:
- NRF2 plays a central role in cellular defense mechanisms against various NCD-related stresses.
- Genetic and pharmacological manipulation of NRF2 in model organisms demonstrates its potential to mitigate NCD pathologies.
- Model organisms provide valuable insights into the molecular pathways affected by NRF2 in NCDs.
Conclusions:
- Targeting NRF2 represents a potential single-agent strategy to address multiple hallmarks of NCDs.
- Model organisms are essential tools for understanding NRF2's role in NCDs and for developing novel therapeutics.
- Further research is needed to overcome challenges in translating NRF2-based therapies from models to clinical practice for NCDs.
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