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Aging and disease    2019, Vol. 10 Issue (3) : 637-651     DOI: 10.14336/AD.2018.0513
Review |
The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases
Wenjun Tu1,2,3, Hong Wang4, Song Li1, Qiang Liu1,*, Hong Sha4,*
1Institute of Radiation Medicine, China Academy of Medical Science & Peking Union Medical College, Tianjin, China
2Department of Neurosurgery, Beijing Tiantan Hospital of Capital Medical University, Beijing, China
3Center for Translational Medicine, Institutes of Stroke, Weifang Medical University, Weifang, China
4Institute of Biomedical Engineering, China Academy of Medical Science & Peking Union Medical College, Tianjin, China
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Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites or [reactive oxygen species (ROS)] and their elimination by through protective mechanisms, including (antioxidants). This Such imbalance leads to damage of cells and important biomolecules and cells, with hence posing a potential adverse impact on the whole organism. At the center of the day-to-day biological response to oxidative stress is the Kelch-like ECH-associated protein 1 (Keap1) - nuclear factor erythroid 2-related factor 2 (Nrf2)- antioxidant response elements (ARE) pathway, which regulates the transcription of many several antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in the maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and pro-apoptotic conditions, which allows us to consider it as a pharmacological target. Herein, we review and discuss the recent advancements in the regulation of the Keap1/Nrf2/ARE system, and its role under physiological and pathophysiological conditions, e.g. such as in exercise, diabetes, cardiovascular diseases, cancer, neurodegenerative disorders, stroke, liver and kidney system, etc. and such.

Keywords Oxidative stress      Reactive oxygen species      Keap1/Nrf2/ARE      Anti-inflammatory      Anti-oxidant      Low-level laser irradiation     
Corresponding Authors: Liu Qiang,Sha Hong   
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These authors contributed equally to this study.

Issue Date: 02 April 2018
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Wenjun Tu
Hong Wang
Song Li
Qiang Liu
Hong Sha
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Wenjun Tu,Hong Wang,Song Li, et al. The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases[J]. Aging and disease, 2019, 10(3): 637-651.
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Figure 1.  Domain structures of Keap1

Keap1 consists of three major functional domains: the BTB, IVR, and the Kelch/β-propeller domains.

Figure 2.  Domain structures of Nrf2

The Nrf2 protein contains7 domains, Neh1-Neh7. The ETGE and DLG motifs in the Neh2 domain are essential for the direct interaction with the Kelch domain of Keap1.

Figure 3.  The Keap1-Nrf2-ARE pathway. Under physiological conditions, Nrf2 is restricted in the cytoplasm via its association with Keap1-Cul3-Rbx1 complex. In response to oxidative stress, Nrf2 is released from Keap1 translocates to the nucleus and heterodimerizes with one of the small Maf (musculoaponeurotic fibrosarcoma oncogene homolog) proteins. This complex activates the ARE-dependent gene expression of a series of antioxidative and cytoprotective proteins.
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