Abstract
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.
Highlights
Oxidative stress, as a concept in redox biology and medicine, has been formulated in 1985 [1]
Oxidative stress had been proposed to be involved in the pathogenesis of play role in many other diseases, such as cancer [7], neurological, and pulmonary diseases, age-related macular degeneration [13], systolic and diastolic heart failure [14], Alzheimer's disease (AD) [15], Parkinson's disease (PD) and amyotrophic lateral sclerosis [16], neurodegenerative diseases [17], microvascular and macrovascular complications in diabetic patients with diabetes [18], and cardiovascular events in patients with chronic kidney disease (CKD) [19]
The Kelch‐like ECH‐associated protein 1 (Keap1)/nuclear factor erythroid 2‐related factor 2 (Nrf2)/antioxidant response elements (ARE) pathway plays a major role in health resilience including inflammatory diseases [65], neurodegenerative diseases [66], PD [67], AD [68], stroke [69], chronic kidney disease [70], atherosclerosis [71], diabetes [72], cardiovascular diseases [73] and rheumatoid arthritis [74]
Summary
As a concept in redox biology and medicine, has been formulated in 1985 [1]. Oxidative stress can activate a variety of transcription factors including nuclear factor kappa light chain enhancer of activated B cells (NF-κB), AP1activator protein 1, p53, HIF-hypoxia-inducible factor 1α, peroxisome proliferator-activated receptor γ (PPAR-γ), β-catenin/Wnt, and Nrf2 Activation of these transcription factors can lead to the expression of over 500 different genes. 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 numerous antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. Nrf can evade Keap1-mediated degradation, translocate to the nucleus, and activate ARE-dependent gene expression of a series of antioxidative and cytoprotective proteins including heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase, quinone 1 (NQO1), c-glutamylcysteine synthetase, glutathione peroxidase 1, glutathionine Stransferase (GST), glutathione reductase (GR), and superoxide dismutase (SOD) [43]. The Keap1/Nrf2/ARE pathway plays a major role in health resilience including inflammatory diseases [65], neurodegenerative diseases [66], PD [67], AD [68], stroke [69], chronic kidney disease [70], atherosclerosis [71], diabetes [72], cardiovascular diseases [73] and rheumatoid arthritis [74]
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