Abstract
Oxidative cellular damage caused by free radicals is known to contribute to the pathogenesis of various diseases such as cancer, diabetes, and neurodegenerative diseases, as well as to aging. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein1 (Keap1) signaling pathways play an important role in preventing stresses including oxidative and inflammatory stresses. Nrf2 is a master regulator of cellular stress responses, induces the expression of antioxidant and detoxification enzymes, and protects against oxidative stress-induced cell damage. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which was originally found to increase insulin synthesis and secretion. It is now widely accepted that GLP-1 has multiple functions beyond glucose control in various tissues and organs including brain, kidney, and heart. GLP-1 and GLP-1 receptor agonists are known to be effective in many chronic diseases, including diabetes, via antioxidative mechanisms. In this review, we summarize the current knowledge regarding the role of GLP-1 in the protection against oxidative damage and the activation of the Nrf2 signaling pathway.
Highlights
Reactive oxygen species (ROS) and free radicals contribute to oxidative stress in healthy cells by damaging DNA, RNA, proteins, and lipids
Glucagon-like peptide-1 (GLP-1)-induced insulin secretion is mainly regulated by cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) and exchange proteins activated by cAMP (Epac)2 signaling pathways [59]
The anti-apoptotic effects of GLP-1 are mediated by increasing the anti-apoptotic proteins Bcl-2 and Bcl-xl and decreasing active caspase-3 [72] through cAMP and activation of phosphatidylinositide 3-kinase (PI3K), PKB, and epidermal growth factor receptor (EGFR)–PI3K signaling pathways [73,74,75]
Summary
Reactive oxygen species (ROS) and free radicals contribute to oxidative stress in healthy cells by damaging DNA, RNA, proteins, and lipids. Nrf2–ARE binding regulates the expression of genes involved in cellular antioxidant and anti-inflammatory responses such as superoxide dismutase, catalase, glutathione peroxidases, thioredoxin, thioredoxin reductase, sulfiredoxin, NADPH:quinone oxidoreductase-1, heme oxygenase-1, glutathione reductase, glutaredoxin, glutamate cysteine ligase, glutathione S-transferase, UDP-glucuronyl transferase, peroxiredoxin sulfotransferase, and γ-glutamate cysteine ligase catalytic subunit [45] (Figure 1). In addition to their location in the cytoskeleton, Nrf and Keap have been detected at the outer mitochondrial membrane, binding to mitochondrial phosphatase phosphoglycerate mutase (PGAM) family member 5 [46] and affecting mitochondrial function. GLP-1R is widely expressed in various tissues including pancreatic islets, pancreatic ducts, kidney, lung, heart, skin, immune cells, and the central and peripheral nervous systems, hypothalamus, hippocampus, and the cortex [58]
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