Nrf2 Signaling Coordinates Oxidative Stress Induced Activation of Antioxidant Enzyme Genes

Oxidative stress plays an important role in the pathophysiology of various age-related diseases and skin aging. Supraphysiological levels of reactive oxygen species (ROS)—such as hydrogen peroxide, superoxide anions, and hydroxyl radicals—severely damage proteins, DNA, and lipids, which results in further tissue damage and organ dysfunction. Environmental stressors (e.g. UV radiation and chronic inflammation) can create and induce excess ROS or free radicals that result in accelerated aging including skin aging. The first line of defense mechanism against excess ROS in the body’s ability to activate and produce natural antioxidant systems within in response to the increased ROS level. There are basically two categories of natural antioxidant system produced in the body for neutralizing ROS: a network of protective enzymatic antioxidants such as glutathione peroxidase, superoxide dismutase, and catalase, and nonenzymatic low-molecular-weight antioxidants such as vitamin E isoforms, vitamin C, glutathione (GSH). Increased amount of ROS upon environmental stimuli will trigger cascade of signal transduction pathways – the result of which is the activation of the genes encoding the antioxidant enzymes. Once the ROS are removed by antioxidant enzymes and ROS level return to physiological level, a negative loop mechanism is activated to turn off the antioxidant enzyme genes.

Nrf-2 signaling pathway is a major mechanism in the cellular defense against oxidative stress. NF-E2-related nuclear factors (Nrf1 and Nrf2) are transcription factors which can bind to a unique DNA sequence in the promoter regions of the antioxidant enzyme genes. This DNA sequence is known as “antioxidant response element”. Transcription of these enzymes is coordinately regulated through antioxidant response elements (AREs). Antioxidant response element (ARE)-mediated induction of antioxidant enzymes is a critical mechanism of protection against chemically induced oxidative stress. Nrf2 is more potent than Nrf1 in activation of ARE-regulated gene activation. Inactive Nrf2 is retained in the cytoplasm by forming the complex to INrf2 (inhibitor of Nrf2) and/or Keap1 . Protein kinase C activation and Map kinase signal transduction routes are involved and activated in Nrf-2 mediated signaling. An increase in oxidative stress leads to the activation of protein kinase C (PKC) and other cytosolic factors. PKC phosphorylation of Nrf2 results in release of Nrf2 from INrf2 and is activated. The activated Nrf2 translocates to the nucleus, forms heterodimers with other proteins, and binds to the ARE. In the nucleus, Nrf2 bind to AREs by interacting with transcription factors in the bZIP family, including CREB, ATF4 and fos or jun. This leads to the coordinated activation of ARE-regulated genes.

Additional nuclear factor including small Mafs (MafG and MafK), large Maf (c-Maf), c-Fos, and Fra1, also bind to ARE and negatively regulate ARE-mediated gene expression. This is the negative loop mechanism for turning off the genes when intracellular ROS is removed and decreased, maintaining a counterbalance to Nrf2 and balancing the oxidation level of the intracellular environment. This is to keep the amount and activities of antioxidant enzymes in check to maintain the cellular defenses active and/or to rapidly restore induced enzymes to normal levels.

There are wide varieties of antioxidant enzymes regulated and activated via Nrf2 signaling. These include, but are not limited to, the following: glutathione transferases, quinone reductase, epoxide hydrolase, heme oxygenase, UDP-glucuronosyl transferases, and gamma-glutamylcysteine synthetase. Oxidative stress is one of the main causes of skin aging as well. There are products on the market that contain ingredients whose activity is targeting the activity of Nrf2. Protandim is one of them which activates Nrf2 and thereby activates the body’s antioxidant enzymes to help protect against oxidative stress. Protandim is clinically proven to reduce oxidative stress in vivo.

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