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Micronutrients in the Prevention and Improvement of the Standard Therapy for Alzheimer’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Normally, ROS is needed to activate Nrf2 which then dissociates itself from Keap1-CuI-Rbx1 complex and translocates in the nucleus where it heterodimerizes with a small Maf protein, binds with ARE, leading to increased expression of target genes coding for several cytoprotective enzymes including antioxidant enzymes.333–335
Basal Redox Status Influences the Adaptive Redox Response to Regular Exercise
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Ethan L. Ostrom, Tinna Traustadóttir
Nrf2 is an inducible redox stress response transcription factor activated by increases in environmental or endogenous oxidative species (Tebay et al., 2015). Figure 6.2 shows a general schematic of the Nrf2 signaling pathway. Under unstressed conditions, Nrf2 is bound by its negative regulator Keap1, which targets Nrf2 for degradation via the 26S proteasome. Nrf2 would be expected to be lowly expressed under those conditions because the majority will be degraded by the proteasome. During an oxidative stress stimulus, solvent-exposed protein thiols on the backbone of Keap1 become oxidized, impairing Keap1’s ability to target Nrf2 for degradation (Fourquet et al., 2010; Eggler et al., 2009; Hu et al., 2011; Zhang and Hannink, 2003). This allows Nrf2 to accumulate in the nucleus, where it heterodimerizes with small Maf proteins, binds to the antioxidant response element (ARE), and increases gene expression responsible for increasing metabolic and redox stress capacity. To our knowledge, direct oxidation of Keap1 in response to acute exercise has not been experimentally verified. However, Nrf2 activation occurs in a duration- and intensity-dependent manner which is associated with the accumulation of reactive species generation (Wang et al., 2015; Li et al., 2015), suggesting that Keap1 is likely oxidatively modified and degraded in response to exercise. Indeed, we have recently found Keap1 to be degraded in an intensity-dependent manner in response to muscle stimulation in mice (Ostrom et al., 2021). In addition, another study demonstrated decreased Keap1 in human skeletal muscle in response to a maximal exercise test, with a concomitant increase in Nrf2 (Gallego-Selles et al., 2020).
The Potential for Reducing Lynch Syndrome Cancer Risk with Nutritional Nrf2 Activators
Published in Nutrition and Cancer, 2021
Nrf2 is encoded by the NFE2L2 gene and has distinct homology from other basic leucine zipper transcription factors like JUN and FOS. Normally, Nrf2 is found in the cytoplasm bound to Kelch-like ECH-associated protein 1 (Keap1) and Cullin three which promote its ubiquitination and degradation. Nrf2 has two specific binding sites, ETGE and DLG, which attract Keap1. When Keap1 is securely bound to Nrf2 at the ETGE and DLG binding sites, Nrf2 function is inhibited through ubiquitination and degradation (32, 33, 35). However, under OS, a disulfide bridge is formed between the cysteine bonds of KEAP1 releasing Nrf2 and allowing it to translocate to the nucleus. Once in the nucleus, it forms a heterodimer with another class of basic leucine zipper transcription factors (Small Maf or musculoaponeurotic fibrosarcoma) to bind to the ARE and promote transcription of the downstream antioxidant genes (34,35,37) (Figure 1).
The Nrf2 pathway in psychiatric disorders: pathophysiological role and potential targeting
Published in Expert Opinion on Therapeutic Targets, 2021
Ranjana Bhandari, Japneet Kaur, Simerpreet Kaur, Anurag Kuhad
Nrf2 is a transcription factor that belongs to the Cap-n-Collar family of basic leucine zipper proteins [11]. Nrf2 controls the expression of cytoprotective genes both at basal and pathological levels [12]. Kelch-like ECH – associated protein 1 (Keap1) is another protein that binds with Nrf2 and promotes its ubiquitination by the 26 S proteasome thus keeping its level low under physiological conditions [13]. Whenever there is an increase in the production of ROS, Keap1 dissociates from Nrf2, therefore letting it affect the transcription of cytoprotective genes. In this way, Keap1 acts as a sensor that under healthy conditions promotes degradation of Nrf2 and in conditions of oxidative stress sets it free so that there is increased production of anti-oxidants. The free Nrf2 dimerizes with small Maf (Masculoaponeuroticfibrosarcoma oncogene homolog) proteins. The heterodimer of Nrf2 and Maf targets specific genes that contain anti-oxidant response elements (ARE) in their promoter region which include anti-oxidant, anti-inflammatory, and cytoprotective genes. This cross-talk of Nrf2 with Keap1 or Maf can be better understood by looking at their structures (Figure 1).
Holistic development of coal tar lotion by embedding design of experiments (DoE) technique: preclinical investigations
Published in Expert Opinion on Drug Delivery, 2020
Mandeep Sharma, Gajanand Sharma, Bhupinder Singh, Vandana Dhiman, Sanjay Kumar Bhadada, O.P. Katare
There was favorable change in the oxidizing environment of skin with all coal tar formulations (maximum with optimized lotion) in comparison to negative control in imiquimod-induced psoriasis model which is beneficial in psoriasis [54,55]. The effect of coal tar on the antioxidant defense system of skin in psoriasis can be explained on the basis of activation of cytosolic aromatic hydrocarbon receptor (AHR) by coal tar molecules (Figure 12). The stimulation of AHR receptor in turn activates cytosolic nuclear-related factor 2 (Nrf-2) by phosphorylation. The Nrf-2 has well-established role in removing the cellular oxidative stress through induction of NAD(P)H quinoneoxidoreductase enzyme 1 (Nqo1) [56]. The activated Nrf-2 shuttles into the nucleus and binds to small Maf proteins. This complex in turn binds to antioxidant response elements (AREs) and induces expression of target genes, e.g., Nqo1 [56–58]. Also, the removal of reactive oxygen species will restore the activity of protein tyrosine phosphatase (1B) enzyme (PTPN1), controller of intracellular signaling of various inflammatory cytokines through dephosphorylation of signal transducer activator 6 (STAT6), the main subcomponent of down signal transduction. Therefore, the activation of PTPN1 will help in improving/normalizing epidermal differentiation and restoration of normal skin morphology [58].