Nrf2–ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms

Abstract

Oxidative stress is the increase in cellular oxidant concentration in comparison to antioxidant titer. Toxic insults and many other diseased conditions are mediated through the formation of such condition. Once the redox equilibrium is disrupted, the cellular antioxidant system functions to bring back the cell to redox homeostasis state. The field players of the cytoprotective machinery are the xenobiotic‐metabolizing enzymes that are transcriptionally controlled by upstream regulatory pathways like the Nrf2–ARE pathway and AhR–XRE pathway. The importance of Nrf2 lies in the fact that it is activated by a variety of compounds and has a wide range of inducers including metals, organic toxicants and so forth. The present review article aims to discuss the role of Nrf2 in cellular protection and also intends to illuminate the regulatory mechanisms that control Nrf2 itself. This can add to our knowledge of how the cell reacts and survives against such stressed conditions.

Chrysin Reduces Oxidative Stress but Does Not Affect Polyol Pathway in the Lenses of Type 1 Diabetic Rats

“…In normal non-stressed conditions, the Nrf2 is connected to its cytoplasmatic inhibitor-Kelch-like ECH-associated protein-1 (Keap1). When oxidative stress increases, Nrf2 is released from Keap1, then translocated to the nucleus where it connects with antioxidant response element (ARE), inducing the expression of Nrf2-ARE dependent genes, including the genes coding antioxidative enzymes [70]. We observed that SOD and CAT activity was significantly increased in the lenses of diabetic rats.…”

Sledgehammer to Scalpel: Broad Challenges to the Heart and Other Tissues Yield Specific Cellular Responses via Transcriptional Regulation of the ER-Stress Master Regulator ATF6α

“…One of the most intriguing features of many regulated transcription factors is their mechanism of activation [6]. For example, certain stress-regulated transcription factors are responsive to oxygen depletion (e.g., hypoxia-inducible factor 1α (HIF1α) [7], oxidative stress (e.g., nuclear factor erythroid 2-like factor 2 (NRF2)) [8] and growth factors (e.g., serum response factor (SRF)) [9]. This review focuses on activating transcription factor 6α (ATF6α), a transcription factor that was originally found to be activated by ER proteotoxic stress [10], i.e., protein-misfolding in the ER, but more recently has been found to be activated by a wider array of stresses [11].…”

Nrf2 Alleviates TNF-α-Induced Oxidative Stress Damage in Type II Alveolar Epithelial Cells by Down-Regulating the Expression of NOX1

“…Nrf2 is a predominant regulator of cellular defense mechanism against oxidative stress because it can regulate the expression activity of various genes which are crucial in response to oxidative stress [10,11] . Recently, Nrf2 has been treated as a potent terminator for oxidative stress injury due to its ability in greatly reducing oxidative stress level in alveolar epithelial cells.…”

“…Nonetheless, the way that Nrf2 suppresses the expression of NOX1 is still undiscovered. Given that the Nrf2-antioxidant response element signaling strongly facilitates to maintain the balance between oxidant system and antioxidant system under oxidative stress condition [11] and that the existence possibility of Nrf2 binding element in the promoter of NOX1, it is reasonable to assume that the predicted binding element plays a pivotal role in the interaction between Nrf2 and NOX1. To con rm this hypothesis, the sequence of Nrf2 binding element was deleted and a deletion mutant of NOX1 promoter were synthesized by overlap extension PCR, after that, two recombinant plasmids were constructed by inserting the sequence of full-length of NOX1 promoter and that of the deletion mutant to the pGL3 basic plasmid and transformed these plasmids into A549 cells under the induction of TNF-α.…”

“…Therefore, reduce NOX1-mediated ROS production might be able to effectively alleviate the in ammation reaction and oxidative stress damage in T 2 AECs under ALI. Nrf2 is an important transcription factor and plays crucial roles in regulating the transcription activity of a wide range of antioxidant genes [10,11] . Generally, Nrf2 is ubiquitinated and degraded because of the mediation of Keap1, however, under oxidative stress challenge, the Nrf2-Keap1 complex is dissociated, which allows Nrf2 to translocate into the nucleus, resulting in the activation of its downstream genes, by which it exerts its role in modulating the levels of oxidative stress, in ammation, apoptosis, and autophagy [10] .…”