NRF2 and the Moirai: Life and Death Decisions on Cell Fates

Abstract

Significance: The transcription factor NRF2 (NF-E2-related factor 2) plays an important role as a master regulator of the cellular defense system by activating transcriptional programs of NRF2 target genes encoding multiple enzymes related to cellular redox balance and xenobiotic detoxication. Comprehensive transcriptional analyses continue to reveal an ever-broadening range of NRF2 target genes, demonstrating the sophistication and diversification of NRF2 biological signatures beyond its canonical cytoprotective roles. Recent Advances: Accumulating evidence indicates that NRF2 has a strong association with the regulation of cell fates by influencing key processes of cellular transitions in the three major phases of the life cycle of the cell ( i.e. , cell birth, cell differentiation, and cell death). The molecular integration of NRF2 signaling into this regulatory program occurs through a wide range of NRF2 target genes encompassing canonical functions and those manipulating cell fate pathways. Critical Issues: A singular focus on NRF2 signaling for dissecting its actions limits in-depth understanding of its intersection with the molecular machinery of cell fate determinations. Compensatory responses of downstream pathways governed by NRF2 executed by a variety of transcription factors and multifactorial signaling crosstalk require further exploration. Future Directions: Further investigations using optimized in vivo models and active engagement of overarching approaches to probe the interplay of widespread pathways are needed to study the properties and capabilities of NRF2 signaling as a part of a large network within the cell fate regulatory domain. Antioxid. Redox Signal. 38, 684–708.

Azadirachtin Attenuates Carcinogen Benzo(a) Pyrene-Induced DNA Damage, Cell Cycle Arrest, Apoptosis, Inflammatory, Metabolic, and Oxidative Stress in HepG2 Cells

“…AZD treatment attenuated the expression of Atg-5 and p62 proteins with no alterations in LC3 proteins, again confirming that the autophagic machinery was not involved. Researchers have reported a cross-talk between SIRT1 and Nrf2 associated with cyclin B1 expression [37]. Our study confirmed this observation via the B(a)P-induced activation of SIRT1, Nrf2, and cyclin B1 expression.…”

“…Increased oxidative stress has also been shown to elevate Nrf2 levels, leading to the significant activation of GST in vitro and in vivo [39,52]. Nrf2 thus plays a central role in balancing cell homeostasis by balancing the production and scavenging of ROS [37]. Our study demonstrated that AZD treatment attenuated the B(a)P-induced activation of Nrf2 and the induction of the GST detoxification enzyme.…”

“…This was again modulated by AZD, which again reaffirms the anti-oxidant potential of AZD. Nrf2 (nuclear factor erythroid 2-related factor), a transcription factor and cellular defense regulator, activates the transcription of anti-oxidative enzymes, and anti-inflammatory and detoxification proteins, and can minimize protein and DNA damage by degrading bioactive molecules [27,37,38]. Increased oxidative stress has also been shown to elevate Nrf2 levels, leading to the significant activation of GST in vitro and in vivo [39,52].…”

“…Nrf2 (nuclear factor erythroid 2-related factor) controls the cellular defense mechanism by regulating the redox balance and the xenobiotic detoxification system [37]. It is known to accumulate in the nucleus in response to oxidative stress and activates the antioxidant response element-dependent target genes [38].…”

Formation of EGCG oxidation self-assembled nanoparticles and their antioxidant activity in vitro and hepatic REDOX regulation activity in vivo

“…An appropriate dose of EGCG can activate the NRF2 antioxidant-responsive element pathway to resist any side effects, including DNA damage or cell death. 21,41,42 Our results also demonstrated that ENPs significantly diminish the suppression of body weight and reduce hepatotoxicity and DNA damage; thus, we systematically explored whether the NRF2 pathway is involved in the effect of ENPs. As shown in Fig.…”