Current Opinion in Toxicology
About: Current Opinion in Toxicology is an academic journal. The journal publishes majorly in the area(s): Oxidative stress & Aryl hydrocarbon receptor. It has an ISSN identifier of 2468-2020. Over the lifetime, 305 publication(s) have been published receiving 3414 citation(s).
TL;DR: A greater understanding of the complex interplay between the NF-κB signaling and oxidative stress may lead to the development of therapeutic strategies for the treatment of a myriad of human diseases for which oxidative stress has an etiologic role.
Abstract: The transcription factor nuclear factor-κB (NF-κB) modulates gene expression in diverse cellular processes such as innate immune response, embryogenesis and organ development, cell proliferation and apoptosis, and stress responses to a variety of noxious stimuli. When cellular production of reactive oxygen species (ROS) overwhelms its antioxidant capacity, it leads to a state of oxidative stress, which in turn contributes to the pathogenesis of several human diseases. Different models of oxidative stress have been studied to elucidate the effects of oxidant stress on NF-κB related activities. ROS can both activate and repress NF-κB signaling in a phase and context dependent manner. The NF-κB pathway can have both anti- and pro-oxidant roles in the setting of oxidative stress. In this review, we focus on role of oxidative stress on different mediators of the NF-κB pathway, and the role of NF-κB activation in the modulation of oxidative stress. A greater understanding of the complex interplay between the NF-κB signaling and oxidative stress may lead to the development of therapeutic strategies for the treatment of a myriad of human diseases for which oxidative stress has an etiologic role.
TL;DR: Small molecule activators of Nrf2 support mitochondrial integrity by promoting mitophagy and conferring resistance to oxidative stress-mediated permeability transition, with implications for stem cell self-renewal, cardiomyocyte regeneration, and neural stem/progenitor cell survival.
Abstract: The transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the master regulator of the cellular redox homeostasis. Nrf2 target genes comprise of a large network of antioxidant enzymes, proteins involved in xenobiotic detoxification, repair and removal of damaged proteins, inhibition of inflammation, as well as other transcription factors. In recent years it has emerged that as part of its role as a regulator of cytoprotective gene expression, Nrf2 impacts mitochondrial function. Increased Nrf2 activity defends against mitochondrial toxins. Reduced glutathione, the principal small molecule antioxidant in the mammalian cell and a product of several of the downstream target genes of Nrf2, counterbalances mitochondrial ROS production. The function of Nrf2 is suppressed in mitochondria-related disorders, such as Parkinson's disease and Friedrich's ataxia. Studies using isolated mitochondria and cultured cells have demonstrated that Nrf2 deficiency leads to impaired mitochondrial fatty acid oxidation, respiration and ATP production. Small molecule activators of Nrf2 support mitochondrial integrity by promoting mitophagy and conferring resistance to oxidative stress-mediated permeability transition. Excitingly, recent studies have shown that Nrf2 also affects mitochondrial function in stem cells with implications for stem cell self-renewal, cardiomyocyte regeneration, and neural stem/progenitor cell survival.
TL;DR: Sies et al. as discussed by the authors defined a global concept of Oxidative Stress as an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage.
Abstract: Oxidative stress as a concept in redox biology and medicine has witnessed fulminant development of the past 30-odd years. It is a global concept, defined as “an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage” (Sies H, Jones DP: Oxidative stress. In Encyclopedia of stress, 2nd Ed., Fink G, Editor. Amsterdam: Elsevier; 2007:45–48). Physiological (low-level) oxidative stress is used in redox signaling and redox regulation, termed oxidative eustress, whereas higher burden (supraphysiological) leads to disrupted redox signaling and/or oxidative damage to biomolecules, termed oxidative distress. There are powerful oxidative stress response systems. The challenge for the future is to design methods to obtain detailed information on spatiotemporal redox patterns and their regulation for application in specific settings.
TL;DR: A molecular mechanism of Nrf2-activation by p62/SQSTM1 is delineated, and its physiological role as well as the pathophysiological significance in autophagy-knockout livers and human hepatocellular carcinoma is described.
Abstract: Nrf2 is a transcription factor responsible for gene expression of a series of anti-oxidant proteins and detoxifying enzymes. Keap1, an adaptor protein of Cullin-3 ubiquitin ligase, senses electrophilic or oxidative stresses and then arrests ubiquitination of Nrf2, leading to Nrf2 activation. In addition to this canonical pathway, one Nrf2 target (p62/SQSTM1) competitively binds to Keap1 to activate Nrf2. The p62/SQSTM1-Keap1-Nrf2 axis is linked to selective autophagy and regulated by post-translational modifications such as sequential phosphorylation and ubiquitination of p62/SQSTM1. Importantly, this non-canonical pathway is hyper-activated in autophagy-deficient mouse livers and tissues of hepatocellular carcinoma. In this review, we delineate a molecular mechanism of Nrf2-activation by p62/SQSTM1, and describe its physiological role as well as the pathophysiological significance in autophagy-knockout livers and human hepatocellular carcinoma.
TL;DR: This review highlights the differences between Cr(VI) and Cr(III) from a chemical and toxicological perspective, describes short-comings in nutritional research of Cr( III), and explains the multiple mechanisms by which Cr( VI) is involved in the process of carcinogenesis.
Abstract: Chromium is a pervasive environmental contaminant that is of great importance because of its toxicity. Hexavalent chromium is a classified group 1 carcinogen with multiple complex mechanisms by which it triggers cancer development. Increased levels of oxidative stress, chromosome breaks, and DNA-adduct formation are some of the major mechanisms by which C(VI) causes cellular damage. Trivalent chromium is another species of chromium that is described as a non-essential metal, and is used in nutritional supplementation. Evidence on nutritional benefit is conflicting which could suggest that humans absorb enough Cr(III) from diet alone, and that extra supplementation is not necessary. This review highlights the differences between Cr(VI) and Cr(III) from a chemical and toxicological perspective, describes short-comings in nutritional research of Cr(III), and explains the multiple mechanisms by which Cr(VI) is involved in the process of carcinogenesis.
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