NRF2 (Scenesse tremendously expresses) counters the damage that Ultra Violet A, B (and gamma, X-ray) does when an electron is pulled from an atom. Amongst other good, it "regulates..Heme and iron metabolism. And NADPH regeneration, detox of superoxid
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NRF2 promotes survival following exposure to ionizing radiation
Highlights
- •
Nrf2 is a ROS detoxification factor.
- •
Nrf2 enhances DNA DSB repair and base excision repair.
- •
Nrf2 suppresses TGF-β signaling.
Abstract
NRF2 is a transcription factor that promotes antioxidant and drug-metabolizing gene expression. It also regulates the transcription of genes involved in carbohydrate and lipid metabolism, NADPH regeneration, heme and iron metabolism, as well as proteasome metabolism. Emerging research has identified NRF2 as a critical factor for promoting survival of mammalian cells subjected to ionizing radiation. At a mechanistic level, NRF2 promotes the repair of DNA damage and drives detoxification of superoxide that is generated hours to days after irradiation. This review summarizes research in these areas and discusses targeting of NRF2 in radiation resistant cancer and NRF2's role in mitigating Acute Radiation Syndrome.
<img class="figure large" id="gabsImg" border="0" alt="Full-size image (11 K)" src="http://origin-ars.els-cdn.com/content/image/1-s2.0-S0891584915002117-fx1.jpg" data-thumbEID="1-s2.0-S0891584915002117-fx1.sml">Abbreviations
- ARE, antioxidant response element;
- ARS, Acute radiation syndrome;
- ATM, Ataxia telangiectasia mutated;
- BRCA1, Breast cancer type 1 susceptibility protein;
- ChIP, Chromatin immunoprecipitation;
- CnC, Cap ‘n’ collar family of basic leucine zipper transcription factors;
- DSB, Double strand break;
- HR, Homologous recombination;
- Keap1, Kelch-like ECH-associated protein 1;
- LD50, Lethal dose for 50% of a population;
- MEF, Mouse embryo fibroblast;
- NADPH, Nicotinamide adenine dinucleotide phosphate;
- NHEJ, Non-homologous end joining;
- NRF2, Human nuclear factor (erythroid-derived 2)-like 2 protein;
- Nrf2, Mouse nuclear factor (erythroid-derived 2)-like 2 protein;
- OGG1, 8-Oxoguanine DNA glycosylase;
- •ΟΗ, Hydroxyl radical;
- PARP1, Poly(ADP-ribose) polymerase 1;
- RNAi, RNA interference;
- ROS, Reactive oxygen species;
- RPA, Replication protein A
Keywords
- Nrf2;
- Ionizing radiation;
- Reactive oxygen species;
- DNA repair;
- Cell and tissue damage
Copyright © 2015 Published by Elsevier Inc.
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NADPH oxidase
The NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Isoforms are designated NOX1, NOX2, NOX3, and NOX4
Under normal circumstances, the complex is latent in neutrophils and is activated to assemble in the membranes during respiratory burst.
NADPH oxidase generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling these to molecular oxygen to produce superoxide anion, a reactive free-radical. Superoxide can be produced in phagosomes, which contain ingested bacteria and fungi, or it can be produced outside of the cell. In a phagosome, superoxide can spontaneously form hydrogen peroxide that will undergo further reactions to generate reactive oxygen species (ROS).
Superoxide kills bacteria and fungi by mechanisms that are not yet fully understood (see article on superoxide), but may inactivate critical metabolic enzymes, initiate lipid peroxidation, and liberate redox-active iron, which allows the generation of indiscriminate oxidants such as the hydroxyl radical. It is presumed that superoxide kills bacteria directly, as the virulence of many pathogens is dramatically attenuated when their superoxide dismutase (SOD) genes are deleted. However, downstream products of superoxide also include hydrogen peroxide and hypochlorous acid, the reactive agent in bleach.
Role in pathology[edit]
NADPH oxidase is a major cause of atherosclerosis, and NADPH oxidase inhibitors may reverse atherosclerosis. Atherosclerosis is caused by the accumulation of macrophages containing cholesterol (foam cells) in artery walls (in the intima). NADPH oxidase produces ROSs. These ROSs activate an enzyme that makes the macrophages adhere to the artery wall (by polymerizing actin fibers). This process is counterbalanced by NADPH oxidase inhibitors, and by antioxidants. An imbalance in favor of ROS produces atherosclerosis. In vitro studies have found that the NADPH oxidase inhibitors apocynin and diphenyleneiodonium, along with the antioxidants N-acetyl-cysteine and resveratrol, depolymerized the actin, broke the adhesions, and allowed foam cells to migrate out of the intima.[1][2]
Mutations in the NADPH oxidase subunit genes cause several Chronic Granulomatous Diseases (CGD), such as
- X-linked chronic granulomatous disease (CGD)
- autosomal recessive cytochrome b-negative CGD
- autosomal recessive cytochrome b-positive CGD type I
- autosomal recessive cytochrome b-positive CGD type II.
In these diseases, cells have a low capacity for phagocytosis, and persistent bacterial infections occur. Areas of infected cells are common, granulomas. A similar disorder called neutrophil immunodeficiency syndrome is linked to a mutation in the RAC2, also a part of the complex.
One study suggests a role for NADPH oxidase in ketamine-induced loss of neuronal parvalbumin and GAD67 expression.[3] Similar loss is observed in schizophrenia, and the results may point at the NADPH oxidase as a possible player in the pathophysiology of the disease.[4] Nitro blue tetrazolium is used in a diagnostic test, in particular, for chronic granulomatous disease, a disease in which there is a defect in NADPH oxidase; therefore, the phagocyte is unable to make the reactive oxygen species or radicals required for bacterial killing, resulting in bacteria thriving within the phagocyte. The higher the blue score the better the cell is at producing reactive oxygen species
MrPoonz1
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Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans
- Elena V. Knatko1,
- Sally H. Ibbotson2,
- Ying Zhang1,
- Maureen Higgins1,
- Jed W. Fahey3,4,
- Paul Talalay3,
- Robert S. Dawe2,
- James Ferguson2,
- Jeffrey T.-J. Huang1,
- Rosemary Clarke5,
- Suqing Zheng6,
- Akira Saito6,
- Sukirti Kalra1,
- Andrea L. Benedict3,
- Tadashi Honda6,7,
- Charlotte M. Proby1,2, and
- Albena T. Dinkova-Kostova1,3,*
+ Author Affiliations
- 1Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, United Kingdom.
- 2Photobiology Unit, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
- 3Lewis B. and Dorothy Cullman Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
- 4Center for Human Nutrition, Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
- 5Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
- 6Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York.
- 7Department of Chemistry, Stony Brook University, Stony Brook, New York.
- ↵*Corresponding Author:
Albena T. Dinkova-Kostova, Division of Cancer Research, Medical Research Institute, James Arrott Drive, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom. Phone: 44-1382-383386; Fax: 44-1382-669993; E-mail: a.dinkov...@dundee.ac.uk
Abstract
The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative, and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity, and burden of solar-simulated UV radiation–mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated are lower than those that arise in their wild-type counterparts. Pharmacologic Nrf2 activation by topical biweekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacologic Nrf2 activation lowers the expression of the pro-inflammatory factors IL6 and IL1β, and COX2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane reduced the degree of solar-simulated UV radiation–induced skin erythema, a quantifiable surrogate endpoint for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation. Cancer Prev Res; 8(6); 475–86. ©2015 AACR.
Footnotes
Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).
- Received October 15, 2014.
- Revision received February 25, 2015.
- Accepted March 13, 2015.
- ©2015 American Association for Cancer Research.
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This Article
- Published OnlineFirst March 24, 2015; doi: 10.1158/1940-6207.CAPR-14-0362 Cancer Prev Res June 2015 8; 475
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This Article
- Published OnlineFirst March 24, 2015; doi: 10.1158/1940-6207.CAPR-14-0362 Cancer Prev Res June 2015 8; 475
- » Abstract
- Figures Only
- Full Text
- Full Text (PDF)
- Supplementary Data
- All Versions of this Article:
- 1940-6207.CAPR-14-0362v1
- 1940-6207.CAPR-14-0362v2
- 8/6/475 most recent
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Plant leaf extract alledged to increase NRF2 and counter skin anti-oxidation.
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During the first day of Antioxidants World Congress 2015, Pr Thornalley from the University of Warwick, UK, will talk about the Screening for antioxidant activators of Nrf2 - Have we been misreading the signals?
Pr Thornalley, from the University of Warwick, Coventry UK, will discuss "Screening for antioxidant activators of Nrf2 - Have we been misreading the signals? Frequency modulated translocational oscillations of Nrf2 regulate the Antioxidant Response Element cytoprotective transcriptional response" during the first day of the 15th International Conference on Oxidative Stress Reduction, Redox Homeostasis and Antioxidants, held on June 22-24 in Pasteur Institute, Paris
The discovery that Nrf2 undergoes translocational oscillations from cytoplasm to nucleus in human cells with frequency modulation linked to activation of a stress-stimulated cytoprotective response raises the prospect that the Nrf2 works mechanistically analogous to a wireless sensor. Herein I consider how this new model of Nrf2 oscillation resolves previous inexplicable experimental findings on Nrf2 regulation and why it is fit-for-purpose. Further investigation is required to assess how generally applicable the oscillatory mechanism is and if characteristics of this regulatory control can be found in vivo. The model identifies multiple re-enforcing receptors for Nrf2 activation, suggesting that potent Nrf2 activation for improved health and treatment of disease may be achieved through combination of Nrf2 system stimulants.
To know more about Antioxidants World Congress 2015 preliminary agenda, click here.
ISANH team