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Regulation of Mitochondrial Functions by Transcription Factor NRF2

  • Narsa M. Reddy
  • Wajiha Qureshi
  • Haranath Potteti
  • Dhananjaya V. Kalvakolanu
  • Sekhar P. ReddyEmail author
Chapter
  • 804 Downloads
Part of the Respiratory Medicine book series (RM, volume 15)

Abstract

Protective and adaptive responses initiated by lung-resident and infiltrated cells play an important role in mitigating the detrimental effects of various toxicants. However, the development of a variety of pulmonary diseases has been attributed to a dysfunctional cellular response following acute or chronic toxicant exposure, resulting from altered gene expression. Although mitochondria have been long thought as cellular powerhouses and regulators of bioenergetics, their biogenesis is promoted by diverse patho-physiological stimuli including cell division, development, exercise, postnatal breathing, metabolism, oxidative stress, and inflammation. Emerging evidence strongly supports the idea that mitochondrial dysfunction caused by various toxicants and pro-oxidants is the origin of pathogenesis and ultimately results in morbidity and mortality. The transcriptional factor nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2 or NRF2), by binding to the antioxidant response element (ARE) of the promoters of redox-sensitive genes, induces the expression of cytoprotective and antioxidative proteins that play a crucial role in mitigating the cellular stress and damage caused by pro-inflammatory and oxidant stimuli. Depending on the extent of its activation, redox signaling can promote either beneficial stress-resolving mitochondrial activity or mitochondrial dysfunction. Accumulating evidence suggests that a deficiency of NRF2 causes mitochondrial dysfunction, culminating in severe lung injury and inflammation. This review discusses the biology and role of NRF2 in regulating mitochondrial functions and summarizes current strategies used to target NRF2 in order to confer protection against pulmonary disorders linked to mitochondrial dysfunction.

Keywords

Autophagy Mitophagy Antioxidants Lung diseases KEAP1 ROS 

Abbreviations

AD

Alzheimer’s disease

ALI

Acute lung injury

ARDS

Acute respiratory distress syndrome

ARE

Antioxidant response element

ATG

Autophagy gene

ATP

Adenosine-5′-triphosphate

BCL

B-cell lymphoma

CDDO-Im

1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole

CO

Carbon monoxide

COPD

Chronic obstructive pulmonary disease

ETC

Electron transport chain

Fas-L

Fas ligand

GCL

Glutamate cysteine ligase

GCLC

Glutamate cysteine ligase catalytic subunit

GCLM

Glutamate cysteine ligase modifier subunit

GPX

Glutathione peroxidase

GR

Glutathione reductase

GSH

Glutathione

GSK3β

Glycogen synthase kinase 3β

GSR

Glutathione reductase

GSSG

Glutathione disulfide

GST

Glutathione transferase

HMOX1

Heme oxygenase1

LPS

Lipopolysaccharide

mGSH

Mitochondrial glutathione

mGSSG

Mitochondrial glutathione disulfide

MOMP

Mitochondrial outer membrane permeabilization

mOXPHOS

Mitochondrial oxidative phosphorylation

mtDNA

Mitochondrial DNA

mtER

Mitochondrial estrogen receptor

mtGR

Mitochondrial glucocorticoid

NQO

NAD(P)H:quinone oxidoreductase

NRF-1

Nuclear respiratory factor-1

NRF-2

Nuclear respiratory factor-2

NRF2

Nuclear factor (erythroid-derived 2)-like 2

Ogg1

8-Oxoguanine DNA glycosylase 1

PD

Parkinson’s disease

PGAM5

Mitochondrial phosphoglycerate mutase family member 5

PGC

Peroxisome proliferator-activated receptor gamma coactivator

PHB

Prohibitin

PKB

Protein kinase B

PPAR

Peroxisome proliferator-activated receptor

PRDXs

Peroxiredoxins

RNS

Nitrogen-based reactive nitrogen species

ROS

Reactive oxygen species

SOD

Superoxide dismutase

SRX

Sulfiredoxin

TFAM

Mitochondrial transcription factor A

TNFα

Tumor necrosis factor-alpha

TXN

Thioredoxin

TXNRD

Thioredoxin reductase

Notes

Acknowledgments

Supported by the NIH grants HL66109, ES11863, DK084445, and ES18998 and the Flight Attendant Medical Research Institute (FAMRI) (to SPR) and NIH grant CA78282 (to DVK).

References

  1. 1.
    Wittig I, Schagger H. Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. Biochim Biophys Acta. 2009;1787:672–80.PubMedGoogle Scholar
  2. 2.
    Chipuk JE, Bouchier-Hayes L, Green DR. Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ. 2006;13:1396–402.PubMedGoogle Scholar
  3. 3.
    Frey TG, Mannella CA. The internal structure of mitochondria. Trends Biochem Sci. 2000;25:319–24.PubMedGoogle Scholar
  4. 4.
    Duchen MR. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med. 2004;25:365–451.PubMedGoogle Scholar
  5. 5.
    Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1–13.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Murphy MP. Mitochondria–a neglected drug target. Curr Opin Investig Drugs. 2009;10: 1022–4.PubMedGoogle Scholar
  7. 7.
    West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS, Ghosh S. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. 2011;472:476–80.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.PubMedGoogle Scholar
  9. 9.
    Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintron M, Chen T, Marcinek DJ, Dorn 2nd GW, Kang YJ, Prolla TA, Santana LF, Rabinovitch PS. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res. 2011;108:837–46.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Leloup C, Tourrel-Cuzin C, Magnan C, Karaca M, Castel J, Carneiro L, Colombani AL, Ktorza A, Casteilla L, Penicaud L. Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes. 2009;58:673–81.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Bonawitz ND, Chatenay-Lapointe M, Pan Y, Shadel GS. Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression. Cell Metab. 2007;5:265–77.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J. 2012;441:523–40.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 2007;6:280–93.PubMedGoogle Scholar
  14. 14.
    Henze K, Martin W. Evolutionary biology: essence of mitochondria. Nature. 2003;426:127–8.PubMedGoogle Scholar
  15. 15.
    Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG. Sequence and organization of the human mitochondrial genome. Nature. 1981;290:457–65.PubMedGoogle Scholar
  16. 16.
    Herrmann JM, Neupert W. Protein transport into mitochondria. Curr Opin Microbiol. 2000;3:210–4.PubMedGoogle Scholar
  17. 17.
    Garesse R, Vallejo CG. Animal mitochondrial biogenesis and function: a regulatory cross-talk between two genomes. Gene. 2001;263:1–16.PubMedGoogle Scholar
  18. 18.
    Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 2004;18:357–68.PubMedGoogle Scholar
  19. 19.
    Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008;88:611–38.PubMedGoogle Scholar
  20. 20.
    Lee HC, Yin PH, Chi CW, Wei YH. Increase in mitochondrial mass in human fibroblasts under oxidative stress and during replicative cell senescence. J Biomed Sci. 2002;9:517–26.PubMedGoogle Scholar
  21. 21.
    Piantadosi CA, Suliman HB. Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes. Biochim Biophys Acta. 1820;2012:532–41.Google Scholar
  22. 22.
    Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005;1:361–70.PubMedGoogle Scholar
  23. 23.
    Scarpulla RC. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann N Y Acad Sci. 2008;1147:321–34.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Halliwell B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. 2006;97:1634–58.PubMedGoogle Scholar
  25. 25.
    Lenaz G. Role of mitochondria in oxidative stress and ageing. Biochim Biophys Acta. 1998;1366:53–67.PubMedGoogle Scholar
  26. 26.
    Linnane AW, Eastwood H. Cellular redox regulation and prooxidant signaling systems: a new perspective on the free radical theory of aging. Ann N Y Acad Sci. 2006;1067:47–55.PubMedGoogle Scholar
  27. 27.
    Barja G. Oxygen radicals, a failure or a success of evolution? Free Radic Res Commun. 1993;18:63–70.PubMedGoogle Scholar
  28. 28.
    Fruehauf JP, Meyskens Jr FL. Reactive oxygen species: a breath of life or death? Clin Cancer Res. 2007;13:789–94.PubMedGoogle Scholar
  29. 29.
    Sies H, Stahl W. Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. Am J Clin Nutr. 1995;62:1315S–21.PubMedGoogle Scholar
  30. 30.
    Ruttkay-Nedecky B, Nejdl L, Gumulec J, Zitka O, Masarik M, Eckschlager T, Stiborova M, Adam V, Kizek R. The role of metallothionein in oxidative stress. Int J Mol Sci. 2013;14:6044–66.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Kalmar B, Greensmith L. Induction of heat shock proteins for protection against oxidative stress. Adv Drug Deliv Rev. 2009;61:310–8.PubMedGoogle Scholar
  32. 32.
    Ho YS, Vincent R, Dey MS, Slot JW, Crapo JD. Transgenic models for the study of lung antioxidant defense: enhanced manganese-containing superoxide dismutase activity gives partial protection to B6C3 hybrid mice exposed to hyperoxia. Am J Respir Cell Mol Biol. 1998;18:538–47.PubMedGoogle Scholar
  33. 33.
    Lee PJ, Choi AM. Pathways of cell signaling in hyperoxia. Free Radic Biol Med. 2003;35: 341–50.PubMedGoogle Scholar
  34. 34.
    Reddy SP. The antioxidant response element and oxidative stress modifiers in airway diseases. Curr Mol Med. 2008;8:376–83.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Comhair SA, Erzurum SC. Antioxidant responses to oxidant-mediated lung diseases. Am J Physiol Lung Cell Mol Physiol. 2002;283:L246–55.PubMedGoogle Scholar
  36. 36.
    Oberst A, Bender C, Green DR. Living with death: the evolution of the mitochondrial pathway of apoptosis in animals. Cell Death Differ. 2008;15:1139–46.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Fennell DA, Swanton C. Unlocking Pandora’s box: personalising cancer cell death in non-small cell lung cancer. EPMA J. 2012;3:6.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407:770–6.PubMedGoogle Scholar
  39. 39.
    Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11:621–32.PubMedGoogle Scholar
  40. 40.
    Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94:491–501.PubMedGoogle Scholar
  41. 41.
    Ma X, Karra S, Guo W, Lindner DJ, Hu J, Angell JE, Hofmann ER, Reddy SP, Kalvakolanu DV. Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase. J Biol Chem. 2001;276:24843–54.PubMedGoogle Scholar
  42. 42.
    Ma X, Karra S, Lindner DJ, Hu J, Reddy SP, Kimchi A, Yodoi J, Kalvakolanu DV. Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination. Oncogene. 2001;20:3703–15.PubMedGoogle Scholar
  43. 43.
    Rossig L, Fichtlscherer B, Breitschopf K, Haendeler J, Zeiher AM, Mulsch A, Dimmeler S. Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. J Biol Chem. 1999;274:6823–6.PubMedGoogle Scholar
  44. 44.
    Kim YM, Talanian RV, Billiar TR. Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J Biol Chem. 1997;272:31138–48.PubMedGoogle Scholar
  45. 45.
    Li J, Bombeck CA, Yang S, Kim YM, Billiar TR. Nitric oxide suppresses apoptosis via interrupting caspase activation and mitochondrial dysfunction in cultured hepatocytes. J Biol Chem. 1999;274:17325–33.PubMedGoogle Scholar
  46. 46.
    Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P. Autophagy: for better or for worse. Cell Res. 2012;22:43–61.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368:651–62.PubMedGoogle Scholar
  48. 48.
    Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282:24131–45.PubMedGoogle Scholar
  49. 49.
    De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92.PubMedGoogle Scholar
  50. 50.
    Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147: 728–41.PubMedGoogle Scholar
  51. 51.
    Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148:1145–59.PubMedGoogle Scholar
  52. 52.
    Rambold AS, Lippincott-Schwartz J. Mechanisms of mitochondria and autophagy crosstalk. Cell Cycle. 2011;10:4032–8.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol. 2004;16:663–9.PubMedGoogle Scholar
  54. 54.
    McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr Biol. 2006;16:R551–60.PubMedGoogle Scholar
  55. 55.
    Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nunez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009;16:3–11.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Huang HC, Nguyen T, Pickett CB. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem. 2002;277: 42769–74.PubMedGoogle Scholar
  57. 57.
    Kitsis RN, Molkentin JD. Apoptotic cell death “Nixed” by an ER-mitochondrial necrotic pathway. Proc Natl Acad Sci U S A. 2010;107:9031–2.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Wallace DC, Fan W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion. 2010;10:12–31.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Davis RE, Williams M. Mitochondrial function and dysfunction: an update. J Pharmacol Exp Ther. 2012;342:598–607.PubMedGoogle Scholar
  60. 60.
    Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999;283:1482–8.PubMedGoogle Scholar
  61. 61.
    Schapira AH. Mitochondrial disease. Lancet. 2006;368:70–82.PubMedGoogle Scholar
  62. 62.
    Copeland WC. Inherited mitochondrial diseases of DNA replication. Annu Rev Med. 2008;59:131–46.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Finsterer J. Treatment of mitochondrial disorders. Eur J Paediatr Neurol. 2010;14:29–44.PubMedGoogle Scholar
  64. 64.
    Poljsak B. Strategies for reducing or preventing the generation of oxidative stress. Oxid Med Cell Longev. 2011;2011:194586.Google Scholar
  65. 65.
    Kang J, Pervaiz S. Mitochondria: redox metabolism and dysfunction. Biochem Res Int. 2012;2012:896751.Google Scholar
  66. 66.
    Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, Maser RS, Tonon G, Foerster F, Xiong R, Wang YA, Shukla SA, Jaskelioff M, Martin ES, Heffernan TP, Protopopov A, Ivanova E, Mahoney JE, Kost-Alimova M, Perry SR, Bronson R, Liao R, Mulligan R, Shirihai OS, Chin L, DePinho RA. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470:359–65.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Lee SJ, Hwang AB, Kenyon C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol. 2010;20:2131–6.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Schumacker PT. Lung cell hypoxia: role of mitochondrial reactive oxygen species signaling in triggering responses. Proc Am Thorac Soc. 2011;8:477–84.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Sommer SP, Sommer S, Sinha B, Leyh RG. Glycine preconditioning to ameliorate pulmonary ischemia reperfusion injury in rats. Interact Cardiovasc Thorac Surg. 2012;14:521–5.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Zmijewski JW, Lorne E, Banerjee S, Abraham E. Participation of mitochondrial respiratory complex III in neutrophil activation and lung injury. Am J Physiol Lung Cell Mol Physiol. 2009;296:L624–34.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Suliman HB, Welty-Wolf KE, Carraway M, Tatro L, Piantadosi CA. Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc Res. 2004;64: 279–88.PubMedGoogle Scholar
  72. 72.
    Simoes DC, Psarra AM, Mauad T, Pantou I, Roussos C, Sekeris CE, Gratziou C. Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma. PLoS ONE. 2012;7:e39183.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, Segel R, Elpeleg O, Nassar S, Frishberg Y. Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet. 2011;88:193–200.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Mishra S, Murphy LC, Murphy LJ. The Prohibitins: emerging roles in diverse functions. J Cell Mol Med. 2006;10:353–63.PubMedGoogle Scholar
  75. 75.
    Liu D, Lin Y, Kang T, Huang B, Xu W, Garcia-Barrio M, Olatinwo M, Matthews R, Chen YE, Thompson WE. Mitochondrial dysfunction and adipogenic reduction by prohibitin silencing in 3T3-L1 cells. PLoS ONE. 2012;7:e34315.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Soulitzis N, Neofytou E, Psarrou M, Anagnostis A, Tavernarakis N, Siafakas N, Tzortzaki EG. Downregulation of lung mitochondrial prohibitin in COPD. Respir Med. 2012;106:954–61.PubMedGoogle Scholar
  77. 77.
    Ruchko M, Gorodnya O, LeDoux SP, Alexeyev MF, Al-Mehdi AB, Gillespie MN. Mitochondrial DNA damage triggers mitochondrial dysfunction and apoptosis in oxidant-challenged lung endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2005;288:L530–5.PubMedGoogle Scholar
  78. 78.
    Reddy SP, Hassoun PM, Brower R. Redox imbalance and ventilator-induced lung injury. Antioxid Redox Signal. 2007;9:2003–12.PubMedGoogle Scholar
  79. 79.
    Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012;122:2731–40.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Rahman I, MacNee W. Antioxidant pharmacological therapies for COPD. Curr Opin Pharmacol. 2012;12:256–65.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Prockop DJ. Mitochondria to the rescue. Nat Med. 2012;18:653–4.PubMedGoogle Scholar
  82. 82.
    Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med. 2004;10:549–57.PubMedGoogle Scholar
  83. 83.
    Kobayashi M, Yamamoto M. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal. 2005;7:385–94.PubMedGoogle Scholar
  84. 84.
    Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A. 2002;99:11908–13.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003;23:7198–209.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116.PubMedGoogle Scholar
  87. 87.
    Nishinaka T, Yabe-Nishimura C. Transcription factor Nrf2 regulates promoter activity of mouse aldose reductase (AKR1B3) gene. J Pharmacol Sci. 2005;97:43–51.PubMedGoogle Scholar
  88. 88.
    Sasaki H, Sato H, Kuriyama-Matsumura K, Sato K, Maebara K, Wang H, Tamba M, Itoh K, Yamamoto M, Bannai S. Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J Biol Chem. 2002;277:44765–71.PubMedGoogle Scholar
  89. 89.
    Tjalkens RB, Luckey SW, Kroll DJ, Petersen DR. Alpha, beta-unsaturated aldehydes mediate inducible expression of glutathione S-transferase in hepatoma cells through activation of the antioxidant response element (ARE). Adv Exp Med Biol. 1999;463:123–31.PubMedGoogle Scholar
  90. 90.
    Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005;45:51–88.PubMedGoogle Scholar
  91. 91.
    Ikeda H, Serria MS, Kakizaki I, Hatayama I, Satoh K, Tsuchida S, Muramatsu M, Nishi S, Sakai M. Activation of mouse Pi-class glutathione S-transferase gene by Nrf2 (NF-E2-related factor 2) and androgen. Biochem J. 2002;364:563–70.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Xue M, Rabbani N, Momiji H, Imbasi P, Anwar MM, Kitteringham N, Park BK, Souma T, Moriguchi T, Yamamoto M, Thornalley PJ. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation. Biochem J. 2012;443: 213–22.PubMedGoogle Scholar
  93. 93.
    Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, Motohashi H. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22:66–79.PubMedGoogle Scholar
  94. 94.
    Piantadosi CA, Carraway MS, Babiker A, Suliman HB. Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res. 2008;103:1232–40.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Kim YJ, Ahn JY, Liang P, Ip C, Zhang Y, Park YM. Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Cancer Res. 2007;67:546–54.PubMedGoogle Scholar
  96. 96.
    Miyamoto N, Izumi H, Miyamoto R, Kondo H, Tawara A, Sasaguri Y, Kohno K. Quercetin induces the expression of peroxiredoxins 3 and 5 via the Nrf2/NRF1 transcription pathway. Invest Ophthalmol Vis Sci. 2011;52:1055–63.PubMedGoogle Scholar
  97. 97.
    Soriano FX, Baxter P, Murray LM, Sporn MB, Gillingwater TH, Hardingham GE. Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin. Mol Cells. 2009;27:279–82.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Dreger H, Westphal K, Weller A, Baumann G, Stangl V, Meiners S, Stangl K. Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res. 2009;83:354–61.PubMedGoogle Scholar
  99. 99.
    Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, Yodoi J. Hemin-induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors. J Biol Chem. 2001;276:18399–406.PubMedGoogle Scholar
  100. 100.
    Sakurai A, Nishimoto M, Himeno S, Imura N, Tsujimoto M, Kunimoto M, Hara S. Transcriptional regulation of thioredoxin reductase 1 expression by cadmium in vascular endothelial cells: role of NF-E2-related factor-2. J Cell Physiol. 2005;203:529–37.PubMedGoogle Scholar
  101. 101.
    Suliman HB, Carraway MS, Tatro LG, Piantadosi CA. A new activating role for CO in cardiac mitochondrial biogenesis. J Cell Sci. 2007;120:299–308.PubMedGoogle Scholar
  102. 102.
    Jin Y, Tanaka A, Choi AM, Ryter SW. Autophagic proteins: new facets of the oxygen paradox. Autophagy. 2012;8:426–8.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Imhoff BR, Hansen JM. Extracellular redox status regulates Nrf2 activation through mitochondrial reactive oxygen species. Biochem J. 2009;424:491–500.PubMedGoogle Scholar
  104. 104.
    Maechler P, Wollheim CB. Mitochondrial function in normal and diabetic beta-cells. Nature. 2001;414:807–12.PubMedGoogle Scholar
  105. 105.
    Lo SC, Hannink M. PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp Cell Res. 2008;314:1789–803.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Niture SK, Jaiswal AK. Inhibitor of Nrf2 (INrf2 or Keap1) protein degrades Bcl-xL via phosphoglycerate mutase 5 and controls cellular apoptosis. J Biol Chem. 2011;286:44542–56.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Niture SK, Jaiswal AK. Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem. 2012;287:9873–86.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012;148:228–43.PubMedGoogle Scholar
  109. 109.
    Lewerenz J, Albrecht P, Tien ML, Henke N, Karumbayaram S, Kornblum HI, Wiedau-Pazos M, Schubert D, Maher P, Methner A. Induction of Nrf2 and xCT are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. J Neurochem. 2009;111:332–43.PubMedGoogle Scholar
  110. 110.
    Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, Colell A. Mitochondrial glutathione: importance and transport. Semin Liver Dis. 1998;18:389–401.PubMedGoogle Scholar
  111. 111.
    Griffith OW, Meister A. Origin and turnover of mitochondrial glutathione. Proc Natl Acad Sci U S A. 1985;82:4668–72.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Ghosh S, Pulinilkunnil T, Yuen G, Kewalramani G, An D, Qi D, Abrahani A, Rodrigues B. Cardiomyocyte apoptosis induced by short-term diabetes requires mitochondrial GSH depletion. Am J Physiol Heart Circ Physiol. 2005;289:H768–76.PubMedGoogle Scholar
  113. 113.
    Winiarska K, Drozak J, Wegrzynowicz M, Fraczyk T, Bryla J. Diabetes-induced changes in glucose synthesis, intracellular glutathione status and hydroxyl free radical generation in rabbit kidney-cortex tubules. Mol Cell Biochem. 2004;261:91–8.PubMedGoogle Scholar
  114. 114.
    Kelner MJ, Montoya MA. Structural organization of the human glutathione reductase gene: determination of correct cDNA sequence and identification of a mitochondrial leader sequence. Biochem Biophys Res Commun. 2000;269:366–8.PubMedGoogle Scholar
  115. 115.
    Tamura T, McMicken HW, Smith CV, Hansen TN. Gene structure for mouse glutathione reductase, including a putative mitochondrial targeting signal. Biochem Biophys Res Commun. 1997;237:419–22.PubMedGoogle Scholar
  116. 116.
    Esposito LA, Kokoszka JE, Waymire KG, Cottrell B, MacGregor GR, Wallace DC. Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene. Free Radic Biol Med. 2000;28:754–66.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Arai M, Imai H, Koumura T, Yoshida M, Emoto K, Umeda M, Chiba N, Nakagawa Y. Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells. J Biol Chem. 1999;274:4924–33.PubMedGoogle Scholar
  118. 118.
    Godeas C, Sandri G, Panfili E. Distribution of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in rat testis mitochondria. Biochim Biophys Acta. 1994;1191:147–50.PubMedGoogle Scholar
  119. 119.
    Imai H, Nakagawa Y. Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic Biol Med. 2003;34:145–69.PubMedGoogle Scholar
  120. 120.
    Cai J, Yang J, Jones DP. Mitochondrial control of apoptosis: the role of cytochrome c. Biochim Biophys Acta. 1998;1366:139–49.PubMedGoogle Scholar
  121. 121.
    Rebrin I, Sohal RS. Comparison of thiol redox state of mitochondria and homogenates of various tissues between two strains of mice with different longevities. Exp Gerontol. 2004;39:1513–9.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Hurd TR, Costa NJ, Dahm CC, Beer SM, Brown SE, Filipovska A, Murphy MP. Glutathionylation of mitochondrial proteins. Antioxid Redox Signal. 2005;7:999–1010.PubMedGoogle Scholar
  123. 123.
    Dalle-Donne I, Rossi R, Giustarini D, Colombo R, Milzani A. S-glutathionylation in protein redox regulation. Free Radic Biol Med. 2007;43:883–98.PubMedGoogle Scholar
  124. 124.
    Hurd TR, Requejo R, Filipovska A, Brown S, Prime TA, Robinson AJ, Fearnley IM, Murphy MP. Complex I within oxidatively stressed bovine heart mitochondria is glutathionylated on Cys-531 and Cys-704 of the 75-kDa subunit: potential role of CYS residues in decreasing oxidative damage. J Biol Chem. 2008;283:24801–15.PubMedCentralPubMedGoogle Scholar
  125. 125.
    Applegate MA, Humphries KM, Szweda LI. Reversible inhibition of alpha-ketoglutarate dehydrogenase by hydrogen peroxide: glutathionylation and protection of lipoic acid. Biochemistry. 2008;47:473–8.PubMedGoogle Scholar
  126. 126.
    Nulton-Persson AC, Starke DW, Mieyal JJ, Szweda LI. Reversible inactivation of alpha-ketoglutarate dehydrogenase in response to alterations in the mitochondrial glutathione status. Biochemistry. 2003;42:4235–42.PubMedGoogle Scholar
  127. 127.
    Mieyal JJ, Gallogly MM, Qanungo S, Sabens EA, Shelton MD. Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal. 2008;10:1941–88.PubMedCentralPubMedGoogle Scholar
  128. 128.
    Jung CH, Thomas JA. S-glutathiolated hepatocyte proteins and insulin disulfides as substrates for reduction by glutaredoxin, thioredoxin, protein disulfide isomerase, and glutathione. Arch Biochem Biophys. 1996;335:61–72.PubMedGoogle Scholar
  129. 129.
    Gladyshev VN, Liu A, Novoselov SV, Krysan K, Sun QA, Kryukov VM, Kryukov GV, Lou MF. Identification and characterization of a new mammalian glutaredoxin (thioltransferase), Grx2. J Biol Chem. 2001;276:30374–80.PubMedGoogle Scholar
  130. 130.
    Johansson C, Lillig CH, Holmgren A. Human mitochondrial glutaredoxin reduces S-glutathionylated proteins with high affinity accepting electrons from either glutathione or thioredoxin reductase. J Biol Chem. 2004;279:7537–43.PubMedGoogle Scholar
  131. 131.
    Lundberg M, Johansson C, Chandra J, Enoksson M, Jacobsson G, Ljung J, Johansson M, Holmgren A. Cloning and expression of a novel human glutaredoxin (Grx2) with mitochondrial and nuclear isoforms. J Biol Chem. 2001;276:26269–75.PubMedGoogle Scholar
  132. 132.
    Hashemy SI, Johansson C, Berndt C, Lillig CH, Holmgren A. Oxidation and S-nitrosylation of cysteines in human cytosolic and mitochondrial glutaredoxins: effects on structure and activity. J Biol Chem. 2007;282:14428–36.PubMedGoogle Scholar
  133. 133.
    Gallogly MM, Starke DW, Leonberg AK, Ospina SM, Mieyal JJ. Kinetic and mechanistic characterization and versatile catalytic properties of mammalian glutaredoxin 2: implications for intracellular roles. Biochemistry. 2008;47:11144–57.PubMedCentralPubMedGoogle Scholar
  134. 134.
    Johansson C, Kavanagh KL, Gileadi O, Oppermann U. Reversible sequestration of active site cysteines in a 2Fe-2S-bridged dimer provides a mechanism for glutaredoxin 2 regulation in human mitochondria. J Biol Chem. 2007;282:3077–82.PubMedGoogle Scholar
  135. 135.
    Lillig CH, Berndt C, Vergnolle O, Lonn ME, Hudemann C, Bill E, Holmgren A. Characterization of human glutaredoxin 2 as iron-sulfur protein: a possible role as redox sensor. Proc Natl Acad Sci U S A. 2005;102:8168–73.PubMedCentralPubMedGoogle Scholar
  136. 136.
    Mitra S, Elliott SJ. Oxidative disassembly of the [2Fe-2S] cluster of human Grx2 and redox regulation in the mitochondria. Biochemistry. 2009;48:3813–5.PubMedGoogle Scholar
  137. 137.
    Gallogly MM, Mieyal JJ. Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress. Curr Opin Pharmacol. 2007;7:381–91.PubMedGoogle Scholar
  138. 138.
    Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL. Nrf2, a Cap‘n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem. 1999;274:26071–8.PubMedGoogle Scholar
  139. 139.
    Venugopal R, Jaiswal AK. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci U S A. 1996;93:14960–5.PubMedCentralPubMedGoogle Scholar
  140. 140.
    Chanas SA, Jiang Q, McMahon M, McWalter GK, McLellan LI, Elcombe CR, Henderson CJ, Wolf CR, Moffat GJ, Itoh K, Yamamoto M, Hayes JD. Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem J. 2002;365:405–16.PubMedCentralPubMedGoogle Scholar
  141. 141.
    Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem. 2000;275:16023–9.PubMedGoogle Scholar
  142. 142.
    Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. 2009;30:42–59.PubMedCentralPubMedGoogle Scholar
  143. 143.
    Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, Biswal S. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest. 2006;116:984–95.PubMedCentralPubMedGoogle Scholar
  144. 144.
    MacGarvey NC, Suliman HB, Bartz RR, Fu P, Withers CM, Welty-Wolf KE, Piantadosi CA. Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis. Am J Respir Crit Care Med. 2012;185:851–61.PubMedCentralPubMedGoogle Scholar
  145. 145.
    Cho H-Y, Jedlicka AE, Reddy SPM, Kensler TW, Yamamoto M, Zhang L-Y, Kleeberger SR. Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol. 2002;26:175–82.PubMedGoogle Scholar
  146. 146.
    Cho HY, Reddy SP, Yamamoto M, Kleeberger SR. The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J. 2004;18:1258–60.PubMedGoogle Scholar
  147. 147.
    Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005;202:47–59.PubMedCentralPubMedGoogle Scholar
  148. 148.
    Papaiahgari S, Kleeberger SR, Cho HY, Kalvakolanu DV, Reddy SP. NADPH oxidase and ERK signaling regulates hyperoxia-induced Nrf2-ARE transcriptional response in pulmonary epithelial cells. J Biol Chem. 2004;279:42302–12.PubMedGoogle Scholar
  149. 149.
    Reddy NM, Kleeberger SR, Bream JH, Fallon PG, Kensler TW, Yamamoto M, Reddy SP. Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling. Oncogene. 2008;27:5821–32.PubMedCentralPubMedGoogle Scholar
  150. 150.
    Reddy NM, Kleeberger SR, Kensler TW, Yamamoto M, Hassoun PM, Reddy SP. Disruption of Nrf2 impairs the resolution of hyperoxia-induced acute lung injury and inflammation in mice. J Immunol. 2009;182:7264–71.PubMedCentralPubMedGoogle Scholar
  151. 151.
    Cho HY, van Houten B, Wang X, Miller-DeGraff L, Fostel J, Gladwell W, Perrow L, Panduri V, Kobzik L, Yamamoto M, Bell DA, Kleeberger SR. Targeted deletion of nrf2 impairs lung development and oxidant injury in neonatal mice. Antioxid Redox Signal. 2012;17: 1066–82.PubMedCentralPubMedGoogle Scholar
  152. 152.
    Reddy NM, Kleeberger SR, Cho HY, Yamamoto M, Kensler TW, Biswal S, Reddy SP. Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants. Am J Respir Cell Mol Biol. 2007;37:3–8.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Reddy NM, Kleeberger SR, Yamamoto M, Kensler TW, Scollick C, Biswal S, Reddy SP. Genetic dissection of the Nrf2-dependent redox signaling regulated transcriptional programs of cell proliferation and cytoprotection. Physiol Genomics. 2007;32:74–81.PubMedGoogle Scholar
  154. 154.
    Morito N, Yoh K, Itoh K, Hirayama A, Koyama A, Yamamoto M, Takahashi S. Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels. Oncogene. 2003;22:9275–81.PubMedGoogle Scholar
  155. 155.
    Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P, Tuder RM, Biswal S. Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med. 2008;178:592–604.PubMedCentralPubMedGoogle Scholar
  156. 156.
    Wilson MA. The role of cysteine oxidation in DJ-1 function and dysfunction. Antioxid Redox Signal. 2011;15:111–22.PubMedCentralPubMedGoogle Scholar
  157. 157.
    Marzec JM, Christie JD, Reddy SP, Jedlicka AE, Vuong H, Lanken PN, Aplenc R, Yamamoto T, Yamamoto M, Cho HY, Kleeberger SR. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J. 2007;21:2237–46.PubMedGoogle Scholar
  158. 158.
    Hua CC, Chang LC, Tseng JC, Chu CM, Liu YC, Shieh WB. Functional haplotypes in the promoter region of transcription factor Nrf2 in chronic obstructive pulmonary disease. Dis Markers. 2010;28:185–93.PubMedCentralPubMedGoogle Scholar
  159. 159.
    Sandford AJ, Malhotra D, Boezen HM, Siedlinski M, Postma DS, Wong V, Akhabir L, He JQ, Connett JE, Anthonisen NR, Pare PD, Biswal S. NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease. Physiol Genomics. 2012;44:754–63.PubMedCentralPubMedGoogle Scholar
  160. 160.
    Harvey CJ, Thimmulappa RK, Sethi S, Kong X, Yarmus L, Brown RH, Feller-Kopman D, Wise R, Biswal S. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci Transl Med. 2011;3:78ra32.PubMedGoogle Scholar
  161. 161.
    Malhotra D, Thimmulappa RK, Mercado N, Ito K, Kombairaju P, Kumar S, Ma J, Feller-Kopman D, Wise R, Barnes P, Biswal S. Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. J Clin Invest. 2011;121:4289–302.PubMedCentralPubMedGoogle Scholar
  162. 162.
    Tufekci KU, Civi Bayin E, Genc S, Genc K. The Nrf2/ARE pathway: a promising target to counteract mitochondrial dysfunction in Parkinson’s disease. Parkinsons Dis. 2011;2011:314082.Google Scholar
  163. 163.
    Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Jordan-Sciutto KL. Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol. 2007;66:75–85.PubMedCentralPubMedGoogle Scholar
  164. 164.
    Bastar I, Seckin S, Uysal M, Aykac-Toker G. Effect of streptozotocin on glutathione and lipid peroxide levels in various tissues of rats. Res Commun Mol Pathol Pharmacol. 1998;102: 265–72.PubMedGoogle Scholar
  165. 165.
    Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A. 2004;101:3381–6.PubMedCentralPubMedGoogle Scholar
  166. 166.
    Fahey JW, Talalay P. Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxification enzymes. Food Chem Toxicol. 1999;37:973–9.PubMedGoogle Scholar
  167. 167.
    Juge N, Mithen RF, Traka M. Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci. 2007;64:1105–27.PubMedGoogle Scholar
  168. 168.
    Liby KT, Yore MM, Sporn MB. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer. 2007;7:357–69.PubMedGoogle Scholar
  169. 169.
    Reddy NM, Suryanaraya V, Yates MS, Kleeberger SR, Hassoun PM, Yamamoto M, Liby KT, Sporn MB, Kensler TW, Reddy SP. The triterpenoid CDDO-imidazolide confers potent protection against hyperoxic acute lung injury in mice. Am J Respir Crit Care Med. 2009;180:867–74.PubMedCentralPubMedGoogle Scholar
  170. 170.
    Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, Sporn MB, Yamamoto M, Kensler TW, Biswal S. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun. 2006;351: 883–9.PubMedCentralPubMedGoogle Scholar
  171. 171.
    Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, Biswal S. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci U S A. 2009;106:250–5.PubMedCentralPubMedGoogle Scholar
  172. 172.
    de Zeeuw D1, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM; BEACON Trial Investigators. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2014;369:2492–503.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Narsa M. Reddy
    • 1
  • Wajiha Qureshi
    • 1
  • Haranath Potteti
    • 1
  • Dhananjaya V. Kalvakolanu
    • 2
  • Sekhar P. Reddy
    • 3
    Email author
  1. 1.Department of PediatricsUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of Microbiology and ImmunologyUniversity of MarylandBaltimoreUSA
  3. 3.Department of Pediatrics, College of MedicineUniversity of Illinois at ChicagoChicagoUSA

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