title: Redox homeostasis: The Golden Mean of healthy living.
abstract: The notion that electrophiles serve as messengers in cell signaling is now widely accepted. Nonetheless, major issues restrain acceptance of redox homeostasis and redox signaling as components of maintenance of a normal physiological steady state. The first is that redox signaling requires sudden switching on of oxidant production and bypassing of antioxidant mechanisms rather than a continuous process that, like other signaling mechanisms, can be smoothly turned up or down. The second is the misperception that reactions in redox signaling involve "reactive oxygen species" rather than reaction of specific electrophiles with specific protein thiolates. The third is that hormesis provides protection against oxidants by increasing cellular defense or repair mechanisms rather than by specifically addressing the offset of redox homeostasis. Instead, we propose that both oxidant and antioxidant signaling are main features of redox homeostasis. As the redox shift is rapidly reversed by feedback reactions, homeostasis is maintained by continuous signaling for production and elimination of electrophiles and nucleophiles. Redox homeostasis, which is the maintenance of nucleophilic tone, accounts for a healthy physiological steady state. Electrophiles and nucleophiles are not intrinsically harmful or protective, and redox homeostasis is an essential feature of both the response to challenges and subsequent feedback. While the balance between oxidants and nucleophiles is preserved in redox homeostasis, oxidative stress provokes the establishment of a new radically altered redox steady state. The popular belief that scavenging free radicals by antioxidants has a beneficial effect is wishful thinking. We propose, instead, that continuous feedback preserves nucleophilic tone and that this is supported by redox active nutritional phytochemicals. These nonessential compounds, by activating Nrf2, mimic the effect of endogenously produced electrophiles (parahormesis). In summary, while hormesis, although globally protective, results in setting up of a new phenotype, parahormesis contributes to health by favoring maintenance of homeostasis.
authors.affiliation: Department of Molecular Medicine, University of Padova, Viale G. Colombo 3, I-35121 Padova, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Ursini
authors.affiliation: Department of Molecular Medicine, University of Padova, Viale G. Colombo 3, I-35121 Padova, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Maiorino
authors.affiliation: Andrus Gerontology Center of the Davis School of Gerontology, University of Southern, California, 3715 McClintock Ave, Los Angeles, CA 90089-0191, USA.
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
mesh_terms: D000975:Antioxidants / Q000378:metabolism* / Q000627:therapeutic use; D006706:Homeostasis / Q000187:drug effects; D059165:Hormesis / Q000235:genetics; D006801:Humans; D007700:Kinetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D064209:Phytochemicals / Q000378:metabolism* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D064209:Phytochemicals; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds
keywords: Hormesis; Kinetics; Oxidative stress; Phytochemicals; Signaling; Thiols
references.citation: J Immunol. 1999 Mar 1;162(5):3005-12
references.pmid: 10072552
references.citation: Nature. 1999 Sep 2;401(6748):79-82
references.pmid: 10485709
references.citation: J Biol Chem. 1999 Nov 19;274(47):33627-36
references.pmid: 10559251
references.citation: J Biol Chem. 2000 May 19;275(20):15466-73
references.pmid: 10747902
references.citation: Nature. 2000 Apr 13;404(6779):787-90
references.pmid: 10783895
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12475-80
references.pmid: 11035812
references.citation: Trends Biochem Sci. 2000 Oct;25(10):459-61
references.pmid: 11050424
references.citation: J Biol Chem. 1975 Feb 25;250(4):1422-6
references.pmid: 1112810
references.citation: J Biol Chem. 2001 May 18;276(20):16683-9
references.pmid: 11278967
references.citation: Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2126-35
references.pmid: 11299214
references.citation: Circ Res. 2001 May 11;88(9):888-94
references.pmid: 11348997
references.citation: Gene. 2001 May 16;269(1-2):131-40
references.pmid: 11376945
references.citation: Am J Respir Cell Mol Biol. 2001 Aug;25(2):254-9
references.pmid: 11509337
references.citation: J Biol Chem. 2002 Feb 1;277(5):3101-8
references.pmid: 11719508
references.citation: J Am Chem Soc. 2001 Dec 19;123(50):12439-48
references.pmid: 11741406
references.citation: Free Radic Biol Med. 2002 Apr 1;32(7):650-62
references.pmid: 11909699
references.citation: J Biol Chem. 2002 Jun 7;277(23):20336-42
references.pmid: 11916965
references.citation: Hum Exp Toxicol. 2002 Feb;21(2):91-7
references.pmid: 12102503
references.citation: Am J Respir Crit Care Med. 2002 Aug 15;166(4):490-5
references.pmid: 12186826
references.citation: Annu Rev Pharmacol Toxicol. 2003;43:233-60
references.pmid: 12359864
references.citation: Chem Res Toxicol. 2002 Nov;15(11):1445-50
references.pmid: 12437335
references.citation: Nitric Oxide. 2002 Dec;7(4):244-53
references.pmid: 12446173
references.citation: J Biol Chem. 2003 Mar 7;278(10):8135-45
references.pmid: 12506115
references.citation: FASEB J. 2003 Mar;17(3):473-5
references.pmid: 12514113
references.citation: J Biol Chem. 2003 Jun 13;278(24):21592-600
references.pmid: 12682069
references.citation: Prog Lipid Res. 2003 Jul;42(4):318-43
references.pmid: 12689622
references.citation: Mol Cell Biol. 2003 Jul;23(13):4673-86
references.pmid: 12808106
references.citation: J Biol Chem. 2003 Nov 7;278(45):44675-82
references.pmid: 12947090
references.citation: J Biol Chem. 2004 Mar 5;279(10):8919-29
references.pmid: 14688281
references.citation: Free Radic Res Commun. 1992;17(4):221-37
references.pmid: 1473734
references.citation: Ann N Y Acad Sci. 2003 Dec;1010:405-16
references.pmid: 15033761
references.citation: Free Radic Biol Med. 2004 May 15;36(10):1199-207
references.pmid: 15110384
references.citation: J Biol Chem. 2004 Jul 30;279(31):32196-204
references.pmid: 15166241
references.citation: Yakugaku Zasshi. 2004 Dec;124(12):937-57
references.pmid: 15577264
references.citation: J Biol Chem. 2005 Apr 29;280(17):16891-900
references.pmid: 15734732
references.citation: IUBMB Life. 2005 Apr-May;57(4-5):283-95
references.pmid: 16036612
references.citation: J Nutr. 2005 Aug;135(8):1841-6
references.pmid: 16046706
references.citation: J Biol Chem. 2005 Nov 25;280(47):39505-9
references.pmid: 16183647
references.citation: J Biol Chem. 2006 Mar 3;281(9):5657-67
references.pmid: 16407283
references.citation: Chem Biol Interact. 2006 Mar 10;160(1):1-40
references.pmid: 16430879
references.citation: Circ Res. 2006 Mar 3;98(4):453-62
references.pmid: 16514078
references.citation: Oncogene. 2006 Sep 7;25(40):5485-94
references.pmid: 16619039
references.citation: Free Radic Res. 2006 Aug;40(8):865-74
references.pmid: 17015265
references.citation: J Biol Chem. 2007 Feb 2;282(5):2871-9
references.pmid: 17132626
references.citation: Am J Respir Cell Mol Biol. 2007 May;36(5):594-9
references.pmid: 17158358
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references.pmid: 17183360
references.citation: Redox Rep. 2007;12(1):101-6
references.pmid: 17263920
references.citation: Biochem Soc Trans. 2007 Apr;35(Pt 2):231-5
references.pmid: 17371246
references.citation: Biochem J. 2007 Jul 15;405(2):251-9
references.pmid: 17407446
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: Cancer Cell. 2007 Sep;12(3):230-8
references.pmid: 17785204
references.citation: Neurochem Int. 2008 Mar-Apr;52(4-5):776-85
references.pmid: 17977619
references.citation: Am J Respir Cell Mol Biol. 2008 Apr;38(4):483-90
references.pmid: 18048804
references.citation: Med Res Rev. 2008 Jul;28(4):569-631
references.pmid: 18058921
references.citation: Cell. 2008 Feb 8;132(3):344-62
references.pmid: 18267068
references.citation: Am J Respir Cell Mol Biol. 2008 Jul;39(1):97-104
references.pmid: 18276794
references.citation: FEBS Lett. 2008 Jun 11;582(13):1913-8
references.pmid: 18501712
references.citation: Nucleic Acids Res. 2008 Aug;36(13):4327-36
references.pmid: 18586825
references.citation: Nature. 2008 Jul 24;454(7203):428-35
references.pmid: 18650913
references.citation: Nature. 2008 Jul 24;454(7203):455-62
references.pmid: 18650916
references.citation: Cell Metab. 2008 Sep;8(3):237-48
references.pmid: 18762024
references.citation: Endocr Rev. 2008 Dec;29(7):777-822
references.pmid: 18971485
references.citation: Trends Biochem Sci. 2009 Apr;34(4):176-88
references.pmid: 19321346
references.citation: Hepatology. 2009 Jun;49(6):1982-91
references.pmid: 19399914
references.citation: Mol Cell. 2009 Jun 26;34(6):663-73
references.pmid: 19560419
references.citation: Antioxid Redox Signal. 2010 Jan;12(1):53-91
references.pmid: 19634988
references.citation: Toxicol Ind Health. 2009 May-Jun;25(4-5):269-78
references.pmid: 19651797
references.citation: Toxicol Appl Pharmacol. 2010 Apr 1;244(1):16-20
references.pmid: 19665035
references.citation: Antioxid Redox Signal. 2010 Feb;12(2):233-48
references.pmid: 19697995
references.citation: Nat Med. 2009 Sep;15(9):1077-81
references.pmid: 19701206
references.citation: Antioxid Redox Signal. 2010 Apr 1;12(7):819-27
references.pmid: 19769463
references.citation: J Cell Sci. 2009 Dec 15;122(Pt 24):4452-64
references.pmid: 19920073
references.citation: Biochem Pharmacol. 2010 Apr 15;79(8):1141-8
references.pmid: 20006591
references.citation: IUBMB Life. 2010 Mar;62(3):237-46
references.pmid: 20232342
references.citation: Cell. 2010 Mar 19;140(6):771-6
references.pmid: 20303867
references.citation: Atherosclerosis. 2010 Nov;213(1):122-8
references.pmid: 20688330
references.citation: Ann N Y Acad Sci. 2010 Aug;1203:35-44
references.pmid: 20716281
references.citation: Circ Res. 2010 Sep 3;107(5):579-91
references.pmid: 20814028
references.citation: Biochem Pharmacol. 2011 Feb 1;81(3):327-36
references.pmid: 20955689
references.citation: Cell Res. 2011 Jan;21(1):103-15
references.pmid: 21187859
references.citation: Antioxid Redox Signal. 2011 Oct 15;15(8):2335-81
references.pmid: 21194351
references.citation: Amino Acids. 2012 May;42(5):1927-35
references.pmid: 21537880
references.citation: Free Radic Biol Med. 2011 Sep 15;51(6):1184-94
references.pmid: 21741475
references.citation: J Biol Chem. 2011 Sep 16;286(37):32651-60
references.pmid: 21784859
references.citation: J Biol Chem. 2012 Feb 10;287(7):4434-40
references.pmid: 21832045
references.citation: Int J Obes (Lond). 2012 Dec;36(12):1503-13
references.pmid: 22430302
references.citation: Trends Cell Biol. 2012 May;22(5):274-82
references.pmid: 22444729
references.citation: Cell. 2012 May 25;149(5):1060-72
references.pmid: 22632970
references.citation: Antioxid Redox Signal. 2012 Dec 15;17(12):1694-713
references.pmid: 22656858
references.citation: Nat Rev Cancer. 2012 Jul 19;12(8):564-71
references.pmid: 22810811
references.citation: Sci Signal. 2012 Sep 18;5(242):pe39
references.pmid: 22990116
references.citation: PLoS One. 2012;7(10):e48393
references.pmid: 23144758
references.citation: Curr Diabetes Rev. 2013 Mar 1;9(2):137-45
references.pmid: 23363332
references.citation: Cell. 2013 Feb 14;152(4):673-84
references.pmid: 23415219
references.citation: Chem Rev. 2013 Jul 10;113(7):4633-79
references.pmid: 23514336
references.citation: Free Radic Biol Med. 2013 Aug;61:95-110
references.pmid: 23542362
references.citation: Free Radic Biol Med. 2013 Oct;63:207-21
references.pmid: 23702245
references.citation: Free Radic Biol Med. 2014 Jan;66:24-35
references.pmid: 23747930
references.citation: Sci Rep. 2013;3:2006
references.pmid: 23774320
references.citation: Curr Drug Targets. 2014 Jan;15(1):65-79
references.pmid: 24387334
references.citation: Cell. 2014 Jan 16;156(1-2):317-331
references.pmid: 24439385
references.citation: Sci Transl Med. 2014 Jan 29;6(221):221ra15
references.pmid: 24477002
references.citation: Cell Metab. 2014 Feb 4;19(2):232-45
references.pmid: 24506865
references.citation: J Cell Sci. 2014 May 1;127(Pt 9):1911-23
references.pmid: 24569874
references.citation: Cell Calcium. 2014 Nov;56(5):390-6
references.pmid: 25224502
references.citation: Cell Death Dis. 2014 Dec 04;5:e1552
references.pmid: 25476900
references.citation: Cell. 2014 Dec 4;159(6):1253-62
references.pmid: 25480291
references.citation: Science. 2015 Mar 13;347(6227):1253-6
references.pmid: 25721504
references.citation: Arch Biochem Biophys. 2015 Apr 1;571:50-7
references.pmid: 25731857
references.citation: Nature. 2015 Apr 2;520(7545):57-62
references.pmid: 25799988
references.citation: Semin Immunol. 2015 May;27(3):200-15
references.pmid: 25857211
references.citation: Free Radic Biol Med. 2015 Nov;88(Pt B):199-204
references.pmid: 26117325
references.citation: Cell Death Differ. 2015 Aug;22(8):1237-8
references.pmid: 26143748
references.citation: Gene. 2015 Nov 15;573(1):1-32
references.pmid: 26216303
references.citation: Free Radic Biol Med. 2015 Nov;88(Pt B):91-92
references.pmid: 26303332
references.citation: Oncotarget. 2015 Sep 15;6(27):24393-403
references.pmid: 26405158
references.citation: Cancers (Basel). 2015 Nov 10;7(4):2262-76
references.pmid: 26569310
references.citation: Trends Cell Biol. 2016 Mar;26(3):165-176
references.pmid: 26653790
references.citation: Environ Health Perspect. 1985 Dec;64:111-26
references.pmid: 3007083
references.citation: Adv Enzyme Regul. 1985;23:217-37
references.pmid: 3907304
references.citation: J Free Radic Biol Med. 1985;1(2):97-101
references.pmid: 3939138
references.citation: Biochim Biophys Acta. 1985 Mar 29;839(1):62-70
references.pmid: 3978121
references.citation: J Clin Invest. 1973 Mar;52(3):741-4
references.pmid: 4346473
references.citation: Biochem Biophys Res Commun. 1974 Oct 8;60(3):1044-50
references.pmid: 4372996
references.citation: J Biol Chem. 1971 Nov 25;246(22):6886-90
references.pmid: 4399476
references.citation: J Biol Chem. 1972 May 25;247(10):3170-5
references.pmid: 4623845
references.citation: J Biol Chem. 1972 Nov 10;247(21):6960-2
references.pmid: 4673289
references.citation: Am J Physiol. 1974 Jun;226(6):1401-7
references.pmid: 4833996
references.citation: FEBS Lett. 1974 May 15;42(1):68-72
references.pmid: 4859511
references.citation: J Biol Chem. 1968 Nov 10;243(21):5753-60
references.pmid: 4972775
references.citation: Biochem Biophys Res Commun. 1969 Sep 10;36(6):891-7
references.pmid: 5388670
references.citation: Am J Pathol. 1984 Nov;117(2):273-85
references.pmid: 6238536
references.citation: Biochim Biophys Acta. 1980 Nov 7;620(2):281-96
references.pmid: 6254573
references.citation: Prostaglandins. 1983 Apr;25(4):531-40
references.pmid: 6410459
references.citation: Biochem J. 1982 Oct 15;208(1):129-40
references.pmid: 7159389
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1978 Nov;45(5):699-704
references.pmid: 730565
references.citation: J Biol Chem. 1994 Feb 18;269(7):4705-8
references.pmid: 7508926
references.citation: J Lipid Mediat Cell Signal. 1995 Jan;11(1):51-61
references.pmid: 7728417
references.citation: J Biol Chem. 1994 Oct 21;269(42):26512-7
references.pmid: 7929374
references.citation: Am J Physiol. 1994 Oct;267(4 Pt 1):L414-21
references.pmid: 7943345
references.citation: J Biol Chem. 1996 Mar 1;271(9):4653-8
references.pmid: 8617728
references.citation: Free Radic Biol Med. 1996;21(3):401-5
references.pmid: 8855453
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14960-5
references.pmid: 8962164
references.citation: Science. 1997 Jan 3;275(5296):90-4
references.pmid: 8974401
references.citation: Toxicol Appl Pharmacol. 1996 Dec;141(2):416-24
references.pmid: 8975766
references.citation: FASEB J. 1997 Apr;11(5):374-5
references.pmid: 9141504
references.citation: Am J Respir Cell Mol Biol. 1998 Mar;18(3):384-91
references.pmid: 9490656
references.citation: EMBO J. 1998 May 1;17(9):2596-606
references.pmid: 9564042
references.citation: J Lipid Res. 1998 Aug;39(8):1529-42
references.pmid: 9717713
references.citation: J Clin Invest. 1998 Dec 1;102(11):1942-50
references.pmid: 9835619
references.citation: Oncogene. 1998 Dec 17;17(24):3145-56
references.pmid: 9872330
references.citation: J Biol Chem. 1999 Jan 22;274(4):2234-42
references.pmid: 9890986