Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders.
Despite the capacity of chaperones and other homeostatic components to restore folding equilibrium, cells appear poorly adapted for chronic oxidative stress that increases in cancer and in metabolic and neurodegenerative diseases. Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This article introduces the concept of hormesis and its applications to the field of neuroprotection. It is argued that the hormetic dose response provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose-response relationships, their mechanistic foundations, and their relationship to the concept of biological plasticity, as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This article describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including sirtuin and Nrf2 and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. Particular attention is given to the emerging role of nitric oxide, carbon monoxide, and hydrogen sulfide gases in hormetic-based neuroprotection and their relationship to membrane radical dynamics and mitochondrial redox signaling.
Calabrese
Vittorio
V
Department of Chemistry, University of Catania, Italy. calabres@unict.it
Cornelius
Carolin
C
Dinkova-Kostova
Albena T
AT
Calabrese
Edward J
EJ
Mattson
Mark P
MP
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009410:Nerve Degeneration; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D008517:Phytotherapy; D037761:Sirtuins / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D018832:Molecular Chaperones; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D037761:Sirtuins
Neurochem Res. 2008 Dec;33(12):2444-71
18629638
Mol Cell Biol. 2003 Nov;23(22):8137-51
14585973
Cell Calcium. 2002 Nov-Dec;32(5-6):269-78
12543089
Regul Toxicol Pharmacol. 2002 Jun;35(3):414-28
12202056
Antioxid Redox Signal. 2002 Apr;4(2):241-8
12006175
Chem Biol Drug Des. 2009 Dec;74(6):619-24
19843076
Anal Biochem. 1988 Mar;169(2):328-36
3382006
Cancer Res. 1951 May;11(5):301-3
14831069
J Neurosci. 1997 Feb 1;17(3):1046-54
8994059
Nature. 2007 Nov 29;450(7170):712-6
18046409
Biomed Biochim Acta. 1990;49(4):293-6
1976302
Hum Exp Toxicol. 2000 Jan;19(1):85-97
10745296
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13943-8
8943040
Crit Rev Toxicol. 2008;38(4):253-348
18432419
Neuromolecular Med. 2006;8(3):389-414
16775390
J Natl Cancer Inst. 1972 May;48(5):1425-30
5030956
Trends Neurosci. 2000 May;23(5):222-9
10782128
Neurotox Res. 2009 Oct;16(3):293-305
19526276
Neurobiol Dis. 2007 Apr;26(1):212-20
17306982
J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Oct 15;877(28):3366-77
19505855
Cancer Res. 1990 Dec 15;50(24):7871-5
2123743
Adv Enzyme Regul. 1982;20:287-300
6180607
Adv Cancer Res. 1953;1:339-96
13057708
Mol Pharmacol. 1993 Jun;43(6):965-9
8391121
Crit Rev Toxicol. 2003;33(3-4):305-53
12809428
Methods Enzymol. 2008;441:329-38
18554543
Annu Rev Pharmacol Toxicol. 2007;47:89-116
16968214
Antioxid Redox Signal. 2010 May 15;12(10):1203-17
19769484
J Neurosci. 1992 Apr;12(4):1558-66
1313498
Br Med Bull. 1947;4(5-6):345-8
20240887
Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9133-6
15184665
Methods Enzymol. 2004;382:449-56
15047116
Int J Mol Med. 2008 Oct;22(4):529-39
18813861
Neurol Res. 2009 Feb;31(1):23-7
18768114
Blood. 2007 Apr 1;109(7):2727-35
17110449
Am J Respir Cell Mol Biol. 2007 Feb;36(2):166-74
16990612
Neuropharmacology. 2008 Sep;55(3):334-44
18402985
Adv Enzyme Regul. 2004;44:335-67
15581500
J Neurosci Res. 1999 Sep 15;57(6):830-9
10467254
Lancet. 2008 Oct 25;372(9648):1463-72
18970976
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 Jan 1;61(Pt 1):153-5
16508120
Biopolymers. 2010 Mar;93(3):229-36
19768782
Science. 2003 Jan 10;299(5604):256-9
12446870
Neuron. 2008 Dec 10;60(5):748-66
19081372
Neurobiol Aging. 2009 Oct;30(10):1523-34
19631409
Crit Rev Toxicol. 2003;33(3-4):215-304
12809427
J Synchrotron Radiat. 2008 May;15(Pt 3):273-6
18421157
Nat Med. 2003 Feb;9(2):183-90
12539038
Br J Dermatol. 2001 Jun;144(6):1114-20
11422029
Br J Pharmacol. 2005 Nov;146(6):769-80
16170327
J Biosci. 2007 Apr;32(3):511-5
17536170
Free Radic Biol Med. 2000 Aug;29(3-4):231-40
11035251
J Neurosci. 2009 Jun 24;29(25):8288-97
19553468
Dose Response. 2007 Sep 30;5(4):308-14
18648564
N Engl J Med. 2005 Oct 6;353(14):1489-501
16207851
Stroke. 2009 Mar;40(3):922-9
19164785
Mutat Res. 2006 May 11;597(1-2):5-10
16414088
N Engl J Med. 2006 Nov 23;355(21):2254-5
17124027
J Cell Sci. 2007 Jan 15;120(Pt 2):299-308
17179207
Toxicol Sci. 2003 Feb;71(2):246-50
12563110
J Neuroimmunol. 2005 Sep;166(1-2):132-43
15993952
Cell Mol Biol (Noisy-le-grand). 2005 Dec 14;51(7):643-54
16359616
Science. 1993 Jan 15;259(5093):381-4
7678352
Diabetes Metab Res Rev. 1999 Jul-Aug;15(4):283-8
10495477
Annu Rev Public Health. 2001;22:15-33
11274508
Nutr Neurosci. 2005 Apr;8(2):101-10
16053242
Crit Rev Toxicol. 2003;33(3-4):355-405
12809429
J Mol Cell Cardiol. 2006 Feb;40(2):313-20
16337960
Pflugers Arch. 2009 Sep;458(5):937-52
19430810
Free Radic Biol Med. 2009 Feb 15;46(4):492-501
19071211
Eur J Cell Biol. 2010 Feb-Mar;89(2-3):262-9
20004495
J Biol Chem. 2006 Dec 15;281(50):38459-65
17008316
Curr Protein Pept Sci. 2009 Oct;10(5):432-46
19538153
Int J Mol Med. 2007 Jan;19(1):165-72
17143561
Cell. 2006 Dec 15;127(6):1109-22
17112576
Ann N Y Acad Sci. 2008 Dec;1147:61-9
19076431
Methods Enzymol. 2004;382:243-58
15047106
Crit Rev Toxicol. 2008;38(5):463-71
18568866
Nature. 1968 Nov 16;220(5168):707-8
5688144
Hum Mol Genet. 2007 Jan 1;16(1):50-60
17116640
Arch Toxicol. 2009 Mar;83(3):227-47
19234688
J Neurosci Res. 2006 Aug 1;84(2):418-26
16634068
Crit Rev Toxicol. 2005 Jul;35(6):463-582
16422392
Carcinogenesis. 2009 Jun;30(6):1024-31
19386581
Dose Response. 2006 May 01;3(3):443-51
18648620
Eur J Pharmacol. 2008 Oct 10;594(1-3):1-8
18680741
Crit Rev Toxicol. 2008;38(5):473-87
18568867
Ageing Res Rev. 2008 Jan;7(1):43-8
17913594
Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):444-77
16677090
Mech Ageing Dev. 2007 May-Jun;128(5-6):412-4
17452047
Antioxid Redox Signal. 2009 Nov;11(11):2759-75
19583493
Nat Rev Drug Discov. 2008 Oct;7(10):841-53
18827827
Biochem Biophys Res Commun. 2007 Aug 3;359(3):665-71
17560549
J Neurosci. 2003 Jul 2;23(13):5789-98
12843283
Antioxid Redox Signal. 2009 Nov;11(11):2717-39
19558211
Front Biosci (Landmark Ed). 2009 Jan 01;14:376-97
19273073
Science. 2003 Feb 7;299(5608):896-9
12574632
EMBO J. 2009 May 6;28(9):1296-307
19339992
Biol Pharm Bull. 2010;33(1):29-34
20045931
Nat Cell Biol. 2010 Mar;12(3):213-23
20173742
Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22
9240432
Prog Lipid Res. 2006 Jan;45(1):42-72
16445986
Aging Cell. 2007 Jun;6(3):337-50
17328689
Nat Rev Drug Discov. 2007 Nov;6(11):917-35
17948022
PLoS One. 2008;3(12):e4090
19116652
J Neurosci. 2008 Nov 5;28(45):11500-10
18987186
J Theor Biol. 1977 Nov 7;69(1):101-12
592862
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):244-9
15611470
Toxicol Sci. 2008 Jul;104(1):218-27
18417483
Photochem Photobiol. 2004 Jun;79(6):494-8
15291298
Biochem Biophys Res Commun. 2009 Jan 2;378(1):6-9
19010308
Biofactors. 2000;12(1-4):5-11
11216505
Biochem J. 2004 Mar 1;378(Pt 2):373-82
14616092
Parkinsonism Relat Disord. 2009 Nov;15(9):649-54
19345133
Cancer Res. 1985 Feb;45(2):546-51
3917849
J Biol Chem. 1969 Dec 10;244(23):6388-94
4390967
Ann Neurol. 2002 Oct;52(4):448-57
12325074
J Biol Chem. 2006 Aug 4;281(31):21745-21754
16751189
J Natl Cancer Inst. 1954 Dec;15(3):519-27
13233906
J Cereb Blood Flow Metab. 2005 Mar;25(3):348-57
15660100
Acta Pharmacol Sin. 2007 Sep;28(9):1343-54
17723168
Science. 2009 Feb 20;323(5917):1063-6
19229036
Dose Response. 2006 Aug 25;5(1):80-90
18648610
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2445-50
10051662
J Biol Chem. 2004 Dec 24;279(52):54750-8
15475350
J Neurochem. 2009 Sep;110(5):1445-56
19558452
J Biol Chem. 2008 May 23;283(21):14430-44
18375950
Nat Neurosci. 2005 May;8(5):657-63
15834418
J Biol Chem. 2000 May 5;275(18):13613-20
10788478
Joint Bone Spine. 2007 Jul;74(4):324-9
17590367
Cell Stress Chaperones. 2009 Jul;14(4):407-15
19105051
J Neurochem. 2007 Apr;101(1):109-19
17394461
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11908-13
12193649
Biochem Biophys Res Commun. 2006 Jan 6;339(1):79-88
16293230
Free Radic Biol Med. 2000 Apr 15;28(8):1303-12
10889462
Crit Rev Toxicol. 2003;33(3-4):407-24
12809430
J Neurotrauma. 2000 Oct;17(10):871-90
11063054
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4584-9
15767573
Antioxid Redox Signal. 2007 Nov;9(11):2035-41
17822366
Oncogene. 2008 Oct 27;27(50):6489-506
18955975
Cell Death Differ. 2007 Jul;14(7):1305-14
17431424
Dose Response. 2008;6(4):333-51
19088900
Trends Cardiovasc Med. 2001 Apr-May;11(3-4):148-55
11686005
Antioxid Redox Signal. 2004 Oct;6(5):811-8
15345140
Dalton Trans. 2007 May 7;(17):1651-60
17443255
Biochemistry. 1986 Jan 14;25(1):152-61
3006748
J Clin Invest. 2001 Nov;108(10):1439-50
11714735
Ann N Y Acad Sci. 2007 Oct;1113:147-58
17656567
J Biol Chem. 2003 Sep 26;278(39):37948-56
12842875
Dose Response. 2008 Feb 01;6(1):1-15
18648574
Rev Neurosci. 1998;9(2):105-16
9711902
Ecotoxicol Environ Saf. 1999 Feb;42(2):135-7
10051361
Int J Toxicol. 2008 Sep-Oct;27(5):369-78
19037807
Crit Rev Toxicol. 2008;38(4):391-418
18432421
Adv Enzyme Regul. 2003;43:121-34
12791387
Hum Exp Toxicol. 2000 Jan;19(1):32-40
10745293
Science. 2007 Jul 27;317(5837):516-9
17588900
Proc Natl Acad Sci U S A. 2009 May 26;106(21):8665-70
19433800
Res Immunol. 1998 Sep-Oct;149(7-8):741-4
9851535
Annu Rev Pharmacol Toxicol. 1997;37:517-54
9131263
Mol Cell. 2003 Mar;11(3):619-33
12667446
J Neurochem. 2008 Jul;106(1):107-20
18346206
Curr Top Cell Regul. 2000;36:181-99
10842752
J Neurosci Res. 1999 Jul 15;57(2):195-206
10398297
Crit Rev Toxicol. 2008;38(7):591-8
18709567
J Biol Chem. 2004 Jul 2;279(27):28733-43
15102845
Methods Enzymol. 2004;382:380-414
15047113
Ann N Y Acad Sci. 2009 Aug;1171:391-8
19723081
Ann N Y Acad Sci. 2007 Oct;1113:178-91
17483209
J Neurosci. 2008 Dec 10;28(50):13574-81
19074031
Antioxid Redox Signal. 2009 Mar;11(3):497-508
18717629
J Biol Chem. 2005 Jun 17;280(24):22925-36
15840590
J Neurochem. 2002 Jul;82(2):420-9
12124443
Circ Res. 2009 Aug 14;105(4):365-74
19608979
Mol Pharmacol. 2008 Oct;74(4):980-9
18621927
Environ Pollut. 2009 Jan;157(1):42-8
18790554
Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):395-403
16677086
Adv Exp Med Biol. 2007;594:78-88
17205677
Trends Biochem Sci. 2007 Aug;32(8):372-80
17629485
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2933-8
19196989
Environ Health Perspect. 2006 Nov;114(11):1631-5
17107845
J Biol Chem. 2008 Oct 31;283(44):29639-43
18723507
Nat Med. 2005 May;11(5):491-8
15852018
Biochem Soc Trans. 2009 Aug;37(Pt 4):692-6
19614577
Cancer Res. 1956 Jun;16(5):450-9
13330038
Crit Rev Toxicol. 2008;38(7):599-617
18709568
J Neurosci Res. 2009 May 15;87(7):1659-69
19125416
J Biol Chem. 2001 Jun 22;276(25):22461-7
11309390
Antioxid Redox Signal. 2009 Feb;11(2):205-14
18754702
Science. 1989 Aug 11;245(4918):574, 621
2669125
Biofactors. 2009 Mar-Apr;35(2):146-60
19449442
Crit Care. 2009;13(4):220
19691819
Br J Clin Pharmacol. 2008 Nov;66(5):594-617
18662293
Dose Response. 2006 Aug 19;4(2):75-90
18648638
Cell. 2007 Sep 7;130(5):769-74
17803898
Stem Cells. 2008 Jan;26(1):254-65
17962704
Hum Exp Toxicol. 2000 Jan;19(1):2-31
10745292
Mol Nutr Food Res. 2008 Sep;52(9):1062-73
18792015
Nat Biotechnol. 1998 Sep;16(9):833-8
9743115
Biochem Biophys Res Commun. 2005 Dec 9;338(1):568-77
16183036
J Neurochem. 2007 May;101(3):709-17
17241115
Trends Pharmacol Sci. 2001 Jun;22(6):285-91
11395156
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9926-30
7937919
Prog Neurobiol. 2006 Jun;79(3):136-71
16920246
J Neurosci. 1997 Jul 1;17(13):5089-100
9185546
Cell Death Differ. 2006 May;13(5):852-60
16397579
Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H246-51
14512282
Exp Gerontol. 2000 Sep;35(6-7):821-30
11053673
Science. 2008 Feb 15;319(5865):916-9
18276881
Mol Cell Biol. 2006 Apr;26(8):2887-900
16581765
Neurotoxicology. 2006 Dec;27(6):1094-100
16959318
Hum Exp Toxicol. 2000 Jan;19(1):76-84
10745295
Adv Enzyme Regul. 1978;17:23-36
393090
J Am Acad Dermatol. 1989 Apr;20(4):601-8
2654206
Cell Metab. 2008 Jul;8(1):38-48
18590691
J Neurochem. 2008 Feb;104(4):1116-31
17995931
Toxicol Sci. 2006 Dec;94(2):368-78
16950854
Methods Enzymol. 2008;441:83-110
18554531
Annu Rev Pharmacol Toxicol. 2003;43:233-60
12359864
Circ Res. 2009 Mar 27;104(6):e42-54
19265038
Redox Rep. 2006;11(5):207-13
17132269
J Am Acad Dermatol. 1994 Jun;30(6):977-81
8188891
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17500-5
17956979
Dose Response. 2006 Sep 23;4(4):327-32
18648588
Antioxid Redox Signal. 1999 Fall;1(3):255-84
11229439
Curr Opin Struct Biol. 2010 Feb;20(1):23-32
20053547
Can J Diet Pract Res. 2004 Fall;65(3):136-8
15363118
Crit Rev Toxicol. 2008;38(4):349-89
18432420
Toxicol Sci. 2001 Aug;62(2):330-8
11452146
Proc Natl Acad Sci U S A. 1986 Feb;83(3):787-91
3080750
Dose Response. 2009;7(1):1-51
19343115
Neurochem Int. 2008 Jan;52(1-2):155-65
17629356
Crit Rev Toxicol. 2008;38(5):453-62
18568865
Neurochem Res. 2007 Apr-May;32(4-5):757-73
17191135
Crit Rev Toxicol. 2008;38(4):249-52
18432418
Neurobiol Aging. 1983 Spring;4(1):37-43
6877486
Nat Rev Neurosci. 2008 Oct;9(10):759-67
18769445
Free Radic Biol Med. 2002 Oct 15;33(8):1047-60
12374616
Cancer Res. 2001 Apr 15;61(8):3299-307
11309284
Cell Calcium. 2002 Nov-Dec;32(5-6):393-404
12543098
Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):534-42
19735878
Biull Eksp Biol Med. 1967 Aug;64(8):86-8
4988397
Exp Neurol. 1999 Feb;155(2):302-14
10072306
Adv Enzyme Regul. 1993;33:281-96
8356913
Dose Response. 2006 Nov 27;4(4):302-8
18648592
Crit Rev Toxicol. 2008;38(5):419-51
18568864
Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G735-47
18687751
J Cell Biol. 2006 Aug 28;174(5):615-23
16923830
Eur J Neurol. 2006 Jun;13(6):604-10
16796584
Mol Cell Biol. 2006 Jan;26(1):221-9
16354693
Trends Neurosci. 2007 Jan;30(1):37-45
17137643
Biochem Pharmacol. 2010 Feb 1;79(3):330-8
19735646
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2040-5
14764894
Neuroscientist. 2008 Feb;14(1):68-77
17911213
Handb Exp Pharmacol. 2006;(172):69-91
16610355
Neuromolecular Med. 2009;11(2):97-100
19554482
Front Biosci. 2007 Jan 01;12:1107-23
17127365
Am J Public Health Nations Health. 1947 Apr;37(4):421-5
20292055
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):E101; author reply E102
19020101
FASEB J. 2006 Feb;20(2):371-3
16354723
J Neurosci Res. 2005 Nov 15;82(4):499-506
16211562
Free Radic Biol Med. 2007 Mar 1;42(5):665-74
17291990
Ann N Y Acad Sci. 2008 Dec;1147:275-82
19076449
Neurochem Int. 2010 Jan;56(1):3-10
19703504
Dose Response. 2006 Dec 21;5(3):230-55
18648608
Sci Total Environ. 1982 Feb;22(3):213-34
7043732
Dose Response. 2006 Dec 06;5(2):123-30
18648601
Dose Response. 2006 Oct 17;5(2):150-62
18648603
Crit Rev Toxicol. 2008;38(6):543-56
18615309
J Neurophysiol. 2008 Mar;99(3):1565-71
18199822
Methods Enzymol. 2004;382:423-48
15047115
J Neurochem. 1999 Aug;73(2):457-65
10428040
FEBS Lett. 2007 Jul 31;581(19):3641-51
17481612
J Neuroimmunol. 1999 Jan 1;93(1-2):53-71
10378869
J Neurosci Res. 1997 Sep 15;49(6):681-97
9335256
J Urol. 2001 Jul;166(1):347-53
11435898
Free Radic Biol Med. 2008 Sep 1;45(5):562-9
18549826
Dose Response. 2007 Aug 06;5(3):174-86
18648607
Mol Biol Cell. 2008 Mar;19(3):1104-12
18199679
J Neurosci. 2005 Nov 2;25(44):10321-35
16267240
Methods Enzymol. 2002;349:331-41
11912924
Science. 2004 Aug 13;305(5686):1010-3
15310905
Trends Pharmacol Sci. 2008 Feb;29(2):84-90
18180046
Adv Exp Med Biol. 2007;594:167-89
17205684
J Mol Med (Berl). 2008 Mar;86(3):267-79
18034222
J Biol Chem. 2004 Dec 31;279(53):56053-60
15509580
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2070-5
14970312
Ageing Res Rev. 2009 Jul;8(3):150-9
19491040
Cancer Res. 1980 Aug;40(8 Pt 1):2820-3
7388831
Neuromolecular Med. 2009;11(1):28-42
19288225
Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15091-6
17015834
Oncogene. 2008 May 29;27(24):3371-83
18223694
Stroke. 2007 Dec;38(12):3280-6
17962605
Biochemistry. 2008 Jun 3;47(22):6007-15
18457423
J Neurosci Res. 2000 Jul 15;61(2):134-9
10878585
J Neurosci. 2000 Aug 1;20(15):5709-14
10908610
Circ Res. 2008 Feb 1;102(2):234-41
17991880
Gerontology. 2009;55(5):550-8
19546513
Neuroscience. 2009 Feb 6;158(3):1021-9
18662748
Prog Neuropsychopharmacol Biol Psychiatry. 2001 Oct;25(7):1341-57
11513350
Chem Res Toxicol. 2005 Dec;18(12):1779-91
16359168
J Biol Chem. 1997 May 9;272(19):12568-74
9139709
Biol Chem. 2006 Oct-Nov;387(10-11):1311-20
17081101
Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15926-31
18838692
Eur J Neurosci. 2003 Aug;18(4):829-40
12925009
Biochem Pharmacol. 1985 Nov 1;34(21):3909-14
4062966
Arch Pharm Res. 2009 Aug;32(8):1103-8
19727602
Nat Rev Neurosci. 2007 Oct;8(10):803-8
17882256
Proc Natl Acad Sci U S A. 1988 Nov;85(21):8261-5
3141925
Biol Pharm Bull. 2003 Nov;26(11):1620-2
14600414
Front Biosci. 2007 Jan 01;12:2588-600
17127265
Mol Cell. 2006 Mar 3;21(5):689-700
16507366
J Biol Chem. 1990 Aug 25;265(24):14648-53
2387873
J Biol Chem. 2005 Jul 1;280(26):25284-90
15879598
Nat Rev Genet. 2007 Nov;8(11):835-44
17909538
J Neurochem. 1999 Mar;72(3):1187-203
10037492
Crit Rev Toxicol. 2008;38(6):489-542
18615308
J Neurochem. 2005 Aug;94(4):995-1004
16092942
J Neurochem. 2009 Jul;110(2):469-85
19457088
J Biol Chem. 2010 Apr 30;285(18):13607-15
20185824
EMBO J. 2007 Apr 4;26(7):1913-23
17347648
Mol Nutr Food Res. 2008 Jun;52 Suppl 1:S128-38
18327872
Genes Dev. 1999 Jan 1;13(1):76-86
9887101
Brain Res Rev. 2009 Mar;59(2):278-92
18822314
Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1305-10
10655526
Dose Response. 2006 Aug 19;5(2):163-73
18648602
Curr Pharm Des. 2004;10(14):1699-711
15134567
Hum Exp Toxicol. 2000 Jan;19(1):41-75
10745294
EMBO J. 2007 Jul 11;26(13):3169-79
17581637
J Biol Chem. 2009 May 15;284(20):13291-5
19182219
J Neurosci. 2003 Apr 15;23(8):3394-406
12716947
Carcinogenesis. 1988 Jan;9(1):131-4
3335037
Proc Natl Acad Sci U S A. 1965 Apr;53:791-6
14324535
Environ Toxicol Chem. 2008 Jul;27(7):1451-74
18275256
Hepatology. 1997 Jan;25(1):122-7
8985277
Ann Med. 2007;39(5):335-45
17701476
Science. 2005 Apr 22;308(5721):518
15845845
J Neurochem. 1998 Jan;70(1):31-9
9422344
J Neurosci. 1998 Jan 15;18(2):687-97
9425011
Crit Rev Toxicol. 2005 Feb-Mar;35(2-3):89-295
15839378
J Am Pharm Assoc Am Pharm Assoc. 1946 May;35:155-8
20982920
Genes Dev. 1998 Dec 15;12(24):3788-96
9869631
Nat Rev Neurosci. 2007 Oct;8(10):766-75
17882254
J Biol Chem. 2007 Feb 16;282(7):4470-4478
17172643
Cytokine. 2010 Jan;49(1):15-23
19900821
J Biol Chem. 1991 Jun 25;266(18):11632-9
1646813
Ageing Res Rev. 2003 Jul;2(3):329-42
12726778
Kidney Blood Press Res. 2005;28(5-6):295-301
16534224
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3404-9
11248091
Aging Cell. 2008 Jan;7(1):101-11
18031569
Ageing Res Rev. 2006 May;5(2):209-20
16697277
Trends Pharmacol Sci. 2009 Mar;30(3):129-37
19217170
Antioxid Redox Signal. 2002 Apr;4(2):309-19
12006182
Nat Rev Neurosci. 2006 Apr;7(4):278-94
16552414
Environ Health Perspect. 1997 Jun;105 Suppl 4:965-70
9255588
Crit Rev Toxicol. 2008;38(6):557-77
18615310
Trends Mol Med. 2009 Sep;15(9):391-404
19726230
FASEB J. 2008 Oct;22(10):3419-31
18567738
Mech Ageing Dev. 2001 Jul 15;122(9):895-908
11348657
Biochim Biophys Acta. 2008 Jun;1782(6):363-9
18373985
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52
18794531
Mol Nutr Food Res. 2005 Nov;49(11):1044-9
16270277
Curr Neurovasc Res. 2005 Oct;2(4):271-85
16181120
Brain Res. 2007 Jan 5;1127(1):26-35
17113054
Eur J Pharmacol. 2004 Feb 23;486(3):349-52
14985058
Neurobiol Learn Mem. 2008 May;89(4):599-603
17881251
Biochem Biophys Res Commun. 2009 Feb 6;379(2):537-41
19118528
FASEB J. 2002 Apr;16(6):601-3
11919167
Dose Response. 2006 Aug 19;5(1):1-10
18648553
Curr Opin Struct Biol. 2008 Feb;18(1):35-42
18242075
Nat Med. 1997 Oct;3(10):1089-95
9334719
J Biol Chem. 2006 Aug 25;281(34):24756-68
16790436
Bioessays. 2008 Oct;30(10):939-42
18800364
Trends Neurosci. 2008 Sep;31(9):454-63
18675468
Adv Exp Med Biol. 2007;594:55-63
17205675
Learn Mem. 2008 Jun 26;15(7):460-7
18583646
Crit Rev Toxicol. 2008;38(7):579-90
18709566
Crit Rev Toxicol. 2008;38(7):633-9
18709572
J Biol Chem. 2003 Mar 14;278(11):9125-33
12511571
Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2394-8
1549602
Genes Dev. 2008 Jun 1;22(11):1427-38
18519635
Adv Enzyme Regul. 2006;46:113-40
16887173
Mol Cell Biol. 2007 Nov;27(21):7511-21
17785452
FEBS Lett. 2009 Aug 20;583(16):2647-53
19393652
Crit Care. 2009;13(3):213
19519960
Antioxid Redox Signal. 2004 Oct;6(5):895-913
15345150
J Cardiometab Syndr. 2009 Spring;4(2):102-6
19614797
Acta Pharmacol Sin. 2007 Nov;28(11):1709-16
17959020
Circ Res. 2005 Feb 18;96(3):280-91
15718508
Crit Rev Toxicol. 2001 Jul;31(4-5):425-70
11504173
EMBO J. 2005 Mar 9;24(5):1068-78
15719013
Proc Natl Acad Sci U S A. 1985 Dec;82(23):8232-6
3934671
Ann Neurol. 2010 Jan;67(1):41-52
20186857
Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19908-12
17167053
Science. 2009 Jun 5;324(5932):1289-93
19498162
Sci Am. 2005 Jun;292(6):48-55
15934652
Biochem J. 1991 Feb 1;273 ( Pt 3):711-7
1900000
Toxicol Appl Pharmacol. 2007 Jul 1;222(1):122-8
17459441
Mol Neurobiol. 2002 Aug;26(1):13-9
12392053
J Neurosci. 2004 Feb 4;24(5):1101-12
14762128
Free Radic Biol Med. 2008 Jan 15;44(2):215-23
18191757
J Exp Med. 1964 Jan 1;119:923-42
14179666
Trends Mol Med. 2004 Nov;10(11):549-57
15519281
Glia. 2008 Aug 1;56(10):1091-103
18442091
Dose Response. 2006 Aug 25;4(4):317-26
18648586
Proc Natl Acad Sci U S A. 1990 Aug;87(16):6258-62
2166952
Biochem Pharmacol. 1980 Oct 15;29(20):2839-44
6159897
J Neurochem. 2009 Apr;109(1):74-84
19183270
J Biol Chem. 2004 Jun 11;279(24):25497-502
15044495
Nitric Oxide. 2009 Nov-Dec;21(3-4):149-56
19635579
Science. 1987 Feb 27;235(4792):1043-6
3029864
Am J Pathol. 2007 Jun;170(6):2068-76
17525273
Exp Neurol. 1997 Sep;147(1):103-14
9294407
Toxicol Appl Pharmacol. 2005 Feb 1;202(3):289-301
15667834
J Cardiovasc Pharmacol. 2009 Sep;54(3):188-95
19687749
J Neurosci. 1995 Sep;15(9):6239-49
7666206
J Neurochem. 1999 Feb;72(2):529-40
9930724
Am J Respir Crit Care Med. 2008 Sep 15;178(6):592-604
18556627
Free Radic Biol Med. 2008 Dec 15;45(12):1705-13
18848879
Methods Enzymol. 2004;382:355-64
15047111
Dose Response. 2006 Aug 19;4(2):91-105
18648582
J Neurochem. 1997 Aug;69(2):570-80
9231714
J Neurosci. 2007 Sep 19;27(38):10240-8
17881530
Appl Physiol Nutr Metab. 2008 Oct;33(5):843-62
18923559
J Neurochem. 2010 Feb;112(3):611-24
19891733
Trends Neurosci. 1998 Feb;21(2):53-7
9498297
Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):768-73
16407140
J Biol Chem. 2008 Oct 10;283(41):27810-27819
18678867
J Neurochem. 2007 Mar;100(5):1364-74
17250676
Curr Pharm Des. 2004;10(8):867-77
15032690
Gene. 2002 Jul 10;294(1-2):1-12
12234662
Carcinogenesis. 1999 May;20(5):911-4
10334211
Cancer Lett. 2006 Aug 28;240(2):243-52
16271437
Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1534-44
18647625
Methods Mol Biol. 2010;610:285-308
20013185
Nat Rev Mol Cell Biol. 2009 Oct;10(10):721-32
19738628
Nat Med. 1996 Jul;2(7):788-94
8673925
Cell. 2008 Jul 25;134(2):279-90
18662543
J Neurochem. 2009 Jul;110(1):412-21
19457105
J Immunol. 2008 Jul 1;181(1):680-9
18566435
J Endocrinol. 2008 Nov;199(2):333-41
18701639
J Biol Chem. 2001 Jan 19;276(3):2132-8
11053438
J Neurochem. 1996 Feb;66(2):869-72
8592164
Chem Res Toxicol. 2008 Apr;21(4):805-12
18361512
J Biol Chem. 2009 Aug 7;284(32):21379-85
19542216
Trends Biochem Sci. 2009 Apr;34(4):176-88
19321346
Arch Toxicol. 2009 Mar;83(3):203-25
19247635
Neurobiol Dis. 2007 Nov;28(2):206-15
17719231
Redox Rep. 2007;12(1):11-5
17263901
Psychopharmacology (Berl). 1985;86(1-2):61-7
3927367
Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2399-403
1549603
J Mol Neurosci. 2000 Oct;15(2):85-97
11220788
J Neurochem. 2006 Sep;98(6):1852-65
16945104
Curr Opin Drug Discov Devel. 2006 Jan;9(1):117-23
16445124
Int J Biochem Cell Biol. 2005 Mar;37(3):604-15
15618017
Neuromolecular Med. 2002;2(2):215-31
12428812
J Biol Chem. 2005 Feb 18;280(7):5892-901
15590663
Nature. 2004 Aug 5;430(7000):631-9
15295589
Nat Genet. 2005 Apr;37(4):349-50
15793589
Exp Gerontol. 2007 Jan-Feb;42(1-2):113-9
16814508
Clin Exp Immunol. 2006 Jul;145(1):101-7
16792679
Circulation. 2003 Dec 16;108(24):3048-53
14638550
Neurosci Lett. 2006 Jan 30;393(2-3):108-12
16233958
Trends Immunol. 2003 Aug;24(8):449-55
12909459
J Biochem. 2009 Nov;146(5):623-6
19605461
Antioxid Redox Signal. 2005 May-Jun;7(5-6):778-80
15890024
Toxicol Sci. 2009 Mar;108(1):35-47
19129213
Nat Cell Biol. 2008 Apr;10(4):385-94
18344989