Skip to main content
SpringerLink
Log in

Keap1/Nrf2/ARE redox-sensitive signaling system as a pharmacological target

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and proapoptotic conditions, which allows us to consider it as a pharmacological target. Here we review the basic regulatory mechanisms of the Keap1/Nrf2/ARE system, key targets for pharmacological intervention, and interconnection of this system with other redox-sensitive transcriptional factors. We also discuss the range of currently available pharmaceuticals. Finally, we promote “indirect” antioxidants as a promising strategy for prevention and treatment of wide range of diseases associated with oxidative stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ARE:

antioxidant-responsive element

CNC:

cap’n’Collar family

Cul3-E3-ligase:

Cullin-3-containing ubiquitin-ligase complex E3

Keap1:

Kelch-like ECH-associated protein 1

MAPK:

mitogen-activated protein kinases

NQO1:

NAD(P)H:quinone oxidoreductase 1

Nrf2:

NF-E2-bound factor 2

ROS:

reactive oxygen species

References

  1. Niture, S. K., Kaspar, J. W., Shen, J., and Jaiswal, A. K. (2010) Toxicol. Appl. Pharmacol., 244, 37–42.

    Article  PubMed  CAS  Google Scholar 

  2. Niture, S. K., and Jaiswal, A. K. (2012) J. Biol. Chem., 287, 9873–9886.

    Article  PubMed  CAS  Google Scholar 

  3. Niture, S. K., and Jaiswal, A. K. (2011) Cell. Death Differ., 18, 439–451.

    Article  PubMed  CAS  Google Scholar 

  4. Huang, J., Tabbi-Anneni, I., Gunda, V., and Wang, L. (2010) Am. J. Physiol. Gastrointest. Liver Physiol., 299, G1211–G1221.

    Article  PubMed  CAS  Google Scholar 

  5. Kwak, M. K., Wakabayashi, N., Greenlaw, J. L., Yamamoto, M., and Kensler, T. W. (2003) Mol. Cell. Biol., 23, 8786–8794.

    Article  PubMed  CAS  Google Scholar 

  6. Maher, J., and Yamamoto, M. (2010) Toxicol. Appl. Pharmacol., 244, 4–15.

    Article  PubMed  CAS  Google Scholar 

  7. Brigelius-Flohe, R., and Flohe, L. (2011) Antioxid. Redox Signal., 15, 2335–2381.

    Article  PubMed  CAS  Google Scholar 

  8. Lukosz, M., Jakob, S., Buchner, N., Zschauer, T. C., Altschmied, J., and Haendeler, J. (2010) Antioxid. Redox Signal., 12, 713–742.

    Article  PubMed  CAS  Google Scholar 

  9. Tanner, J. J., Parsons, Z. D., Cummings, A. H., Zhou, H., and Gates, K. S. (2011) Antioxid. Redox Signal., 15, 77–97.

    Article  PubMed  CAS  Google Scholar 

  10. Hybertson, B. M., Gao, B., Bose, S. K., and McCord, J. M. (2011) Mol. Aspects Med., 32, 234–246.

    Article  PubMed  CAS  Google Scholar 

  11. Tkachev, V. O., Menshchikova, E. B., and Zenkov, N. K. (2011) Biochemistry (Moscow), 76, 407–422.

    PubMed  CAS  Google Scholar 

  12. Baird, L., and Dinkova-Kostova, A. T. (2011) Arch. Toxicol., 85, 241–272.

    Article  PubMed  CAS  Google Scholar 

  13. Eggler, A. L., Gay, K. A., and Mesecar, A. D. (2008) Mol. Nutr. Food Res., 52, 84–94.

    Google Scholar 

  14. Giudice, A., Arra, C., and Turco, M. C. (2010) Methods Mol. Biol., 647, 37–74.

    Article  PubMed  CAS  Google Scholar 

  15. Hayes, J. D., McMahon, M., Chowdhry, S., and Dinkova-Kostova, A. T. (2010) Antioxid. Redox Signal., 13, 1713–1748.

    Article  PubMed  CAS  Google Scholar 

  16. Hur, W., and Gray, N. S. (2011) Curr. Opin. Chem. Biol., 15, 162–173.

    Article  PubMed  CAS  Google Scholar 

  17. Keum, Y. S. (2011) Ann. N. Y. Acad. Sci., 1229, 184–189.

    Article  PubMed  CAS  Google Scholar 

  18. Kundu, J. K., and Surh, Y. J. (2010) Pharm. Res., 27, 999–1013.

    Article  PubMed  CAS  Google Scholar 

  19. Scapagnini, G., Sonya, V., Nader, A. G., Calogero, C., Zella, D., and Fabio, G. (2011) Mol. Neurobiol., 44, 192–201.

    Article  PubMed  CAS  Google Scholar 

  20. Sykiotis, G. P., and Bohmann, D. (2010) Sci. Signal., 3, re3.

    Article  PubMed  CAS  Google Scholar 

  21. Taguchi, K., Motohashi, H., and Yamamoto, M. (2011) Genes Cells, 16, 123–140.

    Article  PubMed  CAS  Google Scholar 

  22. Wakabayashi, N., Slocum, S. L., Skoko, J. J., Shin, S., and Kensler, T. W. (2010) Antioxid. Redox Signal., 13, 1649–1663.

    Article  PubMed  CAS  Google Scholar 

  23. Hayes, J. D., and McMahon, M. (2009) Trends Biochem. Sci., 34, 176–188.

    Article  PubMed  CAS  Google Scholar 

  24. Jain, A. K., Mahajan, S., and Jaiswal, A. K. (2008) J. Biol. Chem., 283, 17712–17720.

    Article  PubMed  CAS  Google Scholar 

  25. Villeneuve, N. F., Lau, A., and Zhang, D. D. (2010) Antioxid. Redox Signal., 13, 1699–1712.

    Article  PubMed  CAS  Google Scholar 

  26. Rada, P., Rojo, A. I., Chowdhry, S., McMahon, M., Hayes, J. D., and Cuadrado, A. (2011) Mol. Cell. Biol., 31, 1121–1133.

    Article  PubMed  CAS  Google Scholar 

  27. Kobayashi, A., Kang, M. I., Watai, Y., Tong, K. I., Shibata, T., Uchida, K., and Yamamoto, M. (2006) Mol. Cell. Biol., 26, 221–229.

    Article  PubMed  CAS  Google Scholar 

  28. Yerlikaya, A. (2012) Protein Pept. Lett., doi: PPL-EPUB-20120604-16 [pii].

  29. Chapple, S. J., Siowand, R. C., and Mann, G. E. (2012) Int. J. Biochem. Cell. Biol., 44, 1315–1320.

    Article  PubMed  CAS  Google Scholar 

  30. Sebens, S., Bauer, I., Geismann, C., Grage-Griebenow, E., Ehlers, S., Kruse, M. L., Arlt, A., and Schafer, H. (2011) J. Biol. Chem., 286, 40911–40921.

    Article  PubMed  CAS  Google Scholar 

  31. Sun, Z., Zhang, S., Chan, J. Y., and Zhang, D. D. (2007) Mol. Cell. Biol., 27, 6334–6349.

    Article  PubMed  CAS  Google Scholar 

  32. Kaspar, J. W., Niture, S. K., and Jaiswal, A. K. (2012) J. Cell. Sci., 125, 1027–1038.

    Article  PubMed  CAS  Google Scholar 

  33. Holland, R., and Fishbein, J. C. (2010) Antioxid. Redox Signal., 13, 1749–1761.

    Article  PubMed  CAS  Google Scholar 

  34. Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M. I., Kobayashi, A., Yamamoto, M., Kensler, T. W., and Talalay, P. (2004) Proc. Natl. Acad. Sci. USA, 101, 2040–2045.

    Article  PubMed  CAS  Google Scholar 

  35. Kobayashi, M., Li, L., Iwamoto, N., Nakajima-Takagi, Y., Kaneko, H., Nakayama, Y., Eguchi, M., Wada, Y., Kumagai, Y., and Yamamoto, M. (2009) Mol. Cell. Biol., 29, 493–502.

    Article  PubMed  CAS  Google Scholar 

  36. He, X., and Ma, Q. (2010) J. Pharmacol. Exp. Ther., 332, 66–75.

    Article  PubMed  CAS  Google Scholar 

  37. Rachakonda, G., Xiong, Y., Sekhar, K. R., Stamer, S. L., Liebler, D. C., and Freeman, M. L. (2008) Chem. Res. Toxicol., 21, 705–710.

    Article  PubMed  CAS  Google Scholar 

  38. Fourquet, S., Guerois, R., Biard, D., and Toledano, M. B. (2010) J. Biol. Chem., 285, 8463–8471.

    Article  PubMed  CAS  Google Scholar 

  39. Niture, S. K., Jain, A. K., and Jaiswal, A. K. (2009) J. Cell. Sci., 122, 4452–4464.

    Article  PubMed  CAS  Google Scholar 

  40. Li, W., and Kong, A. N. (2009) Mol. Carcinog., 48, 91–104.

    Article  PubMed  CAS  Google Scholar 

  41. Magesh, S., Chen, Y., and Hu, L. (2012) Med. Res. Rev., 32, 687–726.

    Article  PubMed  CAS  Google Scholar 

  42. He, X., and Ma, Q. (2009) Mol. Pharmacol., 76, 1265–1278.

    Article  PubMed  CAS  Google Scholar 

  43. Gan, L., Johnson, D. A., and Johnson, J. A. (2010) Eur. J. Neurosci., 31, 967–977.

    Article  PubMed  Google Scholar 

  44. Im, J. Y., Lee, K. W., Woo, J. M., Junn, E., and Mouradian, M. M. (2012) Hum. Mol. Genet., 21, 3013–3024.

    Article  PubMed  CAS  Google Scholar 

  45. Villeneuve, N. F., Sun, Z., Chen, W., and Zhang, D. D. (2009) Cell. Cycle, 8, 3255–3256.

    Article  PubMed  CAS  Google Scholar 

  46. Hancock, R., Bertrand, H. C., Tsujita, T., Naz, S., El-Bakry, A., Laoruchupong, J., Hayes, J. D., and Wells, G. (2012) Free Radic. Biol. Med., 52, 444–451.

    Article  PubMed  CAS  Google Scholar 

  47. Copple, I. M., Lister, A., Obeng, A. D., Kitteringham, N. R., Jenkins, R. E., Layfield, R., Foster, B. J., Goldring, C. E., and Park, B. K. (2010) J. Biol. Chem., 285, 16782–16788.

    Article  PubMed  CAS  Google Scholar 

  48. Kang, H. J., Hong, Y. B., Kim, H. J., and Bae, I. (2010) J. Biol. Chem., 285, 21258–21268.

    Article  PubMed  CAS  Google Scholar 

  49. Sun, Z., Huang, Z., and Zhang, D. D. (2009) PLoS One, 4, e6588.

    Article  PubMed  CAS  Google Scholar 

  50. Bloom, D. A., and Jaiswal, A. K. (2003) J. Cell. Mol. Med., 278, 44675–44682.

    CAS  Google Scholar 

  51. Lee, Y. J., Jeong, H. Y., Kim, Y. B., Won, S. Y., Shim, J. H., Cho, M. K., Nam, H. S., and Lee, S. H. (2012) Food Chem. Toxicol., 50, 116–123.

    Article  PubMed  CAS  Google Scholar 

  52. Zhao, S. G., Li, Q., Liu, Z. X., Wang, J. J., Wang, X. X., Qin, M., and Wen, Q. S. (2011) Hepatogastroenterology, 58, 2106–2111.

    PubMed  CAS  Google Scholar 

  53. Pitha-Rowe, I., Liby, K., Royce, D., and Sporn, M. (2009) Invest. Ophthalmol. Vis. Sci., 50, 5339–5347.

    Article  PubMed  Google Scholar 

  54. Song, N. Y., Kim, D. H., Kim, E. H., Na, H. K., Kim, N. J., Suh, Y. G., and Surh, Y. J. (2011) Chem. Res. Toxicol., 24, 1231–1241.

    Article  PubMed  CAS  Google Scholar 

  55. Lee, C., Park, G. H., and Jang, J. H. (2011) Toxicology, 283, 118–128.

    Article  PubMed  CAS  Google Scholar 

  56. Kawai, Y., Garduno, L., Theodore, M., Yang, J., and Arinze, I. J. (2011) J. Biol. Chem., 286, 7629–7640.

    Article  PubMed  CAS  Google Scholar 

  57. Lee, O. H., Jain, A. K., Papusha, V., and Jaiswal, A. K. (2007) J. Biol. Chem., 282, 36412–36420.

    Article  PubMed  CAS  Google Scholar 

  58. Hanada, N., Takahata, T., Zhou, Q., Ye, X., Sun, R., Itoh, J., Ishiguro, A., Kijima, H., Mimura, J., Itoh, K., Fukuda, S., and Saijo, Y. (2012) BMC Cancer, 12, 66.

    Article  PubMed  CAS  Google Scholar 

  59. Kwak, M. K., Itoh, K., Yamamoto, M., and Kensler, T. W. (2002) Mol. Cell. Biol., 22, 2883–2892.

    Article  PubMed  CAS  Google Scholar 

  60. Kaspar, J. W., and Jaiswal, A. K. (2010) J. Biol. Chem., 285, 21349–21358.

    Article  PubMed  CAS  Google Scholar 

  61. Birringer, M. (2011) Pharm. Res., 28, 2680–2694.

    Article  PubMed  CAS  Google Scholar 

  62. Son, T. G., Camandola, S., and Mattson, M. P. (2008) Neuromolec. Med., 10, 236–246.

    Article  CAS  Google Scholar 

  63. Wakabayashi, N., Itoh, K., Wakabayashi, J., Motohashi, H., Noda, S., Takahashi, S., Imakado, S., Kotsuji, T., Otsuka, F., Roop, D. R., Harada, T., Engel, J. D., and Yamamoto, M. (2003) Nat. Genet., 35, 238–245.

    Article  PubMed  CAS  Google Scholar 

  64. Rieber, N., Hector, A., Kuijpers, T., Roos, D., and Hartl, D. (2012) Clin. Dev. Immunol., 2012, 252460.

    Article  PubMed  Google Scholar 

  65. Kensler, T. W., and Wakabayashi, N. (2010) Carcinogenesis, 31, 90–99.

    Article  PubMed  CAS  Google Scholar 

  66. Chevillard, G., and Blank, V. (2011) Cell. Mol. Life Sci., 68, 3337–3348.

    Article  PubMed  CAS  Google Scholar 

  67. Biswas, M., and Chan, J. Y. (2010) Toxicol. Appl. Pharmacol., 244, 16–20.

    Article  PubMed  CAS  Google Scholar 

  68. Chepelev, N. L., Bennitz, J. D., Huang, T., McBride, S., and Willmore, W. G. (2011) PLoS One, 6, e29167.

    Article  PubMed  CAS  Google Scholar 

  69. Wang, W., Kwok, A. M., and Chan, J. Y. (2007) J. Biol. Chem., 282, 24670–24678.

    Article  PubMed  CAS  Google Scholar 

  70. Ohtsuji, M., Katsuoka, F., Kobayashi, A., Aburatani, H., Hayes, J. D., and Yamamoto, M. (2008) J. Biol. Chem., 283, 33554–33562.

    Article  PubMed  CAS  Google Scholar 

  71. Pepe, A. E., Xiao, Q., Zampetaki, A., Zhang, Z., Kobayashi, A., Hu, Y., and Xu, Q. (2010) Circ. Res., 106, 870–879.

    Article  PubMed  CAS  Google Scholar 

  72. Shivdasani, R. A. (2001) Stem Cells, 19, 397–407.

    Article  PubMed  CAS  Google Scholar 

  73. Menshchikova, E. B., Zenkov, N. K., and Tkachev, V. O. (2010) Mol. Biol. (Moscow), 44, 389–404.

    Google Scholar 

  74. Reichard, J. F., Sartor, M. A., and Puga, A. (2008) J. Biol. Chem., 283, 22363–22370.

    Article  PubMed  CAS  Google Scholar 

  75. Kaspar, J. W., and Jaiswal, A. K. (2010) J. Biol. Chem., 285, 153–162.

    Article  PubMed  CAS  Google Scholar 

  76. Jyrkkanen, H. K., Kuosmanen, S., Heinaniemi, M., Laitinen, H., Kansanen, E., Mella-Aho, E., Leinonen, H., Yla-Herttuala, S., and Levonen, A. L. (2011) Biochem. J., 440, 167–174.

    Article  PubMed  CAS  Google Scholar 

  77. Kim, H., Jung, Y., Shin, B. S., Song, H., Bae, S. H., Rhee, S. G., and Jeong, W. (2010) J. Biol. Chem., 285, 34419–34428.

    Article  PubMed  CAS  Google Scholar 

  78. Vaz, M., Machireddy, N., Irving, A., Potteti, H. R., Chevalier, K., Kalvakolanu, D., and Reddy, S. P. (2012) Mol. Cell. Biol., 32, 1694–1709.

    Article  PubMed  CAS  Google Scholar 

  79. Slocum, S. L., and Kensler, T. W. (2011) Arch. Toxicol., 85, 273–284.

    Article  PubMed  CAS  Google Scholar 

  80. Pan, H., Wang, H., Wang, X., Zhu, L., and Mao, L. (2012) Mediators Inflamm., 2012, ID 217580.

  81. Li, W., Khor, T. O., Xu, C., Shen, G., Jeong, W. S., Yu, S., and Kong, A. N. (2008) Biochem. Pharmacol., 76, 1485–1489.

    Article  PubMed  CAS  Google Scholar 

  82. Toledano, M. B. (2009) Mol. Cell, 34, 637–639.

    Article  PubMed  CAS  Google Scholar 

  83. Chen, W., Jiang, T., Wang, H., Tao, S., Lau, A., Fang, D., and Zhang, D. D. (2012) Antioxid. Redox Signal., 17, 1670–1675.

    Article  PubMed  CAS  Google Scholar 

  84. Faraonio, R., Vergara, P., Di Marzo, D., Pierantoni, M. G., Napolitano, M., Russo, T., and Cimino, F. (2006) J. Biol. Chem., 281, 39776–39784.

    Article  PubMed  CAS  Google Scholar 

  85. Asher, G., Lotem, J., Kama, R., Sachs, L., and Shaul, Y. (2002) Proc. Natl. Acad. Sci. USA, 99, 3099–3104.

    Article  PubMed  CAS  Google Scholar 

  86. Cho, H. Y., and Kleeberger, S. R. (2010) Toxicol. Appl. Pharmacol., 244, 43–56.

    Article  PubMed  CAS  Google Scholar 

  87. Cho, H. Y., Gladwell, W., Wang, X., Chorley, B., Bell, D., Reddy, S. P., and Kleeberger, S. R. (2010) Am. J. Respir. Crit. Care Med., 182, 170–182.

    Article  PubMed  CAS  Google Scholar 

  88. Polvani, S., Tarocchi, M., and Galli, A. (2012) PPAR Res., 2012, ID 641087.

    Article  CAS  Google Scholar 

  89. Ansell, P. J., Lo, S. C., Newton, L. G., Espinosa-Nicholas, C., Zhang, D. D., Liu, J. H., Hannink, M., and Lubahn, D. B. (2005) Mol. Cell. Endocrinol., 243, 27–34.

    Article  PubMed  CAS  Google Scholar 

  90. Zhou, W., Lo, S. C., Liu, J. H., Hannink, M., and Lubahn, D. B. (2007) Mol. Cell. Endocrinol., 278, 52–62.

    Article  PubMed  CAS  Google Scholar 

  91. Kim, Y. W., Kim, Y. M., Yang, Y. M., Kay, H. Y., Kim, W. D., Lee, J. W., Hwang, S. J., and Kim, S. G. (2011) Antioxid. Redox Signal., 14, 733–745.

    Article  PubMed  CAS  Google Scholar 

  92. Lushchak, V. I. (2011) Comp. Biochem. Physiol. Comp. Pharmacol., 153, 175–190.

    Google Scholar 

  93. Speciale, A., Chirafisi, J., Saija, A., and Cimino, F. (2011) Curr. Mol. Med., 11, 770–789.

    Article  PubMed  CAS  Google Scholar 

  94. Turan, B., Tuncay, E., and Vassort, G. (2012) J. Bioenerg. Biomembr., 44, 281–296.

    Article  PubMed  CAS  Google Scholar 

  95. Dinkova-Kostova, A. T., Fahey, J. W., and Talalay, P. (2004) Meth. Enzymol., 382, 423–448.

    Article  PubMed  CAS  Google Scholar 

  96. Erlank, H., Elmann, A., Kohen, R., and Kanner, J. (2011) Free Radic. Biol. Med., 51, 2319–2327.

    Article  PubMed  CAS  Google Scholar 

  97. Zhao, C. R., Gao, Z. H., and Qu, X. J. (2010) Cancer Epidemiol., 34, 523–533.

    Article  PubMed  CAS  Google Scholar 

  98. Elbarbry, F., and Elrody, N. (2011) J. Med. Plants Res., 5, 473–484.

    CAS  Google Scholar 

  99. Lee, Y. J., and Lee, S. H. (2011) J. Korean Med. Sci., 26, 1474–1482.

    Article  PubMed  CAS  Google Scholar 

  100. Hu, C., Eggler, A. L., Mesecar, A. D., and van Breemen, R. B. (2011) Chem. Res. Toxicol., 24, 515–521.

    Article  PubMed  CAS  Google Scholar 

  101. Li, Y., Paonessa, J. D., and Zhang, Y. (2012) PLoS One, 7, e35122.

    Article  PubMed  CAS  Google Scholar 

  102. Boddupalli, S., Mein, J. R., Lakkanna, S., and James, D. R. (2012) Front. Genet., 3, PMC3264924.

    Google Scholar 

  103. Dash, P. K., Zhao, J., Orsi, S. A., Zhang, M., and Moore, A. N. (2009) Neurosci. Lett., 460, 103–107.

    Article  PubMed  CAS  Google Scholar 

  104. Ping, Z., Liu, W., Kang, Z., Cai, J., Wang, Q., Cheng, N., Wang, S., Zhang, J. H., and Sun, X. (2010) Brain Res., 1343, 178–185.

    Article  PubMed  CAS  Google Scholar 

  105. Hong, Y., Yan, W., Chen, S., Sun, C. R., and Zhang, J. M. (2010) Acta Pharmacol. Sin., 31, 1421–1430.

    Article  PubMed  CAS  Google Scholar 

  106. Brandenburg, L. O., Kipp, M., Lucius, R., Pufe, T., and Wruck, C. J. (2010) Inflamm. Res., 59, 443–450.

    Article  PubMed  CAS  Google Scholar 

  107. Clarke, J. D., Hsu, A., Williams, D. E., Dashwood, R. H., Stevens, J. F., Yamamoto, M., and Ho, E. (2011) Pharm. Res., 28, 3171–3179.

    Article  PubMed  CAS  Google Scholar 

  108. Latte, K. P., Appel, K. E., and Lampen, A. (2011) Food Chem. Toxicol., 49, 3287–3309.

    Article  PubMed  CAS  Google Scholar 

  109. A service of the U.S. National Institutes of Health (http://www.clinicaltrials.gov).

  110. Martelli, A., Testai, L., Marino, A., Breschi, M. C., Da Settimo, F., and Calderone, V. (2012) Curr. Med. Chem., 19, 3325–3336.

    Article  PubMed  CAS  Google Scholar 

  111. Predmore, B. L., Kondo, K., Bhushan, S., Zlatopolsky, M. A., King, A. L., Aragon, J. P., Grinsfelder, D. B., Condit, M. E., and Lefer, D. J. (2012) Am. J. Physiol. Heart Circ. Physiol., 302, H2410–H2418.

    Article  PubMed  CAS  Google Scholar 

  112. Shay, K. P., Moreau, R. F., Smith, E. J., and Hagen, T. M. (2008) IUBMB Life, 60, 362–367.

    Article  CAS  Google Scholar 

  113. Shay, K. P., Moreau, R. F., Smith, E. J., Smith, A. R., and Hagen, T. M. (2009) Biochim. Biophys. Acta, 1790, 1149–1160.

    Article  PubMed  CAS  Google Scholar 

  114. Shay, K. P., Michels, A. J., Li, W., Kong, A. N., and Hagen, T. M. (2012) Biochim. Biophys. Acta, 1823, 1102–1109.

    Article  PubMed  CAS  Google Scholar 

  115. Lii, C. K., Liu, K. L., Cheng, Y. P., Lin, A. H., Chen, H. W., and Tsai, C. W. (2010) J. Nutr., 140, 885–892.

    Article  PubMed  CAS  Google Scholar 

  116. Zhang, Y., and Munday, R. (2008) Mol. Cancer Ther., 7, 3470–3479.

    Article  PubMed  CAS  Google Scholar 

  117. Holland, R., Navamal, M., Velayutham, M., Zweier, J. L., Kensler, T. W., and Fishbein, J. C. (2009) Chem. Res. Toxicol., 22, 1427–1434.

    Article  PubMed  CAS  Google Scholar 

  118. Bhattacharyya, S., Zhou, H., Seiner, D. R., and Gates, K. S. (2010) Bioorg. Med. Chem., 18, 5945–5949.

    Article  PubMed  CAS  Google Scholar 

  119. Brooks, S. C., 3rd, Brooks, J. S., Lee, W. H., Lee, M. G., and Kim, S. G. (2009) Pharmacol. Ther., 124, 31–43.

    Article  PubMed  CAS  Google Scholar 

  120. Yu, Z. W., Li, D., Ling, W. H., and Jin, T. R. (2012) World J. Diabetes, 3, 19–28.

    Article  PubMed  Google Scholar 

  121. Glintborg, B., Weimann, A., Kensler, T. W., and Poulsen, H. E. (2006) Free Radic. Biol. Med., 41, 1010–1014.

    Article  PubMed  CAS  Google Scholar 

  122. Kim, S. G., Kim, Y. M., Choi, J. Y., Han, J. Y., Jang, J. W., Cho, S. H., Um, S. H., Chon, C. Y., Lee, D. H., Jang, J. J., Yu, E., and Lee, Y. S. (2011) J. Pharm. Pharmacol., 63, 627–635.

    Article  PubMed  CAS  Google Scholar 

  123. Shehzad, A., Ha, T., Subhan, F., and Lee, Y. S. (2011) Eur. J. Nutr., 50, 151–161.

    Article  PubMed  CAS  Google Scholar 

  124. Wang, X. J., Hayes, J. D., Higgins, L. G., Wolf, C. R., and Dinkova-Kostova, A. T. (2010) Chem. Biol., 17, 75–85.

    Article  PubMed  CAS  Google Scholar 

  125. Dinkova-Kostova, A. T., and Wang, X. J. (2011) Chem. Biol. Interact., 192, 101–106.

    Article  PubMed  CAS  Google Scholar 

  126. Son, T. G., Camandola, S., Arumugam, T. V., Cutler, R. G., Telljohann, R. S., Mughal, M. R., Moore, T. A., Luo, W., Yu, Q. S., Johnson, D. A., Johnson, J. A., Greig, N. H., and Mattson, M. P. (2010) J. Neurochem., 112, 1316–1326.

    Article  PubMed  CAS  Google Scholar 

  127. Grynkiewicz, G., and Slifirski, P. (2012) Acta Biochim. Pol., 59, 201–212.

    PubMed  CAS  Google Scholar 

  128. Aggarwal, B. B. (2010) Annu. Rev. Nutr., 30, 173–199.

    Article  PubMed  CAS  Google Scholar 

  129. Zhou, H., Beevers, C. S., and Huang, S. (2011) Curr. Drug Targets, 12, 332–347.

    Article  PubMed  CAS  Google Scholar 

  130. Farombi, E. O., Shrotriya, S., Na, H. K., Kim, S. H., and Surh, Y. J. (2008) Food Chem. Toxicol., 46, 1279–1287.

    Article  PubMed  CAS  Google Scholar 

  131. Dinkova-Kostova, A. T., and Talalay, P. (1999) Carcinogenesis, 20, 911–914.

    Article  PubMed  CAS  Google Scholar 

  132. Cuomo, J., Appendino, G., Dern, A. S., Schneider, E., McKinnon, T. P., Brown, M. J., Togni, S., and Dixon, B. M. (2011) J. Nat. Prod., 74, 664–669.

    Article  PubMed  CAS  Google Scholar 

  133. Belcaro, G., Cesarone, M. R., Dugall, M., Pellegrini, L., Ledda, A., Grossi, M. G., Togni, S., and Appendino, G. (2010) Altern. Med. Rev., 15, 337–344.

    PubMed  Google Scholar 

  134. Appendino, G., Belcaro, G., Cornelli, U., Luzzi, R., Togni, S., Dugall, M., Cesarone, M. R., Feragalli, B., Ippolito, E., Errichi, B. M., Pellegrini, L., Ledda, A., Ricci, A., Bavera, P., Hosoi, M., Stuard, S., Corsi, M., Errichi, S., and Gizzi, G. (2011) Panminerva Med., 53, 43–49.

    PubMed  CAS  Google Scholar 

  135. Hasko, G., and Pacher, P. (2010) Am. J. Physiol. Heart Circ. Physiol., 299, H10–H12.

    Article  PubMed  CAS  Google Scholar 

  136. Ren, J., Fan, C., Chen, N., Huang, J., and Yang, Q. (2011) Neurochem. Res., 36, 2352–2362.

    Article  PubMed  CAS  Google Scholar 

  137. Zghonda, N., Yoshida, S., Araki, M., Kusunoki, M., Mliki, A., Ghorbel, A., and Miyazaki, H. (2011) Biosci. Biotechnol. Biochem., 75, 1259–1267.

    Article  PubMed  CAS  Google Scholar 

  138. Chiou, Y. S., Tsai, M. L., Nagabhushanam, K., Wang, Y. J., Wu, C. H., Ho, C. T., and Pan, M. H. (2011) J. Agric. Food Chem., 59, 2725–2733.

    Article  PubMed  CAS  Google Scholar 

  139. Abiko, Y., Miura, T., Phuc, B. H., Shinkai, Y., and Kumagai, Y. (2011) Toxicol. Appl. Pharmacol., 255, 32–39.

    Article  PubMed  CAS  Google Scholar 

  140. Rockwell, C. E., Zhang, M., Fields, P. E., and Klaassen, C. D. (2012) J. Immunol., 188, 1630–1637.

    Article  PubMed  CAS  Google Scholar 

  141. Chan, K., and Kan, Y. W. (1999) Proc. Natl. Acad. Sci. USA, 96, 12731–12736.

    Article  PubMed  CAS  Google Scholar 

  142. Zhang, Y., and Munday, R. (2008) Mol. Cancer Ther., 7, 3470–3479.

    Article  PubMed  CAS  Google Scholar 

  143. Thimmulappa, R. K., Fuchs, R. J., Malhotra, D., Scollick, C., Traore, K., Bream, J. H., Trush, M. A., Liby, K. T., Sporn, M. B., Kensler, T. W., and Biswal, S. (2007) Antioxid. Redox Signal., 9, 1963–1970.

    Article  PubMed  CAS  Google Scholar 

  144. Pergola, P. E., Raskin, P., Toto, R. D., Meyer, C. J., Huff, J. W., Grossman, E. B., Krauth, M., Ruiz, S., Audhya, P., Christ-Schmidt, H., Wittes, J., and Warnock, D. G. (2011) N. Engl. J. Med., 365, 327–336.

    Article  PubMed  CAS  Google Scholar 

  145. Hong, D. S., Kurzrock, R., Supko, J. G., He, X., Naing, A., Wheler, J., Lawrence, D., Eder, J. P., Meyer, C. J., Ferguson, D. A., Mier, J., Konopleva, M., Konoplev, S., Andreeff, M., Kufe, D., Lazarus, H., Shapiro, G. I., and Dezube, B. J. (2012) Clin. Cancer Res., 18, 3396–3406.

    Article  PubMed  CAS  Google Scholar 

  146. Ichikawa, T., Li, J., Meyer, C. J., Janicki, J. S., Hannink, M., and Cui, T. (2009) PLoS One, 4, e8391.

    Article  PubMed  CAS  Google Scholar 

  147. Ben-Dor, A., Steiner, M., Gheber, L., Danilenko, M., Dubi, N., Linnewiel, K., Zick, A., Sharoni, Y., and Levy, J. (2005) Mol. Neurobiol., 4, 177–186.

    CAS  Google Scholar 

  148. Linnewiel, K., Ernst, H., Caris-Veyrat, C., Ben-Dor, A., Kampf, A., Salman, H., Danilenko, M., Levy, J., and Sharoni, Y. (2009) Free Radic. Biol. Med., 47, 659–667.

    Article  PubMed  CAS  Google Scholar 

  149. Sahin, K., Tuzcu, M., Sahin, N., Ali, S., and Kucuk, O. (2010) Food Chem. Toxicol., 48, 2670–2674.

    Article  PubMed  CAS  Google Scholar 

  150. Markovitch, D., Tyrrell, R. M., Tauler, P., Frystyk, J., Stokes, K., and Thompson, D. (2009) Nutrition, 25, 668–675.

    Article  PubMed  CAS  Google Scholar 

  151. Velmurugan, K., Alam, J., McCord, J. M., and Pugazhenthi, S. (2009) Free Radic. Biol. Med., 46, 430–440.

    Article  PubMed  CAS  Google Scholar 

  152. Robbins, D., Gu, X., Shi, R., Liu, J., Wang, F., Ponville, J., McCord, J. M., and Zhao, Y. (2010) PLoS One, 5, e11902.

    Article  PubMed  CAS  Google Scholar 

  153. Qureshi, M. M., McClure, W. C., Arevalo, N. L., Rabon, R. E., Mohr, B., Bose, S. K., McCord, J. M., and Tseng, B. S. (2010) J. Diet., 7, 159–178.

    Article  Google Scholar 

  154. Liu, J., Gu, X., Robbins, D., Li, G., Shi, R., McCord, J. M., and Zhao, Y. (2009) PLoS One, 4, e5284.

    Article  PubMed  CAS  Google Scholar 

  155. Papadopoulou, A., D’souza, M., Kappos, L., and Yaldizli, O. (2010) Expert Opin. Investig. Drugs, 19, 1603–1612.

    Article  PubMed  CAS  Google Scholar 

  156. Kappos, L., Gold, R., Miller, D. H., Macmanus, D. G., Havrdova, E., Limmroth, V., Polman, C. H., Schmierer, K., Yousry, T. A., Yang, M., Eraksoy, M., Meluzinova, E., Rektor, I., Dawson, K. T., Sandrock, A. W., and O’Neill, G. N. (2008) Lancet, 372, 1463–1472.

    Article  PubMed  CAS  Google Scholar 

  157. Fox, E. J., and Rhoades, R. W. (2012) Curr. Opin. Neurol., 25, S11–S19.

    Article  PubMed  CAS  Google Scholar 

  158. Calkins, M. J., Johnson, D. A., Townsend, J. A., Vargas, M. R., Dowell, J. A., Williamson, T. P., Kraft, A. D., Lee, J. M., Li, J., and Johnson, J. A. (2009) Antioxid. Redox Signal., 11, 497–508.

    Article  PubMed  CAS  Google Scholar 

  159. Maes, M., Fisar, Z., Medina, M., Scapagnini, G., Nowak, G., and Berk, M. (2012) Inflammopharmacology, 20, 127–150.

    Article  PubMed  CAS  Google Scholar 

  160. Khor, T. O., Yu, S., and Kong, A. N. (2008) Planta Med., 74, 1540–1547.

    Article  PubMed  CAS  Google Scholar 

  161. Heerspink, H. J., and de Zeeuw, D. (2011) Rev. Diabet. Stud., 8, 392–402.

    Article  PubMed  Google Scholar 

  162. Lau, A., Villeneuve, N. F., Sun, Z., Wong, P. K., and Zhang, D. D. (2008) Pharmacol. Res., 58, 262–270.

    Article  PubMed  CAS  Google Scholar 

  163. MacManus, D. G., Miller, D. H., Kappos, L., Gold, R., Havrdova, E., Limmroth, V., Polman, C. H., Schmierer, K., Yousry, T. A., Eraksoy, M., Meluzinova, E., Dufek, M., Yang, M., O’Neill, G. N., and Dawson, K. (2011) J. Neurol., 258, 449–456.

    Article  PubMed  CAS  Google Scholar 

  164. Nakajima, H., Nakajima-Takagi, Y., Tsujita, T., Akiyama, S., Wakasa, T., Mukaigasa, K., Kaneko, H., Tamaru, Y., Yamamoto, M., and Kobayashi, M. (2011) PLoS One, 6, e26884.

    Article  PubMed  CAS  Google Scholar 

  165. Juge, N., Mithen, R. F., and Traka, M. (2007) Cell. Mol. Life Sci., 64, 1105–1127.

    Article  PubMed  CAS  Google Scholar 

  166. Serafini, M., Peluso, I., and Raguzzini, A. (2010) Proc. Nutr. Soc., 69, 273–278.

    Article  PubMed  CAS  Google Scholar 

  167. Palozza, P., Catalano, A., Simone, R., and Cittadini, A. (2012) Acta Biochim. Pol., 59, 21–25.

    PubMed  CAS  Google Scholar 

  168. Shanmugam, M. K., Nguyen, A. H., Kumar, A. P., Tan, B. K., and Sethi, G. (2012) Cancer Lett., 320, 158–170.

    Article  PubMed  CAS  Google Scholar 

  169. Zenkov, N. K., Menshchikova, E. B., Kandalintseva, N. V., Oleynik, A. S., Prosenko, A. E., Gusachenko, O. N., Shklyaeva, O. A., Vavilin, V. A., and Lyakhovich, V. V. (2007) Biochemistry (Moscow), 72, 644–651.

    PubMed  CAS  Google Scholar 

  170. Steel, R., Cowan, J., Payerne, E., O’Connell, M. A., and Searcey, M. (2012) ACS Med. Chem. Lett., 3, 407–410.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Scientific Center of Clinical and Experimental Medicine, Siberian Branch of the Russian Academy of Medical Sciences, ul. Timakova 2, 630117, Novosibirsk, Russia

    N. K. Zenkov, E. B. Menshchikova & V. O. Tkachev

  2. University of Michigan School of Medicine, 1301 Catherine Road, Ann Arbor, MI, 48109, USA

    V. O. Tkachev

Authors
  1. N. K. Zenkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. B. Menshchikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. O. Tkachev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. B. Menshchikova.

Additional information

Original Russian Text © N. K. Zenkov, E. B. Menshchikova, V. O. Tkachev, 2013, published in Biokhimiya, 2013, Vol. 78, No. 1, pp. 27–47.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zenkov, N.K., Menshchikova, E.B. & Tkachev, V.O. Keap1/Nrf2/ARE redox-sensitive signaling system as a pharmacological target. Biochemistry Moscow 78, 19–36 (2013). https://doi.org/10.1134/S0006297913010033

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297913010033

Key words

Search

Navigation