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Antioxidant Inflammation Modulators (AIMs)

AIMs are potent activators of the transcription factor Nrf2. Activation of Nrf2 promotes the production of a wide range of antioxidant, detoxification, and anti-inflammatory genes. Activation of Nrf2 also inhibits NF-κB, a gene that regulates many pro-inflammatory enzymes.  Suppression of Nrf2 and activation of NF-κB has been associated with numerous chronic inflammatory diseases such as CKD, chronic obstructive pulmonary disease (COPD), Alzheimer's disease, and cancer.  Therefore, agents that activate Nrf2 and inhibit NF-κB may be beneficial in the treatment of these chronic inflammatory diseases.

Key Publications

Renal/Cardiovascular Disease

  • Pablo E. Pergola, M.D., Ph.D., Philip Raskin, M.D., Robert D. Toto, M.D., Colin J. Meyer, M.D., J. Warren Huff, J.D., Eric B. Grossman, M.D., Melissa Krauth, M.B.A., Stacey Ruiz, Ph.D., Paul Audhya, M.D., Heidi Christ-Schmidt, M.S.E., Janet Wittes, Ph.D., and David G. Warnock, M.D. for the BEAM Study Investigators. Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes. The New England Journal of Medicine, 2011, 10.1056.

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  • Pablo E. Pergola, Melissa Krauth, J. Warren Huff, Deborah A. Ferguson, Stacey Ruiz, Colin J. Meyer, David G. Warnock, Effect of bardoxolone methyl on Kidney Function in Patients with T2D and Stage 3b-4 CKD, American Journal of Nephrology, 2011. 33: p.469-476

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  • Vaziri, et al. Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure, 2009. Am J Physiol Renal Physiol. 2010 Mar;298(3):F662-71. Epub 2009 Dec 9.

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  • Tanaka Y, Aleksunes LM, Goedken MJ, Chen C, Reisman SA, Manautou JE, and Klaassen CD. 2008. Coordinated induction of Nrf2 target genes protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity. Toxicol Appl Pharmacol. 231(3):364-73.

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  • Wu QQ, Wang Y, Senitko M, Meyer C, Wigley WC, Ferguson DA, Grossman E, Chen J, Zhou XJ, Hartono J, Winterberg P, Chen B, Agarwal A, Lu CY. Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPAR{gamma}, and HO-1. Am J Physiol Renal Physiol. 2011 May;300(5):F1180-92. Epub 2011 Feb 2.

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Respiratory Disease

  • Cho H-Y., Kleeberger, S.R., Nrf2 protects against airway disorders, Toxicology and Applied Pharmacology, 2010. 244 p. 43-56

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CNS Disease

  • Dumont M, Wille E, Calingasan NY, Tampellini D, Williams C, Gouras GK, Liby K, Sporn M, Flint Beal M, and Lin MT. 2009. Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer's disease. J Neurochem. Feb 7 [Epub ahead of print]

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  • Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, and Johnson JA. 2009. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A. 106(8):2933-8

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Liver Disease

Cancer

  • Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, Meyer C, Becerra CR, Fishman M, Antonia S, Sporn MB, Liby KT, Rawal B, Lee JH, Gabrilovich DI. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res. 2010 Mar 15;16(6):1812-23.
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  • Ling X, Konopleva M, Zeng Z, Ruvolo V, Stephens LC, Schober W, McQueen T, Dietrich M, Madden TL, and Andreeff M. 2007. The novel triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid inhibits metastatic murine breast tumor growth through inactivation of STAT3 signaling.
    Cancer Res. 67(9):4210-8

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