The Synthetic Triterpenoids, CDDO and CDDO-Imidazolide, Are Potent Inducers of Heme Oxygenase-1 and Nrf2/ARE Signaling

Abstract

The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its derivative 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are multifunctional molecules with potent antiproliferative, differentiating, and anti-inflammatory activities. At nanomolar concentrations, these agents rapidly increase the expression of the cytoprotective heme oxygenase-1 (HO-1) enzyme in vitro and in vivo. Transfection studies using a series of reporter constructs show that activation of the human HO-1 promoter by the triterpenoids requires an antioxidant response element (ARE), a cyclic AMP response element, and an E Box sequence. Inactivation of one of these response elements alone partially reduces HO-1 induction, but mutations in all three sequences entirely eliminate promoter activity in response to the triterpenoids. Treatment with CDDO-Im also elevates protein levels of Nrf2, a transcription factor previously shown to bind ARE sequences, and increases expression of a number of antioxidant and detoxification genes regulated by Nrf2. The triterpenoids also reduce the formation of reactive oxygen species in cells challenged with tert-butyl hydroperoxide, but this cytoprotective activity is absent in Nrf2 deficient cells. These studies are the first to investigate the induction of the HO-1 and Nrf2/ARE pathways by CDDO and CDDO-Im, and our results suggest that further in vivo studies are needed to explore the chemopreventive and chemotherapeutic potential of the triterpenoids. (Cancer Res 2005; 65(11): 4789-98)

JunB and JunD Regulate Human Heme Oxygenase-1 Gene Expression in Renal Epithelial Cells

“…The Ϫ4.5-kb human HO-1 promoter construct in the human growth hormone (hGH) reporter vector (pHOGH/4.5) or the luciferase reporter (pHOGL3/4.5) (45, 46) was used as the parental clone for the single, double, and triple mutation constructs and have been described previously (40). All mutations were made using the QuikChange XL mutagenesis kit (Stratagene, La Jolla, CA) according to the manufacturer's instructions.…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…In transgenic AD mouse models intrahippocampal injections of the lentiviral vector expressing Nrf2 decreased Aβ plaque, reduced learning deficits, and protected against Aβ-induced cell death [158,159]. Synthetic triterpenoids have been demonstrated to induce expression of Nrf2 and to protect against cell death in both in vitro and in vivo experiments [160,161]. Development of strategies that target this Nrf2/antioxidant response element pathway are at an early stage and require substantial translational research.…”

“…MeDi, opposed to the Western diet, is characterized by the abundant consumption of plant foods such as vegetables, fruits, breads, potatoes, legumes, nuts, [160,161] AD = Alzheimer's disease; mTOR = mammalian target of rapamycin; Aβ = β-amyloid; Nrf2 = nuclear response factor 2 and seeds; olive oil as the source of fat; moderate amounts of dairy, fish, poultry, and eggs; low intake of red meats; and wine during normal meals [173,174,195]. The nutrients within the MeDi influence biological mechanisms affecting vascular, antioxidant, and inflammatory pathways [175,176].…”

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…The synthetic triterpenoid compounds belonging to the bardoxolone methyl (CDDO-Methyl ester) family are potent Nrf2 activators [24,25]. By interacting with the keap1 molecule these compounds facilitate nuclear translocation of Nrf2 and expression of its target genes [26].…”