Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress

Abstract

inflammation ͉ Nrf2 Keap1 ͉ oxidative stress ͉ phase 2 enzymes ͉ NAD(P)Hquinone acceptor oxidoreductase

Allantopyrone A activates Keap1–Nrf2 pathway and protects PC12 cells from oxidative stress-induced cell death

“…Keap1 has reactive thiol groups and is considered as a sensor of oxidants or electrophilic compounds. Some of the electrophilic compounds, for example, sulforaphane, 11 curcumin, 12 zerumbone, 19,20 piperlongumine, 21 bardoxolone methyl 22 and dimethyl fumarate, 23 activate the Keap1-Nrf2 pathway. They bind directly with the thiol group of Keap1 and causes conformational changes to Keap1.…”

Diabetic nephropathy: newer therapeutic perspectives

“…There is emerging evidence to support that reactive oxygen species cause impaired activity of the transcription factor call Nrf-2 (nuclear 1 factor-related factor 2) [61]. A synthetic triterpenoid derivative, bardoxolone methyl, is a potent activator of Nrf-2 that was shown to reduce oxidative stress in rat models [62,63]. …”

Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme

“…We have previously shown that cyanoenones react with cysteine residues in Keap1, the main negative regulator of Nrf2. 6,7,14 In a variety of cell lines and animal tissues, we have demonstrated that Nrf2 activation by cyanoenones leads to the coordinate transcriptional upregulation of NQO1 together with other Nrf2-target genes, such as multiple isoforms of glutathione S-transferase (GST), heme oxygenase 1, -glutamyl cysteine ligase catalytic (GCLC) subunit, as well as an ARE-luciferase reporter, a direct readout of Nrf2-mediated transcription. 6,7,14 Furthermore, Nrf2 is required for the NQO1 inducer activity of cyanoenones as NQO1 induction is not observed in Nrf2-deficient cells.…”

“…6,7,14 In a variety of cell lines and animal tissues, we have demonstrated that Nrf2 activation by cyanoenones leads to the coordinate transcriptional upregulation of NQO1 together with other Nrf2-target genes, such as multiple isoforms of glutathione S-transferase (GST), heme oxygenase 1, -glutamyl cysteine ligase catalytic (GCLC) subunit, as well as an ARE-luciferase reporter, a direct readout of Nrf2-mediated transcription. 6,7,14 Furthermore, Nrf2 is required for the NQO1 inducer activity of cyanoenones as NQO1 induction is not observed in Nrf2-deficient cells. 6,7 The electron affinity of these new compounds can be calculated via the energy of their lowest unoccupied molecular orbital, E (LUMO) in eV, and was quantified at two quantum mechanical levels: the semiempirical AM1, 16 and the density functional theory (DFT) 17 (see Table 1).…”

“…6,7,14 Furthermore, Nrf2 is required for the NQO1 inducer activity of cyanoenones as NQO1 induction is not observed in Nrf2-deficient cells. 6,7 The electron affinity of these new compounds can be calculated via the energy of their lowest unoccupied molecular orbital, E (LUMO) in eV, and was quantified at two quantum mechanical levels: the semiempirical AM1, 16 and the density functional theory (DFT) 17 (see Table 1). Briefly, no solvent model was used for the calculation of the LUMO energies.…”