Activation of the Nrf2/ARE pathway via S-alkylation of cysteine 151 in the chemopreventive agent-sensor Keap1 protein by falcarindiol, a conjugated diacetylene compound

Dietary Diacetylene Falcarindiol Induces Phase 2 Drug-Metabolizing Enzymes and Blocks Carbon Tetrachloride-Induced Hepatotoxicity in Mice through Suppression of Lipid Peroxidation

“…It has been reported that the expression of Nrf2, an important transcription factor of GSTs and NQO1, is higher in liver, small intestine, kidney, and lung where metabolism of endogenous and exogenous xenobiotics is active. 42) Because falcarindiol induces GST and NQO1 via activation of the Keap1/Nrf2/ARE pathway, 8) it is reasonable that the increase in GST and NQO1 activities in falcarindiol-treated mice was observed in the organs expressing Nrf2 at high levels.…”

“…7) Moreover, we elucidated the mechanism of phase 2 DME induction by falcarindiol at both cellular and molecular levels and emphasized that a conjugated diacetylene in the chemical structure of falcarindiol played an important role in the induction mechanism. 8) Phase 2 DMEs, such as glutathione S-transferase (GST) and UDP-glucuronosyltransferase (UGT), and quinone-reducing enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) are involved in the detoxification of carcinogens and function to facilitate their elimination. Therefore, induction of phase 2 DMEs and NQO1 is an effective mechanism for protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by chemical compounds.…”

“…12,13) Most GST and NQO1 inducers, including falcarindiol and sulforaphane, interact with critical cysteines in Kelch-like ECH-associated protein 1 (Keap1) through alkylation, allowing Nrf2 to escape proteasomal degradation and to accumulate in the nucleus. 8,[14][15][16][17] Accumulated Nrf2 activates the expression of multiple categories of genes, including genes for phase 2 DME, anti-inflammatory responses, and molecular chaperones as well as stress response genes such as heme oxygenase-1 (HO-1). 18,19) Thus, the Keap1/Nrf2/ARE signaling pathway plays a central role in cytoprotection against various stress conditions.…”

Intracellular peptide delivery using amphiphilic lipid‐based formulations

“…Interestingly, the delivered proteins retain their activity as demonstrated in functional studies (Cassinelli et al, 2006(Cassinelli et al, , 2009Chiu et al, 2010;Duerr et al, 2009;Giordano et al, 2010;Leshchyns'ka et al, 2006;Moreno et al, 2009;Ohnuma et al, 2010;Okamoto et al, 2011;Rivas et al, 2009;Schafer et al, 2009;Spagnolo et al, 2010;Ying et al, 2007;Zhang et al, 2008).…”

“…In earlier studies, several groups successfully delivered proteins (Ohnuma et al, 2010;Spagnolo et al, 2010;Weill et al, 2008a;Zhang et al, 2008) including antibodies (Cassinelli et al, 2006(Cassinelli et al, , 2009Cortes et al, 2007;Duerr et al, 2009;Okamoto et al, 2011;Weill et al, 2008b;Ying et al, 2007), peptides (Chiu et al, 2010;Giordano et al, 2010;Leshchyns'ka et al, 2006;Moreno et al, 2009;Rivas et al, 2009) as well as quantum-dots (Delehanty et al, 2009) using the proprietary cationic lipid-mediated delivery reagent PULSin. Interestingly, the delivered proteins retain their activity as demonstrated in functional studies (Cassinelli et al, 2006(Cassinelli et al, , 2009Chiu et al, 2010;Duerr et al, 2009;Giordano et al, 2010;Leshchyns'ka et al, 2006;Moreno et al, 2009;Ohnuma et al, 2010;Okamoto et al, 2011;Rivas et al, 2009;Schafer et al, 2009;Spagnolo et al, 2010;Ying et al, 2007;Zhang et al, 2008).…”