TY - JOUR T1 - Characterization of the Potent, Selective Nrf2 Activator, PSTC, in Cellular and In Vivo Models of Pulmonary Oxidative Stress JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.241794 SP - jpet.117.241794 AU - John G Yonchuk AU - Joseph P Foley AU - Brian J Bolognese AU - Gregory A Logan AU - William E Wixted AU - Jen-Pyng Kou AU - Diana G Chalupowicz AU - Heidi G Feldser AU - Yolanda Sanchez AU - Hong Nie AU - James F Callahan AU - Jeffrey K Kerns AU - Patricia L Podolin Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/08/08/jpet.117.241794.abstract N2 - Nrf2 is a key regulator of oxidative stress and cellular repair, and can be activated through inhibition of its cytoplasmic repressor, Keap1. Several small molecule disrupters of the Nrf2-Keap1 complex have recently been tested and/or approved for human therapeutic use but lack either potency or selectivity. The main goal of our work was to develop a potent, selective activator of NRF2 as protection against oxidative stress. In human bronchial epithelial cells our Nrf2 activator, PSTC, induced Nrf2 nuclear translocation, Nrf2-regulated gene expression, and downstream signaling events including induction of NQO1 enzyme activity and HO-1 protein expression, in an Nrf2-dependent manner. As a marker of subsequent functional activity, PSTC restored oxidant (tBHP)-induced glutathione depletion. The compound's engagement of the Nrf2 signaling pathway translated to an in vivo setting, with induction of Nrf2-regulated gene expression and NQO1 enzyme activity, as well as restoration of oxidant (ozone)-induced glutathione depletion, occurring in the lungs of PSTC-treated rodents. Under disease conditions PSTC engaged its target, inducing the expression of Nrf2-regulated genes in human bronchial epithelial cells derived from COPD patients, as well as in the lungs of cigarette smoke-exposed mice. Subsequent to the latter a dose-dependent inhibition of cigarette smoke-induced pulmonary inflammation was observed. Finally, in contrast to CDDO-Me and sulforaphane, PSTC did not inhibit IL-1β-induced NF-κB translocation or insulin-induced S6 phosphorylation in human cells, emphasizing the on-target activity of this compound. In summary, we characterize a potent, selective Nrf2 activator that offers protection against pulmonary oxidative stress in several cellular and in vivo models. ER -