Xanthohumol Analogues as Potent Nrf2 Activators against Oxidative Stress Mediated Damages of PC12 Cells.

The nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor controlling a series of cytoprotective genes, is closely associated with scavenging the reactive oxygen species and maintaining the intracellular redox balance. Accumulating evidence has indicated that activation of Nrf2 is efficient to block or retard oxidative stress mediated neurodegenerative disorders. Small molecules that contribute directly or indirectly to the Nrf2 activation thus are promising therapeutic agents. Herein, we screened xanthohumol and its analogues, and two analogues (11 and 12) were disclosed to possess low cytotoxicity and rescue PC12 cells from the hydrogen peroxide or 6-hydroxydopamine induced injuries. Molecular mechanism studies demonstrated that compounds 11 and 12 are potent Nrf2 activators by promoting the nuclear accumulation of Nrf2 and enhancing the cellular antioxidant defense system. More importantly, genetically silencing the Nrf2 expression shuts down the observed cytoprotection conferred by both compounds, supporting the critical involvement of Nrf2 for the cellular actions of compounds 11 and 12.