Identification of novel Nrf2 activators from Cinnamomum chartophyllum HW Li and their potential application of preventing oxidative insults in human lung epithelial cells

Human lung tissue, directly exposed to the environmental oxidants and toxicants, is apt to be harmed to bring about acute or chronic oxidative insults. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents a central cellular defense mechanism, and is a target for developing agents against oxidative insult-induced human lung diseases. Our previous study found that the EtOH extract of Cinnamomum chartophyllum protected human bronchial epithelial cells against oxidative insults via Nrf2 activation. In this study, a systemic phytochemical investigation of the aerial parts of C. chartophyllum led to the isolation of thirty chemical constituents, which were further evaluated for their Nrf2 inducing potential using NAD(P)H: quinone reductase (QR) assay. Among these purified constituents, a sesquiterpenoid bearing alpha, beta-unsaturated ketone group, 3S-(+)-9-oxonerolidol (NLD), and a diphenyl sharing phenolic groups, 3, 3', 4, 4'-tetrahydroxydiphenyl (THD) significantly activated Nrf2 and its downstream genes, NAD(P)H quinone oxidoreductase 1 (NQO-1), and gamma-glutamyl cysteine synthetase (gamma-GCS), and enhanced the nuclear translocation and stabilization of Nrf2 in human lung epithelial cells. Importantly, NLD and THD had no toxicities under the Nrf2 inducing doses. THD also demonstrated a potential of interrupting Nrf2-Keap1 protein protein interaction (PPI). Furthermore, NLD and THD protected human lung epithelial cells against sodium arsenite [As(III)]-induced cytotoxicity. Taken together, we conclude that NLD and THD are two novel Nrf2 activators with potential application of preventing acute and chronic oxidative insults in human lung tissue.