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Exogenous toxicants (e.g. arsenic, cigarette smoke), trigger oxidative stress, and initiate the pathogenesis of many human diseases. Induction of nuclear factor E2-related factor 2 (Nrf2) counteracts exogenous toxicant-induced oxidative insults. Using a high-throughput screen, we firstly identified a citrus polymethoxyflavone, (2S)-5,6,7,3′,4′-pentamethoxyflavanone (PMF), to be an Nrf2 activator, and an investigation targeting Nrf2 pathway was performed. Our study indicated that: (i) PMF activated Nrf2 and its downstream genes, NQO1 and γ-GCS, and enhanced the stabilization of Nrf2 through inhibiting Nrf2 ubiquitination. (ii) Inhibition of PI3K, p38 MAPK, PKC and PERK by specific kinase inhibitors suppressed PMF-induced activation of Nrf2. (iii) PMF conferred Nrf2-dependent protection against sodium arsenite- and cigarette smoke extract- induced cytotoxicity in lung epithelial cells. Collectively, our data demonstrate that PMF is a novel Nrf2 activator with potential prevention against oxidative insults. The diverse pharmacological functions of citrus polymethoxyflavone might be related to their ability of activating Nrf2 pathway.

Hypericum perforatum L., which includes a wide range of bioactive substances and is sold as a functional food formulation, has been used as an alternative to estrogen replacement treatment to relieve menopausal syndromes. However, methods to track HPL mechanisms and link them to metabolism disorder regulation during menopause periods have been lacking. To investigate HPL function in endocrine-related metabolic recognition, we applied both global and targeted metabolomic methods on ovariectomised rat serum and urine metabolites for treatment-specific metabolic profiling and to explore biomarkers and deduce their mechanisms via 1H-NMR and HPLC–MS/MS techniques. Results from the comparison of metabolite levels of rats that underwent an ovariectomy (OVX) before and after the administration of different doses of HPL showed that HPL can reverse the disordered changes induced in multiple biomarkers by menopausal syndromes. Through screening, identification, and quantification of the differential regulatory metabolites, 23 metabolites involved in 4 major metabolic pathways, including the arginine, taurine, pyruvate and tryptophan metabolic pathways, were highlighted as important for explaining the mechanisms of HPL. These pathways may be applicable for explanations of other menopausal syndrome symptoms, such as depression and hot flashes, and the effects of other herbs rich in flavonoids with menopause remission potential.