Characterization of chemical constituents from Thymelaea hirsuta with PPARα/γ modulation activity

In our previous research, the 95% ethanol extract of Thymelaea hirsuta showed dual activation of PPARα and PPARγ as targets for type 2 diabetes and metabolic disorder. The aim of this study was to isolate bioactive constituents which are responsible for PPARα/γ agonistic effect in T. hirsuta. Bioactivity-guided separation of constituents from T. hirsuta yielded bi- and tricoumarins (daphnoretin and triumbelletin), mono- and biflavonoids (genkwanin, genkwanin 5-O-β-D-glucopyranoside, genkwanin 5-O-β-D-primeveroside, tiliroside, neochamaejasmin B, and daphnodoricin C), and lignans (pinoresinol and syringaresinol). A tricoumarin, triumbelletin, was first time isolated as a free aglycone. Among the isolates, pinoresinol (2.1- and 2.4-fold induction), syringaresinol (2.2- and 2.5-fold induction), and triumbelletin (2.0- and 1.9-fold induction) activated both PPARα and PPARγ at a concentration of 100 µM by luciferase assay in HepG2 cells. This is the first report to reveal the PPARα/γ agonistic action of triumbelletin along with its structure elucidation by the use of NMR and MS spectroscopic data.