Oligostilbenes from the seeds of Paeonia lactiflora as potent GLP-1 secretagogues targeting TGR5 receptor.

One unusual stilbene trimer-flavonoid hybrid, paeonilactiflobenoid (1), together with six known stilbenes (2-7) were isolated from the seeds of Paeonia lactiflora. The structure of 1 was elucidated with the aid of HRESIMS, 1D and 2D NMR, [α] _D spectroscopic data and ECD calculation. Compounds 2-7 showed stimulative effects on GLP-1 secretion with promoting rates of 79.8%-880.4% (25 μM) and 217.6%-1089.4% (50 μM), more potent than the positive control, oleoylethanolamide (250.2% at 50 μM). Moreover, compounds 4 and 6 exhibited agonistic activity on the G protein-coupled receptor (GPCR) TGR5 with stimulative ratios of 40.2% and 40.5% at 50 μM, and 54.2% and 49.1% at 100 μM, respectively. Docking study manifested that 6 well located in the catalytic pocket of TGR5 by hydrogen-bond and hydrophobic interactions. The GLP-1 promotion of 6 could be attenuated by IP ₃ , Ca ²⁺ /CaMKII and MEK/ERK pathway inhibitors, suggesting that these pathways played important roles in GLP-1 secretion. Thus, stilbenes in peony seeds maybe regarded as potential GLP-1 secretagogues through TGR5-IP ₃ -Ca ²⁺ /CaMKII-MEK/ERK pathways.
Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest.
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