The phytoestrogenic potential of flavonoid glycosides from Selaginella moellendorffii via ERα-dependent signaling pathway

Ethnopharmacological relevance: Selaginella moellendorffii (SM) has been applied as an ethnic drug to treat conditions such as osteoporosis, idiopathic thrombocytopenic purpura, and chronic inflammation. It is known to be rich in flavonoids, including apigenin glycosides and unique elements of bioflavonoids.Aim of the study: To investigate estrogen-like constituents of SM and the possible mechanism.Materials and methods: We identified the main components in liquid chromatography and liquid chromatographymass spectrometry. The estrogenic effects were examined using a recombinant yeast screening assay, an E-screen cell proliferation assay, and an in vivo uterotrophic assay.Results: Flavonoid glycosides extract, some flavonoid glycosides, and apigenin showed estrogen agonistic activity in the yeast screening assay. They also induced cell proliferation in estrogen receptor-positive (ER+) cells but not in estrogen receptor-negative (ER-) cells. Consistently, the protein expression of ER alpha, phosphorylation protein kinase B (p-AKT), phosphatidylinositol 3 kinase (PI3K), phosphorylation mammalian target of rapamycin (pmTOR), phosphorylation 38,000-Da protein (p-P38), and phosphorylation extracellular-regulated kinase 1/2 (pERK1/2) elevated following treatment with flavonoid glycoside extract (P < 0.01 or P < 0.05). These effects could be blocked by ER antagonist or ER alpha antagonist but not be blocked by ER beta antagonist. In vivo assay, flavonoid glycoside extract could significantly increase body weight, serum estradiol level, uterine wet weight, alter uterine morphology, and promote ER alpha protein expression (P < 0.01 or P < 0.05). Conclusions: ER alpha induction via mitogen-activated protein kinases (MAPK) and PI3K/Akt/mTOR pathways might be the possible mechanism underlying the phytoestrogen effect of SM, and the flavonoid glycosides might be the critical estrogenic constituents.

Automated summary

In this study, it was found that flavonoid glycosides extract, some flavonoid glycosides, and apigenin in Selaginella moellendorffii have estrogenic activity and induce cell proliferation in estrogen receptor-positive cells. The induction of ER alpha expression through MAPK and PI3K/Akt/mTOR pathways might be the possible mechanism underlying the phytoestrogen effect, and flavonoid glycosides could be the critical estrogenic constituents.