Abstract
Epimedium brevicornum Maxim has a long history of use in the treatment of estrogen deficiency-related diseases. However, the chemical constituents and mechanism of action of this medicinal plant are not fully understood. In the present study, we isolated four new isoprenylated flavonoid glycosides, as well as 16 known flavonoids (13 isoprenylated flavonoids), from this plant. The chemical structures of the new flavonoid glycosides were elucidated by extensive spectroscopic analysis. The new compounds 1–4 were potent promoters of estrogen biosynthesis in human ovarian granulosa-like KGN cells. ZW1, an isoprenylated flavonoid analogue and a specific inhibitor of phosphodiesterase 5 (PDE5), was synthesized and used to explore the mechanism of the isoprenylated analogues on estrogen biosynthesis. ZW1 treatment increased estrogen production by upregulation of aromatase mRNA and protein expression. ZW1 increased the phosphorylation of cAMP response element-binding protein (CREB). Further study showed that the inhibition of PDE5 by ZW1 increased estrogen biosynthesis partly through suppression of phosphodiesterase 3 (PDE3). Our results suggested that the isoprenylated flavonoids from E. brevicornum may produce beneficial health effects through the promotion of estrogen biosynthesis. PDE5 warrants further investigation as a new therapeutic target for estrogen biosynthesis in the prevention and treatment of estrogen-deficiency related diseases.
Highlights
Estrogens play a crucial role in the normal physiology of a variety of tissues, including the mammary glands, reproductive tract, central nervous system, and skeleton
E. brevicornum Maxim has been used for the treatment of estrogen deficiency-related diseases in traditional Chinese herbal medicines for over 2000 years
Modern pharmacological studies and clinical practice have demonstrated that E. brevicornum Maxim and its active compounds possess a wide range of pharmacological actions, in particular, anti-osteoporosis, anti-aging, anti-atherosclerosis, and anti-depressant activity43
Summary
Estrogens play a crucial role in the normal physiology of a variety of tissues, including the mammary glands, reproductive tract, central nervous system, and skeleton. PDE5 inhibition by tadalafil and sildenafil, two specific inhibitors of PDE5 used for the treatment of erectile dysfunction, promoted estrogen production by an increase of aromatase expression through activation of the cGMP/ PKG pathway in human adipocytes. We found the extract of E. brevicornum and icariin promoted the production of estrogen in human ovarian granulosa cells and osteoblastic cells by upregulation of aromatase expression, providing new insight into the mechanism behind their pharmacological effects. We found the extract of E. brevicornum and icariin promoted the production of estrogen in human ovarian granulosa cells and osteoblastic cells by upregulation of aromatase expression, providing new insight into the mechanism behind their pharmacological effects16 It is still unclear whether other compounds extracted from this medicinal plant have similar effects on estrogen biosynthesis and what the mechanism of action of these compounds would be. We isolated compounds from E. brevicornum and examined the effect and underlying mechanism of estrogen biosynthesis-promoting compounds on aromatase expression
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