Combing network phytochemistry with networking pharmacology approaches to elucidate the action mechanism of Traditional Chinese Medicine Formula: chemical constitutes of erxian decoction up-regulated estrogen receptor expression and induced estradiol-biosynthesis for menopause as a study model

Abstract

BACKGROUND: Menopause is an aging process due to estrogen deficiency caused by ovarian aging. Symptoms include osteoporosis etc. Hormone replacement therapy used for relieving menopausal symptoms can increase the incidence of breast carcinoma, cardiovascular disease and stroke. People have turned their attention to Chinese medicine as an alternative. Er-xian Decoction (EXD), an anti-menopausal Chinese medicine formula, has been studied for years. However, scientists find it difficult to study the action mechanism of its chemical constituents due to their complexity. Combining network phytochemistry with networking pharmacology approaches would contribute to ascertain the effective EXD compounds, which up-regulated estrogen receptor expression and induced estradiol-biosynthesis for relieving estrogen deficiency symptoms. METHODS: The TCMSP database and TCM Database@TaiWan were used to ascertain the corresponding phytochemicals in EXD, database STITCH 4.0 to understand chemical-protein interaction information, and Cytoscape 3.1.0 to construct the network profile of molecular pharmacology. RESULTS: Totally 726 compounds are found in EXD. They can interact with 261 proteins and target 333 related diseases. 51 compounds interact with estrogen-related receptors associated with 12 diseases. Five diseases are related to menopause, including breast cancer, postmenopausal symptoms, cardiovascular disease, endocrine-independent cancer, and osteoporosis. Our previous publication demonstrated that 3 of the 51 compounds (palmatine, jatrorrhizine and berberine) were detected in rat ovary after oral administration of EXD. According to information provided by network pharmacology, these 3 compounds can act on 56 signal proteins, 10 of which related to regulation of (CYP19A1, STAR, HSD17B14, HSD17B6, HSD17B12, HSD17B2, HSD3B1, HSD3B2, HSD3B7, and CYP17A1) associated with estradiol biosynthesis and 4 of which related to regulation of estrogen receptor expression (Fig 1). CONCLUSION: The holistic therapeutic efficacy of EXD for relieving estrogen deficiency symptoms associated with menopause, at least, based on the 3 compounds found in ovary after EXD treatment and interaction with 10 signal proteins play the key role in estradiol biosynthesis; and 4 proteins play the key role in regulation of estrogen receptor expression.