Identification of steroidogenic components derived from Gardenia Jasminoides ellis potentially useful for treating postmenopausal syndrome

Abstract

Postmenopausal syndrome occurs when the gonadal hormones fluctuate and eventually decline due to ovarian failure. It has an adverse impact on the quality of life and consequently therapeutic approach is urgently needed. Hormone replacement therapy (HRT) is a highly effective treatment for postmenopausal syndrome. However, it has been criticized that HRT may induce adverse effects and raise safety concerns. The impact of hormonal changes on the biological systems has been investigated extensively, the exact mechanism of postmenopausal syndrome remains to be fully clarified. Neverthelss, novel, safe and effective alternative approaches for the management of postmenopausal syndrome are required. The present study focuses on the following aims: (1) To discuss the usefulness of the menopausal model for the investigation of potential drug candidates; (2) To identify the bioactive compounds derived from Gardenia jasminoides Ellis (GJE) with estrogen-stimulating effects and elucidate their molecular mechanism of action. In first part, the application of the current models in menopausal research has been disclosed. It is often challenging to choose appropriate menopausal models to study the complex pathophysiology of menopause in women due to differences between humans and other species in the context of reproductive senescence. This review explored the suitability of several well-characterized menopausal models in the replication of human ovarian aging and estrogen depletion, as well as evaluation of potential therapeutic strategies against the major postmenopausal syndrome, such as hot flashes (HFs), reproductive senescence, cognitive decline, postmenopausal osteoporosis (PMO) and other negative physiological changes. In second part, the steroidogenic effects of GJE have been investigated. The use of traditional Chinese medicinal (TCM) herbs has been recognized as an alternative approach for management of menopausal syndrome. GJE (Zhizi in Chinese) is a TCM with multiple pharmacological effects. However, the estrogen-stimulating effects of GJE remain an enigma. In this study, network pharmacology-based approaches were applied to identify the impact of GJE on steroidogenesis and to predict the potential bioactive compounds of GJE. Then the major compounds of bioactive fraction derived from GJE, which contained the predicted chemicals, were extracted. Phenotypic approaches indicated that rutin, chlorogenic acid (CGA) and geniposidic acid (GA) exerted estrogen-stimulating effects on ovarian granulosa cells. Besides, the molecular docking data, FSHR inhibition assay results and western blotting studies confirmed the involvement of FSHR-aromatase pathway in the estrogen-stimulating effects of the three compounds. Risk evaluation has been conducted using MTT assays, demonstrating the anti-breast cancer activities of rutin, CGA and GA. Taken together, this thesis reviewed the usefulness and limitations of current models in menopausal research. On the other hand, the GJE study provided evidence that rutin, CGA and GA had stimulatory effects on estrogen production in ovarian granulosa cells and exerted inhibitory effects on viability in breast cancer cells.