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|Title:||Characterization of the estrogenic effects of ginsenoside Rg1 : mechanism involved in achieving tissue selectivity|
Ginseng -- Therapeutic use.
Hong Kong Polytechnic University -- Dissertations
|Publisher:||The Hong Kong Polytechnic University|
|Abstract:||Our previous study demonstrated that ginsenoside Rg1 was a unique class of phytoestrogens which activated estrogen-like activities without direct interaction with the estrogen receptor (ER). It could initiate activation of the estrogen response element (ERE) via phosphorylation of MEK1/2 and ERα in MCF-7 cells. The present study aims to investigate if Rg1 could exert tissue-selective estrogenic effects in ER-positive target tissues and the molecular mechanism involved in its tissue-selective estrogenic effects. The short-term and long-term estrogenic effects of Rg1 were investigated in 21-day-old immature female CD-1 mice and 6-month-old ovariectomized C57BL/6J mice, respectively. The signal transduction pathways that mediate the estrogenic actions of Rg1 were investigated in MCF-7 cells and rat osteoblastic UMR106 cells in comparison to that of 17β-estradiol and estren which was a novel pathway-selective ER ligand. Additionally, MCF-7 cells and SKBR-3 cells were used to evaluate the role of GPR30 in mediating the estrogenic actions of Rg1.|
Our results demonstrated that the estrogenic actions of Rg1 were distinct from those of 17β-estradiol and its effects were tissue selective. The potent estrogenic effect of Rg1 was only observed in mammary gland in immature female CD-1 mice. Chronic administration of Rg1 did not result in bone protective effects and unwanted simulation of reproductive tissues in OVX mice model in a way that was distinct from 17β-estradiol which exerted bone protective effects and also the stimulatory effects in uterus. However, Rg1 exerted potential anti-apoptotic effects on cardiovascular tissues and estrogenic effects on brain tissues. In addition, we demonstrated that Rg1, but not estren, failed to exert stimulatory effects in UMR106 cells with expressed lower level of ER, suggesting that the estrogenic effects of Rg1 in bone may require higher abundance of ER. For the molecular mechanisms study, differential signaling pathways were involved in mediating the estrogenic actions of Rg1 in MCF-7 cells in comparison to 17β-estradiol and estren. 17β-estradiol decreased ERα protein expression in MCF-7 cells, but not Rg1 and estren. 17β-estradiol increased ERα Ser 118 phosphorylation both in the cytoplasm and nucleus, especially in the nucleus. Rg1 increased ERα Ser 118 phosphorylation pricipally in the cytoplasm. Estren increased ERα Ser 118 phosphorylation pricipally in the nucleus. For the estrogen-realted pS2 gene expression, both 17β-estradiol and Rg1 increased pS2 mRNA expression in MCF-7 cells, while estren decreased pS2 mRNA expression. Additionally, both 17β-estradiol and Rg1 induced the recruitment of co-activator SRC-1 to ERE-containing pS2 promoter, but not estren. Furthermore, we are the first to report the possible involvement of GPR30 pathway on the activation of MEK1/2 by Rg1 in MCF-7 cells. In conclusion, the estrogenic effects of Rg1 might be tissue selective. The rapid ER-dependent signaling pathway was involved in the tissue-selective estrogenic effects of Rg1. Differential ER-dependent signaling pathways were involved in the estrogenic effects of 17β-estradiol, Rg1 and estren in MCF-7 cells. Additionally, GPR30 pathway was involved in mediating the estrogenic actions of Rg1. The present study provides new insights to understand the molecular action of ginsenoside Rg1 and its potential application for management of postmenopausal symptoms.
|Description:||xxxi, 288 p. : ill. (some col.) ; 30 cm.|
PolyU Library Call No.: [THS] LG51 .H577P ABCT 2012 Gao
|Rights:||All rights reserved.|
|Appears in Collections:||Thesis|
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Checked on May 21, 2017
Checked on May 21, 2017
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