Abstract
BackgroundTotal steroidal saponins extracted from the rhizome of Paris polyphylla Sm. var. yunnanensis (TSSPs) have been widely used in China for the treatment of abnormal uterine bleeding. We previously studied the main active constituents of TSSPs and their structure-activity relationships with respect to rat myometrial contractions. Tg (pennogenin tetraglycoside) was identified as one of the active ingredients in TSSPs able to induce rat myometrial contractions. However, the mechanisms underlying the pharmacological actions on uterine activity have not been described clearly.MethodsHere Tg was screened for effects on contractile activity in isolated uterine strips from estrogen-primed rats and on MLC20 phosphorylation and related signaling pathways in cultured rat myometrial cells as determined by Western blot. Intracellular calcium ([Ca2+]i) was monitored under a confocal microscope using Fluo-4 AM-loaded myometrial cells.ResultsTg dose-dependently stimulated rat myometrial contractions as well as MLC20 phosphorylation in vitro, which could be completely suppressed by an inhibitor of myosin light chain kinase (MLCK). Use of Ca2+ channel blockers and kinase inhibitors demonstrated that Tg-induced myometrial contractions are mediated by activation of the phospholipase C (PLC)-inositol triphosphate (IP3) signaling pathway, resulting in increased MLC20 phosphorylation. Furthermore, Y27632, a specific inhibitor of Rho kinase (ROK), notably suppressed Tg-stimulated myometrial contractions and decreased MLC20 phosphorylation.ConclusionsThese data provide evidence that rat myometrial contractility induced by Tg results from enhanced MLC20 phosphorylation, while both PLC-IP3 and RhoA/ROK signaling pathways mediate the process. These mechanisms may be responsible for the therapeutic effects of TSSPs on abnormal uterine bleeding.
Highlights
Gongxuening capsule (GXN) based on the yuannanbaiyao formulation, is a single preparation of total steroidal saponins prepared from Paris polyphylla Sm. var. yunnanensis (TSSPs)
We found that Tg, a spirostanol-type compound from the extract of TSSPs (Figure 1), could dose-dependently induce myometrial contractions (Figure 2A), even at a very low concentration (1.25 mM)
These data indicated that Tg can dose- and time-dependently induce rat uterine myometrial contractions, and the effect may be related to MLC20 phosphorylation
Summary
Gongxuening capsule (GXN) based on the yuannanbaiyao formulation, is a single preparation of total steroidal saponins prepared from Paris polyphylla Sm. var. yunnanensis (TSSPs). Yunnanensis have been isolated and studied by several groups [1,2,3], and the total steroidal saponins (GXN) have demonstrated reliable curative rates in the treatment of abnormal uterine bleeding (AUB), which can be attributed to its uterine contractile effects [4]. Based on other work in which TSSPs were isolated and identified [8], we constructed a compound library composed of a series of steroidal saponins purified from Paris polyphylla Smith var. Yunnanensis (TSSPs) have been widely used in China for the treatment of abnormal uterine bleeding. We previously studied the main active constituents of TSSPs and their structure-activity relationships with respect to rat myometrial contractions. Tg (pennogenin tetraglycoside) was identified as one of the active ingredients in TSSPs able to induce rat myometrial contractions. The mechanisms underlying the pharmacological actions on uterine activity have not been described clearly
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