Water-extracted tubers of Cyperus rotundus L. enhance endometrial receptivity through leukemia inhibitory factor-mediated expression of integrin αVβ3 and αVβ5.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Cyperus rotundus L. (CR) has been traditionally used as an herbal medicine in Asian countries to treat diverse gynecological disorders. However, the potential therapeutic effect of CR on endometrial receptivity for successful embryo implantation to treat female infertility has not been fully studied.

AIM OF STUDY:

The aim of this study was to evaluate the effect of water-extracted CR on endometrial receptivity by investigating the expression of leukemia inhibitory factor (LIF) and integrins, cell adhesion, and embryo implantation using mifepristone (RU486; RU)-induced implantation failure model.

MATERIALS AND METHODS:

The water extract of CR was prepared and fingerprinted using high-performance liquid chromatography (HPLC). For the expression and regulation of LIF, reverse transcription polymerase chain reaction (RT-PCR) and western blotting were performed in CR-stimulated Ishikawa cells. To evaluate LIF-mediated integrin expression, knockdown of LIF by shRNA was performed in Ishikawa cells. The effect of CR on endometrial receptivity was determined by an in vitro adhesion assay between JAr cells and CR-induced Ishikawa cells. In vivo, C57BL/6 female mice (n = 7 per group) orally received CR (31.68mg/kg/day), a similar dose as used clinically. Seven days after CR treatment, all female mice were caged with male mice until pregnancy was verified. On day 4 of pregnancy, RU (4mg/kg) was injected subcutaneously to induce embryo implantation failure.

RESULT:

CR increased the expression of LIF through the phosphatidylinositol-3-kinase/ protein kinase B (PI-3K/AKT) signaling pathway in Ishikawa cells. In addition, CR enhanced adhesion of JAr cells onto Ishikawa cells by inducing the expression of LIF-dependent integrins αVβ3 and αVβ5. Furthermore, CR improved the number of implantation sites in pregnant mice despite RU injection.

CONCLUSION:

CR increased the expression of LIF-mediated integrins αVβ3 and αVβ5 on the surface of endometrial cells, which is associated with adhesion of trophoblastic cells to endometrial cells for blastocyst implantation. Our findings provide evidence that CR has therapeutic potential against poor endometrial receptivity.

• Authors: Hee-Jung Choi, Tae-Wook Chung, Mi-Ju Park, Yeon-Seop Jung, Syng-Ook Lee, Keuk-Jun Kim, Ki-Tae Ha
• Journal: Journal of ethnopharmacology (J Ethnopharmacol) Vol. 208 Pg. 16-23 (Aug 17 2017) ISSN: 1872-7573 [Electronic] Ireland
• PMID: 28676452 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Integrin alphaVbeta3
• Leukemia Inhibitory Factor
• Lif protein, mouse
• Plant Extracts
• Receptors, Vitronectin
• integrin alphaVbeta5
• Water
• Mifepristone
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyperus
• Embryo Implantation (drug effects)
• Endometrium (drug effects)
• Female
• Humans
• Integrin alphaVbeta3 (genetics, metabolism)
• Leukemia Inhibitory Factor (genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Mifepristone (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Plant Extracts (pharmacology)
• Plant Tubers (chemistry)
• Pregnancy
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Vitronectin (genetics, metabolism)
• Water (chemistry)