Protopanaxadiol improves endometriosis associated infertility and miscarriage in sex hormones receptors-dependent and independent manners

Abstract

Background: Patients with endometriosis (EMs) have high risks of infertility and spontaneous abortion. How to remodel the fertility of patients with EMs has always been the hot spot and difficulty in the field of reproductive medicine. As an aglycone of ginsenosides, protopanaxadiol (PPD) possesses pleiotropic biological functions and has high medicinal values. We aimed to investigate the effect and potential mechanism of PPD in the treatment of EMs-associated infertility and spontaneous abortion. Methods: The EMs mice models were constructed by allotransplantation. The pregnancy rates, embryo implantation numbers and embryo resorption rates of control and EMs were counted. RNA sequencing, qRT-PCR, enzyme linked immunosorbent assay (ELISA) and FCM analysis were performed to screen and confirm the expression of endometrial receptivity/decidualization-related molecules, inflammation cytokines and NK cell function-related molecules in vitro and/or in vivo . The SWISS Target Prediction, STRING and Cytoscape were carried out to predict the potential cellular sensory proteins, the protein-protein interaction (PPI) network between sensory proteins and fertility-related molecules, respectively. Micro-CT detection, liver and kidney function tests were used to evaluate the safety. Results: Here, we observe that PPD significantly up-regulates endometrial receptivity-related molecules (e.g., Lif, Igfbp1, Mmps, collagens ) and restricts pelvic inflammatory response (low levels of IL-12 and IFN-γ) of macrophage, and further remodel and improve the fertility of EMs mice. Additionally, PPD increases the expression of decidualization-related genes and Collagens , and promotes the proliferation, residence, immune tolerance and anagogic functions of decidual NK cells (low levels of CD16 and NKp30, high levels of Ki67, VEGF, TGF-β) in pregnant EMs mice, and further triggers decidualization, decidual NK cell-mediated maternal-fetal immune tolerance and angiogenesis, preventing pregnant EMs mice from miscarriage. Mechanically, these effects should be dependent on ESRs, PGR and other sensory proteins (e.g., AR). Compared with GnRHa (the clinic first-line drug for EMs), PPD does not lead to the decline of serum estrogen and bone loss. Conclusion: These data suggest that PPD prevents EMs-associated infertility and miscarriage in sex hormones receptors-dependent and independent manners possibly, and provides a potential therapeutic strategy with high efficiency and low side effects to remodels the fertility of patients with EMs.

Protective role of ginseng in endometriosis during covid-19

“…It can promote health and prevent diseases by having immunomodulatory [ 63 , 64 ]. This review summarized a therapeutic potential of KRG as an adjunct for treating and preventing endometriosis [ 13 , [25] , [26] , [27] , 29 , 30 ]. Further focused research is needed to reveal the precise functional effect and the mechanism of action of KRG in endometriosis in conjunction with viral spread of pandemic situation.…”

“…Table 1 lists active herbal alternative and complementary compounds reported to be effective for endometriosis. A number of studies have been reported that KRG and ginsenosides are effective against endometriosis associated symptoms by regulating angiogenic suppression, increasing apoptosis, immune system regulation, and anti- inflammation [ [24] , [25] , [26] , [27] , [28] , [29] , [30] ]. The following section focused on KRG of its effectiveness for endometriosis.…”

“…ERα suppression mediated by PPD can induce autophagy of ectopic endometrial stromal cells, leading to increased NK cell cytotoxicity. These phenomena can enhance the immune surveillance of ectopic lesions thus inhibiting the development of endometriosis [ 24 , 29 ]. In a rat model, Rg3 can inhibit the development of endometriotic lesions induced by endometrial tissue allotransplantation by inhibiting angiogenesis [ 27 ].…”

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…They then were able to explore the most relevant miRNA in endometriosis [148][149][150]. This information is critical since directed therapies depending on endometriosis may provide new elements to control the inflammatory disease and aid in fertilization [148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166]. In addition, exosomes contain miRNA and other proteins.…”

“…Waiyaput and coworkers [162] reported that treatment with combined contraceptive pills increased the migration of NK cells, suppressive macrophages, and tolerogenic T cells to the inflamed endometrium of menopause women. In addition, protopanaxadiol, an antioxidant ginsenoside compound, was reported to induce the expression of tolerogenic antigens on NK cells [163]. Thus, hormone therapy radical scavenging causes a protective response in the endometrium.…”