SCM-198 Prevents Endometriosis by Reversing Low Autophagy of Endometrial Stromal Cell via Balancing ERα and PR Signals.

Background: Endometriosis (EMS), an endocrine-related inflammatory disease, is characterized by estrogen and progesterone imbalance in ectopic lesions. However, its pathogenic mechanism has not been fully elucidated. While SCM-198 is the synthetic form of leonurine and has multiple pharmacological activities such as antioxidation and anti-inflammation, it remains unknown whether it could inhibit the progress of EMS by regulating estrogen signaling and inflammation. Methods: The therapeutic effects of SCM-198 on EMS and its potential mechanism were analyzed by establishing EMS mouse models and performing an RNA sequencing (RNA-seq) assay. ELISA was performed to detect estrogen and tumor necrosis factor (TNF) -α concentrations in normal endometrial stromal cells (nESCs) and ectopic endometrial stromal cells (eESCs) with or without SCM-198 treatment. Western blotting, RNA silencing, and plasmid overexpression were used to analyze the relationship between inflammation, endocrine factors, and autophagy and the regulatory activity of SCM-198 on the inflammation-endocrine-autophagy axis. Results: Increased estrogen-estrogen receptor (ER) α signaling and decreased progesterone receptor isoform B (PRB) expression synergistically led to a hypo-autophagy state in eESCs, which further inhibited the apoptosis of eESCs. The high expression of TNF-α in eESCs enhanced the antiapoptotic effect mediated by low autophagy through the activation of the aromatase-estrogen-ERα signaling pathway. SCM-198 inhibited the growth of ectopic lesions in EMS mice and promoted the apoptosis of eESCs both in vivo and in vitro. The apoptotic effect of SCM-198 on eESCs was attained by upregulating the autophagy level via the inhibition of the TNF-α-activated aromatase-estrogen-ERα signal and the increase in PRB expression. Conclusion: Inflammation facilitated the progress of EMS by disrupting the estrogen regulatory axis. SCM-198 inhibited EMS progression by regulating the inflammation-endocrine-autophagy axis.

SCM-198 Alleviates Endometriosis by Suppressing Estrogen-ERα mediated Differentiation and Function of CD4+CD25+ Regulatory T Cells.

Background: Endometriosis (EMS), a typical endocrine immune disorder, associates with dramatically increased estrogen production and disorganized immune response in ectopic focus. Peritoneal regulatory T cells (Tregs) expansion in women with EMS and their pathogenic role attributable to endometriotic immunotolerance has been reported. Whether local high estrogen promotes EMS by discipling Tregs needs to be further explored. Up to date, there is no effective medicine for the treatment of EMS. SCM-198 is a synthetic leonurine with multiple physiological activities. Whether SCM-198 could regulate Tregs via estrogen and facilitate the radical cure of EMS has not yet been reported. Methods: Proportion of Tregs in peritoneal fluid of patients with EMS was firstly analyzed via flow cytometry. Peritoneal estrogen concentration and the mRNA levels of estrogen receptor α (ERα) and estrogen receptor ß (ERß) of Tregs were detected by ELISA and RT-PCR, respectively. Grouped in vitro induction assays were performed to explore the effects of SCM-198 and estrogen signaling on Tregs. Cell invasion and viability assays were utilized to detect the crosstalk between Tregs and ectopic endometrial stromal cells (eESCs), with or without SCM-198 treatment. Furthermore, EMS mice models were established to verify the therapeutic effects of SCM-198. Results: Increased Tregs were found in peritoneal fluid of EMS patients, accompanied with estrogen-ERα overactivation. Estrogen-ERα triggered the expansion of Tregs and their cytokine production (IL-10 and TGF-ß1), which could be reversed by SCM-198 treatment. Moreover, SCM-198 abated the invasion and viability of eESCs enhanced by Tregs. In vivo experiments confirmed that SCM-198 obviously retarded the growth of ectopic lesions and downregulated the functions of Tregs via estrogen-ERα inactivation. Conclusions: These data suggest that SCM-198 attenuates Tregs expansion via the inhibition of estrogen-ERα signaling in EMS and offer a promising therapy for such a refractory disease.

Leonurine: From Gynecologic Medicine to Pleiotropic Agent.

Leonurus japonicus Houtt, a Chinese traditional herbal medicine, has been widely used to cure gynecological diseases, such as incomplete abortion and menoxenia. Leonurine, a major active alkaloid compound only be found in Leonurus japonicus Houtt, has been successfully extracted and purified. Recent evidence has shown that leonurine can regulate a variety of pathologic processes including oxidative stress, inflammation, fibrosis, apoptosis, and multiple metabolic disorders. Here, we have reviewed the pharmacological actions and biological functions of leonurine, with a focus on the role of leonurine in the amelioration of various pathological processes. Insights into the related signaling pathways and molecular mechanisms have strengthened our understanding on the function of leonurine in the alleviation of multiple pathological states. Our summary of the existing researches should help direct future research into the basic science and clinical applications in related diseases.

Tim-3 and PD-1 regulate CD8+ T cell function to maintain early pregnancy in mice.

During pregnancy, CD8+ T cells are important regulators in the balance of fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are well-recognized negative co-stimulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that CD8+ T cells co-expressing Tim-3 and PD-1 were down-regulated in the deciduae of female mice in abortion-prone matings compared with normal pregnant mice. In addition to their reduced numbers, the Tim-3+PD-1+CD8+ T cells produced lower levels of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10, as well as a higher level of the pro-inflammatory cytokine interferon (IFN)-γ, relative to those from normal pregnancy. Furthermore, normal pregnant CBA/J females challenged with Tim-3- and/or PD-1-blocking antibodies were more susceptible to fetal resorption. These findings indicate that Tim-3 and PD-1 pathways play critical roles in regulating CD8+ T cell function and maintaining normal pregnancy.