期刊
FRONTIERS IN ENDOCRINOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2022.858176
关键词
SCM-198; EMS; estrogen; progesterone; TNF-alpha; autophagy
资金
- National Basic Research Program of China [2021YFE0206500]
- National Natural Science Foundation of China [31970859, 81630036, 91542116]
- Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine [FIRMA200504]
- NHC Key Laboratory of Reproduction Regulation [CX2017-2]
- Innovative research team of high-level local universities in Shanghai
- key laboratory program of the Education Commission of Shanghai Municipality [ZDSYS14005]
- international cooperation project between Macau and Shanghai [20410760300]
This study suggests that the interaction between inflammation and endocrine imbalance plays a significant role in the development of endometriosis (EMS). SCM-198 inhibits the progression of EMS by regulating the inflammation-endocrine-autophagy axis.
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) -alpha 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) alpha 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-alpha in eESCs enhanced the antiapoptotic effect mediated by low autophagy through the activation of the aromatase-estrogen-ER alpha 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-alpha-activated aromatase-estrogen-ER alpha 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.
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