PMID- 38316218 OWN - NLM STAT- MEDLINE DCOM- 20240226 LR - 20240226 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 325 DP - 2024 May 10 TI - Juan-tong-yin potentially impacts endometriosis pathophysiology by enhancing autophagy of endometrial stromal cells via unfolded protein reaction-triggered endoplasmic reticulum stress. PG - 117859 LID - S0378-8741(24)00158-2 [pii] LID - 10.1016/j.jep.2024.117859 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Endometriosis (EMs) is characterized by inflammatory lesions, dysmenorrhea, infertility, and chronic pelvic pain. Single-target medications often fail to provide systemic therapeutic results owing to the complex mechanism underlying endometriosis. Although traditional Chinese medicines-such as Juan-Tong-Yin (JTY)-have shown promising results, their mechanisms of action remain largely unknown. AIM OF THE STUDY: To elucidate the therapeutic mechanism of JTY in EMs, focusing on endoplasmic reticulum (ER) stress-induced autophagy. MATERIALS AND METHODS: The major components of JTY were detected using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The potential mechanism of JTY in EMs treatment was predicted using network pharmacological analysis. Finally, the pathogenesis of EMs was validated in a clinical case-control study and the molecular mechanism of JTY was validated in vitro using endometrial stromal cells (ESCs). RESULTS: In total, 241 compounds were analyzed and identified from JTY using UPLC-MS. Network pharmacology revealed 288 targets between the JTY components and EMs. Results of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses indicated that regulating autophagy, migration, apoptosis, and inflammation were the key mechanisms of JTY in treating EMs. Meanwhile, we found that protein kinase R-like endoplasmic reticulum kinase (PERK), Beclin-1, and microtubule-associated protein light chain 3 B (LC3B) expressions were lower in endometria of patients with EMs than in those with normal eutopic endometria (p < 0.05). Additionally, during in vitro experiments, treatment with 20% JTY-containing serum significantly suppressed ESC proliferation, achieving optimal effects after 48 h. Electron microscopy revealed significantly increased autophagy flux in the JTY group compared with the control group. Moreover, JTY treatment significantly reduced the migratory and invasive abilities of ESCs and upregulated protein expression of PERK, eukaryotic initiation factor 2alpha (eIF2alpha)/phospho-eukaryotic initiation factor 2alpha (p-eIF2alpha), activating Transcription Factor-4 (ATF4), Beclin-1, and LC3BII/I, while subsequently downregulating NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin 18 (IL-18) expression. However, administration of GSK2656157-a highly selective PERK inhibitor-reversed these changes. CONCLUSION: JTY ameliorates EMs by activating PERK associated with unfolded protein reaction, enhancing cell ER stress and autophagy, improving the inflammatory microenvironment, and decreasing the migration and invasion of ESCs. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Meng, Fengyun AU - Meng F AD - Graduate School, Guangxi University of Chinese Medicine, Nanning, China. FAU - Li, Jing AU - Li J AD - Graduate School, Guangxi University of Chinese Medicine, Nanning, China. FAU - Dong, Kun AU - Dong K AD - Department of Organ Transplantation, The First Affiliated Hospital of Guangxi Medical University, Nanning, China. FAU - Bai, Rui AU - Bai R AD - Graduate School, Guangxi University of Chinese Medicine, Nanning, China. FAU - Liu, Qiyu AU - Liu Q AD - Graduate School, Guangxi University of Chinese Medicine, Nanning, China. FAU - Lu, Shijin AU - Lu S AD - Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, China. FAU - Liu, Ying AU - Liu Y AD - Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, China. FAU - Wu, Dekun AU - Wu D AD - Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, China. FAU - Jiang, Chen AU - Jiang C AD - Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, China. FAU - Li, Weihong AU - Li W AD - Department of Nursing, Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, China. Electronic address: 794431024@qq.com. LA - eng PT - Journal Article DEP - 20240203 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Beclin-1) RN - 0 (Peptide Initiation Factors) SB - IM MH - Female MH - Humans MH - *Signal Transduction MH - Beclin-1/metabolism MH - *Endometriosis/pathology MH - Case-Control Studies MH - Chromatography, Liquid MH - Tandem Mass Spectrometry MH - Endoplasmic Reticulum Stress MH - Autophagy MH - Apoptosis MH - Stromal Cells/metabolism/pathology MH - Peptide Initiation Factors/metabolism/pharmacology OTO - NOTNLM OT - Autophagy OT - Endometriosis OT - Endoplasmic reticulum stress OT - Juan-tong-yin OT - Unfolded protein reaction COIS- Declaration of competing interest The authors declare that they have no competing interests. The authors do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. EDAT- 2024/02/06 00:42 MHDA- 2024/02/26 06:42 CRDT- 2024/02/05 19:22 PHST- 2023/11/30 00:00 [received] PHST- 2024/02/01 00:00 [revised] PHST- 2024/02/02 00:00 [accepted] PHST- 2024/02/26 06:42 [medline] PHST- 2024/02/06 00:42 [pubmed] PHST- 2024/02/05 19:22 [entrez] AID - S0378-8741(24)00158-2 [pii] AID - 10.1016/j.jep.2024.117859 [doi] PST - ppublish SO - J Ethnopharmacol. 2024 May 10;325:117859. doi: 10.1016/j.jep.2024.117859. Epub 2024 Feb 3.