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Fu Z, Liu H, Kuang Y, Yang J, Luo M, Cao L, Zheng W. β-elemene, a sesquiterpene constituent from Curcuma phaeocaulis inhibits the development of endometriosis by inducing ferroptosis via the MAPK and STAT3 signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119344. [PMID: 39800242 DOI: 10.1016/j.jep.2025.119344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 01/04/2025] [Accepted: 01/08/2025] [Indexed: 01/15/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The rhizome of Curcuma phaeocaulis Valeton, Curcuma wenyujin Y.H. Chen & C. Ling, or Curcuma kwangsiensis S. G. Lee et C. F. Liang, commonly known as Wen-E-Zhu and E'zhu, has been utilized in traditional Chinese medicine for the treatment of cancer and gynecological diseases since antiquity. This traditional medicinal herb is highly esteemed for its efficacy in promoting blood circulation, dissolving blood stasis, reducing swelling, and alleviating pain. β-Elemene (β-ELE), a sesquiterpene compound derived from Curcuma phaeocaulis, has demonstrated potential in inhibiting tumor cell proliferation and inducing ferroptosis, which have been extensively studied in various malignant neoplasms. Previous studies have confirmed that Sparganium stoloniferum-Curcuma phaeocaulis containing β-ELE may possess anti-endometriotic properties. However, the exact mechanism underlying β-ELE's anti-endometriosis activity remains largely unknown and requires further research and investigation. AIM OF THE STUDY To identify the anti-endometriosis target of β-ELE and elucidate the underlying molecular mechanism of β-ELE in endometriosis, focusing on inducing ferroptosis. MATERIALS AND METHODS The target pathway of β-ELE in endometriosis treatment was predicted through network pharmacology and bioinformatics analysis. Surface plasmon resonance-high performance liquid chromatography-protein mass spectrometry (SPR-HPLC-MS) and molecular docking were used to further identify the potential targets of β-ELE in endometriosis. The immortalized endometriosis epithelial cell line 12Z was used for in vitro study. The effect of β-ELE on cell proliferation and migration was detected by CCK-8, EdU and wound healing assay, and ultrastructural changes were examined via transmission electron microscopy. The effect of β-ELE-induced ferroptosis was determined by western blot, immunohistochemistry staining and flow cytometry. SPR affinity analysis was performed to specific the direct interaction between β-ELE and FTH1, FTL, GPX4, STAT3 and MAPK14. To establish a mouse model of endometriosis and to assess the inhibitory effects of β-ELE and ELE injection on endometriosis in vivo as well as safety profile of administration, and investigate the effects and underlying mechanisms of β-ELE and ELE injection on ferroptosis in ectopic lesions. RESULTS SPR-HPLC-MS was employed to identify 76 potential targets of β-ELE for endometriosis treatment, closely linked to ferroptosis. Molecular docking revealed that glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase 14 (MAPK14) are key action targets of β-ELE in endometriosis. Further investigations revealed that β-ELE inhibited the proliferation and migration of endometriotic cells in vitro while inducing ferroptosis, as evidenced by increased levels of iron, reactive oxygen species (ROS), and lipid peroxidation. In a mouse model, β-ELE inhibited the growth of endometriotic lesions, induced ferroptosis, suppressed fibrosis, and exhibited anti-endometriotic effects. Mechanistically, β-ELE downregulates the expression levels of GPX4, FTH1, and FTL and inhibited the phosphorylation of STAT3 and MAPK14, which may elucidate its underlying molecular mechanisms. CONCLUSION This study demonstrates that the inhibitory effect of β-ELE on endometriosis by inducing ferroptosis in vitro and in vivo. Our results revealed that β-ELE exerts anti-endometriosis effects by inducing ferroptosis via the MAPK and STAT3 signaling pathways.
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Affiliation(s)
- Zhiyi Fu
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Hao Liu
- The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China.
| | - Yanqi Kuang
- The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China.
| | - Jiumei Yang
- The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China.
| | - Meicheng Luo
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Lixing Cao
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Weilin Zheng
- The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China.
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Zhang WY, Wang HB, Deng CY. Effects of miR-214-5p and miR-21-5p in hypoxic endometrial epithelial-cell-derived exosomes on human umbilical cord mesenchymal stem cells. World J Stem Cells 2024; 16:906-925. [DOI: 10.4252/wjsc.v16.i11.906] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 07/24/2024] [Accepted: 10/12/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Thin endometrium seriously affects endometrial receptivity, resulting in a significant reduction in embryo implantation, and clinical pregnancy and live birth rates, and there is no gold standard for treatment. The main pathophysiological characteristics of thin endometrium are increased uterine arterial blood flow resistance, angiodysplasia, slow growth of the glandular epithelium, and low expression of vascular endothelial growth factor, resulting in endometrial epithelial cell (EEC) hypoxia and endometrial tissue aplasia. Human umbilical cord mesenchymal stem cells (HucMSCs) promote repair and regeneration of damaged endometrium by secreting microRNA (miRNA)-carrying exosomes. However, the initiation mechanism of HucMSCs to repair thin endometrium has not yet been clarified.
AIM To determine the role of hypoxic-EEC-derived exosomes in function of HucMSCs and explore the potential mechanism.
METHODS Exosomes were isolated from normal EECs (EEC-exs) and hypoxia-damaged EECs (EECD-exs), before characterization using Western blotting, nanoparticle-tracking analysis, and transmission electron microscopy. HucMSCs were cocultured with EEC-exs or EECD-exs and differentially expressed miRNAs were determined using sequencing. MiR-21-5p or miR-214-5p inhibitors or miR-21-3p or miR-214-5p mimics were transfected into HucMSCs and treated with a signal transducer and activator of transcription 3 (STAT3) activator or STAT3 inhibitor. HucMSC migration was assessed by Transwell and wound healing assays. Differentiation of HucMSCs into EECs was assessed by detecting markers of stromal lineage (Vimentin and CD13) and epithelial cell lineage (CK19 and CD9) using Western blotting and immunofluorescence. The binding of the miRNAs to potential targets was validated by dual-luciferase reporter assay.
RESULTS MiR-21-5p and miR-214-5p were lowly expressed in EECD-ex-pretreated HucMSCs. MiR-214-5p and miR-21-5p inhibitors facilitated the migratory and differentiative potentials of HucMSCs. MiR-21-5p and miR-214-5p targeted STAT3 and protein inhibitor of activated STAT3, respectively, and negatively regulated phospho-STAT3. MiR-21-5p- and miR-214-5p-inhibitor-induced promotive effects on HucMSC function were reversed by STAT3 inhibition. MiR-21-5p and miR-214-5p overexpression repressed HucMSC migration and differentiation, while STAT3 activation reversed these effects.
CONCLUSION Low expression of miR-21-5p/miR-214-5p in hypoxic-EEC-derived exosomes promotes migration and differentiation of HucMSCs into EECs via STAT3 signaling. Exosomal miR-214-5p/miR-21-5p may function as valuable targets for thin endometrium.
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Affiliation(s)
- Wan-Yu Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Han-Bi Wang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, China
| | - Cheng-Yan Deng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, China
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Torelli FR, Rodrigues-Peres RM, Monteiro I, Lopes-Cendes I, Bahamondes L, Juliato CRT. Gene expression associated with unfavorable vaginal bleeding in women using the etonogestrel subdermal contraceptive implant: a prospective study. Sci Rep 2024; 14:11062. [PMID: 38745005 PMCID: PMC11093992 DOI: 10.1038/s41598-024-61751-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 05/09/2024] [Indexed: 05/16/2024] Open
Abstract
To evaluate gene expression associated with unfavorable vaginal bleeding in users of the Etonogestrel (ENG) contraceptive implant. Prospective study involving 100 women who intended to use the ENG implant. Exclusion criteria included abnormal uterine bleeding, inability to attend a 1-year follow-up, and implant removal for reasons unrelated to vaginal bleeding or loss of follow-up. We obtained endometrial biopsies before implant placement and assessed the expression of 20 selected genes. Users maintained a uterine bleeding diary for 12 months post-implant placement. For statistical analysis, we categorized women into those with or without favorable vaginal bleeding at 3 and 12 months. Women with lower CXCL1 expression had a 6.8-fold increased risk of unfavorable vaginal bleeding at 3 months (OR 6.8, 95% CI 2.21-20.79, p < 0.001), while those with higher BCL6 and BMP6 expression had 6- and 5.1-fold increased risks, respectively. By the 12-month follow-up, women with lower CXCL1 expression had a 5.37-fold increased risk of unfavorable vaginal bleeding (OR 5.37, 95% CI 1.63-17.73, p = 0.006). Women with CXCL1 expression < 0.0675, BCL6 > 0.65, and BMP6 > 3.4 had a higher likelihood of experiencing unfavorable vaginal bleeding at 3 months, and CXCL1 < 0.158 at 12 months. Users of ENG contraceptive implants with elevated BCL6 and BMP6 expression exhibited a higher risk of breakthrough bleeding at the 3-month follow-up. Conversely, reduced CXCL1 expression was associated with an elevated risk of bleeding at both the 3 and 12-month follow-ups.
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Affiliation(s)
- Flávia R Torelli
- Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Raquel M Rodrigues-Peres
- Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Ilza Monteiro
- Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Iscia Lopes-Cendes
- Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Luis Bahamondes
- Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Cássia R T Juliato
- Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
- Departamento de Tocoginecologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas - UNICAMP, Rua Alexander Fleming 101, Campinas, SP, 13083-881, Brazil.
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Xu Y, Wu F, Qin C, Lin Y. Paradoxical role of phosphorylated STAT3 in normal fertility and the pathogenesis of adenomyosis and endometriosis†. Biol Reprod 2024; 110:5-13. [PMID: 37930185 DOI: 10.1093/biolre/ioad148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/13/2023] [Accepted: 10/24/2023] [Indexed: 11/07/2023] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3), when phosphorylated at tyrosine 705, plays an important role in endometrial stromal cell decidualization and the receptivity of the endometrial epithelium during embryo implantation. However, the function of phosphorylated STAT3 (p-STAT3) in normal uterine receptivity is distinct from that in adenomyosis and endometriosis. In normal pregnancy, STAT3 phosphorylation in the endometrial epithelium determines the success of embryo implantation by regulating uterine receptivity. Additionally, p-STAT3 promotes cellular proliferation and differentiation during endometrial decidualization, which is crucial for embryonic development. In contrast, excessive STAT3 phosphorylation occurs in adenomyosis and endometriosis, which may lead to disease progression. Therefore, achieving a delicate balance in STAT3 activation is crucial. This review aimed to focus on the current understanding and knowledge gaps regarding the control of p-STAT3 activity in normal and pathological endometrial processes. This topic is important because precise control of p-STAT3 production could alleviate the symptoms of adenomyosis and endometriosis, improve endometrial receptivity, and potentially mitigate infertility without compromising normal fertility processes.
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Affiliation(s)
- Yichi Xu
- Reproductive Medicine Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fan Wu
- Reproductive Medicine Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanmei Qin
- Reproductive Medicine Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Lin
- Reproductive Medicine Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Hiraoka T, Osuga Y, Hirota Y. Current perspectives on endometrial receptivity: A comprehensive overview of etiology and treatment. J Obstet Gynaecol Res 2023; 49:2397-2409. [PMID: 37527810 DOI: 10.1111/jog.15759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/23/2023] [Indexed: 08/03/2023]
Abstract
Recurrent implantation failure (RIF) remains a challenging problem in assisted reproductive technology (ART). Further insights into uterine abnormalities that can disturb embryo implantation should be obtained. This review provides an overview of the effects of organic and non-organic uterine disorders on endometrial receptivity. The results suggest that various uterine pathologies can lead to defective embryo implantation via multiple mechanisms. In particular, uterine adenomyosis dysregulates molecular and cellular interactions that are vital for successful embryo implantation with a background of chronic inflammation, which may be alleviated by pretreatment with a gonadotropin-releasing hormone agonist. Uterine myomas can cause endometrial deformation and adverse alterations in uterine contractility. Nonetheless, the effectiveness of myomectomy remains debated, and endometrial polyp removal may be considered, particularly in patients with RIF. Chronic endometritis abrogates the appropriate uterine immunological environment critical for embryo implantation. Abnormal endometrial microbiota have been suggested to influence endometrial receptivity; however, supporting evidence is currently scarce. Platelet-rich plasma therapy may be a potential treatment for thin endometria; nevertheless, further validation is required. Endometrial receptivity analysis can detect dysregulation of the window of implantation, and new non-invasive methods for predicting endometrial receptivity have recently been proposed. However, numerous issues still need to be fully clarified. Further clinical and basic studies are necessary to investigate the pathophysiology of defective endometrial receptivity and identify optimal treatments for patients undergoing ART, especially those with RIF.
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Affiliation(s)
- Takehiro Hiraoka
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yasushi Hirota
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Maclean A, Barzilova V, Patel S, Bates F, Hapangama DK. Characterising the immune cell phenotype of ectopic adenomyosis lesions compared with eutopic endometrium: A systematic review. J Reprod Immunol 2023; 157:103925. [PMID: 36870297 DOI: 10.1016/j.jri.2023.103925] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/16/2023] [Accepted: 02/28/2023] [Indexed: 03/05/2023]
Abstract
Inflammation is implicated in the symptomatology and the pathogenesis of adenomyosis. Injury at the endo-myometrial interface causes inflammation and may facilitate the invasion of endometrium into the myometrium, forming adenomyosis lesions. Their presence causes local inflammation, resulting in heavy menstrual bleeding, chronic pelvic pain, and subfertility. Immunological differences have been described in the eutopic endometrium from women with adenomyosis compared to healthy endometrium, and differences are also expected in the adenomyotic lesions compared with the correctly sited eutopic endometrium. This systematic review retrieved relevant articles from three databases with additional manual citation chaining from inception to 24th October 2022. Twenty-two eligible studies were selected in accordance with PRISMA guidelines. Risk of bias assessments were performed, and the findings presented thematically. Ectopic endometrial stroma contained an increased density of macrophages compared with eutopic endometrium in adenomyosis. This was associated with an increase in pro-inflammatory cytokines (IL-6, IL-8, ILβ-1, C-X-C Motif Chemokine Receptor 1(CXCR1), Monocyte Chemoattractant Protein-1 (MCP-1)), and an imbalance of anti-inflammatory cytokines (IL-22, IL-37). Cells in ectopic lesions also contained a higher levels of toll-like receptors and immune-mediated enzymes. However, the studies were heterogeneous, with inconsistent reporting of immune cell density within epithelial or stromal compartments, and inclusion of samples from different menstrual cycle phases in the same group for analysis. A detailed understanding of the immune cell phenotypes present in eutopic and ectopic endometrium in adenomyosis and associated dysregulated inflammatory processes will provide further insight into the pathogenesis, to enable identification of fertility-sparing treatments as an alternative to hysterectomy.
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Affiliation(s)
- Alison Maclean
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L8 7SS, United Kingdom; Liverpool Women's Hospital NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, United Kingdom.
| | - Vanya Barzilova
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L8 7SS, United Kingdom
| | - Simran Patel
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L8 7SS, United Kingdom
| | - Faith Bates
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L8 7SS, United Kingdom; School of Life Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, United Kingdom
| | - Dharani K Hapangama
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L8 7SS, United Kingdom; Liverpool Women's Hospital NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, United Kingdom
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The Role of Platelets in the Pathogenesis and Pathophysiology of Adenomyosis. J Clin Med 2023; 12:jcm12030842. [PMID: 36769489 PMCID: PMC9918158 DOI: 10.3390/jcm12030842] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/04/2023] [Accepted: 01/11/2023] [Indexed: 01/24/2023] Open
Abstract
Widely viewed as an enigmatic disease, adenomyosis is a common gynecological disease with bewildering pathogenesis and pathophysiology. One defining hallmark of adenomyotic lesions is cyclic bleeding as in eutopic endometrium, yet bleeding is a quintessential trademark of tissue injury, which is invariably followed by tissue repair. Consequently, adenomyotic lesions resemble wounds. Following each bleeding episode, adenomyotic lesions undergo tissue repair, and, as such, platelets are the first responder that heralds the subsequent tissue repair. This repeated tissue injury and repair (ReTIAR) would elicit several key molecular events crucial for lesional progression, eventually leading to lesional fibrosis. Platelets interact with adenomyotic cells and actively participate in these events, promoting the lesional progression and fibrogenesis. Lesional fibrosis may also be propagated into their neighboring endometrial-myometrial interface and then to eutopic endometrium, impairing endometrial repair and causing heavy menstrual bleeding. Moreover, lesional progression may result in hyperinnervation and an enlarged uterus. In this review, the role of platelets in the pathogenesis, progression, and pathophysiology is reviewed, along with the therapeutic implication. In addition, I shall demonstrate how the notion of ReTIAR provides a much needed framework to tether to and piece together many seemingly unrelated findings and how it helps to make useful predictions.
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Perioperative Suppression of Schwann Cell Dedifferentiation Reduces the Risk of Adenomyosis Resulting from Endometrial–Myometrial Interface Disruption in Mice. Biomedicines 2022; 10:biomedicines10061218. [PMID: 35740240 PMCID: PMC9219744 DOI: 10.3390/biomedicines10061218] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/21/2022] [Accepted: 05/23/2022] [Indexed: 11/16/2022] Open
Abstract
We have recently demonstrated that endometrial–myometrial interface (EMI) disruption (EMID) can cause adenomyosis in mice, providing experimental evidence for the well-documented epidemiological finding that iatrogenic uterine procedures increase the risk of adenomyosis. To further elucidate its underlying mechanisms, we designed this study to test the hypothesis that Schwann cells (SCs) dedifferentiating after EMID facilitate the genesis of adenomyosis, but the suppression of SC dedifferentiation perioperatively reduces the risk. We treated mice perioperatively with either mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated protein kinase (ERK) or c-Jun N-terminal kinase (JNK) inhibitors or a vehicle 4 h before and 24 h, 48 h and 72 h after the EMID procedure. We found that EMID resulted in progressive SCs dedifferentiation, concomitant with an increased abundance of epithelial cells in the myometrium and a subsequent epithelial–mesenchymal transition (EMT). This EMID-induced change was abrogated significantly with perioperative administration of JNK or MEK/ERK inhibitors. Consistently, perioperative administration of a JNK or a MEK/ERK inhibitor reduced the incidence by nearly 33.5% and 14.3%, respectively, in conjunction with reduced myometrial infiltration of adenomyosis and alleviation of adenomyosis-associated hyperalgesia. Both treatments significantly decelerated the establishment of adenomyosis and progression of EMT, fibroblast-to-myofibroblast trans-differentiation and fibrogenesis in adenomyotic lesions. Thus, we provide the first piece of evidence strongly implicating the involvement of SCs in the pathogenesis of adenomyosis induced by EMID.
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