|
1
|
Liu Y, Ma Y, Zhou B, Bian B, Zhou Y, Chen S, Zhang P, Shen L, Chen H. Clofoctol impairs the stemness of gastric cancer and induces TNF-mediated necroptosis by directly binding to RanBP2. Cell Mol Life Sci 2025; 82:194. [PMID: 40325218 PMCID: PMC12052660 DOI: 10.1007/s00018-025-05723-8] [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: 12/04/2024] [Revised: 04/10/2025] [Accepted: 04/21/2025] [Indexed: 05/07/2025]
Abstract
Gastric cancer stem cells (GCSCs) play a crucial role in the initiation, progression, recurrence and therapeutic resistance, contributing to a poor prognosis. Consequently, GCSCs are deemed to be a potential therapeutic target for gastric cancer (GC). Although β-catenin is a well-recognized therapeutic target for GC and several inhibitors have demonstrated potent anti-tumor effects, there is a dearth of therapeutic agents targeting β-catenin for clinical therapy. In this study, we carried out high-throughput screening of clinically approved drugs to identify effective inhibitors of β-catenin. The results revealed that the antibiotic drug, clofoctol (CFT) effectively reduced the β-catenin level, attenuated stemness traits both in vitro and in vivo, and induced necroptosis of GCSCs. Further analyzing of downstream genes and targeted proteins, we found that CFT inhibited GCSCs viability by binding to the SUMO E3 ligase RanBP2, thereby suppressing the SerpinE1/β-catenin axis and activating TNF-mediated necroptosis. These results indicate that CFT may exert potent therapeutic effects against GC by targeting β-catenin and inhibiting the viability of GCSCs.
Collapse
Affiliation(s)
- Yi Liu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanhui Ma
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingqian Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Bingxian Bian
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yunlan Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Shiyu Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Peng Zhang
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Lisong Shen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China.
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Hui Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China.
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
2
|
Sreya M, Tucker DR, Yi J, Alotaibi FT, Lee AF, Noga H, Yong PJ. Nerve Bundle Density and Expression of NGF and IL-1β Are Intra-Individually Heterogenous in Subtypes of Endometriosis. Biomolecules 2024; 14:583. [PMID: 38785989 PMCID: PMC11118880 DOI: 10.3390/biom14050583] [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: 03/15/2024] [Revised: 04/17/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin-1β (IL-1β). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes of endometriosis (deep, superficial peritoneal, endometrioma) at surgery, with at least two surgically excised subtypes available for analysis. Immunolocalization for nerve bundle density around endometriosis using protein gene product 9.5 (PGP9.5), as well as NGF and IL-1β histoscores in endometriosis epithelium/stroma, was performed to evaluate differences in scores between lesions and anatomic subtypes per patient. Intra-individual heterogeneity in scores across lesions was assessed using the coefficient of variation (CV). The degree of score variability between subtypes was evaluated using the percentage difference between mean scores from one subtype to another subtype for each marker. PGP9.5 nerve bundle density was heterogenous across multiple subtypes of endometriosis, ranging from 50.0% to 173.2%, where most patients (8/12) showed CV ≥ 100%. The percentage difference in scores showed that PGP9.5 nerve bundle density and NGF and IL-1β expression were heterogenous between anatomic subtypes within the same patient. Based on these observations of intra-individual heterogeneity, we conclude that markers of neuroproliferation in endometriosis should be stratified by anatomic subtype in future studies of clinical correlation.
Collapse
Affiliation(s)
- Mahfuza Sreya
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6T 2A1, Canada
- Women’s Health Research Institute, Vancouver, BC V6H 2N9, Canada
| | - Dwayne R. Tucker
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6T 2A1, Canada
- Women’s Health Research Institute, Vancouver, BC V6H 2N9, Canada
| | - Jennifer Yi
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6T 2A1, Canada
| | - Fahad T. Alotaibi
- Department of Physiology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia
| | - Anna F. Lee
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada
| | - Heather Noga
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6T 2A1, Canada
- Women’s Health Research Institute, Vancouver, BC V6H 2N9, Canada
- Centre for Pelvic Pain and Endometriosis, BC Women’s Hospital & Health Centre, Vancouver, BC V6H 3N1, Canada
| | - Paul J. Yong
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V6T 2A1, Canada
- Women’s Health Research Institute, Vancouver, BC V6H 2N9, Canada
- Centre for Pelvic Pain and Endometriosis, BC Women’s Hospital & Health Centre, Vancouver, BC V6H 3N1, Canada
| |
Collapse
|
|
3
|
Bai HX, Qiu XM, Xu CH, Guo JQ. MiRNA-145-5p inhibits gastric cancer progression via the serpin family E member 1- extracellular signal-regulated kinase-1/2 axis. World J Gastrointest Oncol 2024; 16:2123-2140. [PMID: 38764835 PMCID: PMC11099451 DOI: 10.4251/wjgo.v16.i5.2123] [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: 01/11/2024] [Revised: 02/19/2024] [Accepted: 03/13/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) regulate gene expression and play a critical role in cancer physiology. However, there is still a limited understanding of the function and regulatory mechanism of miRNAs in gastric cancer (GC). AIM To investigate the role and molecular mechanism of miRNA-145-5p (miR145-5p) in the progression of GC. METHODS Real-time polymerase chain reaction (RT-PCR) was used to detect miRNA expression in human GC tissues and cells. The ability of cancer cells to migrate and invade was assessed using wound-healing and transwell assays, respectively. Cell proliferation was measured using cell counting kit-8 and colony formation assays, and apoptosis was evaluated using flow cytometry. Expression of the epithelial-mesenchymal transition (EMT)-associated protein was determined by Western blot. Targets of miR-145-5p were predicated using bioinformatics analysis and verified using a dual-luciferase reporter system. Serpin family E member 1 (SERPINE1) expression in GC tissues and cells was evaluated using RT-PCR and immunohistochemical staining. The correlation between SERPINE1 expression and overall patient survival was determined using Kaplan-Meier plot analysis. The association between SERPINE1 and GC progression was also tested. A rescue experiment of SERPINE1 overexpression was conducted to verify the relationship between this protein and miR-145-5p. The mechanism by which miR-145-5p influences GC progression was further explored by assessing tumor formation in nude mice. RESULTS GC tissues and cells had reduced miR-145-5p expression and SERPINE1 was identified as a direct target of this miRNA. Overexpression of miR-145-5p was associated with decreased GC cell proliferation, invasion, migration, and EMT, and these effects were reversed by forcing SERPINE1 expression. Kaplan-Meier plot analysis revealed that patients with higher SERPINE1 expression had a shorter survival rate than those with lower SERPINE1 expression. Nude mouse tumorigenesis experiments confirmed that miR-145-5p targets SERPINE1 to regulate extracellular signal-regulated kinase-1/2 (ERK1/2). CONCLUSION This study found that miR-145-5p inhibits tumor progression and is expressed in lower amounts in patients with GC. MiR-145-5p was found to affect GC cell proliferation, migration, and invasion by negatively regulating SERPINE1 levels and controlling the ERK1/2 pathway.
Collapse
Affiliation(s)
- Hong-Xia Bai
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan 250000, Shandong Province, China
- Department of Gastroenterology, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, China
| | - Xue-Mei Qiu
- Department of Reproductive Center, Zaozhuang Maternal and Child Health Care Hospital, Zaozhuang 277000, Shandong Province, China
| | - Chun-Hong Xu
- Department of Gastroenterology, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, China
| | - Jian-Qiang Guo
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan 250000, Shandong Province, China
| |
Collapse
|
|
4
|
Wang Y, Wang J, Gao J, Ding M, Li H. The expression of SERPINE1 in colon cancer and its regulatory network and prognostic value. BMC Gastroenterol 2023; 23:33. [PMID: 36755247 PMCID: PMC9906885 DOI: 10.1186/s12876-022-02625-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/19/2022] [Indexed: 02/10/2023] Open
Abstract
BACKGROUND Serpin Peptidase Inhibitor 1 (SERPINE1) promotes cancer progression by making it easier for cancer cells to spread to surrounding normal tissue. We expect to understand the prognostic value and regulatory network of SERPINE1 in colon cancer using bioinformatics methods. METHODS The expression of target gene SERPINE1 in varying cancers was analyzed by the Tumor Immune Estimation Resource (TIMER) database. SERPINE1 expression in Colon Adenocarcinoma and normal tissue samples was assessed by starBase and UALCAN databases. SERPINE1 expression in clinical tissues was assayed using quantitative reverse transcription Polymerase Chain Reaction (qRT-PCR). SERPINE1 expression was detected in colon cancer patients with various clinical features (age, gender, nodal metastasis status, race, stages, and subtype) using analysis of variance. Survival curve was used to analyze the effect of high and low expression of SERPINE1 on the survival time of patients with different clinical phenotypes. Gene Set Enrichment Analysis (GSEA) was conducted on the results of LinkFinder calculation using LinkInterpreter module, which was combined with Pearson correlation analysis to obtain the kinase targets and miRNA targets, transcription factor targets, and corresponding signaling pathways associated with SERPINE1. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed on GSEA result. Finally, Gene Multiple Association Network Integration Algorithm (GeneMANIA) was utilized to establish a network of genes related to the kinases MAPK1, miR-18a, and SRF_Q, and biological functions were analyzed. RESULTS Based on TIMER, starBase, and UALCAN databases, SERPINE1 was found to be remarkably highly expressed in colon cancer patients, which was further verified by clinical tissue. It was also associated with different clinical features (nodal metastasis status, stages, subtypes). Additionally, survival analysis showed that patients with low expression of SERPINE1 had a longer survival time, suggesting that SERPINE1 was a prognostic risk factor for colon cancer. Pearson correlation analysis revealed that the expression of Integrin Alpha 5 (ITGA5), Matrix Metallopeptidase 19 (MMP19), and ADAM Metallopeptidase with Thrombospondin Type 1 Motif, 4 (ADAMTS4) had the highest correlation with that of SERPINE1. The GSEA results indicated that these genes were mainly enriched in the pathways of RNA expression and kinases. Finally, GeneMANIA analysis was introduced to construct the molecular network of SERPINE1. CONCLUSION Overall, our bioinformatics analyses comprehensively described the networks involved SERPINE1 in colon cancer and the potentially associated molecular mechanisms.
Collapse
Affiliation(s)
- Yigang Wang
- Anus and Intestine Surgery, Tangshan Central Hospital, Tangshan, 063000 Hebei China
| | - Jinyan Wang
- Anus and Intestine Surgery, Tangshan Central Hospital, Tangshan, 063000 Hebei China
| | - Jianchao Gao
- Anus and Intestine Surgery, Tangshan Central Hospital, Tangshan, 063000 Hebei China
| | - Mei Ding
- Anus and Intestine Surgery, Tangshan Central Hospital, Tangshan, 063000 Hebei China
| | - Hua Li
- Department of Gastrointestinal Surgery, Tangshan Central Hospital, Tangshan Youyi Road and Changning Road Interchange Westbound 300 Meters, Tangshan, 063000, China.
| |
Collapse
|
|
5
|
Alotaibi FT, Sediqi S, Klausen C, Bedaiwy MA, Yong PJ. Interleukin-1β and plasminogen activating system members in endometriotic stromal cell migration/invasion. F&S SCIENCE 2023; 4:47-55. [PMID: 36152991 DOI: 10.1016/j.xfss.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 10/14/2022]
Abstract
OBJECTIVE To study the role of interleukin (IL)-1β and the plasminogen activating (PA) system members in endometriotic stromal cell (ESC) migration/invasion. DESIGN Primary cultures of ESCs. SETTING Tertiary referral center for endometriosis and pelvic pain. PATIENT(S) Patients with surgically excised endometriosis. INTERVENTION(S) Interleukin-1β stimulation of primary cultures of ESCs and knockdown of the PA system members urokinase plasminogen activator (uPA), uPA receptor, and plasminogen activator inhibitor-1 (PAI-1). MAIN OUTCOME MEASURE(S) Invasion/migration assays. RESULT(S) In primary cultures, IL-1β-stimulated ESC production of the PA system members uPA, uPA receptor, and PAI-1. Interleukin-1β also enhanced ESC migration and invasion, and these effects were inhibited by the IL-1 receptor-1 antagonist anakinra. Knockdown of each of the 3 PA system members also inhibited ESC migration and invasion. Knockdown of these PA system members further attenuated the impact of IL-1β on migration and invasion, suggesting that they mediated the promigration and proinvasion effects of IL-1β. To supplement the cell culture work, immunohistochemistry was performed on tissue sections of endometriotic epithelium/stroma: uPA, PAI-1, and IL-1β histoscores were not found to be correlated with each other. CONCLUSION(S) In primary cultures of ESCs, IL-1β induces migration and invasion, which is mediated by PA system members and inhibited by the drug anakinra. However, the immunohistochemistry expression of IL-1β, urokinase plasminogen inhibitor-1, and PAI-1 were not correlated, suggesting other regulatory mechanisms for PA system members. Inhibition of IL-1β (e.g., with anakinra) may have potential as a novel treatment approach for the migration/invasion of endometriosis.
Collapse
Affiliation(s)
- Fahad T Alotaibi
- Department of Obstetrics and Gynecology, University of British Columbia, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Sadaf Sediqi
- Department of Obstetrics and Gynecology, University of British Columbia, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Christian Klausen
- Department of Obstetrics and Gynecology, University of British Columbia, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Mohamed A Bedaiwy
- Department of Obstetrics and Gynecology, University of British Columbia, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Paul J Yong
- Department of Obstetrics and Gynecology, University of British Columbia, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
| |
Collapse
|
|
6
|
Fiorentino G, Cimadomo D, Innocenti F, Soscia D, Vaiarelli A, Ubaldi FM, Gennarelli G, Garagna S, Rienzi L, Zuccotti M. Biomechanical forces and signals operating in the ovary during folliculogenesis and their dysregulation: implications for fertility. Hum Reprod Update 2023; 29:1-23. [PMID: 35856663 DOI: 10.1093/humupd/dmac031] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 05/12/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Folliculogenesis occurs in the highly dynamic environment of the ovary. Follicle cyclic recruitment, neo-angiogenesis, spatial displacement, follicle atresia and ovulation stand out as major events resulting from the interplay between mechanical forces and molecular signals. Morphological and functional changes to the growing follicle and to the surrounding tissue are required to produce oocytes capable of supporting preimplantation development to the blastocyst stage. OBJECTIVE AND RATIONALE This review will summarize the ovarian morphological and functional context that contributes to follicle recruitment, growth and ovulation, as well as to the acquisition of oocyte developmental competence. We will describe the changes occurring during folliculogenesis to the ovarian extracellular matrix (ECM) and to the vasculature, their influence on the mechanical properties of the ovarian tissue, and, in turn, their influence on the regulation of signal transduction. Also, we will outline how their dysregulation might be associated with pathologies such as polycystic ovary syndrome (PCOS), endometriosis or premature ovarian insufficiency (POI). Finally, for each of these three pathologies, we will highlight therapeutic strategies attempting to correct the altered biomechanical context in order to restore fertility. SEARCH METHODS For each area discussed, a systematic bibliographical search was performed, without temporal limits, using PubMed Central, Web of Science and Scopus search engines employing the keywords extracellular matrix, mechanobiology, biomechanics, vasculature, angiogenesis or signalling pathway in combination with: ovary, oogenesis, oocyte, folliculogenesis, ovarian follicle, theca, granulosa, cumulus, follicular fluid, corpus luteum, meiosis, oocyte developmental competence, preimplantation, polycystic ovary syndrome, premature ovarian insufficiency or endometriosis. OUTCOMES Through search engines queries, we yielded a total of 37 368 papers that were further selected based on our focus on mammals and, specifically, on rodents, bovine, equine, ovine, primates and human, and also were trimmed around each specific topic of the review. After the elimination of duplicates, this selection process resulted in 628 papers, of which 287 were cited in the manuscript. Among these, 89.2% were published in the past 22 years, while the remaining 8.0%, 2.4% or 0.3% were published during the 1990s, 1980s or before, respectively. During folliculogenesis, changes occur to the ovarian ECM composition and organization that, together with vasculature modelling around the growing follicle, are aimed to sustain its recruitment and growth, and the maturation of the enclosed oocyte. These events define the scenario in which mechanical forces are key to the regulation of cascades of molecular signals. Alterations to this context determine impaired folliculogenesis and decreased oocyte developmental potential, as observed in pathological conditions which are causes of infertility, such as PCOS, endometriosis or POI. WIDER IMPLICATIONS The knowledge of these mechanisms and the rules that govern them lay a sound basis to explain how follicles recruitment and growth are modulated, and stimulate insights to develop, in clinical practice, strategies to improve follicular recruitment and oocyte competence, particularly for pathologies like PCOS, endometriosis and POI.
Collapse
Affiliation(s)
- Giulia Fiorentino
- Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.,Center for Health Technologies, University of Pavia, Pavia, Italy
| | | | | | - Daria Soscia
- Clinica Valle Giulia, GeneraLife IVF, Rome, Italy
| | | | | | - Gianluca Gennarelli
- Obstetrics and Gynecology, Physiopathology of Reproduction and IVF Unit, Department of Surgical Sciences, Sant'Anna Hospital, University of Torino, Turin, Italy.,Livet, GeneraLife IVF, Turin, Italy
| | - Silvia Garagna
- Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.,Center for Health Technologies, University of Pavia, Pavia, Italy
| | - Laura Rienzi
- Clinica Valle Giulia, GeneraLife IVF, Rome, Italy.,Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy
| | - Maurizio Zuccotti
- Laboratory of Developmental Biology, Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.,Center for Health Technologies, University of Pavia, Pavia, Italy
| |
Collapse
|
|
7
|
Egashira EM, Trovó-Marqui AB, Tanaka SCSV, Cintra MTR. Investigation of biomarkers in Endometriosis-associated infertility: Systematic Review. AN ACAD BRAS CIENC 2022; 94:e20211572. [PMID: 36477241 DOI: 10.1590/0001-3765202220211572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/01/2022] [Indexed: 11/30/2022] Open
Abstract
The relationship between endometriosis and infertility is still unknown, but it is possible that genetic polymorphisms influence these two variables. This study aims to identify, in the literature, which polymorphisms are related to infertility in women with endometriosis. A search was performed in databases using the descriptors: polymorphisms genetics and infertility and endometriosis. 386 articles were identified, and after applying the inclusion and exclusion criteria, 33 case-control studies were included. Genes and their respective polymorphisms, which exhibited statistically significant values, were classified into three categories: related to metabolic/cellular processes, steroidogenesis and sex hormone receptors, inflammation and immune response. In summary, the results of these studies suggest that the polymorphisms rs882605 of MUC4 gene, rs16826658 of WNT4 gene, rs10953316 of MUC17 gene, rs10928050 of KAZN gene, rs1799889 of PAI-1 gene, (TA)n repeats of ESR1 gene, (CA)n repeats of ESR2 gene, rs605059 of HSD17B1 gene, rs743572 of CYP17A1 gene, insLQ of LHR gene, p.Ile49Ser of AMH gene, rs12700667 of NPVF/NFE2L3 gene, G1502A of LHβ gene, G + 1730A of ERβ gene, rs7528684 of FCRL3 gene, rs3761549 of FOXP3 gene and rs28362491 of NFKβ1 gene are implicated in the etiology of infertility in women with endometriosis.
Collapse
Affiliation(s)
- Erika M Egashira
- Programa de Pós-Graduação em Ciência e Tecnologia de Materiais, Universidade Federal do Triângulo Mineiro/UFTM, Rua Vigário Carlos, 100, Nossa Senhora da Abadia, 38025-350 Uberaba, MG, Brazil
| | - Alessandra B Trovó-Marqui
- Universidade Federal do Triângulo Mineiro/UFTM, Departamento de Patologia, Genética e Evolução, Campus I, Praça Manoel Terra, 330, Nossa Senhora da Abadia, 38025-015 Uberaba, MG, Brazil
| | - Sarah C S V Tanaka
- Programa de Pós-Graduação em Medicina Tropical e Infectologia, Universidade Federal do Triângulo Mineiro, Av. Getúlio Guaritá, s/n, Abadia, 38025-180 Uberaba, MG, Brazil
| | - Mariangela T R Cintra
- Universidade Federal do Triângulo Mineiro/UFTM, Departamento de Ciências Biológicas, Av. Randolfo Borges Júnior, 1400, Univerdecidade, 38064-200 Uberaba, MG, Brazil
| |
Collapse
|
|
8
|
Huayu Sanjie Enema Liquid Relieves Pain in Endometriosis Model Rats by Inhibiting Inflammation, Peripheral Sensitization, and Pelvic Adhesion. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5256578. [PMID: 35800014 PMCID: PMC9256397 DOI: 10.1155/2022/5256578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 05/14/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022]
Abstract
The objective of this study is to observe the effect of relieving pain of Huayu Sanjie enema liquid (HYSJ-EL) on endometriosis model rats and to explore its mechanism of action. Of 24 female Sprague Dawley rats, six were randomly selected as the sham operation group (normal control group). The remaining rats were used to establish rat models of endometriosis through autologous endometrial transplantation combined with estrogen injection. Successfully modeled rats were randomly divided into the model, indomethacin (Western medicine group), and HYSJ-EL (Chinese herbs group) treatment groups. The thermal pain threshold of rats was measured, and hematoxylin and eosin staining was used to observe pathological changes after sampling. Serum levels of prostaglandin E2 (PGE2), interleukin-6 (IL-6), macrophage inflammatory protein-2 (MIP-2), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor-β (TGF-β) were measured using an enzyme-linked immunosorbent assay (ELISA). Furthermore, the protein and mRNA expression levels of transient receptor potential vanilloid-1 (TRPV1) and tumor necrosis factor-α (TNF-α) in the endometrium and endometriotic lesions were measured using Western blotting and quantitative real-time PCR assays, respectively. Compared to the model group, the heat pain threshold of rats in the HYSJ-EL group was significantly increased (P < 0.01), and the serum levels of PGE2, IL-6, MIP-2, PAI-1, and TGF-β were significantly decreased (P < 0.01), as well as the expression of TRPV1 and TNF-α protein and mRNA in the tissue of the ectopic lesion was significantly decreased (P < 0.05). These results indicate that the Huayu Sanjie enema liquid exerts analgesic effects on endometriosis by inhibiting inflammation, peripheral nerve sensitization, and pelvic adhesion.
Collapse
|
|
9
|
Strath LJ, Meng L, Rani A, Sinha P, Johnson AJ, Huo Z, Foster TC, Edburg JD, Fillingim RB, Cruz-Almeida Y. Accelerated Epigenetic Aging Mediates the Association between Vitamin D Levels and Knee Pain in Community-Dwelling Individuals. J Nutr Health Aging 2022; 26:318-323. [PMID: 35450986 PMCID: PMC10161927 DOI: 10.1007/s12603-022-1758-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVES To examine the relationship between Vitamin D status and pain intensity and disability in individuals with and without knee pain, and to examine the role of epigenetics in this relationship. DESIGN Cross-sectional analysis of data from the UPLOAD-2 study (Understanding Pain and Limitations in OsteoArthritic Disease-2). PARTICIPANTS 189 individuals aged 45-65 years and older. MEASUREMENTS Serum Vitamin D levels, pain related interference and characteristic pain intensity measures, and the epigenetic clock GrimAge derived from blood analyses. RESULTS Lower Vitamin D was associated with advanced epigenetic aging (AgeAccelGrim), greater pain and disability and that (AgeAccelGrim) mediated the relationship between Vitamin D status and self-reported pain (ab = -0.0799; CI [-0.1492, -0.0237]) and disability (ab = -0.0669; CI [-0.1365, -0.0149]) outcomes. CONCLUSION These data support the notion that lifestyle factors such as nutrition status play a key role in aging process, as well as the development and maintenance of age-related diseases such as pain. Modifying nutrition status could help promote healthy aging and reduce pain.
Collapse
Affiliation(s)
- L J Strath
- Yenisel Cruz-Almeida, 1329 SW 16th Street, Suite 5108, Gainesville, FL, 32605, USA, E:
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
The role of plasminogen activator inhibitor-1 in gynecological and obstetrical diseases: an update review. J Reprod Immunol 2022; 150:103490. [DOI: 10.1016/j.jri.2022.103490] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 01/20/2022] [Accepted: 01/25/2022] [Indexed: 11/21/2022]
|
|
11
|
Chen ZY, Zhang LF, Zhang YQ, Zhou Y, Li XY, Huang XF. Blood tests for prediction of deep endometriosis: A case-control study. World J Clin Cases 2021; 9:10805-10815. [PMID: 35047592 PMCID: PMC8678869 DOI: 10.12998/wjcc.v9.i35.10805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/16/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Deep endometriosis (DE) is the most aggressive subtype of endometriosis. The diagnosis may be challenging, and no biomarkers that can discriminate women with DE from those without DE have been developed.
AIM To evaluate the role of blood hemostatic parameters and inflammatory indices in the prediction of DE.
METHODS This case-control study was performed at the Women’s Hospital, Zhejiang University School of Medicine between January 2015 and December 2016. Women with DE and women with benign gynecologic disease (control group) eligible for gynecological surgery were enrolled. Routine plasma hemostatic parameters and inflammatory indices were obtained before surgery. Univariate and multivariate analysis were performed. Receiver operating characteristic (ROC) curves were generated, and areas under the curve (AUC) were calculated to assess the predictive values of the selected parameters.
RESULTS A total of 126 women were enrolled, including 31 with DE and 95 controls. Plasma fibrinogen (Fg, P < 0.01), international normalized ratio (P < 0.05), and C-reactive protein levels (P < 0.01) were significantly higher in women with DE compared with controls. Plasma hemoglobin (HB) levels (P < 0.05) and shortened thrombin time (P < 0.05) were significantly lower in women with DE than in controls. Plasma Fg levels [adjusted OR (aOR) 2.12, 95%confidence interval (CI): 1.31-3.75] and plasma HB levels (aOR 0.48, 95%CI: 0.29-0.78) were significantly associated with DE (both P < 0.05). ROC analysis showed that the diagnostic value of Fg or HB alone for DE was limited. The AUC of the combination of both markers as a dual marker index was 0.773 with improved sensitivity (67.7%) and specificity (78.9%) at cutoffs of 3.09 g/L and 126 g/L, respectively.
CONCLUSION The combination of Fg and HB was a reliable predictor of DE. A larger study is needed to confirm the findings.
Collapse
Affiliation(s)
- Zheng-Yun Chen
- Department of Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Li-Feng Zhang
- Department of Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Yong-Qing Zhang
- Department of Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Yong Zhou
- Department of Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Xiao-Yong Li
- Department of Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Xiu-Feng Huang
- Department of Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| |
Collapse
|
|
12
|
Chen LJ, Hu B, Han ZQ, Liu W, Zhu JH, Chen XX, Li ZP, Zhou H. Repression of FBXW7 by HES5 contributes to inactivation of the TGF-β signaling pathway and alleviation of endometriosis. FASEB J 2021; 35:e20938. [PMID: 33496006 DOI: 10.1096/fj.202000438rrr] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 07/28/2020] [Accepted: 07/31/2020] [Indexed: 12/13/2022]
Abstract
Endometriosis (EMS) is a gynecologic disorder associated with infertility and characterized by the endometrial-type mucosa outside the uterine cavity. Currently available treatment modalities are limited to undesirable effects. Thus, in the present study, we sought to study the pathogenesis mechanism of EMS. For this purpose, the ectopic and eutopic endometrial tissues were resected from 86 patients with EMS and 54 infertile patients without EMS, respectively. The regulatory mechanism among HES family bHLH transcription factor 5 (HES5), transforming growth factor-beta (TGF-β)-induced factor 1 (TGIF1), F-box, and WD repeat domain containing 7 (FBXW7) was studied by performing co-immunoprecipitation, dual-luciferase reporter gene assay, and chromatin immunoprecipitation, respectively. A mouse model of EMS was established to verify the aforementioned regulatory mechanism in vivo. Upregulation of HES5 and TGIF1, as well as downregulation of FBXW7, was observed in EMS endometrial tissues and human endometrial stromal cells (hESCs), respectively. The overexpression of HES5 was found to suppress the FBXW7 transcription and TGIF1 degradation, resulting in the inactivation of the TGF-β signaling pathway, as well as inhibition of hESC proliferation and invasion, thereby enhancing apoptosis. Results from a mouse model of EMS showed that the presence of HES5 contributed to the alleviation of EMS. Collectively, we attempted to provide a mechanistic insight into the unrecognized roles of the HES5/FBXW7 in EMS progression.
Collapse
Affiliation(s)
- Li-Juan Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Hu
- Department of Obstetrics and Gynecology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi-Qiang Han
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Liu
- Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Hua Zhu
- Laboratory of Clinical Immunology, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue-Xing Chen
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zi-Ping Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Zhou
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
13
|
Shi M, Sekulovski N, Whorton AE, MacLean JA, Greaves E, Hayashi K. Efficacy of niclosamide on the intra-abdominal inflammatory environment in endometriosis. FASEB J 2021; 35:e21584. [PMID: 33860549 PMCID: PMC10777336 DOI: 10.1096/fj.202002541rrr] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/24/2022]
Abstract
Endometriosis, a common gynecological disease, causes chronic pelvic pain and infertility in women of reproductive age. Due to the limited efficacy of current therapies, a critical need exists to develop new treatments for endometriosis. Inflammatory dysfunction, instigated by abnormal macrophage (MΦ) function, contributes to disease development and progression. However, the fundamental role of the heterogeneous population of peritoneal MΦ and their potential druggable functions is uncertain. Here we report that GATA6-expressing large peritoneal MΦ (LPM) were increased in the peritoneal cavity following lesion induction. This was associated with increased cytokine and chemokine secretion in the peritoneal fluid (PF), as well as MΦ infiltration, vascularization and innervation in endometriosis-like lesions (ELL). Niclosamide, an FDA-approved anti-helminthic drug, was effective in reducing LPM number, but not small peritoneal MΦ (SPM), in the PF. Niclosamide also inhibits aberrant inflammation in the PF, ELL, pelvic organs (uterus and vagina) and dorsal root ganglion (DRG), as well as MΦ infiltration, vascularization and innervation in the ELL. PF from ELL mice stimulated DRG outgrowth in vitro, whereas the PF from niclosamide-treated ELL mice lacked the strong stimulatory nerve growth response. These results suggest LPM induce aberrant inflammation in endometriosis promoting lesion progression and establishment of the inflammatory environment that sensitizes peripheral nociceptors in the lesions and other pelvic organs, leading to increased hyperalgesia. Our findings provide the rationale for targeting LPM and their functions with niclosamide and its efficacy in endometriosis as a new non-hormonal therapy to reduce aberrant inflammation which may ultimately diminish associated pain.
Collapse
Affiliation(s)
- Mingxin Shi
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
- Center for Reproductive Biology, Washington State University, Pullman, WA, USA
| | - Nikola Sekulovski
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
| | - Allison E. Whorton
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
| | - James A. MacLean
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
- Center for Reproductive Biology, Washington State University, Pullman, WA, USA
| | - Erin Greaves
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK
| | - Kanako Hayashi
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA
- Center for Reproductive Biology, Washington State University, Pullman, WA, USA
| |
Collapse
|
|
14
|
Peng B, Alotaibi FT, Sediqi S, Bedaiwy MA, Yong PJ. Role of interleukin-1β in nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis. Hum Reprod 2021; 35:901-912. [PMID: 32240297 DOI: 10.1093/humrep/deaa017] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 12/21/2019] [Indexed: 02/07/2023] Open
Abstract
STUDY QUESTION Does interleukin-1β (IL-1β) play a role in promoting nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis? SUMMARY ANSWER IL-1β directly stimulates nerve growth factor (NGF) expression in endometriosis and is associated with local neurogenesis around endometriosis and more severe deep dyspareunia. WHAT IS KNOWN ALREADY Local nerve density around endometriosis (using the pan-neuronal marker PGP9.5) is associated with deep dyspareunia in endometriosis, mediated in part by NGF expression. STUDY DESIGN, SIZE, DURATION This in vitro study included endometriotic tissue samples from 45 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was conducted in a university hospital affiliated research institute and included 45 women with surgically excised deep uterosacral/rectovaginal endometriosis (DIE, n = 12), ovarian endometriomas (OMA, n = 14) or superficial peritoneal uterosacral/cul-de-sac endometriosis (SUP, n = 19). Immunolocalisation of IL-1β, IL-1 receptor type 1 (IL-1R1), NGF and PGP9.5 in endometriotic tissues was examined by immunohistochemistry (IHC), and the intensity of IHC staining in the endometriotic epithelium and stroma was semi-quantitatively evaluated using the Histoscore method (H-score). For each case, deep dyspareunia was pre-operatively rated by the patient on an 11-point numeric rating scale (0-10). In addition, primary endometriosis stromal cells were isolated and cultured from surgically excised endometriosis. These cells were treated with IL-1β alone or in combination of Anakinra (an inhibitor of IL-1R1), small inference RNA (siRNA) against IL-1R1, siRNA against c-FOS or NGF neutralising antibody. The mRNA and protein levels of target genes (NGF and c-FOS) were assessed by reverse-transcription qPCR and western blot/ELISA, respectively. Furthermore, immunofluorescent microscopy was used to examine the neurite growth of rat pheochromocytoma PC-12 cells, as an in vitro model of neurogenesis. MAIN RESULTS AND THE ROLE OF CHANCE For IHC, IL-1β expression in the endometriosis epithelium was significantly associated with more severe deep dyspareunia (r = 0.37, P = 0.02), higher nerve fibre bundle density around endometriosis (r = 0.42, P = 0.01) and greater NGF expression by the endometriosis epithelium (r = 0.42, P = 0.01) and stroma (r = 0.45, P = 0.01). In primary endometriosis stromal cells, treatment with exogenous IL-1β significantly increased the mRNA and protein levels of NGF and c-FOS. Pre-treatment with Anakinra, siRNA against IL-1R1, or siRNA against c-FOS, each attenuated IL-1 β-induced increases of NGF expression. In addition, supernatants from IL-1β treated endometriosis stromal cells significantly stimulated PC-12 neurite growth compared to controls, and these effects could be attenuated by pre-treatment with NGF neutralising antibody or Anakinra. LARGE-SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION We did not have data from cultures of endometriosis glandular epithelium, due to the known difficulties with primary cultures of this cell type. WIDER IMPLICATIONS OF THE FINDINGS Our study revealed a mechanism for deep dyspareunia in endometriosis, whereby IL-1β stimulates NGF expression, promoting local neurogenesis around endometriosis, which in turn leads to tender pelvic anatomic sites and thus deep-hitting dyspareunia. There may also be potential for drug targeting of IL-1β and/or NGF in the management of endometriosis-associated pain. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by grants from the Canadian Institutes of Health Research (MOP-142273 and PJT-156084). P.Y. is also supported by a Health Professional Investigator Award from the Michael Smith Foundation for Health Research. MB has financial affiliations with Abbvie and Allergan. Otherwise, there are no conflicts of interest to declare.
Collapse
Affiliation(s)
- Bo Peng
- Department of Obstetrics and Gynaecology, University of British Columbia, BC Children's Hospital Research Institute and Women's Health Research Institute, Vancouver, British Columbia, Canada, V6H3N1
| | - Fahad T Alotaibi
- Department of Obstetrics and Gynaecology, University of British Columbia, BC Children's Hospital Research Institute and Women's Health Research Institute, Vancouver, British Columbia, Canada, V6H3N1
| | - Sadaf Sediqi
- Department of Obstetrics and Gynaecology, University of British Columbia, BC Children's Hospital Research Institute and Women's Health Research Institute, Vancouver, British Columbia, Canada, V6H3N1
| | - Mohamed A Bedaiwy
- Department of Obstetrics and Gynaecology, University of British Columbia, BC Children's Hospital Research Institute and Women's Health Research Institute, Vancouver, British Columbia, Canada, V6H3N1
| | - Paul J Yong
- Department of Obstetrics and Gynaecology, University of British Columbia, BC Children's Hospital Research Institute and Women's Health Research Institute, Vancouver, British Columbia, Canada, V6H3N1
| |
Collapse
|
|
15
|
Yang B, Gu N, Shi S, Zhang C, Chen L, Ouyang J, Lin Y, Sun F, Xu H. Immunoreactivity of Plasminogen Activator Inhibitor 1 and Its Correlation with Dysmenorrhea and Lesional Fibrosis in Adenomyosis. Reprod Sci 2021; 28:2378-2386. [PMID: 33683668 PMCID: PMC8289782 DOI: 10.1007/s43032-021-00513-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 02/21/2021] [Indexed: 12/29/2022]
Abstract
Adenomyosis is associated with dysmenorrhea, infertility, and lesional fibrosis. The pathogenesis of adenomyosis is still unclear. Plasminogen activator inhibitor 1 (PAI-1) plays important roles in pathological activities like tumor metastasis and endometriosis. Our objective was to investigate the expression and localization of PAI-1 in eutopic and ectopic endometrium with adenomyosis and in endometrium without adenomyosis. We also sought to determine the relationship between PAI-1 immunoreactivity and the severity of dysmenorrhea and the extent of lesional fibrosis in adenomyosis. PAI-1 expression was significantly higher in the ectopic endometrium of patients with adenomyosis than in both the eutopic endometrium of patients with adenomyosis and the endometrium of controls. Ectopic PAI-1 expression correlated positively with dysmenorrhea visual analog scale (VAS) scores and the extent of lesional fibrosis in adenomyosis. High PAI-1 expression increased the likelihood of moderate to severe dysmenorrhea in adenomyosis. These results suggest that PAI-1 is involved in the adenomyosis-associated dysmenorrhea and lesional fibrosis, which provide a potential target in treating symptomatic adenomyosis.
Collapse
Affiliation(s)
- Bingxin Yang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Nihao Gu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Shu Shi
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
| | - Chen Zhang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Lan Chen
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Jing Ouyang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
| | - Yu Lin
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| | - Feng Sun
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
| | - Hong Xu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, NO. 910, Heng-Shan Road, Xu-Hui Qu, Shanghai, 200030 China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030 China
| |
Collapse
|
|
16
|
Roomruangwong C, Sirivichayakul S, Matsumoto AK, Michelin AP, de Oliveira Semeão L, de Lima Pedrão JV, Barbosa DS, Moreira EG, Maes M. Menstruation distress is strongly associated with hormone-immune-metabolic biomarkers. J Psychosom Res 2021; 142:110355. [PMID: 33444909 DOI: 10.1016/j.jpsychores.2020.110355] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/25/2020] [Accepted: 12/28/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To examine the associations between menstruation features and symptoms and hormone-immune-metabolic biomarkers. METHODS Forty-one women completed questionnaires assessing characteristic menstruation symptoms, duration of menstrual cycle and number of pads used/day and completed the Daily Record of Severity of Problems (DRSP) during the consecutive days of their menstrual cycle. Menses-related symptoms (MsRS) were computed from the sum of 10 pre- and post-menses symptoms and the menstruation blood and duration index (MBDI) was computed based on the daily number of pads and duration of menses. We assayed serum levels of various biomarkers at days 7, 14, 21, and 28 of the subjects' menstrual cycle. RESULTS MBDI was significantly associated with a) MsRS including low abdominal cramps, and gastro-intestinal (GI) and pain symptoms (positively); b) plasma levels of haptoglobin (Hp), CCL5, insulin growth factor (IGF)-1, and plasminogen activator inhibitor (PAI)1 (all positively); and c) estradiol and paraoxonase (PON)1 arylesterase activity (both inversely). MsRS were significantly predicted by CCL5 and IGF-1 (both positively) and progesterone (inversely). Low-abdominal cramps, and gastro-intestinal and pain symptoms were associated with lower progesterone levels. The MBDI+MsRS score was significantly predicted by the cumulative effects of (in descending order of importance): Hp, IGF-1, PON1 arylesterase, estradiol and PAI. CONCLUSION Menstruation-related features including estimated blood loss, duration of menses, cramps, pain, and gastro-intestinal symptoms are associated with hormone-immune-metabolic biomarkers, which mechanistically may explain those features. Future research should construct a cross-validated algorithm using MBDI+MsRS features in a larger study group to delineate a useful case-definition of menstruation-related distress.
Collapse
Affiliation(s)
- Chutima Roomruangwong
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sunee Sirivichayakul
- Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Andressa Keiko Matsumoto
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - Ana Paula Michelin
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - Laura de Oliveira Semeão
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - João Victor de Lima Pedrão
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - Decio S Barbosa
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - Estefania G Moreira
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Psychiatry, Medical University Plovdiv, Plovdiv, Bulgaria; IMPACT Strategic Research Center, Deakin University, Geelong, Australia.
| |
Collapse
|
|
17
|
Wilson MR, Reske JJ, Holladay J, Neupane S, Ngo J, Cuthrell N, Wegener M, Rhodes M, Adams M, Sheridan R, Hostetter G, Alotaibi FT, Yong PJ, Anglesio MS, Lessey BA, Leach RE, Teixeira JM, Missmer SA, Fazleabas AT, Chandler RL. ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation. Cell Rep 2020; 33:108366. [PMID: 33176148 PMCID: PMC7682620 DOI: 10.1016/j.celrep.2020.108366] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 09/16/2020] [Accepted: 10/16/2020] [Indexed: 12/12/2022] Open
Abstract
Endometriosis affects 1 in 10 women and is characterized by the presence of abnormal endometrium at ectopic sites. ARID1A mutations are observed in deeply invasive forms of the disease, often correlating with malignancy. To identify epigenetic dependencies driving invasion, we use an unbiased approach to map chromatin state transitions accompanying ARID1A loss in the endometrium. We show that super-enhancers marked by high H3K27 acetylation are strongly associated with ARID1A binding. ARID1A loss leads to H3K27 hyperacetylation and increased chromatin accessibility and enhancer RNA transcription at super-enhancers, but not typical enhancers, indicating that ARID1A normally prevents super-enhancer hyperactivation. ARID1A co-localizes with P300 at super-enhancers, and genetic or pharmacological inhibition of P300 in ARID1A mutant endometrial epithelia suppresses invasion and induces anoikis through the rescue of super-enhancer hyperacetylation. Among hyperactivated super-enhancers, SERPINE1 (PAI-1) is identified as an essential target gene driving ARID1A mutant endometrial invasion. Broadly, our findings provide rationale for therapeutic strategies targeting super-enhancers in ARID1A mutant endometrium.
Collapse
Affiliation(s)
- Mike R Wilson
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Jake J Reske
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Jeanne Holladay
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Subechhya Neupane
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Julie Ngo
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Nina Cuthrell
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Marc Wegener
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Mary Rhodes
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Marie Adams
- Genomics Core Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Rachael Sheridan
- Flow Cytometry Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Galen Hostetter
- Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Fahad T Alotaibi
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; Department of Physiology, College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Paul J Yong
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
| | - Michael S Anglesio
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, Vancouver General Hospital, and BC Cancer, Vancouver, BC, Canada
| | - Bruce A Lessey
- Department of Obstetrics and Gynecology, Wake Forest Baptist Health, Winston-Salem, NC 27157, USA
| | - Richard E Leach
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Jose M Teixeira
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Stacey A Missmer
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Asgerally T Fazleabas
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA
| | - Ronald L Chandler
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA; Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
| |
Collapse
|