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Anvari Aliabad R, Hassanpour K, Norooznezhad AH. Cannabidiol as a possible treatment for endometriosis through suppression of inflammation and angiogenesis. Immun Inflamm Dis 2024; 12:e1370. [PMID: 39110084 PMCID: PMC11304901 DOI: 10.1002/iid3.1370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 07/08/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it. OBJECTIVE This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways. FINDINGS Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL-β), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor β1 (TGF-β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1β, IL-6, TNF-α, VEGF, TGFβ, and MMPs in different animal models of diseases. CONCLUSION It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.
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Affiliation(s)
| | - Kamyab Hassanpour
- School of Medicine, Hamadan University of Medical SciencesHamadanIran
| | - Amir Hossein Norooznezhad
- Medical Biology Research Center, Health Technology InstituteKermanshah University of Medical SciencesKermanshahIran
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Calmon MS, Lemos FFB, Silva Luz M, Rocha Pinheiro SL, de Oliveira Silva LG, Correa Santos GL, Rocha GR, Freire de Melo F. Immune pathway through endometriosis to ovarian cancer. World J Clin Oncol 2024; 15:496-522. [PMID: 38689629 PMCID: PMC11056862 DOI: 10.5306/wjco.v15.i4.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/29/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.
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Affiliation(s)
- Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Guo C, Zhang C. Role of the gut microbiota in the pathogenesis of endometriosis: a review. Front Microbiol 2024; 15:1363455. [PMID: 38505548 PMCID: PMC10948423 DOI: 10.3389/fmicb.2024.1363455] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 02/19/2024] [Indexed: 03/21/2024] Open
Abstract
Endometriosis is classically defined as a chronic inflammatory heterogeneous disorder occurring in any part of the body, characterized by estrogen-driven periodic bleeding, proliferation, and fibrosis of ectopic endometrial glands and stroma outside the uterus. Endometriosis can take overwhelmingly serious damage to the structure and function of multi-organ, even impair whole-body systems, resulting in severe dysmenorrhea, chronic pelvic pain, infertility, fatigue and depression in 5-10% women of reproductive age. Precisely because of a huge deficiency of cognition about underlying etiology and complex pathogenesis of the debilitating disease, early diagnosis and treatment modalities with relatively minor side effects become bottlenecks in endometriosis. Thus, endometriosis warrants deeper exploration and expanded investigation in pathogenesis. The gut microbiota plays a significant role in chronic diseases in humans by acting as an important participant and regulator in the metabolism and immunity of the body. Increasingly, studies have shown that the gut microbiota is closely related to inflammation, estrogen metabolism, and immunity resulting in the development and progression of endometriosis. In this review, we discuss the diverse mechanisms of endometriosis closely related to the gut microbiota in order to provide new approaches for deeper exploration and expanded investigation for endometriosis on prevention, early diagnosis and treatment.
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Affiliation(s)
| | - Chiyuan Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
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Ellis K, Wood R. The Comparative Invasiveness of Endometriotic Cell Lines to Breast and Endometrial Cancer Cell Lines. Biomolecules 2023; 13:1003. [PMID: 37371583 DOI: 10.3390/biom13061003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/08/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Endometriosis is an invasive condition that affects 10% of women (and people assigned as female at birth) worldwide. The purpose of this study was to characterize the relative invasiveness of three available endometriotic cell lines (EEC12Z, iEc-ESCs, tHESCs) to cancer cell lines (MDA-MB-231, SW1353 and EM-E6/E7/TERT) and assess whether the relative invasiveness was consistent across different invasion assays. All cell lines were subjected to transwell, spheroid drop, and spheroid-gel invasion assays, and stained for vimentin, cytokeratin, E-Cadherin and N-Cadherin to assess changes in expression. In all assays, endometriotic cell lines showed comparable invasiveness to the cancer cell lines used in this study, with no significant differences in invasiveness identified. EEC12Z cells that had invaded within the assay periods showed declines in E-Cadherin expression compared to cells that had not invaded within the assay period, without significant changes in N-Cadherin expression, which may support the hypothesis that an epithelial-to-mesenchymal transition is an influence on the invasiveness shown by this peritoneal endometriosis cell line.
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Affiliation(s)
- Katherine Ellis
- Department of Chemical and Process Engineering, University of Canterbury, Christchurch 8041, New Zealand
- Endometriosis New Zealand, Christchurch 8041, New Zealand
| | - Rachael Wood
- Department of Chemical and Process Engineering, University of Canterbury, Christchurch 8041, New Zealand
- The Biomolecular Interaction Centre, University of Canterbury, Christchurch 8041, New Zealand
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Deng NH, Zhou ZX, Liu HT, Tian Z, Wu ZF, Liu XY, Xiong WH, Wang Z, Jiang ZS. TRIMs: Generalists Regulating the NLRP3 Inflammasome Signaling Pathway. DNA Cell Biol 2022; 41:262-275. [PMID: 35180350 PMCID: PMC8972007 DOI: 10.1089/dna.2021.0943] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Inflammation is a double-edged sword. The moderate inflammatory response is a fundamental defense mechanism produced by the body's resistance to dangerous stimuli and a repair process of the body itself. Increasing studies have confirmed that the overactivation of the inflammasome is involved in the occurrence and development of inflammatory diseases. Strictly controlling the overactivation of the inflammasome and preventing excessive inflammatory response have always been the research focus on inflammatory diseases. However, the endogenous regulatory mechanism of inflammasome is not completely clear. The tripartite motif (TRIM) protein is one of the members of E3 ligases in the process of ubiquitination. The universality and importance of the functions of TRIM members are recognized, including the regulation of inflammatory response. This article will focus on research on the relationship between TRIMs and NLRP3 Inflammasome, which may help us make some references for future related research and the discovery of treatment methods.
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Affiliation(s)
- Nian-Hua Deng
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China
| | - Zhi-Xiang Zhou
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China
| | - Hui-Ting Liu
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China
| | - Zhen Tian
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China
| | - Ze-Fan Wu
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China
| | - Xi-Yan Liu
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China
| | - Wen-Hao Xiong
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China
| | - Zuo Wang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China
| | - Zhi-Sheng Jiang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, PR China.,Address correspondence to: Zhi-Sheng Jiang, PhD, Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, Hengyang Medical School, University of South China, Hengyang City, Hunan Province 421001, PR China
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Abomaray F, Wagner AK, Chrobok M, Ekblad-Nordberg Å, Gidlöf S, Alici E, Götherström C. The Effect of Mesenchymal Stromal Cells Derived From Endometriotic Lesions on Natural Killer Cell Function. Front Cell Dev Biol 2021; 9:612714. [PMID: 34988070 PMCID: PMC8722454 DOI: 10.3389/fcell.2021.612714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/02/2021] [Indexed: 11/24/2022] Open
Abstract
Endometriosis is an inflammatory disease that presents with ectopic endometriotic lesions. Reduced immunosurveillance of these lesions has been proposed to be playing a role in the pathology of endometriosis. Mesenchymal stromal cells (MSC) are found in ectopic lesions and may decrease immunosurveillance. In the present study, we examined if MSC contribute to reduced immunosurveillance through their immunosuppressive effects on natural killer (NK) cells. Stromal cells from endometriotic ovarian cysts (ESCcyst) and eutopic endometrium (ESCendo) of women with endometriosis and their conditioned medium were used in co-cultures with allogeneic peripheral blood NK cells. Following culture, NK cells were examined phenotypically for their expression of activating, inhibitory, maturation, and adhesion receptors and co-receptors, as well as the degranulation (CD107a) marker and the immunostimulatory (interferon-γ) and immunosuppressive (transforming growth factor beta 1 and interleukin-10) cytokines. Moreover, NK cell cytotoxicity was examined using chromium 51 release killing assays. There were no differences between ESCcyst and ESCendo regarding their effects on NK cell cytotoxicity in both conditioned medium and direct co-culture experiments. Additionally, there were no differences between ESCcyst and ESCendo regarding their impact on NK cells’ phenotype and degranulation in both conditioned medium and direct co-culture experiments. Although there were no differences found for DNAX accessory molecule-1 (DNAM-1) and NKp44, we found that the expression of the NK cell ligand CD155 that binds DNAM-1 and proliferating cell nuclear antigen (PCNA) that binds NKp44 was significantly less on ESCcyst than on ESCendo. These findings were not supported by the results that the expression of the known and unknown ligands on ESCcyst for DNAM-1 and NKp44 using chimeric proteins was not significantly different compared to ESCendo. In conclusion, the results suggest that ectopic MSC may not contribute to reduced immunosurveillance in endometriosis through their inhibitory effects on NK cells. This suggests that NK cell inhibition in the pelvic cavity of women with endometriosis develops due to other factors.
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Affiliation(s)
- Fawaz Abomaray
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- *Correspondence: Fawaz Abomaray, ,
| | - Arnika Kathleen Wagner
- Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michael Chrobok
- Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Åsa Ekblad-Nordberg
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Sebastian Gidlöf
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Obstetrics and Gynecology, Stockholm South General Hospital, Stockholm, Sweden
| | - Evren Alici
- Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Götherström
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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7
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Zhang X, Wei H. Role of Decidual Natural Killer Cells in Human Pregnancy and Related Pregnancy Complications. Front Immunol 2021; 12:728291. [PMID: 34512661 PMCID: PMC8426434 DOI: 10.3389/fimmu.2021.728291] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/09/2021] [Indexed: 12/13/2022] Open
Abstract
Pregnancy is a unique type of immunological process. Healthy pregnancy is associated with a series of inflammatory events: implantation (inflammation), gestation (anti-inflammation), and parturition (inflammation). As the most abundant leukocytes during pregnancy, natural killer (NK) cells are recruited and activated by ovarian hormones and have pivotal roles throughout pregnancy. During the first trimester, NK cells represent up to 50–70% of decidua lymphocytes. Differently from peripheral-blood NK cells, decidual natural killer (dNK) cells are poorly cytolytic, and they release cytokines/chemokines that induce trophoblast invasion, tissue remodeling, embryonic development, and placentation. NK cells can also shift to a cytotoxic identity and carry out immune defense if infected in utero by pathogens. At late gestation, premature activation of NK cells can lead to a breakdown of tolerance of the maternal–fetal interface and, subsequently, can result in preterm birth. This review is focused on the role of dNK cells in normal pregnancy and pathological pregnancy, including preeclampsia, recurrent spontaneous abortion, endometriosis, and recurrent implantation failure. dNK cells could be targets for the treatment of pregnancy complications.
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Affiliation(s)
- Xiuhong Zhang
- Department of Genetics, School of Life Science, Anhui Medical University, Hefei, China
| | - Haiming Wei
- Hefei National Laboratory for Physical Sciences at Microscale, Division of Molecular Medicine, The Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
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8
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Hang Y, Tan L, Chen Q, Liu Q, Jin Y. E3 ubiquitin ligase TRIM24 deficiency promotes NLRP3/caspase-1/IL-1β-mediated pyroptosis in endometriosis. Cell Biol Int 2021; 45:1561-1570. [PMID: 33724611 DOI: 10.1002/cbin.11592] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 02/10/2021] [Accepted: 03/14/2021] [Indexed: 12/11/2022]
Abstract
Endometriosis is an inflammation-dependent disease that shares similarities with malignant tumors including attachment and infiltration. Tripartite motif-containing 24 (TRIM24) has been illustrated in inflammatory responses and gynecological tumors, and Nod-like receptor protein 3 (NLRP3) inflammasome has been implicated in endometriosis. However, the involvement of TRIM24 and the role of NLRP3/caspase-1/interleukin-1β (IL-1β)-mediated pyroptosis in endometriosis remain obscure. In this study, we originally detected the decreased expression of TRIM24 in the ectopic endometrium of endometriosis compared with the normal endometrium. Then we measured the promoted protein expression of pyroptotic biomarkers (NLRP3, procaspase-1, caspase-1, pro-IL-1β, and IL-1β) using Western blot analysis and the stimulated secretion of IL-1β and IL-18 by enzyme-linked immunosorbent assay in ectopic human endometrial stromal cells (hESC) compared with normal hESC. TRIM24-small-interfering RNA (siTRIM24) was used to silence TRIM24, whereas TRIM24-pcDNA3.1 was used for overexpressing TRIM24. The migration of hESC was determined by a Transwell migration assay. Coimmunoprecipitation and ubiquitination analyses were conducted to explore the interaction between TRIM24 and NLRP3. Subsequently, we found that TRIM24 negatively regulated NLRP3/caspase-1/IL-1β-mediated pyroptosis and cell migration of hESC, and CY-09, the specific inhibitor of NLRP3, could reverse the promoted pyroptosis and cell migration induced by siTRIM24. Furthermore, TRIM24 interacted with NLRP3 and the upregulation of TRIM24 facilitated the ubiquitination of NLRP3 in ectopic hESC. Our findings suggest that TRIM24 may participate in the progression of endometriosis through the NLRP3/caspase-1/IL-1β-mediated pyroptotic pathway via ubiquitination of NLRP3, which reveals the significant molecular mechanism underlying endometriosis.
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Affiliation(s)
- Yuanyuan Hang
- Department of Traditional Chinese Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Tan
- Department of Gynecology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qiong Chen
- Department of Traditional Chinese Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiaoli Liu
- Department of Traditional Chinese Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuli Jin
- Department of Gynecology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Maignien C, Santulli P, Chouzenoux S, Gonzalez-Foruria I, Marcellin L, Doridot L, Jeljeli M, Grange P, Reis FM, Chapron C, Batteux F. Reduced α-2,6 sialylation regulates cell migration in endometriosis. Hum Reprod 2019; 34:479-490. [DOI: 10.1093/humrep/dey391] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 11/22/2018] [Accepted: 12/14/2018] [Indexed: 11/14/2022] Open
Affiliation(s)
- Chloé Maignien
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Département de Gynécologie Obstétrique II et Médecine de la Reproduction (Professeur Chapron), 53 Avenue de l'Observatoire, Paris, France
| | - Pietro Santulli
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Département de Gynécologie Obstétrique II et Médecine de la Reproduction (Professeur Chapron), 53 Avenue de l'Observatoire, Paris, France
| | - Sandrine Chouzenoux
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
| | - Iñaki Gonzalez-Foruria
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
- Clinical Institute of Gynecology, Obstetrics, and Neonatology, Hospital Clinic, Universitat de Barcelona, Carrer de Villarroel, 170, Barcelona, Spain
| | - Louis Marcellin
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Département de Gynécologie Obstétrique II et Médecine de la Reproduction (Professeur Chapron), 53 Avenue de l'Observatoire, Paris, France
- Département ‘Development, Reproduction and Cancer’, Institut Cochin, INSERM U1016 (Doctor Vaiman), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
| | - Ludivine Doridot
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
| | - Mohammed Jeljeli
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique–Hôpitaux de Paris (AP–HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Service d’immunologie Biologique (Professeur Batteux), 27 Rue du Faubourg Saint-Jacques, Paris, France
| | - Philippe Grange
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
| | - Fernando M Reis
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
- Department of Obstetrics and Gynecology, Faculty of Medicine, Federal University of Minas Gerais, Av. Pres. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, Brazil
| | - Charles Chapron
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Département de Gynécologie Obstétrique II et Médecine de la Reproduction (Professeur Chapron), 53 Avenue de l'Observatoire, Paris, France
- Département ‘Development, Reproduction and Cancer’, Institut Cochin, INSERM U1016 (Doctor Vaiman), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
| | - Frédéric Batteux
- Département ‘Développement, Reproduction et Cancer’, Institut Cochin, INSERM U1016 (Professeur Batteux), Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Méchain, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique–Hôpitaux de Paris (AP–HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Service d’immunologie Biologique (Professeur Batteux), 27 Rue du Faubourg Saint-Jacques, Paris, France
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Chen Y, Wei J, Zhang Y, Sun W, Li Z, Wang Q, Xu X, Li C, Li P. Anti-endometriosis Mechanism of Jiawei Foshou San Based on Network Pharmacology. Front Pharmacol 2018; 9:811. [PMID: 30093862 PMCID: PMC6071511 DOI: 10.3389/fphar.2018.00811] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 07/09/2018] [Indexed: 12/13/2022] Open
Abstract
Jiawei Foshou San (JFS) is the new formula originated from classic Foshou San formula, composed with ligustrazine, ferulic acid, and tetrahydropalmatine. Previously JFS inhibited the growth of endometriosis (EMS) with unclear mechanism, especially in metastasis, invasion, and epithelial-mesenchymal transition. In this study, network pharmacology was performed to explore potential mechanism of JFS on EMS. Through compound-compound target and compound target-EMS target networks, key targets were analyzed for pathway enrichment. MMP-TIMP were uncovered as one cluster of the core targets. Furthermore, autologous transplantation of EMS rat's model were used to evaluate in vivo effect of JFS on invasion, metastasis and epithelial-mesenchymal transition. JFS significantly suppressed the growth, and reduced the volume of ectopic endometrium, with modification of pathologic structure. In-depth study, invasion and metastasis were restrained after treating with JFS through decreasing MMP-2 and MMP-9, increasing TIMP-1. Meanwhile, JFS promoted E-cadherin, and attenuated N-cadherin, Vimentin, Snail, Slug, ZEB1, ZEB2, Twist. In brief, anti-EMS effect of JFS might be related to the regulation of epithelial-mesenchymal transformation, thereby inhibition of invasion and metastasis. These findings reveal the potential mechanism of JFS on EMS and the benefit for further evaluation.
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Affiliation(s)
- Yi Chen
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Jiahui Wei
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Ying Zhang
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Wenwei Sun
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Zhuoheng Li
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Qin Wang
- Department of Traditional Chinese Medicine and Pharmacy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Xiaoyu Xu
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Cong Li
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Panhong Li
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
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11
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Cho YJ, Lee SH, Park JW, Han M, Park MJ, Han SJ. Dysfunctional signaling underlying endometriosis: current state of knowledge. J Mol Endocrinol 2018; 60:R97-R113. [PMID: 29330150 DOI: 10.1530/jme-17-0227] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 01/11/2018] [Indexed: 12/18/2022]
Abstract
Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. It affects approximately 5-10% of women of reproductive age. Endometriosis is associated with dysmenorrhea, dyspareunia and, often, severe pelvic pain. In addition to pain, women with endometriosis often experience infertility. Defining the molecular etiology of endometriosis is a significant challenge for improving the quality of women's lives. Unfortunately, the pathophysiology of endometriosis is not well understood. Here, we summarize the potential causative factors of endometriosis in the following three categories: (1) dysregulation of immune cells in the peritoneal fluid and endometriotic lesions; (2) alteration of apoptotic signaling in retrograde menstrual tissue and cytotoxic T cells involved in endometriosis progression and (3) dysregulation of oxidative stress. Determining the molecular etiology of these dysregulated cellular signaling pathways should provide crucial clues for understanding initiation and progression of endometriosis. Moreover, improved understanding should suggest new molecular therapeutic targets that could improve the specificity of endometriosis treatments and reduce the side effects associated with current approaches.
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Affiliation(s)
- Yeon Jean Cho
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Seung Hyun Lee
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
| | - Jung Woo Park
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
| | - Myoungseok Han
- Department of Obstetrics and Gynecology, Dong-A University, College of Medicine, Busan, Republic of Korea
| | - Mi Jin Park
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Sang Jun Han
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA
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12
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Yang HL, Zhou WJ, Chang KK, Mei J, Huang LQ, Wang MY, Meng Y, Ha SY, Li DJ, Li MQ. The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β. Reproduction 2017; 154:815-825. [PMID: 28971893 DOI: 10.1530/rep-17-0342] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 08/31/2017] [Accepted: 09/29/2017] [Indexed: 02/04/2023]
Abstract
The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity. The reciprocal communications between endometrial stromal cells (ESCs) and lymphocytes facilitate the development of EMS. However, the mechanism of these communications on cytotoxicity of natural killer (NK) cells in endometriotic milieus is still largely unknown. To imitate the local immune microenvironment, the co-culture systems of ESCs from patients with EMS and monocyte-derived macrophages or of ESCs, macrophages and NK cells were constructed. The cytokine levels in the co-culture unit were evaluated by ELISA. The expression of functional molecules in NK cells was detected by flow cytometry (FCM). The NK cell behaviors in vitro were analyzed by cell counting kit-8 and cytotoxic activation assays. After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1β, IL-10 and transforming growth factor (TGF)-β in the co-culture system of ESCs and macrophages was increased. Exposure with anti-IL-10 receptor β neutralizing antibody (αhIL-10Rβ) or αTGF-β could partly reverse these effects of ESCs and macrophages on NK cells in vitro These results suggest that the interaction between macrophages and ESCs downregulates cytotoxicity of NK cells possibly by stimulating the secretion of IL-10 and TGF-β, and may further trigger the immune escape of ectopic fragments and promote the occurrence and the development of EMS.
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Affiliation(s)
- Hui-Li Yang
- Laboratory for Reproductive ImmunologyHospital of Obstetrics and Gynecology, Fudan University, Shanghai, People's Republic of China.,Key Laboratory of Reproduction Regulation of NPFPCSIPPR, IRD, Fudan University, Shanghai, People's Republic of China
| | - Wen-Jie Zhou
- Laboratory for Reproductive ImmunologyHospital of Obstetrics and Gynecology, Fudan University, Shanghai, People's Republic of China.,Key Laboratory of Reproduction Regulation of NPFPCSIPPR, IRD, Fudan University, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai, People's Republic of China
| | - Kai-Kai Chang
- Laboratory for Reproductive ImmunologyHospital of Obstetrics and Gynecology, Fudan University, Shanghai, People's Republic of China
| | - Jie Mei
- Reproductive Medicine CenterDepartment of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medicine School, Nanjing, People's Republic of China
| | - Li-Qing Huang
- Department of Statistics and PsychologyCollege of Letters and Science, University of California Davis, Davis, California, USA
| | - Ming-Yan Wang
- Laboratory for Reproductive ImmunologyHospital of Obstetrics and Gynecology, Fudan University, Shanghai, People's Republic of China
| | - Yi Meng
- Laboratory for Reproductive ImmunologyHospital of Obstetrics and Gynecology, Fudan University, Shanghai, People's Republic of China
| | - Si-Yao Ha
- Laboratory for Reproductive ImmunologyHospital of Obstetrics and Gynecology, Fudan University, Shanghai, People's Republic of China
| | - Da-Jin Li
- Laboratory for Reproductive ImmunologyHospital of Obstetrics and Gynecology, Fudan University, Shanghai, People's Republic of China.,Key Laboratory of Reproduction Regulation of NPFPCSIPPR, IRD, Fudan University, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai, People's Republic of China
| | - Ming-Qing Li
- Laboratory for Reproductive ImmunologyHospital of Obstetrics and Gynecology, Fudan University, Shanghai, People's Republic of China .,Key Laboratory of Reproduction Regulation of NPFPCSIPPR, IRD, Fudan University, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghai, People's Republic of China
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13
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Kacan T, Yildiz C, Baloglu Kacan S, Seker M, Ozer H, Cetin A. Everolimus as an mTOR Inhibitor Suppresses Endometriotic Implants: an Experimental Rat Study. Geburtshilfe Frauenheilkd 2017; 77:66-72. [PMID: 28190891 DOI: 10.1055/s-0042-115566] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Introduction Mammalian target of rapamycin is a pathway to block apoptosis. Recent studies showed that the activity of mammalian target of rapamycin pathway increases in endometriotic lesions. Aim of the present study was to study the effect of everolimus agent, a rapamycin analog, in an experimental endometriosis model. Materials and Methods Endometriosis established by the autotransplantation of uterine tissue in the peritoneal cavity was confirmed in 24 rats. The animals were then randomly divided into three groups to receive either everolimus (1.5 mg/kg/day, p. o.), anastrozole (0.004 mg/day, p. o.), or normal saline (0.1 mL, i. p.) for 14 days. Endometriotic foci were excised, stained with hematoxylin and eosin, and endometriosis was scored semiquantitatively. In addition, immunohistochemical examination were performed using primary antibodies of vascular endothelial growth factor, CD117, and Bax. Results Both anastrozole and everolimus lowered endometriosis scores. Significant decreases in ovarian follicles were observed following anastrozole treatment but not everolimus treatment. Conclusion Through its apoptosis-promoting effect, everolimus suppressed endometriotic foci without negatively affecting ovarian reserve. These findings support the hypothesis that everolimus merits further study on the way to developing a new endometriosis drug.
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Affiliation(s)
- T Kacan
- Department of Medical Oncology, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - C Yildiz
- Department of Obstetrics and Gynecology, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - S Baloglu Kacan
- Department of Internal Medicine, Sivas Numune Hospital, Sivas, Turkey
| | - M Seker
- Department of Medical Oncology, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - H Ozer
- Department of Pathology, Cumhuriyet University School of Medicine, Sivas, Turkey
| | - A Cetin
- Department of Obstetrics and Gynecology, Cumhuriyet University School of Medicine, Sivas, Turkey
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