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Vastrad B, Vastrad C. Screening and identification of key biomarkers associated with endometriosis using bioinformatics and next-generation sequencing data analysis. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2024; 25:116. [DOI: 10.1186/s43042-024-00572-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 08/23/2024] [Indexed: 01/04/2025] Open
Abstract
Abstract
Background
Endometriosis is a common cause of endometrial-type mucosa outside the uterine cavity with symptoms such as painful periods, chronic pelvic pain, pain with intercourse and infertility. However, the early diagnosis of endometriosis is still restricted. The purpose of this investigation is to identify and validate the key biomarkers of endometriosis.
Methods
Next-generation sequencing dataset GSE243039 was obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) between endometriosis and normal control samples were identified. After screening of DEGs, gene ontology (GO) and REACTOME pathway enrichment analyses were performed. Furthermore, a protein–protein interaction (PPI) network was constructed and modules were analyzed using the Human Integrated Protein–Protein Interaction rEference database and Cytoscape software, and hub genes were identified. Subsequently, a network between miRNAs and hub genes, and network between TFs and hub genes were constructed using the miRNet and NetworkAnalyst tool, and possible key miRNAs and TFs were predicted. Finally, receiver operating characteristic curve analysis was used to validate the hub genes.
Results
A total of 958 DEGs, including 479 upregulated genes and 479 downregulated genes, were screened between endometriosis and normal control samples. GO and REACTOME pathway enrichment analyses of the 958 DEGs showed that they were mainly involved in multicellular organismal process, developmental process, signaling by GPCR and muscle contraction. Further analysis of the PPI network and modules identified 10 hub genes, including vcam1, snca, prkcb, adrb2, foxq1, mdfi, actbl2, prkd1, dapk1 and actc1. Possible target miRNAs, including hsa-mir-3143 and hsa-mir-2110, and target TFs, including tcf3 (transcription factor 3) and clock (clock circadian regulator), were predicted by constructing a miRNA-hub gene regulatory network and TF-hub gene regulatory network.
Conclusions
This investigation used bioinformatics techniques to explore the potential and novel biomarkers. These biomarkers might provide new ideas and methods for the early diagnosis, treatment and monitoring of endometriosis.
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Xu X, Wang Z, Lv L, Liu C, Wang L, Sun YN, Zhao Z, Shi B, Li Q, Hao GM. Molecular regulation of DNA damage and repair in female infertility: a systematic review. Reprod Biol Endocrinol 2024; 22:103. [PMID: 39143547 PMCID: PMC11323701 DOI: 10.1186/s12958-024-01273-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 07/31/2024] [Indexed: 08/16/2024] Open
Abstract
DNA damage is a key factor affecting gametogenesis and embryo development. The integrity and stability of DNA are fundamental to a woman's successful conception, embryonic development, pregnancy and the production of healthy offspring. Aging, reactive oxygen species, radiation therapy, and chemotherapy often induce oocyte DNA damage, diminished ovarian reserve, and infertility in women. With the increase of infertility population, there is an increasing need to study the relationship between infertility related diseases and DNA damage and repair. Researchers have tried various methods to reduce DNA damage in oocytes and enhance their DNA repair capabilities in an attempt to protect oocytes. In this review, we summarize recent advances in the DNA damage response mechanisms in infertility diseases such as PCOS, endometriosis, diminished ovarian reserve and hydrosalpinx, which has important implications for fertility preservation.
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Affiliation(s)
- Xiuhua Xu
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
- Cardiovascular platform, Institute of Health and Disease, Hebei Medical University, Shijiazhuang, 050000, China
| | - Ziwei Wang
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Luyi Lv
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Ci Liu
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Lili Wang
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Ya-Nan Sun
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Zhiming Zhao
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Baojun Shi
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Qian Li
- Cardiovascular platform, Institute of Health and Disease, Hebei Medical University, Shijiazhuang, 050000, China.
| | - Gui-Min Hao
- Hebei Key Laboratory of Infertility and Genetics, Hebei Clinical Research Center for Birth Defects, Hebei Medical Key discipline of Reproductive Medicine, Hebei Collaborative Innovation Center of Integrated Traditional and Western Medicine on Reproductive Disease, Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
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Pant A, Moar K, K Arora T, Maurya PK. Biomarkers of endometriosis. Clin Chim Acta 2023; 549:117563. [PMID: 37739024 DOI: 10.1016/j.cca.2023.117563] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/18/2023] [Accepted: 09/19/2023] [Indexed: 09/24/2023]
Abstract
Endometriosis is one of the most severe female reproductive disorders, affecting 6-10% of women between 18 and 35. It is a gynaecological condition where endometrial tissue develops and settles outside the uterus. The aetiology of endometriosis is primarily influenced by genetic, epigenetic, and non-genetic variables, making it highly challenging to create a therapeutic therapy explicitly targeting the ectopic tissue. The delay in the treatment is due to the limitations in the diagnostic approaches, which are restricted to invasive techniques such as laparoscopy or laparotomy. This accords to 70% of the women being diagnosed at later stages. By understanding the subject, several treatment medications have been produced to lessen the disease's symptoms. Nevertheless, endometriosis cannot be permanently cured. A viable or persuasive standard screening test for endometriosis must be utilized in a clinical context. A helpful assessment method for the early identification of endometriosis could be biomarkers. A major research priority is the identification of a biomarker that is sensitive and specific enough for detecting endometriosis. The present article has reviewed studies published on the expression of biomarkers of endometriosis. It outlines various biomarkers from different sample types, such as serum/plasma and urine, in addition to tissue. This would provide a non-invasive approach to diagnosing the disease at the initial stages without any harmful repercussions. Future high-throughput advances in science and technology are anticipated to result in the creation of a potent remedy for endometriosis. To achieve successful outcomes, it is necessary to research the discussed biomarkers that demonstrate substantial results extensively.
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Affiliation(s)
- Anuja Pant
- Department of Biochemistry, Central University of Haryana, Mahendergarh 123031, India
| | - Kareena Moar
- Department of Biochemistry, Central University of Haryana, Mahendergarh 123031, India
| | - Taruna K Arora
- Reproductive Biology and Maternal Child Health Division, Indian Council of Medical Research, New Delhi 110029, India
| | - Pawan Kumar Maurya
- Department of Biochemistry, Central University of Haryana, Mahendergarh 123031, India.
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Lazim N, Elias MH, Sutaji Z, Abdul Karim AK, Abu MA, Ugusman A, Syafruddin SE, Mokhtar MH, Ahmad MF. Expression of HOXA10 Gene in Women with Endometriosis: A Systematic Review. Int J Mol Sci 2023; 24:12869. [PMID: 37629050 PMCID: PMC10454210 DOI: 10.3390/ijms241612869] [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: 07/12/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
The homeobox A10 (HOXA10) gene is known to be related to endometriosis; however, due to a lack of knowledge/evidence in the pathogenesis of endometriosis, the mechanisms that link HOXA10 to endometriosis still need to be clarified. This review addresses the difference in the expression of the HOXA10 gene in endometriotic women versus non-endometriotic women across populations by country and discusses its influences on women's fertility. An organized search of electronic databases was conducted in Scopus, ScienceDirect, PubMed, and Web of Science. The keywords used were (HOXA10 OR "homeobox A10" OR PL OR HOX1 OR HOX1H OR HOX1.8) AND ("gene expression") AND (endometriosis). The initial search resulted in 623 articles, 10 of which were included in this review. All ten papers included in this study were rated fair in terms of the quality of the studies conducted. The expression of the HOXA10 gene was found to be downregulated in most studies. However, one study provided evidence of the downregulation and upregulation of HOXA10 gene expression due to the localization of endometriotic lesions. Measuring the expression of the HOXA10 gene in women is clinically essential to predicting endometriosis, endometrial receptivity, and the development of pinopodes in the endometrium during the luteal phase.
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Affiliation(s)
- Nurunnajah Lazim
- Advanced Reproductive Centre (ARC) HCTM UKM, Department of Obstetrics & Gynecology, Faculty of Medicine, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; (N.L.); (M.H.E.); (Z.S.); (M.A.A.); (A.K.A.K.)
| | - Marjanu Hikmah Elias
- Advanced Reproductive Centre (ARC) HCTM UKM, Department of Obstetrics & Gynecology, Faculty of Medicine, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; (N.L.); (M.H.E.); (Z.S.); (M.A.A.); (A.K.A.K.)
- Faculty of Medicine & Health Sciences, Universiti Sains Islam Malaysia, Nilai 71800, Negeri Sembilan, Malaysia
| | - Zulazmi Sutaji
- Advanced Reproductive Centre (ARC) HCTM UKM, Department of Obstetrics & Gynecology, Faculty of Medicine, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; (N.L.); (M.H.E.); (Z.S.); (M.A.A.); (A.K.A.K.)
- Faculty of Medicine & Health Sciences, Universiti Sains Islam Malaysia, Nilai 71800, Negeri Sembilan, Malaysia
| | - Abdul Kadir Abdul Karim
- Advanced Reproductive Centre (ARC) HCTM UKM, Department of Obstetrics & Gynecology, Faculty of Medicine, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; (N.L.); (M.H.E.); (Z.S.); (M.A.A.); (A.K.A.K.)
| | - Mohammad Azrai Abu
- Advanced Reproductive Centre (ARC) HCTM UKM, Department of Obstetrics & Gynecology, Faculty of Medicine, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; (N.L.); (M.H.E.); (Z.S.); (M.A.A.); (A.K.A.K.)
| | - Azizah Ugusman
- Department of Physiology, Faculty of Medicine, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; (A.U.); (M.H.M.)
| | - Saiful Effendi Syafruddin
- Medical Molecular Biology Institute, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia;
| | - Mohd Helmy Mokhtar
- Department of Physiology, Faculty of Medicine, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; (A.U.); (M.H.M.)
| | - Mohd Faizal Ahmad
- Advanced Reproductive Centre (ARC) HCTM UKM, Department of Obstetrics & Gynecology, Faculty of Medicine, National University of Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Kuala Lumpur 56000, Malaysia; (N.L.); (M.H.E.); (Z.S.); (M.A.A.); (A.K.A.K.)
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Abramiuk M, Frankowska K, Kułak K, Tarkowski R, Mertowska P, Mertowski S, Grywalska E. Possible Correlation between Urocortin 1 (Ucn1) and Immune Parameters in Patients with Endometriosis. Int J Mol Sci 2023; 24:ijms24097787. [PMID: 37175494 PMCID: PMC10178394 DOI: 10.3390/ijms24097787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
The etiology of endometriosis (EMS) has not been clearly elucidated yet, and that is probably the reason why its diagnostic process is frequently long-lasting and inefficient. Nowadays, the non-invasive diagnostic methods of EMS are still being sought. Our study aimed to assess the serum and peritoneal fluid levels of urocortin 1 (Ucn1) in patients with EMS and healthy women. Moreover, considering the immune background of the disease, the association between Ucn1 and several immune parameters was studied in both groups. We found that the serum Ucn1 level was significantly upregulated in women with EMS compared to healthy patients. Moreover, higher serum Ucn1 levels tended to correspond with more advanced stages of the disease (p = 0.031). Receiver operating characteristic (ROC) analysis revealed that based on serum Ucn1 levels, it is possible to distinguish deep infiltrating endometriosis (DIE) from among other EMS types. Together, these results indicate Ucn1 as a possible promising biomarker of EMS: however, not in isolation, but rather to enhance the effectiveness of other diagnostic methods.
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Affiliation(s)
- Monika Abramiuk
- Independent Laboratory of Minimally Invasive Gynecology and Gynecological Endocrinology, Department of Oncological Gynaecology and Gynaecology, Medical University of Lublin, Staszica 16 St., 20-081 Lublin, Poland
| | - Karolina Frankowska
- 1st Chair and Department of Oncological Gynaecology and Gynaecology, Student Scientific Association, Medical University of Lublin, Staszica 16 St., 20-081 Lublin, Poland
| | - Krzysztof Kułak
- 1st Chair and Department of Oncological Gynaecology and Gynaecology, Medical University of Lublin, Staszica 16 St., 20-081 Lublin, Poland
| | - Rafał Tarkowski
- 1st Chair and Department of Oncological Gynaecology and Gynaecology, Medical University of Lublin, Staszica 16 St., 20-081 Lublin, Poland
| | - Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland
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Alghamdi NJ, Burns CT, Valdes R. The urocortin peptides: biological relevance and laboratory aspects of UCN3 and its receptor. Crit Rev Clin Lab Sci 2022; 59:573-585. [PMID: 35738909 DOI: 10.1080/10408363.2022.2080175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The urocortins are polypeptides belonging to the corticotropin-releasing hormone family, known to modulate stress responses in mammals. Stress, whether induced physically or psychologically, is an underlying cause or consequence of numerous clinical syndromes. Identifying biological markers associated with the homeostatic regulation of stress could provide a clinical laboratory approach for the management of stress-related disorders. The neuropeptide, urocortin 3 (UCN3), and the corticotropin-releasing hormone receptor 2 (CRHR2) constitute a regulatory axis known to mediate stress homeostasis. Dysregulation of this peptide/receptor axis is believed to play a role in several clinical conditions including post-traumatic stress, sleep apnea, cardiovascular disease, and other health problems related to stress. Understanding the physiology and measurement of the UCN3/CRHR2 axis is important for establishing a viable clinical laboratory diagnostic. In this article, we focus on evidence supporting the role of UCN3 and its receptor in stress-related clinical syndromes. We also provide insight into the measurements of UCN3 in blood and urine. These potential biomarkers provide new opportunities for clinical research and applications of laboratory medicine diagnostics in stress management.
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Affiliation(s)
- Norah J Alghamdi
- Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | | | - Roland Valdes
- Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY, USA
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Vannuccini S, Clemenza S, Rossi M, Petraglia F. Hormonal treatments for endometriosis: The endocrine background. Rev Endocr Metab Disord 2022; 23:333-355. [PMID: 34405378 PMCID: PMC9156507 DOI: 10.1007/s11154-021-09666-w] [Citation(s) in RCA: 122] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/15/2021] [Indexed: 12/25/2022]
Abstract
Endometriosis is a benign uterine disorder characterized by menstrual pain and infertility, deeply affecting women's health. It is a chronic disease and requires a long term management. Hormonal drugs are currently the most used for the medical treatment and are based on the endocrine pathogenetic aspects. Estrogen-dependency and progesterone-resistance are the key events which cause the ectopic implantation of endometrial cells, decreasing apoptosis and increasing oxidative stress, inflammation and neuroangiogenesis. Endometriotic cells express AMH, TGF-related growth factors (inhibin, activin, follistatin) CRH and stress related peptides. Endocrine and inflammatory changes explain pain and infertility, and the systemic comorbidities described in these patients, such as autoimmune (thyroiditis, arthritis, allergies), inflammatory (gastrointestinal/urinary diseases) and mental health disorders.The hormonal treatment of endometriosis aims to block of menstruation through an inhibition of hypothalamus-pituitary-ovary axis or by causing a pseudodecidualization with consequent amenorrhea, impairing the progression of endometriotic implants. GnRH agonists and antagonists are effective on endometriosis by acting on pituitary-ovarian function. Progestins are mostly used for long term treatments (dienogest, NETA, MPA) and act on multiple sites of action. Combined oral contraceptives are also used for reducing endometriosis symptoms by inhibiting ovarian function. Clinical trials are currently going on selective progesterone receptor modulators, selective estrogen receptor modulators and aromatase inhibitors. Nowadays, all these hormonal drugs are considered the first-line treatment for women with endometriosis to improve their symptoms, to postpone surgery or to prevent post-surgical disease recurrence. This review aims to provide a comprehensive state-of-the-art on the current and future hormonal treatments for endometriosis, exploring the endocrine background of the disease.
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Affiliation(s)
- Silvia Vannuccini
- Obstetrics and Gynecology, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Careggi University Hospital, Florence, Italy
| | - Sara Clemenza
- Obstetrics and Gynecology, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Careggi University Hospital, Florence, Italy
| | - Margherita Rossi
- Obstetrics and Gynecology, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Careggi University Hospital, Florence, Italy
| | - Felice Petraglia
- Obstetrics and Gynecology, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Careggi University Hospital, Florence, Italy.
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The Role of Selected Chemokines in the Peritoneal Fluid of Women with Endometriosis—Participation in the Pathogenesis of the Disease. Processes (Basel) 2021. [DOI: 10.3390/pr9122229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Endometriosis is a disorder characterized by the presence of endometrial tissue outside the uterine cavity, primarily into the peritoneal cavity. It is known as a complex, chronic inflammatory disease and it is strongly associated with immune dysregulation. Various soluble mediators of the immune and inflammatory responses, including chemokines, play an important role in these processes. The aim of the study was to understand the role of the chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-1 α, MIP-1β, eotaxin 2, eotaxin 3, ENA-78, and fractalkine in the development of endometriosis through their assessment in the peritoneal fluid of women with endometriosis. The study group included 58 women with endometriosis who were diagnosed during laparoscopy and then confirmed by histopathology. In 15 women from the reference group, laparoscopic examination demonstrated a normal status of the pelvic organs without any evidence of endometriosis nor inflammation in the peritoneal cavity. The peritoneal fluid of women with endometriosis and of women from the reference group were examined. To determine the concentration of the studied chemokines, enzyme immunoassays for Luminex® platforms were used. In the peritoneal fluid of women with endometriosis, a statistically significant increase in the concentration of MIP-1β, eotaxin 2, eotaxin 3, ENA-78, and fractalkine and a decrease in the concentration of MCP-1, MCP-2, MCP-3, MCP-4, and MIP-1α were observed compared to the reference group. The concentration of these cytokines depended on the severity of the disease. Changes in the concentration of the studied chemokines in the peritoneal fluid of women with endometriosis suggest their participation in the pathogenesis of the disease. The differences in chemokines concentration observed in different stages of endometriosis may be associated with the presence of inflammation in the peritoneal cavity at each step of disease development.
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Jain M, Samokhodskaya L, Mladova E, Panina O. Mucosal biomarkers for endometrial receptivity: A promising yet underexplored aspect of reproductive medicine. Syst Biol Reprod Med 2021; 68:13-24. [PMID: 34632899 DOI: 10.1080/19396368.2021.1985186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Annually, approximately 2 million assisted reproductive technology (ART) procedures are performed worldwide, of which, only ~25% lead to successful delivery. There are two major factors contributing to successful implantation: embryo quality and endometrial receptivity (ER). Although embryo quality might be assessed through morphological and genetic testing, no clinically approved techniques are available to evaluate ER. Mucus in different parts of the female reproductive tract contains many cytokines, chemokines, growth factors, and nucleic acids, which influence and reflect various implantation-related processes. Therefore, the aim of the present review was to summarize available data regarding noninvasively obtained mucosal biomarkers for ER and to investigate their ability to predict the outcome of ART procedures. A broad literature search was performed to define studies related to noninvasive ER assessments. More than 50 biomarkers detectable in endometrial fluid, embryo transfer cannula leftover cells and mucus, menstrual blood, cervicovaginal washings are discussed herein. The remarkable methodological heterogeneity of the reviewed studies complicates the comparison of their results. Nevertheless, certain promising analytical targets may already be identified, such as urocortin, activin A, IL-1β, TNF-α, IP-10, MCP-1, and several oxidative stress biomarkers. The present review contains a collection of currently available mucosal biomarker-related data, which may provide insights for future studies.Abbreviations: ART: assisted reproductive technology; ER: endometrial receptivity; IVF: in vitro fertilization; ICSI: intracytoplasmic sperm injection; IUI: intrauterine insemination; MeSH: Medical Subject Headings; hDP 200: human decidua-associated protein 200; ET: embryo transfer; IL-18: Interleukin-18; LRG: leucine-rich α2-glycoprotein; ROC: receiver operating characteristic; AUC: area under the ROC-curve; LH: luteinizing hormone; LIF: leukemia inhibitory factor; TNF-α: tumor necrosis factor alpha; IFN-γ: interferon γ; MCP-1: monocyte chemoattractant protein-1; VEGF: vascular endothelial growth factor; SOD: superoxide dismutase; CAT: catalase; LPO: lipid peroxidation; TTG: total thiol groups; TAP: total antioxidant power; CE: chronic endometritis.
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Affiliation(s)
- Mark Jain
- Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia.,Department of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Larisa Samokhodskaya
- Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia.,Department of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
| | | | - Olga Panina
- Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia.,Department of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
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Qi X, Zhang W, Ge M, Sun Q, Peng L, Cheng W, Li X. Relationship Between Dairy Products Intake and Risk of Endometriosis: A Systematic Review and Dose-Response Meta-Analysis. Front Nutr 2021; 8:701860. [PMID: 34368211 PMCID: PMC8339299 DOI: 10.3389/fnut.2021.701860] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
Objective: Diet lifestyle can influence the risk of endometriosis. Therefore, we conducted a systematic meta-analysis to investigate the association between dairy products and the risk of endometriosis. Besides, we performed a dose-response meta-analysis to evaluate the amount of dairy intake affecting the risk of endometriosis. Methods: Relevant studies were searched from Pubmed, Embase databases, Cochrane Library, and Web of Science from the inception to November 6th, 2020. Also, the dose-response meta-analysis was conducted. All the pooled results were performed by risk ratios (RRs). Results: Finally, seven high-quality studies were included in the present meta-analysis. Total dairy intake was inversely associated with the risk of endometriosis, and the risk of endometriosis tended to decrease with a decrease in the risk of endometriosis when dairy products intake was over 21 servings/week (RR 0.87, 95% CI 0.76–1.00; pnon−linearity = 0.04). Similarly, people who consumed more than 18 servings of high-fat dairy products per week had a reduced risk of endometriosis (RR 0.86, 95% CI 0.76–0.96). When stratified-analyses were conducted based on specific dairy product categories, it indicated that people with high cheese intake might have a reduced risk of endometriosis (RR 0.86, 95% CI 0.74–1.00). Other specific dairy products such as whole milk (RR 0.90, 95% CI 0.72–1.12), reduced-fat/skim milk (RR 0.83, 95% CI 0.50–1.73), ice cream (RR 0.83, 95% CI 0.50–1.73), and yogurt (RR 0.83, 95% CI 0.62–1.11) have not shown significant evidence of an association with the risk of endometriosis. However, there is a higher risk of endometriosis in the females with high butter intake compared to females with low butter intake (1.27, 95% CI 1.03–1.55). Conclusions: Overall, dairy products intake was associated with a reduction in endometriosis, with significant effects when the average daily intake ≥3 servings. When analyzed according to the specific type of dairy product, it was shown that females with higher high-fat dairy and cheese intake might have a reduced risk of endometriosis. However, high butter intake might be associated to the increased risk of endometriosis. More future studies are needed to validate and add to this finding.
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Affiliation(s)
- Xiangying Qi
- Department of Obstetrics and Gynecology, Affiliated Hospital of Jining Medical University, Zaozhuang Municipal Hospital, Zaozhuang, China
| | - Wenyan Zhang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Jining Medical University, Zaozhuang Municipal Hospital, Zaozhuang, China
| | - Mingxiu Ge
- Department of Obstetrics and Gynecology, Affiliated Hospital of Jining Medical University, Zaozhuang Municipal Hospital, Zaozhuang, China
| | - Qiang Sun
- Department of Obstetrics and Gynecology, Affiliated Hospital of Jining Medical University, Zaozhuang Municipal Hospital, Zaozhuang, China
| | - Lei Peng
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Shandong University, Jinan, China
| | - Wenke Cheng
- Department of Cardiology, Heart Center Leipzig at University Leipzig, Leipzig, Germany
| | - Xuepeng Li
- Department of Gynecology, Affiliated Hospital of Jining Medical University, Zaozhuang Municipal Hospital, Zaozhuang, China
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11
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Abstract
A clinically reliable non-invasive test for endometriosis is expected to reduce the diagnostic delay. Although varieties of biomarkers have been investigated for decades, and cancer antigen-125, cancer antigen-199, interleukin-6, and urocortin were the most studied ones among hundreds of biomarkers, no clinically reliable biomarkers have been confirmed so far. Some emerging technologies including “omics” technologies, molecular imaging techniques, and microRNAs are promising in solving these challenges, but their utility to detect endometriosis has yet to be verified. New combinations of researched indicators or other non-invasive methods and further exploration of the emerging technologies may be new targets and future research hotspots for non-invasive diagnosis of endometriosis. In conclusion, researches of biomarkers for the detection of endometriosis are still ongoing and may benefit from novel molecular biology, bioinformatics methods and a combination of more diverse monitoring methods. Though it will be a daunting task, the identification of a specific set of diagnostic biomarkers will undoubtedly improve the status of endometriosis.
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12
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Endometriosis: New Perspective for the Diagnosis of Certain Cytokines in Women and Adolescent Girls, as Well as the Progression of Disease Outgrowth: A Systematic Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18094726. [PMID: 33946650 PMCID: PMC8125151 DOI: 10.3390/ijerph18094726] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/19/2021] [Accepted: 04/21/2021] [Indexed: 12/11/2022]
Abstract
Endometriosis is a common chronic gynecological disorder that undoubtedly impacts on quality of life, and is one of the more complex and mysterious illnesses of our century, which is associated with the improper growth of endometrial tissue outside of the uterine cavity. This pathologically implanted tissue can be found most frequently in the minor pelvis, but also in the peritoneal cavity, and can affect many organs, leading to chronic pelvic pain syndrome, infertility, and dysmenorrhea. Endometrial tissue is a particularly dynamic tissue that has a direct impact on the progression of the disease, with altered immunity, as well as cytokine storms within the metaplastic endometriotic site, as possible key factors. Currently, diagnosis of this mysterious chronic illness relies on performing a laparoscopic procedure with tissue sampling. One of the most troublesome outcomes of this unintended progression is that we lack any specific, sensitive, non-invasive diagnostic tools. Currently, the vast majority of regime stewardship options rely on anti-contraceptive drugs, or other remedies that suppress the release of estrogen through the gonads-although in most clinical trials, endometriosis is a chronic progressive disorder that depends mostly on the high concentration of estrogen. Moreover, many specific trials have demonstrated that the eutopic endometrial cells in individuals with endometriosis remain much more resistant to the immunological annihilation process caused by certain elements of the immune system. Nevertheless, eutopic endometrial cells have the potential to similarly escalate the expression of aromatase receptors on the surface of the pathological cells, which in the final cascade cause an increase in the concentration of estrogen, as well as other inflammatory proteins that contribute to pathological outgrowth. Data reveal occurrence among first-degree relatives, suggesting that the specific cascade could be related to inherited as well as epigenetic (acquired) mechanisms. In women with the disease, confirmed by laparoscopic procedures, diagnosis of endometriosis can be established also via detection by gene polymorphism in the genes which are responsible for responsible for the detoxification phase of estrogen receptors and other immunomodulator components. A recent publication aims to reveal a new prospect for the non-invasive diagnosis, detection, and estimation of certain biomarkers for much more specific investigation of the disease's progression.
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13
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Sun ZY, Yu TY, Jiang FX, Wang W. Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes. World J Stem Cells 2021; 13:193-207. [PMID: 33815669 PMCID: PMC8006013 DOI: 10.4252/wjsc.v13.i3.193] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/19/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.
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Affiliation(s)
- Zi-Yi Sun
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Ting-Yan Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Fang-Xu Jiang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Wei Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China.
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14
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Appleyard CB, Flores I, Torres-Reverón A. The Link Between Stress and Endometriosis: from Animal Models to the Clinical Scenario. Reprod Sci 2020; 27:1675-1686. [PMID: 32542543 DOI: 10.1007/s43032-020-00205-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 04/08/2020] [Indexed: 12/18/2022]
Abstract
There is strong evidence from humans and animal models showing that abnormal functioning of the hypothalamic-pituitary-adrenal (HPA) axis and/or the inflammatory response system disrupts feedback regulation of both neuroendocrine and immune systems, contributing to disease. Stress is known to affect the physiology of pelvic organs and to disturb the HPA axis leading to chronic, painful, inflammatory disorders. A link between stress and disease has already been documented for many chronic conditions. Endometriosis is a complex chronic gynecological disease associated with severe pelvic pain and infertility that affects 10% of reproductive-aged women. Patients report the negative impact of endometriosis symptoms on quality of life, work/study productivity, and personal relationships, which in turn cause high levels of psychological and emotional distress. The relationship between stress and endometriosis is not clear. Still, we have recently demonstrated that stress increases the size and severity of the lesions as well as inflammatory parameters in an animal model. Furthermore, the "controllability" of stress influences the pathophysiology in this model, offering the possibility of using stress management techniques in patients. The crosstalk between stress-inflammation-pain through HPA axis activity indicates that stress relief should alleviate inflammation and, in turn, decrease painful responses. This opens up the opportunity of altering brain-body-brain pathways as potential new therapeutic option for endometriosis. The goal of this review is to gather the research evidence regarding the interaction between stress (psychological and physiological) and the development and progression of endometriosis on the exacerbation of its symptoms with the purpose of proposing new lines of emerging research and possible treatment modalities for this still incurable disease.
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Affiliation(s)
- Caroline B Appleyard
- Department of Basic Sciences, Women's Health Division, Ponce Research Institute, Ponce Health Sciences University, Ponce, PR, USA. .,Department of Internal Medicine, Ponce Health Sciences University, Ponce, PR, USA. .,Department of Basic Sciences, Physiology Division, Medical School and Ponce Research Institute, Ponce Health Sciences University, 395 Zona Ind Reparada 2, Ponce, PR, 00716-2347, USA.
| | - Idhaliz Flores
- Department of Basic Sciences, Women's Health Division, Ponce Research Institute, Ponce Health Sciences University, Ponce, PR, USA.,Department of Obstetrics and Gynecology, Ponce Health Sciences University, Ponce, PR, USA
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15
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Zhang X, Liu Y, Qi J, Tian Z, Tang N, Chen D, Li Z. Progress in understanding the roles of Urocortin3 (UCN3) in the control of appetite from studies using animal models. Peptides 2019; 121:170124. [PMID: 31415798 DOI: 10.1016/j.peptides.2019.170124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 07/19/2019] [Accepted: 08/05/2019] [Indexed: 11/19/2022]
Abstract
Urocortin3 (UCN3), the newest member of corticotrophin releasing hormone (CRH) family polypeptides, is an anorexic factor discovered in 2001, which has a strong inhibitory effect on animal appetite regulation. UCN3 is widely distributed in various tissues of animals and has many biological functions. Based on the research progress of UCN3 on mammals and non-mammals, this paper summarized the discovery, tissue distribution, appetite regulation and mechanism of UCN3 in animals, in order to provide a reference for feeding regulation and growth in mammals and fish in further research and production.
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Affiliation(s)
- Xin Zhang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, Sichuan, China; The Key Laboratory of Mariculture, Ministry of Education, Fisheries College, Ocean University of China, 5# Yushan Road, Qingdao, Shandong, China
| | - Yanling Liu
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, Sichuan, China
| | - Jinwen Qi
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, Sichuan, China
| | - Zhengzhi Tian
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, Sichuan, China
| | - Ni Tang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, Sichuan, China
| | - Defang Chen
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, Sichuan, China
| | - Zhiqiong Li
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, Sichuan, China.
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16
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Zhou WJ, Yang HL, Shao J, Mei J, Chang KK, Zhu R, Li MQ. Anti-inflammatory cytokines in endometriosis. Cell Mol Life Sci 2019; 76:2111-2132. [PMID: 30826860 PMCID: PMC11105498 DOI: 10.1007/s00018-019-03056-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 01/29/2019] [Accepted: 02/25/2019] [Indexed: 02/07/2023]
Abstract
Although the pathogenesis of endometriosis is not fully understood, it is often considered to be an inflammatory disease. An increasing number of studies suggest that differential expression of anti-inflammatory cytokines (e.g., interleukin-4 and -10, and transforming growth factor-β1) occurs in women with endometriosis, including in serum, peritoneal fluid and ectopic lesions. These anti-inflammatory cytokines also have indispensable roles in the progression of endometriosis, including by promoting survival, growth, invasion, differentiation, angiogenesis, and immune escape of the endometriotic lesions. In this review, we provide an overview of the expression, origin, function and regulation of anti-inflammatory cytokines in endometriosis, with brief discussion and perspectives on their future clinical implications in the diagnosis and therapy of the disease.
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Affiliation(s)
- Wen-Jie Zhou
- Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200090, People's Republic of China
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China
| | - Hui-Li Yang
- Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200090, People's Republic of China
| | - Jun Shao
- Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200090, People's Republic of China
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, People's Republic of China
| | - Jie Mei
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Reproductive Medicine Center, The Affiliated Hospital of Nanjing University Medicine School, Nanjing, 210000, People's Republic of China
| | - Kai-Kai Chang
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, People's Republic of China
| | - Rui Zhu
- Center for Human Reproduction and Genetics, Suzhou Municipal Hospital, Suzhou, 215008, People's Republic of China
| | - Ming-Qing Li
- Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200090, People's Republic of China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, People's Republic of China.
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17
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Pergialiotis V, Tagkou NM, Tsimpiktsioglou A, Klavdianou O, Neonaki A, Trompoukis P. Urocortin Expression in Endometriosis: A Systematic Review. INTERNATIONAL JOURNAL OF FERTILITY & STERILITY 2019; 13:1-5. [PMID: 30644237 PMCID: PMC6334014 DOI: 10.22074/ijfs.2019.5488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 05/30/2018] [Indexed: 12/16/2022]
Abstract
Urocortin (UCN) is a neuropeptide that belongs to the corticotrophin-releasing hormone family and is expressed by
eutopic and ectopic human endometria. The past years, this expression has been thoroughly investigated in the field
of endometriosis. The objective of this systematic review is to accumulate current evidence related to the expression
of UCN in tissue and blood samples of patients suffering from endometriosis. Literature search was designed accord-
ing to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and primarily
conducted using the Medline (1966-2018), Scopus (2004-2018), EMBASE (1947-2018) and Clinicaltrials.gov (2008-
2018) databases, along with the reference lists of electronically retrieved full-text papers. Overall, eight studies were
retrieved. Current evidence suggests that the expression of UCN is increased in patients with ovarian endometriomas
and that its levels may correlate with the severity of the disease. The diagnostic efficacy of UCN1 plasma levels was
evaluated in three studies. Two of them suggested that the sensitivity and specificity of the method may reach, and
even exceed, 80%. However, the wide variation in outcome reporting and outcome reporting measures in endome-
triosis among the included studies precludes meta-analysis of available data. Therefore, although UCN seems to be a
promising biomarker for the identification and follow-up of patients that suffer from endometriosis, more studies are
needed to reach firm conclusions with respect to its predictive accuracy.
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Affiliation(s)
- Vasilios Pergialiotis
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens, Greece.,Third Department of Obstetrics and Gynecology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.Electronic Address:
| | | | | | - Olga Klavdianou
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens, Greece
| | - Antonia Neonaki
- Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens, Greece
| | - Pantelis Trompoukis
- Third Department of Obstetrics and Gynecology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
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18
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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: 63] [Impact Index Per Article: 7.9] [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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19
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Zhang X, Wu Y, Hao J, Zhu J, Tang N, Qi J, Wang S, Wang H, Peng S, Liu J, Gao Y, Chen D, Li Z. Intraperitoneal injection urocortin-3 reduces the food intake of Siberian sturgeon (Acipenser baerii). Peptides 2016; 85:80-88. [PMID: 27667703 DOI: 10.1016/j.peptides.2016.09.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 09/02/2016] [Accepted: 09/16/2016] [Indexed: 02/06/2023]
Abstract
Urocortin-3 (UCN3), one of the corticotropin releasing factor (CRF) family peptides, which was discovered in 2001, has a variety of biological functions. However, the researches of UCN3 in fish were scarce. In order to understand whether UCN3 play a role in regulating food intake in fish, we first cloned the ucn3 cDNAs sequence of Siberian sturgeon (Acipenser baerii Brandt), and investigated the ucn3 mRNA levels in 11 tissues. The Siberian sturgeon ucn3 cDNA sequence was 1044bp, including an open reading frame (ORF) of 447bp that encoded 148 amino acids with a mature peptide of 40 amino acids, a 5'-terminal untranslated region (5'-UTR) of 162bp and a 3'-terminal untranslated region (3'-UTR) of 435bp. The result of tissue distribution showed that ucn3 widely distributed in 11 tissues with highest expression in brain. We also assessed the effects of periprandial (pre- and post-feeding), fasting and re-feeding on ucn3 mRNAs abundance in brain. The results showed the expression of ucn3 mRNA in brain was significantly elevated after feeding, decreased after fasting 17 days and increased after re-feeding. To further investigate the food intake role of UCN3 in Siberian sturgeon, we performed intraperitoneal (i.p.) injection of Siberian sturgeon UCN3 (SsUCN3) with three doses (60, 120 or 240ng/g) and recorded the food intake. Acute and chronic i.p. injection SsUCN3 reduced the food intake in a dose-dependent pattern. In conclusion, this study indicates that SsUCN3 acts as a satiety factor to inhibit the food intake of Siberian sturgeon.
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Affiliation(s)
- Xin Zhang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Yuanbing Wu
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Jin Hao
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Jieyao Zhu
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Ni Tang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Jinwen Qi
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Shuyao Wang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Hong Wang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Shuang Peng
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Ju Liu
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Yundi Gao
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Defang Chen
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China
| | - Zhiqiong Li
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu, China.
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20
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Carrarelli P, Luddi A, Funghi L, Arcuri F, Batteux F, Dela Cruz C, Tosti C, Reis FM, Chapron C, Petraglia F. Urocortin and corticotrophin-releasing hormone receptor type 2 mRNA are highly expressed in deep infiltrating endometriotic lesions. Reprod Biomed Online 2016; 33:476-483. [PMID: 27567427 DOI: 10.1016/j.rbmo.2016.07.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 07/22/2016] [Accepted: 07/26/2016] [Indexed: 12/20/2022]
Abstract
Ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE) are the most severe forms of endometriosis, but different pathogenetic mechanisms and clinical symptoms distinguish these two forms. Corticotrophin-releasing hormone (CRH) and urocortin (Ucn) are endometrial neuropeptides involved in tissue differentiation and inflammation. The expression of CRH, Ucn, Ucn2, CRH-receptors (type-1 and type-2) and inflammatory enzymes phospholipase-A2 group IIA (PLA2G2A) and cycloxygenase-2 (COX2) were evaluated in OMA (n = 22) and DIE (n = 26). The effect of CRH or Ucn on COX2 mRNA expression was evaluated in cultured human endometrial stromal cells. In DIE lesions, CRH, Ucn and CRH-R2 mRNA levels were significantly higher than in OMA (P < 0.01, P < 0.001 and P < 0.05, respectively); DIE lesions showed a higher expression of COX2 (P < 0.01) and PLA2G2A (P < 0.05) mRNA than OMA, which was positively correlated with CRH-R2 mRNA expression (P < 0.05). Intense immunostaining for CRH and Ucn was shown in DIE. Treatment of cultured endometrial stromal cells with Ucn significantly increased COX2 mRNA expression (P < 0.01); this effect was reversed by the CRH-R2 antagonist astressin-2B. In DIE, DIE lesions highly express neuropeptide and enzyme mRNAs, supporting a strong activation of inflammatory pathways.
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Affiliation(s)
- Patrizia Carrarelli
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
| | - Alice Luddi
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
| | - Lucia Funghi
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
| | - Felice Arcuri
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
| | - Frederic Batteux
- Department of Immunology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), 75014 Paris, France; Sorbonne Paris Cité, Inserm, Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), Université Paris Descartes, Paris, France
| | - Cynthia Dela Cruz
- Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Claudia Tosti
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy
| | - Fernando M Reis
- Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Charles Chapron
- Sorbonne Paris Cité, Inserm, Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), Université Paris Descartes, Paris, France; Sorbone Paris Cité, Faculté de Médecine, Assistance Publique - Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine (Profesor Chapron), Université Paris Descartes, Paris France
| | - Felice Petraglia
- Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
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Benagiano G, Petraglia F, Gordts S, Brosens I. A new approach to the management of ovarian endometrioma to prevent tissue damage and recurrence. Reprod Biomed Online 2016; 32:556-62. [DOI: 10.1016/j.rbmo.2016.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 03/01/2016] [Accepted: 03/02/2016] [Indexed: 01/08/2023]
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Temur M, Yilmaz Ö, Aksun S, Özün Özbay P, Calan M, Küme T, Karakulak M, Korkmaz HA. Increased circulating urocortin-3 levels is associated with polycystic ovary syndrome. Gynecol Endocrinol 2016; 32:218-22. [PMID: 26488073 DOI: 10.3109/09513590.2015.1110135] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
This study was aimed to compare serum urocortin-3 (UCN3) levels in women with polycystic ovary syndrome (PCOS) and healthy women, and establish what role UCN3 levels play in PCOS. Fifty-two patients with PCOS and 55 healthy women were included in the study, matched for age and body mass index. Fasting blood glucose (FBG), insulin, hs-CRP, UCN3 and free-testosterone levels of the all participants were measured. HOMA-IR was used to calculate the insulin resistance. Circulating UCN3 levels were significantly increased in women with PCOS than in control subjects (54.49 ± 5.77 versus 51.28 ± 5.86 pmol/l, p = 0.005). Serum insulin, hs-CRP and HOMA-IR levels were higher in women with PCOS than in control group. UCN3 levels positively correlated with hs-CRP in PCOS group (r = 0.391, p = 0.004). Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curves were 0.732 (95% CI 0.634-0.830, p < 0.001) for UCN3 levels. The optimal cut-off value of UCN3 for detecting PCOS was ≥51.46 pmol/l, at which the sensitivity was 75% and specificity was 68%. Our results suggest that there is a potential link between PCOS and UCN3 levels. The results of this study support the presence of increased UCN3 levels for the association of inflammation with PCOS.
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Affiliation(s)
- Muzaffer Temur
- a Department of Obstetrics and Gynecology , Manisa Merkezefendi State Hospital , Manisa , Turkey
| | - Özgür Yilmaz
- b Department of Obstetrics and Gynecology , Manisa Merkezefendi State Hospital and Manisa Akhisar State Hospital , Manisa , Turkey
| | - Saliha Aksun
- c Department of Medical Biochemistry , İzmir Katipcelebi University Medical School , İzmir , Turkey
| | - Pelin Özün Özbay
- d Department of Obstetrics and Gynecology , Aydın Obstetrics and Pediatrics Hospital , Aydın , Turkey
| | - Mehmet Calan
- e Department of Endocrinology , İzmir Bozyaka Education and Research Hospital , İzmir , Turkey
| | - Tuncay Küme
- f Department of Medical Biochemistry , Dokuz Eylul University Medical School , Izmir , Turkey
| | - Murat Karakulak
- g Department of Obstetrics and Gynecology , Silivri State Hospital , İstanbul , Turkey , and
| | - Hüseyin Anıl Korkmaz
- h Division of Pediatric Endocrinology , Dr Behçet Uz Children Research and Training Hospital , İzmir , Turkey
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23
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Luisi S, Pinzauti S, Regini C, Petraglia F. Serum markers for the noninvasive diagnosis of endometriosis. ACTA ACUST UNITED AC 2015; 11:603-10. [PMID: 26395072 DOI: 10.2217/whe.15.46] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Endometriosis is a disease that affects millions of women worldwide and its diagnosis is still challenging. Medical history, symptoms together with imaging data may address the correct diagnosis, but the gold standard remains laparoscopic assessment with histological confirmation. The development of serum markers as diagnostic tools for endometriosis may allow a prompt and noninvasive diagnosis. Several serum biomarkers have been investigated over the years, but none of these have shown a clinical utility and nowadays the more realistic diagnostic biomarker consists in a panel of biomarkers. The recent introduction of new technologies such as genomics and proteomics may represent the future perspective of endometriosis diagnosis.
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Affiliation(s)
- Stefano Luisi
- Obstetrics & Gynecology, Department of Molecular & Developmental Medicine, University of Siena, Policlinico 'Le Scotte' Viale Bracci, 53100 Siena, Italy
| | - Serena Pinzauti
- Obstetrics & Gynecology, Department of Molecular & Developmental Medicine, University of Siena, Policlinico 'Le Scotte' Viale Bracci, 53100 Siena, Italy
| | - Cristina Regini
- Obstetrics & Gynecology, Department of Molecular & Developmental Medicine, University of Siena, Policlinico 'Le Scotte' Viale Bracci, 53100 Siena, Italy
| | - Felice Petraglia
- Obstetrics & Gynecology, Department of Molecular & Developmental Medicine, University of Siena, Policlinico 'Le Scotte' Viale Bracci, 53100 Siena, Italy
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Liu C, Liu X, Yang J, Duan Y, Yao H, Li F, Zhang X. The effects of vasoactive peptide urocortin 2 on hemodynamics in spontaneous hypertensive rat and the role of L-type calcium channel and CRFR2. Pharmacol Rep 2015; 67:394-8. [DOI: 10.1016/j.pharep.2014.10.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 08/27/2014] [Indexed: 01/28/2023]
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Smith ML, Li J, Ryabinin AE. Increased alcohol consumption in urocortin 3 knockout mice is unaffected by chronic inflammatory pain. Alcohol Alcohol 2014; 50:132-9. [PMID: 25451237 DOI: 10.1093/alcalc/agu084] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
AIMS Stress neurocircuitry may modulate the relationship between alcohol drinking and chronic pain. The corticotropin-releasing factor (CRF) system is crucial for regulation of stress responses. The current study aimed to elucidate the role of the endogenous CRF ligand Urocortin 3 (Ucn3) in the relationship between alcohol drinking behavior and chronic pain using a genetic approach. METHODS Ucn3 (KO) and wildtype (WT) littermates were subjected to a 24-h access drinking procedure prior to and following induction of chronic inflammatory pain. RESULTS Ucn3 KO mice displayed significantly increased ethanol intake and preference compared with WT across the time course. There were no long-term effects of chronic pain on alcohol drinking behavior, regardless of genotype, nor any evidence for alcohol-induced analgesia. CONCLUSION The increased drinking in Ucn3 KO supports a role for this peptide in alcohol-related behavior. These data suggest the necessity for more research exploring the relationship between alcohol drinking, chronic pain and the CRF system in rodent models.
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Affiliation(s)
- Monique L Smith
- Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 SW Sam Jackson Park Road L470, Portland, OR 97239-3098, USA
| | - Ju Li
- Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 SW Sam Jackson Park Road L470, Portland, OR 97239-3098, USA
| | - Andrey E Ryabinin
- Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 SW Sam Jackson Park Road L470, Portland, OR 97239-3098, USA
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26
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Aznaurova YB, Zhumataev MB, Roberts TK, Aliper AM, Zhavoronkov AA. Molecular aspects of development and regulation of endometriosis. Reprod Biol Endocrinol 2014; 12:50. [PMID: 24927773 PMCID: PMC4067518 DOI: 10.1186/1477-7827-12-50] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Accepted: 05/29/2014] [Indexed: 12/11/2022] Open
Abstract
Endometriosis is a common and painful condition affecting women of reproductive age. While the underlying pathophysiology is still largely unknown, much advancement has been made in understanding the progression of the disease. In recent years, a great deal of research has focused on non-invasive diagnostic tools, such as biomarkers, as well as identification of potential therapeutic targets. In this article, we will review the etiology and cellular mechanisms associated with endometriosis as well as the current diagnostic tools and therapies. We will then discuss the more recent genomic and proteomic studies and how these data may guide development of novel diagnostics and therapeutics. The current diagnostic tools are invasive and current therapies primarily treat the symptoms of endometriosis. Optimally, the advancement of "-omic" data will facilitate the development of non-invasive diagnostic biomarkers as well as therapeutics that target the pathophysiology of the disease and halt, or even reverse, progression. However, the amount of data generated by these types of studies is vast and bioinformatics analysis, such as we present here, will be critical to identification of appropriate targets for further study.
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Affiliation(s)
- Yana B Aznaurova
- I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
- The First Open Institute for Regenerative Medicine for Young Scientists, Moscow, Russian Federation
- Federal Research and Clinical Center for Pediatric Hematology, Oncology and Hematology, Moscow, Russian Federation
| | - Marat B Zhumataev
- I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
- The First Open Institute for Regenerative Medicine for Young Scientists, Moscow, Russian Federation
- Federal Research and Clinical Center for Pediatric Hematology, Oncology and Hematology, Moscow, Russian Federation
| | - Tiffany K Roberts
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Alexander M Aliper
- The First Open Institute for Regenerative Medicine for Young Scientists, Moscow, Russian Federation
- Federal Research and Clinical Center for Pediatric Hematology, Oncology and Hematology, Moscow, Russian Federation
- Moscow Institute of Physics and Technology, Moscow, Russian Federation
| | - Alex A Zhavoronkov
- I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
- The First Open Institute for Regenerative Medicine for Young Scientists, Moscow, Russian Federation
- The Biogerontology Research Foundation, London, UK
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Watanabe K, Nemoto T, Akira S, Takeshita T, Shibasaki T. Estrogens downregulate urocortin 2 expression in rat uterus. J Endocrinol 2013; 219:269-78. [PMID: 24109089 DOI: 10.1530/joe-13-0228] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Urocortin 2 (Ucn2) is a member of the corticotropin-releasing factor peptide family and is expressed by various tissues, including reproductive tissues such as the uterus, ovary, and placenta. However, the regulatory mechanisms of Ucn2 expression and the physiological significance of Ucn2 in these tissues remain unclear. We previously showed that passive immunization of immature female rats by i.p. injection of anti-Ucn2 IgG induces earlier onset of puberty. Therefore, this study was designed to clarify the site and regulatory mechanisms of Ucn2 expression in the uterus. Expression levels of Ucn2 mRNA in the uterus were higher in immature (2- and 4-week-old) and aged (17-month-old) rats than in mature (9-week-old) rats in the proestrus phase. In 9-week-old rats, mRNA expression levels and contents in the uterus were lower in the proestrus phase than in the diestrus phase, while plasma Ucn2 concentrations did not differ between the two phases. Ucn2-like immunoreactivitiy was detected in the endometrial gland epithelial cells of the uterus. S.c. injection of estradiol benzoate or an estrogen receptor α (ERα) agonist significantly reduced mRNA expression levels and contents of Ucn2 in the uterus when compared with vehicle-injected ovariectomized rats. By contrast, estradiol benzoate increased Ucn2 mRNA expression levels in the lung. Thus, estrogens downregulate Ucn2 expression in the uterus in a tissue-specific manner, and Ucn2 may play a role in the regulatory mechanisms of maturation of the uterus through ERα and estrous cycle.
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Affiliation(s)
- Kenichiro Watanabe
- Departments of Obstetrics and Gynecology Physiology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
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Yavuzcan A, Cağlar M, Ustün Y, Dilbaz S, Ozdemir I, Yıldız E, Ozkara A, Kumru S. Evaluation of mean platelet volume, neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in advanced stage endometriosis with endometrioma. J Turk Ger Gynecol Assoc 2013; 14:210-5. [PMID: 24592108 DOI: 10.5152/jtgga.2013.55452] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 08/07/2013] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVE We compared the preoperative values of mean platelet volume (MPV) and peripheral systemic inflammatory response (SIR) markers (neutrophil/lymphocyte ratio and platelet/lymphocyte ratio) between patients with advanced-stage (stage 3/4) endometriosis having endometrioma (OMA) and patients with a non-neoplastic adnexal mass other than endometrioma (non-OMA). MATERIAL AND METHODS Patients who underwent operations with the pre-diagnosis of infertility or adnexal mass and who underwent laparoscopic tubal ligation were included. RESULTS Haemoglobin levels, leucocyte count, platelet count, neutrophil count and lymphocyte count were not significantly different between patients with advanced stage endometriosis having OMA, patients with non-OMA and patients in the control group (p=0.970, p=0.902, p=0.373, p=0.501 and p=0.463, respectively). Patients with stage 3/4 endometriosis having OMA, patients with non-OMA and control patients were also not significantly different in terms of MPV (p=0.836), neutrophil/lymphocyte ratio (NLR) (p=0.555) and platelet/lymphocyte ratio (PLR) (p=0.358). Preoperative cancer antigen 125 (Ca-125) levels were significantly higher in patients with OMA (p=0.006). Mean size of the OMAs was significantly lower than non-OMAs (p=0.000). CONCLUSION It is very important to determine advanced stage endometriosis and OMAs during preoperative evaluation in order to inform patients and plan an appropriate surgical approach. We demonstrate that MPV, NLR and PLR values are not useful for this purpose in patients with advanced stage endometriosis that are proven to develop severe inflammation at either the cellular or molecular level.
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Affiliation(s)
- Ali Yavuzcan
- Department of Obstetrics and Gynecology, Düzce University Faculty of Medicine, Düzce, Turkey
| | - Mete Cağlar
- Department of Obstetrics and Gynecology, Düzce University Faculty of Medicine, Düzce, Turkey
| | - Yusuf Ustün
- Department of Obstetrics and Gynecology, Düzce University Faculty of Medicine, Düzce, Turkey
| | - Serdar Dilbaz
- Department of Obstetrics and Gynecology, Düzce University Faculty of Medicine, Düzce, Turkey
| | - Ismail Ozdemir
- Department of Obstetrics and Gynecology, İstanbul Medicana Beylikdüzü Hospital, İstanbul, Turkey
| | - Elif Yıldız
- Department of Obstetrics and Gynecology, Düzce University Faculty of Medicine, Düzce, Turkey
| | - Atilla Ozkara
- Department of Obstetrics and Gynecology, Düzce University Faculty of Medicine, Düzce, Turkey
| | - Selahattin Kumru
- Department of Obstetrics and Gynecology, Düzce University Faculty of Medicine, Düzce, Turkey
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29
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Endometrioma: From Pathogenesis to Clinical Management. JOURNAL OF ENDOMETRIOSIS AND PELVIC PAIN DISORDERS 2013. [DOI: 10.5301/je.5000163] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
An endometrioma (OMA) is the localization of endometriosis in ovary, and it most often develops as a cyst. The pathogenesis of OMA is still an open question and controversial; a cystic hemorrhagic corpus luteum may be a prerequisite, occurring as a transition to an endometriotic cyst. Inversion and progressive invagination of the ovarian cortex after the accumulation of menstrual debris derived from bleeding of superficial endometriotic implants, located on the ovarian surface and adherent to the peritoneum, is another hypothesis. Gene studies show that WNT4 and FN1 are predisposing genes for OMA development. A role of environmental toxicants in the development of OMA is also under investigation; dioxins and dioxin-like compounds (DLCs), interacting with steroid receptors, are possible factors. Even if women with endometriosis have a 1.5 times greater lifetime risk to develop an ovarian carcinoma, an OMA is not to be considered a preneoplastic lesion. The clinical management of OMAs is complex and should be individualized. Ultrasounds and magnetic resonance imaging (MRI) are sensitive but not specific for diagnosis. Treatment is influenced by patient age, desire for pregnancy, pain severity, cyst dimensions and characteristics (unilateral/bilateral), coexistence of deep endometriosis, previous gynecological or obstetrical history and previous surgery. Laparoscopic surgery is considered the treatment of choice in cases of infertile patients with a large OMA or pain, and in patients not responding to medical therapy. It should be performed with proper techniques by trained surgeons to decrease the damage to the remaining ovarian tissue, and to maintain the ovarian reserve after surgery. A medical hormonal and nonhormonal treatment is used for asymptomatic and/or pain-associated OMA (progestins, estroprogestins and antiinflammatory drugs). Considering the relative high recurrence rate after surgery, a medical treatment should be offered.
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Interplay between Misplaced Müllerian-Derived Stem Cells and Peritoneal Immune Dysregulation in the Pathogenesis of Endometriosis. Obstet Gynecol Int 2013; 2013:527041. [PMID: 23843796 PMCID: PMC3697788 DOI: 10.1155/2013/527041] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 05/19/2013] [Accepted: 05/28/2013] [Indexed: 12/26/2022] Open
Abstract
In the genetic regulation of Müllerian structures development, a key role is played by Hoxa and Wnt clusters, because they lead the transcription of different genes according to the different phases of the organogenesis, addressing correctly cell-to-cell interactions, allowing, finally, the physiologic morphogenesis. Accumulating evidence is suggesting that dysregulation of Wnt and/or Hox genes may affect cell migration during organogenesis and differentiation of Müllerian structures of the female reproductive tract, with possible dislocation and dissemination of primordial endometrial stem cells in ectopic regions, which have high plasticity to differentiation. We hypothesize that during postpubertal age, under the influence of different stimuli, these misplaced and quiescent ectopic endometrial cells could acquire new phenotype, biological functions, and immunogenicity. So, these kinds of cells may differentiate, specializing in epithelium, glands, and stroma to form a functional ectopic endometrial tissue. This may provoke a breakdown in the peritoneal cavity homeostasis, with the consequent processes of immune alteration, documented by peripheral mononuclear cells recruitment and secretion of inflammatory cytokines in early phases and of angiogenic and fibrogenic cytokines in the late stages of the disease.
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Vaughan JM, Donaldson CJ, Fischer WH, Perrin MH, Rivier JE, Sawchenko PE, Vale WW. Posttranslational processing of human and mouse urocortin 2: characterization and bioactivity of gene products. Endocrinology 2013; 154:1553-64. [PMID: 23493376 PMCID: PMC3602626 DOI: 10.1210/en.2012-2011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mouse (m) and human (h) urocortin 2 (Ucn 2) were identified by molecular cloning strategies and the primary sequence of their mature forms postulated by analogy to closely related members of the corticotropin-releasing factor (CRF) neuropeptide family. Because of the paucity of Ucn 2 proteins in native tissues, skin, muscle, and pancreatic cell lines were transduced with lentiviral constructs and secretion media were used to isolate and characterize Ucn 2 products and study processing. Primary structures were assigned using a combination of Edman degradation sequencing and mass spectrometry. For mUcn 2, transduced cells secreted a 39 amino acid peptide and the glycosylated prohormone lacking signal peptide; both forms were C-terminally amidated and highly potent to activate the type 2 CRF receptor. Chromatographic profiles of murine tissue extracts were consistent with cleavage of mUcn 2 prohormone to a peptidic form. By contrast to mUcn 2, mammalian cell lines transduced with hUcn 2 constructs secreted significant amounts of an 88 amino acid glycosylated hUcn 2 prohormone but were unable to further process this molecule. Similarly, WM-266-4 melanoma cells that express endogenous hUcn 2 secreted only the glycosylated prohormone lacking the signal peptide and unmodified at the C terminus. Although not amidated, hUcn 2 prohormone purified from overexpressing lines activated CRF receptor 2. Hypoxia and glycosylation, paradigms that might influence secretion or processing of gene products, did not significantly impact hUcn 2 prohormone cleavage. Our findings identify probable Ucn 2 processing products and should expedite the characterization of these proteins in mammalian tissues.
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Capobianco A, Rovere-Querini P. Endometriosis, a disease of the macrophage. Front Immunol 2013; 4:9. [PMID: 23372570 PMCID: PMC3556586 DOI: 10.3389/fimmu.2013.00009] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 01/07/2013] [Indexed: 12/14/2022] Open
Abstract
Endometriosis, a common cause of pelvic pain and female infertility, depends on the growth of vascularized endometrial tissue at ectopic sites. Endometrial fragments reach the peritoneal cavity during the fertile years: local cues decide whether they yield endometriotic lesions. Macrophages are recruited at sites of hypoxia and tissue stress, where they clear cell debris and heme-iron and generate pro-life and pro-angiogenesis signals. Macrophages are abundant in endometriotic lesions, where are recruited and undergo alternative activation. In rodents macrophages are required for lesions to establish and to grow; bone marrow-derived Tie-2 expressing macrophages specifically contribute to lesions neovasculature, possibly because they concur to the recruitment of circulating endothelial progenitors, and sustain their survival and the integrity of the vessel wall. Macrophages sense cues (hypoxia, cell death, iron overload) in the lesions and react delivering signals to restore the local homeostasis: their action represents a necessary, non-redundant step in the natural history of the disease. Endometriosis may be due to a misperception of macrophages about ectopic endometrial tissue. They perceive it as a wound, they activate programs leading to ectopic cell survival and tissue vascularization. Clearing this misperception is a critical area for the development of novel medical treatments of endometriosis, an urgent and unmet medical need.
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Affiliation(s)
- Annalisa Capobianco
- Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute Milan, Italy
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Yang H, Zhou B, Prinz M, Siegel D. Proteomic analysis of menstrual blood. Mol Cell Proteomics 2012; 11:1024-35. [PMID: 22822186 DOI: 10.1074/mcp.m112.018390] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Menstruation is the expulsion of the endometrial lining of the uterus following a nearly month long preparation for embryo implantation and pregnancy. Increasingly, the health of the endometrium is being recognized as a critical factor in female fertility, and proteomes and transcriptomes from endometrial biopsies at different stages of the menstrual cycle have been studied for both diagnostic and therapeutic purposes (1 Kao, L. C., et al. 2003 Endocrinology 144, 2870-2881; Strowitzki, Tet al. 2006 Hum. Reprod. Update 12, 617-630; DeSouza, L., et al. 2005 Proteomics 5, 270-281). Disorders of the uterus ranging from benign to malignant tumors, as well as endometriosis, can cause abnormal menstrual bleeding and are frequently diagnosed through endometrial biopsy (Strowitzki, Tet al. 2006 Hum. Reprod. Update 12, 617-630; Ferenczy, A. 2003 Maturitas 45, 1-14). Yet the proteome of menstrual blood, an easily available noninvasive source of endometrial tissue, has yet to be examined for possible causes or diagnoses of infertility or endometrial pathology. This study employed five different methods to define the menstrual blood proteome. A total of 1061 proteins were identified, 361 were found by at least two methods and 678 were identified by at least two peptides. When the menstrual blood proteome was compared with those of circulating blood (1774 proteins) and vaginal fluid (823 proteins), 385 proteins were found unique to menstrual blood. Gene ontology analysis and evaluation of these specific menstrual blood proteins identified pathways consistent with the processes of the normal endometrial cycle. Several of the proteins unique to menstrual blood suggest that extramedullary uterine hematopoiesis or parenchymal hemoglobin synthesis may be occurring in late endometrial tissue. The establishment of a normal menstrual blood proteome is necessary for the evaluation of its usefulness as a diagnostic tool for infertility and uterine pathologies. Identification of unique menstrual blood proteins should aid the forensic community in distinguishing menstrual blood from circulating blood.
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Affiliation(s)
- Heyi Yang
- New York City Office of Chief Medical Examiner, New York, New York 10016, USA
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