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Molecular Research on Endometriosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 15312

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Dr. David B. Alexander

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Nanotoxicology Project, Nagoya City University, 3-1 Tanabe-dohri, Mizuho-ku, Nagoya 466-8603, Japan
Interests: nanoparticles; carcinogenic potential; lactoferrin; caner therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Endometriosis is a chronic disorder that is estimated to occur in 10% of the general female population. It is a heterogeneous disease with no single cause or treatment. The New York Times (April 27, 2021) states "Yet, it suffers from a branding problem: It falls into the abyss of “women’s diseases” (overlooked), diseases that do not kill you (unimportant), and menstrual problems (taboo)". Menstrual pain should not be considered normal. Endometriosis is not a benign, unimportant disease; it is a common, painful, and, in many cases, debilitating disease. The International Journal of Molecular Sciences introduces Special Issues to create collections of papers on specific topics. The aim is to build a community of authors and readers to discuss the latest research and develop new ideas and research directions. This Special Issue is soliciting contributions on the molecular aspects of endometriosis. These include review articles and original research articles investigating signaling pathways associated with endometriosis, identifying DNA mutations that lead to the development of endometriosis, elucidating the origin of these mutations and determining whether non-familial mutations can be prevented, identifying molecular markers that will help in the diagnosis of endometriosis, and identifying potential targets that can be used in the treatment of endometriosis.

Dr. David B. Alexander
Guest Editor

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Keywords

endometriosis
proliferative mutations
epigenetic regulation of gene expression
estrogen receptor signaling
tissue regeneration

Published Papers (7 papers)

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Research

9 pages, 735 KiB

Open AccessCommunication

Role of Renin-Angiotensin-Aldosterone System and Cortisol in Endometriosis: A Preliminary Report

by Chiara Sabbadin, Carlo Saccardi, Alessandra Andrisani, Amerigo Vitagliano, Loris Marin, Eugenio Ragazzi, Luciana Bordin, Guido Ambrosini and Decio Armanini

Int. J. Mol. Sci. 2023, 24(1), 310; https://doi.org/10.3390/ijms24010310 - 24 Dec 2022

Cited by 1 | Viewed by 1806

Abstract

Endometriosis is a chronic inflammatory disease associated with pelvic pain, infertility, and increased cardiovascular risk. Recent studies suggest a possible role of aldosterone as a pro-inflammatory hormone in the pathogenesis of the disease. Cortisol is also an important mediator of stress reaction, but its role is controversial in endometriosis. The aim of this study was to evaluate aldosterone and cortisol levels and blood pressure values in women with endometriosis. We measured blood pressure, plasma aldosterone, renin, cortisol, and dehydroepiandrosterone sulfate (DHEAS) in 20 women with untreated minimal or mild pelvic endometriosis compared with 20 healthy controls matched for age and body mass index. Aldosterone values were similar in the two groups, while renin was significantly lower and the aldosterone to renin ratio was significantly higher in patients with endometriosis than in controls. Systolic blood pressure was in the normal range, but significantly higher in patients with endometriosis. Morning plasma cortisol was normal, but significantly lower in patients with endometriosis compared with controls, while DHEAS to cortisol ratio was similar in the two groups. These preliminary results are evidence of increased biological aldosterone activity and dysregulation of the hypothalamic-pituitary-adrenal axis in early stages of endometriosis. These alterations could play a role in disease development, suggesting new therapeutic targets for aldosterone receptor blockers. Full article

(This article belongs to the Special Issue Molecular Research on Endometriosis)

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14 pages, 1444 KiB

Open AccessArticle

Decreased Innate Migration of Pro-Inflammatory M1 Macrophages through the Mesothelial Membrane Is Affected by Ceramide Kinase and Ceramide 1-P

by Chee Wai Ku, Joan Yang, Hong Ying Tan, Jerry Kok Yen Chan and Yie Hou Lee

Int. J. Mol. Sci. 2022, 23(24), 15977; https://doi.org/10.3390/ijms232415977 - 15 Dec 2022

Cited by 2 | Viewed by 1893

Abstract

The retrograde flow of endometrial tissues deposited into the peritoneal cavity occurs in women during menstruation. Classically (M1) or alternatively (M2) activated macrophages partake in the removal of regurgitated menstrual tissue. The failure of macrophage egress from the peritoneal cavity through the mesothelium leads to chronic inflammation in endometriosis. To study the migration differences of macrophage phenotypes across mesothelial cells, an in vitro model of macrophage egress across a peritoneal mesothelial cell monolayer membrane was developed. M1 macrophages were more sessile, emigrating 2.9-fold less than M2 macrophages. The M1 macrophages displayed a pro-inflammatory cytokine signature, including IL-1α, IL-1β, TNF-α, TNF-β, and IL-12p70. Mass spectrometry sphingolipidomics revealed decreased levels of ceramide-1-phosphate (C1P), an inducer of migration in M1 macrophages, which correlated with its poor migration behavior. C1P is generated by ceramide kinase (CERK) from ceramide, and blocking C1P synthesis via the action of NVP231, a specific CERK chemical inhibitor, prohibited the emigration of M1 and M2 macrophages up to 6.7-fold. Incubation with exogenously added C1P rescued this effect. These results suggest that M1 macrophages are less mobile and have higher retention in the peritoneum due to lower C1P levels, which contributes to an altered peritoneal environment in endometriosis by generating a predominant pro-inflammatory cytokine environment. Full article

(This article belongs to the Special Issue Molecular Research on Endometriosis)

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12 pages, 3252 KiB

Open AccessArticle

Regulation of Apoptosis and Oxidative Stress by Oral Boswellia Serrata Gum Resin Extract in a Rat Model of Endometriosis

by Ramona D’Amico, Daniela Impellizzeri, Marika Cordaro, Rosalba Siracusa, Livia Interdonato, Rosalia Crupi, Enrico Gugliandolo, Francesco Macrì, Davide Di Paola, Alessio Filippo Peritore, Roberta Fusco, Salvatore Cuzzocrea and Rosanna Di Paola

Int. J. Mol. Sci. 2022, 23(23), 15348; https://doi.org/10.3390/ijms232315348 - 05 Dec 2022

Cited by 1 | Viewed by 1512

Abstract

Endometriosis (EMS) is a gynecological disease characterized by inflammation, oxidative stress, and apoptosis dysregulation. This study aims to evaluate the effect of Boswellia serrata gum resin extract (BS) on the endometriotic lesions in a rat model of endometriosis. We divided female rats into three groups, including Sham, EMS, EMS + BS. In the EMS and EMS + BS groups, pathology was induced and after 7 days by the abdominal high-frequency ultrasound (hfUS) analysis the presence of the endometriotic lesions was confirmed. Subsequently, the EMS + BS group was administered with BS (100 mg/Kg) daily for another 7 days. At the end of the experiment, the hfUS analysis was repeated and the animals were sacrificed to evaluate the size and histoarchitecture of the endometriotic implants. Pelvic ultrasound showed increased size of the endometriotic lesions in the Endo group, while BS administration reduced the lesion size. The macroscopic analysis confirmed the reduced area and volume of the endometriotic lesions of the EMS + BS group. The histological analysis showed reduced characteristic of ectopic stroma and glands in the animals treated with BS. Western blot analyses were conducted to evaluate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. BS increases the expression of Nfr2 in the nucleus and the expression of its downstream antioxidant proteins NQO-1 and HO-1. Moreover, it reduced lipid peroxidation and increased glutathione (GSH) levels, and glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities. BS administration also restored the impaired apoptotic pathway in the lesions by reducing Bcl-2 expression and increasing Bax and cleaved caspase 9 levels. The BS apoptotic effect was also confirmed by the cleavage of PARP, another specific marker of apoptosis, and by the TUNEL assay. Our results show that BS administration resulted in an effective and coordinated suppression of Endo owing to its antioxidant and antiapoptotic activities. Full article

(This article belongs to the Special Issue Molecular Research on Endometriosis)

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18 pages, 4073 KiB

Open AccessArticle

Osteopontin Splicing Isoforms Contribute to Endometriotic Proliferation, Migration, and Epithelial-Mesenchymal Transition in Endometrial Epithelial Cells

by Nguyen-Tuong Ho, Shu-Wei Lin, Yi-Rong Lee, Chii-Ruey Tzeng and Shu-Huei Kao

Int. J. Mol. Sci. 2022, 23(23), 15328; https://doi.org/10.3390/ijms232315328 - 05 Dec 2022

Cited by 7 | Viewed by 1804

Abstract

Osteopontin (OPN) isoforms, including OPNb and OPNc, promote malignancy and may contribute to the pathogenesis of endometriosis, a benign disorder with multiple characteristics resembling malignant tumors. In our experiments, OPNb and OPNc were significantly overexpressed in both endometriosis and adenomyosis compared to the normal endometrium. Upregulation of CD44v and the epithelial–mesenchymal transition (EMT) process was also present in endometriotic lesions. Overexpression of OPNb and OPNc splicing variants in endometriotic cells evoked morphological changes, actin remodeling, cell proliferation, cell migration, and EMT through binding OPN ligand receptors CD44 and αvβ3, subsequently activating the PI3K and NF-ĸB pathways. We elucidated the causal role of OPN splice variants in regulating endometriotic cell growth, which may promote the development of OPN-targeted therapies for patients suffering from endometriotic disorders. Full article

(This article belongs to the Special Issue Molecular Research on Endometriosis)

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22 pages, 2903 KiB

Open AccessArticle

O-Glycosylation Changes in Serum Immunoglobulin G Are Associated with Inflammation Development in Advanced Endometriosis

by Katarzyna Sołkiewicz, Monika Kacperczyk, Hubert Krotkiewski, Marcin Jędryka and Ewa Maria Kratz

Int. J. Mol. Sci. 2022, 23(15), 8087; https://doi.org/10.3390/ijms23158087 - 22 Jul 2022

Cited by 4 | Viewed by 1750

Abstract

Endometriosis is a gynecological disease, the pathogenesis of which seems to be directly related to inflammatory processes with an immune basis. Our study aimed to analyze the O-glycosylation of native serum IgG and IgG isolated from sera of women with advanced endometriosis, without endometriosis but with benign gynecological diseases, and from a control group of healthy women, in the context of its utility for differentiation of advanced endometriosis from the other two groups of women studied. For the analysis of serum IgG O-glycosylation and the expression of multi-antennary N-glycans, lectin-ELISA with lectins specific to O-glycans (MPL, VVL, and Jacalin) and highly branched N-glycans (PHA-L) was used. The relative reactivities of isolated serum IgG O-linked glycans with specific lectins as well as the MPL/VVL O-glycosylation ratio were significantly higher in patients with advanced endometriosis and those with other gynecological diseases when compared to the control group of healthy women. We also showed significantly higher expression of PHA-L-reactive multi-antennary N-glycans in isolated IgG in the advanced endometriosis and the non-endometriosis groups in comparison to the control group. Additionally, significantly higher expression of Jacalin-reactive O-glycans in isolated IgG was observed in the non-endometriosis than in the advanced endometriosis group. The results of the ROC curve and cluster analysis additionally confirmed that the lectin-based analysis of isolated serum IgG O-glycosylation and the expression of highly branched N-glycans may help distinguish women with advanced endometriosis from healthy women. Moreover, the analysis of the expression of Jacalin-reactive i-IgG O-glycans may be helpful in differentiation between women with advanced endometriosis and patients with other gynecological diseases with an inflammatory background. In the case of non-endometriosis patients, the observed differences were most probably caused by increased expression of core 3 type O-glycans. Full article

(This article belongs to the Special Issue Molecular Research on Endometriosis)

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11 pages, 1349 KiB

Open AccessArticle

A Bioinformatics Approach to MicroRNA-Sequencing Analysis Based on Human Saliva Samples of Patients with Endometriosis

by Sofiane Bendifallah, Yohann Dabi, Stéphane Suisse, Ludmila Jornea, Delphine Bouteiller, Cyril Touboul, Anne Puchar and Emile Daraï

Int. J. Mol. Sci. 2022, 23(14), 8045; https://doi.org/10.3390/ijms23148045 - 21 Jul 2022

Cited by 13 | Viewed by 3867

Abstract

Endometriosis, defined by the presence of endometrium-like tissue outside the uterus, affects 2–10% of the female population, i.e., around 190 million women, worldwide. The aim of the prospective ENDO-miRNA study was to develop a bioinformatics approach for microRNA-sequencing analysis of 200 saliva samples for miRNAome expression and to test its diagnostic accuracy for endometriosis. Among the 200 patients, 76.5% (n = 153) had confirmed endometriosis and 23.5% (n = 47) had no endometriosis (controls). Small RNA-seq of 200 saliva samples yielded ~4642 M raw sequencing reads (from ~13.7 M to ~39.3 M reads/sample). The number of expressed miRNAs ranged from 1250 (outlier) to 2561 per sample. Some 2561 miRNAs were found to be differentially expressed in the saliva samples of patients with endometriosis compared with the control patients. Among these, 1.17% (n = 30) were up- or downregulated. Among these, the F1-score, sensitivity, specificity, and AUC ranged from 11–86.8%, 5.8–97.4%, 10.6–100%, and 39.3–69.2%, respectively. Here, we report a bioinformatic approach to saliva miRNA sequencing and analysis. We underline the advantages of using saliva over blood in terms of ease of collection, reproducibility, stability, safety, non-invasiveness. This report describes the whole saliva transcriptome to make miRNA quantification a validated, standardized, and reliable technique for routine use. The methodology could be applied to build a saliva signature of endometriosis. Full article

(This article belongs to the Special Issue Molecular Research on Endometriosis)

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12 pages, 1095 KiB

Open AccessArticle

miR 31-3p Has the Highest Expression in Cesarean Scar Endometriosis

by Maria Szubert, Anna Nowak-Glück, Daria Domańska-Senderowska, Bożena Szymańska, Piotr Sowa, Aleksander Rycerz and Jacek R. Wilczyński

Int. J. Mol. Sci. 2022, 23(9), 4660; https://doi.org/10.3390/ijms23094660 - 22 Apr 2022

Cited by 4 | Viewed by 1793

Abstract

Micro-RNAs expression can vary between different forms of endometriosis, but data on miRNA expression in cesarean scar endometriosis is lacking. The present study is comprised of 30 patients with endometriosis in the cesarean scar (scar endometriosis, SE), 14 patients with deep infiltrating endometriosis (DIE), 47 patients with endometrioma (ovarian endometrial cyst, OE), and 33 patients with healthy ovarian tissue as the control group (CG). In the initial experiment to identify possible dysregulated miRNAs, the levels of 754 miRNAs in formalin-fixed paraffin-embedded tissue (FFPE) samples from OE, high-grade ovarian cancer, endometrioid ovarian cancer, and CG were measured. We identified seven potentially dysregulated miRNAs: miR-1-3p, miR-31-3p, miR-125b-1-3p, miR-200b-3p, miR-548d, miR-502, and miR-503. We then examined the expression profiles of each of these miRNAs individually in the SE, DIE, OE, and CG FFPE samples using RT-qPCR. miR-31-3p had significantly higher levels of expression and miR-125b-1-3p had significantly lower levels of expression in SE compared to the controls. Overall, the higher expression levels of miR-31-3p and the lower expression levels of miR-125b-1-3p are consistent with the benign nature of SE. Importantly, the results of the present study demonstrate the possibility of using miRNA to monitor the risk of malignant transformation of endometriosis tissue. Full article

(This article belongs to the Special Issue Molecular Research on Endometriosis)

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