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15 pages, 3595 KiB

Open AccessArticle

Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain

by Miguel A. Tejada, Ana I. Santos-Llamas, Lesley Escriva, Juan J. Tarin, Antonio Cano, Maria J. Fernández-Ramírez, Paulina Nunez-Badinez, Bianca De Leo, Philippa T. K. Saunders, Victor Vidal, Florent Barthas, Katy Vincent, Patrick J. Sweeney, Rowland R. Sillito, James Douglas Armstrong, Jens Nagel and Raúl Gomez

Biomedicines 2022, 10(2), 501; https://doi.org/10.3390/biomedicines10020501 - 21 Feb 2022

Cited by 7 | Viewed by 2847

Abstract

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions [...] Read more.

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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15 pages, 4125 KiB

Open AccessArticle

Ribosome Biogenesis Serves as a Therapeutic Target for Treating Endometriosis and the Associated Complications

by Cherry Yin-Yi Chang, An-Jen Chiang, Man-Ju Yan, Ming-Tsung Lai, Yun-Yi Su, Hsin-Yi Huang, Chan-Yu Chang, Ya-Hui Li, Pei-Fen Li, Chih-Mei Chen, Tritium Hwang, Chloe Hogg, Erin Greaves and Jim Jinn-Chyuan Sheu

Biomedicines 2022, 10(1), 185; https://doi.org/10.3390/biomedicines10010185 - 17 Jan 2022

Cited by 1 | Viewed by 3555

Abstract

Ribosome biogenesis is a cellular process critical for protein homeostasis during cell growth and multiplication. Our previous study confirmed up-regulation of ribosome biogenesis during endometriosis progression and malignant transition, thus anti-ribosome biogenesis may be effective for treating endometriosis and the associated complications. A [...] Read more.

Ribosome biogenesis is a cellular process critical for protein homeostasis during cell growth and multiplication. Our previous study confirmed up-regulation of ribosome biogenesis during endometriosis progression and malignant transition, thus anti-ribosome biogenesis may be effective for treating endometriosis and the associated complications. A mouse model with human endometriosis features was established and treated with three different drugs that can block ribosome biogenesis, including inhibitors against mTOR/PI3K (GSK2126458) and RNA polymerase I (CX5461 and BMH21). The average lesion numbers and disease frequencies were significantly reduced in treated mice as compared to controls treated with vehicle. Flow cytometry analyses confirmed the reduction of small peritoneal macrophage and neutrophil populations with increased large versus small macrophage ratios, suggesting inflammation suppression by drug treatments. Lesions in treated mice also showed lower nerve fiber density which can support the finding of pain-relief by behavioral studies. Our study therefore suggested ribosome biogenesis as a potential therapeutic target for treating endometriosis. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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11 pages, 5743 KiB

Open AccessArticle

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis

by Yosuke Ono, Takako Kawakita, Osamu Yoshino, Erina Sato, Kuniyuki Kano, Mai Ohba, Toshiaki Okuno, Masami Ito, Kaori Koga, Masako Honda, Akiko Furue, Takehiro Hiraoka, Shinichiro Wada, Takeshi Iwasa, Takehiko Yokomizo, Junken Aoki, Nagamasa Maeda, Nobuya Unno, Yutaka Osuga and Shuji Hirata

Biomedicines 2021, 9(11), 1519; https://doi.org/10.3390/biomedicines9111519 - 22 Oct 2021

Cited by 13 | Viewed by 2268

Abstract

Sphingosine 1-phosphate (S1P), an inflammatory mediator, is abundantly contained in red blood cells and platelets. We hypothesized that the S1P concentration in the peritoneal cavity would increase especially during the menstrual phase due to the reflux of menstrual blood, and investigated the S1P [...] Read more.

Sphingosine 1-phosphate (S1P), an inflammatory mediator, is abundantly contained in red blood cells and platelets. We hypothesized that the S1P concentration in the peritoneal cavity would increase especially during the menstrual phase due to the reflux of menstrual blood, and investigated the S1P concentration in the human peritoneal fluid (PF) from 14 non-endometriosis and 19 endometriosis patients. Although the relatively small number of samples requires caution in interpreting the results, S1P concentration in the PF during the menstrual phase was predominantly increased compared to the non-menstrual phase, regardless of the presence or absence of endometriosis. During the non-menstrual phase, patients with endometriosis showed a significant increase in S1P concentration compared to controls. In vitro experiments using human intra-peritoneal macrophages (MΦ) showed that S1P stimulation biased them toward an M2MΦ-dominant condition and increased the expression of IL-6 and COX-2. An in vivo study showed that administration of S1P increased the size of the endometriotic-like lesion in a mouse model of endometriosis. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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12 pages, 4957 KiB

Open AccessArticle

Phoenixin as a New Target in the Development of Strategies for Endometriosis Diagnosis and Treatment

by Karolina Iwona Kulinska, Mirosław Andrusiewicz, Anna Dera-Szymanowska, Maria Billert, Marek Skrzypski, Krzysztof Szymanowski, Ewa Nowak-Markwitz, Małgorzata Kotwicka and Maria Wołuń-Cholewa

Biomedicines 2021, 9(10), 1427; https://doi.org/10.3390/biomedicines9101427 - 9 Oct 2021

Cited by 11 | Viewed by 2186

Abstract

Small integral membrane protein 20/phoenixin (SMIM20/PNX) and its receptor GPR173 (G Protein-Coupled Receptor 173) play a role in the regulation of the hypothalamic–pituitary–gonadal axis (HPG). The aim of the study was to determine PNX, FSH, LH, and 17β-estradiol association in women with endometriosis, [...] Read more.

Small integral membrane protein 20/phoenixin (SMIM20/PNX) and its receptor GPR173 (G Protein-Coupled Receptor 173) play a role in the regulation of the hypothalamic–pituitary–gonadal axis (HPG). The aim of the study was to determine PNX, FSH, LH, and 17β-estradiol association in women with endometriosis, and the expression of SMIM20/PNX signaling via GPR173. Serum PNX, FSH, LH, and 17β-estradiol concentrations were measured by enzyme and electrochemiluminescence immunoassay. SMIM20/PNX and GPR173 expression in the eutopic and ectopic endometrium was assessed by qPCR and immunohistochemistry. Reduced PNX level, increased LH/FSH ratio and elevated 17β-estradiol concentration were found in patients with endometriosis. No differences in SMIM20 expression were observed between the studied endometria. GPR173 expression was lower in ectopic than in eutopic endometria. SMIM20 expression was mainly restricted to stroma. GPR173 was detected in some eutopic and ectopic stromal cells and in eutopic glandular epithelial cells. Discriminant analysis indicates the diagnostic relevance of PNX and LH/FSH ratio in patients with endometriosis. In women with endometriosis, reduced PNX levels and GPR173 expression may be responsible for HPG axis dysregulation. These new insights may contribute to a better understanding of the pathophysiology of endometriosis and provide the basis for a new strategy for diagnosis and treatment of endometriosis. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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13 pages, 3200 KiB

Open AccessArticle

Participation of Selected Soluble BMP-2 and BMP-7 Bone Morphogenetic Proteins and Their Soluble Type I ALK-1 and Type II BMPR2 Receptors in Formation and Development of Endometriosis

by Joanna Janusz, Aleksandra Janusz, Zdzisława Kondera-Anasz, Justyna Sikora, Marta Smycz-Kubańska, Aleksandra Englisz, Dominika Wendlocha and Aleksandra Mielczarek-Palacz

Biomedicines 2021, 9(10), 1292; https://doi.org/10.3390/biomedicines9101292 - 22 Sep 2021

Cited by 6 | Viewed by 1528

Abstract

Angiogenesis is considered to be one of the key stages in the development of endometriosis. Recent studies indicate that bone morphogenetic proteins (BMPs) and their receptors (BMPR) may play an important role in the angiogenesis process. In the literature, however, there is a [...] Read more.

Angiogenesis is considered to be one of the key stages in the development of endometriosis. Recent studies indicate that bone morphogenetic proteins (BMPs) and their receptors (BMPR) may play an important role in the angiogenesis process. In the literature, however, there is a lack of publications concerning binding BMPs and their receptors with the pathogenesis of endometriosis. The aim of the study was to determine the role of soluble bone morphogenetic proteins, BMP-2 and BMP-7, and their receptors, ALK-1 and BMPR2, in the process of the formation and development of endometriosis. Peritoneal fluid was collected in the proliferative phase of the menstrual cycle, from 80 women aged 21–49 years (mean age 31.3 ± 6.7 years) undergoing laparoscopy to determine the causes of primary infertility. The study involved 60 women in the I, II, III, and IV stages of the disease. The reference group consisted of 20 women who did not have endometriosis or other lesions in the pelvic area. The concentration in the peritoneal fluid of women with endometriosis was compared to the concentration of this parameter in the reference group, and a statistically significant reduction in the concentration of the BMP-2 molecule was found, as well as increasing concentrations of BMP-7, ALK-1, and BMPR2. BMP-2 and BMP-7 and their soluble receptors, ALK-1 and BMPR2, are involved in the formation of endometriosis. The changes in the concentrations of most of the tested parameters demonstrated in the study, especially in the early stages of the disease, may indicate the more effective formation of new blood vessels in this period. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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16 pages, 3566 KiB

Open AccessArticle

Mesenchymal Stromal Cells Isolated from Ectopic but Not Eutopic Endometrium Display Pronounced Immunomodulatory Activity In Vitro

by Alexey Yu. Lupatov, Roza Yu. Saryglar, Valentina V. Vtorushina, Rimma A. Poltavtseva, Oxana A. Bystrykh, Vladimir D. Chuprynin, Lyubov V. Krechetova, Stanislav V. Pavlovich, Konstantin N. Yarygin and Gennady T. Sukhikh

Biomedicines 2021, 9(10), 1286; https://doi.org/10.3390/biomedicines9101286 - 22 Sep 2021

Cited by 2 | Viewed by 1590

Abstract

A comparative analysis of the cell surface markers and immunological properties of cell cultures originating from normal endometrium and endometrioid heterotopias of women with extragenital endometriosis was carried out. Both types of cell cultures expressed surface molecules typical of mesenchymal stromal cells and [...] Read more.

A comparative analysis of the cell surface markers and immunological properties of cell cultures originating from normal endometrium and endometrioid heterotopias of women with extragenital endometriosis was carried out. Both types of cell cultures expressed surface molecules typical of mesenchymal stromal cells and did not express hematopoietic and epithelial markers. Despite similar phenotype, the mesenchymal stromal cells derived from the two sources had different immunomodulation capacities: the cells of endometrioid heterotopias but not eutopic endometrium could suppress dendritic cell differentiation from monocytes as well as lymphocyte proliferation in allogeneic co-cultures. A comparative multiplex analysis of the secretomes revealed a significant increase in the secretion of pro-inflammatory mediators, including IL6, IFN-γ, and several chemokines associated with inflammation by the stromal cells of ectopic lesions. The results demonstrate that the stromal cells of endometrioid heterotopias display enhanced pro-inflammatory and immunosuppressive activities, which most likely impact the pathogenesis and progression of the disease. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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18 pages, 2451 KiB

Open AccessSystematic Review

Association between Endometriosis and Delivery Outcomes: A Systematic Review and Meta-Analysis

by Yoshikazu Nagase, Shinya Matsuzaki, Yutaka Ueda, Mamoru Kakuda, Sahori Kakuda, Hitomi Sakaguchi, Michihide Maeda, Tsuyoshi Hisa and Shoji Kamiura

Biomedicines 2022, 10(2), 478; https://doi.org/10.3390/biomedicines10020478 - 17 Feb 2022

Cited by 4 | Viewed by 1920

Abstract

Endometriosis is a common benign gynecological disorder; however, delivery outcomes concerning pregnancies with endometriosis remain understudied. This study aimed to assess the effect of endometriosis on delivery outcomes, including the rate of instrumental delivery, cesarean delivery (CD), postpartum hemorrhage (PPH), and perioperative complications [...] Read more.

Endometriosis is a common benign gynecological disorder; however, delivery outcomes concerning pregnancies with endometriosis remain understudied. This study aimed to assess the effect of endometriosis on delivery outcomes, including the rate of instrumental delivery, cesarean delivery (CD), postpartum hemorrhage (PPH), and perioperative complications during CD. A systematic literature review was conducted using multiple computerized databases, and 28 studies met the inclusion criteria. Pooled analysis showed that histologically diagnosed endometriosis was associated with an increased rate of instrumental delivery (odds ratio [OR] 1.26, 95% confidence interval [CI] 1.02–1.56) and an increased risk of CD (adjusted OR 2.59, 95%CI 1.32–5.07). In our analysis, histologically diagnosed endometriosis was not associated with an increased rate of PPH; however, one retrospective study reported that endometriosis increased the rate of PPH during CD (adjusted OR 1.7, 95%CI 1.5–2.0). Two studies examined perioperative complications during CD, and women with deep endometriosis had a higher rate of bowel resection or bladder injury than those without endometriosis. Our findings suggest that endometriosis is a significant risk factor for instrumental delivery and CD and may be associated with a higher rate of PPH and intraoperative complications during CD. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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23 pages, 2842 KiB

Open AccessSystematic Review

Placenta Accreta Spectrum Disorder Complicated with Endometriosis: Systematic Review and Meta-Analysis

by Shinya Matsuzaki, Yutaka Ueda, Yoshikazu Nagase, Satoko Matsuzaki, Mamoru Kakuda, Sahori Kakuda, Hitomi Sakaguchi, Tsuyoshi Hisa and Shoji Kamiura

Biomedicines 2022, 10(2), 390; https://doi.org/10.3390/biomedicines10020390 - 6 Feb 2022

Cited by 15 | Viewed by 2719

Abstract

This study aimed to assess the relationship between placenta accreta spectrum disorder (PASD) and endometriosis. The relationships among pregnancy, assisted reproductive technology (ART), placenta previa, ART-conceived pregnancy and PASD were also determined. A systematic literature review was conducted using multiple computerized databases. Forty-eight [...] Read more.

This study aimed to assess the relationship between placenta accreta spectrum disorder (PASD) and endometriosis. The relationships among pregnancy, assisted reproductive technology (ART), placenta previa, ART-conceived pregnancy and PASD were also determined. A systematic literature review was conducted using multiple computerized databases. Forty-eight studies (1990–2021) met the inclusion criteria. According to the adjusted pooled analysis (n = 3), endometriosis was associated with an increased prevalence of PASD (adjusted odds ratio [OR] 3.39, 95% confidence interval [CI] 1.96–5.87). In the included studies, the ART rate ranged from 18.2% to 37.2% for women with endometriosis. According to the adjusted pooled analysis, women who used ART were more likely to have placenta previa (n = 13: adjusted OR 2.96, 95%CI, 2.43–3.60) and PASD (n = 4: adjusted OR 3.54, 95%CI 1.86–6.76) than those who did not use ART. According to the sensitivity analysis using an unadjusted analysis accounting for the type of ART, frozen embryo transfer (ET) was associated with an increased risk of PASD (n = 4: OR 2.79, 95%CI, 1.22−6.37) compared to fresh ET. Endometriosis may be associated with an increased rate of PASD. Women with placenta previa complicated with endometriosis who conceived using frozen ET may be a high risk for PASD. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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23 pages, 2916 KiB

Open AccessSystematic Review

Placenta Previa Complicated with Endometriosis: Contemporary Clinical Management, Molecular Mechanisms, and Future Research Opportunities

by Shinya Matsuzaki, Yoshikazu Nagase, Yutaka Ueda, Mamoru Kakuda, Michihide Maeda, Satoko Matsuzaki and Shoji Kamiura

Biomedicines 2021, 9(11), 1536; https://doi.org/10.3390/biomedicines9111536 - 26 Oct 2021

Cited by 16 | Viewed by 4783

Abstract

Endometriosis is a common gynecological disease characterized by chronic inflammation, with an estimated prevalence of approximately 5–15% in reproductive-aged women. This study aimed to assess the relationship between placenta previa (PP) and endometriosis. We performed a systematic review of the literature until 30 [...] Read more.

Endometriosis is a common gynecological disease characterized by chronic inflammation, with an estimated prevalence of approximately 5–15% in reproductive-aged women. This study aimed to assess the relationship between placenta previa (PP) and endometriosis. We performed a systematic review of the literature until 30 June 2021, and 24 studies met the inclusion criteria. Using an adjusted pooled analysis, we found that women with endometriosis had a significantly increased rate of PP (adjusted odds ratio (OR) 3.17, 95% confidence interval (CI) 2.58–3.89) compared to those without endometriosis. In an unadjusted analysis, severe endometriosis was associated with an increased prevalence of PP (OR 11.86, 95% CI 4.32–32.57), whereas non-severe endometriosis was not (OR 2.16, 95% CI 0.95–4.89). Notably, one study showed that PP with endometriosis was associated with increased intraoperative bleeding (1.515 mL versus 870 mL, p < 0.01) compared to those without endometriosis. Unfortunately, no studies assessed the molecular mechanisms underlying PP in patients with endometriosis. Our findings suggest that there is a strong association between endometriosis and a higher incidence of PP, as well as poor surgical outcomes during cesarean delivery. Therefore, the development of novel therapeutic agents or methods is warranted to prevent PP in women with endometriosis. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 2.0)

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