Glutaminolysis regulates endometrial fibrosis in intrauterine adhesion via modulating mitochondrial function.

BACKGROUND: Endometrial fibrosis, a significant characteristic of intrauterine adhesion (IUA), is caused by the excessive differentiation and activation of endometrial stromal cells (ESCs). Glutaminolysis is the metabolic process of glutamine (Gln), which has been implicated in multiple types of organ fibrosis. So far, little is known about whether glutaminolysis plays a role in endometrial fibrosis. METHODS: The activation model of ESCs was constructed by TGF-ß1, followed by RNA-sequencing analysis. Changes in glutaminase1 (GLS1) expression at RNA and protein levels in activated ESCs were verified experimentally. Human IUA samples were collected to verify GLS1 expression in endometrial fibrosis. GLS1 inhibitor and glutamine deprivation were applied to ESCs models to investigate the biological functions and mechanisms of glutaminolysis in ESCs activation. The IUA mice model was established to explore the effect of glutaminolysis inhibition on endometrial fibrosis. RESULTS: We found that GLS1 expression was significantly increased in activated ESCs models and fibrotic endometrium. Glutaminolysis inhibition by GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES or glutamine deprivation treatment suppressed the expression of two fibrotic markers, α-SMA and collagen I, as well as the mitochondrial function and mTORC1 signaling in ESCs. Furthermore, inhibition of the mTORC1 signaling pathway by rapamycin suppressed ESCs activation. In IUA mice models, BPTES treatment significantly ameliorated endometrial fibrosis and improved pregnancy outcomes. CONCLUSION: Glutaminolysis and glutaminolysis-associated mTOR signaling play a role in the activation of ESCs and the pathogenesis of endometrial fibrosis through regulating mitochondrial function. Glutaminolysis inhibition suppresses the activation of ESCs, which might be a novel therapeutic strategy for IUA.

Abnormal expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium.

Mitochondria play a pivotal role in physiological and metabolic function of the cell. Mitochondrial dynamics orchestrate mitochondrial function and morphology, involving fission and fusion as well as ultrastructural remodeling. Mounting evidence unravels the close link between mitochondria and endometriosis. However, how mitochondrial architecture changes through fission and fusion in eutopic and ectopic tissues of women with ovarian endometriosis remains unknown. We detected the expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium in ovarian endometriosis. The results showed that the expression of DRP1 and LCLAT1 was upregulated in eutopic endometrial stromal cells (ESCs), and the expression of DRP1, OPA1, MFN1, MFN2, and LCLAT1 was significantly downregulated in ectopic ESCs, and reduced number of mitochondria, wider cristae width and narrower cristae junction width was observed, but there was no difference in cell survival rate. The altered mitochondrial dynamics and morphology might, respectively, provide an advantage for migration and adhesion in eutopic ESCs and be the adaptive response in ectopic endometrial cells to survive under hypoxic and oxidative stress environment.

The Clinical Picture and Fecundity of Primary and Recurrent Ovarian Endometriosis with Family History: A Retrospective Analysis.

This study aims to evaluate the role of endometriosis family history on the clinical manifestation and fertility performance of primary and recurrent endometriosis. In total, 312 primary and 323 recurrent endometrioma patients with a histological diagnosis were included in this study. Family history was significantly correlated with recurrent endometriosis (adjusted OR: 3.52, 95% CI: 1.09-9.46, p = 0.008). Patients with a family history showed a significantly higher proportion of recurrent endometriosis (75.76% vs. 49.50%), higher rASRM scores, higher incidence of severe dysmenorrhea, and severe pelvic pain than the sporadic cases. Recurrent endometrioma showed statistical increase in rASRM scores, percentage of rASRM Stage IV, dysmenorrhea, dyschezia, those undergoing semi-radical surgery or unilateral oophorosalpingectomy, postoperative medical treatment, e with a positive family history, while a decrease in the incidence of asymptomatic phenomena and those undergoing ovarian cystectomy compared to those with primary endometriosis. The naturally conceived pregnancy rate was higher in primary endometriosis compared to recurrent endometriosis. Compared to recurrent endometriosis with a negative family history, recurrent endometriosis with a positive family history had a higher incidence of severe dysmenorrhea, chronic pelvic pain, a higher spontaneous abortion rate, and a lower natural pregnancy rate. Primary endometriosis with a family history presented a higher incidence of severe dysmenorrhea than those without a family history. In conclusion, endometriosis patients with a positive family history presented a higher pain severity and lower conception probability compared to the sporadic cases. Recurrent endometriosis showed further-exacerbated clinical manifestations, more pronounced familial tendency, and lower pregnancy rates than primary endometriosis.

Colorectal sessile serrated lesion detection using linked-color imaging versus narrow-band imaging: a parallel randomized controlled trial.

BACKGROUND: Previous studies have reported the effectiveness of narrow-band imaging (NBI) and linked-color imaging (LCI) in improving the detection of colorectal neoplasms. There has however been no direct comparison between LCI and NBI in the detection of colorectal sessile serrated lesions (SSLs). The present study aimed to compare the effectiveness of LCI and NBI in detecting colorectal SSLs. METHODS: A prospective, parallel, randomized controlled trial was conducted. The participants were randomly assigned to the LCI or NBI arms. The primary end point was the SSL detection rate (SDR). RESULTS: 406 patients were involved; 204 in the LCI arm and 202 in the NBI arm. The total polyp detection rate, adenoma detection rate, and SDR were 54.2 %, 38.7 %, and 10.8%, respectively. The SDR was not significantly different between the LCI and NBI arms (12.3 % vs. 9.4 %; P = 0.36). The differences in the detection rate and the per-patient number of polyps, adenomas, diminutive lesions, and flat lesions between LCI and NBI also were not statistically significant. Multivariate analysis showed that LCI and NBI were not independent factors associated with SDR, whereas Boston Bowel Preparation Scale score (odds ratio [OR] 1.35, 95 %CI 1.03-1.76; P = 0.03), withdrawal time (OR 1.13, 95 %CI 1.00-1.26; P = 0.04), and operator experience (OR 3.73, 95 %CI 1.67-8.32; P = 0.001) were independent factors associated with SDR. CONCLUSIONS: LCI and NBI are comparable for SSL detection, as well as for the detection of polyps and adenomas.

Colorectal Sessile Serrated Lesion Detection Using Linked Color Imaging: A Multicenter, Parallel Randomized Controlled Trial.

BACKGROUND & AIMS: Linked color imaging (LCI) is a novel technology that improves the color differences between colorectal lesions and the surrounding mucosa. The present study aims to compare the detection of colorectal sessile serrated lesions (SSL) using LCI with white light imaging (WLI). METHOD: A large-scale, multicenter, parallel prospective randomized controlled trial was conducted in 4 hospitals in China. The participants were randomly assigned to the LCI group and WLI group. The primary endpoint was the SSL detection rate (SDR). RESULTS: A total of 884 patients were involved in the intention-to-treat analysis, with 441 patients in the LCI group and 443 patients in the WLI group. The total polyp detection rate, adenoma detection rate, and SDR were 51.8%, 35.7%, and 8.6%, respectively. The SDR was significantly higher in the LCI group than in the WLI group (11.3% vs 5.9%, P = .004). Furthermore, LCI significantly increased the number of polyps and adenomas detected per patient, when compared with WLI (P < .05). In addition, there was higher detection rate of diminutive and flat lesions in the LCI group (P < .05). Multivariate analysis revealed that LCI is an independent factor associated with SDR (hazard ratio, 1.990; 95% confidence interval, 1.203-3.293; P = .007), along with withdrawal time (hazard ratio, 1.157; 95% confidence interval, 1.060-1.263; P = .001) and operator experience (hazard ratio, 1.850; 95% confidence interval, 1.045-3.273; P = .035). CONCLUSIONS: LCI is significantly superior to WLI for SSL detection, and may improve polyp and adenoma detection. LCI can be recommended as an appropriate method for routine inspection during colonoscopy (http://www.chictr.org.cn number, ChiCTR2000035705).

Comparison of Secondary Prevention Following Hysteroscopic Adhesiolysis in the Improvement of Reproductive Outcomes: A Retrospective Cohort Study.

Intrauterine adhesion (IUA) is primarily caused by endometrial injury, and hysteroscopic adhesiolysis is presently the main treatment. However, postoperative recurrence and poor pregnancy outcomes remain intractable. In this study, we aim to assess the effects of different treatments on clinical symptoms and reproductive outcomes in IUA. This retrospective study was conducted in a tertiary university-affiliated women's hospital. The study included 1449 consecutive women who desired to have a baby and were diagnosed with IUA through hysteroscopy from January 2016 to December 2021. Patients with IUA underwent hysteroscopic electric resection (E) or cold scissors separation (C), as well as hormone therapy and one or both of the following secondary prevention measures: intrauterine devices (IUD) and hyaluronic acid gel (HA). The pregnancy rate (PR) was significantly higher in the E + IUD + HA (90.23% CI: 85.82, 94.64%) than in other groups (p = 0.000) groups. The rates of full-term birth (p = 0.000) and live birth (p = 0.000) were significantly higher in the E + IUD + HA (67.82% and 68.97%, respectively) and E + HA (62.41% and 63.91%, respectively) groups. Multivariate logistic regression analysis revealed a significantly higher PR in women who received second-look hysteroscopy (OR 1.571, 95% CI: 1.009-2.224, p = 0.013) and E + IUD + HA (OR 4.772, 95% CI: 2.534-8.987, p = 0.000). Combining hysteroscopic electric resection with IUDs and HA gel could prevent adhesion recurrence and improve postoperative pregnancy and live birth outcomes in IUA. Furthermore, postoperative second-look hysteroscopy may increase the PR and shorten the waiting period.

Risk factors for coexisting deep endometriosis for patients with recurrent ovarian endometrioma.

Aim: The aim of this study was to assess the risk factors for coexisting deep endometriosis (DE) in patients with recurrent ovarian endometrioma (OE). Methods: We retrospectively reviewed 151 recurrent OE patients who had been diagnosed of OE but not DE at the time of their first surgery and then received a second surgery for recurrent endometriosis with or without DE. Their clinical characteristics at the time of the first and second surgeries were collected. Univariate and multivariate logistic regression analyses were conducted to identify potential risk factors for coexisting DE in patients with recurrent OE. Results: Among the 151 recurrent OE patients, 46 were diagnosed of DE during the recurrent surgery and included in the DE group, while the remaining 105 patients were included in the non-DE group. In univariate analysis, there were significant differences in terms of uterine retroversion during the primary surgery and the follow-up time after the primary surgery between the DE and non-DE groups. The multivariate analysis also showed that both uterine retroversion and the follow-up time (≥5 years) were associated with the coexistence of DE during the recurrent surgery. The odds ratio (OR) for uterine retroversion was 3.72 [95% confidence interval (CI) 1.62-8.53], and the OR for follow-up time (≥5 years) was 5.03 (95% CI 2.29-11.02). Conclusions: Our study suggested that for recurrent OE patients, uterine retroversion during the first surgery and a follow-up time of at least 5 years are risk factors for the coexistence of DE in recurrent surgery, early prevention and full preparation before the recurrent surgery should be emphasized in these conditions.

Hypoxia activates the unfolded protein response signaling network: An adaptive mechanism for endometriosis.

Endometriosis (EMS) is a chronic gynecological disease that affects women of childbearing age. However, the exact cause remains unclear. The uterus is a highly vascularized organ that continuously exposes endometrial cells to high oxygen concentrations. According to the "planting theory" of EMS pathogenesis, when endometrial cells fall from the uterine cavity and retrograde to the peritoneal cavity, they will face severe hypoxic stress. Hypoxic stress remains a key issue even if successfully implanted into the ovaries or peritoneum. In recent years, increasing evidence has confirmed that hypoxia is closely related to the occurrence and development of EMS. Hypoxia-inducible factor-1α (HIF-1α) can play an essential role in the pathological process of EMS by regulating carbohydrate metabolism, angiogenesis, and energy conversion of ectopic endometrial cells. However, HIF-1α alone is insufficient to achieve the complete program of adaptive changes required for cell survival under hypoxic stress, while the unfolded protein response (UPR) responding to endoplasmic reticulum stress plays an essential supplementary role in promoting cell survival. The formation of a complex signal regulation network by hypoxia-driven UPR may be the cytoprotective adaptation mechanism of ectopic endometrial cells in unfavorable microenvironments.

Comparison Between Preincision Traction and On-Demand Traction in Assisting Colorectal Endoscopic Submucosal Dissection.

INTRODUCTION: Adequate exposure of the dissection site is very important for colorectal endoscopic submucosal dissection (ESD). We aimed to investigate the safety and efficacy of the preincision traction (PIT) method using an internal clip-with-spring device in comparison with the conventional on-demand traction (ODT) method in assisting colorectal ESD. METHODS: This was a prospective nested case-control study. A total of 26 patients for PIT-ESD and other 26 patients for ODT-ESD were involved. Data on clinical characteristics and therapeutic outcomes were collected and analyzed. RESULTS: The en bloc resection rate (both 100%) and curative resection rate (92.3% vs 96.2%) showed no significant difference between the 2 groups. Compared with ODT-ESD, PIT-ESD significantly reduced the procedure time (29.8 ± 18.4 vs 57.4 ± 33.7 minutes, P = 0.001) and submucosal injection volume (49.6 ± 32.3 vs 70.8 ± 37.6 mL, P = 0.034), decreased the rate of intraoperative bleeding (26.9% vs 57.7%, P = 0.025) and muscular injury (7.7% vs 34.6%, P = 0.038), and shortened the postoperative hospital stay (1.8 ± 0.8 vs 2.5 ± 1.2, P = 0.015). DISCUSSION: The PIT method could significantly improve the safety and efficacy of colorectal ESD.

Obstetrical and oncological outcomes of twin pregnancies with hydatidiform mole and coexisting fetus.

OBJECTIVE: To evaluate the obstetrical and oncological progression of twin pregnancies with hydatidiform mole coexisting fetus (HMCF). MATERIALS AND METHODS: Using a retrospective method based on patients from the Women's Hospital, Zhejiang University School of Medicine database between January 1990 and October 2020, 17 patients were histologically confirmed as having HMCF, and the patients' prenatal diagnosis, outcomes and development of gestational trophoblastic neoplasia (GTN) were reviewed. RESULTS: Among these 17 cases, 11 (64.71%) cases were complete hydatidiform mole coexisting fetus (CHMCF), and 6 (35.29%) cases were partial hydatidiform mole coexisting fetus (PHMCF). The gestational age at diagnosis of CHMCF was significantly earlier than that of PHMCF [9 (8-24) vs. 18 (11-32) weeks, respectively, P < 0.05]. The live birth rate of PHMCF was slightly higher than that of CHMCF (33.33%; 18.18%), but this difference was not statistically significant. The overall rate of GTN incidence of HMCF was 47.06% (8/17), and the GTN rates of PHMCF and CHMCF were 33.33% (2/6) and 54.55% (6/11), respectively. There was no significant difference in the GTN rate between patients who chose to continue pregnancy and those who terminated pregnancy before 24 weeks of gestation. The GTN rate of patients with term delivery was not significantly higher than that of preterm delivery. CONCLUSION: In HMCF cases, the incidence rate of CHMCF was higher than that of PHMCF, and PHMCF is more difficult to diagnose in the early stage. Continuing pregnancy does not increase the risk of GTN compared to terminating pregnancy. In cases of HMCF, when the fetal karyotype is normal and maternal complications are controlled, it is safe to continue the pregnancy and extend it to term.

miR-31-5p-DMD axis as a novel biomarker for predicting the development and prognosis of sporadic early-onset colorectal cancer.

The incidence of colorectal cancer (CRC) is increasing in young adults, but knowledge regarding the molecular features of sporadic early-onset colorectal cancer (SEOCRC) is limited. The objective of the present study was to investigate potential key tumorigenesis-associated genes and their regulatory microRNAs (miRNAs) in SEOCRC. Using miRNA and mRNA expression screening of SEOCRC and sporadic late-onset colorectal cancer (SLOCRC) by next generation sequencing (NGS) and bioinformatics, the SEOCRC-associated miRNAome and transcriptome were analyzed. In SEOCRC miRNA and mRNA expression profiles, the tumorigenesis-associated genes and their regulatory miRNAs were analyzed according to the miRTarBase database, and specific miRNA-mRNA pairs were selected as the candidate biomarkers in SEOCRC, which were further verified in another cohort of SEOCRC and SLOCRC patients' colon cancer and paracancerous tissues using reverse transcription-quantitative PCR and immunohistochemistry. Moreover, the clinical relevance of these paired signatures to clinicopathological features was determined in 80 patients with SEOCRC. The expression of dystrophin (DMD) was downregulated and that of miR-31-5p was upregulated in SEOCRC tissue compared with adjacent peritumoral tissue. While DMD and miR-31-5p were not differentially expressed in SLOCRC tissues compared with that in adjacent peritumoral tissues. The miR-31-5p-DMD axis was identified as the key regulatory axis specific to SEOCRC, and DMD expression was closely associated with TNM stage and lymph node metastasis. Importantly, Kaplan-Meier analysis revealed that patients with low DMD expression had significantly poorer overall survival, cancer specific survival and recurrence free survival compared with those with high expression of DMD. In conclusion, the miR-31-5p-DMD axis may serve as a novel biomarker in predicting the development of SEOCRC, and DMD can be used as a promising biomarker for the prognosis of SEOCRC.

Diagnosis and treatment of uterine artery pseudoaneurysm: Case series and literature review.

BACKGROUND: Uterine artery pseudoaneurysm (UAP) is a rare but potentially life-threatening cause of hemorrhage. Nonetheless, its knowledge could be insufficient among obstetricians, gynecologists, and radiologists. We aimed to clarify the clinical characteristics, management, and outcomes of UAP. METHODS: We retrospectively analyzed nine female patients diagnosed with UAP at our institute between 2013 and 2020. RESULTS: Seven cases presented with a history of traumatic surgery including cesarean section, dilation and curettage, laparoscopic myomectomy, and cervical conization. Two cases occurred after spontaneous vaginal delivery and second-trimester pregnancy termination. The main symptom was heavy/massive/prolonged vaginal bleeding. All patients were first evaluated by color Doppler ultrasonography and three cases were confirmed by magnetic resonance imaging. Severn patients underwent transarterial embolization (TAE) of the uterine arteries, and two were managed conservatively. All patients had good outcomes. CONCLUSIONS: UAP can develop after traumatic pelvic operations and non-traumatic delivery/abortion. It may be more common than previously considered. The risk of rupture may be correlated with multiple factors other than the mass size. TAE of the uterine artery could be an effective management strategy for ruptured UAP. However, some cases can resolve spontaneously without TAE, suggesting that conservative management can be employed in some women.

Osteopontin Regulates Endometrial Stromal Cell Migration in Endometriosis through the PI3K Pathway : Osteopontin Regulates Endometrial Cell Migration in Endometriosis.

Endometriosis is generally characterized as a tumor-like disease because of its potential for distant metastasis and local tissue invasion, while whether osteopontin (OPN) plays a role in the pathogenesis of endometriosis has not been thoroughly investigated. We investigated the expression of OPN, urokinase plasminogen activator (uPA), phosphatidylinositol 3 kinase (PI3K), and phospho-PI3 kinase (p-PI3K) in endometrial stromal cells (ESCs). The serum concentration of OPN was determined by enzyme-linked immunosorbent assays (ELISA). OPN was downregulated to explore the corresponding change of uPA, p-PI3K, F-actin, and α-tubulin. The expression of OPN, uPA, PI3K, and p-PI3K was evaluated by western blot and quantitative real-time PCR (RT-qPCR) and the expression of F-actin and α-tubulin was confirmed by immunofluorescence assay. The proliferation and migration abilities of ESCs were investigated by CCK8, transwell, and wound scratch assays. Endometrial OPN, p-PI3K, and uPA expressions and serum OPN levels were increased in patients with endometriosis compared with the control. The expressions of p-PI3K, uPA, and α-tubulin were decreased by siRNA-OPN interference in ectopic ESCs. Activation and inhibition of the PI3K pathway apparently upregulate and downregulate uPA expression. Knockdown of OPN and inhibition of the PI3K pathway remarkably inhibited cell migration in ectopic ESCs. Meanwhile, activation of the PI3K pathway promoted the migration ability of ectopic ESCs. OPN may regulate the expression of uPA through the PI3K signal pathway to affect the migration ability of ESCs, indicating that OPN, uPA, and the PI3K pathway may be potential targets for interrupting development of endometriosis.

Expression of cellular adherent and invasive molecules in recurrent ovarian endometriosis.

OBJECTIVE: This study aimed to examine expression of cellular adhesion molecules and metalloproteinases of the extracellular matrix in ectopic endometrium for evaluating their roles in recurrence of endometriosis. METHODS: This study retrospectively analyzed 49 female patients (mean age: 30.1±5.5 years) with endometriomas who had undergone two separate operations. After a maximum follow-up of 80 months, all participants were divided into the recurrent group or nonrecurrent (control) group. Samples were immunostained for epithelial cadherin (E-cadherin), ß-catenin, urokinase plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-2, and extracellular matrix metalloproteinase inducer (EMMPRIN). RESULTS: In the recurrent group, E-cadherin concentrations in the membrane and cytoplasm of ectopic endometrial glandular cells were significantly reduced, while those of MMP-9 and EMMPRIN were higher than those in the control group. Additionally, uPA concentrations in the membrane and cytoplasm of ectopic endometrial glandular, stromal, and vascular endothelial cells were significantly higher in the recurrent group than in the control group. Tissue inhibitor of matrix metalloproteinase-2 and ß-catenin concentrations were similar between the groups. CONCLUSION: E-cadherin, MMP-9, and associated factors may contribute to development of endometriosis. E-cadherin, MMP-9, and uPA may act as potential markers for detection of recurrence of endometriosis.

Rapid prediction of crucial hotspot interactions for icosahedral viral capsid self-assembly by energy landscape atlasing validated by mutagenesis.

Icosahedral viruses are under a micrometer in diameter, their infectious genome encapsulated by a shell assembled by a multiscale process, starting from an integer multiple of 60 viral capsid or coat protein (VP) monomers. We predict and validate inter-atomic hotspot interactions between VP monomers that are important for the assembly of 3 types of icosahedral viral capsids: Adeno Associated Virus serotype 2 (AAV2) and Minute Virus of Mice (MVM), both T = 1 single stranded DNA viruses, and Bromo Mosaic Virus (BMV), a T = 3 single stranded RNA virus. Experimental validation is by in-vitro, site-directed mutagenesis data found in literature. We combine ab-initio predictions at two scales: at the interface-scale, we predict the importance (cruciality) of an interaction for successful subassembly across each interface between symmetry-related VP monomers; and at the capsid-scale, we predict the cruciality of an interface for successful capsid assembly. At the interface-scale, we measure cruciality by changes in the capsid free-energy landscape partition function when an interaction is removed. The partition function computation uses atlases of interface subassembly landscapes, rapidly generated by a novel geometric method and curated opensource software EASAL (efficient atlasing and search of assembly landscapes). At the capsid-scale, cruciality of an interface for successful assembly of the capsid is based on combinatorial entropy. Our study goes all the way from resource-light, multiscale computational predictions of crucial hotspot inter-atomic interactions to validation using data on site-directed mutagenesis' effect on capsid assembly. By reliably and rapidly narrowing down target interactions, (no more than 1.5 hours per interface on a laptop with Intel Core i5-2500K @ 3.2 Ghz CPU and 8GB of RAM) our predictions can inform and reduce time-consuming in-vitro and in-vivo experiments, or more computationally intensive in-silico analyses.

Ezrin T567 phosphorylation regulates migration and invasion of ectopic endometrial stromal cells by changing actin cytoskeleton.

AIMS: The enhanced ability of endometrial cell migration and invasion is the foundation for formation of ectopic lesions in endometriosis. Ezrin has been reported to regulate cell motility by remodeling the cytoskeleton. However, little is known about the mechanisms through which ezrin remodels the cytoskeleton and cell structure to promote cell motility in endometriosis. METHODS: In our study, expression and distribution of ezrin, and Rho pathway were detected through immunohistochemical analysis. The effects of inhibiting ezrin T567 phosphorylation on Rho signaling pathway and cytoskeleton were investigated through western blot, transmission electron microscopy and immunofluorescence analysis. KEY FINDINGS: We found that the expression of ezrin and Rho pathway was higher in ectopic endometrium. NSC305787 inhibited the phosphorylation of ezrin T567, resulting in decreased expression of Rho pathway and reduced filopodia formation in ectopic endometrial stromal cells. SIGNIFICANCE: Taken together, our study suggested that ezrin T567 phosphorylation modulated migration and invasion of ectopic ESCs through actin reconstructions, which may serve as a novel therapeutic target in ovarian endometriosis.

Autocrine Production of Interleukin-34 Promotes the Development of Endometriosis through CSF1R/JAK3/STAT6 signaling.

Interleukin (IL)-34 plays a critical role in cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and immunoregulation. Numerous diseases can be attributed to the dysregulation of IL-34 signaling. This study was performed to investigate the function of IL-34 in the pathogenesis of endometriosis. Firstly, by enzyme linked immunoabsorbent assay, we found that IL-34, VEGF, MMP-2 and MMP-9 were increased in the sera of patients with endometriosis. Secondly, exposure to IL-34 promoted the proliferation, migration and invasion of eutopic endometrial stromal cells (ESCs). Additionally, stimulation with IL-34 up-regulated colony-stimulating factor 1 receptor (CSF1R), p-JAK3, p-STAT6, VEGF, MMP-2 and MMP-9 in these eutopic ESCs. Treatment with AS1517499, an inhibitor of STAT6, remarkably abrogated the alterations induced by IL-34. A Chromatin immunoprecipitation (ChIP) assay demonstrated binding of STAT6 to the IL-34 promoter, further implicating STAT6 in IL-34 signaling. Notably, reverse results were obtained in ectopic ESCs with the application of an IL-34 neutralizing antibody. In vivo, AS1517499 suppressed the maintenance of endometriosis lesions in rats. In summary, autocrine production of IL-34, mediated by STAT6, promoted the development of endometriosis in vitro and in vivo through the CSF1R/JAK3/STAT6 pathway. Our research reveals the function of IL-34 in endometriosis, which may provide insight into novel therapeutic strategies for endometriosis.

Fertility performance and the predictive value of the endometriosis fertility index staging system in women with recurrent endometriosis: A retrospective study.

This study presents the postoperative pregnancy rate of women with recurrent endometriosis and evaluates the predictive value of the endometriosis fertility index (EFI) for the pregnancy.A total of 107 women who wished to conceive after surgery for recurrent endometriosis from January 2007 to December 2016 were included. The EFI score was calculated postoperatively. The receiver operator characteristic (ROC) curve was plotted to determine the most promising contributor to predicting pregnancy, and Kaplan-Meier (K-M) analysis was used to estimate the cumulative pregnancy rate (CPR).A total of 61 pregnancies were registered in 58 women and the remaining 49 patients failed to become pregnant. The EFI score was strongly associated with the postoperative fertility prognosis. The CPRs during the first 2 and 3 years postoperatively were 51.86% and 66.38%, respectively, and increased to 71.98% within the first 5 years postoperatively in patients with EFI scores ≥5. However, the CPR was 26.00% during the first 2 years after surgery in individuals with EFI scores <5, and there was no increase in the CRP thereafter.Women suffering from recurrent endometriosis still experienced a probability of natural pregnancy, especially patients with EFI scores ≥5. The EFI score had good predictive power for postoperative pregnancy in these patients.

Mitochondria and oxidative stress in ovarian endometriosis.

Endometriosis is associated with inflammatory reaction, and reactive oxidative species (ROS) are highly pro-inflammatory factors. Mitochondria are responsible for the production of ROS and energy. However, little is known about how mitochondria regulate ROS generation and energy metabolism in endometriosis. In our study, we investigated mitochondrial structure and function of ectopic endometrial stromal cells (ESCs) in ovarian endometriosis. We found mitochondria in ectopic ESCs generated more ROS and energy than controlled groups. Mitochondrial superoxide dismutase (SOD2), as an antioxidant enzyme, was found highly expressed in ectopic endometrium compared with normal endometrium. Due to its antioxidant role, SOD2 promoted the development of endometriosis by maintaining functional mitochondria to support high energetic metabolism of ectopic ESCs. We also showed that SOD2 promoted cell proliferation and migration in ovarian endometriosis. Inhibiting SOD2 expression reduced proliferation and migration of ectopic ESCS, and increased cell apoptosis. Therefore, understanding the role of mitochondrial dysfunction and SOD2 in ovarian endometriosis may provide new strategies to treat this disease.