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Endometriosis is a common gynecological disease, affecting up to 10% of women of reproductive age and approximately 50% of women with infertility. Circular RNAs (circRNAs) have been shown to be involved in a number of diseases. Dysregulated expression of circRNAs in endometriosis has been reported, and circ_0000673 was significantly downregulated. However, the details of its role in the pathogenesis of endometriosis are still poorly understood. We investigated the location and effects of the downregulation of circ_0000673 in endometriosis. We demonstrated that knockdown of circ_0000673 significantly increased the proliferation and migration of eutopic and normal endometrial cells. Bioinformatics analysis predicted that circ_0000673 might act as a sponge for miR-616-3p. We found that the effect of circ_0000673 knockdown could be recovered by miR-616-3p inhibitor and enhanced by miR-616-3p mimics. qPCR and western blot assays showed that circ_0000673 knockdown could decrease the expression of PTEN and increase the expression of PI3K and p-AKT. PTEN was confirmed to be a target of miR-616-3p. These results demonstrated that the downregulation of circ_0000673 could promote the progression of endometriosis by inactivating PTEN via the deregulation of miR-616-3p.

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Epithelial-mesenchymal transition (EMT) induced by estrogen contributes to the development of adenomyosis. However, the exact underlying mechanism remains mostly obscure. We hypothesized that a transmembrane glycoprotein neuropilin 1 (NRP1) was critical in the EMT induced by estrogen, accelerating the development of adenomyosis. We firstly investigated the expression pattern of NRP1 in endometrium samples from women with adenomyosis. We found that NRP1 expression was significantly increased in the endometrium of uterine adenomyosis, especially in the ectopic endometrium. To determine the role of NRP1 in the EMT in endometrial cells, we used an NRP1 overexpression retrovirus to up-regulate the NPR1 expression in human endometrial cells (HEC-1-A). Endometrial cells infected with NRP1 retroviruses showed a high expression of NRP1 and exerted a mesenchymal phenotype, characterized by down-regulation of E-cadherin and Occludin, up-regulation of α-SMA and N-cadherin, and enhanced migration. Then, we found that 17ß-estradiol (E2) up-regulated the expression of NRP1 in endometrial cells in a dose-dependent manner, which was eliminated by raloxifene, a selective estrogen receptor inhibitor. Importantly, NRP1 shRNA significantly suppressed the EMT induced by E2 in endometrial cells. And NRP1 shRNA significantly inhibited the phosphorylation of Smad3 and restored the expressions of Slug and Snail1 mRNA. Collectively, these data highlight the possible role of NRP1 in the EMT in the development of adenomyosis and provide a potential therapeutic target for adenomyosis patients.

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OBJECTIVE: To measure the expression of OATP4A1 and PGE2 in adenomyosis tissues, and to explore their roles in the incidence and development of adenomyosis-induced dysmenorrhea. METHODS: OATP4A1 mRNA and protein in the Aadenomyosis tissues with/without dysmenorrhea and normal uterus were detected. The expression of PGE2 was measured. RESULTS: OATP4A1 protein was mainly expressed on the cell membrane and in the cytoplasm of endometrial glandular cells. The IRS of OATP4A1 in the two adenomyosis groups were 3.030±1.903, and 5.200±1.789, significantly lower than 9.110±3.457 in the control group (both P<0.05). The expression levels of OATP4A1 protein in the endometrial-myometrial interface (EMI) of adenomyosis women were 15.217±6.106 and 20.085±3.633, considerably lower than 38.873±7.899 in the control group (both P<0.05). The expression levels of OATP4A1 mRNA in the adenomyosis groups were 0.593±0.281 and 0.805±0.440, significantly lower than 1.910±0.499 in the control group (both P<0.05). The expression levels of PGE2 in the three groups were 62.329±6.505, 45.099±3.192, 39.446±3.807 (pg/ml), respectively. OATP4A1 protein was negatively correlated with PGE2 expression in three groups (r = -0.598, P = 0.019; r = -0.967, P = 0.002; r = -0.663, P = 0.007). CONCLUSION: OATP4A1 is negatively correlated with PGE2, suggesting that low expression of OATP4A1 probably causes the topical accumulation of PGE2 which is proportional to the degree of pain.

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In this study, we investigated the expression of interleukin 35 (IL-35) and its receptors in endometriosis, analyzed the function of IL-35 in primary culture model of endometrial stromal cells (ESCs), and evaluated their clinicapathological significance. Peripheral blood (PB) and peritoneal fluid (PF) were collected from 37 women with endometriosis and 24 control women. The ectopic endometrium was obtained from patients with endometriosis undergoing laparoscopic surgery. The eutopic and normal endometrium were collected by endometrial biopsy. Levels of IL-35 in PB and PF were evaluated by enzyme-linked immunosorbent assay. Women with endometriosis had higher levels of IL-35 compared to controls both in PB and in PF. Levels of n IL-35 were increased in patients with advanced stage endometriosis compared to those with early stages in PF. A significant upregulation of IL-35 was observed in patients with ovarian endometriosis accompanied with pelvic implants (PI) compared to those without PI in PB and PF. The relative messenger RNA and protein expression of EBi3 and p35, the subunits of IL-35, were significantly higher in ectopic endometrium than in eutopic and healthy endometrium as measured by immunohistochemistry and quantitative polymerase chain reaction. The ESCs from endometriosis displayed a remarkable overexpression of IL-35 receptor subunits, IL12Rß2 and gp130, compared to those from controls . Moreover, recombined human IL-35 protein stimulated the upregulation of IL12Rß2 and gp130 and facilitated proliferation of ESCs. Our study provides the first evidence that IL-35 was involved in the pathogenesis of endometriosis through suppressing immunoreaction and promoting proliferation of ESCs. IL-35 may potentially serve as a biomarker for endometriosis.

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