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1.
Anticancer Res ; 40(5): 2429-2438, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366386

RESUMO

Endometriosis is an estrogen-dependent disease, which affects 10% of women in the reproductive age. Malignant transformation is an uncommon event, which affects approximately 0.7-2.5% of women, and, when it occurs, it involves ovarian and extraovarian sites in 75% and 25% of the cases, respectively. Endometriosis correlates with presentation of clear cell and endometrioid carcinoma of the ovary. Activation of phosphatidylinositol 3-kinase (PIK3) - protein kinase B (AKT) - mammalian target of rapamycin (mTOR) pathway, aberrant chromatin remodeling due to AT-rich interactive domain-containing protein 1A (ARID1A) mutation and inactivation of estrogen receptor-α signaling seem to play a major role in the carcinogenesis. To date, little data are available regarding endometriosis-associated extraovarian malignancies. The aim of the present study was to review the clinical, pathological and prognostic features of endometriosis-related neoplasms arising from extraovarian sites, with particular focus on intestinal malignancies, urinary tract malignancies and tumors arising from surgical scars.


Assuntos
Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/etiologia , Transformação Celular Neoplásica , Endometriose/complicações , Endometriose/patologia , Biópsia , Carcinoma Endometrioide/terapia , Estudos de Casos e Controles , Progressão da Doença , Endometriose/etiologia , Endometriose/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Estadiamento de Neoplasias , Patologistas
2.
Sci Rep ; 10(1): 1281, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992765

RESUMO

Endometriosis is estrogen-dependent disorder. Two theories provide the explanations for the increased estrogen production. One is the feed-forward loop model linking inflammation and estrogen production. The more recent model evokes the tissue hypoxia resulting from endometrial debris detached and then regurgitated to the peritoneal cavity. Both models tacitly assume that everything occurs within the endometriotic stromal cells, seemingly without the need for exogenous factors. This study was undertaken to investigate as whether platelets may be responsible for local estrogen overproduction. We employed in vitro experimentation that evaluated the 17ß-estradiol (E2) levels in endometriotic stromal cells treated with activated platelets, and the genes and protein expression levels of StAR, HSD3B2, aromatase, and HSD17B1, as well as their upstream genes/proteins such as NF-κB, TGF-ß1, HIF-1α, SF-1 and phosphorylated CREB. In addition, we conducted 2 animal experimentations using platelet depletion/infusion and also neutralization of NF-κB and TGF-ß1, followed by immunohistochemistry analysis of involved in StAR, HSD3B2, aromatase, and HSD17B1, as well as SF-1 and p-CREB. We found that treatment of endometriotic stromal cells by activated platelets increase the E2 production by 4.5 fold, and concomitant with increased gene and protein expression of StAR, HSD3B2, aromatase, and HSD17B1, the four genes/enzymes important to estrogen synthesis, along with their upstream genes HIF-1α, SF-1 and phosphorylated CREB. Moreover, platelets activate these genes through the activation of NF-κB and/or TGF-ß1, and antagonism of either signaling pathway can abolish the induction of the 4 genes and thus increased estrogen production. The two animal experimentations confirmed these changes. Thus, platelets increase the E2 production in endometriotic stromal cells through upregulation of StAR, HSD3B2, aromatase, and HSD17B1 via the activation of NF-κB and/or TGF-ß1. These findings provide a yet another compelling piece of evidence that endometriotic lesions are indeed wounds undergoing repeated tissue injury and repair. They strongly indicate that non-hormonal therapeutics for endometriosis is theoretically viable, with anti-platelet therapy being one promising avenue.


Assuntos
Plaquetas/metabolismo , Endometriose/metabolismo , Endométrio/metabolismo , Estrogênios/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Plaquetas/patologia , Endometriose/patologia , Endométrio/patologia , Feminino , Humanos , Células Estromais/metabolismo , Células Estromais/patologia
4.
Am J Pathol ; 190(1): 145-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610174

RESUMO

Repeated tissue injury and repair and fibrosis play a pivotal role in endometriosis. Fibrotic tissue consists of extracellular matrix proteins, regulated by transcriptional factors promoting cell proliferation and survival. Periostin is one of the putative key extracellular matrix proteins. This study aimed to determine whether transcription factor 21 (TCF21) is involved in the development of endometriosis as an upstream regulatory gene of periostin. Formalin-fixed, paraffin-embedded tissue samples [normal endometrium of women without endometriosis; eutopic endometrium of women with endometriosis; ovarian endometriosis (OE); and deep infiltrating endometriosis (DIE)] and respective cells were analyzed. Basal, transiently stimulated, and knocked down periostin and TCF21 concentrations in stromal cells of women with or without endometriosis were examined. Periostin and TCF21 expressions were undetected in normal endometrium of women without endometriosis, weakly positive in eutopic endometrium of women with endometriosis, moderately positive in OE, and strongly positive in DIE. Type 2 helper T-cell cytokines (IL-4, IL-13, and transforming growth factor-ß1) increased the mRNA expression of periostin and TCF21. These cytokines, periostin, and TCF21 colocalized in the stroma of OE and DIE. siRNA against human TCF21 gene suppressed periostin expression. Transfection of TCF21 plasmid vector into stromal cells of women without endometriosis, which originally expressed neither periostin nor TCF21, resulted in TCF21 and periostin expression. TCF21 and periostin are involved in the regulation of fibrosis in endometriosis. TCF21 may be a promising therapeutic target and biomarker in endometriosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Moléculas de Adesão Celular/metabolismo , Endometriose/patologia , Endométrio/patologia , Fibrose/patologia , Células Estromais/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores , Estudos de Casos e Controles , Moléculas de Adesão Celular/genética , Proliferação de Células , Células Cultivadas , Citocinas , Endometriose/genética , Endometriose/metabolismo , Endométrio/metabolismo , Feminino , Fibrose/genética , Fibrose/metabolismo , Humanos , Células Estromais/metabolismo
5.
Life Sci ; 242: 117190, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31863773

RESUMO

The alteration of PTEN expression may be a vital part of the pathological and physiological mechanisms in infertility-related with endometriosis. However, the potential mechanisms underlying abnormal expression of PTEN and its role in progesterone-resistant endometriosis have not been thoroughly elucidated. In this study, our data showed the PTEN messenger RNA (mRNA) level and protein expression was reduced in progesterone-resistant endometriosis tissue and primary stomal cells. Low levels of PTEN in endometrial stromal cells led to higher cell proliferation and resistance to progesterone. In terms of PTEN suppression in progesterone-resistant endometriosis, the mRNA level of miR-92a was correlated negatively with PTEN level. Transfection of miR-92a mimic reduced PTEN expression and made the stromal cells more resistant to progesterone treatment. Inhibition of miR-92a by its antagomir had the opposite effects. Results of the luciferase reporter assay for the 3'-nontranslated region suggested that miR-92a directly modulated PTEN levels. Moreover, miR-92a inhibition by its antagomir enhanced the therapeutic effect of progesterone, which suppressed stromal cell proliferation, and reduced the formation of ectopic lesions in the mouse model of endometriosis. Hence, this study revealed that miR-92a contributed to the development of progesterone resistant endometriosis by suppression of PTEN expression, and modulation of miR-92a might be a potential medical method of treating endometriosis.


Assuntos
Endometriose/tratamento farmacológico , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Progesterona/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Adulto , Animais , Células Cultivadas , Modelos Animais de Doenças , Resistência a Medicamentos , Endometriose/metabolismo , Feminino , Humanos , Immunoblotting , Camundongos , MicroRNAs/fisiologia , PTEN Fosfo-Hidrolase/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/metabolismo
6.
Reprod Biol Endocrinol ; 17(1): 111, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31878927

RESUMO

BACKGROUND: Previous studies of expression profiles of major endometrial effectors of steroid physiology in endometriosis have yielded markedly conflicting conclusions, presumably because the relative effects of type of endometriosis, fertility history and menstrual cycle phases on the measured variables were not considered. In the present study, endometrial mRNA and protein levels of several effectors of steroid biosynthesis and action in patients with stage III-IV ovarian endometriosis (OE) with known fertility and menstrual cycle histories were compared with the levels in control endometrium to test this concept. METHODS: Endometrial samples were collected from patients without endometriosis (n = 32) or OE stages III-IV (n = 52) with known fertility and cycle histories. qRT-PCR and immunoblotting experiments were performed to measure levels of NR5A1, STAR, CYP19A1, HSD17Bs, ESRs and PGR transcripts and proteins, respectively. Tissue concentrations of steroids (P4, T, E1 and E2) were measured using ELISAs. RESULTS: The levels of expression of aromatase and ERß were lower (P < 0.0001) and 17ß-HSD1 (P < 0.0001) and PRA (P < 0.01) were higher in OE endometrium. Lower aromatase levels and higher 17ß-HSD1 levels were detected in fertile (aromatase: P < 0.05; 17ß-HSD1: P < 0.0001) and infertile (aromatase: P < 0.0001; 17ß-HSD1: P < 0.0001) OE endometrium than in the matched control tissues. Both proliferative (PP) and secretory (SP) phase OE samples expressed aromatase (P < 0.0001) and ERß (PP: P < 0.001; SP: P < 0.01) at lower levels and 17ß-HSD1 (P < 0.0001) and PRA (PP: P < 0.01; SP: P < 0.0001) at higher levels than matched controls. Higher 17ß-HSD1 (P < 0.01) and E2 (P < 0.05) levels and a lower (P < 0.01) PRB/PRA ratio was observed in infertile secretory phase OE endometrium than in control. CONCLUSIONS: We report that dysregulated expression of 17ß-HSD1 and PGR resulting in hyperestrogenism and progesterone resistance during the secretory phase of the menstrual cycle, rather than an anomaly in aromatase expression, was the hallmark of eutopic endometrium from infertile OE patients. Furthermore, the results provide proof of concept that the fertility and menstrual cycle histories exerted relatively different effects on steroid physiology in the endometrium from OE patients compared with the control subjects.


Assuntos
Endometriose/metabolismo , Endométrio/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Doenças Ovarianas/metabolismo , Receptores de Esteroides/metabolismo , 17-Hidroxiesteroide Desidrogenases/análise , 17-Hidroxiesteroide Desidrogenases/genética , Adolescente , Adulto , Aromatase/análise , Aromatase/genética , Endométrio/química , Estradiol/análise , Feminino , Expressão Gênica , Humanos , Infertilidade Feminina/metabolismo , Ciclo Menstrual , Progesterona/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Receptores de Esteroides/genética , Adulto Jovem
7.
Int J Biol Sci ; 15(13): 2783-2797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31853218

RESUMO

Endometriosis (EMS) is the most common gynecological disease in women of reproductive age, and it is associated with chronic pelvic pain, dyspareunia and infertility. As a consequence of genetic, immune and environmental factors, endometriotic lesions have high cyclooxygenase (COX)-2 and COX-2-derived prostaglandin E2 (PGE2) biosynthesis compared with the normal endometrium. The transcription of the PTGS2 gene for COX-2 is associated with multiple intracellular signals, which converge to cause the activation of mitogen-activated protein kinases (MAPKs). COX-2 expression can be regulated by several factors, such as estrogen, hypoxia, proinflammatory cytokines, environmental pollutants, metabolites and metabolic enzymes, and platelets. High concentrations of COX-2 lead to high cell proliferation, a low level of apoptosis, high invasion, angiogenesis, EMS-related pain and infertility. COX-2-derived PGE2 performs a crucial function in EMS development by binding to EP2 and EP4 receptors. These basic findings have contributed to COX-2-targeted treatment in EMS, including COX-2 inhibitors, hormone drugs and glycyrrhizin. In this review, we summarize the most recent basic research in detail and provide a short summary of COX-2-targeted treatment.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Endometriose/enzimologia , Animais , Dinoprostona/metabolismo , Endometriose/genética , Endometriose/metabolismo , Estrogênios/metabolismo , Feminino , Humanos , Dor/metabolismo
8.
Int J Mol Sci ; 20(21)2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31731537

RESUMO

Ovarian cancer and endometriosis are two distinct gynaecological conditions that share many biological aspects incuding proliferation, invasion of surrounding tissue, inflammation, inhibition of apoptosis, deregulation of angiogenesis and the ability to spread at a distance. miRNAs are small non-coding RNAs (19-22 nt) that act as post-transcriptional modulators of gene expression and are involved in several of the aforementioned processes. In addition, a growing body of evidence supports the contribution of oxidative stress (OS) to these gynaecological diseases: increased peritoneal OS due to the decomposition of retrograde menstruation blood facilitates both endometriotic lesion development and fallopian tube malignant transformation leading to high-grade serous ovarian cancer (HGSOC). Furthermore, as HGSOC develops, increased OS levels are associated with chemoresistance. Finally, continued bleeding within ovarian endometrioma raises OS levels and contributes to the development of endometriosis-associated ovarian cancer (EAOC). Therefore, this review aims to address the need for a better understanding of the dialogue between miRNAs and oxidative stress in the pathophysiology of ovarian conditions: endometriosis, EAOC and HGSOC.


Assuntos
Endometriose , MicroRNAs , Neoplasias Ovarianas , Estresse Oxidativo , RNA Neoplásico , Animais , Endometriose/genética , Endometriose/metabolismo , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , RNA Neoplásico/genética , RNA Neoplásico/metabolismo
9.
J Ovarian Res ; 12(1): 98, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639028

RESUMO

BACKGROUND: Endometriosis patients undergoing in vitro fertilization-embryo transfer (IVF-ET) treatment suffer from lower success rates. The success of IVF-ET is related to the receptivity of the uterus and the quality of embryos, and it is well known a patient's endometriosis does not impair the receptivity. Whether endometrioma should be removed surgically before IVF remains controversial. Studies have shown that endometrioma removal decreases peritoneal inflammation, but little information is available regarding the alteration in the cytokines of follicular fluid. The objective of this study was to examine the impact of endometrioma cystectomy on the outcome of IVF and the levels of intrafollicular inflammatory cytokines and to investigate correlations between cytokine concentrations and IVF outcomes. METHOD: A total of 41 women with endometriosis-associated infertility undergoing IVF were recruited; 13 patients (surgery group, S group) had surgery to remove the endometrioma before enrollment, and 28 patients (non-surgery group, NS group) were untreated before IVF. The follicular fluid from a dominant follicle was collected during oocyte retrieval, and the concentrations of sixteen soluble cytokines known to be involved in ovarian function were measured. RESULTS: Among the soluble molecules examined in this study, chemokines and growth factors and a few are inflammatory cytokines were found in the follicular fluid of patients with endometriosis. In addition, the expression levels of chemokines, growth factors, and most inflammatory cytokines did not differ between the S and NS groups, but interleukin (IL)-18 levels were significantly lower in the NS group. However, the levels of IL-18 in the FF did not correlate with IVF cycle parameters. The implantation and clinical pregnancy rates were similar between the two groups, but the anti-Müllerian hormone (AMH) level was lower in the S group than in the NS group. CONCLUSIONS: These findings suggest that endometrioma surgery may potentially reduce the ovarian reserve and has little impact on the success rate of IVF. Ovarian endometriomas are not associated with cytokine profiles in FF from infertile women, and they are not likely to affect the quality of the oocyte and embryo as a result of an inflammatory mechanism.


Assuntos
Citocinas/metabolismo , Endometriose/metabolismo , Endometriose/cirurgia , Fertilização In Vitro , Líquido Folicular/metabolismo , Infertilidade Feminina/etiologia , Adulto , Biomarcadores , Endometriose/complicações , Endometriose/diagnóstico , Feminino , Humanos , Recuperação de Oócitos , Avaliação de Resultados em Cuidados de Saúde , Indução da Ovulação , Índice de Gravidade de Doença , Adulto Jovem
10.
Mol Med Rep ; 20(6): 4781-4790, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638263

RESUMO

Oxidative stress and dysregulation of antioxidant systems are associated with various complications in pregnancy. Endometriosis is a common gynecologic disease that affects women of reproductive age. Recent studies have indicated that oxidative stress may be involved in the pathophysiology of endometriosis. It has been reported that microRNAs can regulate the cellular response to oxidative stress, and mounting evidence indicates that fatty acid binding protein 4 (FABP4) plays an essential role in the regulation of systemic redox capacity. In the present study, we demonstrated that miR­455 is a putative FABP4­targeting miRNA. A luciferase activity assay revealed that miR­455 can successfully bind to the 3'­UTR of FABP4. Overexpression of miR­455 led to the downregulation of FABP4 at both the mRNA and protein levels in a human endometrial stromal cell line. Then, the roles of miR­455 and FABP4 in oxidative stress induced by hydrogen peroxide (H2O2) in human endometrial stromal cells were examined. We found that ectopic expression of miR­455 protected cells from damage caused by H2O2. Further investigation found that forced expression of miR­455 reduced the level of reactive oxygen species (ROS) and malondialdehyde (MDA), while the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH­Px) were promoted. Silencing of FABP4 also generated cytoprotective effects against H2O2 in human endometrial stromal cells. Moreover, overexpression FABP4 abrogated the miR­455­mediated antioxidative stress effects in cells. Taken together, we propose that miR­455 protects human endometrial stromal cells from oxidative stress at least partly via regulation of FABP4.


Assuntos
Endométrio/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , MicroRNAs/genética , Estresse Oxidativo , Apoptose , Linhagem Celular , Regulação para Baixo , Endometriose/genética , Endometriose/metabolismo , Endométrio/citologia , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , MicroRNAs/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo , Regulação para Cima
11.
Artigo em Inglês | MEDLINE | ID: mdl-31574938

RESUMO

Objective: The association between phthalates and endometriosis risk is inconclusive. This meta-analysis aims to evaluate the association between five different phthalate metabolites and endometriosis, based on current evidence. Methods: The literature included PubMed, WOS (web of science), and EMBASE, published until 3 March 2019. We selected the related literature and evaluated the relationship between phthalates exposure and endometriosis risk. All statistical analyses were conducted with STATA version 12.0. Results: Data from eight studies were used in this review. The results of this analysis showed that mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) exposure was potentially associated with endometriosis (OR = 1.246, 95% CI = 1.003-1.549). We have not found positive results in mono(2-ethylhexyl) phthalate (MEHP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) analyses (MEHP: OR = 1.089, 95% CI = 0.858-1.383; MEP: OR = 1.073, 95% CI = 0.899-1.282; MBzP: OR = 0.976, 95% CI = 0.810-1.176; MEOHP: OR = 1.282, 95% CI = 0.874-1.881). In subgroup analyses for regions, the associations were significant between MEHHP and endometriosis in Asia (OR = 1.786, 95% CI = 1.005-3.172, I² = 0%), but not in USA (OR = 1.170, 95% CI = 0.949-1.442, I² = 45.6%). Conclusions: Our findings suggested a potential statistical association between MEHHP exposure and endometriosis, particularly, the exposure of MEHHP might be a potential risk for women with endometriosis in Asia. However, positive associations between the other four Phthalate acid esters (PAEs) and endometriosis was not found. Given the weak strength of the results, well-designed cohort studies, with large sample sizes, should be performed in future.


Assuntos
Endometriose/epidemiologia , Ácidos Ftálicos/metabolismo , Monitoramento Biológico , Endometriose/metabolismo , Feminino , Humanos , Fatores de Risco
12.
Endocrinology ; 160(11): 2495-2516, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504401

RESUMO

Estrogen receptor (ER) ß plays a critical role in endometriosis progression because cytoplasmic ERß stimulates proinflammatory signaling in ectopic lesions and prevents apoptosis to promote their survival. However, the role of "nuclear ERß" in endometriosis progression is not known. This critical knowledge gap obscures our understanding of the full molecular etiology of ERß-mediated endometriosis progression. To fill this void, we generated an ERß-regulated transcriptome and ERß cistrome in ectopic lesions and the eutopic endometrium of mice with endometriosis by using a new endometrium-specific FLAG-tagged human ERß overexpression mouse model. The integration of these omics data sets revealed that ERß stimulated the proliferation activities of ectopic lesions and the eutopic endometrium by directly upregulating MYC and E2 transcription factor target genes and genes associated with the G2/M transition. Additionally, ERß stimulated gene expression associated with TNFα/nuclear factor κB (NF-κB) signaling, epithelial-mesenchymal transition, reactive oxygen species signaling, IL-6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling, and hypoxia signaling and suppressed IFNα signaling in ectopic lesions to enhance endometriosis progression. ERß also stimulated gene expression associated with the unfolded protein response and IL-6/JAK/STAT3 inhibitory signaling and suppressed TNFα/NF-κB signaling in the eutopic endometrium to cause endometriosis-associated endometrial dysfunction. Therefore, nuclear ERß-regulated gene networks provide critical clues to understand the molecular etiology and complexity of endometriosis and endometriosis-associated endometrial dysfunction.


Assuntos
Endometriose/metabolismo , Receptor beta de Estrogênio/metabolismo , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Animais , Endométrio/metabolismo , Feminino , Humanos , Interferons/metabolismo , Camundongos Endogâmicos C57BL
13.
Mol Biol Rep ; 46(5): 4675-4684, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31529342

RESUMO

The purpose of this study was to test the hypothesis that different cytokine profiles may exist in the follicular fluid of endometriosis (EM) patients undergoing in vitro fertilization (IVF), as these differences may provide insights into the pathogenesis of the disease. This was a cross-sectional study conducted at the reproductive center of a medical university hospital. The study included 49 patients receiving IVF. 20 infertile women with proven EM and 29 women without diagnosed EM (control group) were evaluated. Follicular fluid (FF) and serum were collected at the time of follicle aspiration and the concentrations of 38 cytokines were determined by multiplexed immunoassay. The results indicated that the levels of IL-4, IL-13, IL-3 and IL-1α were significantly increased in the FF of women with EM, while levels of IFN-γ, IL-17A, MDC and MIP-1α were decreased compared with in the control subjects. In conclusions, the immune microenvironment of the FF in patients with EM is altered. This may contribute to the pathologic mechanism responsible for the poor outcome of IVF in patients with EM.


Assuntos
Microambiente Celular/imunologia , Endometriose/diagnóstico , Endometriose/etiologia , Folículo Ovariano/imunologia , Biomarcadores , Citocinas/biossíntese , Citocinas/sangue , Endometriose/metabolismo , Feminino , Fertilização In Vitro/efeitos adversos , Líquido Folicular/imunologia , Líquido Folicular/metabolismo , Hormônios/sangue , Hormônios/metabolismo , Humanos , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia
14.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491902

RESUMO

This study aimed to investigate the effect of gonadotropin-releasing hormone agonist (GnRHa) treatment on the expression of neuritin 1 (NRN1) in women with ovarian endometriosis. We collected tissues and serum from women with endometriosis treated with (n = 45) or without (n = 37) GnRHa. NRN1 mRNA and protein levels were measured using qPCR and Western blot. Immunolocalization of NRN1 in endometriotic tissues was examined using immunohistochemistry. In addition, a follow-up study was carried out to monitor the serum level of NRN1 in patients before and after GnRHa treatment. Both mRNA (p = 0.046) and protein (p = 0.0155) levels of NRN1 were significantly lower in endometriotic tissues from patients receiving GnRHa treatment compared to the untreated group. Both epithelial and stromal cells of endometriotic tissues from untreated women with endometriosis exhibited stronger staining of NRN1 but not in those who were treated with GnRHa. The follow-up study showed that the serum level of the NRN1 concentration decreased significantly from 1149 ± 192.3 to 379.2 ± 80.16 pg/mL after GnRHa treatment (p = 0.0098). The expression of NRN1 was significantly lower in women with ovarian endometriosis treated with GnRHa. These results suggest that NRN1 may be a biomarker response to the effect of GnRHa treatment for patients with ovarian endometriosis.


Assuntos
Endometriose/etiologia , Endometriose/metabolismo , Hormônio Liberador de Gonadotropina/agonistas , Neuropeptídeos/genética , Ovário/patologia , Adulto , Biomarcadores , Biópsia , Endometriose/tratamento farmacológico , Endometriose/patologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Pessoa de Meia-Idade , Neuropeptídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
15.
Bull Exp Biol Med ; 167(4): 504-507, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31494765

RESUMO

We studied the expression of ARID1A, prostaglandin E2 synthase, and prostaglandin E2 receptor in the endometrium and ovarian, peritoneal, and intestinal endometrioid heterotopies in women with endometriosis of young and middle reproductive age. ARID1A protein is a tumor suppressor, its expression reduced in different types of cancer. Prostaglandin E2 synthase and prostaglandin E2 receptor are involved in the signaling cascade of inflammatory reactions presumably underlying the development of endometriosis. In endometrioid heterotopies, expression of ARID1A was reduced in 1.2-4.0 times, the expression of prostaglandin E2 synthase and prostaglandin E2 receptor was reduced in 2.9-5.2 times These findings suggest that ARID1A, prostaglandin E2 synthase, and prostaglandin E2 receptor can be used as predictors of malignant transformation of endometrioid heterotopies in women with endometriosis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Dinoprostona/metabolismo , Endometriose/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Proteínas de Ligação a DNA/genética , Dinoprostona/genética , Endometriose/genética , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Fatores de Transcrição/genética , Adulto Jovem
16.
J Pathol ; 249(4): 485-497, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31418859

RESUMO

An elevated level of IL-10 has been considered a critical factor for the development of endometriosis; however, its detailed mechanism and causal relationship remain unclear. This study explored the cellular source and angiogenic activity of local IL-10 during the early stage of endometriosis. Using a surgical murine model, we found that localised treatment with exogenous recombinant IL-10 on the day of surgery significantly enhanced endometriotic lesion growth and angiogenesis, whereas blocking local IL-10 activity using mAbs significantly suppressed those effects. Adoptive transfer of Il10+/+ plasmacytoid dendritic cells into mice significantly enhanced lesion development, whereas Il10-/- plasmacytoid dendritic cells significantly inhibited lesion development. Furthermore, in vitro angiogenesis analyses demonstrated that the IL-10 and IL-10 receptor pathway stimulated the migratory and tube formation ability of HUVECs as well as ectopic endometrial mesenchymal stem cells through, at least in part, a VEGF-dependent pathway. We also found that recombinant IL-10 directly stimulated angiogenesis, based on a Matrigel plug assay as well as a zebrafish model. Pathological results from human endometrioma tissues showed the increased infiltration of CD123+ plasmacytoid dendritic cells and higher percentages of cells that express the IL-10 receptor and CD31 as compared with the corresponding normal counterparts. Taken together, these results show that IL-10 secreted from local plasmacytoid dendritic cells promotes endometriosis development through pathological angiogenesis during the early disease stage. This study provides a scientific basis for a potential therapeutic strategy targeting the IL-10-IL-10 receptor pathway in the endometriotic milieu. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Células Dendríticas/metabolismo , Endometriose/metabolismo , Endométrio/irrigação sanguínea , Interleucina-10/metabolismo , Neovascularização Patológica , Comunicação Parácrina , Transferência Adotiva , Adulto , Animais , Apoptose , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/patologia , Células Dendríticas/transplante , Modelos Animais de Doenças , Endometriose/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Interleucina-10/deficiência , Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Pessoa de Meia-Idade , Receptores de Interleucina-10/metabolismo , Transdução de Sinais , Adulto Jovem , Peixe-Zebra
17.
RNA Biol ; 16(12): 1733-1748, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31425004

RESUMO

The detailed pathogenesis of endometriosis remains largely unclear despite decades of research. Recent studies have demonstrated that miRNAs plays an important role in endometriosis. The expression of miR-142-3p was decreased in ectopic endometrial tissues, while KLF9 and VEGFA expression levels were increased. Overexpression of miR-142-3p or knockdown of KLF9 significantly suppressed CRL-7566 cell proliferation and metastasis, induced cell apoptosis, and decreased both cell autophagy and vascularization. Additionally, KLF9 was confirmed to be a direct target of miR-142-3p and to directly bind to the promoter of the VEGFA gene, regulating its expression. Finally, intraperitoneal injection of miR-142-3p lentivirus significantly attenuated ectopic endometriotic lesions in vivo.miR-142-3p directly targeted KLF9, regulated VEGFA expression, and was protective against the growth of ectopic endometriotic lesions. Therefore, the miR-142-3p/KLF9/VEGFA signalling pathway may be a potential target in endometriosis treatment.


Assuntos
Autofagia/genética , Coristoma/genética , Endometriose/genética , Fatores de Transcrição Kruppel-Like/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Apoptose/genética , Pareamento de Bases , Sequência de Bases , Linhagem Celular , Proliferação de Células , Coristoma/metabolismo , Coristoma/patologia , Modelos Animais de Doenças , Endometriose/metabolismo , Endometriose/patologia , Endométrio/metabolismo , Endométrio/patologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Regiões Promotoras Genéticas , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Reprod Biol ; 19(3): 225-229, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416694

RESUMO

Endometriosis can impair fertility by reducing ovarian reserve and the production of good-quality oocytes. The surgical removal of endometriotic lesions is generally recommended for women who wish to conceive. In this paper we studied whether ovarian cortex adjacent to excised small (diameter ≤ 4 cm) endometriotic cyst (here referred as Cortex Surrounding Endometriotic Cyst, CSEC) showed signs of tissue damages by evaluating the expression of proteins involved in DNA repair and apoptosis. To this end, phosphorylated H2A.X, Chk1 and 2, ATM and ATR, Bcl-2, Bid, phosphorylated and total p53, caspases (9, 8 and 3), XIAP, phosphorylated and total NFκB were analyzed by western blot. Results showed that caspase 8, XIAP, p53/p-p53 and NFκB were more abundantly expressed in all samples of CSEC group in comparison with ovarian cortex of controls. Conversely, the levels of the other proteins were comparable between the two groups. In conclusion, these results suggest that NFκB, caspase 8 and p53/p-p53 elevated expressions in samples of CSEC can be considered as an early sign of tissue injury, indicating that ovarian cortex is already sensitized to apoptosis and inflammation. Therefore, excision of EC should occur very early, to avoid further ovarian damages.


Assuntos
Apoptose/fisiologia , Cistos/patologia , Reparo do DNA/fisiologia , Endometriose/metabolismo , Ovário/metabolismo , Biomarcadores , Cistos/metabolismo , Endometriose/patologia , Feminino , Regulação da Expressão Gênica , Humanos
19.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370190

RESUMO

Endometriosis is characterized by the presence of endometrial tissue outside the uterus. While endometriotic tissue is commonly localized in the pelvic cavity, it can also be found in distant sites, including the brain. The origin and pathophysiology of tissue migration is poorly understood; retrograde menstruation is thought to be the cause, although the presence of endometrium at distant sites is not explained by this hypothesis. To determine whether dissemination occurs via the bloodstream in women with endometriosis, we analyzed circulating blood for the presence of endometrial cells. Circulating endometrial stromal cells were identified only in women with endometriosis but not in controls, while endometrial epithelial cells were not identified in the circulation of either group. Our results support the hypothesis that endometrial stromal cells may migrate through circulation and promote the pathophysiology of endometriosis. The detection of these cells in circulation creates avenues for the development of less invasive diagnostic tools for the disease, and opens possibilities for further study of the origin of endometriosis.


Assuntos
Endometriose/diagnóstico , Endométrio/patologia , Células Estromais/patologia , Adolescente , Adulto , Biomarcadores/metabolismo , Circulação Sanguínea , Estudos de Casos e Controles , Movimento Celular , Endometriose/metabolismo , Endometriose/patologia , Endométrio/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Expressão Gênica , Humanos , Biópsia Líquida , Neprilisina/genética , Neprilisina/metabolismo , Projetos Piloto , Células Estromais/metabolismo
20.
Reprod Biol Endocrinol ; 17(1): 70, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31445519

RESUMO

BACKGROUND: Endometriosis is the growth of uterine lining (endometrium) outside of the uterus. In other chronic inflammatory diseases, mitochondrial dysfunction is suspected of playing a role in disease pathogenesis. However, little is known about endometriosis mitochondrial function or its effects on tissue metabolism. The objectives of this study were to analyze mitochondrial function in nonhuman primate (NHP) endometrium and endometriosis tissue and to identify the metabolic features of these tissues that may contribute to disease. METHODS: Mitochondrial function in endometriosis tissue and endometrium was measured using mitochondrial respirometry analysis to determine if changes in oxidative phosphorylation exist in endometrium and endometriosis tissue compared to control endometrium from clinically healthy NHPs. Targeted metabolomics and multidimensional statistical analysis were applied to quantify key metabolites in energy and amino acid biosynthesis pathways. RESULTS: Mitochondrial respirometry assays showed endometrium from NHPs with endometriosis had reduced complex II-mediated oxygen consumption rates (OCR) across all energy states (basal, p = 0.01; state 3, p = 0.02; state 3u, p = 0.04; state 4o, p = 0.008) and endometriosis tissue had reduced state 3, complex I-mediated OCR (p = 0.02) and respiratory control rates (p = 0.01) compared to normal endometrium. Targeted metabolomics performed on tissue revealed carnitine (p = 0.001), creatine phosphate (p = 0.01), NADH (p = 0.0001), FAD (p = 0.001), tryptophan (p = 0.0009), and malic acid (p = 0.005) were decreased in endometriosis tissue compared to normal endometrium samples. FAD (p = 0.004), tryptophan (p = 0.0004) and malic acid (p = 0.03) were significantly decreased in endometrium from NHPs with endometriosis compared to normal endometrium. Significant metabolites identified in endometriosis and endometrium samples from animals with endometriosis were part of amino acid biosynthesis or energy metabolism pathways. CONCLUSIONS: Here, endometrial mitochondrial energy production and metabolism were decreased in endometrium and endometriosis tissue. Decreased mitochondrial energy production may be due to oxidative stress-induced damage to mitochondrial DNA or membranes, a shift in cell metabolism, or decreased energy substrate; however, the exact cause remains unknown. Additional research is needed to determine the implications of reduced mitochondrial energy production and metabolism on endometriosis and endometrium.


Assuntos
Endometriose/metabolismo , Endométrio/metabolismo , Metabolismo Energético , Macaca fascicularis/metabolismo , Macaca mulatta/metabolismo , Mitocôndrias/metabolismo , Animais , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Endometriose/patologia , Feminino , Humanos , Primatas/classificação , Primatas/metabolismo , Especificidade da Espécie
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