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1.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922064

RESUMO

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions' progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances' therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.


Assuntos
Endometriose/patologia , Mediadores da Inflamação/metabolismo , Inflamação/fisiopatologia , Animais , Endometriose/metabolismo , Feminino , Humanos
2.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925708

RESUMO

Human microbiota refers to living microorganisms which colonize our body and crucially contribute to the metabolism of nutrients and various physiologic functions. According to recently accumulated evidence, human microbiota dysbiosis in the genital tract or pelvic cavity could be involved in the pathogenesis and/or pathophysiology of endometriosis. We aimed to investigate whether the composition of microbiome is altered in the peritoneal fluid in women with endometriosis. We recruited 45 women with histological evidence of ovarian endometrioma and 45 surgical controls without endometriosis. Following the isolation of extracellular vesicles from peritoneal fluid samples from women with and without endometriosis, bacterial genomic DNA was sequenced using next-generation sequencing of the 16S rDNA V3-V4 regions. Diversity analysis showed significant differences in the microbial community at phylum, class, order, family, and genus levels between the two groups. The abundance of Acinetobacter, Pseudomonas, Streptococcus, and Enhydrobacter significantly increased while the abundance of Propionibacterium, Actinomyces, and Rothia significantly decreased in the endometriosis group compared with those in the control group (p < 0.05). These findings strongly suggest that microbiome composition is altered in the peritoneal environment in women with endometriosis. Further studies are necessary to verify whether dysbiosis itself can cause establishment and/or progression of endometriosis.


Assuntos
Líquido Ascítico/microbiologia , Endometriose/microbiologia , Vesículas Extracelulares/microbiologia , Adulto , Líquido Ascítico/patologia , Bactérias/genética , Estudos de Casos e Controles , DNA Bacteriano/genética , Disbiose/complicações , Endometriose/etiologia , Endometriose/metabolismo , Vesículas Extracelulares/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Microbiota/genética , Microbiota/fisiologia , RNA Ribossômico 16S/genética
3.
Life Sci ; 274: 119291, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667515

RESUMO

AIMS: Most therapeutic drugs of endometriosis have been contraceptives but symptoms recur in up to 75% of cases, which makes it a presses need to try to find novel and safer therapeutic drugs. Imperatorin is a furanocoumarin existing in many plants, possessing multiple activities, including anti-inflammatory. The purpose of this study was to assess the effects and mechanisms of imperatorin in endometriosis. MAIN METHODS: Ectopic endometrial volume and hematoxylin-eosin staining were used to estimate the effects of imperatorin in experimental endometriosis model rats. Potential mechanisms of imperatorin in endometriosis were systematically analyzed by network pharmacology and molecular docking. Western blotting and enzyme-linked immunosorbent assay were employed to evaluate proteins expression and cytokines levels in PI3K/Akt/NF-κB pathway. KEY FINDINGS: Imperatorin could significantly inhibit the growth and ameliorate the histopathological features of ectopic endometrium in experimental endometriosis rats. Network pharmacology approaches showed that imperatorin might regulate inflammatory response and cellular function via primarily affecting PI3K-Akt pathway, Endocrine resistance, Th17 cell differentiation in endometriosis. Moreover, 7 core targets (PIK3CA, AKT1, SRC, MAPK8, MAPK14, ERBB2 and CCND1) resulted from the intersection of KEGG and PPI network topological analysis were used to dock with imperatorin, which indicated that imperatorin could preferably fit in the binding pocket of the above target proteins, except for CCND1. Lastly, imperatorin markedly inhibited the activation of PI3K/Akt/NF-κB pathway via suppressing the phosphorylation levels of PI3K, Akt and p65 in the ectopic endometrium tissue. SIGNIFICANCE: Our findings revealed that imperatorin is a significant multi-target natural active ingredient for treatment endometriosis.


Assuntos
Endometriose/tratamento farmacológico , Furocumarinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Endometriose/metabolismo , Endometriose/patologia , Feminino , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
4.
Gynecol Obstet Invest ; 86(1-2): 1-12, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33395684

RESUMO

The aim of this review is to investigate the oxidant/antioxidant status and its regulatory mechanisms in patients with endometriosis and to summarize the antioxidant therapy as an alternative to hormonal therapy for endometriosis. Each keyword alone or in combination was used to search from PubMed and Embase by applying the filters of the title and the publication years between January 2000 and March 2020. Endometriosis is a chronic inflammatory disease characterized by repeated episodes of hemorrhage. Methemoglobin in repeated hemorrhage produces large amounts of superoxide anion via the autoxidation of hemoglobin. Excessive free-radical production causes redox imbalance, leading to inadequate antioxidant defenses and damage to endometrial cells, but may contribute to endometrial cell growth and survival through activation of various signaling pathways. In addition, to overcome excessive oxidative stress, estradiol participates in the induction of antioxidants such as superoxide dismutase in mitochondria. Several antioxidants that suppress free radicals may be effective in endometriosis-related pain. We searched for 23 compounds and natural substances that could reduce the pain caused by superoxide/reactive oxygen species in basic research and animal models. Next, we built a list of 16 drugs that were suggested to be effective against endometriosis other than hormone therapy in preclinical studies and clinical trials. Of the 23 and 16 drugs, 4 overlapping drugs could be potential candidates for clinically reducing endometriosis-related pain caused by superoxide anion/reactive oxygen species. These drugs include polyphenols (resveratrol and polydatin), dopamine agonists (cabergoline), and statins (simvastatin). However, no randomized controlled trials have evaluated the efficacy of these drugs. In conclusion, this review summarizes the following 2 points: superoxide anion generation by methemoglobin is enhanced in endometriosis, resulting in redox imbalance; and some compounds and natural substances that can suppress free radicals may be effective in endometriosis-related pain. Further randomized clinical trials based on larger series are mandatory to confirm the promising role of antioxidants in the nonhormonal management of endometriosis.


Assuntos
Antioxidantes/farmacologia , Cabergolina/farmacologia , Agonistas de Dopamina/farmacologia , Endometriose/metabolismo , Glucosídeos/farmacologia , Resveratrol/farmacologia , Sinvastatina/farmacologia , Estilbenos/farmacologia , Animais , Feminino , Humanos , Metemoglobina/metabolismo , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxidos/metabolismo
5.
Molecules ; 26(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430114

RESUMO

Endometriosis is an estrogen-linked gynecological disease defined by the presence of endometrial tissue on extrauterine sites where it forms invasive lesions. Alterations in estrogen-mediated cellular signaling seems to have an essential role in the pathogenesis of endometriosis. Higher estrogen receptor (ER)-ß levels and enhanced ER-ß activity were detected in endometriotic tissues. It is well known that ER-ß interacts with components of the cytoplasmic inflammasome-3 (NALP-3), the NALP-3 activation increases interleukin (IL)-1ß and IL-18, enhancing cellular adhesion and proliferation. Otherwise, the inhibition of ER-ß activity suppresses the ectopic lesions growth. The present study aims to investigate the potential effect of α-lipoic acid (ALA) on NALP-3 and ER-ß expression using a western blot analysis, NALP-3-induced cytokines production by ELISA, migration and invasion of immortalized epithelial (12Z) and stromal endometriotic cells (22B) using a 3D culture invasion assay, and matrix-metalloprotease (MMPs) activity using gelatin zymography. ALA significantly reduces ER-ß, NALP-3 protein expression/activity and the secretion of IL-1ß and IL-18 in both 12Z and 22B cells. ALA treatment reduces cellular adhesion and invasion via a lower expression of adhesion molecules and MMPs activities. These results provide convincing evidence that ALA might inhibit endometriosis progression.


Assuntos
Endometriose/metabolismo , Endométrio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ácido Tióctico/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Endometriose/tratamento farmacológico , Endometriose/patologia , Endométrio/patologia , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
7.
Adv Exp Med Biol ; 1287: 47-57, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034025

RESUMO

The human endometrium is a unique, highly dynamic tissue that undergoes cyclic changes of cell proliferation, differentiation, and death. Endometrial cancer is the most common malignancy among women in developed countries. Importantly, the incidence of endometrial cancer is rising in high-income countries. Currently histological classification is used for subtyping of endometrial cancer, while ongoing research is evaluating markers for more accurate molecular classification. Evolutionary conserved Notch signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and cell invasion. Accumulating evidence links aberrant Notch signaling with diseases such as hyperplasia and endometrial cancer. This chapter summarizes the current state of Notch signaling investigations in the endometrium, endometriosis, and endometrial cancer.


Assuntos
Neoplasias do Endométrio , Endometriose , Receptores Notch/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endometriose/metabolismo , Endometriose/patologia , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Transdução de Sinais
8.
Transl Res ; 227: 15-29, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32640290

RESUMO

Endometriosis is a common gynecological disease in which ovarian dysfunction can be an important cause of infertility. Elevated progesterone (P4) levels during the follicular phase is possibly associated with impaired oocyte quality and pregnancy outcome in endometriosis. Beclin-1 (BECN1), an essential mediator of autophagy, has been shown to be related to the development and progression of endometriosis. This study aimed to investigate the autophagic activity in ovarian granulosa cells (GCs) of patients with endometriosis and to clarify the role of BECN1 in preovulatory P4 elevation. Our results demonstrated that serum P4/estradiol (E2) ratio and P4-to-follicle index (the average P4 secretion per follicle) on the day of human chorionic gonadotropin administration were elevated in women with ovarian endometriosis. Increased expression of BECN1 and enhanced autophagy were observed in GCs of patients with ovarian endometriomas. In cultured GCs, BECN1 knockdown reduced P4 secretion and the expression of key steroidogenic enzymes; whereas overexpression of BECN1 resulted in induced P4 production with activated biosynthesis pathway. Moreover, inhibition of autophagy by BECN1 knockdown significantly attenuated low-density lipoprotein (LDL)-induced P4 synthesis. These findings provide new insights into the role of BECN1 in late follicular P4 elevation in patients with endometriosis by promoting the degradation pathway of LDL for P4 biosynthesis via lysosome activation in GCs, and have potential therapeutic implications for the improvement of oocyte quality in women affected by endometriosis.


Assuntos
Autofagia/fisiologia , Proteína Beclina-1/fisiologia , Endometriose/metabolismo , Células da Granulosa/metabolismo , Folículo Ovariano/metabolismo , Progesterona/metabolismo , Colesterol/metabolismo , Feminino , Humanos , Gravidez , Transdução de Sinais , Injeções de Esperma Intracitoplásmicas , Regulação para Cima
9.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33179107

RESUMO

Endometriosis is closely associated with inflammatory reactions and angiogenesis. Whether PPARγ is a target for the treatment of endometriosis remains unknown. The present study was designed to investigate the impact of a PPARγ agonist (rosiglitazone, RSG) on endometriosis in a rat model and to identify the underlying mechanism. The endometriosis model was established in rats. The pathological state of the endometrium was examined using hematoxylin­eosin staining. The microstructures of interest were visualized using electron microscopy. Western blot analysis and reverse transcription­quantitative polymerase chain reaction were used to detect PPARγ and MAT2A expression. VEGF and caspase­3 expression were investigated using immunohistochemistry. Pathological analysis revealed transparent and red nodules in the model group, and that vasoganglions were present all over the nodules. Endometrial epithelial hyperplasia was observed in the model group, and the shape was columnar. Increased interstitial cell numbers, with compact structure and abundant blood supply, were detected in the model group. Compared with the model group, incomplete epithelial structures with sparse interstitial cells and loose structure were observed in the pathological images from RSG treatment groups. Numerous inflammatory cells and poor blood supply were observed in the endometrial tissues, and the gland was filled mostly with vacuolar cells. Electron microscopy revealed that the tissue structure was integrated. Many vacuoles were formed within the endometrial tissue and the classical morphological changes of apoptotic cells were observed in RSG­treated groups. Caspase­3 and PPARγ expression increased and expression of VEGF and MAT2A decreased in RSG­treated groups. Taken together, these results revealed that RSG impacts the development and progression of endometriosis likely by inhibiting angiogenesis and inducing apoptosis.


Assuntos
Endometriose/tratamento farmacológico , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Metionina Adenosiltransferase/genética , PPAR gama/genética , Rosiglitazona/administração & dosagem , Animais , Caspase 3/genética , Caspase 3/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Endometriose/etiologia , Endometriose/genética , Endometriose/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , PPAR gama/agonistas , Ratos , Rosiglitazona/farmacologia , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321760

RESUMO

Endometriosis is a chronic, inflammatory, hormone-dependent disease characterized by histological lesions produced by the presence of endometrial tissue outside the uterine cavity. Despite the fact that an estimated 176 million women are affected worldwide by this gynecological disorder, risk factors that cause endometriosis have not been properly defined and current treatments are not efficient. Although the interaction between diet and human health has been the focus of many studies, little information about the correlation of foods and their bioactive derivates with endometriosis is available. In this framework, Brassica crops have emerged as potential candidates for ameliorating the chronic inflammatory condition of endometriosis, due to their abundant content of health-promoting compounds such as glucosinolates and their hydrolysis products, isothiocyanates. Several inflammation-related signaling pathways have been included among the known targets of isothiocyanates, but those involving aquaporin water channels have an important role in endometriosis. Therefore, the aim of this review is to highlight the promising effects of the phytochemicals present in Brassica spp. as major candidates for inclusion in a dietary approach aiming to improve the inflammatory condition of women affected with endometriosis. This review points out the potential roles of glucosinolates and isothiocyanates from Brassicas as anti-inflammatory compounds, which might contribute to a reduction in endometriosis symptoms. In view of these promising results, further investigation of the effect of glucosinolates on chronic inflammatory diseases, either as diet coadjuvants or as therapeutic molecules, should be performed. In addition, we highlight the involvement of aquaporins in the maintenance of immune homeostasis. In brief, glucosinolates and the modulation of cellular water by aquaporins could shed light on new approaches to improve the quality of life for women with endometriosis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Brassica/química , Endometriose/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Animais , Aquaporinas/metabolismo , Endometriose/metabolismo , Feminino , Humanos
11.
Front Endocrinol (Lausanne) ; 11: 604648, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362719

RESUMO

Endometriosis is an inflammatory gynecological disorder characterized by endometrial tissue growth located outside of the uterine cavity in addition to chronic pelvic pain and infertility. In this study, we aim to develop a potential therapeutic treatment based on the pathogenesis and mechanism of Endometriosis. Our preliminary data showed that the expression of estrogen receptor ß (ERß) was significantly increased, while ERα was significantly decreased, in endometriotic cells compared to normal endometrial cells. Further investigation showed that betulinic acid (BA) treatment suppressed ERß expression through epigenetic modification on the ERß promoter, while had no effect on ERα expression. In addition, BA treatment suppresses ERß target genes, including superoxide dismutase 2 (SOD2), nuclear respiratory factor-1 (NRF1), cyclooxygenase 2 (COX2), and matrix metalloproteinase-1 (MMP1), subsequently increasing oxidative stress, triggering mitochondrial dysfunction, decreasing elevated proinflammatory cytokines, and eventually suppressing endometriotic cell proliferation, mimicking the effect of ERß knockdown. On the other hand, gain of ERß by lentivirus infection in normal endometrial cells resulted in increased cell proliferation and proinflammatory cytokine release, while BA treatment diminished this effect through ERß suppression with subsequent oxidative stress and apoptosis. Our results indicate that ERß may be a major driving force for the development of endometriosis, while BA inhibits Endometriosis through specific suppression of the ERß signaling pathway. This study provides a novel therapeutic strategy for endometriosis treatment through BA-mediated ERß suppression.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Endometriose/tratamento farmacológico , Receptor beta de Estrogênio/antagonistas & inibidores , Regulação da Expressão Gênica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Apoptose , Proliferação de Células , Células Cultivadas , Endometriose/metabolismo , Endometriose/patologia , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos
12.
Gene ; 757: 144926, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32621951

RESUMO

Endometriosis is a frequent gynecologic disease in the world. CircRNAs can exert a crucial role in various diseases. Nevertheless, little is known about its roles in endometriosis. We investigated the involvement of circ_0061140 in endometriosis. Tissues from endometriosis women displayed an increased expression of circ_0061140. Then, we found loss of circ_0061140 significantly repressed ectopic endometrial cell proliferation, migration and invasion. Meanwhile,miR-140-3pcan demonstrate an important role in several cancers.Here, we reported miR-140-3p was reduced in ectopic endometrial cells and it acted as a target of circ_0061140. Moreover, miR-140-3p was able to reverse the effect of circ_0061140 on ectopic endometrial cells. Furthermore, Notch2 was predicted as a putative target of miR-140-3p. A positive correlation between circ_0061140 and Notch2 was indicated. miR-140-3p and Notch2 were operated as downstream effectors in the circ_0061140 mediated signaling in endometriosis. Decrease of circ_0061140 could depress endometriosis progression through modulating miR-140-3p and Notch2.


Assuntos
Movimento Celular , Proliferação de Células , Endometriose/genética , RNA Circular/genética , Células Cultivadas , Regulação para Baixo , Endometriose/metabolismo , Endometriose/patologia , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo
13.
Sci Rep ; 10(1): 9467, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528066

RESUMO

Endometriosis are characterized by dense fibrous tissue. Numerous studies have investigated roles of inflammation on the pathophysiology of endometriosis. However, the interplay of inflammation and fibrosis remains to be clarified. Here we show that low levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-alpha (TNFα) promoted a fibrotic phenotype, whereas high levels of IL-1ß and TNFα inactivated the fibrotic phenotype of endometriotic stromal cells (Ectopic-ES). IL-1ß 10 pg/mL and TNFα 100 and 1,000 pg/mL had minimal effects, whereas the highest dose of IL-1ß (100 pg/mL) significantly decreased collagen gel contraction in Ectopic-ES. Furthermore, in Ectopic-ES, low levels of IL-1ß (1 pg/mL) and/or TNFα 10 pg/mL significantly increased Col I mRNA expression, whereas higher doses of IL-1ß (10 and/or 100 pg/mL) and/or TNFα (100 and/or 1,000 pg/mL) significantly decreased Col I and/or αSMA mRNA expression and the percentage of cells with Col I + and/or αSMA + stress fibers. In contrast, in either menstrual endometrial stromal cells of patients with endometriosis or those of healthy women, varying doses of IL-1ß and/or TNFα had no significant effects on either Col I or αSMA mRNA/protein expression. The present findings bring into question whether we should still continue to attempt anti-inflammatory treatment strategies for endometriosis.


Assuntos
Endométrio/metabolismo , Fibrose/metabolismo , Interleucina-1beta/metabolismo , Células Estromais/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Células Cultivadas , Endometriose/metabolismo , Feminino , Humanos , RNA Mensageiro/metabolismo , Adulto Jovem
14.
PLoS Genet ; 16(6): e1008601, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555663

RESUMO

Programmed cellular responses to cycling ovarian-derived steroid hormones are central to normal endometrial function. Abnormalities therein, as in the estrogen-dependent, progesterone-"resistant" disorder, endometriosis, predispose to infertility and poor pregnancy outcomes. The endometrial stromal fibroblast (eSF) is a master regulator of pregnancy success. However, the complex hormone-epigenome-transcriptome interplay in eSF by each individual steroid hormone, estradiol (E2) and/or progesterone (P4), under physiologic and pathophysiologic conditions, is poorly understood and was investigated herein. Genome-wide analysis in normal, early and late stage eutopic eSF revealed: i) In contrast to P4, E2 extensively affected the eSF DNA methylome and transcriptome. Importantly, E2 resulted in a more open versus closed chromatin, confirmed by histone modification analysis. Combined E2 with P4 affected a totally different landscape than E2 or P4 alone. ii) P4 responses were aberrant in early and late stage endometriosis, and mapping differentially methylated CpG sites with progesterone receptor targets from the literature revealed different but not decreased P4-targets, leading to question the P4-"resistant" phenotype in endometriosis. Interestingly, an aberrant E2-response was noted in eSF from endometriosis women; iii) Steroid hormones affected specific genomic contexts and locations, significantly enriching enhancers and intergenic regions and minimally involving proximal promoters and CpG islands, regardless of hormone type and eSF disease state. iv) In eSF from women with endometriosis, aberrant hormone-induced methylation signatures were mainly due to existing DNA methylation marks prior to hormone treatments and involved known endometriosis genes and pathways. v) Distinct DNA methylation and transcriptomic signatures revealed early and late stage endometriosis comprise unique disease subtypes. Taken together, the data herein, for the first time, provide significant insight into the hormone-epigenome-transcriptome interplay of each steroid hormone in normal eSF, and aberrant E2 response, distinct disease subtypes, and pre-existing epigenetic aberrancies in the setting of endometriosis, provide mechanistic insights into how endometriosis affects endometrial function/dysfunction.


Assuntos
Metilação de DNA , Endometriose/genética , Epigênese Genética , Estradiol/metabolismo , Progesterona/metabolismo , Transcriptoma , Adulto , Cromatina/genética , Cromatina/metabolismo , Ilhas de CpG , Endometriose/metabolismo , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Estradiol/farmacologia , Feminino , Humanos , Progesterona/farmacologia
15.
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
16.
Sci Rep ; 10(1): 8442, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439908

RESUMO

BACKGROUND: Endometriosis is a frequently occurring disease in women, which seriously affects their quality of life. However, its etiology and pathogenesis are still unclear. METHODS: To identify key genes/pathways involved in the pathogenesis of endometriosis, we recruited 3 raw microarray datasets (GSE11691, GSE7305, and GSE12768) from Gene Expression Omnibus database (GEO), which contain endometriosis tissues and normal endometrial tissues. We then performed in-depth bioinformatic analysis to determine differentially expressed genes (DEGs), followed by gene ontology (GO), Hallmark pathway enrichment and protein-protein interaction (PPI) network analysis. The findings were further validated by immunohistochemistry (IHC) staining in endometrial tissues from endometriosis or control patients. RESULTS: We identified 186 DEGs, of which 118 were up-regulated and 68 were down-regulated. The most enriched DEGs in GO functional analysis were mainly associated with cell adhesion, inflammatory response, and extracellular exosome. We found that epithelial-mesenchymal transition (EMT) ranked first in the Hallmark pathway enrichment. EMT may potentially be induced by inflammatory cytokines such as CXCL12. IHC confirmed the down-regulation of E-cadherin (CDH1) and up-regulation of CXCL12 in endometriosis tissues. CONCLUSIONS: Utilizing bioinformatics and patient samples, we provide evidence of EMT in endometriosis. Elucidating the role of EMT will improve the understanding of the molecular mechanisms involved in the development of endometriosis.


Assuntos
Biomarcadores/metabolismo , Biologia Computacional/métodos , Endometriose/patologia , Endométrio/patologia , Transição Epitelial-Mesenquimal , Regulação da Expressão Gênica , Adulto , Estudos de Casos e Controles , Endometriose/genética , Endometriose/metabolismo , Endométrio/metabolismo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Prognóstico , Mapas de Interação de Proteínas
17.
Sci Rep ; 10(1): 4897, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184413

RESUMO

Endometriosis shares similarities with several autoimmune diseases. The human leukocyte antigen (HLA)-C genotype is associated with several human autoimmune diseases. HLA-C is a ligand of killer cell immunoglobulin receptors (KIRs) and is an essential regulator of natural killer cell activity, which is associated with endometriosis progression. Polymorphisms in HLA-C and KIR affect the activity of NK cells and susceptibility to several diseases. Therefore, we attempted to investigate an association between HLA-C genotype and KIR polymorphism and the occurrence of endometriosis. We tested the association of certain KIR and HLA-C combinations and the development of endometriosis by characterizing both KIR and HLA-C genes in 147 women with endometriosis and 117 controls. The HLA-C genotypes and KIR polymorphisms were analyzed via DNA-based method for higher-resolution genotyping. We found that the occurrence of HLA-C*03:03*01 was increased in endometriosis than in control groups. Analysis of various KIR haplotypes revealed differences between the endometriosis and control cohorts. The number of KIR centromeric A/A haplotypes was increased in the endometriosis group than controls. Moreover, the endometriosis cohort was characterized by reduced number of KIR2DS2-positive individuals in the Han Chinese population. Our current findings suggest that the KIR and HLA-C genotypes are associated with the pathogenesis of endometriosis.


Assuntos
Endometriose/metabolismo , Antígenos HLA-C/metabolismo , Receptores KIR/metabolismo , Adulto , Endometriose/genética , Feminino , Predisposição Genética para Doença/genética , Genótipo , Antígenos HLA-C/genética , Humanos , Pessoa de Meia-Idade , Receptores KIR/genética
18.
Expert Opin Pharmacother ; 21(8): 893-903, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32164462

RESUMO

INTRODUCTION: Endometriosis is estimated to affect 10% of reproductive-aged women. The gold standard for treatment is surgery; however, surgery carries a significant morbidity and cost burden. There is an ongoing need for safe, effective medical therapies for endometriosis patients, both in conjunction with and independent of surgical interventions. Most conventional therapies for endometriosis work by a similar mechanism, and efficacy is variable. In recent years, there has been increased interest in the development and testing of novel pharmacotherapies for endometriosis. AREAS COVERED: This review discusses both conventional and emerging treatments for endometriosis. The authors present the application of these drugs in different presentations of endometriosis across the lifespan and discuss how emerging therapies might fit into future medical management of endometriosis. Conventional therapies include nonsteroidal anti-inflammatory drugs, combined oral contraceptives, progestins, GnRH agonists/antagonists, and aromatase inhibitors. Emerging therapies are focused on disease-specific targets such as endothelial growth factor receptors. EXPERT OPINION: The field of endometriosis therapy is moving toward modifying the immune and inflammatory milieu surrounding endometrial implants. If these drugs show efficacy in clinical trials, combining them with current medical treatment is expected to result in a profound impact on symptom and disease burden for patients who suffer from endometriosis worldwide.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Anticoncepcionais Orais Combinados/uso terapêutico , Endometriose/tratamento farmacológico , Hormônio Liberador de Gonadotropina , Antagonistas de Hormônios/uso terapêutico , Progestinas/uso terapêutico , Adulto , Endometriose/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Humanos , Longevidade
19.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32099996

RESUMO

Endometriosis is an inflammatory disease that primarily affects women during their reproductive years, and since current hormonal therapies are of concern, new hormone-independent treatment regimens are needed. The orphan nuclear receptor 4A1 (NR4A1, Nur77) is expressed in patient-derived (stromal) endometriotic cells and also epithelial cell lines, and we observed that knockdown of NR4A1 in patient-derived ectopic endometrium-isolated ovarian endometrioma (ESECT)-7 and ESECT-40 cells decreased cell proliferation and induced apoptosis. Moreover, the treatment of these cells with bis-indole derived NR4A1 ligands 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and its buttressed 3-chloro-5-methoxy analog (DIM-C-pPhOH-3-Cl-5-OCH3) inhibited cell growth and induced apoptosis and related genes. The compounds exhibit NR4A1 antagonist activities in both functional and transactivation assays whereas these effects were not observed in normal endometrial cells. We also observed that NR4A1 knockdown and treatment with NR4A1 antagonists decreased fibrosis, α-smooth muscle actin, and related pro-fibrotic genes in ESECT-7 and ESECT-40 cells, and similar results were observed in epithelial-derived endometriotic cell lines. Moreover, in an endometriosis mouse model with auto-transplantation and also in severe combined immune deficiency mice transplanted with human endometriotic cells treatment with 25 mg/kg/day DIM-C-pPhOH-3-Cl-5-OCH3 significantly inhibited growth and expansion of endometriotic lesions. Thus, bis-indole-derived NR4A1 ligands represent a novel class of drugs as nonhormonal therapy for endometriosis.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Endometriose/tratamento farmacológico , Endométrio/efeitos dos fármacos , Indóis/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Fenóis/farmacologia , Animais , Modelos Animais de Doenças , Endometriose/metabolismo , Endométrio/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Indóis/uso terapêutico , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fenóis/uso terapêutico
20.
Reprod Sci ; 27(1): 110-118, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32046378

RESUMO

Endometriosis (Ems) is a common gynecological disease with the characteristics of infertility, pelvic pain, and sexual intercourse difficulty. Our present study aimed to investigate the effect of miR-199a-5p on cell mobility and epithelial-mesenchymal transition (EMT) in Ems. Ectopic endometrial stromal cells (EcSCs) and control endometrial stromal cells (CSCs) were isolated in our in vitro experiments. The level of miR-199a-5p in EcSCs was found much lower than that in CSCs. Besides, miR-199a-5p mimic suppressed the invasion and migration ability of EcSCs. At the same time, EMT was also found to be suppressed by miR-199a-5p mimic in EcSCs. Our further bioinformatics analysis and luciferase reporter assay revealed that ZEB1, a marker of EMT, was a direct target of miR-199a-5p. In addition, the combination of pcDNA3.1-ZEB1 weakened the inhibiting effect of miR-199a-5p mimic on the mobility and EMT of EcSCs. What is more, the PI3K/Akt/mTOR signal pathway was demonstrated to be inactivated by miR-199a-5p mimic. And then, the inducer of PI3K/Akt/mTOR signal pathway, IGF-1, abolished the effect of miR-199a-5p mimic on Ems progression. At last, an Ems rat model was established, and we found that miR-199a-5p agomir effectively suppressed the expression of vascular endothelial growth factor (VEGF) and EMT in vivo. The PI3K/Akt/mTOR signal pathway was also inactivated by miR-199a-5p agomir in our Ems rat model. Taken together, we concluded that miR-199a-5p targeted ZEB1 to inhibit the EMT of ovarian ectopic endometrial stromal cells via PI3K/Akt/mTOR signal pathway in vitro and in vivo, advancing our understanding of miR-199a-5p as regulators of Ems progression and making contribution to the treatment of Ems.


Assuntos
Endometriose/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , MicroRNAs/metabolismo , Transdução de Sinais/fisiologia , Células Estromais/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Adulto , Animais , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
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