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1.
J Int Med Res ; 51(1): 3000605221147183, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36597409

RESUMO

OBJECTIVE: Endometriosis (EMS) is a chronic gynecological disorder with an urgent need of a reliable non-invasive diagnostic strategy. Recently, there has been increasing interest in using the contents of exosomes, especially exosomal microRNAs (miRNAs), as potential biomarkers for various types of diseases. In this study, we assessed the differentially expressed miRNAs in exosomes derived from primary normal and ectopic endometrial cells. METHODS: We used miRNA microarray analysis to identify differentially expressed exosomal miRNAs. Among the selected exosomal miRNAs, we focused on hsa-miR-202-3p and hsa-miR-202-5p and validated their expression levels using quantitative reverse transcription polymerase chain reaction analysis. We then further examined their expression in exosomes derived from vaginal discharge (leukorrhea) from patients with EMS and the negative control group. RESULTS: The data show that hsa-miR-202-3p and hsa-miR-202-5p were expressed significantly higher in leukorrhea-derived exosomes from EMS patients compared with the negative controls. CONCLUSION: Taken together, our results suggest that leukorrhea-derived exosomal hsa-miR-202 could serve as a potential useful biomarker for diagnosing EMS.


Assuntos
Endometriose , Exossomos , Leucorreia , MicroRNAs , Feminino , Humanos , Endometriose/diagnóstico , Endometriose/genética , Endometriose/metabolismo , Leucorreia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Exossomos/genética
2.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675136

RESUMO

The aim of this study was to investigate the relationship between lactoferrin and iron and its binding proteins in women with endometriosis by simultaneously measuring these parameters in plasma and peritoneal fluid. Ninety women were evaluated, of whom 57 were confirmed as having endometriosis. Lactoferrin was measured by ELISA, transferrin, ferritin and iron on a Cobas 8000 analyser. Lactoferrin and transferrin in peritoneal fluid were lower compared to plasma, in contrast to ferritin and iron. In plasma, lactoferrin showeds associations with iron and transferrin in endometriosis and with ferritin in the group without endometriosis. Lactoferrin in peritoneal fluid correlated with lactoferrin, iron and transferrin of plasma in patients without endometriosis. The ratio of lactoferrin concentration in peritoneal fluid to plasma differentiated stage I versus IV of endometriosis and was negatively correlated with the iron ratio in patients without endometriosis. The ferritin ratio differentiated women with and without endometriosis. The very high ferritin ratios, especially in advanced stages of endometriosis, suggest the protective involvement of this protein in peritoneal fluid and the loss of this role by lactoferrin. The results demonstrate the validity of assessing iron metabolism in women with endometriosis, which may be useful as a marker of the disease and its progression.


Assuntos
Líquido Ascítico , Endometriose , Humanos , Feminino , Líquido Ascítico/metabolismo , Lactoferrina/metabolismo , Endometriose/metabolismo , Ferro/metabolismo , Ferritinas/metabolismo , Transferrina/metabolismo
3.
Sci Total Environ ; 864: 161028, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36549535

RESUMO

BACKGROUND: Endometriosis is a disease affecting 10-15 % of women worldwide, consisting in the ectopic growth of endometrial cells outside the uterine cavity. Whist the pathogenetic mechanisms of endometriosis remain elusive and contemplating even environmental causes, iron deposits are common in endometrial lesions, indicating an altered iron metabolism at this level. This study was undertaken to reveal a possible relationship between iron dysmetabolism and accumulation of environmental metals. METHODS: By combining histological and histochemical analysis (H&E and Perl's staining) with µ- and nano- synchrotron-based (SR-based) X-ray Fluorescence (XRF) microscopy, we investigated the distribution of iron and other elements in the ovarian endometriomas of 12 endometriosis patients and in 7 healthy endometrium samples. RESULTS: XRF microscopy expanded the findings obtained by Perl's staining, revealing with an exceptional sensitivity intracellular features of iron accumulation in the epithelial endometrium, stroma and macrophages of the endometriotic lesions. XRF evidenced that iron was specifically accumulated in multiple micro aggregates, reaching concentrations up to 10-20 % p/p. Moreover, by XRF analysis we revealed for the first time the retention of a number of exogenous and potentially toxic metals such as Pb, Br, Ti, Al Cr, Si and Rb partially or totally co-localizing with iron. CONCLUSION: µXRF reveals accumulation and colocalization of iron and environmental metals in human ovarian endometriosis, suggesting a role in the pathogenesis of endometriosis.


Assuntos
Endometriose , Doenças Uterinas , Humanos , Feminino , Endometriose/metabolismo , Endometriose/patologia , Ferro/toxicidade , Ferro/metabolismo , Endométrio/metabolismo , Endométrio/patologia , Doenças Uterinas/metabolismo , Doenças Uterinas/patologia , Células Epiteliais/patologia
4.
Reproduction ; 165(3): 249-268, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36488194

RESUMO

In brief: Incidence of uteropathies has increased in recent times, possibly due to exposure to endocrine-disrupting chemicals during early development. The present study shows that various uteropathies like endometrial cancer, adenomyosis, and endometriosis are interlinked and occur due to the dysfunction of tissue-resident, very small embryonic-like stem cells (VSELs). Abstract: Underlying pathomechanisms leading to the initiation of uteropathies including non-receptive endometrium, hyperplasia, adenomyosis, endometriosis, fibroids, and cancer remain elusive. Two populations of stem cells exist in mouse uterus including pluripotent VSELs and 'progenitors' termed endometrial stem cells (EnSCs) which express ERα, ERß, PR, and FSHR, participate in the regular remodelling, and maintain life-long homeostasis. The present study aimed to delineate possible stem cell origins for various uteropathies. For this, mouse pups were treated with oestradiol or diethylstilbestrol and were studied for adult onset of various uteropathies. Treatment resulted in disrupted oestrous cycles, reduced uterine weights, and marked hyperplasia in both epithelial and myometrial compartments, and the stromal compartment was also affected. VSELs were increased in numbers as judged by flow cytometry and increased expression of transcripts specific for Oct-4A, Sox-2, and Nanog, but their further differentiation into a receptive endometrium was affected. Reduced 5-methyl cytosine expression suggested global hypomethylation and was associated with several oncogenic events including loss of tumour-suppressor genes (Pten, p53), dysregulated DNA mismatch repair axis, and repair enzymes. Stem cells were epigenetically altered and showed increased expression of DNMTs, loss of imprinting loci (Igf2-H19, Dlk1-Meg3), and Ezh2. Increased co-expression of CD166 and ALDHA1 with OCT-4 in stem cells was associated with increased Esr-2 and reduced Pr in the endometrium, while both were several folds upregulated in the myometrium. Study results suggest that various uteropathies ensue due to the dysfunction of tissue-resident stem cells and provide huge scope for further research.


Assuntos
Adenomiose , Endometriose , Humanos , Feminino , Camundongos , Animais , Hiperplasia/metabolismo , Endometriose/metabolismo , Útero/metabolismo , Células-Tronco Embrionárias
5.
Front Endocrinol (Lausanne) ; 13: 1035158, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36523599

RESUMO

Background: Epithelial-mesenchymal transition (EMT) is a complex event that drives polar epithelial cells transform from adherent cells to motile mesenchymal cells, in which are involved immune cells and stroma cells. EMT plays crucial roles in migration and invasion of endometriosis. The interaction of endometrial implants with the surrounding peritoneal micro-environment probably affects the development of peritoneal endometriosis. To date, very few studies have been carried out on peritoneal endometriosis sub-type classification and micro-environment analysis based on EMT. The purpose of this study is to investigate the potential application of EMT-based classification in precise diagnosis and treatment of peritoneal endometriosis. Method: Based on EMT hallmark genes, 76 peritoneal endometriosis samples were classified into two clusters by consistent cluster classification. EMT scores, which calculated by Z score of 8 epithelial cell marker genes and 8 mesenchymal cell marker genes, were compared in two clusters. Then, immune scores and the abundances of corresponding immune cells, stroma scores and the abundances of corresponding stroma cells were analyzed by the "xCell" package. Futhermore, a diagnostic model was constructed based on 9 diagnostic markers which related to immune score and stroma score by Lasso-Logistic regression analysis. Finally, based on EMT classification, a total of 8 targeted drugs against two clusters were screened out by drug susceptibility analysis via "pRRophetic" package. Results: Hallmark epithelial-mesenchymal transition was the mainly enriched pathway of differentially expressed genes between peritoneal endometriosis tissues and endometrium tissues. Compared with cluster 2, EMT score and the abundances of most infiltrating stroma cell were significantly higher, while the abundances of most infiltrating immune cells were dramatically less. The diagnostic model could accurately distinguish cluster 1 from cluster 2. Pathway analysis showed drug candidates targeting cluster 1 mainly act on the IGF-1 signaling pathway, and drug candidates targeting cluster 2 mainly block the EGFR signaling pathway. Conclusion: In peritoneal endometriosis, EMT was probably promoted by stroma cell infiltration and inhibited by immune cell infiltration. Besides, our study highlighted the potential uses of the EMT classification in the precise diagnosis and treatment of peritoneal endometriosis.


Assuntos
Endometriose , Feminino , Humanos , Endometriose/genética , Endometriose/metabolismo , Transição Epitelial-Mesenquimal/genética , Endométrio , Células Epiteliais/metabolismo , Transdução de Sinais
6.
Int J Mol Sci ; 23(24)2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36555618

RESUMO

The retrograde flow of endometrial tissues deposited into the peritoneal cavity occurs in women during menstruation. Classically (M1) or alternatively (M2) activated macrophages partake in the removal of regurgitated menstrual tissue. The failure of macrophage egress from the peritoneal cavity through the mesothelium leads to chronic inflammation in endometriosis. To study the migration differences of macrophage phenotypes across mesothelial cells, an in vitro model of macrophage egress across a peritoneal mesothelial cell monolayer membrane was developed. M1 macrophages were more sessile, emigrating 2.9-fold less than M2 macrophages. The M1 macrophages displayed a pro-inflammatory cytokine signature, including IL-1α, IL-1ß, TNF-α, TNF-ß, and IL-12p70. Mass spectrometry sphingolipidomics revealed decreased levels of ceramide-1-phosphate (C1P), an inducer of migration in M1 macrophages, which correlated with its poor migration behavior. C1P is generated by ceramide kinase (CERK) from ceramide, and blocking C1P synthesis via the action of NVP231, a specific CERK chemical inhibitor, prohibited the emigration of M1 and M2 macrophages up to 6.7-fold. Incubation with exogenously added C1P rescued this effect. These results suggest that M1 macrophages are less mobile and have higher retention in the peritoneum due to lower C1P levels, which contributes to an altered peritoneal environment in endometriosis by generating a predominant pro-inflammatory cytokine environment.


Assuntos
Endometriose , Humanos , Feminino , Endometriose/metabolismo , Macrófagos/metabolismo , Ceramidas/metabolismo , Epitélio/metabolismo , Interleucina-12/metabolismo
7.
Braz J Med Biol Res ; 55: e12375, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36515351

RESUMO

The objective of this study was to evaluate the immunohistochemical expression of Dicer, Drosha, and Exportin-5 in the eutopic and ectopic endometrium of women with adenomyosis. Twenty-two paired ectopic and eutopic endometrium from women with adenomyosis and 10 eutopic endometrium samples from control women undergoing hysterectomy were included in the study. Paraffin-embedded tissue blocks were cut and stained for immunohistochemistry. The percentage of epithelial cells positively marked was identified digitally after an automated slide scanning process. Mann-Whitney test or Wilcoxon signed-rank test was performed for independent and paired groups, respectively. A lower expression of Drosha was observed in the eutopic endometrium of women with adenomyosis than in the eutopic endometrium of women without the disease (69.9±3.4% vs 85.2±2.9%, respectively) (P=0.016; 95%CI: 3.4 to 27.4%). We also detected lower Drosha expression in the ectopic endometrium of women with adenomyosis than in the eutopic endometrium of the same women (59.6±3.2% vs 69.9±3.4%, respectively) (P=0.004; 95%CI: 2.3 to 16.7%). Additionally, we observed a correlation between Drosha expression in the ectopic and paired eutopic endometrium (P=0.034, rho=0.454). No significant difference in Dicer or Exportin expression was observed. Predominant pattern of cytoplasmic staining for the anti-Drosha antibody and both a nuclear and cytoplasmic pattern for the anti-Exportin antibody were observed. Drosha expression was significantly lower in the endometrium of women with adenomyosis compared to the eutopic endometrium of asymptomatic women without the disease. Furthermore, its expression was lower in the ectopic endometrium but correlated to the paired eutopic endometrium.


Assuntos
Adenomiose , Endometriose , Feminino , Humanos , Adenomiose/metabolismo , Endométrio/metabolismo , Imuno-Histoquímica , Histerectomia , Células Epiteliais/metabolismo , Endometriose/metabolismo , Ribonuclease III/metabolismo
8.
Biomolecules ; 12(12)2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36551177

RESUMO

The TGF-ß superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in endometriosis. Herein, we investigated the modulation of the TGF-ß type III receptor (betaglycan or BG) by activin A and inhibin A in endometriosis in vitro. Often, BG undergoes ectodomain shedding releasing soluble BG (sBG) which frequently antagonizes TGF-ß signaling. The effects of activin A on BG shedding and signaling pathways involved were evaluated with the inhibitors LY364947 and SIS3, siRNA knockdown in human endometrial cells (12Z, THESC, Ishikawa, and primary stromal cells) and were quantified with BG ELISAs. The effects of activin A and inhibin A on the secretion of MMP2 and MMP3 were analyzed using ELISAs. The effects of activin A on the BG expression were analyzed using RT-qPCR and western blot. The CCK-8 and BrdU assays were used to evaluate the effects of the recombinant BG on cell viability and proliferation. Activin A stimulation resulted in a significant time- and dose-dependent reduction in BG shedding, which was found to be activin A/ALK-4/SMAD3- but not SMAD2-dependent. Activin A increased the BG mRNA expression but had no effect on the protein expression. Likewise, inhibin A was found to block BG shedding. Activin A, but not inhibin A, significantly enhanced the secretion of MMP2 and MMP3. The recombinant BG had no effect on the viability and proliferation of endometriotic cells. Together, these observations support a novel role for activin A with BG in modulating the TGF-ß superfamily ligands in endometrial cells in vitro.


Assuntos
Receptores de Ativinas Tipo I , Ativinas , Endometriose , Receptores de Fatores de Crescimento Transformadores beta , Feminino , Humanos , Ativinas/farmacologia , Ativinas/metabolismo , Endometriose/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo
9.
Endocrinology ; 164(2)2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36524678

RESUMO

The mechanism by which endometriosis, a common gynecological disease characterized by chronic pelvic pain and infertility, causes infertility remains elusive. Luteinized unruptured follicle syndrome, the most common type of ovulatory dysfunction, is a cause of endometriosis-associated infertility involving reduced numbers of retrieved and mature oocytes. Ovulation is controlled by luteinizing hormone and paracrine signals produced within the follicle microenvironment. Generally, interleukin (IL)-1ß is elevated in endometriosis follicular fluid, whereby it amplifies ovulation signals by activating extracellular-regulated kinase 1/2 and CCAAT/enhancer binding protein ß pathways. However, this amplification of ovulation by IL-1ß does not occur in patients with endometriosis. To illuminate the mechanism of ovulatory dysfunction in endometriosis, we analyzed the effect of oxidative stress and IL-1ß expression on endometriosis follicles. We found that oxidative stress decreased EZH2 expression and reduced H3K27Me3 levels in endometriosis ovarian granulosa cells (GCs). Selective Ezh2 depletion in mice ovarian GCs reduced fertility by disturbing cumulus-oocyte complex expansion and reducing epidermal growth factor-like factor expression. Gene expression and H3K27Me3 ChIP-sequencing (ChIP-Seq) of GCs revealed IL-1 receptor 2 (IL-1R2), a high-affinity IL-1ß-receptor that suppresses IL-1ß-mediated inflammatory cascades during ovulation, as a crucial target gene of the EZH2-H3K27Me3 axis. Moreover, IL-1ß addition did not restore ovulation upon Ezh2 knockdown, indicating a vital function of IL-1R2 in endometriosis. Thus, our findings show that reducing EZH2 and H3K27Me3 in GCs suppressed ovulatory signals by increasing IL-1R2 expression, which may ultimately contribute to endometriosis-associated infertility.


Assuntos
Endometriose , Infertilidade Feminina , Animais , Feminino , Camundongos , Endometriose/complicações , Endometriose/genética , Endometriose/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Células da Granulosa/metabolismo , Histonas/metabolismo , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , Receptores Tipo II de Interleucina-1/genética , Receptores Tipo II de Interleucina-1/metabolismo , Humanos
10.
Int J Mol Sci ; 23(24)2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36555313

RESUMO

Laparoscopy as a diagnostic tool for patients with suspected endometriosis is associated with several potentially life-threatening complications. Therefore, it is imperative to identify reliable, non-invasive biomarkers of the disease. The aim of this study was to analyse the concentrations of fibronectin and type IV collagen in peritoneal fluid and plasma to assess their role as potential biomarkers in the diagnosis of endometriosis. Fibronectin and collagen IV protein levels were assessed by surface plasmon resonance imaging (SPRi) biosensors with the usage of monoclonal antibodies. All patients enrolled in the study were referred for laparoscopy for the diagnosis of infertility or chronic pelvic pain (n = 84). The study group included patients with endometriosis confirmed during surgery (n = 49). The concentration of fibronectin in the plasma (329.3 ± 98.5 mg/L) and peritoneal fluid (26.8 ± 11.1 µg/L) in women with endometriosis was significantly higher than in the control group (251.2 ± 84.0 mg/L, 7.0 ± 5.9 µg/L). Fibronectin levels were independent of endometriosis stage (p = 0.874, p = 0.469). No significant differences were observed in collagen IV levels (p = 0.385, p = 0.465). The presence of elevated levels of fibronectin may indicate abnormalities in cell-ECM signalling during the course of endometriosis, and may be a potential biomarker for early detection.


Assuntos
Endometriose , Humanos , Feminino , Endometriose/metabolismo , Líquido Ascítico/metabolismo , Fibronectinas/metabolismo , Colágeno Tipo IV/metabolismo , Biomarcadores/metabolismo
11.
Front Endocrinol (Lausanne) ; 13: 942368, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339397

RESUMO

Endometriosis is a gynecological disease prevalent in women of reproductive age, and it is characterized by the ectopic presence and growth of the eutopic endometrium. The pathophysiology and diagnostic biomarkers of endometriosis have not yet been comprehensively determined. To discover molecular markers and pathways underlying the pathogenesis of endometriosis, we identified differentially expressed genes (DEGs) in three Gene Expression Omnibus microarray datasets (GSE11691, GSE23339, and GSE7305) and performed gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network analyses. We also validated the identified genes via immunohistochemical analysis of tissues obtained from patients with endometriosis or healthy volunteers. A total of 118 DEGs (79 upregulated and 39 downregulated) were detected in each dataset with a lower (fold change) FC cutoff (log2|FC| > 1), and 17 DEGs (11 upregulated and six downregulated) with a higher FC cutoff (log2|FC| > 2). KEGG and GO functional analyses revealed enrichment of signaling pathways associated with inflammation, complement activation, cell adhesion, and extracellular matrix in endometriotic tissues. Upregulation of seven genes (C7, CFH, FZD7, LY96, PDLIM3, PTGIS, and WISP2) out of 17 was validated via comparison with external gene sets, and protein expression of four genes (LY96, PDLIM3, PTGIS, and WISP2) was further analyzed by immunohistochemistry and western blot analysis. Based on these results, we suggest that TLR4/NF-κB and Wnt/frizzled signaling pathways, as well as estrogen receptors, regulate the progression of endometriosis. These pathways may be therapeutic and diagnostic targets for endometriosis.


Assuntos
Endometriose , Humanos , Feminino , Endometriose/diagnóstico , Endometriose/genética , Endometriose/metabolismo , Biologia Computacional/métodos , Mapas de Interação de Proteínas/genética , Biomarcadores/metabolismo , Via de Sinalização Wnt
12.
Biomolecules ; 12(11)2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36359004

RESUMO

Endometriosis is a chronic inflammatory disease causing distressing symptoms and requiring a life-long management strategy. The objective of this review is to evaluate endometriosis-related pathways and identify novel therapies to treat it. We focused on the crucial role of inflammation and inflammatory molecules in order to define new perspectives for non-hormonal treatment of the disease by targeting inflammation, nuclear factor kappa B and cytokines, or reactive oxygen species, apoptotic and autophagic pathways, regulators of epithelial-mesenchymal transition, and angiogenesis and neuroangiogenesis. Novel non-steroidal therapies targeting these pathways for endometriosis were explored, but multiple challenges remain. While numerous agents have been investigated in preclinical trials, few have reached the clinical testing stage because of use of inappropriate animal models, with no proper study design or reporting of preclinical strategies. Targeting estrogens is still the best way to control endometriosis progression and inflammation.


Assuntos
Endometriose , Humanos , Feminino , Animais , Endometriose/tratamento farmacológico , Endometriose/metabolismo , Estrogênios/metabolismo , Inflamação/tratamento farmacológico , Neovascularização Patológica , Citocinas
13.
Molecules ; 27(22)2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36431970

RESUMO

Leaves and aerial parts of Malva neglecta Wallr. have been traditionally used in Anatolia for the treatment of pain, inflammation, hemorrhoids, renal stones, constipation, and infertility. This study investigated the effects of M. neglecta leaves in a rat endometriosis model. The dried plant material was extracted with n-hexane, ethyl acetate, and methanol, successively. Experimental endometriosis was surgically induced in six-week-old female, non-pregnant, Wistar albino rats by autotransplant of endometrial tissue to the abdominal wall. After twenty-eight days, rats were evaluated for a second laparotomy. Endometrial foci areas were assessed, and intraabdominal adhesions were scored. Rats were divided into five groups as control, n-hexane, ethyl acetate, methanol, and aqueous extracts, as well as reference. At the end of the treatment, all rats were sacrificed and endometriotic foci areas and intraabdominal adhesions were re-evaluated and compared with the previous findings. Moreover, peritoneal fluid was collected to detect tumor necrosis factor- α (TNF-α), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) levels, and cDNA synthesis, and a quantitative real-time polymerase chain reaction (PCR) test was done. The phytochemical content of the most active extract was determined using High-Performance Liquid Chromatography (HPLC). Both endometrial volume and adhesion score decreased significantly in the group treated with methanol extract. In addition, significant decreases were observed in TNF-α, VEGF, and IL-6 levels in animals administered methanol extract. HPLC results showed that the activity caused by the methanol extract of M. neglecta was due to the polyphenols. Taken together, these novel findings indicate that M. neglecta may be a promising alternative for the treatment of endometriosis.


Assuntos
Endometriose , Malva , Humanos , Animais , Feminino , Ratos , Endometriose/tratamento farmacológico , Endometriose/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neglecta , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Metanol , Ratos Wistar , Compostos Fitoquímicos/farmacologia
14.
Comput Math Methods Med ; 2022: 6890790, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36285283

RESUMO

Endometriosis (EMs) is a benign disease with the characteristics of invasion and migration, and its pathogenesis is related to hypoxia. The abnormal activation of glioma-associated oncogene homolog 1 (GLI1) plays an important role in the metastasis of multiple types of tumors. However, it is not clear whether GLI1 regulates the migration and invasion of endometrial stromal cells under hypoxic condition. Therefore, we use comprehensive analysis to explore the effects of hypoxic on GLI1 expression and their regulation on the pathogenesis of EMs. In this study, from immunohistochemistry, RT-qPCR, and western blot analysis, we discovered that the expression of hypoxia-induced factor-1α (HIF-1α) and GLI1 was significantly increased in eutopic and ectopic endometrium of patients with EMs. In human primary eutopic endometrial stromal cells (ESCs), hypoxia can increase the expression of HIF-1α and GLI1 in a time-dependent manner. And hypoxia could promote GLI1 expression in a HIF-1α-dependent manner. Moreover, data from transwell assays manifested that the migration and invasion ability of ESCs was significantly enhanced under hypoxia, and this effect could be reversed by silencing GLI1. Furthermore, the expression of MMP2 and MMP9 was also increased under hypoxia, while silencing GLI1 could reverse this event. In summary, our research verified that GLI1, which activated by hypoxia, may contribute to the migration and invasion of ESCs through the upregulation of MMP2 and MMP9 and can be a novel therapeutic target in EMs.


Assuntos
Endometriose , Feminino , Humanos , Endometriose/genética , Endometriose/metabolismo , Endometriose/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/farmacologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/farmacologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/farmacologia , Movimento Celular/genética , Células Cultivadas , Células Estromais/metabolismo , Células Estromais/patologia , Hipóxia/metabolismo , Hipóxia/patologia
15.
BMC Complement Med Ther ; 22(1): 254, 2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36184634

RESUMO

Endometriosis is a common gynecological disease, and its underlying mechanisms remain elusive. Patients are at a higher risk of recurrence after surgery or drug withdrawal. In this study, to identify a potentially effective and safe therapy for endometriosis, we screened potential target genes of kaempferol on endometriosis using network pharmacology and further validation. Network pharmacology showed kaempferol may suppress migratory and invasive properties by modulating the phosphoinositide 3-kinase (PI3K) pathway and its downstream target matrix metalloproteinase (MMP)9. Furthermore, in vitro experiments showed that kaempferol repressed the migration and invasion of endometrial cells, and this effect may be involved in mediating the PI3K-related genes, phosphatase and tensin homolog (PTEN) and MMP9. Network pharmacology and in vitro experiments showed that kaempferol, repressed the implantation of endometrial cells and formation of ectopic lesions by inhibiting migration and invasion and regulating PTEN and MMP9, which may be associated with the PI3K pathway.


Assuntos
Endometriose , Movimento Celular , Endometriose/tratamento farmacológico , Endometriose/genética , Endometriose/metabolismo , Feminino , Humanos , Quempferóis/farmacologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/farmacologia , Farmacologia em Rede , Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases/metabolismo , Tensinas
16.
Eur Rev Med Pharmacol Sci ; 26(20): 7594-7599, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36314331

RESUMO

OBJECTIVE: The aim of the study was to investigate the existence of neuroendocrine cells and to compare the density of those in normal ovarian tissue, endometriotic and non-endometriotic benign ovarian cysts. PATIENTS AND METHODS: Twenty patients with the diagnosis of endometrioma and 30 control subjects consisting of ovarian serous cystadenoma (n=10), ovarian mucinous cystadenoma (n=10) and normal ovarian tissue (n=10) were included. The tissues were prepared and assessed according to staining density by using the H-score method. RESULTS: Tissues with mucinous cystadenoma were significantly more stained with PAS and VanGieson, when compared to women with endometrioma. Macrophage deposition was higher in cyst samples with endometrioma and in normal ovarian tissue when compared to serous cystadenoma and mucinous cystadenoma. Normal ovarian tissue was significantly more stained with PGP9.5, NSE and SYN when compared to endometrioma and non-endometriotic benign ovarian cyst. PGP9.5 staining was higher in normal ovarian tissue when compared with endometriotic lesions (p<.001). Endometrioma samples were significantly more stained with p53 when compared to non-endometriotic cysts and normal ovarian tissue. c-Kit staining was mild and not statistically significant among all groups. CONCLUSIONS: During endometrioma transformation, expression intensity of neuroendocrine markers decreases compared to normal ovarian tissue and other benign ovarian cysts.


Assuntos
Cistadenoma Mucinoso , Cistadenoma Seroso , Endometriose , Cistos Ovarianos , Neoplasias Ovarianas , Humanos , Feminino , Endometriose/metabolismo , Cistos Ovarianos/metabolismo , Neoplasias Ovarianas/patologia
17.
J Cell Mol Med ; 26(22): 5634-5646, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36259314

RESUMO

1,25(OH)2D3 has anti-inflammatory and growth inhibitory effects. Our study explored the effect of 1,25(OH)2D3 treatment on the expression of monocyte chemotactic protein-1 (MCP-1), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1) by peripheral blood mononuclear cells (PBMCs), peritoneal fluid mononuclear cells (PFMCs), endometrial stromal cells (ESCs), and its effect on the proliferation of PBMCs and PFMCs of patients with endometriosis compared with controls. PBMCs, PFMCs, and ESCs were obtained from 10 endometriosis patients and 10 non-endometriotic individuals. After treating cells with 0.1 µM of 1,25(OH)2D3 for 6, 24, and 48 h, the gene and protein expression of mentioned factors were evaluated by real-time PCR and ELISA methods, respectively. 1,25(OH)2D3 treatment significantly reduced the protein expression of MCP-1, HGF, and IGF-1 in PBMCs and PFMCs of endometriotic patients at 48 h (p < 0.05-<0.01). Also, this treatment significantly reduced MCP-1, HGF, and IGF-1 gene and/or protein expression in EESCs and EuESCs at 24 and 48 h (p < 0.05-<0.01). 1,25(OH)2D3 treatment also reduced the proliferation of PBMCs and PFMCs of endometriotic patients compared with controls (p < 0.01). 1,25(OH)2D3 can be considered as a potentially effective agent in the prevention and treatment of endometriosis along with other therapies.


Assuntos
Endometriose , Humanos , Feminino , Endometriose/tratamento farmacológico , Endometriose/genética , Endometriose/metabolismo , Líquido Ascítico/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Leucócitos Mononucleares/metabolismo , Células Estromais/metabolismo , Células Cultivadas , Endométrio/metabolismo
18.
Int J Mol Sci ; 23(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36232884

RESUMO

Endometriosis is a disease of complex etiology. Hormonal, immunological, and environmental factors are involved in its formation. In recent years, special attention has been paid to genetic mechanisms that can have a significant impact on the increased incidence of endometriosis. The study aimed to analyze the expression of four long non-coding RNA (lncRNA) genes, UCA1, MALAT1, TC0101441, and H19, in the context of the risk of developing endometriosis. The material for genetic testing for the expression of lncRNA genes were tissue slices embedded in paraffin blocks from patients with endometriosis (n = 100) and the control group (n = 100). Gene expression was determined by the RT-PCR technique. The expression of the H19 gene in endometriosis patients was statistically significantly lower than in the control group. A statistically significant association was found between H19 gene expression in relation to The Revised American Society for Reproductive Medicine classification of endometriosis (rASRM) in the group of patients with endometriosis. Research suggests that H19 expression plays an important role in the pathogenesis of endometriosis.


Assuntos
Endometriose , RNA Longo não Codificante/metabolismo , Endometriose/metabolismo , Endometriose/patologia , Feminino , Humanos , Parafina
19.
Front Endocrinol (Lausanne) ; 13: 950866, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36204107

RESUMO

Endometriosis is a chronic, multifactorial, estrogen-dependent disease. The abnormal endocrine microenvironment of endometriosis lesions is considered a main feature and multiple enzymatic pathways leading to local increased synthesis of estrogens have been identified. However, the relevance of intracrinology in clinical practice is still lacking. Medline, Embase, Scopus database were systematically searched for studies reporting on local estrogens metabolism of endometriotic lesions. The main enzymatic pathways involved in the intracrinology of endometriosis such as aromatase (CYP19A1), 17ß-hydroxysteroid dehydrogenase (HSD17B) type 1, type 2 and type 5, steroid sulfatase (STS), estrogen sulfotransferase (SULT1E1) were assessed with a critical perspective on their role in disease endocrine phenotyping, drug resistance and as therapeutic targets. Overall, studies heterogeneity and missing clinical data affect the interpretation of the clinical role of these enzymes. Although the use of some drugs such as aromatase inhibitors has been proposed in clinical practice for two decades, their potential clinical value is still under investigation as well as their modality of administration. A closer look at new, more realistic drug targets is provided and discussed. Altered expression of these key enzymes in the lesions have far reaching implication in the development of new drugs aimed at decreasing local estrogenic activity with a minimal effect on gonadal function; however, given the complexity of the evaluation of the expression of the enzymes, multiple aspects still remains to be clarified. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022311329, identifier CRD42022311329.


Assuntos
Endometriose , Esteril-Sulfatase , Aromatase/metabolismo , Inibidores da Aromatase/uso terapêutico , Endometriose/metabolismo , Estrogênios/metabolismo , Feminino , Humanos , Esteril-Sulfatase/metabolismo
20.
Reprod Biol ; 22(4): 100697, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36306654

RESUMO

Endometriosis is a gynecological disorder seriously affecting the health and life of women of reproductive age. Neuropilin 2 (NRP2) has been indicated to display a high level in ectopic endometrium. Nevertheless, the specific function of NRP2 in endometriosis is unanswered. RT-qPCR was utilized to detect expression of NRP2 and SMAD family member 2 (SMAD2) in endometrial tissues or endometrial stromal cells (ESCs). Protein levels of transforming growth factor beta (TGF-ß) signaling-associated markers and epithelial-mesenchymal transition (EMT)-related markers were examined by western blotting. Transwell assays were utilized for detecting the impact of NRP2 on ectopic ESC phenotypes. ChIP and luciferase reporter assays were performed for identification of the relationship between NRP2 and SMAD2. In this study, NRP2 was overexpressed in ectopic endometria in comparison to eutopic endometria. Depletion of NRP2 restrained ectopic ESC migration, invasiveness and EMT. TGF-ß signaling-mediated activation of SMAD2 transcriptionally upregulated NRP2 expression in ectopic ESCs. TGF-ß treatment could rescue NRP2 silencing-induced suppressive impact on the behaviors of ectopic ESCs. Overall, the activation of TGF-ß signaling contributes to the migration and invasiveness of ectopic ESCs by targeting NRP2.


Assuntos
Endometriose , Neuropilina-2 , Fator de Crescimento Transformador beta , Feminino , Humanos , Movimento Celular/genética , Endometriose/metabolismo , Endométrio/metabolismo , Neuropilina-2/genética , Neuropilina-2/metabolismo , Células Estromais/metabolismo , Fator de Crescimento Transformador beta/metabolismo
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