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Background. Although radiation exposure is of great concern to expecting patients, little information is available on the fetal radiation dose associated with prophylactic internal iliac artery balloon occlusion (IIABO). Here we estimated the fetal radiation dose associated with prophylactic IIABO in Caesarean section (CS). Cases. We report our experience with the IIABO procedure in three consecutive patients with suspected placenta previa/accreta. Fetal radiation dose measurements were conducted prior to each CS by using an anthropomorphic phantom. Based on the simulated value, we calculated the fetal radiation dose as the absorbed dose. We found that the fetal radiation doses ranged from 12.88 to 31.6 mGy. The fetal radiation dose during the prophylactic IIABOs did not exceed 50 mGy. Conclusion. The IIABO procedure could result in a very small increase in the risk of harmful effects to the fetus.
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Mayer-Rokitanski-Kuster-Hauser (MRKH) syndrome is a rare disease. A 27-year-old woman was admitted for primary amenorrhea and cyclic pelvic pain. Magnetic resonance imaging (MRI) revealed bilateral Müllerian remnants with functioning endometrium and a pelvic mass considered to be an endometriotic cyst. Bilateral Müllerian remnants were removed, and right ovarian cystectomy was performed at laparoscopic surgery. Accurate evaluation before the operation and informed consent are necessary to treat patients with MRKH syndrome.
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Successful human pregnancy requires extensive invasion of maternal uterine tissues by the placenta. Invasive extravillous trophoblasts derived from cytotrophoblast progenitors remodel maternal arterioles to promote blood flow to the placenta. In the pregnancy complication preeclampsia, extravillous trophoblasts invasion and vessel remodeling are frequently impaired, likely contributing to fetal underperfusion and maternal hypertension. We recently demonstrated in mouse trophoblast stem cells that hypoxia-inducible factor-2 (HIF-2)-dependent Lim domain kinase 1 (LIMK1) expression regulates invasive trophoblast differentiation by modulating the trophoblast cytoskeleton. Interestingly, in humans, LIMK1 activity promotes tumor cell invasion by modulating actin and microtubule integrity, as well as by modulating matrix metalloprotease processing. Here, we tested whether HIF-2α and LIMK1 expression patterns suggested similar roles in the human placenta. We found that LIMK1 immunoreactivity mirrored HIF-2α in the human placenta in utero and that LIMK1 activity regulated human cytotrophoblast cytoskeletal integrity, matrix metallopeptidase-9 secretion, invasion, and differentiation in vitro. Importantly, we also found that LIMK1 levels are frequently diminished in the preeclampsia setting in vivo. Our results therefore validate the use of mouse trophoblast stem cells as a discovery platform for human placentation disorders and suggest that LIMK1 activity helps promote human placental development in utero.
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Regulación del Desarrollo de la Expresión Génica , Quinasas Lim/metabolismo , Preeclampsia/metabolismo , Trofoblastos/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular , Movimiento Celular , Citoesqueleto/metabolismo , Regulación hacia Abajo , Femenino , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Microscopía Fluorescente , Placenta/metabolismo , Placentación , Embarazo , Tercer Trimestre del Embarazo , Transducción de Señal , Células Madre/citología , Trofoblastos/citologíaRESUMEN
While mature cystic teratoma of the ovary is the most common ovarian tumor in young women, immature teratoma is a very rare tumor, representing only 1% of all ovarian cancers. In the three cases presented here, young women who were suspected to have mature cystic teratoma, based on CT scan and MRI, were ultimately diagnosed with immature teratoma Ic (b) G1 after laparoscopic operation. They underwent salpingo-oophorectomy of the affected side only and have shown no sign of recurrence during follow-up. We sometimes encounter patients with immature teratoma who have no findings pointing to malignancy on CT or MRI. Generally, if the components of immature nerve cells that represent immature teratoma are very few, it is difficult to diagnose the entity as immature teratoma with imaging evaluations such as CT or MRI. In many hospitals, laparoscopic surgery is selected for patients with ovarian mature teratoma. Therefore, it is essential to attempt as much as possible not to disseminate the fluid content of the tumor into the intra-abdominal space during laparoscopic operation, because in rare cases the tumor turns out not to be benign mature teratoma.
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CONTEXT: During the development of endometriotic lesions, excess fibrosis may lead to scarring and to the alterations of tissue function that are the characteristic features of this disease. Enhanced extracellular matrix contractility of endometriotic stromal cells (ECSC) mediated by the mevalonate-Ras homology (Rho)/Rho-associated coiled-coil-forming protein kinase (ROCK) pathway has been shown to contribute to the pathogenesis of endometriosis. DESIGN: To assess the use of fasudil, a selective ROCK inhibitor, for the medical treatment of endometriosis-associated fibrosis, the effects of this agent on the cell proliferation, apoptosis, cell cycle, morphology, cell density, and contractility of ECSC were investigated. The effects of fasudil on the expression of contractility-related, apoptosis-related, and cell cycle-related molecules in ECSC were also evaluated. RESULTS: Fasudil significantly inhibited the proliferation and contractility of ECSC and induced the cell cycle arrest in the G2/M phase and apoptosis of these cells. Morphological observation revealed the suppression of ECSC attachment to collagen fibers and decrease of cell density by fasudil. The expression of α-smooth muscle actin, RhoA, ROCK-I, and ROCK-II proteins was inhibited by fasudil administration. The expression of the antiapoptotic factors, Bcl-2 and Bcl-X(L), in two-dimensional cultured ECSC were down-regulated by the addition of fasudil, whereas, the expression of p16(INK4a) and p21(Waf1/Cip1) was up-regulated by the addition of fasudil. CONCLUSIONS: The present findings suggest that fasudil is a promising agent for the treatment of endometriosis. The inhibition of cell proliferation, contractility, and myofibroblastic differentiation, the attenuation of attachment to collagen fibers, the decrease of cell density, and the induction of cell cycle arrest and apoptosis of ECSC are involved in the active mechanisms of fasudil.
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1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Endometriosis/patología , Enfermedades del Ovario/patología , Inhibidores de Proteínas Quinasas/farmacología , Células del Estroma/efectos de los fármacos , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Adulto , Endometriosis/metabolismo , Endometrio/efectos de los fármacos , Endometrio/patología , Femenino , Humanos , Enfermedades del Ovario/metabolismo , Células del Estroma/metabolismo , Células del Estroma/patologíaRESUMEN
Endometriosis, a disease affecting 3% to 10% of women of reproductive age, is characterized by the ectopic growth of endometrial tissue under the influence of estrogen. It is also becoming recognized as a condition in which ectopic endometrial cells exhibit abnormal proliferative and apoptotic regulation in response to appropriate stimuli. Apoptosis plays a critical role in maintaining tissue homeostasis and represents a normal function to eliminate excess or dysfunctional cells. Accumulated evidence suggests that, in healthy women, endometrial cells expelled during menstruation do not survive in ectopic locations because of programmed cell death, while decreased apoptosis may lead to the ectopic survival and implantation of these cells, resulting in the development of endometriosis. Both the inability of endometrial cells to transmit a "death" signal and the ability of endometrial cells to avoid cell death have been associated with increased expression of antiapoptotic factors and decreased expression of preapoptotic factors. Further investigations may elucidate the role of apoptosis-associated molecules in the pathogenesis of endometriosis. Medical treatment with apoptosis-inducing agents may be novel and promising therapeutic strategy for endometriosis.
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Apoptosis/fisiología , Endometriosis/metabolismo , Endometriosis/patología , Endometrio/metabolismo , Apoptosis/genética , Endometriosis/tratamiento farmacológico , Endometriosis/genética , Endometrio/citología , Endometrio/fisiología , Femenino , Regulación de la Expresión Génica , Genes bcl-2 , Genes cdc , Humanos , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
OBJECTIVE: Endometriosis is characterized by the ectopic growth of endometrial tissue. One of the first steps to the spread of endometriosis in the peritoneal cavity is the attachment of endometriotic cells to peritoneal surfaces after they have been released into the peritoneal fluid from pre-existing endometriotic lesions. The increased adhesive and proliferative potential of endometriotic cells in response to specific extracellular matrix (ECM) components has been suggested to contribute to the pathogenesis of endometriosis. STUDY DESIGN: Adhesive properties of endometriotic stromal cells (ECSC) and normal eutopic endometrial cells (NESC) to various extracellular matrix proteins were investigated by in vitro cell adhesion assays. The expression levels of integrins in these cells were also examined by Western blot analysis. RESULTS: Both ECSC and NESC significantly adhered to collagen type I and collagen type IV. ECSC revealed higher adhesive properties to these ECM proteins than NESC did. ECSC, but not NESC, adhered to fibronectin and laminin. Higher levels integrin of α1, α2, αv, ß1, and ß3 protein expression were observed in ECSC than in NESC. On the other hand, the levels of integrin α3 and αL proteins were lower in ECSC than in NESC. CONCLUSIONS: The results suggest that endometriotic cells possess stronger adhesion to ECM proteins, and that increase may be mediated, in part, through integrins. These findings may elucidate one of the mechanisms underlying the formation of peritoneal endometriotic lesions.
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Endometriosis/fisiopatología , Endometrio/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Matriz Extracelular/fisiología , Adulto , Adhesión Celular , Células Cultivadas , Colágeno/metabolismo , Endometrio/citología , Femenino , Fibronectinas/metabolismo , Humanos , Integrinas/metabolismo , Laminina/metabolismo , Subunidades de Proteína/metabolismo , Células del Estroma/fisiologíaRESUMEN
Triptolide (TPL), a bioactive component of the Chinese medicinal herb Tripterygium wilfordii Hook F, induces apoptosis in some lines of human tumor cells. However, the effect of TPL on gynecologic cancer cells has not yet been well-described. We investigated the effects of TPL on cell growth, cell cycle, and apoptosis in endometrial and ovarian cancer cell lines. Furthermore, we examined global changes in gene expression after treatment with TPL. By using a list of 20 differentially expressed genes, Western blot analyses were performed on five endometrial and ovarian cancer cell lines. All cell lines were sensitive to the growth-inhibitory effect of TPL. TPL increased the proportion of cells in the S-phase of the cell cycle and induced apoptosis. cDNA microarray assay demonstrated that the treatment with TPL changed the expression of cell cycle regulators, apoptosis-related factors and cell proliferation markers. Of the gene expression changes induced by TPL treatment, up-regulation of LRAP, CDH4, and SFRP1 and down-regulation of cystatin, TNNT 1, and L1-CAM were confirmed using Western blot analysis in all the cell lines examined. We found a strong anticancer activity of TPL and identified some potential target genes of this drug, raising hopes that TPL may become a useful therapy for endometrial and ovarian cancers.
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Diterpenos/farmacología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Fenantrenos/farmacología , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Compuestos Epoxi/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Tripterygium/químicaRESUMEN
OBJECTIVE: To assess the use of heparin for the medical treatment of endometriosis-associated fibrosis. DESIGN: The effects of heparin on the endometriotic stromal cells (ECSCs)-mediated contractility were investigated. SETTING: Research laboratory at a medical school. PATIENT(S): Endometriotic tissues from nine patients were used. INTERVENTION(S): Endometriotic stromal cells were cultured three dimensionally in the presence of heparin. MAIN OUTCOME MEASURE(S): The contractility of ECSCs was assessed by collagen gel contraction assay. Heparin-induced morphological changes of ECSCs were evaluated by laser scanning microscopy. The expression of contractility-related molecules in ECSCs was examined by Western blot analysis. RESULT(S): In the presence of 10% fetal bovine serum, treated ECSCs showed significant collagen gel contractility (75.9% decrease in surface area after 48 hour vs. 0 hour controls). Endometriotic stromal cell-mediated gel contraction was significantly attenuated in the presence of heparin in a dose-dependent manner (55.7% reduction of the gel contraction at a concentration of 100 microg/mL of heparin sodium versus untreated controls after 48 hours). Heparin suppressed the ECSC attachment to collagen fibers. The expression of alpha-smooth muscle actin, Ras homology (Rho) A, Rho-associated coiled-coil-forming protein kinase (ROCK)-I, and ROCK-II was down-regulated by heparin administration. CONCLUSION(S): The present study suggests that heparin is a promising agent for the treatment of endometriosis-associated fibrosis. The inhibition of myofibroblastic differentiation, the attenuation of attachment to collagen fibers, and the suppression of Rho-ROCK-mediated pathway activation in ECSCs are involved in the action mechanisms of heparin.
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Endometriosis/tratamiento farmacológico , Endometriosis/patología , Heparina/uso terapéutico , Adulto , Animales , Bovinos , Células Cultivadas , Colágeno/fisiología , Endometrio/efectos de los fármacos , Endometrio/patología , Femenino , Fibrosis , Heparina/fisiología , Humanos , Células del Estroma/efectos de los fármacos , Células del Estroma/patología , PorcinosRESUMEN
Simvastatin significantly inhibited the proliferation of endometriotic stromal cells, attenuated the collagen gel contraction mediated by these cells, and suppressed endometriotic stromal cell attachment to collagen fibers. Simvastatin is considered to be a promising agent for the treatment of endometriosis-associated fibrosis, which is among the major pathologies caused by endometriosis.
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Endometriosis/tratamiento farmacológico , Endometriosis/patología , Simvastatina/farmacología , Células del Estroma/efectos de los fármacos , Células del Estroma/patología , División Celular/efectos de los fármacos , Células Cultivadas , Colágeno/metabolismo , Femenino , Fibrosis , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Técnicas In Vitro , Células del Estroma/metabolismoRESUMEN
CONTEXT: Decidualization of the endometrium involves the morphological and biochemical reprogramming of the estrogen-primed proliferative endometrial stromal compartment under the continuing influence of progesterone. OBJECTIVES: The aim of this study was to evaluate the involvement of the extracellular matrix contractility of eutopic and ectopic endometrial stromal cells during the tissue remodeling processes associated with decidualization. DESIGN: The effect of decidualization on the contractile profile of the endometriotic cyst stromal cells and eutopic endometrial stromal cells with or without endometriosis in the three-dimensional collagen gel culture was investigated using laser scanning microscopy, collagen gel contraction assays, and Western blot analysis. RESULTS: Decidualized ectopic and eutopic endometrial stromal cells in the three-dimensional collagen gel culture mimicked the morphology of decidual tissue in vivo. In vitro decidualization inhibited the contractility of these eutopic and ectopic endometrial stromal cells. Down-regulation of integrin alpha1beta1 and alpha2beta1 expression, suppression of Ras homology A (Rho A), Rho-associated coiled-coil-forming protein kinase (ROCK)-I and ROCK-II expression, inhibition of the differentiation into the myofibroblastic phenotype, and induction of differentiation into epithelioid decidual phenotype were observed in these cells during decidualization. CONCLUSIONS: It is suggested that the attenuation of eutopic endometrial stromal cell-mediated contractility by decidualization is a novel and integral mechanism of the physiological endometrial tissue remodeling process during menstrual cycles. Although ectopic endometrial stromal cells have enhanced contractile profile, decidualization can attenuate the contractility of these cells. These findings may be one of the action mechanisms by which oral contraceptives and progestins ameliorate endometriosis.
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Decidua/efectos de los fármacos , Decidua/fisiología , Endometriosis/fisiopatología , Endometrio/fisiología , Hormonas/farmacología , Células del Estroma/fisiología , Enfermedades Uterinas/fisiopatología , Adulto , Bucladesina/administración & dosificación , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Células Cultivadas , Coristoma/tratamiento farmacológico , Coristoma/patología , Coristoma/fisiopatología , Decidua/metabolismo , Decidua/patología , Endometriosis/tratamiento farmacológico , Endometriosis/patología , Endometrio/efectos de los fármacos , Endometrio/metabolismo , Endometrio/patología , Femenino , Hormonas/uso terapéutico , Humanos , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Progestinas/administración & dosificación , Progestinas/farmacología , Progestinas/uso terapéutico , Prolactina/metabolismo , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Enfermedades Uterinas/tratamiento farmacológico , Enfermedades Uterinas/patología , Adulto JovenRESUMEN
OBJECTIVE: The aim of this study is to evaluate the involvement of tumor necrosis factor (TNF)-alpha in endometrial tissue remodeling during the perimenstrual period. STUDY DESIGN: Human endometrial stromal cells (ESCs) were isolated from eight premenopausal patients in the late secretory phase. The effects of TNF-alpha on the contractility of cultured ESCs were investigated by collagen gel contraction assay. The effects of TNF-alpha on the proliferation of ESCs were also assessed by a modified methylthiazoletetrazolium assay. RESULTS: TNF-alpha significantly upregulated the collagen gel contractility of ESCs in a dose-dependent manner. TNF-alpha did not affect ESC proliferation. CONCLUSION: The results suggest that TNF-alpha may promote endometrial tissue repair by stimulating the contraction of the extracellular matrix by ESCs. By regulating ESC function during the perimenstrual period, TNF-alpha may be involved in the physiological tissue remodeling of the cyclic endometrium.
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Citocinas/farmacología , Endometrio/citología , Células del Estroma/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Cicatrización de Heridas/efectos de los fármacos , Adulto , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Ciclo Menstrual/metabolismo , PremenopausiaRESUMEN
PROBLEM: To investigate the role of platelet-activating factor (PAF) in human ovulation, we studied the regulation of interleukin (IL)-8 and growth-regulated oncogene (GRO) alpha in cultured human immortalized granulosa cell line (GC1a). METHOD OF STUDY: GC1a was cultured in serum-free medium, and incubated with carbamyl-PAF (C-PAF) and/or PAF receptor antagonist (WEB 2086). The supernatants were collected, and IL-8 and GRO alpha were measured by enzyme-linked immunosorbent assay. RESULTS: After treatment with C-PAF, the levels of IL-8 and GROalpha increased in a time-dependent manner. The levels of IL-8 and GROalpha were significantly increased after treatment with C-PAF in a dose-dependent manner. However, the levels of IL-8 and GROalpha were significantly decreased by treatment with C-PAF and with increasing concentrations of WEB 2086. CONCLUSION: Our data indicated that IL-8 and GROalpha were regulated by C-PAF. The results suggested that PAF may play an important role in human pre-ovulatory processes involving IL-8 and GROalpha production.
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Quimiocina CXCL1/metabolismo , Células de la Granulosa/metabolismo , Interleucina-8/metabolismo , Éteres Fosfolípidos/farmacología , Factor de Activación Plaquetaria/inmunología , Azepinas/farmacología , Línea Celular , Quimiocina CXCL1/biosíntesis , Quimiocina CXCL1/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/inmunología , Humanos , Interleucina-8/biosíntesis , Interleucina-8/inmunología , Ovulación , Inhibidores de Agregación Plaquetaria/farmacología , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Glicoproteínas de Membrana Plaquetaria/inmunología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/inmunología , Triazoles/farmacologíaRESUMEN
OBJECTIVE: The aim of this study is to evaluate the effects of interleukin (IL)-13, a Th2 cytokine, on the production of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in human oviductal cells in vitro. STUDY DESIGN: Human oviductal epithelial cells (OECs) were isolated from five premenopausal patients. The secretion of VEGF(165) and sFlt-1 by cultured OECs in response to IL-13 was measured using an enzyme-linked immunosorbent assay. RESULTS: The secretion of VEGF(165) and sFlt-1 was detected in cultured OECs under untreated conditions. IL-13 enhanced the secretion of VEGF(165) and sFlt-1 by OECs in a dose-dependent manner. CONCLUSION: The present findings suggest that IL-13 is a regulatory factor of VEGF and sFlt-1 production in the human fallopian tubes. IL-13 in the local environment may stimulate oviductal vascular permeability by inducing the production of VEGF by oviductal cells. The modulation of VEGF secretion by IL-13 secreted by the peri-implantation embryo may contribute to the normal and pathological processes of human reproduction during the peri-implantation period.
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Trompas Uterinas/metabolismo , Interleucina-13/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Trompas Uterinas/citología , Trompas Uterinas/efectos de los fármacos , Femenino , Humanos , Interleucina-13/farmacologíaRESUMEN
BACKGROUND: Excessive fibrosis is frequently associated with endometriosis. To evaluate the involvement of the extracellular matrix contractility of endometriotic stromal cells (ECSCs) in the pathogenesis of endometriosis-associated fibrosis, we compared the collagen gel contractility of cultured ECSCs with that of normal endometrial stromal cells. To clarify the mechanism underlying collagen gel contraction by ECSCs, we also evaluated the effect of (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride, monohydrate (Y-27632), a selective Rho-associated coiled-coil-forming protein kinase (ROCK) inhibitor, on the collagen gel contraction by ECSCs. METHODS AND RESULTS: ECSCs showed enhanced collagen gel contractility in comparison with NESCs. Myofibroblastic differentiation and the increased expression of fibronectin, RhoA, ROCK-I and ROCK-II proteins were observed with ECSCs using the 3D culture. Y-27632 significantly inhibited the collagen gel contractility of ECSCs without cytotoxicity. CONCLUSIONS: The present findings suggest that the enhanced collagen contractility in ECSCs is associated with myofibroblastic differentiation, the increased expression of fibronectin and the activation of the Rho-ROCK-mediated signalling pathway, all of which may be involved in the pathogenesis of endometriosis-associated fibrosis. These results suggest that the inhibition of the Rho-ROCK-mediated signalling pathway may provide a novel strategy for the treatment of this disease. In addition, our experimental system of ECSCs using 3D collagen gel culture would be suitable for evaluating novel treatments for endometriosis.
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Colágeno/metabolismo , Endometriosis/patología , Endometrio/citología , Fibrosis/patología , Células del Estroma/citología , Actinas/metabolismo , Adulto , Amidas/farmacología , Diferenciación Celular , Colágeno/química , Endometriosis/complicaciones , Endometriosis/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibroblastos/metabolismo , Fibrosis/etiología , Geles , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/farmacología , Sales de Tetrazolio/farmacología , Tiazoles/farmacología , Quinasas Asociadas a rhoRESUMEN
Most of the current medical treatments for endometriosis aim to downregulate estrogen activity. However, a high recurrence rate after medical treatment has been the most significant problem. BAY 11-7085, a soluble inhibitor of NK-kappaB activation, has been shown to inhibit cell proliferation and induce apoptosis of a variety of cells. To examine the potential application of BAY 11-7085 in the treatment of endometriosis, we investigated the effects of this agent on the cell proliferation and apoptosis of cultured ovarian endometriotic cyst stromal cells (ECSCs) by a modified methylthiazole tetrazolium assay, a 5-bromo-2'-deoxyuridine incorporation assay, and internucleosomal DNA fragmentation assays. The effect of BAY 11-7085 on the cell cycle of ECSCs was also determined by flow cytometry. The expression of apoptosis-related molecules was examined in ECSCs with Western blot analysis. BAY 11-7085 significantly inhibited the cell proliferation and DNA synthesis of ECSCs and induced apoptosis and the G0/G1 phase cell cycle arrest of these cells. Additionally, downregulation of the B-cell lymphoma/leukemia-2 (Bcl-2) and Bcl-X(L) expression with simultaneous activation of caspase-3, -8, and -9 was observed in ECSCs after treatment with BAY 11-7085. These results suggest that BAY 11-7085 induces apoptosis of ECSCs by suppressing antiapoptotic proteins, and that caspase-3-, -8-, and -9-mediated cascades are involved in this mechanism. Therefore, BAY 11-7085 could be used as a therapeutic agent for the treatment of endometriosis.
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Endometriosis/tratamiento farmacológico , FN-kappa B/antagonistas & inhibidores , Nitrilos/uso terapéutico , Sulfonas/uso terapéutico , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Nitrilos/farmacología , Sulfonas/farmacologíaRESUMEN
Tumor necrosis factor-alpha stimulates the secretion of vascular endothelial growth factor by cultured human oviductal epithelial cells and stromal fibroblasts. Tumor necrosis factor-alpha-stimulated vascular endothelial growth factor secretion by these cells may control oviductal fluid secretion by regulating vascular permeability.
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Células Epiteliales/metabolismo , Trompas Uterinas/metabolismo , Fibroblastos/metabolismo , Factor de Necrosis Tumoral alfa/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Trompas Uterinas/citología , Trompas Uterinas/efectos de los fármacos , Femenino , Fibroblastos/efectos de los fármacos , Humanos , Células del Estroma/metabolismoRESUMEN
The aim of the present study was to evaluate the effects of interleukin (IL)-1beta on the production of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in the human fallopian tube. Human oviductal epithelial cells (OECs) and oviductal stromal fibroblasts (OSFs) were isolated from ten premenopausal patients. The secretion of VEGF and sFlt-1 by cultured OECs and OSFs in response to IL-1beta and IL-1 receptor antagonist (IL-1RA) was measured using an enzyme-linked immunosorbent assay. The secretion of VEGF and sFlt-1 was detected in cultured OECs and OSFs under untreated conditions; secretion of these angiogenic modulators was significantly stimulated with IL-1beta administration in these cells. IL-1beta-induced production of VEGF and sFlt-1 by these cells was significantly inhibited by the addition of IL-1RA. The present findings suggest that IL-1beta in the local environment may stimulate oviductal vascular permeability by inducing the production of VEGF by oviductal cells via both autocrine and paracrine mechanisms. Simultaneous upregulation of sFlt-1 secretion by these cells after IL-1beta stimulation may prevent an excessive upregulation of vascular permeability. The modulation of the ratio of VEGF and sFlt-1 in the fallopian tube may contribute to the normal and pathological processes of oviductal fluid secretion by regulating oviductal vascular permeability during the menstrual cycle and during the peri-implantation period.
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Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Interleucina-1beta/farmacología , Oviductos/efectos de los fármacos , Oviductos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto , Animales , Células Cultivadas , Femenino , Fibroblastos , Humanos , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/metabolismo , Solubilidad , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismoRESUMEN
PROBLEM: To evaluate the site-specific immunoregulatory mechanisms against bacterial infection in the human fallopian tubes. METHOD OF STUDY: We investigated the effects of lipopolysaccharide (LPS) on the production of CXC chemokines by cultured oviductal epithelial cells (OEC) and oviductal stromal fibroblasts (OSF). The expression of Toll-like receptor (TLR) 4 and CD14 protein in OEC and OSF were evaluated. The phosphorylation of the inhibitor kappaB-alpha (IkappaB-alpha) protein after LPS stimulation was also examined. RESULTS: Lipopolysaccharide stimulated the secretion of granulocyte chemotactic protein-2, growth-regulated oncogene-alpha, and epithelial neutrophil activating peptide-78 by OSF, but not by OEC. The phosphorylation of the IkappaB-alpha protein was not detected in OEC after stimulation by LPS, whereas IkappaB-alpha phosphorylation was observed in OSF after stimulation by LPS. The expression of the TLR4 protein and mRNA was detected only in OSF but not in OEC. The expression of CD14 was not detected in either OEC or OSF. CONCLUSION: These results suggest that epithelial cells and fibroblasts in the human fallopian tube have evolved a unique, site-specific mechanism for recognizing Gram-negative pathogens. The lack of TLR4 in OEC may be important for avoiding a state of unnecessary inflammation that could disrupt the epithelial barrier and cause irreversible tubal scarring.
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Trompas Uterinas/citología , Fibroblastos/inmunología , Membrana Mucosa/inmunología , Polisacáridos Bacterianos/farmacología , Células del Estroma/citología , Receptor Toll-Like 4/biosíntesis , Células Cultivadas , Quimiocinas CXC/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Inmunidad Mucosa/inmunología , Membrana Mucosa/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 4/genéticaRESUMEN
OBJECTIVE: The aim of the current study is to evaluate the effect of insulin-like growth factor-I (IGF-I) on the production of vascular endothelial growth factor (VEGF) in the human fallopian tube. METHODS: Human oviductal epithelial cells (OEC) and oviductal stromal fibroblasts (OSF) were isolated from the ampullary segment of the fallopian tubes of six premenopausal patients in the proliferative phase of the menstrual cycle. The secretion of VEGF165 by cultured OEC and OSF in response to IGF-I was measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The secretion of VEGF165 was detected in cultured OEC and OSF under untreated conditions. The secretion of VEGF165 was significantly stimulated with IGF-I administration in these cells. CONCLUSION: The present findings suggest that IGF-I in the local environment may stimulate oviductal vascular permeability by inducing the production of VEGF by oviductal cells through autocrine and paracrine mechanisms. The modulation of the VEGF production in the fallopian tube may contribute to the normal and pathologic processes of oviductal fluid secretion by regulating oviductal vascular permeability during the menstrual cycle and in the peri-implantation period.