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1.
J Cell Mol Med ; 24(24): 14571-14582, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33174363

RESUMO

Cranial radiotherapy induces endocrine disorders and reproductive abnormalities, particularly in long-term female cancer survivors, and this might in part be caused by injury to the pituitary gland, but the underlying mechanisms are unknown. The aim of this study was to investigate the influence of cranial irradiation on the pituitary gland and related endocrine function. Female Wistar rat pups on postnatal day 11 were subjected to a single dose of 6 Gy whole-head irradiation, and hormone levels and organ structure in the reproductive system were examined at 20 weeks after irradiation. We found that brain irradiation reduced cell proliferation and induced persistent inflammation in the pituitary gland. The whole transcriptome analysis of the pituitary gland revealed that apoptosis and inflammation-related pathways were up-regulated after irradiation. In addition, irradiation led to significantly decreased levels of the pituitary hormones, growth hormone, adrenocorticotropic hormone, thyroid-stimulating hormone and the reproductive hormones testosterone and progesterone. To conclude, brain radiation induces reduction of pituitary and reproduction-related hormone secretion, this may due to reduced cell proliferation and increased pituitary inflammation after irradiation. Our results thus provide additional insight into the molecular mechanisms underlying complications after head irradiation and contribute to the discovery of preventive and therapeutic strategies related to brain injury following irradiation.


Assuntos
Irradiação Craniana , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Hipófise/metabolismo , Hipófise/efeitos da radiação , Hormônios Hipofisários/biossíntese , Hormônio Adrenocorticotrópico/biossíntese , Animais , Biomarcadores , Proliferação de Células/efeitos da radiação , Biologia Computacional/métodos , Irradiação Craniana/efeitos adversos , Modelos Animais de Doenças , Ciclo Estral/efeitos da radiação , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos da radiação , Hipopituitarismo/patologia , Imuno-Histoquímica , Hipófise/patologia , Hormônios Hipofisários/deficiência , Lesões por Radiação/complicações , Ratos , Transdução de Sinais/efeitos da radiação , Transcriptoma , Proteína Supressora de Tumor p53/metabolismo
2.
EBioMedicine ; 18: 157-170, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28336389

RESUMO

Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial-stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K-Akt-NFκB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.


Assuntos
Metformina/farmacologia , Síndrome do Ovário Policístico/patologia , Útero/efeitos dos fármacos , Animais , Gonadotropina Coriônica/farmacologia , Modelos Animais de Doenças , Implantação do Embrião/efeitos dos fármacos , Estradiol/sangue , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônio Foliculoestimulante/sangue , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/patologia , Insulina/farmacologia , Hormônio Luteinizante/sangue , Metformina/uso terapêutico , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Testosterona/sangue , Útero/metabolismo , Útero/patologia , Proteína Wnt4/genética , Proteína Wnt4/metabolismo
3.
J Ovarian Res ; 10(1): 10, 2017 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-28193283

RESUMO

BACKGROUND: MicroRNAs (miRNAs) regulate the expression of genes involved in various cellular functions related to metabolism, inflammation, and reproduction. This study evaluated the effects of sex hormones and obesity on the expression of circulating miR-23a and miR-23b in women with polycystic ovary syndrome (PCOS) and healthy women. METHODS: Serum sex hormones concentrations and body mass index (BMI) were measured in 18 women with PCOS and in 30 healthy women from the East China area and these measurements were correlated with serum miR-23a/b levels. The effect of miR-23a and miR-23b risk factors on occurrence of PCOS and predisposing factors of PCOS on these miRNA expressions were evaluated. RESULTS: The expressions of miR-23a/b were significantly lower in the women with PCOS than the normal women, and the expression levels of miR-23a/b were positively correlated with each other in the normal women (p = 0.001) but not in the women with PCOS (p > 0.05). In the women with PCOS, miR-23a was positively correlated with BMI (p = 0.03). However, no correlations were found between the levels of miR-23a/b and the sex hormones in the normal and PCOS women. On the other hand, without considering the presence or absence of PCOS, increase in BMI had a positive effect on the levels of circulating miR-23b; while testosterone had negative effects on the levels of circulating miR-23a. Furthermore, the likelihood of women with PCOS decreased by 0.01-fold for every 1 fold increase of miR-23a expression. CONCLUSIONS: Both reduced levels and discordance between the expressions of miR-23a/b were observed in the women with PCOS and miR-23a/b were affected from testosterone and BMI, reversely. Therefore, miR-23a alteration in contrast with miR-23b is a better indicator for evaluation of PCOS than the miR-23b.


Assuntos
Expressão Gênica , MicroRNAs/genética , Síndrome do Ovário Policístico/genética , Adulto , Biomarcadores , Índice de Massa Corporal , Estudos de Casos e Controles , China , Hormônios do Corpo Lúteo/sangue , Feminino , Hormônio Foliculoestimulante , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Hormônios Esteroides Gonadais/sangue , Humanos , MicroRNAs/sangue , Obesidade/sangue , Obesidade/complicações , Obesidade/metabolismo , Razão de Chances , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/etiologia , Interferência de RNA , Adulto Jovem
4.
Sci Rep ; 6: 30679, 2016 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-27461373

RESUMO

Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3ß (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients.


Assuntos
Glucose/metabolismo , Hiperandrogenismo/patologia , Resistência à Insulina/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Síndrome do Ovário Policístico/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Gonadotropina Coriônica/farmacologia , Células Epiteliais/patologia , Feminino , Proteínas Facilitadoras de Transporte de Glucose/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicólise/genética , Humanos , Insulina/farmacologia , Resistência à Insulina/fisiologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Útero/patologia
5.
Data Brief ; 6: 135-42, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26858978

RESUMO

In this data, non-pregnant women during the menstrual cycle, women with normal intrauterine pregnancy (IUP), and women with tubal ectopic pregnancy (EP) after informed consent were included. The serum levels of 17ß-estradiol, progesterone, testosterone, beta-human chorionic gonadotropin, interleukin (IL)-1ß, IL-4, IL-6, IL-7, IL-8, IL-10, tumor necrosis factor α (TNFα), and interferon-γ (IFN-γ), epidermal growth factor, the Chlamydia (C.) trachomatis IgG and HSP60 were analyzed. Receiver operating characteristic analysis was used to assess the diagnostic discrimination of tubal EP and gestational age-matched IUP. Our data show that C. trachomatis infection is associated with IL-8 levels, which had excellent discriminative validity in positively identifying tubal EP (concomitant with C. trachomatis infection) from IUP and non-pregnant conditions regardless of C. trachomatis infection.

6.
N Engl J Med ; 374(3): 223-32, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26789871

RESUMO

Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other ß-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one ß-tubulin polypeptide (α/ß-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed ß-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/ß-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).


Assuntos
Infertilidade Feminina/genética , Meiose/genética , Microtúbulos/patologia , Mutação , Oócitos/fisiologia , Fuso Acromático/fisiologia , Tubulina (Proteína)/genética , Adulto , Animais , Feminino , Humanos , Meiose/fisiologia , Camundongos , Microtúbulos/fisiologia , RNA
7.
BBA Clin ; 4: 85-91, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26675316

RESUMO

Background Determination of the role of steroid hormones in expression and regulation of endometrial glucose transport 4 (GLUT4) in humans is important for understanding endometrial disorders such as polycystic ovary syndrome (PCOS), a common hormone-imbalance disease. Methods Endometrial biopsy samples were collected from non-PCOS patients with regular menstrual cycles or with hyperplasia and from PCOS patients with or without hyperplasia. In addition, endometrial tissues from postmenopausal women were incubated with human chorionic gonadotropin (hCG, 10 IU/ml), 17ß-estradiol (E2, 10 nM), progesterone (P4, 100 nM), or a combination of E2 and P4 for 24 h. The expression of GLUT4 was measured at the mRNA level using quantitative real-time polymerase chain reaction (qRT-PCR) and at the protein level using Western blot analysis and immunohistochemistry. Results A cyclical change in GLUT4 expression pattern was observed in non-PCOS patients, and a high level of GLUT4 expression was seen in the proliferative phase compared to the secretory phase. Low levels of GLUT4 expression were found in PCOS patients compared to menstrual cycle phase-matched non-PCOS patients, and there was no significant change in GLUT4 expression in PCOS patients during the menstrual cycle. GLUT4 was localized in both epithelial and stromal cells, with notable changes in epithelial cells. We postulate that decreased GLUT4 expression might be regulated by steroid hormones. In support of this, we showed that in cultured endometrial tissues hCG and E2 alone had no effect on GLUT4 expression. However, P4 alone and P4 in combination with E2 decreased GLUT4 expression. Compared with non-PCOS controls, PCOS patients with endometrial hyperplasia exhibited decreased GLUT4 expression in particular in the epithelial cells. Conclusion We conclude that P4 can induce changes in endometrial GLUT4 expression during the menstrual cycle and that abnormal hormonal conditions such as PCOS disrupt normal patterns of GLUT4 expression in endometrial cells.

8.
Int J Biol Sci ; 11(12): 1376-89, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26681917

RESUMO

The failure of reproductive success in polycystic ovary syndrome (PCOS) patients could be in part due to endometrial dysfunction. However, no studies have investigated any causality between androgen, androgen receptor (AR) expression, and adenosine monophosphate activated protein kinase (AMPK) activation in the endometrium under physiological and pathological conditions. In the present study, we show that 1) endometrial AR expression levels fluctuate in non-PCOS and PCOS patients during the menstrual cycle; 2) the menstrual phase-dependent alteration of p-AMPKα expression occurs in non-PCOS patients but not in PCOS patients; 3) AR expression is higher in PCOS patients than non-PCOS patients during hyperplasia while AMPKα activation (indicated by the ratio of p-AMPKα to AMPKα); and 4) co-localization of AR and Ki-67 in epithelial cell nuclei is observed in endometrial hyperplasia. Importantly, using in vitro human tissue culture and an in vivo 5α-dihydrotestosterone-treated rat model, we show that the action of androgen on AMPKα activation is likely mediated through nuclear AR, especially in epithelial cells. Collectively, we present evidence that AR expression and AMPKα activation depend on menstrual cycle phase and the presence of PCOS, and the data suggest that AR-mediated regulation of AMPKα activation might play a role in the development of endometrial hyperplasia.


Assuntos
Adenilato Quinase/metabolismo , Endométrio/metabolismo , Síndrome do Ovário Policístico/metabolismo , Receptores Androgênicos/metabolismo , Animais , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Di-Hidrotestosterona/farmacologia , Endométrio/enzimologia , Feminino , Flutamida/farmacologia , Humanos , Técnicas In Vitro , Antígeno Ki-67/metabolismo , Fosforilação , Síndrome do Ovário Policístico/enzimologia , Ratos , Ratos Wistar
9.
Reprod Biol Endocrinol ; 13: 40, 2015 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-25967158

RESUMO

BACKGROUND: The fallopian tube transports the gametes to the fertilization site and delivers the embryo to the uterus at the optimal time for implantation. Progesterone and the classical progesterone receptor are involved in regulating both tubal ciliary beating and muscular contractions, likely via both genomic and non-genomic actions. METHODS: To provide more details of the underlying mechanisms, we investigated the effect of progesterone on gene expression in mice fallopian tubes in vitro at 20 min, 2 h and 8 h post progesterone treatment using microarray and/or quantitative PCR. In parallel, oocyte cumulus complex transport was investigated in ovulating mice that were injected with one of the progesterone receptor antagonists, Org 31710 or CDB2194. RESULTS: Microarray analyses did not reveal any apparently regulated genes 20 min after progesterone treatment, consistent with the proposed non-genomic action of progesterone controlling ciliary beating. After 2 h, 11 genes were identified as up-regulated. Analyses using quantitative PCR at 2 h and 8 h showed a consistent up-regulation of endothelin1 and a down-regulation of its receptor Endothelin receptor A by progesterone. We also confirmed that treatment with progesterone receptor antagonists before ovulation accelerates the transport of the oocyte cumulus complex. CONCLUSIONS: This is the first study showing that progesterone regulates the expression of endothelin1 and endothelin receptor A in the fallopian tube. Together with previous studies of the effects of endothelin on muscular contractions in the fallopian tube, the results from this study suggest that endothelin is a mediator of the progesterone-controlled effects on muscular contraction and eventually gamete transport in the fallopian tube.


Assuntos
Movimento Celular/efeitos dos fármacos , Células do Cúmulo/metabolismo , Tubas Uterinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Oócitos/metabolismo , Progesterona/farmacologia , Animais , Movimento Celular/fisiologia , Tubas Uterinas/fisiologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Progesterona/fisiologia
10.
Fertil Steril ; 102(6): 1545-52.e1, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25439799

RESUMO

OBJECTIVE: To investigate whether allogeneic uterine grafts in a rat model, with tacrolimus immunosuppression, can harbor pregnancies that result in offspring with normal postnatal growth. DESIGN: Experimental animal study. SETTING: University hospital. ANIMAL(S): Lewis rats as uterus donors and Piebald-Virol-Glaxo rats as recipients. INTERVENTION(S): Animals were allocated to one of the following three groups: allogeneic uterus transplantation with end-to-side anastomosis to the external iliac vessels and immunosuppression with tacrolimus (UT+Tac; n = 10); sham surgery and immunosuppression with tacrolimus (Sham+Tac; n = 10); or sham surgery (Sham; n = 10). The rats were subsequently introduced to male rats with proven fertility and in the event of resulting pregnancy cesarean sections were performed on day 22 of pregnancy. MAIN OUTCOME MEASURE(S): Graft viability, fertility rate, perinatal death, birth weight, postnatal birth trajectory. RESULT(S): Pregnancy rate was higher in the control groups (70% Sham and 80% Sham+Tac) than in the transplanted group (50% UT+Tac), although these differences did not reach the significance threshold. There were no differences between groups regarding number of living pups or neonatal deaths. Pups born from UT+Tac mothers had birth weights similar to external control animals from our breeding colony (BC): UT+Tac males 6.2 ± 0.2 g, UT+Tac females 5.5 ± 0.6 g, BC males 5.8 ± 0.2 g, BC females 5.2 ± 0.3 g; n.s. Evaluation of uteri and placentas of pregnant animals revealed a somewhat reduced vascular density in both tissues in the UT+Tac group, and that was not seen in the Sham+Tac group. CONCLUSION(S): Allogeneic uterus transplantation and immunosuppression with tacrolimus is compatible with normal pregnancy and perinatal outcome in a rat model.


Assuntos
Imunossupressores/uso terapêutico , Prenhez/imunologia , Tacrolimo/uso terapêutico , Útero/transplante , Animais , Feminino , Sobrevivência de Enxerto , Tamanho da Ninhada de Vivíparos , Masculino , Gravidez , Prenhez/fisiologia , Ratos , Ratos Endogâmicos Lew , Doadores de Tecidos , Transplante Homólogo
11.
J Exp Clin Cancer Res ; 33: 41, 2014 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-24887156

RESUMO

Although a number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and antimetastatic effects of metformin in multiple cancer cell types, its cellular and molecular mechanisms of anti-cancer action in the endometrium of women with polycystic ovary syndrome (PCOS) have not yet been fully elucidated. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are known to be involved in metformin uptake and excretion in cells. In this article, we discuss the novel therapeutic possibilities for early-stage endometrial carcinoma (EC) in women with PCOS focusing on metformin, which might have a direct effect in the endometrium through the OCTs and MATEs. We then review the molecular mechanism(s) of the action of metformin in the endometrium and highlight possible mechanistic insights into the inhibition of cell proliferation and tumor growth and, ultimately, the reversal of early-stage EC into normal endometria in women with PCOS.


Assuntos
Antineoplásicos/farmacologia , Carcinoma/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Endométrio/efeitos dos fármacos , Metformina/farmacologia , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Endométrio/metabolismo , Feminino , Humanos , Metformina/uso terapêutico , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Comunicação Parácrina , Células Estromais/metabolismo
12.
J Cancer ; 5(3): 173-81, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24563672

RESUMO

BACKGROUND: Young women with polycystic ovary syndrome (PCOS) have a high risk of developing endometrial carcinoma. There is a need for the development of new medical therapies that can reduce the need for surgical intervention so as to preserve the fertility of these patients. The aim of the study was to describe and discuss cases of PCOS and insulin resistance (IR) women with early endometrial carcinoma while being co-treated with Diane-35 and metformin. METHODS: Five PCOS-IR women who were scheduled for diagnosis and therapy for early endometrial carcinoma were recruited. The hospital records and endometrial pathology reports were reviewed. All patients were co-treated with Diane-35 and metformin for 6 months to reverse the endometrial carcinoma and preserve their fertility. Before, during, and after treatment, endometrial biopsies and blood samples were obtained and oral glucose tolerance tests were performed. Endometrial pathology was evaluated. Body weight (BW), body mass index (BMI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), sex hormone-binding globulin (SHBG), free androgen index (FAI), insulin area under curve (IAUC), and homeostasis model assessment of insulin resistance (HOMA-IR) were determined. RESULTS: Clinical stage 1a, low grade endometrial carcinoma was confirmed before treatment. After 6 months of co-treatment, all patients showed normal epithelia. No evidence of atypical hyperplasia or endometrial carcinoma was found. Co-treatment resulted in significant decreases in BW, BMI, TT, FAI, IAUC, and HOMA-IR in parallel with a significant increase in SHBG. There were no differences in the FSH and LH levels after co-treatment. CONCLUSIONS: Combined treatment with Diane-35 and metformin has the potential to revert the endometrial carcinoma into normal endometrial cells in PCOS-IR women. The cellular and molecular mechanisms behind this effect merit further investigation.

13.
Am J Cancer Res ; 4(1): 73-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24482740

RESUMO

Endometrial cancer (EC) is the most common gynecological malignancy in women and is the leading cause of cancer-related deaths worldwide. Estrogenic stimulation significantly increases endometrial cell proliferation, and both insulin resistance and hyperinsulinemia are associated with the development of EC in women. It has long been known that insulin resistance occurs in women with polycystic ovary syndrome (PCOS) and/or obesity, but one important unanswered question is whether the insulin resistance associated with PCOS and obesity is part of the etiology of the initiation and development of EC. Therefore, research efforts to understand the common and specific underlying endometrial responses to insulin resistance in women with PCOS and obesity could provide further therapeutic options for early endometrial carcinoma.

14.
Am J Transl Res ; 6(2): 104-13, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24489989

RESUMO

Endometriosis is a complex and challenging disease that involves aberrant adhesion, growth, and progression of endometrial tissues outside of the uterine cavity, and there is evidence to suggest that estrogen plays a key role in its development and progression. Numerous in vivo clinical studies have described the ectopic expression and regulation of estrogen receptor (ER) and progesterone receptor (PR) in the different types of endometriosis compared to normal or eutopic endometrium. However, we have noticed that conflicting and contradictory results have been presented in terms of ER subtype (ERα and ERß) and PR isoform (PRA and PRB) expression. Both ER and PR are transcription factors and ER/PR-mediated responses depend on the coordinated, opposing, and compensatory functions of ER subtypes and PR isoforms. Moreover, analysis of the uterine phenotypes of ERα/ERß and PRA/PRB knockout mice indicates that different ER subtypes and PR isoforms mediate distinct responses to steroid hormones and play different roles in uterine function. In this review, we outline studies that have elucidated the molecules and signaling pathways that are linked to ER and/or PR signaling pathways in the development and progression of endometriosis.

15.
J Biomed Sci ; 21: 2, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24405633

RESUMO

Polycystic ovary syndrome (PCOS) is a state of altered steroid hormone production and activity. Chronic estrogen exposure or lack of progesterone due to ovarian dysfunction can result in endometrial hyperplasia and carcinoma. A key contributor to our understanding of progesterone as a critical regulator for normal uterine function has been the elucidation of progesterone receptor (PR) expression, regulation, and signaling pathways. Several human studies indicate that PR-mediated signaling pathways in the nucleus are associated with progesterone resistance in women with PCOS. The aim of this review is to provide an overview of endometrial progesterone resistance in women with PCOS; to present the PR structure, its different isoforms, and their expression in the endometrium; to illustrate the possible regulation of PR and PR-mediated signaling in progesterone resistance in women with PCOS; and to discuss current clinical treatments for atypical endometrial hyperplasia and endometrial carcinoma in women with PCOS and accompanying progesterone resistance.


Assuntos
Endométrio/anormalidades , Síndrome do Ovário Policístico/genética , Progesterona/biossíntese , Progesterona/genética , Doenças Uterinas/genética , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Progesterona/metabolismo , Transdução de Sinais
16.
Int J Clin Exp Pathol ; 7(1): 64-79, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24427327

RESUMO

Human ectopic pregnancy (EP) is a leading cause of pregnancy-related death, but the molecular basis underlying the onset of tubal EP is largely unknown. Female Dicer1 conditional knockout mice are infertile with dysfunctional Fallopian tube and have a different miRNA expression profile compared to wild-type mice, and we speculated that Dicer-mediated regulation of miRNA expression and specific miRNA-controlled targets might contribute to the onset of tubal EP. In the present study, we used microarray analysis and quantitative RT-PCR to examine the expression of miRNAs and core miRNA regulatory components in Fallopian tube tissues from women with EP. We found that the levels of DICER1, four miRNAs (let-7i, miR-149, miR-182, and miR-424), and estrogen receptor α distinguished the tubal implantation site from the non-implantation site. Computational algorithms and screening for interactions with the estrogen and progesterone receptor signaling pathways showed that the four miRNAs were predicted to target ten genes, including NEDD4, TAF15, and SPEN. Subsequent experiments showed differences in NEDD4 mRNA and protein levels between the implantation and non-implantation sites. Finally, we revealed that increases in smooth muscle cell NEDD4 and stromal cell TAF15, in parallel with a decrease in epithelial cell SPEN, were associated with tubal implantation. Our study suggests that changes in miRNA levels by the DICER-mediated miRNA-processing machinery result in aberrant expression of cell type-specific proteins that are potentially involved in the onset of tubal EP.


Assuntos
Tubas Uterinas/metabolismo , MicroRNAs/genética , Gravidez Tubária/genética , Adulto , Western Blotting , RNA Helicases DEAD-box , Tubas Uterinas/patologia , Feminino , Humanos , Imuno-Histoquímica , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Gravidez Tubária/patologia , Reação em Cadeia da Polimerase em Tempo Real , Ribonuclease III , Transcriptoma
17.
BBA Clin ; 2: 7-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26674650

RESUMO

Young women with polycystic ovary syndrome (PCOS) have a high risk of developing endometrial cancer (EC). There is an urgent need for non-surgical prevention and treatment strategies for these patients who fail to respond to progesterone treatment and wish to preserve their fertility. Recently, we have reported that the combined treatment with metformin and progesterone-based oral contraceptives has successfully reversed the early-stage EC into normal endometria in addition to improvement of insulin resistance in women with PCOS. More importantly, one of these treated women has successfully delivered a healthy newborn baby. However, before such treatment can be recommended to the clinical practice, the molecular basis of metformin in the endometrium under physiological and pathological conditions must be elucidated.

18.
Proc Natl Acad Sci U S A ; 110(40): 16199-204, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24048027

RESUMO

Glucagon-like peptide 1 (GLP-1), produced in the intestine and the brain, can stimulate insulin secretion from the pancreas and alleviate type 2 diabetes. The cytokine interleukin-6 (IL-6) may enhance insulin secretion from ß-cells by stimulating peripheral GLP-1 production. GLP-1 and its analogs also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS, but otherwise are poorly understood. The cytokines IL-6 and interleukin 1ß (IL-1ß) may exert an anti-obesity effect in the CNS during health. Here we found that central injection of a clinically used GLP-1 receptor agonist, exendin-4, potently increased the expression of IL-6 in the hypothalamus (11-fold) and the hindbrain (4-fold) and of IL-1ß in the hypothalamus, without changing the expression of other inflammation-associated genes. Furthermore, hypothalamic and hindbrain interleukin-associated intracellular signals [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and suppressor of cytokine signaling-1 (SOCS1)] were also elevated by exendin-4. Pharmacologic disruption of CNS IL-1 receptor or IL-6 biological activity attenuated anorexia and body weight loss induced by central exendin-4 administration in a rat. Simultaneous blockade of IL-1 and IL-6 activity led to a more potent attenuation of exendin-4 effects on food intake. Mice with global IL-1 receptor gene knockout or central IL-6 receptor knockdown showed attenuated decrease in food intake and body weight in response to peripheral exendin-4 treatment. GLP-1 receptor activation in the mouse neuronal Neuro2A cell line also resulted in increased IL-6 expression. These data outline a previously unidentified role of the central IL-1 and IL-6 in mediating the anorexic and body weight loss effects of GLP-1 receptor activation.


Assuntos
Regulação do Apetite/fisiologia , Peso Corporal/fisiologia , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Obesidade/metabolismo , Receptores de Glucagon/metabolismo , Análise de Variância , Animais , Western Blotting , Técnicas de Silenciamento de Genes , Receptor do Peptídeo Semelhante ao Glucagon 1 , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-1/genética
19.
Int J Clin Exp Pathol ; 6(4): 810-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23573332

RESUMO

More than 98% of ectopic pregnancies occur in the Fallopian tube. Because many facets of tubal ectopic pregnancy remain unclear, prediction, prevention and treatment of tubal ectopic pregnancy are still a major clinical challenge. Compelling evidence suggests that angiogenic growth factors are involved in normal and abnormal implantation. While acknowledging the importance of an intrauterine pregnancy requires the development of a local blood supply and angiogenesis, we hypothesize that the hypoxic- and estrogen-dependent regulation of vascular endothelial growth factor/placental growth factor expression, secretion, and signaling pathways that are possibly involved in the pathophysiology of tubal ectopic pregnancy. Our hypothesis may also lead to a new therapeutic strategy for women with tubal ectopic pregnancy.


Assuntos
Proteínas da Gravidez/fisiologia , Gravidez Ectópica/fisiopatologia , Gravidez Tubária/fisiopatologia , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Estrogênios/fisiologia , Feminino , Humanos , Hipóxia/fisiopatologia , Neovascularização Patológica/fisiopatologia , Fator de Crescimento Placentário , Gravidez , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia
20.
Am J Transl Res ; 5(2): 116-25, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23573357

RESUMO

Ectopic pregnancy is a common reproductive disorder of unknown etiology and is a leading cause of maternal and fetal mortality. Because of the asymptomatic nature of early tubal ectopic pregnancy and the lack of specific biomarkers for early diagnosis, a better understanding of the complex cellular and molecular interactions that contribute to tubal ectopic pregnancy is required. DNA methylation is the most studied epigenetic process in various tissues and cells, and the goal of this article is to provide a brief review of recent work describing the potential mechanisms of DNA methylation and the biological function of such methylation in normal intrauterine pregnancy. Further, novel findings from our laboratory highlight the possible role of DNA methylation in human Fallopian tube dysfunction and suggest a possible correlation between methylation of estrogen receptor α in women and the occurrence of tubal ectopic pregnancies.

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