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1.
Medicine (Baltimore) ; 98(43): e17559, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651857

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths among males and the second leading cause among females worldwide. Numerous studies have linked estrogen status to lung cancer outcome. However, there are studies with conflicting results about the effect of ERß on survival of lung cancer. The aim of this meta-analysis is to evaluate the prognostic impact of estrogen receptor beta expression on survival among NSCLC patients. METHODS: We will search 15 electronic databases, including PubMed, Web of Science, EMBASE, Cochrane Library, and CNKI from inception to June 1, 2019. We will include all cohort studies comparing overall survival of NSCLC patients with high or low estrogen receptor beta expression. The database searches will be supplemented by searching through citations and references. Two reviewers will independently screen search results to identify eligible articles, complete data collection, and conduct quality assessment. All disagreements will be resolved by an independent third reviewer. Methodological quality of the included studies will be assessed using the Newcastle- Ottawa scale. Discrepancies will be resolved by consensus or by consulting a third author. Meta-analyses will be performed, and findings will be reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. RESULTS: The results will be submitted to a peer-reviewed journal for publication. CONCLUSION: This review will provide a comprehensive evaluation of the evidence on the prognostic impact of ERß expression among NSCLC patients and will help clinicians find potential treatments based on estrogen signaling.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptor beta de Estrogênio/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Projetos de Pesquisa , Análise de Sobrevida , Revisão Sistemática como Assunto
2.
J Biol Regul Homeost Agents ; 33(5): 1395-1403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507154

RESUMO

Nitric oxide (NO) plays a key role in inflammation. It is partly produced by three forms of NOS: eNOS of inflammatory cells, nNOS of neural cells and iNOS (inducible isoform). Estrogens can cause an anti-inflammatory effect, although it is not yet clear through which NOS isoforms. The aim of this study was to evaluate the role of the different NOS isoforms, as well as estrogen receptors (ERs) α and ß, on the anti-inflammatory effects of estrogens. To avoid the influence of endogenous glucocorticoids or sexual hormones, male rats were hypophysectomized. Animals were segregated into two control groups (no-treatment control group and SHAM-operated animals) and three hypophysectomized groups (no-hormonal treatment, with estradiol-17ß, or with testosterone replacement treatment). Freund's complete adjuvant (1 mg) was administered to the footpad of all animals. Measurements were made based on footpad inflammation (with a plethysmometer) such as eNOS, nNOS, iNOS and ER α and ß protein expression (by immunohistochemistry principle/method) on days 1, 7 and 14. Only estradiol decreased inflammation, accompanied by increased levels of eNOS and nNOS and differential expression of ERs α and ß in the inflammatory infiltrate. The higher levels of estradiol-induced eNOS and nNOS ocurred perhaps through the activation of ER ß.


Assuntos
Estradiol/farmacologia , Receptor beta de Estrogênio/metabolismo , Inflamação/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Estrogênios , Masculino , Ratos
3.
Zhonghua Fu Chan Ke Za Zhi ; 54(7): 464-469, 2019 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-31365959

RESUMO

Objective: To evaluate the effects of parthenolide on estradiol-synthesizing enzyme, steroidogenic acute regulatory protein (StAR), and ER isoforms,VEGF in human endometriotic stromal cells. Methods: Primary endometriotic stromal cells were treated with different concentrations (1, 5, 10 and 20 µmol/L) of parthenolide. The mRNA of StAR, ER isoforms (ERα and ERß), PR, vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), tumour necrosis factor-α (TNFα), tumour necrosis factor receptor (TNFR) 1, TNFR2 were measured by real-time PCR. The levels of estradiol and progesterone in the cell supernatant were measured by ELISA. Results: Different concentrations of parthenolide could up-regulate the mRNA of StAR in primary endometriotic stromal cells (F=5.722, P<0.05); the mRNA of StAR in the group of 20 µmol/L was significantly higher than that of the control group [2.6±0.3 versus 1.0, P<0.01]. Different concentrations of parthenolide could down-regulate the mRNA of ERα (F=6.921, P<0.01); the mRNA of ERα in the group of 20 µmol/L and 10 µmol/L were significantly lower than those of the control group [0.2±0.3 versus 0.3±0.3 versus 1.0, all P<0.05]. Different concentrations of parthenolide could down-regulate the ratios of ERα/ERß mRNA levels (F=4.209, P<0.05). Different concentrations of parthenolide could up-regulate the mRNA of VEGF and TNFR1 (F=10.964, P<0.01; F=7.286, P<0.01). There were no statiscal significances with different concentrations of parthenolide on the mRNA of ERß, PR, IL-6, TNFα and TNFR2, and the levels of estradiol and progesterone in the cell supernatant (all P>0.05). Conclusions: Parthenolide may regulate the expression of estradiol-synthesizing enzyme, ER isoforms and angiogenesis in endometriotic stromal cells. Parthenolide may promote the development of endometriosis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Endometriose , Endométrio/efeitos dos fármacos , Sesquiterpenos/farmacologia , Células Estromais/metabolismo , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endometriose/induzido quimicamente , Endometriose/genética , Endométrio/metabolismo , Endométrio/patologia , Estradiol , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoformas de Proteínas , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Fator de Necrose Tumoral alfa/metabolismo
4.
Hypertension ; 74(4): 967-974, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378106

RESUMO

The pregnancy-augmented uterine vasodilation is linked to increased AT2R (angiotensin type-2 receptor) that mediates the vasodilatory effects of angiotensin II. However, the mechanisms controlling AT2R expression during pregnancy remain unclear. Estrogens are known to play a role in vascular adaptations during pregnancy. We hypothesized that estrogen stimulates uterine artery AT2R expression via ER (estrogen receptor)-ß-dependent transcription in a pregnancy-specific endothelium-dependent manner. Plasma estradiol levels increased and peaked in late pregnancy and returned to prepregnant levels post-partum, correlating with uterine artery AT2R and ERß upregulation. Estradiol stimulated AT2R mRNA expression in endothelium-intact but not endothelium-denuded late pregnant and nonpregnant rat uterine artery ex vivo. Consistently, estradiol stimulated AT2R mRNA expression in late pregnant but not nonpregnant primary human uterine artery endothelial cells in vitro, which was abolished by ER antagonist ICI 182,780. Higher ERα protein bound to ER-responsive elements in AT2R promoter in the nonpregnant arteries whereas higher ERß bound in the pregnant state. ERα protein levels were similar but higher ERß protein levels were expressed in pregnant versus nonpregnant human uterine artery endothelial cells. Estradiol stimulation recruited ERα to the AT2R promoter in the nonpregnant state and ERß to the AT2R promoter in pregnancy; however, only ERß recruitment mediated transactivation of the AT2R reporter gene in pregnant human uterine artery endothelial cells. Estradiol-induced AT2R expression was abolished by the specific ERß (not ERα) antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) and mimicked by the specific ERß (not ERα) agonist 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) in pregnant human uterine artery endothelial cells in vitro. This study demonstrates a novel role of pregnancy-augmented ERß in AT2R upregulation in the uterine artery and provides new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.


Assuntos
Células Endoteliais/efeitos dos fármacos , Estradiol/farmacologia , Receptor beta de Estrogênio/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Artéria Uterina/efeitos dos fármacos , Animais , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Estradiol/sangue , Feminino , Gravidez , Ratos , Regulação para Cima/efeitos dos fármacos , Artéria Uterina/metabolismo
5.
Cell Physiol Biochem ; 53(1): 186-199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31278696

RESUMO

BACKGROUND/AIMS: Estrogen could play a key role in the mechanisms underlying sex-related disparity in the incidence of thrombotic events. We investigated whether estrogen receptors (ERs) were expressed in human red blood cells (RBCs), and if they affected cell signaling of erythrocyte constitutive isoform of endothelial NO-synthase (eNOS) and nitric oxide (NO) release. METHODS: RBCs from 29 non-smoker volunteers (15 males and 14 females) aged between 20 and 40 years were analyzed by cytometry and western blot. In particular, content and distribution of ER-α and ER-ß, tyrosine kinases and eNOS phosphorylation and NO release were analyzed. RESULTS: We demonstrated that: i) both ER-α and ER-ß were expressed by RBCs; ii) they were both functionally active; and iii) ERs distribution and function were different in males and females. In particular, ERs modulated eNOS phosphorylation and NO release in RBCs from both sexes, but they induced the phosphorylation of specific tyrosine residues of kinases linked to eNOS activation and NO release in the RBCs from females only. CONCLUSION: Collectively, these data suggest that ERs could play a critical role in RBC intracellular signaling. The possible implication of this signaling in sex-linked risk disparity in human cardiovascular diseases, e.g. in thrombotic events, may not be ruled out.


Assuntos
Receptores Estrogênicos/metabolismo , Transdução de Sinais , Adulto , Dronabinol/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
6.
Chemosphere ; 235: 543-549, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31279116

RESUMO

PURPOSE: Nonylphenol (NP) is one widely distributed representative of environmental estrogens that disturb reproductive activities, bone metabolism and brain function through interfering diverse signal pathways leading to hormone metabolic dysfunctions, immunologic derangement, and tumorigenesis. Few of previous studies have observed the subacute toxicity on rodents, and little has been focused on the mechanism underneath the toxicities observed. METHODS: The 32 male Sprague-Dawley (SD) rats were randomly divided into four groups, the negative control group (corn oil) NP low, medium and high dose groups [30, 90, 270 mg/(kg·d)]. SD rats administrated with different dosage of NP every other day for 28d. Elisa and RT-PCR was employed to observe estrogen metabolism markers or mRNA expressions. RESULTS: In serum, NP exposure caused testosterone (T) (p < 0.001), progesterone (PROG) (p < 0.05) and estrone (E1) (p < 0.05) increased. In testicle, NP exposure caused T (p < 0.001), PROG (p < 0.05), E1 (p < 0.05), 17ß-estradiol (E2) (p < 0.05) and ERα mRNA (p < 0.01) increased, while P450 aromatizing enzyme (p < 0.001) decreased in NPL and ERß mRNA (p < 0.001) decreased in NPM and NPH. In liver, NP exposure caused 17ß-HSD2 mRNA (p < 0.01) increased, while P450 aromatizing enzyme decreased (p < 0.05). CONCLUSION: NP exposure exhibited general and estrogenic toxicity in rats through disturbing estrogen secretion network and estrogen receptor expression network, inducing abnormal metabolism of estrogen, whether in serum, liver and testicle.


Assuntos
Disruptores Endócrinos/toxicidade , Estrogênios/metabolismo , Fígado/metabolismo , Fenóis/toxicidade , Testículo/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Estrona/metabolismo , Feminino , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Estrogênicos/metabolismo , Testosterona/metabolismo , Testes de Toxicidade
7.
Neoplasma ; 66(5): 847-857, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31288527

RESUMO

The aim of this work was to determine the expression of the ERß (estrogen receptor ß) and multidrug resistance, namely MDR1 (P-glycoprotein, P-gp), in 152 samples of non-small cell lung cancer. The expression pattern of ERß and MDR1 were assessed by the quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry. We also analyzed the correlation between ERß and MDR1 with clinical and pathological data. The co-expression pattern of ERß and individual MDR1 proteins was assessed by correspondence analysis and chi-squared tests. In the present study, we found that patients with tumor stage I-II showed higher ERß mRNA expression levels and decreased expression of ERß protein with increasing tumor grade, which is opposite to MDR1 expression. In addition, an opposite co-expression pattern of ERß and individual MDR1 proteins was also observed. In conclusion, the results can be used to better understand the expression control of MDR1 and may allow for the establishment of new cancer chemistry strategies that will control P-gp expression in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Receptor beta de Estrogênio/metabolismo , Neoplasias Pulmonares/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Exp Parasitol ; 204: 107721, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31288023

RESUMO

BACKGROUND: Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan able to infect humans and it is common in pregnant women. During pregnancy and lactation, there are changes in the concentration of 17ß-estradiol (E2), progesterone (Prg), and prolactin (PRL). It is known that a proinflamatory response reduces the susceptibility to be infected, and this response may change according to hormonal impairment. Monocytes and macrophages are the main barrier against many intracellular microorganisms, due to their ability to produce cytokines. The aim of this work was to determine the effect of E2, progesterone, and PRL on the infective capacity of T. gondii, proinflamatory immune response modulation and the expression of hormonal receptors on THP-1 cell stimulated with T. gondii. METHODS: The THP-1 cells were infected with 1500 T. gondii tachyzoites, of RH strain. Stimuli were conducted with recombinant PRL (200 ng/mL), E2 (40 nM) y Prg (40 nM). MTT assays were performed to evaluate cellular viability. Western blot assays were carried out to evaluate the expression of the hormonal receptors (PRLR, ERα, and ERß). Cytokines produced were measured with a magnetic bead kit directed to 17 cytokines. RESULTS: Stimuli with E2 and Prg increased T. gondii infection in monocytes after 48 h; however, no differences in infection were observed in PRL stimulus. The E2 decreased the secretion of IL-12 and IL-1ß and PRL did not modify the production of these cytokines in THP-1 cells stimulated with T. gondii; however, both hormones increased the production of IL-10. Besides, PRL augmented the production of IL-4 and IL-13. In contrast, Prg reduced these cytokines. Our results show that T. gondii induces the expression of ERα and ERß and lowers PRLR. The hormones modify the expression of the receptors of other hormones: Prg decreases PRLR, ERß and increases ERα; E2 diminishes PRLR; and PRL decreases ERα and ERß expression. CONCLUSION: The hormones can increase T. gondii infection and could be mediating an anti-inflammatory response in THP-1 cells. T. gondii induces changes in the expression of hormonal receptors.


Assuntos
Citocinas/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Receptores da Prolactina/metabolismo , Células THP-1/metabolismo , Toxoplasma/fisiologia , Animais , Corantes , Estradiol/metabolismo , Feminino , Humanos , Camundongos , Progesterona/metabolismo , Prolactina/metabolismo , Isoformas de Proteínas/metabolismo , Células THP-1/imunologia , Células THP-1/parasitologia , Sais de Tetrazólio , Tiazóis , Toxoplasma/crescimento & desenvolvimento
9.
Environ Sci Pollut Res Int ; 26(23): 23491-23504, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201698

RESUMO

This study was conducted to investigate the effects of maternal exposure to bisphenol A (BPA) on testis development of F1 male mice. The BPA exposure model of pregnant mice was prepared by intragastric administration of BPA at the doses of 0, 2.5, 5, 10, 20, and 40 mg/kg/day at gestation day (GD) 0.5-17.5. The testis index of the offspring mice was calculated at postnatal day (PND) 21 and PND 56. The results showed that maternal exposure to 20 mg/kg BPA during pregnancy significantly increased the testicular index of F1 males at PND 21, and 40 mg/kg BPA significantly decreased the testicular index of F1 males at PND 56 (P < 0.01). BPA significantly reduced serum testosterone (T) and estradiol (E2) levels, and improved testicular ERα and ERß levels in F1 males at both PND 21 and PND 56. BPA exposure also upregulated transcription of testicular Dnmt1 and inhibited the transcription of testicular Dnmt3A and Dnmt3B in F1 mice at PND 21. BPA reduced the transcriptional level of testicular DNA methyltransferase (Dnmt), increased the expression of testicular caspase-7, caspase-9, and bax, and decreased the expression of bcl-2 in F1 mice at PND 56. Consistent with that, BPA improved the apoptosis rate in the testis at PND 56 (P < 0.01 or P < 0.05). Our study indicates that BPA disrupts the secretion of testosterone, estradiol, and estrogen receptors by interfering with the transcription of testicular DNA methyltransferase (Dnmt) in offspring males, which damages testicular tissues and affects the potential reproductive function.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Testículo/crescimento & desenvolvimento , Animais , DNA (Citosina-5-)-Metiltransferases , Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Masculino , Exposição Materna , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Proteínas Proto-Oncogênicas c-bcl-2 , Receptores Estrogênicos/metabolismo , Diferenciação Sexual , Testículo/efeitos dos fármacos , Testosterona/sangue , Testes de Toxicidade
10.
Mol Med Rep ; 19(6): 5087-5096, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059046

RESUMO

The present study aimed to investigate the inhibitory effects and the mechanisms underlying 17ß­estradiol (E2) effects on triglyceride synthesis and insulin resistance in skeletal muscle tissues and cells. Ovariectomy (OVX) was performed on 6­month­old female rats treated with or without E2. Subsequently, various serum biochemical markers were measured. Additionally, pathological alterations of the uterus, liver and skeletal muscle were analyzed, and the content of triglycerides (TG) in muscle was detected. Differentiated myotubes formed by C2C12 cells were treated with palmitic acid (PA) or pretreated with E2, estrogen receptor (ESR) 1 agonist propylpyrazoletriol (PPT) and ESR2 agonist diarylpropionitrile (DPN). Subsequently, the mRNA or protein expression levels of ESR1/2, peroxisome proliferator activated receptor α (PPARα), CD36 molecule (CD36), fatty acid synthase (FASN), perilipin 2 (PLIN2), phosphorylated acetyl­CoA carboxylase α (p­ACACA), p­AKT serine/threonine kinase (p­AKT) and p­mitogen­activated protein kinase 8 (p­MAPK8) were analyzed in skeletal muscle or in C2C12 cells by reverse transcription­semi­quantitative polymerase chain reaction and western blotting. The present results suggested that treatment with E2 inhibited OVX­induced body weight gain, TG accumulation and insulin resistance. The protein or mRNA expression levels of ESR1, CD36, PPARα, p­ACACA and p­AKT were decreased, whereas the protein or mRNA expression levels of ESR2, PLIN2, FASN and p­MAPK8 were increased in the OVX group. Of note, treatment with E2 restored the expression levels of the aforementioned factors. In C2C12 cells, treatment with E2 or PPT reversed the alterations induced by treatment with PA. In contrast, pretreatment with DPN did not influence the effect of PA. Collectively, E2 was able to interact with ESR1, thus activating the CD36­PPARα pathway, decreasing the level of TG in the muscles and improving insulin resistance in skeletal muscles and C2C12 cells.


Assuntos
Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Triglicerídeos/biossíntese , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Resistência à Insulina , Camundongos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Ovariectomia , Ácido Palmítico/farmacologia , Perilipina-2/genética , Perilipina-2/metabolismo , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
11.
J Vet Sci ; 20(2): e11, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30944534

RESUMO

Mammary lesions in sows can prevent suckling piglets from consuming colostrum that provides fundamental nutrients and protective immunity. Although mammary gross lesions are frequently found in sows at farms or slaughterhouses, with the exception of mastitis, they have received little research attention. In this study, we investigated mammary lesions observed in South Korean sows between 2015 and 2016. Mammary tissue samples of 82 sows showing gross lesions during meat inspection were histologically classified and immunohistochemical analysis was conducted to assess the expression of estrogen receptor (ER)-α, ER-ß, and progesterone receptor (PR) for mammary hyperplastic lesions as well as that of cluster of differentiation (CD) 3, CD79a, interleukin (IL)-1α, IL-1ß, IL-6, and IL-8 for mastitis. Furthermore, 20 swab samples were cultured, and the isolated bacteria were identified using polymerase chain reactions for 16S ribosomal RNA genes. The lesions were classified as hyperplasia, mastitis, or hyperplasia with mastitis. Immunohistochemistry results revealed that there was neither expression of ER-α nor of ER-ß, but all examined hyperplastic samples expressed PR. In addition, there was a significant correlation between CD3 and IL-1ß expressions, as well as between IL-1ß and IL-6 expressions. Regarding the identity of the isolated bacteria, Pseudomonas spp. were most frequently detected. The results of this study have revealed the incidence and characteristics of porcine mammary lesions.


Assuntos
Doenças Mamárias/veterinária , Citocinas/metabolismo , Glândulas Mamárias Animais/patologia , Receptores Estrogênicos/metabolismo , Doenças dos Suínos/patologia , Matadouros , Animais , Doenças Mamárias/metabolismo , Doenças Mamárias/microbiologia , Doenças Mamárias/patologia , Complexo CD3/metabolismo , Antígenos CD79/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/microbiologia , Mastite/metabolismo , Mastite/microbiologia , Mastite/patologia , Mastite/veterinária , Pseudomonas , Receptores de Progesterona/metabolismo , Suínos , Doenças dos Suínos/classificação , Doenças dos Suínos/metabolismo , Doenças dos Suínos/microbiologia
12.
Zhonghua Fu Chan Ke Za Zhi ; 54(4): 249-254, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31006191

RESUMO

Objective: To elucidate whether metformin could regulate the mRNA expression level of estrogen synthetase and ER in human uterine leiomyoma tissues. Methods: (1) Seventeen pairs of uterine leiomyoma tissues and adjacent myometrium (>2 cm) were collected from patients underwent hysterectomy in Peking University First Hospital between December 2016 and January 2017. Real-time PCR was used to measure the mRNA expression level of estrogen synthetase [including cytochrome P450 cholesterol side chain cleavage enzyme (P450scc), cytochrome P450 17α-hydroxylase (P450c17), 3-beta-hydroxysteroid dehydrogenase type 2 (3ß-HSD-2), 17-beta-hydroxysteroid dehydrogenase type 1 (17ß-HSD-1) and aromatase cytochrome P450 (P450arom)] and ER (including ERα and ERß) in the uterine leiomyoma tissues and adjacent myometrium. (2) Uterine leiomyoma cells derived from uterine leiomyoma tissues were identified by immunocytochemistry method and cultured to the third generation. The treatment groups were cultured with different concentrations of metformin (10, 50 and 100 µmol/L) for 48 hours, and the control group was cultured with deionized water for 48 hours. The mRNA expression level of estrogen synthetase and estrogen receptor subtypes were measured by real-time PCR. Results: (1) P450scc, P450c17, 3ß-HSD-2, 17ß-HSD-1, P450arom mRNA median expression levels were 112, 4, 13, 42 and 194 in the uterine leiomyoma tissues, and were respectively 114, 5, 11, 32 and 6 in the myometrium. Compared to those of the myometrium, 3ß-HSD-2 and P450arom mRNA expression levels in the uterine leiomyoma tissue were significantly higher (P<0.05), while there were no significant change of mRNA expression levels among P450scc, P450c17 and 17ß-HSD-1 (P>0.05). ERα and ERß mRNA median expression levels were 208 and 116 in the uterine leiomyoma tissues, and were 24 and 95 in the myometrium. Compared to that of the myometrium, ERα mRNA level in the uterine leiomyoma tissue was significantly higher (P=0.001), while there were no significant change of ERß mRNA level (P=0.193). (2) After cultured with different concentrations of metformin (10, 50 and 100 µmol/L), the P450arom mRNA levels in the uterine leiomyoma tissues were 9±4, 8±5 and 8±3 respectively in the treatment groups and was 16±5 in the control group. Compared to that of the control group, P450arom mRNA expression levels in the treatment groups were significantly declined (P<0.05). There were no significant different change of mRNA expression levels among 3ß-HSD-2, ERα and ERß between the treatment groups and the control group (P>0.05). Conclusions: Metformin could down-regulate the mRNA expression level of aromatase in the uterine leiomyoma cells. These results indicate that metformin may inhibit the local estrogen synthesis and therefore suppress the development of uterine leiomyoma.


Assuntos
Aromatase/efeitos dos fármacos , Aromatase/genética , Sistema Enzimático do Citocromo P-450/genética , Receptor beta de Estrogênio/metabolismo , Expressão Gênica , Leiomioma/metabolismo , Metformina/farmacologia , Neoplasias Uterinas/metabolismo , Aromatase/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Feminino , Regulação da Expressão Gênica , Humanos , Leiomioma/patologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Uterinas/patologia
13.
J Steroid Biochem Mol Biol ; 191: 105312, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30995525

RESUMO

ERbeta (ERß) celebrated its 20th birthday in 2016 and although the overwhelming data in the literature indicate a role for this receptor in the control of epithelial proliferation, neurodegeneration and immune function, no ERß agonists have yet made it to the clinics. This is the situation, despite the fact that very good safe ERß agonists have been synthesized and at least one has been donated to the NIH for distribution to researchers, who want to study its possible clinical use. Clinical trials are ongoing for the use of ERß agonists in prostate cancer and schizophrenia but even today reviewers of our grants still make comments like "The grant is excellent except that the focus of the grant is ERß". There are multiple reasons for the non-acceptance of the value of ERß and in this paper we will discuss issues raised by labs which do not support a role for ERß in physiology or pathology.


Assuntos
Receptor beta de Estrogênio/metabolismo , Animais , Anticorpos/imunologia , Descoberta de Drogas , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/imunologia , Expressão Gênica , Humanos , Imunidade , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo
14.
Int J Mol Sci ; 20(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974833

RESUMO

Ring finger protein 146 (RNF146) is an E3 ubiquitin ligase whose activity prevents poly (ADP-ribose) polymerase 1 (PARP1)-dependent neurodegeneration in Parkinson's disease (PD). Previously, we reported that rhododendrin is a chemical inducer that increases RNF146 expression. However, the molecular mechanism of rhododendrin-induced RNF146 expression is largely unknown and its translational application for the treatment of Parkinson's disease remains unexplored. Here we found that rhododendrin increased RNF146 expression via estrogen receptor ß (ERß) activation. Rhododendrin stimulated ERß nuclear translocation and binding to the RNF146 promoter, thereby enhancing its transcription. Rhododendrin is cytoprotective against 6-hydroxydopamine (6-OHDA)-induced cell death, which is largely dependent on ERß activity and RNF146 expression. Finally, we demonstrated that rhododendrin treatment resulted in RNF146 expression in dopaminergic neurons in mice. Moreover, dopaminergic neuron viability was markedly enhanced by pretreatment with rhododendrin in 6-OHDA-induced mouse models for PD. Our findings indicate that estrogen receptor activation plays a neuroprotective role and that rhododendrin could be a potential therapeutic agent in preventing PARP1-dependent dopaminergic cell loss in PD.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Receptor beta de Estrogênio/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glicosídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/efeitos adversos , Fenóis/farmacologia , Ubiquitina-Proteína Ligases/biossíntese , Animais , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/patologia , Receptor beta de Estrogênio/genética , Regulação Enzimológica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Estresse Oxidativo/genética , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ubiquitina-Proteína Ligases/genética
15.
Int J Med Mushrooms ; 21(4): 381-392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002633

RESUMO

We studied Phellinus lonicerinus to determine the cytotoxic effect and the dual estrogenic activities of methyl-hispolon and their relation to estrogen signals in vivo and in vitro. The Glide scores of methyl-hispolon-estrogen receptor α (ERα) and methyl-hispolon-ERß docked complexes were -7.29 kcal/mol and -6.68 kcal/mol in docking simulations. Methyl-hispolon had a significant antiproliferative effect for estrogen-sensitive ER(+) MCF-7 cells in the absence of estrogen, and it exhibited dual estrogen activities. Methyl-hispolon increased the serum E2 in rats with premature ovarian failure and fulfilled the estrogenic function in the uterus and ovary. Methyl-hispolon significantly inhibited the expression of Ras, API, ERα, C-myc, and cyclinDl, as well as their gene transcription in RL95-2 cells. The phosphorylation of ERK1/2 was inhibited by methyl-hispolon. Thus, methyl-hispolon has potential use in treating estrogen deficiency-related diseases, with good antitumor effects and estrogenic activity.


Assuntos
Senilidade Prematura/tratamento farmacológico , Basidiomycota/química , Catecóis/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Estrogênios/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Catecóis/química , Proliferação de Células/efeitos dos fármacos , Moduladores de Receptor Estrogênico/química , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Terapia de Reposição Hormonal , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Ovário/efeitos dos fármacos , Fosforilação , Fitoestrógenos/metabolismo , Ratos , Ratos Sprague-Dawley , Útero/efeitos dos fármacos
16.
Cell Physiol Biochem ; 52(3): 468-485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873822

RESUMO

BACKGROUND/AIMS: Breast cancer is a clinically and molecularly heterogeneous disease. Patients with triple-negative breast cancer (TNBC) have poorer outcomes than those with other breast cancer subtypes due to lack of effective molecular targets for therapy. The present study aimed to the identification of estrogen receptor (ER)ß as a novel mitochondrial target in TNBC cells, together with underlying mechanisms. METHODS: Expression of ERß in clinical breast samples were examined by qRT-PCR, immunohistochemistry and immunoblotting. Subcellular distribution and binding of ERß-Grp75 was determined by confocal microscopic analysis, co-immunoprecipitation experiments, and limited-detergent extraction of subcellular organelles. The effect of mitocondrial ERß(mitoERß) overexpression on cell proliferation and cell cycle distribution were assessed CCK-8 assays and FACS. Mitochondrial ROS, membrane potential, and Ca²âº level were measured using the specific fluorescent probes Mito-Sox, TMRE, and Rhod-2AM. The tumorigenic effect of mitoERß overexpression was assessed using an anchorage-independent growth assay, sphere formation and a mouse orthotopic xenograft model. RESULTS: ERß expression was lower in tumor tissue than in adjacent normal tissue of patients with breast cancer, and low levels of mitochondrial ERß (mitoERß) also were associated with increased tumor recurrence after surgery. Overexpression of mitoERß inhibited the proliferation of TNBC cells and tumor masses in an animal model. Moreover, overexpression of mitoERß increased ATP production in TNBC cells and normal breast MCF10A cells, with the latter completely reversed by mitoERß knockdown in MCF10A cells. Grp75 was found to positively regulate ERß translocation into mitochondria via a direct interaction. Coimmunoprecipitation and subcellular fractionation experiments revealed that ERß-Grp75 complex is stable in mitochondria. CONCLUSION: These results suggest that the up-regulation of mitoERß in TNBC cells ensures proper mitochondrial transcription, activating the OXPHOS system to produce ATP. Studying the effects of mitoERß on mitochondrial activity and specific mitochondrial gene expression in breast cancer might help predict tumor recurrence, inform clinical decision-making, and identify novel drug targets in the treatment of TNBC.


Assuntos
Trifosfato de Adenosina/biossíntese , Receptor beta de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Neoplasias de Mama Triplo Negativas/genética , Animais , Cálcio/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Feminino , Corantes Fluorescentes/química , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Camundongos , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/metabolismo , Estadiamento de Neoplasias , Fosforilação Oxidativa , Ligação Proteica , Transporte Proteico , RNA Interferente Pequeno/biossíntese , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Oncol Rep ; 41(5): 2967-2974, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864727

RESUMO

Estrogen receptor ß (ERß) is an important ER subtype in lung adenocarcinoma. However, the functions and mechanisms of ERß have not been fully elucidated. The aim of the present study was to investigate the biological effects and relevant mechanisms of ERß in lung adenocarcinoma. The protein expression of ERß was found to be higher in lung adenocarcinoma tissues compared with that in adjacent non­cancerous tissues (n=75, P<0.001). Of note, ERß protein expression was significantly correlated with tumor size (P=0.018), lymph node metastasis (P=0.041), clinical stage (P=0.041) and differentiation (P<0.001). In addition, ERß protein expression in A549 cells was found to be higher compared with that in human bronchial epithelial cells (HBEs). Furthermore, knockdown of ERß expression inhibited colony formation and cell invasion in vitro, whereas the number of metastatic tumors in the lungs of mice was decreased in vivo. Western blot analysis demonstrated that the expression of phosphorylated extracellular signal­regulated kinase (pERK), matrix metalloproteinase (MMP)­2 and MMP­9 was decreased by downregulation of ERß. Therefore, ERß may play an important role in lung adenocarcinoma progression via the MEK/ERK signaling axis, and it may represent a novel therapeutic target for lung adenocarcinoma in the future.


Assuntos
Adenocarcinoma de Pulmão/patologia , Receptor beta de Estrogênio/metabolismo , Neoplasias Pulmonares/patologia , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Receptor beta de Estrogênio/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Pulmão/patologia , Metástase Linfática/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Med Rep ; 19(5): 3555-3563, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864712

RESUMO

Previous studies demonstrated that estrogen receptor ß (ERß) signaling alleviates systemic inflammation in animal models, and suggested that ERß­selective agonists may deactivate microglia and suppress T cell activity via downregulation of nuclear factor κ­light­chain­enhancer of activated B cells (NF­κB). In the present study, the role of ERß in lipopolysaccharide (LPS)­induced inflammation and association with NF­κB activity were investigated in PC­3 and DU145 prostate cancer cell lines. Cells were treated with LPS to induce inflammation, and ELISA was performed to determine the expression levels of inflammatory cytokines, including tumor necrosis factor­α (TNF­α), monocyte chemoattractant protein 1 (MCP­1), interleukin (IL)­1ß and IL­6. MTT and Transwell assays, and Annexin V/propidium iodide staining were conducted to measure cell viability, apoptosis and migration, respectively. Protein expression was determined via western blot analysis. LPS­induced inflammation resulted in elevated expression levels of TNF­α, IL­1ß, MCP­1 and IL­6 compared with controls. ERß overexpression significantly inhibited the LPS­induced production of TNF­α, IL­1ß, MCP­1 and IL­6. In addition, the results indicated that ERß suppressed viability and migration, and induced apoptosis in prostate cancer cells, which was further demonstrated by altered expression of proliferating cell nuclear antigen, B­cell lymphoma 2­associated X protein, caspase­3, E­cadherin and matrix metalloproteinase­2. These effects were reversed by treatment with the ERß antagonist PHTPP or ERß­specific short interfering RNA. ERß overexpression reduced the expression levels of p65 and phosphorylated NF­κB inhibitor α (IκBα), but not total IκBα expression in LPS­treated cells. In conclusion, ERß suppressed the viability and migration of the PC­3 and DU145 prostate cancer cell lines and induced apoptosis. Furthermore, it reduced inflammation and suppressed the activation of the NF­κB pathway, suggesting that ERß may serve roles as an anti­inflammatory and anticancer agent in prostate cancer.


Assuntos
Receptor beta de Estrogênio/metabolismo , Inflamação/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Receptor beta de Estrogênio/genética , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , NF-kappa B/metabolismo , Neoplasias da Próstata/genética , Transdução de Sinais
19.
Aquat Toxicol ; 209: 159-167, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30780113

RESUMO

The expression of estrogen receptors (ERs) and their roles in important cell processes such as apoptosis in the macrophages exposed to estrogen/xenoestrogen have remained a complex secret. This study focused on the expression of estrogen receptors (ERs) and the stimulation of apoptosis in the macrophages from the two sexes of goldfish (Carassius auratus) exposed to 17-ßestradiol (E2) and nonylphenol (NP) under in vivo and in vitro conditions. For the in vivo experiment, fish were exposed to NP (10-6 M and 10-7 M) and E2 (10-6 M) for 24 days. Then, the head kidney macrophages from the male and the female goldfish were isolated and assayed. For the in vitro experiments, the macrophages derived from the two sexes were cultured in L-15 medium and exposed to E2 (150 nM) and NP (10 nM and 150 nM) for 3 days. The results showed that the three isoforms of ERs (ERα, ERß1, ERß2) were expressed in the goldfish macrophages. After the exposure of macrophages to NP and E2, sex-specific increase of ERs expression and apoptosis were observed (P < 0.05). The expression of ERα after NP treatment showed the highest alteration, with the response being concentration-dependent. The most alteration of ERs expression were observed in the in vivo experiment. This study provides insight to understand how exposure of the goldfish macrophages to E2 and NP can up-regulate the transcript levels of estrogen receptor subtypes and stimulate apoptosis.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Estrogênios/toxicidade , Carpa Dourada/metabolismo , Macrófagos/metabolismo , Modelos Biológicos , Fenóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Carpa Dourada/genética , Macrófagos/efeitos dos fármacos , Masculino , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade
20.
Ecotoxicol Environ Saf ; 172: 504-513, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738973

RESUMO

Zearalenone (ZEA) - a fungal mycotoxin is reported to both cause the oxidative stress associated with death of cells as well as induction of the proliferation of cells, depending on its concentration and the type of cells. ZEA due to its structural similarity to naturally occurring estrogens is able to bind to estrogen receptors and triggers estrogen-associated signaling pathways. The aim of this study is to evaluate whether the induction of oxidative stress in normal epithelial prostate PNT1A cells is associated with estrogenic activity of ZEA. We observed that ZEA-induced oxidative stress in PNT1A cells is associated with a decrease in the oxidative stress defense enzymes expression, cell cycle arrest in G2/M cell cycle phase as well as the decreased migration of cells. The results also suggest that the observed effect might be associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)- hypoxia inducible factor 1 alpha (HIF-1α) signaling pathway. The usage of estrogen receptor ß (ERß) selective antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-phenol PHTPP showed that ERß activity is able to decrease the ZEA-induced oxidative stress, but is not enough to counteract it, indicating that ZEA-induced oxidative stress is only partially associated with estrogenic activity of ZEA.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Próstata/citologia , Zearalenona/toxicidade , Catalase/metabolismo , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/metabolismo , Estrogênios/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , NF-kappa B/metabolismo , Próstata/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
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