Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.573
Filtrar
1.
Biochemistry (Mosc) ; 84(11): 1306-1328, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760920

RESUMO

Focal brain injuries (in particular, stroke and traumatic brain injury) induce with high probability the development of delayed (months, years) cognitive and depressive disturbances which are frequently comorbid. The association of these complications with hippocampal alterations (in spite of the lack of a primary injury of this structure), as well as the lack of a clear dependence between the probability of depression and dementia development and primary damage severity and localization served as the basis for a new hypothesis on the distant hippocampal damage as a key link in the pathogenesis of cognitive and psychiatric disturbances. According to this hypothesis, the excess of corticosteroids secreted after a focal brain damage, in particular in patients with abnormal stress-response due to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction, interacts with corticosteroid receptors in the hippocampus inducing signaling pathways which stimulate neuroinflammation and subsequent events including disturbances in neurogenesis and hippocampal neurodegeneration. In this article, the molecular and cellular mechanisms associated with the regulatory role of the HPAA and multiple functions of brain corticosteroid receptors in the hippocampus are analyzed. Functional and structural damage to the hippocampus, a brain region selectively vulnerable to external factors and responding to them by increased cytokine secretion, forms the basis for cognitive function disturbances and psychopathology development. This concept is confirmed by our own experimental data, results of other groups and by prospective clinical studies of post-stroke complications. Clinically relevant biochemical approaches to predict the risks and probability of post-stroke/post-trauma cognitive and depressive disturbances are suggested using the evaluation of biochemical markers of patients' individual stress-response. Pathogenetically justified ways for preventing these consequences of focal brain damage are proposed by targeting key molecular mechanisms underlying hippocampal dysfunction.


Assuntos
Lesões Encefálicas/patologia , Hipocampo/metabolismo , Animais , Lesões Encefálicas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Humanos , Estresse Oxidativo , Sistema Hipófise-Suprarrenal , Receptores de Esteroides/metabolismo
2.
Nat Cell Biol ; 21(10): 1206-1218, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31548609

RESUMO

Cholesterol activates the master growth regulator, mTORC1 kinase, by promoting its recruitment to the surface of lysosomes by the Rag guanosine triphosphatases (GTPases). The mechanisms that regulate lysosomal cholesterol content to enable mTORC1 signalling are unknown. Here, we show that oxysterol binding protein (OSBP) and its anchors at the endoplasmic reticulum (ER), VAPA and VAPB, deliver cholesterol across ER-lysosome contacts to activate mTORC1. In cells lacking OSBP, but not other VAP-interacting cholesterol carriers, the recruitment of mTORC1 by the Rag GTPases is inhibited owing to impaired transport of cholesterol to lysosomes. By contrast, OSBP-mediated cholesterol trafficking drives constitutive mTORC1 activation in a disease model caused by the loss of the lysosomal cholesterol transporter, Niemann-Pick C1 (NPC1). Chemical and genetic inactivation of OSBP suppresses aberrant mTORC1 signalling and restores autophagic function in cellular models of Niemann-Pick type C (NPC). Thus, ER-lysosome contacts are signalling hubs that enable cholesterol sensing by mTORC1, and targeting the sterol-transfer activity of these signalling hubs could be beneficial in patients with NPC.


Assuntos
Colesterol/metabolismo , Retículo Endoplasmático/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Doenças de Niemann-Pick/metabolismo , Receptores de Esteroides/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células HEK293 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Receptores de Esteroides/genética , Transdução de Sinais , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
3.
Chemosphere ; 237: 124551, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31549662

RESUMO

To characterize the potential endocrine-disrupting chemicals (EDCs) in the environment that interact with the crustacean ecdysone receptor (EcR), we established a method involving in silico modeling/molecular docking and in vitro reporter gene assay. Cherry shrimp (Neocaridina davidi) EcR (NdEcR) and retinoid X receptor (NdRxR) were identified and cloned for use in this method. A theoretical 3D model of NdEcR ligand-binding domain (LBD) was built in silico based on sequence homology with the established X-ray structure of insect EcR. The interaction of the NdEcR LBD with ecdysteroids, diacylhydrazine (DAH) pesticides, and other potential EDCs was evaluated using molecular docking programs. The results revealed that the ligand-binding pocket in the NdEcR LBD was flexible and adaptive for accommodating ligands of different shapes. The agonistic and antagonistic activities of the candidate compounds were further assessed by in vitro reporter gene assay using human cell lines transiently transfected with NdEcR and NdRxR expression plasmids and a reporter plasmid containing synthesized ecdysone response element. The assay was validated by the dose-dependent responses of EcR-mediated gene transcription after treating the transfected cell lines with ecdysteroids, 20-hydroxyecdysone, and ponasterone A. Examination of the candidate compounds using the reporter gene assay revealed restricted functional specificity to ecdysteroids and DAHs. Three of the tested DAH pesticides originally targeting the insect EcR were found to be weak agonists and strong antagonists of NdEcR. These results suggest that DAHs are potential EDCs for crustaceans that disrupt their ecdysteroid signals by functioning as EcR agonists or antagonists.


Assuntos
Crustáceos/efeitos dos fármacos , Ecdisteroides/farmacologia , Praguicidas/toxicidade , Receptores de Esteroides/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Crustáceos/metabolismo , Ecdisona/metabolismo , Ecdisona/farmacologia , Ecdisteroides/toxicidade , Ecdisterona/análogos & derivados , Ecdisterona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Simulação de Acoplamento Molecular , Praguicidas/química , Praguicidas/metabolismo , Filogenia , Receptores de Esteroides/agonistas , Receptores de Esteroides/antagonistas & inibidores , Receptores de Esteroides/genética , Receptores X Retinoide/química , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo
4.
Pestic Biochem Physiol ; 159: 85-90, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400788

RESUMO

RNA interference (RNAi) is a potentially useful pest control method because of its high specificity. Silencing the expression of important RNAi target genes of pests will block important biological processes and reduce pest damage. Ecdysone is a unique arthropod hormone and the ecdysone receptor (EcR) is a key factor in molting pathway. We investigated the possibility that dsRNA targeting of the EcR of Tetranychus cinnabarinus (TcEcR) could effectively block development from larvae to adults. The mRNA level of TcEcR was highest in the larva stage, and 73.1% of the mites failed to survive the larva stage when TcEcR expression was silenced. Only 11.7% of T. cinnabarinus ingesting dsRNA successfully developed into adults, while 86.7% in the control succeeded in molting across each stage. RNAi significantly increased the developmental intervals of T. cinnabarinus. Under the effects of dsRNA, development times for the larva and first nymph doubled. Phenotype of body size change and death were observed during the development of T. cinnabarinus ingesting dsRNA. These findings suggest that RNAi is a potential means for the control of T. cinnabarinus. Genes in hormone pathways such as EcR are possible RNAi targets.


Assuntos
Larva/metabolismo , Interferência de RNA/fisiologia , Receptores de Esteroides/metabolismo , Tetranychidae/metabolismo , Animais , Tamanho Corporal , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Plantas Geneticamente Modificadas/metabolismo , RNA de Cadeia Dupla/genética , Receptores de Esteroides/genética , Tetranychidae/crescimento & desenvolvimento
5.
Inorg Chem ; 58(17): 11782-11792, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31433630

RESUMO

Reproduction of the dominant vector of Zika and dengue diseases, Aedes aegypti mosquito, is controlled by an active heterodimer complex composed of the 20-hydroxyecdysone receptor (EcR) and ultraspiracle protein. Although A. aegypti EcR shares the structural and functional organization with other nuclear receptors, its C-terminus has an additional long F domain (AaFEcR). Recently, we showed that the full length AaFEcR is intrinsically disordered with the ability to specifically bind divalent metal ions. Here, we describe the details of the exhaustive structural and thermodynamic properties of Zn2+- and Cu2+-complexes with the AaFEcR domain, based on peptide models of its two putative metal binding sites (Ac-HGPHPHPHG-NH2 and Ac-QQLTPNQQQHQQQHSQLQQVHANGS-NH2). Unexpectedly, only in the presence of increasing concentrations of Cu2+ ions, the Ac-HGPHPHPHG-NH2 peptide gained a metal ion-induced poly-l-proline type II helical structure, which is unique for members of the family of nuclear receptors.


Assuntos
Aedes/efeitos dos fármacos , Antivirais/farmacologia , Cobre/farmacologia , Compostos Organometálicos/farmacologia , Peptídeos/farmacologia , Receptores de Esteroides/antagonistas & inibidores , Animais , Antivirais/química , Sítios de Ligação/efeitos dos fármacos , Cobre/química , Dengue/tratamento farmacológico , Dengue/metabolismo , Estrutura Molecular , Compostos Organometálicos/química , Peptídeos/química , Receptores de Esteroides/metabolismo , Termodinâmica , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/metabolismo
6.
Reprod Biol ; 19(2): 210-217, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262644

RESUMO

Clinical outcomes of fresh embryo transfer in non-hCG triggered in vitro maturation (IVM) cycles are inferior compared to vitrified-warmed embryo transfer. This is a prospective observational pilot study in a consecutive cohort of 31 polycystic ovary syndrome (PCOS) patients and 37 normo-ovulatory egg donors who underwent IVM without fresh embryo transfer between July 2009 and June 2014. All subjects received 150 IU of highly purified menotropin (HP-hMG) daily for three days. On cycle day 6, all patients started transdermal oestradiol (E2) at a daily dose of 9 mg. There was no human chorionic gonadotropin (hCG) trigger before oocyte retrieval (OR). Vaginal micronized progesterone was commenced on the evening after OR, at a daily dose of 600 mg. Additional luteal phase support (LPS) was administered as follows: Group A: no additional LPS; Group B: 1500 IU of hCG administered 4 h after OR and Group C: 5000 IU of hCG administered 4 h after OR + an additional injection of 5000 IU of hCG 1 day before endometrial biopsy. Endometrial biopsy for histology and immunohistochemistry (IHC) was performed on day 5 or 6 after OR. Instead of being downregulated, both PR-B and ERα in endometrial glands and stroma were moderately to strongly expressed in all three protocols, suggesting that the mid-luteal histological signature of endometrial receptivity is deficient in a non-hCG-triggered IVM cycle. Poor clinical outcomes after fresh embryo transfer following IVM are probably related to inappropriate endometrial development which may be linked to the short follicular phase of IVM cycles.


Assuntos
Gonadotropina Coriônica/farmacologia , Endométrio/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Síndrome do Ovário Policístico/metabolismo , Receptores de Esteroides/metabolismo , Adulto , Gonadotropina Coriônica/administração & dosagem , Estudos de Coortes , Estradiol/administração & dosagem , Estradiol/farmacologia , Feminino , Humanos , Técnicas de Maturação in Vitro de Oócitos , Projetos Piloto , Progesterona/administração & dosagem , Progesterona/farmacologia , Estudos Prospectivos , Receptores de Esteroides/genética , Adulto Jovem
7.
Insect Biochem Mol Biol ; 112: 103184, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31295549

RESUMO

The rate of carbohydrate metabolism is tightly coordinated with developmental transitions in Drosophila, and fluctuates depending on the requirements of a particular developmental stage. These successive metabolic switches result from changes in the expression levels of genes encoding glycolytic, tricarboxylic acid cycle (TCA), and oxidative phosphorylation enzymes. In this report, we describe a repressive action of ecdysone signaling on the expression of glycolytic genes and enzymes of glycogen metabolism in Drosophila development. The basis of this effect is an interaction between the ecdysone receptor (EcR) and the estrogen-related receptor (ERR), a specific regulator of the Drosophila glycolysis. We found an overlapping DNA-binding pattern for the EcR and ERR in the Drosophila S2 cells. EcR was detected at a subset of the ERR target genes responsible for carbohydrate metabolism. The 20-hydroxyecdysone treatment of both the Drosophila larvae and the S2 cells decreased transcriptional levels of ERR targets. We propose a joint action mode for both the EcR and ERR, for at least a subset of the glycolytic genes. We find that both receptors bind to the same regulatory regions and may form or be part of a joint transcriptional regulatory complex in the Drosophila S2 cells.


Assuntos
Metabolismo dos Carboidratos/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Esteroides/metabolismo , Animais , Linhagem Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Ecdisterona/farmacologia , Regulação da Expressão Gênica no Desenvolvimento , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Estrogênicos/genética , Receptores de Esteroides/genética
8.
Int J Mol Sci ; 20(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151315

RESUMO

Sex steroids, including androgens, estrogens, and progestogens, are known to have widespread physiological actions beyond the reproductive system via binding to the sex hormone receptors, members of the nuclear receptor superfamily that function as ligand-inducible transcription factors [...].


Assuntos
Hormônios Esteroides Gonadais/metabolismo , Neoplasias/metabolismo , Receptores de Esteroides/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Receptores Androgênicos/metabolismo
9.
Mol Med Rep ; 20(2): 1025-1038, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173207

RESUMO

Hepatocellular carcinoma (HCC) accounts for ~85% of primary liver cancer cases and is a leading cause of mortality worldwide. Effective early diagnosis is difficult for HCC; however, effective biomarkers may be beneficial for diagnosis. In the current study, serum samples, and HCC and adjacent tissue samples were obtained from patients with HCC for the detection of biomarkers using 2­D gel electrophoresis (2­DE) and matrix­assisted laser desorption/ionization­time of flight (TOF)/TOF mass spectrometry. The crude serum samples did not need to be prepared for removal of high abundance proteins. The mRNA expression levels of HCC­associated proteins were detected in tissues using reverse transcription­quantitative PCR. Statistical analysis and database matching were used to identify the differentially expressed proteins detected in the serum and tissue groups. Immunohistochemistry (IHC) was performed to detect the expression of significant proteins in HCC and adjacent tissues. The results revealed ~800 protein spots on a 2­DE gel that were detected in serum samples, and 1,200 spots were identified in the tissue samples. The protein and mRNA expression levels of oxysterol binding protein­like 11 (OSBPL11) in HCC serum and tissue samples were consistent. Pathway analysis demonstrated that members of the apolipoprotein family, particularly apolipoprotein E (APOE), and RAS family members were closely associated in HCC, either directly or via ferratin heavy polypeptide 1. IHC results demonstrated that the APOE protein serves an important role in liver cancer development. The lysis buffer used in the current study was effective for serum protein separation in 2­DE sample preparation. In addition, the present study revealed that downregulated OSBPL11 may be a potential indicator for HCC, and the apolipoprotein family, particularly APOE, and the RAS family may cooperatively serve an important role.


Assuntos
Apolipoproteínas E/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Receptores de Esteroides/genética , Idoso , Apolipoproteínas E/sangue , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Detecção Precoce de Câncer , Eletroforese em Gel Bidimensional , Feminino , Ferritinas/genética , Ferritinas/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Oxirredutases/genética , Oxirredutases/metabolismo , Receptores de Esteroides/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Análise de Sobrevida , Proteínas ras/genética , Proteínas ras/metabolismo
10.
J Steroid Biochem Mol Biol ; 192: 105387, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31173874

RESUMO

Steroid hormones have far-ranging biological impacts and more are continuously being uncovered. Over the last decades, proteomics approaches have become key to better understand biological processes. Due to multiple technical breakthroughs allowing for the concurrent identification and/or quantification of thousands of analytes using mass spectrometers, researchers employing proteomics tools today can now obtain truly holistic views of multiple facets of the human proteome. Here, we review how the field of proteomics has contributed to discoveries about steroid hormones, their receptors and their impact on human pathologies. In particular, the involvement of steroid receptors in cancer initiation, development, metastasis and treatment will be highlighted. Techniques at the forefront of the proteomics field will also be discussed to present how they can contribute to a better understanding of steroid hormone receptors.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Proteoma/metabolismo , Receptores de Esteroides/metabolismo , Animais , Humanos , Proteoma/análise
11.
Reprod Biol Endocrinol ; 17(1): 48, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226998

RESUMO

BACKGROUND: Puberty in male Atlantic salmon in aquaculture can start as early as after the first winter in seawater, stunts growth and entails welfare problems due to the maturation-associated loss of osmoregulation capacity in seawater. A better understanding of the regulation of puberty is the basis for developing improved cultivation approaches that avoid these problems. Our aim here was to identify morphological and molecular markers signaling the initiation of, and potential involvement in, testis maturation. METHODS: In the first experiment, we monitored for the first time in large Atlantic salmon males several reproductive parameters during 17 months including the first reproductive cycle. Since testicular growth accelerated after the Winter solstice, we focused in the second experiment on the 5 months following the winter solstice, exposing fish from February 1 onwards to the natural photoperiod (NL) or to continuous additional light (LL). RESULTS: In the first experiment, testis weight, plasma androgens and pituitary gonadotropin transcript levels increased with the appearance of type B spermatogonia in the testis, but testicular transcript levels for gonadotropin or androgen receptors did not change while being clearly detectable. In the second experiment, all males kept under NL had been recruited into puberty until June. However, recruitment into puberty was blocked in ~ 40% of the males exposed to LL. The first morphological sign of recruitment was an increased proliferation activity of single spermatogonia and Sertoli cells. Irrespective of the photoperiod, this early sign of testis maturation was accompanied by elevated pituitary gnrhr4 and fshb and testicular igf3 transcript levels as well as increased plasma androgen levels. The transition into puberty occurred again with stable testicular gonadotropin and androgen receptor transcript levels. CONCLUSIONS: The sensitivity to reproductive hormones is already established before puberty starts and up-regulation of testicular hormone receptor expression is not required to facilitate entry into puberty. The increased availability of receptor ligands, on the other hand, may result from an up-regulation of pituitary Gnrh receptor expression, eventually activating testicular growth factor and sex steroid release and driving germ and Sertoli cell proliferation and differentiation.


Assuntos
Hormônios Esteroides Gonadais/metabolismo , Receptores de Esteroides/metabolismo , Salmo salar/metabolismo , Maturidade Sexual , Testículo/metabolismo , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica/efeitos da radiação , Masculino , Fotoperíodo , Hipófise/metabolismo , Receptores do FSH/genética , Receptores do FSH/metabolismo , Receptores de Esteroides/genética , Reprodução/genética , Reprodução/fisiologia , Salmo salar/genética , Estações do Ano , Água do Mar
12.
Int. microbiol ; 22(2): 169-179, jun. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-184824

RESUMO

Oxysterol-binding protein is an important non-vesicular trafficking protein involved in the transportation of lipids in eukaryotic cells. Oxysterol-binding protein is identified as oxysterol-binding protein-related proteins (ORPs) in mammals and oxysterol-binding protein homologue (Osh) in yeast. Research has described the function and structure of oxysterol-binding protein in mammals and yeast, but little information about the protein's structure and function in filamentous fungi has been reported. This article focuses on recent advances in the research of Osh proteins in yeast and filamentous fungi, such as Aspergillus oryzae, Aspergillus nidulans, and Candida albicans. Furthermore, we point out some problems in the field, summarizing the membrane contact sites (MCS) of Osh proteins in yeast, and consider the future of Osh protein development


No disponible


Assuntos
Fungos/genética , Receptores de Esteroides/genética , Leveduras/genética , Proteínas de Transporte/genética , Proteínas Fúngicas/genética , Fungos/metabolismo , Receptores de Esteroides/metabolismo , Leveduras/metabolismo , Proteínas de Transporte/metabolismo , Proteínas Fúngicas/metabolismo , Fungos/química , Metabolismo dos Lipídeos , Domínios Proteicos , Receptores de Esteroides/química , Leveduras/química
13.
Methods Mol Biol ; 1966: 1-5, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041734

RESUMO

In this chapter, we summarize the birth of the field of nuclear receptors. These receptors exhibit a multitude of roles in cell biology and hence have attracted a great deal of interest in the drug discovery field. It is not certain whether these receptors evolved independently or an ancestral protein acquired various functions upon binding to preexisting small molecules, ligands. Currently, members of this receptor superfamily are categorized in six groups, including "orphan receptors." Research in the area has resulted in several clinically used drugs and continues to reveal further previously unknown roles for these receptors paving the road toward more valuable discoveries in the future.


Assuntos
Receptores Nucleares Órfãos/metabolismo , Receptores de Esteroides/metabolismo , Transdução de Sinais , Animais , Humanos , Ligantes , Receptores Nucleares Órfãos/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de Esteroides/fisiologia
14.
BMC Cancer ; 19(1): 442, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088410

RESUMO

BACKGROUND: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), has been shown to increase the efficacy of endocrine therapies in hormone receptor (HR)-positive metastatic breast cancer. However, because breast cancer is a highly heterogeneous disease, the responses of different patients to everolimus may vary. Therefore, we performed this study to better select patients who will benefit most from or be resistant to everolimus. METHODS: Patients with HR-positive breast cancer who were treated with everolimus at the Cancer Hospital, Chinese Academy of Medical Sciences from February 2014 to March 2017 were enrolled in the present study. Mutations in ctDNA were assayed in 1021 tumor-related genes via gene panel target capture-based next-generation sequencing. RESULTS: In total, 120 patients with metastatic breast cancer who were treated with everolimus were enrolled in the present study. The median progression-free survival (PFS) of all patients was 5.1 months (95% confidence interval [CI] 3.9-6.3 months). No difference in survival was observed between patients who received endocrine drugs used in previous treatment regimens and patients who did not receive these drugs (median PFS 5.2 and 5.1 months, respectively, p > 0.05). Additionally, we did not find any difference in outcomes between patients who had primary resistance to previously used endocrine drugs and patients who had nonprimary resistance to previous treatments (p > 0.05). Multivariate analysis showed that < 3 metastatic sites, < 2 lines of previous endocrine therapy, < 2 lines of previous chemotherapy, and treatment with everolimus combined with fulvestrant were associated with improved survival (p < 0.05). Sixteen patients underwent ctDNA analysis before everolimus treatment. The frequency of PIK3CA gene mutations was 62.5%, and H1047R was the most frequently detected mutation. Patients with the PIK3CA/H1047R mutation had longer PFS than patients with wild-type or other mutant forms of PIK3CA, and the median PFS in these two groups of patients was 8.8 and 4.1 months, respectively (p < 0.05). CONCLUSIONS: Our data suggest that patients who receive more lines of chemotherapy or endocrine therapy are less likely to benefit from everolimus. For everolimus combination therapy, we can even select endocrine drugs that gave rise to primary resistance in previous treatments. Additionally, the PIK3CA/H1047R mutation may be a potential biomarker of sensitivity to everolimus.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Everolimo/administração & dosagem , Fulvestranto/administração & dosagem , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Everolimo/uso terapêutico , Feminino , Fulvestranto/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Seleção de Pacientes , Medicina de Precisão , Receptores de Esteroides/metabolismo , Estudos Retrospectivos , Análise de Sequência de DNA , Análise de Sobrevida , Resultado do Tratamento
15.
J Exp Clin Cancer Res ; 38(1): 230, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142340

RESUMO

Stromal stimuli mediated by growth factor receptors, leading to ligand-independent activation of steroid hormone receptors, have long been implicated in development of breast cancer resistance to endocrine therapy. Mutations in fibroblast growth factor receptor (FGFR) genes have been associated with a higher incidence and progression of breast cancer. Increasing evidence suggests that FGFR-mediated interaction between luminal invasive ductal breast carcinoma (IDC) and its microenvironment contributes to the progression to hormone-independence. Therapeutic strategies based on FGFR inhibitors hold promise for overcoming resistance to the ER-targeting treatment. A series of excellent reviews discuss a potential role of FGFR in development of IDC. Here, we provide a concise updated summary of existing literature on FGFR-mediated signalling with an emphasis on an interaction between FGFR and estrogen/progesterone receptors (ER/PR) in IDC. Focusing on the regulatory role of tumour microenvironment in the activity of steroid hormone receptors, we compile the available functional data on FGFRs-mediated signalling, as a fundamental mechanism of luminal IDC progression and failure of anti-ER treatment. We also highlight the translational value of the presented findings and summarize ongoing oncologic clinical trials investigating FGFRs inhibition in interventional studies in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Esteroides/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/metabolismo , Feminino , Humanos , Terapia de Alvo Molecular , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Microambiente Tumoral
16.
Environ Sci Process Impacts ; 21(6): 988-998, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31093631

RESUMO

The contamination of surface water and ground water by human activities, such as fossil fuel extraction and agriculture, can be difficult to assess due to incomplete knowledge of the chemicals and chemistry involved. This is particularly true for the potential contamination of drinking water by nearby extraction of oil and/or gas from wells completed by hydraulic fracturing. A case that has attracted considerable attention is unconventional natural gas extraction in Susquehanna County, Pennsylvania, particularly around Dimock, Pennsylvania. We analyzed surface water and groundwater samples collected throughout Susquehanna County with complementary biological assays and high-resolution mass spectrometry. We found that Ah receptor activity was associated with proximity to impaired gas wells. We also identified certain chemicals, including disclosed hydraulic fracturing fluid additives, in samples that were either in close proximity to impaired gas wells or that exhibited a biological effect. In addition to correlations with drilling activity, the biological assays and high-resolution mass spectrometry detected substances that arose from other anthropogenic sources. Our complementary approach provides a more comprehensive picture of water quality by considering both biological effects and a broad screening for chemical contaminants.


Assuntos
Monitoramento Ambiental/métodos , Fraturamento Hidráulico , Poluentes Químicos da Água/análise , Bioensaio , Linhagem Celular Tumoral , Cromatografia Líquida , Água Doce/análise , Humanos , Espectrometria de Massas , Campos de Petróleo e Gás , Pennsylvania , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Esteroides/metabolismo , Poluentes Químicos da Água/farmacologia
17.
Sci Total Environ ; 676: 97-104, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029904

RESUMO

The use of organic Ultraviolet (UV) filters has increased in the last years, either in sunscreens, other cosmetics, or even food packaging. These filters may end up in soil and water since the Wastewater Treatment Plants may not successfully remove them. Among them, benzophenones are known to act as endocrine disruptors. However, most of the studies are directed towards vertebrates and aquatic invertebrates, while there is a lack of information on the molecular mechanisms affected by these compounds on soil dwelling invertebrates. Here, we study the impact of direct acute (48 h) contact of 4-hydroxybenzophenone (4-OHBP) at two sublethal concentrations (0.02 and 0.2 mg/mL) on gene expression of the earthworm Eisenia fetida. Investigated genes were involved in endocrine pathways, stress response, detoxification mechanisms, genotoxicity, energy metabolism and epigenetics. Three of them were identified for the first time in earthworms. Our results suggest that exposure to 4-OHBP affected endocrine pathways, causing an increase in the Ecdysone receptor gene (EcR) expression. Moreover, the UV filter induced changes in the CuZn superoxide dismutase gene (CuZn SOD), indicating an effect in the stress response. Finally, significant changes were detected for glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) expression, indicating that energy metabolism is influenced by the 4-OHBP and highlighting the risks of using GAPDH as an internal reference for Real Time PCR.


Assuntos
Disruptores Endócrinos/toxicidade , Oligoquetos/fisiologia , Protetores Solares/toxicidade , Animais , Sistema Endócrino/efeitos dos fármacos , Receptores de Esteroides/metabolismo , Superóxido Dismutase/metabolismo
18.
Gen Comp Endocrinol ; 280: 54-61, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980804

RESUMO

The relationship between stress and immunosuppression was investigated in peripheral blood leucocytes (PBL) in rainbow trout, with reference to corticosteroid receptor (CR) expression and responses to cortisol- and/or lipopolysaccharide (LPS)-administration. Confinement stress in shallow water resulted in a sustained elevation of plasma cortisol, whereas lysozyme and immunoglobin levels were suppressed. Significant increases in mRNA levels of caspase-6 and insulin-like growth factor (IGF)-I were observed in PBL isolated from stressed fish. Confinement stress also suppressed proinflammatory cytokine, interleukin (IL)-1ß, expression in PBL. There were decreasing tendencies for the mRNA levels of CRs in PBL of stressed fish. In-vitro treatment of cortisol and LPS on isolated PBL from unstressed trout increased both IL-1 ß and CR mRNA expression. However, in PBL from stressed fish, cortisol and LPS treatment increased IL-1 ß but not CR mRNA levels. Proliferative activities estimated as in-vitro incorporation of bromodeoxyuridine (BrdU) were decreased by cortisol in PBL from the unstressed and stressed fish groups; however, LPS-stimulated proliferation was observed only in the unstressed fish. Ratios of apoptotic PBL quantified as cell fragmentation using an automated cell counter were increased by cortisol in both groups; however, LPS-stimulated apoptosis was observed only in the stressed fish. Our study reveals cortisol has immune-suppressive effects in stressed fish, irrespective of CR down-regulation and desensitization. The complexity of immune-endocrine interaction is shown by the stress-induced attenuation of LPS effects.


Assuntos
Regulação para Baixo/genética , Leucócitos/metabolismo , Oncorhynchus mykiss/genética , Oncorhynchus mykiss/fisiologia , Receptores de Esteroides/genética , Estresse Fisiológico/genética , Animais , Citocinas/genética , DNA Complementar/genética , Regulação para Baixo/efeitos dos fármacos , Hidrocortisona/sangue , Lipopolissacarídeos/farmacologia , Muramidase/sangue , Oncorhynchus mykiss/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Esteroides/metabolismo
19.
Drugs ; 79(7): 779-783, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31006078

RESUMO

Brexanolone (ZULRESSO™) is an intravenously administered, small molecule, neuroactive steroid GABAA receptor positive allosteric modulator that was developed by Sage Therapeutics under license to the University of California for the treatment of postpartum depression (PPD). The formulation is a mixture of allopregnanolone, an endogenous inhibitory pregnane neurosteroid, and sulfobutylether-beta-cyclodextrin (a solubilizing agent). In mid-March 2019 brexanolone received its first global approval in the USA for the treatment of PPD in adult women. This article summarizes the milestones in the development of brexanolone leading to its first approval for the treatment of adult women with PPD.


Assuntos
Depressão Pós-Parto/tratamento farmacológico , Pregnanolona/farmacocinética , beta-Ciclodextrinas/farmacocinética , Administração Intravenosa/métodos , Adolescente , Adulto , Regulação Alostérica/efeitos dos fármacos , Aprovação de Drogas , Combinação de Medicamentos , Quimioterapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pregnanolona/administração & dosagem , Pregnanolona/efeitos adversos , Pregnanolona/farmacologia , Pregnanolona/uso terapêutico , Receptores de Esteroides/metabolismo , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/efeitos adversos , beta-Ciclodextrinas/farmacologia , beta-Ciclodextrinas/uso terapêutico
20.
Endocrinology ; 160(5): 1275-1288, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30958537

RESUMO

In mammals, the grainyhead-like transcription factor (GRHL) family is composed of three nuclear proteins that are responsible for driving epithelial cell fate: GRHL1, GRHL2, and GRHL3. GRHL2 is important in maintaining proper tubulogenesis during development and in suppressing the epithelial-to-mesenchymal transition. Within the last decade, evidence indicates both tumor-suppressive and oncogenic roles for GRHL2 in various types of cancers. Recent studies suggest that GRHL2 may be especially important in hormone-dependent cancers, as correlative relationships exist between GRHL2 and various steroid receptors, such as the androgen and estrogen receptors. Acting as a pioneer factor and coactivator, GRHL2 may directly affect steroid receptor transcriptional activity. This review will highlight recent discoveries of GRHL2 activity in cancer and in maintaining the epithelial state, while also exploring recent literature on the role of GRHL2 in hormone-dependent cancers and epigenetics.


Assuntos
Proteínas de Ligação a DNA/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Receptores de Esteroides/genética , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Ligação a DNA/metabolismo , Transição Epitelial-Mesenquimal/genética , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Esteroides/metabolismo , Fatores de Transcrição/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA