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1.
Anticancer Res ; 39(10): 5285-5296, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570423

RESUMO

Triple-negative breast cancer (TNBC) is characterized by a lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) and unfortunately is not associated with good prognosis. Treatment of breast cancer mainly depends on chemotherapy, due to the lack of specifically approved targeted therapies for TNBC. It is of paramount importance to find new therapeutic approaches, as resistance to chemotherapy frequently occurs. Herein, we present clinical studies published within the last five years, in order to reveal possible targeted therapies against TNBC. We aimed to discuss factors against TNBC, such as tyrosine kinase inhibitors, anti-androgens, poly ADP-ribose polymerase-1 (PARP-1) inhibitors, anti-angiogenic factors, immune checkpoints and histone deacetylase inhibitors (HDACI). Furthermore, the PI3K/AKT/mTOR pathway seems to be a promising field for the development of new anti-TNBC targeted therapies. Data from 18 clinical trials with patients suffering from TNBC were summarized and presented descriptively.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ensaios Clínicos como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto Jovem
2.
Zhonghua Zhong Liu Za Zhi ; 41(9): 681-685, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550858

RESUMO

Objective: To investigate the expression discordances of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor2 (HER-2) and Ki-67 in primary and metastatic breast cancer specimens and explore the clinical significances. Methods: Biopsies of metastatic lesions were performed in 203 patients with breast cancer recurrence and metastasis indicated by physical examination and/or imaging examination. We confirmed pathological properties and assessed the expressions of ER, PR, HER-2 and Ki-67 in primary and metastatic lesions, their relationships with prognosis were also analyzed. Results: Biopsy failed in 3 patients, the pathology and immunohistochemitry results of metastatic lesions were not obtained. One person was diagnosed as tuberculosis and another was primary lung cancer. Among the 198 cases of primary and metastatic lesions, the discordance rates of ER, PR, HER-2 and Ki-67 were 27.3%, 34.3%, 11.8% and 15.1%, respectively.The expressions of ER, HER-2 and Ki-67 were not significantly different between the primary and metastatic lesions, however, the expressions of PR were more likely to turn negative in the metastases (P<0.001). The disease-free survival (DFS) of patients with ER, PR positive, HER-2 negative and low expression of Ki-67 in metastatic lesion was much longer (P<0.05). Conclusions: The expressions of ER, PR, HER-2 and Ki-67 in metastatic lesions are associated with the prognosis of breast cancer patients.Their expression discordances between primary and metastatic lesions can guide the treatment and evaluate the risks of recurrence and prognosis.


Assuntos
Neoplasias da Mama/metabolismo , Antígeno Ki-67/metabolismo , Recidiva Local de Neoplasia/metabolismo , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Biópsia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Taxa de Sobrevida
3.
Pol J Pathol ; 70(2): 91-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556559

RESUMO

Currently, breast cancer chemotherapy response can be predicted based on various parameters, with common reporting of tumour grade and Ki67 proliferation index. We analysed their association with pathological complete response (pCR) in a multivariate approach. The study was carried out in a group of 353 patients, treated by preoperative chemotherapy and prospectively observed. In selected patients, parallel to routing core needle biopsy assessment, gene expression profile of tumour was analysed by oligonucleotide microarrays. Tumour parameters associated with pCR in univariate analysis were: tumour grade, nuclear grade, mitotic index, Ki67, oestrogen and progesterone receptor (all p < 0.0001), and triple-negative status (p = 0.0032). The highest increase of pCR chance was observed in patients with high-grade tumours and with Ki67 ≥ 20%. In multivariate analysis, only tumour grade and oestrogen receptor status were predictive for pCR independently of other variables, with high grade increasing the odds of pCR 2.42 fold, and high ER decreasing the chance of pCR 0.41 fold. Tumour grading reflects important biological features of breast cancer and is not inferior to proliferation markers, including Ki67. It should be taken into account in decision-making for preoperative chemotherapy in parallel to breast cancer biologic subtypes, because grade 3 tumours exhibit a higher proportion of pCR.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Gradação de Tumores , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/cirurgia , Feminino , Humanos , Antígeno Ki-67/metabolismo , Estudos Prospectivos , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Resultado do Tratamento
4.
Br J Radiol ; 92(1103): 20190417, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31398071

RESUMO

OBJECTIVES: In magnetic resonance imaging (MRI), background parenchymal enhancement (BPE) is associated with breast cancer risk, but the associations between BPE and clinical characteristics and histological features are unknown. This study aimed to investigate the association between BPE and clinical characteristics (including age, menopausal status, and tumor histological characteristics) in patients with invasive breast cancer. METHODS: This was a retrospective study of 163 patients with invasive breast cancer (164 lesions, 1 patient had bilateral cancer) confirmed by surgery and pathological examination, treated between January 2014 and December 2016 at our university (Kunming Medical University). The patients were divided into two groups: extremely minimal and mild enhancement (low BPE group, n = 78) vs moderate and marked enhancement (high BPE group, n = 86). RESULTS: Compared with the low BPE group, the high BPE group showed higher frequencies of patients < 50 years of age (88% vs 38%, p < 0.0001), premenopausal (87% vs 29%, p < 0.0001), T1 staging (35% vs 15%, p = 0.027), Grade II (57% vs 37%, p = 0.03), lymphovascular invasion (83% vs 13%, p < 0.0001), and positive estrogen receptor (ER) (79% vs 42%, p < 0.0001). The Spearman correlation coefficients (r) between BPE and age, menopausal status, lymphovascular invasion, and ER status were -0.521 (p < 0.0001), -0.588 (p < 0.0001), 0.697 (p < 0.0001), and 0.377 (p < 0.0001), respectively. CONCLUSION: BPE is negatively associated with age and menopausal status, and is positively associated with lymphovascular invasion and positive ER status. ADVANCES IN KNOWLEDGE: BPE is not correlated with T staging and histological classification in patients with invasive breast cancer.


Assuntos
Neoplasias da Mama/patologia , Receptores Estrogênicos/metabolismo , Adulto , Idoso , Feminino , Humanos , Metástase Linfática , Imagem por Ressonância Magnética , Menopausa/psicologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos , Adulto Jovem
5.
Cell Prolif ; 52(5): e12666, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31407423

RESUMO

OBJECTIVES: Cartilaginous tissue degradation occurs because of the lack of survival of chondrocytes. Here, we ascertained whether bakuchiol (BAK) has the capability of activating chondrocyte proliferation. MATERIALS AND METHODS: The effect of BAK on the proliferation of rat chondrocytes at a concentration of 10 and 20 µmol/L was investigated. The molecular mechanisms involving target binding and signalling pathways were elucidated by RNA-sequencing, qPCR, molecular docking and Western blotting. Matrigel mixed with bakuchiol was implanted locally into rat knee articular cartilage defects to verify the activation of chondrocytes due to bakuchiol in vivo. RESULTS: Bakuchiol implantation resulted in the activation of rat chondrocyte proliferation in a dose-dependent manner. RNA-sequencing revealed 107 differentially expressed genes (DEGs) with 75 that were up-regulated and 32 that were down-regulated, indicating increased activation of the PI3K-Akt and cell cycle pathways. Activation of the phosphorylation of Akt, ERK1/2 and their inhibitors blocked the proliferative effect of bakuchiol treatment, confirming its direct involvement in these signal transduction pathways. Molecular docking and siRNA silencing revealed that estrogen receptor-α (ERα) was the target of bakuchiol in terms of its cell proliferative effect via PI3K activation. Two weeks after implantation of bakuchiol, the appearance and physiological structure of the articular cartilage was more integrated with abundant chondrocytes and cartilage matrix compared to that of the control. CONCLUSIONS: Bakuchiol demonstrated significant bioactivity towards chondrocyte proliferation via the PI3K-Akt and ERK1/2 pathways mediated by estrogen receptor activation and exhibited enhanced promotion of the remodelling of injured cartilage.


Assuntos
Cartilagem Articular/fisiologia , Proliferação de Células/efeitos dos fármacos , Fenóis/farmacologia , Receptores Estrogênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Condrócitos/citologia , Condrócitos/metabolismo , Regulação para Baixo/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos
6.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(6): 699-703, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31315726

RESUMO

OBJECTIVE: To investigate influences of estrogen-related receptor α(ERRα) on pulmonary vascular endothelium of rats undergoing sepsis. METHODS: Male Sprague-Dawley (SD) rats were divided into four groups according to the random number table method (12 in each group): normal control group (NC group), sham operation group (Sham group), sepsis model caused by cecal ligation and puncture (CLP) group (CLP group), XCT790 intervention group (XCT790 group, given the XCT790 2.5 mg/kg via intraperitoneal injection 30 minutes before CLP). After 24 hours, rats were sacrificed and the organs were harvested. The pathological changes of lung tissue were observed using hematoxylin and eosin (HE) staining, and the ultrastructural changes of lung tissue were observed by double staining of uranium citrate with lead acetate, the degree of apoptosis of pulmonary capillary endothelial cells were observed by TdT-mediated dUTP nike end labeling stain (TUNEL), the permeability of lung vascular endothelial was detected by Evans blue (EB) staining, the levels of serum cytokines were detected by enzyme linked immunosorbent assay (ELISA), and white blood cell count in bronchial alveolar lavage fluid (BALF) was detected. RESULTS: Compared with NC group and Sham group, the CLP group and XCT790 group had severe pathological damage and increased lung tissue permeability, the levels of serum cytokines and white blood cell count in BALF were increased. Compared with CLP group, the pathological changes of lung tissue, the degree of ultrastructural damage of lung tissue, the degree of apoptosis of lung capillary endothelial cells in XCT790 group further intensified, the permeability of lung endothelial barrier further increased [the content of EB (µg/g): 116.00±15.46 vs. 60.19±19.79, P < 0.05], and the level of serum cytokines further increased [interleukin-1ß (IL-1ß, ng/L): 71.38±4.01 vs. 56.58±2.45, interleukin-6 (IL-6, ng/L): 741.62±88.94 vs. 534.22±72.70, tumor necrosis factor-α (TNF-α, ng/L): 188.55±7.41 vs. 143.33±11.27, all P < 0.05], the white blood cell count in the BALF increased further (×104/L: 193.79±27.46 vs. 99.34±36.41, P < 0.05). CONCLUSIONS: ERRα can aggravate inflammation in sepsis rats, destroy lung tissue and increase pulmonary permeability.


Assuntos
Endotélio Vascular/metabolismo , Receptores Estrogênicos/metabolismo , Sepse/patologia , Animais , Modelos Animais de Doenças , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
7.
Clin Biochem ; 71: 52-57, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276668

RESUMO

BACKGROUND: Although the function of microRNA-21 and microRNA-206 in breast cancer cells have been investigated in vitro, their association with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are not reported. METHODS: ER, PR, HER2, and Ki-67 staining pattern were utilized to classify 75 breast cancer patients recruited. The malignancy was predicted with tumor nodes metastases (TNM) classification. RT-qPCR was performed to detect the relative expression of ER, PR, and HER2 in tumor samples and microRNA-21 and microRNA-206 in the serum. Spearman's correlation analysis was used to determine the association between different molecules. According to the staining pattern, the breast cancer patients were classified into five types. RESULTS: microRNA-21 was up-regulated in HER2 positive and Basal-like breast cancer types, while microRNA-206 was up-regulated in Luminal A and B types of breast cancer. microRNA-21 expression negatively correlated with the level of ER and PR but positively correlated with HER2 expression and tumor malignancy, while microRNA-206 showed the opposite trend. Neither microRNA-21 nor microRNA-206 showed any significant correlation with the age of the patients. CONCLUSION: Both microRNA-21 and microRNA-206 closely correlate with ER, PR, and HER2 expression, which can be considered as clinical biomarkers.


Assuntos
Neoplasias da Mama/metabolismo , MicroRNAs/metabolismo , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Feminino , Humanos
8.
J Agric Food Chem ; 67(31): 8649-8659, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31283213

RESUMO

Spent coffee grounds (SCG) are the most abundant coffee byproduct and are generally discarded as waste. The horticultural use of SCG and SCG compost (SCGC) has become popular due to a growing interest in environmentally friendly measures for waste disposal. Estrogen-like endocrine disrupting chemicals in the soil can be absorbed by plants and subsequently by humans who consume these plants. The objectives of this study are to determine the phytochemical profiles of extracts of SCG and SCGC and to evaluate the estrogen-like activities of SCG, SCGC, and the major coffee phenolic acids, specifically, 5-O-caffeoylquinic acid (CQA), caffeic acid, and ferulic acid. Their inductive effects on estrogen receptor (ER)-mediated gene transcription have been examined in cultured cell lines. CQA was the most abundant phenolic acid in SCG and SCGC and was further examined for its ER-mediated estrogen-like activity using various assays. This is the first study to report the estrogen-like signaling activities of coffee byproducts and their major constituents.


Assuntos
Coffea/química , Hidroxibenzoatos/metabolismo , Fitoestrógenos/metabolismo , Extratos Vegetais/metabolismo , Receptores Estrogênicos/genética , Ativação Transcricional , Resíduos/análise , Animais , Ácidos Cafeicos/análise , Ácidos Cafeicos/metabolismo , Linhagem Celular , Compostagem , Feminino , Genes Reporter , Humanos , Hidroxibenzoatos/química , Fitoestrógenos/química , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Receptores Estrogênicos/metabolismo , Sementes/química
9.
Pan Afr Med J ; 33: 22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312338

RESUMO

Breast cancer is a complex disease characterized by the accumulation of multiple molecular alterations giving each tumor phenotype and an own evolutionary potential. This study aimed to describe the distribution of the profile and molecular subtypes of breast cancers followed at Surgical Oncology Unit of Donka National Hospital. This was retrospective and descriptive study on cases of breast cancer in which the hormone receptor status and expression of the Her2 oncogene have been performed from 2007 to 2016. We recorded 58 cases including 56 (96.6%) women and 2 (3.4%) men. The average age was 48.2 ± 10.9. Invasive ductal carcinoma accounted for 50 (86.2%) cases. The SBR grade was II in 31(53.4%) cases, III in 21 (36.2%) cases and I in 6 (10.3%) cases. The tumor was classified as T4 in 36 (62.1%) cases; it was metastatic in 11(19.0%) cases. Estrogen receptors were positive in 29 (50.0%) cases, progesterone receptors positive in 25 (43.1%) cases, the Her2 oncogene was positive in 22 (39.3%) cases. The distribution of molecular sub-types was: 20 (34.5%) luminal A, 15 (25.9%) triple negative, 13 (22.4%) Her2 overexpressed, 8 (13.8%) luminal B and 2 (3.2%) undetermined. This preliminary study showed the poor accessibility of immunohistochemistry for the molecular diagnosis of breast cancer in our country. Luminal A subtypes and triple negatives were more common. The determination of molecular subtypes is a rational basis for hormone therapy and targeted therapy, thus personalizing the treatment of breast cancer.


Assuntos
Neoplasias da Mama Masculina/patologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/genética , Carcinoma Ductal de Mama/epidemiologia , Feminino , Guiné/epidemiologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Receptor ErbB-2/genética , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/epidemiologia
10.
Virchows Arch ; 475(3): 313-323, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31267199

RESUMO

Breast cancer is a highly heterogeneous disease. The efficacy of tailored therapeutic strategies relies on the precise detection of diagnostic biomarkers by immunohistochemistry (IHC). Therefore, considering the increasing incidence of breast cancer cases, a concomitantly time-efficient and accurate diagnosis is clinically highly relevant. Microfluidics is a promising innovative technology in the field of tissue diagnostic, enabling for rapid, reliable, and automated immunostaining. We previously reported the microfluidic-based HER2 (human epidermal growth factor receptor 2) detection in breast carcinomas to greatly correlate with the HER2 gene amplification level. Here, we aimed to develop a panel of microfluidic-based IHC protocols for prognostic and therapeutic markers routinely assessed for breast cancer diagnosis, namely HER2, estrogen/progesterone receptor (ER/PR), and Ki67 proliferation factor. The microfluidic IHC protocol for each marker was optimized to reach high staining quality comparable to the standard procedure, while concomitantly shortening the staining time to 16 min-excluding deparaffinization and antigen retrieval step-with a turnaround time reduction up to 7 folds. Comparison of the diagnostic score on 50 formaldehyde-fixed paraffin-embedded breast tumor resections by microfluidic versus standard staining showed high concordance (overall agreement: HER2 94%, ER 95.9%, PR 93.6%, Ki67 93.7%) and strong correlation (ρ coefficient: ER 0.89, PR 0.88, Ki67 0.87; p < 0.0001) for all the analyzed markers. Importantly, HER2 genetic reflex test for all discordant cases confirmed the scores obtained by the microfluidic technique. Overall, the microfluidic-based IHC represents a clinically validated equivalent approach to the standard chromogenic staining for rapid, accurate, and automated breast cancer diagnosis.


Assuntos
Neoplasias da Mama/diagnóstico , Técnicas Analíticas Microfluídicas/métodos , Microfluídica/métodos , Biomarcadores Tumorais/metabolismo , Mama/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente , Antígeno Ki-67/metabolismo , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
11.
Environ Pollut ; 253: 29-38, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302400

RESUMO

Over 80,000 endocrine-disrupting chemicals (EDCs) are considered emerging contaminants (ECs), which are of great concern due to their effects on human health. Quantitative structure-activity relationship (QSAR) models are a promising alternative to in vitro methods to predict the toxicological effects of chemicals on human health. In this study, we assessed a deep-learning based QSAR (DL-QSAR) model to predict the qualitative and the quantitative effects of EDCs on the human endocrine system, and especially sex-hormone binding globulin (SHBG) and estrogen receptor (ER). Statistical analyses of the qualitative responses indicated that the accuracies of all three DL-QSAR methods were above 90%, and greater than the other statistical and machine learning models, indicating excellent classification performance. The quantitative analyses, as assessed using deep-neural-network-based QSAR (DNN-QSAR), resulted in a coefficient of determination (R2) of 0.80 and predictive square correlation coefficient (Q2) of 0.86, which implied satisfactory goodness of fit and predictive ability. Thus, DNN was able to transform sparse molecular descriptors into higher dimensional spaces, and was superior for assessment qualitative responses. Moreover, DNN-QSAR demonstrated excellent performance in the discipline of computational chemistry by handling multicollinearity and overfitting problems.


Assuntos
Aprendizado Profundo , Ecotoxicologia , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Relação Quantitativa Estrutura-Atividade , Biologia Computacional , Disruptores Endócrinos/metabolismo , Poluentes Ambientais/metabolismo , Humanos , Redes Neurais (Computação) , Receptores Estrogênicos/metabolismo , Globulina de Ligação a Hormônio Sexual
12.
Cell Prolif ; 52(5): e12663, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31347748

RESUMO

OBJECTIVE: Induction of secondary necrosis/pyroptosis contributes to the toxicity of chemotherapeutic drugs, in which gasdermin E (GSDME) plays critical roles. This study aimed to explore whether GSDME is involved in mediating the cytotoxic effects of cisplatin and doxorubicin on mouse macrophages. METHODS: RAW 264.7 cells and bone marrow-derived macrophages (BMDMs) were treated with cisplatin or doxorubicin. Propidium iodide staining was used to assay necrosis, and immunoblotting was performed to detect protein expression. GSDME was knocked down by using small interfering RNA. Mice were injected intraperitoneally to evaluate toxicity to macrophages in vivo. Flow cytometry and immunofluorescence microscopy were adopted to analyse phenotypes of peritoneal cells. Cytokine levels were assayed by cytometric bead array. RESULTS: Both cisplatin and doxorubicin dose-dependently induced necrosis in mouse RAW 264.7 macrophages and BMDMs. Accompanying this, multiple caspases were activated, concomitant with the cleavage of poly (ADP-ribose) polymerase. Consistent with caspase-3 activation, GSDME was cleaved to generate its N-terminal fragment (GSDME-NT), thus leading to secondary necrosis/pyroptosis. Inhibition of caspase-3 significantly attenuated the generation of GSDME-NT concurrently with decreased necrosis in macrophages. GSDME knockdown also evidently decreased the necrosis in RAW 264.7 and BMDMs. Besides, cisplatin administration depleted peritoneal macrophages in mice, which was associated with caspase-3 activation and GSDME-NT generation. Consistent with the macrophage depletion, cisplatin administration significantly decreased survival of mice with bacterial infection. CONCLUSION: Chemotherapeutic cisplatin and doxorubicin exerted their cytotoxicity on macrophages partly by inducing caspase-3/GSDME-mediated secondary necrosis.


Assuntos
Caspase 3/metabolismo , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Piroptose/efeitos dos fármacos , Receptores Estrogênicos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/mortalidade , Infecções por Escherichia coli/patologia , Infecções por Escherichia coli/veterinária , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/genética , Taxa de Sobrevida
13.
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
14.
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
15.
Gynecol Oncol ; 154(3): 531-538, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31227223

RESUMO

OBJECTIVE: Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. METHODS: Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Thirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%-78%) and was similar at 6 months (61%, 95% CI 43%-75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3-25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2-11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. CONCLUSIONS: Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity.


Assuntos
Anastrozol/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Receptores Estrogênicos/metabolismo , Adulto , Idoso , Anastrozol/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Pós-Menopausa , Intervalo Livre de Progressão , Estudos Prospectivos , Qualidade de Vida , Receptores de Progesterona/metabolismo , Adulto Jovem
16.
Chem Soc Rev ; 48(13): 3497-3512, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31214680

RESUMO

Icosahedral carboranes in medicine are still an emerging class of compounds with potential beneficial applications in drug design. These highly hydrophobic clusters are potential "new keys for old locks" which open up an exciting field of research for well-known, but challenging important therapeutic substrates, as demonstrated by the numerous examples discussed in this review.


Assuntos
Boranos/química , Animais , Boranos/farmacologia , Desenho de Drogas , Enzimas/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Fator 1 Induzível por Hipóxia/metabolismo , Ligantes , Receptores Androgênicos/metabolismo , Receptores de Calcitriol/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Purinérgicos/metabolismo
17.
Anticancer Res ; 39(6): 2821-2827, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177119

RESUMO

BACKGROUND/AIM: Tumour cells of the profile CD44+/CD24low/- have a high tumorigenic potential. Salinomycin can specifically inhibit the growth of these cells. Herein, we investigated the effects of salinomycin on the viability and migration of triple negative breast cancer cells. MATERIALS AND METHODS: We analysed two cell lines: i) triple-negative MDA-MB 231 breast cancer cells and ii) a cytokeratin 18-transfected, re-differentiated subclone of the MDA-MB 231 cell line. The viability was determined using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test, and the migration was determined using 24-h videography. The expression of oestrogen receptor was determined using immunohistochemistry. RESULTS: Salinomycin reduces all migration parameters in MDA-MB 231 cells. A significant correlation was found between increasing salinomycin concentrations and loss of cell viability, which was significantly less noticeable in the transfected control cells. CONCLUSION: With salinomycin there is a specific inhibition of MDA-MB 231 cells. Since MDA-MB 231 has over 90% cells with the profile CD44+/CD24low/-, these might represent a possible point of attack for salinomycin.


Assuntos
Queratina-18/genética , Piranos/farmacologia , Receptores Estrogênicos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Queratina-18/metabolismo , Transfecção , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
18.
J Manag Care Spec Pharm ; 25(5): 578-586, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31039059

RESUMO

BACKGROUND: Adjuvant endocrine therapy (AET) is a critical therapy in that it improves survival in women with hormone receptor-positive (HR+) breast cancer (BC), but adherence to AET is suboptimal. The purpose of this study was to fill scientific gaps about predictors of adherence to AET among black and white women diagnosed with BC. OBJECTIVE: To assess AET adherence in black and white insured women using multiple measures, including one that uses an innovative statistical approach. METHODS: Black and white women newly diagnosed with HR+ BC were identified from 2 health maintenance organizations. Pharmacy records captured the type of oral AET prescriptions and all fill dates. Multivariable logistic regression was used to identify predictors of adherence defined in terms of proportion of days covered (PDC; ≥ 80%) and medication gap of ≤ 10 days. A zero-inflated negative binomial (ZINB) regression model was used to identify variables associated with the total number of days of medication gaps. RESULTS: 1,925 women met inclusion criteria. 80% were PDC adherent (> 80%); 44% had a medication gap of ≤ 10 days; and 24% had no medication gap days. Race and age were significant in all multivariable models. Black women were less likely to be adherent based on PDC than white women (OR = 0.72, 95% CI = 0.57-0.90, P < 0.01), and they were less likely to have a medication gap of ≤ 10 days (OR = 0.65, 95% CI = 0.54-0.79, P < 0.001). Women aged 25-49 years were less likely to be PDC adherent than women aged 65-93 years (OR = 0.65, 95% CI = 0.48-0.87, P < 0.001). In the ZINB model, women were without their medication for an average of 37 days (SD = 50.5). CONCLUSIONS: Racial disparities in adherence to AET in the study highlight a need for interventions among insured women. Using various measures of adherence may help better understand this multidimensional concept. There might be benefits from using both more common dichotomous measures (e.g., PDC) and integrating novel statistical approaches to allow tailoring adherence to patterns within a specific sample. DISCLOSURES: This research was funded by the National Institutes of Health (R01CA154848). It was also supported in part by the NIH-NCI Cancer Center Support Grant P30 CA016059, the Laboratory of Telomere Health P30 CA51008, and the TSA Award No. UL1TR002649 from the National Center for Advancing Translational Sciences. The contents of this study are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Bosworth reports grants from Sanofi, Otsuka, Johnson & Johnson, and Blue Cross/Blue Shield of NC and consulting fees from Sanofi and Otsuka. The other authors have nothing to disclose. The datasets generated during and/or analyzed during the current study are not publicly available due to privacy reasons but are available from the corresponding author on reasonable request. The author does not own these data. Data use was granted to the author as part of a data use agreement between specific agencies and organizations.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/terapia , Sobreviventes de Câncer/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Adesão à Medicação/estatística & dados numéricos , Adulto , Afro-Americanos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Estados Unidos
19.
Chemosphere ; 230: 384-395, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31112861

RESUMO

Recently, environment contaminants including pesticides, fungicides, mycotoxin and others chemicals have been suggested to be responsible for the decline in the human spermatozoa quality especially motility and the increase in infertility rate. Chlorothalonil is used widely for protection of vegetables and crops because it is a broad spectrum fungicide. It has been reported that chronic occupational exposure to fungicides was associated with poor spermatozoa morphology in young men. The pubertal period is very important for the male reproductive system development due to spermatogonial cell proliferation, the expansion of meiotic and haploid germ cells. Although some investigations have studied the male reproductive toxicity of chlorothalonil, almost no studies focused on spermatogenesis. The aim of our current investigation was to explore the impacts of chlorothalonil on spermatogenesis and the underlying mechanisms. It demonstrates: i) chlorothalonil decreased boar spermatozoa motility in vitro and increased the cell apoptosis; ii) chlorothalonil inhibited mouse spermatogenesis in vivo; iii) chlorothalonil disturbed spermatogenesis through the disruption of estrogen receptor signalling; iv) chlorothalonil disrupted histone methylation and DNA methylation which might be through estrogen signalling pathways. Due to the over use or incorrect use, chlorothalonil might cause serious problems to human health, especially spermatogenesis. Therefore we strongly recommend that greater attention should be paid to this fungicide to minimise its impact on human health especially spermatogenesis.


Assuntos
Metilação de DNA/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Fungicidas Industriais/toxicidade , Histonas/metabolismo , Nitrilos/toxicidade , Receptores Estrogênicos/metabolismo , Espermatogênese/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Transdução de Sinais , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/genética , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia , Suínos
20.
Environ Pollut ; 248: 1067-1078, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31091639

RESUMO

Estrogenic endocrine disrupting chemicals (EDCs) are natural hormones, synthetic compounds or industrial chemicals that mimic estrogens due to their structural similarity with estrogen's functional moieties. They typically enter aquatic environments through wastewater treatment plant effluents or runoff from intensive livestock operations. Globally, most natural and synthetic estrogens in receiving aquatic environments are in the low ng/L range, while industrial chemicals (such as bisphenol A, nonylphenol and octylphenol) are present in the µg to low mg/L range. These environmental concentrations often exceed laboratory-based predicted no effect concentrations (PNECs) and have been evidenced to cause negative reproductive impacts on resident aquatic biota. In vertebrates, such as fish, a well-established indicator of estrogen-mediated endocrine disruption is overexpression of the egg yolk protein precursor vitellogenin (Vtg) in males. Although the vertebrate Vtg has high sensitivity and specificity to estrogens, and the molecular basis of its estrogen inducibility has been well studied, there is growing ethical concern over the use of vertebrate animals for contaminant monitoring. The potential utility of the invertebrate Vtg as a biomonitor for environmental estrogens has therefore gained increasing attention. Here we review evidence providing support that the molluscan Vtg holds promise as an invertebrate biomarker for exposure to estrogens. Unlike vertebrates, estrogen signalling in invertebrates remains largely unclarified and the classical genomic pathway only partially explains estrogen-mediated activation of Vtg. In light of this, in the latter part of this review, we summarise recent progress towards understanding the molecular mechanisms underlying the activation of the molluscan Vtg gene by estrogens and present a hypothetical model of the interplay between genomic and non-genomic pathways in the transcriptional regulation of the gene.


Assuntos
Disruptores Endócrinos/análise , Moluscos/metabolismo , Vitelogeninas/análise , Poluentes Químicos da Água/análise , Poluição da Água/análise , Animais , Compostos Benzidrílicos/análise , Biomarcadores/análise , Disruptores Endócrinos/toxicidade , Estrogênios/análise , Estrona/análise , Feminino , Peixes/metabolismo , Masculino , Fenóis/análise , Receptores Estrogênicos/metabolismo , Reprodução , Poluentes Químicos da Água/toxicidade
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