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1.
Cancer Med ; 8(17): 7244-7252, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31642204

RESUMO

BACKGROUND: Total mesorectal excision following neoadjuvant chemoradiotherapy (nCRT) is recommended in the latest treatment of locally advanced rectal cancer (LARC). OBJECTIVE: To predict whether patients with LARC can achieve pathologic complete response (pCR), comparing MRI-based radiomics between before and after neoadjuvant radiotherapy (nRT) was performed. METHODS: One hundred and sixty-five MRI-based radiomics features in axial T2-weighted images were obtained quantitatively from Imaging Biomarker Explorer Software. The specific features of conventional and developing radiomics were selected with the analysis of least absolute shrinkage and selection operator logistic regression, of which the predictive performance was analyzed with receiver operating curve and calibration curve, and applied to an independent cohort. RESULTS: One hundred and thirty-one target patients were enrolled in the present study. A radiomics signature founded on seven radiomics features was generated in the primary cohort. A remarkable difference about Rad-score between pCR and non-pCR group occurred in both of primary (P < .001) or validation cohorts (P < .001). The value of area under the curves was 0.92 (95% CI, 0.86-0.99) and 0.87 (95% CI, 0.74-1.00) in the primary and validation cohorts, respectively. The Rad-score (OR = 23.581; P < .001) from multivariate logistic regression analysis was significant as an independent factor of pCR. CONCLUSION: Our predictive model based on radiomics features was an independent predictor for pCR in LARC and could be a candidate in clinical practice.

2.
FASEB J ; 33(11): 12760-12767, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31480859

RESUMO

Chemotherapy resistance is one of the most common causes of death among patients with ovarian cancer, and identifying novel antitumor agents is a priority. Here, we report that the novel molecule 2-(anaphthoyl)ethyltrimethylammonium iodide (α-NETA) induces epithelial ovarian cancer (EOC) cell pyroptosis through the gesdermin-d (GSDMD)/caspase-4 pathway. Furthermore, Cell Counting Kit-8 fluorescence-activated cell sorting analysis showed that α-NETA treatment led to cell death in different ovarian cancer cell lines, including Ho8910, Ho8910PM, and A2780. Morphologic examination by electron microscopy indicated that cells treated with α-NETA produced multiple microbubbles, typical of cells undergoing pyroptosis. α-NETA also significantly increased expression of pyroptosis-associated molecules including caspase-4 and GSDMD in EOC cells. Knockdown of either caspase-4 or GSDMD in ovarian cancer cells strongly interfered with α-NETA cell-killing activity, indicating that α-NETA acts through the pyroptosis pathway. In vivo, α-NETA treatment dramatically decreased the size of EOC tumors in mice. Our findings suggest that α-NETA represents a potential new antitumor molecule or lead compound for EOC chemotherapy.-Qiao, L., Wu, X., Zhang, J., Liu, L., Sui, X., Zhang, R., Liu, W., Shen, F., Sun, Y., Xi, X. α-NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase-4 pathway.

3.
Front Oncol ; 9: 552, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293979

RESUMO

Background: Conventional methods for predicting treatment response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) are limited. Methods: This study retrospectively recruited 134 LARC patients who underwent standard nCRT followed by total mesorectal excision surgery in our institution. Based on pre-operative axial T2-weighted images, machine learning radiomics was performed. A receiver operating characteristic (ROC) curve was performed to test the efficiencies of the predictive model. Results: Among the 134 patients, 32 (23.9%) achieved pathological complete response (pCR), 69 (51.5%) achieved a good response, and 91 (67.9%) achieved down-staging. For prediction of pCR, good-response, and down-staging, the predictive model demonstrated high classification efficiencies, with an AUC value of 0.91 (95% CI: 0.83-0.98), 0.90 (95% CI: 0.83-0.97), and 0.93 (95% CI: 0.87-0.98), respectively. Conclusion: Our machine learning radiomics model showed promise for predicting response to nCRT in patients with LARC. Our predictive model based on the commonly used T2-weighted images on pelvic Magnetic Resonance Imaging (MRI) scans has the potential to be adapted in clinical practice. Novelty and Impact Statements: Methods for predicting the response of the locally advanced rectal cancer (LARC, T3-4, or N+) to neoadjuvant chemoradiotherapy (nCRT) is lacking. In the present study, we developed a new machine learning radiomics method based on T2-weighted images. As a non-invasive tool, this method facilitates prediction performance effectively. It achieves a satisfactory overall diagnostic accuracy for predicting of pCR, good response, and down-staging show an AUC of 0.908, 0.902, and 0.930 in LARC patients, respectively.

4.
Therap Adv Gastroenterol ; 12: 1756284819862154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360223

RESUMO

Background: There is no conclusion about the most important contributor to the upswing of locally advanced colorectal cancer (LACRC) survival. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) database was extracted to identify colorectal adenocarcinoma cancer patients at stage II and III diagnosed in the two periods 1989-1990 and 2009-2010. The statistical methods included Pearson's chi-squared test, log-rank test, Cox regression model and propensity score matching. Results: The Cox regression model showed that hazard ratio (HR) of non-surgery dropped from 11.529 to 3.469 in right colon cancer (RCC), 5.214 to 2.652 in left colon cancer (LCC) and 3.275 to 3.269 in rectal cancer (RC) from 1989-1990 to 2009-2010. The 95% confidence intervals (CIs) for surgical resection in 2009-2010 were narrower than those in 1989-1990. HR became greater in LACRC without chemotherapy (from 1.337 to 1.779 in RCC, 1.269 to 2.017 in LCC, 1.317 to 1.811 in RC). There was no overlapping about the 95% CI of chemotherapy between the two groups. The progress of surgery was not linked to the improvement of overall survival (OS) of RCC (p = 0.303) and RC (p = 0.660). Chemotherapy had a significant association with OS of all colorectal cancer (CRC) patients (p = 0.017 in RCC; p = 0.006 in LCC; p = 0.001 in RC). Conclusions: Advancements in chemotherapy regimen were the main contributor to the upswing of CRC survival. The improvements in surgery had a limited effect on improvements in CRC survival.

5.
Molecules ; 24(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151312

RESUMO

Curcuma zedoaria (dry stenophora of Curcuma phaeocaulis Val., Curcuma kwangsiensis S. G. Lee et C. F. Liang, or Curcuma wenyujin Y. H. Chen et C.Ling) is a representative herb with clinical effects on liver diseases after being vinegar-processed. The crude Curcuma zedoaria and the processed Curcuma zedoaria (vinegar-boil) have been widely used as mixtures, but their equivalence has not been fully investigated. In this manuscript, quality markers of processed (vinegar-boil) Curcuma zedoaria were investigated by comparison of the compounds and hepatoprotective activities with the crude (three spices) ones. First, GC-MS-based untargeted metabolomics were applied to reveal the discriminatory components and discover potential markers. As a result, a total of six components were identified as potential markers. Then, the hepatoprotective activities were evaluated by dual cell damage models induced by a certain concentration of H2O2 or tertbutyl hydfroperoxide (t-BHP) (55 µM H2O2 or 40 µM t-BHP), which highlighted the potential of the processed Curcuma zedoaria on oxidative stress. Finally, epicurzerenone was identified as its quality marker on oxidative liver injury based on the above results and the cell-based biological assay. Overall, vinegar-processed Curcuma zedoaria was more suitable for the treatment of oxidative liver diseases, and epicurzerenone could be considered as its quality marker.


Assuntos
Ácido Acético , Curcuma/química , Hepatopatias/etiologia , Hepatopatias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores , Hepatopatias/tratamento farmacológico , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Solventes
6.
J Invest Surg ; : 1-10, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31116055

RESUMO

Purpose: To identify the clinical predictive factors of tumor response and to evaluate the significance of primary gross tumor volume (pGTV), obtained from radiotherapy planning, in predicting tumor response. Materials and Methods: We retrospectively analyzed data of consecutive locally advanced rectal cancer (LARC) patients who were treated with neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery at our institution between March 2009 and December 2017. We identify independent predictors of tumor response to nCRT by statistical analysis. Disease-free survival (DFS) starting from the time of surgery was calculated by the Kaplan-Meier method, and log-rank tests were performed to compare DFS between patients with superior and inferior tumor response. Results: Overall, 185 LARC patients received nCRT, of whom 89 (48.11%) achieved superior tumor response. Diminutive pGTV (p = 0.038) and distance from the anal verge (DAV) (p = 0.006) were independent predictive factors of superior tumor response. Meanwhile, pGTV can be regarded as an independent predictor of pathologic complete response (pCR) (p = 0.036). The log-rank test revealed that DFS was longer in the diminutive pGTV group than in the giant pGTV group (p = 0.001). Conclusions: pGTV, as a measure of tumor size, is not only an important prognostic indicator but also an independent predictive factor of tumor response, even pCR.

7.
Autoimmunity ; 52(1): 21-26, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30822156

RESUMO

OBJECTIVES: Recent evidence has demonstrated that UBASH3A play a pivotal role in multiple autoimmune diseases. In this study, we explored the association between UBASH3A gene single-nucleotide polymorphisms (SNPs) and rheumatoid arthritis (RA) in a Chinese Han population. We also comparatively evaluated the UBASH3A expression profile in peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls. METHODS: Four UBASH3A polymorphisms (rs1893592, rs11203203, rs2277798, and rs3788013) were studied in 553 patients with RA and 587 controls in a Chinese population. Genotyping was performed using the Fluidigm 192.24 Dynamic Array Integrated Fluidic Circuit (IFC). For gene expression study, UBASH3A mRNA levels of 30 RA patients and 31 healthy individuals were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Data were analyzed by SPSS 19.0 software. RESULTS: A significant association between rs1893592 polymorphism and RA was found under all genetic models (all p<.05). We also discovered a significant association between rs3788013 polymorphism and RA in the allele and genotype distributions, as well as the recessive model (all p<.05). Moreover, we found the genotype distribution and allele frequency of rs1893592 were significantly associated with RF phenotype in the RA patients (χ2 = 6.786, p=.034; χ2 = 4.534, p=.033; respectively). We also found the genotype distribution and allele frequency of rs2277798 were significantly associated with anti-CCP phenotype in the RA patients (χ2 = 7.873, p=.020; χ2 = 4.473, p=.034; respectively). However, we did not detect any significant associations between rs11203203 and RA susceptibility and autoantibody profiles (all p>.05). The mRNA expression of UBASH3A was increased in PBMCs of patients with RA when compared to healthy controls (p=.001). CONCLUSIONS: Our observations suggested that the dysregulation of UBASH3A might be associated with the pathogenesis of RA, and UBASH3A gene polymorphisms (rs1893592 and rs3788013) might contribute to RA susceptibility in Chinese Han population.

8.
Exp Ther Med ; 16(6): 5424, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30555540

RESUMO

[This corrects the article DOI: 10.3892/etm.2018.6297.].

9.
Cell Death Dis ; 9(9): 884, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158641

RESUMO

Among the gynaecological cancers, epithelial ovarian cancer (EOC) has the highest lethality because of the high incidence of tumour progression and metastasis. Exploration of the detailed mechanisms underlying EOC metastasis and the identification of crucial targets is important to better estimate the prognosis and improve the treatment of this disease. The present study aimed to identify the role of miR-520h in the prognosis of patients with EOC, and the mechanisms of its involvement in EOC progression. We showed that miR-520h was upregulated in 116 patients with EOC, especially in those with advanced-stage disease, and high miR-520h expression predicted poor outcome. Furthermore, ectopic expression of miR-520h enhanced EOC cell proliferation, migration and invasion, and induced epithelial-mesenchymal transition in vitro and in vivo. miR-520h promoted EOC progression by downregulating Smad7, and subsequently activating the TGF-ß signalling pathway. Most importantly, TGF-ß1 stimulation increased miR-520h expression in EOC cells by upregulating its transcription factor c-Myb. In conclusion, we described the role of the TGF-ß1/c-Myb/miR-520h/Smad7 axis in EOC metastasis, and highlighted the possible use of miR-520h as a prognostic marker for EOC.


Assuntos
Carcinoma Epitelial do Ovário/genética , MicroRNAs/genética , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas c-myb/genética , Proteína Smad7/genética , Animais , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Ovarianas/patologia , Prognóstico , Fator de Crescimento Transformador beta1/genética , Regulação para Cima/genética
10.
Exp Ther Med ; 16(2): 1350-1354, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30116385

RESUMO

The present study intended to investigate the effect of fluvastatin on cardiomyocyte apoptosis after myocardial infarction in rats. Eighty myocardial infarction rat models were established and randomly divided into 4 groups (n=20): experimental group (n=20) was given fluvastatin treatment; sham operation group (n=20) and normal control group (n=20) were given saline. The dose of fluvastatin was 20 mg/(kg·d), and irrigation gavage was given for 1 week. Western blot analysis and reverse transcription-quantitative PCR (RT-qPCR) were used to detect the expression of TLR4 mRNA and protein in cardiomyocytes. TUNEL method was used to detect the apoptosis of cardiomyocytes. After fluvastatin treatment for 1 week, RT-qPCR found that compared with myocardial infarction group, the TLR4 mRNA expression of fluvastatin treatment group and normal control group was significantly increased, and the differences between groups were a statistically significant difference (P<0.05). Western blot analysis showed that compared with the myocardial infarction group, the expression of TLR4 protein in normal control group, sham operation group and fluvastatin treatment group were significantly decreased, and they all were statistically significant (P<0.05). TUNEL method found that compared with the myocardial infarction group, the fluvastatin treatment group could significantly reduce the apoptosis of cardiomyocytes (19.2±3.8%), and the difference was statistically significant (P<0.05). Fluvastatin can inhibit myocardial infarction and decrease cardiomyocyte apoptosis by increasing the expression of TLR4-like receptor.

11.
Cancer Med ; 2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29777575

RESUMO

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) plays a vital role in the development of malignant tumors; however, its biological role and underlying mechanism in epithelial ovarian cancer (EOC) remain unclear. In this study, we aimed to investigate the biological function and clinical significance of LGR5 in human EOC. We evaluated LGR5 expression in EOC cell lines and tissues from ovarian cancer patients by qPCR, Western blotting, and immunohistochemical analysis. Cell proliferation, colony formation, transwell invasion assay, and scratch-wound assays were conducted to evaluate the expansion and invasion abilities of EOC cells. Tumor xenograft experiments were performed in female BALB/c athymic nude mice to test cell proliferation in vivo. Western blot analysis was performed to confirm the expression of epithelial-to-mesenchymal transition (EMT) signature proteins and their association with Notch1 signaling. The results demonstrated that LGR5 was overexpressed in EOC tissues and cell lines. Aberrant expression of LGR5 was significantly associated with patient age (P = 0.006), tumor histologic type (P < 0.001), and distant metastasis (P = 0.025). Consistent with these findings, suppression of LGR5 expression led to decreased proliferation and metastasis of EOC cell lines. Furthermore, LGR5 could induce EMT and regulate the Notch1 signaling pathway. Taken together,LGR5 may have an important role in the promotion of tumorigenesis and metastasis of EOC and is a potential therapeutic target for EOC management.

12.
J Ethnopharmacol ; 210: 318-339, 2018 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-28887216

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Forsythiae Fructus (called Lianqiao in Chinese), the fruit of Forsythia suspensa (Thunb.) Vahl, is utilized as a common traditional medicine in China, Japan and Korea. It is traditionally used to treat pyrexia, inflammation, gonorrhea, carbuncle and erysipelas. Depending on the different harvest time, Forsythiae Fructus can be classified into two forms, namely Qingqiao and Laoqiao. The greenish fruits that start to ripen are collected as Qingqiao, while the yellow fruits that are fully ripe are collected as Laoqiao. Both are applied to medical use. This review aims to provide a systematic summary of F. suspensa (Forsythia suspensa (Thunb.) Vahl) and to reveal the correlation between the traditional uses and pharmacological activities so as to offer inspiration for future research. MATERIALS AND METHODS: All corresponding information about F. suspensa was searched by Scifinder and obtained from scientific databases including Springer, Science Direct, Wiley, Pubmed and China Knowledge Resource Integrated (CNKI). Local dissertations and books were searched as well. RESULTS: According to classical Chinese herbal texts and Chinese Pharmacopoeia, Forsythiae Fructus dominantly displays heat-clearing and detoxifying effects in TCM prescriptions. In modern research, more than 230 compounds were separated and identified from F. suspensa. 211 Of them were isolated from fruits. Lignans and phenylethanoid glycosides are considered as the characteristic and active constituents of this herb, such as forsythiaside, phillyrin, rutin and phillygenin. They exhibited anti-inflammatory, antioxidant, antibacterial, anti-virus, anti-cancer and anti-allergy effects, etc. Currently, there is no report on the toxicity of Forsythiae Fructus, despite slight toxicity of forsythiaside reported in local publications. Compared to Laoqiao, Qingqiao contains higher levels of forsythiaside, forsythoside C, cornoside, rutin, phillyrin, gallic acid and chlorogenic acid and lower levels of rengyol, ß-glucose and S-suspensaside methyl ether. CONCLUSION: Heat-clearing actions of Forsythiae Fructus are based on the anti-inflammatory and antioxidant properties of lignans and phenylethanoid glycosides. Detoxifying effects attribute to the antibacterial, antiviral and anti-cancer activities of Forsythiae Fructus. And traditional Chinese medicine (TCM) characteristics of Forsythiae Fructus (bitter flavor, slightly cold nature and lung meridian) supported its strong anti-inflammatory effects. In addition, the remarkable anti-inflammatory and antioxidant capacities of Forsythiae Fructus contribute to its anti-cancer and neuroprotective activities. The higher proportion of lignans and phenylethanoid glycosides in Qingqiao than Laoqiao might explain the better antioxidant ability of Qingqiao and more frequent uses of Qingqiao in TCM prescriptions. For future research, more in vivo experiments and clinical studies are encouraged to further clarify the relation between traditional uses and modern applications. Regarding to Qingqiao and Laoqiao, they remain to be differentiated by all-round quality control methods, and the chemical compositions and clinical effects between them should be compared.


Assuntos
Forsythia/química , Medicina Tradicional do Leste Asiático , Extratos Vegetais/farmacologia , Animais , Etnofarmacologia , Frutas , Humanos , Fitoterapia/métodos , Extratos Vegetais/química , Controle de Qualidade
13.
Cell Physiol Biochem ; 42(1): 185-197, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28535511

RESUMO

BACKGROUND AND AIM: Increasing evidence shows that the calpain regulatory subunit Capn4 can modulate the proliferation and metastasis of cancer cells, and plays an important role in the development of malignant tumors. However, there is no information on the clinical significance of Capn4 in epithelial ovarian carcinoma (EOC) or the molecular mechanisms by which Capn4 promotes the growth and metastasis of EOC. Therefore, the aim of this study was to clarify the role of Capn4 in EOC. METHODS: We evaluated Capn4 and osteopontin (OPN) expression in EOC cell lines and tissues from patients with ovarian cancer by western blotting and immunohistochemical analysis. We then created cell lines with downregulated and upregulated Capn4 expression, using Capn4-targeting small interfering RNA and a pcDNA3.1-Capn4 overexpression vector, respectively, to investigate its function in EOC in vitro. In addition, we investigated the potential mechanism underlying the function of Capn4 by examining the effect of modifying Capn4 expression on Wnt/ß-catenin signaling pathway-related genes by western blotting. RESULTS: Capn4 was overexpressed in clinical EOC tissues compared with that in normal ovarian epithelial tissue, and was associated with poor clinical outcomes. Upon silencing or overexpressing Capn4 in EOC cells, we concluded that Capn4 promotes cell proliferation and migration in vitro. Furthermore, Capn4 promoted EOC metastasis by interacting with the Wnt/ß-catenin signaling pathway to upregulate OPN expression. CONCLUSION: Our study indicates that Capn4 plays a critical role in the progression and metastasis of EOC, and could be a potential therapeutic target for EOC management.


Assuntos
Calpaína/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Osteopontina/metabolismo , Neoplasias Ovarianas/patologia , Via de Sinalização Wnt , beta Catenina/metabolismo , Calpaína/antagonistas & inibidores , Calpaína/genética , Carcinoma Epitelial do Ovário , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/mortalidade , Osteopontina/antagonistas & inibidores , Osteopontina/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Plasmídeos/genética , Plasmídeos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Regulação para Cima , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/genética
14.
Biochem Biophys Res Commun ; 486(1): 191-197, 2017 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-28286267

RESUMO

Chromatin Assembly Factor 1, subunit A (CHAF1A) can regulate cell proliferation, DNA repair and epigenetic changes in embryonic stem cells and it has been reported that over-expression of CHAF1A is associated with several human diseases including cancer. However, the expression and function of CHAF1A in Epithelial Ovarian Cancer (EOC) are rarely reported at present. In this study, we found that the positive staining of CHAF1A in EOC was higher than that in normal tissues and over-expression of CHAF1A was strongly associated with cancer stage and lymph node metastasis. Knockdown of CHAF1A by siRNA in EOC inhibited cell proliferation, reduced colony formation, caused G0/G1 phase arrest and promoted cell apoptosis. Taken together, the high expression of CHAF1A promotes cell proliferation and inhibits cell apoptosis and CHAF1A may be developed as a prognosis biomarker and potential therapeutic target of EOC.


Assuntos
Apoptose , Proliferação de Células , Fator 1 de Modelagem da Cromatina/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Western Blotting , Carcinoma Epitelial do Ovário , Linhagem Celular , Linhagem Celular Tumoral , Fator 1 de Modelagem da Cromatina/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Interferência de RNA , Fatores de Transcrição
15.
Elife ; 62017 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-28134614

RESUMO

SNX6 is a ubiquitously expressed PX-BAR protein that plays important roles in retromer-mediated retrograde vesicular transport from endosomes. Here we report that CNS-specific Snx6 knockout mice exhibit deficits in spatial learning and memory, accompanied with loss of spines from distal dendrites of hippocampal CA1 pyramidal cells. SNX6 interacts with Homer1b/c, a postsynaptic scaffold protein crucial for the synaptic distribution of other postsynaptic density (PSD) proteins and structural integrity of dendritic spines. We show that SNX6 functions independently of retromer to regulate distribution of Homer1b/c in the dendritic shaft. We also find that Homer1b/c translocates from shaft to spines by protein diffusion, which does not require SNX6. Ablation of SNX6 causes reduced distribution of Homer1b/c in distal dendrites, decrease in surface levels of AMPAR and impaired AMPAR-mediated synaptic transmission. These findings reveal a physiological role of SNX6 in CNS excitatory neurons.


Assuntos
Região CA1 Hipocampal/fisiologia , Células Piramidais/fisiologia , Nexinas de Classificação/deficiência , Memória Espacial , Sinapses/fisiologia , Animais , Proteínas de Arcabouço Homer/metabolismo , Camundongos Knockout , Receptores de Glutamato/metabolismo , Nexinas de Classificação/metabolismo
16.
Proc Natl Acad Sci U S A ; 113(38): E5645-54, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27601647

RESUMO

AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in full-length GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1-2-1-2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides.


Assuntos
Encéfalo/metabolismo , Receptores de AMPA/química , Animais , Encéfalo/patologia , Dimerização , Humanos , Conformação Proteica , Sinais Direcionadores de Proteínas/genética , Ratos , Receptores de AMPA/genética , Transmissão Sináptica
17.
Neurobiol Dis ; 91: 209-220, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27001149

RESUMO

Human studies, and especially laboratory studies, provide evidence that early life exposure to general anesthesia may affect neurocognitive development via largely unknown mechanisms. We explored whether hippocampal histone acetylation had a role in neurodevelopmental effects of sevoflurane administered to neonatal rats. Male Sprague-Dawley rats were exposed to 3% sevoflurane or were subjected to maternal separation only for 2h daily at postnatal days 6, 7, and 8. The histone deacetylase inhibitor, sodium butyrate (250mg/kg, intraperitoneally), or saline was administered starting 2h prior to anesthesia or maternal separation and continued daily until the end of behavioral tests, which were performed between postnatal days 33 and 50. Upon completion of the behavioral tests, the brain tissues were harvested for further analysis. Rats neonatally exposed to sevoflurane exhibited decreased freezing time in the fear conditioning contextual test and increased escape latency, decreased time in target quadrant, and number of platform crossings in the Morris water maze test. The sevoflurane-exposed rats had lower hippocampal density of dendritic spines, reduced levels of the brain-derived neurotrophic factor, c-fos protein, microtubule-associated protein 2, synapsin1, postsynaptic density protein 95, pCREB/CREB, CREB binding protein, and acetylated histones H3 and H4, and increased levels of histone deacetylases 3 and 8. These neurobehavioral abnormalities were normalized in the sevoflurane-exposed rats treated with sodium butyrate. Our findings provide evidence that neonatal exposure to sevoflurane induces neurobehavioral abnormalities and long-lasting alterations in histone acetylation; normalization of histone acetylation may alleviate the neurodevelopmental side effects of the anesthetic.


Assuntos
Hipocampo/efeitos dos fármacos , Histonas/metabolismo , Éteres Metílicos/farmacologia , Acetilação/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Privação Materna , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Sevoflurano , Tempo
18.
Brain Behav Immun ; 51: 109-18, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26254234

RESUMO

Microglial activation plays a key role in the development of postoperative cognitive dysfunction (POCD). Nox2, one of the main isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the central nervous system, is a predominant source of reactive oxygen species (ROS) overproduction in phagocytes including microglia. We therefore hypothesized that Nox2-induced microglial activation is involved in the development of POCD. Sixteen-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. Behavioral tests were performed at 6 and 7 d post-surgery with open field and fear conditioning tests, respectively. The levels of Nox2, 8-hydroxy-2'-deoxyguanosine (8-OH-dG, a marker of DNA oxidation), CD11b (a marker of microglial activation), interleukin-1ß (IL-1ß), and brain-derived neurotrophic factor (BDNF) were determined in the hippocampus and prefrontal cortex at 1 d and 7 d post-surgery, respectively. For the interventional study, mice were treated with a NADPH oxidase inhibitor apocynin (APO). Our results showed that exploratory laparotomy with isoflurane anesthesia impaired the contextual fear memory, increased expression of Nox2, 8-OH-dG, CD11b, and IL-1ß, and down-regulated BDNF expression in the hippocampus at 7 d post-surgery. The surgery-induced microglial activation and neuroinflammation persisted to 7 d after surgery in the hippocampus, but only at 1 d in the prefrontal cortex. Notably, administration with APO could rescue these surgery-induced cognitive impairments and associated brain pathology. Together, our data suggested that Nox2-derived ROS in hippocampal microglia, at least in part, contributes to subsequent neuroinflammation and cognitive impairments induced by surgery in aged mice.


Assuntos
Hipocampo/enzimologia , Glicoproteínas de Membrana/metabolismo , Transtornos da Memória/enzimologia , Microglia/enzimologia , NADPH Oxidases/metabolismo , Complicações Pós-Operatórias/enzimologia , Complicações Pós-Operatórias/psicologia , Espécies Reativas de Oxigênio/metabolismo , Acetofenonas/administração & dosagem , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Encefalite/complicações , Encefalite/enzimologia , Inibidores Enzimáticos/administração & dosagem , Medo/efeitos dos fármacos , Medo/fisiologia , Hipocampo/efeitos dos fármacos , Laparotomia , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , NADPH Oxidase 2 , NADPH Oxidases/antagonistas & inibidores , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/enzimologia
19.
Psychopharmacology (Berl) ; 233(3): 405-15, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26514555

RESUMO

RATIONALE: Growing evidence suggests that downregulated clearance of glutamate and signaling pathways involving brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a role in morphological changes in the hippocampus of depressed patients. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is the most attractive antidepressant, although precise mechanisms are unknown. OBJECTIVE: In this study, we examined whether hippocampal BDNF-TrkB signaling underlies the antidepressant effects of ketamine via upregulating glutamate transporter 1 (GLT-1) in rats, subjected to the chronic unpredictable stress (CUS) for 42 days. The rats received a single injection of ketamine (10 mg/kg, i.p.) and/or a TrkB inhibitor, K252a (1 µl, 2 mM, intracerebroventicular (i.c.v.)) on day 43. Behavioral tests and brain sample collection were evaluated 24 h later. RESULTS: The CUS-exposed rats exhibited depression- and anxiety-like behaviors; decreased number of glial fibrillary acidic protein (GFAP)-positive (but not NeuN-positive) cells in the dentate gyrus (DG), CA1, and CA3 areas; increased number of cleaved caspase-3-positive astrocytes; reduced spine density; lower ratio of Bcl2 to Bax; and decreased levels of BDNF, phosphorylated cAMP response element binging protein (CREB), GLT-1, and postsynaptic density 95 (PSD95) proteins in the hippocampus. Ketamine alleviated the CUS-induced abnormalities. The effects of ketamine were antagonized by pretreatment with K252a. CONCLUSIONS: Our findings suggest that regulation of GLT-1 on astrocytes, responsible for 90 % of glutamate reuptake from the synapse, through BDNF-TrkB signaling is involved in mediation of the therapeutic effects of ketamine on behavioral abnormalities and morphological changes in the hippocampus of the CUS-exposed rats.


Assuntos
Antidepressivos/farmacologia , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtorno Depressivo/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Transportador 2 de Aminoácido Excitatório/biossíntese , Transportador 2 de Aminoácido Excitatório/genética , Ketamina/farmacologia , Receptor trkB/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Carbazóis/farmacologia , Doença Crônica , Transtorno Depressivo/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Alcaloides Indólicos/farmacologia , Injeções Intraventriculares , Masculino , Ratos , Ratos Sprague-Dawley , Receptor trkB/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
20.
Front Mol Neurosci ; 8: 52, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26441515

RESUMO

Postoperative cognitive dysfunction (POCD) is a recognized clinical entity characterized with cognitive deficits after anesthesia and surgery, especially in aged patients. Previous studies have shown that histone acetylation plays a key role in hippocampal synaptic plasticity and memory formation. However, its role in POCD remains to be determined. Here, we show that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, attenuates POCD in aging Mice. After exposed to the laparotomy, a surgical procedure involving an incision into abdominal walls to examine the abdominal organs, 16- but not 3-month old male C57BL/6 mice developed obvious cognitive impairments in the test of long-term contextual fear conditioning. Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 µg/2 µl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice. SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95). Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD.

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