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1.
J Cancer ; 10(27): 6848-6857, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839819

RESUMO

Adenylate cyclase 1 (ADCY1 or AC1) is a member of ADCY superfamily and was primarily found to be expressed in the brain. ADCY1 is responsible for catalyzing ATP to cyclic AMP (cAMP). As a secondary messenger, cAMP can regulate plenty of cellular activities. cAMP can perform its regulation in cellular transport through the binding to cAMP dependent protein kinases (PKAs), cAMP-activated guanine exchange factors (EPACs) and cyclic nucleotide-gated channels functioning in transduction of sensory signals (CNGs). Lung cancer is one of the leading factors of cancer-related death worldwide. Platinum-based chemotherapy is the first-line treatment for advanced lung cancer patients. In addition, surgical treatment, radiation treatment, and molecular targeted therapy are also therapeutic options for lung cancer patients in clinical settings. However, drug resistance and toxicity are the major obstacles that affect chemotherapy outcome and prognosis of lung cancer patients. And the therapeutic efficiency and adverse effects are varying with each individual. In recent years, investigations based on genetic sequencing have revealed the emerging role of ADCY1 mutations in affecting drug efficiency in various cancers such as lung cancer, esophageal cancer and colorectal cancer. The potential function of ADCY1 in chemotherapy resistance is of great importance to be noticed and investigated.

2.
J Cancer ; 10(27): 6910-6914, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31839826

RESUMO

CCL18 is a cytokine secreted by M2 type tumor associated macrophages, which frequently over-expressed in diverse human cancers. However, the clinical significance of serum CCL18 in patients with laryngeal squamous cell carcinoma (LSCC) remains unknown. In this study, serum CCL18 was initially quantified by enzyme-linked immunosorbent assay (ELISA) in 146 patients with LSCC, 25 patients with precancerous lesions and 72 healthy volunteers. In addition, the correlations between serum CCL18 and clinicopathological parameters were analyzed. Our data revealed that serum CCL18 was obviously increased in patients with LSCC. Moreover, serum CCL18 level was significantly associated with primary tumor site (Glottic vs Others), T classification (T1+T2 vs T3+T4), clinical stage (I+II vs III+IV) and lymph node metastasis (N0 vs N+). Survival analysis demonstrated that patients with high serum CCL18 displayed a shorter survival time than those in patients with low serum CCL18. Importantly, serum CCL18 level and clinical stage were independent prognostic factors in patients with LSCC. Taken together, serum CCL18 could be used as a promising biomarker in patients with LSCC.

3.
J Immunol ; 203(9): 2520-2531, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31562213

RESUMO

The innate immune sensing of allergens or allergen-associated components regulate the development of type 2 inflammatory responses. However, the underlying molecular basis by which allergens or allergen-associated components are detected by innate immune receptors remains elusive. In this study, we report that the most common aeroallergen, house dust mite (HDM), harbors a dsRNA species (HDM-dsRNA) that can activate TLR3-mediated IFN responses and counteract the development of an uncontrolled type 2 immune response. We demonstrate that the mouse strains defective in the dsRNA-sensing pathways show aggravated type 2 inflammation defined by severe eosinophilia, elevated level of type 2 cytokines, and mucus overproduction in a model of allergic lung inflammation. The inability to sense HDM-dsRNA resulted in significant increases in airway hyperreactivity. We further show that the administration of the purified HDM-dsRNA at a low dose is sufficient to induce an immune response to prevent the onset of a severe type 2 lung inflammation. Collectively, these results unveil a new role for the HDM-dsRNA/TLR3-signaling axis in the modulation of a type 2 lung inflammation in mice.

4.
J Cell Mol Med ; 23(4): 2689-2701, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30768878

RESUMO

Metastasis is one of the primary causes for high mortality in patients with squamous cell carcinoma of the head and neck (SCCHN). Our previous study showed that chemokine (C-C motif) ligand 18 (CCL18), derived from tumour-associated macrophages (TAMs), regulates SCCHN metastasis by promoting epithelial-mesenchymal transition (EMT) and preserving stemness. However, the underlying mechanism needs to be further investigation. Interestingly, metadherin (MTDH) expression was induced when SCCHN cells were stimulated with recombinant CCL18 protein in this study. Suppressing MTDH expression reversed CCL18-induced migration, invasion and EMT in SCCHN cells. Furthermore, the NF-κB signalling pathway was involved in the MTDH knock-down cells with CCL18 stimulation. We performed ELISA to evaluate the CCL18 levels in the serums of 132 treatment-naive SCCHN patients, 25 patients with precancerous lesion and 32 healthy donors. Our results demonstrated that serum CCL18 levels were significantly higher in SCCHN patients than patients with precancerous lesion and healthy individuals. CCL18 levels were found to be significantly correlated with tumour classification, clinical stage, lymph node metastasis and histological grade in SCCHN patients. Thus, our findings suggest that CCL18 may serve as a potential biomarker for diagnosis of SCCHN and promote SCCHN invasion, migration and EMT by MTDH-NF-κB signalling pathway.

5.
J Cancer ; 9(19): 3593-3602, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30310517

RESUMO

Long non-coding RNAs (lncRNAs) are potentially critical regulators of cancer malignant behaviours. Aberrant expression and dysfunction of lncRNA PVT1 have been reported in multiple human cancers. However, its role in squamous cell carcinoma of the head and neck (SCCHN) remains largely unknown. Our current study demonstrated that PVT1 expression was increased in SCCHN. High PVT1 expression was positively correlated with SCCHN clinical parameters including T classification, clinical stages and cervical lymph node metastasis. More importantly, high PVT1 expression predicted a poor prognosis in SCCHN patients. Gain-of function and loss-of function studies further indicated that PVT1 promoted the proliferation and invasion of SCCHN both in vitro and in vivo, which was accompanied by epithelial-mesenchymal transition and enhanced cancer stem cell-like properties. Further mechanistic investigation revealed that PVT1 activated Wnt/ß-catenin signalling pathway, and inhibition of Wnt/ß-catenin signalling reversed the malignant progression caused by PVT1 overexpression. Together, our study reveals that PVT1 accelerates the malignant progression of SCCHN and represents a potential biomarker and therapeutic target in SCCHN.

6.
Cancer Cell Int ; 18: 120, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30181713

RESUMO

Background: Alternatively activated macrophages in tumor microenvironment is defined as M2 tumor-associated macrophages (M2 TAMs) that promote cancer progression. However, communicative mechanisms between M2 TAMs and cancer cells in squamous cell carcinoma of head and neck (SCCHN) remain largely unknown. Methods: Quantitative real-time PCR, western blotting, enzyme-linked immunosorbent assay and flow cytometry were applied to quantify mRNA and protein expression of genes related to M2 TAMs, epithelial-mesenchymal transition (EMT) and stemness. Wounding-healing and Transwell invasion assays were performed to detect the invasion and migration. Sphere formation assay was used to detect the stemness of SCCHN cells. RNA-sequencing and following bioinformatics analysis were used to determine the alterations of transcriptome. Results: THP-1 monocytes were successfully polarized into M2-like TAMs, which was manifested by increased mRNA and protein expression of CCL18, IL-10 and CD206. Conditioned medium from M2-like TAMs promoted the migration and invasion of SCCHN cells, which was accompanied by the occurrence of EMT and enhanced stemness. Importantly, CCL18 neutralizing antibody partially abrogated these effects that caused by conditional medium from M2-like TAMs. In addition, recombinant human CCL18 (rhCCL18) correspondingly promoted the malignant biological behaviors of SCCHN in vitro. Finally, RNA-sequencing analysis identified 331 up-regulated and 363 down-regulated genes stimulated by rhCCL18, which were statistically enriched in 10 cancer associated signaling pathways. Conclusion: These findings indicate that CCL18 derived from M2-like TAMs promotes metastasis via inducing EMT and cancer stemness in SCCHN in vitro.

7.
Zhen Ci Yan Jiu ; 43(8): 476-9, 2018 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-30232848

RESUMO

Since the invention of optogenetic technology, it has greatly promoted the development of neuroscience. Currently, optogenetic approaches have been mostly used to map neural circuits and new neuropharmacology but are rarely seen in the research field of acupuncture analgesia. The mechanism of neural circuits contributing to acupuncture analgesia, an important research hotspot in recent years, has not been fully determined. The optogenetic techniques can be used to modulate and control specific cells, provides highly precise spatial and temporal resolution, is repeatable, and may functionally dissect neuronal networks in vivo. The neuronal activities and their information transmission, processing and storage in intercluster neural networks in different brain regions, and the correlation between behavioral changes and electrical activities of neurons in vivo studies are mainly captured by the implanted microelectropode array, etc. If these two (or more) approaches are combined together, it is definitely and highly helpful to reveal the driving dynamics of neural circuits, plasticity and temporal-spatial activity mode of neurons, as well as behavioral reactions of animals with chronic pain during acupuncture analgesia and may open a new prospect for the application of acupuncture analgesia study.


Assuntos
Analgesia por Acupuntura , Optogenética , Animais , Encéfalo , Neurônios
8.
J Cancer ; 9(1): 198-204, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29290786

RESUMO

Purpose: Lysine demethylase (KDM) 5B, as a member of the histone lysine demethylase family, is overexpressed and functions abnormally in various human cancers. However, its expression in the squamous cell carcinoma of the head and neck (SCCHN) remains unclear. Methods: KDM5B expression was analyzed by immunohistochemistry and correlated with clinicopathological parameters in 103 archival SCCHN tissue samples and 24 adjacent noncancerous epithelial tissues. Results: We found that KDM5B expression was higher in SCCHN than that in adjacent noncancerous tissues. This was closely associated with lymph node metastasis and tumor recurrence. In addition, Kaplan-Meier analysis revealed that patients with high KDM5B expression had shorter disease-free and overall survival times than those with low KDM5B expression. Importantly, both univariate and multivariate analysis demonstrated that KDM5B level was an independent prognostic factor in SCCHN patients. Conclusions: These results indicate that KDM5B is a valuable biomarker that can be used to predict SCCHN patient outcome.

9.
Oncol Rep ; 38(5): 2893-2900, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28901527

RESUMO

Hypoxia is a hallmark of progressive cancer. Hypoxic cancer cells trigger glycolysis in response to a decreased O2 supply to meet metabolic and bioenergetic demands. Meanwhile, these responses to hypoxia and alterations of the microenvironment promote cancer cell metastasis by increasing transcription of hypoxia-inducible factor (HIF)-regulated genes. However, the detailed mechanism by which hypoxia regulates cancer cell metastasis and glycolysis remains to be investigated. In the present study, we identified that metadherin (MTDH), a multifaceted oncogene, is involved in the regulation of head and neck squamous cell carcinoma (HNSCC) metastasis and invasion under hypoxic conditions. Furthermore, the study indicated that there is a positive feedback loop between HIF-1α and MTDH in HNSCC cells, and that hypoxia promotes HNSCC cell metastasis and epithelial-mesenchymal transition by mediating the HIF-1α-MTDH loop. These findings implicate HIF-1α-MTDH as a promising target for anticancer drugs in solid tumors, and help to explain the pro-tumorigenic and unfavorable effect of MTDH on HNSCC observed in our previous studies.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Moléculas de Adesão Celular/metabolismo , Glicólise , Neoplasias de Cabeça e Pescoço/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Carcinoma de Células Escamosas de Cabeça e Pescoço
10.
J Cancer ; 8(12): 2336-2345, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28819438

RESUMO

Derlin-1 is over-expressed to function as an oncoprotein in breast, lung and colon cancers. However, the implications of Derlin-1 involved in squamous cell carcinoma of the head and neck (SCCHN) remain unknown. This study aims to investigate the effects of Derlin-1 expression on SCCHN tissues and cells. The potential mechanism of Derlin-1 regulating SCCHN cell proliferation, apoptosis and metastasis was also indicated in this work. Western blot and immunohistochemistry (IHC) assays showed that Derlin-1 was over-expressed in 114 SCCHN samples and five SCCHN cell lines. We found that the expression of Derlin-1 was positively associated with lymph node metastasis, clinical stage and recurrence in our SCCHN patients' samples. Survival analysis indicated that high expression of Derlin-1 was significantly associated with shorter overall survival (OS) and disease-free survival (DFS). Knock down expression of Derlin-1 in SCCHN cell lines was found to inhibit cell proliferation, metastasis and promote cell apoptosis. Further experiments showed that signals of PI3K/Akt, p53 and Smad2/3 may involve in these processes. In all, Derlin-1 might be a novel prognostic marker of SCCHN patients and plays an oncogenic role in SCCHN cell progression.

11.
Am J Cancer Res ; 7(12): 2554-2565, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29312808

RESUMO

PURPOSE: MicroRNAs function through regulating specific target mRNA expression and then participate in the development and progression of diverse human cancers. MiR-98 shows aberrant expression and dysfunction in tumors. However, its clinical significance and exact role in squamous cell carcinoma of the head and neck (SCCHN) remain elusive. METHODS: MiR-98 expression was examined by qRT-PCR and correlated with clinicopathological variables and prognosis in SCCHN patients. Effects of miR-98 on epithelial-mesenchymal transition (EMT) and the malignant phenotypes of SCCHN were studied. Finally, the role of target gene metadherin (MTDH) in miR-98 mediated effects were assayed. RESULTS: Our results demonstrated that miR-98, as an endogenous inhibitor of MTDH via directly binding to its 3'-untranslated region (UTR) region, decreased significantly in SCCHN tissues. Decreased miR-98 expression was negatively correlated with T classification, clinical stage, lymph node metastasis and a shorter survival status in SCCHN patients. Loss-of-function and gain-of-function analyses confirmed that miR-98 inhibited cell proliferation, migration and invasion of SCCHN cells in vitro. Moreover, miR-98 repression led to increased MTDH expression and induced EMT alteration. Importantly, ectopic expression of MTDH partially reversed the effects caused by miR-98 overexpression. CONCLUSIONS: Our study identifies that miR-98 serves as a suppressor in SCCHN progression via targeting oncogene MTDH.

12.
Jundishapur J Microbiol ; 9(10): e37897, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27942365

RESUMO

BACKGROUND: Due to the overuse of antibiotics in livestock as a growth-promoting agent, the emergence of multi-antibiotic resistant bacteria is becoming a concern. OBJECTIVES: In this study, we aimed to detect the presence and discover the molecular determinants of foodborne bacteria in retail sausages resistant towards the antibacterial agent amoxicillin-clavulanate. METHODS: Two grams of sausages were chopped into small pieces and transferred into sterile Luria-Bertani (LB) enrichment broths overnight before they were plated on MacConkey agar petri dishes. The bacteria isolated were then screened for amoxicillin-clavulanate resistance, and an antimicrobial susceptibility test of each isolate was performed by using the disc diffusion method. Double synergy and phenotypic tests were carried out to detect the presence of extended spectrum ß-lactamase (ESBL). API 20E kit was used to identify the Enterobacteriaceae. All isolates were further examined by polymerase chain reaction (PCR) for resistant genes blaOXA-1, blaOXA-10, plasmid-mediated AmpC (blaCMY and blaDHA), and the chromosome-mediated AmpC, Sul1, blaTEM, and blaSHV genes. RESULTS: A total of 18 amoxicillin-clavulanate resistant isolates were obtained from seven different types of retail sausages. Only half of them were identified as Enterobacteriaceae, but none were ESBL-producers. All the 18 isolated strains demonstrated resistance towards amoxicillin-clavulanate, penicillin and oxacillin (100%), cefotaxime (71.4%), cefpodoxime (66.7%), and ampicillin (83.3%). blaTEM was the most frequently detected ß-lactamase gene. Both plasmid- and chromosomal-bound blaTEM genes were detected in all of the isolated Enterobacteriaceae. blaSHV and Sul1 accounted for 22.2% and 11.1% of the amoxicillin-clavulanate resistant isolates, respectively, whereas blaAMPC, blaCMY, blaDHA, blaOXA-1, and blaOXA-10 were not found in any of the isolates. The only one ESBL-producing bacteria detected in this study was Chryseobacterium meningosepticum, which harbored the blaTEM gene. CONCLUSIONS: The multidrug resistant bacteria that carry antibiotic resistant genes from retail sausages may increase the risk of transmission to humans via the consumption of contaminated sausages. Stricter measures must be taken to address the use of antibiotics in animal agriculture and to consider their potential impact on human health.

13.
Oncol Rep ; 36(4): 1861-7, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27498905

RESUMO

Paclitaxel chemoresistance restricts the therapeutic efficacy and prognosis of patients with nasopharyngeal carcinoma (NPC). Accumulating evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) contributes to cancer progression. Therefore, we aimed to identify lncRNAs associated with paclitaxel resistance in NPC. First, paclitaxel-resistant CNE-2 cells (CNE-2-Pr) were successfully established and confirmed to be 33.26±8.70 times more resistant than parental CNE-2 cells. Then, differential expression profile of lncRNAs associated with NPC paclitaxel resistance, which contained a total of 2,670 known lncRNAs and 4,820 novel lncRNAs, was constructed via next generation sequencing technology. Our qRT-PCR confirmed that 7 of the top 8 lncRNAs were expressed with the same trend as the prediction, including 4 known lncRNAs (n375709, n377806, n369241 and n335785) and 3 novel lncRNAs (Unigene6646, Unigene6644 and Unigene1654). Our group initially focused on lncRNA n375709, which was the most significantly overexpressed lncRNA of the known lncRNAs. CCK-8 assays demonstrated that further inhibition of lncRNA n375709 increased the paclitaxel sensitivity in NPC 5-8F and 6-10B cells. In conclusion, the present study provided an overview of the expression profiles of lncRNAs correlated with paclitaxel resistance. lncRNA n375709 was identified to be involved in the regulation of NPC paclitaxel resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/genética , Antineoplásicos Fitogênicos/farmacologia , Carcinoma , Linhagem Celular Tumoral , Humanos , Carcinoma Nasofaríngeo , Paclitaxel/farmacologia , Reação em Cadeia da Polimerase , Transfecção
14.
Biomed Res Int ; 2015: 137024, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26636095

RESUMO

Segmentation of retinal blood vessels is significant to diagnosis and evaluation of ocular diseases like glaucoma and systemic diseases such as diabetes and hypertension. The retinal blood vessel segmentation for small and low contrast vessels is still a challenging problem. To solve this problem, a new method based on cake filter is proposed. Firstly, a quadrature filter band called cake filter band is made up in Fourier field. Then the real component fusion is used to separate the blood vessel from the background. Finally, the blood vessel network is got by a self-adaption threshold. The experiments implemented on the STARE database indicate that the new method has a better performance than the traditional ones on the small vessels extraction, average accuracy rate, and true and false positive rate.


Assuntos
Algoritmos , Técnicas de Diagnóstico Oftalmológico , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Reconhecimento Automatizado de Padrão/métodos , Vasos Retinianos/anatomia & histologia , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Processamento de Sinais Assistido por Computador
15.
Medicine (Baltimore) ; 94(6): e502, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25674742

RESUMO

Our previous study indicated overexpression of metadherin (MTDH) is an adverse prognostic factor in squamous cell carcinoma of the head and neck (SCCHN) and promotes SCCHN cell proliferation and invasion. However, its mechanism remains unclear. Recent studies have indicated that MTDH is a cancer-metastasis-associated molecule that participates in the process of angiogenesis. Therefore, the study is aimed to investigate that whether vascular endothelial growth factor (VEGF), as one of the most potent proangiogenic cytokines, is regulated by MTDH and the role of the phosphatidylinositide 3-kinases/Protein Kinase B (PI3K/Akt) pathway in this process of regulation and the clinical significance of both MTDH and VEGF in SCCHN.Immunohistochemistry was used to assay the expression of MTDH and VEGF in a cohort of 189 SCCHN patients with intact follow-up information. The expression of MTDH was then upregulated or inhibited by lentivirus-mediated MTDH Complementary deoxyribonucleic acid or MTDH short hairpin ribonucleic acid (shRNA) to observe the resulting alterations in VEGF expression and the PI3K/Akt signaling pathway in SCCHN cell lines. In addition, the PI3K/Akt pathway was modulated to observe the resulting changes in the MTDH-mediated expression of VEGF.The immunohistochemistry data showed that MTDH expression is positively correlated with VEGF expression in SCCHN tissues. Moreover, the overexpression of MTDH in SCCHN Tu686 and 5-8F cells led to increases in the expression of VEGF, and this effect was accompanied by activation of the PI3K/Akt pathway. Conversely, shRNA-mediated knockdown of MTDH led to decreased VEGF expression. In addition, inhibition of the Akt signaling pathway reversed the upregulation of VEGF resulting from MTDH overexpression. Moreover, the survival analysis revealed that VEGF is an independent prognostic factor, and a combined survival analysis based on both MTDH and VEGF showed synergistic effects in the prognosis evaluation of SCCHN patients.The findings of the present study demonstrate that MTDH regulates the expression of VEGF via the PI3K/Akt signaling pathway, indicating the potential role of the MTDH-mediated activation of VEGF signaling pathway in SCCHN angiogenesis and metastasis.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Moléculas de Adesão Celular/fisiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Western Blotting , Carcinoma de Células Escamosas/mortalidade , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Imuno-Histoquímica , Prognóstico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , RNA Interferente Pequeno/fisiologia , Transdução de Sinais/fisiologia , Transfecção , Regulação para Cima
16.
Epigenomics ; 7(2): 143-53, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25496457

RESUMO

AIM: Overexpression of histone demethylase PHF8 has been reported to function as an oncoprotein in many cancers; however, the implications of PHF8 involvement in laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) remain unclear. This study aims to explore the expression of PHF8 and its clinical significance in LHSCC. MATERIALS & METHODS: Western blotting and immunohistochemistry were performed to evaluate PHF8 protein expression in fresh and archived LHSCC samples. Global expressions of H3K27 and H3K9 methylation were analyzed in a cell line with PHF8 siRNA treatment. RESULTS & CONCLUSION: In our study, PHF8 was upregulated in fresh LHSCC tissues. Immunohistochemical staining revealed that the expression of PHF8 was positively associated with T classification, clinical stage, primary tumor position and tumor relapse. Survival analysis demonstrated that high PHF8 expression was significantly associated with shorter overall survival and disease-free survival. Moreover, PHF8 regulates the levels of H3K9me2 and H3K27me2 in LHSCC. Taken together, PHF8 might be a novel prognostic marker for this disease.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/mortalidade , Histona Desmetilases/metabolismo , Neoplasias Hipofaríngeas/enzimologia , Neoplasias Hipofaríngeas/mortalidade , Neoplasias Laríngeas/enzimologia , Neoplasias Laríngeas/mortalidade , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Feminino , Histonas/metabolismo , Humanos , Masculino , Metilação , Prognóstico , Análise de Sobrevida
17.
Behav Pharmacol ; 25(8): 717-24, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25325286

RESUMO

Norepinephrine is involved in the arousal of attention and the treatment of affective disorders. Therefore, we hypothesized that adrenergic receptors underpinned individual differences in attention regulation and emotional processes of healthy populations. Here, we investigated to what extent the expression of ADRA2B, an adrenergic receptor, modulated attention regulation and emotional processes. We evaluated orientation of attention, emotion regulation, and pleasantness ratings of expressions and words in 665 college students, and then genotyped the +901 Ins/Del variants in ADRA2B of these participants. The results indicated that +901 Ins/Del significantly modulated orientation of attention to facial expressions and emotional words, such that the Del allele facilitated reorientation to the originally attended locations. However, this polymorphism exerted no significant effects on emotional regulation of attention and pleasantness ratings of emotional stimulus. These findings suggest that ADRA2B is closely related to the individual difference in human attention orientation, but not to the individual difference in emotional processing.


Assuntos
Atenção/fisiologia , Emoções/fisiologia , Expressão Facial , Deleção de Genes , Orientação/fisiologia , Receptores Adrenérgicos alfa 2/genética , Adulto , Análise de Variância , Sinais (Psicologia) , Feminino , Genótipo , Humanos , Masculino , Estimulação Luminosa , Vocabulário , Adulto Jovem
18.
J Med Chem ; 57(10): 4273-88, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24738581

RESUMO

A novel series of nonsteroidal mineralocorticoid receptor (MR) antagonists identified as part of our strategy to follow up on the clinical candidate PF-03882845 (2) is reported. Optimization departed from the previously described pyrazoline 3a and focused on improving the selectivity for MR versus the progesterone receptor (PR) as an approach to avoid potential sex-hormone-related adverse effects and improving biopharmaceutical properties. From this effort, (R)-14c was identified as a potent nonsteroidal MR antagonist (IC50 = 4.5 nM) with higher than 500-fold selectivity versus PR and other related nuclear hormone receptors, with improved solubility as compared to 2 and pharmacokinetic properties suitable for oral administration. (R)-14c was evaluated in vivo using the increase of urinary Na(+)/K(+) ratio in rat as a mechanism biomarker of MR antagonism. Treatment with (R)-14c by oral administration resulted in significant increases in urinary Na(+)/K(+) ratio and demonstrated this novel compound acts as an MR antagonist.


Assuntos
Antagonistas de Receptores de Mineralocorticoides/síntese química , Ácidos Nicotínicos/síntese química , Pirazóis/síntese química , Animais , Descoberta de Drogas , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Simulação de Acoplamento Molecular , Ácidos Nicotínicos/farmacologia , Potássio/urina , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Mineralocorticoides/química , Sódio/urina , Relação Estrutura-Atividade
19.
Front Pharmacol ; 4: 115, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24133446

RESUMO

The mineralocorticoid receptor (MR) antagonists PF-03882845 and eplerenone were evaluated for renal protection against aldosterone-mediated renal disease in uninephrectomized Sprague-Dawley (SD) rats maintained on a high salt diet and receiving aldosterone by osmotic mini-pump for 27 days. Serum K(+) and the urinary albumin to creatinine ratio (UACR) were assessed following 14 and 27 days of treatment. Aldosterone induced renal fibrosis as evidenced by increases in UACR, collagen IV staining in kidney cortex, and expression of pro-fibrotic genes relative to sham-operated controls not receiving aldosterone. While both PF-03882845 and eplerenone elevated serum K(+) levels with similar potencies, PF-03882845 was more potent than eplerenone in suppressing the rise in UACR. PF-03882845 prevented the increase in collagen IV staining at 5, 15 and 50 mg/kg BID while eplerenone was effective only at the highest dose tested (450 mg/kg BID). All doses of PF-03882845 suppressed aldosterone-induced increases in collagen IV, transforming growth factor-ß 1 (Tgf-ß 1), interleukin-6 (Il-6), intermolecular adhesion molecule-1 (Icam-1) and osteopontin gene expression in kidney while eplerenone was only effective at the highest dose. The therapeutic index (TI), calculated as the ratio of the EC50 for increasing serum K(+) to the EC50 for UACR lowering, was 83.8 for PF-03882845 and 1.47 for eplerenone. Thus, the TI of PF-03882845 against hyperkalemia was 57-fold superior to that of eplerenone indicating that PF-03882845 may present significantly less risk for hyperkalemia compared to eplerenone.

20.
Parasit Vectors ; 6: 168, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23742078

RESUMO

BACKGROUND: Toxoplasma gondii is an intracellular protozoan parasite that infects almost all warm-blooded animals, including humans, with a worldwide distribution. There have been limited reports about the seroprevalence of T. gondii infection in equids around the world and little is known about the seroprevalence of T. gondii in equids in southwestern China, in particular in Yunnan Province. The objective of the present investigation was to estimate the seroprevalence of T. gondii infection in equids in this area. METHODS: A total of 399 serum samples (266 from horses and 133 from donkeys) were collected in 2012, and assayed for T. gondii antibodies by Indirect Haemagglutination (IHA) test using a commercially available kit. RESULTS: A total of 108 (27.1%) equids, including 81 (30.5%) horses and 27 (20.3%) donkeys were positive for T. gondii antibodies, and the seroprevalence ranged from 18.8% to 37.5% among different sampling areas. The seroprevalence was 27.4% and 26.8% for male and female equids, respectively, and the difference was not statistically significant (P > 0.05). The seroprevalence ranged from 21% to 32.9% among different age groups, and the difference was not statistically significant (P > 0.05). CONCLUSIONS: The results of the present survey indicated the existence of high T. gondii seroprevalence in Yunnan Province, southwestern China, which has significant public health concern. Therefore, it is imperative that improved integrated measures be carried out to prevent and control T. gondii infection in equids in the studied region.


Assuntos
Anticorpos Antiprotozoários/sangue , Doenças dos Cavalos/epidemiologia , Toxoplasma/imunologia , Toxoplasmose Animal/epidemiologia , Animais , China/epidemiologia , Equidae , Feminino , Testes de Hemaglutinação , Cavalos , Masculino , Estudos Soroepidemiológicos
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