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1.
Fish Shellfish Immunol ; 89: 170-178, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30928663

RESUMO

Peroxiredoxin 6 (Prx6) is an important member of the peroxiredoxin family that plays critical roles in protecting host against the toxicity of oxidative stress and participates in cell signaling. Herein, we report Prx6 gene from red swamp crayfish, Procambarus clarkii. The cDNA fragment of PcPrx6 was 660 bp, encoding a 219 amino acid residues protein. The quantitative real time PCR analysis showed ubiquitous expression of PcPrx6 mRNA in the tested tissues. The challenge with peptidoglycan and Poly I:C remarkably suppressed the mRNA level of PcPrx6 in hepatopancreas at 3, 12, 48 h compared with the PBS control. However, the expression level significantly increased after 36 h of their treatment. The knockdown of PcPrx6 by small interference RNA significantly enhanced the transcript levels of Toll pathway-responsive genes at 24 h. Recombinant PcPrx6 protein was purified using affinity chromatography and analyzed for its biological role. The results revealed that the recombinant PcPrx6 protein manifested the ability to protect supercoiled DNA damage from oxidative stress elicited by mixed function oxidative assay. Altogether, PcPrx6 may have multiple functional roles in the physiology of P. clarkii, since it negatively regulates the Toll signaling transduction and protects supercoiled DNA damage from oxidative stress.


Assuntos
Astacoidea/genética , Astacoidea/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Peroxirredoxina VI/genética , Peroxirredoxina VI/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Cromatografia de Afinidade , Dano ao DNA , DNA Super-Helicoidal/fisiologia , Perfilação da Expressão Gênica , Estresse Oxidativo , Peptidoglicano/farmacologia , Peroxirredoxina VI/química , Filogenia , Poli I-C/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Alinhamento de Sequência
2.
Medicine (Baltimore) ; 97(17): e0451, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29702997

RESUMO

RATIONALE: Anuria is a severe symptom indicating severe kidney damage. Patient recovery from prolonged anuria is rarely reported. PATIENT CONCERNS: A 15-year-old boy received gender- and weight-mismatch heart transplantation (HT) due to dilated cardiomyopathy. He developed severe hypotension, and heart failure 24 hours after surgery, which were relieved by preload reduction treatments. Although, routine examinations did not show any abnormalities in renal function before surgery, anuria occurred 4 days after preload reduction treatments (24-hour urine volume was 23 mL). DIAGNOSIS: The patient was diagnosed with acute kidney injury (AKI). INTERVENTIONS: He was admitted to continuous renal replacement therapy (CRRT) or hemodialysis. OUTCOMES: Surprisingly, his urine volume was gradually, and miraculously, restored to more than 1000 mL/24 hours after over 300 days of anuria. Hemodialysis was not needed in the twentieth month after surgery. Moreover, he partially, recovered renal function. LESSONS: This case indicates the likelihood of recovery from long-term anuria.


Assuntos
Lesão Renal Aguda/etiologia , Anuria/etiologia , Transplante de Coração/efeitos adversos , Lesão Renal Aguda/terapia , Adolescente , Anuria/terapia , Humanos , Doença Iatrogênica , Masculino , Diálise Renal
3.
Fish Shellfish Immunol ; 75: 216-222, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29408672

RESUMO

Peroxiredoxin (Prx) family members play a key role in host defense against oxidative stress, and modulate immune responses following microbial infection. Here, we cloned and characterized Procambarus clarkii Prx4 (Peroxiredoxin 4) cDNA, a regulator of oxidative stress and its expression analysis upon lipopolysaccharide (LPS) and polyriboinosinic polyribocytidylic acid (Poly I:C) infection. The cDNA fragment of PcPrx4 was 744 bp in length, encoding a putative protein of 248 amino acid residues. Real-time quantitative reverse transcription-PCR (qRT-PCR) analysis showed that the PcPrx4 was expressed in all the examined tissues, and it was highest in the hepatopancreas followed by the hemocytes and gill. The challenge with LPS and Poly I:C significantly up-regulated the expression of PcPrx4 in hepatopancreas, hemocytes and gill when compared with the control. Recombinant PcPrx4 protein was used to investigate the antioxidant function in vitro by mixed-function oxidase assay. The results demonstrated a dose-dependent inhibition of DNA damage by rPcPrx4 protein. Altogether, our results imply that PcPrx4 is implicated in defense against microbial pathogens and oxidants in P. clarkii.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Penaeidae/genética , Penaeidae/imunologia , Peroxirredoxinas/genética , Peroxirredoxinas/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Perfilação da Expressão Gênica , Lipopolissacarídeos/farmacologia , Peroxirredoxinas/química , Filogenia , Poli I-C/farmacologia , Distribuição Aleatória , Proteínas Recombinantes/genética , Alinhamento de Sequência
4.
Clin Respir J ; 12(3): 974-985, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28139879

RESUMO

INTRODUCTION: The inflammatory marker patterns of community-acquired Pneumonia (CAP) induced by different microorganisms in adult patients remained unclear. OBJECTIVES: We aim to explore the inflammatory marker patterns of adult CAP patients induced by different pathogens. METHODS: Adult CAP patients with definite etiologies were enrolled from September 2010 to June 2012. They were divided into three groups according to the causative pathogens: typical bacteria, Mycoplasma pneumoniae (MP), and viruses. Twenty-seven cytokines and bactericidal/permeability-increasing protein (BPI) levels of serum collected within 7 days onset in these groups were compared. RESULTS: One hundred twenty-four cases were enrolled for serum detection and analysis, including 10 typical bacterial pneumonia patients, 56 cases with MP pneumonia and 58 with viral pneumonia. Three kinds (PDGF-BB, IP-10, RANTES) of 27 cytokines and BPI levels were significantly elevated in patients with acute pneumonia than healthy controls. Distinct inflammatory marker patterns were released by different pathogens: typical bacterial pneumonia patients had highest levels of BPI, IL-6, IL-8, IL-1rα; while patients caused by MP presented higher levels of PDGF-BB, IL-17A, G-CSF than those caused by viruses. Rhinovirus owned a higher inflammatory response level than the other viruses. The area under the curve (AUC) of PDGF-BB to differentiate MP and virus infection was biggest, which was 0.708. CONCLUSION: Distinct inflammatory marker patterns were released by different pathogens during acute pneumonia. Significantly increased level of PDGF-BB was observed in acute pneumonia for the first time. It showed a better ability to differentiate MP and virus infection.


Assuntos
Biomarcadores/sangue , Infecções Comunitárias Adquiridas/sangue , Pneumonia Bacteriana/diagnóstico , Pneumonia por Mycoplasma/diagnóstico , Pneumonia Viral/diagnóstico , Pneumonia/diagnóstico , Proteínas Proto-Oncogênicas c-sis/sangue , Adulto , Idoso , Becaplermina , Proteínas de Transporte/sangue , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/virologia , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycoplasma pneumoniae/isolamento & purificação , Pneumonia/sangue , Pneumonia/microbiologia , Pneumonia/virologia , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/microbiologia , Pneumonia por Mycoplasma/sangue , Pneumonia por Mycoplasma/microbiologia , Pneumonia Viral/sangue , Pneumonia Viral/virologia , Estudos Prospectivos , Rhinovirus/isolamento & purificação
5.
Surgery ; 163(1): 104-111, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29128180

RESUMO

BACKGROUND: Medullary thyroid cancer portends poor survival once liver metastasis occurs. We hypothesize that Notch3 overexpression in medullary thyroid cancer liver metastasis will decrease proliferation and growth of the tumor. METHODS: TT cells were modified genetically to overexpress Notch3 in the presence of doxycycline, creating the TT-Notch3 cell line. Mice were injected intrasplenically with either TT-Notch3 or control vector TT-TRE cells. Each cell line had 3 treatment groups: control with 12 weeks of standard chow, early DOX with doxycycline chow at day 0 and for 70 days thereafter, and late DOX with doxycycline chow at 8 weeks. Each animal underwent micro-computed tomography to evaluate for tumor formation and tumor quantification was performed. Animals were killed at 12 weeks, and the harvested liver was stained with Ki-67, hematoxylin and eosin, and Notch3. RESULTS: Induction of Notch3 did not prevent formation of medullary thyroid cancer liver metastases as all mice in the early DOX group developed tumors. However, induction of Notch after medullary thyroid cancer liver tumor formation decreased tumor size, as seen on micro-computed tomography scans (late DOX group). This translated to a 37-fold decrease in tumor volume (P = .001). Notch3 overexpression also resulted in decreased Ki-67 index (P = .038). Moreover, Notch3 induction led to increased areas of neutrophil infiltration and necrosis on hematoxylin and eosin staining of the tumors CONCLUSION: Notch3 overexpression demonstrates an antiproliferative effect on established metastatic medullary thyroid cancer liver tumors and is a potential therapeutic target in treatment.


Assuntos
Carcinoma Neuroendócrino/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Receptor Notch3/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Animais , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/secundário , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas Experimentais/secundário , Masculino , Camundongos Nus , Terapia de Alvo Molecular , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Fish Shellfish Immunol ; 71: 246-254, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29032038

RESUMO

Cathepsin L is one of the crucial enzyme superfamilies and involved in the immune responses. In the present study, cathepsin L gene from the red crayfish Procambarus clarkii, named PcCTSL, was cloned and characterized. The cDNA fragment of PcCTSL was 1026 bp in length, which encoded a putative protein of 341 amino acid residues with a molecular weight of 37.884 kDa. The theoretical isoelectric point was 5.218. The prepro-cathepsin L was comprised of a typical signal peptide (Met1-Ala18), a prodomain proregion peptide (Trp29-Phe89) and a mature peptide (Leu124-Leu340). Homology analysis indicated that PcCTSL exhibited 53.2%-87.1% identity to other selected species. The recombinant protein of PcCTSL was successfully expressed in Escherichia coli and rabbit anti-PcCTSL polyclonal antibodies were prepared. Real-time quantitative reverse transcription-PCR (qPCR) analysis revealed that the PcCTSL was expressed in all examined tissues, while the greatest mRNA level was observed in hepatopancreas. The expression of PcCTSL mRNA was clearly up regulated in hepatopancreas after challenge by lipopolysaccharide (LPS) and polyriboinosinic polyribocytidylic acid (Poly I:C). RNA interference of PcCTSL affected the gene expression of members of the Toll pathway. Our results suggest that the PcCTSL may play an important role to defend P. clarkii against the pathogens infection.


Assuntos
Astacoidea/genética , Astacoidea/imunologia , Catepsina L/genética , Catepsina L/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Catepsina L/química , Perfilação da Expressão Gênica , Hepatopâncreas/imunologia , Lipopolissacarídeos/farmacologia , Filogenia , Poli I-C/farmacologia , Reação em Cadeia da Polimerase , Alinhamento de Sequência
7.
Oncotarget ; 8(38): 63360-63369, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28968996

RESUMO

Anaphase promoting complex/cyclosome (APC/C) is essential for cell cycle progression. Recently, its non-mitotic functions were also reported but less studied in several tissues including hematopoietic cells. Here, we developed an inducible Anapc2 (a core subunit of APC/C) knockout mice. The animals displayed a fatal bone marrow failure within 7 days after knockout induction. Their hematopoietic stem and progenitor cells (HSPCs) demonstrated a sharp decline and could form little colony. Further, the results of BrdU label-retaining cell assay showed that the dormant HPSCs lost rapidly. Analysis of cell cycle regulators, Skp2, P27, Cdk2, and Cyclin E1, suggested that these quiescent stem cells underwent a shift from quiescence to mitosis followed by apoptosis. We next detected Anapc2-expression in the CD34+ HSPCs of patients with aplastic anemia. CD34+ cells were markedly decreased in the bone marrow and Anapc2-expression in the residual CD34+ cells was undetectable, suggesting that APC/C was deficient and might have a relationship with the pathogenesis of aplastic anemia.

8.
Oncotarget ; 8(15): 24457-24468, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28160550

RESUMO

BACKGROUND: EDC1 is a novel type of antibody-drug conjugate which binds and inhibits the Na,K-ATPase on the surface of cancer cells expressing dysadherin. The purpose of this study was to determine the expression of dysadherin in different types of thyroid carcinoma, and evaluate the therapeutic potential of EDC1 for thyroid carcinomas. METHODS: Thyroid tissues from 158 patients were examined for dysadherin expression and correlation with clinicopathological features. Thyroid cancer cell lines were examined for the expression of dysadherin and effective dose range of EDC1. RESULTS: One in 53 benign thyroid tissues and 62% of thyroid cancers expressed dysadherin. All anaplastic and a majority of papillary thyroid cancers overexpressed dysadherin, while 25% of follicular thyroid cancers was found to be positive for dysadherin. Dysadherin expression significantly correlated with extrathyroidal extension and lymph node metastases in papillary thyroid cancer. Five of six human thyroid cancer cell lines analyzed expressed high levels of dysadherin. Of those cells lines sensitive to EDC1, half maximal effective concentrations (EC50) were observed to be between 0.125 nM and 1 nM. CONCLUSIONS: EDC1 showed selective inhibition of growth in thyroid cancer cells with moderate to high expression of dysadherin, thus could be a specific and effective treatment.


Assuntos
Glicoproteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
9.
Surgery ; 161(1): 195-201, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27847111

RESUMO

BACKGROUND: Epstein-Barr virus is associated with lymphoid and epithelial malignancies and has been reported to infect thyroid cells. The Epstein-Barr virus protein, EBNA2, regulates viral and cellular promoters by binding to RBP-jκ. Similarly, NOTCH1, a tumor suppressor protein in thyroid epithelial cells, competes with EBNA2 for binding to overlapping sites on RBP-jκ. EBNA2 activates a subset of NOTCH-responsive genes in lymphocytes and myocytes; however, the effect of EBNA2 expression on NOTCH targets in epithelial cells is unknown. Here we have explored whether EBNA2 activates NOTCH1 targets in thyroid cancer lines and examined its effect on cellular proliferation. METHODS: Two human thyroid cancer lines, follicular FTC-236 and anaplastic HTh7, were transfected with EBNA2, NOTCH1, or control vectors. Notch targets were measured using quantitative reverse transcriptase polymerase chain reaction. Cellular proliferation was measured by MTT analysis. RESULTS: EBNA2 activated only a subset of NOTCH1 targets. Expression of HES1 and HEY1 were increased 10-fold in FTC-236 and HTh7 cells, respectively, but the majority of NOTCH1 targets examined were not affected. In contrast to NOTCH1, EBNA2 did not suppress proliferation. CONCLUSION: EBNA2 does not activate most Notch1-responsive genes or suppress proliferation in human thyroid cancer cells. Instead, EBNA2 may compete with NOTCH1 for limiting amounts of RBP-jκ in epithelial cells and inhibit certain aspects of NOTCH1 signaling.


Assuntos
Proteínas de Transporte/genética , Herpesvirus Humano 4/genética , Receptor Notch1/genética , Neoplasias da Glândula Tireoide/virologia , Ativação Transcricional/genética , Linhagem Celular , Regulação Viral da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Amostragem , Sensibilidade e Especificidade , Transdução de Sinais , Neoplasias da Glândula Tireoide/genética
10.
Cancer ; 123(5): 769-782, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27861750

RESUMO

BACKGROUND: Thyroid tumorigenesis is characterized by a progressive loss of differentiation exhibited by a range of disease variants. The Notch receptor family (1-4) regulates developmental progression in both normal and cancerous tissues. This study sought to characterize the third Notch isoform (Notch3) across the various differentiated states of thyroid cancer, and determine its clinical impact. METHODS: Notch3 expression was analyzed in a tissue microarray of normal and pathologic thyroid biopsies from 155 patients. The functional role of Notch3 was then investigated by upregulating its expression in a follicular thyroid cancer (FTC) cell line. RESULTS: Notch3 expression regressed across decreasingly differentiated, increasingly malignant thyroid specimens, correlated with clinicopathological attributes reflecting poor prognosis, and independently predicted survival following univariate and multivariate analyses. Overexpression of the active Notch3 intracellular domain (NICD3) in a gain-of-function FTC line led to functional activation of centromere-binding protein 1, while increasing thyroid-specific gene transcription. NICD3 induction also reduced tumor burden in vivo and initiated the intrinsic apoptotic cascade, alongside suppressing cyclin and B-cell lymphoma 2 family expression. CONCLUSIONS: Loss of Notch3 expression may be fundamental to the process of dedifferentiation that accompanies thyroid oncogenesis. Conversely, activation of Notch3 in thyroid cancer exerts an antiproliferative effect and restores elements of a differentiated phenotype. These findings provide preclinical rationale for evaluating Notch3 as a disease prognosticator and therapeutic target in advanced thyroid cancer. Cancer 2017;123:769-82. © 2016 American Cancer Society.


Assuntos
Carcinogênese/genética , Prognóstico , Receptor Notch3/biossíntese , Neoplasias da Glândula Tireoide/genética , Animais , Apoptose/genética , Biópsia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Receptor Notch3/genética , Transdução de Sinais , Neoplasias da Glândula Tireoide/classificação , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Zhongguo Zhong Yao Za Zhi ; 42(23): 4624-4630, 2017 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-29376262

RESUMO

Anoectochilus roxburghii is a traditional Chinese medicine and natural health products. In the modern cultivation system, A. roxburghii is micropropagated in tissue culture, and the plants are transferred to soil cultivation for months. However, it remains unclear about the necessity of soil cultivation for the accumulation of health beneficial compounds. In this paper, we performed nontargeted metabolomic analysis using GC-TOF-MS and UPLC-Q-TOF-MS, on A. roxburghii plants at tissue culture stage or after 3 months of soil cultivation. The results showed that the primary metabolites such as alcohols and organic acids are abundant in the tissue culture plants. In contrast, polysaccharide, nucleoside, esters and secondary metabolites such as flavonoids, terpenoids were significantly accumulated in cultivated seedlings. Flavonoids and polysaccharides are considered as the principle effective components in A. roxburghii. Soil cultivation period is therefore essential for the accumulation of these metabolites.


Assuntos
Metaboloma , Orchidaceae/crescimento & desenvolvimento , Orchidaceae/metabolismo , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Compostos Fitoquímicos/análise , Metabolismo Secundário
12.
Am J Pathol ; 186(6): 1662-73, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27060227

RESUMO

Anaplastic thyroid cancer is an aggressive and highly lethal cancer for which conventional therapies have proved ineffective. Cancer stem-like cells (CSCs) represent a small fraction of cells in the cancer that are resistant to chemotherapy and radiation therapy and are responsible for tumor reoccurrence and metastasis. We characterized CSCs in thyroid carcinomas and generated clones of CSC lines. Our study showed that anaplastic thyroid cancers had significantly more CSCs than well-differentiated thyroid cancers. We also showed that Aldefluor-positive cells revealed significantly higher expression of stem cell markers, self-renewal properties, thyrosphere formation, and enhanced tumorigenicity. In vivo passaging of Aldefluor-positive cells resulted in the growth of larger, more aggressive tumors. We isolated and generated two clonal spheroid CSC lines derived from anaplastic thyroid cancer that were even more enriched with stem cell markers and more tumorigenic than the freshly isolated Aldefluor-positive cells. Resveratrol and valproic acid treatment of one of the CSC lines resulted in a significant decrease in stem cell markers, Aldefluor expression, proliferation, and invasiveness, with an increase in apoptosis and thyroid differentiation markers, suggesting that these cell lines may be useful for discovering new adjuvant therapies for aggressive thyroid cancers. For the first time, we have two thyroid CSC lines that will be useful tools for the study of thyroid CSC targeted therapies.


Assuntos
Células-Tronco Neoplásicas/efeitos dos fármacos , Estilbenos/farmacologia , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Ácido Valproico/farmacologia , Animais , Antioxidantes/farmacologia , Western Blotting , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Citometria de Fluxo , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Resveratrol
13.
Clin Cancer Res ; 22(14): 3582-92, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-26847059

RESUMO

PURPOSE: Notch1, a transmembrane receptor, has been recently shown to aid in the determination of thyroid cell fate associated with tumorigenesis. This study aimed to investigate the clinical relevance of Notch1 and its role in the regulation of differentiated thyroid cancer (DTC) behavior. EXPERIMENTAL DESIGN: We examined Notch1 expression level and its relationship with clinicopathologic features and outcomes of DTC. Notch1 intracellular domain (NICD) was further characterized both in vitro and in vivo by gain-of-function assays using an inducible system. RESULTS: Notch1 expression levels were downregulated in primary DTC tissue samples compared with contralateral nontumor and benign thyroid tissues. Decreased Notch1 expression in DTC was associated with advanced patient age (P = 0.032) and the presence of extrathyroidal invasion (P = 0.005). Patients with lower Notch1 expression had a significantly higher recurrence rate (P = 0.038). Restoration of NICD in a stably doxycycline-inducible metastatic DTC cell line reduced cell growth and migration profoundly. Using an orthotopic thyroid cancer model, NICD induction significantly reduced the growth of the primary thyroid tumor and inhibited the development of lung metastasis. Serpin peptidase inhibitor, clade E, member 1 (SERPINE1) was discovered by microarray as the most significant gene downregulated by NICD. Further validation showed that the induction of NICD reduced SERPINE1 expression in a dose-dependent manner, whereas restoration of a relative higher level of SERPINE1 was observed with NICD back to minimal level. In addition, SERPINE1 knock-down inhibited DTC cell migration. CONCLUSIONS: Notch1 regulates the aggressive phenotypes of DTC, which could be mediated by SERPINE1 inhibition. Notch1/SERPINE1 axis warrants further investigation as a novel therapeutic target for advanced DTC. Clin Cancer Res; 22(14); 3582-92. ©2016 AACR.


Assuntos
Diferenciação Celular/fisiologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais/fisiologia , Neoplasias da Glândula Tireoide/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
14.
BMC Infect Dis ; 15: 89, 2015 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-25812108

RESUMO

BACKGROUND: Better knowledge of distribution of respiratory viruses (RVs) in adolescents and adults with community-acquired pneumonia (CAP) is needed. METHODS: To investigate the RVs etiology among adolescents and adults with CAP, according to age and pneumonia severity index (PSI), a multi-center, prospective study was conducted from November 2010 to April 2012. Fifteen RVs were tested by polymerase chain reaction (PCR). Bacteria were detected by urinary antigen, conventional culture and PCR. RESULTS: Mean (SD) age and median (IQR) PSI score of 954 patients enrolled was 45.2 (19.5) years (range 14-94) and 42 (36). RVs were found in 262 patients (27.5%): influenza virus A (IFV A, 9.9%) comprised of pandemic H1N1 (6.7%) and seasonal H3N2 (3.5%), human rhinovirus (4.3%), adenovirus (4.2%), human metapneumovirus (1.8%), parainfluenza virus 1, 3 and 2 (1.7%, 1.5% and 1.2%). Influenza virus B, enterovirus, respiratory syncytial virus, human coronavirus and parainfluenza virus 4 were rarely detected (<1%). Frequency of IFV A was highest among patients aged between 45-64 years (p < 0.001), while adenovirus among patients aged 14-17 years (p < 0.001), no differences was found in other RVs. The proportion of pandemic H1N1 increased with severity of pneumonia evaluated by PSI (P < 0.05). CONCLUSIONS: The proportion of RVs in CAP is higher than previously reported. IFV A pneumonia are usually found in patients older than 45 years, while, adenovirus pneumonia are common in adolescents and young adults. Pandemic H1N1 virus is still recognized by PSI as a high-severity pathogen. The findings contribute baseline data on viral CAP study in China.


Assuntos
Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/virologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/microbiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
15.
J Exp Bot ; 66(3): 695-707, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25297548

RESUMO

Melatonin is a well-known agent that plays multiple roles in animals. Its possible function in plants is less clear. In the present study, we tested the effect of melatonin (N-acetyl-5-methoxytryptamine) on soybean growth and development. Coating seeds with melatonin significantly promoted soybean growth as judged from leaf size and plant height. This enhancement was also observed in soybean production and their fatty acid content. Melatonin increased pod number and seed number, but not 100-seed weight. Melatonin also improved soybean tolerance to salt and drought stresses. Transcriptome analysis revealed that salt stress inhibited expressions of genes related to binding, oxidoreductase activity/process, and secondary metabolic processes. Melatonin up-regulated expressions of the genes inhibited by salt stress, and hence alleviated the inhibitory effects of salt stress on gene expressions. Further detailed analysis of the affected pathways documents that melatonin probably achieved its promotional roles in soybean through enhancement of genes involved in cell division, photosynthesis, carbohydrate metabolism, fatty acid biosynthesis, and ascorbate metabolism. Our results demonstrate that melatonin has significant potential for improvement of soybean growth and seed production. Further study should uncover more about the molecular mechanisms of melatonin's function in soybeans and other crops.


Assuntos
Melatonina/farmacologia , Reguladores de Crescimento de Planta/farmacologia , Proteínas de Plantas/genética , Soja/fisiologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Plantas/metabolismo , Soja/efeitos dos fármacos , Soja/crescimento & desenvolvimento , Estresse Fisiológico/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
16.
Mol Cancer Ther ; 14(2): 499-512, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25512616

RESUMO

Notch1-3 are transmembrane receptors that appear to be absent in medullary thyroid cancer (MTC). Previous research has shown that induction of Notch1 has a tumor-suppressor effect in MTC cell lines, but little is known about the biologic consequences of Notch3 activation for the progression of the disease. We elucidate the role of Notch3 in MTC by genetic (doxycycline-inducible Notch3 intracellular domain) and pharmacologic [AB3, novel histone deacetylase (HDAC) inhibitor] approaches. We find that overexpression of Notch3 leads to the dose-dependent reduction of neuroendocrine tumor markers. In addition, Notch3 activity is required to suppress MTC cell proliferation, and the extent of growth repression depends on the amount of Notch3 protein expressed. Moreover, activation of Notch3 induces apoptosis. The translational significance of this finding is highlighted by our observation that MTC tumors lack active Notch3 protein and reinstitution of this isoform could be a therapeutic strategy to treat patients with MTC. We demonstrate, for the first time, that overexpression of Notch3 in MTC cells can alter malignant neuroendocrine phenotype in both in vitro and in vivo models. In addition, our study provides a strong rationale for using Notch3 as a therapeutic target to provide novel pharmacologic treatment options for MTC.


Assuntos
Receptores Notch/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Neuroendócrino , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos Nus , Sistemas Neurossecretores/metabolismo , Sistemas Neurossecretores/patologia , Fenótipo , Receptor Notch3 , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia
17.
Oncologist ; 19(11): 1148-55, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25260367

RESUMO

Anaplastic thyroid cancer (ATC), accounting for less than 2% of all thyroid cancer, is responsible for the majority of death from all thyroid malignancies and has a median survival of 6 months. The resistance of ATC to conventional thyroid cancer therapies, including radioiodine and thyroid-stimulating hormone suppression, contributes to the very poor prognosis of this malignancy. This review will cover several cellular signaling pathways and mechanisms, including RET/PTC, RAS, BRAF, Notch, p53, and histone deacetylase, which are identified to play roles in the transformation and dedifferentiation process, and therapies that target these pathways. Lastly, novel approaches and agents involving the Notch1 pathway, nuclear factor κB, Trk-fused gene, cancer stem-like cells, mitochondrial mutation, and tumor immune microenvironment are discussed. With a better understanding of the biological process and treatment modality, the hope is to improve ATC outcome in the future.


Assuntos
Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/terapia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Terapia Genética , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Terapia de Alvo Molecular , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Carcinoma Anaplásico da Tireoide/patologia , Quinases raf/genética , Quinases raf/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
18.
Am J Pathol ; 184(8): 2342-54, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24946010

RESUMO

Thyroid carcinoma is the most common endocrine malignancy, and papillary thyroid carcinoma represents the most common thyroid cancer. Papillary thyroid carcinomas that invade locally or metastasize are associated with a poor prognosis. We found that, during epithelial-mesenchymal transition (EMT) induced by transforming growth factor-ß1 (TGF-ß1), papillary thyroid carcinoma cells acquired increased cancer stem cell-like features and the transcription factor paired-related homeobox protein 1 (PRRX1; alias PRX-1), a newly identified EMT inducer, was markedly up-regulated. miR-146b-5p was also transiently up-regulated during EMT, and in siRNA experiments miR-146b-5p had an inhibitory role on cell proliferation and invasion during TGF-ß1-induced EMT. We conclude that papillary thyroid carcinoma tumor cells exhibit increased cancer stem cell-like features during TGF-ß1-induced EMT, that miR-146b-5p has a role in cell proliferation and invasion, and that PRRX1 plays an important role in papillary thyroid carcinoma EMT and disease progression.


Assuntos
Carcinoma/patologia , Transição Epitelial-Mesenquimal/fisiologia , Proteínas de Homeodomínio/metabolismo , MicroRNAs/metabolismo , Neoplasias da Glândula Tireoide/patologia , Animais , Western Blotting , Carcinoma Papilar , Linhagem Celular Tumoral , Progressão da Doença , Citometria de Fluxo , Imunofluorescência , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Câncer Papilífero da Tireoide , Análise Serial de Tecidos , Transfecção , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
19.
J Surg Res ; 190(1): 191-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24679699

RESUMO

BACKGROUND: Anaplastic thyroid cancer (ATC) remains refractory to available surgical and medical interventions. Histone deacetylase (HDAC) inhibitors are an emerging targeted therapy with antiproliferative activity in a variety of thyroid cancer cell lines. Thailandepsin A (TDP-A) is a novel class I HDAC inhibitor whose efficacy remains largely unknown in ATC. Therefore, we aimed to characterize the effect of TDP-A on ATC. METHODS: Human-derived ATC cells were treated with TDP-A. IC50 was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) rapid colorimetric assay, and cell proliferation was measured by viable cell count. Molecular mechanisms of cell growth inhibition were investigated by Western blot analysis of canonical apoptosis markers, intrinsic and extrinsic apoptosis regulators, and cell cycle regulatory proteins. Cell cycle staging was determined with propidium iodide flow cytometry. RESULTS: TDP-A dose- and time-dependently reduced cell proliferation. Increased cleavage of the apoptosis markers Caspase-9, Caspase-3, and poly adenosine diphosphate ribose polymerase were observed with TDP-A treatment. Levels of the intrinsic apoptosis pathway proteins BAD, Bcl-XL, and BAX remained unchanged. Importantly, the extrinsic apoptosis activator cleaved Caspase-8 increased dose-dependently, and the antiapoptotic proteins Survivin and Bcl-2 decreased. Among the cell cycle regulatory proteins, levels of CDK inhibitors p21/WAF1 and p27/KIP increased. Flow cytometry showed that ATC cells were arrested in G2/M phase with diminished S phase after TDP-A treatment. CONCLUSIONS: TDP-A induces a notable dose- and time-dependent antiproliferative effect on ATC, which is mainly attributed to extrinsic apoptosis with concomitant cell cycle arrest. TDP-A therefore warrants further preclinical and clinical investigations.


Assuntos
Proliferação de Células/efeitos dos fármacos , Depsipeptídeos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide/patologia , Proteína Supressora de Tumor p53/análise
20.
Chest ; 145(1): 79-86, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24551881

RESUMO

BACKGROUND: Since 2008, severe cases of emerging human adenovirus (HAdV) type 55 (HAdV-55) were reported sporadically in China. But no comparative studies had been conducted to discern the differences in epidemiologic and clinical abnormalities between HAdV-55 and other types (HAdV-7, HAdV-3, HAdV-14, HAdV-50, and HAdV-C). METHODS: A multicenter surveillance study for adult and adolescent community-acquired pneumonia (CAP) was conducted prospectively in Beijing and Yan Tai between November 2010 and April 2012. A standardized data form was used to record clinical information. The viral DNA extracted from the clinical samples or adenovirus viral isolates was sequenced. RESULTS: Among 969 cases, 48 (5%) were identified as adenovirus pneumonia. Six branches were clustered: HAdV-55 in 21, HAdV-7 in 11, HAdV-3 in nine, HAdV-14 in four, HAdV-50 in two, and HAdV-C in one. Most HAdV-55 cases were identified during February and March. All the hypervariable regions of the hexon genes of the 21 HAdV-55 strains were completely identical. Patients who had HAdV-55 were about 10 years older ( P = .027) and had higher pneumonia severity index scores ( P = .030) compared with those with other types (HAdV-7, HAdV-3, HAdV-14, HAdV-50, and HAdV-C). Systemic BP was also higher among patients in the HAdV-55 group ( P = .006). Unilateral or bilateral consolidations were the most common radiologic findings in both patients with HAdV-55 and those with other types (57.9% vs 36%). More than one-half of the patients were admitted to hospital; oxygen therapy was given to 29.2% of the 48 patients, and two needed mechanical ventilation. CONCLUSIONS: HAdV-55 has established itself as a major pneumonia pathogen in the Chinese population, and further surveillance and monitoring of this agent as a cause of CAP is warranted.


Assuntos
Infecções por Adenovirus Humanos/epidemiologia , Adenovírus Humanos/isolamento & purificação , Infecções Comunitárias Adquiridas/epidemiologia , Pneumonia Viral/epidemiologia , Infecções por Adenovirus Humanos/diagnóstico , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/genética , Adulto , Idoso , China/epidemiologia , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/virologia , DNA Viral/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Prospectivos , Adulto Jovem
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