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1.
Front Immunol ; 10: 2449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824476

RESUMO

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by mucosa damage associated with an uncontrolled inflammatory response. This immunological impairment leads to altered inflammatory mediators such as IL-33, which is shown to increase in the mucosa of active UC (aUC) patients. MicroRNAs present a distorted feature in inflamed colonic mucosa and are potential IL-33 regulating candidates in UC. Therefore, we studied the microRNA and mRNA profiles in inflamed colonic samples of UC patients, evaluating the effect of a microRNA (selected by in silico analysis and its expression in UC patients), on IL-33 under inflammatory conditions. We found that inflamed mucosa (n = 8) showed increased expression of 40 microRNAs and 2,120 mRNAs, while 49 microRNAs and 1,734 mRNAs were decreased, as determined by microarrays. In particular, IL-33 mRNA showed a 3.8-fold increase and eight members of a microRNA family (miR-378), which targets IL-33 mRNA in the 3'UTR, were decreased (-3.9 to -3.0 times). We selected three members of the miR-378 family (miR-378a-3p, miR-422a, and miR-378c) according to background information and interaction energy analysis, for further correlation analyses with IL-33 expression through qPCR and ELISA, respectively. We determined that aUC (n = 24) showed high IL-33 levels, and decreased expression of miR-378a-3p and miR-422a compared to inactive UC (n = 10) and controls (n = 6). Moreover, both microRNAs were inversely correlated with IL-33 expression, while miR-378c does not show a significant difference. To evaluate the effect of TNFα on the studied microRNAs, aUC patients with anti-TNF therapy were compared to aUC receiving other treatments. The levels of miR-378a-3p and miR-378c were higher in aUC patients with anti-TNF. Based on these findings, we selected miR-378a-3p to exploring the molecular mechanism involved by in vitro assays, showing that over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence ß-gal-reporter gene in HEK293 cells. Stable miR-378a-3p over-expression/inhibition inversely modulated IL-33 content and altered viability of HT-29 cells. Additionally, in an inflammatory context, TNFα decreased miR-378a-3p levels in HT-29 cells enhancing IL-33 expression. Together, our results propose a regulatory mechanism of IL-33 expression exerted by miR-378a-3p in an inflammatory environment, contributing to the understanding of UC pathogenesis.

2.
J Cell Physiol ; 234(8): 13659-13679, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30637720

RESUMO

Osteosarcomas are bone tumors that frequently metastasize to the lung. Aberrant expression of the transcription factor, runt-related transcription factor 2 (RUNX2), is a key pathological feature in osteosarcoma and associated with loss of p53 and miR-34 expression. Elevated RUNX2 may transcriptionally activate genes mediating tumor progression and metastasis, including the RUNX2 target gene osteopontin (OPN/SPP1). This gene encodes a secreted matricellular protein produced by osteoblasts to regulate bone matrix remodeling and tissue calcification. Here we investigated whether and how the RUNX2/OPN axis regulates lung metastasis of osteosarcoma. Importantly, RUNX2 depletion attenuates lung metastasis of osteosarcoma cells in vivo. Using next-generation RNA-sequencing, protein-based assays, as well as the loss- and gain-of-function approaches in selected osteosarcoma cell lines, we show that osteopontin messenger RNA levels closely correlate with RUNX2 expression and that RUNX2 controls the levels of secreted osteopontin. Elevated osteopontin levels promote heterotypic cell-cell adhesion of osteosarcoma cells to human pulmonary microvascular endothelial cells, but not in the presence of neutralizing antibodies. Collectively, these findings indicate that the RUNX2/OPN axis regulates the ability of osteosarcoma cells to attach to pulmonary endothelial cells as a key step in metastasis of osteosarcoma cells to the lung.

3.
Rev. chil. infectol ; 34(5): 468-475, oct. 2017. graf
Artigo em Espanhol | LILACS-Express | ID: biblio-899744

RESUMO

Resumen A 46 años de la identificación de los primeros polyomavirus en humanos (PyV), la preocupación por encontrar nuevos tipos relacionados a patologías de distintos órganos en pacientes inmunosuprimidos persiste. Hasta el momento de esta revisión, 15 PyV han sido descritos, muchos de ellos sin estar claramente asociados a enfermedades. En nuestro país, al igual que en gran parte de Sudamérica, el conocimiento y la pesquisa de estos agentes infecciosos son insuficientes por lo que sistematizamos aquello que se sabe sobre estos virus y su relación con los diferentes sistemas del cuerpo humano, con énfasis en los inmunosuprimidos y señalamos aquellos datos publicados en nuestro continente. Esperamos así incentivar un mayor estudio de estas infecciones virales.


Forty-six years after the identification of the first polyomaviruses in humans (PyV) still there are strong concerns to find new types related to pathologies of different organs in immunocompromised patients. At the time of this review, 15 PyV have been described, many of them without being clearly associated with diseases. In our country, as in much of South America, the knowledge and research of these infectious agents are insufficient, so we systematized what is known about these viruses and their relationship with different human systems with emphasis on immunocompromised and we pointed out data published in our continent. Thus, we hope to encourage the study of these infections.

4.
Sci Rep ; 7(1): 10180, 2017 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-28860510

RESUMO

The ST2/IL33 signalling pathway has been associated with ulcerative colitis (UC). ST2, encoded by the IL1RL1 gene, is expressed as both a membrane-anchored receptor (ST2L) activated by IL33 and as a soluble receptor (sST2) with anti-inflammatory properties. In UC patients, sST2 is further increased by corticosteroid treatment; however, the glucocorticoid-mediated molecular regulation remains unknown. We therefore tested whether genetic variants in the IL1RL1 distal promoter are involved in UC and affect glucocorticoid-mediated ST2 expression. Serum ST2 levels and genetic variants in the IL1RL1 distal promoter were examined by ELISA and PCR sequencing in UC patients receiving corticosteroids. Glucocorticoid-mediated ST2 production was evaluated in intestinal mucosa cultures. Molecular regulation of glucocorticoid-mediated ST2 was assessed by RT-qPCR, ChIP assay and luciferase reporter assay. Dexamethasone effect on ST2 transcript expression was analyzed in leukocytes and related to IL1RL1 variants. Sequencing of a distal IL1RL1 promoter region demonstrated that SNPs rs6543115(C) and rs6543116(A) are associated with increased sST2 in UC patients on corticosteroids. Dexamethasone up-regulated sST2 transcription through interaction with the glucocorticoid-response element (GRE) carrying rs6543115(C) variant. Our data indicate that IL1RL1 SNPs rs6543115(C) confer susceptibility to UC and is contained in the GRE, which may modulate glucocorticoid-induced sST2 expression.


Assuntos
Corticosteroides/farmacologia , Colite Ulcerativa/tratamento farmacológico , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Polimorfismo de Nucleotídeo Único , Regulação para Cima , Corticosteroides/uso terapêutico , Adulto , Células Cultivadas , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/efeitos dos fármacos , Análise de Sequência de DNA
5.
Molecules ; 22(7)2017 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-28678175

RESUMO

The molybdenum cluster [Mo6Cl14]2- is a fluorescent component with potential for use in cell labelling and pharmacology. Biological safety and antiviral properties of the cluster are as yet unknown. Here, we show the effect of acute exposition of human cells and red blood cells to the molybdenum cluster and its interaction with proteins and antiviral activity in vitro. We measured cell viability of HepG2 and EA.hy926 cell lines exposed to increasing concentrations of the cluster (0.1 to 250 µM), by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Hemolysis and morphological alterations of red blood cells, obtained from healthy donors, exposed to the cluster (10 to 200 µM) at 37 °C were analyzed. Furthermore, quenching of tryptophan residues of albumin was performed. Finally, plaque formation by rotavirus SA11 in MA104 cells treated with the cluster (100 to 300 µM) were analyzed. We found that all doses of the cluster showed similar cell viability, hemolysis, and morphology values, compared to control. Quenching of tryptophan residues of albumin suggests a protein-cluster complex formation. Finally, the cluster showed antiviral activity at 300 µM. These results indicate that the cluster [Mo6Cl14]2- could be intravenously administered in animals at therapeutic doses for further in vivo studies and might be studied as an antiviral agent.


Assuntos
Antivirais/farmacologia , Molibdênio/química , Compostos Organometálicos/farmacologia , Rotavirus/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise , Células Hep G2 , Humanos , Técnicas In Vitro , Compostos Organometálicos/química , Albumina Sérica Humana/metabolismo
6.
Rev Chilena Infectol ; 34(5): 468-475, 2017 Oct.
Artigo em Espanhol | MEDLINE | ID: mdl-29488589

RESUMO

Forty-six years after the identification of the first polyomaviruses in humans (PyV) still there are strong concerns to find new types related to pathologies of different organs in immunocompromised patients. At the time of this review, 15 PyV have been described, many of them without being clearly associated with diseases. In our country, as in much of South America, the knowledge and research of these infectious agents are insufficient, so we systematized what is known about these viruses and their relationship with different human systems with emphasis on immunocompromised and we pointed out data published in our continent. Thus, we hope to encourage the study of these infections.


Assuntos
Imunocompetência/imunologia , Hospedeiro Imunocomprometido/imunologia , Infecções por Polyomavirus/imunologia , Polyomavirus/classificação , Polyomavirus/patogenicidade , Humanos , América do Sul
7.
Rev Chilena Infectol ; 33(3): 298-302, 2016 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-27598279

RESUMO

INTRODUCTION: Polyomavirus BK (BKPyV) and JC (JCPyV) are persistent pathogens able to reactivate in im-munocompromised patients, involving mostly urinary and central nervous system. There are no Chilean studies in HIV positive patients. OBJECTIVE: To detect BKPyV and JCPyV in blood of Chilean HIV positive adult patients and to correlate these results with clinical-related variables. MATERIALS AND METHODS: 96 stored blood samples from HIV patients belonging to the north area of Santiago were analyzed. Viral genomes of both viruses were detected by real-time PCR. For statistical analysis, chi-square (Pearson) and Mann-Whitney tests were used and p-values < 0.05 were considered significant. RESULTS: 33% of the samples were positive for BKPyV and a significant correlation was found between the presence of BKPyV genome and the absence of detectable HIV viral load. We demonstrated the need to consider more than one amplification target to detect the BKPyV genome. All the samples were negative for JCPyV genome. DISCUSSION: BKPyV prevalence in Chilean HIV patients is higher than most of international studies. New studies regarding the interaction between both viruses are required. These patients should undergo periodic evaluations by urologist and nephrologist.


Assuntos
Vírus BK/isolamento & purificação , Infecções por HIV/virologia , Vírus JC/isolamento & purificação , Leucócitos/virologia , Adolescente , Adulto , Fatores Etários , Idoso , Chile , Eletroforese em Gel de Ágar , Feminino , Genoma Viral , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Fatores Sexuais , Estatísticas não Paramétricas , Carga Viral , Adulto Jovem
8.
Rev. chil. infectol ; 33(3): 298-302, jun. 2016. ilus, tab
Artigo em Espanhol | LILACS-Express | ID: lil-791023

RESUMO

Introducción: Polyomavirus BK (BKPyV) y JC (JCPyV) son patógenos persistentes con capacidad de reactivación en inmunocomprometidos, afectando principalmente el sistema urinario y el sistema nervioso central, respectivamente. No existen estudios chilenos en población infectada por VIH. Objetivo: Detectar la presencia de BKPyV y JCPyV en muestras de sangre de pacientes adultos, chilenos, con infección por VIH y correlacionar los resultados con variables clínicas. Materiales y Métodos: Analizamos 96 muestras de extractos leucocitarios de pacientes del área norte de Santiago. El genoma viral se detectó mediante RPC en tiempo real. Para el análisis estadístico se utilizó las pruebas chi-cuadrado de Pearson y Mann-Whitney, considerando significativo un valor de p < 0,05. Resultados: 33% de las muestras resultaron positivas para BKPyV y se encontró una correlación significativa entre la presencia de genoma de BKPyV y la ausencia de carga viral de VIH. Se evidenció la necesidad de considerar más de un blanco de amplificación del genoma de BKPyV. Todas las muestras fueron negativas para JCPyV. Discusión: La prevalencia de BKPyV en pacientes chilenos con infección por VIH es superior a la informada en la mayoría de los reportes internacionales. Se requiere estudios que evalúen la interacción entre ambos virus. Estos pacientes deberían ser sometidos a controles urológicos y nefrológicos periódicos.


Introduction: Polyomavirus BK (BKPyV) and JC (JCPyV) are persistent pathogens able to reactivate in im-munocompromised patients, involving mostly urinary and central nervous system. There are no Chilean studies in HIV positive patients. Objective: To detect BKPyV and JCPyV in blood of Chilean HIV positive adult patients and to correlate these results with clinical-related variables. Materials and Methods: 96 stored blood samples from HIV patients belonging to the north area of Santiago were analyzed. Viral genomes of both viruses were detected by real-time PCR. For statistical analysis, chi-square (Pearson) and Mann-Whitney tests were used and p-values < 0.05 were considered significant. Results: 33% of the samples were positive for BKPyV and a significant correlation was found between the presence of BKPyV genome and the absence of detectable HIV viral load. We demonstrated the need to consider more than one amplification target to detect the BKPyV genome. All the samples were negative for JCPyV genome. Discussion: BKPyV prevalence in Chilean HIV patients is higher than most of international studies. New studies regarding the interaction between both viruses are required. These patients should undergo periodic evaluations by urologist and nephrologist.

9.
PLoS One ; 10(4): e0123029, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25830243

RESUMO

We have previously shown a functional interaction between human papillomavirus type 16 (HPV-16) E6 and E7 oncoproteins and cigarette smoke condensate (CSC) in lung cells suggesting cooperation during carcinogenesis. The molecular mechanisms of such interaction, however, remain to be elucidated. Here we first present evidence showing that cigarette smoke condensate (CSC) has the ability to activate the HPV-16 p97 promoter by acting on the long control region (LCR) in lung epithelial cells. Interestingly, we observed that CSC-induced p97 promoter activation occurs in a dose-dependent manner in both tumor A-549 (lung adenocarcinoma), H-2170 (bronchial carcinoma), SiHa or Hela (cervical carcinoma) cells but not in non-tumor BEAS-2B (bronchial) or NL-20 (alveolar) lung cells unless they ectopically expressed the HPV-16 E6 and E7 oncogenes. In addition, we also observed a significant increase of primary DNA damage in tumor and non-tumor CSC-treated lung cells expressing HPV-16 E6 and E7 oncogenes suggesting a cooperative effect in this process, even though the contribution of E7 was significantly higher. Taken together, our results strongly suggest that tobacco smoke is able to induce the activation of the HPV-16 p97 promoter in cooperation with HPV-16 E6 and E7 oncogenes that, in turn, sensitize lung cells to tobacco smoke-induced DNA damage.


Assuntos
Papillomavirus Humano 16/genética , Neoplasias Pulmonares/virologia , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Proteínas Repressoras/genética , Fumar/efeitos adversos , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/virologia , Linhagem Celular Tumoral , Dano ao DNA , Regulação Viral da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Proteínas Oncogênicas Virais/metabolismo , Oxirredução , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Regiões Promotoras Genéticas , Proteínas Repressoras/metabolismo , Risco
10.
J Clin Virol ; 61(1): 138-44, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24994006

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV) and rhinovirus (HRV) are the main cause of acute lower respiratory tract infections (ALRTIs) in infants. Viral and host-related risk factors for severe disease have also not been clearly established. OBJECTIVE: To assess whether certain viral features of RSV and, or HRV are associated with severe ALRTI. STUDY DESIGN: RSV and HRV were studied in nasopharyngeal samples of infants by immunofluorescence, Luminex(®) and/or real-time RT-PCR assays. Quantitation and genotyping of RSV and HRV by PCR were done. RESULTS: Of 124 virus positive specimens, 74 (59.7%) had RSV; 22 (17.7%) HRV and 28 (22.6%) RSV-HRV co-infection. Hospitalization was required in 57/74 RSV infants (77.0%); in 10/22 HRV cases (45.5%) (p=0.006) and in 15/28 co-infected by both viruses (53.6%) (p=0.003). Severe cases were 33/74 (44.6%) RSV infections, 2/22 HRV cases (9.1%), (p<0.002) and 6/28 (21.4%) patients co-infected by RSV-HRV (p<0.026). Three genotypes (NA1, B7, B9) of RSV circulated during the study. In 33 severe infants, NA1 was detected in 19 cases (57.6%); B7 in 13 (39.4%) and B9 in 1 (3.0%) (p<0.01; OR=10.0). RSV loads were similar between outpatients and hospitalized infants (p=0.7) and among different severities (p=0.7). NA1 loads were higher than other strains (p=0.049). Three geno-groups of HRV circulated homogeneously. CONCLUSION: In very young infants, RSV cause more severe disease than HRV. Co-infection does not increase the severity of illness. NA1 RSV genotype was associated with major frequency of hospitalization, severe respiratory disease and higher viral load.


Assuntos
Vírus Sincicial Respiratório Humano/isolamento & purificação , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Rhinovirus/isolamento & purificação , Chile/epidemiologia , Feminino , Genótipo , Humanos , Imunoensaio , Lactente , Masculino , Nasofaringe/virologia , Infecções por Picornaviridae/epidemiologia , Infecções por Picornaviridae/patologia , Infecções por Picornaviridae/virologia , Reação em Cadeia da Polimerase em Tempo Real , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/classificação , Vírus Sincicial Respiratório Humano/genética , Infecções Respiratórias/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rhinovirus/classificação , Rhinovirus/genética , Resultado do Tratamento , Carga Viral
11.
Indian J Sex Transm Dis AIDS ; 32(1): 30-3, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21799573

RESUMO

To identify clinical parameters in association with human papilloma virus (HPV) genotypes and histopathology diagnosis in HIV-positive patients with external condylomata acuminata (ECA), 400 Chilean HIV-positive patients were included in the study. Forty-seven patients presented ECA. Clinical parameters and socio demographic data were recorded. Histopathology study and HPV linear array genotyping assay were performed. Intraepithelial neoplasia (IEN) grade 2 or 3 was found in 8.5% of patients, associated to HPV-16. Patients were mainly single, MSM, with history of sexually transmitted disease (STD), multiple sexual partners, receiving antiretroviral therapy and with recurrent lesions. All ECA were mainly perianal, grey or pink colored, exophytic with less than two years evolution. No clinical parameter could predict the development of high grade IEN in HIV patients with ECA. It seems necessary to perform biopsy and genotype all HIV positive patients with ECA.

12.
Virus Res ; 149(1): 104-8, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20036292

RESUMO

Genomic replication and partial assembly of Rotavirus takes place in cytoplasmic viral structures called viroplasms. NSP5 is a viral phosphoprotein localized in viroplasms and its expression is imperative for viral cycle progress. During infection three isoforms of NSP5 can be observed by SDS-PAGE (26, 28 and 33-35kDa) and previous reports suggested that they differ in their phosphorylation patterns. In this study we obtained NSP5 from infected cells and by mass spectrometry we were able to identify nine phosphorylation sites. We detected that in all the isoforms the same residues can be found either phosphorylated or unmodified. Quantitative analysis showed that the 28kDa isoform has a higher phosphorylation level than the 26kDa isoform suggesting that migration properties depend on the total number of phosphorylated residues. Moreover, we identified two not previously described modifications for this protein: an N-acetylation in Serine-2 and an intramolecular disulfide bond in a highly conserved motif, CXXC which is located between two charged alpha-helix motifs.


Assuntos
Espectrometria de Massas , Rotavirus/fisiologia , Proteínas não Estruturais Virais/química , Replicação Viral , Acetilação , Sequência de Aminoácidos , Animais , Dissulfetos , Macaca mulatta , Dados de Sequência Molecular , Peso Molecular , Fosforilação , Isoformas de Proteínas/química , Rotavirus/química , Alinhamento de Sequência , Proteínas não Estruturais Virais/isolamento & purificação
13.
J Med Virol ; 81(2): 340-4, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19107972

RESUMO

Human metapneumovirus (hMPV) is a significant cause of acute lower respiratory tract infection in all age groups, particularly in children. Two genetic groups and four subgroups of hMPV have been described. They co-circulate during an epidemic in variable proportions. The aims were to characterize the genotypes of hMPV recovered from children hospitalized for acute lower respiratory tract infection and to establish the molecular epidemiology of strains circulating in Santiago of Chile during a 2-year period. The detection of the N gene by reverse-transcription polymerase chain reaction was carried out for screening 545 infants hospitalized for acute lower respiratory tract infection in Santiago during 2003-2004. The genetic typing of hMPV was performed by analyzing the fusion gene sequences. hMPV was detected in 10.2% (56/545 cases). Phylogenetic analysis of F gene sequences from 39 Chilean hMPV strains identified the two groups and four subgroups previously described. Strains clustered into group A were split further into the sub lineages A1, A2, and A3. Most Chilean strains clustered into the proposed novel A3 sub lineage (59%). A3 viruses were present in both years, while A1 and A2 circulated just in 1 year. In conclusion, hMPV is a relevant cause of acute lower respiratory infection in Chilean children and the potential novel cluster of group A emphasize the need for further regional genetic variability studies.


Assuntos
Variação Genética , Metapneumovirus/genética , Infecções por Paramyxoviridae/virologia , Infecções Respiratórias/virologia , Chile/epidemiologia , Humanos , Lactente , Recém-Nascido , Metapneumovirus/classificação , Metapneumovirus/isolamento & purificação , Infecções por Paramyxoviridae/epidemiologia , Filogenia , RNA Viral/genética , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/genética , Fatores de Tempo
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