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1.
Viruses ; 13(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34452405

RESUMO

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.


Assuntos
Antivirais/uso terapêutico , Dengue/tratamento farmacológico , Transcriptoma , Adenosina Trifosfatases/antagonistas & inibidores , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/uso terapêutico , Antivirais/farmacologia , Encéfalo/metabolismo , Simulação por Computador , Dengue/sangue , Dengue/genética , Dengue/metabolismo , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Fígado/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , NF-kappa B/metabolismo , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Dengue Grave/sangue , Dengue Grave/tratamento farmacológico , Dengue Grave/genética , Dengue Grave/metabolismo , Baço/metabolismo
2.
Open Forum Infect Dis ; 7(10): ofaa407, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33123608

RESUMO

Early recognition of severe forms of coronavirus disease 2019 (COVID-19) is essential for an opportune and effective intervention, reducing life-risking complications. An altered inflammatory immune response seems to be associated with COVID-19's pathogenesis and progression to severity. Here we demonstrate the utility of early nasopharyngeal swab samples for detection of the early expression of immune markers and the potential value of CCL2/MCP-1 in predicting disease outcome.

3.
Rev. inf. cient ; 99(4): 321-330, jul.-ago. 2020. tab
Artigo em Espanhol | LILACS | ID: biblio-1139192

RESUMO

RESUMEN Introducción: La lucha contra la tuberculosis es una responsabilidad social y profesional que requiere de su caracterización, la que no se ha realizado en Guantánamo en la última década. Objetivo: Caracterizar la tuberculosis en pacientes de la provincia Guantánamo durante el periodo comprendido entre 2012 y 2019. Método: El universo se constituyó por el total de pacientes diagnosticados (n=136). Se estudiaron las siguientes variables: edad, sexo, localización de la enfermedad, resultados de la baciloscopía, categoría al egreso y grupos de riesgo de tuberculosis. La información se obtuvo mediante los registros de enfermedades de declaración obligatoria cada año, y las encuestas epidemiológicas de los controles de focos realizados, y se resumió en números absolutos y porcentajes. Resultados: En el 80,1 % de los casos la tuberculosis se localizó en los pulmones, y fue más común el diagnóstico de pacientes con baciloscopía positiva (63,2 %). El 76,7 % de los pacientes con baciloscopía positiva fueron masculinos. Los grupos de riesgos para tuberculosis más usuales fueron: fumadores (26,4 %), inmunodeprimidos (21,6 %) y el alcoholismo (19,1 %). Conclusiones: En la provincia Guantánamo prevalece la tuberculosis de localización pulmonar y los pacientes con bacteriología positiva. Los afectados sobre todo son hombres, tienen edad entre 45 a 54 años y son de reciente diagnóstico. La enfermedad incide más en aquellos con antecedente de ser fumadores, inmunodeprimidos y los alcohólicos.


ABSTRACT Introduction: The fight against tuberculosis is a social and professional responsibility, which requires its characterization, which has not been carried out in Guantánamo in the last decade. Objective: To characterize tuberculosis in patients in the Guantánamo province during the period between 2012 and 2019. Method: The universe was made up of the total number of diagnosed patients (n = 136). The following variables were studied: age, sex, location of the disease, smear results, category at discharge, and tuberculosis risk groups. The information was obtained through the notifiable disease registries for each year and the epidemiological surveys of the outbreak controls carried out, and was summarized in absolute numbers and percentages. Results: In 80.1% of cases, tuberculosis is in the lungs, and the diagnosis of patients with positive smear microscopy (63.2%) is more common. 76.7% of smear-positive patients are male. The most common risk groups for tuberculosis are: smokers (26.4%), immunosuppressed (21.6%) and alcoholism (19.1%). Conclusions: In Guantánamo province, pulmonary localization tuberculosis and patients with positive bacteriology prevail. Those affected are mainly men, they are between 45 and 54 years old and have recently been diagnosed. The disease affects more in those with a history of being smokers, immunosuppressed and alcoholics.


Assuntos
Humanos , Tuberculose/classificação , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Fatores de Risco , Tuberculose Pulmonar , Estudo Observacional
4.
Biomolecules ; 10(4)2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283759

RESUMO

The relationship of uric acid with macrophages has not been fully elucidated. We investigated the effect of uric acid on the proinflammatory ability of human macrophages and then examined the possible molecular mechanism involved. Primary human monocytes were differentiated into macrophages for subsequent exposure to 0, 0.23, 0.45, or 0.9 mmol/L uric acid for 12 h, in the presence or absence of 1 mmol/L probenecid. Flow cytometry was used to measure proinflammatory marker production and phagocytic activity that was quantified as a percentage of GFP-labeled Escherichia coli positive macrophages. qPCR was used to measure the macrophage expression of the urate anion transporter 1 (URAT1). As compared to control cells, the production of tumor necrosis factor-alpha (TNF-alpha), toll-like receptor 4 (TLR4), and cluster of differentiation (CD) 11c was significantly increased by uric acid. In contrast, macrophages expressing CD206, CX3C-motif chemokine receptor 1 (CX3CR1), and C-C chemokine receptor type 2 (CCR2) were significantly reduced. Uric acid progressively increased macrophage phagocytic activity and downregulated URAT1 expression. Probenecid-a non-specific blocker of URAT1-dependent uric acid transport-inhibited both proinflammatory cytokine production and phagocytic activity in macrophages that were exposed to uric acid. These results suggest that uric acid has direct proinflammatory effects on macrophages possibly via URAT1.


Assuntos
Escherichia coli/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/patologia , Macrófagos/patologia , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Fagocitose/efeitos dos fármacos , Ácido Úrico/toxicidade , Adolescente , Adulto , Receptor 1 de Quimiocina CX3C/metabolismo , Células Cultivadas , Humanos , Interleucina-1beta/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Lectinas de Ligação a Manose/metabolismo , Probenecid/farmacologia , Receptores CCR2/metabolismo , Receptores de Superfície Celular/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
5.
Infect Genet Evol ; 62: 60-72, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29673983

RESUMO

Population genetics theory predicted that rare frequent markers would be the main contributors for heritability of complex diseases, but meta-analyses of genome-wide association studies are revealing otherwise common markers, present in all population groups, as the identified candidate genes. In this work, we applied a population-genetics informed meta-analysis to 10 markers located in seven genes said to be associated with dengue fever disease. Seven markers (in PLCE1, CD32, CD209, OAS1 and OAS3 genes) have high-frequency and the other three (in MICB and TNFA genes) have intermediate frequency. Most of these markers have high discriminatory power between population groups, but their frequencies follow the rules of genetic drift, and seem to have not been under strong selective pressure. There was a good agreement in directional consistency across trans-ethnic association signals, in East Asian and Latin American cohorts, with heterogeneity generated by randomness between studies and especially by low sample sizes. This led to confirm the following significant associations: with DF, odds ratio of 0.67 for TNFA-rs1800629-A; with DHF, 0.82 for CD32-rs1801274-G; with DSS, 0.55 for OAS3-rs2285933-G, 0.80 for PLCE1-rs2274223-G and 1.32 for MICB-rs3132468-C. The overall genetic risks confirmed sub-Saharan African populations and descendants as the best protected against the severer forms of the disease, while Southeast and Northeast Asians are the least protected ones. European and close neighbours are the best protected against dengue fever, while, again, Southeast and Northeast Asians are the least protected ones. These risk scores provide important predictive information for the largely naïve European and North American regions, as well as for Africa where misdiagnosis with other hemorrhagic diseases is of concern.


Assuntos
Dengue/genética , Predisposição Genética para Doença , Regulação da Expressão Gênica , Marcadores Genéticos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
6.
PLoS Pathog ; 13(2): e1006220, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28241052

RESUMO

Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.


Assuntos
Metabolismo dos Lipídeos/genética , Receptores de Esteroides/genética , Receptor X Retinoide alfa/genética , Dengue Grave/genética , Grupo com Ancestrais do Continente Africano/genética , Cuba/etnologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Dengue Grave/etnologia
7.
Rev. colomb. anestesiol ; 45(supl.1): 45-49, Jan.-June 2017. ilus
Artigo em Inglês | LILACS, COLNAL | ID: biblio-900394

RESUMO

Patients with traumatic injuries of the cervical spine who undergo a surgical intervention are a great challenge to the anesthesiologist. The airway management inherently involves movements of the cervical spine that may aggravate pre-existing injury. Currently there is not a consensus for the technique of intubation of these patients. We present three patients with traumatic injuries associated neurological symptoms and cervical spine. All intubations were assisted with fiber bronchoscope, without removing the cervical collar and patients remained awake. All patients were examined again after intubation with no evidence of worsening of their neurological symptoms. We can conclude that the fiberoptic assisted intubation has several advantages in the care of these patients.


Los pacientes con lesiones traumáticas de la columna cervical que se someten a un control quirúrgico de las mismas suponen un gran reto para el anestesiólogo. El manejo de la vía aérea conlleva de forma inherente movimientos de la columna cervical que podrían agravar la lesión preexistente. Actualmente no existe un claro consenso en la técnica de intubación de estos pacientes. Presentamos tres pacientes con lesiones traumáticas de columna cervical y clínica neurológica asociada en los que se indicó cirugía. En todos ellos se realizó una intubación asistida con fibrobroncoscopio con el paciente despierto y sin retirar el collarín cervical. Todos los pacientes fueron nuevamente explorados tras la intubación sin evidenciarse en ninguno de ellos agravamiento de sus síntomas neurológicos. Podemos concluir que la intubación asistida con fibrobroncoscopio presenta varias ventajas en el cuidado de estos pacientes.


Assuntos
Humanos
8.
Microbes Infect ; 16(1): 40-50, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24157267

RESUMO

Any of the four dengue serotypes can cause a severe disease, partly due to systemic inflammation orchestrated by mediators like cytokines and chemokines. We addressed the role of CCR1 and its ligands CCL3/MIP-1α and CCL5/RANTES in dengue infection using three different approaches: an ex vivo model exploring memory immune response in subjects with a well characterized dengue immune background, an in vivo study in patients with primary or secondary dengue infection, and an approach in fatal dengue. CCR1 and CCL3/MIP-1α gene expression showed differences after homotypic and heterotypic challenge according to dengue immune background of subjects, in correspondence with previous observations in Cuban dengue outbreaks. CCL5/RANTES gene expression was higher after homotypic challenge. CCR1 and CCL3/MIP-1α gene expression was higher in patients with secondary infection during critical days of the dengue disease, while the increase in RANTES expression started earlier than the observed for CCR1 and CCL3/MIP-1α. CCR1 and CCL3/MIP-1α gene expression was as high in brain as in spleen tissue from necropsy. Our results confirm the strong influence of previous immunity in subsequent dengue infections, and confer a possible pathogenic role to CCR1 and CCL3/MIP-1α in dengue disease and a possible protective role for CCL5/RANTES, probably through CCR5 interaction.


Assuntos
Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Dengue/metabolismo , Receptores CCR1/metabolismo , Adulto , Encéfalo/metabolismo , Encéfalo/virologia , Quimiocina CCL3/genética , Quimiocina CCL5/genética , Cuba , Dengue/genética , Dengue/imunologia , Vírus da Dengue/imunologia , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Ligantes , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Receptores CCR1/genética , Baço/imunologia , Baço/metabolismo , Baço/virologia , Adulto Jovem
9.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 30(10): 621-623, dic. 2012. tab
Artigo em Espanhol | IBECS | ID: ibc-106386

RESUMO

Introducción Los cambios fisiopatológicos que determinan la severidad del dengue son aún poco conocidos, de ahí la importancia de aclarar su posible relación con la genética del huésped. Métodos Se determinó la posible asociación entre las variantes genéticas del receptor FcγRIIa y signos clínicos en individuos que sufrieron la infección por dengue en 2006 empleando tablas de contingencia. Resultados Solo el sangrado mostró asociación significativa para el genotipo HH (80%). Conclusiones En la infección clínica por dengue el sangrado podría estar relacionado al receptor FcγRIIa-HH (AU)


Introduction: The pathophysiological changes that determine the severity of dengue are still not wellknown, therefore it is important to study the probable relationship with the host genetic. Methods: We analyzed the possible association between the Fc RIIa polymorphism and clinical signs in individuals who suffered dengue infection in 2006, using contingency tables. Results: We found that bleeding was significantly associated to Fc RIIa H/H131 genotype (80%).Conclusion: Our results suggest that in clinical dengue infection the bleeding could be associated toFc RIIa H/H131 genotype (AU)


Assuntos
Humanos , Dengue/complicações , Polimorfismo Genético , Vírus da Dengue/patogenicidade , Dengue Grave/genética , Predisposição Genética para Doença
10.
Am J Trop Med Hyg ; 87(3): 538-47, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22802438

RESUMO

Secondary heterologous dengue infection is a risk factor for severe disease manifestations because of the immune-enhancement phenomenon. Succeeding clinical infections are seldom reported, and the clinical course of tertiary and quaternary dengue infections is not clear. Cuba represents a unique environment to study tertiary/quaternary dengue infections in a population with known clinical and serologic dengue markers and no dengue endemicity. We took advantage of this exceptional epidemiologic condition to study the effect of primary, secondary, tertiary, and quaternary dengue infection exposure on the expression of pro-inflammatory and regulatory cytokines, critical in dengue infection pathogenesis, by using a dengue infection ex vivo model. Whereas secondary exposure induced a high cytokine response, we found a significantly lower expression of tumor necrosis factor-α, interferon-γ, interleukin-10, and tumor growth factor-ß after tertiary and quaternary infectious challenge. Significant differences in expression of the cytokines were seen between the dengue immune profiles, suggesting that the sequence in which the immune system encounters serotypes may be important in determining the nature of the immune response to subsequent infections.


Assuntos
Vírus da Dengue/imunologia , Dengue/sangue , Interferon gama/sangue , Interleucina-10/sangue , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Antígenos Virais/imunologia , Cuba , Dengue/imunologia , Vírus da Dengue/classificação , Estudos Epidemiológicos , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
11.
Enferm Infecc Microbiol Clin ; 30(10): 621-3, 2012 Dec.
Artigo em Espanhol | MEDLINE | ID: mdl-22817980

RESUMO

INTRODUCTION: The pathophysiological changes that determine the severity of dengue are still not well known, therefore it is important to study the probable relationship with the host genetic. METHODS: We analyzed the possible association between the FcγRIIa polymorphism and clinical signs in individuals who suffered dengue infection in 2006, using contingency tables. RESULTS: We found that bleeding was significantly associated to FcγRIIa H/H131 genotype (80%). CONCLUSION: Our results suggest that in clinical dengue infection the bleeding could be associated to FcγRIIa H/H131 genotype.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Dengue Grave/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cuba/epidemiologia , Surtos de Doenças , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/etiologia , Estudos Retrospectivos , Dengue Grave/sangue , Dengue Grave/complicações , Dengue Grave/epidemiologia , Trombocitopenia/etiologia , Adulto Jovem
12.
Hum Immunol ; 72(10): 904-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21762746

RESUMO

Dengue viruses (DV) are one of the most important arthropod-borne viral diseases in the developing world. DV can cause syndromes that are either self-limiting or severe. Allelic variants of human leukocyte antigen (HLA) genes have been demonstrated to be associated with disease susceptibility. Here we report the association of nonclassical HLA class I MICA-MICB genes with disease outcome during DV infection. A sequencing-based typing method and genotyping of MICA and MICB in a well-characterized group of Cuban individuals with dengue hemorrhagic fever (DHF), dengue fever (DF), or asymptomatic dengue infection (ADI) was performed. Statistical analysis revealed a tendency for MICA*008 and MICB*008 to associate with susceptibility to illness when symptomatic versus asymptomatic cases (odds ratio [OR] = 2.1, p(v) = 0.03, and OR = 10.4, p = 0.0096, respectively) were compared. Surprisingly, a stronger association of both allelic forms was observed for the DF patients compared with the ADI group (MICA*008, OR = 5.2, p = 0.0001; and MICB*008, OR = 13.2, p = 0.0025) rather than the severe cases. Major histocompatibility class I-related gene-related natural killer cells and/or γδ and αß T-cell activation might regulate the development of symptomatic DF and DHF.


Assuntos
Vírus da Dengue/imunologia , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Dengue Grave/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Infecções Assintomáticas , Cuba/epidemiologia , Feminino , Frequência do Gene , Genótipo , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Células Matadoras Naturais/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Tipagem Molecular , Polimorfismo Genético , Dengue Grave/epidemiologia , Dengue Grave/imunologia , Dengue Grave/virologia , Índice de Gravidade de Doença , Linfócitos T/imunologia
13.
Int J Infect Dis ; 15(1): e38-43, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21112804

RESUMO

OBJECTIVES: The acute manifestations of dengue are well known. The clinical symptoms that present during the convalescent phase of infection are less well characterized, but may be autoimmune-based. This study was undertaken to determine the prevalence of persistent clinical symptoms among individuals infected during the 2006 Cuban epidemic and to evaluate the immunological and genetic factors associated with their occurrence. METHODS: In 2008, clinical data and blood samples were collected from a random sample of adult individuals diagnosed during the 2006 epidemic with dengue fever (DF, n=68), dengue hemorrhagic fever (DHF, n=29), or an asymptomatic infection (AI, n=42). The presence of persistent symptoms was evaluated in all individuals and a psychological assessment was performed. IgG titers and the Fc receptor (FcR) were also evaluated. The following autoimmune markers were assessed in a subset (n=26) of symptomatic individuals: complement factors C3/C4, rheumatoid factor (RF), C-reactive protein (CRP), antinuclear antibodies (ANA), and immune complex (IC). RESULTS: Over half (55/97) the individuals with a prior of diagnosis of DF or DHF had persistent clinical symptoms in the 2 years following infection. The sequelae were unrelated to the initial diagnosis and were more common among women (44/55). No symptoms were reported in the AI group and all study participants had normal mental and cognitive function. Persistent clinical symptoms were associated with HH polymorphic variant (p=0.027) and high IgG titer (p=0.041). Autoimmune marker alterations were common (20/26) in the subset of symptomatic individuals evaluated. CONCLUSIONS: Clinical sequelae after recovery from an acute dengue virus infection are common in the 2 years following infection. The results obtained in this study suggest that persistent symptoms are associated with alterations in some immunological parameters and FcγRIIa gene polymorphism. This could suggest an autoimmune-based disturbance.


Assuntos
Doenças Autoimunes/virologia , Dengue/complicações , Dengue/imunologia , Adulto , Anticorpos Antivirais/sangue , Doenças Autoimunes/imunologia , Biomarcadores/sangue , Cuba , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores de IgG/genética , Receptores de IgG/imunologia
14.
Dalton Trans ; 39(42): 10186-96, 2010 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-20882255

RESUMO

The synthesis and full characterization of new half-sandwich ruthenium(II) complexes containing κ(3)(N,N,N)-hydridotris(pyrazolyl)borate (κ(3)(N,N,N)-Tp) and the water-soluble phosphanes 1,3,5-triaza-7-phosphatricyclo[3.3.1.1(3,7)]decane (PTA) and 1-methyl-3,5-diaza-1-azonia-7-phosphatricyclo[3.3.1.1(3,7)]decane (1-CH(3)-PTA) has been explored. Single crystal X-ray diffraction analysis for complex [RuCl{κ(3)(N,N,N)-Tp}(PMe(2)Ph)(1-CH(3)-PTA)][CF(3)SO(3)]·2NCMe is also reported. DNA binding properties of the ruthenium complexes have been evaluated by mobility shift assay and MALDI-TOF mass spectrometry. The in vitro antitumor activity of these compounds was assessed by examining their ability to inhibit cell proliferation in a number of human cancer cell lines (NCI-H460, SF-268, MCF-7) and non-tumor human umbilical vein endothelial cells (HUVEC). Some of these new compounds show promising cytotoxic activity with IC(50) values in the low micromolar range, and display differential effects on cancer and normal cell growth.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fosfinas/química , Pirazóis/química , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/genética , DNA/metabolismo , Eletroquímica , Humanos , Compostos Organometálicos/síntese química , Compostos Organometálicos/metabolismo
15.
Hum Immunol ; 71(11): 1135-40, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20732366

RESUMO

Dengue virus infection has emerged as one of the most important arthropod-borne viral diseases. Some dengue infected individuals develop the severe, life-threatening form of the disease, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Host genetic factors may be relevant and may predispose some individuals to the severe illness. Human leukocyte antigen (HLA), FcγR, tumor necrosis factor (TNF)-α, and dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), among others genes have been associated with the pathogenesis of dengue. Little is known, however, about the predictive value of cytokine genotypes for the clinical outcome of dengue infection. In this study, the TNF-α, interleukin (IL)-6, interferon (IFN)-γ, IL-10 and transforming growth factor (TGF)-ß1 gene single nucleotide polymorphisms (SNP) were studied by polymerase chain reaction-sequence-specific primer in a group of individuals with the antecedent of DHF during a secondary infection in the sequence dengue 1/dengue 2. A control group was also included. TNF-α (-308) A allele and IL-10 (-1082/-819/-592) ACC/ATA haplotype were significantly associated with DHF. TNF-α (-308) GG and TGF-ß1 (c25) GG genotypes were associated with protection. Our results suggest that genetic predisposition to a high TNF-α production and a low IL-10 production seems to increase the susceptibility to DHF during a secondary dengue 2 infection, whereas TGF-ß1 high producers might be protected for developing DHF.


Assuntos
Vírus da Dengue/imunologia , Interleucina-10/genética , Dengue Grave/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Vírus da Dengue/patogenicidade , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Valor Preditivo dos Testes , Dengue Grave/genética , Dengue Grave/fisiopatologia , Choque
16.
Cytokine ; 52(3): 175-83, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20650649

RESUMO

Dengue virus has become endemic in most tropical urban areas throughout the world, and DHF has appeared concomitantly with this expansion. The intensity of dengue virus replication during the early stages of infection could determine clinical outcomes; therefore, it is important to understand the impact of dengue virus infection on the earliest immune defense against microbial infection, which also strongly regulates the adaptive immune responses. This study was aimed at evaluating the expression of the CC-chemokines MIP-1α/CCL3 and MCP-1/CCL2 in peripheral blood leukocytes using an ex vivo model resembling dengue infection in vivo, in subjects with a well characterized dengue immune background, due to the exceptional Cuban epidemiological situation in dengue. The expression of IFNγ, TNFα and IL10 was also evaluated, giving insight about the role of MCP-1 and MIP-1α in the interplay between innate and adaptive immunity. From individuals with different dengue immune background after dengue virus challenge, increased and different expression of the chemokines and cytokines studied was verified in peripheral blood mononuclear cells, thus demonstrating that the previous immunity to a dengue virus serotype has a strong influence on the early immune response after dengue re-infection.


Assuntos
Quimiocina CCL2/metabolismo , Quimiocina CCL3/metabolismo , Dengue/imunologia , Modelos Biológicos , Adulto , Dengue/metabolismo , Vírus da Dengue/genética , Vírus da Dengue/isolamento & purificação , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Viral
17.
Am J Trop Med Hyg ; 82(6): 1153-6, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20519616

RESUMO

The role of human Fcgamma receptors (FcgammaR) has been recognized considerably over the last years. These receptors vary in their affinity for IgG subclasses and the intracellular signals elicited by them. Allelic variants of FcgammaR genes may influence the biological phagocyte activity, accounting for an inherited pre-disposition to disease. The specific FcgammaRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated to a reduced risk for developing dengue hemorrhagic fever (DHF). Here, we investigated the role of this polymorphism in a very well-characterized group of Cuban individuals with antecedents of DHF, dengue fever (DF), or subclinical dengue infection. The HH131 genotype was significantly associated with dengue disease, either DF (*P = 0.016; odds ratio = 4.425; 95% confidence interval = 1.10-20.52) or DHF (P = 0.00018; odds ratio = 10.56; 95% confidence interval = 2.33-54.64) with respect to the subclinical infection.


Assuntos
Dengue/diagnóstico , Dengue/imunologia , Receptores de IgG/genética , Receptores de IgG/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Cuba/epidemiologia , Dengue/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem
18.
Bioorg Med Chem ; 18(14): 5301-9, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20538470

RESUMO

The synthesis of new 1,4-bisalkylamino (2-4) and 1-alkylamino-4-chloro (5-6) substituted benzo[g]phthalazines is reported. Compounds 2-4 and 6 were prepared both in the free and heteroaromatic ring protonated forms. Bifunctional 6 contains the 1,4-bisaminopropylpiperazine chain as a linker between the two heteroaromatic units, whereas 5 is its monofunctional analogue. The in vitro antitumour activity of the synthesized compounds has been tested against human colon, breast and lung carcinoma cells, and also against human glioblastoma cells. Results obtained show that all of them are active in all cases, but bifunctional 6.2HCl is remarkably effective against the four cell lines tested, exhibiting IC50 values in the range of 10(-7) M, similar to those found for doxorubicin. The bifunctional structure of 6.2HCl enhances activity with respect to the monofunctional related compounds 5 and 7, leading to the highest activity among all the compounds tested. Molecular modelling of 6 suggests that those results could be indicative of DNA bisintercalation, which should be specially favoured in the diprotonated form 6.2HCl, a compound suitable for being studied more in depth in further biological tests. Measure of the DNA thermal melting curves show that the linear rise in Tm for bifunctional 6.2HCl is nearly twice than that one obtained for monofunctional 5, and supports the DNA-binding hypothesis.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , DNA/metabolismo , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Substâncias Intercalantes/síntese química , Modelos Moleculares , Neoplasias/tratamento farmacológico , Desnaturação de Ácido Nucleico/efeitos dos fármacos , Ftalazinas/síntese química , Ftalazinas/química , Ftalazinas/farmacologia , Piperazina , Piperazinas/síntese química
19.
Cell Immunol ; 262(2): 134-40, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20219186

RESUMO

Increased serum levels of cytokines released by cells of the immune response have been detected in patients suffering from dengue disease. Likewise, secondary infections by a different dengue virus serotype result in a highest risk of development of the severe dengue disease. Both findings suggest that the memory immune response is one of the key players in the pathogenesis of this disease. Here we take advantage of the particular Cuban epidemiological situation in dengue to analyze a broad spectrum of cell-mediated immune response mediators at mRNA and protein level. Evidences for a regulatory immune pattern in homologous (TGF-beta, IL-10) vs. pro-inflammatory pattern (IFN-gamma, TNF-alpha) in heterologous dengue virus re-challenge were found, suggesting a possible association with the higher incidence of severe dengue cases in the latter case.


Assuntos
Dengue/imunologia , Memória Imunológica/imunologia , Inflamação/imunologia , Adulto , Cuba/epidemiologia , Citocinas/sangue , Citocinas/imunologia , Dengue/sangue , Dengue/epidemiologia , Vírus da Dengue/imunologia , Feminino , Humanos , Sistema Imunitário/imunologia , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
20.
Bioorg Med Chem ; 17(17): 6422-31, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19647439

RESUMO

Isocombretastatins A are 1,1-diarylethene isomers of combretastatins A. We have synthesized the isomers of combretastatin A-4, deoxycombretastatin A-4, 3-amino-deoxycombretastatin A-4 (AVE-8063), naphthylcombretastatin and the N-methyl- and N-ethyl-5-indolyl analogues of combretastatin A-4. Analogues with a 2,3,4-trimethoxyphenyl ring instead of the 3,4,5-trimethoxyphenyl ring have also been prepared. The isocombretastatins A strongly inhibit tubulin polymerization and are potent cytotoxic compounds, some of them with IC(50)s in the nanomolar range. This new family of tubulin inhibitors shows higher or comparable potency when compared to phenstatin or combretastatin analogues. These results suggest that one carbon bridges with a geminal diaryl substitution can successfully replace the two carbon bridge of combretastatins and that the carbonyl group of phenstatins is not essential for high potency.


Assuntos
Bibenzilas/química , Moduladores de Tubulina/química , Tubulina (Proteína)/química , Bibenzilas/síntese química , Bibenzilas/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Isomerismo , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/toxicidade
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