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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.
Front Immunol ; 12: 617251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717109

RESUMO

Typically occurring during secondary dengue virus (DENV) infections, dengue hemorrhagic fever (DHF) causes abnormal immune responses, as well as endothelial vascular dysfunction, for which the responsible viral factor remains unclear. During peak viremia, the plasma levels of virion-associated envelope protein domain III (EIII) increases to a point at which cell death is sufficiently induced in megakaryocytes in vitro. Thus, EIII may constitute a virulence factor for endothelial damage. In this study, we examined endothelial cell death induced by treatment with DENV and EIII in vitro. Notably, pyroptosis, the major type of endothelial cell death observed, was attenuated through treatment with Nlrp3 inflammasome inhibitors. EIII injection effectively induced endothelial abnormalities, and sequential injection of EIII and DENV-NS1 autoantibodies induced further vascular damage, liver dysfunction, thrombocytopenia, and hemorrhage, which are typical manifestations in DHF. Under the same treatments, pathophysiological changes in the Nlrp3 inflammasome-deficient mice were notably reduced compared with those in the wild-type mice. These results suggest that the Nlrp3 inflammasome constitutes a potential therapeutic target for treating DENV-induced hemorrhage in DHF.


Assuntos
Vírus da Dengue/fisiologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Domínios e Motivos de Interação entre Proteínas/imunologia , Dengue Grave/etiologia , Dengue Grave/metabolismo , Proteínas do Envelope Viral/imunologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Autoanticorpos/imunologia , Citocinas/metabolismo , Vírus da Dengue/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Nitrilas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/imunologia , Dengue Grave/patologia
3.
Biomed Res Int ; 2021: 6650596, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628800

RESUMO

Background: Severe dengue (SD), experienced by only a fraction of dengue patients, can be lethal. Due to the lack of early markers that can predict the evolution of SD, all dengue patients have to be monitored under hospital care. We discovered early oxidative stress markers of SD to identify patients who can benefit from early intervention before the symptoms appear. Methods: The expression of inducible nitric oxide synthase (iNOS) in peripheral blood cells (PBC), nitric oxide (NO), and oxidized low-density lipoprotein (oxLDL) levels in plasma and saliva collected at early stages of dengue infection from 20 nonsevere dengue fever (DF) patients and 20 patients who later developed SD were analyzed in a retrospective nested case-control study. Results: The expression of iNOS is significantly (P < 0.05) lower in patients who developed SD than in DF patients at admission within 4 days from fever onset. Median plasma NO concentration within 4 days from fever onset is also significantly (P < 0.05) lower in patients who developed SD (17.9 ± 1.6 µmol/L) than DF (23.0 ± 2.1 µmol/L). Median oxLDL levels in plasma within 3 days from fever onset is significantly (P < 0.05) lower in patients who developed SD (509.4 ± 224.1 ng/mL) than DF (740.0 ± 300.0 ng/mL). Median salivary oxLDL levels are also significantly (P < 0.05) lower in patients who developed SD (0.8 ± 0.5 ng/mL) than DF (3.6 ± 2.6 ng/mL) within 4 days from fever onset. Conclusions: These findings suggest that the expression of iNOS (73% sensitivity, 86% specificity) and plasma NO (96% sensitivity, 61% specificity at 22.3 µmol/L; P < 0.05) may serve as early markers of SD within 3 days from fever onset. Salivary oxLDL levels may serve as early noninvasive markers of SD with a sensitivity and specificity, respectively, of 57% and 91% at 0.9 ng/mL; 76% and 55% at 2.3 ng/mL; and 100% and 50% at 4.6 ng/mL (P < 0.05) within 4 days from fever onset.


Assuntos
Lipoproteínas LDL/análise , Óxido Nítrico Sintase Tipo II/sangue , Óxido Nítrico/análise , Saliva/química , Dengue Grave , Adolescente , Adulto , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estudos Retrospectivos , Sensibilidade e Especificidade , Dengue Grave/diagnóstico , Dengue Grave/epidemiologia , Dengue Grave/genética , Dengue Grave/metabolismo , Adulto Jovem
4.
PLoS One ; 15(8): e0237141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764789

RESUMO

Severe dengue can be lethal caused by manifestations such as severe bleeding, fluid accumulation and organ impairment. This study aimed to investigate the role of dengue non-structural 1 (NS1) protein and host factors contributing to severe dengue. Electrical cell-substrate impedance sensing system was used to investigate the changes in barrier function of microvascular endothelial cells treated NS1 protein and serum samples from patients with different disease severity. Cytokines and metabolites profiles were assessed using a multiplex cytokine assay and liquid chromatography mass spectrometry respectively. The findings showed that NS1 was able to induce the loss of barrier function in microvascular endothelium in a dose dependent manner, however, the level of NS1 in serum samples did not correlate with the extent of vascular leakage induced. Further assessment of host factors revealed that cytokines such as CCL2, CCL5, CCL20 and CXCL1, as well as adhesion molecule ICAM-1, that are involved in leukocytes infiltration were expressed higher in dengue patients in comparison to healthy individuals. In addition, metabolomics study revealed the presence of deregulated metabolites involved in the phospholipid metabolism pathway in patients with severe manifestations. In conclusion, disease severity in dengue virus infection did not correlate directly with NS1 level, but instead with host factors that are involved in the regulation of junctional integrity and phospholipid metabolism. However, as the studied population was relatively small in this study, these exploratory findings should be confirmed by expanding the sample size using an independent cohort to further establish the significance of this study.


Assuntos
Citocinas/sangue , Vírus da Dengue/imunologia , Interações Hospedeiro-Patógeno/imunologia , Dengue Grave/sangue , Proteínas não Estruturais Virais/sangue , Linhagem Celular , Citocinas/imunologia , Citocinas/metabolismo , Vírus da Dengue/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Fosfolipídeos/metabolismo , Cultura Primária de Células , Dengue Grave/imunologia , Dengue Grave/metabolismo , Dengue Grave/patologia , Proteínas não Estruturais Virais/imunologia
5.
Am J Trop Med Hyg ; 102(5): 943-950, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32124729

RESUMO

Dengue is the most common mosquito-borne flaviviral infection in the world today. Several factors contribute and act synergistically to cause severe infection. One of these is dysregulated host immunological mediators that cause transient pathophysiology during infection. These mediators act on the endothelium to increase vascular permeability, which leads to plasma leakage compromising hemodynamics and coagulopathy. We conducted a prospective study to explore the expression of pro- and anti-inflammatory cytokines and how they relate to clinical dengue manifestations, by assessing their dynamics through acute dengue infection in adults admitted to the Hospital for Tropical Diseases, Bangkok, Thailand. We performed cytokine analysis at three phases of infection for 96 hospitalized adults together with serotyping of confirmed dengue infection during the outbreaks of 2015 and 2016. The serum concentrations of seven cytokines (interleukin [IL]-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha, and interferon gamma) were measured in duplicate using a commercial kit (Bio-Plex Human Cytokine Assay). In this study, the cytokine profile was suggestive of a T-helper 2 response. Most patients had secondary infection, and the levels of viremia were higher in patients with plasma leakage than those without plasma leakage. In addition, we observed that bleeding and hepatitis were associated with significantly higher levels of IL-8 during the early phases of infection. Furthermore, IL-6 levels in the early phase of infection were also elevated in bleeding patients with plasma leakage. These results suggest that IL-6 and IL-8 may act in synergy to cause bleeding in patients with plasma leakage.


Assuntos
Citocinas/metabolismo , Dengue/metabolismo , Hemorragia/etiologia , Hepatite Viral Humana/etiologia , Dengue Grave/metabolismo , Adulto , Citocinas/sangue , Dengue/complicações , Dengue/patologia , Feminino , Hemorragia/metabolismo , Hemorragia/virologia , Hepatite Viral Humana/metabolismo , Hepatite Viral Humana/virologia , Humanos , Interferon gama/sangue , Interferon gama/metabolismo , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-4/sangue , Interleucina-4/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Interleucina-8/sangue , Interleucina-8/metabolismo , Masculino , Estudos Prospectivos , Dengue Grave/complicações , Dengue Grave/patologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
6.
Emerg Microbes Infect ; 8(1): 1626-1635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31711408

RESUMO

Dengue fever is one of those unique diseases where host immune responses largely determine the pathogenesis and its severity. Earlier studies have established the fact that dengue virus (DENV) infection causes haemorrhagic fever and shock syndrome, but it is not directly responsible for exhibiting these clinical symptoms. It is noteworthy that clinically, vascular leakage syndrome does not develop for several days after infection despite a robust innate immune response that elicits the production of proinflammatory and proangiogenic cytokines. The onset of hyperpermeability in severe cases of dengue disease takes place around the time of defervescence and after clearance of viraemia. Extracellular vesicles are known to carry biological information (mRNA, miRNA, transcription factors) from their cells of origin and have emerged as a significant vehicle for horizontal transfer of stress signals. In dengue virus infection, the relevance of exosomes can be instrumental since the majority of the immune responses in severe dengue involve heavy secretion and circulation of pro-inflammatory cytokines and chemokines. Here, we present an updated review which will address the unique and puzzling features of hyperpermeability associated with DENV infection with a special focus on the role of secreted extracellular vesicles.


Assuntos
Vírus da Dengue/fisiologia , Exossomos/virologia , Dengue Grave/virologia , Animais , Citocinas/genética , Citocinas/metabolismo , Vírus da Dengue/genética , Exossomos/genética , Exossomos/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Humanos , Dengue Grave/genética , Dengue Grave/metabolismo
7.
Sci Rep ; 9(1): 523, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679503

RESUMO

To detect drug candidates for dengue haemorrhagic fever (DHF), we employed a computational drug repositioning method to perform an integrated multiple omics analysis based on transcriptomic, proteomic, and interactomic data. We identified 3,892 significant genes, 389 proteins, and 221 human proteins by transcriptomic analysis, proteomic analysis, and human-dengue virus protein-protein interactions, respectively. The drug candidates were selected using gene expression profiles for inverse drug-disease relationships compared with DHF patients and healthy controls as well as interactomic relationships between the signature proteins and chemical compounds. Integrating the results of the multiple omics analysis, we identified eight candidates for drug repositioning to treat DHF that targeted five proteins (ACTG1, CALR, ERC1, HSPA5, SYNE2) involved in human-dengue virus protein-protein interactions, and the signature proteins in the proteomic analysis mapped to significant pathways. Interestingly, five of these drug candidates, valparoic acid, sirolimus, resveratrol, vorinostat, and Y-27632, have been reported previously as effective treatments for flavivirus-induced diseases. The computational approach using multiple omics data for drug repositioning described in this study can be used effectively to identify novel drug candidates.


Assuntos
Biologia Computacional/métodos , Reposicionamento de Medicamentos/métodos , Dengue Grave/tratamento farmacológico , Humanos , Terapia de Alvo Molecular/métodos , Mapas de Interação de Proteínas/efeitos dos fármacos , Dengue Grave/genética , Dengue Grave/metabolismo , Transcriptoma/efeitos dos fármacos
8.
Sci Rep ; 8(1): 2688, 2018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29426910

RESUMO

Since the hemorrhage in severe dengue seems to be primarily related to the defect of the platelet, the possibility that dengue virus (DENV) is selectively tropic for one of its surface receptors was investigated. Flow cytometric data of DENV-infected megakaryocytic cell line superficially expressing human glycoprotein Ib (CD42b) and glycoprotein IIb/IIIa (CD41 and CD41a) were analyzed by our custom-written software in MATLAB. In two-dimensional analyses, intracellular DENV was detected in CD42b+, CD41+ and CD41a+ cells. In three-dimensional analyses, the DENV was exclusively detected in CD42b+ cells but not in CD42b- cells regardless of the other expressions. In single-cell virus-protein analyses, the amount of DENV was directly correlated with those of CD42b at the Pearson correlation coefficient of 0.9. Moreover, RT- PCR and apoptosis assays showed that DENV was able to replicate itself and release its new progeny from the infected CD42b+ cells and eventually killed those cells. These results provide evidence for the involvement of CD42b in DENV infection.


Assuntos
Vírus da Dengue/fisiologia , Complexo Glicoproteico GPIb-IX de Plaquetas/fisiologia , Plaquetas/metabolismo , Linhagem Celular , Células Cultivadas , Dengue/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/patogenicidade , Citometria de Fluxo/métodos , Humanos , Megacariócitos/fisiologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Glicoproteína IIb da Membrana de Plaquetas/fisiologia , Dengue Grave/metabolismo , Tropismo , Tropismo Viral/fisiologia
9.
Mediators Inflamm ; 2017: 5197592, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28827898

RESUMO

BACKGROUND: Cytokines play important roles in the physiopathology of dengue infection; therefore, the suppressors of cytokine signaling (socs) that control the type and timing of cytokine functions could be involved in the origin of immune alterations in dengue. OBJECTIVE: To explore the association of cytokine and socs levels with disease severity in dengue patients. METHODS: Blood samples of 48 patients with confirmed dengue infection were analyzed. Amounts of interleukins IL-2, IL-4, IL-6, and IL-10, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α were quantified by flow cytometry, and the relative expression of socs1 and socs3 mRNA was quantified by real-time RT-PCR. RESULTS: Increased levels of IL-10 and socs3 and lower expression of socs1 were found in patients with dengue hemorrhagic fever (DHF) with respect to those with dengue fever (DF) (p < 0.05). Negative correlations were found between socs1 and both IL-10 and socs3 (p < 0.01). The cutoff values of socs3 (>199.8-fold), socs1 (<1.94-fold), and IL-10 (>134 pg/ml) have the highest sensitivity and specificity to discriminate between DF and DHF. CONCLUSION: Simultaneous changes in IL-10 and socs1/socs3 could be used as prognostic biomarkers of dengue severity.


Assuntos
Interleucina-10/metabolismo , Dengue Grave/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Biomarcadores/metabolismo , Feminino , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Masculino , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Semin Immunopathol ; 39(5): 563-574, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28401256

RESUMO

Dengue remains one of the most important mosquito-borne diseases worldwide. Infection with one of the serologically related dengue viruses (DENVs) can lead to a wide range of clinical manifestations and severity. Severe dengue is characterized by plasma leakage and abnormal bleeding that can lead to shock and death. There is currently no specific treatment for severe dengue due to gaps in understanding of the underlying mechanisms. The transient period of vascular leakage is usually followed by a rapid recovery and is suggestive of the effects of short-lived biological mediators. Both the innate and the adaptive immune systems are activated in severe dengue and contribute to the cytokine production. We discuss the immunological events elicited during a DENV infection and identify candidate cytokines that may play a key role in the severe manifestations of dengue and possible interventions.


Assuntos
Citocinas/metabolismo , Vírus da Dengue/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Dengue Grave/imunologia , Dengue Grave/metabolismo , Imunidade Adaptativa , Animais , Humanos , Sistema Imunitário/citologia , Imunidade Inata , Fenótipo , Dengue Grave/diagnóstico , Dengue Grave/virologia , Ativação Viral
11.
Sci Rep ; 7: 44016, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28276456

RESUMO

Dengue haemorrhagic fever (DHF) sometimes occurs after recovery from the disease caused by Dengue virus (DENV), and is often fatal. However, the mechanism of DHF has not been determined, possibly because no suitable methodologies are available to analyse this disease. Therefore, more innovative methods are required to analyse the gene expression profiles of DENV-infected patients. Principal components analysis (PCA)-based unsupervised feature extraction (FE) was applied to the gene expression profiles of DENV-infected patients, and an integrated analysis of two independent data sets identified 46 genes as critical for DHF progression. PCA using only these 46 genes rendered the two data sets highly consistent. The application of PCA to the 46 genes of an independent third data set successfully predicted the progression of DHF. A fourth in vitro data set confirmed the identification of the 46 genes. These 46 genes included interferon- and heme-biosynthesis-related genes. The former are enriched in binding sites for STAT1, STAT2, and IRF1, which are associated with DHF-promoting antibody-dependent enhancement, whereas the latter are considered to be related to the dysfunction of spliceosomes, which may mediate haemorrhage. These results are outcomes that other type of bioinformatic analysis could hardly achieve.


Assuntos
Bases de Dados de Ácidos Nucleicos , Regulação da Expressão Gênica , Dengue Grave/genética , Dengue Grave/metabolismo , Humanos , Dengue Grave/patologia
12.
BMC Syst Biol ; 11(1): 34, 2017 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-28284213

RESUMO

BACKGROUND: Dengue causes considerable morbidity and mortality in Sri Lanka. Inflammatory mediators such as cytokines, contribute to its evolution from an asymptotic infection to severe forms of dengue. The majority of previous studies have analysed the association of individual cytokines with clinical disease severity. In contrast, we view evolution to Dengue Haemorrhagic Fever as the behaviour of a complex dynamic system. We therefore, analyse the combined effect of multiple cytokines that interact dynamically with each other in order to generate a mathematical model to predict occurrence of Dengue Haemorrhagic Fever. We expect this to have predictive value in detecting severe cases and improve outcomes. Platelet activating factor (PAF), Sphingosine 1- Phosphate (S1P), IL-1ß, TNFα and IL-10 are used as the parameters for the model. Hierarchical clustering is used to detect factors that correlated with each other. Their interactions are mapped using Fuzzy Logic mechanisms with the combination of modified Hamacher and OWA operators. Trapezoidal membership functions are developed for each of the cytokine parameters and the degree of unfavourability to attain Dengue Haemorrhagic Fever is measured. RESULTS: The accuracy of this model in predicting severity level of dengue is 71.43% at 96 h from the onset of illness, 85.00% at 108 h and 76.92% at 120 h. A region of ambiguity is detected in the model for the value range 0.36 to 0.51. Sensitivity analysis indicates that this is a robust mathematical model. CONCLUSIONS: The results show a robust mathematical model that explains the evolution from dengue to its serious forms in individual patients with high accuracy. However, this model would have to be further improved by including additional parameters and should be validated on other data sets.


Assuntos
Biologia Computacional/métodos , Citocinas/metabolismo , Progressão da Doença , Modelos Biológicos , Dengue Grave/metabolismo , Análise por Conglomerados , Lógica Fuzzy , Humanos , Dengue Grave/patologia
13.
Antiviral Res ; 141: 7-18, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28188818

RESUMO

High viral load with liver injury is exhibited in severe dengue virus (DENV) infection. Mitogen activated protein kinases (MAPKs) including ERK1/2 and p38 MAPK were previously found to be involved in the animal models of DENV-induced liver injury. However, the role of JNK1/2 signaling in DENV-induced liver injury has never been investigated. JNK1/2 inhibitor, SP600125, was used to investigate the role of JNK1/2 signaling in the BALB/c mouse model of DENV-induced liver injury. SP600125-treated DENV-infected mice ameliorated leucopenia, thrombocytopenia, hemoconcentration, liver transaminases and liver histopathology. DENV-induced liver injury exhibited induced phosphorylation of JNK1/2, whereas SP600125 reduced this phosphorylation. An apoptotic real-time PCR array profiler was used to screen how SP600125 affects the expression of 84 cell death-associated genes to minimize DENV-induced liver injury. Modulation of caspase-3, caspase-8 and caspase-9 expressions by SP600125 in DENV-infected mice suggests its efficiency in restricting apoptosis via both extrinsic and intrinsic pathways. Reduced expressions of TNF-α and TRAIL are suggestive to modulate the extrinsic apoptotic signals, where reduced p53 phosphorylation and induced anti-apoptotic Bcl-2 expression indicate the involvement of the intrinsic apoptotic pathway. This study thus demonstrates the pivotal role of JNK1/2 signaling in DENV-induced liver injury and how SP600125 modulates this pathogenesis.


Assuntos
Antracenos/farmacologia , Fígado/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Dengue Grave/metabolismo , Dengue Grave/patologia , Animais , Antracenos/administração & dosagem , Antracenos/uso terapêutico , Apoptose/efeitos dos fármacos , Caspases/efeitos dos fármacos , Vírus da Dengue/efeitos dos fármacos , Modelos Animais de Doenças , Leucopenia/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/virologia , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Dengue Grave/tratamento farmacológico , Dengue Grave/virologia , Ligante Indutor de Apoptose Relacionado a TNF/genética , Fator de Necrose Tumoral alfa/genética , Carga Viral , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Biomedica ; 36(0): 148-55, 2016 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-27622804

RESUMO

INTRODUCTION: Dengue is currently among the mosquito-borne diseases of greatest global impact. The clinical course of the disease can be unpredictable, so proper handling in its early stages is critical to ensure optimal outcomes.  OBJECTIVE: To evaluate serum regulators of endothelial integrity (VEGF, sICAM-1, sEndoglina, Ang-1, and Ang-2) as predictive markers of dengue severity.  MATERIALS AND METHODS: We conducted a case-control study nested in an appropriate cohort. Endothelial regulator levels were first measured by ELISA, after which analysis was performed using logistic regression of clinical and regulatory variables, with severity as an output variable. A possible severity prediction model, based on the variables of interest and output, was defined using the best area under the ROC curve.  RESULTS: The median subject age was 24 years. Severe cases were associated with Ang-2 serum levels of ≥1,490 ng/ml (OR=3.1; p=0.015). Serum levels of Ang-2 (≥1,490 ng/ml) contributed to the severity prediction model, as did a 0.73 area under the ROC curve, together with the variables rash, impaired consciousness and abdominal pain, with an OR of 3.2 (CI 95%: 1.16 to 8.9; p=0.024).  CONCLUSION: The endothelial regulator Ang-2 could be a predictor of severity in dengue.


Assuntos
Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Biomarcadores/sangue , Dengue/sangue , Dengue Grave/sangue , Angiopoietina-1/química , Estudos de Casos e Controles , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Humanos , Curva ROC , Dengue Grave/metabolismo
15.
Sci Rep ; 6: 31855, 2016 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-27546060

RESUMO

Vascular leakage is a life-threatening complication of dengue virus (DENV) infection. Previously, association between "paracellular" endothelial hyperpermeability and plasma leakage had been extensively investigated. However, whether "transcellular" endothelial leakage is involved in dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) remained unknown. We thus investigated effects of DENV (serotype 2) infection on transcellular transport of albumin, the main oncotic plasma protein, through human endothelial cell monolayer by Western blotting, immunofluorescence staining, fluorescence imaging, and fluorometry. The data showed that Alexa488-conjugated bovine serum albumin (Alexa488-BSA) was detectable inside DENV2-infected cells and its level was progressively increased during 48-h post-infection. While paracellular transport could be excluded using FITC-conjugated dextran, Alexa488-BSA was progressively increased and decreased in lower and upper chambers of Transwell, respectively. Pretreatment with nystatin, an inhibitor of caveolae-dependent endocytic pathway, significantly decreased albumin internalization into the DENV2-infected cells, whereas inhibitors of other endocytic pathways showed no significant effects. Co-localization of the internalized Alexa488-BSA and caveolin-1 was also observed. Our findings indicate that DENV infection enhances caveolae-mediated albumin transcytosis through human endothelial cells that may ultimately induce plasma leakage from intravascular compartment. Further elucidation of this model in vivo may lead to effective prevention and better therapeutic outcome of DHF/DSS.


Assuntos
Cavéolas/metabolismo , Células Endoteliais/metabolismo , Albumina Sérica Humana/metabolismo , Dengue Grave/metabolismo , Permeabilidade Capilar , Linhagem Celular , Vírus da Dengue/fisiologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/virologia , Humanos , Modelos Biológicos , Nistatina/farmacologia , Transcitose/efeitos dos fármacos
17.
An. pediatr. (2003, Ed. impr.) ; 82(1): e165-e169, ene. 2015. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-131704

RESUMO

El dengue es causado por uno de 4 serotipos del virus dengue. En España, solo se han comunicado casos importados. Las manifestaciones clínicas más frecuentes son fiebre y exantema, aunque puede haber formas graves, especialmente en infecciones secundarias. Presentamos a 5 niños con dengue no grave, infección primaria, diagnosticados por sospecha clínica y antecedente epidemiológico mediante inmunocromatografía y ELISA. Evolución favorable en todos los casos. Es importante considerar este diagnóstico en todo viajero internacional que presenta fiebre dentro de los 14 días tras volver de un área endémica, para un diagnóstico precoz, un adecuado tratamiento y un buen pronóstico


Dengue is caused by one of 4 serotypes of dengue virus. Only imported cases have been reported in Spain. The main clinical findings are fever and exanthema, although there may be severe forms, particularly in secondary infections. Five children with a primary, non severe dengue infection are presented. The diagnosis was based on clinical suspicion and epidemiological history, and confirmed by immunochromatography and ELISA tests. The outcome was favourable in all cases. It is important to consider this diagnosis in international travellers that present with fever within the 14 days of returning from an endemic area, in order to get an early diagnosis, adequate treatment and a good prognosis


Assuntos
Humanos , Masculino , Feminino , Criança , Dengue Grave/complicações , Dengue Grave/diagnóstico , Dengue Grave/metabolismo , Infecções por Arbovirus/complicações , Infecções por Arbovirus/diagnóstico , Sinais e Sintomas/classificação , Dengue Grave/classificação , Dengue Grave/prevenção & controle , Infecções por Arbovirus/epidemiologia , Infecções por Arbovirus/prevenção & controle , Infecções por Arbovirus/transmissão , Sinais e Sintomas/métodos , Centros de Saúde
18.
J Infect ; 69(4): 366-74, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24907421

RESUMO

OBJECTIVE: Suppressors of cytokine signalling (SOCS) proteins regulate cytokine responses and control immune balance. The objective of our study was to determine whether the expression of SOCS1 and its potential regulatory microRNAs (miRNAs) in leukocytes is correlated to the development of dengue haemorrhagic fever (DHF). METHODS: We performed a case-control study to investigate the SOCS1 and miRNA expression in leukocytes for patients with DF and DHF in a DENV-2 outbreak that occurred in Taiwan between 2002 and 2003. We performed reverse transcription polymerase chain reaction to evaluate the expression of SOCS1 and its regulatory miRNAs in mononuclear leukocytes obtained from patients with or without DHF. The reciprocal relationship between SOCS1 and miR-150 expression was validated in DENV-2-infected peripheral mononuclear cells (PBMCs). RESULTS: SOCS1 expression and lower IFN-γ level were significantly reduced in DHF patients, but not in patients with DF. Elevated SOCS1 and reduced miR-150 levels were detected 24 h after DENV-2 infection in PBMCs. Transfection of a miR-150 mimic into CD14(+) cells infected with DENV-2 suppressed the induction of SOCS1 expression in a dose-dependent manner. CONCLUSION: We demonstrate for the first time that augmented miR-150 expression with depressed SOCS1 expression in CD14(+) cells are associated with the pathogenesis of DHF.


Assuntos
MicroRNAs/biossíntese , Dengue Grave/genética , Dengue Grave/metabolismo , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Adulto , Idoso , Estudos de Casos e Controles , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Masculino , MicroRNAs/imunologia , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Dengue Grave/imunologia , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
19.
PLoS One ; 9(2): e88944, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24533162

RESUMO

Dengue virus (DENV) infections range from asymptomatic or mild illness to a severe and potentially life threatening disease, dengue hemorrhagic fever (DHF). DHF occurs in primary DENV infections during early infancy. A prospective clinical study of DENV infections during infancy was conducted in San Pablo, Philippines. We found that infants who developed DHF with a primary DENV infection had higher WHO weight-for-age z scores before and at the time of infection compared to infants with primary DENV infections who did not develop DHF. In addition, TLR 7/8-stimulated tumor necrosis factor-α (TNF-α) production from myeloid-derived cells was higher among well-nourished infants. Leptin augmented TLR 7/8-mediated TNF-α production in monocytes and decreased intracellular cAMP levels. Circulating leptin levels were elevated during early infancy and correlated with WHO weight-for-age z scores. Our data support a plausible hypothesis as to why well-nourished infants are at risk for developing DHF with their first DENV infection.


Assuntos
Adiposidade , Modelos Estatísticos , Dengue Grave/epidemiologia , Dengue Grave/metabolismo , Adulto , AMP Cíclico/metabolismo , Humanos , Lactente , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Leptina/sangue , Masculino , Desnutrição/metabolismo , Desnutrição/virologia , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Risco , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
20.
J Biomed Sci ; 20: 42, 2013 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-23806052

RESUMO

Dengue virus (DENV) infection can cause life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage and abnormal hemorrhage are the two major pathogenic changes found in these patients. From previous studies, it is known that both antibodies and cytokines induced in response to DENV infection are involved in the immunopathogenesis of DHF/DSS. However, the role of viral factors during DENV infection remains unclear. Nonstructural protein 1 (NS1), which is secreted in the sera of patients, is a useful diagnostic marker for acute DENV infection. Nevertheless, the roles of NS1 and its antibodies in the pathogenesis of DHF/DSS are unclear. The focus of this review is to evaluate the possible contributions of NS1 and the antibodies it induces to vascular leakage and abnormal hemorrhage during DENV infection, which may provide clues to better understanding the pathogenesis of DHF/DSS.


Assuntos
Anticorpos Antivirais/imunologia , Vírus da Dengue/patogenicidade , Dengue/virologia , Proteínas não Estruturais Virais/metabolismo , Anticorpos Antivirais/sangue , Dengue/imunologia , Dengue/metabolismo , Vírus da Dengue/imunologia , Vírus da Dengue/metabolismo , Humanos , Dengue Grave/imunologia , Dengue Grave/metabolismo , Dengue Grave/virologia
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