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Resultados 1 - 20 de 19.469

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response.

JCI Insight; 2(9)2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28469088


Development of antiviral therapy against acute viral diseases, such as dengue virus (DENV), suffers from the narrow window of viral load detection in serum during onset and clearance of infection and fever. We explored a biomarker approach using 18F-fluorodeoxyglucose (18F-FDG) PET in established mouse models for primary and antibody-dependent enhancement infection with DENV. 18F-FDG uptake was most prominent in the intestines and correlated with increased virus load and proinflammatory cytokines. Furthermore, a significant temporal trend in 18F-FDG uptake was seen in intestines and selected tissues over the time course of infection. Notably, 18F-FDG uptake and visualization by PET robustly differentiated treatment-naive groups from drug-treated groups as well as nonlethal from lethal infections with a clinical strain of DENV2. Thus, 18F-FDG may serve as a novel DENV infection-associated inflammation biomarker for assessing treatment response during therapeutic intervention trials.

A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses.

MBio; 8(3)2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28465426


The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy's potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3- ]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity. The type I interferon system is part of the innate immune response that has evolved in vertebrates as a first line of broad-spectrum immunological defense against an unknowable diversity of microbial, especially viral, pathogens. Here, we characterize a novel small molecule that artificially activates this response and in so doing generates a cellular state antagonistic to growth of currently emerging viruses: Zika virus, Chikungunya virus, and dengue virus. We also show that this molecule is capable of eliciting cellular responses that are predictive of establishment of adaptive immunity. As such, this agent may represent a powerful and multipronged therapeutic tool to combat emerging and other viral diseases.

Conformational and energy evaluations of novel peptides binding to dengue virus envelope protein.

J Mol Graph Model; 74: 273-287, 2017 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-28458006


Effective novel peptide inhibitors which targeted the domain III of the dengue envelope (E) protein by blocking dengue virus (DENV) entry into target cells, were identified. The binding affinities of these peptides towards E-protein were evaluated by using a combination of docking and explicit solvent molecular dynamics (MD) simulation methods. The interactions of these complexes were further investigated by using the Molecular Mechanics-Poisson Boltzmann Surface Area (MMPBSA) and Molecular Mechanics Generalized Born Surface Area (MMGBSA) methods. Free energy calculations of the peptides interacting with the E-protein demonstrated that van der Waals (vdW) and electrostatic interactions were the main driving forces stabilizing the complexes. Interestingly, calculated binding free energies showed good agreement with the experimental dissociation constant (K ) values. Our results also demonstrated that specific residues might play a crucial role in the effective binding interactions. Thus, this study has demonstrated that a combination of docking and molecular dynamics simulations can accelerate the identification process of peptides as potential inhibitors of dengue virus entry into host cells.

Prolonged viremia in dengue virus infection in hematopoietic stem cell transplant recipients and patients with hematological malignancies.

Transpl Infect Dis; 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28475281


Fever, skin rash, headache, and thrombocytopenia are considered hallmarks of dengue infection. However, these symptoms are frequently observed in infectious and non-infectious complications of hematopoietic stem cell transplant recipients and oncohematological patients. Thus, laboratory confirmation of dengue is relevant for prompt intervention and proper management of dengue in endemic and non-endemic regions. Because no prospective study of dengue has been conducted in these populations, the actual morbidity and mortality of dengue is unknown. In the present series, we describe five cases of dengue in patients living in endemic areas, emphasizing the prolonged course of the disease and the occurrence of prolonged viremia. This article is protected by copyright. All rights reserved.

Simultaneous detection of chikungunya virus, dengue virus and human pathogenic Leptospira genomes using a multiplex TaqMan® assay.

BMC Microbiol; 17(1): 105, 2017 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-28468604


BACKGROUND: In 2005-2006 a major epidemics of Chikungunya disease occurred in South-West Indian Ocean islands. In Reunion Island, the magnitude of Chikungunya infection related symptoms was high and with over 38% of serological prevalence in the population. This epidemics illustrated the potential threat of emerging arboviral diseases for inhabitants of Reunion Island and elsewhere since vectors are worldwide distributed. A sentinel surveillance network was set-up to detect emerging pathogens associated with fever over 38 °C and in the absence of known etiologic causes. Leptospirosis is caused by a pathogenic spirochete of the Leptospira genus and is an endemic and recurrent seasonal disease of great concern in Reunion Island. To accurately diagnose potentially infected patients and to advise Health authorities on the presence of emerging pathogens, a rapid diagnostic test was needed that could differentiate between these 3 pathogens. METHODS: A one-step multiplex real-time PCR assay was developed that can simultaneously detect RNA of Chikungunya and Dengue viruses and leptospiral DNA with good performance for a routine diagnostic use. RESULTS: Simplex protocols already published were used with key modifications to implement a triplex assay which was set-up with a small reaction volume to improve cost efficiency. CONCLUSIONS: This approach has enabled greater diagnostic capacity in our laboratory. We established a multiplex approach validated and valuable for cost savings, and with the concurrent detection of 3 pathogens of public health concern.

Modification of -Adenosyl-l-Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation.

Drug Target Insights; 11: 1177392817701726, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28469408


Dengue fever is still a major threat worldwide, approximately threatening two-fifths of the world's population in tropical and subtropical countries. Nonstructural protein 5 (NS5) methyltransferase enzyme plays a vital role in the process of messenger RNA capping of dengue by transferring methyl groups from -adenosyl-l-methionine to N7 atom of the guanine bases of RNA and the RNA ribose group of 2'OH, resulting in -adenosyl-l-homocysteine (SAH). The modification of SAH compound was screened using molecular docking and molecular dynamics simulation, along with computational ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) test. The 2 simulations were performed using Molecular Operating Environment (MOE) 2008.10 software, whereas the ADME-Tox test was performed using various software. The modification of SAH compound was done using several functional groups that possess different polarities and properties, resulting in 3460 ligands to be docked. After conducting docking simulation, we earned 3 best ligands (SAH-M331, SAH-M2696, and SAH-M1356) based on ΔG and molecular interactions, which show better results than the standard ligands. Moreover, the results of molecular dynamics simulation show that the best ligands are still able to maintain the active site residue interaction with the binding site until the end of the simulation. After a series of molecular docking and molecular dynamics simulation were performed, we concluded that SAH-M1356 ligand is the most potential SAH-based compound to inhibit NS5 methyltransferase enzyme for treating dengue fever.

Seroprevalence of Asymptomatic Dengue Virus Infection and Its Antibodies Among Healthy/Eligible Saudi Blood Donors: Findings From Holy Makkah City.

Virology (Auckl); 8: 1-5, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28469422


BACKGROUND: Threat to blood transfusion-transmitted dengue virus (DENV) and its antibodies has recently emerged worldwide. Dengue fever is an endemic disease in Saudi Arabia, particularly in its Western region. The aim of this study was to estimate the seroprevalence of asymptomatic DENV infection and its antibodies among eligible Saudi blood donors. METHODS: Serum samples from 910 healthy/eligible adult male Saudi blood donors, who reside in Holy Makkah City of Saudi Arabia, were collected between March 2015 and August 2016 and screened for the detection of DENV nonstructural protein 1 (NS1) antigen and anti-DENV IgM and IgG antibodies using commercial enzyme-linked immunosorbent assay kits (Panbio, Brisbane, QLD, Australia). RESULTS: Among the tested donors, 48 (5.3%) were seropositive for DENV-NS1 antigen, whereas 50 (5.5%) and 354 (38.9%) were seropositive for anti-DENV IgM and IgG antibodies, respectively. Seropositivity for DENV-NS1 antigen and/or anti-DENV IgM antibody among the tested donors reflects their ongoing asymptomatic viremic infectious stage with DENV during their donation time, whereas high prevalence of anti-DENV IgG seropositivity reflects the high endemicity of dengue disease in this region of Saudi Arabia. CONCLUSIONS: These results show high prevalence of asymptomatic DENV infection and its antibodies among Saudi blood donors, raising the importance of establishing blood screening for dengue disease at different blood donation services and units in Saudi Arabia to improve the guarantee of blood transfusions and to control DENV dissemination.

Cost-Effectiveness of Dengue Vaccination Programs in Brazil.

Am J Trop Med Hyg; 96(5): 1227-1234, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28500811


AbstractThe first approved dengue vaccine, CYD-TDV, a chimeric, live-attenuated, tetravalent dengue virus vaccine, was recently licensed in 13 countries, including Brazil. In light of recent vaccine approval, we modeled the cost-effectiveness of potential vaccination policies mathematically based on data from recent vaccine efficacy trials that indicated that vaccine efficacy was lower in seronegative individuals than in seropositive individuals. In our analysis, we investigated several vaccination programs, including routine vaccination, with various vaccine coverage levels and those with and without large catch-up campaigns. As it is unclear whether the vaccine protects against infection or just against disease, our model incorporated both direct and indirect effects of vaccination. We found that in the presence of vaccine-induced indirect protection, the cost-effectiveness of dengue vaccination decreased with increasing vaccine coverage levels because the marginal returns of herd immunity decreases with vaccine coverage. All routine dengue vaccination programs that we considered were cost-effective, reducing dengue incidence significantly. Specifically, a routine dengue vaccination of 9-year-olds would be cost-effective when the cost of vaccination per individual is less than $262. Furthermore, the combination of routine vaccination and large catch-up campaigns resulted in a greater reduction of dengue burden (by up to 93%) than routine vaccination alone, making it a cost-effective intervention as long as the cost per course of vaccination is $255 or less. Our results show that dengue vaccination would be cost-effective in Brazil even with a relatively low vaccine efficacy in seronegative individuals.

RIG-I-like Receptor Triggering by Dengue Virus Drives Dendritic Cell Immune Activation and T 1 Differentiation.

J Immunol; 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28507028


Dengue virus (DENV) causes 400 million infections annually and is one of several viruses that can cause viral hemorrhagic fever, which is characterized by uncontrolled immune activation resulting in high fever and internal bleeding. Although the underlying mechanisms are unknown, massive cytokine secretion is thought to be involved. Dendritic cells (DCs) are the main target cells of DENV, and we investigated their role in DENV-induced cytokine production and adaptive immune responses. DENV infection induced DC maturation and secretion of IL-1ß, IL-6, and TNF. Inhibition of DENV RNA replication abrogated these responses. Notably, silencing of RNA sensors RIG-I or MDA5 abrogated DC maturation, as well as cytokine responses by DENV-infected DCs. DC maturation was induced by type I IFN responses because inhibition of IFN-α/ß receptor signaling abrogated DENV-induced DC maturation. Moreover, DENV infection of DCs resulted in CCL2, CCL3, and CCL4 expression, which was abrogated after RIG-I and MDA5 silencing. DCs play an essential role in T cell differentiation, and we show that RIG-I and MDA5 triggering by DENV leads to T 1 polarization, which is characterized by high levels of IFN-γ. Notably, cytokines IL-6, TNF, and IFN-γ and chemokines CCL2, CCL3, and CCL4 have been associated with disease severity, endothelial dysfunction, and vasodilation. Therefore, we identified RIG-I and MDA5 as critical players in innate and adaptive immune responses against DENV, and targeting these receptors has the potential to decrease hemorrhagic fever in patients.

Epidemiological and molecular characteristics of emergent dengue virus in Yunnan Province near the China-Myanmar-Laos border, 2013-2015.

BMC Infect Dis; 17(1): 331, 2017 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-28482813


BACKGROUND: Yunnan Province is located in southwestern China and neighbors the Southeast Asian countries, all of which are dengue-endemic areas. In 2000-2013, sporadic imported cases of dengue fever (DF) were reported almost annually in Yunnan Province. During 2013-2015, we confirmed that a large-scale indigenous DF outbreak emerged in cities of Yunnan Province near the China-Myanmar-Laos border. METHODS: Epidemiological characteristics of DF in Yunnan Province during 2013-2015 were evaluated by retrospective analysis. A total of 232 dengue virus (DENV)-positive sera were randomly collected for sequence analysis of the capsid/premembrane region of DENV from patients with DF in Yunnan Province. The envelope gene of DENV isolates was also amplified and sequenced. Phylogenetic analyses were performed using the neighbor-joining method with the Tajima-Nei model. RESULTS: Phylogenetically, all DENV-positive samples could be classified into DENV-1 genotype I and DENV-2 Asian I genotype during 2013-2015 and DENV-4 genotype I in 2015 from Ruili City; and DENV-3 genotype II in 2013 and DENV-2 Cosmopolitan genotype in 2015 from Xishuangbanna Prefecture. CONCLUSIONS: Our results indicated that imported DF from patients from Laos and Myanmar was the primary cause of the DF epidemic in Yunnan Province. Additionally, DENV strains of all four serotypes were identified in indigenous cases in Yunnan Province during the same time period, while the dengue epidemic pattern observed in southwestern Yunnan showed characteristics of a hypoendemic nature: circulation of DENV-1 and DENV-2 over consecutive years.

Dengue Virus Entry and Replication Does Not Lead to Productive Infection in Platelets.

Open Forum Infect Dis; 4(2): ofx051, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28491890


Thrombocytopenia is a characteristic feature during the acute phase of dengue infection and has been found to associate with vascular leakage in severe dengue. Although dengue antigens have been observed in platelets, there is no strong evidence to suggest a direct infection of platelets by dengue virus as a contributing factor for thrombocytopenia. We show that dengue virus can enter platelets but replicate viral ribonucleic acid to a minimal extent and, therefore, cannot produce infectious virus. Dengue antigen was undetectable in platelets isolated from dengue patients; however, we observed an increase in CD14 CD16 monocyte-platelet complexes, suggesting a mechanism for platelet clearance.

Predictors of Dengue-Related Mortality and Disease Severity in a Tertiary Care Center in North India.

Open Forum Infect Dis; 4(2): ofx056, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28491893


BACKGROUND: There is lack of reliable predictors of disease severity and mortality in dengue. The present study was carried out to identify these predictors during the 2015 outbreak in India. METHODS: This prospective observational study included confirmed adult dengue patients hospitalized between August and November 2015 in a tertiary care centre in New Delhi, India. Appropriate statistical tests were used to compare clinicolaboratory characteristics, derive predictors of severe disease and mortality, and compute a predictive score for mortality. Serotyping was done. RESULTS: Data of 369 patients were analyzed (mean age, 30.9 years; 67% males). Of these, 198 (54%) patients had dengue fever, 125 (34%) had dengue hemorrhagic fever (grade 1 or 2), and 46 (12%) developed dengue shock syndrome (DSS). Twenty-two (6%) patients died. Late presentation to the hospital (≥5 days after onset) and dyspnea at rest were identified as independent predictors of severe disease. Age ≥24 years, dyspnea at rest and altered sensorium were identified as independent predictors of mortality. A clinical risk score was developed (12*age + 14*sensorium + 10*dyspnea), which, if ≥22, predicted mortality with a high sensitivity (81.8%) and specificity (79.2%). The predominant serotypes in Delhi (2015) were dengue virus DENV2 and DENV4. CONCLUSION: Age ≥24 years, dyspnea at rest, and altered sensorium were identified as independent predictors of mortality. Platelet counts did not determine outcome in dengue patients. Timely referral/access to healthcare is important. The clinical risk score for mortality prediction that was developed in this study can be used in all healthcare settings, after validation in larger cohorts.

Ascertaining the impact of public rapid transit system on spread of dengue in urban settings.

Sci Total Environ; 598: 1151-1159, 2017 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-28499330


Urbanization is an important factor contributing to the global spread of dengue in recent decades, especially in tropical regions. However, the impact of public transportation system on local spread of dengue in urban settings remains poorly understood, due to the difficulty in collecting relevant locality, transportation and disease incidence data with sufficient detail, and in suitably quantifying the combined effect of proximity and passenger flow. We quantify proximity and passenger traffic data relating to 2014-2015 dengue outbreaks in Kaohsiung, Taiwan by introducing a "Risk Associated with Metro Passengers Presence" (RAMPP), which considers the passenger traffic of stations located within a fixed radius, giving more weight to the busier and/or closer stations. In order to analyze the contagion risk associated with nearby presence of one or more Kaohsiung Rapid Transit (KRT) stations, we cluster the Li's (the fourth level administrative subdivision in Taiwan) of Kaohsiung based on their RAMPP value using the K-means algorithm. We then perform analysis of variance on distinct clusterings and detect significant differences for both years. The subsequent post hoc tests (Dunn) show that yearly incidence rate observed in the areas with highest RAMPP values is always significantly greater than that recorded with smaller RAMPP values. RAMPP takes into account of population mobility in urban settings via the use of passenger traffic information of urban transportation system, that captures the simple but important idea that large amount of passenger flow in and out of a station can dramatically increase the contagion risk of dengue in the neighborhood. Our study provides a new perspective in identifying high-risk areas for transmissions and thus enhances our understanding of how public rapid transit system contributes to disease spread in densely populated urban areas, which could be useful in the design of more effective and timely intervention and control measures for future outbreaks.

Neurological complications and death in children with dengue virus infection: report of two cases.

Artigo em Inglês | MEDLINE | ID: mdl-28465676


BACKGROUND: Dengue virus infection can have different complications; the best known is hemorrhagic dengue fever. However, other effects such as neurological disorders may endanger the lives of patients. Dengue neurological manifestations can be confused with encephalitis symptoms and can lead to cerebral edema and death. Therefore, we consider important in the endemic areas to take into account the diagnosis of dengue encephalitis in patients with neurological disorders, and to request the determination of serology in cerebrospinal fluid for the NS1 antigen test. CASE PRESENTATION: We present the cases of two patients from the state of Morelos, Mexico, with 17 and 14 years of age. Both cases presented a rapid evolution characterized by fever, seizures and neurological deterioration secondary to severe cerebral edema that evolved to cerebral death in both cases. The diagnosis of brain death was confirmed by electroencephalogram in both patients. The two patients were submitted to serology for NS1 that tested positive in both cases. They died between the second and fifth day after admission. CONCLUSIONS: Retrospective studies have found that up to 4% of the patients have dengue virus infections, which leads us to believe that in endemic areas, this infection should be suspected in cases of encephalic and febrile symptoms. RT-PCR should be performed to identify cases of encephalitis caused by the dengue virus, and early interventions should be performed to attempt to reduce the morbidity and mortality of these cases.

Differential expression of NADPH oxidase-2 (Nox-2) and nuclear factor-erythroid 2-related factor 2 (Nrf2) transcripts in peripheral blood mononuclear cells isolated from dengue patients.

Virusdisease; 28(1): 54-60, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28466056


The role of oxidative stress in the pathogenesis of dengue infection is not completely known. A recent study reveals the involvement of oxidative stress responsive molecules in the generation of host immune responses to dengue virus in vitro. Objective of the present study was to analyse the changes in the expression of oxidant-antioxidant genes Nox-2 (NADPH oxidase) and Nrf2 (nuclear factor-erythroid 2-related factor 2) in patients with dengue during the early phase of infection compared to other febrile illness (OFI) cases and healthy controls using Real-time qPCR assay. The study enrolled 88 dengue patients, 31 OFI cases, and 63 healthy individuals as controls. Out of 88 dengue cases, 32 were classified as severe dengue cases (SD) and remaining 56 patients as non-severe dengue (NSD). Blood samples were collected firstly at the time of admission and a second sampling was done from the available individuals (38 dengue and 13 OFI cases) at the time of defervescence. Total RNA was extracted from the Peripheral blood mononuclear cells and the transcripts level of Nox-2 and Nrf2 were analysed by qPCR. On DOA, both Nox-2 and Nrf2 expression was found to be down regulated in dengue and OFI cases ( < 0.05) compared to healthy controls. Interestingly at defervescence, the transcript levels were found to be significantly increased in dengue cases unlike OFI, where no such increment was evidenced. From DOA to DOD, the study observed a signficant increase in the levels of Nox-2 transcripts ( < 0.05) both in SD and NSD cases. But a significant Nrf2 activation was not observed in SD cases as we found in NSD cases. Thus  a steady and significant increase in Nox-2 transcript level in severe, non-severe and secondary dengue infected groups observed in the current study supports the earlier reports on the involvement of anti-oxidant response in dengue severity. However further studies on its protein levels and mechanistic action would decipher the exact role of these potential molecules in the disease virulence.

Serum Metabolomics Investigation of Humanized Mouse Model with Dengue Infection.

J Virol; 2017 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-28468882


Dengue is an acute febrile illness caused by dengue virus (DENV) and a major cause of morbidity and mortality in tropical and subtropical regions of the world. The lack of an appropriate small-animal model of dengue infection has greatly hindered the study of dengue pathogenesis and the development of therapeutics. In this study, we conducted a mass spectrometry-based serum metabolic profiling from a humanized mice (humice) model with DENV serotype 2 infection at 0, 3, 7, 14 and 28 days post infection (dpi). Forty-eight differential metabolites were identified, including fatty acids, purines and pyrimidines, acylcarnitines, acylglycines, phospholipids, sphingolipids, amino acid and derivatives, free fatty acids, bile acid, etc. These metabolites showed a reversible change trend - most were significantly perturbed at 3 or 7 dpi and returned to control levels at 14 or 28 dpi, indicating that these metabolites might serve as prognostic markers of the disease in humice. Major perturbed metabolic pathways included purine and pyrimidine metabolism, fatty acid -oxidation, phospholipid catabolism, arachidonic acid and linoleic acid metabolism, sphingolipid metabolism, tryptophan metabolism, phenylalanine metabolism, lysine biosynthesis and degradation, bile acid biosynthesis, etc. Most of these disturbed pathways are similar to our previous metabolomics findings in a longitudinal cohort of adult human dengue patients across different infection stages. Our analyses revealed the commonalities of host responses between humice and human to DENV infections and suggested that humice could be a useful small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics. Dengue virus is the most widespread arbovirus, causing an estimated 390 million dengue infections worldwide every year. As yet, there is currently no effective treatment against the disease, and the lack of an appropriate small-animal model of dengue infection has greatly increased the challenges in the study of dengue pathogenesis and the development of therapeutics. Metabolomics provides global views of small molecule metabolites and is a useful tool of finding metabolic pathways related to disease processes. Here we conducted serum metabolomics study on a humanized mice model, which has significant levels of human platelets, monocytes/macrophages, and hepatocytes, with dengue infection. Forty-eight differential metabolites were identified, and the underlying perturbed metabolic pathways are quite similar to the pathways altered in dengue patients in previous metabolomics studies, indicating that humanized mice could be a highly relevant small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics.

Coffee, its roasted form, and their residues cause birth failure and shorten lifespan in dengue vectors.

Artigo em Inglês | MEDLINE | ID: mdl-28470499


In dengue mosquitoes, successful embryonic development and long lifespan are key determinants for the persistence of both virus and vector. Therefore, targeting the egg stage and vector lifespan would be expected to have greater impacts than larvicides or adulticides, both strategies that have lost effectiveness due to the development of resistance. Therefore, there is now a pressing need to find novel chemical means of vector control. Coffee contains many chemicals, and its waste, which has become a growing environmental concern, is as rich in toxicants as the green coffee beans; these chemicals do not have a history of resistance in insects, but some are lost in the roasting process. We examined whether exposure to coffee during embryonic development could alter larval eclosion and lifespan of dengue vectors. A series of bioassays with different coffee forms and their residues indicated that larval eclosion responses of Aedes albopictus and Ae. aegypti were appreciably lower when embryonic maturation occurred in environments containing coffee, especially roasted coffee crude extract (RCC). In addition, the lifespan of adults derived from eggs that hatched successfully in a coffee milieu was reduced, but this effect was less pronounced with roasted and green coffee extracts (RCU and GCU, respectively). Taken together, these findings suggested that coffee and its residues have embryocidal activities with impacts that are carried over onto the adult lifespan of dengue vectors. These effects may significantly reduce the vectorial capacity of these insects. Reutilizing coffee waste in vector control may also represent a realistic solution to the issues associated with its pollution.

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond.

Nat Rev Drug Discov; 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28473729


Infections with flaviviruses, such as dengue, West Nile virus and the recently re-emerging Zika virus, are an increasing and probably lasting global risk. This Review summarizes and comments on the opportunities for broad-spectrum agents that are active against multiple flaviviruses. Broad-spectrum activity is particularly desirable to prepare for the next flaviviral epidemic, which could emerge from as-yet unknown or neglected viruses. Potential molecular targets for broad-spectrum antiflaviviral compounds include viral proteins, such as the viral protease or polymerase, and host targets that are exploited by these viruses during entry and replication, including α-glucosidase and proteins involved in nucleoside biosynthesis. Numerous compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For other compounds, broad-spectrum activity can be anticipated because of their mode of action and molecular targets.
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