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1.
Carbohydr Polym ; 227: 115280, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590855

RESUMO

A water-soluble polysaccharide from Monostroma nitidum, designated MWS, was isolated using water extraction, anion-exchange and size-exclusion chromatography. MWS was a sulfated glucuronorhamnan consisting of →3)-α-l-Rhap-(1→, →4)-ß-d-GlcpA-(1→ and →2)-α-l-Rhap-(1→ units. Sulfate ester groups located at C-4/C-2 of →3)-α-l-Rhap-(1→ and C-4/C-3 of →2)-α-l-Rhap-(1→ units. In in vitro tests, it was proved that MWS possessed broad spectrum against different viruses, especially for enterovirus 71 (EV71) with nearly no toxicity in relation to cell lines used. MWS may largely inhibit EV71 infection before or during viral adsorption through binding to virus particles and block some early steps of virus life cycle by down-regulating host phosphoinositide 3-kinase /protein kinase B signaling pathway. Intramuscular injection of MWS markedly reduced viral titers in EV71-infected mice. The data demonstrated that MWS could have great promising to become an antiviral drug for prevention and therapy of EV71 infection.


Assuntos
Antivirais/uso terapêutico , Clorófitas , Enterovirus Humano A/efeitos dos fármacos , Infecções por Enterovirus/tratamento farmacológico , Mananas/uso terapêutico , Sulfatos/uso terapêutico , Animais , Antivirais/química , Antivirais/farmacologia , Chlorocebus aethiops , Cães , Infecções por Enterovirus/virologia , Feminino , Células Madin Darby de Rim Canino , Mananas/química , Mananas/farmacologia , Camundongos Endogâmicos ICR , Estrutura Molecular , Alga Marinha , Sulfatos/química , Sulfatos/farmacologia , Células Vero
2.
Virol J ; 16(1): 94, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366366

RESUMO

BACKGROUND: Although enterovirus 71 (EV71) is an important public health threat, especially in the Asia-Pacific region, there are still no effective drugs or vaccines to treat and prevent EV71 infection. Therefore, it is critical to develop prophylactic and therapeutic agents against EV71. Rosmarinic acid (RA), a phytochemical, has been discovered to possess a broad spectrum of biological activities. METHODS: The virucidal effects of RA on EV71 were determined by MTT, western blot, median cell culture infectious dose, apoptosis detection, plaque reduction, semi-quantitative real-time polymerase chain reaction, immunofluorescence detection, molecular docking analysis, and mouse protection assay. RESULTS: RA showed a strong protective effect against EV71 infection in human rhabdomyosarcoma cells when the multiplicity of infection was 1, with a low IC50 value (4.33 ± 0.18 µM) and high therapeutic index (340). RA not only protected cells from EV71-induced cytopathic effects, but also from EV71-induced apoptosis. The results of time-of-addition analysis demonstrated that the inhibitory activity of RA was highest at the early stage of viral infection. Consistent with this, the infectivity of EV71 in the early stage of viral infection also was observed to be limited in neonatal mice treated with RA. Further, molecular docking predicts that RA could replace the natural pocket factor within the VP1 capsid-binding hydrophobic pocket. CONCLUSIONS: This study suggests that RA has the potential to be developed as an antiviral agent against initial EV71 infection to prevent or reduce EV71-induced pathogenesis and complications, since RA can effectively reduce EV71 infection in the early stages of viral infection.


Assuntos
Antivirais/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Infecções por Enterovirus/tratamento farmacológico , Animais , Animais Recém-Nascidos , Linhagem Celular Tumoral , Efeito Citopatogênico Viral , Enterovirus Humano A/fisiologia , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Replicação Viral/efeitos dos fármacos
3.
Int J Mol Med ; 44(2): 737-749, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173159

RESUMO

A number of studies have demonstrated that resveratrol (RES) has a variety of biological functions, including cardiovascular protective effects, treatment of mutations, and anti­inflammatory, anti­tumor and antiviral effects. In the present study, RES­loaded nanoparticles (RES­NPs) were used to protect rhabdosarcoma (RD) cells from enterovirus 71 (EV71) infection, and the relevant mechanisms were also explored. An amphiphilic copolymer, monomethoxy poly (ethylene glycol)­b­poly (D,L­lactide), was used as vehicle material, and RES­NPs with necessitated drug­loading content and suitable sizes were prepared under optimized conditions. RES­NPs exhibited the ability to inhibit the increase of intracellular oxidative stress. The prospective mechanism for the function of RES­NPs suggested was that RES­NPs may inhibit the oxidative stress­mediated PERK/eIF2α/ATF4 signaling pathway, downregulate the autophagy pathway and resist EV71­induced RD cells injury. Furthermore, RES­NPs treatment markedly inhibited the secretion of inflammatory factors, including interleukin (IL)­6, IL­8 and tumor necrosis factor­α elicited by EV71 infection. Concomitantly, inhibitors of oxidative stress, endoplasmic reticulum stress (ERS) or autophagy were demonstrated to negate the anti­inflammatory and antiviral effects of RES­NPs on EV71­infected RD cells. These results demonstrated that RES­NPs attenuated EV71­induced viral replication and inflammatory effects by inhibiting the oxidative stress­mediated ERS/autophagy signaling pathway. In view of their safety and efficiency, these RES­NPs have potential applications in protecting RD cells from EV71 injury.


Assuntos
Antivirais/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Resveratrol/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/administração & dosagem , Autofagia/efeitos dos fármacos , Linhagem Celular , Portadores de Fármacos/química , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Humanos , Nanopartículas/química , Resveratrol/administração & dosagem
4.
PLoS Pathog ; 15(5): e1007760, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31071193

RESUMO

Enterovirus A71 (EV-A71) is a non-polio neurotropic enterovirus with pandemic potential. There are no antiviral agents approved to prevent or treat EV-A71 infections. We here report on the molecular mechanism by which a novel class of tryptophan dendrimers inhibits (at low nanomolar to high picomolar concentration) EV-A71 replication in vitro. A lead compound in the series (MADAL385) prevents binding and internalization of the virus but does not, unlike classical capsid binders, stabilize the particle. By means of resistance selection, reverse genetics and cryo-EM, we map the binding region of MADAL385 to the 5-fold vertex of the viral capsid and demonstrate that a single molecule binds to each vertex. By interacting with this region, MADAL385 prevents the interaction of the virus with its cellular receptors PSGL1 and heparan sulfate, thereby blocking the attachment of EV-A71 to the host cells.


Assuntos
Antivirais/farmacologia , Capsídeo/metabolismo , Infecções por Enterovirus/metabolismo , Enterovirus/efeitos dos fármacos , Heparitina Sulfato/metabolismo , Glicoproteínas de Membrana/metabolismo , Triptofano/farmacologia , Antivirais/química , Capsídeo/efeitos dos fármacos , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Dendrímeros/química , Dendrímeros/farmacologia , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/virologia , Células HeLa , Heparitina Sulfato/antagonistas & inibidores , Humanos , Glicoproteínas de Membrana/antagonistas & inibidores , Conformação Proteica , Triptofano/química , Replicação Viral/efeitos dos fármacos
5.
Curr Med Sci ; 39(2): 237-242, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31016516

RESUMO

Few effective treatments for chronic Keshan disease have been available till now. The efficacy of long-term selenium supplementation in the treatment of chronic Keshan disease with congestive heart failure is inconclusive. This study aimed to determine whether selenium supplementation is associated with a decreased risk of cardiac death in chronic Keshan disease with congestive heart failure by ten years of follow-up. A retrospective long-term follow-up analysis was performed on a monitored cohort consisting of 302 chronic Keshan disease patients with a mean age of 40.8±11.4 years. Of the 302 chronic Keshan disease patients, 170 (56.3%) were given selenium supplementation until the end point of follow-up. Cox proportional hazards regression models were used to identify the independent predictors of cardiac events. Our results showed that during the follow-up, there were 101 deaths of patients with chronic Keshan disease in the selenium supplementation group (101/170, 59.4%) and 98 in non-selenium supplementation group (98/132, 74.2%). Multivariate analyses suggested that selenium supplementation was associated with a decreased risk of cardiac death (HR 0.39, 95% CI 0.28-0.53) after adjustment for baseline age, sex, cigarette smoking, family history of Keshan disease, body mass index (BMI), heart rate, electrocardiogram (ECG) abnormalities, blood pressure, initial cardiothoracic ratio, left ventricular ejection fractions (LVEF) and whole-blood selenium concentration. Our ten-year follow-up analysis indicated that selenium supplementation, specifically combined with the use of angiotensin-converting enzyme inhibitor and beta blocker therapy, improved the survival of patients with chronic Keshan disease with congestive heart failure. BMI, selenium deficiency, male, combined ECG abnormalities, LVEF, and fast heart rate increased the risk of cardiac events.


Assuntos
Cardiomiopatias/tratamento farmacológico , Infecções por Enterovirus/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Selênio/administração & dosagem , Adulto , Cardiomiopatias/fisiopatologia , Doença Crônica , Suplementos Nutricionais , Eletrocardiografia/métodos , Infecções por Enterovirus/fisiopatologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos
6.
Diabetologia ; 62(5): 744-753, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30675626

RESUMO

In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.


Assuntos
Antivirais/uso terapêutico , Diabetes Mellitus Tipo 1/virologia , Infecções por Enterovirus/prevenção & controle , Pâncreas/fisiopatologia , Vacinas Virais/uso terapêutico , Imunidade Adaptativa , Autoimunidade , Bancos de Espécimes Biológicos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Infecções por Enterovirus/complicações , Infecções por Enterovirus/tratamento farmacológico , Humanos , Imunidade Inata , Células Secretoras de Insulina/metabolismo , Pâncreas/virologia , Vacinas Virais/economia
7.
J Virol ; 93(7)2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30674624

RESUMO

Enterovirus D68 (EV-D68) is a viral pathogen that leads to severe respiratory illness and has been linked with the development of acute flaccid myelitis (AFM) in children. No vaccines or antivirals are currently available for EV-D68 infection, and treatment options for hospitalized patients are limited to supportive care. Here, we report the expression of the EV-D68 2A protease (2Apro) and characterization of its enzymatic activity. Furthermore, we discovered that telaprevir, an FDA-approved drug used for the treatment of hepatitis C virus (HCV) infections, is a potent antiviral against EV-D68 by targeting the 2Apro enzyme. Using a fluorescence resonance energy transfer-based substrate cleavage assay, we showed that the purified EV-D68 2Apro has proteolytic activity selective against a peptide sequence corresponding to the viral VP1-2A polyprotein junction. Telaprevir inhibits EV-D68 2Apro through a nearly irreversible, biphasic binding mechanism. In cell culture, telaprevir showed submicromolar-to-low-micromolar potency against several recently circulating neurotropic strains of EV-D68 in different human cell lines. To further confirm the antiviral drug target, serial viral passage experiments were performed to select for resistance against telaprevir. An N84T mutation near the active site of 2Apro was identified in resistant viruses, and this mutation reduced the potency of telaprevir in both the enzymatic and cellular antiviral assays. Collectively, we report for the first time the in vitro enzymatic activity of EV-D68 2Apro and the identification of telaprevir as a potent EV-D68 2Apro inhibitor. These findings implicate EV-D68 2Apro as an antiviral drug target and highlight the repurposing potential of telaprevir to treat EV-D68 infection.IMPORTANCE A 2014 EV-D68 outbreak in the United States has been linked to the development of acute flaccid myelitis in children. Unfortunately, no treatment options against EV-D68 are currently available, and the development of effective therapeutics is urgently needed. Here, we characterize and validate a new EV-D68 drug target, the 2Apro, and identify telaprevir-an FDA-approved drug used to treat hepatitis C virus (HCV) infections-as a potent antiviral with a novel mechanism of action toward 2Apro 2Apro functions as a viral protease that cleaves a peptide sequence corresponding to the VP1-2A polyprotein junction. The binding of telaprevir potently inhibits its enzymatic activity, and using drug resistance selection, we show that the potent antiviral activity of telaprevir was due to 2Apro inhibition. This is the first inhibitor to selectively target the 2Apro from EV-D68 and can be used as a starting point for the development of therapeutics with selective activity against EV-D68.


Assuntos
Antivirais/farmacologia , Enterovirus Humano D/efeitos dos fármacos , Infecções por Enterovirus/tratamento farmacológico , Oligopeptídeos/farmacologia , Células A549 , Linhagem Celular , Células HEK293 , Células HeLa , Humanos
8.
Virology ; 526: 146-154, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30390563

RESUMO

Enterovirus D68 (EV-D68) is unique among enteroviruses because of the ability to cause severe respiratory disease as well as neurological disease. We developed separate models of respiratory and neurological disease following EV-D68 infection in AG129 mice that respond to antiviral treatment with guanidine. In four-week-old mice infected intranasally, EV-D68 replicates to high titers in lung tissue increasing the proinflammatory cytokines MCP-1 and IL-6. The respiratory infection also produces an acute viremia. In 10-day-old mice infected intraperitoneally, EV-D68 causes a neurological disease with weight-loss, paralysis, and mortality. In our respiratory model, treatment with guanidine provides a two-log reduction in lung virus titers, reduces MCP-1 and IL-6, and prevents histological lesions in the lungs. Importantly, viremia is prevented by early treatment with guanidine. In our neurological model, guanidine treatment protects mice from weight-loss, paralysis, and mortality. These results demonstrate the utility of these models for evaluation of antiviral therapies for EV-D68 infection.


Assuntos
Antivirais/uso terapêutico , Modelos Animais de Doenças , Enterovirus Humano D , Infecções por Enterovirus/tratamento farmacológico , Guanidina/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Animais , Citocinas/metabolismo , Infecções por Enterovirus/patologia , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/virologia , Masculino , Camundongos , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/virologia , Infecções Respiratórias/patologia , Infecções Respiratórias/fisiopatologia , Infecções Respiratórias/virologia , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Viremia/prevenção & controle
9.
Antiviral Res ; 162: 61-70, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30521834

RESUMO

Enterovirus D68 (EV-D68) is a non-polio enterovirus that affects the respiratory system and can cause serious complications, especially in children and older people with weakened immune systems. As an emerging virus, there are no current antiviral therapies or vaccines available. Our goal was to develop a mouse model of human EV-D68 infection that mimicked the disease observed in humans and could be used for evaluation of experimental therapeutics. This is the first report of a respiratory disease model for EV-D68 infection in mice. We adapted the virus by 30 serial passages in AG129 mice, which are deficient in IFN- α/ß and -γ receptors. Despite a lack of weight loss or mortality in mice, lung function measured by plethysmography, showed an increase in enhanced pause (Penh) on days 6 and 7 post-infection. In addition, as virus adapted to mice, virus titer in the lungs increased 50-fold, and the pro-inflammatory cytokines MCP-1 and RANTES increased 15-fold and 2-fold in the lung, respectively. In addition, a time course of mouse-adapted EV-D68 infection was determined in lung, blood, liver, kidney, spleen, leg muscle, spinal cord and brain. Virus in the lung replicated rapidly after intranasal inoculation of adapted virus, 106 CCID50/mL by 4 h and 108.3 CCID50/mL by 24 h. Virus then spread to the blood and other tissues, including spinal cord and brain. This mouse model for EV-D68 infection includes enhanced pause (Penh) as an indicator of morbidity, and viremia, virus titers and proinflammatory cytokines in the lung, and lung histopathology as indicators of disease. Our mouse-adapted virus has a similar antiviral profile to the original isolate as well as another respiratory picornavirus, rhinovirus-14. This model will be valuable in evaluating experimental therapies in the future.


Assuntos
Modelos Animais de Doenças , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Pulmão/virologia , Infecções Respiratórias/virologia , Animais , Antivirais/uso terapêutico , Quimiocinas/imunologia , Citocinas/imunologia , Enterovirus Humano D , Infecções por Enterovirus/tratamento farmacológico , Feminino , Masculino , Camundongos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/imunologia , Carga Viral , Viremia
10.
Arch Dis Child ; 104(6): 552-557, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30530486

RESUMO

OBJECTIVES: This study aimed to prospectively collect detailed clinical information for all enterovirus (EV) and human parechovirus (HPeV) meningitis cases in infants aged <90 days in the UK and Ireland. PARTICIPANTS, DESIGN AND SETTING: Prospective, active national surveillance during July 2014 to July 2015 through the British Paediatric Surveillance Unit. Reporting paediatricians completed questionnaires requesting information on clinical presentation, investigations, management and outcomes at hospital discharge and after 12 months. MAIN OUTCOME MEASURES: To describe the clinical burden of EV and HPeV meningitis in infants aged <90 days. RESULTS: During the 13-month surveillance period, 703 cases (668 EV, incidence0.79/1,000 live- births; 35 HPeV, 0.04/1,000 live-births) were identified. The most common clinical presentations were fever (EV: 570/668(85%); HPeV: 28/35(80%)), irritability (EV: 441/668(66%); HPeV: 23/35(66%)) and reduced feeding (EV: 363/668(54%); HPeV 23/35(66%)). Features of circulatory shock were present in 27% (182/668) of EV and 43% (15/35) of HPeV cases. Overall, 11% (76/668) of EV and 23% (8/35) of HPeV cases required intensive care support. Nearly all cases (678/703, 96%) were confirmed by cerebrospinal fluid (CSF) PCR, with 52% (309/600) having normal CSF white cell count for age. Two infants with EV meningitis died (2/668, 0.3%) and four survivors (4/666, 0.6%) had long-term complications at 12 months' follow-up. Infants with HPeV meningitis survived without sequelae. Overall 189 infants had a formal hearing test and none had sensorineural hearing loss. CONCLUSION: The incidence of laboratory-confirmed EV/HPeV meningitis in young infants is more than twice that for bacterial meningitis. Less than 1% will develop severe neurological complications or die of their infection. Further studies are required to formally assess long-term neurodevelopmental sequelae.


Assuntos
Infecções por Enterovirus/epidemiologia , Meningite Viral/epidemiologia , Parechovirus , Infecções por Picornaviridae/epidemiologia , Antivirais/uso terapêutico , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/tratamento farmacológico , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Irlanda/epidemiologia , Masculino , Meningite Viral/diagnóstico , Meningite Viral/tratamento farmacológico , Meningite Viral/virologia , Admissão do Paciente/estatística & dados numéricos , Infecções por Picornaviridae/diagnóstico , Infecções por Picornaviridae/tratamento farmacológico , Vigilância da População , Prognóstico , Estudos Prospectivos , Estações do Ano , Resultado do Tratamento , Reino Unido/epidemiologia
11.
Int J Antimicrob Agents ; 53(2): 128-136, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30063999

RESUMO

Human enterovirus 71 (EV-A71) infections cause a wide array of diseases ranging from diarrhoea and rashes to hand-foot-and-mouth disease and, in rare cases, severe neurological disorders. No specific antiviral drug therapy is currently available. Extracts from 75 Chinese medicinal plants selected for antiviral activity based on the Chinese pharmacopeia and advice from traditional Chinese medicine clinicians were tested for activity against EV-A71. The aqueous extract of the rhizome of Cimicifuga heracleifolia (Sheng Ma) and Arnebia euchroma (Zi Cao) showed potent antiviral activity. The active fractions were isolated by bioassay-guided purification, and identified by a combination of high-resolution mass spectrometry and nuclear magnetic resonance. Fukinolic acid and cimicifugic acid A and J, were identified as active anti-EV-A71 compounds for C. heracleifolia, whereas for A. euchroma, two caffeic acid derivatives were tentatively deduced. Commercially available fukinolic acid analogues such as L-chicoric acid and D-chicoric also showed in vitro micromolar activity against EV-A71 lab-strain and clinical isolates.


Assuntos
Antivirais/farmacologia , Boraginaceae/química , Ácidos Cafeicos/farmacologia , Cimicifuga/química , Enterovirus Humano A/efeitos dos fármacos , Fenilacetatos/farmacologia , Extratos Vegetais/farmacologia , Succinatos/farmacologia , Cisteína Endopeptidases , Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/virologia , Humanos , Espectrometria de Massas , Medicina Tradicional Chinesa , Testes de Sensibilidade Microbiana , Ressonância Magnética Nuclear Biomolecular , Proteínas Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos
12.
PLoS One ; 13(9): e0202316, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30192893

RESUMO

BACKGROUND: Our previous study demonstrated that pediatricians prescribe antibiotics without proper clinical justification to patients with enterovirus infection, although antibiotics are not effective in treating the infections caused by these viruses. To improve the quality of healthcare, we aim to evaluate the association of clinical and demographic characteristics of patients and further to identify the determining factors for prescribing antibiotics to children experiencing enterovirus infection. METHODS: We retrospectively reviewed the medical records of children who were hospitalized between January 2008 and December 2016 with a diagnosis of herpangina or hand-foot-mouth disease (HFMD). We identified those children who were prescribed antibiotics for at least 24 hours during admission. We conducted a retrospective descriptive study to analyze data in order to determine the factors associated with pediatrician antibiotics prescribing for enterovirus infection. RESULTS: In the nine years of study period, the rate of antibiotics use was about 13% in these patients. A total of 3659 patients were enrolled during 2008~2012 and analyzed in detail. Elevated levels of C-reactive protein (CRP) and presence of leukocytosis in blood (WBC) were both significantly associated with pediatrician antibiotic prescribing for enterovirus infection (p<0.001). Between different specialistic devisions, there was significantly different proportion of antibiotics utilization for patients. In further analysis of antibiotics prescribing by Receiver operating characteristic (ROC) curve method, the level of CRP significantly had more the area under curve (0.708) compared with the count of WBC (p<0.05). CONCLUSIONS: The present study indicates that higher serum level of CRP is strongly associated with pediatricians prescribing antibiotics for children experiencing herpangina or HFMD. Antibiotic prescribing is a complex process. Pediatricians should be more judicious in decision-making time by their specialistics. Our findings would shed new light on process and allay the concern about inappropriate antibiotics.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Enterovirus/tratamento farmacológico , Enterovirus/efeitos dos fármacos , Padrões de Prática Médica , Adolescente , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Enterovirus/fisiologia , Infecções por Enterovirus/sangue , Infecções por Enterovirus/virologia , Feminino , Doença de Mão, Pé e Boca/sangue , Doença de Mão, Pé e Boca/tratamento farmacológico , Doença de Mão, Pé e Boca/virologia , Herpangina/sangue , Herpangina/tratamento farmacológico , Herpangina/virologia , Humanos , Lactente , Leucocitose/sangue , Masculino , Estudos Retrospectivos
13.
J Med Chem ; 61(18): 8402-8416, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30153009

RESUMO

Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 µM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.


Assuntos
Antivirais/química , Antivirais/farmacologia , Desenho de Fármacos , Infecções por Enterovirus/tratamento farmacológico , Pirazóis/química , Rhinovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Infecções por Enterovirus/virologia , Células HeLa , Humanos , Masculino , Testes para Micronúcleos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Rhinovirus/genética , Relação Estrutura-Atividade
14.
Curr Opin Pharmacol ; 43: 11-19, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30064099

RESUMO

The development of islet autoimmunity and type 1 diabetes has long been linked with enteroviral infection but a causal relationship has proven hard to establish. This is partly because much of the epidemiological evidence derives from studies of neutralising antibody generation in blood samples while less attention has been paid to the pancreatic beta cell as a site of infection. Nevertheless, recent studies have revealed that beta cells express specific enteroviral receptors and that they can sustain a productive enteroviral infection. Importantly, they can also mount antiviral responses which attenuate viral replication and may favour the establishment of a persistent enteroviral infection. Together, these responses combine to create the Trojan horse by which enteroviruses might precipitate islet autoimmunity.


Assuntos
Antivirais/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Infecções por Enterovirus/tratamento farmacológico , Enterovirus/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Antivirais/efeitos adversos , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/virologia , Desenho de Fármacos , Enterovirus/patogenicidade , Infecções por Enterovirus/sangue , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Hipoglicemiantes/efeitos adversos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/virologia , Fatores de Risco
15.
Int Immunopharmacol ; 60: 111-120, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29730555

RESUMO

Enterovirus 71 (EV71) infection of young children can cause neurological manifestations, which is mainly responsible for the fatality. Although a vaccine is recently available for preventing enterovirus 71 infection, its efficacy remains to be seen. Therefore, there is a pressing need for anti-viral agents for the treatment of EV71 infection. By screening a natural compound library for inhibitory activity of EV71 replication, we identified a small molecule, harmine, that inhibited EV71 replication by targeting NF-κB signaling pathway. Harmine is a ß-carboline alkaloid found in the medicinal plant Peganum harmala, which is used as a folk antitumor medicine in China and other parts of the Asia. The estimated EC50 value for harmine to block EV71 infection was 20 µM, while the CC50 was estimated at 500 µM in vitro. Harmine inhibited replication of EV71, as evidenced by its ability to diminish plague formation induced by EV71 and to reduce the level of viral RNA and protein. Mechanistic studies indicated that harmine suppressed EV71 replication through inhibition of NF-κB signaling pathway. Harmine treatment also reduced EV71-induced reactive oxygen species (ROS) formation, which was associated with a decline in EV71-associated NF-κB activation. In addition, the harmine treatment could protect AG129 mice against EV71 replication in vivo. These findings suggest that harmine may present as a candidate antiviral drug for the treatment of EV71 infection.


Assuntos
Antivirais/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Harmina/farmacologia , NF-kappa B/metabolismo , Animais , Antivirais/uso terapêutico , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Harmina/uso terapêutico , Células HeLa , Humanos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
16.
Nat Rev Microbiol ; 16(6): 368-381, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29626210

RESUMO

The genus Enterovirus (EV) of the family Picornaviridae includes poliovirus, coxsackieviruses, echoviruses, numbered enteroviruses and rhinoviruses. These diverse viruses cause a variety of diseases, including non-specific febrile illness, hand-foot-and-mouth disease, neonatal sepsis-like disease, encephalitis, paralysis and respiratory diseases. In recent years, several non-polio enteroviruses (NPEVs) have emerged as serious public health concerns. These include EV-A71, which has caused epidemics of hand-foot-and-mouth disease in Southeast Asia, and EV-D68, which recently caused a large outbreak of severe lower respiratory tract disease in North America. Infections with these viruses are associated with severe neurological complications. For decades, most research has focused on poliovirus, but in recent years, our knowledge of NPEVs has increased considerably. In this Review, we summarize recent insights from enterovirus research with a special emphasis on NPEVs. We discuss virion structures, host-receptor interactions, viral uncoating and the recent discovery of a universal enterovirus host factor that is involved in viral genome release. Moreover, we briefly explain the mechanisms of viral genome replication, virion assembly and virion release, and describe potential targets for antiviral therapy. We reflect on how these recent discoveries may help the development of antiviral therapies and vaccines.


Assuntos
Antivirais/farmacologia , Infecções por Enterovirus/prevenção & controle , Infecções por Enterovirus/virologia , Enterovirus/fisiologia , Replicação Viral/fisiologia , Animais , Antivirais/uso terapêutico , Enterovirus/genética , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/epidemiologia , Regulação Viral da Expressão Gênica , Saúde Global , Humanos , Replicação Viral/genética
17.
Semin Perinatol ; 42(3): 191-197, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29526382

RESUMO

Nonpolio enteroviruses and parechoviruses are frequent causes of neonatal infection. Clinical manifestations of infection range from asymptomatic infection to mild infection without sequelae to septic shock with muiltiorgan failure. Neonates with clinically apparent infection typically have mothers and/or other contacts with recent symptoms consistent with a viral illness. Severe neonatal infection with nonpolio enterovirus or parechovirus cannot be differentiated clinically from serious bacterial infection. The preferred method for diagnosing neonatal nonpolio enterovirus or parechovirus infection is PCR as it is rapid, sensitive, specific, and commercially available for the detection of virus from various clinical specimens. Investigational agents such as the capsid inhibitors pleconaril and pocapavir show promise for treatment of neonatal enterovirus infections, and other investigational agents are being developed. This review focuses on the epidemiology, diagnosis, and treatment of neonatal nonpolio enterovirus and parechovirus infections.


Assuntos
Infecções por Enterovirus/epidemiologia , Infecções por Picornaviridae/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Antivirais/uso terapêutico , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/epidemiologia , Enterovirus/genética , Infecções por Enterovirus/congênito , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/tratamento farmacológico , Feminino , Fômites , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Oxidiazóis/uso terapêutico , Parechovirus/genética , Éteres Fenílicos/uso terapêutico , Infecções por Picornaviridae/congênito , Infecções por Picornaviridae/diagnóstico , Infecções por Picornaviridae/tratamento farmacológico , Reação em Cadeia da Polimerase , Gravidez
18.
PLoS One ; 13(1): e0191617, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29370243

RESUMO

EV71 is a positive-sense single-stranded RNA virus that belongs to the Picornaviridae family. EV71 infection may cause various symptoms ranging from hand-foot-and-mouth disease to neurological pathological conditions such as aseptic meningitis, ataxia, and acute transverse myelitis. There is currently no effective treatment or vaccine available. Various compounds have been examined for their ability to restrict EV71 replication. However, most experiments have been performed in rhabdomyosarcoma or Vero cells. Since the gastrointestinal tract is the entry site for this pathogen, we anticipated that orally ingested agents may exert beneficial effects by decreasing virus replication in intestinal epithelial cells. In this study, curcumin (diferuloylmethane, C21H20O6), an active ingredient of turmeric (Curcuma longa Linn) with anti-cancer properties, was investigated for its anti-enterovirus activity. We demonstrate that curcumin treatment inhibits viral translation and increases host cell viability. Curcumin does not exert its anti-EV71 effects by modulating virus attachment or virus internal ribosome entry site (IRES) activity. Furthermore, curcumin-mediated regulation of mitogen-activated protein kinase (MAPK) signaling pathways is not involved. We found that protein kinase C delta (PKCδ) plays a role in virus translation in EV71-infected intestinal epithelial cells and that curcumin treatment decreases the phosphorylation of this enzyme. In addition, we show evidence that curcumin also limits viral translation in differentiated human intestinal epithelial cells. In summary, our data demonstrate the anti-EV71 properties of curcumin, suggesting that ingestion of this phytochemical may protect against enteroviral infections.


Assuntos
Curcumina/metabolismo , Curcumina/uso terapêutico , Infecções por Enterovirus/tratamento farmacológico , Linhagem Celular , Curcumina/farmacologia , Enterovirus/efeitos dos fármacos , Enterovirus Humano A/genética , Infecções por Enterovirus/virologia , Células Epiteliais/efeitos dos fármacos , Células HT29 , Doença de Mão, Pé e Boca/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Sítios Internos de Entrada Ribossomal , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestinos/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , RNA Viral/genética , Proteínas Virais/genética , Replicação Viral/efeitos dos fármacos
19.
PLoS Pathog ; 14(1): e1006778, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29324904

RESUMO

A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropathogenesis has hampered the development of effective therapeutic options. Here, using a two-dimensional proteomics approach combined with mass spectrometry, we have identified a unique panel of host proteins that were differentially and dynamically modulated during EV71 infection of motor-neuron NSC-34 cells, which are found at the neuromuscular junctions where EV71 is believed to enter the central nervous system. Meta-analysis with previously published proteomics studies in neuroblastoma or muscle cell lines revealed minimal overlapping which suggests unique host-pathogen interactions in NSC-34 cells. Among the candidate proteins, we focused our attention on prohibitin (PHB), a protein that is involved in multiple cellular functions and the target of anti-cancer drug Rocaglamide (Roc-A). We demonstrated that cell surface-expressed PHB is involved in EV71 entry into neuronal cells specifically, while membrane-bound mitochondrial PHB associates with the virus replication complex and facilitates viral replication. Furthermore, Roc-A treatment of EV71-infected neuronal cells reduced significantly virus yields. However, the inhibitory effect of Roc-A on PHB in NSC-34 cells was not through blocking the CRAF/MEK/ERK pathway as previously reported. Instead, Roc-A treated NSC-34 cells had lower mitochondria-associated PHB and lower ATP levels that correlated with impaired mitochondria integrity. In vivo, EV71-infected mice treated with Roc-A survived longer than the vehicle-treated animals and had significantly lower virus loads in their spinal cord and brain, whereas virus titers in their limb muscles were comparable to controls. Together, this study uncovers PHB as the first host factor that is specifically involved in EV71 neuropathogenesis and a potential drug target to limit neurological complications.


Assuntos
Membrana Celular/virologia , Enterovirus Humano A/fisiologia , Interações Hospedeiro-Patógeno , Membranas Mitocondriais/virologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/virologia , Proteínas Repressoras/metabolismo , Animais , Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Enterovirus Humano A/efeitos dos fármacos , Enterovirus Humano A/patogenicidade , Enterovirus Humano A/ultraestrutura , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/patologia , Infecções por Enterovirus/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/ultraestrutura , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Proteômica/métodos , Interferência de RNA , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Organismos Livres de Patógenos Específicos , Análise de Sobrevida , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
20.
Int Immunopharmacol ; 55: 142-150, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29253820

RESUMO

Outbreaks of hand, foot and mouth disease (HFMD), which is caused by Enterovirus 71 (EV71), have erupted in recent years. Andrographolide sulfonate (Trade name: Xiyanping injection) has been recommended to treat severe HFMD in China because of its conventional antithermic and antitoxic activities, but its actual mechanism has not been revealed clearly until now. To explore its therapeutic efficacy and mechanism, a Xiyanping injection treatment mouse model was established. Based on the therapeutic model, routine clinical parameters and histopathologic changes were investigated, in the same time, viral loads, immune cells, inflammatory molecules and cell signaling pathways were determined. Xiyanping injection treatment protected mice from lethal EV71 challenge in a therapeutic regimen-dependent manner, which may mostly depend on its direct immunomodulatory activities on neutrophil and T lymphocyte. Reduced inflammatory molecular production of neutrophil and elevated T lymphocyte activity may result from its marked inhibition of some signaling pathways. Taken together, Xiyanping injection was an effective treatment for severe HFMD by improving hosts' immunity.


Assuntos
Antivirais/uso terapêutico , Diterpenos/uso terapêutico , Enterovirus Humano A/imunologia , Infecções por Enterovirus/tratamento farmacológico , Doença de Mão, Pé e Boca/tratamento farmacológico , Animais , China , Modelos Animais de Doenças , Humanos , Imunomodulação , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos ICR , Modelos Biológicos , Mortalidade
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