RESUMO
Here we introduce a first-in-class microRNA-sensitive oncolytic Zika virus (ZIKV) for virotherapy application against central nervous system (CNS) tumors. The described methodology produced two synthetic modified ZIKV strains that are safe in normal cells, including neural stem cells, while preserving brain tropism and oncolytic effects in tumor cells. The microRNA-sensitive ZIKV introduces genetic modifications in two different virus sites: first, in the established 3'UTR region, and secondly, in the ZIKV protein coding sequence, demonstrating for the first time that the miRNA inhibition systems can be functional outside the UTR RNA sites. The total tumor remission in mice bearing human CNS tumors, including metastatic tumor growth, after intraventricular and systemic modified ZIKV administration, confirms the promise of this virotherapy as a novel agent against brain tumors-highly deadly diseases in urgent need of effective advanced therapies.
Assuntos
Neoplasias do Sistema Nervoso Central , MicroRNAs , Terapia Viral Oncolítica , Vírus Oncolíticos , Infecção por Zika virus , Zika virus , Humanos , Camundongos , Animais , Vírus Oncolíticos/genética , Zika virus/genética , MicroRNAs/genética , Infecção por Zika virus/terapia , Terapia Viral Oncolítica/métodosRESUMO
The Leishmaniasis treatment currently available involves some difficulties, such as high toxicity, variable efficacy, high cost, therefore, it is crucial to search for new therapeutic alternatives. Over the past few years, research on new drugs has focused on the use of natural compounds such as chalcones and nanotechnology. In this context, this research aimed at assessing the in vitro leishmanicidal activity of free 4-nitrochalcone (4NC) on promastigotes and encapsulated 4NC on L. amazonensis-infected macrophages, as well as their action mechanisms. Free 4NC was able to reduce the viability of promastigotes, induce reactive oxygen species production, decrease mitochondrial membrane potential, increase plasma membrane permeability, and expose phosphatidylserine, in addition to altering the morphology and lowering parasite cellular volume. Treatment containing encapsulated 4NC in beeswax-copaiba oil nanoparticles (4NC-beeswax-CO Nps) did not alter the viability of macrophages. Furthermore, 4NC-beeswax-CO Nps reduced the percentage of infected macrophages and the number of amastigotes per macrophages, increasing the production of reactive oxygen species, NO, TNF-α, and IL-10. Therefore, free 4NC proved to exert anti-promastigote effect, while 4NC-beeswax-CO Nps showed a leishmanicidal effect on L. amazonensis-infected macrophages by activating the macrophage microbicidal machinery.
Assuntos
Chalconas/farmacologia , Portadores de Fármacos , Fabaceae , Leishmania/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Macrófagos Peritoneais/efeitos dos fármacos , Nanopartículas , Óleos de Plantas/química , Tripanossomicidas/farmacologia , Ceras/química , Animais , Apoptose/efeitos dos fármacos , Chalconas/química , Citocinas/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Fabaceae/química , Mediadores da Inflamação/metabolismo , Leishmania/crescimento & desenvolvimento , Leishmania/ultraestrutura , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óleos de Plantas/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Tripanossomicidas/químicaRESUMO
INTRODUCTION: Describing the general aspects of American tegumentary leishmaniasis enables the identification of the epidemiological scenario of the disease and the development of preventive actions. METHODS: We analyzed the records of patients with American tegumentary leishmaniasis in north Paraná between 2010 and 2015. RESULTS: We identified 108 cases (mostly in 2014) with the following characteristics: male individuals, rural workers, and ages averaging 56.8 years. Isolated ulcerated lesions were predominant, and Glucantime® was the most frequently used drug. CONCLUSIONS: American tegumentary leishmaniasis remains endemic and affects mostly men found in areas surrounded by woods; its treatment is partially efficient considering its side effects and incidence of recurrences.
Assuntos
Leishmaniose Cutânea/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Criança , Pré-Escolar , Doenças Endêmicas , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise Espaço-Temporal , Adulto JovemRESUMO
Abstract INTRODUCTION: Describing the general aspects of American tegumentary leishmaniasis enables the identification of the epidemiological scenario of the disease and the development of preventive actions. METHODS: We analyzed the records of patients with American tegumentary leishmaniasis in north Paraná between 2010 and 2015. RESULTS: We identified 108 cases (mostly in 2014) with the following characteristics: male individuals, rural workers, and ages averaging 56.8 years. Isolated ulcerated lesions were predominant, and Glucantime® was the most frequently used drug. CONCLUSIONS: American tegumentary leishmaniasis remains endemic and affects mostly men found in areas surrounded by woods; its treatment is partially efficient considering its side effects and incidence of recurrences.