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1.
J Neurochem ; 166(4): 763-776, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37497817

RESUMO

Maternal infections are among the main risk factors for cognitive impairments in the offspring. Zika virus (ZIKV) can be transmitted vertically, causing a set of heterogeneous birth defects, such as microcephaly, ventriculomegaly and corpus callosum dysgenesis. Nuclear distribution element like-1 (Ndel1) oligopeptidase controls crucial aspects of cerebral cortex development underlying cortical malformations. Here, we examine Ndel1 activity in an animal model for ZIKV infection, which was associated with deregulated corticogenesis. We observed here a reduction in Ndel1 activity in the forebrain associated with the congenital syndrome induced by ZIKV isolates, in an in utero and postnatal injections of different inoculum doses in mice models. In addition, we observed a strong correlation between Ndel1 activity and brain size of animals infected by ZIKV, suggesting the potential of this measure as a biomarker for microcephaly. More importantly, the increase of interferon (IFN)-beta signaling, which was used to rescue the ZIKV infection outcomes, also recovered Ndel1 activity to levels similar to those of uninfected healthy control mice, but with no influence on Ndel1 activity in uninfected healthy control animals. Taken together, we demonstrate for the first time here an association of corticogenesis impairments determined by ZIKV infection and the modulation of Ndel1 activity. Although further studies are still necessary to clarify the possible role(s) of Ndel1 activity in the molecular mechanism(s) underlying the congenital syndrome induced by ZIKV, we suggest here the potential of monitoring the Ndel1 activity to predict this pathological condition at early stages of embryos or offspring development, during while the currently employed methods are unable to detect impaired corticogenesis leading to microcephaly. Ndel1 activity may also be possibly used to follow up the positive response to the treatment, such as that employing the IFN-beta that is able to rescue the ZIKV-induced brain injury.


Assuntos
Microcefalia , Infecção por Zika virus , Zika virus , Animais , Camundongos , Infecção por Zika virus/complicações , Infecção por Zika virus/congênito , Infecção por Zika virus/patologia , Endofenótipos , Proteínas de Transporte
2.
Immunology ; 162(3): 290-305, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33112414

RESUMO

Elevated frequency of Th17-like cells expressing Toll-like receptors (TLRs) has been recently associated with relapsing-remitting multiple sclerosis (MS) pathogenesis, a chronic inflammatory demyelinating autoimmune disease of the central nervous system. We aimed to investigate the impact of current major depressive disorder (MDD) on the behaviour of these cells following in vitro stimulation with TLR2, TLR4, TLR5 and TLR9 agonists. Here, the level of both cell proliferation and cytokine production related to Th17/Tc17 phenotypes in response to TLR2 (Pam3C) and TLR4 (LPS) ligands was significantly higher in CD4+ and CD8+ T-cell cultures from MS/MDD patients when compared to non-depressed patients. These cytokine levels were positively associated with neurological disabilities in patients. No difference for responsiveness to TLR5 (flagellin) and TLR9 (ODN) agonists was observed. LPS, but not Pam3C, induced significant IL-10 release, mainly in patients without MDD. Interestingly, more intense expression of TLR2 and TLR4 on these cells was observed in MDD patients. Finally, in vitro addition of serotonin and treatment of MDD patients with selective serotonin reuptake inhibitors (SSRIs) reduced the production of Th17/Tc17-related cytokines by CD4+ and CD8+ T cells in response to Pam3C and LPS. However, only SSRI therapy diminished the frequency and intensity of TLR2 and TLR4 expression on circulating CD4+ and CD8+ T cells. In summary, although preliminary, our findings suggest that adverse events that elevate circulating levels of TLR2 and TLR4 ligands can affect MS pathogenesis, particularly among depressed patients.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Fluoxetina/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Esclerose Múltipla Recidivante-Remitente/imunologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Células Th17/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fenótipo , Células Th17/imunologia , Células Th17/metabolismo , Resultado do Tratamento , Adulto Jovem
3.
J Nat Prod ; 84(5): 1666-1670, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33909429

RESUMO

Three known compounds, 20-deoxyphorbol-5ß-hydroxy-12-tiglate-13-isobutyrate (1), 20-deoxyphorbol-5ß-hydroxy-12-tiglate-13-phenylacetate (2), and 4-deoxy-4ß-phorbol-12-tiglate-13-phenylacetate (3), were reisolated from the latex of Euphorbia umbellata through a bioguided fractionation process to target HIV-1 latency reactivation. The in vitro bioassay using infected T-cell lymphoblasts (J-Lat 10.6), complemented with surface CD4 receptor downregulation assessment, led to isolation of the compounds as a highly active ternary mixture. Effective purification of the individual compounds was achieved by first subjecting a phorbol-enriched fraction (previously prepared from crude latex) to MPLC, followed by semipreparative HPLC and characterization by 1D and 2D NMR spectroscopy and (+)-HRESIMS. Compared with a positive control, the isolated compounds were effective in reactivating 68-75% of the virus latency in the range of 9.7-0.097 µM for compound 1, 8.85-0.088 µM for compound 2, and 9.1-0.091 µM for compound 3, with the latter maintaining steady effectiveness down to a 10-5 dilution. Accordingly, compound 3 may serve as a promising lead compound for the development of anti-HIV drugs based on latency reactivation therapy.


Assuntos
Euphorbia/química , HIV-1/efeitos dos fármacos , Ésteres de Forbol/farmacologia , Latência Viral/efeitos dos fármacos , Brasil , Linhagem Celular , Humanos , Látex/química , Estrutura Molecular , Linfócitos T/virologia
4.
Genet Mol Biol ; 37(1): 120-6, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24688299

RESUMO

Engineered nucleases such as zinc finger nucleases (ZFN) and transcription activator-like effector nucleases (TALEN) are one of the most promising tools for modifying genomes. These site-specific enzymes cause double-strand breaks that allow gene disruption or gene insertion, thereby facilitating genetic manipulation. The major problem associated with this approach is the labor-intensive procedures required to screen and confirm the cellular modification by nucleases. In this work, we produced a TALEN that targets the human CCR5 gene and developed a heteroduplex mobility assay for HEK 293T cells to select positive colonies for sequencing. This approach provides a useful tool for the quick detection and easy assessment of nuclease activity.

5.
Dis Model Mech ; 17(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38415826

RESUMO

The Zika virus received significant attention in 2016, following a declaration by the World Health Organization of an epidemic in the Americas, in which infections were associated with microcephaly. Indeed, prenatal Zika virus infection is detrimental to fetal neural stem cells and can cause premature cell loss and neurodevelopmental abnormalities in newborn infants, collectively described as congenital Zika syndrome. Contrastingly, much less is known about how neonatal infection affects the development of the newborn nervous system. Here, we investigated the development of the dentate gyrus of wild-type mice following intracranial injection of the virus at birth (postnatal day 0). Through this approach, we found that Zika virus infection affected the development of neurogenic regions within the dentate gyrus and caused reactive gliosis, cell death and a decrease in cell proliferation. Such infection also altered volumetric features of the postnatal dentate gyrus. Thus, we found that Zika virus exposure to newborn mice is detrimental to the subgranular zone of the dentate gyrus. These observations offer insight into the cellular mechanisms that underlie the neurological features of congenital Zika syndrome in children.


Assuntos
Infecção por Zika virus , Zika virus , Humanos , Criança , Lactente , Feminino , Gravidez , Animais , Camundongos , Infecção por Zika virus/complicações , Neurogênese , Morte Celular , Proliferação de Células
6.
Viruses ; 15(12)2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-38140578

RESUMO

Congenital Zika syndrome (CZS) is a set of birth defects caused by Zika virus (ZIKV) infection during pregnancy. Microcephaly is its main feature, but other brain abnormalities are found in CZS patients, such as ventriculomegaly, brain calcifications, and dysgenesis of the corpus callosum. Many studies have focused on microcephaly, but it remains unknown how ZIKV infection leads to callosal malformation. To tackle this issue, we infected mouse embryos in utero with a Brazilian ZIKV isolate and found that they were born with a reduction in callosal area and density of callosal neurons. ZIKV infection also causes a density reduction in PH3+ cells, intermediate progenitor cells, and SATB2+ neurons. Moreover, axonal tracing revealed that callosal axons are reduced and misrouted. Also, ZIKV-infected cultures show a reduction in callosal axon length. GFAP labeling showed that an in utero infection compromises glial cells responsible for midline axon guidance. In sum, we showed that ZIKV infection impairs critical steps of corpus callosum formation by disrupting not only neurogenesis, but also axon guidance and growth across the midline.


Assuntos
Microcefalia , Malformações do Sistema Nervoso , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Gravidez , Feminino , Humanos , Animais , Camundongos , Corpo Caloso , Malformações do Sistema Nervoso/etiologia , Neurogênese
8.
PLoS Negl Trop Dis ; 14(3): e0008060, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32163415

RESUMO

The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak took place in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the quantity of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.


Assuntos
Morte Celular/efeitos dos fármacos , Microcefalia/patologia , Intoxicação/complicações , Intoxicação/patologia , Saxitoxina/toxicidade , Infecção por Zika virus/complicações , Infecção por Zika virus/patologia , Animais , Toxinas Bacterianas/análise , Toxinas Bacterianas/toxicidade , Encéfalo/patologia , Brasil/epidemiologia , Células Cultivadas , Toxinas de Cianobactérias , Modelos Animais de Doenças , Surtos de Doenças , Feminino , Humanos , Incidência , Toxinas Marinhas/análise , Toxinas Marinhas/toxicidade , Camundongos Endogâmicos C57BL , Microcistinas/análise , Microcistinas/toxicidade , Modelos Teóricos , Neurotoxinas/análise , Neurotoxinas/toxicidade , Saxitoxina/análise , Água/química
9.
Science ; 369(6508): 1255-1260, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32703910

RESUMO

Brazil currently has one of the fastest-growing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemics in the world. Because of limited available data, assessments of the impact of nonpharmaceutical interventions (NPIs) on this virus spread remain challenging. Using a mobility-driven transmission model, we show that NPIs reduced the reproduction number from >3 to 1 to 1.6 in São Paulo and Rio de Janeiro. Sequencing of 427 new genomes and analysis of a geographically representative genomic dataset identified >100 international virus introductions in Brazil. We estimate that most (76%) of the Brazilian strains fell in three clades that were introduced from Europe between 22 February and 11 March 2020. During the early epidemic phase, we found that SARS-CoV-2 spread mostly locally and within state borders. After this period, despite sharp decreases in air travel, we estimated multiple exportations from large urban centers that coincided with a 25% increase in average traveled distances in national flights. This study sheds new light on the epidemic transmission and evolutionary trajectories of SARS-CoV-2 lineages in Brazil and provides evidence that current interventions remain insufficient to keep virus transmission under control in this country.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Número Básico de Reprodução , Teorema de Bayes , Betacoronavirus/classificação , Brasil/epidemiologia , COVID-19 , Teste para COVID-19 , Cidades/epidemiologia , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Europa (Continente) , Evolução Molecular , Genoma Viral , Humanos , Modelos Genéticos , Modelos Estatísticos , Pandemias/prevenção & controle , Filogenia , Filogeografia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , SARS-CoV-2 , Análise Espaço-Temporal , Viagem , População Urbana
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