Development and biological evaluation of a new nanotheranostic for tuberculosis.

In this study, we developed, characterized, and tested in vivo polymeric nanoparticle of ethambutol labeled with 99mTc as nanoradiopharmaceutical for early diagnosis of tuberculosis by single-photon emission computed tomography, also as a therapeutic choice. Nanoparticles were developed by double emulsification. All characterization tests were performed, as scanning electron microscopy and dynamic light scattering. The labeling process with 99mTc was performed using the direct labeling process. In vitro and in vivo assays were performed with animals and cells. The results showed that a spherical ethambutol nanoparticle with a size range of 280-300 nm was obtained. The stability test showed that the nanoparticles were well labeled with 99mTc (> 99.1%) and keep labeled over 24 h. The biodistribution assay showed that almost 18% of the nanoparticles were uptake by the lung in infected mice (male C57Bl/6) with Mycobacterium bovis BCG (4 × 105 CFU/cavity), corroborating its use as a nanodrug for tuberculosis imaging. The results for the cell assay corroborate its therapeutical effect. We developed and efficiently tested a new nanodrug that can be used for both imaging and therapy of tuberculosis, acting as a novel nanotheranostic.

A influência do status socioeconômico sobre as habilidades motoras grossas nas crianças em idade escolar / The influence of socioeconomic status on gross motor skills in school-age children

O processo de desenvolvimento motor ocorre de acordo com o padrão estabelecido por fatores biológicos e também pela influência de fatores ambientais/sociais. O status socioeconômico familiar pode ser um importante fator interveniente nas possibilidades de adquirir as habilidades motoras fundamentais necessárias ao desenvolvimento geral da criança, com sérias implicações futuras. Este trabalho tem como objetivo analisar as possíveis relações entre status socioeconômico sobre as habilidades motoras grossas em indivíduos em idade escolar. Metodologicamente utilizamos uma revisão sistemática com as as palavras-chave (children, fundamental motor skills, motor skills, gross motor skills, motor ability, motor competence, gross motor competence, motor skill proficiency, socioeconomic status, low economic income) para identificar artigos de banco de dados eletrônicos Scopus e PubMed, resultando em 19 artigos que formaram esta revisão. Os critérios de inclusão foram: a) escolares com idades entre 6 e 15 anos; b) avaliação das habilidades motoras grossas; c) houvesse dois ou mais grupos da amostra classificados quanto ao status socioeconômico e d) crianças hígidas. Os principais resultados mostraram uma prevalência de crianças de alto status socioeconômico com maior pontuação nas habilidades motoras em relação às crianças de baixo status socioeconômico, mas este resultado não foi homogêneo. (AU)

The motor development process occurs according to the pattern established by biological factors and by environmental/social factors influence. Family socioeconomic status can be an important intervening factor in the possibilities of acquiring the fundamental motor skills necessary for the general development of the child, with serious future implications. This work aimed to analyze the possible relationships between socioeconomic status on gross motor skills in school age individuals. Methodologically, we used a systematic review with the following keywords (children, fundamental motor skills, motor skills, motor ability, motor competence, motor skill proficiency, socioeconomic status, low economic income) to identify data, resulting in 19 articles that composed this review. The inclusion criteria were: a) schoolchildren aged between 6 and 15 years; b) gross motor skills performance evaluation; c) two or more sample groups classified as socioeconomic status and d) healthy children. The main results showed a prevalence of high socioeconomic status children with higher scores in motor skills compared to low socioeconomic status children, but this result was not homogeneous. (AU)

The cannabinoid 2 receptor agonist ß-caryophyllene modulates the inflammatory reaction induced by Mycobacterium bovis BCG by inhibiting neutrophil migration.

OBJECTIVE AND DESIGN: ß-Caryophyllene (BCP) is a sesquiterpene that binds to the cannabinoid 2 (CB2) receptor and exerts anti-inflammatory effects. In this study, we investigated the anti-inflammatory effect of BCP and another CB2 agonist, GP1a in inflammatory experimental model induced by Mycobacterium bovis (BCG). METHODS: C57Bl/6 mice were pretreated orally with BCP (0.5-50 mg/kg) or intraperitonealy with GP1a (10 mg/kg) 1 h before the induction of pleurisy or pulmonary inflammation by BCG. The direct action of CB2 agonists on neutrophils function was evaluated in vitro. RESULTS: ß-Caryophyllene (50 mg/kg) impaired BCG-induced neutrophil accumulation in pleurisy without affecting mononuclear cells or the production of TNF-α and CCL2/MCP-1. However, BCP inhibited CXCL1/KC, leukotriene B4 (LTB4), IL-12, and nitric oxide production. GP1a had a similar effect to BCP. Preincubation of neutrophils with BCP (10 µM) impaired chemotaxis toward LTB4 and adhesion to endothelial cells stimulated with TNF-α, and both, BCP and GP1a, impaired LTB4-induced actin polymerization. CONCLUSION: These results suggest that the CB2 receptor may represent a new target for modulating the inflammatory reaction induced by mycobacteria.

Anti-inflammatory Effect of Methyl Gallate on Experimental Arthritis: Inhibition of Neutrophil Recruitment, Production of Inflammatory Mediators, and Activation of Macrophages.

Methyl gallate (MG) is a prevalent phenolic acid in the plant kingdom, and its presence in herbal medicines might be related to its remarkable biological effects, such as its antioxidant, antitumor, and antimicrobial activities. Although some indirect evidence suggests anti-inflammatory activity for MG, there are no studies demonstrating this effect in animal models. Herein, we demonstrated that MG (0.7-70 mg/kg) inhibited zymosan-induced experimental arthritis in a dose-dependent manner. The oral administration of MG (7 mg/kg) attenuates arthritis induced by zymosan, affecting edema formation, leukocyte migration, and the production of inflammatory mediators (IL-1ß, IL-6, TNF-α, CXCL-1, LTB4, and PGE2). Pretreatment with MG inhibited in vitro neutrophil chemotaxis elicited by CXCL-1, as well as the adhesion of these cells to TNF-α-primed endothelial cells. MG also impaired zymosan-stimulated macrophages by inhibiting IL-6 and NO production, COX-2 and iNOS expression, and intracellular calcium mobilization. Thus, MG is likely to present an anti-inflammatory effect by targeting multiple cellular events such as the production of various inflammatory mediators, as well as leukocyte activation and migration.

Synthesis and antitubercular activity of new L-serinyl hydrazone derivatives.

A series of 32 L-serinyl hydrazone derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv, being also evaluated their cell viabilities in non infected and infected macrophages with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). The compounds 8c, 8e, 8h and 8i, were non-cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity between 25 and 100 µg/mL, which can be compared with that of the tuberculostatic drug D-cicloserine (5-20 µg/mL).

Avaliação do papel de células mesoteliais na pleurisia induzida por Mycobacterium bovis - BCG / Evaluation of the role of mesothelial cells induced pleurisy in Mycobacterium bovis - BCG

A tuberculose pleural é a mais importante manifestação extrapulmonar da tuberculose, ocorrendo em aproximadamente 30 por cento dos pacientes. A cavidade pleural é formada por uma monocamada de células mesoteliais, apresentando estas, células alta atividade metabólica. Neste trabalho, caracterizamos o influxo de leucócitos no modelo de pleurisia induzida pelo M bovis-BCG, analisando três diferentes tempos da reação. Para isso, camundongos C57BL/6, machos, foram injetados com M. bovis-BCG (4 x 105 UFC/cavidade). Após 4h, 24h e 15 dias os camundongos foram sacrificados por inalação de CO2 e a cavidade torácica foi lavada com 1 mL de PBS heparinizado para análise total e diferencial do acúmulo leucocitário. As drogas utilizadas no pré-tratamento: WEB 2170 (i.p.), diacereína (p.o.), CP-105696 (i.p.) L-NAME (i.p.) ou talidomida (s.c.) foram utilizadas 1h, 13 dias e 14 dias antes da infecção com o BCG. Após 4h, somente o antagonista de PAF, o WEB 2170, inibiu o acúmulo de neutrófilos. A neutrofilia em 24h foi inibida pelo antagonista de LTB4 CP-105696, o inibidor de NO, L-NAME, o inibidor de TNF-alpha, a talidomida e o inibidor de IL-1 a diacereína. Após 15 dias apenas o L-NAME falhou em inibir o acúmulo de neutrófilos. Além disto, nós demonstramos que as células mesoteliais pleurais participam da resposta inflamatória induzida pelo Mycobacterium bovis bacillus Calmette-Guérin (BCG). A infecção destas células leva a uma produção de mediadores ativando vias de sinalização intracelulares. Nós observamos que a entrada do BCG nas células mesoteliais in vitro depende do rearranjo dos filamentos de actina. Uma vez estimuladas, as células mesoteliais são capazes de liberar NO, MCP-1/CCL2, KC/CXCL1, TNF-alpha e IL-6, paralelamente a ativação de p38 MAPK e p-JNK, sem ativar, contudo as vias de ERK-2 e AKT. Nós observamos a subunidade p65 de NFkappaB no extrato nuclear de células mesoteliais infectadas e demonstramos que a produção de IL-6, KC/CXCL1 e NO depende da translocação nuclear deste fator. Por outro lado, o tratamento com LXA4 em diferentes concentrações foi capaz de reduzir a liberação destes mediadores. Nós demonstramos que células mesoteliais liberam mediadores que podem contribuir para o controle da inflamação pleural induzida pela bactéria. Estes dados foram confirmados pelo tratamento com o antagonista da LXA4, o BOC-1. Observamos que o tratamento com BOC-1 foi capaz de reduzir o número de UFC tanto in vivo quanto in vitro. Tomados em conjunto, nossos resultados sugerem que o acúmulo de neutrófilos induzido pelo BCG é orquestrado por diferentes mediadores durante as diferentes fases da reação inflamatória. As células mesoteliais são ativamente infectadas pelo BCG, contribuindo para a efusão pleural tuberculosa, permitindo a estocagem das micobactérias, bem como a liberação de mediadores inflamatórios via MAPquinases, tendo aparentemente a LXA4 um papel antiinflamatório neste processo.