The Inhibition of Inflammasome by Brazilian Propolis (EPP-AF)

Propolis extracts have gained the attention of consumers and researchers due to their unique chemical compositions and functional properties such as its anti-inflammatory activity. Recently, it was described a complex that is also important in inflammatory processes, named inflammasome. The inflammasomes are a large molecular platform formed in the cell cytosol in response to stress signals, toxins, and microbial infections. Once activated, the inflammasome induces caspase-1, which in turn induces the processing of inflammatory cytokines such as IL-1β and IL-18. So, to understand inflammasomes regulation becomes crucial to treat several disorders including autoinflammatory diseases. Since green propolis extracts are able to regulate inflammatory pathways, this work purpose was to investigate if this extract could also act on inflammasomes regulation. First, the extract was characterized and it demonstrated the presence of important compounds, especially Artepillin C. This extract was effective in reducing the IL-1β secretion in mouse macrophages and this reduction was correlated with a decrease in activation of the protease caspase-1. Furthermore, we found that the extract at a concentration of 30 μg/mL was not toxic to the cells even after a 18-hour treatment. Altogether, these data indicate that Brazilian green propolis (EPP-AF) extract has a role in regulating the inflammasomes

CYP450 Metabolism of a Semisynthetic Naphthoquinone, an Anticancer Drug Candidate, by Human Liver Microsomes

CNFD (6b,7-dihydro-5H-cyclopenta[b]naphtho[2,1-d]furan-5,6(9aH)-dione) is a semisynthetic naphthoquinone derived from lawsone that has cytotoxic action in different tumor lines and anticancer activity in vivo. Therefore, this molecule is a relevant candidate for drug development, but there is still no information on its human metabolism and systemic elimination. This study aimed to investigate the in vitro metabolism of this naphthoquinone by human liver microsomes. Initially, in order to determine the in vitro enzymatic kinetic parameters, a high performance liquid chromatography (HPLC) method to quantify the CNFD was developed and validated. In addition, the enzymatic kinetic data, the predicted pharmacokinetic in vivo parameters and the phenotyping study were presented. The main metabolism sites and metabolites have been suggested in silico. The developed HPLC method was linear, reproducible, selective, accurate, and stable. The enzymatic kinetic parameters revealed a sigmoidal profile. In vitro to in vivo extrapolation hepatic metabolic clearance was 10.39 mL min-1 kg-1 protein and the liver extraction rate was 51%. The clearance in vivo associated with a hepatic extraction ratio indicates that the hepatic metabolism is the main route of elimination. Although all cytochrome P450 enzymes evaluated metabolized CNFD, CYP2C9 and CYP3A4 showed higher metabolic capacity. For the first time, metabolism studies of CNFD were demonstrated.</div

Pre-clinical evaluation of quinoxaline-derived chalcones in tuberculosis.

New effective compounds for tuberculosis treatment are needed. This study evaluated the effects of a series of quinoxaline-derived chalcones against laboratorial strains and clinical isolates of M. tuberculosis. Six molecules, namely N5, N9, N10, N15, N16, and N23 inhibited the growth of the M. tuberculosis H37Rv laboratorial strain. The three compounds (N9, N15 and N23) with the lowest MIC values were further tested against clinical isolates and laboratory strains with mutations in katG or inhA genes. From these data, N9 was selected as the lead compound for further investigation. Importantly, this chalcone displayed a synergistic effect when combined with moxifloxacin. Noteworthy, the anti-tubercular effects of N9 did not rely on inhibition of mycolic acids synthesis, circumventing important mechanisms of resistance. Interactions with cytochrome P450 isoforms and toxic effects were assessed in silico and in vitro. The chalcone N9 was not predicted to elicit any mutagenic, genotoxic, irritant, or reproductive effects, according to in silico analysis. Additionally, N9 did not cause mutagenicity or genotoxicity, as revealed by Salmonella/microsome and alkaline comet assays, respectively. Moreover, N9 did not inhibit the cytochrome P450 isoforms CYP3A4/5, CYP2C9, and CYP2C19. N9 can be considered a potential lead molecule for development of a new anti-tubercular therapeutic agent

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved