The high incidence of fungal infections has become a worrisome public health issue, having been aggravated by an increase in host predisposition factors. Despite all the drugs available on the market to treat these diseases, their efficiency is questionable, and their side effects cannot be neglected. Bearing that in mind, it is of upmost importance to synthetize new and innovative carriers for these medicines not only to fight emerging fungal infections but also to avert the increase in drug-resistant strains. Although it has revealed to be a difficult job, new nano-based drug delivery systems and even new cellular targets and compounds with antifungal potential are now being investigated. This article will provide a summary of the state-of-the-art strategies that have been studied in order to improve antifungal therapy and reduce adverse effects of conventional drugs. The bidirectional relationship between Mycology and Nanotechnology will be also explained. Furthermore, the article will focus on new compounds from the marine environment which have a proven antifungal potential and may act as platforms to discover drug-like characteristics, highlighting the challenges of the translation of these natural compounds into the clinical pipeline.
BackgroundMLK3 gene mutations were described to occur in about 20% of microsatellite unstable gastrointestinal cancers and to harbor oncogenic activity. In particular, mutation P252H, located in the kinase domain, was found to have a strong transforming potential, and to promote the growth of highly invasive tumors when subcutaneously injected in nude mice. Nevertheless, the molecular mechanism underlying the oncogenic activity of P252H mutant remained elusive.MethodsIn this work, we performed Illumina Whole Genome arrays on three biological replicas of human HEK293 cells stably transfected with the wild-type MLK3, the P252H mutation and with the empty vector (Mock) in order to identify the putative signaling pathways associated with P252H mutation.ResultsOur microarray results showed that mutant MLK3 deregulates several important colorectal cancer- associated signaling pathways such as WNT, MAPK, NOTCH, TGF-beta and p53, helping to narrow down the number of potential MLK3 targets responsible for its oncogenic effects. A more detailed analysis of the alterations affecting the WNT signaling pathway revealed a down-regulation of molecules involved in the canonical pathway, such as DVL2, LEF1, CCND1 and c-Myc, and an up-regulation of DKK, a well-known negative regulator of canonical WNT signaling, in MLK3 mutant cells. Additionally, FZD6 and FZD10 genes, known to act as negative regulators of the canonical WNT signaling cascade and as positive regulators of the planar cell polarity (PCP) pathway, a non-canonic WNT pathway, were found to be up-regulated in P252H cells.ConclusionThe results provide an overall view of the expression profile associated with mutant MLK3, and they support the functional role of mutant MLK3 by showing a deregulation of several signaling pathways known to play important roles in the development and progression of colorectal cancer. The results also suggest that mutant MLK3 may be a novel modulator of WNT signaling, and pinpoint the activation of PCP pathway as a possible mechanism underlying the invasive potential of MLK3 mutant cells.
Background and Aims: Wines aged in wood barrels are likely to contain Brettanomyces yeasts, which are able to produce off-flavour compounds such as ethylphenols and vinylphenols. In this work, both off-flavoured and pleasant phenol compounds were quantified in Portuguese wines with an improved analytical technology. Methods and Results: A novel one-step dispersive liquid-liquid microextraction method with simultaneous derivatisation followed by fast low-pressure GC/MS was optimised and applied to 49 red wine samples of commercial and private origin. The analytical performance demonstrated the ability of the proposed method to accurately measure all the analytes under study.Conclusions: Ethyl and vinylphenols were present in most of the wines, at a concentration frequently higher than their preference threshold, and thus high enough to affect the overall aroma of the wine. Home-made wines had a higher concentration of off-flavour compounds in contrast with that of commercial wines, which had a high concentration of pleasant flavour compounds. Statistical analysis showed that less expensive wines exhibited a significantly lower concentration of syringol, and there was a tendency for the concentration of vinylphenols and ethylphenols to increase throughout wine aging.Significance of the Study: The presence of off-flavour phenols is a major concern of the wine industry, requiring great attention during the different stages of the winemaking process, so that wine aroma is not negatively affected. Figure 1. Formation of ethylphenols from hydroxycinnamic acids: A two-step reaction, adapted from Carrillo and Tena (2007) and Kheir et al. (2013).
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