Acetylcholinesterase inhibitory activity of oxazole derivatives

Comunicação oral sob a forma de painelAlzheimer’s disease (AD) is the most common form of dementia among persons over 65 years of age. It is a brain neurodegenerative disorder characterised by loss of memory and cognition. Current treatment is symptomatic, with the major therapeutic strategy based on the “cholinergic hypothesis”, specifically acetylcholinesterase (AChE) inhibition. Tacrine (THA) was the first and one of the few drugs approved in the last decade for the treatment of AD. However, due to the important adverse effects, such as hepatotoxicity, it is no longer widely used. Therefore, more potent and less aggressive THA analogues are necessary. This prompted us to evaluate the AChE inhibitory activity of new oxazole derivatives (compounds 1-5), presenting a pyridine ring (compounds 2,3) or a benzene ring (compounds 4,5) in the molecule (1). The biological activity of the compounds was evaluated by measuring the AChE inhibitory activity by an adaptation of the method reported by Ellman et al (2). The reaction rates were compared and the percent of inhibition by the test compounds was calculated. Assays were performed in quadruplicate in at least two independent experiments, and THA was used as a reference compound. At the maximum soluble concentrations, compounds 1 and 2 inhibited AChE activity by nearly 50%, while the inhibition by the derivative 3 was only around 30%. In contrast, the oxazolo-derivatives 4 and 5 were devoid of any inhibitory activity, which we can speculate to be due to the absence of the N atom in the benzene ring in these compounds. Collectively, these preliminary findings point to a potential interest of precursor 1 and THA-derivative 2 for AD therapeutics, although structural modifications are needed to improve the solubility of the compounds, which is an essential step to enhance their activity. References: 1. Carreiras MC, Eleutério A, Marco-Contelles J, unpublished results. 2. Ellman, G. L. et al. Biochem. Pharmacol. 1961; 7: 88-95.Financial support: Centro de Estudos de Ciências Farmacêuticas, Centro de Patogénese Molecular – UBMBE and Instituto de Química Orgánica General – CSIC

Biomass and leaf area in Eucalyptus clones in crop-livestock-forestry systems: implications for pruning.

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XPS and FTIR studies of DC reactive magnetron sputtered TiO2 thin films on natural based-cellulose fibers

FEDER, through Programa Operacional Factores de Competitividade - COMPETE and Fundacao para a Ciencia e a Tecnologia - FCT by the project UID/FIS/00068/2019; FEDER, through POACORES - Valorizacao e Desenvolvimento de Produtos da Conteira (Hedychium gardnerianum) - 01-0247-FEDER-000011; Regional Government of the Azores-Fundo Regional da Ciencia e Tecnologia (Fellowship M3.1.a/F/040/2015).Natural based-cellulosic fibers are trending due to the global awareness regarding environmental health and because their properties make them a great alternative to the synthetic fibers. However, these fibers also have some hindrances that can be solved with their functionalization. The present study concerns modification of the surface of natural based-cellulosic fibers extracted from stems of the ginger lily plant (Hedychium gardnerianum) with TiO2 films deposited by DC magnetron sputtering using a titanium (Ti) target. A detailed characterization of the TiO2-coated fibers was investigated by Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The results revealed that the sputtered TiO2 films can be attached to the ginger lily fibers mainly by their OH groups. XPS analysis further shows that C-OH group is not dominant, which means that no pure cellulose is present at the surface.publishersversionpublishe

Realising Variability in Dynamic Software Product Line Solutions

Modern systems need to be able to self-adapt to changes in user needs, and changes affecting the system itself or its environment. Dynamic software product line (DSPL) is an engineering approach for developing self-adaptive systems based on commonalities and variabilities for a family of similar systems. Currently, many DSPL approaches fail to meet all adaptability requirements, and in many cases, they are developed in a such unstructured manner that the controller is not explicitly represented, for example. We specify a two-dimension taxonomy to address basic technical issues for realising variability in DSPLs. The self-adaptation dimension classifies the different design choices for the adaptability requirements. The DSPL variability dimension classifies different design choices for implementing variability schemes and for creating different kinds of feature models. Our study was substantiated by surveying several DSPL approaches, and evaluating and comparing their different design strategies. We also summarise practical issues and difficulties, identify major trends in actual DSPL proposals, and suggest directions for future

Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management

The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma. HM displayed remarkable superior antiproliferative activity towards various cancer cell lines compared with temozolomide (TMZ), a triazene drug in clinical use, that acts through DNA alkylation. In B16-F10 cells, HM induced a cell cycle arrest at phase G0/G1 with a 2.8-fold decrease in cell proliferation index. Also, compared to control cells, HM led to a concentration-dependent reduction in tyrosinase activity and increase in caspase 3/7 activity. To maximize the therapeutic performance of HM in vivo, its incorporation in long blood circulating liposomes, containing poly(ethylene glycol) (PEG) at their surface, was performed for passively targeting tumour sites. HM liposomes (LIP HM) exhibited high stability in biological fluids. Preclinical studies demonstrated its safety for systemic administration and in a subcutaneous murine melanoma model, significantly reduced tumour progression. In a metastatic murine melanoma model, a superior antitumour effect was also observed for mice receiving LIP HM, with markedly reduction of lung metastases compared to positive control group (TMZ). Biodistribution studies using 111In-labelled LIP HM demonstrated its ability for passively targeting tumour sites, thus correlating with the high therapeutic effect observed in the two experimental murine melanoma models. Overall, our proposed nanotherapeutic strategy was validated as an effective and safe alternative against melanoma.</p

Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management

The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma. HM displayed remarkable superior antiproliferative activity towards various cancer cell lines compared with temozolomide (TMZ), a triazene drug in clinical use, that acts through DNA alkylation. In B16-F10 cells, HM induced a cell cycle arrest at phase G0/G1 with a 2.8-fold decrease in cell proliferation index. Also, compared to control cells, HM led to a concentration-dependent reduction in tyrosinase activity and increase in caspase 3/7 activity. To maximize the therapeutic performance of HM in vivo, its incorporation in long blood circulating liposomes, containing poly(ethylene glycol) (PEG) at their surface, was performed for passively targeting tumour sites. HM liposomes (LIP HM) exhibited high stability in biological fluids. Preclinical studies demonstrated its safety for systemic administration and in a subcutaneous murine melanoma model, significantly reduced tumour progression. In a metastatic murine melanoma model, a superior antitumour effect was also observed for mice receiving LIP HM, with markedly reduction of lung metastases compared to positive control group (TMZ). Biodistribution studies using 111In-labelled LIP HM demonstrated its ability for passively targeting tumour sites, thus correlating with the high therapeutic effect observed in the two experimental murine melanoma models. Overall, our proposed nanotherapeutic strategy was validated as an effective and safe alternative against melanoma