Design and synthesis of new inhibitors of p53–MDM2 interaction with a chalcone scaffold

The virtual screening of a library of chalcone derivatives led us to the identification of potential new MDM2 ligands. The chalcones with the best docking scores obeying the Lipinski rule of five were subsequently prepared by base-catalyzed aldol reactions. The activity of these compounds as inhibitors of p53–MDM2 interaction was investigated using a yeast-based screening assay. Using this approach two chalcones (3 and 4) were identified as putative small molecule inhibitors of p53–MDM2 interaction. The activity of both chalcones was further investigated in a panel of human tumor cells. Chalcones 3 and 4 revealed a pronounced tumor cell growth inhibitory effect on tumor cell lines. Additionally, chalcone 4 caused alterations in the cell cycle profile, induced apoptosis and increased the levels of p53, p21 and PUMA proteins in NCI-H460 cells. Computational docking studies allowed to predict that, like nutlin-3A (a well-known small-molecule inhibitor of p53–MDM2 interaction), chalcones 3 and 4 bind to the p53-binding site of MDM2. The results here presented will be valuable for the structure-based design of novel and potent p53–MDM2 inhibitors.This research was partially supported by the Strategic Funding UID/Multi/04423/2013 , ERDF , COMPETE , and FCT under the projects PTDC/MAR-BIO/4694/2014, and INNOVMAR – Innovation and Sustainability in the Management and Exploitation of Marine Resources, reference NORTE-01-0145-FEDER-000035 , Research Line NOVELMAR . This work also received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007265) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/QUI/50006/2013 and the FCT project PTDC/DTP-FTO/1981/2014, “PEst-C/SAU/LA0003/2013”, “NORTE-07-0162-FEDER-00018 – Contributos para o reforço da capacidade do IPATIMUP enquanto actor do sistema regional de inovação” and NORTE-07-0162-FEDER-000067 – Reforço e consolidação da capacidade infraestrutural do IPATIMUP para o sistema regional de inovação”, both supported by ON.2 – O Novo Norte, through FEDER funds under the QREN. IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT. The authors also thank FCT for the grants of R.T. Lima ( SFRH/BPD/68787/2010 ), J. Soares ( SFRH/BD/78971/2011 ), and S. Gomes ( SFRH/BD/96189/2013 ; Doctoral Programme BiotechHealth), L. Raimundo ( PD/BI/113926/2015 , Doctoral Programme BiotechHealth)

The present and future offshore wind resource in the Southwestern African region

In the last decades, offshore wind harvesting has increased enormously, and is seen as a renewable energy resource with great potential in many regions of the world. Therefore, it is crucial to understand how this resource will evolve in a warming climate. In the present study, offshore wind resource in the Southwestern African region is analysed for the present and future climates. A ROM (REMO-OASIS-MPIOM) climate simulation in uncoupled and coupled atmosphere–ocean mode, at 25 km horizontal resolution, and a multi-model ensemble built with a set of regional climate models from the CORDEX-Africa experiment at 0.44° resolution were used. The projected changes of the offshore wind energy density throughout the twenty-first century are examined following the RCP4.5 and RCP8.5 greenhouse gas emissions scenarios. Characterised by strong coastal-parallel winds, the Southwestern African offshore region shows high values of wind energy density at 100 m, up to 1500 Wm⁻² near the coast, particularly offshore Namibia and west South Africa. Conversely, along Angola’s coast the available offshore wind energy density is lower. Throughout the twenty-first century, for the weaker climate mitigation scenario (RCP8.5), an increase of the offshore wind resource is projected to occur along Namibia and South African western coasts, more pronounced at the end of the century (+ 24%), while a decrease is projected along Angola’s coasts, reaching a negative anomaly of about − 32%. Smaller changes but with the same pattern are projected for the stronger climate mitigation scenario (RCP4.5). The future deployment of offshore floating hub turbines placed at higher heights may allow higher production of energy in this region. Along offshore Namibia and west South Africa, the wind energy density at 250 m showed differences that range between 30 and 50% relative to wind energy density at 100 m

Bacterial cellulose as a novel stabilizer and texturizer for cosmetic and food applications

Book of Abstracts of CEB Annual Meeting 2017[Excerpt] Bacterial nanocellulose (BNC) is a sophisticated material produced biotechnologically by different microorganisms, but most efficiently by acetic acid bacteria from the genera Gluconacetobacter. While chemically identical to plant cellulose, BNC is chemically pure. Each BNC nanofiber is a bundle of cellulose nanofibrils. Due to their nano-size, these aggregates of extended cellulose chains have a rather large surface area. The unique properties of BNC account for an extraordinary physico-chemical and mechanical behaviour. For industrial applications, hydrocolloidal microcrystalline cellulose from vegetable sources is widely used to regulate the texture, rheology, stability and organoleptic properties of the formulations [1]. Several studies are being carried out to investigate the technological role of BNC. Preliminary results already showed that BNC is technically superior to these vegetable celluloses, and can outperform plant celluloses in several applications within the food industry. As a novel hydrocolloid, BNC presents important features such as the stabilization of heterogeneous systems (air-liquid, solid-liquid and liquidliquid): it is able to stabilize aerogels, increasing the incorporation of air in the liquid matrix (overrun), so it can be used as an additive in ice cream, smoothies and whipped cream; it can stabilize solid particles in a liquid matrix (e.g. cocoa particles in chocolate milk); BNC also stabilizes of oil-in-water emulsions, in spoonable and pourable dressings, without the need to add any other emulsifying agents. [...]info:eu-repo/semantics/publishedVersio

Prevalence of noncarious cervical lesions among adults:a systematic review

Objectives: This study aims to systematically review the literature on noncarious cervical lesions (NCCLs) and calculate an overall prevalence estimate. Methods: The protocol of this systematic review was prepared according to PRISMA and MOOSE guidelines. The MEDLINE-PubMed and Cochrane-CENTRAL databases were searched. Relevant published papers that provided information regarding the prevalence or number of NCCLs among general or specific populations were included. Results: The initial search identified 569 titles and abstracts, 24 of which met the eligibility criteria involving 14,628 participants. The weighted mean prevalence of NCCLs among the whole studied population was 46.7 % (95 % CI: 38.2; 55.3 %), ranging from 9.1%–93%. Based on sub-analyses, studies with populations older than 30 years revealed higher weighted prevalence (53 %) than those with populations younger than 30 years (43 %). Regarding the diagnostic method, when visual or tactile clinical examination was used, the prevalence was lower than when the Smith and Knight tooth wear index was used. When different definitions were used, the weighted mean prevalence varied from 28 % to 62 %. As to the terms used to address the lesions, the prevalence was higher when “noncarious cervical lesion” was used and lower when “root defects,” “abrasion,” or “abfraction” were used. When geographical regions were compared, South America had the highest reported prevalence of NCCLs, while the United States had the lowest. Moreover, general populations presented the highest prevalence, slightly higher than dental populations, whose members frequented dental practices. Conclusion: The overall prevalence of NCCLs was 46.7 % and higher in older populations. Visual and tactile clinical examination underestimate this prevalence compared to the established index. The terms and definitions used also influenced the prevalence data. Distinct geographical differences were observed, and general populations were more inclined to present NCCLs

Can water remediated by manganese spinel ferrite nanoparticles be safe for marine bivalves?

In the last few years the use of nanoparticles (NPs) such as the manganese spinel ferrite (MnFe2O4) has been increasing, with a vast variety of applications including water remediation from pollutants as metal(oid)s. Although an increasing number of studies already demonstrated the potential toxicity of NPs towards aquatic systems and inhabiting organisms, there is still scarce information on the potential hazard of the remediated water using NPs. The present study aimed to evaluate the ecotoxicological safety of Pb contaminated seawater remediated with MnFe2O4, NPs, assessing the toxicity induced in mussels Mytilus galloprovincialis exposed to contaminated seawater and to water that was remediated using MnFe2O4, NPs. The results obtained demonstrated that seawater contaminated with Pb, NPs or the mixture of both (Pb + NPs) induced higher toxicity in mussels compared to organisms exposed to Pb, NPs and Pb + NPs after the remediation process. In particular, higher metabolic depression, oxidative stress and neurotoxicity were observed in mussels exposed to contaminated seawater in comparison to mussels exposed to remediated seawater.publishe

Adjuvant requirement for successful immunization with recombinant derivatives of Plasmodium vivax merozoite surface protein-1 delivered via the intranasal route

Recently, we generated two bacterial recombinant proteins expressing 89 amino acids of the C-terminal domain of the Plasmodium vivax merozoite surface protein-1 and the hexa-histidine tag (His6MSP1(19)). One of these recombinant proteins contained also the amino acid sequence of the universal pan allelic T-cell epitope (His(6)MSP1(19)-PADRE). in the present study, we evaluated the immunogenic properties of these antigens when administered via the intra-nasal route in the presence of distinct adjuvant formulations. We found that C57BL/6 mice immunized with either recombinant proteins in the presence of the adjuvants cholera toxin (CT) or the Escherichia coli heat labile toxin ( LT) developed high and long lasting titers of specific serum antibodies. the induced immune responses reached maximum levels after three immunizing doses with a prevailing IgG1 subclass response. in contrast, mice immunized by intranasal route with His(6)MSP1(19)-PADRE in the presence of the synthetic oligonucleotides adjuvant CpG ODN 1826 developed lower antibody titers but when combined to CT, CpG addition resulted in enhanced IgG responses characterized by lower IgG1 levels. Considering the limitations of antigens formulations that can be used in humans, mucosal adjuvants can be a reliable alternative for the development of new strategies of immunization using recombinant proteins of P. vivax.Universidade Federal de São Paulo, Dept Microbiol Imunol Parasitol, Escola Paulista Med, BR-04044010 São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Interdisciplinar Terapia Genica, Escola Paulista Med, BR-04044010 São Paulo, BrazilUniv São Paulo, Dept Microbiol, Inst Ciencias Biomed, São Paulo, BrazilUniv São Paulo, Dept Anal Clin & Toxicol, Fac Ciencias Farmaceut, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Imunol Parasitol, Escola Paulista Med, BR-04044010 São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Interdisciplinar Terapia Genica, Escola Paulista Med, BR-04044010 São Paulo, BrazilWeb of Scienc

A Pyranoxanthone as a potent antimitotic and sensitizer of cancer cells to low doses of Paclitaxel

Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic arrest followed by cell death. This antimitotic activity of MTAs is dependent on the spindle assembly checkpoint (SAC), which monitors the integrity of the mitotic spindle and proper chromosome attachments to microtubules in order to ensure accurate chromosome segregation and timely anaphase onset. However, the cytotoxic activity of MTAs is restrained by drug resistance and/or toxicities, and had motivated the search for new compounds and/or alternative therapeutic strategies. Here, we describe the synthesis and mechanism of action of the xanthone derivative pyranoxanthone 2 that exhibits a potent anti-growth activity against cancer cells. We found that cancer cells treated with the pyranoxanthone 2 exhibited persistent defects in chromosome congression during mitosis that were not corrected over time, which induced a prolonged SAC-dependent mitotic arrest followed by massive apoptosis. Importantly, pyranoxanthone 2 was able to potentiate apoptosis of cancer cells treated with nanomolar concentrations of paclitaxel. Our data identified the potential of the pyranoxanthone 2 as a new potent antimitotic with promising antitumor potential, either alone or in combination regimens.Portugal 2020: PTDC/SAU-PUB/28736/2017 (POCI-01-0145-FEDER-028736; FCT: SFRH/BD/116167/2016/ SFRH/BD/140844/2018/ PD/00016/2012info:eu-repo/semantics/publishedVersio

Remediation of Arsenic from contaminated seawater using manganese spinel ferrite nanoparticles: ecotoxicological evaluation in Mytilus galloprovincialis

In the last decade different approaches have been applied for water remediation purposes, including the use of nanoparticles (NPs) to remove metals and metalloids from water. Although studies have been done on the toxic impacts of such NPs, very scarce information is available on the impacts of water after decontamination when discharged into aquatic environments. As such, in the present study we aimed to evaluate the ecotoxicological safety of seawater previously contaminated with arsenic (As) and remediated by using manganese-ferrite (MnFe2O4-NPs) NPs. For this, mussels Mytilus galloprovincialis were exposed for 28 days to different conditions, including clean seawater (control), As (1000 μg L−1) contaminated and remediated (As 70 μg L−1) seawater, water containing MnFe2O4- NPs (50 mg L−1) with and without the presence of As. At the end of exposure, concentrations of As in mussels tissues were quantified and biomarkers related to mussels’ metabolism and oxidative stress status were evaluated. Results revealed that mussels exposed to water contaminated with As and to As + NPs accumulated significantly more As (between 62% and 76% more) than those exposed to remediated seawater. Regarding biomarkers, our findings demonstrated that in comparison to remediated seawater (conditions a, b, c) mussels exposed to contaminated seawater (conditions A, B, C) presented significantly lower metabolic activity, lower expenditure of energy reserves, activation of antioxidant and biotransformation defences, higher lipids and protein damages and greater AChE inhibition. Furthermore, organisms exposed to As, NPs or As + NPs revealed similar biochemical effects, both before and after water decontamination. In conclusion, the present study suggests that seawater previously contaminated with As and remediated by MnFe2O4-NPs presented significantly lower toxicity than As contaminated water, evidencing the potential use of these NPs to remediate seawater contaminated with As and its safety towards marine systems after discharges to these environments.publishe

Enhanced dissolution efficiency of tamoxifen combined with methacrylate copolymers in amorphous solid dispersions

Amorphous solid dispersions (SDs) containing poorly soluble tamoxifen dispersed in a meth(acrylate) copolymer combination were proposed as a controlled release system. The objective of this work was to investigate the characteristics and performance of the tamoxifen–polymer mixture and evaluate the changes in functionality through a supersaturating dissolution study condition while comparing it to a physical mixture at a fixed drug-loading proportion. Two polymers, Eudragit® L 100 and Eudragit® RL 100, were used to prepare SDs with a 1:1 polymer ratio, containing 10%, 20%, or 30% (wt/wt%) of tamoxifen, by the solvent evaporation method. A physical mixture containing 30% of tamoxifen was also prepared for comparison. SDs were characterized by X-ray diffraction, Fourier-transform infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Dissolution tests were conducted under non-sink conditions to verify the occurrence of drug recrystallization upon its release. Solid-state characterizations confirmed that the drug was in the amorphous state within the polymeric matrix. Tamoxifen release in an acidic medium was mainly affected by the increase in drug concentration caused by the possible loss of interactions that characterize the main polymer functionalities. At pH 7.4, supersaturation was slowly achieved while also contributing to the increase in the kinetic solubility of the drug. The physical mixture demonstrated the best overall performance, suggesting that the polymeric interactions may have negatively affected the drug release. The combination of polymers in the composing SD proved to be a promising strategy to tailor the delivery of poorly soluble drugs. Our study highlights important information on the behavior of tamoxifen as a poorly soluble drug in supersaturating dissolution conditions while released from SD systems.This work was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil), by the Portuguese Science and Technology Foundation (FCT/MCT), and European Funds (PRODER/COMPETE) under the projects M-ERA-NET/0004/2015 and UIDB/04469/2020 (strategic fund) and co-financed by FEDER under the Partnership Agreement PT2020.info:eu-repo/semantics/publishedVersio

Complexidade Sistêmica: Uma Proposta de Construto de Visão Multidimensional

Na modernidade, o desenvolvimento organizacional depende fundamentalmente dos sistemas de informação. Estes, por sua vez, estão imbricados em cenários complexos, especialmente porque envolvem domínios de atividade humana e porque sofrem com a emergência dos pressupostos da imprevisibilidade, da instabilidade e da incerteza. Com o propósito de buscar uma alternativa de avaliação para tais cenários, este estudo apresenta uma proposta de construto de visão multidimensional para orientar o desenvolvimento de sistemas de informação e servir de parâmetro de avaliação para prospecção de contexto