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

Desenvolvimento de um betão com elevada resistência ao ataque por ácido sulfúrico contendo resíduos de borracha de pneus

Os resíduos de pneus representam um problema ambiental de gravidade crescente, actualmente 1.000 milhões de pneus atingem o fim da sua vida útil a cada ano que passa e prevê-se que a partir do ano 2030 seja necessário reciclar 5000 milhões de pneus anualmente. O presente artigo apresenta resultados sobre a resistência à compressão e a resistência ao ataque por ácido sulfúrico de betões com razãoA/L=0,35), com substituição de areia por resíduos de borracha de pneus e de cimento por cinzas volantes e metacaulino. Os resultados mostram que a incorporação de resíduos de borracha se traduz em relevantes reduções da resistência à compressão, as quais são no entanto minimizadas pelo efeito sinérgico entre as cinzas volantes e o metacaulino. Os resultados mostram também que as misturas com 45% de cinzas volantes e 15% de metacaulino apresentam uma elevada resistência ao ataque por ácido sulfúrico independentemente da percentagem de borracha utilizada, pelo menos até 15%, revelando uma elevada aptidão para serem utilizadas em meios de elevada agressividade química, como sejam as manilhas utilizadas na drenagem de águas residuais

Properties and durability of HPC with tyre rubber wastes

Author's personal copyAn estimated 1000 million tyres reach the end of their useful lives every year and 5000 millions more are expected to be discarded in a regular basis by the year 2030. Up to now a small part is recycled and millions of tyres are just stockpiled, landfilled or buried. This paper presents results about the properties and the durability of HPC with partial replacement of sand by tyre rubber wastes. Fly ash and metakaolin are used as partial cement replacement. The durability performance was assessed by means of capillary water absorption and resistance to sulphuric acid attack. The results show the existence of a synergetic effect between fly ash and metakaolin that minimizes the strength loss associated to the use of rubber waste. Results also show that is possible to use rubber waste up to 15% and still maintain a high resistance to acid attack. The mixes with 45% fly ash and 15% metakaolin show a much higher resistance to sulphuric acid attack than the reference mix independently of the rubber waste content

Biometric evaluation of morpho-agronomic traits in pepper lines and hybrids

Objetivou-se avaliar linhagens e h?bridos de pimenta (Capsicum chinense e C. annuum) afim de obter informa??es sobre o desempenho agron?mico, heterose, heterobeltiose, correla??es fenot?picas e dissimilaridade gen?tica. Foram avaliadas as linhagens PIM-030, BGH-433, BGH-4285, Numex Sweet, Numex Garnet e os h?bridos simples Numex Sweet x PIM-030, Numex Garnet x PIM-030 e BGH-4285 x BGH-433. O experimento foi conduzido com oito tratamentos e quatro repeti??es, em casa de vegeta??o, no campus JK da UFVJM. Foram avaliadas 22 caracter?sticas morfoagron?micas. No h?brido BGH-4285 x BGH-433 foi observado maior heterose e heterobeltiose para produtividade total de frutos e produtividade de massa seca total de frutos, sendo interessante aos futuros programas de melhoramento. Observa-se que plantas de maior porte tendem a ser mais produtivas com maiores massas fresca dos frutos e frutos com pericarpo mais espesso, frutos maiores com maiores pedicelos e com sementes mais densas, sendo importante para a produ??o de p?prica. As linhagens BGH-433, BGH-4285 e PIM-030 s?o as mais recomendadas para uso em programas de melhoramento.In this study, we aimed to evaluate pepper lines and hybrids (Capsicum chinense and C. annuum) in order to obtain information on agronomic performance, heterosis, heterobeltiosis, phenotypic correlations and genetic dissimilarity. We evaluated lines PIM-030, BGH-433, BGH-4285, Numex Sweet, Numex Garnet and simple hybrids Numex Sweet x PIM-030, Numex Garnet x PIM-030 and BGH-4285 x BGH-433. The research was conducted with eight treatments and four replications in a greenhouse, at campus JK of UFVJM. Twenty two agronomic traits were evaluated. The hybrid BGH-4285 x BGH-433 presents higher heterosis and heterobeltiosis for total fruit productivity and productivity of total fruit dry mass, information of great value for future breeding studies. The authors noticed that larger plants tend to be more productive and present higher fruit fresh mass and also fruits with thicker pericarp, as well as larger fruits having longer pedicels with denser seeds, important for production of paprika. Lines BGH-433, BGH-4285 and PIM-030 are the most recommended to be used in breeding programs

School Evasion in the Brazilian trends: analyzing the vectors that influence students’ decision to interrupt their formative process

Research data demonstrate that the analyzes built around School Evasion considers, primarily, the quantitative metrics of studentsrsquo; entry and exit and also the monetary losses, especially because it would be incoherent not to take as reference the goals and objectives outlined for education school system. However, analyzing the vectors that influence studentsrsquo; decision to interrupt their formative process, according to purely numerical criteria, would imply in ignoring the function of educational institutions and the real causes/reasons stemming from the social and relational demand of students' passage on educational institutions. For this reason, problematizing some of the recurring issues and incidents generated by certain investigations seems instigating and challenging. If in on the one hand, the attitude of understanding the conceptualization, the investigative tendencies and the characteristics of the studies give rise to certain criticisms that put in check the complexity of the object in question, on the other, it can stimulate the construction of other tendencies, new pathways, other possible ways of overcoming the gaps identified in the studies about School Evasion in Brazil

Yicathins B and C and analogues: total synthesis, lipophilicity and biological activities

Natural products had always be an important source of new hits and leads in drug discovery. The marine environment has been regarded as a significant souce of novel and exquisite bioactive compounds. Yicathins B and C are two marine derived xanthones that have shown antibacterial and antifungal activities. Herein, the total synthesis of these yicathins is reported for the first time as well as six novel analogues. As marine natural products tend to bear very lipophilic scaffolds, the lipophilicity of yicathins and its analogues was evaluated using the classical octanol:water system and a biomimetic model based system. As the xanthonic nucleus is a â privileged structureâ , other biological activities were evaluated, namely antitumor and anti-inflammatory activities. An interesting anti-inflammatory activity was identified for yicathins analogues that paves the way for the design of dual activity (anti-infective and anti-inflammatory) marine inspired xanthones derivatives.This work was supported through national funds provided by FCT/MCTES - Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE - Programa Operacional Factores de Competitividade (POFC) programme, under the projects PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599 - Promover a ProducAo Cientifica e Desenvolvimento Tecnologico e a ConstituicAo de Redes Tematicas (3599-PPCDT)) and PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER- 028736) in the framework of the programme PT2020. D. R. P. L. is grateful for research grant PTDC/MAR-BIO/4694/2014-BI-2017-003. J. X. S. thanks the FCT PhD Programmes and Programa Operacional Capital Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences), reference PD/00016/2012; through the FCT and POCH for PhD grants (SFRH/BD/98105/2013 and SFRH/BD/116167/2016). The authors would like to thank Sara Cravo and Gisela Adriano for the technical support, the Centro de Apoio Cientifico e Tecnoloxico a Investigation (C.A.C.T.I., University of Vigo, Pontevedra, Spain) for HRMS analysis, the Centro de Materiais da Universidade do Porto (CEMUP, Porto, Portugal) for HRMS, and the Departamento de Quimica da Universidade de Aveiro (Portuguese NMR network) for the NMR analysis

Probe-dependent negative allosteric modulators of the long-chain free fatty acid receptor FFA4

High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein–coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential of free fatty acid receptor 4 (FFA4) as a novel therapeutic target for the treatment of type II diabetes, the broad distribution pattern of this receptor suggests it may play a range of roles beyond glucose homeostasis in different cells and tissues. To date, a single molecule, 4-methyl-N-9H-xanthen-9-yl-benzenesulfonamide (AH-7614), has been described as an FFA4 antagonist; however, its mechanism of antagonism remains unknown. We synthesized AH-7614 and a chemical derivative and demonstrated these to be negative allosteric modulators (NAMs) of FFA4. Although these NAMs did inhibit FFA4 signaling induced by a range of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many anticancer drugs suggests that a novel close chemical analog of AH-7614 devoid of FFA4 activity, 4-methyl-N-(9H-xanthen-9-yl)benzamide (TUG-1387), will also provide a useful control compound for future studies assessing FFA4 function. Using TUG-1387 alongside AH-7614, we show that endogenous activation of FFA4 expressed by murine C3H10T1/2 mesenchymal stem cells is required for induced differentiation of these cells toward a more mature, adipocyte-like phenotype