From a multitarget antidiabetic glycosyl isoflavone towards new molecular entities against diabetes and Alzheimer’s disease : generation of lead series and target assessment

Type 2 diabetes and Alzheimer’s disease are closely related amyloid diseases globally affecting millions of people. However, the pathophysiological mechanisms connecting both diseases still require further investigation. In this work, we compile the existing evidence in the literature to allow the establishment of etiological links needed for drug discovery against diabetes-induced dementia. Furthermore, we provide an extensive revision of bioactive lead molecules that encourage further studies, particularly focusing on polyphenol sugar conjugates endowed with antidiabetic and neuroprotective activities. The state-of-the-art synthetic approaches for the generation of these types of molecules are also covered, thus setting the organic chemistry background for the original research work here developed. The use of carbohydrate-based molecules in drug research and development has multiple recognized benefits. In addition to enhanced solubility, bioavailability, and antidiabetic effects as previously reported, in this work we show, for the first time, that C-glucosylation is able to reverse the membrane dipole potential decrease induced by planar lipophilic polyphenols, elsewhere described as Pan-Assay Interference Compounds. This is a relevant discovery for drug development, particularly in the context of this thesis due to the polyphenolic nature of the compounds here presented. One of these compounds, 8-β-D-glucosylgenistein, was investigated in a diet-induced obese mouse of type 2 diabetes and found to exert a multitarget antidiabetic mechanism of action that goes beyond prior conjectures. Indeed, this antihyperglycemic glucosyl isoflavone reduces the renal threshold for glucose reabsorption, ameliorates diabetes-associated non-alcoholic fatty liver disease and hypercholesterolemia, normalizes insulin-degrading enzyme expression, and increases glucosestimulated insulin secretion. However, the detected inability of this polyphenol to permeate the blood brain barrier and to exert neuroprotective effects encouraged the pursuit of new scaffolds with therapeutic potential against diabetes-induced dementia. The role of amyloid β in the neurodegenerative processes occurring in Alzheimer’s disease and diabetes-induced dementia is, nowadays, unquestionable. Yet, targeted therapies aimed at inhibiting amyloid secretion or aggregation have, so far, failed clinical trials. In the past decade, the role of the cellular prion protein (PrPC) – a high-affinity ligand of amyloid β oligomers (Aβo) – has, in fact, been regarded as the limiting step in the cascade of events leading to neurodegeneration. Fyn kinase is one of the key players in this cascade, which culminates with the formation of neurofibrillary tangles composed by hyperphosphorylated tau, eventually leading to cell death. In this perspective, we have identified innovative N-methylpiperazinyl flavones and their glucosyl derivatives as Aβo-binders and non-toxic disruptors of Aβo-PrPC interactions. Furthermore, easily accessed glucosyl polyphenols with improved pharmacokinetic properties were also investigated and revealed to inhibit Aβ-induced Fyn activation with concomitant decrease in tau phosphorylation. Fyn kinase inhibition is considered a novel therapeutic strategy for Alzheimer’s disease, and these compounds are the first to accomplish this goal, with proven downstream effects. These molecules thus share the potential for further development against Alzheimer’s disease and diabetes-induced dementia. The work presented in this thesis elucidates the therapeutic relevance of natural and nature-inspired C-glucosyl polyphenols in the studied biological context, and highlights the usefulness of carbohydrate-based molecules for medicinal chemistry applications

Where Do We Stand?

Funding: Centro de Química Estrutural is a Research Unit funded by Fundação para a Ciência e Tecnologia through projects UIDB/00100/2020 and UIDP/00100/2020. Institute of Molecular Sciences is an Associate Laboratory funded by FCT through project LA/P/0056/2020. A.M. Matos thanks FCT, CQE, and Faculdade de Ciências da Universidade de Lisboa for her CEECInst Junior Researcher Contract, and FCT for funding through the Individual Call for Scientific Employment Stimulus (2022.07037.CEECIND). CBIOS—Universidade Lusófona’s Research Center for Biosciences & Health Technologies is a Research Unit funded by Fundação para a Ciência e Tecnologia through projects grants UIDB/04567/2020 and UIDP/04567/2020 to CBIOS. R.M. also thanks FCT and CBIOS for her CEECInst Assistant Researcher Contract (CEEC/04567/CBIOS/2020) and COFAC/ILIND—Cooperativa De Formação e Animação Cultural CRL/Instituto Lusófono de Investigação e Desenvolvimento (grant COFAC/ILIND/CBIOS/2/2021).The type 2 diabetes epidemic is real and hardly coming to an end in the upcoming years. The efforts of the scientific community to develop safer and more effective compounds for type 2 diabetes based on the structure of natural (poly)phenols are remarkable and have indeed proven worthwhile after the introduction of gliflozins in clinical practice. However, low-quality reports on the antidiabetic potential of plant-derived lipophilic (poly)phenols continue to pile up in the literature. Many of these compounds continue to be published as promising functional nutrients and antidiabetic pharmaceutical leads without consideration of their Pan-Assay Interference Compounds (PAINS) profile. This evidence-based opinion article conveys the authors' perspectives on the natural (poly)phenol artillery as a valuable and reliable source of bioactive compounds for diabetes. Ultimately, in light of the already established membrane-perturbing behavior of lipophilic (poly)phenols, together with the multiple benefits that may come with the introduction of a C-glucosyl moiety in bioactive compounds, we aim to raise awareness of the importance of contemplating the shift to (poly)phenol-carbohydrate combinations in the development of functional nutrients, as well as in the early stages of antidiabetic drug discovery.publishersversionpublishe

O tratamento oncológico e a sua relação com a xerostomia

Dissertação para obtenção do grau de Mestre no Instituto Superior de Ciências da Saúde Egas MonizA xerostomia é definida como uma sensação de boca seca, que pode ou não estar acompanhada de uma disfunção salivar. Nos últimos anos, tem sido discutida a sua etiologia como um resultado dos tratamentos oncológicos não cirúrgicos geralmente empregues nos casos de carcinomas das células escamosas da cabeça e do pescoço, nomeadamente radioterapia e quimioterapia. Ambas as terapias antitumorais têm sido associadas a um decréscimo do fluxo salivar. A presente revisão bibliográfica tem como principal objetivo reunir todos os conhecimentos básicos acerca da xerostomia como uma complicação da radioterapia da cabeça e do pescoço e da quimioterapia. A saliva é um componente fundamental para a homeostase da saúde oral, e uma vez comprometida, podem surgir inúmeras complicações orais ou até mesmo da saúde geral. Desta forma, a xerostomia passa a ter um papel preponderante na vida dos doentes oncológicos, constituindo um novo problema para além da doença maligna. Ao longo da presente revisão são abordados os princípios básicos da radio e da quimioterapia e a relação destas com a xerostomia, os mecanismos subjacentes, o diagnóstico da patologia, bem como medidas de prevenção e de tratamento empregues e em investigação na atualidade. Este conhecimento permitirá aos Médicos Dentistas atuar de forma eficaz no acompanhamento odontológico dos doentes oncológicos com patologia da cabeça e do pescoço, procurando sempre manter a saúde oral e melhorar a qualidade de vida

Mental Health and Interpersonal Relationships Impact in Psychological and Physical Symptoms During Adolescence

This article aims to understand and characterize the impact of factors of mental health and interpersonal relationships on physical and psychological symptoms in adolescents. It includes 8215 students, of which 4327 are girls (52.7%), with an average age of 14.36 years (SD=2.28) that participate in the study Health Behavior in School aged Children/HBSC. Descriptive statistics, ANOVA analysis and logistic regressions were performed for two dependent variables in study – psychological symptoms and physical symptoms. In general, girls show values in relation to physical and psychological symptoms, anxiety/stress and depression that are less positive when compared to boys. Older adolescents show values that are less positive in the same variables, except for anxiety/stress, which presents higher values in younger adolescents. Girls and older adolescents have lower positive values with regard to relationships with family, teachers and colleagues, than boys and younger adolescents. The female gender, higher values of depression followed by less support from the family contribute strongly to the explanation of psychological and physical symptoms. It is possible to verify that the variance explained by gender and by depression is higher in the case of psychological symptoms when compared to physical symptoms, and that the variance explained by family relationship is higher in the case of physical symptoms when compared with psychological symptoms. This study identifies a positive relationship between mental health (less physical and psychological symptoms, lower depression and lower anxiety) and more positive relationships with family, colleagues and teachers, as well as gender and age specificities. These results have important implications in terms of public policies for the family and the school contextsEste artículo tuvo como objetivo examinar el impacto de los factores de salud mental y de las relaciones interpersonales sobre los síntomas físicos y psicológicos en adolescentes. La muestra estuvo formada por 8215 estudiantes, de los cuales 4327 fueron niñas (52,7%), con una edad media de 14,36 años (DT = 2,28), que participaron en el estudio Health Behavior in School aged Children/HBSC. Se realizaron estadísticos descriptivos, ANOVA y regresiones logísticas para dos variables dependientes en este estudio: los síntomas psicológicos y los síntomas físicos. En general, las niñas mostraron valores de síntomas físicos y psicológicos, ansiedad / estrés y depresión que fueron menos positivos en comparación con los niños. Los adolescentes mayores mostraron asimismo valores menos positivos en dichas variables, excepto en la variable ansiedad / estrés, que presenta valores más altos en adolescentes más jóvenes. Las niñas y los adolescentes mayores tuvieron valores positivos más bajos con respecto a las relaciones con la familia, los maestros y los compañeros que los niños y los adolescentes más jóvenes. El género femenino, mayores valores de depresión y un menor apoyo de la familia contribuyeron fuertemente a la explicación de los síntomas psicológicos y físicos. La varianza explicada por género y por depresión fue mayor en el caso de síntomas psicológicos en comparación con los síntomas físicos, mientras que la varianza explicada por las relaciones familiares fue mayor en el caso de los síntomas físicos que en los síntomas psicológicos. Este estudio identifica una relación positiva entre la salud mental (menos síntomas físicos y psicológicos, y menor depresión y ansiedad) y relaciones más positivas con la familia, los compañeros y profesores, además de algunas diferencias por género y edad. Estos resultados tienen importantes implicaciones en términos de políticas públicas para el contexto familiar y escola

Untargeted Metabolomics Reveals Antidepressant Effects in a Marine Photosynthetic Organism: The Diatom Phaeodactylum tricornutum as a Case Study

The increased use of antidepressants, along with their increased occurrence in aquatic environments, is of concern for marine organisms. Although these pharmaceutical compounds have been shown to negatively affect marine diatoms, their mode of action in these non-target, single-cell phototrophic organisms is yet unknown. Using a Fourier-transform ion cyclotron-resonance mass spectrometer (FT-ICR-MS) we evaluated the effects of fluoxetine in the metabolomics of the model diatom Phaeodactylum tricornutum, as well as the potential use of the identified metabolites as exposure biomarkers. Diatom growth was severely impaired after fluoxetine exposure, particularly in the highest dose tested, along with a down-regulation of photosynthetic and carbohydrate metabolisms. Notably, several mechanisms that are normally down-regulated by fluoxetine in mammal organisms were also down-regulated in diatoms (e.g., glycerolipid metabolism, phosphatidylinositol signalling pathway, vitamin metabolism, terpenoid backbone biosynthesis and serotonin remobilization metabolism). Additionally, the present work also identified a set of potential biomarkers of fluoxetine exposure that were up-regulated with increasing fluoxetine exposure concentration and are of high metabolic significance following the disclosed mode of action, reinforcing the use of metabolomics approaches in ecotoxicology.info:eu-repo/semantics/publishedVersio

Inflammatory bowel disease, alpha-synuclein aggregates and Parkinson’s disease: the InflamaSPark protocol

Communication abstract: Proceedings of the 5th International Congress of CiiEM - Reducing inequalities in Health and Society, held at Egas Moniz’ University Campus in Monte de Caparica, Almada, from June 16th to 18th, 2021.This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The hallmark of Parkinson’s disease (PD) is the accumulation of alpha-synuclein (AS) aggregates. Prior to the central nervous system involvement, PD establishes itself in the gut as a result of the complex interplay between microbiota, the host’s immune/neural systems and increased intestinal permeability. Inflammatory Bowel Disease (IBD) patients present a higher number of AS aggregates in the intestinal wall and an increased risk of developing PD. By studying AS aggregates in gut biopsy specimens of IBD patients and controls, this project aims to further clarify the pathophysiology of PD and to explore the potential of gut a biopsy for AS aggregates as a biomarker for prodromal PD.info:eu-repo/semantics/publishedVersio

Phylogeography of hepatitis B virus: the role of Portugal in the early dissemination of HBV worldwide

Copyright: © 2022 Marcelino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.In Portugal, the genetic diversity, origin of HBV and the Portuguese role in the dissemination of HBV worldwide were never investigated. In this work, we studied the epidemic history and transmission dynamics of HBV genotypes that are endemic in Portugal. HBV pol gene was sequenced from 130 patients followed in Lisbon. HBV genotype A was the most prevalent (n = 54, 41.5%), followed by D (n = 44, 33.8%), and E (n = 32, 24.6%). Spatio-temporal evolutionary dynamics was reconstructed in BEAST using a Bayesian Markov Chain Monte Carlo method, with a GTR nucleotide substitution model, an uncorrelated lognormal relaxed molecular clock model, a Bayesian skyline plot, and a continuous diffusion model. HBV subgenotype D4 was the first to be introduced in Portugal around 1857 (HPD 95% 1699-1931) followed by D3 and A2 a few decades later. HBV genotype E and subgenotype A1 were introduced in Portugal later, almost simultaneously. Our results indicate a very important role of Portugal in the exportation of subgenotypes D4 and A2 to Brazil and Cape Verde, respectively, in the beginning of the XX century. This work clarifies the epidemiological history of HBV in Portugal and provides new insights in the early and global epidemic history of this virus.This work was performed in the context of Rute Marcelino PhD study, whose student’s fellowship (SFRH/BD/99507/2014) was supported by the Portuguese Agency for Scientific Research, Fundação para a Ciência e Tecnologia (FCT), POCH program, Portugal 2020, and European Union/Social European Fund (FSE). This work was also supported by FCT through funds of AA's projects GHTM-UID/Multi/04413/2013 and GHTM-UID/04413/2020 and also NT's projects UIDB/04138/2020 and UIDP/04138/2020.info:eu-repo/semantics/publishedVersio

Radio‐cephalic fistula recovered with drainage to median basilic vein by straightening of the forearm cephalic vein: A case report

The distal arteriovenous fistula (AVF) has less complications and better patency than the proximal fistula, when it works properly. The complications of outflow of the fistula are complex, and it is necessary to analyze all solutions to solve the problem. We introduce a novel approach to solve outflow problems of a radio-cephalic AVF by straightening of the forearm cephalic vein with drainage into the median basilic vein.info:eu-repo/semantics/publishedVersio

Study of social and personal factors related to depressive symptoms in adolescence in the COVID-19 Pandemic

O presente trabalho tem como objetivo principal a compreensão dos sintomas depressivos na adolescência durante a pandemia COVID-19 numa perspetiva biopsicossocial. Participaram no estudo 826 adolescentes residentes na área geográfica da Câmara Municipal de Famalicão (Portugal). Os resultados revelaram que dos adolescentes em estudo, 30,7 % referiu ter sintomas depressivos, 34,9% sentiu tristeza tão grande que parece não aguentar. Destaca-se que 80,6% sentiu preocupações e 86,2% tem uma perceção positiva da sua saúde. Ter sintomas depressivos está negativamente associado a ter competências socioemocionais, com perceção de bem-estar e, com o conjunto de sintomas físicos e psicológicos. Por outro lado, ter sintomas depressivos está positivamente associado a sentir tristeza tão grande que parece não aguentar e preocupações, ter-se autolesionado e com ter as expectativas futuras afetadas pela COVID-19.The main objective of this study is to understand the depressive symptoms in adolescence during the COVID-19 pandemic from a bio-psychosocial perspective. A total of 826 adolescents with a mean age of 14.30±2.40 years participated in the study, from Câmara Municipal de Famalicão (Portugal). The results reveal of the adolescents under study, 30.7 % reported having depressive symptoms, 34.9% felt sadness so great that it does not seem to hold. It is noteworthy that 80.6% felt worried and 86.2% have a positive perception of their health. Depressive symptoms were negatively associated with having socio-emotional skills, with perceived well-being and with the set of physical and psychological symptoms. On the other hand, depressive symptoms were positively associated with feeling so sad that they cannot seem to cope and worry, having self-injured and having future expectations affected by COVID-19

Evaluating radiological response in pancreatic neuroendocrine tumours treated with sunitinib : comparison of Choi versus RECIST criteria (CRIPNET_ GETNE1504 study)

The purpose of our study was to analyse the usefulness of Choi criteria versus RECIST in patients with pancreatic neuroendocrine tumours (PanNETs) treated with sunitinib. A multicentre, prospective study was conducted in 10 Spanish centres. Computed tomographies, at least every 6 months, were centrally evaluated until tumour progression. One hundred and seven patients were included. Median progression-free survival (PFS) by RECIST and Choi were 11.42 (95% confidence interval [CI], 9.7-15.9) and 15.8 months (95% CI, 13.9-25.7). PFS by Choi (Kendall's τ = 0.72) exhibited greater correlation with overall survival (OS) than PFS by RECIST (Kendall's τ = 0.43). RECIST incorrectly estimated prognosis in 49.6%. Partial response rate increased from 12.8% to 47.4% with Choi criteria. Twenty-four percent of patients with progressive disease according to Choi had stable disease as per RECIST, overestimating treatment effect. Choi criteria predicted PFS/OS. Changes in attenuation occurred early and accounted for 21% of the variations in tumour volume. Attenuation and tumour growth rate (TGR) were associated with improved survival. Choi criteria were able to capture sunitinib's activity in a clinically significant manner better than RECIST; their implementation in standard clinical practice shall be strongly considered in PanNET patients treated with this drug