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Funding Information: This study was supported by FCT–Fundação para a Ciência e a Tecnologia (grants UIDB/04567/2020 and UIDP/ 04567/2020 to CBIOS, PTDC/BIA-MOL/31104/2017, and PhD grants PD/BD/135504/2018 to AFR and UI/BD/151421/2021 to SF. RM is funded by FCT Scientific Employment Stimulus contract with the reference number CEEC/04567/ CBIOS/2020. Authors also acknowledge COFAC/ILIND – Cooperativa De Formação e Animação Cultural CRL/Instituto Lusófono de Investigação e Desenvolvimento (grant COFAC/ILIND/CBIOS/2/2021). iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is cofunded by Fundação para a Ciência e Tecnologia (FCT) / Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged (UIDB/04462/2020 and UIDP/04462/2020). CNS acknowledge the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 804229. JAB gratefully acknowledges FCT-Fundação para a Ciência e a Tecnologia, I.P. through MOSTMICRO-ITQB R&D Unit-UIDB/04612/2020 and LS4FUTURE Associated Laboratory-LA/P/0087/2020, and by the framework of Article 23 of Decree-Law No.57/2017 of August 29. Publisher Copyright: Copyright © 2022 Raimundo, Ferreira, Pobre, Lopes-da-Silva, Brito, dos Santos, Saraiva, dos Santos and Menezes. Introduction: Diabetes is one of the major metabolic diseases worldwide. Despite being a complex systemic pathology, the aggregation and deposition of Islet Amyloid Polypeptide (IAPP), or amylin, is a recognized histopathological marker of the disease. Although IAPP proteotoxicity represents an important trigger of β-cell dysfunction and ultimately death, its exploitation as a therapeutic tool remains underdeveloped. The bioactivity of (poly)phenols towards inhibition of pathological protein aggregation is well known, however, most of the identified molecules have limited bioavailability. Methods: Using a strategy combining in silico, cell-free and cell studies, we scrutinized a unique in-house collection of (poly)phenol metabolites predicted to appear in the human circulation after (poly)phenols ingestion. Results: We identified urolithin B as a potent inhibitor of IAPP aggregation and a powerful modulator of cell homeostasis pathways. Urolithin B was shown to affect IAPP aggregation pattern, delaying the formation of amyloid fibrils and altering their size and morphology. The molecular mechanisms underlying urolithin B-mediated protection include protein clearance pathways, mitochondrial function, and cell cycle ultimately rescuing IAPP-mediated cell dysfunction and death. Discussion: In brief, our study uncovered urolithin B as a novel small molecule targeting IAPP pathological aggregation with potential to be exploited as a therapeutic tool for mitigating cellular dysfunction in diabetes. Resulting from the colonic metabolism of dietary ellagic acid in the human body, urolithin B bioactivity has the potential to be explored in nutritional, nutraceutical, and pharmacological perspectives. publishersversion published

Funding: This study was supported by the Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência e do Ensino Superior; grant numbers PTDC/BIA-MOL/31104/2017 (RM), UID/QUI/50006/2020 (MF), UIDB/04567/2020 and UIDP/04567/2020 (CBIOS); UIDB/04539/2020 and UIDBP/4539/2020 (CIBB). COMPETE-FEDER funds (POCI-01-0145-FEDER-007440 and POCI-01-0145-FEDER-031712). The authors would like to acknowledge the support of the iNOVA4Health Research Unit (LISBOA—01– 0145—FEDER—007344), which is co-funded by the FCT/Ministério da Ciência e do Ensino Superior and by FEDER under the PT2020 Partnership Agreement. The authors would also like to acknowledge the COFAC/ILIND–Cooperativa De Formação E Animação Cultural CRL/Instituto Lusófono de Investigação e Desenvolvimento (grant COFAC/ILIND/CBIOS/2/2021), and the FCT for the financial support to RM (CEEC/04567/CBIOS/2020) and to MF (2020.04126.CEECIND/CP1596/CT0006). MF also thanks LAQV/EQUIMTE for her contract under the reference LA/P/0008/2020. This research was additionally supported by the National Research Project GREENCOF (Ref.: PID2020-114102RB-I00) funded by the Spanish Ministry of Science and Innovation. (Poly)phenols have anti-diabetic properties that are mediated through the regulation of the main biomarkers associated with type 2 diabetes mellitus (T2DM) (fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), insulin resistance (IR)), as well as the modulation of other metabolic, inflammatory and oxidative stress pathways. A wide range of human and pre-clinical studies supports these effects for different plant products containing mixed (poly)phenols (e.g., berries, cocoa, tea) and for some single compounds (e.g., resveratrol). We went through some of the latest human intervention trials and pre-clinical studies looking at (poly)phenols against T2DM to update the current evidence and to examine the progress in this field to achieve consistent proof of the anti-diabetic benefits of these compounds. Overall, the reported effects remain small and highly variable, and the accumulated data are still limited and contradictory, as shown by recent meta-analyses. We found newly published studies with better experimental strategies, but there were also examples of studies that still need to be improved. Herein, we highlight some of the main aspects that still need to be considered in future studies and reinforce the messages that need to be taken on board to achieve consistent evidence of the anti-diabetic effects of (poly)phenols. publishersversion published

Funding Information: Funding: This study was funded by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência e do Ensino Superior, grant numbers PTDC/BIA-MOL/31104/2017 (RM) and UIDB/04567/2020 and UIDP/ 04567/2020 (CBIOS). iNOVA4Health Research Unit (LISBOA—01–0145—FEDER—007344), which is cofunded by FCT/Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is also acknowledged. Authors would like to acknowledge FCT for the financial support of AFR (PD/BD/135504/2018); SF (UI/BD/151421/2021), and RM (CEEC/04567/CBIOS/2020). Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes. publishersversion published

2020.09555BD UIDB/04551/2020 CEEC/04567/CBIOS/2020 PTDC/BIA-MOL/31104/2017 UIDB/04567/2020 UIDP/04567/2020 Rice is one of the most cultivated and consumed cereals worldwide. It is composed of starch, which is an important source of diet energy, hypoallergenic proteins, and other bioactive compounds with known nutritional functionalities. Noteworthy is that the rice bran (outer layer of rice grains), a side-stream product of the rice milling process, has a higher content of bioactive compounds than white rice (polished rice grains). Bran functional ingredients such as γ-oryzanol, phytic acid, ferulic acid, γ-aminobutyric acid, tocopherols, and tocotrienols (vitamin E) have been linked to several health benefits. In this study, we reviewed the effects of rice glycemic index, macronutrients, and bioactive compounds on the pathological mechanisms associated with diabetes, identifying the rice compounds potentially exerting protective activities towards disease control. The effects of starch, proteins, and bran bioactive compounds for diabetic control were reviewed and provide important insights about the nutritional quality of rice-based foods. publishersversion published

Funding: This work was supported by iNOVA4Health – UID/Multi/04462/2019, a program financially supported by Fundação para a Ciência e Tecnologia/ Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement, Funding from INTERFACE Programme, through the Innovation, Technology and Circular Economy Fund (FITEC), FCT via PTDC/BIA-MOL/31104/2017 and UID/Multi/04462/2019-SubProj iNOVA4Health C44 (to RM), PD/BD/135504/2018 (to AFR), Sociedade Portuguesa de Diabetologia for the Nuno Castelo-Branco Prize – 2016 (to RM), and ICM acknowledges FCT-MCTES Program “Concurso de Estímulo ao Emprego Científico” (CEECIND/01670/2017). Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions worldwide. Due to population ageing, the incidence of AD is increasing. AD patients develop cognitive decline and dementia, features for which is known, requiring permanent care. This poses a major socio-economic burden on healthcare systems as AD patients' relatives and healthcare workers are forced to cope with rising numbers of affected people. Despite recent advances, AD pathological mechanisms are not fully understood. Nevertheless, it is clear that the amyloid beta (Aβ) peptide, which forms amyloid plaques in AD patients' brains, plays a key role. Type 2 diabetes, the most common form of diabetes, affects hundreds of million people globally. Islet amyloid polypeptide (IAPP) is a hormone co-produced and secreted with insulin in pancreatic β-cells, with a key role in diabetes, as it helps regulate glucose levels and control adiposity and satiation. Similarly to Aβ, IAPP is very amyloidogenic, generating intracellular amyloid deposits that cause β-cell dysfunction and death. It is now clear that IAPP can also have a pathological role in AD, decreasing cognitive function. IAPP harms the blood-brain barrier, directly interacts and co-deposits with Aβ, promoting diabetes-associated dementia. IAPP can cause a metabolic dysfunction in the brain, leading to other diabetes-related forms of AD. Thus, here we discuss IAPP association with diabetes, Aβ and dementia, in the context of what we designate a 'diabetes brain phenotype' AD hypothesis. Such approach helps to set a conceptual framework for future IAPP-based drugs against AD. publishersversion published

Tese de mestrado em Biologia Molecular e Genética, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, em 2018 Submitted by Cristina Manessiez (camanessiez@fc.ul.pt) on 2018-04-10T15:09:18Z No. of bitstreams: 1 ulfc124152_tm_Filipa_Félix.pdf: 2856772 bytes, checksum: 9733801c6fa51787f140adb061683f60 (MD5) Made available in DSpace on 2018-04-10T15:09:31Z (GMT). No. of bitstreams: 1 ulfc124152_tm_Filipa_Félix.pdf: 2856772 bytes, checksum: 9733801c6fa51787f140adb061683f60 (MD5) Previous issue date: 2018