Two-way attack on IAPP proteotoxicity with implications for diabetes

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.publishersversionpublishe

Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase

Funding Information: This work was supported by FEDER and Fundação para a Ciência e a Tecnologia , I. P. through iMed.ULisboa (Projects UIDB/04138/2020 and UIDP/04138/2020 ), iNOVA4Health ( UIDB/04462/2020 , UIDP/04462/2020 ) and LS4FUTURE Associated Laboratory ( LA/P/0087/2020 ) and research project PTDC/BIA-BQM/29570/2017 . Publisher Copyright: © 2023 The Author(s)Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is associated with ACADM gene mutations, leading to an impaired function and/or structure of MCAD. Importantly, after import into the mitochondria, MCAD must incorporate a molecule of flavin adenine dinucleotide (FAD) per subunit and assemble into tetramers. However, the effect of MCAD amino acid substitutions on FAD incorporation has not been investigated. Herein, the commonest MCAD variant (p.K304E) and 11 additional rare variants (p.Y48C, p.R55G, p.A88P, p.Y133C, p.A140T, p.D143V, p.G224R, p.L238F, p.V264I, p.Y372N, and p.G377V) were functionally and structurally characterized. Half of the studied variants presented a FAD content <65 % compared to the wild-type. Most of them were recovered as tetramers, except the p.Y372N (mainly as dimers). No correlation was found between the levels of tetramers and FAD content. However, a correlation between FAD content and the cofactor's affinity, proteolytic stability, thermostability, and thermal inactivation was established. We showed that the studied amino acid changes in MCAD may alter the substrate chain-length dependence and the interaction with electron-transferring-flavoprotein (ETF) necessary for a proper functioning electron transfer thus adding additional layers of complexity to the pathological effect of ACADM missense mutations. Although the majority of the variant MCADs presented an impaired capacity to retain FAD during their synthesis, some of them were structurally rescued by cofactor supplementation, suggesting that in the mitochondrial environment the levels and activity of those variants may be dependent of FAD's availability thus contributing for the heterogeneity of the MCADD phenotype found in patients presenting the same genotype.publishersversionpublishe

Preparation Of Nife 2o 4 Thin Films By A New Route Sol-gel

NiFe 2O 4 thin films were prepared using new route sol-gel process. The films were heated at 300°C for 5 min. The magnetic properties were also determined at room temperature by applying magnetic fields up to 4 kOe perpendicular to the surface of the samples by means of a SQUID magnetometer.Chen, K.C., (1986) Mater. Res. Soc. Symp. Porc., 73, p. 731Miroslav, S., Ladislav, P., (1991) Ceramics International, 21, p. 21Duque, J.G.S., (2000) Phys. Stat. Sol. (b), 220, p. 413Duque, J.G.S., (2001) J. Magn. Magn. Mater., 226-230, p. 1424Guyot, M., (1996) Applied Surface Science, 96-98, p. 80

Bafe12o19 Thin Film Grown By An Aqueous Sol-gel Process

In this communication we present a new sol-gel route to obtain high quality BaFe12O19 thin films. X-ray analysis confirmed the crystal structure with a crystal size of 32 nm. Atomic force microscopy images determined the film thickness to be around 250 nm and a roughness factor of less than 40 nm where the grain size averaged around 150 nm. SQUID magnetometer data shows a magnetic behavior similar to films grown by other techniques, namely, a coercive field (Hc = 4 kOe), a normalized remanence close to 0.6 and saturation field of 15 kOe and Ms = 80 emu/cm3. © 2003 Published by Elsevier Science Ltd.3405/08/15565567Bayard, B., Chatelon, J., Leberre, M., Joisten, H., Rousseau, J., Barbier, D., The effects of deposition and annealing conditions on crystallographic properties of sputtered barium ferrite thick films (2002) Sens. Actuators, A, 3292, pp. 1-6Nakagawa, S., Matsushita, N., Naoe, M., Perpendicular magnetic recording media using hexagonal ferrite thin films deposited on Pt underlayers and interlayers (2001) J. Magn. Magn. Mater., 235, pp. 337-341Koleva, M., Atanasov, P., Tomov, R., Vankov, O., Matin, C., Ristoscu, C., (2000) Applied Surface Science, 154-155, pp. 485-491. , I. Mihailov (Ed.), Pulsed laser deposition of barium hexaferrite (BaFe12O19) thin filmsWane, I., Bessandou, A., Cosset, F., Célérier, A., Giramet, C., Decossas, J., Vareille, J., Thick barium hexaferrite (Ba-M) films prepared by electron-beam evaporation for microwave application (2000) J. Magn. Magn. Mater., 211, pp. 309-313Pignard, S., Vicent, H., Sénateur, J., Epitaxial and polycrystalline BaFe12O19 thin films grown by chemical vapour deposition (1999) Thin Solid Films, 350, pp. 119-123Surig, C., Hempel, K., Bonnenberg, D., Formation and microwave-absorption of barium and strontium ferrite prepared by sol-gel technique (1993) Appl. Phys. Lett., 63 (20), pp. 2836-2838Ishikawa, A., Tanahashi, K., Futamoto, M., Magnetic and structural properties of Ba-ferrite films prepared by sol-gel processing (1996) J. Appl. Phys., 79 (9), pp. 7080-7083Duque, J., Macedo, M., Moreno, N., An alternative method to prepare CoFe2O4 thin films (2000) Phys. Stat. Sol. (B), 220 (1), pp. 413-415Duque, J., Macedo, M., Moreno, N., Lopez, J., Pfanes, H.-D., Magnetic and structural properties of CoFe2O4 thin films synthesized via a sol-gel process (2001) J. Magn. Magn. Mater., 226-230, pp. 1424-1425Macedo, M., Processo de Fabricação de Camadas Finas Óxidas Utilizando a Água de Coco Processada (Acp), , Patent Pending, 9804719-1/B

Probing the aurone scaffold against Plasmodium falciparum: design, synthesis and antimalarial activity

© 2014 Elsevier Masson SAS. All rights reserved.A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.This work was supported by Fundação para a Ciência e Tecnologia (FCT, Portugal) through projects PTDC/SAU-FAR/118459/2010 and Pest-OE/SAL/UI4013/2011. A.S.N. and M.P.C. acknowledge FCT for grants SFRH/BD/41276/2007 and SFRH/BD/61611/2009, respectively. P.J.R. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist.info:eu-repo/semantics/publishedVersio