Vescalagin and castalagin reduce the toxicity of amyloid-beta42 oligomers through the remodelling of its secondary structure

Accepted Manuscript ; "First published on 10 Feb 2020"The isomers vescalagin and castalagin protect SH-SY5Y cells from Aβ42-mediated death. This is achieved better by vescalagin due to the spatial organization of its OH group at the C1 position of the glycosidic chain, improving its capacity to remodel the secondary structure of toxic Aβ42 oligomers.We acknowledge the financial support from the EC (FORECAST - 668983 and THE DISCOVERIES CTR – 739572), “Programa Operacional Regional do Norte”, “Fundo Social Europeu”, Norte2020 TERM&SC, for the PhD grant NORTE-08-5369-FSE-000044; PT acknowledges Agencia Estatal de Investigación (AEI) for Project MAT2016-80266-R, and “Xunta de Galicia” for grants “Grupo de Referencia Competitiva” ED431C 2018/26 and “Agrupación Estratégica en Materiales-AEMAT” ED431E 2018/08, respectively. ERDF funds are also acknowledged

Deciphering the interaction of lactoferrin with V-ATPase towardsa deeper understanding of its mechanisms of action

Lactoferrin (Lf), a bioactive milk protein, exhibits strong anticancer and antifungal activities. The search for Lf targets and mechanisms of action is of utmost importance to enhance its effective applications. A common feature among Lf-treated cancer and fungal cells is the inhibition of a proton pump called V-ATPase. Lf-driven V-ATPase inhibition leads to cytosolic acidification, ultimately causing cell death of cancer and fungal cells. Given that a detailed elucidation of how Lf and V-ATPase interact is still missing, in this work we aimed to fill this gap by employing a multilevel computational approach. Molecular dynamics (MD) simulations of both proteins were performed to obtain a robust sampling of their conformational landscape, followed by clustering and protein-protein docking. Subsequently, MD simulations of the docked complexes and free binding energy calculations were carried out to evaluate the dynamic binding process and build the final ranking. This computational pipeline allowed the unraveling of the putative mechanism by which Lf inhibits V-ATPase and the identification of key binding residues that will certainly aid in the rational design of follow-up experimental studies, bridging in this way computational and experimental biochemistry.info:eu-repo/semantics/publishedVersio

Mismatch Negativity contribution in Multiple Sclerosis patients

Mismatch Negativity is a functional index of the supratemporal auditory cortex. AIM: The aim of the present study on Mismatch Negativity (MMN) in multiple sclerosis (MS) patients was to evaluate if the MMN can be correlated with cognitive deficits assessed by the Paced Auditory Addition Task - PASAT. METHOD: a clinical study in forty females and 20 males separated in two groups: control individuals and those with a definite diagnosis of MS underwent a duration and frequncy MMN. The MMN latencies and negative amplitudes obtained from the MS group were compared to the ones from the control group. The scores from the Paced Auditory Addition Task were correlated either with the presence or the absence of MMN. RESULTS: MMN was found in 60% of the individuals with multiple sclerosis within the auditory stimulation protocol with varied durations, and in 45 % within the auditory stimulation protocol with frequency variations. There were no statistically significant differences in latencies and amplitudes when compared to controls. We found a statistically significant correlation for the lack of MMN wave together with cognitive disorder asserted by the PASAT. CONCLUSIONS: The MMN correlated to the cognitive deficit assessed by the PASAT.O Mismatch Negativity (MMN) é um potencial evocado auditivo endógeno, gerado por mudanças no processo de discriminação que ocorrem no córtex auditivo que avalia a memória sensorial auditiva. OBJETIVOS: Avaliar se, quando presente, o MMN pode ser utilizado como um índice funcional do córtex auditivo supratemporal e correlacionar com comprometimento cognitivo, avaliado pelo Teste Auditivo Compassado de Adição Seriada (PASAT). MATERIAL E MÉTODOS: Um grupo controle e outro com diagnóstico definido de EM foram submetidos ao registro do MMN com estímulos auditivos com variação de duração e de freqüência. O grupo de EM foi submetido ao PASAT. As latências e as amplitudes negativas do MMN foram comparadas entre os grupos. Os escores do PASAT foram correlacionados com a presença ou ausência do MMN nos dois protocolos de estimulação auditiva. RESULTADOS: O MMN esteve presente em 60% dos indivíduos no grupo de EM no protocolo de estimulação auditiva com variação de duração, e em 45% no protocolo de estimulação auditiva com variação de freqüência. Encontrou-se uma correlação estatisticamente significante entre a ausência da onda do MMN com a presença de comprometimento cognitivo avaliado pelo PASAT. CONCLUSÕES: A ausência do MMN se correlaciona com comprometimento cognitivo avaliado pelo PASAT.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Programa de Pós-graduação em Otorrinolaringologia e Cirurgia de Cabeça em PescoçoUniversidade Federal de São Paulo (UNIFESP)UFMG Faculdade de MedicinaUFMG Departamento de PsicologiaUFMGPontifícia Universidade Católica de São PauloUniversidade Federal de Minas GeraisUNIFESP, EPM, Programa de Pós-graduação em Otorrinolaringologia e Cirurgia de Cabeça em PescoçoUNIFESPSciEL

Synthesis and cytotoxicity assessment of citrate-coated calcium and manganese ferrite nanoparticles for magnetic hyperthermia

Calcium-doped manganese ferrite nanoparticles (NPs) are gaining special interest in the biomedical field due to their lower cytotoxicity compared with other ferrites, and the fact that they have improved magnetic properties. Magnetic hyperthermia (MH) is an alternative cancer treatment, in which magnetic nanoparticles promote local heating that can lead to the apoptosis of cancer cells. In this work, manganese/calcium ferrite NPs coated with citrate (CaxMn1−xFe2O4 (x=0, 0.2, 1), were synthesized by the sol-gel method, followed by calcination, and then characterized regarding their crystalline structure (by X-ray diffraction, XRD), size and shape (by Transmission Electron Microscopy, TEM), hydrodynamic size and zeta potential (by Dynamic Light Scattering, DLS), and heating efficiency (measuring the Specific Absorption Rate, SAR, and Intrinsic Loss Power, ILP) under an alternating magnetic field. The obtained NPs showed a particle size within the range of 10 nm to 20 nm (by TEM) with a spherical or cubic shape. Ca0.2Mn0.8Fe2O4 NPs exhibited the highest SAR value of 36.3 W/g at the lowest field frequency tested, and achieved a temperature variation of ~7 °C in 120 s, meaning that these NPs are suitable magnetic hyperthermia agents. In vitro cellular internalization and cytotoxicity experiments, performed using the human cell line HEK 293T, confirmed cytocompatibility over 0–250 µg/mL range and successful internalization after 24 h. Based on these studies, our data suggest that these manganese-calcium ferrite NPs have potential for MH application and further use in in vivo systems.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of CEB (UIDB/04469/2020), CBMA (UIDB/04050/2020) and CF-UM-UP (UIDB/04650/2020) units. R.G.D. Andrade and S.R.S. Veloso acknowledge FCT for the PhD grants 2020.05781.BD and SFRH/BD/144017/2019, respectively.info:eu-repo/semantics/publishedVersio

Selection of a new peptide homing SK-BR-3 breast cancer cells

Breast cancer diagnosis remains a challenge, mostly due to its heterogeneity. This reality translates in delayed treatments, increasing treatment aggressiveness and lower chances of overall survival. The conventional detection techniques, although becoming increasingly sophisticated each year, still lack the ability to provide reliable conclusions without being time consuming, expensive and uncomfortable for the patients. The identification of novel biomarkers for breast cancer research is therefore of utmost relevance for an early diagnosis. Moreover, breast cancer specific peptide moieties can be used to develop novel targeted drug delivery systems. In this work we used phage display to identify a novel peptide with specificity to the SK-BR-3 breast cancer cell line. Cytometry assays confirmed its specificity, while bioinformatics and docking studies predicted the potential biomarkers at the SK-BR-3 cells surface. These findings can be potentially useful in the clinical context, contributing to more specific and targeted therapeutic solutions against HER2-positive breast cancer subtypes.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2020 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Débora Ferreira and Ana Cláudia Pereira are recipient of fellowships supported by a doctoral advanced training (call NORTE-69-2015-15) funded by the European Social Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Cátia Santos-Pereira acknowledges the PhD fellowship PD/BD/128032/2016 funded by FCT under the scope of the doctoral programme in Applied and Environmental Microbiology (DP_AEM). The authors also acknowledge César Pimenta from NOVA Institute of Chemical and Biological Technology António Xavier (NOVA ITQB) for the docking insights.info:eu-repo/semantics/publishedVersio

Exploring the perfusion modifications occurring with massage in the human lower limbs by non-contact polarized spectroscopy

A circulatory adaptation affecting the circulation of both lower limbs seems to be part of a distal circulatory homeostatic mechanisms, in animals as in humans. This was also observed during massage with the contralateral limb responding similarly to the intervened limb. The present study is meant to explore this cooperation between limbs during massage, using a recently available non-contact polarized spectroscopy method. Six healthy volunteers (44.83 ± 12.64 years), both sexes, were submitted to two massage protocols applied in one random limb, using the other as control. Each protocol included three phases - I rest, II massage and III recovery. Laser Doppler Flowmetry (LDF) and Tissue Viability Imager (TiVi) signals were obtained from both limbs and analyzed (p<0.05). Our results confirm previous observations where any intervention, massage included, affecting circulation in one of the lower limbs evokes a contralateral response in the non-intervened limb that seems to be part of the distal circulation regulation, affecting both limbs to maintain circulatory homeostasis

The prognostic value of worsening renal function and its timing

Copyright © 2023 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.INTRODUCTION: Acute decompensated heart failure (ADHF) admissions are frequently complicated by different patterns of serum creatinine (SCr) elevation. We aimed to assess the prognostic impact of worsening renal function (WRF) based on the timing of its occurrence. METHODS: This was a retrospective cohort of patients admitted for ADHF. Standard WRF was defined as an increase in SCr of ≥0.3 mg/dl during hospitalization. WRF timing was classified as early (within 48 hours of admission) or late (>48 hours). Acute kidney injury (AKI) at admission was defined as a rise in SCr of ≥0.3 mg/dl from outpatient baseline measurement to first measurement at admission. The primary endpoint was a composite of all-cause mortality or hospitalization for cardiovascular events at one-year follow-up. RESULTS: Overall, 249 patients were included (mean age 77±11 years, 62% with preserved left ventricular ejection fraction). Early WRF occurred in 49 patients (19.7%) and was associated with a higher risk of the primary outcome (HR 2.49; 95% CI 1.66-3.73), whereas late WRF was not (p=0.411). After stratification for the presence of early WRF and/or AKI at admission, only patients with early WRF but no AKI at admission and patients with both AKI at admission and early WRF showed a higher risk of the primary outcome after multivariate Cox regression. CONCLUSION: Early WRF was associated with a higher risk of the primary outcome. The timing of WRF seems to be an important factor to take into account when considering the prognostic impact of creatinine variations during hospitalization for ADHF.proofepub_ahead_of_prin

Chemical Constituents and Evaluation of Antimicrobial and Cytotoxic Activities of Kielmeyera coriacea

Many essential oils (EOs) of different plant species possess interesting antimicrobial effects on buccal microorganisms and cytotoxic properties. EOs of Kielmeyera coriacea Mart. & Zucc. were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). The EO from leaves is rich in sesquiterpenes hydrocarbons and oxygenated sesquiterpenes. The three major compounds identified were germacrene-D (24.2%), (E)-caryophyllene (15.5%), and bicyclogermacrene (11.6%). The inner bark EO is composed mainly of sesquiterpenes hydrocarbons and the major components are alpha-copaene (14.9%) and alpha-(E)-bergamotene (13.0%). The outer bark EO is composed mainly of oxygenated sesquiterpenes and long-chain alkanes, and the major components are alpha-eudesmol (4.2%) and nonacosane (5.8%). The wood EO is mainly composed of long-chain alkanes and fatty acids, and the major components are nonacosane (9.7%) and palmitic acid (16.2%). The inner bark EO showed the strongest antimicrobial activity against the anaerobic bacteria Prevotella nigrescens (minimum inhibitory concentration-MIC of 50 µg mL−1). The outer bark and wood EOs showed MICs of 100 µg mL−1 for all aerobic microorganisms tested. The EOs presented low toxicity to Vero cells. These results suggest that K. coriacea, a Brazilian plant, provide initial evidence of a new and alternative source of substances with medicinal interest