Editorial on special issue “Lipid nanosystems for local drug delivery”

info:eu-repo/semantics/publishedVersio

Numerical simulation of the deadliest flood event of Portugal: Unravelling the causes of the disaster

The flood event of November 25 and 26, 1967 corresponds to the deadliest storm affecting Portugal in recent centuries being responsible for >500 fatalities. The main trigger was the heavy rain that fell in just a few hours, provoking a rapid increase in river flows, although other concurrent circumstances had to occur to reach the dramatic water levels estimated in some affected places. However, even today, several important uncertainties related to water levels achieved and timing of floods remain. Here we aim to clarify some of the pending issues by applying suitable high performance numerical tools to elucidate the main conditioning factors that played a key role in the intensification of this dramatic flood. In particular, the analysis has been focused on Quintas village, the location most affected, where >100 fatalities were recorded, close to 2/3 of its total population at the time. The main conclusion provided by the numerical simulations was that a plugging of water flow downstream of Quintas village, favoured by a poor terrain maintenance coupled with the bottleneck created by topographic features, caused the critical over-elevation of water levels. Simulations also corroborate the rapid increase in water levels in Quintas village, with an estimated rise of >2 m in just two hours, as well as the occurrence of the flood during the night, preventing many people to be aware of the extreme danger they were facing and safeguarding themselves.Universidade de Vigo/CISU

Omega-3- and resveratrol-loaded lipid nanosystems for potential use as topical formulations in autoimmune, inflammatory, and cancerous skin diseases

Resveratrol (RSV) and omega 3 (3), because of their biological favorable properties, have become subjects of interest for researchers in dermocosmetic and pharmaceutical industries; however, these bioactives present technological limitations that hinder their effective delivery to the target skin layer. To overcome the stability and skin permeation limitations of free bioactives, this work proposes a combined strategy involving two different lipid nanosystems (liposomes and lipid nanoparticles) that include 3 in their lipid matrix. Additionaly, RSV is only encapsulated in liposomes that provid an adequate amphiphilic environment. Each formulation is thoroughly characterized regarding their physicalchemical properties. Subsequently, the therapeutic performance of the lipid nanosystems is evaluated based on their protective roles against lipid peroxidation, as well as inhibition of cicloxygenase (COX) and nitric oxid (NO) production in the RWA264.7 cell line. Finally, the lipid nanosystems are incorporated in hydrogel to allow their topical administration, then rheology, occlusion, and RSV releasediffusion assays are performed. Lipid nanoparticles provide occlusive effects at the skin surface. Liposomes provide sustained RSV release and their flexibility conferred by edge activator components enhances RSV diffusion, which is required to reach NO production cells and COX cell membrane enzymes. Overall, the inclusion of both lipid nanosystems in the same semisolid base constitutes a promising strategy for autoimmune, inflammatory, and cancerous skin diseases.This research was funded by FCT/MCTES—Foundation for Science and Technology I.P. from the Minister of Science, Technology, and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) by the COMPETE—Programa Operacional Factores de Competitividade (POFC) through the project CONCERT (POCI-01-0145-FEDER-032651 and PTDC/NAN-MAT/326512017) and the Strategic Funding UID/Multi/04546/2019, UIDP/04423/2020 (Group of Natural Products and Medicinal Chemistry CIIMAR), and “Contrato-Programa” UIDB/04469/2020 (CF-UM-UP) and UIDB/04050/2020 (CBMA), and UIDB/04469/2020 (CEB), as well as the Research Center of the Portuguese Oncology Institute of Porto (project no. PI86-CI-IPOP-66-2019), and BioTecNorte operation (NORTE-01-0145-FEDER- 000004) funded by the European Regional Development Fund under the scope of Norte 2020 - Programa Operacional Regional do Norte. Marlene Lúcio thanks FCT and ERDF for her doctoral position (CTTI-150/18-CF (1) within the scope of the CONCERT project. Raul Machado acknowledges FCT I.P. for funding within the Scientific Employment Stimulus project (CEECIND/00526/2018).info:eu-repo/semantics/publishedVersio

NATIONAL SURVEY OF CAT TUMORS IN 2019: A RETROSPECTIVE STUDY

Cancer is one of the most common causes of death in cats. Besides its clinical importance, small animals with spontaneous tumours are attractive comparative models for Oncologic studies. Cancer registries are important to provide increased information, which can be used in epidemiological studies and prophylactic and treatment strategies. The aim of this study was to characterize the current distribution of feline tumors in Portugal. A total of 752 feline histopathology records obtained in 2019 were included and data regarding breed, sex, age, type of tumor and malignancy were recorded. Statistical analysis was conducted to detect associations between variables using an alpha value of 0.05. One or more tumours were present in 417 animals, and a total of 475 tumors were reported (63.2%, n=475/752), of which 74.7% were malignant (n=355/475). Mammary tumors were the most common (43.7%, n= 207/475), including carcinoma (n=158) and adenoma (n=36). Mammary tumors were followed in frequency by tumors of the soft/mesenchymal tissue (19.6%, n=93/475) and epithelial skin (18.4%, n=87/475), which differs from published data in other countries. Similarly, to mammary tumors, soft/mesenchymal (64,5%, n=60/93) and epithelial skin tumors (18.4%, n=87/475) were also highly malignant. In the soft/mesenchymal tumors, lipoma (18.3%, n=17/93) and fibrosarcoma (17.2%, n=16/93) were the most common types; nevertheless, other tumors were also frequent, such as mastocitoma, lymphoma and hemangiosarcoma. Finally, in the epithelial skin tumours, the most prevalent was the squamous cell carcinoma (48.3%, n=42/87). Tumor malignancy was associated with older ages (mean 10.6 ± 3.4 years, p<0,001), whereas no association was obtained between breed and tumor type or tumor malignancy. Sex was associated with tumor type, as females presented a higher risk of developing mammary tumors. To our best knowledge this is the first retrospective study of this type conducted in Portugal. Given the high frequency of malignant tumors, early diagnosis and screening for nodules is of paramount importance, both at home and at veterinary consultations

Formulation, characterization, and cytotoxicity evaluation of lactoferrin functionalized lipid nanoparticles for riluzole delivery to the brain

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a very poor prognosis. Its treatment is hindered by a lack of new therapeutic alternatives and the existence of the blood–brain barrier (BBB), which restricts the access of drugs commonly used in ALS, such as riluzole, to the brain. To overcome these limitations and increase brain targeting, riluzole-loaded nanostructured lipid carriers (NLC) were prepared and functionalized with lactoferrin (Lf), facilitating transport across the BBB by interacting with Lf receptors expressed in the brain endothelium. NLC were characterized with respect to their physicochemical properties (size, zeta potential, polydispersity index) as well as their stability, encapsulation efficiency, morphology, in vitro release profile, and biocompatibility. Moreover, crystallinity and melting behavior were assessed by DSC and PXRD. Nanoparticles exhibited initial mean diameters between 180 and 220 nm and a polydispersity index below 0.3, indicating a narrow size distribution. NLC remained stable over at least 3 months. Riluzole encapsulation efficiency was very high, around 94–98%. FTIR and protein quantification studies confirmed the conjugation of Lf on the surface of the nanocarriers, with TEM images showing that the functionalized NLC presented a smooth surface and uniform spherical shape. An MTT assay revealed that the nanocarriers developed in this study did not cause a substantial reduction in the viability of NSC-34 and hCMEC/D3 cells at a riluzole concentration up to 10 μM, being therefore biocompatible. The results suggest that Lf-functionalized NLC are a suitable and promising delivery system to target riluzole to the brain.info:eu-repo/semantics/publishedVersio

Gut status in Parkinson’s disease: the GutSPark 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 neuropathological hallmark of Parkinson’s disease (PD) is the accumulation of alpha–synuclein (AS) aggregates. The identification of AS aggregates in gut biopsy specimens from people with PD may provide an opportunity to identify PD at a very early stage, prior to symptom onset. Changes in gut microbiota and inflammatory conditions (such as periodontitis) may be linked with PD onset/evolution. This project aims to explore the concept of microbiota–gut–brain axis in PD, studying gut biopsy specimens for AS aggregates, oral and intestinal microbiota, associated digestive disorders and oral health, of both patients with PD and controls.info:eu-repo/semantics/publishedVersio

More than just exosomes: distinct Leishmania infantum extracellular products potentiate the establishment of infection

The use of secretion pathways for effector molecule delivery by microorganisms is a trademark of pathogenesis. Leishmania extracellular vesicles (EVs) were shown to have significant immunomodulatory potential. Still, they will act in conjunction with other released parasite-derived products that might modify the EVs effects. Notwithstanding, the immunomodulatory properties of these non-vesicular components and their influence in the infectious process remains unknown. To address this, we explored both in vitro and in vivo the immunomodulatory potential of promastigotes extracellular material (EXO), obtained as a whole or separated in two different fractions: EVs or vesicle depleted EXO (VDE). Using an air pouch model, we observed that EVs and VDE induced a dose-dependent cell recruitment profile different from the one obtained with parasites, attracting significantly fewer neutrophils and more dendritic cells (DCs). Additionally, when we co-inoculated parasites with extracellular products a drop in cell recruitment was observed. Moreover, in vitro, while VDE (but not EVs) downregulated the expression of DCs and macrophages activation markers, both products were able to diminish the responsiveness of these cells to LPS. Finally, the presence of Leishmania infantum extracellular products in the inoculum promoted a dose-dependent infection potentiation in vivo, highlighting their relevance for the infectious process. In conclusion, our data demonstrate that EVs are not the only relevant players among the parasite exogenous products. This, together with the dose-dependency observed, opens new avenues to the comprehension of Leishmania infectious process. The approach presented here should be exploited to revisit existing data and considered for future studies in other infection models.NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work was also funded by FEDER through the Operational Competitiveness Programme – COMPETE and by National Funds through FCT – Fundação para a Ciência e a Tecnologia under the project FCOMP-01-0124-FEDER-019648 (PTDC/BIA-MIC/118644/2010). PC was supported by Foundation for Science and Technology (FCT), Portugal, through the individual grant SFRH/BD/121252/2016info:eu-repo/semantics/publishedVersio

The GO-DACT protocol : a multicentre, randomized, double-blind, parallel-group study to compare the efficacy of golimumab in combination with methotrexate (MTX) versus MTX monotherapy

© 2001-2020 Sociedade Portuguesa de ReumatologiaThe GO-DACT is an investigator-initiated, national, multicentric randomized placebo-controlled double-blinded trial, that assesses dactylitis as primary endpoint. Psoriatic arthritis patients naïve to methotrexate and biologic disease modifying anti-rheumatic drugs, with at least one active dactylitis, were assigned to golimumab in combination with methotrexate or placebo in combination with methotrexate, for 24 weeks. Both clinical (dactylitis severity score and the Leeds dactylitis index) and imaging (high resolution magnetic resonance imaging), among others, were assessed as outcomes. The main objective of GO-DACT is to provide evidence to improve the treatment algorithm and care of psoriatic arthritis patients with active dactylitis. In this manuscript we describe the GO-DACT protocol and general concepts of the methodology of this trial.info:eu-repo/semantics/publishedVersio

GO-DACT : a phase 3b randomised, double-blind, placebo-controlled trial of GOlimumab plus methotrexate (MTX) versus placebo plus MTX in improving DACTylitis in MTX-naive patients with psoriatic arthritis

© author(s) (or their employer(s)) 2020. Re-use permitted under CC BY- nC. no commercial re-use. see rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license.Objectives: To assess the efficacy of golimumab in combination with methotrexate (MTX) versus MTX monotherapy in psoriatic arthritis (PsA) dactylitis. Methods: Multicentre, investigator-initiated, randomised, double-blind, placebo-controlled, parallel-design phase 3b trial in 11 Portuguese rheumatology centres. Patients with PsA along with active dactylitis and naive to MTX and biologic disease-modifying antirheumatic drugs (bDMARDs) were randomly assigned to golimumab or placebo, both in combination with MTX. The primary endpoint was Dactylitis Severity Score (DSS) change from baseline to week 24. Key secondary endpoints included DSS and Leeds Dactylitis Index (LDI) response, and changes from baseline in the LDI and MRI dactylitis score. Analysis was by intention-to-treat for the primary endpoint. Results: Twenty-one patients received golimumab plus MTX and 23 MTX monotherapy for 24 weeks. One patient from each arm discontinued. Patient inclusion was halted at 50% planned recruitment due to a favourable interim analysis. Median baseline DSS was 6 in both arms. By week 24, patients treated with golimumab plus MTX exhibited significantly greater improvements in DSS relative to MTX monotherapy (median change of 5 vs 2 points, respectively; p=0.026). In the golimumab plus MTX arm, significantly higher proportions of patients achieved at least 50% or 70% improvement in DSS and 20%, 50% or 70% improvement in LDI in comparison to MTX monotherapy. Conclusions: The combination of golimumab and MTX as first-line bDMARD therapy is superior to MTX monotherapy for the treatment of PsA dactylitis.info:eu-repo/semantics/publishedVersio