Osteogenic differentiation of human mesenchymal stem cells by the single action of luminescent polyurea oxide biodendrimers

Fundação para a Ciência e a Tecnologia for financial support through project PTDC/MEC-ONC/29327/2017 and the PhD grant SFRH/BD/109006/2015 (R.F.P.). We also thank Dr. Luisa Maia (UCIBIO, FCT-UNL) for EPR measurements.Polyurea oxide (PURO) biodendrimers are a class of dendrimers that can trigger osteogenic differentiation of human mesenchymal stem cells (hMSCs). PURO biodendrimers are prepared by simple, solventless oxidation of polyurea dendrimers using hydrogen peroxide as the oxidant in quantitative yield, retaining both biocompatibility (up to 10 mg/mL for higher generations) and the non-traditional intrinsic luminescence. The effect of PURO biodendrimers in the differentiation of hMSCs was found by the single addition to a standard growth medium for MSCs differentiation (without differentiation inducers). After 21 days of incubation, the formation of osteoblasts was confirmed by the alizarin red staining assay and alkaline phosphatase activity. This is the first report of in vitro osteodifferentiation fully regulated by synthetic soft polymers such as dendrimers. Current osteogenic differentiation protocols rely on an in vitro inducing formulation (including dexamethasone, ascorbic acid, and β-glycerophosphate), which lacks therapeutic potential in vivo. The outstanding role of dendrimers in nanomedicine, under clinic translation, combined with this feature is envisaged to foster PURO dendrimers as an important strategy in cell therapy and regenerative medicine.publishersversionpublishe

Intrinsic acetamide brush-off by polyurea biodendrimers dagger

The presence of genotoxic impurities in active pharmaceutical ingredients (APIs) is a major concern for the pharmaceutical industry. Acetamide is a common genotoxic byproduct found in synthetic routes of many APIs, mainly due to acetonitrile hydrolysis, and selective scavenging is a still a challenging task. Herein, as a proof-of-concept, we evaluate polyurea (PURE) biodendrimers as strategic nanopolymers to prepare safe drug nanoformulations from mixtures containing acetamide, using (S)-ibuprofen (IBF) as a model drug. Furthermore, computational molecular dynamics (MD) simulations were conducted to rationalize in vitro results and to identify the key intermolecular interactions within mixtures. Experimental data were corroborated by MD simulations which showed that acetamide, IBF and carboxyfluorescein interactions with PURE biodendrimers are mostly at the surface. Also, PURE nanoformulations appear to be driven by hydrogen bonding, electrostatic and hydrophobic interactions

Discovering ethnic minority business research directions using text mining and topic modelling

Moro, S., Pires, G., Rita, P., Cortez, P., & Ramos, R. F. (2022). Discovering ethnic minority business research directions using text mining and topic modelling. Journal of Research in Marketing and Entrepreneurship. https://doi.org/10.1108/JRME-01-2022-0004Abstract Purpose This study aims to unveil within the current academic literature the principal directions in the ethnic entrepreneurship and small business marketing research context. Design/methodology/approach An automated literature analysis procedure was undertaken, attempting to cover all literature published on the subject since 1962. A total of 188 articles were analysed using text mining and topic modelling. Findings The results show a lack of framing of ethnic entrepreneurship literature outside the narrower scope of migration. Some core themes were found (e.g. network, diversity) around which several other themes orbit, including both related issues to the ethnic factor (e.g. barriers and minorities) and managerial issues (e.g. marketing and production). Originality/value Ethnic minority business and small business marketing research has seen a growing number of publications. However, a careful review of existing work is missing.authorsversionepub_ahead_of_prin

Validação do método de Mohr para determinação do teor de Cloreto em águas de consumo humano

O ião Cloreto encontra-se normalmente associado aos catiões sódio, cálcio, magnésio e potássio. Uma concentração excessiva de cloreto na água acelera a corrosão dos metais das redes de distribuição, em função da alcalinidade da água. Validação do método de Mohr (SMEWW 21th Edition 2005), utilizado no Laboratório de Saúde Pública de Bragança para determinação do teor de Cloreto em águas de consumo humano, com base no documento normativo NP EN ISO/IEC 17025:2005, com o objectivo final da Acreditação deste ensaio. Através do estudo de validação efectuado foi possível a Acreditação do método de Mohr (SMEWW, 21th Edition, 2005) para determinação do teor de Cloreto em águas de consumo humano. O reconhecimento da competência técnica para a execução do método referido foi conferido pelo Instituto Português de Acreditação (IPAC) mediante a emissão de um certificado de acreditação n.º L0432

Angolan cymbopogon citratus used for therapeutic benefits: nutritional composition and influence of solvents in phytochemicals content and antioxidant activity of leaf extracts

Folk medicine is a relevant and effective part of indigenous healthcare systems which are, in practice, totally dependent on traditional healers. An outstanding coincidence between indigenous medicinal plant uses and scientifically proved pharmacological properties of several phytochemicals has been observed along the years. This work focused on the leaves of a medicinal plant traditionally used for therapeutic benefits (Angolan Cymbopogon citratus), in order to evaluate their nutritional value. The bioactive phytochemical composition and antioxidant activity of leaf extracts prepared with different solvents (water, methanol and ethanol) were also evaluated. The plant leaves contained ~60% of carbohydrates, protein (~20%), fat (~5%), ash (~4%) and moisture (~9%). The phytochemicals screening revealed the presence of tannins, flavonoids, and terpenoids in all extracts. Methanolic extracts also contained alkaloids and steroids. Several methods were used to evaluate total antioxidant capacity of the different extracts (DPPH; NO; and H2O2 scavenging assays, reducing power, and FRAP). Ethanolic extracts presented a significantly higher antioxidant activity (p < 0.05) except for FRAP, in which the best results were achieved by the aqueous extracts. Methanolic extracts showed the lowest radical scavenging activities for both DPPH; and NO; radicals

Tailor made degradable ureteral stents from natural origin polysaccharides

A urinary stent is defined as a thin tube, which is inserted in the ureter to prevent or treat the obstruction of urine flow from the kidney. Silicone, latex, polyvinylchloride and polyurethanes are the most widely used materials for the preparation of stents. Nonetheless, severe clinical complications may result from the use of these materials such as fracture, encrustation and infection. In some of the cases, the ureteral stents are temporary and it is often required a second surgery to remove the stent. The main complications with ureteral stents are dislocation, infection, and blockage by encrustation [1]. Recently, a tendency has been noticed favouring less invasive approaches (e.g. pharmacological or catheterization) in treating patients who exhibit symptoms or signs of urinary retention [2]. Currently, nearly 100% of the people who have an urological stent are likely to develop a bacterial infection within 30 days, which increases morbidity threefold [1]. Different types of temporary and permanent stents have been introduced into urological practice to relieve obstructions [3]. Particular attention should be devoted to polymers as they represent a highly versatile class of materials. Despite the fact that silicon continues to be the gold standard material for urological stents, there have been fast developments in manufacturing processes, as well as the introduction of new biodegradable materials in order to overcome the drawbacks of the available products. Polyurethane continues to be the most widely used material for polymeric stents; however it frequently promotes biofilm formation and bacterial adhesion leading to severe infections [2]. The concerns regarding existing stents are the motivation to design new biodegradable urological stent systems based on natural polymers, specifically polysaccharides, which present inherent biocompatibility, anti-bacterial properties and that can be tailor-made into a custom suitable stent for a particular patient

Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance

The research was funded by iNOVA4Health—UID/Multi/04462/, a program financially supported by the Fundação para a Ciência e a Tecnologia—Ministério da Educação e Ciência (FCT-MCTES), through nationalfunds and co-funded by FEDER under the PT2020 Partnership Agreement. We also acknowledge funding from FCT-MCTES through the project DREAM—PTDC/MEC-ONC/29327/2017 and FAI2017 from IPOLFG internal funding.: Ovarian cancer is a highly lethal disease, mainly due to chemoresistance. Our previous studies on metabolic remodeling in ovarian cancer have supported that the reliance on glutathione (GSH) bioavailability is a main adaptive metabolic mechanism, also accounting for chemoresistance to conventional therapy based on platinum salts. In this study, we tested the effects of the in vitro inhibition of GSH synthesis on the restoration of ovarian cancer cells sensitivity to carboplatin. GSH synthesis was inhibited by exposing cells to l-buthionine sulfoximine (l-BSO), an inhibitor of -glutamylcysteine ligase (GCL). Given the systemic toxicity of l-BSO, we developed a new formulation using polyurea (PURE) dendrimers nanoparticles (l-BSO@PUREG4-FA2), targeting l-BSO delivery in a folate functionalized nanoparticle.publishersversionpublishe

Novel Perspectives in Management of Angiogenesis and Cancer Therapy

Funding: The project was funded by IPOLFG EPE and by iNOVA4Health (UID/Multi/04462/2019) a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds. We also acknowledge funding from FCT-MCTES through the project DREAM—PTDC/MEC-ONC/29327/2017. FL-C PhD fellowship was funded by FCT (PD/BD/128337/2017).The activation of endothelial cells (ECs) is a crucial step on the road map of tumor angiogenesis and expanding evidence indicates that a pro-oxidant tumor microenvironment, conditioned by cancer metabolic rewiring, is a relevant controller of this process. Herein, we investigated the contribution of oxidative stress-induced ferroptosis to ECs activation. Moreover, we also addressed the anti-angiogenic effect of Propranolol. We observed that a ferroptosis-like mechanism, induced by xCT inhibition with Erastin, at a non-lethal level, promoted features of ECs activation, such as proliferation, migration and vessel-like structures formation, concomitantly with the depletion of reduced glutathione (GSH) and increased levels of oxidative stress and lipid peroxides. Additionally, this ferroptosis-like mechanism promoted vascular endothelial cadherin (VE-cadherin) junctional gaps and potentiated cancer cell adhesion to ECs and transendothelial migration. Propranolol was able to revert Erastin-dependent activation of ECs and increased levels of hydrogen sulfide (H2S) underlie the mechanism of action of Propranolol. Furthermore, we tested a dual-effect therapy by promoting ECs stability with Propranolol and boosting oxidative stress to induce cancer cell death with a nanoformulation comprising selenium-containing chrysin (SeChry) encapsulated in a fourth generation polyurea dendrimer (SeChry@PUREG4). Our data showed that novel developments in cancer treatment may rely on multi-targeting strategies focusing on nanoformulations for a safer induction of cancer cell death, taking advantage of tumor vasculature stabilization.publishersversionpublishe

Development of pH-Sensitive magnetoliposomes containing shape anisotropic nanoparticles for potential application in combined cancer therapy

Late diagnosis and systemic toxicity associated with conventional treatments make oncological therapy significantly difficult. In this context, nanomedicine emerges as a new approach in the prevention, diagnosis and treatment of cancer. In this work, pH-sensitive solid magnetoliposomes (SMLs) were developed for controlled release of the chemotherapeutic drug doxorubicin (DOX). Shape anisotropic magnetic nanoparticles of magnesium ferrite with partial substitution by calcium (Mg0.75Ca0.25Fe2O4) were synthesized, with and without calcination, and their structural, morphological and magnetic properties were investigated. Their superparamagnetic properties were evaluated and heating capabilities proven, either by exposure to an alternating magnetic field (AMF) (magnetic hyperthermia) or by irradiation with near-infrared (NIR) light (photothermia). The Mg0.75Ca0.25Fe2O4 calcined nanoparticles were selected to integrate the SMLs, surrounded by a lipid bilayer of DOPE:Ch:CHEMS (45:45:10). DOX was encapsulated in the nanosystems with an efficiency above 98%. DOX release assays showed a much more efficient release of the drug at pH = 5 compared to the release kinetics at physiological pH. By subjecting tumor cells to DOX-loaded SMLs, cell viability was significantly reduced, confirming that they can release the encapsulated drug. These results point to the development of efficient pH-sensitive nanocarriers, suitable for a synergistic action in cancer therapy with magnetic targeting, stimulus-controlled drug delivery and dual hyperthermia (magnetic and plasmonic) therapy.This work was funded by the Portuguese Foundation for Science and Technology (FCT) within the framework of the Strategic Funding of Research Units UIDB/04650/2020 (CF-UM-UP), UIDB/00319/2020 (ALGORITMI), UIDB/04077/2020 (MEtRICs), UIDB/04436/2020 (CMEMS) and UIDB/00511/2020 (LEPABE). FCT, POCI, FEDER and NORTE2020 are acknowledged for funding through research projects PTDC/QUI-QFI/28020/2017, EXPL/EMD-EMD/0650/2021, PTDC/EEI-EEE/2846/2021 and NORTE-01-0145-FEDER-000054. MINECO (Spain) is acknowledged for project MAT2016-76824-C3-2-R. B.D.C. and V.M.C. acknowledge FCT for PhD grants SFRH/BD/141936/2018 (B.D.C.) and UI/BD/151028/2021 (V.M.C.). R.O.R. thanks FCT for contract 2020.03975.CEECIND

Dextrin hydrogel loaded with a macroporous Bonelike® scaffold and dental pulp stem cells for critical-sized defect repair

Regeneration of severe bone defects remains a challenge. A formulation of synthetic glass-reinforced hydroxyapatite bone substitute, Bonelike® Poro (BL®P), 250500 µm-diameter, with a dextrin-based hydrogel (HG), further loaded with human dental pulp stem cells (hDPSCs) with osteogenic differentiation ability, was tested for the management of critical-sized defects in an ovine model. Morphology, calcium release, and mechanical strength of HG + BL®P were analyzed. Then, BL®P, HG + BL®P, and 106 hDPSCs-loaded HG + BL®P were implanted in ovine critical-sized 14 mm-diameter calvaria defects. Bone samples were collected after 3 and 6 weeks for histological and micro-CT analysis. BL®P exhibits a suitable porous size for cell ingrowth, from the nm (>200 nm) to the µm (5 µm) range. The addition of BL®P granules to the HG resulted in increased compressive elastic modulus and ultimate tensile strength. The mildly acidic nature of the HG contributed to a faster dissolution of granules. In vivo results confirmed the HG suitability as a carrier, providing better defect filling, easy handling, and injectability of BL®P without compromising new bone formation nor biocompatibility. The HG + BL®P formulations can successfully regenerate critical-sized defects; however, addition of hDPSCs did not significantly enhance new bone formation under these conditions. Granular BL®P provides an effective alternative to autologous grafts. The HG acts as a biocompatible carrier of granular bone substitutes and cells, conferring injectability and cohesivity.Alexandra Machado and Isabel Pereira were supported by the grants SFRH/BD/132000/2017 and UMINHO/BI/131/2018 respectively, from Portuguese Foundation for Science and Technology (FCT), Portugal. The authors acknowledge the funding from FEDER and NORTE 2020 through the project no. 003262 titled “iBONE therapies: advanced solutions for bone regeneration”. This study was supported by FCT under the scope of the strategic funding of UID/BIO/04469 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684) 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. The participation of Isabel Pires, Justina Prada, Luís Maltez and José Eduardo Pereira was funded by the projects UIDB/CVT/00772/2020 and LA/P/0059/2020 supported by FCT. The participation of Rui Alvites, Ana Catarina Sousa, Mariana Branquinho, Ana Rita Caseiro, Sílvia Santos Pedrosa and Ana Colette Maurício was funded by Projects PEst-OE/AGR/UI0211/2011, UIDB/CVT/00772/2020 and LA/P/0059/2020. Mariana Vieira Branquinho (SFRH/BD/146172/2019) and Ana Catarina Sousa (SFRH/BD/146689/2019) acknowledge FCT, for financial support.info:eu-repo/semantics/publishedVersio