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Madureira A.R.,Catholic University of Portugal | Campos D.,Catholic University of Portugal | Gullon B.,Catholic University of Portugal | Marques C.,University of Porto | And 9 more authors.
Food and Function | Year: 2016

Solid lipid nanoparticles (SLNs) can be used for oral delivery of phenolic compounds in order to protect them from the harsh conditions of digestion and improve their bioavailability in the intestinal epithelium. Recently, the production and characterization of SLNs loaded with rosmarinic acid (RA) and herbal extracts was performed for future use as functional food ingredients. Diet components have been shown to have a huge impact on gut microbiota viability and metabolic activity. Hence, SLNs loaded with RA, sage and savoury extracts have been evaluated for their effect on intestinal microbiota growth and the metabolic products generated. Fermentations in anaerobic batch cultures using volunteer human faeces were performed during 24 h. Dynamic bacterial population changes were analysed using PCR-real time, as well as the generation of fatty acids and the quantification of phenolic compounds by analytical methods. Solid lipid nanoparticles released phenolic compounds at non-inhibitory bacterial growth concentrations. Released herbal extract phenolic compounds showed a beneficial effect on gut microbiota growth (e.g. bifidogenic effects) and were used as substrates. Acetate, formate, lactate and butyrate were produced in higher concentrations. The released phenolic compounds also induced PUFA and trans fatty acids metabolic activity, the production of saturated fatty acids, as well of potential beneficial conjugated linoleic acid isomers. Solid lipid nanoparticles modulate gut microbiota and metabolic activities. © The Royal Society of Chemistry 2016.


da Silva S.B.,University of Porto | da Silva S.B.,Catholic University of Portugal | Ferreira D.,University of Porto | Pintado M.,Catholic University of Portugal | And 2 more authors.
International Journal of Biological Macromolecules | Year: 2016

In this study, chitosan nanoparticles were used to encapsulate antioxidant rosmarinic acid, Salvia officinalis (sage) and Satureja montana (savory) extracts as rosmarinic acid natural vehicles. The nanoparticles were prepared by ionic gelation using chitosan and sodium tripolyphosphate (TPP) in a mass ratio of 7:1, at pH 5.8. Particle size distribution analysis and transmission electron microscopy (TEM) confirmed the size ranging from 200 to 300nm, while surface charge of nanoparticles ranged from 20 to 30mV. Nanoparticles demonstrate to be safe without relevant cytotoxicity against retina pigment epithelium (ARPE-19) and human cornea cell line (HCE-T). The permeability study in HCE monolayer cell line showed an apparent permeability coefficient Papp of 3.41±0.99×10-5 and 3.24±0.79×10-5cm/s for rosmarinic acid loaded chitosan nanoparticles and free in solution, respectively. In ARPE-19 monolayer cell line the Papp was 3.39±0.18×10-5 and 3.60±0.05×10-5cm/s for rosmarinic acid loaded chitosan nanoparticles and free in solution, respectively. Considering the mucin interaction method, nanoparticles indicate mucoadhesive proprieties suggesting an increased retention time over the ocular mucosa after instillation. These nanoparticles may be promising drug delivery systems for ocular application in oxidative eye conditions. © 2015 Elsevier B.V.


Madureira A.R.,Catholic University of Portugal | Nunes S.,University of Coimbra | Campos D.A.,Catholic University of Portugal | Fernandes J.C.,University of Coimbra | And 11 more authors.
International Journal of Nanomedicine | Year: 2016

Rosmarinic acid (RA) possesses several protective bioactivities that have attracted increasing interest by nutraceutical/pharmaceutical industries. Considering the reduced bioavailability after oral use, effective (and safe) delivery systems are crucial to protect RA from gastrointestinal degradation. This study aims to characterize the safety profile of solid lipid nanoparticles produced with Witepsol and Carnauba waxes and loaded with RA, using in vitro and in vivo approaches, focused on genotoxicity and cytotoxicity assays, redox status markers, hematological and biochemical profile, liver and kidney function, gut bacterial microbiota, and fecal fatty acids composition. Free RA and sage extract, empty nanoparticles, or nanoparticles loaded with RA or sage extract (0.15 and 1.5 mg/mL) were evaluated for cell (lymphocytes) viability, necrosis and apoptosis, and antioxidant/prooxidant effects upon DNA. Wistar rats were orally treated for 14 days with vehicle (control) and with Witepsol or Carnauba nanoparticles loaded with RA at 1 and 10 mg/kg body weight/d. Blood, urine, feces, and several tissues were collected for analysis. Free and loaded RA, at 0.15 mg/mL, presented a safe profile, while genotoxic potential was found for the higher dose (1.5 mg/mL), mainly by necrosis. Our data suggest that both types of nanoparticles are safe when loaded with moderate concentrations of RA, without in vitro genotoxicity and cytotoxicity and with an in vivo safety profile in rats orally treated, thus opening new avenues for use in nutraceutical applications. © 2016 Madureira et al.


Da Silva S.B.,University of Porto | Da Silva S.B.,Catholic University of Portugal | Amorim M.,Catholic University of Portugal | Fonte P.,Institute of Health science North | And 5 more authors.
Pharmaceutical Biology | Year: 2015

Context: Nanotechnology can be applied to deliver and protect antioxidants in order to control the oxidative stress phenomena in several chronic pathologies. Chitosan (CS) nanoparticles are biodegradable carriers that may protect antioxidants with potent biological activity such as rosmarinic acid (RA) in Salvia officinalis (sage) and Satureja montana (savory) extracts for safe and innovative therapies. Objective: Development and characterization of CS nanoparticles as a stable and protective vehicle to deliver RA for medical applications using natural extracts as sage and savory. Materials and methods: Antioxidant-CS based nanoparticles were prepared by ionic gelation with sodium tripolyphosphate (TPP), at pH 5.8 with a mass ratio of 7:1 (CS:TPP), with a theoretical antioxidant-CS loading of 40-50%. The nanoparticles were then characterized by different methods such as photon correlation spectroscopy, laser Doppler anemometry, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR), high-performance liquid chromatographic (HPLC), association efficiency, and antioxidant activity. Results and discussion: Individual and small sizing nanoparticles, around 300 nm, were obtained. SEM confirmed smooth and spherical nanoparticles after freeze-drying. No chemical interactions were found between antioxidants and CS, after encapsulation, by DSC and FTIR. The association efficiency was 51.2% for RA (with 40% loading) and 96.1 and 98.2% for sage and savory nanoparticles, respectively (both with 50% loading). Antioxidant activity values were higher than 0.0348 eq [Asc. Ac.] g/L/g extract and 0.4251 μmol/eq Trolox/g extract. Conclusion: The extracts under study are promising vehicles for RA drug delivery in CS nanocarriers. © 2014 Informa Healthcare USA, Inc. All rights reserved.


PubMed | University of Porto, University of Vigo, Catholic University of Portugal and Institute of Health science North
Type: Journal Article | Journal: Food & function | Year: 2016

Solid lipid nanoparticles (SLNs) can be used for oral delivery of phenolic compounds in order to protect them from the harsh conditions of digestion and improve their bioavailability in the intestinal epithelium. Recently, the production and characterization of SLNs loaded with rosmarinic acid (RA) and herbal extracts was performed for future use as functional food ingredients. Diet components have been shown to have a huge impact on gut microbiota viability and metabolic activity. Hence, SLNs loaded with RA, sage and savoury extracts have been evaluated for their effect on intestinal microbiota growth and the metabolic products generated. Fermentations in anaerobic batch cultures using volunteer human faeces were performed during 24 h. Dynamic bacterial population changes were analysed using PCR-real time, as well as the generation of fatty acids and the quantification of phenolic compounds by analytical methods. Solid lipid nanoparticles released phenolic compounds at non-inhibitory bacterial growth concentrations. Released herbal extract phenolic compounds showed a beneficial effect on gut microbiota growth (e.g. bifidogenic effects) and were used as substrates. Acetate, formate, lactate and butyrate were produced in higher concentrations. The released phenolic compounds also induced PUFA and trans fatty acids metabolic activity, the production of saturated fatty acids, as well of potential beneficial conjugated linoleic acid isomers. Solid lipid nanoparticles modulate gut microbiota and metabolic activities.


Martins T.,University of Coimbra | Baptista S.,University of Coimbra | Goncalves J.,University of Coimbra | Leal E.,Center for Neuroscience and Cell Biology | And 8 more authors.
Brain Research | Year: 2011

Methamphetamine (METH) is a powerful stimulant drug of abuse that has steadily gained popularity worldwide. It is known that METH is highly neurotoxic and causes irreversible damage of brain cells leading to neurological and psychiatric abnormalities. Recent studies suggested that METH-induced neurotoxicity might also result from its ability to compromise blood-brain barrier (BBB) function. Due to the crucial role of BBB in the maintenance of brain homeostasis and protection against toxic molecules and pathogenic organisms, its dysfunction could have severe consequences. In this study, we investigated the effect of an acute high dose of METH (30 mg/kg) on BBB permeability after different time points and in different brain regions. For that, young adult mice were sacrificed 1 h, 24 h or 72 h post-METH administration. METH increased BBB permeability, but this effect was detected only at 24 h after administration, being therefore a transitory effect. Interestingly, we also found that the hippocampus was the most susceptible brain region to METH, comparing to frontal cortex and striatum. Moreover, in an attempt to identify the key players in METH-induced BBB dysfunction we further investigated potential alterations in tight junction (TJ) proteins and matrix metalloproteinase-9 (MMP-9). METH was able to decrease the protein levels of zonula occludens (ZO)-1, claudin-5 and occludin in the hippocampus 24 h post-injection, and increased the activity and immunoreactivity of MMP-9. The pre-treatment with BB-94 (30 mg/kg), a matrix metalloproteinase inhibitor, prevented the METH-induced increase in MMP-9 immunoreactivity in the hippocampus. Overall, the present data demonstrate that METH transiently increases the BBB permeability in the hippocampus, which can be explained by alterations on TJ proteins and MMP-9. © 2011 Elsevier B.V. All rights reserved.


Baptista S.,University of Coimbra | Lasgi C.,Institute Curie | Benstaali C.,Institute Curie | Milhazes N.,University of Porto | And 6 more authors.
Stem Cell Research | Year: 2014

Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse that negatively interferes with neurogenesis. In fact, we have previously shown that METH triggers stem/progenitor cell death and decreases neuronal differentiation in the dentate gyrus (DG). Still, little is known regarding its effect on DG stem cell properties. Herein, we investigate the impact of METH on mice DG stem/progenitor cell self-renewal functions. METH (10nM) decreased DG stem cell self-renewal, while 1nM delayed cell cycle in the G0/G1-to-S phase transition and increased the number of quiescent cells (G0 phase), which correlated with a decrease in cyclin E, pEGFR and pERK1/2 protein levels. Importantly, both drug concentrations (1 or 10nM) did not induce cell death. In accordance with the impairment of self-renewal capacity, METH (10nM) decreased Sox2+/Sox2+ while increased Sox2-/Sox2- pairs of daughter cells. This effect relied on N-methyl-d-aspartate (NMDA) signaling, which was prevented by the NMDA receptor antagonist, MK-801 (10μM). Moreover, METH (10nM) increased doublecortin (DCX) protein levels consistent with neuronal differentiation. In conclusion, METH alters DG stem cell properties by delaying cell cycle and decreasing self-renewal capacities, mechanisms that may contribute to DG neurogenesis impairment followed by cognitive deficits verified in METH consumers. © 2014.

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