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Dive into the research topics where Liliana Bernardino is active.

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Featured researches published by Liliana Bernardino.


The Journal of Neuroscience | 2005

Modulator effects of interleukin-1beta and tumor necrosis factor-alpha on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures.

Liliana Bernardino; Sara Xapelli; Ana P. Silva; Birthe Jakobsen; Frantz Rom Poulsen; Catarina R. Oliveira; Annamaria Vezzani; João O. Malva; Jens Zimmer

The inflammatory cytokines interleukin-1β and tumor necrosis factor-α (TNF-α) have been identified as mediators of several forms of neurodegeneration in the brain. However, they can produce either deleterious or beneficial effects on neuronal function. We investigated the effects of these cytokines on neuronal death caused by exposure of mouse organotypic hippocampal slice cultures to toxic concentrations of AMPA. Either potentiation of excitotoxicity or neuroprotection was observed, depending on the concentration of the cytokines and the timing of exposure. A relatively high concentration of mouse recombinant TNF-α (10 ng/ml) enhanced excitotoxicity when the cultures were simultaneously exposed to AMPA and to this cytokine. Decreasing the concentration of TNF-α to 1 ng/ml resulted in neuroprotection against AMPA-induced neuronal death independently on the application protocol. By using TNF-α receptor (TNFR) knock-out mice, we demonstrated that the potentiation of AMPA-induced toxicity by TNF-α involves TNF receptor-1, whereas the neuroprotective effect is mediated by TNF receptor-2. AMPA exposure was associated with activation and proliferation of microglia as assessed by macrophage antigen-1 and bromodeoxyuridine immunohistochemistry, suggesting a functional recruitment of cytokine-producing cells at sites of neurodegeneration. Together, these findings are relevant for understanding the role of proinflammatory cytokines and microglia activation in acute and chronic excitotoxic conditions.


Journal of Controlled Release | 2016

Nanoparticle-mediated brain drug delivery: Overcoming blood–brain barrier to treat neurodegenerative diseases

Cláudia Saraiva; Catarina Praça; Raquel Ferreira; Tiago Santos; Lino Ferreira; Liliana Bernardino

The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBBs unique and protective features control brain homeostasis as well as ion and molecule movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuroinflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimers (AD) and Parkinsons disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate molecules with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB composition and characteristics and how these features are altered in pathology, namely in stroke, AD and PD. Additionally, factors influencing an efficient intravenous delivery of polymeric and inorganic NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed.


Stem Cells | 2008

Tumor Necrosis Factor‐α Modulates Survival, Proliferation, and Neuronal Differentiation in Neonatal Subventricular Zone Cell Cultures

Liliana Bernardino; Fabienne Agasse; Bruno A. Silva; Raquel Ferreira; Sofia Grade; João O. Malva

Tumor necrosis factor (TNF)‐α has been reported to modulate brain injury, but remarkably, little is known about its effects on neurogenesis. We report that TNF‐α strongly influences survival, proliferation, and neuronal differentiation in cultured subventricular zone (SVZ) neural stem/progenitor cells derived from the neonatal P1–3 C57BL/6 mice. By using single‐cell calcium imaging, we developed a method, based on cellular response to KCl and/or histamine, that allows the functional evaluation of neuronal differentiation. Exposure of SVZ cultures to 1 and 10 ng/ml mouse or 1 ng/ml human recombinant TNF‐α resulted in increased differentiation of cells displaying a neuronal‐like profile of [Ca2+]i responses, compared with the predominant profile of immature cells observed in control, nontreated cultures. Moreover, by using neutralizing antibodies for each TNF‐α receptor, we found that the proneurogenic effect of 1 ng/ml TNF‐α is mediated via tumor necrosis factor receptor 1 activation. Accordingly, the percentage of neuronal nuclear protein‐positive neurons was increased following exposure to mouse TNF‐α. Interestingly, exposure of SVZ cultures to 1 ng/ml TNF‐α induced cell proliferation, whereas 10 and 100 ng/ml TNF‐α induced apoptotic cell death. Moreover, we found that exposure of SVZ cells to TNF‐α for 15 minutes or 6 hours caused an increase in the phospho‐stress‐activated protein kinase/c‐Jun N‐terminal kinase immunoreactivity initially in the nucleus and then in growing axons, colocalizing with tau, consistent with axonogenesis. Taken together, these results show that TNF‐α induces neurogenesis in neonatal SVZ cell cultures of mice. TNF‐α, a proinflammatory cytokine and a proneurogenic factor, may play a central role in promoting neurogenesis and brain repair in response to brain injury and infection.


Epilepsia | 2006

Inactivation of Caspase-1 in Rodent Brain : A Novel Anticonvulsive Strategy

Teresa Ravizza; Sian Marie Lucas; Silvia Balosso; Liliana Bernardino; George Ku; Francesco Noé; João O. Malva; John C. R. Randle; Stuart M. Allan; Annamaria Vezzani

Summary:  Purpose: Cytokines and related inflammatory mediators are rapidly synthesized in the brain during seizures. We previously found that intracerebral administration of interleukin‐1 (IL‐1)‐β has proconvulsant effects, whereas its endogenous receptor antagonist (IL‐1Ra) mediates potent anticonvulsant actions in various models of limbic seizures. In this study, we investigated whether seizures can be effectively inhibited by blocking the brain production of IL‐1β, by using selective inhibitors of interleukin‐converting enzyme (ICE/caspase‐1) or through caspase‐1 gene deletion.


Stem Cells | 2008

Neuropeptide Y Promotes Neurogenesis in Murine Subventricular Zone

Fabienne Agasse; Liliana Bernardino; Heidi Kristiansen; Søren H. Christiansen; Raquel Ferreira; Bruno A. Silva; Sofia Grade; David P. D. Woldbye; João O. Malva

Stem cells of the subventricular zone (SVZ) represent a reliable source of neurons for cell replacement. Neuropeptide Y (NPY) promotes neurogenesis in the hippocampal subgranular layer and the olfactory epithelium and may be useful for the stimulation of SVZ dynamic in brain repair purposes. We describe that NPY promotes SVZ neurogenesis. NPY (1 μM) treatments increased proliferation at 48 hours and neuronal differentiation at 7 days in SVZ cell cultures. NPY proneurogenic properties are mediated via the Y1 receptor. Accordingly, Y1 receptor is a major active NPY receptor in the mouse SVZ, as shown by functional autoradiography. Moreover, short exposure to NPY increased immunoreactivity for the phosphorylated form of extracellular signal‐regulated kinase 1/2 in the nucleus, compatible with a trigger for proliferation, whereas 6 hours of treatment amplified the phosphorylated form of c‐Jun‐NH2‐terminal kinase signal in growing axons, consistent with axonogenesis. NPY, as a promoter of SVZ neurogenesis, is a crucial factor for future development of cell‐based brain therapy.


Journal of Neurochemistry | 2008

Inflammatory events in hippocampal slice cultures prime neuronal susceptibility to excitotoxic injury: a crucial role of P2X7 receptor‐mediated IL‐1β release

Liliana Bernardino; Silvia Balosso; Teresa Ravizza; Nicola Marchi; George Ku; John C. R. Randle; João O. Malva; Annamaria Vezzani

We investigated the consequences of transient application of specific stimuli mimicking inflammation to hippocampal tissue on microglia activation and neuronal cell vulnerability to a subsequent excitotoxic insult. Two‐week‐old organotypic hippocampal slice cultures, from 7‐day‐old C57BL/6 donor mice, were exposed for 3 h to lipopolysaccharide (LPS; 10 ng/mL) followed by 3 h co‐incubation with 1 mM ATP, or 100 μM 2′3′‐O‐(4‐benzoyl‐benzoyl) adenosine 5′‐triphosphate triethylammonium, a selective P2X7 receptor agonist. These treatments in combination, but not individually, induced a pronounced activation and apoptotic‐like death of macrophage antigen‐1 (MAC‐1)‐positive microglia associated with a massive release of interleukin (IL)‐1β exceeding that induced by LPS alone. Antagonists of P2X7 receptors prevented these effects. Transient pre‐exposure of slice cultures to a combination of LPS and P2X7 receptor agonists, but not either one or the other alone, significantly exacerbated CA3 pyramidal cell loss induced by subsequent 12 h exposure to 8 μM α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propinate (AMPA). Potentiation of AMPA toxicity was prevented when IL‐1β production or its receptor signaling were blocked by an inhibitor of interleukin‐converting‐enzyme or IL‐1 receptor antagonist during application of LPS + ATP. The same treatments did not prevent microglia apoptosis‐like death. These findings show that transient exposure to specific pro‐inflammatory stimuli in brain tissue can prime neuronal susceptibility to a subsequent excitotoxic insult. P2X7 receptor stimulation, and the consequent IL‐1β release, is mandatory for exacerbation of neuronal loss. These mechanisms may contribute to determine cell death/survival in acute and chronic neurodegenerative conditions associated with inflammatory events.


ACS Nano | 2012

Polymeric Nanoparticles to Control the Differentiation of Neural Stem Cells in the Subventricular Zone of the Brain

Tiago Santos; Raquel Ferreira; João Maia; Fabienne Agasse; Sara Xapelli; Luísa Cortes; José Bragança; João O. Malva; Lino Ferreira; Liliana Bernardino

Herein, we report the use of retinoic acid-loaded polymeric nanoparticles as a potent tool to induce the neuronal differentiation of subventricular zone neural stem cells. The intracellular delivery of retinoic acid by the nanoparticles activated nuclear retinoic acid receptors, decreased stemness, and increased proneurogenic gene expression. Importantly, this work reports for the first time a nanoparticle formulation able to modulate in vivo the subventricular zone neurogenic niche. The work further compares the dynamics of initial stages of differentiation between SVZ cells treated with retinoic acid-loaded polymeric nanoparticles and solubilized retinoic acid. The nanoparticle formulation developed here may ultimately offer new perspectives to treat neurodegenerative diseases.


ACS Nano | 2011

Controlling the Neuronal Differentiation of Stem Cells by the Intracellular Delivery of Retinoic Acid-Loaded Nanoparticles

João Maia; Tiago Santos; Sezin Aday; Fabienne Agasse; Luísa Cortes; João O. Malva; Liliana Bernardino; Lino Ferreira

The manipulation of endogenous stem cell populations from the subventricular zone (SVZ), a neurogenic niche, creates an opportunity to induce neurogenesis and influence brain regenerative capacities in the adult brain. Herein, we demonstrate the ability of polyelectrolyte nanoparticles to induce neurogenesis exclusively after being internalized by SVZ stem cells. The nanoparticles are not cytotoxic for concentrations equal or below 10 μg/mL. The internalization process is rapid, and nanoparticles escape endosomal fate in a few hours. Retinoic acid-loaded nanoparticles increase the number of neuronal nuclear protein (NeuN)-positive neurons and functional neurons responding to depolarization with KCl and expressing NMDA receptor subunit type 1 (NR1). These nanoparticles offer an opportunity for in vivo delivery of proneurogenic factors and neurodegenerative disease treatment.


Journal of Neuroinflammation | 2012

Histamine modulates microglia function

Raquel Ferreira; Tiago Santos; Joana Gonçalves; Graça Baltazar; Lino Ferreira; Fabienne Agasse; Liliana Bernardino

BackgroundHistamine is commonly acknowledged as an inflammatory mediator in peripheral tissues, leaving its role in brain immune responses scarcely studied. Therefore, our aim was to uncover the cellular and molecular mechanisms elicited by this molecule and its receptors in microglia-induced inflammation by evaluating cell migration and inflammatory mediator release.MethodsFirstly, we detected the expression of all known histamine receptor subtypes (H1R, H2R, H3R and H4R), using a murine microglial cell line and primary microglia cell cultures from rat cortex, by real-time PCR analysis, immunocytochemistry and Western blotting. Then, we evaluated the role of histamine in microglial cell motility by performing scratch wound assays. Results were further confirmed using murine cortex explants. Finally, interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels were evaluated by ELISA measurements to determine the role of histamine on the release of these inflammatory mediators.ResultsAfter 12 h of treatment, 100 μM histamine and 10 μg/ml histamine-loaded poly (lactic-co-glycolic acid) microparticles significantly stimulated microglia motility via H4R activation. In addition, migration involves α5β1 integrins, and p38 and Akt signaling pathways. Migration of microglial cells was also enhanced in the presence of lipopolysaccharide (LPS, 100 ng/ml), used as a positive control. Importantly, histamine inhibited LPS-stimulated migration via H4R activation. Histamine or H4R agonist also inhibited LPS-induced IL-1β release in both N9 microglia cell line and hippocampal organotypic slice cultures.ConclusionsTo our knowledge, we are the first to show a dual role of histamine in the modulation of microglial inflammatory responses. Altogether, our data suggest that histamine per se triggers microglia motility, whereas histamine impedes LPS-induced microglia migration and IL-1β release. This last datum assigns a new putative anti-inflammatory role for histamine, acting via H4R to restrain exacerbated microglial responses under inflammatory challenge, which could have strong repercussions in the treatment of CNS disorders accompanied by microglia-derived inflammation.


The Journal of Neuroscience | 2010

The Angiogenic Factor Angiopoietin-1 Is a Proneurogenic Peptide on Subventricular Zone Stem/Progenitor Cells

Alexandra Isabel Rosa; Joana Gonçalves; Luísa Cortes; Liliana Bernardino; João O. Malva; Fabienne Agasse

In the adult mammalian brain, the subventricular zone (SVZ) hosts stem cells constantly generating new neurons. Angiopoietin-1 (Ang-1) is an endothelial growth factor with a critical role in division, survival, and adhesion of endothelial cells via Tie-2 receptor activity. Expression of Tie-2 in nonendothelial cells, especially neurons and stem cells, suggests that Ang-1 may be involved in neurogenesis. In the present work, we investigated the putative role of Ang-1 on SVZ neurogenesis. Immature cells from SVZ-derived neurospheres express Ang-1 and Tie-2 mRNA, suggesting a role for the Ang-1/Tie-2 system in the neurogenic niche. Moreover, we also found that Tie-2 protein expression is retained on differentiation in neurons and glial cells. Ang-1 triggered proliferation via activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) mitogen-activated protein kinase (MAPK) kinase pathway but did not induce cell death. Accordingly, coincubation with an anti-Tie-2 neutralizing antibody prevented the pro-proliferative effect of Ang-1. Furthermore, Ang-1 increased the number of NeuN (neuronal nuclear protein)-positive neurons in cultures treated for 7 d, as well as the number of functional neurons, as assessed by monitoring [Ca2+]i rises after application of specific stimuli for neurons and immature cells. The proneurogenic effect of Ang-1 is mediated by Tie-2 activation and subsequent mTOR (mammalian target of rapamycin kinase) mobilization. In agreement, neuronal differentiation significantly decreased after exposure to an anti-Tie-2 neutralizing antibody and to rapamycin. Moreover, Ang-1 elicited the activation of the SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase) MAPK, involved in axonogenesis. Our work shows a proneurogenic effect of Ang-1, highlighting the relevance of blood vessel/stem cell cross talk in health and disease.

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Raquel Ferreira

University of Beira Interior

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Tiago Santos

University of Beira Interior

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Cláudia Saraiva

University of Beira Interior

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