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1.
Int J Mol Sci ; 24(12)2023 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-37373273

RESUMEN

The deposition of stem cells at sites of injury is a clinically relevant approach to facilitate tissue repair and angiogenesis. However, insufficient cell engraftment and survival require the engineering of novel scaffolds. Here, a regular network of microscopic poly(lactic-co-glycolic acid) (PLGA) filaments was investigated as a promising biodegradable scaffold for human Adipose-Derived Stem Cell (hADSC) tissue integration. Via soft lithography, three different microstructured fabrics were realized where 5 × 5 and 5 × 3 µm PLGA 'warp' and 'weft' filaments crossed perpendicularly with pitch distances of 5, 10 and 20 µm. After hADSC seeding, cell viability, actin cytoskeleton, spatial organization and the secretome were characterized and compared to conventional substrates, including collagen layers. On the PLGA fabric, hADSC re-assembled to form spheroidal-like structures, preserving cell viability and favoring a nonlinear actin organization. Moreover, the secretion of specific factors involved in angiogenesis, the remodeling of the extracellular matrix and stem cell homing was favored on the PLGA fabric as compared to that which occurred on conventional substrates. The paracrine activity of hADSC was microstructure-dependent, with 5 µm PLGA fabric enhancing the expression of factors involved in all three processes. Although more studies are needed, the proposed PLGA fabric would represent a promising alternative to conventional collagen substrates for stem cell implantation and angiogenesis induction.


Asunto(s)
Ácido Poliglicólico , Andamios del Tejido , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Andamios del Tejido/química , Ácido Poliglicólico/química , Ácido Láctico/química , Ingeniería de Tejidos , Células Cultivadas , Colágeno/química , Células Madre/ultraestructura
2.
Pharmacol Res ; 172: 105816, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34391933

RESUMEN

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), in which myeloid cells sustain inflammation, take part in priming, differentiation, and reactivation of myelin-specific T cells, and cause direct myelin damage. N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a proinflammatory enzyme induced by phlogosis and overexpressed in macrophages and microglia of EAE mice. Targeting these cell populations by inhibiting NAAA may be a promising pharmacological strategy to modulate the inflammatory aspect of MS and manage disease progression. To address this goal, we used ARN16186, a small molecule specifically designed and synthesized as a pharmacological tool to inhibit NAAA. We assessed whether enzyme inhibition affected the severity of neurological symptoms and modulated immune cell infiltration into the central nervous system of EAE mice. We found that preventive chronic treatment with ARN16186 was efficacious in slowing disease progression and preserving locomotor activity in EAE mice. Furthermore, NAAA inhibition reduced the number of immune cells infiltrating the spinal cord and modulated the overactivation of NF-kB and STAT3 transcription factors, leading to less expansion of Th17 cells over the course of the disease.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Linfocitos T/efectos de los fármacos , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Locomoción/efectos de los fármacos , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/metabolismo , Linfocitos T/inmunología
3.
Brain Behav Immun ; 81: 138-150, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31175999

RESUMEN

Immune system alterations have been implicated in various dopamine-related disorders, such as schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder (ADHD). How immunity might be influenced by dopaminergic dysfunction and impact on clinically-relevant behaviors is still uncertain. We performed a peripheral and cerebral immunophenotyping in mice bearing dopaminergic alteration produced by genetic liability (hypofunction of the dopamine transporter DAT) and psychostimulant (amphetamine) administration. We found that DAT hypofunction influences immune tolerance by increasing functional Tregs and adrenomedullin levels in the thymus and spleen, while reducing microglia activation and infiltration of brain monocyte-derived macrophages (mo-MΦ). Remarkably, both DAT hypofunction and amphetamine treatment are associated with a weaker activation of the choroid plexus (CP) gateway. Conversely, amphetamine reactivated the CP in the setting of DAT hypofunction, paralleling its paradoxical ADHD-relevant behavioral effects. These findings add new knowledge on dopaminergic immunopharmacology and support the immunomodulation of CP functionality as a promising therapeutic strategy for neurodevelopmental and psychiatric disorders.


Asunto(s)
Plexo Coroideo/metabolismo , Inmunomodulación/efectos de los fármacos , Inmunomodulación/fisiología , Anfetamina/farmacología , Animales , Trastorno por Déficit de Atención con Hiperactividad , Trastorno Bipolar , Estimulantes del Sistema Nervioso Central/farmacología , Plexo Coroideo/efectos de los fármacos , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esquizofrenia
4.
Biotechnol Appl Biochem ; 66(3): 273-280, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30588719

RESUMEN

Ultraviolet (UV) light exposure is the primary factor responsible for skin photoaging, affecting all the skin layers, mainly through the production of reactive oxygen species (ROS), activation of inflammatory responses, and apoptosis. In keeping with this evidence, exogenous supplementation with dietary antioxidants has been shown to provide photoprotective benefits. Moreover, oral administration of hyaluronic acid (HA) has been proved to reduce the signs of aged skin, such as wrinkles, and increase hydration and elasticity. The combination of different biologically active substances in order to slow down the onset of skin aging could represent a promising preventive strategy against photoaging. In the present study, we investigated the effects of a dietary supplement (IALUTEC® RED), consisting of high-molecular-weight HA (HMW-HA) combined with red orange extract (ROC-Red Orange Complex® ), in human fibroblasts exposed to ultra violet light B-induced oxidative stress. Our study suggests that, in fibroblasts exposed to UVB light, IALUTEC® RED is active in decreasing both the inflammatory response and the generation of ROS, two events that are involved in skin photoaging.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Citoprotección/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/efectos de la radiación , Ácido Hialurónico/farmacología , Pigmentos Biológicos/farmacología , Rayos Ultravioleta , Antiinflamatorios/química , Antioxidantes/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Ácido Hialurónico/química , Peso Molecular , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo
5.
Biomed Pharmacother ; 175: 116677, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38701570

RESUMEN

The current pharmacological approaches to multiple sclerosis (MS) target its inflammatory and autoimmune components, but effective treatments to foster remyelination and axonal repair are still lacking. We therefore selected two targets known to be involved in MS pathogenesis: N-acylethanolamine-hydrolyzing acid amidase (NAAA) and glycogen synthase kinase-3ß (GSK-3ß). We tested whether inhibiting these targets exerted a therapeutic effect against experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The combined inhibition of NAAA and GSK-3ß by two selected small-molecule compounds, ARN16186 (an NAAA inhibitor) and AF3581 (a GSK-3ß inhibitor), effectively mitigated disease progression, rescuing the animals from paralysis and preventing a worsening of the pathology. The complementary activity of the two inhibitors reduced the infiltration of immune cells into the spinal cord and led to the formation of thin myelin sheaths around the axons post-demyelination. Specifically, the inhibition of NAAA and GSK-3ß modulated the over-activation of NF-kB and STAT3 transcription factors in the EAE-affected mice and induced the nuclear translocation of ß-catenin, reducing the inflammatory insult and promoting the remyelination process. Overall, this work demonstrates that the dual-targeting of key aspects responsible for MS progression could be an innovative pharmacological approach to tackle the pathology.


Asunto(s)
Amidohidrolasas , Encefalomielitis Autoinmune Experimental , Glucógeno Sintasa Quinasa 3 beta , Ratones Endogámicos C57BL , Esclerosis Múltiple , Animales , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Ratones , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Femenino , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , FN-kappa B/metabolismo , Inhibidores Enzimáticos/farmacología , Vaina de Mielina/metabolismo , Vaina de Mielina/efectos de los fármacos
6.
Stem Cells ; 27(10): 2469-77, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19593794

RESUMEN

Abscisic acid (ABA) is a hormone involved in pivotal physiological functions in higher plants, such as response to abiotic stress and control of seed dormancy and germination. Recently, ABA was demonstrated to be autocrinally produced by human granulocytes, beta pancreatic cells, and mesenchymal stem cells (MSC) and to stimulate cell-specific functions through a signaling pathway involving the second messenger cyclic ADP-ribose (cADPR). Here we show that ABA expands human uncommitted hemopoietic progenitors (HP) in vitro, through a cADPR-mediated increase of the intracellular calcium concentration ([Ca(2+)](i)). Incubation of CD34(+) cells with micromolar ABA also induces transcriptional effects, which include NF-kappaB nuclear translocation and transcription of genes encoding for several cytokines. Human MSC stimulated with a lymphocyte-conditioned medium produce and release ABA at concentrations sufficient to exert growth-stimulatory effects on co-cultured CD34(+) cells, as demonstrated by the inhibition of colony growth in the presence of an anti-ABA monoclonal antibody. These results provide a remarkable example of conservation of a stress hormone and of its second messenger from plants to humans and identify ABA as a new hemopoietic growth factor involved in the cross-talk between HP and MSC.


Asunto(s)
Ácido Abscísico/farmacología , Proliferación Celular/efectos de los fármacos , ADP-Ribosa Cíclica/metabolismo , Células Madre Hematopoyéticas/efectos de los fármacos , Sistemas de Mensajero Secundario/fisiología , Ácido Abscísico/metabolismo , Antígenos CD34/metabolismo , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Citocinas/efectos de los fármacos , Citocinas/genética , Células Madre Hematopoyéticas/metabolismo , Humanos , Células Madre Mesenquimatosas/metabolismo , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Neovascularización Fisiológica/fisiología , Reguladores del Crecimiento de las Plantas/farmacología , Sistemas de Mensajero Secundario/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/fisiología
7.
Mol Neurobiol ; 56(9): 6276-6292, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30746640

RESUMEN

Cultured hippocampal neurons represent the most widely used experimental substrate for in vitro electrophysiological studies. Nevertheless, in most cases, the nature of neuron under study is not identified as excitatory or inhibitory, or even worse, recorded neurons are considered as excitatory because of the paucity of GABAergic interneurons. Thus, the definition of reliable criteria able to guarantee an unequivocal identification of excitatory and inhibitory cultured hippocampal neurons is an unmet need. To reach this goal, we compared the electrophysiological properties and the localization and size of the axon initial segment (AIS) of cultured hippocampal neurons, taking advantage from GAD67-GFP knock-in mice, which expressing green fluorescent protein (GFP) in gamma-aminobutyric acid (GABA)-containing cells, allowed to unambiguously determine the precise nature of the neuron under study. Our results demonstrate that the passive electrophysiological properties, the localization and size of the AIS, and the shape and frequency of the action potential (AP) are not reliable to unequivocally identify neurons as excitatory or inhibitory. The only parameter, related to the shape of the single AP, showing minimal overlap between the sample-point distributions of the two neuronal subpopulations, was the AP half-width. However, the estimation of the AP failure ratio evoked by a short train of high-current steps applied at increasing frequency (40-140 Hz) resulted to be indisputably the safer and faster way to identify the excitatory or inhibitory nature of an unknown neuron. Our findings provide a precise framework for further electrophysiological investigations of in vitro hippocampal neurons.


Asunto(s)
Potenciales de Acción/fisiología , Hipocampo/citología , Inhibición Neural/fisiología , Neuronas/fisiología , Animales , Axones/metabolismo , Células Cultivadas , Femenino , Glutamato Descarboxilasa/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Cinética , Masculino , Ratones Endogámicos C57BL
8.
Adv Mater ; 23(47): 5645-50, 2011 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-22095932

RESUMEN

Superparamagnetic nanocarriers with tunable pH dependence of the surface charge are designed by a simple co-precipitation method. By exploiting electrostatic interactions, cationic or anionic payloads can be adsorbed and desorbed depending on the pH. On three different resulting nanocarrier systems, experiments of loading and release of gold nanoparticles as well as effective siRNA loading and in vitro delivery on human cells are performed.


Asunto(s)
Portadores de Fármacos/química , Oro/química , Magnetismo , Nanopartículas del Metal/química , ARN Interferente Pequeño/administración & dosificación , Aniones/química , Cationes/química , Portadores de Fármacos/farmacología , Humanos , Concentración de Iones de Hidrógeno , Microscopía Fluorescente , ARN Interferente Pequeño/farmacología , Dispersión de Radiación
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