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Therapeutic factors secreted by mesenchymal stem cells (MSCs) promote angiogenesis in vivo. However, delivery of MSCs in the absence of a cytoprotective environment offers limited efficacy due to low cell retention, poor graft survival, and the nonmaintenance of a physiologically relevant dose of growth factors at the injury site. The delivery of stem cells on an extracellular matrix (ECM)-based platform alters cell behavior, including migration, proliferation, and paracrine activity, which are essential for angiogenesis. We demonstrate the biophysical and biochemical effects of preconditioning human MSCs (hMSCs) for 96 h on a three-dimensional (3D) ECM-based microgel platform. By altering the macromolecular concentration surrounding cells in the microgels, the proangiogenic phenotype of hMSCs can be tuned in a controlled manner through cell-driven changes in extracellular stiffness and "outside-in" integrin signaling. The softest microgels were tested at a low cell dose (5 × 104 cells) in a preclinical hindlimb ischemia model showing accelerated formation of new blood vessels with a reduced inflammatory response impeding progression of tissue damage. Molecular analysis revealed that several key mediators of angiogenesis were up-regulated in the low-cell-dose microgel group, providing a mechanistic insight of pathways modulated in vivo. Our research adds to current knowledge in cell-encapsulation strategies by highlighting the importance of preconditioning or priming the capacity of biomaterials through cell-material interactions. Obtaining therapeutic efficacy at a low cell dose in the microgel platform is a promising clinical route that would aid faster tissue repair and reperfusion in "no-option" patients suffering from peripheral arterial diseases, such as critical limb ischemia (CLI).
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Células Madre Mesenquimatosas/química , Células Madre Mesenquimatosas/citología , Microgeles/química , Neovascularización Fisiológica , Animales , Proliferación Celular , Células Inmovilizadas/química , Células Inmovilizadas/citología , Células Inmovilizadas/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Miembro Posterior/irrigación sanguínea , Miembro Posterior/metabolismo , Miembro Posterior/cirugía , Humanos , Integrinas/genética , Integrinas/metabolismo , Isquemia/fisiopatología , Isquemia/cirugía , Isquemia/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones DesnudosRESUMEN
A range of adverse, early life environmental influences such as viral infection and social deprivation are thought to increase risk of psychiatric illness later in life. Here, we used peripheral administration of the viral infection mimic polyriboinosinic-polyribocytidylic acid (polyI:C) to compare the consequences of peripubertal infection and isolation rearing. Isolation rearing induced deficits in sensorimotor gating and recognition memory while no changes in social interaction or spatial learning were observed. PolyI:C injection during the peripubertal period markedly increased expression of interferon-stimulated genes (Ifit2, Prkr, Mx2 and Irf7) in the hippocampal dentate gyrus demonstrating that peripheral administration of the viral mimic in the adolescent animal does have direct effects in the brain. Peripubertal infection mimicry induced a similar but later emerging behavioural deficit in prepulse inhibition implying the existence of a peripubertal window of opportunity for viral-mediated cytokine increases to impact brain development and function. PolyI:C treatment also impaired novel object recognition but did not alter spatial reference memory or social interaction. Combining the polyI:C challenge with social isolation did not exacerbate the behavioural deficits seen with isolation rearing alone. Using Irf7 as a marker, peripubertal viral infection mimicry, isolation rearing and a combination of both were all seen to produce a long-lasting molecular imprint on the interferon-associated signalling pathway in the principal neuron population of the hippocampal dentate gyrus. The data suggest that the sensitivity of brain structure and function to disruption by viral infection extends into the peripubertal period. Moreover, augmented interferon signalling in hippocampus may represent a common molecular imprint of environmental insults associated with neuropsychiatric illnesses like schizophrenia.
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Conducta Animal , Giro Dentado , Inductores de Interferón/farmacología , Factor 7 Regulador del Interferón , Interferones/metabolismo , Poli I-C/farmacología , Virosis/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Proteínas de Unión al GTP/efectos de los fármacos , Proteínas de Unión al GTP/metabolismo , Factor 7 Regulador del Interferón/efectos de los fármacos , Factor 7 Regulador del Interferón/metabolismo , Masculino , Proteínas de Resistencia a Mixovirus , Ratas , Ratas Wistar , Filtrado Sensorial/efectos de los fármacos , Filtrado Sensorial/fisiología , Maduración Sexual/fisiología , Aislamiento SocialRESUMEN
Energy production and storage has become a pressing issue in recent decades and its solutions bring new problems. This paper reviews the literature on the human and environmental risks associated with the production, use, and disposal of increasingly common lithium-ion batteries. Popular electronic databases were used for this purpose focused on the period since 2000. Assessment of the toxicological and environmental impact of batteries should then have a holistic scope to precede and guide the introduction of appropriate safety measures. In this short review the authors will try to touch upon this complex subject and point out some important issues related to an unprecedented development of lithium ion batteries-powered world. Given the multi-billion dollar business with the risks associated with the development of new technologies requires careful consideration of whether the balance of profits and losses is beneficial to humans and the planet. Int J Occup Med Environ Health. 2023;36(1):3-20.
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Suministros de Energía Eléctrica , Litio , Humanos , IonesRESUMEN
The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.
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Corteza Cerebral/metabolismo , Regulación de la Expresión Génica/fisiología , Aislamiento Social/psicología , Animales , Conducta Animal/fisiología , Corteza Cerebral/química , Corteza Cerebral/ultraestructura , Biología Computacional , ADN/biosíntesis , ADN/genética , Masculino , Microdiálisis , Actividad Motora/fisiología , Familia de Multigenes , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/biosíntesis , ARN/genética , ARN Complementario/biosíntesis , ARN Complementario/genética , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estrés Psicológico/genética , Estrés Psicológico/psicología , Sinapsis/fisiología , Factores de TranscripciónRESUMEN
This work features a review of literature discussing the health effects of environmental and occupational exposure to aluminum (Al) and its compounds. The sources of exposure, absorption routes and metabolism are discussed in detail. The role of Al and its compounds in the etiology of some diseases, related to both environmental exposure and exposure in the work environment, is also presented. Aluminum toxicity most often affects the central nervous system, the skeletal system, the hematopoietic system, the urinary tract and the respiratory system. An increased effect of active forms of oxygen can stimulate the formation of amyloid deposits. The clinical image of aluminum smelters was dominated by ataxia, memory impairment, impaired abstract thinking and depressive states. Aluminum compounds have a detrimental effect not only on the psychic but also motor skills. Med Pr. 2020;71(1):79-88.
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Aluminio/efectos adversos , Exposición Profesional/efectos adversos , Aluminio/toxicidad , HumanosRESUMEN
Purpose: Alteration in the extracellular matrix (ECM) of the optic nerve head (ONH) causes lamina cribrosa (LC) fibrosis and affects the mechanical integrity of the ONH. Increased ECM tissue stiffness drives myofibroblast activation leading to tissue fibrosis throughout the body. Here using primary human LC cells, we investigate the effect of substrate stiffness on profibrotic changes, which might be a key molecular mechanism driving ECM remodeling of the LC in primary open-angle glaucoma (POAG) glaucoma. Methods: Primary human LC cells from normal and age-matched POAG glaucoma donors were cultured on substrates with defined mechanical properties of 5 and 100 kPa to replicate the range of mechanical microenvironments that cells may experience in vivo. Cell morphology, spread area, actin stress fibers, vinculin-focal adhesion formation, and α-smooth muscle actin (α-SMA) signal were examined using immunofluorescence staining. The elastic modulus of cells was measured using atomic force microscopy (AFM). Results: Significantly greater cell spread area along with increased actin filament development, and vinculin-focal adhesion formation (number and size) were found in both normal and glaucoma LC cells cultured on stiff substrates. These changes were positively associated with elevated cell stiffness measured by AFM. Changes in spreading and cytoskeleton organization of glaucoma LC cells were significantly more pronounced than those in normal cells. The transformation to a myofibroblast-like cell phenotype was identified in both LC cells exposed to stiffer substrates, as indicated by an increased α-SMA signal and its colocalization with the actin stress fibers. Conclusions: These findings demonstrated that a stiffer cell microenvironment activates a myofibroblastic transformation in human LC cells, and therefore contributes to LC remodelling and fibrosis in glaucoma.