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JOURNAL/nrgr/04.03/01300535-202501000-00030/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery. Our previous in vitro study demonstrated that exosomes/small extracellular vesicles (sEVs) isolated from cerebral endothelial cells (CEC-sEVs) of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a (miR-27a) is an elevated miRNA in ischemic CEC-sEVs. In the present study, we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a (27a-sEVs) further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs. 27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector. Small EVs isolated from CECs transfected with a scramble vector (Scra-sEVs) were used as a control. Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs. An array of behavior assays was used to measure neurological function. Compared with treatment of ischemic stroke with Scra-sEVs, treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side, and significantly improved neurological outcomes. In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth. Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone, while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a, and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone. Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs. Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes. Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
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Understanding the neural basis of infant social behaviors is crucial for elucidating the mechanisms of early social and emotional development. In this work, we report a specific population of somatostatin-expressing neurons in the zona incerta (ZISST) of preweaning mice that responds dynamically to social interactions, particularly those with their mother. Bidirectional neural activity manipulations in pups revealed that widespread connectivity of preweaning ZISST neurons to sensory, emotional, and cognitive brain centers mediates two key adaptive functions associated with maternal presence: the reduction of behavior distress and the facilitation of learning. These findings reveal a population of neurons in the infant mouse brain that coordinate the positive effects of the relationship with the mother on an infant's behavior and physiology.
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Neuronas , Conducta Social , Interacción Social , Somatostatina , Zona Incerta , Animales , Femenino , Masculino , Ratones , Emociones , Aprendizaje , Conducta Materna , Neuronas/metabolismo , Neuronas/fisiología , Somatostatina/metabolismo , Zona Incerta/metabolismo , Zona Incerta/fisiologíaRESUMEN
To prepare a soft magnetic powder core, the magnetic powder surface has to be insulated by phosphating treatment. Organic chemicals such as ethanol and acetone are generally used as solvents for phosphoric acid, which may cause serious environmental problems. This work proposed deionized water as the environmentally friendly phosphating solvent for FeSiCr powder. The soft magnetic composites (SMCs) were prepared using phosphoric acid for inorganic coating and modified silicon polymer for organic coating. The effect of different phosphating solvents, including deionized water, ethanol, and acetone, on the structure and magnetic properties of SMCs were investigated. It is found that the solvent affects the phosphating solution's stability and the phosphoric acid's ionization. The phosphoric acid is more stable in deionized water than in ethanol and acetone. The phosphating reaction in deionized water is also more stable in deionized water, resulting in a dense phosphate coating on the particle surface. The effects of phosphoric acid concentration and temperature on the magnetic properties of FeSiCr-based SMCs were further studied. With the increase in phosphoric acid concentration and temperature, the magnetic permeability and saturation magnetization of the powder core decrease, and the core loss decreases, followed by an increase. The optimized combination of properties was obtained for the SMCs phosphated with 0.2 wt.% phosphoric acid in deionized water at 35 °C, including a high effective permeability µe of 25.7, high quality factor Q of 80.2, low core loss Pcv of 709.5 mW/cm3 measured at 0.05 T @ 100 kHz, and high withstanding voltage of 276 V, due to the formation of uniform and dense insulating coating layers. In addition, the SMCs prepared with phosphated powder show good corrosion resistance. The anti-corrosion properties of the SMCs using deionized water as a phosphating solvent are better than those using ethanol and acetone.
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The magnetic properties of magnetic nanocomposites consisting of hard and soft magnetic phases are dependent not only on the intrinsic properties but also on the grain structure and volume ratio of the two phases. In this study, we performed a systematic micromagnetic simulation on the magnetic properties of Ce2Fe14B/α-Fe and Nd2Fe14B/α-Fe nanocomposites. The volume fractions of the hard magnetic Nd2Fe14B or Ce2Fe14B phase were varied from 80% to 40%, and the grain sizes of the hard magnetic phase and the soft magnetic α-Fe phase were changed independently from 10 nm to 40 nm. The results show that when the grain size of both hard and soft phases is 10 nm and the volume fraction of the hard phase is 70%, the highest maximum magnetic energy product can be obtained in both Ce2Fe14B/α-Fe and Nd2Fe14B/α-Fe nanocomposites. The hard magnetic properties of Ce2Fe14B/α-Fe nanocomposite decrease significantly when the volume fraction of the α-Fe phase exceeds 30%. However, for the Nd2Fe14B/α-Fe system, this situation only occurs when the α-Fe volume fraction exceeds 40%. The reason for this is not only because of the low anisotropic field and the smaller exchange coupling length between the soft and hard magnetic phases, but also because of the lower saturation magnetization of the hard phase. The grain size has greater effects on the magnetic properties compared to the volume fraction of the hard magnetic phase. The main reason is that as the grain size increases, the remanence of the nanocomposite decreases sharply, which also leads to a rapid decrease in the maximum magnetic energy product. The simulation results on the effects of phase ratio and grain size have been verified by experiments on melt-spun Ce2Fe14B/α-Fe alloys with various compositions prepared by melt-spinning followed by annealing for various lengths of time. Due to the influence of demagnetization energy, the hard magnetic phase with high saturation magnetization is preferred for the preparation of high-performance nanocomposite magnets.
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Back extrusion is an important process to prepare radially oriented NdFeB ring magnets. In this work, we fabricate the ring magnets using amorphous magnetic powders as the raw material. The microstructure, magnetic properties, corrosion resistance, and mechanical properties of the backward extruded magnet at different positions along the axial direction have been investigated, and the inhomogeneity of the magnet is clarified. The results showed that the grains in the middle region of the ring magnet exhibit a strong c-axis orientation, whereas the grains at the bottom and top regions are disordered with random orientation. The microstructure variation is related to the distribution of the grain boundary phase and the degree of grain deformation. Due to the microstructure difference, the magnetic properties, temperature stability, corrosion resistance, and mechanical properties in the middle region of the magnet are higher than those in the top and bottom regions. The exchange coupling between grains also varies in different regions, which is related to the grain size and grain boundary thickness. In addition, different Co element segregations were observed in different regions, which has a crucial effect on the Curie temperature and thermal stability of the magnet. The microstructure difference also leads to the variation of corrosion resistance and mechanical properties for the samples from different regions of the magnet. This work suggests that the amorphous powder can be used to directly prepare radially oriented ring magnets, and the inhomogeneity of the magnet should be fully understood.
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A novel ZnO-MoO3-ZnMoO3@graphene GZM composite catalyst prepared by microwave hydrothermal process for personal protective equipment textiles (PPE) is presented in this study. The results indicated that the GZM with defect vacancy sites of two types as observed by EPR showed significantly superior inactivation of the E. coli bacteria compared to GZM without the lower defect vacancy sites and concomitant lower electron densities. Photocatalytic activated oxidation by the GZM composites coatings was observed to proceed in acceptable times as well as the bacterial inactivation (log bact. C/Co > 107 within 3 h). Defect sites in the GZM seem to be important leading to the bacterial inactivation process. DFT calculations on the GZM with and without catalyst defect sites were carried out. The electron densities were estimated by the Fourier mapping. The results found in this study showed the potential of GZM-PPE for practical applications.
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Escherichia coli , Luz , Oxidación-Reducción , CatálisisRESUMEN
To inhibit the magnetic dilution effect of Ce in Nd-Ce-Fe-B magnets, a dual-alloy method is employed to prepare hot-deformed dual-main-phase (DMP) magnets using mixed nanocrystalline Nd-Fe-B and Ce-Fe-B powders. A REFe2 (1 : 2, where RE is a rare earth element) phase can only be detected when the Ce-Fe-B content exceeds 30 wt%. The lattice parameters of the RE2Fe14B (2 : 14 : 1) phase exhibit non-linear variation with the increasing Ce-Fe-B content due to the mixed valence states of Ce ions. Owning to inferior intrinsic properties of Ce2Fe14B compared to Nd2Fe14B, the magnetic properties of DMP Nd-Ce-Fe-B magnets almost decrease with the increase of Ce-Fe-B addition, but interestingly, the magnet with 10 wt% Ce-Fe-B addition exhibits an abnormally increased intrinsic coercivity H cj of 1215 kA m-1, together with the higher temperature coefficients of remanence (α = -0.110%/K) and coercivity (ß = -0.544%/K) in the temperature range of 300-400 K than the single-main-phase (SMP) Nd-Fe-B magnet with H cj = 1158 kA m-1, α = -0.117%/K and ß = -0.570%/K. The reason may be partly attributed to the increase of Ce3+ ions. Different from the Nd-Fe-B powders, the Ce-Fe-B powders in the magnet are difficult to deform into a platelet-like shape because of the lack of low melting point RE-rich phase due to the precipitation of the 1 : 2 phase. The inter-diffusion behavior between the Nd-rich region and Ce-rich region in the DMP magnets has been investigated by microstructure analysis. The significant diffusion of Nd and Ce into Ce-rich and Nd-rich grain boundary phases, respectively, was demonstrated. At the same time, Ce prefers to stay in the surface layer of Nd-based 2 : 14 : 1 grains, but less Nd diffuses into Ce-based 2 : 14 : 1 grains due to the 1 : 2 phase presented in the Ce-rich region. The modification of the Ce-rich grain boundary phase by Nd diffusion and the distribution of Nd in the Ce-rich 2 : 14 : 1 phase are beneficial for magnetic properties.
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Background and purpose: Non-alcoholic fatty liver disease (NAFLD) is known to adversely affect stroke recovery. However, few studies investigate how stroke elicits liver dysfunction, particularly, how stroke in type 2 diabetes mellitus (T2DM) exacerbates progression of NAFLD. In this study, we test whether exosomes harvested from human umbilical cord blood (HUCBC) derived CD133 + cells (CD133 + Exo) improves neuro-cognitive outcome as well as reduces liver dysfunction in T2DM female mice. Methods: Female, adult non-DM and T2DM mice subjected to stroke presence or absence were considered. T2DM-stroke mice were randomly assigned to receive PBS or Exosome treatment group. CD133 + Exo (20 µg/200 µl PBS, i.v.) was administered once at 3 days after stroke. Evaluation of neurological (mNSS, adhesive removal test) and cognitive function [novel object recognition (NOR) test, odor test] was performed. Mice were sacrificed at 28 days after stroke and brain, liver, and serum were harvested. Results: Stroke induces severe and significant short-term and long-term neurological and cognitive deficits which were worse in T2DM mice compared to non-DM mice. CD133 + Exo treatment of T2DM-stroke mice significantly improved neurological function and cognitive outcome indicated by improved discrimination index in the NOR and odor tests compared to control T2DM-stroke mice. CD133 + Exo treatment of T2DM stroke significantly increased vascular and white matter/axon remodeling in the ischemic brain compared to T2DM-stroke mice. However, there were no differences in the lesion volume between non-DM stroke, T2DM-stroke and CD133 + Exo treated T2DM-stroke mice. In T2DM mice, stroke induced earlier and higher TLR4, NLRP3, and cytokine expression (SAA, IL1ß, IL6, TNFα) in the liver compared to heart and kidney, as measured by Western blot. T2DM-stroke mice exhibited worse NAFLD progression with increased liver steatosis, hepatocellular ballooning, fibrosis, serum ALT activity, and higher NAFLD Activity Score compared to T2DM mice and non-DM-stroke mice, while CD133 + Exo treatment significantly attenuated the progression of NAFLD in T2DM stroke mice. Conclusion: Treatment of female T2DM-stroke mice with CD133 + Exo significantly reduces the progression of NAFLD/NASH and improves neurological and cognitive function compared to control T2DM-stroke mice.
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The TET family of dioxygenases promote DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Hypothalamic agouti-related peptide-expressing (AGRP-expressing) neurons play an essential role in driving feeding, while also modulating nonfeeding behaviors. Besides AGRP, these neurons produce neuropeptide Y (NPY) and the neurotransmitter GABA, which act in concert to stimulate food intake and decrease energy expenditure. Notably, AGRP, NPY, and GABA can also elicit anxiolytic effects. Here, we report that in adult mouse AGRP neurons, CRISPR-mediated genetic ablation of Tet3, not previously known to be involved in central control of appetite and metabolism, induced hyperphagia, obesity, and diabetes, in addition to a reduction of stress-like behaviors. TET3 deficiency activated AGRP neurons, simultaneously upregulated the expression of Agrp, Npy, and the vesicular GABA transporter Slc32a1, and impeded leptin signaling. In particular, we uncovered a dynamic association of TET3 with the Agrp promoter in response to leptin signaling, which induced 5hmC modification that was associated with a chromatin-modifying complex leading to transcription inhibition, and this regulation occurred in both the mouse models and human cells. Our results unmasked TET3 as a critical central regulator of appetite and energy metabolism and revealed its unexpected dual role in the control of feeding and other complex behaviors through AGRP neurons.
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Ansiolíticos , Dioxigenasas , 5-Metilcitosina/metabolismo , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Animales , Ansiolíticos/farmacología , Cromatina/metabolismo , Dioxigenasas/genética , Dioxigenasas/metabolismo , Humanos , Hipotálamo/metabolismo , Leptina/metabolismo , Ratones , Neuronas/metabolismo , Neuropéptido Y/metabolismo , Ácido gamma-Aminobutírico/genética , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Dysregulation of long interspersed nuclear element 1 (LINE-1, L1), a dominant class of transposable elements in the human genome, has been linked to neurodegenerative diseases, but whether elevated L1 expression is sufficient to cause neurodegeneration has not been directly tested. Here, we show that the cerebellar expression of L1 is significantly elevated in ataxia telangiectasia patients and strongly anti-correlated with the expression of epigenetic silencers. To examine the role of L1 in the disease etiology, we developed an approach for direct targeting of the L1 promoter for overexpression in mice. We demonstrated that L1 activation in the cerebellum led to Purkinje cell dysfunctions and degeneration and was sufficient to cause ataxia. Treatment with a nucleoside reverse transcriptase inhibitor blunted ataxia progression by reducing DNA damage, attenuating gliosis, and reversing deficits of molecular regulators for calcium homeostasis in Purkinje cells. Our study provides the first direct evidence that L1 activation can drive neurodegeneration.
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Elementos Transponibles de ADN , Inhibidores de la Transcriptasa Inversa , Animales , Humanos , Ratones , Ataxia/metabolismo , Calcio/metabolismo , Cerebelo/metabolismo , Nucleósidos/metabolismo , Células de Purkinje/fisiología , Inhibidores de la Transcriptasa Inversa/metabolismo , Elementos de Nucleótido Esparcido LargoRESUMEN
The ventromedial hypothalamus (VMH) is known to regulate body weight and counterregulatory response. However, how VMH neurons regulate lipid metabolism and energy balance remains unknown. O-linked ß-d-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), catalyzed by O-GlcNAc transferase (OGT), is considered a cellular sensor of nutrients and hormones. Here, we report that genetic ablation of OGT in VMH neurons inhibits neuronal excitability. Mice with VMH neuron-specific OGT deletion show rapid weight gain, increased adiposity, and reduced energy expenditure, without significant changes in food intake or physical activity. The obesity phenotype is associated with adipocyte hypertrophy and reduced lipolysis of white adipose tissues. In addition, OGT deletion in VMH neurons down-regulates the sympathetic activity and impairs the sympathetic innervation of white adipose tissues. These findings identify OGT in the VMH as a homeostatic set point that controls body weight and underscore the importance of the VMH in regulating lipid metabolism through white adipose tissue-specific innervation.
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Lipólisis , N-Acetilglucosaminiltransferasas , Obesidad , Tejido Adiposo/metabolismo , Animales , Peso Corporal , Hipotálamo/metabolismo , Lipólisis/genética , Ratones , Obesidad/genética , Obesidad/metabolismoRESUMEN
Hypothalamic agouti-related peptide and neuropeptide Y-expressing (AgRP) neurons have a critical role in both feeding and non-feeding behaviors of newborn, adolescent, and adult mice, suggesting their broad modulatory impact on brain functions. Here we show that constitutive impairment of AgRP neurons or their peripubertal chemogenetic inhibition resulted in both a numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice. These changes were accompanied by alteration of oscillatory network activity in mPFC, impaired sensorimotor gating, and altered ambulatory behavior that could be reversed by the administration of clozapine, a non-selective dopamine receptor antagonist. The observed AgRP effects are transduced to mPFC in part via dopaminergic neurons in the ventral tegmental area and may also be conveyed by medial thalamic neurons. Our results unmasked a previously unsuspected role for hypothalamic AgRP neurons in control of neuronal pathways that regulate higher-order brain functions during development and in adulthood.
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Hipotálamo , Neuropéptido Y , Animales , Ratones , Proteína Relacionada con Agouti/metabolismo , Neuronas Dopaminérgicas/metabolismo , Hipotálamo/metabolismo , Neuropéptido Y/metabolismo , Corteza Prefrontal/metabolismoRESUMEN
Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown. Here, we show that levels of lysophosphatidic acid (LPA) species in the blood and cerebrospinal fluid are elevated after overnight fasting and lead to higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia, and is decreased following inhibition of LPA synthesis. Mice expressing a human mutation (Prg-1R346T) leading to higher synaptic lipid-mediated cortical excitability display increased fasting-induced hyperphagia. Accordingly, human subjects with this mutation have higher body mass index and prevalence of type 2 diabetes. We further show that the effects of LPA following fasting are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation of circulating LPAs, as well as cortical excitability, while blunting hyperphagia. These findings reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal route by which the hypothalamus can exert a robust impact on the cortex and thereby affect food intake.
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Diabetes Mellitus Tipo 2 , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Conducta Alimentaria/fisiología , Humanos , Hiperfagia/metabolismo , Lisofosfolípidos/metabolismo , Lisofosfolípidos/farmacología , Ratones , Neuronas/metabolismo , Sinapsis/metabolismoRESUMEN
BACKGROUND: Estriol (E3) is a steroid hormone formed only during pregnancy in primates including humans. Although E3 is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E3 have been found to impact reproductive organs and the brain. Here, we explore potential effects of E3 on fetal development using mouse as a model system. RESULTS: We administered E3 to pregnant mice, exposing the fetus to E3. Adult females exposed to E3 in utero (E3-mice) had increased fertility and superior pregnancy outcomes. Female and male E3-mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E3-mice were distinct from controls. E3 promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E3 functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation. CONCLUSIONS: We identify an unexpected functional role for E3 in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency.
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Estrógenos , Receptores de Estrógenos , Animales , Encéfalo/metabolismo , Epigénesis Genética , Estriol , Estrógenos/genética , Estrógenos/metabolismo , Femenino , Feto/metabolismo , Masculino , Ratones , Embarazo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , EsteroidesRESUMEN
Background: Cardiac function is associated with cognitive function. Previously, we found that stroke and traumatic brain injury evoke cardiac dysfunction in mice. In this study, we investigate whether bilateral common carotid artery stenosis (BCAS), a model that induces vascular dementia (VaD) in mice, induces cardiac dysfunction. Methods: Late-adult (6-8 months) C57BL/6J mice were subjected to sham surgery (n = 6) or BCAS (n = 8). BCAS was performed by applying microcoils (0.16 mm internal diameter) around both common carotid arteries. Cerebral blood flow and cognitive function tests were performed 21-28 days post-BCAS. Echocardiography was conducted in conscious mice 29 days after BCAS. Mice were sacrificed 30 days after BCAS. Heart tissues were isolated for immunohistochemical evaluation and real-time PCR assay. Results: Compared to sham mice, BCAS in mice significantly induced cerebral hypoperfusion and cognitive dysfunction, increased cardiac hypertrophy, as indicated by the increased heart weight and the ratio of heart weight/body weight, and induced cardiac dysfunction and left ventricular (LV) enlargement, indicated by a decreased LV ejection fraction (LVEF) and LV fractional shortening (LVFS), increased LV dimension (LVD), and increased LV mass. Cognitive deficits significantly correlated with cardiac deficits. BCAS mice also exhibited significantly increased cardiac fibrosis, increased oxidative stress, as indicated by 4-hydroxynonenal and NADPH oxidase-2, increased leukocyte and macrophage infiltration into the heart, and increased cardiac interleukin-6 and thrombin gene expression. Conclusions: BCAS in mice without primary cardiac disease provokes cardiac dysfunction, which, in part, may be mediated by increased inflammation and oxidative stress.
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Hypothalamic feeding circuits have been identified as having innate synaptic plasticity, mediating adaption to the changing metabolic milieu by controlling responses to feeding and obesity. However, less is known about the regulatory principles underlying the dynamic changes in agouti-related protein (AgRP) perikarya, a region crucial for gating of neural excitation and, hence, feeding. Here we show that AgRP neurons activated by food deprivation, ghrelin administration, or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter GABA released by AgRP neurons that evoked this astrocytic response; this in turn resulted in increased glial ensheetment of AgRP perikarya by glial processes and increased excitability of AgRP neurons. We also identified astrocyte-derived prostaglandin E2, which directly activated - via EP2 receptors - AgRP neurons. Taken together, these observations unmasked a feed-forward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding, and overfeeding.
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Proteína Relacionada con Agouti , Astrocitos/metabolismo , Hambre , Hipotálamo/metabolismo , Plasticidad Neuronal , Neuronas/metabolismo , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Animales , Masculino , Ratones , Ratones Transgénicos , Subtipo EP2 de Receptores de Prostaglandina E/metabolismoRESUMEN
Plasminogen is involved in the process of angiogenesis; however, the underlying mechanism is unclear. Here, we investigated the potential contribution of plasmin/plasminogen in mediating angiogenesis and thereby contributing to functional recovery post-stroke. Wild-type plasminogen naive (Plg+/+) mice and plasminogen knockout (Plg-/-) mice were subjected to unilateral permanent middle cerebral artery occlusion (MCAo). Blood vessels were labeled with FITC-dextran. Functional outcomes, and cerebral vessel density were compared between Plg+/+ and Plg-/- mice at different time points after stroke. We found that Plg-/- mice exhibited significantly reduced functional recovery, associated with significantly decreased vessel density in the peri-infarct area in the ipsilesional cortex compared with Plg+/+ mice. In vitro, cerebral endothelial cells harvested from Plg-/- mice exhibited significantly reduced angiogenesis assessed using tube formation assay, and migration, as evaluated using Scratch assays, compared to endothelial cells harvested from Plg+/+ mice. In addition, using Western blots, expression of thrombospondin (TSP)-1 and TSP-2 were increased after MCAo in the Plg-/- group compared to Plg+/+ mice, especially in the ipsilesional side of brain. Taken together, our data suggest that plasmin/plasminogen down-regulates the expression level of TSP-1 and TSP-2, and thereby promotes angiogenesis in the peri-ischemic brain tissue, which contributes to functional recovery after ischemic stroke.
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Neovascularización Patológica/fisiopatología , Plasminógeno/deficiencia , Recuperación de la Función/fisiología , Accidente Cerebrovascular/fisiopatología , Animales , Masculino , RatonesRESUMEN
The hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons are crucial for the regulation of whole-body energy homeostasis. Here, we show that fasting-induced AgRP neuronal activation is associated with dynamin-related peptide 1 (DRP1)-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking Dnm1l in adult AgRP neurons (Drp1 cKO) show decreased fasting- or ghrelin-induced AgRP neuronal activity and feeding and exhibited a significant decrease in body weight, fat mass, and feeding accompanied by a significant increase in energy expenditure. In support of the role for mitochondrial fission and fatty acids oxidation, Drp1 cKO mice showed attenuated palmitic acid-induced mitochondrial respiration. Altogether, our data revealed that mitochondrial dynamics and fatty acids oxidation in hypothalamic AgRP neurons is a critical mechanism for AgRP neuronal function and body-weight regulation.