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Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke.
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Enhancing wheat productivity by implementing a comprehensive approach that combines irrigation, nutrition, and organic amendments shows potential for collectively enhancing crop performance. This study examined the individual and combined effects of using irrigation systems (IS), foliar potassium bicarbonate (PBR) application, and compost application methods (CM) on nine traits related to the growth, physiology, and yield of the Giza-171 wheat cultivar. Analysis of variance revealed significant (P ≤ 0.05) main effects of IS, PBR, and CM on wheat growth, physiology, and yield traits over the two growing seasons of the study. Drip irrigation resulted in a 16% increase in plant height, leaf area index, crop growth rate, yield components, and grain yield compared to spray irrigation. Additionally, the application of foliar PBR at a concentration of 0.08 g/L boosted these parameters by up to 22% compared to the control. Furthermore, the application of compost using the role method resulted in enhanced wheat performance compared to the treatment including mix application. Importantly, the combined analysis revealed that the three-way interaction between the three factors had a significant effect (P ≤ 0.05) on all the studied traits, with drip irrigation at 0.08 g PBR rate and role compost application method (referred as Drip_0.08g_Role) resulting in the best performance across all traits, while sprinkle irrigation without PBR and conventional mixed compost method (referred as sprinkle_CK_Mix) produced the poorest results. This highlights the potential to synergistically improve wheat performance through optimized agronomic inputs.
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Riego Agrícola , Triticum , Triticum/crecimiento & desarrollo , Triticum/metabolismo , Riego Agrícola/métodos , Fertilizantes , Bicarbonatos/metabolismo , Compostaje/métodos , Compuestos de Potasio , Suelo/químicaRESUMEN
In the context of rapid urban expansion, the interaction between humanity and nature has become more prominent. Urban land and rivers often exist as distinct entities with limited material exchange. However, during rainfall, these two systems interconnect, resulting in the transfer of land-derived pollutants into rivers. Such transfer significantly increases river pollutant levels, adversely affecting water quality. Therefore, developing a water quality simulation and prediction model is crucial. This model should effectively illustrate pollutant movement and dispersion during rain events. This study proposes a comprehensive model that merges the Storm Water Management Model (SWMM) with the Environmental Fluid Dynamics Code (EFDC). This integrated model assesses the spread and dispersion of pollutants, including Ammonia Nitrogen (NH3-N), Total Phosphorus (TP), Total Nitrogen (TN), and Chemical Oxygen Demand (COD), within urban water cycles for various rainfall conditions, thus offering critical theoretical support for managing the water environment. The application of this model under different rainfall intensities (light, moderate and heavy) provides vital insights. During light rainfall, the river's natural purification process can sustain surface water quality at Class IV. Moderate rainfall causes accumulation of pollutants, reducing water quality to Class V. Conversely, heavy rainfall rapidly increases pollutant concentrations due to higher inflow, pushing the river to a degraded Class V status, which is beyond its natural purification capacity, necessitating engineering solutions to reattain Class IV quality. Furthermore, pollutant accumulation in downstream river sections is more influenced by flow rate than by rainfall intensity. In summary, the SWMM-EFDC integrated model proves highly effective in predicting river water quality, thereby significantly aiding urban water pollution control.
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Contaminantes Ambientales , Contaminantes Químicos del Agua , Monitoreo del Ambiente/métodos , Contaminantes Ambientales/análisis , Contaminantes Químicos del Agua/análisis , Calidad del Agua , Fósforo/análisis , Lluvia , Nitrógeno/análisis , ChinaRESUMEN
Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury.
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Lesiones Encefálicas , Microglía , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Encéfalo/metabolismo , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Hematoma/complicaciones , Hematoma/metabolismo , Hematoma/patología , Enfermedades Neuroinflamatorias , Lectina 2 Similar a Ig de Unión al Ácido Siálico/antagonistas & inhibidores , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Animales , RatonesRESUMEN
KEY MESSAGE: Genetic resources contributes to the sustainable protein production in soybean. Soybean is an important crop for food, oil, and forage and is the main source of edible vegetable oil and vegetable protein. It plays an important role in maintaining balanced dietary nutrients for human health. The soybean protein content is a quantitative trait mainly controlled by gene additive effects and is usually negatively correlated with agronomic traits such as the oil content and yield. The selection of soybean varieties with high protein content and high yield to secure sustainable protein production is one of the difficulties in soybean breeding. The abundant genetic variation of soybean germplasm resources is the basis for overcoming the obstacles in breeding for soybean varieties with high yield and high protein content. Soybean has been cultivated for more than 5000 years and has spread from China to other parts of the world. The rich genetic resources play an important role in promoting the sustainable production of soybean protein worldwide. In this paper, the origin and spread of soybean and the current status of soybean production are reviewed; the genetic characteristics of soybean protein and the distribution of resources are expounded based on phenotypes; the discovery of soybean seed protein-related genes as well as transcriptomic, metabolomic, and proteomic studies in soybean are elaborated; the creation and utilization of high-protein germplasm resources are introduced; and the prospect of high-protein soybean breeding is described.
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Glycine max , Proteínas de Soja , Humanos , Glycine max/genética , Proteómica , ChinaRESUMEN
BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization and subsequent inflammatory response may be a potential adjunct therapy to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory and pro-resolving properties in models of cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced microglia/macrophage polarization has not yet been fully elucidated. METHODS: We retrospectively collected blood samples from AIS patients who underwent successful recanalization by EVT and analyzed ANXA1 levels longitudinally before and after EVT and correlation between ANXA1 levels and 3-month clinical outcomes. We also established a C57BL/6J mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro model of oxygen-glucose deprivation and reoxygenation (OGD/R) in BV2 microglia and HT22 neurons to explore the role of Ac2-26, a pharmacophore N-terminal peptide of ANXA1, in regulating the I/R-induced microglia/macrophage activation and polarization. RESULTS: The baseline levels of ANXA1 pre-EVT were significantly lower in 23 AIS patients, as compared with those of healthy controls. They were significantly increased to the levels found in controls 2-3 days post-EVT. The increased post-EVT levels of ANXA1 were positively correlated with 3-month clinical outcomes. In the mouse model, we then found that Ac2-26 administered at the start of reperfusion shifted microglia/macrophage polarization toward anti-inflammatory M2-phenotype in ischemic penumbra, thus alleviating blood-brain barrier leakage and neuronal apoptosis and improving outcomes at 3 days post-tMCAO/R. The protection was abrogated when mice received Ac2-26 together with WRW4, which is a specific antagonist of formyl peptide receptor type 2/lipoxin A4 receptor (FPR2/ALX). Furthermore, the interaction between Ac2-26 and FPR2/ALX receptor activated the 5' adenosine monophosphate-activated protein kinase (AMPK) and inhibited the downstream mammalian target of rapamycin (mTOR). These in vivo findings were validated through in vitro experiments. CONCLUSIONS: Ac2-26 modulates microglial/macrophage polarization and alleviates subsequent cerebral inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway. It may be investigated as an adjunct strategy for clinical prevention and treatment of cerebral I/R injury after recanalization. Plasma ANXA1 may be a potential biomarker for outcomes of AIS patients receiving EVT.
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Anexina A1/metabolismo , Diferenciación Celular , Infarto de la Arteria Cerebral Media/prevención & control , Macrófagos , Microglía/metabolismo , Daño por Reperfusión/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Anciano , Animales , Anexina A1/farmacología , Anexina A1/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Femenino , Proteínas de Homeodominio/metabolismo , Humanos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Persona de Mediana Edad , Péptidos/uso terapéutico , Receptores de Formil Péptido/metabolismo , Daño por Reperfusión/inmunología , Estudios RetrospectivosRESUMEN
DNA methylation is a heritable epigenetic modification that plays an essential role in mammalian development. Genomic methylation patterns are dynamically maintained, with DNA methyltransferases mediating inheritance of methyl marks onto nascent DNA over cycles of replication. A recently developed experimental technique employing immunoprecipitation of bromodeoxyuridine labeled nascent DNA followed by bisulfite sequencing (Repli-BS) measures post-replication temporal evolution of cytosine methylation, thus enabling genome-wide monitoring of methylation maintenance. In this work, we combine statistical analysis and stochastic mathematical modeling to analyze Repli-BS data from human embryonic stem cells. We estimate site-specific kinetic rate constants for the restoration of methyl marks on >10 million uniquely mapped cytosines within the CpG (cytosine-phosphate-guanine) dinucleotide context across the genome using Maximum Likelihood Estimation. We find that post-replication remethylation rate constants span approximately two orders of magnitude, with half-lives of per-site recovery of steady-state methylation levels ranging from shorter than ten minutes to five hours and longer. Furthermore, we find that kinetic constants of maintenance methylation are correlated among neighboring CpG sites. Stochastic mathematical modeling provides insight to the biological mechanisms underlying the inference results, suggesting that enzyme processivity and/or collaboration can produce the observed kinetic correlations. Our combined statistical/mathematical modeling approach expands the utility of genomic datasets and disentangles heterogeneity in methylation patterns arising from replication-associated temporal dynamics versus stable cell-to-cell differences.
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Biología Computacional/métodos , Metilación de ADN/fisiología , Animales , Bromodesoxiuridina/química , Islas de CpG , Citosina/metabolismo , ADN/metabolismo , Metilasas de Modificación del ADN/genética , Células Madre Embrionarias/metabolismo , Epigénesis Genética/genética , Epigénesis Genética/fisiología , Epigenómica/métodos , Genoma , Genómica , Humanos , Cinética , Modelos Estadísticos , Modelos Teóricos , Procesos EstocásticosRESUMEN
Drought stress, which is increasing with climate change, is a serious threat to agricultural sustainability worldwide. Seed germination is an essential growth phase that ensures the successful establishment and productivity of soybean, which can lose substantial productivity in soils with water deficits. However, only limited genetic information is available about how germinating soybean seeds may exert drought tolerance. In this study, we examined the germinating seed drought-tolerance phenotypes and genotypes of a panel of 259 released Chinese soybean cultivars panel. Based on 4616 Single-Nucleotide Polymorphisms (SNPs), we conducted a mixed-linear model GWAS that identified a total of 15 SNPs associated with at least one drought-tolerance index. Notably, three of these SNPs were commonly associated with two drought-tolerance indices. Two of these SNPs are positioned upstream of genes, and 11 of them are located in or near regions where QTLs have been previously mapped by linkage analysis, five of which are drought-related. The SNPs detected in this study can both drive hypothesis-driven research to deepen our understanding of genetic basis of soybean drought tolerance at the germination stage and provide useful genetic resources that can facilitate the selection of drought stress traits via genomic-assisted selection.
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Sequías , Regulación del Desarrollo de la Expresión Génica , Estudio de Asociación del Genoma Completo , Germinación , Glycine max/genética , Polimorfismo de Nucleótido Simple , Semillas/genética , Mapeo Cromosómico , Regulación de la Expresión Génica de las Plantas , Genotipo , Desequilibrio de Ligamiento , Fenotipo , Proteínas de Plantas/genética , Sitios de Carácter Cuantitativo , Semillas/crecimiento & desarrollo , Glycine max/crecimiento & desarrollo , Estrés FisiológicoRESUMEN
Intervertebral disc degeneration (IDD) is a main cause of diseases such as discogenic low back pain, cervical and lumbar disc herniation, degenerative spinal stenosis, and lumbar spondylolisthesis. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important transcription factor, regulates antioxidant genes and induces cellular defense mechanisms against oxidative stress. In this study, the protective effect of plant antioxidant lycopene on nucleus pulposus cells (NPCs) under oxidative stress was investigated. The results indicated that Nrf2 expression decreased in degenerated NPCs. We further found that lycopene was protective in NP tissue under oxidative stress and alleviated oxidative stress-induced apoptosis of degenerative human NPCs via Nrf2. The results also showed that lycopene reduced H2O2-induced decomposition of cartilage extracellular matrix in NPCs. In conclusion, our findings suggested that lycopene may alleviate disc degeneration under oxidative stress through the Nrf2 signaling pathway.
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Antioxidantes/farmacología , Matriz Extracelular/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Licopeno/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Núcleo Pulposo/metabolismo , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/genética , Matriz Extracelular/patología , Humanos , Peróxido de Hidrógeno/toxicidad , Inmunohistoquímica , Degeneración del Disco Intervertebral/genética , Licopeno/metabolismo , Núcleo Pulposo/citología , Núcleo Pulposo/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Corn (Zea mays L.) is an important food crop and feedstuff worldwide. However, Corn stalk rot, caused by multiple pathogens, is globally an economic soil-borne disease worldwide. In September 2019, a survey was carried out to characterize pathogenic fungi in corn stalks in Nehe city (48.48°N 124.88°E), Heilongjiang Province, China. Stalk rot incidence was approximately 5% in three of the fields sampled (5 ha/per field). Symptoms included wilting of whole plants, drooping ears or rapid death of the upper leaves or whole plant from blister stage to physiological maturity (growth stages R2- R6) stage with drooping ears or rapid death of the upper leaves or whole plant. A brown to black dry rot or necrosis was observed throughout the central pith and internal tissues of the stalk and crown were observed, which resulted in hollow and soft stalks. Fifteen tissue samples (0.25 cm2) from 15 individual diseased plants were surface disinfested with 75% ethanol for 2 s, followed by 0.5% NaOCl for 5 min, rinsed three times in sterile distilled water and cultured on potato dextrose agar (PDA) with 50 µg/mL streptomycin at 26°C in darkness. After 3 days, a total of eight fungal isolates with consistent characteristics were obtained from three sampling points and subcultured by transferring hyphal tips onto a new PDA plate. Single-conidium isolates were generated with methods reported previously (Leslie and Summerell 2006). Cultures on PDA were honey to olivaceous buff in the center with dense aerial mycelia and wide buff colored margins. The dimensions of conidia from 30-day-old PDA cultures were 4.5 to 15.3 µm × 1.5 to 4.3 µm (n = 50). Often, one to two oil bodies were present within the conidia. Based on these morphological features, the isolates were identified as Didymella americana (Aveskamp et al. 2010; Gorny et al. 2016). Genomic DNA was extracted from a representative isolate YJDA8 and the internal transcribed spacer regions (ITS) and translation elongation factor 1-alpha gene (TEF-1É) were amplified and sequenced using the primers ITS1/ITS4 (Yin et al. 2012) and EF1-728F/EF1-986R (Carbone and Kohn 1999), respectively. The sequences of YJDA8 (accession nos. MT995077 for ITS and MW003707 for TEF-1a ) showed 99.6% (529/531 bp) and 97.6% (283/290 bp), identity to the sequences of D. americana isolate YSGYE6 (accession no. MK945663.1) and isolate K_INSO2_6_10 (MN554764.1) respectively. Pathogenicity tests were conducted by root injection of corn plants at the blister stage in the field. Conidia were obtained from 30-day-old PDA cultures grown at 20°C with a 12 h photoperiod. A conidial suspension (1.5 ml of 1×105 conidia/mL) was injected into the base of the maize stems using a 5 ml syringe. For each treatment, 5 plants were inoculated. Plants injected with 1.5 ml distilled sterile water served as the control. After inoculation, the plants were managed using conventional methods. All inoculated plants showed symptoms 25 days after inoculation that were similar to those observed in the field, while no symptoms were observed on the control plants. The fungus was re-isolated and confirmed to be D. americana. D. americana has previously been reported on corn roots and soybean pods in the USA (Aveskamp et al. 2009 as Peyronellaea americana), on lima bean in Delaware and Maryland (Everts et al. 2020). To our knowledge, this is the first report of D. americana causing stalk rot on corn in China. Therefore, its distribution needs to be investigated, monitored and managed with effective disease management strategies to protect corn.
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The activation of microglia and the various substances they produce have been linked to the pathologic development of Parkinson's disease (PD), but the precise role of microglia in PD remains to be defined. The survival of microglia depends on colony-stimulating factor 1 receptor (CSF1R) signaling, and CSF1R inhibition results in rapid elimination of microglia in the central nervous system. Using a mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment, we showed that the depletion of microglia via the CSF1R inhibitor PLX3397 exacerbated the impairment of locomotor activities and the loss of dopaminergic neurons. Further, depletion of microglia augmented the production of inflammatory mediators and infiltration of leukocytes in the brain after MPTP exposure. Microglia depletion-induced aggravation of MPTP neurotoxicity was also seen in lymphocyte-deficient mice. In addition, the depletion of microglia did not affect the production of brain-derived neurotrophic factor, but it dramatically augmented the production of inflammatory mediators by astrocytes after MPTP treatment. Our findings suggest microglia play a protective role against MPTP-induced neuroinflammation and dopaminergic neurotoxicity.-Yang, X., Ren, H., Wood, K., Li, M., Qiu, S., Shi, F.-D., Ma, C., Liu, Q. Depletion of microglia augments the dopaminergic neurotoxicity of MPTP.
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Neuronas Dopaminérgicas/metabolismo , Mediadores de Inflamación/metabolismo , Leucocitos/metabolismo , Intoxicación por MPTP/metabolismo , Microglía/metabolismo , Aminopiridinas/farmacología , Animales , Neuronas Dopaminérgicas/patología , Leucocitos/patología , Intoxicación por MPTP/patología , Masculino , Ratones , Ratones Noqueados , Microglía/patología , Pirroles/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidoresRESUMEN
BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. As a key component of the innate immune system, the NOD-like receptor (NLR) family, NLRP3 (pyrin domain-containing protein 3) inflammasome, when activated after ICH, promotes neuroinflammation and brain edema. MCC950 is a potent, selective, small-molecule NLRP3 inhibitor that blocks NLRP3 activation at nanomolar concentrations. Here, we examined the effect of MCC950 on brain injury and inflammation in 2 models of ICH in mice. METHODS: In mice with ICH induced by injection of autologous blood or bacterial collagenase, we determined the therapeutic potential of MCC950 and its mechanisms of neuroprotection. RESULTS: MCC950 reduced IL-1ß (interleukin-1ß) production and attenuated neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In mice with autologous blood-induced ICH, the protection of MCC950 was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6. MCC950 improved blood-brain barrier integrity and diminished cell death. Notably, the protective effect of MCC950 was abolished in mice depleted of either microglia or Gr-1+ myeloid cells. CONCLUSIONS: These results indicate that the NLRP3 inflammasome inhibitor, MCC950, attenuates brain injury and inflammation after ICH. Hence, NLRP3 inflammasome inhibition is a potential therapy for ICH that warrants further investigation.
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Lesiones Encefálicas/tratamiento farmacológico , Hemorragia Cerebral/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Lesiones Encefálicas/etiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patología , Femenino , Interleucina-1beta/metabolismo , Masculino , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory response has emerged as a prominent contributor to the pathophysiological processes of traumatic brain injury (TBI). Recently, a potent, selective, small-molecule NLRP3 inflammasome inhibitor, MCC950, was described. Here, we investigated the effect of MCC950 on inflammatory brain injury and long-term neurological outcomes in a mouse model of TBI. Male C57/BL6 mice were subjected to TBI using the controlled cortical impact injury (CCI) system. Western blotting, flow cytometry, and immunofluorescence assays were utilized to analyze post-traumatic NLRP3 inflammasome expression and determine its cellular source. We found that NLRP3 inflammasome expression was significantly increased in the peri-contusional cortex and that microglia were the primary source of this expression. The effects of MCC950 on mice with TBI were then determined using post-assessments including analyses of neurological deficits, brain water content, traumatic lesion volume, neuroinflammation, blood-brain barrier (BBB) integrity, and cell death. MCC950 treatment resulted in a better neurological outcome after TBI by alleviating brain edema, reducing lesion volume, and improving long-term motor and cognitive functions. The therapeutic window for MCC950 against TBI was as long as 6â¯h. Furthermore, the neuroprotective effect of MCC950 was associated with reduced microglial activation, leukocyte recruitment, and pro-inflammatory cytokine production. In addition, MCC950 preserved BBB integrity, alleviated TBI-induced loss of tight junction proteins, and attenuated cell death. Notably, the efficacy of MCC950 was abolished in microglia-depleted mice. These results indicate that microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to TBI, and specific NLRP3 inflammasome inhibition using MCC950 may be a promising therapeutic approach for patients with TBI.
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Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sulfonas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Furanos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Indenos , Inflamasomas/antagonistas & inhibidores , Inflamasomas/biosíntesis , Inflamasomas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Distribución Aleatoria , Sulfonamidas , Sulfonas/farmacología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. After ICH, the immediate infiltration of leukocytes and activation of microglia are accompanied by a rapid up-regulation of the 18-kDa translocator protein (TSPO). TSPO ligands have shown anti-inflammatory and neuroprotective properties in models of CNS injury. In this study, we determined the impact of a TSPO ligand, etifoxine, on brain injury and inflammation in 2 mouse models of ICH. TSPO was up-regulated in Iba1+ cells from brains of patients with ICH and in CD11b+CD45int cells from mice subjected to collagenase-induced ICH. Etifoxine significantly reduced neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In collagenase-induced ICH mice, the protection of etifoxine was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6 and TNF-α. Etifoxine improved blood-brain barrier integrity and diminished cell death. Notably, the protective effect of etifoxine was abolished in mice depleted of microglia by using a colony-stimulating factor 1 receptor inhibitor. These results indicate that the TSPO ligand etifoxine attenuates brain injury and inflammation after ICH. TSPO may be a viable therapeutic target that requires further investigations in ICH.-Li, M., Ren, H., Sheth, K. N., Shi, F.-D., Liu, Q. A TSPO ligand attenuates brain injury after intracerebral hemorrhage.
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Ansiolíticos/farmacología , Hemorragia Cerebral/patología , Oxazinas/farmacología , Receptores de GABA/metabolismo , Animales , Edema Encefálico/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica/fisiología , Ratones , Regulación hacia ArribaRESUMEN
OBJECTIVE: This study aims to investigate whether bidirectional degeneration occurs within the visual pathway and, if so, the extent of such changes in neuromyelitis optica spectrum disorder (NMOSD). METHODS: In total, 36 NMOSD and 24 healthy controls (HCs) were enrolled. Three-dimensional T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging were used to analyze damage to the posterior visual pathway. Damage to the anterior visual pathway was measured by optical coherence tomography. RESULTS: In total, 24 NMOSD with prior optic neuritis (NMOON) patients showed significant reduction of peripapillary retinal nerve fiber layer, inner and outer retinal thickness, lateral geniculate nucleus volume, primary visual cortex volume, and decreased integrity of optic radiations, compared with 12 NMOSD without prior optic neuritis (NMONON) patients and 24 HCs. In NMONON, only the inner retinal thickness and the integrity of optic radiations were significantly reduced in comparison with HCs. Moreover, patients with optic neuritis showed severe bidirectional degeneration, the loss of the RNFL was greater than the atrophy of V1. CONCLUSION: Our study indicated the presence of trans-synaptic degeneration in NMOSD. Damage to the inner retina and optic radiations can be observed even in NMONON. After an episode of optic neuritis, the anterior visual pathway damage is greater than the posterior visual pathway damage.
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Degeneración Nerviosa/patología , Neuromielitis Óptica/patología , Corteza Visual/patología , Vías Visuales/patología , Adulto , Estudios Transversales , Imagen de Difusión Tensora , Femenino , Humanos , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/diagnóstico por imagen , Neuromielitis Óptica/diagnóstico por imagen , Tomografía de Coherencia Óptica , Corteza Visual/diagnóstico por imagen , Vías Visuales/diagnóstico por imagenRESUMEN
Traumatic brain injury (TBI) results in severe neurological impairments without effective treatments. Inflammation appears to be an important contributor to key pathogenic events such as secondary brain injury following TBI and therefore serves as a promising target for novel therapies. We have recently demonstrated the ability of a molecular construct comprised of the human leukocyte antigen (HLA)-DRα1 domain linked covalently to mouse (m)MOG-35-55 peptide (DRα1-MOG-35-55 construct) to reduce CNS inflammation and tissue injury in animal models of multiple sclerosis and ischemic stroke. The aim of the current study was to determine if DRα1-MOG-35-55 treatment of a fluid percussion injury (FPI) mouse model of TBI could reduce the lesion size and improve disease outcome measures. Neurodeficits, lesion size, and immune responses were determined to evaluate the therapeutic potential and mechanisms of neuroprotection induced by DRα1-MOG-35-55 treatment. The results demonstrated that daily injections of DRα1-MOG-35-55 given after FPI significantly reduced numbers of infiltrating CD74+ and CD86+ macrophages and increased numbers of CD206+ microglia in the brain concomitant with smaller lesion sizes and improvement in neurodeficits. Conversely, DRα1-MOG-35-55 treatment of TBI increased numbers of circulating CD11b+ monocytes and their expression of CD74 but had no detectable effect on cell numbers or marker expression in the spleen. These results demonstrate that DRα1-MOG-35-55 therapy can reduce CNS inflammation and significantly improve histological and clinical outcomes after TBI. Future studies will further examine the potential of DRα1-MOG-35-55 for treatment of TBI.
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Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Animales , Antígenos de Diferenciación de Linfocitos B/metabolismo , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/patología , Antígeno CD11b/metabolismo , Clonación Molecular , Antígenos de Histocompatibilidad Clase II/metabolismo , Recuento de Leucocitos , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Enfermedades del Sistema Nervioso/etiología , Fármacos Neuroprotectores/síntesis química , Proteínas Recombinantes de Fusión/síntesis química , Resultado del TratamientoRESUMEN
BACKGROUND: Cognition and sleep deficits occur in amnestic mild cognitive impairment (aMCI) and vascular cognitive impairment-no dementia (VCIND). However, how memory and sleep deficits differ between aMCI and VCIND remains unclear. METHODS: Fifty aMCI and 50 VCIND patients and 38 sex- and age-matched healthy controls (HCs) were administered the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test-A/B (TMT-A/B), Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Benton Judgment of Line Orientation (JLO) test, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Insomnia Severity Index (ISI) to quantify cognitive deficits and subjective sleep disturbance. RESULTS: Compared with VCIND patients, aMCI patients had lower HVLT-R scores for total recall (p < 0.001), delayed recall (p < 0.001) and recognition (p = 0.001), and for total-recall (p = 0.002) and delayed-recall (p < 0.001) semantic clustering ratios (SCRs). However, VCIND patients exhibited more obvious executive dysfunction (TMT-A, p < 0.001; TMT-B, p < 0.001; WCST, p < 0.001), lower information processing speed (PASAT, p = 0.003; SDMT, p < 0.001), and more severe sleep disturbance (PSQI, p < 0.001; ESS, p < 0.001; ISI, p < 0.001). Additionally, sleep quality and efficiency were related to total and delayed recall (all r values from -0.31 to -0.60, p < 0.05) in aMCI and VCIND. CONCLUSIONS: aMCI and VCIND differ in cognitive function, memory strategy and sleep impairment; these characteristics are helpful to identify and distinguish patients with very early cognitive impairment. Our results also suggest that memory deficits are associated with sleep disturbance in aMCI and VCIND.
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Amnesia/fisiopatología , Disfunción Cognitiva/fisiopatología , Demencia/etiología , Demencia/psicología , Memoria , Semántica , Sueño/fisiología , Anciano , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/psicología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Recuerdo Mental , Pruebas NeuropsicológicasRESUMEN
Emerging evidence has highlighted the capacity of hematogenous cells in skull and vertebral bone marrow to enter the meningeal borders via ossified vascular channels and maintain immune homeostasis in the central nervous system (CNS). CNS-adjacent skull and vertebral bone marrow comprises hematopoietic niches that can sense CNS injury and supply specialized immune cells to fine-tune inflammatory responses. Here, we review recent advances in our understanding of skull and vertebral bone marrow-derived immune cells in homeostasis and inflammatory CNS diseases. Further, we discuss the implications for future development of therapies to mitigate CNS inflammation and its detrimental sequelae in neurological disorders.
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Several aberrant alternative splicing (AS) events and their regulatory mechanisms are widely recognized in multiple sclerosis (MS). Yet the cell-type specific AS events have not been extensively examined. Here we assessed the diversity of AS events using web-based RNA-seq data of sorted CD15-CD11b+ microglia in white matter (WM) region from 10 patients with MS and 11 control subjects. The GSE111972 dataset was downloaded from GEO and ENA databases, aligned to the GRCh38 reference genome from ENSEMBL via STAR. rMATS was used to assess five types of AS events, alternative 3'SS (A3SS), alternative 5'SS (A5SS), skipped exon (SE), retained intron (RI) and mutually exclusive exons (MXE), followed by visualizing with rmats2sashimiplot and maser. Differential genes or transcripts were analyzed using the limma R package. Gene ontology (GO) analysis was performed with the clusterProfiler R package. 42,663 raw counts of AS events were identified and 132 significant AS events were retained based on the filtered criteria: 1) average coverage >10 and 2) delta percent spliced in (ΔPSI) >0.1. SE was the most common AS event (36.36%), followed by MXE events (32.58%), and RI (18.94%). Genes related to telomere maintenance and organization primarily underwent SE splicing, while genes associated with protein folding and mitochondrion organization were predominantly spliced in the MXE pattern. Conversely, genes experiencing RI were enriched in immune response and immunoglobulin production. In conclusion, we identified microglia-specific AS changes in the white matter of MS patients, which may shed light on novel pathological mechanisms underlying MS.