RESUMO
Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.
Assuntos
Astrócitos , Doenças do Sistema Nervoso Central , Regulação da Expressão Gênica , Fatores de Transcrição , Transcrição Gênica , Animais , Astrócitos/metabolismo , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/patologia , Cromatina/genética , Cromatina/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Análise de Sequência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The Casparian strip (CS) is a cell wall modification made of lignin that functions as an apoplastic barrier in the root endodermis to restrict nutrient and water transport between the soil and stele. CS formation is affected by nutritional conditions, and its physiological roles have been discussed. This study found that low K condition affects CS permeability, lignin deposition, and MYB36 mRNA accumulation. To understand the mechanism underlying these findings, we focused on nitric oxide (NO). NO is known to act as a signaling molecule and participates in cell wall synthesis, especially for lignin composition. However, the mechanism by which NO affects lignin deposition and corrects CS formation in the plant roots remains unclear. Through combining fluorescent observation with histological stains, we demonstrated that the root endodermal cell lignification response to low-potassium (K) conditions is mediated by NO through the MYB36-associated lignin-polymerizing pathway. Furthermore, we discovered the noteworthy ability of NO to maintain nutrient homeostasis for adaptation to low K conditions by affecting the correct apoplastic barrier formation of CS. Collectively, our results suggest that NO is required for the lignification and apoplastic barrier formation in the root endodermis during adaptation to low K conditions, which revealing the novel physiological roles of CS under low nutrient conditions and making a significant contribution to CS biology.
Assuntos
Arabidopsis , Arabidopsis/genética , Óxido Nítrico/metabolismo , Lignina/metabolismo , Raízes de Plantas/metabolismo , Parede Celular/metabolismo , Diferenciação CelularRESUMO
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury1-3, but efficient reversal of this regrowth failure remains elusive4. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity2,5-9, (ii) growth-supportive substrate10,11 and (iii) chemoattraction12,13-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI14,15; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor16,17 delivered via spatially and temporally controlled release from biomaterial depots18,19, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
Assuntos
Axônios/fisiologia , Regeneração Nervosa/fisiologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapia , Animais , Astrócitos/patologia , Cicatriz/patologia , Eletrofisiologia , Fator de Crescimento Epidérmico/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Hidrogéis , Laminina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/metabolismo , Proteoglicanas/metabolismo , Ratos , Ratos Endogâmicos Lew , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/reabilitação , Regeneração da Medula Espinal , Células Estromais/patologiaRESUMO
Legacy and emerging per- and polyfluoroalkyl substances (PFAS) have attracted growing attention due to their potential adverse effects on humans. We developed a method to simultaneously determine thirty-three PFAS (legacy PFAS, precursors, and alternatives) in human plasma and serum using solid phase extraction coupled to ultra-performance liquid chromatography-tandem mass spectrometry (SPE-UPLC-MS/MS). The method yielded good linearity (>0.995) and excellent limits of detection (LODs) (0.0005~0.012 ng mL-1 in plasma and 0.002~0.016 ng mL-1 in serum). The relative recoveries ranged from 80.1 to 116%, with intra- and inter-day precision less than 14.3%. The robustness of this method has been tested continuously for 10 months (coefficients of variation <14.9%). Our method was successfully applied to the PFAS analysis of 42 real human plasma and serum samples collected from women. The proposed method is attractive for the biomonitoring of multi-class PFAS in human health risk assessment and epidemiological studies.
Assuntos
Fluorocarbonos , Espectrometria de Massas em Tandem , Humanos , Feminino , Cromatografia Líquida , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Soro/química , Fluorocarbonos/análise , Extração em Fase Sólida/métodosRESUMO
Hyaline protoplasmic astrocytopathy (HPA) describes a rare histologic finding of eosinophilic, hyaline cytoplasmic inclusions in astrocytes, predominantly in the cerebral cortex. It has mainly been observed in children and adults with a history of developmental delay and epilepsy, frequently with focal cortical dysplasia (FCD), but the nature and significance of these inclusions are unclear. In this study, we review the clinical and pathologic features of HPA and characterize the inclusions and brain tissue in which they are seen in surgical resection specimens from five patients with intractable epilepsy and HPA compared to five patients with intractable epilepsy without HPA using immunohistochemistry for filamin A, previously shown to label these inclusions, and a variety of astrocytic markers including aldehyde dehydrogenase 1 family member L1 (ALDH1L1), SRY-Box Transcription Factor 9 (SOX9), and glutamate transporter 1/excitatory amino acid transporter 2 (GLT-1/EAAT2) proteins. The inclusions were positive for ALDH1L1 with increased ALDH1L1 expression in areas of gliosis. SOX9 was also positive in the inclusions, although to a lesser intensity than the astrocyte nuclei. Filamin A labeled the inclusions but also labeled reactive astrocytes in a subset of patients. The immunoreactivity of the inclusions for various astrocytic markers and filamin A as well as the positivity of filamin A in reactive astrocytes raise the possibility that these astrocytic inclusions may be the result of an uncommon reactive or degenerative phenomenon.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Criança , Adulto , Humanos , Filaminas/metabolismo , Hialina , Encéfalo/patologia , Astrócitos/patologiaRESUMO
Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.
Assuntos
Astrócitos/patologia , Axônios/fisiologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiologia , Cicatriz/patologia , Modelos Biológicos , Regeneração Nervosa , Animais , Sistema Nervoso Central/citologia , Proteoglicanas de Sulfatos de Condroitina/biossíntese , Cicatriz/prevenção & controle , Feminino , Genômica , Camundongos , Reprodutibilidade dos Testes , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/patologiaRESUMO
Objective To investigate the clinical and magnetic resonance imaging(MRI) manifestations of Rosai-Dorfman disease(RDD) in central nervous system. Method The clinical and MRI data of 5 cases of RDD in central nervous system confirmed by pathology in the PLA General Hospital were analyzed retrospectively. Results The 5 cases included 4 males and 1 female,aged(39.8±21.7) years on average.Among them,4 cases were located in the intracranial area and 1 case in the thoracic spinal canal.The lesion showed isointense signal on T1 weighted image and iso,slight-hypo,and slight-hyperintense signals on T2 weighted image,and it presented intensively homogeneous enhancement in contrast-enhanced MRI.Two cases showed compressed brain area with edema around the left parietal and left frontotemporal dura,thickening and enhancement in the adjacent dura,and dural tail sign.Three cases presented bone destruction in adjacent diploe and thoracic vertebrae.One case showcased slight-hypo perfusion of the left parietal dura in arterial spin labeling. Conclusions RDD lesion usually appears as iso,slight hypo and slight hyper-intense signals on T2 weighted image and presents intensively homogeneous enhancement in contrast-enhanced MRI.The disease may involve the adjacent bone and the lesion shows slight hypo-perfusion on perfusion images.The MRI manifestations of RDD are characteristic,which are helpful for preoperative diagnosis and evaluation of RDD.
Assuntos
Histiocitose Sinusal , Sistema Nervoso Central/patologia , Feminino , Cabeça , Histiocitose Sinusal/diagnóstico por imagem , Histiocitose Sinusal/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Estudos RetrospectivosRESUMO
Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal by definition. Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE). Astrocyte-specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses showed that EAE-induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex, and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord during chronic EAE involved decreases in expression of cholesterol synthesis genes while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. The potential role of cholesterol synthesized by astrocytes during EAE and MS is discussed. Together, this provides proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions during multifocal neurological diseases.
Assuntos
Astrócitos/fisiologia , Encefalomielite Autoimune Experimental/metabolismo , Esclerose Múltipla/patologia , Transcriptoma/fisiologia , Animais , Colesterol/biossíntese , Regulação para Baixo , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Homeostase/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
Astroglial scars surround damaged tissue after trauma, stroke, infection, or autoimmune inflammation in the CNS. They are essential for wound repair, but also interfere with axonal regrowth. A better understanding of the cellular mechanisms, regulation, and functions of astroglial scar formation is fundamental to developing safe interventions for many CNS disorders. We used wild-type and transgenic mice to quantify and dissect these parameters. Adjacent to crush spinal cord injury (SCI), reactive astrocytes exhibited heterogeneous phenotypes as regards proliferation, morphology, and chemistry, which all varied with distance from lesions. Mature scar borders at 14 d after SCI consisted primarily of newly proliferated astroglia with elongated cell processes that surrounded large and small clusters of inflammatory, fibrotic, and other cells. During scar formation from 5 to 14 d after SCI, cell processes deriving from different astroglia associated into overlapping bundles that quantifiably reoriented and organized into dense mesh-like arrangements. Selective deletion of STAT3 from astroglia quantifiably disrupted the organization of elongated astroglia into scar borders, and caused a failure of astroglia to surround inflammatory cells, resulting in increased spread of these cells and neuronal loss. In cocultures, wild-type astroglia spontaneously corralled inflammatory or fibromeningeal cells into segregated clusters, whereas STAT3-deficient astroglia failed to do so. These findings demonstrate heterogeneity of reactive astroglia and show that scar borders are formed by newly proliferated, elongated astroglia, which organize via STAT3-dependent mechanisms to corral inflammatory and fibrotic cells into discrete areas separated from adjacent tissue that contains viable neurons.
Assuntos
Cicatriz/patologia , Inflamação/patologia , Neuroglia/metabolismo , Fator de Transcrição STAT3/metabolismo , Traumatismos da Medula Espinal/patologia , Animais , Bromodesoxiuridina/metabolismo , Proliferação de Células , Células Cultivadas , Cicatriz/etiologia , Cicatriz/metabolismo , Modelos Animais de Doenças , Fibronectinas/metabolismo , Proteína Glial Fibrilar Ácida/genética , Inflamação/etiologia , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/patologia , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição STAT3/genética , Traumatismos da Medula Espinal/complicações , Timidina Quinase/metabolismo , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: Stroke treatment is constrained by limited treatment windows and the clinical inefficacy of agents that showed preclinical promise. Yet animal and clinical data suggest considerable poststroke plasticity, which could allow treatment with recovery-modulating agents. Memantine is a well-tolerated N-methyl-D-aspartate glutamate receptor antagonist in common use for Alzheimer disease. METHODS: Memantine, 30 mg/kg per day, or vehicle, was delivered chronically in drinking water beginning >2 hours after photothrombotic stroke. RESULTS: Although there was no difference in infarct size, behavior, or optical intrinsic signal maps in the first 7 days after stroke, mice treated chronically with memantine showed significant improvements in motor control, measured by cylinder test and grid-walking performance, compared with vehicle-treated animals. Optical intrinsic signal revealed an increased area of forepaw sensory maps at 28 days after stroke. There was decreased reactive astrogliosis and increased vascular density around the infarcted cortex. Peri-infarct Western blots revealed increased brain-derived neurotrophic factor and phosphorylated-tropomyosin-related kinase-B receptor expression. CONCLUSIONS: Our results suggest that memantine improves stroke outcomes in an apparently non-neuroprotective manner involving increased brain-derived neurotrophic factor signaling, reduced reactive astrogliosis, and improved vascularization, associated with improved recovery of sensory and motor cortical function. The clinical availability and tolerability of memantine make it an attractive candidate for clinical translation.
Assuntos
Córtex Cerebral , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memantina/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/patologia , Infarto Cerebral/fisiopatologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Memantina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Método Simples-Cego , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologiaRESUMO
Estrogen has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the CNS, including autoimmune inflammation, traumatic injury, stroke, and neurodegenerative diseases. The beneficial effects of estrogens in CNS disorders include mitigation of clinical symptoms, as well as attenuation of histopathological signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a number of different cell types express estrogen receptors in the peripheral immune system and the CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor-α (ERα) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ERα ligand-mediated neuroprotective effects in a well-characterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERα ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERα from astrocytes, whereas conditional deletion of ERα from neurons had no significant effect. These findings show that signaling through ERα in astrocytes, but not through ERα in neurons, is essential for the beneficial effects of ERα ligand in EAE. Our findings reveal a unique cellular mechanism for estrogen-mediated CNS neuroprotective effects by signaling through astrocytes, and have implications for understanding the pathophysiology of sex hormone effects in diverse CNS disorders.
Assuntos
Encefalomielite Autoimune Experimental/patologia , Receptor alfa de Estrogênio/fisiologia , Fármacos Neuroprotetores/farmacologia , Animais , Astrócitos/patologia , Células Cultivadas , Receptor alfa de Estrogênio/deficiência , Inflamação/prevenção & controle , Ligantes , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/prevenção & controle , Neurônios/patologiaRESUMO
Two new pi-conjugated pyridine-based tetrathiafulvalene derivatives, 2-(2- (4,5-bis(methylthio)-1,3-dithiol-2-ylidene)-6-phenyl-[1,3]dithiolo[4,5-b][1,4]dithiin-5-yl)pyridine (2a) and 3-(2-(4,5-bis(methylthio)-1,3-dithiol-2-ylidene)-6-(pyridin-2-yl) -[1,3]dithiolo[4,5-b][1,4]dithiin-5-yl)quinoline (2b), have been synthesized and characterized by 1H NMR, elemental analysis and mass spectroscopies. The compound 2a has also been studied by X-ray crystallography and theoretical calculations using density functional theory (DFT) framework with B3LYP/6-311+G(d,p) level of theory. Its crystal structure is triclinic system, space group P1-. The unit cell dimensions are: a = 8.813(3) Å, b = 11.082(3) Å, c = 12.620(4) Å, alfa = 88.805(5)°, beta = 80.440(5)°, gama = 75.680(5)°, V = 1177.3(6) Å3, Z = 2. The molecule exhibits one classical C-H···N intermolecular hydrogen bonds, two kinds of short intermolecular S···S interactions and two types of C-H···pi supramolecular interactions.
RESUMO
Polyfluoroalkyl phosphate esters (PAPs) are emerging substitutes for legacy per- and polyfluoroalkyl substances (PFAS), which are widely applied in consumer products and closely related to people's daily lives. Increasing concern has been raised about the safety of PAPs due to their metabolism into perfluorooctanoic acid (PFOA) and other perfluorinated carboxylates (PFCAs) in vivo. This review summarizes the current knowledge on PAPs and highlights the knowledge gaps. PAPs dominated the PFAS profiles in wastewater, sludge, household dust, food-contact materials, paper products, paints, and cosmetics. They exhibit biomagnification due to their higher levels in top predators. PAPs have been detected in human blood worldwide, with the highest mean levels being found in the United States (1.9 ng/mL) and China (0.4 ng/mL). 6:2 diPAP is the predominant PAP among all identified matrices, followed by 8:2 diPAP. Toxicokinetic studies suggest that after entering the body, most PAPs undergo biotransformation, generating phase â (i.e., PFCAs), phase II, and intermediate products with toxicity to be verified. Several epidemiological and toxicological studies have reported the antiandrogenic effect, estrogenic effect, thyroid disruption, oxidative damage, and reproductive toxicity of PAPs. More research is urgently needed on the source and fate of PAPs, human exposure pathways, toxicity other than reproductive and endocrine systems, toxic effects of metabolites, and mixed exposure effects.
Assuntos
Fluorocarbonos , Humanos , Fluorocarbonos/toxicidade , Fluorocarbonos/metabolismo , Organofosfatos/toxicidade , Biotransformação , Ácidos Carboxílicos , FosfatosRESUMO
Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes; however, fundamental features of these cells are poorly understood. Here we show that following spinal cord injury or stroke, 90% and 10% of border-forming astrocytes derive, respectively, from proliferating local astrocytes and oligodendrocyte progenitor cells in adult mice of both sexes. Temporal transcriptome analysis, single-nucleus RNA sequencing and immunohistochemistry show that after focal CNS injury, local mature astrocytes dedifferentiate, proliferate and become transcriptionally reprogrammed to permanently altered new states, with persisting downregulation of molecules associated with astrocyte-neuron interactions and upregulation of molecules associated with wound healing, microbial defense and interactions with stromal and immune cells. These wound repair astrocytes share morphologic and transcriptional features with perimeningeal limitans astrocytes and are the predominant source of neuroprotective borders that re-establish CNS integrity around lesions by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.
Assuntos
Astrócitos , Traumatismos da Medula Espinal , Acidente Vascular Cerebral , Cicatrização , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Camundongos , Masculino , Cicatrização/fisiologia , Cicatrização/genética , Feminino , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/genética , Camundongos Endogâmicos C57BL , Reprogramação Celular/fisiologia , Células Precursoras de Oligodendrócitos/metabolismo , Proliferação de Células/fisiologiaRESUMO
Inflammation features in CNS disorders such as stroke, trauma, neurodegeneration, infection, and autoimmunity in which astrocytes play critical roles. To elucidate how inflammatory mediators alter astrocyte functions, we examined effects of transforming growth factor-ß1 (TGF-ß1), lipopolysaccharide (LPS), and interferon-gamma (IFNγ), alone and in combination, on purified, mouse primary cortical astrocyte cultures. We used microarrays to conduct whole-genome expression profiling, and measured calcium signaling, which is implicated in mediating dynamic astrocyte functions. Combinatorial exposure to TGF-ß1, LPS, and IFNγ significantly modulated astrocyte expression of >6800 gene probes, including >380 synergistic changes not predicted by summing individual treatment effects. Bioinformatic analyses revealed significantly and markedly upregulated molecular networks and pathways associated in particular with immune signaling and regulation of cell injury, death, growth, and proliferation. Highly regulated genes included chemokines, growth factors, enzymes, channels, transporters, and intercellular and intracellular signal transducers. Notably, numerous genes for G-protein-coupled receptors (GPCRs) and G-protein effectors involved in calcium signaling were significantly regulated, mostly down (for example, Cxcr4, Adra2a, Ednra, P2ry1, Gnao1, Gng7), but some up (for example, P2ry14, P2ry6, Ccrl2, Gnb4). We tested selected cases and found that changes in GPCR gene expression were accompanied by significant, parallel changes in astrocyte calcium signaling evoked by corresponding GPCR-specific ligands. These findings identify pronounced changes in the astrocyte transcriptome induced by TGF-ß1, LPS, and IFNγ, and show that these inflammatory stimuli upregulate astrocyte molecular networks associated with immune- and injury-related functions and significantly alter astrocyte calcium signaling stimulated by multiple GPCRs.
Assuntos
Astrócitos/metabolismo , Astrócitos/patologia , Sinalização do Cálcio/genética , Mediadores da Inflamação/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Transcriptoma/genética , Animais , Animais Recém-Nascidos , Células Cultivadas , Regulação para Baixo/genética , Feminino , Interferon gama/fisiologia , Lipopolissacarídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/genética , Fator de Crescimento Transformador beta1/fisiologia , Regulação para Cima/genéticaRESUMO
Xanthoceras sorbifolium has high oil content and important biomass energy value, but its development is limited by the problem of low yield. This study investigated the relationship between the canopy microclimate, fruit yield, and fruit quality of Xanthoceras sorbifolium. Difference between the distributions of canopy microclimate factors as well as fruit and seed parameters in the inner and outer canopies of the lower layer, as well as between the inner and outer canopies of the upper layer, were investigated for a period of one year. Canopy structure induced significant differences between canopy microclimate factors during various periods of the year. Light intensity and temperature of the outer and upper canopies were higher than those of inner and lower canopies. However, relative humidity showed an opposing trend. Light intensity was significantly and positively correlated with fruit set percentage, fruit yield, and seed yield. Temperature was significantly and positively correlated with fruit yield and seed yield, but significantly negatively correlated with the oil concentration of seed kernels. Fruit and seed yields significantly decreased from the outer to the inner canopy and from the upper to the lower canopy. Fruit set percentage in the outer canopy was also significantly higher than that in the inner canopy. However, oil concentrations in the seed kernels of the lower layer were significantly higher than those of the upper layer. Additionally, regression analysis was used to construct evaluation models for microclimate, fruit, and seed parameters. Regression equations corresponding to the association between single microclimatic factors during different periods and the fruit and seed parameters may provide a reference for canopy pruning and help develop an optimal regression model that may be used to predict and estimate fruit and seed parameters.
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Frutas , Sapindaceae , Microclima , Luz , SementesRESUMO
Diet, including drinking water, and demographic characteristics have been associated with PFAS exposure levels in the general population. But data in pregnant women are scarce. We aimed to examine the PFAS levels in relation to these factors in early pregnancy and included 2545 pregnant women in early pregnancy from the Shanghai Birth Cohort. Ten PFAS were measured using high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in plasma samples at around 14 weeks of gestation. Geometric mean (GM) ratios were used to estimate the associations between demographic characteristics, food intake and source of drinking water and concentrations of nine PFAS with a detection rate of at least 70%, and the total perfluoroalkyl carboxylic acids (∑PFCA), perfluoroalkyl sulfonic acids (∑PFSA) and all the PFAS concentrations (∑PFAS). Median concentrations of plasma PFAS ranged from 0.03 ng/mL for PFBS to 11.56 ng/mL for PFOA. In the multivariable linear models, maternal age, parity, parental education level, marine fish, freshwater fish, shellfish, shrimps, crabs, animal kidneys, animal liver, eggs, and bone soup in early pregnancy were positively associated with plasma concentrations of certain PFAS. Whereas pre-pregnancy BMI, plant-based foods, and drinking bottled water were negatively associated with some PFAS concentrations. In summary, this study suggested that fish and seafood, animal offal, and high-fat foods (eggs and bone soup) were significant sources of PFAS. PFAS exposure may be reduced by consuming more plant-based foods and potential interventions, such as drinking water treatment.
Assuntos
Ácidos Alcanossulfônicos , Água Potável , Poluentes Ambientais , Fluorocarbonos , Animais , Gravidez , Feminino , Humanos , Gestantes , China , Paridade , DietaRESUMO
BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been previously linked to polycystic ovarian syndrome (PCOS), but only a few legacy PFAS were examined. OBJECTIVES: This study aimed to explore this association with a variety of PFAS, including legacy, branched-chain isomers, and emerging alternatives, as well as a PFAS mixture. METHODS: From 2014 to 2016, we conducted a multicenter, hospital-based case-control study on environmental endocrine disruptors and infertility in China. Three hundred sixty-six women with PCOS-related infertility and 577 control participants without PCOS were included in the current analysis. Twenty-three PFAS, including 3 emerging PFAS alternatives, 6 linear and branched PFAS isomers, 6 short-chain PFAS, and 8 legacy PFAS, were quantified in the plasma. Logistic regression and two multipollutant models [quantile-based g-computation (QGC) and Bayesian kernel machine regression (BKMR) methods] were used to assess the association of individual PFAS and PFAS mixture with PCOS, as well as the potential interactions among the congeners. RESULTS: After adjusting for potential confounders, Each 1-standard deviation higher difference in ln-transformed 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA) and hexafluoropropylene oxide dimer acid (HFPO-DA) level was significantly associated with a 29% (95% CI: 1.11, 1.52) and 39% (95% CI:1.16, 1.68) higher odds of PCOS, respectively. Meanwhile, branched isomers of perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) (i.e., br-PFHxS, n-PFOS, 1m-PFOS, Σ3,4,5m-PFOS), short-chain PFAS (i.e., PFPeS and PFHxA) and other legacy PFAS [i.e., total concentrations of PFOS (T-PFOS), and perfluorododecanoic acid (PFDoA)] were significantly associated with increased odds of PCOS. The PFAS mixture was positively related to PCOS in the BKMR model. A similar trend was observed in QGC model, a ln-unit increase in the PFAS mixture was associated with a 20% increased risk of PCOS [adjusted odds ratio (aOR)=1.20 (95% CI: 1.06, 1.37)]. After controlling for other PFAS homologs, 6:2 Cl-PFESA, HFPO-DA, Σ3,4,5m-PFOS, and PFDoA were the major contributors based on the QGC and BKMR models. The associations were more pronounced in overweight/obese women. CONCLUSIONS: In this group of women, environmental exposure to a PFAS mixture was associated with an elevated odds of PCOS, with 6:2 Cl-PFESA, HFPO-DA, Σ3,4,5m-PFOS, and PFDoA being the major contributors, especially in overweight/obese women. https://doi.org/10.1289/EHP11814.
Assuntos
Ácidos Alcanossulfônicos , Poluentes Ambientais , Fluorocarbonos , Infertilidade , Síndrome do Ovário Policístico , Humanos , Feminino , Síndrome do Ovário Policístico/epidemiologia , Estudos de Casos e Controles , Teorema de Bayes , Sobrepeso , Exposição Ambiental , Ácidos Alcanossulfônicos/análise , Alcanossulfonatos/análise , ObesidadeRESUMO
The endoribonuclease, Dicer, is indispensable for generating the majority of mature microRNAs (miRNAs), which are posttranscriptional regulators of gene expression involved in a wide range of developmental and pathological processes in the mammalian CNS. Although functions of Dicer-dependent miRNA pathways in neurons and oligodendrocytes have been extensively investigated, little is known about the role of Dicer in astrocytes. Here, we report the effect of Cre-loxP-mediated conditional deletion of Dicer selectively from postnatal astroglia on brain development. Dicer-deficient mice exhibited normal motor development and neurological morphology before postnatal week 5. Thereafter, mutant mice invariably developed a rapidly fulminant neurological decline characterized by ataxia, severe progressive cerebellar degeneration, seizures, uncontrollable movements, and premature death by postnatal week 9-10. Integrated transcription profiling, histological, and functional analyses of cerebella showed that deletion of Dicer in cerebellar astrocytes altered the transcriptome of astrocytes to be more similar to an immature or reactive-like state before the onset of neurological symptoms or morphological changes. As a result, critical and mature astrocytic functions including glutamate uptake and antioxidant pathways were substantially impaired, leading to massive apoptosis of cerebellar granule cells and degeneration of Purkinje cells. Collectively, our study demonstrates the critical involvement of Dicer in normal astrocyte maturation and maintenance. Our findings also reveal non-cell-autonomous roles of astrocytic Dicer-dependent pathways in regulating proper neuronal functions and implicate that loss of or dysregulation of astrocytic Dicer-dependent pathways may be involved in neurodegeneration and other neurological disorders.