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1.
Cell ; 187(8): 1990-2009.e19, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38513664

RESUMO

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the cellular dynamics of MS by modeling temporal and regional rates of disease progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing single-cell spatial expression profiling using in situ sequencing (ISS), we annotated disease neighborhoods and found centrifugal evolution of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course. Single-cell spatial mapping of human archival MS spinal cords confirmed the differential distribution of homeostatic and DA-glia, enabled deconvolution of active and inactive lesions into sub-compartments, and identified new lesion areas. By establishing a spatial resource of mouse and human MS neuropathology at a single-cell resolution, our study unveils the intricate cellular dynamics underlying MS.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Medula Espinal , Animais , Humanos , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Camundongos , Análise da Expressão Gênica de Célula Única , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Neuroglia/metabolismo , Neuroglia/patologia
2.
Diabetes ; 70(7): 1486-1497, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33863803

RESUMO

Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of those with obesity and to what extent these are normalized by weight loss are unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and insulin response in subcutaneous WAT by RNA sequencing in 23 women with obesity before and 2 years after bariatric surgery. To control for effects of surgery, women postsurgery were matched to never-obese women. Multidimensional analyses of 138 samples allowed us to classify the effects of insulin into three distinct expression responses: a common set was present in all three groups and included genes encoding several lipid/cholesterol biosynthesis enzymes; a set of obesity-attenuated genes linked to tissue remodeling and protein translation was selectively regulated in the two nonobese states; and several postobesity-enriched genes encoding proteins involved in, for example, one-carbon metabolism were only responsive to insulin in the women who had lost weight. Altogether, human WAT displays a selective insulin response in the obese state, where most genes are normalized by weight loss. This comprehensive atlas provides insights into the transcriptional effects of insulin in WAT and may identify targets to improve insulin action.


Assuntos
Tecido Adiposo Branco/metabolismo , Resistência à Insulina , Obesidade/metabolismo , Feminino , Humanos , Metabolismo dos Lipídeos
3.
Sci Rep ; 7(1): 11458, 2017 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-28904364

RESUMO

Caffeine is a widely consumed psychoactive substance, but little is known about the effects of caffeine stimulation on global gene expression changes in neurons. Here, we conducted gene expression profiling of human neuroepithelial stem cell-derived neurons, stimulated with normal consumption levels of caffeine (3 µM and 10 µM), over a period of 9 h. We found dosage-dependent activation of immediate early genes after 1 h. Neuronal projection development processes were up-regulated and negative regulation of axon extension processes were down-regulated at 3 h. In addition, genes involved in extracellular matrix organization, response for wound healing, and regulation of immune system processes were down-regulated by caffeine at 3 h. This study identified novel genes within the neuronal projection guidance pathways that respond to acute caffeine stimulation and suggests potential mechanisms for the effects of caffeine on neuronal cells.


Assuntos
Cafeína/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/genética , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transcriptoma , Biomarcadores , Diferenciação Celular , Células Cultivadas , Biologia Computacional/métodos , Relação Dose-Resposta a Droga , Imunofluorescência , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Anotação de Sequência Molecular , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurônios/citologia , Fenótipo
4.
Cell Rep ; 16(9): 2317-26, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27545890

RESUMO

Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial white adipose tissue gene expression pattern. However, this observation stems from fasting studies when insulin levels are low. We investigated adipose gene expression by 5'Cap-mRNA sequencing in 17 healthy non-obese (NO), 21 insulin-sensitive severely obese (ISO), and 30 insulin-resistant severely obese (IRO) subjects, before and 2 hr into a hyperinsulinemic euglycemic clamp. ISO and IRO subjects displayed a clear but globally similar transcriptional response to insulin, which differed from the small effects observed in NO subjects. In the obese, 231 genes were altered; 71 were enriched in ISO subjects (e.g., phosphorylation processes), and 52 were enriched in IRO subjects (e.g., cellular stimuli). Common cardio-metabolic risk factors and gender do not influence these findings. This study demonstrates that differences in the acute transcriptional response to insulin are primarily driven by obesity per se, challenging the notion of healthy obese adipose tissue, at least in severe obesity.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Resistência à Insulina/genética , Insulina/administração & dosagem , Obesidade/genética , Transcrição Gênica , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Glicemia/metabolismo , Pressão Sanguínea , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Jejum , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Técnica Clamp de Glucose , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Obesidade/metabolismo , Obesidade/patologia , Índice de Gravidade de Doença , Triglicerídeos/sangue
5.
Plant Physiol Biochem ; 75: 55-69, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24374350

RESUMO

The non-specific lipid transfer proteins (nsLTPs) are characterized by a compact structure with a central hydrophobic cavity very suitable for binding hydrophobic ligands, such as lipids. The nsLTPs are encoded by large gene families in all land plant lineages, but seem to be absent from green algae. The nsLTPs are classified to different types based on molecular weight, sequence similarity, intron position or spacing between the cysteine residues. The Type G nsLTPs (LTPGs) have a GPI-anchor in the C-terminal region which may attach the protein to the exterior side of the plasma membrane. Here, we present the first characterization of nsLTPs from an early diverged plant, the moss Physcomitrella patens. Moss LTPGs were heterologously produced and purified from Pichia pastoris. The purified moss LTPGs were found to be extremely heat stable and showed a binding preference for unsaturated fatty acids. Structural modeling implied that high alanine content could be important for the heat stability. Lipid profiling revealed that cutin monomers, such as C16 and C18 mono- and di-hydroxylated fatty acids, could be identified in P. patens. Expression of a moss LTPG-YFP fusion revealed localization to the plasma membrane. The expressions of many of the moss LTPGs were found to be upregulated during drought and cold treatments.


Assuntos
Bryopsida/metabolismo , Proteínas de Transporte/metabolismo , Temperatura Baixa , Secas , Ácidos Graxos Insaturados/metabolismo , Proteínas Ligadas por GPI/metabolismo , Proteínas de Plantas/metabolismo , Alanina/metabolismo , Sequência de Aminoácidos , Bryopsida/química , Proteínas de Transporte/química , Membrana Celular/metabolismo , Proteínas Ligadas por GPI/química , Interações Hidrofóbicas e Hidrofílicas , Lipídeos de Membrana/metabolismo , Dados de Sequência Molecular , Filogenia , Proteínas de Plantas/química , Ligação Proteica , Estresse Fisiológico , Regulação para Cima
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