RESUMEN
Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Síndrome de Smith-Magenis , Transactivadores , Factores de Transcripción , Animales , Ratones , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Homeostasis , Hipotálamo/metabolismo , Neuronas/metabolismo , Obesidad/genética , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Peso CorporalRESUMEN
The association between neutrophil extracellular traps (NETs) and response to inhaled corticosteroids (ICS) in asthma is unclear. To better understand this relationship, we analyzed the blood transcriptomes from children with controlled and uncontrolled asthma in the Taiwanese Consortium of Childhood Asthma Study using weighted gene coexpression network analysis and pathway enrichment methods. We identified 298 uncontrolled asthma-specific differentially expressed genes and one gene module associated with neutrophil-mediated immunity, highlighting a potential role for neutrophils in uncontrolled asthma. We also found that NET abundance was associated with nonresponse to ICS in patients. In a neutrophilic airway inflammation murine model, steroid treatment could not suppress neutrophilic inflammation and airway hyperreactivity. However, NET disruption with deoxyribonuclease I (DNase I) efficiently inhibited airway hyperreactivity and inflammation. Using neutrophil-specific transcriptomic profiles, we found that CCL4L2 was associated with ICS nonresponse in asthma, which was validated in human and murine lung tissue. CCL4L2 expression was also negatively correlated with pulmonary function change after ICS treatment. In summary, steroids fail to suppress neutrophilic airway inflammation, highlighting the potential need to use alternative therapies such as leukotriene receptor antagonists or DNase I that target the neutrophil-associated phenotype. Furthermore, these results highlight CCL4L2 as a potential therapeutic target for individuals with asthma refractory to ICS.
Asunto(s)
Asma , Trampas Extracelulares , Animales , Niño , Humanos , Ratones , Corticoesteroides/farmacología , Corticoesteroides/uso terapéutico , Desoxirribonucleasa I/metabolismo , Desoxirribonucleasa I/uso terapéutico , Trampas Extracelulares/metabolismo , Inflamación/metabolismo , Neutrófilos/metabolismo , Quimiocina CCL4/metabolismoAsunto(s)
Gastroenterología/organización & administración , Enfermedad del Hígado Graso no Alcohólico , Guías de Práctica Clínica como Asunto , Adolescente , Asia , Cirugía Bariátrica , Carcinoma Hepatocelular/etiología , Ácido Quenodesoxicólico/administración & dosificación , Ácido Quenodesoxicólico/análogos & derivados , Niño , Dieta , Ejercicio Físico , Ácidos Grasos Omega-3/administración & dosificación , Humanos , Neoplasias Hepáticas/etiología , Trasplante de Hígado , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/terapia , Obesidad/complicaciones , Obesidad/cirugía , Islas del Pacífico , Riesgo , Revisiones Sistemáticas como Asunto , Tiazolidinedionas/administración & dosificación , Vitamina E/administración & dosificaciónRESUMEN
BACKGROUND: The aim of this study was to establish a model to identify term breast-fed infants who are at risk of developing significant neonatal hyperbilirubinemia. METHODS: A prospective study was designed to investigate the effects of birth weight, mode of delivery, cephalohematoma, glucose-6-phosphate dehydrogenase (G6PD) deficiency, predischarge total serum bilirubin, variant uridine 5'diphospho-glucuronosyltransferase 1A1 (UGT1A1) gene, and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene on significant hyperbilirubinemia in term breast-fed neonates. Significant hyperbilirubinemia was defined as a bilirubin level exceeding the hour-specific phototherapy treatment threshold recommended by the American Academy of Pediatrics in 2004. RESULTS: Of 240 exclusively breast-fed term neonates, 26 (10.8%) had significant hyperbilirubinemia. The predischarge total serum bilirubin on the third day (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.87-3.70; P < 0.001) and the variant UGT1A1 gene at nucleotide 211 (OR = 5.00; 95% CI: 1.08-23.03; P < 0.05) were significant risk factors. The area under the receiver operating characteristic (ROC) curve of the predictive probability was 0.964 (95% CI: 0.932-0.984; P < 0.0001). CONCLUSION: Combining the total serum bilirubin on the third day and the variant UGT1A1 gene at nucleotide 211 can predict hyperbilirubinemia well in term breast-fed infants.