RESUMEN
Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called "browning") would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.
Asunto(s)
Adipocitos Marrones/metabolismo , Proteínas Portadoras/genética , Regulación de la Expresión Génica , Glicoproteínas/genética , Metabolismo de los Lípidos/genética , Células 3T3-L1 , Adipocitos Marrones/citología , Adipocitos Marrones/efectos de los fármacos , Adipoquinas , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Ligasas de Carbono-Carbono/genética , Ligasas de Carbono-Carbono/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Proteínas Portadoras/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Glicoproteínas/metabolismo , Imidazoles/farmacología , Isoquinolinas/farmacología , Lipasa/genética , Lipasa/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factor Nuclear 1 de Respiración/genética , Factor Nuclear 1 de Respiración/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Piridinas/farmacología , Transducción de Señal , Sulfonamidas/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
Autism is known as a severe neurobehavioral syndrome, with males affected more often than females. Previous studies have revealed that microRNAs (miRNAs) play a critical role in the search for novel therapeutic strategies for autism. Therefore, we evaluate the ability of miR-153 to influence brain-derived neurotrophic factor (BDNF) of autism as well as proliferation and apoptosis of hippocampal neuron through the janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway by targeting leptin receptor (LEPR). Firstly, the autistic mice models were established and Morris water maze was employed for the analysis of the learning ability and memory of the mice. Besides, in vitro experiments were conducted with the transfection of different mimic, inhibitor, or siRNA into the hippocampal neuron cells, after which the effect of miR-153 on LEPR and the JAK-STAT signaling pathway-related factors was investigated. Next, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay and flow cytometry assay were conducted to evaluate cell proliferation, cell cycle, and apoptosis respectively following transfection. The results revealed that there was a significant decrease in learning ability and memory in the autistic mice along with a reduction in the positive expression rate of BDNF and serious inflammatory reaction. LEPR was confirmed as a target gene of miR-153 by the dual luciferase reporter gene assay. After transfection of overexpressed miR-153, LEPR and the JAK-STAT signaling pathway were inhibited followed by an increase in BDNF and enhancement of cell proliferation. In conclusion, the high expression of miR-153 can inhibit activation of JAK-STAT signaling pathway by LEPR, thus improving BDNF expression and the proliferative ability of hippocampal neurons.
Asunto(s)
Trastorno Autístico/genética , Factor Neurotrófico Derivado del Encéfalo/genética , MicroARNs/genética , Receptores de Leptina/genética , Animales , Apoptosis/genética , Trastorno Autístico/patología , Ciclo Celular/genética , Proliferación Celular/genética , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/genética , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Quinasas Janus/genética , Ratones , Neuronas/metabolismo , ARN Interferente Pequeño/genética , Factores de Transcripción STATRESUMEN
In this study, 44 compounds in the petroleum ether extract of Maqian (Zanthoxylum myriacanthum var. pubescens) bark, a traditional Dai herbal medicine, were identified by GC-MS. Major components included 3(2H)-benzofuranone, asarinin and (dimethoxymethyl)-3-methoxy-benzene. A total of 18 compounds were isolated from the ethyl acetate extracts of Maqian bark by column chromatography and identified by chemical and spectral analyses. Rhoifoline B, zanthoxyline dimethoxy derivative, N-nortidine, nitidine, decarine are the major alkaloids. Both the petroleum ether and ethyl acetate extracts showed significant inhibition on NO production, which imply anti-inflammatory activity, in lipopolysaccharide-induced RAW 264.7 cells without cell toxicity. Decarine is the major anti-inflammatory constituent with NO IC50 values of 48.43 µM on RAW264.7 cells. The petroleum ether extract, the ethyl acetate extract and decarine showed anti-inflammatory activities through inhibiting TNF-α and IL-1ß production in lipopolysaccharide-stimulated THP-1 cells without cell toxicity too. Decarine showed anti-inflammatory activity on human colon cells by reducing IL-6 and IL-8 production in TNF-α+IL-1ß-induced Caco-2 cells. These results support the use of Maqian bark as a remedy for enteritis and colitis recorded by Dai medicine in China, and elucidate the major pharmacological compounds in Maqian bark.