RESUMEN
BACKGROUND: Anorexia-cachexia is a common and severe cancer-related complication but the underlying mechanisms are largely unknown. Here, using a mouse model for tumour-induced anorexia-cachexia, we screened for proteins that are differentially expressed in the hypothalamus, the brain's metabolic control centre. METHODS: The hypothalamus of tumour-bearing mice with implanted methylcholanthrene-induced sarcoma (MCG 101) displaying anorexia and their sham-implanted pair-fed or free-fed littermates was examined using two-dimensional electrophoresis (2-DE)-based comparative proteomics. Differentially expressed proteins were identified by liquid chromatography-tandem mass spectrometry. RESULTS: The 2-DE data showed an increased expression of dynamin 1, hexokinase, pyruvate carboxylase, oxoglutarate dehydrogenase, and N-ethylmaleimide-sensitive factor in tumour-bearing mice, whereas heat-shock 70 kDa cognate protein, selenium-binding protein 1, and guanine nucleotide-binding protein Gα0 were downregulated. The expression of several of the identified proteins was similarly altered also in the caloric-restricted pair-fed mice, suggesting an involvement of these proteins in brain metabolic adaptation to restricted nutrient availability. However, the expression of dynamin 1, which is required for receptor internalisation, and of hexokinase, and pyruvate carboxylase were specifically changed in tumour-bearing mice with anorexia. CONCLUSION: The identified differentially expressed proteins may be new candidate molecules involved in the pathophysiology of tumour-induced anorexia-cachexia.
Asunto(s)
Anorexia/metabolismo , Caquexia/metabolismo , Regulación Neoplásica de la Expresión Génica , Hipotálamo/metabolismo , Sarcoma Experimental/metabolismo , Animales , Modelos Animales de Enfermedad , Dinamina I/biosíntesis , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/biosíntesis , Proteínas HSP70 de Choque Térmico/biosíntesis , Hexoquinasa/biosíntesis , Complejo Cetoglutarato Deshidrogenasa/biosíntesis , Metilcolantreno , Ratones , Ratones Endogámicos C57BL , Proteínas Sensibles a N-Etilmaleimida/biosíntesis , Biosíntesis de Proteínas , Proteínas/metabolismo , Piruvato Carboxilasa/biosíntesis , Sarcoma Experimental/inducido químicamente , Proteínas de Unión al Selenio/biosíntesisAsunto(s)
Anticuerpos Antibacterianos , Anticuerpos Monoclonales , Antígenos Bacterianos/inmunología , Coxiella burnetii/inmunología , Desoxiazúcares/análisis , Lipopolisacáridos/inmunología , Fiebre Q/diagnóstico , Animales , Antígenos Bacterianos/química , Técnicas Bacteriológicas/métodos , Biomarcadores , Coxiella burnetii/química , Desoxiazúcares/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Lipopolisacáridos/química , Sensibilidad y EspecificidadAsunto(s)
Coxiella burnetii/química , Lípido A/química , Lípido A/aislamiento & purificación , Complicaciones Infecciosas del Embarazo/veterinaria , Fiebre Q/veterinaria , Enfermedades de los Porcinos/microbiología , Animales , Coxiella burnetii/aislamiento & purificación , Femenino , Cobayas , Estructura Molecular , Placenta/microbiología , Embarazo , Complicaciones Infecciosas del Embarazo/microbiología , Fiebre Q/microbiologíaRESUMEN
Tumor necrosis factor-alpha (TNF) is a major mediator of apoptosis as well as immunity and inflammation. Inappropriate production of TNF or sustained activation of TNF signaling has been implicated in the pathogenesis of a wide spectrum of human diseases, including cancer, osteoporosis, sepsis, diabetes, and autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TNF binds to two specific receptors, TNF-receptor type I (TNF-R1, CD120a, p55/60) and TNF-receptor type II (TNF-R2, CD120b, p75/80). Signaling through TNF-R1 is extremely complex, leading to both cell death and survival signals. Many findings suggest an important role of phosphorylation of the TNF-R1 by number of protein kinases. Role of TNF-R2 phosphorylation on its signaling properties is understood less than TNF-R1. Other cellular substrates as TRADD adaptor protein, TRAF protein family and RIP kinases are reviewed in relation to TNF receptor-mediated apoptosis or survival pathways and regulation of their actions by phosphorylation.
Asunto(s)
Apoptosis/fisiología , Supervivencia Celular/fisiología , Modelos Biológicos , Fosfotransferasas/metabolismo , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , HumanosRESUMEN
The ability of various strains of Coxiella burnetii (C.b.) and their phase I and II lipopolysaccharides (LPSs) to induce tumor necrosis factor alpha (TNF-alpha) in peritoneal Balb/c mouse macrophages in vitro was investigated. Considerable differences in the induction ability were observed in dependence on the strain applied. In a TNF-alpha bioassay, the most effective inducers were both corpuscles and LPSs of the strains Priscilla and Scurry, followed by Nine Mile, Luga, and Henzerling I. In contrast, in ELISA, the most effective inducers were LPSs of the strains Luga and Henzerling, followed by Nine Mile, Priscilla, and Scurry. The role of toll-like receptor 4 (TLR4) in the induction was confirmed by the use of C3H/HeJ mouse macrophages. Thus, the induction of TNF-alpha was much higher in Balb/c mouse macrophages than that in TLR4-deficient C3H/HeJ mouse macrophages. Differences in the results of the bioassay and those of ELISA suggest a role of another secreted factor(s) induced with C.b. in murine macrophages that could act synergically with TNF-alpha in L929 cells in the bioassay. The observed differences in TNF-alpha induction might play a role in the pathobiology of Q fever.