The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils of polycythemia vera.

BACKGROUND: The JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils, while no information is available concerning other leukocyte subtypes. DESIGN AND METHODS: We evaluated correlations between JAK2V617F mutation and the count of circulating basophils, the number of activated CD63(+) basophils, their response in vitro to agonists as well as the effects of a JAK2 inhibitor. RESULTS: We found that basophil count was increased in patients with JAK2V617F -positive myeloproliferative neoplasms, particularly in those with polycythemia vera, and was correlated with the V617F burden. The burden of V617F allele was similar in neutrophils and basophils from patients with polycythemia vera, while total JAK2 mRNA content was remarkably greater in the basophils; however, the content of JAK2 protein in basophils was not increased. The number of CD63(+) basophils was higher in patients with polycythemia vera than in healthy subjects or patients with essential thrombocythemia or primary myelofibrosis and was correlated with the V617F burden. Ultrastructurally, basophils from patients with polycythemia vera contained an increased number of granules, most of which were empty suggesting cell degranulation in vivo. Ex vivo experiments revealed that basophils from patients with polycythemia vera were hypersensitive to the priming effect of interleukin-3 and to f-MLP-induced activation; pre-treatment with a JAK2 inhibitor reduced polycythemia vera basophil activation. Finally, we found that the number of circulating CD63(+) basophils was significantly greater in patients suffering from aquagenic pruritus, who also showed a higher V617F allele burden. CONCLUSIONS: These data indicate that the number of constitutively activated and hypersensitive circulating basophils is increased in polycythemia vera, underscoring a role of JAK2V617F in these cells’ abnormal function and, putatively, in the pathogenesis of pruritus

Realimentación con ácido linoleico conjugado aumenta colesterol sérico y altera el perfil de ácidos grasos después de 48 horas de ayuno en ratas

No hay consenso acerca de los efectos del ácido linoleico conjugado (CLA) sobre el metabolismo lipídico, especialmente en animales alimentados con una dieta alta en grasa. Por lo tanto, el objetivo del presente estudio fue evaluar la incorporación de isómeros de CLA en el suero, hígado y tejido adiposo, así como el estrés oxidativo generado en ratas realimentadas con dietas altas en grasa después de 48 horas de ayuno. Los animales fueron realimentados con dietas que contenían aceite de soja, rico en ácido linoleico [7% (Groupo Control - C)], o 20% (Groupo LA)], CLA [Groupo CLA - 20% de mezcla de CLA (39,32% moles del c9,t11-CLA y 40.59% moles del t10,c12-CLA)], aceite de soja + CLA (Grupo LA+- CLA - 15.4 % de aceite de soja y 4,6% de CLA) o grasa animal (Grupo AF, 20% de manteca de cerdo). El grupo CLA tuvo menor aumento de peso y menor peso hepático después de la realimentación, así como aumento del colesterol total em el suero. La dieta alta en grasa indujo la acumulación de grasa y un aumento de α-tocoferol en el hígado, que no se observaron en el grupo CLA. El α-tocoferol serico fue mayor en los grupos CLA y LA+CLA. Las dietas altas en grasa redujeron la actividad de la catalasa hepática. Isómeros de CLA fueron incorporados em el suero y tejidos. En este modelo de realimentación de corto prlazo, el CLA ha impedido la acumulación de grasa hepática, aunque genero un aumento del colesterol total sérico.There is no consensus about the effects of conjugated linoleic acid (CLA) on lipid metabolism, especially in animals fed a high-fat diet. Therefore, the objective of the present study was to evaluate the incorporation of CLA isomers into serum, liver and adipose tissue, as well as the oxidative stress generated in rats refed with high-fat diets after a 48 hour fast. Rats were refed with diets containing soybean oil, rich in linoleic acid [7% (Control Group - C) or 20% (LA Group)], CLA [CLA Group – 20% CLA mixture (39.32 mole% c9,t11-CLA and 40.59 mole% t10,c12- CLA)], soybean oil + CLA (LA+CLA Group - 15.4% soybean oil and 4.6% CLA) or animal fat (AF, 20% lard). The CLA group showed lower weight gain and liver weight after refeeding, as well as increased serum cholesterol. The high dietary fat intake induced fat accumulation and an increase in α-tocopherol in the liver, which were not observed in the CLA group. Circulating α-tocopherol was increased in the CLA and CLA+LA groups. The high-fat diets reduced liver catalase activity. CLA isomers were incorporated into serum and tissues. In this shortterm refeeding experimental model, CLA prevented hepatic fat accumulation, although it produced an increase in serum cholesterol.Fil: Castro, Gabriela Salim de. Universidade de Sao Paulo; BrasilFil: Andreoli, Maria Florencia. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Ciencias Biológicas. Cátedra de Bromatología y Nutrición; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; ArgentinaFil: Illesca, Paola Guadalupe. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Ciencias Biológicas. Cátedra de Bromatología y Nutrición; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; ArgentinaFil: Payão Ovídio, Paula. Universidade de Sao Paulo; BrasilFil: Bernal, Claudio Adrian. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Ciencias Biológicas. Cátedra de Bromatología y Nutrición; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; ArgentinaFil: Jordão, Alceu A.. Universidade de Sao Paulo; BrasilFil: Vannucchi, Helio. Universidade de Sao Paulo; Brasi

Interferon-beta induces S phase slowing via up-regulated expression of PML in squamous carcinoma cells.

Interferon-β induces S phase slowing via up-regulated expression of PML in squamous carcinoma cell