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Traves P.G.,Institute Investigaciones Biome dicas Alberto Sols | Pardo V.,Institute Investigaciones Biome dicas Alberto Sols | Pardo V.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Pimentel-Santillana M.,Institute Investigaciones Biome dicas Alberto Sols | And 12 more authors.
Cell Death and Disease | Year: 2014

Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been suggested as an attractive target to improve insulin sensitivity in different cell types. In the present work, we have investigated the effect of PTP1B deficiency on the response of human and murine macrophages. Using in vitro and in vivo approaches in mice and silencing PTP1B in human macrophages with specific siRNAs, we have demonstrated that PTP1B deficiency increases the effects of pro-inflammatory stimuli in both human and rodent macrophages at the time that decreases the response to alternative stimulation. Moreover, the absence of PTP1B induces a loss of viability in resting macrophages and mainly after activation through the classic pathway. Analysis of early gene expression in macrophages treated with pro-inflammatory stimuli confirmed this exacerbated inflammatory response in PTP1Bdeficient macrophages. Microarray analysis in samples from wild-type and PTP1B-deficient macrophages obtained after 24 h of pro-inflammatory stimulation showed an activation of the p53 pathway, including the excision base repair pathway and the insulin signaling pathway in the absence of PTP1B. In animal models of lipopolysaccharide (LPS) and D-galactosamine challenge as a way to reveal in vivo inflammatory responses, animals lacking PTP1B exhibited a higher rate of death. Moreover, these animals showed an enhanced response to irradiation, in agreement with the data obtained in the microarray analysis. In summary, these results indicate that, although inhibition of PTP1B has potential benefits for the treatment of diabetes, it accentuates pro-inflammatory responses compromising at least macrophage viability. © 2014 Macmillan Publishers Limited All rights reserved. Source


Quisenberry L.,Texas Tech University Health Sciences Center | Calvo R.-M.,Institute Investigaciones Biome dicas Alberto Sols | Obregon M.-J.,Institute Investigaciones Biome dicas Alberto Sols | Lado-Abeal J.,Texas Tech University Health Sciences Center | Lado-Abeal J.,University of Santiago de Compostela
Journal of Molecular Endocrinology | Year: 2013

Non-thyroidal illness syndrome (NTIS) is part of the neuroendocrine response to stress, but the significance of this syndrome remains uncertain. The aim of this study was to investigate the effect of lipopolysaccharide (LPS)-induced NTI Sonthyroidhormone (TH) levels and TH molecular targets, as well as the relationship between septic shock nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and TH receptor β (THRB) gene expression at a multi-tissue level in a pig model. Prepubertal domestic pigs were given i.v. saline or LPS for 48 h. Serum and tissue TH was measured by chemilum in escence and RIA. Expression of THRs and co factors was measured by real-time PCR, and deiodinase (DIO) activity was measured by enzyme essays. Tissue NF-kB nuclear binding activity was evaluated by EMSA. LPS-treated pigs had decreased TH levels in serum and most tissues. DIO1 expression in liver and kidney and DIO1 activity in kidney decreased after LPS. No changes in DIO2 activity were observed between groups. LPS induced an increase in hypothalamus, thyroid, and liver DIO3 activity. Among the other studied genes, monocarboxylate transporter 8 and THRB were the most commonly repressed in endotoxemic pigs. LPS-induced NF-kB activation was associated with a decrease in THRB gene expression only in frontal lobe, adrenal gland, and kidney cortex. We conclude that LPS-induced NTIS in pigs is characterized by hypothyroidism and tissue-specific reduced TH sensitivity. The role of NF-kB in regulating THRB expression during endotoxemia, if any, is restricted to a limited number of tissues. © 2013 Society for Endocrinology. Source


Rodrigues T.B.,Institute Investigaciones Biome dicas Alberto Sols | Violante I.R.,Institute Investigaciones Biome dicas Alberto Sols | Violante I.R.,University of Coimbra | Cerdan S.,Institute Investigaciones Biome dicas Alberto Sols
Magnetic Resonance in Medicine | Year: 2010

We used high-field 13C NMR (18.8 T) to assign unambiguously the isotopic shifts induced by the deuterium substitutions of the H3proR and H3proS hydrogens of (2-13C) glutamate in extracts of the brain from deuterated animals. Monodeuterated H3R or H3S glutamate diastereoisomers were produced stereospecifically either by chemical synthesis or by coupling the reactions of isocitrate dehydrogenase and aspartate aminotransferase in deuterated medium, respectively. We show that the (3S- 2H) or (3R-2H) deuterations induce characteristic small (Δ2 5 20.058 parts per million (ppm)) or large (Δ2 = 20.071 ppm) vicinal isotopic shifts upfield of the perprotonated (2-13C) glutamate resonance (at 55.5 ppm). Isotopically shifted (2-13C, 3S-2H) or (2-13C, 3R- 2H) glutamate singlets are conveniently observed by high-field 13C NMR in brain extracts from deuterated rats. Since the (3S- 2H) or (3R-2H) glutamate diastereoisomers are produced stereospecifically by the cytosolic or mitochondrial isoforms of aconitase and isocitrate dehydrogenase, our results will facilitate the 13C NMR investigation of these enzymatic activities and their role in subcellular glutamate trafficking. Magn Reson Med 63:1088-1091, 2010. © 2010 Wiley-Liss, Inc. Source

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