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Cantero J.M.B.,Hospital Universitario Reina Sofia | Cantero J.M.B.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba Imibic | Sanchez V.G.,Hospital Universitario Reina Sofia | Sanchez V.G.,Instituto Maimonides Of Investigacion Biomedica Of Cordoba Imibic | And 3 more authors.
Medicine (Spain)

Introduction Corticosteroids have been considered the treatment of choice for induction of remission in patients with active Crohn's disease. However, a significant number of patients have an inadequate response or adverse events to these drugs. Therapeutic management In this setting, immunosuppressants, thiopurines and methotrexate, and biologic drugs, mainly anti-TNF, have achieved a long-term free steroid clinical remission. Prognosis In addition, the early and combined use of these drugs has been associated with a better prognosis with lower rates of relapse, hospitalization and surgery. Source

Mennerich D.,University of Oulu | Kietzmann T.,University of Oulu | Sanchez-Perez P.,Autonomous University of Madrid | Sanchez-Perez P.,Institute Investigacion Sanitaria Princesa IIS IP | And 2 more authors.
Redox Biology

Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases. © 2015 . Source

R-Grau M.D.C.,Institute Investigacion Sanitaria Princesa IIS IP | Chaparro M.,Institute Investigacion Sanitaria Princesa IIS IP | Mesonero F.,Ramon y Cajal | Barreiro-de Acosta M.,Clinico de Santiago | And 15 more authors.
Digestive and Liver Disease

Background: Anti-TNF treatment is effective for Crohn's disease (CD); however, some patients did not achieve remission with these drugs. Aims: To evaluate the short-term effectiveness of a second anti-TNF in CD patients who did not achieve remission with the first one and to assess its durability. Methods: Patients who did not achieve remission with their first anti-TNF were included. The short-term response of the second anti-TNF was assessed, the long-term response was evaluated in patients who achieved remission (Kaplan-Meier). Cox-regression was performed to identify predictors of loss of efficacy. Results: In all, 118 CD patients received a second anti-TNF after primary failure of the first. The first anti-TNF was discontinued because of non-response in 54% of patients and partial response in 46%. Fifty-one percent of patients achieved remission in the short-term. The probability of remission was lower in patients for whom the drug indication was perianal disease (OR = 0.3, 95% CI = 0.1-0.7, P = 0.005). The dose was increased in 33% of patients, and 37% achieved/regained remission. The probability of maintaining remission was 76%, 68% and 64% at 12, 18 and 24 months, respectively. Conclusions: Approximately half of the patients achieved remission with a second anti-TNF after primary failure of the first, this strategy was less effective in patients with perianal disease. © 2016 Editrice Gastroenterologica Italiana S.r.l. Source

Perez-Hernandez D.,Autonomous University of Madrid | Perez-Hernandez D.,Centro Nacionalde Investigaciones Cardiovasculares | Gutierrez-Vazquez C.,Centro Nacionalde Investigaciones Cardiovasculares | Jorge I.,Centro Nacionalde Investigaciones Cardiovasculares | And 7 more authors.
Journal of Biological Chemistry

Extracellular vesicles are emerging as a potent mechanism of intercellular communication because they can systemically exchange genetic and protein material between cells. Tetraspanin molecules are commonly used as protein markers of extracellular vesicles, although their role in the unexplored mechanisms of cargo selection into exosomes has not been addressed. For that purpose, we have characterized the intracellular tetraspanin-enriched microdomain (TEM) interactome by high throughput mass spectrometry, in both human lymphoblasts and their derived exosomes, revealing a clear pattern of interaction networks. Proteins interacting with TEM receptors cytoplasmic regions presented a considerable degree of overlap, although some highly specific CD81 tetraspanin ligands, such as Rac GTPase, were detected. Quantitative proteomics showed that TEM ligands account for a great proportion of the exosome proteome and that a selective repertoire of CD81-associated molecules, including Rac, is not correctly routed to exosomes in cells from CD81-deficient animals. Our data provide evidence that insertion into TEM may be necessary for protein inclusion into the exosome structure. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Lopez-Bernardo E.,Autonomous University of Madrid | Lopez-Bernardo E.,Institute Investigacion Sanitaria Princesa IIS IP | Anedda A.,Institute Investigacion Sanitaria Princesa IIS IP | Sanchez-Perez P.,Autonomous University of Madrid | And 3 more authors.
Free Radical Biology and Medicine

4-Hydroxy-2-nonenal (HNE) is a highly cytotoxic product of lipid peroxidation. Nevertheless, at low concentrations, it is able to mediate cell signaling and to activate protective pathways, including that of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). In addition, HNE activates uncoupling proteins (UCPs), mitochondrial inner membrane proteins that mediate uncoupling of oxidative phosphorylation and have been proposed to protect against oxidative stress. It is not known, however, whether HNE might induce UCP expression via Nrf2 to cause mitochondrial uncoupling. We investigated the effects of HNE on UCP3 expression in mouse cardiomyocytes and the involvement of Nrf2. HNE induced the nuclear accumulation of Nrf2 and enhanced UCP3 expression, effects prevented by the antioxidant N-acetylcysteine. ChIP assays indicated that Nrf2 bound to the Ucp3 promoter after HNE treatment, increasing its expression. Cardiomyocytes treated with Nrf2- or UCP3-specific siRNA were less tolerant to HNE as reflected by increased cell death, and Nrf2 siRNA prevented HNE-induced UCP3 upregulation. The treatment with HNE greatly altered cardiomyocyte bioenergetics, increasing the proton leak across the inner mitochondrial membrane and severely decreasing the maximal respiratory capacity and the respiratory reserve capacity. These findings confirm that low HNE doses activate Nrf2 in cardiomyocytes and provide the first evidence of Nrf2 binding to the Ucp3 promoter in response to HNE, leading to increased protein expression. These results suggest that the upregulation of UCP3 mediated by Nrf2 in response to HNE might be important in the protection of the heart under conditions of oxidative stress such as ischemia-reperfusion. © 2015 Elsevier Inc. Source

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