Institute Investigacion Sanitaria Princesa IIS IP

Madrid, Spain

Institute Investigacion Sanitaria Princesa IIS IP

Madrid, Spain
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Navarro E.,Autonomous University of Madrid | Navarro E.,Institute Investigacion Sanitaria Princesa IIS IP | Gonzalez-Lafuente L.,Autonomous University of Madrid | Perez-Liebana I.,Autonomous University of Madrid | And 13 more authors.
Antioxidants and Redox Signaling | Year: 2017

Aims: A loss in brain acetylcholine and cholinergic markers, subchronic inflammation, and impaired mitochondrial function, which lead to low-energy production and high oxidative stress, are common pathological factors in several neurodegenerative diseases (NDDs). Glial cells are important for brain homeostasis, and microglia controls the central immune response, where α7 acetylcholine nicotinic receptors (nAChR) seem to play a pivotal role; however, little is known about the effects of this receptor in metabolism. Therefore, the aim of this study was to evaluate if glial mitochondrial energetics could be regulated through α7 nAChR. Results: Primary glial cultures treated with the α7 nicotinic agonist PNU282987 increased their mitochondrial mass and their mitochondrial oxygen consumption without increasing oxidative stress; these changes were abolished when nuclear erythroid 2-related factor 2 (Nrf2) was absent, heme oxygenase-1 (HO-1) was inhibited, or peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) was silenced. More specifically, microglia of animals treated intraperitoneally with the α7 nAChR agonist PNU282987 (10 mg/kg) showed a significant increase in mitochondrial mass. Interestingly, LysMcre-Hmox1Δ/Δ and PGC-1α-/- animals showed lower microglial mitochondrial levels and treatment with PNU282987 did not produce effects on mitochondrial levels. Innovation: Increases in microglial mitochondrial mass and metabolism can be achieved via α7 nAChR by a mechanism that implicates Nrf2, HO-1, and PGC-1α. This signaling pathway could open a new strategy for the treatment of NDDs, such as Alzheimer's, characterized by a reduction of cholinergic markers. Conclusion: α7 nAChR signaling increases glial mitochondrial mass, both in vitro and in vivo, via HO-1 and PCG-1α. These effects could be of potential benefit in the context of NDDs. Antioxid. Redox Signal. 27, 93-105. © Copyright 2017, Mary Ann Liebert, Inc. 2017.


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 | Year: 2016

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.


Garcia-Casarrubios E.,Institute of Biomedicine Alberto Sols CSIC UAM | de Moura C.,Institute of Biomedicine Alberto Sols CSIC UAM | de Moura C.,University of Coimbra | Arroba A.I.,Institute of Biomedicine Alberto Sols CSIC UAM | And 18 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2016

New onset diabetes after transplantation (NODAT) is a metabolic disorder that affects 40% of patients on immunosuppressive agent (IA) treatment, such as rapamycin (also known as sirolimus). IAs negatively modulate insulin action in peripheral tissues including skeletal muscle, liver and white fat. However, the effects of IAs on insulin sensitivity and thermogenesis in brown adipose tissue (BAT) have not been investigated. We have analyzed the impact of rapamycin on insulin signaling, thermogenic gene-expression and mitochondrial respiration in BAT. Treatment of brown adipocytes with rapamycin for 16 h significantly decreased insulin receptor substrate 1 (IRS1) protein expression and insulin-mediated protein kinase B (Akt) phosphorylation. Consequently, both insulin-induced glucose transporter 4 (GLUT4) translocation to the plasma membrane and glucose uptake were decreased. Early activation of the N-terminal Janus activated kinase (JNK) was also observed, thereby increasing IRS1 Ser 307 phosphorylation. These effects of rapamycin on insulin signaling in brown adipocytes were partly prevented by a JNK inhibitor. In vivo treatment of rats with rapamycin for three weeks abolished insulin-mediated Akt phosphorylation in BAT. Rapamycin also inhibited norepinephrine (NE)-induced lipolysis, the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and uncoupling protein (UCP)-1 in brown adipocytes. Importantly, basal mitochondrial respiration, proton leak and maximal respiratory capacity were significantly decreased in brown adipocytes treated with rapamycin. In conclusion, we demonstrate, for the first time the important role of brown adipocytes as target cells of rapamycin, suggesting that insulin resistance in BAT might play a major role in NODAT development. © 2016 Elsevier B.V.


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 | Year: 2015

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 .


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) | Year: 2016

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.


PubMed | Institute Investigacion Sanitaria Princesa IIS IP, Clinico de Santiago, Infanta Sofia, Clinico Universitario Lozano Blesa and 11 more.
Type: Journal Article | Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | Year: 2016

Anti-TNF treatment is effective for Crohns disease (CD); however, some patients did not achieve remission with these drugs.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.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.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.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.


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 | Year: 2015

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.


Perez-Perez R.,Hospital Universitario 12 Of Octubre I12 | Perez-Perez R.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | Lobo-Jarne T.,Hospital Universitario 12 Of Octubre I12 | Lobo-Jarne T.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | And 20 more authors.
Cell Reports | Year: 2016

Mitochondrial respiratory chain (MRC) complexes I, III, and IV associate into a variety of supramolecular structures known as supercomplexes and respirasomes. While COX7A2L was originally described as a supercomplex-specific factor responsible for the dynamic association of complex IV into these structures to adapt MRC function to metabolic variations, this role has been disputed. Here, we further examine the functional significance of COX7A2L in the structural organization of the mammalian respiratory chain. As in the mouse, human COX7A2L binds primarily to free mitochondrial complex III and, to a minor extent, to complex IV to specifically promote the stabilization of the III2+IV supercomplex without affecting respirasome formation. Furthermore, COX7A2L does not affect the biogenesis, stabilization, and function of the individual oxidative phosphorylation complexes. These data show that independent regulatory mechanisms for the biogenesis and turnover of different MRC supercomplex structures co-exist. © 2016 The Author(s)


PubMed | Institute Investigacion Sanitaria Princesa IIS IP and Autonomous University of Madrid
Type: Journal Article | Journal: Free radical biology & medicine | Year: 2015

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.

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