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Martinez-Vega R.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Martinez-Vega R.,Institute Salud Carlos III | Partearroyo T.,University of San Pablo - CEU | Vallecillo N.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | And 6 more authors.
Journal of Nutritional Biochemistry | Year: 2015

Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients well known for their beneficial effects, among others on cognitive development and maintenance, inflammation and oxidative stress. Previous studies have shown an inverse association between high plasma levels of PUFAs and age-related hearing loss, and the relationship between low serum folate and elevated plasma homocysteine levels and hearing loss. Therefore, we used C57BL/6J mice and long-term omega-3 supplementation to evaluate the impact on hearing by analyzing their auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) thresholds. The omega-3 group showed significantly lower ABR hearing thresholds (~25 dB sound pressure level) and higher DPOAE amplitudes in mid-high frequencies when compared to the control group. These changes did not correlate with alterations between groups in plasma homocysteine or serum folate levels as measured by high-performance liquid chromatography and a microbiological method, respectively. Aging in the control group was associated with imbalanced cytokine expression toward increased proinflammatory cytokines as determined by quantitative reverse transcriptase polymerase chain reaction; these changes were prevented by omega-3 supplementation. Genes involved in homocysteine metabolism showed decreased expression during aging of control animals, and only alterations in Bhmt and Cbs were significantly prevented by omega-3 feeding. Western blotting showed that omega-3 supplementation precluded the CBS protein increase detected in 10-month-old controls but also produced an increase in BHMT protein levels. Altogether, the results obtained suggest a long-term protective role of omega-3 supplementation on cochlear metabolism and progression of hearing loss. © 2015 The Authors.


Berenguer J.,Hospital General Universitario Gregorio Maranon | Berenguer J.,Hospital Universitario La Paz | Zamora F.X.,Hospital Donostia | Zamora F.X.,Hospital Universitari La Fe Valencia | And 103 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2014

Objective: We assessed the effects of sustained viral response (SVR), after treating with interferon-ribavirin (IF-RB), on mortality, liver-related (LR) events (decompensation, hepatocellular carcinoma), HIV progression, and liver stiffness in HIV/hepatitis C virus (HCV)-coinfected patients with nonadvanced liver fibrosis. Methods: From a cohort of HIV/HCV-coinfected patients treated with IF-RB, we selected those with baseline liver fibrosis stages F0, F1, or F2 according to METAVIR. The study started when IF-RB was stopped and ended at death or at the last follow-up visit. Results: A total of 695 patients were included (HCV genotype 1 or 4, 431; F0, 77; F1, 290; and F2, 328), and 274 patients achieved SVR. After a median follow-up of 4.9 years, the adjusted hazard ratio (aHR) [95% confidence interval (CI)] of LR events or overall death, for patients with SVR taking the group of patients with no SVR as a reference was 0.217 (0.079 to 0.599) (P = 0.003) for the whole cohort with F0 to F2. For patients with F0, the aHR (95% CI) was 0.514 (0.040 to 6.593) (P = 0.609), for patients with F1, the aHR (95% CI) was 0.305 (0.053 to 1.762) (P = 0.185), and for patients with F2, it was 0.075 (0.009 to 0.662) (P = 0.020). We also found that, in comparison with no SVR, SVR was followed by less frequent HIV progression for the entire population (F0 to F2) and less frequent liver stiffness across all categories of fibrosis. Conclusions: SVR in HIV/HCV-coinfected patients with moderate stages of liver fibrosis is associated with a reduction of mortality and LR events, and with a reduction of progression of HIV and liver fibrosis. Copyright © 2014 by Lippincott Williams & Wilkins.


Pajares M.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Pajares M.,Institute Investigacion Sanitaria La Paz IdiPAZ | Pajares M.,CIBER ISCIII | Jimenez-Moreno N.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | And 13 more authors.
Redox Biology | Year: 2015

Intracellular proteolysis is critical to maintain timely degradation of altered proteins including oxidized proteins. This review attempts to summarize the most relevant findings about oxidant protein modification, as well as the impact of reactive oxygen species on the proteolytic systems that regulate cell response to an oxidant environment: the ubiquitin-proteasome system (UPS), autophagy and the unfolded protein response (UPR). In the presence of an oxidant environment, these systems are critical to ensure proteostasis and cell survival. An example of altered degradation of oxidized proteins in pathology is provided for neurodegenerative diseases. Future work will determine if protein oxidation is a valid target to combat proteinopathies. © 2015 The Authors.


Dao V.T.-V.,Maastricht University | Casas A.I.,Maastricht University | Maghzal G.J.,Victor Chang Cardiac Research Institute | Seredenina T.,University of Geneva | And 14 more authors.
Antioxidants and Redox Signaling | Year: 2015

Significance: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. Recent Advances: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. Critical Issues: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. Future Directions: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine. Antioxid. Redox Signal. 23, 1113-1129. © 2015, Mary Ann Liebert, Inc.


Gonzalez-Rodriguez A.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Gonzalez-Rodriguez A.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas Ciberdem | Gonzalez-Rodriguez A.,Hospital Universitario Santa Cristina | Santamaria B.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | And 18 more authors.
Molecular Nutrition and Food Research | Year: 2015

Scope: Mice with deletion of insulin receptor substrate (IRS) 2 develop hyperglycaemia, impaired hepatic insulin signaling and elevated gluconeogenesis. Protein tyrosine phosphatase 1B (PTP1B) inhibition by resveratrol improves peripheral insulin sensitivity of these mice. Although resveratrol activates Sirtuin1 (Sirt1), the mechanisms underlying its beneficial effects are not totally elucidated. In this study, we have investigated whether Sirt1 mediates the effects of resveratrol in controlling insulin resistance in diabetic mice. Methods and results: We attempted to ameliorate peripheral insulin resistance in two diabetic models, Irs2-deficient (Irs2-/-) mice and streptozotocin (STZ)-injected mice by resveratrol treatment or Sirt1 overexpression. Resveratrol improved systemic insulin sensitivity of Irs2-deficient mice. Irs2-deficient mice are characterized by high levels of PTP1B expression in liver and muscle. Interestingly, resveratrol decreased PTP1B in both tissues, thereby restoring IRS1-mediated insulin signaling. Moreover, resveratrol also restored insulin sensitivity and hepatic insulin signaling in STZ-diabetic mice. In contrast, moderate overexpression of Sirt1 neither normalized PTP1B levels nor restored insulin signaling in Irs2-deficient mice or STZ-diabetic mice. Conclusion: Resveratrol improves peripheral insulin signaling independently of Sirt1 in diabetic mice in association with the inhibition of PTP1B and, therefore, this polyphenol could be an effective adjuvant for the treatment of diabetes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Jazwa A.,Research Center Biomedica en Red Sobre Enfermedades Neurodegenerativas | Jazwa A.,Jagiellonian University | Rojo A.I.,Research Center Biomedica en Red Sobre Enfermedades Neurodegenerativas | Rojo A.I.,Complutense University of Madrid | And 12 more authors.
Antioxidants and Redox Signaling | Year: 2011

Current therapies for motor symptoms of Parkinson's disease (PD) are based on dopamine replacement. However, the disease progression remains unaffected, because of continuous dopaminergic neuron loss. Since oxidative stress is actively involved in neuronal death in PD, pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor NF-E2-related factor 2 (Nrf2) on brain protection against the parkinsonian toxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Intraperitoneal administration of the potent Nrf2 activator ulforaphane (SFN) increased Nrf2 protein levels in the basal ganglia and led to upregulation of phase II antioxidant enzymes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO1). In wild-type mice, but not in Nrf2-knockout mice, SFN protected against MPTP-induced death of nigral dopaminergic neurons. The neuroprotective effects were accompanied by a decrease in astrogliosis, microgliosis, and release of pro-inflammatory cytokines. These results provide strong pharmacokinetic and biochemical evidence for activation of Nrf2 and phase II genes in the brain and also offer a neuroprotective strategy that may have clinical relevance for PD therapy. © 2011 Mary Ann Liebert, Inc.


Schmidt H.H.H.W.,Maastricht University | Stocker R.,Victor Chang Cardiac Research Institute | Stocker R.,University of New South Wales | Vollbracht C.,Fresenius University of Applied Sciences | And 7 more authors.
Antioxidants and Redox Signaling | Year: 2015

Significance: It is generally accepted that reactive oxygen species (ROS) scavenging molecules or antioxidants exert health-promoting effects and thus their consumption as food additives and nutraceuticals has been greatly encouraged. Antioxidants may be beneficial in situations of subclinical deficiency and increased demand or acutely upon high-dose infusion. However, to date, there is little clinical evidence for the long-term benefit of most antioxidants. Alarmingly, recent evidence points even to health risks, in particular for supplements of lipophilic antioxidants. Recent Advances: The biological impact of ROS depends not only on their quantities but also on their chemical nature, (sub)cellular and tissue location, and the rates of their formation and degradation. Moreover, ROS serve important physiological functions; thus, inappropriate removal of ROS may cause paradoxical reductive stress and thereby induce or promote disease. Critical Issues: Any recommendation on antioxidants must be based on solid clinical evidence and patient-relevant outcomes rather than surrogate parameters. Future Directions: Such evidence-based use may include site-directed application, time-limited high dosing, (functional) pharmacological repair of oxidized biomolecules, and triggers of endogenous antioxidant response systems. Ideally, these approaches need guidance by patient stratification through predictive biomarkers and possibly imaging modalities. Antioxid. Redox Signal. 23, 1130-1143. © 2015, Mary Ann Liebert, Inc.


Perez C.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Perez-Zuniga F.J.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Garrido F.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Reytor E.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | And 5 more authors.
PLoS ONE | Year: 2016

Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular localization of these isoenzymes are also detected. All these alterations result in a reduced content of the moderate (MAT I) and high Vmax (MAT III) isoenzymes, whereas the low Vmax (MAT II) isoenzyme increases and nuclear accumulation of MAT I is observed. These changes derive in a reduced availability of cytoplasmic S-adenosylmethionine, together with an effort to meet its needs in the nucleus of damaged cells, rendering enhanced levels of certain epigenetic modifications. In this context, the putative role of protein-protein interactions in the control of S-adenosylmethionine synthesis has been scarcely studied. Using yeast two hybrid and a rat liver library we identified PDRG1 as an interaction target for MATα1 (catalytic subunit of MAT I and MAT III), further confirmation being obtained by immunoprecipitation and pull-down assays. Nuclear MATα interacts physically and functionally with the PDRG1 oncogene, resulting in reduced DNA methylation levels. Increased Pdrg1 expression is detected in acute liver injury and hepatoma cells, together with decreased Mat1a expression and nuclear accumulation of MATα1. Silencing of Pdrg1 expression in hepatoma cells alters their steady-state expression profile on microarrays, downregulating genes associated with tumor progression according to GO pathway analysis. Altogether, the results unveil the role of PDRG1 in the control of the nuclear methylation status through methionine adenosyltransferase binding and its putative collaboration in the progression of hepatic diseases. © 2016 Pérez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Garcia-Yague A.J.,Institute Investigaciones Biomedicas Alberto Sols | Rada P.,Institute Investigaciones Biomedicas Alberto Sols | Rada P.,Autonomous University of Madrid | Rada P.,Institute Investigacion Sanitaria La Paz IDIPAZ | And 13 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Little is known about the regulation of transcription factor Nurr1. Results: We identified a bipartite NLS and two NES signals implicated in its subcellular trafficking, and we report that oxidative stress induces nuclear export of Nurr1. Conclusion: Nurr1 shuttles between the cytoplasm and nucleus, and its subcellular localization is modified by stress. Significance: Nurr1 subcellular localization will help understand its function under physiopathological conditions. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Rada P.,Research Center Biomedica en Red Sobre Enfermedades Neurodegenerativas | Rada P.,Institute Investigaciones Biomedicas Alberto Sols | Rada P.,Institute Investigacion Sanitaria la Paz IdiPaz | Rada P.,Autonomous University of Madrid | And 17 more authors.
Antioxidants and Redox Signaling | Year: 2015

Aims: Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of oxidant and xenobiotic metabolism, but it is unknown how it is regulated to provide basal expression of this defense system. Here, we studied the putative connection between NRF2 and the canonical WNT pathway, which modulates hepatocyte metabolism. Results: WNT-3A increased the levels of NRF2 and its transcriptional signature in mouse hepatocytes and HEK293T cells. The use of short interfering RNAs in hepatocytes and mouse embryonic fibroblasts which are deficient in the redox sensor Kelch-like ECH-associated protein 1 (KEAP1) indicated that WNT-3A activates NRF2 in a β-Catenin- and KEAP1-independent manner. WNT-3A stabilized NRF2 by preventing its GSK-3-dependent phosphorylation and subsequent SCF/β-TrCP-dependent ubiquitination and proteasomal degradation. Axin1 and NRF2 were physically associated in a protein complex that was regulated by WNT-3A, involving the central region of Axin1 and the Neh4/Neh5 domains of NRF2. Axin1 knockdown increased NRF2 protein levels, while Axin1 stabilization with Tankyrase inhibitors blocked WNT/NRF2 signaling. The relevance of this novel pathway was assessed in mice with a conditional deletion of Axin1 in the liver, which showed upregulation of the NRF2 signature in hepatocytes and disruption of liver zonation of antioxidant metabolism. Innovation: NRF2 takes part in a protein complex with Axin1 that is regulated by the canonical WNT pathway. This new WNT-NRF2 axis controls the antioxidant metabolism of hepatocytes. Conclusion: These results uncover the participation of NRF2 in a WNT-regulated signalosome that participates in basal maintenance of hepatic antioxidant metabolism. Antioxid. Redox Signal. 22, 555-571. © Copyright 2015, Mary Ann Liebert, Inc. 2015.

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