Institute Investigacion Sanitaria la Paz
Institute Investigacion Sanitaria la Paz
Diaz-Lopez A.,Autonomous University of Madrid |
Diaz-Martin J.,University of Seville |
Moreno-Bueno G.,Autonomous University of Madrid |
Moreno-Bueno G.,Translational Research Laboratory |
And 9 more authors.
International Journal of Cancer | Year: 2015
Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR-200 family regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. © 2014 UICC.
Pilar Valdecantos M.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM |
Pilar Valdecantos M.,Institute Investigacion Sanitaria La Paz |
Prieto-Hontoria P.L.,University of Navarra |
Pardo V.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM |
And 23 more authors.
Free Radical Biology and Medicine | Year: 2015
Excess of saturated free fatty acids, such as palmitic acid (PA), in hepatocytes has been implicated in nonalcoholic fatty liver disease. α-Lipoic acid (LA) is an antioxidant that protects against oxidative stress conditions. We have investigated the effects of LA in the early activation of oxidative and endoplasmic reticulum stress, lipid accumulation, and Nrf2-mediated antioxidant defenses in hepatocytes treated with PA or in rats fed a high-fat diet. In primary human hepatocytes, a lipotoxic concentration of PA triggered endoplasmic reticulum stress, induced the apoptotic transcription factor CHOP, and increased the percentage of apoptotic cells. Cotreatment with LA prevented these effects. Similar results were found in mouse hepatocytes in which LA attenuated PA-mediated activation of caspase 3 and reduced lipid accumulation by decreasing PA uptake and increasing fatty acid oxidation and lipophagy, thereby preventing lipoapoptosis. Moreover, LA augmented the proliferation capacity of hepatocytes after PA challenge. Antioxidant effects of LA ameliorated reactive oxygen species production and endoplasmic reticulum stress and protected against mitochondrial apoptosis in hepatocytes treated with PA. Cotreatment with PA and LA induced an early nuclear translocation of Nrf2 and activated antioxidant enzymes, whereas reduction of Nrf2 by siRNA abolished the benefit of LA on PA-induced lipoapoptosis. Importantly, posttreatment with LA reversed the established damage induced by PA in hepatocytes, as well as preventing obesity-induced oxidative stress and lipoapoptosis in rat liver. In conclusion, our work has revealed that in hepatocytes, Nrf2 is an essential early player in the rescue of oxidative stress by LA leading to protection against PA-mediated lipoapoptosis. © 2015 Elsevier Inc. All rights reserved.
Martinez-Vega R.,Institute for Biomedical Research Alberto Sols CSIC UAM |
Martinez-Vega R.,Institute Salud Carlos III |
Garrido F.,Institute for Biomedical Research Alberto Sols CSIC UAM |
Partearroyo T.,University of San Pablo - CEU |
And 11 more authors.
FASEB Journal | Year: 2015
Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-related hearing loss. The purpose of this study was to address the impact of folate deficiency on hearing loss and to examine the underlying mechanisms. For this purpose, 2-mo-old C57BL/6J mice (Animalia Chordata Mus musculus) were randomly divided into 2 groups (n = 65 each) that were fed folate-deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7-fold decline in serum folate and a 3-fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL-positive-apoptotic cochlear cells. RT-quantitative PCR and Western blotting showed reduced levels of enzymes catalyzing homocysteine (Hcy) production and recycling, together with a 30% increase in protein homocysteinylation. Redox stress was demonstrated by decreased expression of catalase, glutathione peroxidase 4, and glutathione synthetase genes, increased levels of manganese superoxide dismutase, and NADPH oxidase-complex adaptor cytochrome b-245, α-polypeptide (p22phox) proteins, and elevated concentrations of glutathione species. Altogether, our findings demonstrate, for the first time, that the relationship between hyperhomocysteinemia induced by folate deficiency and premature hearing loss involves impairment of cochlear Hcy metabolism and associated oxidative stress. © FASEB.
Frijhoff J.,Maastricht University |
Winyard P.G.,University of Exeter |
Zarkovic N.,Ruder Boskovic Institute |
Davies S.S.,Vanderbilt University |
And 18 more authors.
Antioxidants and Redox Signaling | Year: 2015
Significance: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. Critical Issues: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. Future Directions: Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 23, 1144-1170. © 2015 Mary Ann Liebert, Inc.
Soriano V.,Hospital Universitario La Paz |
Soriano V.,Institute Investigacion Sanitaria la Paz |
Berenguer J.,Hospital General Universitario Gregorio Maranon |
Berenguer J.,Institute Investigacion Sanitaria Gregorio Maranon
Current Opinion in HIV and AIDS | Year: 2015
Purpose of review HIV infection facilitates progression of hepatitis C virus (HCV)-related liver fibrosis, thus increasing the risk of cirrhosis and decompensated liver disease. Although the primary target of HCV infection is the liver, extrahepatic manifestations related to HCV contribute significantly to morbidity and mortality in patients with chronic hepatitis C. We review current data on extrahepatic comorbidities associated with HCV in HIV-infected patients. Recent findings A large proportion of individuals coinfected with HIV/HCV has extrahepatic manifestations that may be indirectly or directly related to HCV infection. Extrahepatic manifestations include autoimmune and/or lymphoproliferative disorders, and cardiovascular, renal, metabolic, and central nervous system manifestations. Chronic immune activation and systemic inflammation, hallmarks of both HIV and HCV infection, may contribute greatly to extrahepatic comorbidities of HCV in this population group. There is substantial evidence that successful antiviral therapy might reduce both hepatic and extrahepatic manifestations of HCV infection in patients coinfected with HIV/HCV. Summary A substantial burden of the morbidity and the mortality related to HCV in patients with or without HIV infection depends on its extrahepatic manifestations. HCV eradication following successful antiviral therapy might reduce both. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.