38 results on '"Aurrekoetxea, Igor"'
Search Results
2. Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance
- Author
-
Martínez-Sánchez, Noelia, Seoane-Collazo, Patricia, Contreras, Cristina, Varela, Luis, Villarroya, Joan, Rial-Pensado, Eva, Buqué, Xabier, Aurrekoetxea, Igor, Delgado, Teresa C., Vázquez-Martínez, Rafael, González-García, Ismael, Roa, Juan, Whittle, Andrew J., Gomez-Santos, Beatriz, Velagapudi, Vidya, Tung, Y.C. Loraine, Morgan, Donald A., Voshol, Peter J., Martínez de Morentin, Pablo B., López-González, Tania, Liñares-Pose, Laura, Gonzalez, Francisco, Chatterjee, Krishna, Sobrino, Tomás, Medina-Gómez, Gema, Davis, Roger J., Casals, Núria, Orešič, Matej, Coll, Anthony P., Vidal-Puig, Antonio, Mittag, Jens, Tena-Sempere, Manuel, Malagón, María M., Diéguez, Carlos, Martínez-Chantar, María Luz, Aspichueta, Patricia, Rahmouni, Kamal, Nogueiras, Rubén, Sabio, Guadalupe, Villarroya, Francesc, and López, Miguel
- Published
- 2017
- Full Text
- View/download PDF
3. S-Adenosylmethionine increases circulating very-low density lipoprotein clearance in non-alcoholic fatty liver disease
- Author
-
Martínez-Uña, Maite, Varela-Rey, Marta, Mestre, Daniela, Fernández-Ares, Larraitz, Fresnedo, Olatz, Fernandez-Ramos, David, Juan, Virginia Gutiérrez-de, Martin-Guerrero, Idoia, García-Orad, Africa, Luka, Zigmund, Wagner, Conrad, Lu, Shelly C., García-Monzón, Carmelo, Finnell, Richard H., Aurrekoetxea, Igor, Buqué, Xabier, Martínez-Chantar, M. Luz, Mato, José M., and Aspichueta, Patricia
- Published
- 2015
- Full Text
- View/download PDF
4. THU-210 Dysfunctional activation of the DNA damage response is associated with MASLD progression through an E2F2-dependent mechanism
- Author
-
Santos, Beatriz Gómez, Fernández-Puertas, Idoia, Gomez-Jauregui, Paul, Sainz-Ramírez, Natalia, Alfaro-Jiménez, Kendall, Castillero, Estibaliz, Nieva-Zuluaga, Ane, Apodaka-Biguri, Maider, Aurrekoetxea, Igor, Delgado, Igotz, Lopategi, Aritz, Iglesias, Ainhoa, González, Lorena Mosteiro, Olartekoetxea, Gaizka Errazti, Gaztambide, Sonia, González, Luis A. Castaño, Bujanda, Luis, Banales, Jesus Maria, Buque, Xabier, Zubiaga, Ana, and Aspichueta, Patricia
- Published
- 2024
- Full Text
- View/download PDF
5. TOP-229-YI The E2F2 target glycerophosphodiester phosphodiesterase domain containing 3 is involved in MASLD progression to HCC and related dyslipidemias
- Author
-
Apodaka-Biguri, Maider, Muñoz-Llanes, Nerea, Gonzalez-Romero, Francisco, Aurrekoetxea, Igor, Santos, Beatriz Gómez, Delgado, Igotz, Buque, Xabier, Nieva-Zuluaga, Ane, de Gauna, Mikel Ruiz, Fernández-Puertas, Idoia, Gomez-Jauregui, Paul, Sainz-Ramírez, Natalia, Alfaro-Jiménez, Kendall, Castillero, Estibaliz, Congregado, Daniela Mestre, Woodhoo, Ashwin, Varela-Rey, Marta, Lujambio, Amaia, Zubiaga, Ana, and Aspichueta, Patricia
- Published
- 2024
- Full Text
- View/download PDF
6. FRI-472-YI Mitochondrial metabolism is disrupted by ciprofloxacin preventing cholangiocarcinoma cell proliferation
- Author
-
de Gauna, Mikel Ruiz, Alfaro-Jiménez, Kendall, Nieva-Zuluaga, Ane, Apodaka-Biguri, Maider, Markaide, Enara, Izquierdo-Sánchez, Laura, Rae, Colin, González-Romero, Francisco, Gomez-Jauregui, Paul, Sainz-Ramírez, Natalia, Santos, Beatriz Gómez, Buque, Xabier, Aurrekoetxea, Igor, Delgado, Igotz, Fernández-Puertas, Idoia, Iglesias, Ainhoa, Rourke, Colm O., Rodrigues, Pedro Miguel, Andersen, Jesper, Calvisi, Diego, Morton, Jennifer, Braconi, Chiara, Zubiaga, Ana, Banales, Jesus Maria, and Aspichueta, Patricia
- Published
- 2024
- Full Text
- View/download PDF
7. FRI-343-YI APAP induced liver damage is prevented by activation of PPARgamma and PPAR-alpha
- Author
-
Gomez-Jauregui, Paul, Gonzalez-Romero, Francisco, Santos, Beatriz Gómez, Apodaka-Biguri, Maider, Buque, Xabier, Crespo, Maria, Mora, Alfonso, Mesquita, Mariana, Aurrekoetxea, Igor, Delgado, Igotz, Nieva-Zuluaga, Ane, de Gauna, Mikel Ruiz, Fernández-Puertas, Idoia, Sainz-Ramírez, Natalia, Alfaro-Jiménez, Kendall, Irizar, María Esther, Iglesias, Ainhoa, Cubero, Francisco Javier, Sabio, Guadalupe, Zubiaga, Ana, and Aspichueta, Patricia
- Published
- 2024
- Full Text
- View/download PDF
8. OS-101-YI Remodelling of hepatocyte cholesterol metabolism mediates colorectal liver metastasis
- Author
-
Nieva-Zuluaga, Ane, Arteta, Beatriz, de Gauna, Mikel Ruiz, Apodaka-Biguri, Maider, Fernández-Puertas, Idoia, González-Romero, Francisco, Gomez-Jauregui, Paul, Sainz-Ramírez, Natalia, Alfaro-Jiménez, Kendall, Santos, Beatriz Gómez, Delgado, Igotz, Valdivieso, Andres, Bustamante, Javier, Bujanda, Luis, Banales, Jesus Maria, Giannou, Anastasios, Huber, Samuel, Aurrekoetxea, Igor, Buque, Xabier, and Aspichueta, Patricia
- Published
- 2024
- Full Text
- View/download PDF
9. Deregulated neddylation in liver fibrosis
- Author
-
Zubiete‐Franco, Imanol, Fernández‐Tussy, Pablo, Barbier‐Torres, Lucía, Simon, Jorge, Fernández‐Ramos, David, Lopitz‐Otsoa, Fernando, Gutiérrez‐de Juan, Virginia, de Davalillo, Sergio López, Duce, Antonio Martín, Iruzubieta, Paula, Taibo, Daniel, Crespo, Javier, Caballeria, Juan, Villa, Erica, Aurrekoetxea, Igor, Aspichueta, Patricia, Varela‐Rey, Marta, Lu, Shelly C, Mato, José M., Beraza, Naiara, Delgado, Teresa C., and Martínez‐Chantar, María L
- Published
- 2017
- Full Text
- View/download PDF
10. Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids.
- Author
-
Ruiz de Gauna, Mikel, Biancaniello, Francesca, González‐Romero, Francisco, Rodrigues, Pedro M., Lapitz, Ainhoa, Gómez‐Santos, Beatriz, Olaizola, Paula, Di Matteo, Sabina, Aurrekoetxea, Igor, Labiano, Ibone, Nieva‐Zuluaga, Ane, Benito‐Vicente, Asier, Perugorria, María J., Apodaka‐Biguri, Maider, Paiva, Nuno A., Sáenz de Urturi, Diego, Buqué, Xabier, Delgado, Igotz, Martín, César, and Azkargorta, Mikel
- Published
- 2022
- Full Text
- View/download PDF
11. Serum oxidizability and antioxidant status in patients undergoing in vitro fertilization
- Author
-
Aurrekoetxea, Igor, Ruiz-Sanz, José Ignacio, del Agua, Ainhoa Ruiz, Navarro, Rosaura, Hernández, M. Luisa, Matorras, Roberto, Prieto, Begoña, and Ruiz-Larrea, M. Begoña
- Published
- 2010
- Full Text
- View/download PDF
12. Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity.
- Author
-
Hamidi, Mohaddase, Eriz, Ainhoa, Mitxelena, Jone, Fernandez-Ares, Larraitz, Aurrekoetxea, Igor, Aspichueta, Patricia, Iglesias-Ara, Ainhoa, and Zubiaga, Ana M.
- Subjects
PROTEIN metabolism ,REVERSE transcriptase polymerase chain reaction ,DNA ,ANIMAL experimentation ,CELL cycle proteins ,GENE expression ,CELLULAR signal transduction ,BIOINFORMATICS ,TRANSCRIPTION factors ,PHYSIOLOGICAL research ,CELL lines ,PROSTATE tumors ,ANIMALS ,MICE - Abstract
Simple Summary: E2F1 and E2F2 are highly expressed in many cancer types, but their contribution to malignancy is not well understood. Here we aimed to define the impact of E2F1/E2F2 deregulation in prostate cancer. We show that inhibition of E2F sensitizes prostate cancer cells to drug-induced replication stress and cell death. We found that E2F target genes involved in nucleotide biosynthesis contribute to maintaining genome stability in prostate cancer cells, but their enzymatic activity is insufficient to prevent replication stress after E2F1/E2F2 depletion. Instead, E2F1/E2F2 hinder premature CDK1 activation during S phase, which is key to ensure genome stability and viability of prostate cancer cells. From a therapeutic perspective, inhibiting E2F activity provokes catastrophic levels of replication stress and blunts xenograft growth in combination with drugs targeting nucleotide biosynthesis or DNA repair. Our results highlight the suitability of targeting E2F for the treatment of prostate cancer. E2F1/E2F2 expression correlates with malignancy in prostate cancer (PCa), but its functional significance remains unresolved. To define the mechanisms governed by E2F in PCa, we analyzed the contribution of E2F target genes to the control of genome integrity, and the impact of modulating E2F activity on PCa progression. We show that silencing or inhibiting E2F1/E2F2 induces DNA damage during S phase and potentiates 5-FU-induced replication stress and cellular toxicity. Inhibition of E2F downregulates the expression of E2F targets involved in nucleotide biosynthesis (TK1, DCK, TYMS), whose expression is upregulated by 5-FU. However, their enzymatic products failed to rescue DNA damage of E2F1/E2F2 knockdown cells, suggesting additional mechanisms for E2F function. Interestingly, targeting E2F1/E2F2 in PCa cells reduced WEE1 expression and resulted in premature CDK1 activation during S phase. Inhibition of CDK1/CDK2 prevented DNA damage induced by E2F loss, suggesting that E2F1/E2F2 safeguard genome integrity by restraining CDK1/CDK2 activity. Importantly, combined inhibition of E2F and ATR boosted replication stress and dramatically reduced tumorigenic capacity of PCa cells in xenografts. Collectively, inhibition of E2F in combination with drugs targeting nucleotide biosynthesis or DNA repair is a promising strategy to provoke catastrophic levels of replication stress that could be applied to PCa treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
13. WED-408 - E2F2-promoted DNA damage in NASH worsens the metabolic scenario
- Author
-
Santos, Beatriz Gómez, Fernández-Puertas, Idoia, Gomez-Jauregui, Paul, Muñoz-Llanes, Nerea, Sainz-Ramírez, Natalia, Nieva-Zuluaga, Ane, de Gauna, Mikel Ruiz, Apodaka-Biguri, Maider, González-Romero, Francisco, Delgado, Igotz, Aurrekoetxea, Igor, González, Lorena Mosteiro, Olartekoetxea, Gaizka Errazti, Gaztambide, Sonia, Castaño González, Luis A, Bujanda, Luis, Banales, Jesus Maria, Buque, Xabier, Zubiaga, Ana, and Aspichueta, Patricia
- Published
- 2023
- Full Text
- View/download PDF
14. WED-404 - The E2F2-miR34a-5p axis is involved in the biliary metabolism dysregulation in NASH
- Author
-
Apodaka-Biguri, Maider, Gonzalez-Romero, Francisco, Simão, André L., Congregado, Daniela Mestre, Aurrekoetxea, Igor, Santos, Beatriz Gómez, Delgado, Igotz, Buque, Xabier, Nieva-Zuluaga, Ane, de Gauna, Mikel Ruiz, Fernández-Puertas, Idoia, Iglesias, Ainhoa, Aransay, Ana María, Lozano, Juanjo, Martín, Cesar Augusto, Bernales, Irantzu, Rodrigues, Pedro Miguel, Banales, Jesus Maria, Zubiaga, Ana, Castro, Rui E., and Aspichueta, Patricia
- Published
- 2023
- Full Text
- View/download PDF
15. SAT-215 - Targeting the E2F/MCM axis in cholangiocarcinoma halts disease progression in experimental models by rewiring lipid metabolism
- Author
-
de Gauna, Mikel Ruiz, Nieva-Zuluaga, Ane, Apodaka-Biguri, Maider, González-Romero, Francisco, Muñoz-Llanes, Nerea, Gomez-Jauregui, Paul, Sainz-Ramírez, Natalia, Alfaro-Jiménez, Kendall, Santos, Beatriz Gómez, Buque, Xabier, Aurrekoetxea, Igor, Delgado, Igotz, Fernández-Puertas, Idoia, Iglesias, Ainhoa, Rodrigues, Pedro Miguel, Calvisi, Diego, Zubiaga, Ana, Banales, Jesus Maria, and Aspichueta, Patricia
- Published
- 2023
- Full Text
- View/download PDF
16. FRI-395 - E2F2 deficiency protects from acetaminophen-induced hepatotoxicity while E2F1 is required to prevent the devastating effects
- Author
-
Buque, Xabier, Gonzalez-Romero, Francisco, Apodaka-Biguri, Maider, Crespo, Maria, Mesquita, Mariana, Aurrekoetxea, Igor, Santos, Beatriz Gómez, Delgado, Igotz, Nieva-Zuluaga, Ane, de Gauna, Mikel Ruiz, Fernández-Puertas, Idoia, Gomez-Jauregui, Paul, Muñoz-Llanes, Nerea, Sainz-Ramírez, Natalia, Iglesias, Ainhoa, Cubero, Francisco Javier, Sabio, Guadalupe, Zubiaga, Ana, and Aspichueta, Patricia
- Published
- 2023
- Full Text
- View/download PDF
17. Detection of catechol-O-methyltransferase Val158Met polymorphism by a simple one-step tetra-primer amplification refractory mutation system-PCR
- Author
-
Ruiz-Sanz, José Ignacio, Aurrekoetxea, Igor, del Agua, Ainhoa Ruiz, and Ruiz-Larrea, María Begoña
- Published
- 2007
- Full Text
- View/download PDF
18. Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis
- Author
-
Martínez-Uña, Maite, Varela-Rey, Marta, Cano, Ainara, Fernández-Ares, Larraitz, Beraza, Naiara, Aurrekoetxea, Igor, Martínez-Arranz, Ibon, García-Rodríguez, Juan L., Buqué, Xabier, Mestre, Daniela, Luka, Zigmund, Wagner, Conrad, Alonso, Cristina, Finnell, Richard H., Lu, Shelly C., Martínez-Chantar, Luz M., Aspichueta, Patricia, and Mato, José M.
- Published
- 2013
- Full Text
- View/download PDF
19. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice
- Author
-
Cano, Ainara, Buqué, Xabier, Martínez-Uña, Maite, Aurrekoetxea, Igor, Menor, Ariane, García-Rodríguez, Juan L., Lu, Shelly C., Martínez-Chantar, Luz M., Mato, José M., Ochoa, Begoña, and Aspichueta, Patricia
- Published
- 2011
- Full Text
- View/download PDF
20. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice
- Author
-
Cano, Ainara, Buqué, Xabier, Martínez-Uña, Maite, Aurrekoetxea, Igor, Menor, Ariane, García-Rodríguez, Juan L., Lu, Shelly C., Martínez-Chantar, Luz M., Mato, José M., Ochoa, Begoña, and Aspichueta, Patricia
- Published
- 2010
- Full Text
- View/download PDF
21. Doxorubicin Increases Intracellular Diacylglycerol by the Mobilization of Choline-Enriched Phospholipids in Rat Hepatocytes
- Author
-
MARTÍNEZ, ROSA, NAVARRO, ROSAURA, MARTÍN, CÉSAR, AURREKOETXEA, IGOR, HERNÁNDEZ, M. LUISA, LACORT, MERCEDES, RUIZ-SANZ, JOSÉ IGNACIO, and RUIZ-LARREA, M. BEGOÑA
- Published
- 2002
22. Intracellular Diacylglycerol Accumulation Induced by Doxorubicin in Rat Hepatocytes: Potential Involvement of Phospholipases C and D
- Author
-
MARTÍNEZ, ROSA, NAVARRO, ROSAURA, MARTÍN, CÉSAR, AURREKOETXEA, IGOR, HERNÁNDEZ, M. LUISA, LACORT, MERCEDES, RUIZ-SANZ, JOSÉ IGNACIO, and RUIZ-LARREA, M. BEGOÑA
- Published
- 2002
23. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models
- Author
-
Dervan Peter A, Shelly Martin J, Aurrekoetxea Igor, Blanco Alfonso, Cottell David C, Hudson Lance, Donatello Simona, Kell Malcolm R, Stokes Maurice, Hill Arnold DK, and Hopkins Ann M
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Methods Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. Results Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. Conclusions Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.
- Published
- 2011
- Full Text
- View/download PDF
24. Liver osteopontin is required to prevent the progression of age‐related nonalcoholic fatty liver disease.
- Author
-
Gómez‐Santos, Beatriz, Saenz de Urturi, Diego, Nuñez‐García, Maitane, Gonzalez‐Romero, Francisco, Buque, Xabier, Aurrekoetxea, Igor, Gutiérrez de Juan, Virginia, Gonzalez‐Rellan, Maria J., García‐Monzón, Carmelo, González‐Rodríguez, Águeda, Mosteiro, Lorena, Errazti, Gaizka, Mifsut, Patricia, Gaztambide, Sonia, Castaño, Luis, Martin, Cesar, Nogueiras, Rubén, Martinez‐Chantar, María L., Syn, Wing‐Kin, and Aspichueta, Patricia
- Subjects
FATTY liver ,OSTEOPONTIN ,ANIMAL models for aging ,LIVER ,LIPID metabolism ,P53 antioncogene ,LIVER cells - Abstract
Osteopontin (OPN), a senescence‐associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age‐dependent hepatosteatosis. Thus, we investigated the role of OPN in the age‐related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild‐type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN‐deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN‐KO mice liver were associated with the decrease of 78 kDa glucose‐regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53‐OPN axis is required to inhibit the onset of age‐related hepatosteatosis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
25. PS-008-E2F2 mediated repression of fatty acid B-oxidation is mitigated through CREB1 in progressive non-alcoholic fatty liver disease
- Author
-
Gonzalez-Romero, Francisco, Mestre, Daniela, Aurrekoetxea, Igor, Urturi, Diego Sáenz de, Gomez-Santos, Beatriz, Nuñez-García, Maitane, Buqué, Xabier, Delgado, Igotz, Palomo-Irigoyen, Marta, Tamayo-Caro, Miguel, Woodhoo, Ashwin, Varela-Rey, Marta, Martínez-Chantar, María Luz, Iglesias, Ainhoa, Lee, Richard, Bhanot, Sanjay, Zubiaga, Ana, and Aspichueta, Patricia
- Published
- 2019
- Full Text
- View/download PDF
26. Role of aramchol in steatohepatitis and fibrosis in mice.
- Author
-
Iruarrizaga‐Lejarreta, Marta, Varela‐Rey, Marta, Fernández‐Ramos, David, Martínez‐Arranz, Ibon, Delgado, Teresa C., Simon, Jorge, Gutiérrez‐de Juan, Virginia, delaCruz‐Villar, Laura, Azkargorta, Mikel, Lavin, José L., Mayo, Rebeca, Van Liempd, Sebastiaan M., Aurrekoetxea, Igor, Buqué, Xabier, Delle Cave, Donatella, Peña, Arantza, Rodríguez‐Cuesta, Juan, Aransay, Ana M., Elortza, Felix, and Falcón‐Pérez, Juan M.
- Abstract
Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine‐ and choline‐deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of patients with NAFLD, which supports the potential use of Aramchol in NASH treatment. (Hepatology Communications 2017;1:911–927) [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
27. Ala16Val SOD2 polymorphism is associated with higher pregnancy rates in in vitro fertilization cycles
- Author
-
Ruiz-Sanz, José Ignacio, Aurrekoetxea, Igor, Matorras, Roberto, and Ruiz-Larrea, M. Begoña
- Subjects
- *
GENETIC polymorphisms , *GENETIC code , *UNIVERSITY hospitals , *FERTILIZATION in vitro , *REPRODUCTIVE technology , *MANGANESE , *SUPEROXIDE dismutase , *MITOCHONDRIA , *LONGITUDINAL method , *MEDICINE case studies - Abstract
Objective: To investigate whether the Ala16Val polymorphism in the SOD2 gene, encoding for mitochondrial manganese superoxide dismutase (SOD), is associated with [1] infertility and [2] the pregnancy rate (PR) in IVF cycles. Design: Prospective case-control study. Setting: Public university and public university hospital. Patient(s): A total of 362 newborns (nonselected population) and 148 infertile women undergoing an IVF cycle, from which 44 became pregnant and 104 did not. Intervention(s): Blood samples extracted from the patients and newborn umbilical cord. Main Outcome Measure(s): Genotype and allele distribution of the Ala16Val polymorphism in the SOD2 gene using the tetra-primer amplification refractory mutation system–polymerase chain reaction (PCR). Result(s): The polymorphism distribution of the subfertile women was similar to that of a nonselected population. The SOD2 Ala allele frequency was 49% both in controls and IVF patients. In IVF population the Ala/Ala SOD2 genotype was 25%, with a 28% Val/Val homozygous. In contrast, the Ala/Ala genotype was associated with higher PRs in IVF (47% in Ala/Ala vs. 23% in no Ala/Ala). A multivariate logistic regression analysis revealed that the Ala/Ala genotype was an independent predictor of pregnancy (odds ratio [OR] = 3.29), followed by the number of transferred embryos (OR = 2.37) and age (OR = 0.84). Conclusion(s): The Ala/Ala SOD2 genotype is a significant independent predictor of the occurrence of pregnancy in IVF. Data also support a role for antioxidant defense, particularly in the mitochondria, in conception in IVF. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
28. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models.
- Author
-
Donatello, Simona, Hudson, Lance, Cottell, David C., Blanco, Alfonso, Aurrekoetxea, Igor, Shelly, Martin J., Dervan, Peter A., Kell, Malcolm R., Stokes, Maurice, Hill, Arnold D. K., and Hopkins, Ann M.
- Subjects
CELL proliferation ,TUMORS ,BREAST cancer ,CANCER invasiveness ,SEX hormones ,STEROID hormones - Abstract
Background: Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Methods: Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. Results: Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. Conclusions: Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
29. Characterization of high-capacity adenovirus production by the quantitative real-time polymerase chain reaction: a comparative study of different titration methods.
- Author
-
Crettaz, Julien, Olague, Cristina, Vales, Africa, Aurrekoetxea, Igor, Berraondo, Pedro, Otano, Itziar, Kochanek, Stephan, Prieto, Jesús, and González-Aseguinolaza, Gloria
- Abstract
Background High-capacity adenoviruses (HC-Ad) hold great promise for the treatment of many diseases. The major drawbacks for the clinical application of this vector concern difficulties with respect to large-scale production, and the absence of standardized methods for production and titration. In the present study, we compare the different methods found in the literature for characterizing HC-Ad production. Methods Two productions of the HC-Ad carrying murine IL-12 gene were obtained. The viral titer and adenovirus-helper contamination as well as viral particle concentration of both productions were determined using different methods: (i) quantification of total viral particles by spectrophotometry and plaque assay to estimate first-generation (FG)-helper-Ad contamination; (ii) quantification of HC-Ad and FG-helper-Ad genomes by the quantitative polymerase chain reaction (qPCR) directly from viral stock; (iii) quantification of viral genomes after cell infection by the slot-blot hybridization assay and (iv) qPCR. Results Dramatic differences with respect to viral titer were found depending on the method used. The first method overestimates HC-Ad titer and underestimates FG-helper-Ad contamination and no information on the infectivity of the HC-Ad is obtained. qPCR analysis of viral stock is more sensitive and accurate, but information about infectivity remains unknown and FG-helper-Ad contamination is overestimated. Quantification of HC-Ad and FG-helper-Ad infectious units by-slot blot DNA hybridization and qPCR assay are found to be equally sensitive and accurate. Conclusions The results of the present study demonstrate that a standardized method should be developed for HC-Ad characterization for future clinical applications of this vector. Quantification of HC-Ad production by qPCR is a fast, safe and reliable method for determining HC-Ad and FG-helper-Ad particles and infectious units. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
30. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves.
- Author
-
Gomez-Sanchez, Jose A., Carty, Lucy, Iruarrizaga-Lejarreta, Marta, Palomo-Irigoyen, Marta, Varela-Rey, Marta, Griffith, Megan, Hantke, Janina, Macias-Camara, Nuria, Azkargorta, Mikel, Aurrekoetxea, Igor, De Juan, Virginia Gutiérrez, Jefferies, Harold B. J., Aspichueta, Patricia, Elortza, Félix, Aransay, Ana M., Martinez-Chantar, María L., Baas, Frank, Mato, José M., Mirsky, Rhona, and Woodhoo, Ashwin
- Subjects
- *
SCHWANN cells , *AUTOPHAGY , *MYELIN , *PERIPHERAL nervous system , *CYTOLOGICAL research - Abstract
Although Schwann cell myelin breakdown is the universal outcome of a remarkably wide range of conditions that cause disease or injury to peripheral nerves, the cellular and molecular mechanisms that make Schwann cell-mediated myelin digestion possible have not been established. We report that Schwann cells degrade myelin after injury by a novel form of selective autophagy, myelinophagy. Autophagy was up-regulated by myelinating Schwann cells after nerve injury, myelin debris was present in autophagosomes, and pharmacological and genetic inhibition of autophagy impaired myelin clearance. Myelinophagy was positively regulated by the Schwann cell JNK/c-Jun pathway, a central regulator of the Schwann cell reprogramming induced by nerve injury. We also present evidence that myelinophagy is defective in the injured central nervous system. These results reveal an important role for inductive autophagy during Wallerian degeneration, and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
31. Treatment of Chronic Viral Hepatitis in Woodchucks by Prolonged Intrahepatic Expression of Interleukin-12.
- Author
-
Crettaz, Julien, Otano, Itziar, Ochoa, Laura, Benito, Alberto, Paneda, Astrid, Aurrekoetxea, Igor, Berraondo, Pedro, Rodríguez-Madoz, Juan Roberto, Astudillo, Aurora, Kreppel, Florian, Kochanek, Stefan, Ruiz, Juan, Menne, Stephan, Prieto, Jesus, and Gonzalez-Aseguinolaza, Gloria
- Subjects
- *
HEPATITIS B , *LIVER diseases , *MORTALITY , *GENE therapy , *IMMUNOGLOBULINS , *IMMUNITY - Abstract
Chronic hepatitis B is a major cause of liver-related death worldwide. Interleukin-12 (IL-12) induction accompanies viral clearance in chronic hepatitis B virus infection. Here, we tested the therapeutic potential of IL-12 gene therapy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), an infection that closely resembles chronic hepatitis B. The woodchucks were treated by intrahepatic injection of a helper-dependent adenoviral vector encoding IL-12 under the control of a liver-specific RU486-responsive promoter. All woodchucks with viral loads below 1010 viral genomes (vg)/ml showed a marked and sustained reduction of viremia that was accompanied by a reduction in hepatic WHV DNA, a loss of e antigen and surface antigen, and improved liver histology. In contrast, none of the woodchucks with higher viremia levels responded to therapy. The antiviral effect was associated with the induction of T-cell immunity against viral antigens and a reduction of hepatic expression of Foxp3 in the responsive animals. Studies were performed in vitro to elucidate the resistance to therapy in highly viremic woodchucks. These studies showed that lymphocytes from healthy woodchucks or from animals with low viremia levels produced gamma interferon (IFN-γ) upon IL-12 stimulation, while lymphocytes from woodchucks with high viremia failed to upregulate IFN-γ in response to IL-12. In conclusion, IL-12-based gene therapy is an efficient approach to treat chronic hepadnavirus infection in woodchucks with viral loads below 1010 vg/ml. Interestingly, this therapy is able to break immunological tolerance to viral antigens in chronic WHV carriers. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
32. Pro-oxidant and antioxidant potential of catecholestrogens against ferrylmyoglobin-induced oxidative stress
- Author
-
Martınez, Rosa, Quintana, Kristina, Navarro, Rosaura, Martın, César, Hernández, M. Luisa, Aurrekoetxea, Igor, Ruiz-Sanz, José Ignacio, Lacort, Mercedes, and Ruiz-Larrea, M. Begoña
- Subjects
- *
HEMOPROTEINS , *CATECHOL estrogens , *LIPIDS - Abstract
Ferryl heme proteins may play a major role in vivo under certain pathological conditions. Catecholestrogens, the estradiol-derived metabolites, can act either as antioxidants or pro-oxidants in iron-dependent systems. The aim of the present work was (1) to determine the effects of ferrylmyoglobin on hepatocyte cytotoxicity, and (2) to assess the pro/antioxidant potential of a series of estrogens (phenolic, catecholic and stilbene-derived) against ferrylmyoglobin induced lipid peroxidation in rat hepatocytes. Cells were exposed to metmyoglobin plus hydrogen peroxide to form ferrylmyoglobin in the presence of the transition metal chelator diethylentriaminepentaacetic acid. Results showed that ferrylmyoglobin induced an initial oxidative stress, mainly reflected in an early lipid peroxidation and further decrease in GSH and ATP. However, cells gradually adapted to this situation, by recovering the endogenous ATP and GSH levels at longer incubation times. Phenolic and stilbene-derived estrogens inhibited ferrylmyoglobin-induced lipid peroxidation to different degrees: diethylstilbestrol>estradiol>resveratrol. Catecholestrogens at concentrations higher than 1 μM also inhibited lipid peroxidation with similar efficacy. The ability of estrogens to reduce ferrylmyoglobin to metmyoglobin may account for their antioxidant activity. In contrast, physiological concentrations (100 pM–100 nM) of the catecholestrogens exerted pro-oxidant activities, 4-hydroxyestradiol being more potent than 2-hydroxyestradiol. The implications of these interactions should be considered in situations where local myoglobin or hemoglobin microbleeding takes place. [Copyright &y& Elsevier]
- Published
- 2002
33. Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway.
- Author
-
Gil-Pitarch C, Serrano-Maciá M, Simon J, Mosca L, Conter C, Rejano-Gordillo CM, Zapata-Pavas LE, Peña-Sanfélix P, Azkargorta M, Rodríguez-Agudo R, Lachiondo-Ortega S, Mercado-Gómez M, Delgado TC, Porcelli M, Aurrekoetxea I, Sutherland JD, Barrio R, Xirodimas D, Aspichueta P, Elortza F, Martínez-Cruz LA, Nogueiras R, Iruzubieta P, Crespo J, Masson S, McCain MV, Reeves HL, Andrade RJ, Lucena MI, Mayor U, Goikoetxea-Usandizaga N, González-Recio I, and Martínez-Chantar ML
- Subjects
- Animals, Humans, Mice, Male, Liver metabolism, Liver pathology, Liver drug effects, Mice, Inbred C57BL, Mice, Transgenic, Hepatocytes metabolism, Hepatocytes drug effects, Hepatocytes pathology, Signal Transduction drug effects, Ubiquitin-Activating Enzymes metabolism, Ubiquitin-Activating Enzymes genetics, Ubiquitin-Activating Enzymes antagonists & inhibitors, Acetaminophen adverse effects, NEDD8 Protein metabolism, NEDD8 Protein genetics, Pyrimidines pharmacology, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Chemical and Drug Induced Liver Injury drug therapy, Cardiolipins metabolism, Cyclopentanes pharmacology
- Abstract
Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (
bio NEDD8) and ubiquitin (bio UB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
34. In Vivo Hepatic Triglyceride Secretion Rate in Antisense Oligonucleotide (ASO)-Treated Mice.
- Author
-
Gomez-Santos B, Saenz de Urturi D, Buqué X, Aurrekoetxea I, Nieva A, Fernández-Puertas I, and Aspichueta P
- Subjects
- Mice, Animals, Triglycerides metabolism, Oligonucleotides, Antisense genetics, Oligonucleotides, Antisense metabolism, Liver metabolism, Lipoproteins, VLDL metabolism, Fatty Liver metabolism
- Abstract
The liver is a central organ in regulating the whole body metabolic homeostasis, and, among many other processes, it plays a crucial role in lipoprotein metabolism. The liver controls the secretion of very-low-density lipoproteins (VLDLs), particles specialized in the transport of liver lipids, mainly triglycerides (TGs), to the adipose tissue, heart, and muscle, among other tissues, providing fatty acids to be stored or to be used as an energy source. The analysis of this metabolic process provides relevant information about the crosstalk between the liver and other organs. It also helps to identify how the liver is able to secrete lipids to reduce its accumulation. This protocol shows how to analyze the liver TG secretion rate blocking the VLDL clearance from the blood by the administration of poloxamer 407. In addition, it shows how to isolate the VLDL produced by the liver at the end of the experiment, so that the apolipoprotein and lipid content and size can be measured. Using antisense oligonucleotides (ASOs) for silencing target proteins involved in metabolic diseases has emerged as a new promising therapeutic approach. Thus, the usage of ASOs has also been included in this protocol. As a conclusion, evaluation of TG secretion rate in mice provides key information to understand the organ crosstalk in metabolic diseases and the capacity of the liver to secrete lipids to blood., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
35. In Vivo Tissue Lipid Uptake in Antisense Oligonucleotide (ASO)-Treated Mice.
- Author
-
Aurrekoetxea I, Gomez-Santos B, Apodaka-Biguri M, Ruiz de Gauna M, Gonzalez-Romero F, Buqué X, and Aspichueta P
- Subjects
- Mice, Animals, Triglycerides metabolism, Fatty Acids metabolism, Obesity genetics, Mice, Inbred C57BL, Oligonucleotides, Antisense genetics, Dietary Fats
- Abstract
The prevalence of obesity has increased to pandemic levels over the past years. Associated comorbidities linked with the accumulation of lipids in different tissues and blood are responsible for the high mortality in these patients. The increased dietary lipid uptake contributes to these metabolic diseases. Identifying which pathways might be dysregulated in these patients will contribute to find new therapeutic targets. Thus, here, a protocol to follow up the distribution of dietary lipids in blood and tissues is provided. For this, radiolabeled triglyceride in olive oil is administered by oral gavage. To ascertain more precisely the capacity of each tissue for fatty acid uptake, not considering the intestinal barrier, the intravenous (IV) administration of radiolabeled lipids is also described., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
- Full Text
- View/download PDF
36. E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment.
- Author
-
González-Romero F, Mestre D, Aurrekoetxea I, O'Rourke CJ, Andersen JB, Woodhoo A, Tamayo-Caro M, Varela-Rey M, Palomo-Irigoyen M, Gómez-Santos B, de Urturi DS, Núñez-García M, García-Rodríguez JL, Fernández-Ares L, Buqué X, Iglesias-Ara A, Bernales I, De Juan VG, Delgado TC, Goikoetxea-Usandizaga N, Lee R, Bhanot S, Delgado I, Perugorria MJ, Errazti G, Mosteiro L, Gaztambide S, Martinez de la Piscina I, Iruzubieta P, Crespo J, Banales JM, Martínez-Chantar ML, Castaño L, Zubiaga AM, and Aspichueta P
- Subjects
- Animals, Carcinogens, Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular metabolism, Carnitine O-Palmitoyltransferase genetics, Carnitine O-Palmitoyltransferase metabolism, Diet, High-Fat adverse effects, E2F1 Transcription Factor genetics, E2F2 Transcription Factor genetics, Gene Expression Regulation, Liver Neoplasms etiology, Liver Neoplasms metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Prognosis, Promoter Regions, Genetic, Carcinoma, Hepatocellular pathology, Carnitine O-Palmitoyltransferase antagonists & inhibitors, E2F1 Transcription Factor metabolism, E2F2 Transcription Factor metabolism, Lipids analysis, Liver Neoplasms pathology, Non-alcoholic Fatty Liver Disease complications
- Abstract
Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. E2f1
-/- and E2f2-/- mice were resistant to DEN-HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN-HFD in E2f1-/- and E2f2-/- mice enhanced fatty acid oxidation (FAO) and increased expression of Cpt2 , an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN-HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1-E2F2-CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis. SIGNIFICANCE: These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2874/F1.large.jpg., (©2021 American Association for Cancer Research.)- Published
- 2021
- Full Text
- View/download PDF
37. Involvement of G-463A MPO gene polymorphism in the response of postmenopausal women to hormone therapy.
- Author
-
del Agua AR, Aurrekoetxea I, Elorriaga MA, Rodriguez F, Guéraud F, Ruiz-Larrea MB, and Ruiz-Sanz JI
- Subjects
- Acetylcysteine analogs & derivatives, Acetylcysteine urine, Antioxidants analysis, Female, Humans, Intercellular Adhesion Molecule-1 blood, Lipids blood, Malondialdehyde blood, Middle Aged, Postmenopause genetics, Raloxifene Hydrochloride therapeutic use, Selective Estrogen Receptor Modulators therapeutic use, Uric Acid blood, alpha-Tocopherol blood, Estradiol therapeutic use, Hormone Replacement Therapy methods, Peroxidase genetics, Polymorphism, Genetic, Postmenopause drug effects, Progesterone therapeutic use
- Abstract
Objective: The aims of this work were to determine (1) the effects of estrogen plus progestogen therapy (EPT) and raloxifene on oxidative stress and cardiovascular risk biomarkers in postmenopausal women and (2) the involvement of the functional G-463A polymorphism of the myeloperoxidase (MPO) gene in the therapy responses., Methods: Postmenopausal women (45-55 y old) were assigned to three groups receiving (1) EPT (continuous 50 μg transdermal estradiol daily and 200 mg/d micronized progesterone orally the first 14 d of each month; n = 21), (2) raloxifene (60 mg daily; n = 17), and (3) no treatment (control; n = 21). Blood and urine samples were taken before and after 6 months of therapy. Measurements were serum lipid profile, C-reactive intercellular adhesion molecule 1 (ICAM-1), α-tocopherol, γ-tocopherol, uric acid, total antioxidant activity (TAA), malondialdehyde, and urinary 1,4-dihydroxynonane-mercapturic acid (the major urinary 4-hydroxynonenal metabolite). The G-463A MPO polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism., Results: EPT significantly decreased TAA and the levels of ICAM-1, not modifying other cardiovascular risk or oxidative stress markers. The raloxifene and control groups experienced no modifications in oxidative stress or endothelial dysfunction markers. The MPO genotype specifically influenced the outcomes in the EPT group. Thus, TAA decreased significantly in GG (high-expression genotype) homozygotes, whereas ICAM-1 levels were reduced in A allele carriers., Conclusions: EPT exerted a negative action on the serum oxidant/antioxidant balance in the MPO GG homozygotes and a positive effect on the ICAM-1 endothelial dysfunction marker in carriers of the low-expression A allele. This observation provides evidence of the importance of this polymorphism in the response to EPT.
- Published
- 2011
- Full Text
- View/download PDF
38. Pro-oxidant and antioxidant potential of catecholestrogens against ferrylmyoglobin-induced oxidative stress.
- Author
-
Martínez R, Quintana K, Navarro R, Martín C, Hernández ML, Aurrekoetxea I, Ruiz-Sanz JI, Lacort M, and Ruiz-Larrea MB
- Subjects
- Animals, Hepatocytes drug effects, Hepatocytes metabolism, Lipid Peroxidation drug effects, Male, Rats, Rats, Sprague-Dawley, Antioxidants pharmacology, Estrogens, Catechol pharmacology, Metmyoglobin pharmacology, Oxidative Stress, Reactive Oxygen Species pharmacology
- Abstract
Ferryl heme proteins may play a major role in vivo under certain pathological conditions. Catecholestrogens, the estradiol-derived metabolites, can act either as antioxidants or pro-oxidants in iron-dependent systems. The aim of the present work was (1) to determine the effects of ferrylmyoglobin on hepatocyte cytotoxicity, and (2) to assess the pro/antioxidant potential of a series of estrogens (phenolic, catecholic and stilbene-derived) against ferrylmyoglobin induced lipid peroxidation in rat hepatocytes. Cells were exposed to metmyoglobin plus hydrogen peroxide to form ferrylmyoglobin in the presence of the transition metal chelator diethylentriaminepentaacetic acid. Results showed that ferrylmyoglobin induced an initial oxidative stress, mainly reflected in an early lipid peroxidation and further decrease in GSH and ATP. However, cells gradually adapted to this situation, by recovering the endogenous ATP and GSH levels at longer incubation times. Phenolic and stilbene-derived estrogens inhibited ferrylmyoglobin-induced lipid peroxidation to different degrees: diethylstilbestrol>estradiol>resveratrol. Catecholestrogens at concentrations higher than 1 microM also inhibited lipid peroxidation with similar efficacy. The ability of estrogens to reduce ferrylmyoglobin to metmyoglobin may account for their antioxidant activity. In contrast, physiological concentrations (100 pM-100 nM) of the catecholestrogens exerted pro-oxidant activities, 4-hydroxyestradiol being more potent than 2-hydroxyestradiol. The implications of these interactions should be considered in situations where local myoglobin or hemoglobin microbleeding takes place.
- Published
- 2002
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.