42 results on '"García-Domínguez, Irene"'
Search Results
2. Cricket Protein as an Innovative Emulsifier for Avocado Oil: Formulation and Characterization of Sustainable Emulsions
- Author
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Trujillo-Cayado, Luis A., primary, García-Domínguez, Irene, additional, Rodríguez-Luna, Azahara, additional, Hurtado-Fernández, Elena, additional, and Santos, Jenifer, additional
- Published
- 2024
- Full Text
- View/download PDF
3. Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour
- Author
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García-Domínguez, Irene, Suárez-Pereira, Irene, Santiago, Marti, Pérez-Villegas, Eva M., Bravo, Lidia, López-Martín, Carolina, Roca-Ceballos, María Angustias, García-Revilla, Juan, Espinosa-Oliva, Ana M., Rodríguez-Gómez, José A., Joseph, Bertrand, Berrocoso, Esther, Armengol, José Ángel, Venero, José L., Ruiz, Rocío, and de Pablos, Rocío M.
- Published
- 2021
- Full Text
- View/download PDF
4. Cricket Protein as an Innovative Emulsifier for Avocado Oil: Formulation and Characterization of Sustainable Emulsions
- Author
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Universidad de Sevilla. Departamento de Ingeniería Química, Trujillo-Cayado, Luis Alfonso, García Domínguez, Irene, Rodríguez Luna, Azahara María, Hurtado-Fernández, Elena, Santos García, Jenifer, Universidad de Sevilla. Departamento de Ingeniería Química, Trujillo-Cayado, Luis Alfonso, García Domínguez, Irene, Rodríguez Luna, Azahara María, Hurtado-Fernández, Elena, and Santos García, Jenifer
- Abstract
The use of cricket protein in emulsions is in line with the growing interest in sustainable food sources, as crickets require minimal resources and produce lower greenhouse gas emissions than traditional livestock. Research in this area suggests that incorporating cricket protein into emulsions not only improves their nutritional value but also contributes to the development of environmentally friendly and functional food products. This study proposes the use of cricket protein for the stabilization of emulsions formulated with avocado oil as a dispersed phase. This oil is rich in monounsaturated fats, particularly oleic acid, and a variety of bioactive compounds. In the first part of this study, we assessed the influence of the emulsifier concentration and found that 2 wt.% is the optimum because a depletion flocculation effect was produced. Subsequently, processing was optimized using ultrasonication so that the higher energy input produced emulsions with a droplet diameter of less than 700 nm. Finally, rhamsan gum was added to the formulation, producing emulgels with improved pseudoplastic behavior and physical stability. This study demonstrates that cricket protein in combination with rhamsan gum is capable of forming stable, low-droplet-size emulgels with potential applications in encapsulation systems.
- Published
- 2024
5. HERC1 Ubiquitin Ligase Is Required for Normal Axonal Myelination in the Peripheral Nervous System
- Author
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Bachiller, Sara, Roca-Ceballos, María Angustias, García-Domínguez, Irene, Pérez-Villegas, Eva María, Martos-Carmona, David, Pérez-Castro, Miguel Ángel, Real, Luis Miguel, Rosa, José Luis, Tabares, Lucía, Venero, José Luis, Armengol, José Ángel, Carrión, Ángel Manuel, and Ruiz, Rocío
- Published
- 2018
- Full Text
- View/download PDF
6. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
- Author
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Stratoulias, Vassilis, primary, Ruiz, Rocío, additional, Kanatani, Shigeaki, additional, Osman, Ahmed M., additional, Keane, Lily, additional, Armengol, Jose A., additional, Rodríguez-Moreno, Antonio, additional, Murgoci, Adriana-Natalia, additional, García-Domínguez, Irene, additional, Alonso-Bellido, Isabel, additional, González Ibáñez, Fernando, additional, Picard, Katherine, additional, Vázquez-Cabrera, Guillermo, additional, Posada-Pérez, Mercedes, additional, Vernoux, Nathalie, additional, Tejera, Dario, additional, Grabert, Kathleen, additional, Cheray, Mathilde, additional, González-Rodríguez, Patricia, additional, Pérez-Villegas, Eva M., additional, Martínez-Gallego, Irene, additional, Lastra-Romero, Alejandro, additional, Brodin, David, additional, Avila-Cariño, Javier, additional, Cao, Yang, additional, Airavaara, Mikko, additional, Uhlén, Per, additional, Heneka, Michael T., additional, Tremblay, Marie-Ève, additional, Blomgren, Klas, additional, Venero, Jose L., additional, and Joseph, Bertrand, additional
- Published
- 2023
- Full Text
- View/download PDF
7. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
- Author
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Stratoulias, Vassilis, Ruiz, Rocío, Kanatani, Shigeaki, Osman, Ahmed M., Keane, Lily, Armengol, Jose A., Rodríguez-Moreno, Antonio, Murgoci, Adriana-Natalia, García-Domínguez, Irene, Alonso-Bellido, Isabel, González Ibáñez, Fernando, Picard, Katherine, Vázquez-Cabrera, Guillermo, Posada-Pérez, Mercedes, Vernoux, Nathalie, Tejera, Dario, Grabert, Kathleen, Cheray, Mathilde, González-Rodríguez, Patricia, Pérez-Villegas, Eva M., Martínez-Gallego, Irene, Lastra-Romero, Alejandro, Brodin, David, Avila-Cariño, Javier, Cao, Yang, Airavaara, Mikko, Uhlén, Per, Heneka, Michael T., Tremblay, Marie-Ève, Blomgren, Klas, Venero, Jose L., Joseph, Bertrand, Stratoulias, Vassilis, Ruiz, Rocío, Kanatani, Shigeaki, Osman, Ahmed M., Keane, Lily, Armengol, Jose A., Rodríguez-Moreno, Antonio, Murgoci, Adriana-Natalia, García-Domínguez, Irene, Alonso-Bellido, Isabel, González Ibáñez, Fernando, Picard, Katherine, Vázquez-Cabrera, Guillermo, Posada-Pérez, Mercedes, Vernoux, Nathalie, Tejera, Dario, Grabert, Kathleen, Cheray, Mathilde, González-Rodríguez, Patricia, Pérez-Villegas, Eva M., Martínez-Gallego, Irene, Lastra-Romero, Alejandro, Brodin, David, Avila-Cariño, Javier, Cao, Yang, Airavaara, Mikko, Uhlén, Per, Heneka, Michael T., Tremblay, Marie-Ève, Blomgren, Klas, Venero, Jose L., and Joseph, Bertrand
- Abstract
Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1– microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
- Published
- 2023
- Full Text
- View/download PDF
8. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Ciencia e Innovación (MICIN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Junta de Andalucía, Universidad de Sevilla, Stratoulias, Vassilis, Ruiz Laza, Agustín, Kanatani, Shigeaki, Osman, Ahmed Mohamed, Keane, Lily, Armengol, Jose A., García Domínguez, Irene, Alonso Bellido, Isabel María, Venero Recio, José Luis, Joseph, Bertrand, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Ciencia e Innovación (MICIN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Junta de Andalucía, Universidad de Sevilla, Stratoulias, Vassilis, Ruiz Laza, Agustín, Kanatani, Shigeaki, Osman, Ahmed Mohamed, Keane, Lily, Armengol, Jose A., García Domínguez, Irene, Alonso Bellido, Isabel María, Venero Recio, José Luis, and Joseph, Bertrand
- Abstract
Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1– microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
- Published
- 2023
9. ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain
- Author
-
Karolinska Institute, Swedish Research Council, Swedish Brain Foundation, Sigrid Juselius Foundation, Academy of Finland, Swedish Cultural Foundation, Swedish Cancer Society, Consejo Nacional de Ciencia y Tecnología (México), Fonds de la Recherche en Sante du Québec, Wenner-Gren Foundation, Ake Wiberg Foundation, Ministerio de Ciencia e Innovación (España), European Commission, Junta de Andalucía, Swedish Childhood Cancer Foundation, Canada Research Chairs, Stratoulias, Vassilis, Ruiz, Rocío, Kanatani, Shigeaki, Osman, Ahmed M., Keane, Lily, Armengol, José Ángel, Rodríguez-Moreno, Antonio, Murgoci, Adriana-Natalia, García-Domínguez, Irene, Alonso-Bellido, Isabel María, González Ibáñez, Fernando, Picard, Katherine, Vázquez Cabrera, Guillermo, Posada-Pérez, Mercedes, Vernoux, Nathalie, Tejera, Dario, Grabert, Kathleen, Cheray, Mathilde, González-Rodríguez, Patricia, Pérez-Villegas, Eva María, Martínez-Gallego, Irene, Lastra-Romero, Alejandro, Brodin, David, Ávila-Cariño, Javier, Cao, Yang, Airavaara, Mikko, Uhlén, Per, Heneka, Michael T., Tremblay, Marie-Ève, Blomgren, Klas, Venero, José L., Joseph, Bertrand, Karolinska Institute, Swedish Research Council, Swedish Brain Foundation, Sigrid Juselius Foundation, Academy of Finland, Swedish Cultural Foundation, Swedish Cancer Society, Consejo Nacional de Ciencia y Tecnología (México), Fonds de la Recherche en Sante du Québec, Wenner-Gren Foundation, Ake Wiberg Foundation, Ministerio de Ciencia e Innovación (España), European Commission, Junta de Andalucía, Swedish Childhood Cancer Foundation, Canada Research Chairs, Stratoulias, Vassilis, Ruiz, Rocío, Kanatani, Shigeaki, Osman, Ahmed M., Keane, Lily, Armengol, José Ángel, Rodríguez-Moreno, Antonio, Murgoci, Adriana-Natalia, García-Domínguez, Irene, Alonso-Bellido, Isabel María, González Ibáñez, Fernando, Picard, Katherine, Vázquez Cabrera, Guillermo, Posada-Pérez, Mercedes, Vernoux, Nathalie, Tejera, Dario, Grabert, Kathleen, Cheray, Mathilde, González-Rodríguez, Patricia, Pérez-Villegas, Eva María, Martínez-Gallego, Irene, Lastra-Romero, Alejandro, Brodin, David, Ávila-Cariño, Javier, Cao, Yang, Airavaara, Mikko, Uhlén, Per, Heneka, Michael T., Tremblay, Marie-Ève, Blomgren, Klas, Venero, José L., and Joseph, Bertrand
- Abstract
Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1+ microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1+ microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe, Clec7a, Igf1, Lgals3 and Mgl2, compared to ARG1- microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions.
- Published
- 2023
10. The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, Junta de Andalucía, Instituto de Salud Carlos III, European Union (UE), Suárez Pereira, Irene, García Domínguez, Irene, Bravo, L., Santiago Pavón, Martiniano, García Revilla, Juan, Espinosa Oliva, Ana María, Alonso Bellido, Isabel María, López Martín, César, Pérez Villegas, Eva María, Armengol, J. A., Berrocoso, E., Venero Recio, José Luis, Martínez de Pablos, Rocío, Ruiz Laza, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, Junta de Andalucía, Instituto de Salud Carlos III, European Union (UE), Suárez Pereira, Irene, García Domínguez, Irene, Bravo, L., Santiago Pavón, Martiniano, García Revilla, Juan, Espinosa Oliva, Ana María, Alonso Bellido, Isabel María, López Martín, César, Pérez Villegas, Eva María, Armengol, J. A., Berrocoso, E., Venero Recio, José Luis, Martínez de Pablos, Rocío, and Ruiz Laza, Rocío
- Abstract
In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.
- Published
- 2022
11. Gal3 Plays a Deleterious Role in a Mouse Model of Endotoxemia
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Fernández Martín, Juan Carlos, Espinosa Oliva, Ana María, García Domínguez, Irene, Rosado Sánchez, Isaac, Pacheco, Yolanda M., Moyano, Rosario, Monterde, José G., Venero Recio, José Luis, Martínez de Pablos, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Fernández Martín, Juan Carlos, Espinosa Oliva, Ana María, García Domínguez, Irene, Rosado Sánchez, Isaac, Pacheco, Yolanda M., Moyano, Rosario, Monterde, José G., Venero Recio, José Luis, and Martínez de Pablos, Rocío
- Abstract
Lipopolysaccharide (LPS)-induced endotoxemia induces an acute systemic inflammatory response that mimics some important features of sepsis, the disease with the highest mortality rate worldwide. In this work, we have analyzed a murine model of endotoxemia based on a single intraperitoneal injection of 5 mg/kg of LPS. We took advantage of galectin-3 (Gal3) knockout mice and found that the absence of Gal3 decreased the mortality rate oflethal endotoxemia in the first 80 h after the administration of LPS, along with a reduction in the tissular damage in several organs measured by electron microscopy. Using flow cytometry, we demonstrated that, in control conditions, peripheral immune cells, especially monocytes, exhibited high levels of Gal3, which were early depleted in response to LPS injection, thus suggesting Gal3 release under endotoxemia conditions. However, serum levels of Gal3 early decreased in response to LPS challenge (1 h), an indication that Gal3 may be extravasated to peripheral organs. Indeed, analysis of Gal3 in peripheral organs revealed a robust up-regulation of Gal3 36 h after LPS injection. Taken together, these results demonstrate the important role that Gal3 could play in the development of systemic inflammation, a well-established feature of sepsis, thus opening new and promising therapeutic options for these harmful conditions.
- Published
- 2022
12. The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior
- Author
-
Ministerio de Economía y Competitividad (España), Junta de Andalucía, European Commission, Plan Nacional sobre Drogas (España), Ministerio de Sanidad (España), Instituto de Salud Carlos III, Campus de Excelencia Internacional del Mar (España), Instituto de Investigación e Innovación Biomédica de Cádiz, Universidad de Sevilla, Suárez-Pereira, Irene, García-Domínguez, Irene, Bravo, Lidia, Santiago, Marti, García-Revilla, Juan, Espinosa-Oliva, Ana M., Alonso-Bellido, Isabel María, López-Martín, Carolina, Pérez-Villegas, Eva María, Armengol, José Ángel, Berrocoso, Esther, Venero, José L., Pablos, Rocío M. de, Ruiz, Rocío, Ministerio de Economía y Competitividad (España), Junta de Andalucía, European Commission, Plan Nacional sobre Drogas (España), Ministerio de Sanidad (España), Instituto de Salud Carlos III, Campus de Excelencia Internacional del Mar (España), Instituto de Investigación e Innovación Biomédica de Cádiz, Universidad de Sevilla, Suárez-Pereira, Irene, García-Domínguez, Irene, Bravo, Lidia, Santiago, Marti, García-Revilla, Juan, Espinosa-Oliva, Ana M., Alonso-Bellido, Isabel María, López-Martín, Carolina, Pérez-Villegas, Eva María, Armengol, José Ángel, Berrocoso, Esther, Venero, José L., Pablos, Rocío M. de, and Ruiz, Rocío
- Abstract
In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.
- Published
- 2022
13. Gal3 Plays a Deleterious Role in a Mouse Model of Endotoxemia
- Author
-
Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, Instituto de Salud Carlos III, Fernández-Martín, Juan Carlos, Espinosa-Oliva, Ana M., García-Domínguez, Irene, Rosado-Sánchez, Isaac, Pacheco, Yolanda M., Moyano, Rosario, García Monterde, José, Venero, José L., Pablos, Rocío M. de, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, Instituto de Salud Carlos III, Fernández-Martín, Juan Carlos, Espinosa-Oliva, Ana M., García-Domínguez, Irene, Rosado-Sánchez, Isaac, Pacheco, Yolanda M., Moyano, Rosario, García Monterde, José, Venero, José L., and Pablos, Rocío M. de
- Abstract
Lipopolysaccharide (LPS)-induced endotoxemia induces an acute systemic inflammatory response that mimics some important features of sepsis, the disease with the highest mortality rate worldwide. In this work, we have analyzed a murine model of endotoxemia based on a single intraperitoneal injection of 5 mg/kg of LPS. We took advantage of galectin-3 (Gal3) knockout mice and found that the absence of Gal3 decreased the mortality rate oflethal endotoxemia in the first 80 h after the administration of LPS, along with a reduction in the tissular damage in several organs measured by electron microscopy. Using flow cytometry, we demonstrated that, in control conditions, peripheral immune cells, especially monocytes, exhibited high levels of Gal3, which were early depleted in response to LPS injection, thus suggesting Gal3 release under endotoxemia conditions. However, serum levels of Gal3 early decreased in response to LPS challenge (1 h), an indication that Gal3 may be extravasated to peripheral organs. Indeed, analysis of Gal3 in peripheral organs revealed a robust up-regulation of Gal3 36 h after LPS injection. Taken together, these results demonstrate the important role that Gal3 could play in the development of systemic inflammation, a well-established feature of sepsis, thus opening new and promising therapeutic options for these harmful conditions.
- Published
- 2022
14. Gal3 Plays a Deleterious Role in a Mouse Model of Endotoxemia
- Author
-
Fernández-Martín, Juan Carlos, primary, Espinosa-Oliva, Ana María, additional, García-Domínguez, Irene, additional, Rosado-Sánchez, Isaac, additional, Pacheco, Yolanda M., additional, Moyano, Rosario, additional, Monterde, José G., additional, Venero, José Luis, additional, and de Pablos, Rocío M., additional
- Published
- 2022
- Full Text
- View/download PDF
15. Galectin-3 Deletion Reduces LPS and Acute Colitis-Induced Pro-Inflammatory Microglial Activation in the Ventral Mesencephalon
- Author
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Espinosa-Oliva, Ana M., primary, García-Miranda, Pablo, additional, Alonso-Bellido, Isabel María, additional, Carvajal, Ana E., additional, González-Rodríguez, Melania, additional, Carrillo-Jiménez, Alejandro, additional, Temblador, Arturo J., additional, Felices-Navarro, Manuel, additional, García-Domínguez, Irene, additional, Roca-Ceballos, María Angustias, additional, Vázquez-Carretero, María D., additional, García-Revilla, Juan, additional, Santiago, Marti, additional, Peral, María J., additional, Venero, José Luis, additional, and de Pablos, Rocío M., additional
- Published
- 2021
- Full Text
- View/download PDF
16. Arg1+ microglia are critical for shaping cognition in female mice
- Author
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Stratoulias, Vassilis, primary, Ruiz, Rocío, additional, Kanatani, Shigeaki, additional, Osman, Ahmed M., additional, Armengol, Jose A., additional, Rodríguez-Moreno, Antonio, additional, Murgoci, Adriana-Natalia, additional, García-Domínguez, Irene, additional, Keane, Lily, additional, Vázquez-Cabrera, Guillermo, additional, Alonso-Bellido, Isabel, additional, Vernoux, Nathalie, additional, Tejera, Dario, additional, Grabert, Kathleen, additional, Cheray, Mathilde, additional, González-Rodríguez, Patricia, additional, Pérez-Villegas, Eva M., additional, Martinez-Gallego, Irene, additional, Brodin, David, additional, Avila-Cariño, Javier, additional, Airavaara, Mikko, additional, Uhlén, Per, additional, Heneka, Michael T., additional, Tremblay, Marie-Ève, additional, Blomgren, Klas, additional, Venero, Jose L., additional, and Joseph, Bertrand, additional
- Published
- 2021
- Full Text
- View/download PDF
17. Galectin-3 Deletion Reduces LPS and Acute Colitis-Induced Pro-Inflammatory Microglial Activation in the Ventral Mesencephalon
- Author
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Espinosa Oliva, Ana María, García Miranda, Pablo, Alonso Bellido, Isabel María, Carvajal Vázquez, Ana Eloisa, González Rodríguez, Melania, Carrillo Jiménez, Alejandro, García Domínguez, Irene, Vázquez Carretero, María Dolores, García Revilla, Juan, Santiago Pavón, Martiniano, Peral Rubio, María José, Venero Recio, José Luis, Martínez de Pablos, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla. Departamento de Fisiología, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, and Junta de Andalucía
- Subjects
Neuroinflammation ,Parkinson’s disease ,Peripheral inflammation ,Galectin-3 ,Microglia - Abstract
Parkinson’s disease is a highly prevalent neurological disorder for which there is currently no cure. Therefore, the knowledge of risk factors as well as the development of new putative molecular targets is mandatory. In this sense, peripheral inflammation, especially the originated in the colon, is emerging as a predisposing factor for suffering this disease. We have largely studied the pleiotropic roles of galectin-3 in driving microglia-associated immune responses. However, studies aimed at elucidating the role of galectin-3 in peripheral inflammation in terms of microglia polarization are lacking. To achieve this, we have evaluated the effect of galectin-3 deletion in two different models of acute peripheral inflammation: intraperitoneal injection of lipopolysaccharide or gut inflammation induced by oral administration of dextran sodium sulfate. We found that under peripheral inflammation the number of microglial cells and the expression levels of pro-inflammatory mediators take place specifically in the dopaminergic system, thus supporting causative links between Parkinson’s disease and peripheral inflammation. Absence of galectin-3 highly reduced neuroinflammation in both models, suggesting an important central regulatory role of galectin-3 in driving microglial activation provoked by the peripheral inflammation. Thus, modulation of galectin-3 function emerges as a promising strategy to minimize undesired microglia polarization states. Ministerio de Ciencia, Innovación y Universidades RTI 2018-098830-B-I00 Junta de Andalucía P18-RT-1372, US-1264806 and CTS 5884
- Published
- 2021
18. Galectin-3 Deletion Reduces LPS and Acute Colitis-Induced Pro-Inflammatory Microglial Activation in the Ventral Mesencephalon
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla. Departamento de Fisiología, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Junta de Andalucía, Espinosa Oliva, Ana María, García Miranda, Pablo, Alonso Bellido, Isabel María, Carvajal Vázquez, Ana Eloisa, González Rodríguez, Melania, Carrillo Jiménez, Alejandro, García Domínguez, Irene, Vázquez Carretero, María Dolores, García Revilla, Juan, Santiago Pavón, Martiniano, Peral Rubio, María José, Venero Recio, José Luis, Martínez de Pablos, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla. Departamento de Fisiología, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Junta de Andalucía, Espinosa Oliva, Ana María, García Miranda, Pablo, Alonso Bellido, Isabel María, Carvajal Vázquez, Ana Eloisa, González Rodríguez, Melania, Carrillo Jiménez, Alejandro, García Domínguez, Irene, Vázquez Carretero, María Dolores, García Revilla, Juan, Santiago Pavón, Martiniano, Peral Rubio, María José, Venero Recio, José Luis, and Martínez de Pablos, Rocío
- Abstract
Parkinson’s disease is a highly prevalent neurological disorder for which there is currently no cure. Therefore, the knowledge of risk factors as well as the development of new putative molecular targets is mandatory. In this sense, peripheral inflammation, especially the originated in the colon, is emerging as a predisposing factor for suffering this disease. We have largely studied the pleiotropic roles of galectin-3 in driving microglia-associated immune responses. However, studies aimed at elucidating the role of galectin-3 in peripheral inflammation in terms of microglia polarization are lacking. To achieve this, we have evaluated the effect of galectin-3 deletion in two different models of acute peripheral inflammation: intraperitoneal injection of lipopolysaccharide or gut inflammation induced by oral administration of dextran sodium sulfate. We found that under peripheral inflammation the number of microglial cells and the expression levels of pro-inflammatory mediators take place specifically in the dopaminergic system, thus supporting causative links between Parkinson’s disease and peripheral inflammation. Absence of galectin-3 highly reduced neuroinflammation in both models, suggesting an important central regulatory role of galectin-3 in driving microglial activation provoked by the peripheral inflammation. Thus, modulation of galectin-3 function emerges as a promising strategy to minimize undesired microglia polarization states.
- Published
- 2021
19. Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Instituto de Salud Carlos III, Junta de Andalucía, García Domínguez, Irene, Suárez Pereira, Irene, Santiago Pavón, Martiniano, Pérez Villegas, Eva M., Bravo, Lidia, López Martín, Carolina, Roca Ceballos, María Angustias, García Revilla, Juan, Espinosa Oliva, Ana María, Rodríguez Gómez, José Antonio, Joseph, Bertrand, Berrocoso, Esther, Armengol, José Ángel, Venero Recio, José Luis, Ruiz Laza, Rocío, Martínez de Pablos, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Instituto de Salud Carlos III, Junta de Andalucía, García Domínguez, Irene, Suárez Pereira, Irene, Santiago Pavón, Martiniano, Pérez Villegas, Eva M., Bravo, Lidia, López Martín, Carolina, Roca Ceballos, María Angustias, García Revilla, Juan, Espinosa Oliva, Ana María, Rodríguez Gómez, José Antonio, Joseph, Bertrand, Berrocoso, Esther, Armengol, José Ángel, Venero Recio, José Luis, Ruiz Laza, Rocío, and Martínez de Pablos, Rocío
- Abstract
Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing. Here, we have analysed the effect of caspase-3 depletion on the development of catecholaminergic neurons and performed a wide array of neurochemical, ultrastructural and behavioural assays. To achieve this, we performed selective deletion of the Casp3 gene in tyrosine hydroxylase (TH)-expressing cells using Cre-loxP-mediated recombination. Histological evaluation of most relevant catecholaminergic nuclei revealed the ventral mesencephalon as the most affected region. Stereological analysis demonstrated an increase in the number of TH-positive neurons in both the substantia nigra and ventral tegmental area along with enlarged volume of the ventral midbrain. Analysis of main innervating tissues revealed a rather contrasting profile. In striatum, basal extracellular levels and potassium-evoked DA release were significantly reduced in mice lacking Casp3, a clear indication of dopaminergic hypofunction in dopaminergic innervating tissues. This view was sustained by analysis of TH-labelled dopaminergic terminals by confocal and electron microscopy. Remarkably, at a behavioural level, Casp3-deficient mice exhibited impaired social interaction, restrictive interests and repetitive stereotypies, which are considered the core symptoms of autism spectrum disorder (ASD). Our study revitalizes the potential involvement of dopaminergic transmission in ASD and provides an excellent model to get further insights in ASD pathogenesis.
- Published
- 2021
20. Galectin-3 Deletion Reduces LPS and Acute Colitis-Induced Pro-Inflammatory Microglial Activation in the Ventral Mesencephalon
- Author
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Ministerio de Ciencia, Innovación y Universidades (España), Junta de Andalucía, Asociación Española Contra el Cáncer, Espinosa-Oliva, Ana M., García-Miranda, Pablo, Alonso-Bellido, Isabel María, Carvajal, Ana E., González-Rodríguez, Melania, Carrillo-Jiménez, Alejandro, Temblador, Arturo J., Felices-Navarro, Manuel, García-Domínguez, Irene, Roca-Ceballos, María Angustias, Vázquez-Carretero, María D., García-Revilla, Juan, Santiago, Marti, Peral, María J., Venero, José L., Pablos, Rocío M. de, Ministerio de Ciencia, Innovación y Universidades (España), Junta de Andalucía, Asociación Española Contra el Cáncer, Espinosa-Oliva, Ana M., García-Miranda, Pablo, Alonso-Bellido, Isabel María, Carvajal, Ana E., González-Rodríguez, Melania, Carrillo-Jiménez, Alejandro, Temblador, Arturo J., Felices-Navarro, Manuel, García-Domínguez, Irene, Roca-Ceballos, María Angustias, Vázquez-Carretero, María D., García-Revilla, Juan, Santiago, Marti, Peral, María J., Venero, José L., and Pablos, Rocío M. de
- Abstract
Parkinson’s disease is a highly prevalent neurological disorder for which there is currently no cure. Therefore, the knowledge of risk factors as well as the development of new putative molecular targets is mandatory. In this sense, peripheral inflammation, especially the originated in the colon, is emerging as a predisposing factor for suffering this disease. We have largely studied the pleiotropic roles of galectin-3 in driving microglia-associated immune responses. However, studies aimed at elucidating the role of galectin-3 in peripheral inflammation in terms of microglia polarization are lacking. To achieve this, we have evaluated the effect of galectin-3 deletion in two different models of acute peripheral inflammation: intraperitoneal injection of lipopolysaccharide or gut inflammation induced by oral administration of dextran sodium sulfate. We found that under peripheral inflammation the number of microglial cells and the expression levels of pro-inflammatory mediators take place specifically in the dopaminergic system, thus supporting causative links between Parkinson’s disease and peripheral inflammation. Absence of galectin-3 highly reduced neuroinflammation in both models, suggesting an important central regulatory role of galectin-3 in driving microglial activation provoked by the peripheral inflammation. Thus, modulation of galectin-3 function emerges as a promising strategy to minimize undesired microglia polarization states.
- Published
- 2021
21. Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour
- Author
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Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Instituto de Salud Carlos III, Junta de Andalucía, Centro de Investigación Biomédica en Red Salud Mental (España), García-Domínguez, Irene, Suárez-Pereira, Irene, Santiago, Marti, Pérez-Villegas, Eva María, Bravo, Lidia, López-Martín, Carolina, Roca-Ceballos, María Angustias, García-Revilla, Juan, Espinosa-Oliva, Ana M., Rodríguez-Gómez, José A., Joseph, Bertrand, Berrocoso, Esther, Armengol, José Ángel, Venero, José L., Ruiz, Rocío, Pablos, Rocío M. de, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Instituto de Salud Carlos III, Junta de Andalucía, Centro de Investigación Biomédica en Red Salud Mental (España), García-Domínguez, Irene, Suárez-Pereira, Irene, Santiago, Marti, Pérez-Villegas, Eva María, Bravo, Lidia, López-Martín, Carolina, Roca-Ceballos, María Angustias, García-Revilla, Juan, Espinosa-Oliva, Ana M., Rodríguez-Gómez, José A., Joseph, Bertrand, Berrocoso, Esther, Armengol, José Ángel, Venero, José L., Ruiz, Rocío, and Pablos, Rocío M. de
- Abstract
Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing. Here, we have analysed the effect of caspase-3 depletion on the development of catecholaminergic neurons and performed a wide array of neurochemical, ultrastructural and behavioural assays. To achieve this, we performed selective deletion of the Casp3 gene in tyrosine hydroxylase (TH)-expressing cells using Cre-loxP-mediated recombination. Histological evaluation of most relevant catecholaminergic nuclei revealed the ventral mesencephalon as the most affected region. Stereological analysis demonstrated an increase in the number of TH-positive neurons in both the substantia nigra and ventral tegmental area along with enlarged volume of the ventral midbrain. Analysis of main innervating tissues revealed a rather contrasting profile. In striatum, basal extracellular levels and potassium-evoked DA release were significantly reduced in mice lacking Casp3, a clear indication of dopaminergic hypofunction in dopaminergic innervating tissues. This view was sustained by analysis of TH-labelled dopaminergic terminals by confocal and electron microscopy. Remarkably, at a behavioural level, Casp3-deficient mice exhibited impaired social interaction, restrictive interests and repetitive stereotypies, which are considered the core symptoms of autism spectrum disorder (ASD). Our study revitalizes the potential involvement of dopaminergic transmission in ASD and provides an excellent model to get further insights in ASD pathogenesis.
- Published
- 2021
22. Implicación de las caspasas-3 y -8 en el trastorno del espectro autista y la enfermedad de Parkinson
- Author
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García Domínguez, Irene, Venero Recio, José Luis, Martínez de Pablos, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, and Venero, José L.
- Abstract
Tesis doctoral.-- Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular., [ES] El trastorno del espectro autista (TEA) y la enfermedad de Parkinson (EP) son dos desórdenes neurológicos que presentan elevada prevalencia con un coste socioeconómico importante y una fuerte carga para los pacientes y sus familiares, por lo que sus causas son un importante objeto de estudio. Estos dos desórdenes tienen en común la implicación del sistema dopaminérgico (DAérgico). Se ha demostrado que las caspasas asesinas, entre ellas caspasa-3 y caspasa-8, tienen otras muchas funciones aparte de su conocida participación en fenómenos de apoptosis. Así, por ejemplo, nuestro grupo es el primero en demostrar que a nivel neuronal las caspasas asesinas juegan un importante papel en el neurodesarrollo y en la homeostasis neuronal del sistema DAérgico. Con estos antecedentes, en el presente trabajo se han estudiado dos modelos animales delecionados en caspasa-3 o caspasa-8 en el linaje catecolaminérgico; Caspasa 3f/d TH-IRESCre (Caspasa 3 floxeado/delecionado Tyrosine hydroxylase-internal ribosomal entry sequence) y Caspasa 8f/d TH-IRES-Cre, para así dilucidar el papel de estas caspasas en la funcionalidad y desarrollo del sistema DAérgico, así como su posible implicación en el TEA y la EP. Nuestro estudio muestra importantes alteraciones en las vías DAérgicas para ambos modelos animales, principalmente en la vía nigro-estriada, aunque se presumen posibles cambios en las vías mesolímbica y mesocortical. Además, los animales carentes de caspasa3 y caspasa-8 presentan rasgos fenotípicos muy acordes con el TEA, principalmente a nivel conductual, así como aspectos bioquímicos de este desorden que, de hecho, podrían justificar sus síntomas principales. Por ello, concluimos que la carencia de caspasa-3 o caspasa-8 en el linaje catecolaminérgico podría dar lugar a un modelo animal que mimetice algunas características biomoleculares y conductuales de esta enfermedad, completando los estudios existentes hasta ahora en cuanto a modelos animales para el TEA. Por otro lado, la muerte de las neuronas DAérgicas es la principal característica neuropatológica de la EP y la principal causante de sus síntomas. Además, existen evidencias de apoptosis extrínseca e intrínseca y de la implicación de las caspasas-3 y -8 durante la enfermedad. Para nuestro estudio se utilizó un modelo animal sub-agudo de EP por tratamiento con la neurotoxina 1-metil-4-fenil,6-tetrahidropiridina (MPTP), que induce la muerte apoptótica DAérgica. Teniendo en cuenta la participación de las caspasas asesinas en la apoptosis de las neuronas DAérgicas que acontece a la EP y en la regulación de fenómenos de muerte celular, se postuló que la ausencia de las caspasas-3 y -8 en el linaje catecolaminérgico, podría proteger frente a la muerte neuronal DAérgica tras el tratamiento. Nuestro estudio muestra cómo la ausencia de caspasa-3 o caspasa-8 no protege frente a la depleción DAérgica tras el tratamiento, ya que los fenómenos de muerte celular continúan desarrollándose. De hecho, la ausencia de caspasa-3 parece ser especialmente perjudicial, ya que la muerte neuronal en estas condiciones se desvía a necrosis, con fenómenos inflamatorios asociados importantes, junto a una mayor degeneración neuronal DAérgica. La ausencia de caspasa-8 sin embargo, no produce cambios en la degeneración, ya que se desarrollan fenómenos de apoptosis intrínseca, normales en el modelo, evitando la respuesta inflamatoria., [EN] Autism spectrum disorder (ASD) and Parkinson's disease (PD) are two neurological disorders that produce an important socioeconomic impact and a heavy burden for both patients and their families. These two disorders have in common the involvement of the DAergic system. It has been shown that killer caspases, including caspase-3 and caspase-8, have many other functions apart from their involvement in apoptosis phenomena. For example, our study is the first one to address that killer caspases play an important role in the development and the homeostasis of the DAergic system. Considering this background, we studied two knock-out (KO) animal models in the catecholaminergic lineage (Caspase 3 f/d TH-IRES-Cre and Caspase 8 f/d TH-IRES-Cre) to elucidate the role of these enzymes in the functionality of the DAergic system and their possible implication in ASD and PD. Our study shows important alterations in DAergic pathways in both animal models, mainly in the nigro-striatal pathway, although possible changes in the mesolimbic and mesocortical pathways are presumed. In addition, animals lacking caspase-3 and caspase-8 showed robust phenotypic features congruent with ASD, mainly behavioural, although we also observed biochemical aspects of this disorder that could justify their main symptoms. Therefore, we conclude that caspase-3 or caspase-8 depletion in the catecholaminergic lineage could lead to an animal model that mimics biomolecular and behavioural aspects of the disease. On the other hand, the death of DAergic neurons is the main neuropathological characteristic of PD and the main cause of its motor symptoms. Likewise, there is evidence of extrinsic and intrinsic apoptosis with the involvement of caspase-3 and -8 during the disease. For our study, we used a sub-acute MPTP model of PD in strains lacking caspase-3 and -8, which caused permanent symptoms of the disease by inducing death of DAergic neurons in the SN. Taking into account the involvement of killer caspases in the apoptosis phenomena and in the regulation of cell death, it was postulated that the absence of either caspase-3 or - 8 in the catecholaminergic lineage could protect against DAergic depletion. However, our study shows that absence of caspase-3 or caspase-8 does not protect against DAergic depletion after MPTP treatment, due to other cell death phenomena continue in development. In fact, the absence of caspase-3 seems to be especially detrimental, since in these conditions neuronal death switch to necrosis, with important associated inflammatory phenomena along with greater DAergic degeneration. On the contrary, caspase-8 absence does not produce changes in neuronal degeneration, since an intrinsic apoptotic occurs, although avoiding the inflammatory response.
- Published
- 2020
23. TET2 Regulates the Neuroinflammatory Response in Microglia
- Author
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Carrillo Jiménez, Alejandro, Deniz, Özgen, Niklison-Chirou, Maria Victoria, Ruiz Laza, Rocío, Tayara, Khadija, García Domínguez, Irene, García Revilla, Juan, Fernández Martín, Juan Carlos, Espinosa Oliva, Ana María, Venero Recio, José Luis, Burguillos García, Miguel Ángel, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, European Union (UE), Ministerio de Ciencia, Innovación y Universidades (MICINN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), and Ministerio de Economía y Competitividad (MINECO). España
- Abstract
Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with LPS. We observed that microglia associated with amyloid β plaques expressed TET2 in brain tissue from individuals with Alzheimer's disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders European Union Seventh Framework Programme (FP7/2007-2013) España Ministerio de Ciencia, Innovación y Universidades/FEDER/UE RTI2018-098645-B-100 España MINECO(Programa Ramón y Cajal: RYC-2017-21804)
- Published
- 2020
24. Implicación de las caspasas-3 y -8 en el trastorno del espectro autista y la enfermedad de Parkinson
- Author
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Venero Recio, José Luis, Martínez de Pablos, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, García Domínguez, Irene, Venero Recio, José Luis, Martínez de Pablos, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, and García Domínguez, Irene
- Abstract
El trastorno del espectro autista (TEA) y la enfermedad de Parkinson (EP) son dos desórdenes neurológicos que presentan elevada prevalencia con un coste socioeconómico importante y una fuerte carga para los pacientes y sus familiares, por lo que sus causas son un importante objeto de estudio. Estos dos desórdenes tienen en común la implicación del sistema dopaminérgico (DAérgico). Se ha demostrado que las caspasas asesinas, entre ellas caspasa-3 y caspasa-8, tienen otras muchas funciones aparte de su conocida participación en fenómenos de apoptosis. Así, por ejemplo, nuestro grupo es el primero en demostrar que a nivel neuronal las caspasas asesinas juegan un importante papel en el neurodesarrollo y en la homeostasis neuronal del sistema DAérgico. Con estos antecedentes, en el presente trabajo se han estudiado dos modelos animales delecionados en caspasa-3 o caspasa-8 en el linaje catecolaminérgico; Caspasa 3f/d TH-IRESCre (Caspasa 3 floxeado/delecionado Tyrosine hydroxylase-internal ribosomal entry sequence) y Caspasa 8f/d TH-IRES-Cre, para así dilucidar el papel de estas caspasas en la funcionalidad y desarrollo del sistema DAérgico, así como su posible implicación en el TEA y la EP. Nuestro estudio muestra importantes alteraciones en las vías DAérgicas para ambos modelos animales, principalmente en la vía nigro-estriada, aunque se presumen posibles cambios en las vías mesolímbica y mesocortical. Además, los animales carentes de caspasa3 y caspasa-8 presentan rasgos fenotípicos muy acordes con el TEA, principalmente a nivel conductual, así como aspectos bioquímicos de este desorden que, de hecho, podrían justificar sus síntomas principales. Por ello, concluimos que la carencia de caspasa-3 o caspasa-8 en el linaje catecolaminérgico podría dar lugar a un modelo animal que mimetice algunas características biomoleculares y conductuales de esta enfermedad, completando los estudios existentes hasta ahora en cuanto a modelos animales para el TEA. Por otro lado, la muert, Autism spectrum disorder (ASD) and Parkinson's disease (PD) are two neurological disorders that produce an important socioeconomic impact and a heavy burden for both patients and their families. These two disorders have in common the involvement of the DAergic system. It has been shown that killer caspases, including caspase-3 and caspase-8, have many other functions apart from their involvement in apoptosis phenomena. For example, our study is the first one to address that killer caspases play an important role in the development and the homeostasis of the DAergic system. Considering this background, we studied two knock-out (KO) animal models in the catecholaminergic lineage (Caspase 3 f/d TH-IRES-Cre and Caspase 8 f/d TH-IRES-Cre) to elucidate the role of these enzymes in the functionality of the DAergic system and their possible implication in ASD and PD. Our study shows important alterations in DAergic pathways in both animal models, mainly in the nigro-striatal pathway, although possible changes in the mesolimbic and mesocortical pathways are presumed. In addition, animals lacking caspase-3 and caspase-8 showed robust phenotypic features congruent with ASD, mainly behavioural, although we also observed biochemical aspects of this disorder that could justify their main symptoms. Therefore, we conclude that caspase-3 or caspase-8 depletion in the catecholaminergic lineage could lead to an animal model that mimics biomolecular and behavioural aspects of the disease. On the other hand, the death of DAergic neurons is the main neuropathological characteristic of PD and the main cause of its motor symptoms. Likewise, there is evidence of extrinsic and intrinsic apoptosis with the involvement of caspase-3 and -8 during the disease. For our study, we used a sub-acute MPTP model of PD in strains lacking caspase-3 and -8, which caused permanent symptoms of the disease by inducing death of DAergic neurons in the SN. Taking into account the involvement of killer caspases
- Published
- 2020
25. Implicación de las caspasas-3 y -8 en el trastorno del espectro autista y la enfermedad de Parkinson
- Author
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Venero, José L., Martínez de Pablos, Rocío, García-Domínguez, Irene, Venero, José L., Martínez de Pablos, Rocío, and García-Domínguez, Irene
- Abstract
[ES] El trastorno del espectro autista (TEA) y la enfermedad de Parkinson (EP) son dos desórdenes neurológicos que presentan elevada prevalencia con un coste socioeconómico importante y una fuerte carga para los pacientes y sus familiares, por lo que sus causas son un importante objeto de estudio. Estos dos desórdenes tienen en común la implicación del sistema dopaminérgico (DAérgico). Se ha demostrado que las caspasas asesinas, entre ellas caspasa-3 y caspasa-8, tienen otras muchas funciones aparte de su conocida participación en fenómenos de apoptosis. Así, por ejemplo, nuestro grupo es el primero en demostrar que a nivel neuronal las caspasas asesinas juegan un importante papel en el neurodesarrollo y en la homeostasis neuronal del sistema DAérgico. Con estos antecedentes, en el presente trabajo se han estudiado dos modelos animales delecionados en caspasa-3 o caspasa-8 en el linaje catecolaminérgico; Caspasa 3f/d TH-IRESCre (Caspasa 3 floxeado/delecionado Tyrosine hydroxylase-internal ribosomal entry sequence) y Caspasa 8f/d TH-IRES-Cre, para así dilucidar el papel de estas caspasas en la funcionalidad y desarrollo del sistema DAérgico, así como su posible implicación en el TEA y la EP. Nuestro estudio muestra importantes alteraciones en las vías DAérgicas para ambos modelos animales, principalmente en la vía nigro-estriada, aunque se presumen posibles cambios en las vías mesolímbica y mesocortical. Además, los animales carentes de caspasa3 y caspasa-8 presentan rasgos fenotípicos muy acordes con el TEA, principalmente a nivel conductual, así como aspectos bioquímicos de este desorden que, de hecho, podrían justificar sus síntomas principales. Por ello, concluimos que la carencia de caspasa-3 o caspasa-8 en el linaje catecolaminérgico podría dar lugar a un modelo animal que mimetice algunas características biomoleculares y conductuales de esta enfermedad, completando los estudios existentes hasta ahora en cuanto a modelos animales para el TEA. Por otro lado, la, [EN] Autism spectrum disorder (ASD) and Parkinson's disease (PD) are two neurological disorders that produce an important socioeconomic impact and a heavy burden for both patients and their families. These two disorders have in common the involvement of the DAergic system. It has been shown that killer caspases, including caspase-3 and caspase-8, have many other functions apart from their involvement in apoptosis phenomena. For example, our study is the first one to address that killer caspases play an important role in the development and the homeostasis of the DAergic system. Considering this background, we studied two knock-out (KO) animal models in the catecholaminergic lineage (Caspase 3 f/d TH-IRES-Cre and Caspase 8 f/d TH-IRES-Cre) to elucidate the role of these enzymes in the functionality of the DAergic system and their possible implication in ASD and PD. Our study shows important alterations in DAergic pathways in both animal models, mainly in the nigro-striatal pathway, although possible changes in the mesolimbic and mesocortical pathways are presumed. In addition, animals lacking caspase-3 and caspase-8 showed robust phenotypic features congruent with ASD, mainly behavioural, although we also observed biochemical aspects of this disorder that could justify their main symptoms. Therefore, we conclude that caspase-3 or caspase-8 depletion in the catecholaminergic lineage could lead to an animal model that mimics biomolecular and behavioural aspects of the disease. On the other hand, the death of DAergic neurons is the main neuropathological characteristic of PD and the main cause of its motor symptoms. Likewise, there is evidence of extrinsic and intrinsic apoptosis with the involvement of caspase-3 and -8 during the disease. For our study, we used a sub-acute MPTP model of PD in strains lacking caspase-3 and -8, which caused permanent symptoms of the disease by inducing death of DAergic neurons in the SN. Taking into account the involvement of killer casp
- Published
- 2020
26. Reformulating Pro-Oxidant Microglia in Neurodegeneration
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, García Revilla, Juan, Alonso Bellido, Isabel María, Burguillos García, Miguel Ángel, Herrera Carmona, Antonio José, Espinosa Oliva, Ana María, Ruiz Laza, Rocío, Cruz Hernández, Luis, García Domínguez, Irene, Roca Ceballos, María Angustias, Santiago Pavón, Martiniano, Rodríguez Gómez, José Antonio, Sarmiento Soto, Manuel, Martínez de Pablos, Rocío, Venero Recio, José Luis, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, García Revilla, Juan, Alonso Bellido, Isabel María, Burguillos García, Miguel Ángel, Herrera Carmona, Antonio José, Espinosa Oliva, Ana María, Ruiz Laza, Rocío, Cruz Hernández, Luis, García Domínguez, Irene, Roca Ceballos, María Angustias, Santiago Pavón, Martiniano, Rodríguez Gómez, José Antonio, Sarmiento Soto, Manuel, Martínez de Pablos, Rocío, and Venero Recio, José Luis
- Abstract
In neurodegenerative diseases, microglia-mediated neuroinflammation and oxidative stress are central events. Recent genome-wide transcriptomic analyses of microglial cells under different disease conditions have uncovered a new subpopulation named disease-associated microglia (DAM). These studies have challenged the classical view of the microglia polarization state's proinflammatory M1 (classical activation) and immunosuppressive M2 (alternative activation). Molecular signatures of DAM and proinflammatory microglia (highly pro-oxidant) have shown clear differences, yet a partial overlapping gene profile is evident between both phenotypes. The switch activation of homeostatic microglia into reactive microglia relies on the selective activation of key surface receptors involved in the maintenance of brain homeostasis (a.k.a. pattern recognition receptors, PRRs). Two relevant PRRs are toll-like receptors (TLRs) and triggering receptors expressed on myeloid cells-2 (TREM2), whose selective activation is believed to generate either a proinflammatory or a DAM phenotype, respectively. However, the recent identification of endogenous disease-related ligands, which bind to and activate both TLRs and TREM2, anticipates the existence of rather complex microglia responses. Examples of potential endogenous dual ligands include amyloid β, galectin-3, and apolipoprotein E. These pleiotropic ligands induce a microglia polarization that is more complicated than initially expected, suggesting the possibility that different microglia subtypes may coexist. This review highlights the main microglia polarization states under disease conditions and their leading role orchestrating oxidative stress.
- Published
- 2019
27. TET2 Regulates the Neuroinflammatory Response in Microglia
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Carrillo Jiménez, Alejandro, Ruiz Laza, Rocío, García Domínguez, Irene, García Revilla, Juan, Espinosa Oliva, Ana María, Venero Recio, José Luis, Burguillos García, Miguel Ángel, Tayara, Khadija, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Carrillo Jiménez, Alejandro, Ruiz Laza, Rocío, García Domínguez, Irene, García Revilla, Juan, Espinosa Oliva, Ana María, Venero Recio, José Luis, Burguillos García, Miguel Ángel, and Tayara, Khadija
- Abstract
Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with LPS. We observed that microglia associated with amyloid β plaques expressed TET2 in brain tissue from individuals with Alzheimer's disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders.
- Published
- 2019
28. TET2 Regulates the Neuroinflammatory Response in Microglia
- Author
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Carrillo-Jimenez, Alejandro, primary, Deniz, Özgen, additional, Niklison-Chirou, Maria Victoria, additional, Ruiz, Rocio, additional, Bezerra-Salomão, Karina, additional, Stratoulias, Vassilis, additional, Amouroux, Rachel, additional, Yip, Ping Kei, additional, Vilalta, Anna, additional, Cheray, Mathilde, additional, Scott-Egerton, Alexander Michael, additional, Rivas, Eloy, additional, Tayara, Khadija, additional, García-Domínguez, Irene, additional, Garcia-Revilla, Juan, additional, Fernandez-Martin, Juan Carlos, additional, Espinosa-Oliva, Ana Maria, additional, Shen, Xianli, additional, St George-Hyslop, Peter, additional, Brown, Guy Charles, additional, Hajkova, Petra, additional, Joseph, Bertrand, additional, Venero, Jose Luis, additional, Branco, Miguel Ramos, additional, and Burguillos, Miguel Angel, additional
- Published
- 2019
- Full Text
- View/download PDF
29. Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease
- Author
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Tayara, Khadija, primary, Espinosa-Oliva, Ana M., additional, García-Domínguez, Irene, additional, Ismaiel, Afrah Abdul, additional, Boza-Serrano, Antonio, additional, Deierborg, Tomas, additional, Machado, Alberto, additional, Herrera, Antonio J., additional, Venero, José L., additional, and de Pablos, Rocío M., additional
- Published
- 2018
- Full Text
- View/download PDF
30. Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an in vivo MPTP Model of Parkinson’s Disease
- Author
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García-Domínguez, Irene, primary, Veselá, Karolina, additional, García-Revilla, Juan, additional, Carrillo-Jiménez, Alejandro, additional, Roca-Ceballos, María Angustias, additional, Santiago, Marti, additional, de Pablos, Rocío M., additional, and Venero, José L., additional
- Published
- 2018
- Full Text
- View/download PDF
31. Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, Tayara, Khadija, Espinosa Oliva, Ana María, García Domínguez, Irene, Ismaiel, Afrah Abdul, Boza Serrano, Antonio, Deierborg, Tomas, Martínez de Pablos, Rocío, Machado de la Quintana, Alberto, Herrera Carmona, Antonio José, Venero Recio, José Luis, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, Tayara, Khadija, Espinosa Oliva, Ana María, García Domínguez, Irene, Ismaiel, Afrah Abdul, Boza Serrano, Antonio, Deierborg, Tomas, Martínez de Pablos, Rocío, Machado de la Quintana, Alberto, Herrera Carmona, Antonio José, and Venero Recio, José Luis
- Abstract
The oral antidiabetic drug metformin is known to exhibit anti-inflammatory properties through activation of AMP kinase, thus protecting various brain tissues as cortical neurons, for example. However, the effect of metformin on the substantia nigra (SN), the main structure affected in Parkinson’s disease (PD), has not yet been studied in depth. Inflammation is a key feature of PD and it may play a central role in the neurodegeneration that takes place in this disorder. The aim of this work was to determine the effect of metformin on the microglial activation of the SN of rats using the animal model of PD based on the injection of the pro-inflammogen lipopolysaccharide (LPS). In vivo and in vitro experiments were conducted to study the activation of microglia at both the cellular and molecular levels. Our results indicate that metformin overall inhibits microglia activation measured by OX-6 (MHCII marker), IKKβ (pro-inflammatory marker) and arginase (anti-inflammatory marker) immunoreactivity. In addition, qPCR experiments reveal that metformin treatment minimizes the expression levels of several pro- and anti-inflammatory cytokines. Mechanistically, the drug decreases the phosphorylated forms of mitogen-activated protein kinases (MAPKs) as well as ROS generation through the inhibition of the NADPH oxidase enzyme. However, metformin treatment fails to protect the dopaminergic neurons of SN in response to intranigral LPS. These findings suggest that metformin could have both beneficial and harmful pharmacological effects and raise the question about the potential use of metformin for the prevention and treatment of PD.
- Published
- 2018
32. Beta-Cyanoalanine synthase action in root hair elongation is exerted at early steps of the root hair elongation pathway and is independent of direct cyanide inactivation of NADPH oxidase
- Author
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Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Arenas Alfonseca, Lucía, Gotor Martínez, Cecilia, Romero González, Luis Carlos, García Domínguez, Irene, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Arenas Alfonseca, Lucía, Gotor Martínez, Cecilia, Romero González, Luis Carlos, and García Domínguez, Irene
- Abstract
In Arabidopsis thaliana, cyanide is produced concomitantly with ethylene biosynthesis and is mainly detoxified by the ß-cyanoalanine synthase CAS-C1. In roots, CAS-C1 activity is essential to maintain a low level of cyanide for proper root hair development. Root hair elongation relies on polarized cell expansion at the growing tip, and we have observed that CAS-C1 locates in mitochondria and accumulates in root hair tips during root hair elongation, as shown by observing the fluorescence in plants transformed with the translational construct ProC1:CASC1-GFP, containing the complete CAS-C1 gene fused to GFP. Mutants in the SUPERCENTIPEDE (SCN1) gene, that regulate the NADPH oxidase RHD2/AtrbohC, are affected at the very early steps of the development of root hair that do not elongate and do not show a preferential localization of the GFP accumulation in the tips of the root hair primordia. Root hairs of mutants in CAS-C1 or RHD2/AtrbohC, which catalyzes the generation of ROS and the Ca2+ gradient, correctly start to grow out but they do not elongate either. Genetic crosses between the cas-c1 mutant and scn1 or rhd2 mutants were performed and the detail phenotypic and molecular characterization of the double mutants demonstrate that scn1 mutation is epistatic to cas-c1 and cas-c1 is epistatic to rhd2 mutation, indicating that CAS-C1 acts in early steps of the root hair development process. Moreover, our results show that the role of CAS-C1 in root hair elongation is independent of H2O2 production and of a direct NADPH oxidase inhibition by cyanide
- Published
- 2018
33. Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an in vivo MPTP Model of Parkinson’s Disease
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), García Domínguez, Irene, Veselá, Karolina, García Revilla, Juan, Carrillo Jiménez, Alejandro, Roca Ceballos, María Angustias, Santiago Pavón, Martiniano, Martínez de Pablos, Rocío, Venero Recio, José Luis, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), García Domínguez, Irene, Veselá, Karolina, García Revilla, Juan, Carrillo Jiménez, Alejandro, Roca Ceballos, María Angustias, Santiago Pavón, Martiniano, Martínez de Pablos, Rocío, and Venero Recio, José Luis
- Abstract
The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson’s disease. Brain inflammation, microglia and astroglia activation, disruption of the blood–brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.p. injection of LPS, MPTP or the combination of both. Our results showed that combinative treatment exacerbates microglia activation and enhances (i) the appearance of galectin-3-positive microglia, recently identified as microglial disease-associated phenotypic marker, (ii) the up-regulation of pro-inflammatory cytokines, (iii) the occurrence of A1 neurotoxic astrocytes, (iv) the breakdown of the BBB, and (v) the loss of dopaminergic neurons in the substantia nigra. Microglia activation was triggered earlier than other degenerative events, suggesting that over-activation of microglia (including different polarization states) may induce dopaminergic neuron loss by itself, initiating the endless cycle of inflammation/degeneration. Our study revitalizes the importance of peripheral inflammation as a potential risk factor for Parkinson’s disease and raises the possibility of using new anti-inflammatory therapies to improve the course of neurodegenerative diseases, including those directly aimed at modulating the deleterious activity of disease-associated microglia.
- Published
- 2018
34. HERC1 Ubiquitin Ligase Is Required for Normal Axonal Myelination in the Peripheral Nervous System
- Author
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Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Dirección General de Investigación Científica y Técnica (DGICYT). España, Fundación Ramón Areces, Ministerio de Economía y Competitividad (MINECO). España, Junta de Andalucía, Bachiller, Sara, Roca Ceballos, María Angustias, García Domínguez, Irene, Pérez Villegas, Eva María, Martos Carmona, David, Pérez Castro, Miguel Ángel, Real Navarrete, Luis Miguel, Rosa, José Luis, Tabares, Lucía, Venero Recio, José Luis, Armengol, José Ángel, Carrión, Ángel Manuel, Ruiz Laza, Rocío, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Dirección General de Investigación Científica y Técnica (DGICYT). España, Fundación Ramón Areces, Ministerio de Economía y Competitividad (MINECO). España, Junta de Andalucía, Bachiller, Sara, Roca Ceballos, María Angustias, García Domínguez, Irene, Pérez Villegas, Eva María, Martos Carmona, David, Pérez Castro, Miguel Ángel, Real Navarrete, Luis Miguel, Rosa, José Luis, Tabares, Lucía, Venero Recio, José Luis, Armengol, José Ángel, Carrión, Ángel Manuel, and Ruiz Laza, Rocío
- Abstract
A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gait in tambaleante (tbl) mice. Recently, we have shown that before cerebellar degeneration takes place, the tbl mouse suffers from a reduction in the number of vesicles available for release at the neuromuscular junction (NMJ). The aim of the present work was to study to which extent the alteration in HERC1 may affect other cells in the nervous system and how this may influence the motor dysfunction observed in these mice. The functional analysis showed a consistent delay in the propagation of the action potential in mutant mice in comparison with control littermates. Morphological analyses of glial cells in motor axons revealed signs of compact myelin damage as tomacula and local hypermyelination foci. Moreover, we observed an alteration in non-myelinated terminal Schwann cells at the level of the NMJ. Additionally, we found a significant increment of phosphorylated Akt-2 in the sciatic nerve. Based on these findings, we propose a molecular model that could explain how mutated HERC1 in tbl mice affects the myelination process in the peripheral nervous system. Finally, since the myelin abnormalities found in tbl mice are histological hallmarks of neuropathic periphery diseases, tbl mutant mice could be considered as a new mouse model for this type of diseases.
- Published
- 2018
35. Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an in vivo MPTP Model of Parkinson’s Disease
- Author
-
Ministerio de Economía y Competitividad (España), European Commission, García-Domínguez, Irene, Veselá, Karolina, García-Revilla, Juan, Carrillo-Jiménez, Alejandro, Roca-Ceballos, María Angustias, Santiago, Marti, Pablos, Rocío M. de, Venero, José L., Ministerio de Economía y Competitividad (España), European Commission, García-Domínguez, Irene, Veselá, Karolina, García-Revilla, Juan, Carrillo-Jiménez, Alejandro, Roca-Ceballos, María Angustias, Santiago, Marti, Pablos, Rocío M. de, and Venero, José L.
- Abstract
The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson’s disease. Brain inflammation, microglia and astroglia activation, disruption of the blood–brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.p. injection of LPS, MPTP or the combination of both. Our results showed that combinative treatment exacerbates microglia activation and enhances (i) the appearance of galectin-3-positive microglia, recently identified as microglial disease-associated phenotypic marker, (ii) the up-regulation of pro-inflammatory cytokines, (iii) the occurrence of A1 neurotoxic astrocytes, (iv) the breakdown of the BBB, and (v) the loss of dopaminergic neurons in the substantia nigra. Microglia activation was triggered earlier than other degenerative events, suggesting that over-activation of microglia (including different polarization states) may induce dopaminergic neuron loss by itself, initiating the endless cycle of inflammation/degeneration. Our study revitalizes the importance of peripheral inflammation as a potential risk factor for Parkinson’s disease and raises the possibility of using new anti-inflammatory therapies to improve the course of neurodegenerative diseases, including those directly aimed at modulating the deleterious activity of disease-associated microglia.
- Published
- 2018
36. Bufalin Is a Steroid Receptor Coactivator Inhibitor—Letter
- Author
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Calderón-Montaño, José Manuel, primary, Burgos-Morón, Estefanía, additional, Orta, Manuel Luis, additional, García-Domínguez, Irene, additional, Maldonado-Navas, Dolores, additional, and López-Lázaro, Miguel, additional
- Published
- 2015
- Full Text
- View/download PDF
37. Evaluating the cancer therapeutic potential of cardiac glycosides
- Author
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Universidad de Sevilla. Departamento de Farmacología, Calderón Montaño, José Manuel, Burgos Morón, Estefanía, Orta Vázquez, Manuel Luis, Maldonado Navas, Dolores, García Domínguez, Irene, López Lázaro, Miguel, Universidad de Sevilla. Departamento de Farmacología, Calderón Montaño, José Manuel, Burgos Morón, Estefanía, Orta Vázquez, Manuel Luis, Maldonado Navas, Dolores, García Domínguez, Irene, and López Lázaro, Miguel
- Abstract
Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na(+)/K(+)-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies
- Published
- 2014
38. Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides
- Author
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Calderón-Montaño, José Manuel, primary, Burgos-Morón, Estefanía, additional, Orta, Manuel Luis, additional, Maldonado-Navas, Dolores, additional, García-Domínguez, Irene, additional, and López-Lázaro, Miguel, additional
- Published
- 2014
- Full Text
- View/download PDF
39. Geminivirus C2 protein represses genes involved in sulphur assimilation and this effect can be counteracted by jasmonate treatment
- Author
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Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Lozano Durán, Rosa, García Domínguez, Irene, Huguet, Stéphanie, Balzergue, Sandrine, Romero González, Luis Carlos, Bejarano, Eduardo R., Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Lozano Durán, Rosa, García Domínguez, Irene, Huguet, Stéphanie, Balzergue, Sandrine, Romero González, Luis Carlos, and Bejarano, Eduardo R.
- Abstract
Geminiviruses are plant viruses that infect a broad range of crops and cause extensive losses worldwide, having an important economic impact. C2, a multifunctional pathogenicity factor encoded by geminiviruses, has been recently shown to suppress the responses to jasmonates in the host plant, which might at least partially explain its well-established role in pathogenicity. Sulphur is one of the essential macro-elements for plant life, and is considered to have a role in plant defence, in a phenomenon named sulphur-induced resistance (SIR) or sulphur-enhanced defence (SED). In this work, we show that geminivirus C2 protein represses the expression of genes involved in the sulphur assimilation pathway in Arabidopsis, but, interestingly, this effect can be neutralized by exogenous jasmonate treatment. These preliminary results may raise the idea that geminiviruses might be affecting sulphur metabolism, and maybe counteracting SIR/SED, through the manipulation of the jasmonate signalling pathway, which would define a novel strategy in plant-virus interactions and may unveil SIR/SED as an important player in the plant defence against viruses.
- Published
- 2012
40. Inhibition of Arabidopsis O-acetylserine (Thiol)lyase A1 by tyrosine-nitration
- Author
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Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Álvarez Núñez, Consolación, Lozano Juste, Jorge, Romero González, Luis Carlos, García Domínguez, Irene, Gotor Martínez, Cecilia, León, José, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Álvarez Núñez, Consolación, Lozano Juste, Jorge, Romero González, Luis Carlos, García Domínguez, Irene, Gotor Martínez, Cecilia, and León, José
- Abstract
The last step of sulfur assimilation is catalyzed by O-acetylserine(thiol)lyase (OASTL) enzymes. OASTLs are encoded by a multigene family in the model plant Arabidopsis thaliana. Cytosolic OASA1 enzyme is the main source of OASTL activity and thus crucial for cysteine homeostasis. We found that nitrating conditions after exposure to peroxynitrite strongly inhibited OASTL activity. Among OASTLs, OASA1 was markedly sensitive to nitration as demonstrated by the comparative analysis of OASTL activity in nitrated crude protein extracts from wild type and different oastl mutants. Furthermore, nitration assays on purified recombinant OASA1 protein led to 90% reduction of the activity due to inhibition of the enzyme, as no degradation of the protein occurred under these conditions. The reduced activity was due to nitration of the protein because selective scavenging of peroxynitrite with epicatechin impaired OASA1 nitration and the concomitant inhibition of OASTL activity. Inhibition of OASA1 activity upon nitration correlated with the identification of a modified OASA1 protein containing 3-nitroTyr302 residue. The essential role of the Tyr302 residue for the catalytic activity was further demonstrated by the loss of OASTL activity of a Y302A-mutated version of OASA1. Inhibition caused by Tyr302 nitration on OASA1 activity seems to be due to a drastically reduced O-acetylserine substrate binding to the nitrated protein, and also to reduced stabilization of the pyridoxal-5′-phosphate cofactor through hydrogen bonds. This is the first report identifying a Tyr nitration site of a plant protein with functional effect and the first post-translational modification identified in OASA1 enzyme.
- Published
- 2011
41. Inhibition of Arabidopsis O-acetylserine (Thiol)lyase A1 by tyrosine-nitration
- Author
-
Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Álvarez Núñez, Consolación, Lozano Juste, Jorge, Romero González, Luis Carlos, García Domínguez, Irene, Gotor Martínez, Cecilia, León, José, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Álvarez Núñez, Consolación, Lozano Juste, Jorge, Romero González, Luis Carlos, García Domínguez, Irene, Gotor Martínez, Cecilia, and León, José
- Abstract
The last step of sulfur assimilation is catalyzed by O-acetylserine(thiol)lyase (OASTL) enzymes. OASTLs are encoded by a multigene family in the model plant Arabidopsis thaliana. Cytosolic OASA1 enzyme is the main source of OASTL activity and thus crucial for cysteine homeostasis. We found that nitrating conditions after exposure to peroxynitrite strongly inhibited OASTL activity. Among OASTLs, OASA1 was markedly sensitive to nitration as demonstrated by the comparative analysis of OASTL activity in nitrated crude protein extracts from wild type and different oastl mutants. Furthermore, nitration assays on purified recombinant OASA1 protein led to 90% reduction of the activity due to inhibition of the enzyme, as no degradation of the protein occurred under these conditions. The reduced activity was due to nitration of the protein because selective scavenging of peroxynitrite with epicatechin impaired OASA1 nitration and the concomitant inhibition of OASTL activity. Inhibition of OASA1 activity upon nitration correlated with the identification of a modified OASA1 protein containing 3-nitroTyr302 residue. The essential role of the Tyr302 residue for the catalytic activity was further demonstrated by the loss of OASTL activity of a Y302A-mutated version of OASA1. Inhibition caused by Tyr302 nitration on OASA1 activity seems to be due to a drastically reduced O-acetylserine substrate binding to the nitrated protein, and also to reduced stabilization of the pyridoxal-5′-phosphate cofactor through hydrogen bonds. This is the first report identifying a Tyr nitration site of a plant protein with functional effect and the first post-translational modification identified in OASA1 enzyme.
- Published
- 2010
42. Reformulating Pro-Oxidant Microglia in Neurodegeneration.
- Author
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García-Revilla, Juan, Alonso-Bellido, Isabel M., Burguillos, Miguel A., Herrera, Antonio J., Espinosa-Oliva, Ana M., Ruiz, Rocío, Cruz-Hernández, Luis, García-Domínguez, Irene, Roca-Ceballos, María A., Santiago, Marti, Rodríguez-Gómez, José A., Soto, Manuel Sarmiento, de Pablos, Rocío M., and Venero, José L.
- Subjects
MICROGLIA ,PATTERN perception receptors ,TOLL-like receptors ,NEURODEGENERATION ,CELL analysis - Abstract
In neurodegenerative diseases, microglia-mediated neuroinflammation and oxidative stress are central events. Recent genome-wide transcriptomic analyses of microglial cells under different disease conditions have uncovered a new subpopulation named disease-associated microglia (DAM). These studies have challenged the classical view of the microglia polarization state's proinflammatory M1 (classical activation) and immunosuppressive M2 (alternative activation). Molecular signatures of DAM and proinflammatory microglia (highly pro-oxidant) have shown clear differences, yet a partial overlapping gene profile is evident between both phenotypes. The switch activation of homeostatic microglia into reactive microglia relies on the selective activation of key surface receptors involved in the maintenance of brain homeostasis (a.k.a. pattern recognition receptors, PRRs). Two relevant PRRs are toll-like receptors (TLRs) and triggering receptors expressed on myeloid cells-2 (TREM2), whose selective activation is believed to generate either a proinflammatory or a DAM phenotype, respectively. However, the recent identification of endogenous disease-related ligands, which bind to and activate both TLRs and TREM2, anticipates the existence of rather complex microglia responses. Examples of potential endogenous dual ligands include amyloid β, galectin-3, and apolipoprotein E. These pleiotropic ligands induce a microglia polarization that is more complicated than initially expected, suggesting the possibility that different microglia subtypes may coexist. This review highlights the main microglia polarization states under disease conditions and their leading role orchestrating oxidative stress. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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