48 results on '"Cediel, Rafael"'
Search Results
2. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative
- Author
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Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis A., Montoliu, Lluís, Carracedo, Angel, Millán, José M., Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José Antonio, Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodríguez de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto, Sanz, Pascual, Rubio, Vicente, and Llácer, José L.
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Biomedical Research ,Epidemiology ,Novel genes ,Research network ,New therapeutic approaches ,Rare diseases ,Rare Diseases ,Diagnòstic ,Diagnosis ,Genetics ,Humans ,Malalties rares ,Epidemiologia ,Genètica ,Genetics (clinical) - Abstract
13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A, CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research., This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation
- Published
- 2022
3. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative
- Author
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Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto [0000-0002-1334-5273], Sanz, Pascual [0000-0002-2399-4103], Rubio, Vicente [0000-0001-8124-1196], Llácer, José L. [0000-0001-5304-1795], Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis Alberto, Montoliu, Lluís, Carracedo, Ángel, Millán, José María, Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José A., Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodriguez-de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana Belén, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto [0000-0002-1334-5273], Sanz, Pascual [0000-0002-2399-4103], Rubio, Vicente [0000-0001-8124-1196], Llácer, José L. [0000-0001-5304-1795], Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis Alberto, Montoliu, Lluís, Carracedo, Ángel, Millán, José María, Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José A., Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodriguez-de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana Belén, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., and Nieto, M. Ángela
- Abstract
CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research.
- Published
- 2022
4. Investigación básica en la hipoacusia inducida por ruido: ¿qué podemos aprender de los modelos animales?
- Author
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Cediel, Rafael, Cervantes, Blanca, Contreras, Julio, Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Varela-Nieto, Isabel, Cediel, Rafael, Cervantes, Blanca, Contreras, Julio, Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, and Varela-Nieto, Isabel
- Published
- 2022
5. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative
- Author
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Luque, Juan, Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, de Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis A., Montoliu, Lluís, Carracedo, Angel, Millan, Jose M., Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa M., Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José Antonio, Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero, Rosa, Jiménez-Estrada, Juan Andrés, Manguán García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona, Rosario, Rivera-Barahona, Ana, Rodríguez de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Heredia, Miguel, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto [0000-0002-1334-5273], Sanz, Pascual [0000-0002-2399-4103], Rubio, Vicente [0000-0001-8124-1196], and Llácer, José L. [0000-0001-5304-1795]
- Subjects
Novel genes ,Genetics ,Research network ,New therapeutic approaches ,Rare diseases - Abstract
13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research. This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation
- Published
- 2022
6. Design of a reverberant chamber for noise exposure experiments with small animals
- Author
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Cobo, Pedro, Murillo-Cuesta, Silvia, Cediel, Rafael, Moreno, Antonio, Lorenzo-García, Patricia, and Varela-Nieto, Isabel
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- 2009
- Full Text
- View/download PDF
7. Drug development for noise-induced hearing loss
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European Commission, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Calvino, Miryam, Cediel, Rafael, Lassaletta, Luis, European Commission, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Calvino, Miryam, Cediel, Rafael, and Lassaletta, Luis
- Abstract
[Introduction]: Excessive exposure to noise is a common occurrence that contributes to approximately 50% of the non-genetic hearing loss cases. Researchers need to develop standardized preclinical models and identify molecular targets to effectively develop prevention and curative therapies., [Areas covered]: In this review, the authors discuss the many facets of human noise-induced pathology, and the primary experimental models for studying the basic mechanisms of noise-induced damage, making connections and inferences among basic science studies, preclinical proofs of concept and clinical trials., [Expert opinion]: Whilst experimental research in animal models has helped to unravel the mechanisms of noise-induced hearing loss, there are often methodological variations and conflicting results between animal and human studies which make it difficult to integrate data and translate basic outcomes to clinical practice. Standardization of exposure paradigms and application of -omic technologies will contribute to improving the effectiveness of transferring newly gained knowledge to clinical practice.
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- 2020
8. Drug development for noise-induced hearing loss
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Varela-Nieto, Isabel, primary, Murillo-Cuesta, Silvia, additional, Calvino, Miryam, additional, Cediel, Rafael, additional, and Lassaletta, Luis, additional
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- 2020
- Full Text
- View/download PDF
9. Melanin precursors prevent premature age-related and noise-induced hearing loss in albino mice
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Murillo-Cuesta, Silvia, Contreras, Julio, Zurita, Esther, Cediel, Rafael, Cantero, Marta, Varela-Nieto, Isabel, and Montoliu, Lluís
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- 2010
- Full Text
- View/download PDF
10. Molecular basis of deafness caused by insulin-like growth factor type 1 deficiency
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Rodriguez-de la Rosa, Lourdes, Bermúdez-Muñoz, Jose Mª, López, Marina, Sanz, Almudena, Mertens, Melaine, Celaya, Adelaida M., Morales, Jose M., Calvino, Miryam, Lassaletta, Luis, Cediel, Rafael, Contreras, Julio, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), and European Commission
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AKT ,otorhinolaryngologic diseases ,IGF-1 ,p38 ,Hearing loss ,MEF2 - Abstract
Resumen del póster presentado al 6th Symposium on Biomedical Research: Advances and Perspectives in Molecular Endocrinology "In Homage to Gabriella Morreale", celebrado en el Instituto de Investigaciones Biomédicas Alberto Sols (IIBM-CSIC) el 31 de mayo de 2019., World Health Organization estimates that around 466 million people worldwide have disabling hearing loss (HL), and 34 million of these are children. The most common is sensorineural hearing loss (SNHL), a heterogeneous disorder which is produced mainly by the irreversible loss of sensory cells or neurons in the cochlea. Insulin like growth factor type 1 (IGF-1) is a neurotrophic factor key for the regulation of postnatal cochlear growth and differentiation. Human IGF-1 deficiency is a rare disease (ORPHA73272) associated with growth retardation, microcephaly and SNHL. The mouse model lacking the Igf1 gene reproduces the syndrome and presents dwarfism and SNHL. IGF-1 deficiency causes important cellular alterations in the mouse cochlea, such as the early apoptosis of auditory neurons and the deficit in myelination. Analysis of downstream signalling in the Igf1-/- cochlea has shown the activation of p38 MAPK pathway, involved in response to stress, whereas ERK1/2 and AKT pathways, which regulate proliferation and survival, are impaired. A transcriptomic study carried out in the Igf1-/- showed the altered expression of the cell cycle modulator Foxm1 and of the myocyte enhancer factor-2 (Mef2), a key factor for cellular differentiation, during inner ear development and early postnatal ages.IGF-1 haploinsufficiency has been also associated with growth retardation and HL in human genetic disorders such as Laron syndrome. In contrast, the Igf1+/- mouse does not show congenital HL, but adult mice hearing thresholds progressively increase with ageing and mice show increased susceptibility to noise insult. Adult Igf1+/- cochleae show unbalanced redox and inflammation biomarkers, as well as altered IGF-1 downstream signalling, which have been proposed as molecular mechanism underlying susceptibility. Mouse models of IGF-1 deficiency constitute a valuable tool to study the molecular bases of deafness and to identify potential targets to develop new HL therapies., This work was supported by grants from the Spanish MINECO/FEDER (SAF2014-53979-R and SAF2017-86107-R) and FP7-PEOPLE-2013-IAPP TARGEAR to IVN. SMC and LRdR holds a contract supported by CIBERER (Institute of Health Carlos III) co-financed with FEDER funds.
- Published
- 2019
11. Molecular basis of deafness caused by insulin-like growth factor type 1 deficiency
- Author
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Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Rodriguez-de la Rosa, Lourdes, Bermúdez-Muñoz, Jose Mª, López, Marina, Sanz, Almudena, Mertens, Melaine, Celaya, Adelaida M., Morales, Jose M., Calvino, Miryam, Lassaletta, Luis, Cediel, Rafael, Contreras, Julio, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Rodriguez-de la Rosa, Lourdes, Bermúdez-Muñoz, Jose Mª, López, Marina, Sanz, Almudena, Mertens, Melaine, Celaya, Adelaida M., Morales, Jose M., Calvino, Miryam, Lassaletta, Luis, Cediel, Rafael, Contreras, Julio, Varela-Nieto, Isabel, and Murillo-Cuesta, Silvia
- Abstract
World Health Organization estimates that around 466 million people worldwide have disabling hearing loss (HL), and 34 million of these are children. The most common is sensorineural hearing loss (SNHL), a heterogeneous disorder which is produced mainly by the irreversible loss of sensory cells or neurons in the cochlea. Insulin like growth factor type 1 (IGF-1) is a neurotrophic factor key for the regulation of postnatal cochlear growth and differentiation. Human IGF-1 deficiency is a rare disease (ORPHA73272) associated with growth retardation, microcephaly and SNHL. The mouse model lacking the Igf1 gene reproduces the syndrome and presents dwarfism and SNHL. IGF-1 deficiency causes important cellular alterations in the mouse cochlea, such as the early apoptosis of auditory neurons and the deficit in myelination. Analysis of downstream signalling in the Igf1-/- cochlea has shown the activation of p38 MAPK pathway, involved in response to stress, whereas ERK1/2 and AKT pathways, which regulate proliferation and survival, are impaired. A transcriptomic study carried out in the Igf1-/- showed the altered expression of the cell cycle modulator Foxm1 and of the myocyte enhancer factor-2 (Mef2), a key factor for cellular differentiation, during inner ear development and early postnatal ages.IGF-1 haploinsufficiency has been also associated with growth retardation and HL in human genetic disorders such as Laron syndrome. In contrast, the Igf1+/- mouse does not show congenital HL, but adult mice hearing thresholds progressively increase with ageing and mice show increased susceptibility to noise insult. Adult Igf1+/- cochleae show unbalanced redox and inflammation biomarkers, as well as altered IGF-1 downstream signalling, which have been proposed as molecular mechanism underlying susceptibility. Mouse models of IGF-1 deficiency constitute a valuable tool to study the molecular bases of deafness and to identify potential targets to develop new HL therapies.
- Published
- 2019
12. Trophic effects of insulin-like growth factor-I (IGF-I) in the inner ear
- Author
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Varela-Nieto, Isabel, Morales-Garcia, Jose A., Vigil, Patricia, Diaz-Casares, Amelia, Gorospe, Itziar, Sánchez-Galiano, Susana, Cañon, Susana, Camarero, Guadalupe, Contreras, Julio, Cediel, Rafael, and Leon, Yolanda
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- 2004
- Full Text
- View/download PDF
13. A comparative study of drug delivery methods targeted to the mouse inner ear: bullostomy versus transtympanic injection
- Author
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Murillo-Cuesta, Silvia, Vallecillo, Néstor, Cediel, Rafael, Celaya, Adelaida M, Lassaletta, Luis, Varela-Nieto, Isabel, Contreras, Julio, Ministerio de Economía y Competitividad (España), and European Commission
- Subjects
Microsurgery ,Tympanic Membrane ,Local drug delivery ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,Rodents ,Injections ,Mice ,Drug Delivery Systems ,Evoked Potentials, Auditory, Brain Stem ,otorhinolaryngologic diseases ,Animals ,Minimally Invasive Surgical Procedures ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Intratympanic ,Auditory brainstem response ,Hearing loss ,Cochlea ,Issue 121 ,Auditory brainstem responses ,Disease Models, Animal ,Hydrogel ,Round Window, Ear ,vehicle ,Medicine ,sense organs ,Otologic Surgical Procedures - Abstract
Video Article: https://www.jove.com/video/54951, We present two minimally invasive microsurgical techniques in rodents for specific drug delivery into the middle ear so that it may reach the inner ear. The first procedure consists of perforation of the tympanic bulla, termed bullostomy; the second one is a transtympanic injection. Both emulate human clinical intratympanic procedures. Chitosan-glycerophosphate (CGP) and Ringer´s Lactate buffer (RL) were used as biocompatible vehicles for local drug delivery. CGP is a nontoxic biodegradable polymer widely used in pharmaceutical applications. It is a viscous liquid at RT but it congeals to a semi solid phase at body temperature. RL is an isotonic solution used for intravenous administrations in humans. A small volume of this vehicle is precisely placed on the Round Window (RW) niche by means of a bullostomy. A transtympanic injection fills the middle ear and allows less control but broader access to the inner ear. The safety profiles of both techniques were studied and compared by using functional and morphological tests. Hearing was evaluated by registering the Auditory Brainstem Response (ABR) before and several times after microsurgery. The cytoarchitecture and preservation level of cochlear structures were studied by conventional histological techniques in paraformaldehyde-fixed and decalcified cochlear samples. In parallel, unfixed cochlear samples were taken and immediately frozen to analyze gene expression profiles of inflammatory markers by quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). Both procedures are suitable as drug delivery methods into the mouse middle ear, although transtympanic injection proved to be less invasive compared to bullostomy., This work was supported by grants of the Spanish "Ministerio de Economia y Competitividad" (FEDER-SAF2014-53979-R) and the European Union (FP7-AFHELO and FP7-PEOPLE-TARGEAR) to IVN.
- Published
- 2017
14. A comparative study of drug delivery methods targeted to the mouse inner ear: bullostomy versus transtympanic injection
- Author
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Ministerio de Economía y Competitividad (España), European Commission, Murillo-Cuesta, Silvia, Vallecillo, Néstor, Cediel, Rafael, Celaya, Adelaida M., Lassaletta, Luis, Varela-Nieto, Isabel, Contreras, Julio, Ministerio de Economía y Competitividad (España), European Commission, Murillo-Cuesta, Silvia, Vallecillo, Néstor, Cediel, Rafael, Celaya, Adelaida M., Lassaletta, Luis, Varela-Nieto, Isabel, and Contreras, Julio
- Abstract
We present two minimally invasive microsurgical techniques in rodents for specific drug delivery into the middle ear so that it may reach the inner ear. The first procedure consists of perforation of the tympanic bulla, termed bullostomy; the second one is a transtympanic injection. Both emulate human clinical intratympanic procedures. Chitosan-glycerophosphate (CGP) and Ringer´s Lactate buffer (RL) were used as biocompatible vehicles for local drug delivery. CGP is a nontoxic biodegradable polymer widely used in pharmaceutical applications. It is a viscous liquid at RT but it congeals to a semi solid phase at body temperature. RL is an isotonic solution used for intravenous administrations in humans. A small volume of this vehicle is precisely placed on the Round Window (RW) niche by means of a bullostomy. A transtympanic injection fills the middle ear and allows less control but broader access to the inner ear. The safety profiles of both techniques were studied and compared by using functional and morphological tests. Hearing was evaluated by registering the Auditory Brainstem Response (ABR) before and several times after microsurgery. The cytoarchitecture and preservation level of cochlear structures were studied by conventional histological techniques in paraformaldehyde-fixed and decalcified cochlear samples. In parallel, unfixed cochlear samples were taken and immediately frozen to analyze gene expression profiles of inflammatory markers by quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). Both procedures are suitable as drug delivery methods into the mouse middle ear, although transtympanic injection proved to be less invasive compared to bullostomy.
- Published
- 2017
15. Transforming growth factor β1 inhibition protects from swept-sine violet noise-induced damage
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Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Celaya, Adelaida M., Camarero, Guadalupe, Cediel, Rafael, Sanz, Lorena, Cobo, Pedro, Rivera, Teresa, Avendaño, Carlos, Varela-Nieto, Isabel, European Commission, Instituto de Salud Carlos III, Digna Biotech, and Ministerio de Economía y Competitividad (España)
- Subjects
otorhinolaryngologic diseases - Abstract
Resumen del póster presentado al 3rd Symposium on Biomedical Research: "Advances and Perspectives in Neuroscience", celebrado en la Universidad Autónoma de Madrid el 22 de abril de 2016., Noise-induced hearing loss (NIHL) is the most common form of acquired deafness and a public health priority in developed countries. Excessive noise damages the principal cochlear structures leading to hearing impairment, inflammatory and immune responses being central mechanisms. Transforming growth factor ß (TGF-ß) is a key regulator of both responses and high levels of this factor have been associated with HL. Refined and reproducible NIHL mice models are essential tools for the evaluation of potential therapeutic drugs. Here we evaluated i) hearing by registering the auditory brainstem response (ABR); ii) cochlear morphology in cresyl-violet stained paraffin sections and iii) protein levels of oxidative stress markers and TGF-ß related genes expression by Western blotting and RT-qPCR, respectively, in mice exposed to a swept-sine-violet (SSV) noise and treated with TGF-ß1 peptidic inhibitors. SSV noise is enriched in frequencies to fit better with the mouse auditory range, two sound levels and frequency range were tested.Results indicate that SSV NIHL mice model is suitable to induce a scalable high frequency cochlear damage depending on the sound level and frequency composition. In addition, we showed that systemic administration of TGF-ß1 inhibitors significantly ameliorate the increase of hearing thresholds, the degenerative cochlear changes and the changes in the inflammatory and redox state induced by noise-exposure. These therapeutic effects were dose-dependent and more effective if the TGF-ß1 inhibitors were administered before noise injury. In conclusion, inhibition of TGF-ß1 actions represents a new, promising therapeutic strategy for the prevention and repair of noise-induced cochlear damage., TGF-ß1 inhibitors were a generous gift of DIGNA biotech. This study was supported by grants from MINECO (SAF2011-24391) and European FP7-INNOVA2-AFHELO to IVN and FIS PI 10/00394 for TR. SM-C and LRdR hold contracts from CIBERER.
- Published
- 2016
16. A comparative study of drug delivery methods targeted to the mouse inner ear: bullostomy versus transtympanic injection
- Author
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Vallecillo, Néstor, Celaya, Adelaida M., Contreras, Julio, Cediel, Rafael, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Ministerio de Economía y Competitividad (España), and European Commission
- Abstract
Resumen del póster presentado al 3rd Symposium on Biomedical Research: "Advances and Perspectives in Neuroscience", celebrado en la Universidad Autónoma de Madrid el 22 de abril de 2016., Drug delivery to the inner ear is a challenge for the development of preclinical studies of novel drugs for the treatment of hearing loss (1). Two micro-surgery approaches for drug delivery to the inner ear, bullostomy and transtympanic injection were developed and compared in terms of impact on hearing, cochlear cytoarchitecture and expression of inflammatory cytokines. Bullostomy has been previously used for the delivery of TGFß inhibitors. Here we study the toxicity window of the oxysterol dendrogenin B (DDB) that has been proposed to be an ototoprotector targeting LXRs. Two month-old male C57BL/6J mice were operated by bullostomy or transtympanic injection. DDB at 7.7, 11.4, 45.6 and 76 mM was delivered close to the round window niche. Hearing was assessed with auditory brainstem responses before noise and 7, 14, and 28 days after surgery. Cochlear samples were taken 28 days after surgery and subjected to RT-qPCR analysis of inflammatory markers. Cochlear morphology was evaluated at the end of the experiment on hematoxylin-eosin stained paraffin sections. Neither surgical technique induced functional or morphological alterations in the cochlea. Local administration of DDB up to 45.6 mM caused no evident alterations but 76 mM was toxic, thus the toxicity threshold was established. Bullostomy was associated with a transitory increase in the expression levels of Il1b, Il6, Tnfa and Tgfb1 pro-inflammatory cytokines, whereas transtympanic injection reversibly up-regulated Il6 expression. Thus, these microsurgery methods represent a feasible and secure approach to test the ototoxicy of drugs as well as the efficiency of novel molecules. The transtympanic approach had the lowest impact., We thank Affichem (France) for providing synthetic DDB. Research funded by the European Commission, under FP7-HEALTH-2012-INNOVATION2-AFHELO and SAF2014-53979-R (IVN).
- Published
- 2016
17. A Comparative Study of Drug Delivery Methods Targeted to the Mouse Inner Ear: Bullostomy Versus Transtympanic Injection
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Murillo-Cuesta, Silvia, primary, Vallecillo, Néstor, primary, Cediel, Rafael, primary, Celaya, Adelaida M., primary, Lassaletta, Luis, primary, Varela-Nieto, Isabel, primary, and Contreras, Julio, primary
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- 2017
- Full Text
- View/download PDF
18. Proceedings of the 9th international symposium on veterinary rehabilitation and physical therapy
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Nemery, Elodie, primary, Gabriel, Annick, additional, Cassart, Dominique, additional, Bayrou, Calixte, additional, Piret, Joëlle, additional, Antoine, Nadine, additional, Nilsson, Monika, additional, Steinwall, Lars, additional, Jacobson, Inger, additional, Martins, Ângela, additional, Carvalho, Carla, additional, Viegas, Inês, additional, Marcellin-Little, Denis J., additional, Harrysson, Ola L. A., additional, Crimi, Christopher S., additional, Levine, David, additional, Calatayud, María, additional, Resano, María, additional, Mucha, Marion, additional, Virac, Ivonne, additional, Lang, Cornelia, additional, Wittek, Kathleen, additional, Tichy, Alexander, additional, Bockstahler, Barbara, additional, Randy Walker, J., additional, Swogger, Āren, additional, Gibson, Tavis, additional, Ryan, Janice, additional, Gilligan, Chris, additional, Haulcomb, Katie, additional, Norris, Leigh Anne, additional, Powers, Matt, additional, Pugh, Tracy, additional, Purkey, Seth, additional, Pulkkinen, Hanna, additional, Lappalainen, Anu, additional, Laitinen-Vapaavuori, Outi, additional, Hyytiäinen, Heli, additional, Essner, Ann, additional, Sjöström, Rita, additional, Zetterberg, Lena, additional, Hellström, Karin, additional, Gustås, Pia, additional, Högberg, Hans, additional, Hielm-Björkman, Anna, additional, Orrfors, Charlotte, additional, Sundelin, Gunnevi, additional, Gonçalves, Luísa, additional, Niza-Ribeiro, João, additional, Millis, Darryl L., additional, de Matos, Augusto José, additional, Teeling, Marinette, additional, Ross, Kate, additional, Geddes, Victoria, additional, Carstens, Ann, additional, Kriel, Tineka, additional, du Toit, Karien, additional, Pauw, Jeanette, additional, Martindale, Gillian, additional, Mylo, Kristine, additional, van den Berg, Sybrand S., additional, Ogasawara, Morito, additional, Noguchi, Hiromi, additional, Minami, Takeo, additional, Zdeb, Krzysztof, additional, Baumgart, Urszula, additional, Ribeiro, Ana M., additional, Palas, Ricardo, additional, Capelão, Martinho, additional, Speciani, Mila, additional, De Luca, Alessandra, additional, Anzolin, Elisa, additional, Pirinen, Nina, additional, Pastell, Matti, additional, Mykkänen, Anna, additional, Jokisalo, Jonna, additional, Niinistö, Kati, additional, Hänninen, Laura, additional, McGowan, Catherine, additional, Holt, Alexandria, additional, Subirats, Marta, additional, Perez, Maria, additional, Hernández, Tatiana, additional, Gutierrez-Cepeda, Luna, additional, Cediel, Rafael, additional, Román, Javier López-San, additional, Boström, Anna F., additional, Savolainen, Lotta, additional, Lappalainen, Anu K., additional, Stadig, Sarah, additional, Lundström, Linda, additional, Bergh, Anna, additional, Ley, Charles, additional, Olsén, Lena, additional, Ingvast-Larsson, Carina, additional, Diniz, Renata, additional, Nicolau, Cristina, additional, Gamundi, Antonio, additional, Akaarir, Mourad, additional, Roberts, Elizabeth, additional, McLennan, Leander, additional, Cartildge, Helen C., additional, Evans, Lucy K. M., additional, Baugh, Stephen, additional, Stenfeldt, Pernilla, additional, Ericson, Cajsa, additional, Söderberg, Linnéa, additional, Sjöström, Lennart, additional, Colborne, Robert, additional, Byström, Anna, additional, Drum, Marti, additional, de Swarte, Marie, additional, Morandi, Federica, additional, Guevara, José, additional, Hickey, Dawn, additional, Camp, Ellen, additional, and Dickson, Rachel, additional
- Published
- 2016
- Full Text
- View/download PDF
19. A comparative study of drug delivery methods targeted to the mouse inner ear: bullostomy versus transtympanic injection
- Author
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Ministerio de Economía y Competitividad (España), European Commission, Vallecillo, Néstor, Celaya, Adelaida M., Contreras, Julio, Cediel, Rafael, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Ministerio de Economía y Competitividad (España), European Commission, Vallecillo, Néstor, Celaya, Adelaida M., Contreras, Julio, Cediel, Rafael, Varela-Nieto, Isabel, and Murillo-Cuesta, Silvia
- Abstract
Drug delivery to the inner ear is a challenge for the development of preclinical studies of novel drugs for the treatment of hearing loss (1). Two micro-surgery approaches for drug delivery to the inner ear, bullostomy and transtympanic injection were developed and compared in terms of impact on hearing, cochlear cytoarchitecture and expression of inflammatory cytokines. Bullostomy has been previously used for the delivery of TGFß inhibitors. Here we study the toxicity window of the oxysterol dendrogenin B (DDB) that has been proposed to be an ototoprotector targeting LXRs. Two month-old male C57BL/6J mice were operated by bullostomy or transtympanic injection. DDB at 7.7, 11.4, 45.6 and 76 mM was delivered close to the round window niche. Hearing was assessed with auditory brainstem responses before noise and 7, 14, and 28 days after surgery. Cochlear samples were taken 28 days after surgery and subjected to RT-qPCR analysis of inflammatory markers. Cochlear morphology was evaluated at the end of the experiment on hematoxylin-eosin stained paraffin sections. Neither surgical technique induced functional or morphological alterations in the cochlea. Local administration of DDB up to 45.6 mM caused no evident alterations but 76 mM was toxic, thus the toxicity threshold was established. Bullostomy was associated with a transitory increase in the expression levels of Il1b, Il6, Tnfa and Tgfb1 pro-inflammatory cytokines, whereas transtympanic injection reversibly up-regulated Il6 expression. Thus, these microsurgery methods represent a feasible and secure approach to test the ototoxicy of drugs as well as the efficiency of novel molecules. The transtympanic approach had the lowest impact.
- Published
- 2016
20. El déficit de IGF-I predispone a la pérdida auditiva inducida por ruido
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Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Avendaño, Carlos, Contreras, Julio, Varela-Nieto, Isabel, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Mutua Madrileña, European Commission, and Ministerio de Economía y Competitividad (España)
- Abstract
Póster presentado al XXXVII Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Granada del 9 al 12 de septiembre de 2014., La deficiencia del factor de crecimiento similar a insulina tipo I (IGF-I) causa sordera neurosensorial sindrómica en el hombre (ORPHA73272, OMIM608747), situación que se reproduce en ratones modificados genéticamente que no expresan este gen. El IGF-I es un agente neurotrófico durante el desarrollo y neuroprotector en el adulto. Los niveles de IGF-I circulante descienden de forma fisiológica con el envejecimiento lo que se ha asociado con deterioro cognitivo en el hombre. Nuestro objetivo ha sido estudiar si el déficit parcial en este factor predispone a la pérdida auditiva y los mecanismos moleculares responsables de la potencial respuesta agravada al daño. Para ello se ha estudiado la susceptibilidad de ratones Igf1+/- y Igf1+/+ al daño causado por exposición excesiva al ruido a diferentes edades, utilizando técnicas neurofisiológicas (potenciales auditivos del tronco cerebral), morfológicas (histología coclear, cuantificación estereológica de células ciliadas) y moleculares (RT-qPCR, Western blotting). Los ratones de 1-3 meses de edad de ambos genotipos resultaron igualmente sensibles al daño, por el contrario los ratones Igf1+/- de 6 meses de edad presentaron una mayor susceptibilidad al daño inducido por ruido que los ratones Igf1+/+. Con respecto a los animales control, los ratones Igf1+/- presentaron un incremento de umbrales auditivos acusado e irreversible, una mayor pérdida de células ciliadas, así como alteraciones en las principales vías de señalización del IGF-I y en la expresión génica de marcadores celulares y moleculares de neuroinflamación. En su conjunto los resultados sugieren una mayor activación de la respuesta inflamatoria tras el trauma acústico en la situación de déficit parcial en IGF-I. Estos resultados apoyan la idea de que bajos niveles de IGF-I predisponen a una mayor susceptibilidad al daño inducido por ruido y contribuyen a identificar las dianas moleculares que participan en este proceso. Así, las terapias basadas en IGF-I podrían contribuir a prevenir o mejorar la pérdida auditiva inducida por ruido., Este trabajo ha recibido el apoyo del SAF2011-24391, de la Fundación de Investigación Médica Mutua Madrileña 2012 y del proyecto AFHELO (FP7, European Union). LRR y SMC disfrutan de contratos del CIBERER y AC de AFHELO.
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- 2014
21. Insulin-like growth factor 1 deficiency and hearing loss
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Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, and Cediel, Rafael
- Subjects
otorhinolaryngologic diseases - Abstract
Resumen del trabajo presentado al 36th Annual MidWinter Meeting of the Association for Research in Otolaryngology, celebrado en Baltimore (US) del 16 al 20 de febrero de 2013., Insulin like growth factor 1 (IGF-1) plays a central role in embryonic development and adult tissue homeostasis. Accordingly, it is an essential factor for the regulation of cochlear development through controlling apoptosis and late neuronal differentiation. In the cochlea, IGF-1 actions are mediated by a network of protein kinases (RAF, AKT and p38 MAPK) that modulate the expression and activity of transcription factors (AP1, MEF2, FoxG1 and FoxM1) leading to the regulation of cell cycle and metabolism. IGF-1deficiency causes hearing loss in mice and men, whereas low serum levels of IGF-1are associated with human syndromes showing hearing lossand with premature presbyacusis. Animal models are fundamental to understand the genetic, epigenetic, and environmental factors that contribute to human hearing loss. Mouse IGF-1 plasmatic levels decrease with ageing, concomitantly hearing loss and retinal degeneration occur, in a normal ageing process that is accelerated in the heterozygous Igf1-/+mouse.Furthermore, low IGF-1 levels predispose to increased damage after noise-exposure. In the Igf1 null mouse, hearing-loss is caused byearly neuronal loss and age-related stria vascularis alterations. In summary, our data suggest that serum IGF-1 levels could be a novel diagnostic tool for hearing loss and support the hypothesis that IGF-1-based treatments have potential for the protection or repair of hearing loss.
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- 2013
22. El déficit de IGF-I en ratones predispone a la pérdida auditiva inducida por ruido
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Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Avendaño, Carlos, Contreras, Julio, Varela-Nieto, Isabel, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Mutua Madrileña, European Commission, and Ministerio de Economía y Competitividad (España)
- Abstract
Póster presentado al XXXVI Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Madrid del 3 al 6 de septiembre de 2013., La deficiencia del factor de crecimiento similar a insulina tipo (IGF-I) en el hombre se asocia a sordera sindrómica (ORPHA73272, OMIM608747). Así mismo, el ratón nulo Igf1-/- presenta sordera congénita profunda. Además, el IGF-I es un agente neuroprotector y el descenso fisiológico asociado con la edad de los niveles de IGF-I circulante ha sido relacionado con alteraciones cerebrales y cognitivas. Los animales heterocigotos Igf1+/- y silvestres Igf1+/+ muestran, especialmente a partir de los 6 meses de edad, un descenso en los niveles circulantes del factor que ha sido relacionado con la edad y que correlaciona con un incremento de los umbrales auditivos. Hemos estudiado en diferentes edades la susceptibilidad de animales Igf1+/- y Igf1+/+ a la pérdida auditiva inducida por ruido, a través de estudios funcionales (potenciales auditivos del tronco cerebral), morfológicos (histología coclear, cuantificación estereológica de células ciliadas) y moleculares (RTqPCR, Western blotting). En animales de 1 y 3 meses de edad sometidos a ruido, ambos genotipos resultaron igualmente sensibles a la exposición. Sin embargo, animales Igf1+/-de 6 meses de edad presentaron una mayor susceptibilidad al daño inducido por ruido, mostrando mayores incrementos de umbral y una peor recuperación en comparación con animales Igf1+/+. Los animales Igf1+/-presentaron una mayor pérdida de células ciliadas, así como alteraciones en las principales vías de señalización del IGF-I y variaciones en la expresión génica. Estos resultados apoyan la idea de que bajos niveles de IGF-I predisponen a una mayor susceptibilidad al daño inducido por ruido y contribuyen a identificar las dianas moleculares que participan este proceso. Así, las terapias basadas en IGF-I podrían contribuir a prevenir o mejorar la pérdida auditiva inducida por ruido., Este trabajo ha recibido el apoyo del SAF2011-24391, de la Fundación de Investigación Médica Mutua Madrileña 2012 y del proyecto AFHELO (FP7, European Union). LRR y SMC disfrutan de contratos del CIBERER y AC de AFHELO.
- Published
- 2013
23. Folate deficiency alters homocysteine cycle in the cochlea and causes premature hearing loss in mice
- Author
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Martínez-Vega, Raquel, Garrido, Francisco, Varela-Moreiras, Gregorio, Partearroyo, Teresa, Cediel, Rafael, Vallecillo, Néstor, Pajares, María A., Varela-Nieto, Isabel, Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), and Puleva
- Subjects
Folic acid ,otorhinolaryngologic diseases ,BHMT ,sense organs ,Deafness ,ABR ,Homocysteine - Abstract
Póster presentado en el 50th Inner Ear Biology Workshop (IEB), celebrado en Alcalá de Henares del 10 al 13 de septiembre de 2013., The methionine/homocysteine cycle is modulated by nutritional factors and its alterations have been associated to several pathologies including deafness (1). We have studied the impact of a dietary-induced folic acid deficiency on cochlear methionine metabolism and in hearing. C57BL/6J mice were fed with normal diet or folate deficient (FD) for 8 weeks. Hearing was evaluated by ABR threshold analyses and cochlear morphology was evaluated by hematoxylin-eosin staining and immunohistochemistry. RT-qPCR and Western blotting were used to determine cochlear levels of the methionine cycle enzymes, peptide mass fingerprint was carried out for protein identification, and plasma Hcy (pHcy) levels were determined by HPLC. The control group showed normal ABR thresholds (8 to 28 kHz, 27-48 dB SPL) whereas the FD group presented moderate to profound hearing loss (8 to 28 kHz, 52-85 dB SPL). Folic acid deficiency caused a reduction in plasma folate levels whilst pHcy levels were increased. All Hcy cycle enzymes studied were expressed in the cochlea. But some of them showed altered mobility in Western blotting as compared to the reference liver mobility patterns, suggesting post-translational modifications in the cochlea. In summary our data indicate that: i) the main enzymes of Hcy metabolism are expressed in the cochlea; ii) alterations in the methionine cycle secondary to folic acid deficit caused hearing loss; and iii) hearing loss correlated with alterations in the expression of Hcy cycle enzymes, and elevations of systemic pHcy.[1] Cohen-Salmon, M. et al. “Connexin30 deficiency causes instrastrial fluid-blood barrier disruption within the cochlear stria vascularis”, Proc Natl Acad Sci U S A 104: 6229-6234, 2007., RMV holds a JAE-CSIC fellowship. Ministerio de Economía y competitividad (SAF2011-24391, BFU2009-08977) and PULEVA.
- Published
- 2013
24. IGF-1 deficit predisposes to noise-induced hearing loss in mice
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Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Contreras, Julio, Avendaño, Carlos, Varela-Nieto, Isabel, European Commission, Ministerio de Ciencia e Innovación (España), and Centro de Investigación Biomédica en Red Enfermedades Raras (España)
- Abstract
Póster presentado en el 50th Inner Ear Biology Workshop (IEB), celebrado en Alcalá de Henares del 10 al 13 de septiembre de 2013.-- Tambien presentado al ARO 36th Annual MidWinter Meeting, celebrado en baltimore (US) del 16 al 20 de febrero de 2013., [Background]: Human IGF-I deficiency (ORPHA73272, OMIM608747) is a rare disease associated with poor growth rates, mental retardation and syndromic hearing loss. Equally, Igf1−/− mice are dwarfs with poor survival rates and congenital profound deafness1. IGF-I is a neuroprotective agent, and accordingly, low circulating IGF-I levels have been related to cognitive and brain alterations. Igf1−/− mice present undetectable serum levels of IGF-I throughout their life, whereas Igf1+/- and Igf1+/+ littermates show an agedependent decrease in IGF-I serum levels, especially from 6 months of age on2,3, which correlates with the increase in ABR thresholds. There is little information on the potential protective actions of IGF-I against noiseinduced hearing loss (NIHL). [Methods]: We have studied the susceptibility of Igf1+/- and Igf1+/+mice to NIHL at different ages, with functional (auditory brainstem responses, ABR), morphological (cochlear histology and stereological hair-cell quantification) and molecular (Western Blotting) studies. [Results]: Noise-exposure experiments with 3 months-old mice did not reveal differences between genotypes. However, 6 month-old Igf1+/- mice presented a greater susceptibility to noise damage, with higher threshold shifts and a poorer recovery compared to control mice. Igf1+/- mice showed severe morphological changes, as well as an altered intracellular signaling response to IGF-I. These changes correlated with low IGF-I serum levels in the heterozygous mice, compared to wild type. [Conclusion]: These results support the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related and noise-induced hearing loss., This research was funded by grants from the Spanish Ministry of Science and Innovation SAF2011-24391 and Intra-CIBERER programs to IV-N. SMC and LRR hold contracts from CIBERER. Project AFHELO.
- Published
- 2013
25. Cámara acústica sonoamortiguada para la evaluación de la función auditiva en animales de laboratorio
- Author
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Cobo, Pedro, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Navares Zaera, Ramón, Martínez-Vega, Raquel, and Cediel, Rafael
- Abstract
Cámara acústica sonoamortiguada para la evaluación de la función auditiva en animales de laboratorio. Es una cámara acústica (1) sonoamortiguada para la evaluación de la función auditiva en animales de laboratorio, especialmente roedores, diseñada para llevar a cabo estudios funcionales "in vivo", principalmente potenciales evocados auditivos, productos de distorsión de las emisiones otoacústicas y microfónicos cocleares. Para ello, la cámara acústica (1) ofrece un entorno controlado acústica y electromagnéticamente que permite la toma de datos funcionales de forma estandarizada, reproducible y no invasiva (sin necesidad de cirugía), lo que facilita el seguimiento de los animales en estudios longitudinales. Además, permite anestesiar al animal, manteniendo y controlando sus constantes vitales., Consejo Superior de Investigaciones Científicas, Universidad Complutense de Madrid, A1 Solicitud de patente con informe sobre el estado de la técnica
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- 2010
26. Corrigendum to: Swept-sine noise-induced damage as a hearing loss model for preclinical assays
- Author
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Sanz, Lorena, primary, Murillo-Cuesta, Silvia, additional, Cobo, Pedro, additional, Cediel, Rafael, additional, Contreras, Julio, additional, Rivera, Teresa, additional, Varela-Nieto, Isabel, additional, and Avendaño, Carlos, additional
- Published
- 2015
- Full Text
- View/download PDF
27. El déficit de IGF-I predispone a la pérdida auditiva inducida por ruido
- Author
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Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Mutua Madrileña, European Commission, Ministerio de Economía y Competitividad (España), Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Avendaño, Carlos, Contreras, Julio, Varela-Nieto, Isabel, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Mutua Madrileña, European Commission, Ministerio de Economía y Competitividad (España), Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Avendaño, Carlos, Contreras, Julio, and Varela-Nieto, Isabel
- Abstract
La deficiencia del factor de crecimiento similar a insulina tipo I (IGF-I) causa sordera neurosensorial sindrómica en el hombre (ORPHA73272, OMIM608747), situación que se reproduce en ratones modificados genéticamente que no expresan este gen. El IGF-I es un agente neurotrófico durante el desarrollo y neuroprotector en el adulto. Los niveles de IGF-I circulante descienden de forma fisiológica con el envejecimiento lo que se ha asociado con deterioro cognitivo en el hombre. Nuestro objetivo ha sido estudiar si el déficit parcial en este factor predispone a la pérdida auditiva y los mecanismos moleculares responsables de la potencial respuesta agravada al daño. Para ello se ha estudiado la susceptibilidad de ratones Igf1+/- y Igf1+/+ al daño causado por exposición excesiva al ruido a diferentes edades, utilizando técnicas neurofisiológicas (potenciales auditivos del tronco cerebral), morfológicas (histología coclear, cuantificación estereológica de células ciliadas) y moleculares (RT-qPCR, Western blotting). Los ratones de 1-3 meses de edad de ambos genotipos resultaron igualmente sensibles al daño, por el contrario los ratones Igf1+/- de 6 meses de edad presentaron una mayor susceptibilidad al daño inducido por ruido que los ratones Igf1+/+. Con respecto a los animales control, los ratones Igf1+/- presentaron un incremento de umbrales auditivos acusado e irreversible, una mayor pérdida de células ciliadas, así como alteraciones en las principales vías de señalización del IGF-I y en la expresión génica de marcadores celulares y moleculares de neuroinflamación. En su conjunto los resultados sugieren una mayor activación de la respuesta inflamatoria tras el trauma acústico en la situación de déficit parcial en IGF-I. Estos resultados apoyan la idea de que bajos niveles de IGF-I predisponen a una mayor susceptibilidad al daño inducido por ruido y contribuyen a identificar las dianas moleculares que participan en este proceso. Así, las terapias basadas en IGF-I podrían co
- Published
- 2014
28. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism
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Martínez‐Vega, Raquel, primary, Garrido, Francisco, additional, Partearroyo, Teresa, additional, Cediel, Rafael, additional, Zeisel, Steven H., additional, Martinez‐Alvarez, Concepción, additional, Varela‐Moreiras, Gregorio, additional, Varela‐Nieto, Isabel, additional, and Pajares, María A., additional
- Published
- 2014
- Full Text
- View/download PDF
29. Method for designing a reverberating acoustic chamber for hearing tests with animals
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Cobo, Pedro, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, and Cediel, Rafael
- Subjects
Computer Science::Sound ,Cámaras acústicas ,Acústica ,Ensayos con animales - Abstract
[EN] The principal objective of this 1 invention is a method for designing a reverberating acoustic chamber with dimensions (L1, L2, L3) and with a spatially and spectrally uniform acoustic field; the steps of the method are: select one of the dimensions L3; obtain the functions Lpm (L1,L2) (mean value of the acoustic field) and σ(L1,L2) (mean quadratic deviation of the acoustic field); and select, on the basis of the functions obtained in the previous step, the optimum L1 and L2 dimensions that provide the most uniform acoustic field., [ES] Resumen: El objeto principal de la presente invención es procedimiento para diseñar una cámara acústica reverberante de dimensiones (L1,L2, L3) cuyo campo acústico sea homogéneo espacial y espectralmente; las operaciones del procedimiento son: elegir una de las dimensiones L3; obtener las funciones Lpm (L1,L2) (valor medio del campo acústico) y σ(Ll,L2) (desviación cuadrática media del campo acústico); y seleccionar, con base en las funciones obtenidas en la operación anterior, las dimensiones L1 y L2 óptimas que proporcionan el campo acústico más uniforme., Consejo Superior de Investigaciones Científicas (España), Universidad Complutense de Madrid (UCM), A1 Solicitud de patentes con informe sobre el estado de la técnica
- Published
- 2008
30. Acciones neurotróficas del factor de crecimiento similar a la insulina de tipo I en el oído interno
- Author
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Rodriguez-de la Rosa, Lourdes, Contreras, Julio, Cediel, Rafael, León, Yolanda, Sánchez-Calderón, Hortensia, Murillo-Cuesta, Silvia, Riquelme, Raquel, and Varela-Nieto, Isabel
- Abstract
6 páginas, 4 figuras.-- et al., [ES]: [Introducción]: La pérdida de audición constituye una de las deficiencias sensoriales invalidantes más frecuentes en el mundo desarrollado. En la actualidad se estudian diferentes abordajes terapéuticos, entre los que se incluyen el tratamiento con células madre, la manipulación genética y la protección farmacológica. [Objetivo]: Evaluar el papel del factor de crecimiento similar a la insulina de tipo I (IGF-I) en el desarrollo, el mantenimiento y la reparación de la función auditiva. [Desarrollo]: El desarrollo del oído interno depende de la adecuada coordinación de los procesos celulares de proliferación, diferenciación, neurogénesis y muerte celular programada, que se encuentran regulados por distintos factores entre los que se encuentra el IGF-I. Durante la embriogénesis del oído interno, este factor se expresa abundantemente y es fundamental para la supervivencia celular y el mantenimiento de los precursores neuronales. El estudio del ratón nulo Igf-1¿/¿ ha puesto de manifiesto su importancia en el desarrollo y mantenimiento funcional del oído interno. Los ratones deficientes en este gen presentan alteraciones morfológicas que se corresponden con graves deficiencias funcionales, confirmadas mediante el análisis de los potenciales evocados auditivos de tronco cerebral. El déficit de IGF-I en humanos también se acompaña de hipoacusia sensorial profunda. [Conclusión]: En este escenario, se perfila el IGF-I como un factor clave para el desarrollo de la función auditiva y un candidato para la terapia regenerativa del oído interno., [EN]: [Introduction]: Loss of hearing constitutes one of the most frequent disabling sensory impairments in the developed world. Different therapeutic approaches are currently being studied, including treatment with stem cells, genetic manipulation and pharmacological protection. [Aim]: To evaluate the role played by insulin-like growth factor-I (IGF-I) in the development, maintenance and repair of auditory functioning. [Development]: Proper development of the inner ear is dependent on a suitable coordination of the cell processes of proliferation, differentiation, neurogenesis and programmed cell death, which are regulated by different factors, one of which is IGF-I. During the embryogenesis of the inner ear, this factor is expressed in abundance and is essential for cell survival and maintaining neuronal precursors. Studies conducted in Igf-1–/– null mice have highlighted its importance in the development and continued functioning of the inner ear. Mice with a deficit in this gene display morphological disorders that correspond to severe functional deficiencies, which are confirmed by analysing brainstem auditory evoked potentials. A deficit of IGF-I in humans is also accompanied by profound sensory hypoacusis. [Conclusions]: In a scenario like this, IGF-I appears as a key factor in the development of auditory functioning and a candidate for regenerative therapy of the inner ear., Trabajo financiado en parte gracias a los siguientes proyectos de investigación: FIS03/203, BMC03-07751, PIO05, BFU05, CAM IV PRICIT, y a la colaboración de la empresa DIGNA Biotech. H. Sánchez-Calderón disfruta de un contrato posdoctoral I3P del CSIC.
- Published
- 2007
31. Sensorineural hearing loss in insulin-like growth factor I-null mice: A new model of human deafness
- Author
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Cediel, Rafael, Riquelme, Raquel, Contreras, Julio, and Varela-Nieto, Isabel
- Subjects
otorhinolaryngologic diseases - Abstract
It has been reported that mutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic hearing loss. To study the precise role of IGF-I in auditory function and to hypothesize the possible morphological and electrophysiological changes that may occur in the human inner ear, we have analysed the auditory brainstem response in a mouse model of IGF-I deficiency. We show here that homozygous Igf-1-/- mice present an all-frequency involved bilateral sensorineural hearing loss. Igf-1-/- mice also present a delayed response to acoustic stimuli; this increases along the auditory pathway, indicating a contribution of the central nervous system to the hearing loss in Igf-1-/- mice. These results support the use of the Igf-1-/- mouse as a new model for the study of human syndromic deafness. © The Authors (2006)., This work was supported in part by grants from Ministerio de Educación (BMC03 ⁄ 07751-C03-02), Fondo de Investigaciones Sanitarias (G03 ⁄ 203) and Comunidad de Madrid (SAL ⁄ 0873 ⁄ 2004). R.R and A.D. were supported by postdoctoral contracts of Comunidad de Madrid and the I3P CSIC programme, respectively.
- Published
- 2006
32. Treatment with N- and C-Terminal Peptides of Parathyroid Hormone-Related Protein Partly Compensate the Skeletal Abnormalities in IGF-I Deficient Mice
- Author
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Rodríguez-de la Rosa, Lourdes, primary, López-Herradón, Ana, additional, Portal-Núñez, Sergio, additional, Murillo-Cuesta, Silvia, additional, Lozano, Daniel, additional, Cediel, Rafael, additional, Varela-Nieto, Isabel, additional, and Esbrit, Pedro, additional
- Published
- 2014
- Full Text
- View/download PDF
33. El déficit de IGF-I en ratones predispone a la pérdida auditiva inducida por ruido
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Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Mutua Madrileña, European Commission, Ministerio de Economía y Competitividad (España), Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Avendaño, Carlos, Contreras, Julio, Varela-Nieto, Isabel, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Mutua Madrileña, European Commission, Ministerio de Economía y Competitividad (España), Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Avendaño, Carlos, Contreras, Julio, and Varela-Nieto, Isabel
- Abstract
La deficiencia del factor de crecimiento similar a insulina tipo (IGF-I) en el hombre se asocia a sordera sindrómica (ORPHA73272, OMIM608747). Así mismo, el ratón nulo Igf1-/- presenta sordera congénita profunda. Además, el IGF-I es un agente neuroprotector y el descenso fisiológico asociado con la edad de los niveles de IGF-I circulante ha sido relacionado con alteraciones cerebrales y cognitivas. Los animales heterocigotos Igf1+/- y silvestres Igf1+/+ muestran, especialmente a partir de los 6 meses de edad, un descenso en los niveles circulantes del factor que ha sido relacionado con la edad y que correlaciona con un incremento de los umbrales auditivos. Hemos estudiado en diferentes edades la susceptibilidad de animales Igf1+/- y Igf1+/+ a la pérdida auditiva inducida por ruido, a través de estudios funcionales (potenciales auditivos del tronco cerebral), morfológicos (histología coclear, cuantificación estereológica de células ciliadas) y moleculares (RTqPCR, Western blotting). En animales de 1 y 3 meses de edad sometidos a ruido, ambos genotipos resultaron igualmente sensibles a la exposición. Sin embargo, animales Igf1+/-de 6 meses de edad presentaron una mayor susceptibilidad al daño inducido por ruido, mostrando mayores incrementos de umbral y una peor recuperación en comparación con animales Igf1+/+. Los animales Igf1+/-presentaron una mayor pérdida de células ciliadas, así como alteraciones en las principales vías de señalización del IGF-I y variaciones en la expresión génica. Estos resultados apoyan la idea de que bajos niveles de IGF-I predisponen a una mayor susceptibilidad al daño inducido por ruido y contribuyen a identificar las dianas moleculares que participan este proceso. Así, las terapias basadas en IGF-I podrían contribuir a prevenir o mejorar la pérdida auditiva inducida por ruido.
- Published
- 2013
34. IGF-1 deficit predisposes to noise-induced hearing loss in mice
- Author
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European Commission, Ministerio de Ciencia e Innovación (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Contreras, Julio, Avendaño, Carlos, Varela-Nieto, Isabel, European Commission, Ministerio de Ciencia e Innovación (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Celaya, Adelaida M., Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Contreras, Julio, Avendaño, Carlos, and Varela-Nieto, Isabel
- Abstract
[Background]: Human IGF-I deficiency (ORPHA73272, OMIM608747) is a rare disease associated with poor growth rates, mental retardation and syndromic hearing loss. Equally, Igf1−/− mice are dwarfs with poor survival rates and congenital profound deafness1. IGF-I is a neuroprotective agent, and accordingly, low circulating IGF-I levels have been related to cognitive and brain alterations. Igf1−/− mice present undetectable serum levels of IGF-I throughout their life, whereas Igf1+/- and Igf1+/+ littermates show an agedependent decrease in IGF-I serum levels, especially from 6 months of age on2,3, which correlates with the increase in ABR thresholds. There is little information on the potential protective actions of IGF-I against noiseinduced hearing loss (NIHL). [Methods]: We have studied the susceptibility of Igf1+/- and Igf1+/+mice to NIHL at different ages, with functional (auditory brainstem responses, ABR), morphological (cochlear histology and stereological hair-cell quantification) and molecular (Western Blotting) studies. [Results]: Noise-exposure experiments with 3 months-old mice did not reveal differences between genotypes. However, 6 month-old Igf1+/- mice presented a greater susceptibility to noise damage, with higher threshold shifts and a poorer recovery compared to control mice. Igf1+/- mice showed severe morphological changes, as well as an altered intracellular signaling response to IGF-I. These changes correlated with low IGF-I serum levels in the heterozygous mice, compared to wild type. [Conclusion]: These results support the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related and noise-induced hearing loss.
- Published
- 2013
35. Folate deficiency alters homocysteine cycle in the cochlea and causes premature hearing loss in mice
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Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Puleva, Martínez-Vega, Raquel, Garrido, Francisco, Varela-Moreiras, Gregorio, Partearroyo, Teresa, Cediel, Rafael, Vallecillo, Néstor, Pajares, María A., Varela-Nieto, Isabel, Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Puleva, Martínez-Vega, Raquel, Garrido, Francisco, Varela-Moreiras, Gregorio, Partearroyo, Teresa, Cediel, Rafael, Vallecillo, Néstor, Pajares, María A., and Varela-Nieto, Isabel
- Abstract
The methionine/homocysteine cycle is modulated by nutritional factors and its alterations have been associated to several pathologies including deafness (1). We have studied the impact of a dietary-induced folic acid deficiency on cochlear methionine metabolism and in hearing. C57BL/6J mice were fed with normal diet or folate deficient (FD) for 8 weeks. Hearing was evaluated by ABR threshold analyses and cochlear morphology was evaluated by hematoxylin-eosin staining and immunohistochemistry. RT-qPCR and Western blotting were used to determine cochlear levels of the methionine cycle enzymes, peptide mass fingerprint was carried out for protein identification, and plasma Hcy (pHcy) levels were determined by HPLC. The control group showed normal ABR thresholds (8 to 28 kHz, 27-48 dB SPL) whereas the FD group presented moderate to profound hearing loss (8 to 28 kHz, 52-85 dB SPL). Folic acid deficiency caused a reduction in plasma folate levels whilst pHcy levels were increased. All Hcy cycle enzymes studied were expressed in the cochlea. But some of them showed altered mobility in Western blotting as compared to the reference liver mobility patterns, suggesting post-translational modifications in the cochlea. In summary our data indicate that: i) the main enzymes of Hcy metabolism are expressed in the cochlea; ii) alterations in the methionine cycle secondary to folic acid deficit caused hearing loss; and iii) hearing loss correlated with alterations in the expression of Hcy cycle enzymes, and elevations of systemic pHcy.[1] Cohen-Salmon, M. et al. “Connexin30 deficiency causes instrastrial fluid-blood barrier disruption within the cochlear stria vascularis”, Proc Natl Acad Sci U S A 104: 6229-6234, 2007.
- Published
- 2013
36. Cámara acústica sonoamortiguada para la evaluación de la función auditiva en animales de laboratorio
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Cobo, Pedro, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Navares Zaera, Ramón, Martínez-Vega, Raquel, Cediel, Rafael, Cobo, Pedro, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Navares Zaera, Ramón, Martínez-Vega, Raquel, and Cediel, Rafael
- Abstract
Cámara acústica sonoamortiguada para la evaluación de la función auditiva en animales de laboratorio. Es una cámara acústica (1) sonoamortiguada para la evaluación de la función auditiva en animales de laboratorio, especialmente roedores, diseñada para llevar a cabo estudios funcionales "in vivo", principalmente potenciales evocados auditivos, productos de distorsión de las emisiones otoacústicas y microfónicos cocleares. Para ello, la cámara acústica (1) ofrece un entorno controlado acústica y electromagnéticamente que permite la toma de datos funcionales de forma estandarizada, reproducible y no invasiva (sin necesidad de cirugía), lo que facilita el seguimiento de los animales en estudios longitudinales. Además, permite anestesiar al animal, manteniendo y controlando sus constantes vitales.
- Published
- 2012
37. Albino and pheomelanic mice are more susceptible and present a poorer recovery after noise-induced hearing loss compared to eumelanic mice
- Author
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Murillo-Cuesta, Silvia, Contreras, Julio, Cantero, Marta, Cediel, Rafael, Martínez-Vega, Raquel, Zurita, Esther, Fernández López, Almudena, Varela-Nieto, Isabel, Montoliu, Lluís, Murillo-Cuesta, Silvia, Contreras, Julio, Cantero, Marta, Cediel, Rafael, Martínez-Vega, Raquel, Zurita, Esther, Fernández López, Almudena, Varela-Nieto, Isabel, and Montoliu, Lluís
- Published
- 2011
38. The role of insulin-like growth factor-I in the physiopathology of hearing
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Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Lassaletta, Luis, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Rodriguez-de la Rosa, Lourdes, Cediel, Rafael, Lassaletta, Luis, and Varela-Nieto, Isabel
- Abstract
Insulin-like growth factor-I (IGF-I) belongs to the family of polypeptides of insulin, which play a central role in embryonic development and adult nervous system homeostasis by endocrine, autocrine, and paracrine mechanisms. IGF-I is fundamental for the regulation of cochlear development, growth, and differentiation, and its mutations are associated with hearing loss in mice and men. Low levels of IGF-I have been shown to correlate with different human syndromes showing hearing loss and with presbyacusis. Animal models are fundamental to understand the genetic, epigenetic, and environmental factors that contribute to human hearing loss. In the mouse, IGF-I serum levels decrease with aging and there is a concomitant hearing loss and retinal degeneration. In the Igf1(-/-) null mouse, hearing loss is due to neuronal loss, poor innervation of the sensory hair cells, and age-related stria vascularis alterations. In the inner ear, IGF-I actions are mediated by intracellular signaling networks, RAF, AKT, and p38 MAPK protein kinases modulate the expression and activity of transcription factors, as AP1, MEF2, FoxM1, and FoxP3, leading to the regulation of cell cycle and metabolism. Therapy with rhIGF-I has been approved in humans for the treatment of poor linear growth and certain neurodegenerative diseases. This review will discuss these findings and their implications in new IGF-I-based treatments for the protection or repair of hearing loss.
- Published
- 2011
39. Procedimiento para diseñar una cámara acústica reverberante para ensayos auditivos con animales
- Author
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Cediel, Rafael, Murillo-Cuesta, Silvia, Varela-Nieto, Isabel, Cobo, Pedro, Cediel, Rafael, Murillo-Cuesta, Silvia, Varela-Nieto, Isabel, and Cobo, Pedro
- Abstract
Procedimiento para diseñar una cámara acústica reverberante para ensayos auditivos con animales. El objeto principal de la presente invención es procedimiento para diseñar una cámara acústica reverberante de dimensiones (L1, L2, L3) cuyo campo acústico sea homogéneo espacial y espectralmente; las operaciones del procedimiento son: elegir una de las dimensiones L3; obtener las funciones (valor medio del campo acústico) y (desviación cuadrática media del campo acústico); y seleccionar, con base en las funciones obtenidas en la operación anterior, las dimensiones L1 y L2 óptimas que proporcionan el campo acústico más uniforme.
- Published
- 2011
40. Comparison of different aminoglycoside antibiotic treatments to refine ototoxicity studies in adult mice
- Author
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Murillo-Cuesta, Silvia, Contreras, Julio, Cediel, Rafael, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Contreras, Julio, Cediel, Rafael, and Varela-Nieto, Isabel
- Abstract
Hearing and balance receptors in the inner ear are highly susceptible to damage caused by a wide variety of toxic substances, including aminoglycosides. This class of antibiotics is commonly used in medicine, even though they may produce irreversible bilateral neurosensorial deafness. To identify potential ototoxic agents and novel therapeutic targets, it is necessary to generate standardized animal models of aminoglycoside ototoxicity, which will also serve to explore otic cell repair and regeneration. Although the mouse is the species most often used in biomedical research, due to the genetic information and genetically-modified strains available, there are few standard models of aminoglycoside ototoxicity in adult mice. Most protocols to produce ototoxicity in adult mice employ high doses of aminoglycosides for long periods of time, which causes systemic toxicity, side-effects and high mortality rates. Here, we compare the effects of systemic treatment with four different, yet common, aminoglycoside antibiotics in two mouse strains, evaluating their effects on mortality, cochlear morphology and auditory brainstem responses. Our data indicate that gentamicin and neomycin caused high mortality in the adult mouse without significantly changing the auditory threshold. Amikacin produced a tolerable rate of mortality but at doses that did not exhibit ototoxicity. Finally, intramuscular injection of kanamycin in C57BL/6JOlaHsd mice induced significant dosedependent bilateral hearing loss with a moderate rate of mortality and less discomfort than following subcutaneous administration.
- Published
- 2010
41. A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice
- Author
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Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Digna Biotech, Riquelme, Raquel, Cediel, Rafael, Contreras, Julio, Rodriguez-de la Rosa, Lourdes, Murillo-Cuesta, Silvia, Hernández-Sánchez, Catalina, Zubeldia, José M., Cerdán, Sebastián, Varela-Nieto, Isabel, Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Digna Biotech, Riquelme, Raquel, Cediel, Rafael, Contreras, Julio, Rodriguez-de la Rosa, Lourdes, Murillo-Cuesta, Silvia, Hernández-Sánchez, Catalina, Zubeldia, José M., Cerdán, Sebastián, and Varela-Nieto, Isabel
- Abstract
Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1(-/-) null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1(+/+) and null Igf1(-/-) mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1(-/-) null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1(+/+) wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1(-/-) null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate ag
- Published
- 2010
42. Procedimiento para diseñar una cámara acústica reverberante para ensayos auditivos con animales
- Author
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Cobo, Pedro, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, Cediel, Rafael, Cobo, Pedro, Varela-Nieto, Isabel, Murillo-Cuesta, Silvia, and Cediel, Rafael
- Abstract
Procedimiento para diseñar una cámara acústica reverberante para ensayos auditivos con animales. El objeto principal de la presente invención es procedimiento para diseñar una cámara acústica reverberante de dimensiones (L1, L2, L3) cuyo campo acústico sea homogéneo espacial y espectralmente; las operaciones del procedimiento son: elegir una de las dimensiones L3; obtener las funciones (valor medio del campo acústico) y (desviación cuadrática media del campo acústico); y seleccionar, con base en las funciones obtenidas en la operación anterior, las dimensiones L1 y L2 óptimas que proporcionan el campo acústico más uniforme.
- Published
- 2010
43. The Role of Insulin-Like Growth Factor-I in the Physiopathology of Hearing
- Author
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Murillo-Cuesta, Silvia, primary, Rodríguez-de la Rosa, Lourdes, primary, Cediel, Rafael, primary, Lassaletta, Luis, primary, and Varela-Nieto, Isabel, primary
- Published
- 2011
- Full Text
- View/download PDF
44. Melanin precursors prevent premature age-related and noise-induced hearing loss in albino mice
- Author
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Murillo-Cuesta, Silvia, primary, Contreras, Julio, additional, Zurita, Esther, additional, Cediel, Rafael, additional, Cantero, Marta, additional, Varela-Nieto, Isabel, additional, and Montoliu, Lluís, additional
- Published
- 2009
- Full Text
- View/download PDF
45. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism.
- Author
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Martínez-Vega, Raquel, Garrido, Francisco, Partearroyo, Teresa, Cediel, Rafael, Zeisel, Steven H., Martínez-Ávarez, Concepción, Varela-Moreiras, Gregorio, Varela-Nieto, Isabel, and Pajares, María Á.
- Subjects
FOLIC acid deficiency ,VITAMIN B deficiency ,RISK of deafness ,OXIDATIVE stress ,HOMOCYSTEINE in the body - Abstract
Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-related hearing loss. The purpose of this study was to address the impact of folate deficiency on hearing loss and to examine the underlying mechanisms. For this purpose, 2-mo-old C57BL/6J mice (Animalia Chordata Mus musculus) were randomly divided into 2 groups (n =65 each) that were fed folate-deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7-fold decline in serum folate and a 3-fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL-positive- apoptotic cochlear cells. RT-quantitative PCR and Western blotting showed reduced levels of enzymes catalyzing homocysteine (Hcy) production and recycling, together with a 30% increase in protein homocysteinylation. Redox stress was demonstrated by decreased expression of catalase, glutathione peroxidase 4, and glutathione synthetase genes, increased levels of manganese superoxide dismutase, and NADPH oxidase-complex adaptor cytochrome b-245, α-polypeptide (p22phox) proteins, and elevated concentrations of glutathione species. Altogether, our findings demonstrate, for the first time, that the relationship between hyperhomocysteinemia induced by folate deficiency and premature hearing loss involves impairment of cochlear Hcy metabolism and associated oxidative stress. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
46. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism
- Author
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Martínez-Álvarez, Concepción, Zeisel, Steven, Varela-Moreiras, Gregorio, Martínez-Vega, Raquel, Garrido, Francisco, Pajares, María, Cediel, Rafael, Partearroyo, Teresa, and Varela-Nieto, Isabel
- Subjects
3. Good health - Abstract
Nutritional imbalance is emerging as a causative factor of hearing loss (HL). Epidemiological studies have linked HL to elevated plasma homocysteine (pHcy) and folate deficiency, and showed that folate supplementation lowers pHcy levels potentially ameliorating age-related HL. The purpose of this study was to address the potential impact of folate deficiency in HL and to unveil the underlying mechanisms. For this purpose, two-month old C57BL/6J-mice (Animalia Chordata Mus musculus) were randomly divided in two groups (n=65 each) that were fed folate-deficient or standard diets for 8 weeks. HPLC analysis demonstrated 7-fold decline in serum folate and 3-fold increase in pHcy levels. Auditory brainstem recordings showed that only folate-deficient mice exhibited severe HL and cochlear TUNEL+-apoptotic cells. RTqPCR and Western-blotting showed reduced levels of enzymes involved in Hcy production and recycling, together with 30% increased protein homocysteinylation. Redox stress was evidenced by decreased expression of Cat, Gpx4 and Gss genes, increased levels of the proteins MnSOD and the NOX-complex adaptor p22phox, and elevated concentrations of glutathione species. Altogether, our findings show for the first time that the relationship between folate-induced hyperhomocysteinemia and premature HL involves impairment of cochlear Hcy metabolism and associated oxidative stress.
47. Factores nutricionales que modulan la progresión de la pérdida auditiva asociada al envejecimiento en el ratón: ácido fólico y ácidos grasos omega-3
- Author
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Martínez-Vega, Raquel, Varela Nieto, Isabel, Cediel Algovia, Rafael, Pajares Tarancón, María de los Ángeles, Varela-Nieto, Isabel, Cediel, Rafael, Pajares, María A., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), and Puleva
- Subjects
Ciclo de la metionina ,Hiperhomocisteinemia ,Oxidative stress ,Hair cell loss ,Apoptosis ,Restricción dietética ,Nutrición y cuidado de los animales ,Presbiacusia - Abstract
Memoria para optar al grado de Doctora presentada por Raquel Martínez Vega en la Facultad de Veterinaria (Departamento de Medicina y Cirugía Animal) de la Universidad Complutense de Madrid (UCM) y realizada en el Instituto de Investigaciones Biomédicas Alberto Sols de Madrid (CSIC-UAM)., [ES]: El descenso en la funcionalidad del organismo como consecuencia del envejecimiento está asociado con la aparición de una variedad de enfermedades crónicas que incluyen el cáncer, la diabetes, la osteoporosis y las enfermedades cardiovasculares. El tratamiento de estos trastornos representa un grave problema socioeconómico en la mayor parte de las poblaciones envejecidas, como las de los países occidentales, donde la demanda global de tratamientos terapéuticos ha aumentado dramáticamente con la industrialización y la esperanza de vida. Además, de manera concomitante al proceso de envejecimiento, se observa una discapacidad multisensorial progresiva, siendo la medida de la función auditiva una de las propuestas para su uso como marcador del descenso cognitivo. De acuerdo con los datos publicados recientemente por la Organización Mundial de la Salud (OMS), alrededor de 360 millones de personas en el mundo padecen sordera de moderada a profunda. La incidencia de la sordera varía en función del sector poblacional. Así, mientras que en el sector infantil afecta aproximadamente a un 10% de la población, este porcentaje aumenta hasta el 30% en la población adulta con más de 65 años, incrementando exponencialmente a partir de esta edad. La pérdida auditiva puede deberse a factores ambientales, genéticos o a una combinación de ambos. La pérdida auditiva asociada al envejecimiento o presbiacusia se considera una sordera con un origen multifactorial, viéndose involucrados tanto factores genéticos como ambientales. Además, en contraste con la sordera congénita, no se conocen apenas los factores genéticos que contribuyen a la presbiacusia, derivándose la mayor parte de la información disponible de los estudios realizados en modelos animales. Dentro de los posibles factores asociados a la, pérdida auditiva, se encuentran los nutricionales y, entre ellos, la insuficiencia alimentaria o metabólica de vitaminas o sus precursores. Una de estas moléculas es el folato, vitamina que ha de ingerirse como parte habitual de la dieta dado que el hombre no es capaz de sintetizarla. Los folatos se encuentran en abundancia en muchos alimentos, entre los que se hallan los vegetales de hoja verde, algunas frutas, los huevos, los mariscos, la carne corral, el hígado o el riñón. Muy poco tiempo tras la síntesis de esta molécula se vio que resultaba efectiva en el tratamiento de las anemias megaloblásticas de todos los tipos, siendo particularmente útil en aquellas relacionadas con gestación o malnutrición. El folato que permanece en el interior celular, va a tener un papel metabólico como donante y receptor de unidades de carbono. La transferencia de estas unidades de carbono durante el ciclo de los folatos, es esencial en muchos procesos entre los que se encuentran la síntesis de purinas y pirimidinas para la formación de ácidos nucleicos, las reacciones de metilación, el metabolismo de los aminoácidos y la síntesis de mielina o de neurotransmisores. El nodo metabólico de unión entre los ciclos del folato y la metionina, y la vía de transulfuración, es la homocisteína (Hcy). Una de las formas de eliminación del aminoácido azufrado Hcy es mediante la remetilación a metionina. Esta reacción es catalizada por dos enzimas, la metionina sintasa (MTR) y la betaína homocisteína metriltransferasa (BHMT), que emplean 5´-metiltetrahidrofolato y betaína, respectivamente, como donantes de grupos metilo. La metionina generada se emplea para la síntesis de S-adenosilmetionina, el principal donante en los procesos de transmetilación celular. El correcto funcionamiento de esta ruta depende así del suministro constante de 5´-metiltetrahidrofolato, que se recicla en el ciclo de los folatos. Varios tipos de sordera, incluyendo la sordera asociada al envejecimiento y la sordera por ruido, se han asociado con niveles bajos de folato en glóbulos rojos y suero en pacientes. Además, algunos estudios han mostrado la relación directa entre niveles inadecuados de ácido fólico con un mayor grado de pérdida auditiva. Asimismo, estudios en varios modelos animales han generado una serie de datos, que tomados en conjunto, apoyan la hipótesis de que la deficiencia en ácido fólico y el metabolismo de la homocisteína juegan un papel clave en las alteraciones auditivas. Existen muchos agentes, que causan sordera e inducen inflamación y problemas de microvascularización. Numerosos estudios, realizados con el objetivo de paliar el efecto de estos agentes, han encontrado que ciertos nutrientes, como los ácidos grasos poliinsaturados (PUFAs), poseen una gran capacidad anti-inflamatoria y vasodilatadora. Los omega-3 y omega-6 son PUFAs esenciales precursores de ácidos grasos de cadena larga. Existen tres tipos de PUFAs implicados en la fisiología humana: el ácido α- linolénico o ALA (aceite vegetal: algas), el ácido eicosapentaenoico o EPA y el ácido docosahexaenoico o DHA (origen animal: aceites de pescado, de huevo o de calamar). Los PUFAs, a su vez, poseen funciones energéticas y estructurales en las membranas celulares, y controlan el metabolismo de los eicosanoides, que intervienen en procesos tan importantes como la inflamación o la señalización celular. En este trabajo nos hemos centrado en los ácidos grasos omega-3. Como consecuencia del efecto antiinflamatorio que estos ácidos grasos han mostrado en muchos estudios en relación con patologías como las enfermedades cardiovasculares o neurodegenerativas, en los últimos años se han llevado a cabo estudios en los que se ha buscado el posible efecto de estas moléculas sobre la sordera en pacientes. En conjunto, los datos epidemiológicos obtenidos en estudios llevados a cabo con el ácido fólico y los ácidos grasos omega-3 sugieren la existencia de una relación entre estas moléculas y la sordera. Sin embargo, los mecanismos moleculares que conducen a esta relación aún no han sido estudiados., [EN]: The decline in the functionality of the organism as a consequence of ageing is associated with the onset of chronic diseases including cancer, diabetes, osteoporosis and cardiovascular diseases. The treatment of these disorders is a serious socioeconomic problem in most of the aged populations, such as those of the Western countries, where the global demand for therapeutic treatments has increased dramatically due to industrialization and life expectancy growth. Furthermore, concomitantly with the aging process, a progressive multisensory disability emerges. For this reason, the assessment of the auditory function, among others, has been proposed as a marker to assess cognitive decline. According to recent World Health Organization (WHO) data, moderate-toprofound hearing loss affects over 360million people worldwide. Its incidence depends on the population segment studied. Thus, while hearing loss affects approximately 10% of children, this percentage rises up to 30% in adults over 65 years old, increasing further with age. Hearing loss can be caused by genetic and environmental factors, or their combination. The origin of age-related hearing loss (ARHL) or presbyacusis has been considered as multifactorial where both genetic and environmental factors are involved. In contrast with congenital hearing loss, the genetic factors that contribute to age-related hearing loss, are yet to be discovered, most of the available information being derived from the studies conducted in animal models. Nutritional factors are amongst some of the elements that have, been related to hearing loss, being the metabolic insufficiency of essential nutrients and their precursors one of the most common. Folate belongs to this category of molecules. This vitamin has to be incorporated as a regular part of the diet since humans cannot synthesize it. Folates are abundant in many foods including green leafy vegetables, some fruits, eggs, seafood, pork, poultry, liver or kidney. Shortly after this molecule was first synthesized, its effectiveness against all types of megaloblastic anemias was proven, being particularly useful in those anemias related to pregnancy or malnutrition. During its metabolism the folate remaining in the interior of the cell will have a metabolic role as donor and receiver of carbon units. The transfer of these units is essential in many processes like the synthesis of purines and pyrimidines for the formation of nucleic acids, methylation reactions, the amino acid metabolism and the synthesis of neurotransmitters or myelin. Homocysteine (Hcy) constitutes a metabolic branch point linking the methionine and folate cycles and the transsulfuration pathway. A way to eliminate this amino acid is through its remethylation to methionine. This reaction is catalyzed by either cobalamin-dependent methionine synthase (MTR) or betaine homocysteine methyltransferase (BHMT), enzymes that use 5´methyltetrahydrofolate and betaine as methyl donors, respectively. Both reactions generate methionine that is, in turn, used to synthesize S-adenosylmethionine, the main methyl donor for cellular transmethylations. The correct function of the pathway depends on a continuous supply of 5´-methyltetrahydrofolate that is recycled in the folate cycle. Several epidemiological studies have shown an association of low levels of folate in serum and red cells with diverse types of hearing loss, including presbyacusis and noise-induced hearing loss. In addition to this, numerous studies have shown a direct relationship between insufficient levels of folate and a higher degree of hearing loss. Besides, studies conducted in animal models have generated data that, collectively taken, support the hypothesis that folate and homocysteine metabolisms have a central role in hearing pathophysiology. However, the mechanisms by which cochlear function is affected remain poorly understood. There are a number of agents that cause hearing loss and induce inflammation and microvascularization problems., Several studies have been conducted with the purpose of palliating the effect of these agents finding that certain nutrients, like polyunsaturated fatty acids (PUFAs), have a great anti- inflammatory and vasodilatory capacity. The omega-3 and omega-6 are essential PUFAs precursors of long chain fatty acids. There are three types of PUFAs involved in human physiology: the α-linolenic or ALA (oil of vegetable origin: algae), the eicosapenthaenoic acid or EPA and the docosahexaenoic acid or DHA (oil of animal origin: fish oil, eggs and squid). PUFAs also have energy and structural functions on cellular membranes and are the molecules responsible for eicosanoides metabolism. Eicosanoids are implicated in very important processes for the body such as inflammation or cell signaling. The present work is exclusively focused on omega-3 fatty acids. Studies investigating the possible effect of these molecules on hearing loss in patients have been conducted, specially, as a consequence of the anti-inflammatory effect shown by these fatty acids in studies related to numerous pathologies including cardiovascular and neurodegenerative diseases. Altogether, the epidemiological data obtained so far from folic acid and omega-3 fatty acids studies suggest that there is a relationship between these molecules and deafness. However, the molecular mechanisms that might mediate their actions are yet to be discovered., Este trabajo ha sido realizado con el apoyo del programa predoctoral JAE-CSIC. Asimismo, la financiación del trabajo ha sido posible gracias a los proyectos del Ministerio de Ciencia e Innovación (SAF2011-24391), la Unión Europea (FP7-AFHELO y TARGEAR) y Puleva Biofood.
- Published
- 2015
48. A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice.
- Author
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Riquelme R, Cediel R, Contreras J, la Rosa Lourdes RD, Murillo-Cuesta S, Hernandez-Sanchez C, Zubeldia JM, Cerdan S, and Varela-Nieto I
- Abstract
Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1(-/-) null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1(+/+) and null Igf1(-/-) mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1(-/-) null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1(+/+) wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1(-/-) null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related hearing loss.
- Published
- 2010
- Full Text
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