47 results on '"Silvia Murillo-Cuesta"'
Search Results
2. Protection of lipopolysaccharide-induced otic injury by a single dose administration of a novel dexamethasone formulation
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Silvia Murillo-Cuesta, Ester Lara, Jose M. Bermúdez-Muñoz, Elena Torres-Campos, Lourdes Rodríguez-de la Rosa, Pilar López-Larrubia, Signe R. Erickson, and Isabel Varela-Nieto
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Corticosteroids ,Bacterial infection ,DEX-nanoformulation ,Inflammation ,Innate immune response ,MRI ,Medicine - Abstract
Abstract Background The blood-labyrinth barrier (BLB) separates the inner ear from the circulation and is critical for maintaining ionic homeostasis and limiting the entry of deleterious agents. BLB integrity is disrupted by bacterial lipopolysaccharide (LPS), which elicits a strong inflammatory response in the inner ear leading to irreversible otic damage. Prolonged administration of systemic corticosteroids is the available treatment, but it shows both limited efficacy and major adverse effects. SPT-2101 is a novel in situ-forming gel formulation of dexamethasone allowing slow and sustained drug release after single intratympanic administration. Methods We used a rat model of LPS-induced injury to define the functional, cellular and molecular mechanisms associated to BLB dysfunction and the protection by SPT-2101. Hearing was assessed by auditory brainstem response (ABR) recording, BLB permeability by gadolinium dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and Evans blue extravasation. Gross cochlear histology and cellular alterations were studied by hematoxylin-eosin staining and immunofluorescence. RT-qPCR, PCR array and western blotting were used to assess transcriptional and protein changes. Results LPS-challenged rats showed BLB breakdown and altered permeability as shown by the progressive increase in cochlear gadolinium uptake and Evans blue incorporation. LPS administration increased the cochlear expression of the LPS toll-like receptors Tlr2 and co-receptor Cd14, pro-inflammatory cytokines and receptors such as Il1b and ll1r1, and also the oxidative stress and inflammasome mediators NRF2 and NLRP3. LPS also increased IBA1-positive macrophage infiltration in the lateral wall and spiral ganglion. A single intratympanic injection of SPT-2101 protected BLB integrity and prevented otic injury. Comparable effects were obtained by repeated administration of systemic dexamethasone, but not by a single dose. SPT-2101 administration normalized molecular inflammatory mediators and suppressed macrophage infiltration. Conclusions Our data indicate that single local administration of dexamethasone formulated as SPT-2101 protects BLB functional integrity during endotoxemia, providing a novel therapeutic opportunity to treat diseases related to BLB dysfunction.
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- 2023
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3. Use of Radical Oxygen Species Scavenger Nitrones to Treat Oxidative Stress-Mediated Hearing Loss: State of the Art and Challenges
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Isabel Varela-Nieto, Silvia Murillo-Cuesta, Lourdes Rodríguez-de la Rosa, María Jesús Oset-Gasque, and José Marco-Contelles
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antioxidants ,free radicals ,sensorineural hearing loss ,N-acetyl-L-cysteine ,NXY-059 ,4-OHPBN ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Nitrones are potent antioxidant molecules able to reduce oxidative stress by trapping reactive oxygen and nitrogen species. The antioxidant potential of nitrones has been extensively tested in multiple models of human diseases. Sensorineural hearing loss has a heterogeneous etiology, genetic alterations, aging, toxins or exposure to noise can cause damage to hair cells at the organ of Corti, the hearing receptor. Noxious stimuli share a battery of common mechanisms by which they cause hair cell injury, including oxidative stress, the generation of free radicals and redox imbalance. Therefore, targeting oxidative stress-mediated hearing loss has been the subject of much attention. Here we review the chemistry of nitrones, the existing literature on their use as antioxidants and the general state of the art of antioxidant treatments for hearing loss.
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- 2021
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4. Therapeutic efficiency of the APAF‐1 antagonist LPT99 in a rat model of cisplatin‐induced hearing loss
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Silvia Murillo‐Cuesta, Adelaida M Celaya, Blanca Cervantes, Jose M Bermúdez‐Muñoz, Lourdes Rodríguez‐de la Rosa, Julio Contreras, Isabel Sánchez‐Pérez, and Isabel Varela‐Nieto
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Medicine (General) ,R5-920 - Published
- 2021
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5. The Value of Mouse Models of Rare Diseases: A Spanish Experience
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Silvia Murillo-Cuesta, Rafael Artuch, Fernando Asensio, Pedro de la Villa, Mara Dierssen, Jose Antonio Enríquez, Cristina Fillat, Stéphane Fourcade, Borja Ibáñez, Lluis Montoliu, Eduardo Oliver, Aurora Pujol, Eduardo Salido, Mario Vallejo, and Isabel Varela-Nieto
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orphan diseases ,animal models ,preclinical research ,novel therapies ,ethics ,transparency ,Genetics ,QH426-470 - Abstract
Animal models are invaluable for biomedical research, especially in the context of rare diseases, which have a very low prevalence and are often complex. Concretely mouse models provide key information on rare disease mechanisms and therapeutic strategies that cannot be obtained by using only alternative methods, and greatly contribute to accelerate the development of new therapeutic options for rare diseases. Despite this, the use of experimental animals remains controversial. The combination of respectful management, ethical laws and transparency regarding animal experimentation contributes to improve society’s opinion about biomedical research and positively impacts on research quality, which eventually also benefits patients. Here we present examples of current advances in preclinical research in rare diseases using mouse models, together with our perspective on future directions and challenges.
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- 2020
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6. Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss
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Adelaida M Celaya, Isabel Sánchez-Pérez, Jose M Bermúdez-Muñoz, Lourdes Rodríguez-de la Rosa, Laura Pintado-Berninches, Rosario Perona, Silvia Murillo-Cuesta, and Isabel Varela-Nieto
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apoptosis ,cochlea ,dual phosphatases ,inflammation ,sensorineural hearing loss ,oxidative stress ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Mitogen-activated protein kinases (MAPK) such as p38 and the c-Jun N-terminal kinases (JNKs) are activated during the cellular response to stress signals. Their activity is regulated by the MAPK-phosphatase 1 (DUSP1), a key component of the anti-inflammatory response. Stress kinases are well-described elements of the response to otic injury and the otoprotective potential of JNK inhibitors is being tested in clinical trials. By contrast, there are no studies exploring the role of DUSP1 in hearing and hearing loss. Here we show that Dusp1 expression is age-regulated in the mouse cochlea. Dusp1 gene knock-out caused premature progressive hearing loss, as confirmed by auditory evoked responses in Dusp1–/– mice. Hearing loss correlated with cell death in hair cells, degeneration of spiral neurons and increased macrophage infiltration. Dusp1–/– mouse cochleae showed imbalanced redox status and dysregulated expression of cytokines. These data suggest that DUSP1 is essential for cochlear homeostasis in the response to stress during ageing.
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- 2019
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7. Autophagy resolves early retinal inflammation in Igf1-deficient mice
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Ana I. Arroba, Lourdes Rodríguez-de la Rosa, Silvia Murillo-Cuesta, Laura Vaquero-Villanueva, Juan M. Hurlé, Isabel Varela-Nieto, and Ángela M. Valverde
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Autophagy ,IGF-1 ,Neurodegeneration ,Neuroinflammation ,Retina ,Medicine ,Pathology ,RB1-214 - Abstract
Insulin-like growth factor-1 (IGF-1) is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1−/−), present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1−/− mice. Tnfa and Il1b mRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1−/− mice compared to those in age-matched Igf1+/+ controls. In 6-month-old Igf1−/− retinas, increased mRNA levels of the autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1) protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1−/− mice, Nlrp3 mRNA, processing of the IL1β pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1+/+ controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1+/+ and Igf1−/− mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL), inner plexiform layer (IPL) and inner nuclear layer (INL), and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1−/− mice. Moreover, reactive gliosis was exclusively detected in the retinas from 12-month-old blind Igf1−/− mice. In conclusion, this study provides new evidence in a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during ageing.
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- 2016
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8. Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss
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Meritxell Espino Guarch, Mariona Font-Llitjós, Silvia Murillo-Cuesta, Ekaitz Errasti- Murugarren, Adelaida M Celaya, Giorgia Girotto, Dragana Vuckovic, Massimo Mezzavilla, Clara Vilches, Susanna Bodoy, Ignasi Sahún, Laura González, Esther Prat, Antonio Zorzano, Mara Dierssen, Isabel Varela-Nieto, Paolo Gasparini, Manuel Palacín, and Virginia Nunes
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LAT2 ,Slc7a8 ,hearing loss ,age-related hearing loss ,knock-out mouse model ,auditory brainstem response ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Age-related hearing loss (ARHL) is the most common sensory deficit in the elderly. The disease has a multifactorial etiology with both environmental and genetic factors involved being largely unknown. SLC7A8/SLC3A2 heterodimer is a neutral amino acid exchanger. Here, we demonstrated that SLC7A8 is expressed in the mouse inner ear and that its ablation resulted in ARHL, due to the damage of different cochlear structures. These findings make SLC7A8 transporter a strong candidate for ARHL in humans. Thus, a screening of a cohort of ARHL patients and controls was carried out revealing several variants in SLC7A8, whose role was further investigated by in vitro functional studies. Significant decreases in SLC7A8 transport activity was detected for patient’s variants (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu) further supporting a causative role for SLC7A8 in ARHL. Moreover, our preliminary data suggest that a relevant proportion of ARHL cases could be explained by SLC7A8 mutations.
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- 2018
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9. The Role of Insulin-Like Growth Factor 1 in the Progression of Age-Related Hearing Loss
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Lourdes Rodríguez-de la Rosa, Luis Lassaletta, Miryam Calvino, Silvia Murillo-Cuesta, and Isabel Varela-Nieto
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ARHL ,GH ,IGF system ,presbycusis ,rare diseases ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Aging is associated with impairment of sensorial functions and with the onset of neurodegenerative diseases. As pari passu circulating insulin-like growth factor 1 (IGF-1) bioavailability progressively decreases, we see a direct correlation with sensory impairment and cognitive performance in older humans. Age-related sensory loss is typically caused by the irreversible death of highly differentiated neurons and sensory receptor cells. Among sensory deficits, age-related hearing loss (ARHL), also named presbycusis, affects one third of the population over 65 years of age and is a major factor in the progression of cognitive problems in the elderly. The genetic and molecular bases of ARHL are largely unknown and only a few genes related to susceptibility to oxidative stress, excitotoxicity, and cell death have been identified. IGF-1 is known to be a neuroprotective agent that maintains cellular metabolism, activates growth, proliferation and differentiation, and limits cell death. Inborn IGF-1 deficiency leads to profound sensorineural hearing loss both in humans and mice. IGF-1 haploinsufficiency has also been shown to correlate with ARHL. There is not much information available on the effect of IGF-1 deficiency on other human sensory systems, but experimental models show a long-term impact on the retina. A secondary action of IGF-1 is the control of oxidative stress and inflammation, thus helping to resolve damage situations, acute or made chronic by aging. Here we will review the primary actions of IGF-1 in the auditory system and the underlying molecular mechanisms.
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- 2017
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10. Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss On CBA/Ca Mice.
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Raquel Martinez-Vega, Silvia Murillo-Cuesta, Teresa Partearroyo, Gregorio Varela-Moreiras, Isabel Varela-Nieto, and Maria Angeles Pajares
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Cochlea ,Homocysteine ,Hyperhomocysteinemia ,hearing impairment ,dietary intervention ,Vitamin deficiency ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after two-months, corroborating the epidemiological association previously described between vitamin deficiency and this sensory impairment. However, this strain is prone to early hearing loss, and hence we decided to analyze whether the effects exerted by folate deprivation follow the same pattern in a mouse strain such as CBA/Ca, which is resistant to hearing impairment. Here, we show results of a long-term study on hearing carried out on CBA/Ca mice subjected to dietary folate deprivation. Systemic changes included decreased serum folate levels, hyperhomocysteinemia and signs of anemia in the group fed the folate-deficient diet. Initial signs of hearing loss were detected in this strain after 8-months of vitamin deficiency, and correlated with histological damage in the cochleae. In conclusion, the data presented reinforce the importance of adequate folic acid levels for the auditory system and suggest that the impact of dietary deficiencies may depend on the genetic background.
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- 2016
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11. Treatment with N- and C-terminal peptides of parathyroid hormone-related protein partly compensate the skeletal abnormalities in IGF-I deficient mice.
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Lourdes Rodríguez-de la Rosa, Ana López-Herradón, Sergio Portal-Núñez, Silvia Murillo-Cuesta, Daniel Lozano, Rafael Cediel, Isabel Varela-Nieto, and Pedro Esbrit
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Medicine ,Science - Abstract
Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1-36) and PTHrP (107-111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a , cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1-36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1-36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone.
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- 2014
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12. A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice
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Raquel Riquelme, Rafael Cediel, Julio Contreras, Lourdes Rodríguez-de La Rosa, Silvia Murillo-Cuesta, Catalina Hernandez, Jose M Zubeldia, Sebastian Cerdan, and Isabel Varela-Nieto
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Deafness ,Ageing ,auditory brainstem responses ,in vivo brain imaging ,presbyacusis ,Igf1-/- null mouse ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Human anatomy ,QM1-695 - 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.
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- 2010
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13. Genetic, molecular and biochemical basis of the auditory aging: lessons from experimental models
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Blanca Cervantes, Jose M. Bermúdez-Muñoz, Carmen Ruiz-García, Luis Lassaletta, Julio Contreras, Silvia Murillo-Cuesta, and Isabel Varela-Nieto
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presbiacusia ,estrés oxidativo ,neuroinflamation ,apoptosis ,oxidative stress ,General Medicine ,modelos animales ,neuroiflamación ,ARHL ,animal models - Abstract
Age-related hearing loss (ARHL) affects one in three people older than 65 years and is the most prevalent sensorineural deficit. This type of hearing loss precedes and accelerates the onset of cognitive impairment and is associated with an increased risk for neurodegenerative diseases such as dementia and Alzheimer disease. The onset and progression of ARHL is influenced by genetic factors, which are still poorly understood, and environmental factors, which in particular include exposure to excessive noise and ototoxic substances. At present, no effective drug treatments are available for ARHL prevention or treatment, and therefore research in this field is a priority. In the research field, animal models offer a crucial tool for i) identifying new genes associated with ARHL, ii) understanding the cellular and molecular basis of auditory ageing and iii) defining new therapeutic targets and evaluating candidate treatments. La presbiacusia afecta a una de cada tres personas mayores de 65 años y constituye el déficit neurosensorial más prevalente. Antecede a la aparición de la fragilidad cognitiva, la acelera y se asocia con un mayor riesgo de padecer enfermedades neurodegenerativas como la demencia o el Alzheimer. La aparición y evolución de la presbiacusia están influidas por factores genéticos, todavía poco conocidos, y ambientales, entre los que destacan la exposición a ruido excesivo o a sustancias ototóxicas. En la actualidad no disponemos de tratamientos farmacológicos eficaces para prevenir o tratar la presbiacusia, por lo que la investigación en este campo es prioritaria. En este contexto, los modelos animales son una herramienta esencial para: a) identificar nuevos genes de presbiacusia, b) comprender las bases celulares y moleculares del envejecimiento auditivo, y c) definir nuevas dianas terapéuticas y evaluar posibles tratamientos.
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- 2022
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14. Therapeutic efficiency of the APAF‐1 antagonist LPT99 in a rat model of cisplatin‐induced hearing loss
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Adelaida M. Celaya, Isabel Sánchez-Pérez, Julio Contreras, Lourdes Rodriguez-de la Rosa, Silvia Murillo-Cuesta, Jose M Bermúdez-Muñoz, Isabel Varela-Nieto, Blanca Cervantes, Centro de Investigación Biomédica en Red Enfermedades Raras (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), and Agencia Estatal de Investigación (España)
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Cisplatin ,Medicine (General) ,business.industry ,Hearing loss ,Rat model ,Antagonist ,Medicine (miscellaneous) ,Apoptosis ,Pharmacology ,Letter to Editor ,Cochlea ,Rats ,Disease Models, Animal ,Text mining ,Apoptotic Protease-Activating Factor 1 ,R5-920 ,Molecular Medicine ,Medicine ,Animals ,medicine.symptom ,business ,Hearing Loss ,Cells, Cultured ,medicine.drug - Abstract
© 2021 The Authors, Cis-diammine-dichloroplatinum[II] (cisplatin) is a potent and widely used chemotherapeutic agent with significant efficacy against several forms of cancer in adults and children. Unfortunately, cisplatin has multiple adverse effects and causes irreversible hearing loss (HL) in a large proportion of patients, which severely impacts their quality of life.1 Here, we confirm that treatment with LPT99, a small molecule inhibitor of the apoptosome, preserves hearing levels in a rat model of cisplatin-induced HL and prevents apoptosis in cisplatin-exposed HEI-OC1 cells. These data are encouraging and support the potential of LPT99 for the prevention of the secondary effects of cisplatin for HL., This work was supported by a SPIRALTHCIBERER ER17PE12 grant to SMC. SMC and LRR hold CIBERER contracts. BC, AMC, and JMB contracts were supported in part by projects from FP7-PEOPLE-2013-IAPP-TARGEAR and from MINECO/FEDER SAF2017- 86107-R to IVN.
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- 2021
15. Insulin-like growth factor 1 signaling in mammalian hearing
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Silvia Murillo-Cuesta, Blanca Cervantes, Lourdes Rodriguez-de la Rosa, Ángela García-Mato, Isabel Varela-Nieto, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Instituto de Salud Carlos III, and Centro de Investigación Biomédica en Red Cáncer (España)
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medicine.medical_treatment ,Review ,QH426-470 ,Receptor tyrosine kinase ,Insulin-like growth factor ,Hearing ,Inner ear ,medicine ,Genetics ,Animals ,Humans ,Insulin-Like Growth Factor I ,Neurodegeneration ,Receptor ,Protein kinase B ,Genetics (clinical) ,Tissue homeostasis ,Insulin-like growth factor 1 receptor ,biology ,Growth factor ,AKT ,Hearing loss ,RAF ,IGF system ,IGF1 mutations ,Cell biology ,GH ,Rare diseases ,Insulin receptor ,Ageing ,Mutation ,biology.protein ,Signal Transduction - Abstract
© 2021 by the authors., Insulin-like growth factor 1 (IGF-1) is a peptide hormone belonging to the insulin family of proteins. Almost all of the biological effects of IGF-1 are mediated through binding to its high-affinity tyrosine kinase receptor (IGF1R), a transmembrane receptor belonging to the insulin receptor family. Factors, receptors and IGF-binding proteins form the IGF system, which has multiple roles in mammalian development, adult tissue homeostasis, and aging. Consequently, mutations in genes of the IGF system, including downstream intracellular targets, underlie multiple common pathologies and are associated with multiple rare human diseases. Here we review the contribution of the IGF system to our understanding of the molecular and genetic basis of human hearing loss by describing, (i) the expression patterns of the IGF system in the mammalian inner ear; (ii) downstream signaling of IGF-1 in the hearing organ; (iii) mouse mutations in the IGF system, including upstream regulators and downstream targets of IGF-1 that inform cochlear pathophysiology; and (iv) human mutations in these genes causing hearing loss., This research was funded by Spanish FEDER/CM, B2017/BMD-3688; FEDER/MICIN, PID2020-115274RB-I00-THEARPY and EU H2020-INTERREG, 0551_PSL_6_E grants to I.V.-N. and ACCI/ISCIII, ER19P5AC761 grant to L.R.-d.l.R. Á.G.-M. holds a FPU (FPU16/03308; MECD) contract. S.M.-C. and L.R.-d.l.R. hold CIBER ISCIII researcher contracts.
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- 2021
16. Drug development for noise-induced hearing loss
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Miryam Calvino, Isabel Varela-Nieto, Rafael Cediel, Silvia Murillo-Cuesta, Luis Lassaletta, European Commission, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), and Agencia Estatal de Investigación (España)
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medicine.medical_specialty ,Hearing loss ,Drug Evaluation, Preclinical ,Cochlear injury ,Audiology ,Deafness ,03 medical and health sciences ,Preclinical research ,0302 clinical medicine ,Drug Development ,Species Specificity ,Hidden hearing loss ,Drug Discovery ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,030304 developmental biology ,0303 health sciences ,business.industry ,ROS ,medicine.disease ,Animal models ,Noise ,Disease Models, Animal ,Hearing Loss, Noise-Induced ,Synaptopathy ,030220 oncology & carcinogenesis ,medicine.symptom ,business ,Noise-induced hearing loss ,NIHL - 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., This work was supported by the grants Multi Target and View FEDER/CM-B2017/BMD-3688 from the Consejería de Educación e Investigación, Comunidad de Madrid and MINECO/FEDER SAF2017-86107-R from the Ministerio de Economía, Industria y Competitividad, Gobierno de España.
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- 2020
17. Betaine-homocysteine
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Teresa, Partearroyo, Silvia, Murillo-Cuesta, Néstor, Vallecillo, Jose M, Bermúdez-Muñoz, Lourdes, Rodríguez-de la Rosa, Giacomo, Mandruzzato, Adelaida M, Celaya, Steven H, Zeisel, María A, Pajares, Gregorio, Varela-Moreiras, and Isabel, Varela-Nieto
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Male ,Mice, Knockout ,Time Factors ,Genotype ,Gene Expression Profiling ,Research ,Hyperhomocysteinemia ,Apoptosis ,Prognosis ,Cochlea ,Mice, Inbred C57BL ,Mice ,Betaine-Homocysteine S-Methyltransferase ,Hearing ,Hearing Loss, Noise-Induced ,otorhinolaryngologic diseases ,Animals ,Female ,Homocysteine ,Chromatography, High Pressure Liquid - Abstract
Betaine-homocysteine S-methyltransferases (BHMTs) are methionine cycle enzymes that remethylate homocysteine; hence, their malfunction leads to hyperhomocysteinemia. Epidemiologic and experimental studies have revealed a correlation between hyperhomocysteinemia and hearing loss. Here, we have studied the expression of methionine cycle genes in the mouse cochlea and the impact of knocking out the Bhmt gene in the auditory receptor. We evaluated age-related changes in mouse hearing by recording auditory brainstem responses before and following exposure to noise. Also, we measured cochlear cytoarchitecture, gene expression by RNA-arrays and quantitative RT-PCR, and metabolite levels in liver and plasma by HPLC. Our results indicate that there is an age-dependent strain-specific expression of methionine cycle genes in the mouse cochlea and a further regulation during the response to noise damage. Loss of Bhmt did not cause an evident impact in the hearing acuity of young mice, but it produced higher threshold shifts and poorer recovery following noise challenge. Hearing loss was associated with increased cochlear injury, outer hair cell loss, altered expression of cochlear methionine cycle genes, and hyperhomocysteinemia. Our results suggest that BHMT plays a central role in the homeostasis of cochlear methionine metabolism and that Bhmt2 up-regulation could carry out a compensatory role in cochlear protection against noise injury in the absence of BHMT.—Partearroyo, T., Murillo-Cuesta, S., Vallecillo, N., Bermúdez-Muñoz, J. M., Rodríguez-de la Rosa, L., Mandruzzato, G., Celaya, A. M., Zeisel, S. H., Pajares, M. A., Varela-Moreiras, G., Varela-Nieto, I. Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated with plasma hyperhomocysteinemia.
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- 2019
18. Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
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Giacomo Mandruzzato, Adelaida M. Celaya, Teresa Partearroyo, María A. Pajares, Gregorio Varela-Moreiras, Lourdes Rodriguez-de la Rosa, Isabel Varela-Nieto, Steven H. Zeisel, Silvia Murillo-Cuesta, Jose M Bermúdez-Muñoz, Néstor Vallecillo, Ministerio de Economía, Industria y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), National Institutes of Health (US), European Commission, Banco Santander, and Puleva
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0301 basic medicine ,medicine.medical_specialty ,Hyperhomocysteinemia ,Homocysteine ,Hearing loss ,Betaine—homocysteine S-methyltransferase ,Cochlear injury ,Biochemistry ,ARHL ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,otorhinolaryngologic diseases ,Methionine cycle ,Molecular Biology ,Methionine ,business.industry ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Hair cell ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Noise-induced hearing loss ,Homeostasis ,NIHL ,Biotechnology - Abstract
Betaine-homocysteine S-methyltransferases (BHMTs) are methionine cycle enzymes that remethylate homocysteine; hence, their malfunction leads to hyperhomocysteinemia. Epidemiologic and experimental studies have revealed a correlation between hyperhomocysteinemia and hearing loss. Here, we have studied the expression of methionine cycle genes in the mouse cochlea and the impact of knocking out the Bhmt gene in the auditory receptor. We evaluated age-related changes in mouse hearing by recording auditory brainstem responses before and following exposure to noise. Also, we measured cochlear cytoarchitecture, gene expression by RNA-arrays and quantitative RT-PCR, and metabolite levels in liver and plasma by HPLC. Our results indicate that there is an age-dependent strain-specific expression of methionine cycle genes in the mouse cochlea and a further regulation during the response to noise damage. Loss of Bhmt did not cause an evident impact in the hearing acuity of young mice, but it produced higher threshold shifts and poorer recovery following noise challenge. Hearing loss was associated with increased cochlear injury, outer hair cell loss, altered expression of cochlear methionine cycle genes, and hyperhomocysteinemia. Our results suggest that BHMT plays a central role in the homeostasis of cochlear methionine metabolism and that Bhmt2 up-regulation could carry out a compensatory role in cochlear protection against noise injury in the absence of BHMT.—Partearroyo, T., Murillo-Cuesta, S., Vallecillo, N., Bermúdez-Muñoz, J. M., Rodríguez-de la Rosa, L., Mandruzzato, G., Celaya, A. M., Zeisel, S. H., Pajares, M. A., Varela-Moreiras, G., Varela-Nieto, I. Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia., This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO)/ FEDER SAF2017-86107-R to I.V.-N., U.S. National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (Grant DK056350 to S.H.Z.), CEU-Banco Santander precompetitive project (MUSPB047) and CEUBanco Santander consolidation project (MBS18C12) to T.P., and Puleva BioFoods (to I.V.-N., G.V.-M., and M.A.P.). G.M. was supported by TARGEAR (FP7 PEOPLE 2013 IAPP612261).
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- 2019
19. Solid Lipid Nanoparticles Loaded with Glucocorticoids Protect Auditory Cells from Cisplatin-Induced Ototoxicity
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Silvia Murillo-Cuesta, Marina Bruno, Lide Arana, Blanca Cervantes, Isabel Varela-Nieto, Itziar Alkorta, Ministerio de Economía y Competitividad (España), European Commission, and Comunidad de Madrid
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intratympanic dexamethasone ,Hydrocortisone ,carriers ,lcsh:Medicine ,dexamethasone ,Pharmacology ,Article ,Dexamethasone ,Rhodamine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ototoxicity ,Solid lipid nanoparticle ,Medicine ,hydrocortisone ,otic protection ,030304 developmental biology ,Cisplatin ,0303 health sciences ,mechanisms ,nanocarriers ,business.industry ,lcsh:R ,sustains ,Stearic acid-based solid lipid nanoparticle (SLN) ,General Medicine ,medicine.disease ,sensorineural hearing-loss ,In vitro ,Otic protection ,drug-delivery ,body regions ,HEI-OC1 cells ,polymeric nanoparticles ,chemistry ,030220 oncology & carcinogenesis ,Drug delivery ,stearic acid-based solid lipid nanoparticle (SLN) ,Nanocarriers ,business ,management ,medicine.drug ,cancer-therapy - Abstract
© 2019 by the authors., Cisplatin is a chemotherapeutic agent that causes the irreversible death of auditory sensory cells, leading to hearing loss. Local administration of cytoprotective drugs is a potentially better option co-therapy for cisplatin, but there are strong limitations due to the difficulty of accessing the inner ear. The use of nanocarriers for the efficient delivery of drugs to auditory cells is a novel approach for this problem. Solid lipid nanoparticles (SLNs) are biodegradable and biocompatible nanocarriers with low solubility in aqueous media. We show here that stearic acid-based SLNs have the adequate particle size, polydispersity index and ζ-potential, to be considered optimal nanocarriers for drug delivery. Stearic acid-based SLNs were loaded with the fluorescent probe rhodamine to show that they are efficiently incorporated by auditory HEI-OC1 (House Ear Institute-Organ of Corti 1) cells. SLNs were not ototoxic over a wide dose range. Glucocorticoids are used to decrease cisplatin-induced ototoxicity. Therefore, to test SLNs’ drug delivery efficiency, dexamethasone and hydrocortisone were tested either alone or loaded into SLNs and tested in a cisplatin-induced ototoxicity in vitro assay. Our results indicate that the encapsulation in SLNs increases the protective effect of low doses of hydrocortisone and lengthens the survival of HEI-OC1 cells treated with cisplatin., B.C. was supported by an MSC postdoctoral contract, FP7-PEOPLE2013-IAPP TARGEAR. This work was supported by grants MINECO/FEDER (SAF2017-86107-R) and Comunidad de Madrid/FEDER MULTITARGET&VIEW-CM (B2017/BMD-3688) to I.V.N. and ELKARTEK (2017 KK-2017/00008) to I.A.
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- 2019
20. Author response: Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss
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Laura Pintado-Berninches, Lourdes Rodriguez-de la Rosa, Silvia Murillo-Cuesta, Adelaida M. Celaya, Rosario Perona, Jose M Bermúdez-Muñoz, Isabel Sánchez-Pérez, and Isabel Varela-Nieto
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medicine.medical_specialty ,Endocrinology ,biology ,Chemistry ,Internal medicine ,Mitogen-activated protein kinase ,Phosphatase ,medicine ,biology.protein ,Progressive hearing loss - Published
- 2018
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21. Author response: Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss
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Meritxell Espino Guarch, Mariona Font-Llitjós, Silvia Murillo-Cuesta, Ekaitz Errasti- Murugarren, Adelaida M Celaya, Giorgia Girotto, Dragana Vuckovic, Massimo Mezzavilla, Clara Vilches, Susanna Bodoy, Ignasi Sahún, Laura González, Esther Prat, Antonio Zorzano, Mara Dierssen, Isabel Varela-Nieto, Paolo Gasparini, Manuel Palacín, and Virginia Nunes
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- 2018
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22. Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss
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Mara Dierssen, Clara Vilches, Esther Prat, Dragana Vuckovic, Giorgia Girotto, Isabel Varela-Nieto, Ekaitz Errasti-Murugarren, Mariona Font-Llitjós, Adelaida M. Celaya, Silvia Murillo-Cuesta, Laura González, Massimo Mezzavilla, Paolo Gasparini, Virginia Nunes, Susanna Bodoy, Antonio Zorzano, Ignasi Sahún, Manuel Palacín, Meritxell Espino Guarch, Universitat de Barcelona, Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Qatar National Research Fund, Guarch, Meritxell Espino, Font-Llitjós, Mariona, Murillo-Cuesta, Silvia, Errasti-Murugarren, Ekaitz, Celaya, Adelaida M., Girotto, Giorgia, Vuckovic, Dragana, Mezzavilla, Massimo, Vilches, Clara, Bodoy, Susanna, Sahún, Ignasi, González, Laura, Prat, Esther, Zorzano, Antonio, Dierssen, Mara, Varela-Nieto, Isabel, Gasparini, Paolo, Palacín, Manuel, and Nunes, Virginia
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0301 basic medicine ,Genetics and Molecular Biology (all) ,medicine ,Etiology ,Mouse ,Immunology and Microbiology (all) ,Disease ,Audiology ,Biochemistry ,Persones grans ,Mice ,knock-out mouse model ,0302 clinical medicine ,Medicine ,chromosome ,Biology (General) ,genes ,age-related hearing lo ,General Neuroscience ,Fusion Regulatory Protein 1, Light Chains ,human biology ,Human biology ,General Medicine ,hearing lo ,Presbycusis ,3. Good health ,age-related hearing loss ,medicine.anatomical_structure ,Genes and Chromosomes ,Etiologia ,medicine.symptom ,Research Article ,Human ,chromosomes ,medicine.medical_specialty ,Amino Acid Transport System y+ ,Hearing loss ,QH301-705.5 ,Science ,L-Type Amino Acid Transporter ,Age-related hearing loss ,General Biochemistry, Genetics and Molecular Biology ,Chromosomes ,Novel gene ,03 medical and health sciences ,Trastorns auditius ,otorhinolaryngologic diseases ,Animals ,Humans ,Inner ear ,human ,Genetic Testing ,LAT2 ,Slc7a8 ,auditory brainstem response ,hearing loss ,mouse ,Neuroscience (all) ,Biochemistry, Genetics and Molecular Biology (all) ,gene ,Human Biology and Medicine ,Gene ,General Immunology and Microbiology ,business.industry ,Mutació (Biologia) ,Mutation (Biology) ,Hearing disorders ,030104 developmental biology ,Auditory brainstem response ,Genes ,Mutation ,Older people ,business ,030217 neurology & neurosurgery ,Gene Deletion - Abstract
Age-related hearing loss (ARHL) is the most common sensory deficit in the elderly. The disease has a multifactorial etiology with both environmental and genetic factors involved being largely unknown. SLC7A8/SLC3A2 heterodimer is a neutral amino acid exchanger. Here, we demonstrated that SLC7A8 is expressed in the mouse inner ear and that its ablation resulted in ARHL, due to the damage of different cochlear structures. These findings make SLC7A8 transporter a strong candidate for ARHL in humans. Thus, a screening of a cohort of ARHL patients and controls was carried out revealing several variants in SLC7A8, whose role was further investigated by in vitro functional studies. Significant decreases in SLC7A8 transport activity was detected for patient’s variants (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu) further supporting a causative role for SLC7A8 in ARHL. Moreover, our preliminary data suggest that a relevant proportion of ARHL cases could be explained by SLC7A8 mutations., eLife digest Age-related hearing loss affects about one in three individuals between the ages of 65 and 74. The first symptom is difficulty hearing high-pitched sounds like children’s voices. The disease starts gradually and worsens over time. Changes in the ear, the nerve that connects it to the brain, or the brain itself can cause hearing loss. Sometimes all three play a role. Genetics, exposure to noise, disease, and aging may all contribute. The condition is so complex it is difficult for scientists to pinpoint a primary suspect or develop treatments. Now, Guarch, Font-Llitjós et al. show that errors in a protein called SLC7A8 cause age-related hearing loss in mice and humans. The SLC7A8 protein acts like a door that allows amino acids – the building blocks of proteins – to enter or leave a cell. This door is blocked in mice lacking SLC7A8 and damage occurs in the part of their inner ear responsible for hearing. As a result, the animals lose their hearing. Next, Guarch, Font-Llitjós et al. scanned the genomes of 147 people from isolated villages in Italy for mutations in the gene for SLC7A8. The people also underwent hearing tests. Mutations in the gene for SLC7A8 that partially block the door and prevent the flow of amino acids were found in people with hearing loss. Some mutations in SLC7A8 that allow the door to stay open where found in people who could hear. The experiments suggest that certain mutations in the gene for SLC7A8 are likely an inherited cause of age-related hearing loss. It is possible that other proteins that control the flow of amino acids into or out of cells also may play a role in hearing. More studies are needed to see if it is possible to fix errors in the SLC7A8 protein to delay or restore the hearing loss.
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- 2018
23. MPZL2, Encoding the Epithelial Junctional Protein Myelin Protein Zero-like 2, Is Essential for Hearing in Man and Mouse
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Adelaida M. Celaya, Helger G. Yntema, Suzanne E. de Bruijn, Kees Okkersen, Jaap Oostrik, H. Kremer, Elisabeth H. Hoefsloot, R.J. Stokroos, Erwin van Wijk, Nicol C. Voermans, Stefan H. Lelieveld, H.H.W. de Gier, Theo A. Peters, Henricus P. M. Kunst, M.F. van Dooren, Elena Gómez-Rosas, Carel B. Hoyng, S.G.M. Frints, Ronald J.C. Admiraal, I. Feenstra, Rolien Free, Andy J. Beynon, Hans J. P. M. Koenen, Ilse Feenstra, Isabel Varela-Nieto, A. J. van Essen, Peter Lichtner, L.J.C. Rotteveel, M.P. van der Schroeff, Margit Schraders, Jack Weeda, Ignacio del Castillo, S.G. Kant, J.R. Hof, R.J.E. Pennings, Els K. Vanhoutte, H.G. Yntema, R.J.C. Admiraal, Irma Joosten, Pau Serra, Silvia Murillo-Cuesta, Ronald J.E. Pennings, Mieke Wesdorp, Bas P. Hartel, Hannie Kremer, J.S. Klein-Wassink, Anne M.M. Oonk, Ministerio de Economía y Competitividad (España), European Commission, and Instituto de Salud Carlos III
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0301 basic medicine ,Male ,Pathology ,Deiters cells ,cochlea ,MathematicsofComputing_GENERAL ,Degeneration (medical) ,Deafness ,Epithelium ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Myelin ,Mice ,Hearing ,Genetics (clinical) ,Neurons ,Homozygote ,TheoryofComputation_GENERAL ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Cochlea ,medicine.anatomical_structure ,Female ,Spiral Ganglion ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,medicine.medical_specialty ,hair cells ,MPZL2 ,Hearing Loss, Sensorineural ,Biology ,Deiters Cells ,Mpzl2 ,Hair Cells ,Hearing Impairment ,Human ,Mouse ,Article ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Hair Cells, Auditory ,Genetics ,medicine ,Cell Adhesion ,otorhinolaryngologic diseases ,Animals ,Humans ,Inner ear ,human ,Spiral ganglion ,mouse ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Myelin protein zero ,hearing impairment ,Mice, Inbred C57BL ,030104 developmental biology ,Organ of Corti ,Mutation ,sense organs ,Cell Adhesion Molecules - Abstract
DOOFNL Consortium., In a Dutch consanguineous family with recessively inherited nonsyndromic hearing impairment (HI), homozygosity mapping combined with whole-exome sequencing revealed a MPZL2 homozygous truncating variant, c.72del (p.Ile24Metfs∗22). By screening a cohort of phenotype-matched subjects and a cohort of HI subjects in whom WES had been performed previously, we identified two additional families with biallelic truncating variants of MPZL2. Affected individuals demonstrated symmetric, progressive, mild to moderate sensorineural HI. Onset of HI was in the first decade, and high-frequency hearing was more severely affected. There was no vestibular involvement. MPZL2 encodes myelin protein zero-like 2, an adhesion molecule that mediates epithelial cell-cell interactions in several (developing) tissues. Involvement of MPZL2 in hearing was confirmed by audiometric evaluation of Mpzl2-mutant mice. These displayed early-onset progressive sensorineural HI that was more pronounced in the high frequencies. Histological analysis of adult mutant mice demonstrated an altered organization of outer hair cells and supporting cells and degeneration of the organ of Corti. In addition, we observed mild degeneration of spiral ganglion neurons, and this degeneration was most pronounced at the cochlear base. Although MPZL2 is known to function in cell adhesion in several tissues, no phenotypes other than HI were found to be associated with MPZL2 defects. This indicates that MPZL2 has a unique function in the inner ear. The present study suggests that deleterious variants of Mplz2/MPZL2 affect adhesion of the inner-ear epithelium and result in loss of structural integrity of the organ of Corti and progressive degeneration of hair cells, supporting cells, and spiral ganglion neurons., This work was supported by a grant from the Heinsius Houbolt Foundation (to H.K., R.J.E.P., and H.P.M.K.) and partially by grants from the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (Fonds Europeen de Developpement Economique et Regional, [FEDER]: SAF2014-53979-R) and from FEDER, CIBERER, and Instituto de Salud Carlos III (ISCIII) (to I.V.N.), and a grant from ISCIII to I.d.C. (PI14/01162; Plan Estatal de IþDþI 2013-2016, with co-funding from the European Regional Development Fund). S.M., A.M.C., and E.G.R. hold CIBERER ISCIII researcher contracts.
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- 2018
24. A Comparative Study of Drug Delivery Methods Targeted to the Mouse Inner Ear: Bullostomy Versus Transtympanic Injection
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Néstor Vallecillo, Adelaida M. Celaya, Silvia Murillo-Cuesta, Luis Lassaletta, Julio Contreras, Isabel Varela-Nieto, and Rafael Cediel
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medicine.medical_specialty ,General Chemical Engineering ,medicine.medical_treatment ,Perforation (oil well) ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,otorhinolaryngologic diseases ,medicine ,Inner ear ,030223 otorhinolaryngology ,Cochlea ,Round window ,General Immunology and Microbiology ,business.industry ,General Neuroscience ,Microsurgery ,Surgery ,medicine.anatomical_structure ,Auditory brainstem response ,Drug delivery ,Middle ear ,sense organs ,business ,030217 neurology & neurosurgery ,Biomedical engineering - 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.
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- 2017
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25. The expression of oxidative stress response genes is modulated by a combination of resveratrol and N-acetylcysteine to ameliorate ototoxicity in the rat cochlea
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Fernando García-Alcántara, Sara Pulido, Teresa Rivera, Jose M Bermúdez-Muñoz, Marta Milo, Silvia Murillo-Cuesta, Isabel Varela-Nieto, Raquel Martínez-Vega, Ministerio de Economía y Competitividad (España), European Commission, Instituto de Salud Carlos III, and Consejo Superior de Investigaciones Científicas (España)
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0301 basic medicine ,Male ,GPX1 ,Inflammation ,Apoptosis ,Pharmacology ,Resveratrol ,medicine.disease_cause ,Antioxidants ,Acetylcysteine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ototoxicity ,Hearing ,Furosemide ,Kanamycin ,medicine ,Evoked Potentials, Auditory, Brain Stem ,Reaction Time ,Animals ,Auditory Fatigue ,Rats, Wistar ,Hearing Loss ,business.industry ,Aminoglycoside ,medicine.disease ,Sensory Systems ,3. Good health ,Cochlea ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,chemistry ,Gene Expression Regulation ,Cytoprotection ,Drug Therapy, Combination ,medicine.symptom ,Inflammation Mediators ,business ,030217 neurology & neurosurgery ,Oxidative stress ,medicine.drug ,Brain Stem - Abstract
Aminoglycoside antibiotics are used widely in medicine despite their ototoxic side-effects. Oxidative stress and inflammation are key mechanisms determining the extent and severity of the damage. Here we evaluate the protective effect of a treatment with resveratrol plus N-acetylcysteine on the ototoxic actions of kanamycin and furosemide in the rat. Resveratrol (10 mg/kg) and N-acetylcysteine (400 mg/kg) were administered together to Wistar rats on 5 consecutive days. The second day, a concentrated solution of kanamycin and furosemide was placed on the round window to induce ototoxicity. Hearing was assessed by recording auditory brainstem responses before and 5, 16 and 23 days after the beginning of the treatment. Cochlear samples were taken at day 5 (end of the treatment) and at day 23, and targeted PCR arrays or RT-qPCR were performed to analyze oxidative balance and inflammation related genes, respectively. In addition, the cytoarchitecture and the presence of apoptosis, oxidative stress and inflammation markers were evaluated in cochlear sections. Results indicate that administration of resveratrol plus N-acetylcysteine reduced the threshold shifts induced by ototoxic drugs at high frequencies (≈10 dB), although this protective effect fades after the cessation of the treatment. Gene expression analysis showed that the treatment modulated the expression of genes involved in the cellular oxidative (Gpx1, Sod1, Ccs and Noxa1) and inflammatory (Il1b, Il4, Mpo and Ncf) responses to injury. Thus, co-administration of resveratrol and NAC, routinely used individually in patients, could reduce the ototoxic secondary effects of aminoglycosides., This work was supported by the European Commission FP7-PEOPLE-2013-IAPP TARGEAR and Spanish Ministerio de Economía y Competitividad (MINECO) FEDER/SAF2014-53979-R to IV-N, and FEDER-ERDF FIS PI10/00394 to TR. SM holds a CIBERER ISCIII researcher contract. SP is supported by a FPI predoctoral fellowship (BES-2015-071311) funded by MINECO and the European Social Fund JMBM and RMV held CSIC predoctoral contracts. SP and MM were further supported by a STSM from MouseAge (COST-BM1402) and by CIBERER (ISCIII, Spain).
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- 2016
26. Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss On CBA/Ca Mice
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María A. Pajares, Raquel Martínez-Vega, Gregorio Varela-Moreiras, Teresa Partearroyo, Silvia Murillo-Cuesta, Isabel Varela-Nieto, Ministerio de Economía y Competitividad (España), European Commission, and Consejo Superior de Investigaciones Científicas (España)
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0301 basic medicine ,Aging ,Hyperhomocysteinemia ,medicine.medical_specialty ,Homocysteine ,Anemia ,Hearing loss ,Cognitive Neuroscience ,cochlea ,Physiology ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Audiology ,lcsh:RC321-571 ,03 medical and health sciences ,chemistry.chemical_compound ,folic acid ,0302 clinical medicine ,Vitamin deficiency ,Dietary folate ,dietary intervention ,medicine ,otorhinolaryngologic diseases ,hyperhomocysteinemia ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Cochlea ,Original Research ,business.industry ,homocysteine ,hearing impairment ,medicine.disease ,3. Good health ,030104 developmental biology ,chemistry ,Folic acid ,vitamin deficiency ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Neuroscience - Abstract
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)., Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after two-months, corroborating the epidemiological association previously described between vitamin deficiency and this sensory impairment. However, this strain is prone to early hearing loss, and hence we decided to analyze whether the effects exerted by folate deprivation follow the same pattern in a mouse strain such as CBA/Ca, which is resistant to hearing impairment. Here, we show results of a long-term study on hearing carried out on CBA/Ca mice subjected to dietary folate deprivation. Systemic changes included decreased serum folate levels, hyperhomocysteinemia and signs of anemia in the group fed the folate-deficient diet. Initial signs of hearing loss were detected in this strain after 8-months of vitamin deficiency, and correlated with histological damage in the cochleae. In conclusion, the data presented reinforce the importance of adequate folic acid levels for the auditory system and suggest that the impact of dietary deficiencies may depend on the genetic background., RM was a fellow of the JAE-CSIC predoctoral program. This work was supported by grants of the Ministerio de Economía y Competitividad (SAF2014-53979-R to IV; BFU2009-08977 to MP), the European Union (FP7-AFHELO and TARGEAR to IV).
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- 2016
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27. Age-related functional and structural retinal modifications in the Igf1−/− null mouse
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Laura Fernández-Sánchez, L. Rodriguez-de la Rosa, Isabel Varela-Nieto, Nicolás Cuenca, P. de la Villa, Francisco Germain, Silvia Murillo-Cuesta, Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, and Neurobiología del Sistema Visual y Terapia de Enfermedades Neurodegenerativas (NEUROVIS)
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Male ,Oncology ,Aging ,medicine.medical_specialty ,endocrine system ,Mice, 129 Strain ,genetic structures ,Vision Disorders ,Biología Celular ,Deafness ,Biology ,Audiology ,Retina ,lcsh:RC321-571 ,Mice ,chemistry.chemical_compound ,Internal medicine ,Age related ,Electroretinography ,medicine ,Animals ,Insulin-Like Growth Factor I ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Mice, Knockout ,Deaf-blindness ,INSULIN-LIKE GROWTH FACTOR I DEFICIENCY ,IGF1 ,Retinal ,Disease Models, Animal ,Neurology ,chemistry ,Degeneration ,Deaf blindness ,Female ,Christian ministry ,Null Mouse ,sense organs ,hormones, hormone substitutes, and hormone antagonists - Abstract
[Background]: Mutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic neurosensorial deafness. To understand the precise role of IGF-I in retinal physiology, we have studied the morphology and electrophysiology of the retina of the Igf1(-/-) mice in comparison with that of the Igf1(+/-) and Igf1(+/+) animals during aging. [Methods]: Serological concentrations of IGF-I, glycemia and body weight were determined in Igf1(+/+), Igf1(+/-) and Igf1(-/-) mice at different times up to 360days of age. We have analyzed hearing by recording the auditory brainstem responses (ABR), the retinal function by electroretinographic (ERG) responses and the retinal morphology by immunohistochemical labeling on retinal preparations at different ages. [Results]: IGF-I levels are gradually reduced with aging in the mouse. Deaf Igf1(-/-) mice had an almost flat scotopic ERG response and a photopic ERG response of very small amplitude at postnatal age 360days (P360). At the same age, Igf1(+/-) mice still showed both scotopic and photopic ERG responses, but a significant decrease in the ERG wave amplitudes was observed when compared with those of Igf1(+/+) mice. Immunohistochemical analysis showed that P360 Igf1(-/-) mice suffered important structural modifications in the first synapse of the retinal pathway, that affected mainly the postsynaptic processes from horizontal and bipolar cells. A decrease in bassoon and synaptophysin staining in both rod and cone synaptic terminals suggested a reduced photoreceptor output to the inner retina. Retinal morphology of the P360 Igf1(+/-) mice showed only small alterations in the horizontal and bipolar cell processes, when compared with Igf1(+/+) mice of matched age. [Conclusions]: In the mouse, IGF-I deficit causes an age-related visual loss, besides a congenital deafness. The present results support the use of the Igf1(-/-) mouse as a new model for the study of human syndromic deaf-blindness., This research was funded by grants from the Spanish Ministry of Science and InnovationSAF2010-21879 and RETICSRD07/0062/0008 to PdlV; BFU2009-07793/BFI, Fundaluce, ONCE and RETICSRD07/0062/0012 to NC; and SAF2008-0064, SAF2011-24391 and Intra-CIBERER programs to IV-N.
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- 2012
28. Direct drug application to the round window: A comparative study of ototoxicity in rats
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Jon Alexander Sistiaga, Guadalupe Camarero, Teresa Rivera, Elena Vacas, Isabel Varela-Nieto, Silvia Murillo-Cuesta, and Fernando García-Alcántara
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Male ,Hearing loss ,Administration, Topical ,Injections, Subcutaneous ,medicine.medical_treatment ,Random Allocation ,Ototoxicity ,Furosemide ,Kanamycin ,Evoked Potentials, Auditory, Brain Stem ,medicine ,Animals ,Rats, Wistar ,Hearing Loss ,Saline ,Round window ,business.industry ,medicine.disease ,Cochlea ,Rats ,Auditory brainstem response ,medicine.anatomical_structure ,Round Window, Ear ,Otorhinolaryngology ,Anesthesia ,Injections, Intravenous ,Systemic administration ,Surgery ,medicine.symptom ,business ,medicine.drug - Abstract
[Objective]: To assess the validity of inducing ototoxicity in rats by applying a sponge soaked in kanamycin and furosemide on the round window. [Study Design]: Basic, randomized, nonblind experimental study. [Setting]: Animal models of cochlear damage and reliable methods of local drug delivery are fundamental to study hearing loss and to design new therapies. [Subjects and Methods]: Four experimental groups of six Wistar rats with different methods of drug administration were used: (1) injection of subcutaneous kanamycin (400 mg/kg) and intravenous furosemide (100 mg/kg); (2) local application of a sponge soaked in saline close to the round window; (3) animals for which the sponge was soaked in a solution containing kanamycin (200 mg/mL) and furosemide (50 mg/mL); and (4) sham-operated rats. The tympanic bulla was exposed using a ventral approach, and a bullostomy was performed to visualize the round window membrane. Cochlear function was assessed by measuring the auditory brainstem response, and hearing thresholds in response to click and tone burst stimuli were determined as peak and interpeak latencies. At the end of the study, cochlear histology was analyzed. [Results]: Systemic administration of kanamycin and furosemide induced profound hearing loss and severe hair cell damage. Local delivery of these ototoxic drugs caused comparable damage but avoided the systemic side effects of the drug. Sham-operated and saline control animals did not experience functional alterations. [Conclusion]: Situating a sponge soaked in kanamycin and furosemide on the round window membrane through the ventral approach is a reliable method to provoke local ototoxicity in rats. © 2009 American Academy of Otolaryngology-Head and Neck Surgery Foundation.
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- 2009
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29. Melanin precursors prevent premature age-related and noise-induced hearing loss in albino mice
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Rafael Cediel, Lluis Montoliu, Esther Zurita, Isabel Varela-Nieto, Julio Contreras, Silvia Murillo-Cuesta, and Marta Cantero
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Genetically modified mouse ,medicine.medical_specialty ,Tyrosine hydroxylase ,Hearing loss ,Tyrosinase ,Dermatology ,Biology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Melanin ,Endocrinology ,Oncology ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Albinism ,sense organs ,medicine.symptom ,Cochlea ,Noise-induced hearing loss - Abstract
Strial melanocytes are required for normal development and correct functioning of the cochlea. Hearing deficits have been reported in albino individuals from different species, although melanin appears to be not essential for normal auditory function. We have analyzed the auditory brainstem responses (ABR) of two transgenic mice: YRT2, carrying the entire mouse tyrosinase (Tyr) gene expression-domain and undistinguishable from wild-type pigmented animals; and TyrTH, non-pigmented but ectopically expressing tyrosine hydroxylase (Th) in melanocytes, which generate the precursor metabolite, L-DOPA, but not melanin. We show that young albino mice present a higher prevalence of profound sensorineural deafness and a poorer recovery of auditory thresholds after noise-exposure than transgenic mice. Hearing loss was associated with absence of cochlear melanin or its precursor metabolites and latencies of the central auditory pathway were unaltered. In summary, albino mice show impaired hearing responses during ageing and after noise damage when compared to YRT2 and TyrTH transgenic mice, which do not show the albino-associated ABR alterations. These results demonstrate that melanin precursors, such as L-DOPA, have a protective role in the mammalian cochlea in age-related and noise-induced hearing loss.
- Published
- 2009
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30. Corrigendum: Transforming growth factor β1 inhibition protects from noise-induced hearing loss
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Guadalupe Camarero, Adelaida M. Celaya, Julio Contreras, Lourdes Rodriguez-de la Rosa, Isabel Varela-Nieto, Teresa Rivera, and Silvia Murillo-Cuesta
- Subjects
Gerontology ,Aging ,Cognitive Neuroscience ,MEDLINE ,medicine.disease ,protection ,lcsh:RC321-571 ,noise-induced hearing loss ,TGF-ß ,inflammation ,medicine ,cochlear injury ,Psychology ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Noise-induced hearing loss ,Transforming growth factor ,Neuroscience - Abstract
Unfortunately, the second author affiliation in the originally published article was incorrectly stated as being “Centre for Biomedical Network Research (CIBER), Institute of Health Carlos III (ISCIII), Madrid, Spain.” The correct author's affiliation is “Centre for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain.”
- Published
- 2015
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31. Corrigendum to: Swept-sine noise-induced damage as a hearing loss model for preclinical assays
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Silvia Murillo-Cuesta, Lorena Sanz, Isabel Varela-Nieto, Rafael Cediel, Carlos Avendaño, Pedro Cobo, Julio Contreras, and Teresa Rivera
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Aging ,hair cells ,GeneralLiterature_INTRODUCTORYANDSURVEY ,Noise induced ,Hearing loss ,Speech recognition ,Cognitive Neuroscience ,cytocochleogram ,computer.software_genre ,Hair cells ,GeneralLiterature_MISCELLANEOUS ,lcsh:RC321-571 ,Medicine ,Sine ,Hearing Loss ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,hearing loss ,business.industry ,InformationSystems_INFORMATIONSYSTEMSAPPLICATIONS ,transtympanic ,Transtympanic ,Data mining ,medicine.symptom ,business ,TGF-β inhibition ,computer ,violet noise ,Neuroscience - Abstract
Unfortunately, one of the affiliations included in the online published article is wrong. The complete and correct author's affiliation list is given here.
- Published
- 2015
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32. Transforming growth factor β1 inhibition protects from noise-induced hearing loss
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Silvia, Murillo-Cuesta, Lourdes, Rodríguez-de la Rosa, Julio, Contreras, Adelaida M, Celaya, Guadalupe, Camarero, Teresa, Rivera, and Isabel, Varela-Nieto
- Subjects
noise-induced hearing loss ,TGF-ß ,General Commentary ,inflammation ,cochlear injury ,protection ,Neuroscience - Published
- 2015
33. Comparative gene expression study of the vestibular organ of the Igf1 deficient mouse using whole-transcript arrays
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Sandra Falagan, Hortensia Sánchez-Calderón, Joaquín Dopazo, Silvia Murillo-Cuesta, Isabel Varela-Nieto, Julio Contreras, Lourdes Rodriguez-de la Rosa, Carlos Avendaño, Marta Milo, Instituto de Salud Carlos III, and European Commission
- Subjects
Heterozygote ,Insulin like growth factor 1m ,Genotype ,mRNAs ,Vestibular Nerve ,Biology ,p38 Mitogen-Activated Protein Kinases ,Transcriptome ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,medicine ,otorhinolaryngologic diseases ,Insulin like growth factor 1 ,Animals ,Cluster Analysis ,Affymetrix mouse gene 1.1. ST arrays ,False Positive Reactions ,Inner ear ,RNA, Messenger ,Insulin-Like Growth Factor I ,Transcriptomics ,Cochlea ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,Mice, Knockout ,Neurons ,Vestibular system ,Regulation of gene expression ,Genetics ,0303 health sciences ,Gene Expression Profiling ,Vestibular nerve ,Immunohistochemistry ,Sensory Systems ,Cell biology ,RNAs ,Gene expression profiling ,Phenotype ,medicine.anatomical_structure ,Gene Expression Regulation ,RNA, Long Noncoding ,Vestibule, Labyrinth ,sense organs ,030217 neurology & neurosurgery - Abstract
The auditory and vestibular organs form the inner ear and have a common developmental origin. Insulin like growth factor 1 (IGF-1) has a central role in the development of the cochlea and maintenance of hearing. Its deficiency causes sensorineural hearing loss in man and mice. During chicken early development, IGF-1 modulates neurogenesis of the cochleovestibular ganglion but no further studies have been conducted to explore the potential role of IGF-1 in the vestibular system. In this study we have compared the whole transcriptome of the vestibular organ from wild type and Igf1-/- mice at different developmental and postnatal times. RNA was prepared from E18.5, P15 and P90 vestibular organs of Igf1-/- and Igf1+/+ mice and the transcriptome analysed in triplicates using Affymetrix® Mouse Gene 1.1 ST Array Plates. These plates are whole-transcript arrays that include probes to measure both messenger (mRNA) and long intergenic non-coding RNA transcripts (lincRNA), with a coverage of over 28 thousand coding transcripts and over 7 thousands non-coding transcripts. Given the complexity of the data we used two different methods VSN-RMA and mmBGX to analyse and compare the data. This is to better evaluate the number of false positives and to quantify uncertainty of low signals. We identified a number of differentially expressed genes that we described using functional analysis and validated using RT-qPCR. The morphology of the vestibular organ did not show differences between genotypes and no evident alterations were observed in the vestibular sensory areas of the null mice. However, well-defined cellular alterations were found in the vestibular neurons with respect their number and size. Although these mice did not show a dramatic vestibular phenotype, we conducted a functional analysis on differentially expressed genes between genotypes and across time. This was with the aim to identify new pathways that are involved in the development of the vestibular organ as well as pathways that maybe affected by the lack of IGF-1 and be associated to the morphological changes of the vestibular neurons that we observed in the Igf1-/- mice., This study was supported by grants from FP7-PEOPLE-2013-IAPP 612261-TARGEAR to IVN, and CIBERER-INTRA/09/761.2 to IVN and JD. We thank Begoña Rodriguez for expert technical assistance with the celloidin material. LR-dlR and SM-C hold CIBERER contracts.
- Published
- 2015
34. Transforming growth factor ß1 inhibition protects from noise-induced hearing loss
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Silvia Murillo-Cuesta, Isabel Varela-Nieto, Teresa Rivera, Adelaida M. Celaya, Lourdes RodrÃguez-de la Rosa, Julio Contreras, Guadalupe Camarero, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, and Centro de Investigación Biomédica en Red Enfermedades Raras (España)
- Subjects
TGF-β ,Aging ,Pathology ,medicine.medical_specialty ,Hearing loss ,Cognitive Neuroscience ,Cochlear injury ,Inflammation ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Pharmacology ,medicine.disease_cause ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,otorhinolaryngologic diseases ,Inner ear ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,030304 developmental biology ,Original Research ,0303 health sciences ,Protection ,business.industry ,medicine.disease ,protection ,3. Good health ,noise-induced hearing loss ,medicine.anatomical_structure ,TGF-ß ,inflammation ,Systemic administration ,medicine.symptom ,cochlear injury ,Noise-induced hearing loss ,business ,030217 neurology & neurosurgery ,Oxidative stress ,Transforming growth factor ,Neuroscience - Abstract
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)., Excessive exposure to noise damages the principal cochlear structures leading to hearing impairment. Inflammatory and immune responses are central mechanisms in cochlear defensive response to noise but, if unregulated, they contribute to inner ear damage and hearing loss. Transforming growth factor ß (TGF-ß) is a key regulator of both responses and high levels of this factor have been associated with cochlear injury in hearing loss animal models. To evaluate the potential of targeting TGF-ß as a therapeutic strategy for preventing or ameliorating noise-induced hearing loss, we studied the auditory function, cochlear morphology, gene expression and oxidative stress markers in mice exposed to noise and treated with TGF-ß1 peptidic inhibitors P17 and P144, just before or immediately after noise insult. Our results indicate that systemic administration of both peptides significantly improved both the evolution of hearing thresholds and the degenerative changes induced by noise-exposure in lateral wall structures. Moreover, treatments ameliorated the inflammatory state and redox balance. These therapeutic effects were dose-dependent and more effective if the TGF-ß1 inhibitors were administered prior to inducing the injury. In conclusion, inhibition of TGF-ß1 actions with antagonistic peptides represents a new, promising therapeutic strategy for the prevention and repair of noise-induced cochlear damage., This study was supported by grants from the Ministerio de Ciencia e Innovación (SAF2011-24391), DIGNA Biotech, the 7th Framework Programme projects AFHELO and TARGEAR for IVN and FIS PI 10/00394 for TR. SM-C, LRdR and GC hold contracts from CIBERER (SM, LRdR) and CSIC Junta para la Ampliación de Estudios programs (GC).
- Published
- 2015
35. IGF-I deficiency and hearing loss: molecular clues and clinical implications
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Isabel, Varela-Nieto, Silvia, Murillo-Cuesta, Lourdes, Rodríguez-de la Rosa, Luis, Lassatetta, and Julio, Contreras
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Adult ,Disease Models, Animal ,Ear, Inner ,Hearing Loss, Sensorineural ,Animals ,Humans ,Insulin-Like Growth Factor I ,Child - Abstract
Sensorineural hearing loss is a clinical heterogeneous disorder and a significant health-care problem with tremendous socio-economic impact. According to WHO, "Over 5% of the world's population has disabling hearing loss -328 million adults and 32 million children-". In children, early hearing loss affects language acquisition. Hearing deficits are generally associated with the loss of the sensory "hair" cells and/or neurons caused by primary genetic defects or secondary to environmental factors including infections, noise and ototoxic drugs. Hearing loss cannot be reversed and currently the available treatment is limited to hearing aids and cochlear implants. Studies are being conducted to develop alternative treatments combining both preventive and reparative strategies. Human insulin like growth factor (IGF) I deficiency is a rare disease associated with hearing loss, poor growth rates and mental retardation (ORPHA73272, OMIM608747). Similarly, lgf1-/- mice are dwarfs with poor survival rates and congenital profound sensorineural deafness. IGF-I is known to be a neuroprotective agent that maintains cellular metabolism, activates growth, proliferation and differentiation, and limits cell death. Here we will discuss the basic mechanisms underlying IGF-I actions in the auditory system and their clinical implications to pursue novel treatments to ameliorate hearing loss.
- Published
- 2013
36. Treatment with N- and C-terminal peptides of parathyroid hormone-related protein partly compensate the skeletal abnormalities in IGF-I deficient mice
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Lourdes Rodriguez-de la Rosa, Pedro Esbrit, Isabel Varela-Nieto, Ana López-Herradón, Daniel Lozano, Sergio Portal-Núñez, Rafael Cediel, and Silvia Murillo-Cuesta
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Male ,Anatomy and Physiology ,Mouse ,medicine.medical_treatment ,Parathyroid hormone ,lcsh:Medicine ,Gene Expression ,Biochemistry ,chemistry.chemical_compound ,Mice ,Molecular Cell Biology ,Membrane Receptor Signaling ,Femur ,Insulin-Like Growth Factor I ,Receptor ,lcsh:Science ,Musculoskeletal System ,Growth Disorders ,Cellular Stress Responses ,Multidisciplinary ,Chemistry ,Mechanisms of Signal Transduction ,Osteoblast ,Animal Models ,Signaling Cascades ,medicine.anatomical_structure ,Phenotype ,Osteocyte ,Female ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,Research Article ,musculoskeletal diseases ,medicine.medical_specialty ,Histology ,Hearing Loss, Sensorineural ,Bone and Mineral Metabolism ,Endocrine System ,Signaling Pathways ,Cell Growth ,Model Organisms ,Osteoprotegerin ,Internal medicine ,medicine ,Animals ,Biology ,Osteoblasts ,Parathyroid hormone-related protein ,Growth factor ,lcsh:R ,Parathyroid Hormone-Related Protein ,Peptide Fragments ,Radiography ,Oxidative Stress ,Endocrinology ,Metabolism ,Gene Expression Regulation ,Sclerostin ,lcsh:Q - Abstract
Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1-36) and PTHrP (107-111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a , cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1-36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1-36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone.
- Published
- 2013
37. Programmed cell senescence during mammalian embryonic development
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Gonzalo Gómez-López, Isabel Varela-Nieto, Daniel Muñoz-Espín, Manuel Serrano, Antonio Maraver, Alfonso Rodríguez-Baeza, Jesús Ruberte, Silvia Murillo-Cuesta, Manuel Collado, Marta Cañamero, Julio Contreras, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Centro Nacional de Investigaciones Oncológicas (España), Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Comunidad de Madrid, European Commission, European Research Council, Fundación Ramón Areces, Fundación Botín, AXA Research Fund, and Fundación Mutua Madrileña
- Subjects
Senescence ,0303 health sciences ,DNA damage ,Biochemistry, Genetics and Molecular Biology(all) ,Mesonephros ,SMAD ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Endolymphatic sac ,3. Good health ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Apoptosis ,030220 oncology & carcinogenesis ,medicine ,Senolytic ,PI3K/AKT/mTOR pathway ,030304 developmental biology - Abstract
et al., Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence., D.M.-E. has been funded by the Juan de la Cierva Program. A.M. and M. Collado were funded by the Miguel Servet Program. S.M.-C. holds a CIBERER (ISCIII) postdoctoral contract. Work in the laboratory of M.S. is funded by the CNIO and by grants from the MICINN (SAF), the Regional Government of Madrid, the European Research Council (Advanced ERC Grant), the Botín Foundation, the Ramón Areces Foundation, and the AXA Foundation. Work in the I.V.-N. group is supported by grants from MINECO (SAF2011-24391), Fundación de Investigación Médica Mutua Madrileña (2012), and AFHELO (FP7, European Union).
- Published
- 2013
38. Insulin receptor substrate 2 (IRS2)-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine phosphatase 1B (PTP1B) loss of function
- Author
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Águeda González-Rodríguez, Lourdes Rodriguez-de la Rosa, Carlos Avendaño, Deborah J. Burks, Silvia Murillo-Cuesta, Isabel Varela-Nieto, Guadalupe Camarero, Ángela M. Valverde, UAM. Departamento de Anatomía, Histología y Neurociencia, Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Instituto de Salud Carlos III, and Consejo Superior de Investigaciones Científicas (España)
- Subjects
Male ,medicine.medical_specialty ,Insulin Receptor Substrate Proteins ,Medicina ,Hearing loss ,medicine.medical_treatment ,Mice, Transgenic ,Mice ,Internal medicine ,Insulin receptor substrate ,Genetics ,medicine ,otorhinolaryngologic diseases ,Animals ,Hearing Loss ,Molecular Biology ,Genetics (clinical) ,Spiral ganglion ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,biology ,Insulin ,Articles ,medicine.disease ,IRS2 ,Cochlea ,Insulin receptor ,Endocrinology ,medicine.anatomical_structure ,biology.protein ,Molecular Medicine ,Sensorineural hearing loss ,Protein Tyrosine Phosphatase ,medicine.symptom ,Mitogen-Activated Protein Kinases - Abstract
The insulin receptor substrate (IRS) proteins are key mediators of insulin and insulinlike growth factor 1 (IGF-1) signaling. Protein tyrosine phosphatase (PTP)-1B dephosphorylates and inactivates both insulin and IGF-1 receptors. IRS2-deficient mice present altered hepatic insulin signaling and β-cell failure and develop type 2-like diabetes. In addition, IRS2 deficiency leads to developmental defects in the nervous system. IGF1gene mutations cause syndromic sensorineural hearing loss in humans and mice. However, the involvement of IRS2 and PTP1B, two IGF-1 downstream signaling mediators, in hearing onset and loss has not been studied. Our objective was to study the hearing function and cochlear morphology of Irs2-null mice and the impact of PTP1B deficiency. We have studied the auditory brainstem responses and the cochlear morphology of systemic Irs2 -/-Ptpn1 +/+, Irs2 +/+Ptpn1 -/- and Irs2 -/-Ptpn1 -/- mice at different postnatal ages. The results indicated that Irs2 -/-Ptpn1 +/+ mice present a profound congenital sensorineural deafness before the onset of diabetes and altered cochlear morphology with hypoinnervation of the cochlear ganglion and aberrant stria vascularis, compared with wild-type mice. Simultaneous PTP1B deficiency in Irs2 -/-Ptpn1 -/- mice delays the onset of deafness. We show for the first time that IRS2 is essential for hearing and that PTP1B inhibition may be useful for treating deafness associated with hyperglycemia and type 2 diabetes., This work was supported by the Ministerio de Ciencia e Innovacion (SAF2008-00470 and SAF2011 to I Varela-Nieto and SAF2009-08114 to AM Valverde) and the Fundacion Mutua Madrileña to IV Varela-Nieto. S Murillo-Cuesta, A González-Rodríguez and G Camarero hold postdoctoral contracts from the CIBERER, CIBERDEM and CSIC Junta para la Ampliación de Estudios (JAE) programs, respectively.
- Published
- 2011
39. Modelos animales para el estudio de la sordera
- Author
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Silvia Murillo-Cuesta
- Published
- 2010
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40. Melanin precursors prevent premature age-related and noise-induced hearing loss in albino mice
- Author
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Silvia, Murillo-Cuesta, Julio, Contreras, Esther, Zurita, Rafael, Cediel, Marta, Cantero, Isabel, Varela-Nieto, and Lluís, Montoliu
- Subjects
Melanins ,Aging ,Tyrosine 3-Monooxygenase ,Albinism ,Monophenol Monooxygenase ,Hearing Loss, Sensorineural ,Aging, Premature ,Mice, Transgenic ,Gene Expression Regulation, Enzymologic ,Levodopa ,Disease Models, Animal ,Mice ,Hearing Loss, Noise-Induced ,Albinism, Oculocutaneous ,Evoked Potentials, Auditory, Brain Stem ,Animals ,Genetic Predisposition to Disease - Abstract
Strial melanocytes are required for normal development and correct functioning of the cochlea. Hearing deficits have been reported in albino individuals from different species, although melanin appears to be not essential for normal auditory function. We have analyzed the auditory brainstem responses (ABR) of two transgenic mice: YRT2, carrying the entire mouse tyrosinase (Tyr) gene expression-domain and undistinguishable from wild-type pigmented animals; and TyrTH, non-pigmented but ectopically expressing tyrosine hydroxylase (Th) in melanocytes, which generate the precursor metabolite, L-DOPA, but not melanin. We show that young albino mice present a higher prevalence of profound sensorineural deafness and a poorer recovery of auditory thresholds after noise-exposure than transgenic mice. Hearing loss was associated with absence of cochlear melanin or its precursor metabolites and latencies of the central auditory pathway were unaltered. In summary, albino mice show impaired hearing responses during ageing and after noise damage when compared to YRT2 and TyrTH transgenic mice, which do not show the albino-associated ABR alterations. These results demonstrate that melanin precursors, such as L-DOPA, have a protective role in the mammalian cochlea in age-related and noise-induced hearing loss.
- Published
- 2009
41. Erratum to: IGF-1 deficiency causes atrophic changes associated with upregulation of VGluT1 and downregulation of MEF2 transcription factors in the mouse cochlear nuclei
- Author
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Julio Contreras, Juan Carlos Alvarado, L. Rodriguez-de la Rosa, Verónica Fuentes-Santamaría, Silvia Murillo-Cuesta, José M. Juiz, and Isabel Varela-Nieto
- Subjects
Mef2 ,Histology ,biology ,General Neuroscience ,Vesicular glutamate transporter 1 ,Cochlear nucleus ,Glutamatergic ,medicine.anatomical_structure ,Downregulation and upregulation ,Synaptic plasticity ,otorhinolaryngologic diseases ,biology.protein ,medicine ,sense organs ,Anatomy ,Neuroscience ,Spiral ganglion ,Neurotrophin - Abstract
Insulin-like growth factor 1 (IGF-1) is a neurotrophic protein that plays a crucial role in modulating neuronal function and synaptic plasticity in the adult brain. Mice lacking the Igf1 gene exhibit profound deafness and multiple anomalies in the inner ear and spiral ganglion. An issue that remains unknown is whether, in addition to these peripheral abnormalities, IGF-1 deficiency also results in structural changes along the central auditory pathway that may contribute to an imbalance between excitation and inhibition, which might be reflected in abnormal auditory brainstem responses (ABR). To assess such a possibility, we evaluated the morphological and physiological alterations in the cochlear nucleus complex of the adult mouse. The expression and distribution of the vesicular glutamate transporter 1 (VGluT1) and the vesicular inhibitory transporter (VGAT), which were used as specific markers for labeling excitatory and inhibitory terminals, and the involvement of the activity-dependent myocyte enhancer factor 2 (MEF2) transcription factors in regulating excitatory synapses were assessed in a 4-month-old mouse model of IGF-1 deficiency and neurosensorial deafness (Igf1−/− homozygous null mice). The results demonstrate decreases in the cochlear nucleus area and cell size along with cell loss in the cochlear nuclei of the deficient mouse. Additionally, our results demonstrate that there is upregulation of VGluT1, but not VGAT, immunostaining and downregulation of MEF2 transcription factors together with increased wave II amplitude in the ABR recording. Our observations provide evidence of an abnormal neuronal cytoarchitecture in the cochlear nuclei of Igf1−/− null mice and suggest that the increased efficacy of glutamatergic synapses might be mediated by MEF2 transcription factors.
- Published
- 2014
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42. OR06-6 IRS2-deficient mice show sensorineural hearing loss that is delayed by concomitant PTP1B loss of function
- Author
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L. Rodriguez-de la Rosa, Silvia Murillo-Cuesta, Águeda González-Rodríguez, Ángela M. Valverde, and Isabel Varela-Nieto
- Subjects
medicine.medical_specialty ,Insulin Receptor Substrate Proteins ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Audiology ,Gene mutation ,medicine.disease ,IRS2 ,Endocrinology ,Internal medicine ,Diabetes mellitus ,otorhinolaryngologic diseases ,Medicine ,Sensorineural hearing loss ,PTPN1 ,Receptor ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Insulin-like growth factor I (IGF-I) signaling is mediated by insulin receptor substrate proteins (IRS). In turn, protein tyrosine phosphatase 1B (PTP1B) dephosphorylates and inactivates insulin and IGF-I receptors. IRS2-deficient mice present developmental defects in the nervous system, altered hepatic insulin signalling b-cell failure and develop type 2-like diabetes. IGF1 gene mutations cause syndromic sensorineural hearing loss in men and mice. However, the involvement of IRS2 and PTP1B, two IGF-1 downstream signaling mediators, in hearing onset and loss has not been studied. We have studied here, the hearing function and cochlear morphology of IRS2 null mice and the impact of PTP1B deficiency. Auditory brainstem responses and cochlear morphology of systemic Irs2−/−Ptpn1+/+, Irs2+/+Ptpn1-/and Irs2−/−Ptpn1−/− mice were studied at different postnatal ages. The results indicated that Irs2−/−Ptpn1+/+ mice present a profound congenital sensorineural deafness before the onset of diabetes and altered cochlear morphology compared to wild type mice. Simultaneous PTP1B deficiency in Irs2−/−Ptpn1−/− mice delays the onset of deafness. We show for the first time that IRS2 is essential for hearing and that PTP1B inhibition may be useful for the treatment of deafness associated to hyperglycemia and type 2-diabetes. We warmly thank the support of our colleagues Carlos Avendano, Deborah Burks and Lupe Camarero.
- Published
- 2012
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43. P01-30 IGF-I deficiency predisposes to presbycusis and noise-induced hearing loss in a mice model
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Rafael Cediel, L. Rodriguez-de la Rosa, Isabel Varela-Nieto, Julio Contreras, and Silvia Murillo-Cuesta
- Subjects
medicine.medical_specialty ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine ,Presbycusis ,Audiology ,IGF-I Deficiency ,medicine.disease ,business ,Noise-induced hearing loss - Published
- 2012
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44. P03-3 Insulin-like growth factor I-deficiency causes skeletal defects that can be partially compensated by parathyroid hormone-related protein in mice
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Isabel Varela-Nieto, L. Rodíguez-de la Rosa, A. Lopez-Herradon, P. Esbrit, S. Portal-Núñez, Silvia Murillo-Cuesta, and D. Lozano
- Subjects
medicine.medical_specialty ,INSULIN-LIKE GROWTH FACTOR I DEFICIENCY ,Endocrinology ,Parathyroid hormone-related protein ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Internal medicine ,medicine - Published
- 2012
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45. Parathyroid hormone-related protein (PTHRP) (1–36) and PTHRP (107–111) (osteostatin) display different osteogenic actions in insulin growth factor I null micE
- Author
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L. Rodríguez-de la Rosa, Silvia Murillo-Cuesta, Ana López-Herradón, Sergio Portal-Núñez, Isabel Varela-Nieto, P. Esbrit, Daniel Lozano, and Adela García-Martín
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Null mice ,medicine.medical_specialty ,Histology ,Parathyroid hormone-related protein ,Physiology ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Growth factor ,Osteostatin ,Biology ,Endocrinology ,Internal medicine ,medicine - Published
- 2012
- Full Text
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46. S228 – Direct Round Window Drug Application and Ototoxicity in Rats
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Rivera, Teresa, primary, Alcantara, Fernando García, additional, Suarez, Jon Alexander Sistiaga, additional, Silvia, Murillo‐Cuesta, additional, Elena, Vacas, additional, Rodríguez, Julio Contreras, additional, and Varela‐Nieto, Isabel, additional
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- 2008
- Full Text
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47. Acciones neurotróficas del factor de crecimiento similar a la insulina de tipo I en el oído interno
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L. Rodriguez-de la Rosa, J Contreras-Rodríguez, Isabel Varela-Nieto, Yolanda León, J I de Diego-Sastre, María Pilar Prim-Espada, R Cediel-Algovia, Hortensia Sánchez-Calderón, R Riquelme-Galiana, Grupo de Neurobiología de la Audición, and Silvia Murillo-Cuesta
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Philosophy ,Neurology (clinical) ,General Medicine ,Humanities - Abstract
Introduccion. La perdida de audicion constituye una de las deficiencias sensoriales invalidantes mas frecuentes en el mundo desarrollado. En la actualidad se estudian diferentes abordajes terapeuticos, entre los que se incluyen el tratamiento con celulas madre, la manipulacion genetica y la proteccion farmacologica. Objetivo. Evaluar el papel del factor de crecimiento similar a la insulina de tipo I (IGF-I) en el desarrollo, el mantenimiento y la reparacion de la funcion auditiva. Desarrollo. El desarrollo del oido interno depende de la adecuada coordinacion de los procesos celulares de proliferacion, diferenciacion, neurogenesis y muerte celular programada, que se encuentran regulados por distintos factores entre los que se encuentra el IGF-I. Durante la embriogenesis del oido interno, este factor se expresa abundantemente y es fundamental para la supervivencia celular y el mantenimiento de los precursores neuronales. El estudio del raton nulo Igf-1?/? ha puesto de manifiesto su importancia en el desarrollo y mantenimiento funcional del oido interno. Los ratones deficientes en este gen presentan alteraciones morfologicas que se corresponden con graves deficiencias funcionales, confirmadas mediante el analisis de los potenciales evocados auditivos de tronco cerebral. El deficit de IGF-I en humanos tambien se acompana de hipoacusia sensorial profunda. Conclusion. En este escenario, se perfila el IGF-I como un factor clave para el desarrollo de la funcion auditiva y un candidato para la terapia regenerativa del oido interno.
- Published
- 2007
- Full Text
- View/download PDF
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