G6PD overexpression protects from oxidative stress and age-related hearing loss

Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose-6-phosphate dehydrogenase (G6PD), which catalyzes the rate-limiting step in the pentose phosphate pathway. We show here that G6PD transgenic mice (G6PD-Tg), which show enhanced constitutive G6PD activity and NADPH production along life, have lower auditory thresholds than wild-type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3-month-old G6PD-Tg mice than in wild-type counterparts, whereas the levels of pro-apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL apoptotic cells were all lower in 9-month-old G6PD-Tg than in wild-type counterparts. Unexpectedly, G6PD overexpression triggered low-grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression.Secretaría de Estado de Investigación, Desarrollo e Innovación, Grant/Award Number: MINECO/FEDER SAF2017-86107-R; Comunidad de Madrid, Grant/Award Number: FEDER/CM-B2017/BMD-368

Dual-Specificity Phosphatase 1 (DUSP1) Has a Central Role in Redox Homeostasis and Inflammation in the Mouse Cochlea.

Stress-activated protein kinases (SAPK) are associated with sensorineural hearing loss (SNHL) of multiple etiologies. Their activity is tightly regulated by dual-specificity phosphatase 1 (DUSP1), whose loss of function leads to sustained SAPK activation. Dusp1 gene knockout in mice accelerates SNHL progression and triggers inflammation, redox imbalance and hair cell (HC) death. To better understand the link between inflammation and redox imbalance, we analyzed the cochlear transcriptome in Dusp1-/- mice. RNA sequencing analysis (GSE176114) indicated that Dusp1-/- cochleae can be defined by a distinct profile of key cellular expression programs, including genes of the inflammatory response and glutathione (GSH) metabolism. To dissociate the two components, we treated Dusp1-/- mice with N-acetylcysteine, and hearing was followed-up longitudinally by auditory brainstem response recordings. A combination of immunofluorescence, Western blotting, enzymatic activity, GSH levels measurements and RT-qPCR techniques were used. N-acetylcysteine treatment delayed the onset of SNHL and mitigated cochlear damage, with fewer TUNEL+ HC and lower numbers of spiral ganglion neurons with p-H2AX foci. N-acetylcysteine not only improved the redox balance in Dusp1-/- mice but also inhibited cytokine production and reduced macrophage recruitment. Our data point to a critical role for DUSP1 in controlling the cross-talk between oxidative stress and inflammation

Bases genéticas, moleculares y bioquímicas del envejecimiento auditivo ¿Qué nos enseñan los modelos experimentales

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

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Çédille, revista de estudios franceses

Presentació

XVI International Congress of Control Electronics and Telecommunications: "Techno-scientific considerations for a post-pandemic world intensive in knowledge, innovation and sustainable local development"

Este título, sugestivo por los impactos durante la situación de la Covid 19 en el mundo, y que en Colombia lastimosamente han sido muy críticos, permiten asumir la obligada superación de tensiones sociales, políticas, y económicas; pero sobre todo científicas y tecnológicas. Inicialmente, esto supone la existencia de una capacidad de la sociedad colombiana por recuperar su estado inicial después de que haya cesado la perturbación a la que fue sometida por la catastrófica pandemia, y superar ese anterior estado de cosas ya que se encontraban -y aún se encuentran- muchos problemas locales mal resueltos, medianamente resueltos, y muchos sin resolver: es decir, habrá que rediseñar y fortalecer una probada resiliencia social existente - producto del prolongado conflicto social colombiano superado parcialmente por un proceso de paz exitoso - desde la tecnociencia local; como lo indicaba Markus Brunnermeier - economista alemán y catedrático de economía de la Universidad de Princeton- en su libro The Resilient Society…La cuestión no es preveerlo todo sino poder reaccionar…aprender a recuperarse rápido.This title, suggestive of the impacts during the Covid 19 situation in the world, and which have unfortunately been very critical in Colombia, allows us to assume the obligatory overcoming of social, political, and economic tensions; but above all scientific and technological. Initially, this supposes the existence of a capacity of Colombian society to recover its initial state after the disturbance to which it was subjected by the catastrophic pandemic has ceased, and to overcome that previous state of affairs since it was found -and still is find - many local problems poorly resolved, moderately resolved, and many unresolved: that is, an existing social resilience test will have to be redesigned and strengthened - product of the prolonged Colombian social conflict partially overcome by a successful peace process - from local technoscience; As Markus Brunnermeier - German economist and professor of economics at Princeton University - indicates in his book The Resilient Society...The question is not to foresee everything but to be able to react...learn to recover quickly.Bogot

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

MKP1 deficit causes hair cell loss, spiral ganglion degeneration and progressive hearing loss

Resumen del póster presentado al 1st Joint Meeting of the French-Portuguese-Spanish Biochemical and Molecular Biology Societies y al XL Spanish Society of Biochemistry and Molecular Biology (SEBBM) Congress, celebrado en Barcelona (España) del 23 al 26 de octubre de 2017.Age-related hearing loss (ARHL) is the most prevalent sensorial impairment of the elderly (WHO, February 2017). Its onset and progression rely on not well-characterized genetic factors, often aggravated by noxious factors such as noise and ototoxic agents. Stress kinases, p38 and JNK, activation precedes cellular loss and its pharmacological inhibition has proved to be otoprotective in animal models. The MAP kinase phosphatases (MKP) are natural regulators of the activity of stress kinases and central elements in the cellular response triggered by these enzymes but their role in hearing loss has not been studied. ABR and DPOAE hearing thresholds were measured, data analysis showed that Mkp1-/- mice suffered premature and progressive hearing loss. Higher ABR latencies of wave I indicated delayed transmission. Functional decline along life correlated with morphological and cellular cochlear alterations. Histological analysis and immunohistochemistry revealed loss of sensory cells in the organ of Corti, degeneration of afferent spiral neurons, loss of the spiral ligament fibrocytes and increased macrophages infiltration. Gene expression data (RNA-Seq and RT-qPCR) confirmed the altered transcriptome profile of null mice, concretely deregulation of GSH biosynthesis and antioxidant enzymes, unbalance of pro- and anti- inflammatory cytokines. In summary, we show here that MKP1 deficiency causes an exacerbated inflammatory response and accelerates progressive hearing loss.This Work was supported by grants FEDER/SAF2014-AGEAR and FP7-TARGEAR to IVN. JMB and AMC are supported, respectively, by CSIC and CIBERER predoctoral contracts.Peer Reviewe

The role of dual phosphatase MKP1 in progressive hearing loss

Trabajo presentado al 42nd FEBS Congress: "From molecules to cells and back", celebrado en Jerusalem (Israel) del 10 al 14 de septiembre de 2017.Hearing loss is the most prevalent sensorial impairment of the elderly according to WHO. Age-related hearing loss (ARHL) is mainly caused by the death of irreplaceable cellular populations in the cochlea. ARHL is commonly associated with cognitive deficit, social isolation and depression. The onset and progression of the pathology rely on genetic factors that are not well characterized, and are often aggravated by environmental factors such as noise exposure or ototoxic agents.This work was supported by Spanish SAF2014-53979-R.Peer Reviewe

G6PD overexpression protects from oxidative stress and ameliorates ARHL progression

Trabajo presentado en el 56th Inner Ear Biology Workshop, celebrado en Padua (Italia) del 7 al 10 de septiembre de 2019.Ageing of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative-derived damage in macromolecules, which contribute to cellular malfunction, compromise cell viability and, finally, causes functional decline. The cellular detoxification power partially relies in NADPH production, which serves as cofactor for the activity of major cellular antioxidant enzymes. NADPH is mainly produced by glucose-6-phosphate dehydrogenase (G6PD), an enzyme that catalyzes the rate-limiting step in the pentose phosphate pathway. We show here that the transgenic mouse G6PD-Tg, which shows enhanced NADPH production along life, maintains lower auditory thresholds than wild type mice during ageing. G6PD overexpression preserves irreplaceable cochlear cell populations, thus G6PD-Tg mice exhibit higher number of inner and outer hair cells (OHC), more widespread OHC innervation and higher number of synapses per IHC than wild type mice. Transcripts for antioxidant enzymes and pro-apoptotic proteins levels were increased and reduced respectively in 3-month-old G6PD-Tg. Accordingly, tyrosine modification by nitration in proteins and mitochondrial damage was reduced in 9-month-old G6PD-Tg compared with wild type mice. As well, as lesser TUNEL positive apoptotic cells were detected in whole mount preparations in G6PD-Tg mice. Interestingly, G6PD overexpression turned out to trigger an inflammatory response effectively resolved without cellular damage or macrophage infiltration in the cochlea. In conclusion, we propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the generation of ROS and the cell detoxification power along ageing and, therefore to prevent hearing loss progression. Acknowledgements. This work was supported by FP7-2013-TARGEAR and FEDER/SAF 2014-AGEAR and 2017-HEARCOD