Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress

Background Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy. Methods and results In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, nuclear translocation of pNRF2 and increased 3′-nitrotyrosine levels, and collagen maturation remodeling, all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression. Conclusions Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients

Non-Excitatory Amino Acids, Melatonin, and Free Radicals: Examining the Role in Stroke and Aging

The aim of this review is to explore the relationship between melatonin, free radicals, and non-excitatory amino acids, and their role in stroke and aging. Melatonin has garnered significant attention in recent years due to its diverse physiological functions and potential therapeutic benefits by reducing oxidative stress, inflammation, and apoptosis. Melatonin has been found to mitigate ischemic brain damage caused by stroke. By scavenging free radicals and reducing oxidative damage, melatonin may help slow down the aging process and protect against age-related cognitive decline. Additionally, non-excitatory amino acids have been shown to possess neuroprotective properties, including antioxidant and anti-inflammatory in stroke and aging-related conditions. They can attenuate oxidative stress, modulate calcium homeostasis, and inhibit apoptosis, thereby safeguarding neurons against damage induced by stroke and aging processes. The intracellular accumulation of certain non-excitatory amino acids could promote harmful effects during hypoxia-ischemia episodes and thus, the blockade of the amino acid transporters involved in the process could be an alternative therapeutic strategy to reduce ischemic damage. On the other hand, the accumulation of free radicals, specifically mitochondrial reactive oxygen and nitrogen species, accelerates cellular senescence and contributes to age-related decline. Recent research suggests a complex interplay between melatonin, free radicals, and non-excitatory amino acids in stroke and aging. The neuroprotective actions of melatonin and non-excitatory amino acids converge on multiple pathways, including the regulation of calcium homeostasis, modulation of apoptosis, and reduction of inflammation. These mechanisms collectively contribute to the preservation of neuronal integrity and functions, making them promising targets for therapeutic interventions in stroke and age-related disorders.This work was supported by MICIU (grant number PID2021-128133NB-I00/AEI/FEDER10.13039/501100011033) to J.M.H.-G. and V.J.C. enjoys a contract from the CAM “Investigo” program (PIP/2022-09971). A.R. thanks UCJC (INFLAMAMEL 2022-07 project) for its continued support

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Promising Molecular Targets in Pharmacological Therapy for Neuronal Damage in Brain Injury

The complex etiopathogenesis of brain injury associated with neurodegeneration has sparked a lot of studies in the last century. These clinical situations are incurable, and the currently available therapies merely act on symptoms or slow down the course of the diseases. Effective methods are being sought with an intent to modify the disease, directly acting on the properly studied targets, as well as to contribute to the development of effective therapeutic strategies, opening the possibility of refocusing on drug development for disease management. In this sense, this review discusses the available evidence for mitochondrial dysfunction induced by Ca2+ miscommunication in neurons, as well as how targeting phosphorylation events may be used to modulate protein phosphatase 2A (PP2A) activity in the treatment of neuronal damage. Ca2+ tends to be the catalyst for mitochondrial dysfunction, contributing to the synaptic deficiency seen in brain injury. Additionally, emerging data have shown that PP2A-activating drugs (PADs) suppress inflammatory responses by inhibiting different signaling pathways, indicating that PADs may be beneficial for the management of neuronal damage. In addition, a few bioactive compounds have also triggered the activation of PP2A-targeted drugs for this treatment, and clinical studies will help in the authentication of these compounds. If the safety profiles of PADs are proven to be satisfactory, there is a case to be made for starting clinical studies in the setting of neurological diseases as quickly as possible

Proyecto del PN ParticiPat “Patrimonio y participación social: propuesta metodológica y revisión crítica”

El proyecto del PN “Patrimonio y participación social: propuesta metodológica y revisión crítica”, ParticiPat, (HAR2014-54869-R) se centra en la utilización de técnicas participativas en lugares patrimoniales. Se plantea un triple objetivo: (1) analizar el papel que están jugando las técnicas participativas en políticas patrimoniales; (2) analizar la vinculación entre participación pública y procesos de patrimonialización; (3) analizar el vínculo entre dicha participación e instituciones patrimoniales. El contexto de la actual situación de crisis hace que sea especialmente relevante la elaboración de nuevas propuestas sobre la función del patrimonio. A su vez, este contexto de crisis está provocando nuevas fórmulas de participación en patrimonio pero también la participación se está instrumentalizando desde los discursos patrimoniales autorizados. En estudios anteriores se ha detectado que las técnicas participativas empleadas en procesos de patrimonialización reproducen enfoques no participativos y son usados con finalidad “cosmética” (Quintero 2011, Bendix et al. 2013, Sánchez-Carretero 2013, Coca 2008: 567). Teniendo en cuenta la importancia de la participación en los modelos alternativos de gestión patrimonial, un paso previo al abordaje de los mismos, es conocer los usos, ausencia de usos e instrumentalizaciones de las técnicas participativas en los procesos de patrimonialización. Este proyecto pretende dar respuesta al reto social que supone establecer puentes entre políticas públicas y movimientos vecinales, analizando el vínculo participación y patrimonio en diferentes procesos de patrimonialización, con el objetivo final de proporcionar una base empírica sobre la que proponer modelos alternativos de gestión patrimonial.MINECO: HAR2014-54869-RPeer reviewe

Whole-Exome Sequencing of 24 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Keratoconus

Keratoconus is a corneal dystrophy that is one of the main causes of corneal transplantation and for which there is currently no effective treatment for all patients. The presentation of this disease in pediatric age is associated with rapid progression, a worse prognosis and, in 15–20% of cases, the need for corneal transplantation. It is a multifactorial disease with genetic variability, which makes its genetic study difficult. Discovering new therapeutic targets is necessary to improve the quality of life of patients. In this manuscript, we present the results of whole-exome sequencing (WES) of 24 pediatric families diagnosed at the University Hospital La Paz (HULP) in Madrid. The results show an oligogenic inheritance of the disease. Genes involved in the structure, function, cell adhesion, development and repair pathways of the cornea are proposed as candidate genes for the disease. Further studies are needed to confirm the involvement of the candidate genes described in this article in the development of pediatric keratoconus