Relevancia del metabolismo del folato en el contexto de enfermedades neurodegenerativas

Introduction: Several neurodegenerative disorders are associated with alterations in folate metabolism, having essential physiopathological, clinical and therapeutic implications.    Objective: To assess the relevance of folate metabolism in neurodegenerative disorders, highlighting its physiopathological, clinical and therapeutic significance.Material and Methods: Specialized biomedical databases were searched for studies published up to March 2020. Descriptors and Boolean operators were used. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies.Results: Strong evidence of the association between folate metabolism and neurodegenerative disorders were identified. Enzyme-coding genes involved in folate metabolism and epigenetic DNA modifications associated with increased risk or disease severity in Alzheimer´s, Parkinson´s, and Huntington´s diseases, Essential Tremor, and Spinocerebellar ataxia type 2 were also identified.  Associations between neurodegenerative disorders and altered levels of folate metabolites and the frequency of micronuclei were found. A number of observational and experimental studies have demonstrated that the supplementation with folic acid and vitamin B6 and B12 has therapeutic potential in the context of neurodegenerative disorders.Conclusions: Folate metabolism is of physiopathological, clinical and therapeutic relevance for neurodegenerative disorders. The use of strategies to normalize folate levels or enzyme cofactors involved in folate metabolism or to reduce homocysteine levels has potential therapeutic applications for these disorders.Introducción: Varias enfermedades neurodegenerativas están asociadas a alteraciones en el metabolismo del folato, lo que tiene sustanciales implicaciones fisiopatológicas, clínicas y terapéuticas potenciales.Objetivo: Reflejar la relevancia del metabolismo del folato para enfermedades neurodegenerativas, destacando su significación fisiopatológica y clínica, y sus implicaciones terapéuticas.Material y métodos: Se consultaron las bases de datos especializadas en busca de artículos publicados hasta marzo de 2020. Se emplearon descriptores específicos y operadores booleanos. Se empleó la estrategia de búsqueda avanzada para la selección de los artículos, teniendo en cuenta la calidad metodológica o validez de los estudios.Desarrollo: Fueron identificadas evidencias de asociación entre alteraciones del metabolismo del folato y enfermedades neurodegenerativas. Se han identificado variantes en genes que codifican enzimas involucradas en el metabolismo del folato, y modificaciones en patrones de metilación de ADN, asociadas al riesgo o a la gravedad clínica de las enfermedades de Alzheimer, Parkinson, Huntington, Temblor Esencial y Ataxia Espinocerebelosa tipo 2. Fueron encontradas asociaciones entre enfermedades neurodegenerativas y alteraciones en los niveles de metabolitos del folato, y la frecuencia de micronúcleos. Se han realizado varios estudios observacionales o experimentales que indican que la suplementación con ácido fólico y vitaminas B6 y B12, tiene utilidad terapéutica potencial en el contexto de enfermedades neurodegenerativas.Conclusiones: El metabolismo del folato es de relevancia fisiopatológica, clínica y terapéutica para enfermedades neurodegenerativas. El uso de estrategias dirigidas a restaurar los niveles normales de folatos o de co-factores enzimáticos involucrados en el metabolismo del folato, o a reducir la acumulación de homocisteína, tiene potenciales aplicaciones terapéuticas en el contexto de estas enfermedades

Potencial uso terapéutico del ARN de interferencia contra la COVID-19

Introduction: SARS-CoV-2 is the causal agent of COVID-19, a respiratory disease that has caused thousands of deaths globally for which there is no effective curative therapy.Objective: To demonstrate the potential relevance of RNA interference (RNAi) technology as a therapeutic alternative in the treatment of COVID-19.Materials and methods: Specialized biomedical databases were searched looking for studies published until April 2020. The search was carried out using descriptors and Boolean operators. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies.Results: Evidence of experimental application of RNAi technology against SARS-CoV was identified. Several small interfering RNAs and small loop-structured RNAs oriented to the silencing of essential SARS-CoV genes including those encoding the S, RdRp, M, E, N, 3a/3b and 7a/7b proteins have been designed and evaluated. The effectiveness of RNAi for silencing its target genes was proven. Although most of these research studies have been conducted in in vitro systems, the therapeutic effectiveness of the intranasal administration of small RNA interference has also been proven in an in vivo SARS-CoV model.Conclusions: RNAi technology has demonstrated to be a potential therapeutic strategy against SARS-CoV in cellular and animal models. Given the similarities at the genomic level and in terms of the pathogenic process between SARS-CoV and SARS-CoV-2, this technology has a potential applicability for the treatment of COVID-19.Introducción: El SARS-CoV-2 es el agente causal de la COVID-19, enfermedad respiratoria que ha causado miles de víctimas fatales a escala global, y para la cual no existe ninguna terapia curativa efectiva.Objetivo: Reflejar la relevancia potencial de la tecnología de ARN de interferencia (ARNi), como alternativa terapéutica contra la COVID-19.Material y métodos: Se consultaron las bases de datos especializadas en busca de artículos publicados hasta abril de 2020. Se emplearon descriptores específicos y operadores booleanos. Se empleó la estrategia de búsqueda avanzada para la selección de los artículos, teniendo en cuenta la calidad metodológica o validez de los estudios.Desarrollo: Fueron identificadas evidencias de aplicación a nivel experimental de la tecnología de ARNi contra el SARS-CoV. Se han diseñado y evaluado varios ARNs pequeños interferentes y ARNs pequeños con estructura en lazo, orientados al silenciamiento de genes esenciales del SARS-CoV, incluyendo aquellos que codifican las proteínas S, RdRp, M, E, N, 3a/3b y 7a/7b. Se comprobó la efectividad de los ARNi en el silenciamiento de sus genes diana. Aunque la mayoría de estas investigaciones se han realizado en sistemas in vitro, también se ha comprobado la utilidad terapéutica de la administración intranasal de ARNi en un modelo de SARS-CoV in vivo.Conclusiones: La tecnología de ARNi ha mostrado potencialidades como estrategia terapéutica contra el SARS-CoV en modelos celulares y animales. Dadas las similitudes a nivel genómico y en cuanto al proceso patogénico entre SARS-CoV y SARS-CoV-2, esta tecnología es potencialmente aplicable el tratamiento de la COVID-19

Spinocerebellar Ataxia Type 2 Is Associated with the Extracellular Loss of Superoxide Dismutase but Not Catalase Activity

BackgroundSpinocerebellar ataxia type 2 (SCA2) is an inherited and still incurable neurodegenerative disorder. Evidence suggests that pro-oxidant agents as well as factors involved in antioxidant cellular defenses are part of SCA2 physiopathology.AimTo assess the influence of superoxide dismutase (SOD3) and catalase (CAT) enzymatic activities on the SCA2 syndrome.MethodClinical, molecular, and electrophysiological variables, as well as SOD3 and CAT enzymatic activities were evaluated in 97 SCA2 patients and in 64 age- and sex-matched control individuals.ResultsSpinocerebellar ataxia type 2 patients had significantly lower SOD3 enzymatic activity than the control group. However, there were no differences between patients and controls for CAT enzymatic activity. The effect size for the loss of patients’ SOD3 enzymatic activity was 0.342, corresponding to a moderate effect. SOD3 and CAT enzymatic activities were not associated with the CAG repeat number at the ATXN2 gene. SOD3 and CAT enzymatic activities did not show significant associations with the age at onset, severity score, or the studied electrophysiological markers.ConclusionThere is a reduced SOD3 enzymatic activity in SCA2 patients with no repercussion on the clinical phenotype

Redox Imbalance Associates with Clinical Worsening in Spinocerebellar Ataxia Type 2

Background. Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease presenting with redox imbalance. However, the nature and implications of redox imbalance in SCA2 physiopathology have not been fully understood. Objective. The objective of this study is to assess the redox imbalance and its association with disease severity in SCA2 mutation carriers. Methods. A case-control study was conducted involving molecularly confirmed SCA2 patients, presymptomatic individuals, and healthy controls. Several antioxidant parameters were assessed, including serum thiol concentration and the superoxide dismutase, catalase, and glutathione S-transferase enzymatic activities. Also, several prooxidant parameters were evaluated, including thiobarbituric acid-reactive species and protein carbonyl concentrations. Damage, protective, and OXY scores were computed. Clinical correlates were established. Results. Significant differences were found between comparison groups for redox markers, including protein carbonyl concentration (F=3.30; p=0.041), glutathione S-transferase activity (F=4.88; p=0.009), and damage (F=3.20; p=0.045), protection (F=12.75; p<0.001), and OXY (F=7.29; p=0.001) scores. Protein carbonyl concentration was positively correlated with CAG repeat length (r=0.27; p=0.022), while both protein carbonyl concentration (r=−0.27; p=0.018) and OXY score (r=−0.25; p=0.013) were inversely correlated to the disease duration. Increasing levels of antioxidants and decreasing levels of prooxidant parameters were associated with clinical worsening. Conclusions. There is a disruption of redox balance in SCA2 mutation carriers which depends on the disease stage. Besides, redox changes associate with markers of disease severity, suggesting a link between disruption of redox balance and SCA2 physiopathology