RESUMEN
This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences cellular stress responses through Rac1 activation, Forkhead-type transcription factors inactivation, and mitochondria-mediated apoptosis, alongside modulatory effects of gut microbiota-derived metabolites and endotoxins. Employing an integrative approach, the review synthesizes findings from a broad array of studies, including molecular biology techniques and analyses of microbial metabolites' impacts on host cellular pathways. The results underscore a complex interplay between microbial metabolites, p66Shc activation, and mitochondrial dysfunction, highlighting the significance of the gut microbiome in influencing disease outcomes through oxidative stress pathways. Conclusively, the review posits that targeting the gut microbiota-p66Shc-mitochondrial axis could offer novel therapeutic strategies for mitigating the development and progression of metabolic diseases. This underscores the potential of dietary interventions and microbiota modulation in managing oxidative stress and inflammation, pivotal factors in chronic disease etiology.
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Enfermedades Metabólicas , Humanos , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/genética , Proteínas Adaptadoras Transductoras de Señales , Factores de Transcripción Forkhead , MitocondriasRESUMEN
Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by wrinkled, inelastic skin, frequently associated with a neurologic involvement and multisystem disease. Next generation sequencing was performed in genetically unsolved patients with progeroid features, neurological and eye involvement to assess the underlying etiology. We describe an 6 month old child, diagnosed with a novel, homozygous nonsense mutation c.2339T>C in exon 18 of the ALDH18A1 gene, and reviewed all reported P5CS patients. So far 10 patients were described with mutations in ALDH18A1. Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay. Furthermore, abnormal fat distribution, retinal abnormalities, undescended testis, and retinitis pigmentosa have never been described in ALDH18A1. Some features described as unique in ALDH18A1 have been observed in PYCR1 patients, thus suggesting that the phenotypic overlap is higher than previously shown. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is diverse, with variable degree of progeria in children, but always in association with neurologic disease. We suggest genetic testing for possible ALDH18A1 mutations in all patients with progeroid features, like wrinkled or parchment-like skin, abnormal growth, especially with central nervous system involvement and microcephaly.
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Tejido Adiposo/patología , Aldehído Deshidrogenasa/genética , Cutis Laxo/genética , Mutación/genética , Enfermedades de la Retina/genética , Familia de Aldehído Deshidrogenasa 1 , Preescolar , Cutis Laxo/complicaciones , Cutis Laxo/patología , Humanos , Masculino , Retinal-Deshidrogenasa , Enfermedades de la Retina/complicaciones , Enfermedades de la Retina/patologíaRESUMEN
OBJECTIVE: To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities. METHODS: We identified 2 families with cerebellar ataxia, eye movement abnormalities, and global developmental delay. We performed genetic analyses including single nucleotide polymorphism genotyping, linkage analysis, array comparative genomic hybridization, quantitative PCR, and Sanger sequencing. We obtained eye movement recordings of mutant mice deficient for the ortholog of the identified candidate gene, and performed immunohistochemistry using human and mouse brain specimens. RESULTS: All affected individuals had ataxia, eye movement abnormalities, most notably tonic upgaze, and delayed speech and cognitive development. Homozygosity mapping identified the disease locus on chromosome 4q. Within this region, a homozygous deletion of GRID2 exon 4 in the index family and compound heterozygous deletions involving GRID2 exon 2 in the second family were identified. Grid2-deficient mice showed larger spontaneous and random eye movements compared to wild-type mice. In developing mouse and human cerebella, GRID2 localized to the Purkinje cell dendritic spines. Brain MRI in 2 affected children showed progressive cerebellar atrophy, which was more severe than that of Grid2-deficient mice. CONCLUSIONS: Biallelic deletions of GRID2 lead to a syndrome of cerebellar ataxia and tonic upgaze in humans. The phenotypic resemblance and similarity in protein expression pattern between humans and mice suggest a conserved role for GRID2 in the synapse organization between parallel fibers and Purkinje cells. However, the progressive and severe cerebellar atrophy seen in the affected individuals could indicate an evolutionarily unique role for GRID2 in the human cerebellum.
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Ataxia Cerebelosa/genética , Trastornos de la Motilidad Ocular/genética , Receptores de Glutamato/genética , Adolescente , Animales , Niño , Preescolar , Exones/genética , Femenino , Genes Recesivos/genética , Humanos , Masculino , Ratones , Eliminación de Secuencia/genética , SíndromeAsunto(s)
Terapia Enzimática , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/tratamiento farmacológico , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Humanos , Infusiones Intravenosas , Isoenzimas/uso terapéutico , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/diagnóstico , Mucopolisacaridosis/tratamiento farmacológico , N-Acetilgalactosamina-4-Sulfatasa/uso terapéutico , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , alfa-Galactosidasa/uso terapéuticoAsunto(s)
Síndrome de Job/complicaciones , Enfermedades Pulmonares/diagnóstico por imagen , Infecciones por Mycobacterium/diagnóstico por imagen , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium/tratamiento farmacológico , Infecciones por Mycobacterium/inmunología , Radiografía , Estudios Retrospectivos , Factores Sexuales , Esputo/microbiología , Adulto JovenRESUMEN
Over 27 cases of liver transplant, kidney transplant and combined liver-kidney transplant have been reported for the treatment of methylmalonic aciduria. We describe a case of a 5-year-old boy who underwent combined liver-kidney transplant (CLKT) for phenotypic mut0 disease. His history was notable for more than 30 hospitalizations for severe acidosis, metabolic strokes, liver disease, pancreatic disease, chronic renal insufficiency with interstitial nephritis, and decreased quality of life. Post-CLKT, there was a marked reduction in serum (80%) and urine MMA levels (90%) as well as a cessation of metabolic decompensations. Neurologic deterioration continued post-CKLT manifested as a cerebellar stroke. The clinical details and therapeutic implications of solid organ transplant for methylmalonic aciduria are discussed.