Limb-girdle muscular dystrophy R3, a rare genetic disorder affecting the limb proximal muscles, is caused by mutations in the α-sarcoglycan gene (Sgca) and aggravated by an immune-mediated damage, finely modulated by the extracellular (e)ATP/purinoceptors axis. Currently, no specific drugs are available. The aim of this study was to evaluate the therapeutic effectiveness of a selective P2X7 purinoreceptor antagonist, A438079. Sgca knockout mice were treated with A438079 every two days at 3 mg/Kg for 24 weeks. The P2X7 antagonist improved clinical parameters by ameliorating mice motor function and decreasing serum creatine kinase levels. Histological analysis of muscle morphology indicated a significant reduction of the percentage of central nuclei, of fiber size variability and of the extent of local fibrosis and inflammation. A cytometric characterization of the muscle inflammatory infiltrates showed that A438079 significantly decreased innate immune cells and upregulated the immunosuppressive regulatory T cell subpopulation. In α-sarcoglycan null mice, the selective P2X7 antagonist A438079 has been shown to be effective to counteract the progression of the dystrophic phenotype and to reduce the inflammatory response. P2X7 antagonism via selective inhibitors could be included in the immunosuppressant strategies aimed to dampen the basal immune-mediated damage and to favor a better engraftment of gene-cell therapies.

RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro- or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F₁F_o ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma- and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients.

This study investigates the differences in gut microbiota composition between DMD patients with (DMD +) and without (DMD −) intellectual disability (ID) and its potential role in cognitive outcomes. In this study, we assessed the gut microbiota in 50 genetically confirmed DMD patients (median age 13.1 years) using 16S rRNA gene sequencing. Cognitive assessment was performed using the Wechsler Intelligence Scales, with ID defined as an IQ < 70. Stool samples were analyzed, and statistical methods were used to assess alpha- and beta-diversity. Thirty-four percent of patients had ID. No significant differences were found in alpha-diversity or in the Firmicutes/Bacteroidetes ratio. However, beta-diversity analysis revealed significant differences between DMD + and DMD − groups, including, in DMD + , an increased abundance of Propionibacterium and Bifidobacterium, and a reduction in Bulleidia. These bacteria are involved in metabolic pathways that can influence neurological health through the gut-brain axis, particularly via the production of short-chain fatty acids. While these preliminary findings suggest a possible association between gut microbiota profile and cognitive impairment in DMD, further research is needed to explore a causal relationship and consider microbiota-targeted therapeutic strategies.