microRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.

Caloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.

Nanodevices for the Efficient Codelivery of CRISPR-Cas9 Editing Machinery and an Entrapped Cargo: A Proposal for Dual Anti-Inflammatory Therapy.

In this article, we report one of the few examples of nanoparticles capable of simultaneously delivering CRISPR-Cas9 gene-editing machinery and releasing drugs for one-shot treatments. Considering the complexity of inflammation in diseases, the synergistic effect of nanoparticles for gene-editing/drug therapy is evaluated in an in vitro inflammatory model as proof of concept. Mesoporous silica nanoparticles (MSNs), able to deliver the CRISPR/Cas9 machinery to edit gasdermin D (GSDMD), a key protein involved in inflammatory cell death, and the anti-inflammatory drug VX-765 (GSDMD45CRISPR-VX-MSNs), were prepared. Nanoparticles allow high cargo loading and CRISPR-Cas9 plasmid protection and, thus, achieve the controlled codelivery of CRISPR-Cas9 and the drug in cells. Nanoparticles exhibit GSDMD gene editing by downregulating inflammatory cell death and achieving a combined effect on decreasing the inflammatory response by the codelivery of VX-765. Taken together, our results show the potential of MSNs as a versatile platform by allowing multiple combinations for gene editing and drug therapy to prepare advanced nanodevices to meet possible biomedical needs.