Subcutaneous Administration of a Nitric Oxide-Releasing Nanomatrix Gel Ameliorates Obesity and Insulin Resistance in High-Fat Diet-Induced Obese Mice.

Nitric oxide (NO) is a gaseous signaling molecule, which plays crucial roles in various biological processes, including inflammatory responses, metabolism, cardiovascular functions, and cognitive function. NO bioavailability is reduced with aging and cardiometabolic disorders in humans and rodents. NO stimulates the metabolic rate by increasing the mitochondrial biogenesis and brown fat activation. Therefore, we propose a novel technology of providing exogenous NO to improve the metabolic rate and cognitive function by promoting the development of brown adipose tissue. In the present study, we demonstrate the effects of the peptide amphiphiles-NO-releasing nanomatrix gel (PANO gel) on high-fat diet-induced obesity, insulin resistance, and cognitive functions. Eight-week-old male C57BL/6 mice were subcutaneously injected in the brown fat area with the PANO gel or vehicle (PA gel) every 2 weeks for 12 weeks. The PANO gel-injected mice gained less body weight, improved glucose tolerance, and decreased fasting serum insulin and leptin levels compared with the PA gel-injected mice. Insulin signaling in the muscle, liver, and epididymal white adipose tissue was improved by the PANO gel injection. The PANO gel reduced inflammation, increased lipolysis in the epididymal white adipose tissue, and decreased serum lipids and liver triglycerides. Interestingly, the PANO gel stimulated uncoupled protein 1 gene expression in the brown and beige fat tissues. Furthermore, the PANO gel increased the cerebral blood flow and improved learning and memory abilities. Our results suggest that using the PANO gel to supply exogenous NO is a novel technology to treat metabolic disorders and cognitive dysfunctions.

Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts.

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.