37 research outputs found
Uridine inhibits the stemness of intestinal stem cells in 3D intestinal organoids and mice
The activity of intestinal stem cells (ISCs) is foremost in maintaining homeostasis and repair of intestines. As a pivotal substrate of RNA and DNA biosynthesis, uridine plays essential roles in nutritional and disease monitoring. Whether uridine influences ISC activity remains undefined. To answer this question, 3-dimensional (3D) mouse intestinal organoids and living mice were used as a model. It was found that uridine causes a significant decrease in the number of crypts per intestinal organoid. Uridine also significantly decreases mRNA expression and protein levels with markers of ISCs in intestinal organoids in a dose-dependent manner, which was instructed via mTOR. In parallel, uridine decreases the expression of marker of ISCs in mouse intestine in vivo. Our findings are the first to demonstrate that uridine is able to govern the functions of ISCs in intestinal organoid and mouse models. Thus, this study may provide a useful reference for developing novel functional food bioactives that maintain intestinal homeostasis
Integrating Display and Delivery Functionality with a Cell Penetrating Peptide Mimic as a Scaffold for Intracellular Multivalent Multitargeting
The
construction of a multivalent ligand is an effective way to
increase affinity and selectivity toward biomolecular targets with
multiple-ligand binding sites. Adopting this strategy, we used a known
cell-penetrating peptide (CPP) mimic as a scaffold to develop a series
of multivalent ligand constructs that bind to the expanded dCTG (CTG<sup>exp</sup>) and rCUG nucleotide repeats (CUG<sup>exp</sup>) known
to cause myotonic dystrophy type I (DM1), an incurable neuromuscular
disease. By assembling this polyvalent construct, the hydrophobic
ligands are solubilized and delivered into cell nuclei, and their
enhanced binding affinity leads to the inhibition of ribonuclear foci
formation and a reversal of splicing defects, all at low concentrations.
Some of the multivalent ligands are shown to inhibit selectively the <i>in vitro</i> transcription of (CTG·CAG)<sub>74</sub>, to
reduce the concentration of the toxic CUG RNA in DM1 model cells,
and to show phenotypic improvement <i>in vivo</i> in a <i>Drosophila</i> model of DM1. This strategy may be useful in
drug design for other trinucleotide repeat disorders and more broadly
for intracellular multivalent targeting