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Fmo induction as a tool to screen for pro-longevity drugs
Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2. Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2, and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans. Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2, whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2, indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans, and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds.This work was funded by the Glenn Foundation for Medical Research and NIH grant R01AG075061 to S.F.L12 month embargo; first published 24 May 2024This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
The Use of Minimal RNA Toeholds to Trigger the Activation of Multiple Functionalities
Current work reports the use of single-stranded
RNA toeholds of different lengths to promote the reassociation of
various RNA–DNA hybrids, which results in activation of multiple
split functionalities inside human cells. The process of reassociation
is analyzed and followed with a novel computational multistrand secondary
structure prediction algorithm and various experiments. All of our
previously designed RNA/DNA nanoparticles employed single-stranded
DNA toeholds to initiate reassociation. The use of RNA toeholds is
advantageous because of the simpler design rules, the shorter toeholds,
and the smaller size of the resulting nanoparticles (by up to 120
nucleotides per particle) compared to the same hybrid nanoparticles
with single-stranded DNA toeholds. Moreover, the cotranscriptional
assemblies result in higher yields for hybrid nanoparticles with ssRNA
toeholds