Attenuating monocytic inflammaging via the miR-146a/TLR4 axis: Characterization and bioactivity of a
Liana Cerioni1, Mattia Tiboni1, Noemi Pappagallo1
1Department of Biomolecular Sciences, DISB, University of Urbino Carlo Bo, Urbino, PU, Italy.
Abstract:
Inflammaging, driven by monocyte dysregulation, is a hallmark of immunosenescence. Toll-like Receptor 4 (TLR4) pathway hyper-activation accelerates cellular senescence and systemic inflammatory damage, while microRNA-146a (miR-146a) constrains pro-inflammatory cytokine release by targeting IRAK-1. Plant-derived triterpenoids are promising geroprotective agents, but standardized, scalable biotechnological production remains challenging. We established a sustainable in vitro callus culture from Red Sentinel to obtain a standardized triterpenoid-rich extract (RSE). GC-MS/FID analysis quantified its pentacyclic triterpene content (ursolic and oleanolic acids) within a soluble phytocomplex matrix, while X-ray Photoelectron Spectroscopy (XPS), Ultraviolet Photoelectron Spectroscopy (UPS), and thermal analysis (TGA/DSC) characterized surface elemental states, work function, and thermal stability. Biological efficacy was tested in human U937 monocytes, and molecular docking was performed against the TLR4/MD-2 complex. RSE showed high thermal stability and distinct surface chemistry, with specific oxygenated carbon functional states. In U937 monocytes, RSE non-cytotoxically attenuated pro-inflammatory signaling, significantly upregulating miR-146a, down-regulating IRAK-1, and reducing IL-6 secretion. Docking confirmed strong interactions between the pentacyclic triterpenes and the TLR4/MD-2 hydrophobic pocket. These results indicate that plant cell culture technology can generate standardized phytocomplexes capable of modulating the miR-146a/IRAK-1/IL-6 axis, counteracting monocytic inflammaging, and support the value of combining surface physics and molecular biology in anti-aging nutraceutical research.
