Ferroptosis-Inhibitory Effect and Possible Mechanisms of Ellagitannin Geraniin.

The search for safe and effective ferroptosis-inhibitors has become an important topic. Geraniin, an ellagitannin bearing hexahydroxydiphenoyl (HHDP) and dehydrohexahydroxydiphenoyl (DHHDP) groups, was observed to inhibit erastin-induced ferroptosis in bone marrow-derived mesenchymal stem cells (bmMSCs). To determine the mechanism, geraniin was further analyzed using UV-vis spectra and several colorimetric assays, where its IC50 values were always much lower than that of the Trolox positive control. When interacted with several free radicals, geraniin gave no radical adduct formation (RAF) peak in the ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. In conclusion, geraniin exhibits ferroptosis-inhibitory potential towards erastin-treated bmMSCs; such potential may mainly stem from its strong lipid peroxidation (LPO)-inhibition, Fe2+ -chelating, and antioxidant actions. Geraniin gives neither dimer nor radical adduct, owing to the bulky HHDP (or DHHDP) group; thus, it is considered as a safe and effective ferroptosis-inhibitor.

Covalent Bridging of Corilagin Improves Antiferroptosis Activity: Comparison with 1,3,6-Tri-O-galloyl-ß-d-glucopyranose.

The ellagitannin corilagin and its analogue 1,3,6-tri-O-galloyl-ß-d-glucopyranose (TGG) were found to protect bone marrow-derived mesenchymal stem cells (bmMSCs) against erastin-induced ferroptosis by cellular assays. However, the antiferroptosis bioactivity of corilagin was higher than that of TGG. Corilagin also exhibited higher antioxidant and Fe2+-chelation levels than TGG. Treated with 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, corilagin and TGG yielded a corilagin- and a TGG-DPPH adduct, respectively. The corilagin-DPPH adduct retained the covalent bridge throughout the ultrahigh-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS) analysis. The strength of the covalent bridge is attributable to enhancement of its partial π-π conjugation. Thus, the bridge has sufficient strength to twist the chair conformation of the glucopyranosyl ring and to assemble two large aromatic rings, thereby improving the antioxidant (including Fe2+-chelation) reactivities. The bridge can also stabilize the product intermediate via partial π-π conjugation. Hence, corilagin is a superior ferroptosis inhibitor and antioxidant compared to TGG.