Inhibitory Effect and Mechanism of Action of Quercetin and Quercetin Diels-Alder anti-Dimer on Erastin-Induced Ferroptosis in Bone Marrow-Derived Mesenchymal Stem Cells

Abstract

In this study, the anti-ferroptosis effects of catecholic flavonol quercetin and its metabolite quercetin Diels-Alder anti-dimer (QDAD) were studied using an erastin-treated bone marrow-derived mesenchymal stem cell (bmMSCs) model. Quercetin exhibited higher anti-ferroptosis levels than QDAD, as indicated by 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid (C11-BODIPY), 2′,7′-dichlorodihydrofluoroscein diacetate (H2DCFDA), lactate dehydrogenase (LDH) release, cell counting kit-8 (CCK-8), and flow cytometric assays. To understand the possible pathways involved, the reaction product of quercetin with the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH●) was measured using ultra-performance liquid-chromatography coupled with electrospray-ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS). Quercetin was found to produce the same clusters of molecular ion peaks and fragments as standard QDAD. Furthermore, the antioxidant effects of quercetin and QDAD were compared by determining their 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide radical-scavenging, Cu2+-reducing, Fe3+-reducing, lipid peroxidation-scavenging, and DPPH●-scavenging activities. Quercetin consistently showed lower IC50 values than QDAD. These findings indicate that quercetin and QDAD can protect bmMSCs from erastin-induced ferroptosis, possibly through the antioxidant pathway. The antioxidant pathway can convert quercetin into QDAD—an inferior ferroptosis-inhibitor and antioxidant. The weakening has highlighted a rule for predicting the relative anti-ferroptosis and antioxidant effects of catecholic flavonols and their Diels-Alder dimer metabolites.

Relationships between Structure and Antioxidant Capacity and Activity of Glycosylated Flavonols

“…The MS/MS spectra showed that the quasi-molecular ion of the dimeric product from Q was 601.2 m / z , with only one fragment ion at 299.0 m / z . Considering the MW of Q (302.24), the result indicated that the dimer was one of a quercetin Diels–Alder dimer ( Figure 5 E) [ 32 ]. A likely pathway for the dimer formation is one quercetin losing H atoms and being converted to an o -quinone, which gives a Diels–Alder reaction with another quercetin to form the dimer with an MW of 602.…”

Antioxidant, Antimicrobial and Antiviral Properties of Herbal Materials

“…Many researchers have reported the biomedical applications of herbal medicines [ 346 , 347 , 348 , 349 , 350 , 351 , 352 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 ]. Antibiotics and other chemical antimicrobial agents including metal oxide and metal nanoparticles can inhibit bacteria growth but also lead to ROS generation and other side effects.…”

Quercetin alleviates acute kidney injury by inhibiting ferroptosis

“…QCT was also reported to possess protective effect on diabetic nephropathy [16] , and even have the ability of iron chelation [17] , [18] . Another recent publication reported that QCT could protect bone marrow-derived mesenchymal stem cell from erastin-induced ferroptosis, possibly through the antioxidant pathway [19] . In spite of the attention QCT drew and the wide effects already discovered, the effect of QCT on AKI ferroptosis remains undescribed.…”