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.
Highlights
Ferroptosis is a regulated cell death that depends on ironIt ismediated directly by Ferroptosis is a regulated cell death processprocess that depends on iron [1,2]
Erastin was originally identified from the high-throughput screening of anticancer drugs, and it has been widely used to create ferroptosis models [29,59]
The erastin-treated bone marrow-derived mesenchymal stem cell (bmMSCs) were stained with 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid (C11-BODIPY)
Summary
Ferroptosis is a regulated cell death that depends on iron. It ismediated directly by Ferroptosis is a regulated cell death processprocess that depends on iron [1,2] It is[1,2]. Directly mediated by the accumulation of lipid peroxidation (LPO). Reactive oxygen species the accumulation of lipid peroxidation (LPO) and reactive oxygen species (ROS) [3,4,5]. The positive modulation of ferroptosis can be used to procedurally hand, the positive modulation of ferroptosis can be used to procedurally kill cancer cells, andkill cancer cells, and offers a potential approach for the cancer therapy [1,2]. On the modulation other hand, of offers a potential approach for cancer therapy [1,2]. The negative the negative modulation ofdeath ferroptosis can inhibit cellular of death to improve the feasibility ferroptosis can inhibit cellular to improve the feasibility transplantation application to of treat transplantation application to treat ferroptosis-related diseases, e.g., Parkinson’s disease [6,7,8]
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