Simultaneous Study of Anti-Ferroptosis and Antioxidant Mechanisms of Butein and (S)-Butin

Abstract

To elucidate the mechanism of anti-ferroptosis and examine structural optimization in natural phenolics, cellular and chemical assays were performed with 2′-hydroxy chalcone butein and dihydroflavone (S)-butin. C11-BODIPY staining and flow cytometric assays suggest that butein more effectively inhibits ferroptosis in erastin-treated bone marrow-derived mesenchymal stem cells than (S)-butin. Butein also exhibited higher antioxidant percentages than (S)-butin in five antioxidant assays: linoleic acid emulsion assay, Fe3+-reducing antioxidant power assay, Cu2+-reducing antioxidant power assay, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radical (PTIO•)-trapping assay, and α,α-diphenyl-β-picrylhydrazyl radical (DPPH•)-trapping assay. Their reaction products with DPPH• were further analyzed using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q-TOF-MS). Butein and (S)-butin produced a butein 5,5-dimer (m/z 542, 271, 253, 225, 135, and 91) and a (S)-butin 5′,5′-dimer (m/z 542, 389, 269, 253, and 151), respectively. Interestingly, butein forms a cross dimer with (S)-butin (m/z 542, 523, 433, 419, 415, 406, and 375). Therefore, we conclude that butein and (S)-butin exert anti-ferroptotic action via an antioxidant pathway (especially the hydrogen atom transfer pathway). Following this pathway, butein and (S)-butin yield both self-dimers and cross dimers. Butein displays superior antioxidant or anti-ferroptosis action to (S)-butin. This can be attributed the decrease in π-π conjugation in butein due to saturation of its α,β-double bond and loss of its 2′-hydroxy group upon biocatalytical isomerization.

Oxidative Stress: Pathogenetic Role in Diabetes Mellitus and Its Complications and Therapeutic Approaches to Correction

“…Curcumin is considered suitable for the prevention and reduction of the risk of DM complications, due to its anti-inflammatory and antioxidant activity [80]. Butein, an antioxidant polyphenol, inhibits the formation of NO in vitro, protects pancreatic β-cells under conditions of excessive inflammation, and can be used to prevent the progression of DM1 [65]. Resveratrol modulates the expression of genes associated with the DM2 development by inducing the expression of several β-cell genes and insulin expression in pancreatic α-cells [50].…”

Ferroptosis-Inhibitory Difference between Chebulagic Acid and Chebulinic Acid Indicates Beneficial Role of HHDP

“…These data suggested that ( i ) chebulagic acid and chebulinic acid are very strong antioxidants, and ( ii ) the relative antioxidant levels of chebulagic acid and chebulinic acid correlate with their ferroptosis inhibition levels ( Figure 2 and Figure 3 ). Therefore, on the basis of the above results and previous studies [ 22 , 23 , 24 , 25 , 44 , 45 ], the ferroptosis inhibition of both tannins was presumed to be via an antioxidant mechanism, attributed to the presence of multiple phenolic –OH groups [ 21 , 46 , 47 ]. It is worth mentioning that, the so-called “antioxidant mechanism” also includes SET-PT (single electron transfer–proton transfer) and SPLET (sequential proton loss electron transfer), apart from the above hydrogen atom transfer [ 48 , 49 ].…”

“…Therefore, there is an urgent need to screen for safe and effective ferroptosis inhibitors from natural products. Previous studies have stated that flavonoid and monostilbenes could act as natural ferroptosis inhibitors [ 22 , 23 , 24 , 25 ], whereby the ferroptosis-inhibitory effect may arise from the presence of the phenolic –OH group.…”

Tannic Acid as a Natural Ferroptosis Inhibitor: Mechanisms and Beneficial Role of 3’‐O‐Galloylation

“…Fer‐1 was not evaluated for its insolubility (Table 1). However, in the FRAP and ABTS .+ ‐trapping assays, Fer‐1 increases in a dose‐dependent manner, suggesting the ET potential of Fer‐1, [44–47] which confirms the recycling of the catalyst (Figure 6). Similar effectiveness is observed for the two gallotannins.…”