Dataset Information

Theoretical Study of Radical Inactivation, LOX Inhibition, and Iron Chelation: The Role of Ferulic Acid in Skin Protection against UVA Induced Oxidative Stress.

ABSTRACT: Ferulic acid (FA) is used in skin formulations for protection against the damaging actions of the reactive oxygen species (ROS) produced by UVA radiation. Possible underlying protective mechanisms are not fully elucidated. By considering the kinetics of proton-coupled electron transfer (PCET) and radical-radical coupling (RRC) mechanisms, it appears that direct scavenging could be operative, providing that a high local concentration of FA is present at the place of •OH generation. The resulting FA phenoxyl radical, after the scavenging of a second •OH and keto-enol tautomerization of the intermediate, produces 5-hydroxyferulic acid (5OHFA). Inhibition of the lipoxygenase (LOX) enzyme, one of the enzymes that catalyse free radical production, by FA and 5OHFA were analysed. Results of molecular docking calculations indicate favourable binding interactions of FA and 5OHFA with the LOX active site. The exergonicity of chelation reactions of the catalytic Fe2+ ion with FA and 5OHFA indicate the potency of these chelators to prevent the formation of •OH radicals via Fenton-like reactions. The inhibition of the prooxidant LOX enzyme could be more relevant mechanism of skin protection against UVA induced oxidative stress than iron chelation and assumed direct scavenging of ROS.

SUBMITTER: Amic A

PROVIDER: S-EPMC8389219 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Theoretical Study of Radical Inactivation, LOX Inhibition, and Iron Chelation: The Role of Ferulic Acid in Skin Protection against UVA Induced Oxidative Stress.

Amić Ana A Dimitrić Marković Jasmina M JM Marković Zoran Z Milenković Dejan D Milanović Žiko Ž Antonijević Marko M Mastiľák Cagardová Denisa D Rodríguez-Guerra Pedregal Jaime J

Antioxidants (Basel, Switzerland) 20210818 8

Ferulic acid (FA) is used in skin formulations for protection against the damaging actions of the reactive oxygen species (ROS) produced by UVA radiation. Possible underlying protective mechanisms are not fully elucidated. By considering the kinetics of proton-coupled electron transfer (PCET) and radical-radical coupling (RRC) mechanisms, it appears that direct scavenging could be operative, providing that a high local concentration of FA is present at the place of <sup>•</sup>OH generation. The ...[more]

PMID: 34439551

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Project description:Increasing data implicate iron accumulation in tumorigenesis of the kidney, particularly the clear cell renal cell carcinoma (ccRCC) subtype. The von Hippel Lindau (VHL)/hypoxia inducible factor-α (HIF-α) axis is uniquely dysregulated in ccRCC and is a major regulator and regulatory target of iron metabolism, yet the role of iron in ccRCC tumorigenesis and its potential interplay with VHL inactivation remains unclear. We investigated whether ccRCC iron accumulation occurs due to increased cell dependency on iron for growth and survival as a result of VHL inactivation. Free iron levels were compared between four VHL-mutant ccRCC cell lines (786-0, A704, 769-P, RCC4) and two benign renal tubule epithelial cell lines (RPTEC, HRCEp) using the Phen Green SK fluorescent iron stain. Intracellular iron deprivation was achieved using two clinical iron chelator drugs, deferasirox (DFX) and deferoxamine (DFO), and chelator effects were measured on cell line growth, cell cycle phase, apoptosis, HIF-1α and HIF-2α protein levels and HIF-α transcriptional activity based on expression of target genes CA9, OCT4/POU5F1 and PDGFβ/PDGFB. Similar assays were performed in VHL-mutant ccRCC cells with and without ectopic wild-type VHL expression. Baseline free iron levels were significantly higher in ccRCC cell lines than benign renal cell lines. DFX depleted cellular free iron more rapidly than DFO and led to greater growth suppression of ccRCC cell lines (>90% at ~30-150 µM) than benign renal cell lines (~10-50% at up to 250 µM). Similar growth responses were observed using DFO, with the exception that a prolonged treatment duration was necessary to deplete cellular iron adequately for differential growth suppression of the less susceptible A704 ccRCC cell line relative to benign renal cell lines. Apoptosis and G1-phase cell cycle arrest were identified as potential mechanisms of chelator growth suppression based on their induction in ccRCC cell lines but not benign renal cell lines. Iron chelation in ccRCC cells but not benign renal cells suppressed HIF-1α and HIF-2α protein levels and transcriptional activity, and the degree and timing of HIF-2α suppression correlated with the onset of apoptosis. Restoration of wild-type VHL function in ccRCC cells was sufficient to prevent chelator-induced apoptosis and G1 cell cycle arrest, indicating that ccRCC susceptibility to iron deprivation is VHL inactivation-dependent. In conclusion, ccRCC cells are characterized by high free iron levels and a cancer-specific dependency on iron for HIF-α overexpression, cell cycle progression and apoptotic escape. This iron dependency is introduced by VHL inactivation, revealing a novel interplay between VHL/HIF-α dysregulation and ccRCC iron metabolism. Future study is warranted to determine if iron deprivation using chelator drugs provides an effective therapeutic strategy for targeting HIF-2α and suppressing tumor progression in ccRCC patients.

Dataset Information

Theoretical Study of Radical Inactivation, LOX Inhibition, and Iron Chelation: The Role of Ferulic Acid in Skin Protection against UVA Induced Oxidative Stress.

Publications

Theoretical Study of Radical Inactivation, LOX Inhibition, and Iron Chelation: The Role of Ferulic Acid in Skin Protection against UVA Induced Oxidative Stress.

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