Simultaneous binding of quercetin and catechin to FOXO3 enhances IKKα transcription inhibition and suppression of oxidative stress-induced acute alcoholic liver injury in rats

Hui Guan; Wenyuan Zhang; Hui Liu; Yang Jiang; Feng Li; Dan Wang; Yang Liu; Fatao He; Maoyu Wu; Geoffrey Ivan Neil Waterhouse; Dongxiao Sun-Waterhouse; Dapeng Li

doi:10.1016/j.jare.2024.01.030

Simultaneous binding of quercetin and catechin to FOXO3 enhances IKKα transcription inhibition and suppression of oxidative stress-induced acute alcoholic liver injury in rats

J Adv Res. 2024 Jan 28:S2090-1232(24)00043-2. doi: 10.1016/j.jare.2024.01.030. Online ahead of print.

Authors

Affiliations

¹ College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China.
² College of Life Sciences, Shandong Agricultural University, State Key Laboratory of Crop Biology, Shandong Key Laboratory of Crop Biology, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China.
³ Jinan Fruit Research Institute of All China Federation of Supply & Marketing Cooperatives, 16001 East Road Jingshi, Jinan 250220, Shandong, People's Republic of China.
⁴ School of Chemical Sciences, The University of Auckland, Auckland, New Zealand.
⁵ College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China; School of Chemical Sciences, The University of Auckland, Auckland, New Zealand. Electronic address: dx.sun-waterhouse@auckland.ac.nz.
⁶ College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China. Electronic address: dpli73@sdau.edu.cn.

PMID: 38286301
DOI: 10.1016/j.jare.2024.01.030

Abstract

Introduction: Oxidative stress is one of the major contributors to acute alcoholic liver injury (AALI), which is a common alcoholic liver disease. Quercetin and catechin are flavonoid antioxidants present in plant foods and possess chemopreventive and chemotherapeutic activities. Quercetin and catechin are often included in the same meal and ingested together. While they show cooperative actions against oxidative damage, the underlying mechanisms behind their counteracting effects against oxidative stress-induced AALI remain poorly understood.

Objectives: The aim of this study was to understand the mechanism underlying the enhanced antioxidant effect of quercetin-catechin combination to alleviate AALI in rats.

Methods: The ethanol (EtOH)-treated rats and H₂O₂-treated liver cells were used to demonstrate the enhanced antioxidant effect of quercetin and catechin. Then we used RNA-sequencing to compare quercetin alone, catechin alone and quercetin-catechin combination and then identified the critical role of IKKα combining with gene silencing and overexpression techniques. Its transcription factor, FOXO3 was found through yeast one-hybrid assay, luciferase reporter assay, EMSA and ChIP assay. Finally, the interaction between quercetin, catechin and FOXO3 was verified through molecular docking, UV-Vis absorption spectroscopy, fluorescence spectroscopy, and CD spectroscopy.

Results: The study demonstrated the enhanced antioxidant effect of a quercetin-catechin combination in EtOH-treated rats and in H₂O₂-treated liver cells. Quercetin and catechin cooperatively inhibited IKKα/p53 pathway and activated Nrf2 signaling pathway. IKKα was a critical negative regulator in their joint action. FOXO3 bound to IKKα promoter to regulate IKKα transcription. Quercetin and catechin influenced FOXO3-IKKα binding through attaching directly to FOXO3 at different sites and altering FOXO3's secondary structures.

Conclusion: Our study revealed the mechanism of quercetin and catechin against oxidative stress-induced AALI through jointly interacting with transcription factor. This research opens new vistas for examining the joint effect of therapeutics towards functional proteins and confirms the chemopreventive effects of multiple flavonoids via co-regulation.

Keywords: Anti-oxidative stress; Catechin; Quercetin; Spectroscopy techniques; Transcription factor.