2-Fluorofucose Attenuates Hydrogen Peroxide-Induced Oxidative Stress in HepG2 Cells via Nrf2/keap1 and NF-κB Signaling Pathways.

Mengjue Tu,Jianan Shi,Xiaole Xu,Yuqin Wang,Xingshuo Fan,Shengnan Jing

doi:10.3390/life12030406

Abstract

Fucosylation is one of the most important glycan terminal modifications that affects multiple biological activities of proteins. 2-Fluorofucose (2FF), its specific inhibitor, has recently been reported to reveal numerous biological effects by blocking fucosylation both in vitro and in vivo. The current study aimed to evaluate the effect of 2FF on hydrogen peroxide (H2O2)-induced oxidative damage in vitro. In our study, treatment with H2O2 increased the level of fucosylation, and 2FF improved the cell viability in H2O2-treated HepG2 cells. Our study also showed that 2FF significantly decreased the overproduction of reactive oxygen species (ROS) induced by H2O2 and the activities of catalase, glutathione and Mn-superoxide dismutase were remarkably increased by 2FF pretreatment. Furthermore, 2FF attenuated H2O2-induced early mitochondria dysfunction. The second part of the study revealed that 2FF enhanced antioxidant capacity by affecting Nrf2/keap1 and NF-κB signaling pathways in HepG2 cells. Being pretreated with 2FF significantly increased the nuclear translocation of Nrf2 and simultaneously promoted the expression of downstream proteins, such as HO-1 and NQO1. Moreover, 2FF remarkably suppressed the expression of inflammation-associated proteins. Taken together, these data suggest that 2FF might have a potential therapeutic effect for oxidative stress.

Highlights

Oxidative stress is defined as the imbalance between reactive oxygen species (ROS)generation and clearance, which is involved in the development and progression of many diseases, including cancer, diabetes type II, and neurodegenerative and liver diseases [1–3]
The level of fucosylation was upregulated after H2O2 induction (Figure 1A), which suggested that altered fucosylation might affect the process of oxidative damage
Whether pretreated with 2FF or not, the levels of lactate dehydrogenase (LDH) significantly increased after H2O2 induction, while 2FF pretreatment significantly suppressed the increase induced by H2O2 (Figure 2A)

Summary

Introduction

Oxidative stress is defined as the imbalance between reactive oxygen species (ROS)generation and clearance, which is involved in the development and progression of many diseases, including cancer, diabetes type II, and neurodegenerative and liver diseases [1–3]. The impairment caused by excessive ROS is generally thought to be the result of proteins, lipids and DNA damage, eventually leading to cellular dysfunction and cell death [2]. Many studies have shown that numerous defense systems are induced to relieve oxidative damage in vivo. The nuclear factor erythroid 2-related factor 2 (Nrf2) is considered to be one of the key factors in the cellular antioxidative defense system in vivo [2,4]. Nrf activity is depressed by binding to Kelch-like ECH-associated protein 1 (keap1) in the cytoplasm. Nrf breaks away from the Nrf2-keap complex and transports to the nucleus. It encodes detoxifying enzymes and antioxidant enzymes, including NAD(P) H:quinine oxidoreductase 1(NQO1), heme oxygenase 1(HO-1) and glutathione-S-transferases (GST) [5]

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Results