Neohesperidin Dihydrochalcone versus CCl4‑Induced Hepatic Injury through Different Mechanisms: The Implication of Free Radical Scavenging and Nrf2 Activation

• Published in: Journal of agricultural and food chemistry 2015-06, Vol.63 (22), p.5468-5475
• Main Authors: Su, Chuanyang, Xia, Xiaomin, Shi, Qiong, Song, Xiufang, Fu, Juanli, Xiao, Congxue, Chen, Hongjun, Lu, Bin, Sun, Zhiyin, Wu, Shanmei, Yang, Siyu, Li, Xuegang, Ye, Xiaoli, Song, Erqun, Song, Yang
• Format: Article
• Language: English
• Subjects: Animals; antioxidant activity; Carbon Tetrachloride - adverse effects; Chalcones - administration & dosage; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Citrus; flavonoids; free radical scavengers; Free Radical Scavengers - administration & dosage; free radicals; heme oxygenase (biliverdin-producing); Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hesperidin - administration & dosage; Hesperidin - analogs & derivatives; Humans; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; Liver - drug effects; Liver - metabolism; Mice; mitogen-activated protein kinase; NADP (coenzyme); NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress - drug effects; Reactive Oxygen Species - metabolism; signal transduction; Signal Transduction - drug effects; ubiquitination
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.5b01750

Neohesperidin dihydrochalcone (NHDC), a sweetener derived from citrus, belongs to the family of bycyclic flavonoids dihydrochalcones. NHDC has been reported to act against CCl4-induced hepatic injury, but its mechanism is still unclear. We first discovered that NHDC showed a strong ability to scavenge free radicals. In addition, NHDC induces the phase II antioxidant enzymes heme oxygenase 1 (HO-1) and NAD­(P)­H/quinone oxidoreductase 1 (NQO1) through the activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/antioxidant response element (ARE) signaling. Further assays demonstrated that NHDC induces accumulation of Nrf2 in the nucleus and augmented Nrf2-ARE binding activity. Moreover, NHDC inhibits the ubiquitination of Nrf2 and suggests the modification of Kelch-like ECH-associated protein 1 (Keap1) and the disruption of the Keap1/Nrf2 complex. c-Jun N-terminal kinase (JNK) and p38 but not extracellular signal-regulated protein kinase (ERK) phosphorylations were up-regulated by NHDC treatment. Taken together, NHDC showed its protective antioxidant effect against CCl4-induced oxidative damage via the direct free radical scavenging and indirect Nrf2/ARE signaling pathway.