title: Neohesperidin Dihydrochalcone versus CCl₄-Induced Hepatic Injury through Different Mechanisms: The Implication of Free Radical Scavenging and Nrf2 Activation.
abstract: 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.
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Chuanyang
authors.initials: C
authors.lastname: Su
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Xia
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Song
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Juanli
authors.initials: J
authors.lastname: Fu
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Congxue
authors.initials: C
authors.lastname: Xiao
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Chen
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Zhiyin
authors.initials: Z
authors.lastname: Sun
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Shanmei
authors.initials: S
authors.lastname: Wu
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Siyu
authors.initials: S
authors.lastname: Yang
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Xuegang
authors.initials: X
authors.lastname: Li
authors.affiliation: ‡College of Life Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ye
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Erqun
authors.initials: E
authors.lastname: Song
authors.affiliation: †Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, People's Republic of China, 400715.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects; D047188:Chalcones / Q000008:administration & dosage*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006569:Hesperidin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047188:Chalcones; D016166:Free Radical Scavengers; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; C013613:neohesperidin dihydrochalcone; D002251:Carbon Tetrachloride; D006569:Hesperidin; D051547:Heme Oxygenase-1; D048031:JNK Mitogen-Activated Protein Kinases
keywords: HO-1; Keap1; MAPK; NHDC; NQO1; liver; ubiquitination