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.

Antioxidant and Hepatoprotective Effect of Swertiamarin on Carbon Tetrachloride-Induced Hepatotoxicity via the Nrf2/HO-1 Pathway

“…And STM treatment further augmented HO-1 protein expression following CCl 4 treatment, which suggests that a strong inductive response of HO-1 by STM is to protect hepatocytes from CCl 4 -induced oxidative cellular injuries. NQO1 is a phase II detoxifying enzyme which can be used for catalyzing the two-electron reduction and detoxification of quinones and other redoxcycling endogenous and exogenous chemicals [50]. In our study, STM treatment also reversed the expression of NQO1 down-regulated by CCl 4 .…”

Gallic Acid and Dodecyl Gallate Prevents Carbon Tetrachloride-Induced Acute and Chronic Hepatotoxicity by Enhancing Hepatic Antioxidant Status and Increasing p53 Expression

“…8,15,23,[30][31][32] The metabolic process of CCl 4 generates free radicals, which covalently bind to the cell proteins and increases lipid peroxidation and mem- brane disintegration, with eventually cell fibrosis and necrosis. 6,19,33) Damages to the parenchymal and non-parenchymal liver cells result in elevations of the both ALT, AST and GGT, which have been widely accepted as major biomarkers to assess the hepatic injury.…”

“…We chose the maximum dose of 100 mg/kg to avoid hepatic damages according to previous studies. 8,15) In the both models, 24 h after CCl 4 injection animals were killed by an overdose of ketamine/xilasine. Blood samples were collected and separated by centrifugation at 800×g for 10 min and the serum samples were biochemicaly analysed.…”

“…Several studies have shown that natural compounds with antioxidant activity are effective in protecting the liver from oxidative damages besides up regulating a group of cytoprotective genes. [6][7][8] Gallic acid (3,4,5-trihydroxy benzoic acid, GA) is a natural botanical phenolic compound, which is widely distributed in grapes, green tea and pomegrate. Studies have shown that GA processes a lot of biological activities, such as anti-inflammatory, antimutagenic, antioxidant and antitumoral.…”

Novel Neohesperidin Dihydrochalcone Analogue Inhibits Adipogenic Differentiation of Human Adipose-Derived Stem Cells through the Nrf2 Pathway

“…After simple hydrogenation, neohesperidin becomes neohesperidin dihydrochalcone (NHDC), which is widely used as a sweetener. NHDC showed strong free-radical scavenging and Nrf2 activation effects [28]. However, no studies have elucidated whether NHDC can suppress adipogenic differentiation and inhibit obesity development.…”