isonaringin and Liver-Diseases--Alcoholic

Alcohol-associated liver disease (ALD) encompasses a range of hepatic abnormalities, including isolated alcoholic steatosis, steatohepatitis, and cirrhosis. The flavanone-7-O-glycoside narirutin (NRT), the primary flavonoid in citrus peel, has antioxidant, anti-inflammatory, and lipid-lowering activity. We investigated the effects of NRT on liver injury induced by alcohol and explored the underlying mechanisms.. Zebrafish larvae were used to investigate the effects of NRT on acute exposure to ethanol (EtOH). Liver phenotypic, morphological, and biochemical assessments were performed to evaluate the hepatoprotective effects of NRT. Network pharmacology and molecular docking analyses were conducted to identify candidate targets of NRT in EtOH-induced liver injury. A drug affinity responsive target stability (DARTS) assay was conducted to evaluate the binding of NRT to mitogen-activated protein kinase 14 (MAPK14). The mechanism of action of NRT was validated by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analysis.. The liver phenotypic, morphological, and biochemical assessments revealed that NRT has potential therapeutic effects against acute EtOH-induced liver injury. RT-qPCR confirmed that NRT reversed the change in the expression of genes related to oxidative stress, lipogenesis, and the endoplasmic reticulum (ER)/unfolded protein response pathway. Network pharmacology and molecular docking analyses identified potential targets of NRT's protective effects and confirmed that NRT regulates the p38 MAPK signaling pathway by targeting mitogen-activated protein kinase 14 (MAPK14).. NRT mitigates alcohol-induced liver injury by preventing lipid formation, protecting the antioxidant system, and suppressing ER stress-induced apoptosis through MAPK14 modulation.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury, Chronic; Ethanol; Fatty Liver; Flavanones; Lipids; Liver Diseases, Alcoholic; Mitogen-Activated Protein Kinase 14; Molecular Docking Simulation; Zebrafish

This study aimed to demonstrate protective activities of the narirutin fraction from peels of Citrus unshiu against ethanol-induced hepatic damage through an animal study. Citrus narirutin fraction (CNF), contained 75% of narirutin, was obtained by an ultra-sonicated extraction and further purification. ICR mice were divided into four groups; normaldiet control, ethanol control (6.5g ethanol/kg), low-CNF (ethanol+150mg CNF/kg) and high-CNF (ethanol+300mg CNF/kg) groups. Consumption of alcohol for 8weeks induced severe liver damage with increases in prognostic indicators such as aspartate transaminase, alanine transaminase in serum whereas co-administration of CNF suppressed their increases. Excessive accumulations in liver TG and TC in ethanol control group were also suppressed by co-administration of CNF. Co-administration of CNF maintained SOD activity, GSH and malondialdehyde levels close to those of the normal diet group. Chronic consumption of alcohol also stimulated abrupt increases in pro-inflammatory cytokines such as nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α and interleukin (IL)-1β in liver otherwise co-administration of CNF effectively suppressed production of these cytokines dose-dependently. These results indicate that co-administration of CNF with alcohol can alleviate alcohol induced liver damage through preventing lipid formation, protecting antioxidant system and suppressing productions of pro-inflammatory cytokines.

Topics: Animals; Body Weight; Citrus; Disaccharides; Flavanones; Glutathione; Interleukin-1beta; Liver; Liver Diseases, Alcoholic; Male; Malondialdehyde; Mice; Mice, Inbred ICR; NF-kappa B; Organ Size; Superoxide Dismutase; Tumor Necrosis Factor-alpha