forsythiaside and Chemical-and-Drug-Induced-Liver-Injury

Forsythiae Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a commonly used traditional Chinese medicine and possesses various pharmacological activities, including anti-inflammation, anti-oxidant and liver protection.. Although acetaminophen (APAP) has been frequently used for its antipyretic and analgesic effects, it leads to liver injury at an overdose or long-term medication. Forsythiaside A (FA), the principal active component of Forsythiae Fructus, exerts prominent antioxidant, anti-inflammatory and hepatoprotective effects. However, the protective property and underlying mechanism of FA against APAP challenge have not yet been elucidated. Therefore, we aimed to explore the hepatoprotective effect and action mechanism of FA against APAP-induced liver injury in zebrafish.. In this study, liver-specific transgenic zebrafish larvae (lfabp: EGFP) were used to investigate the protective effect of FA against overdose APAP exposure. The liver phenotype, morphological and biochemical assessments were carried out to evaluate the hepatoprotective effect of FA. Network pharmacology and molecular docking study were conducted to analyze the potential targets of FA in the treatment of APAP-induced liver injury. Finally, the mechanism of action was verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR).. The liver phenotype, morphological and biochemical assessments indicated that FA could mitigate APAP-triggered liver injury. Network pharmacology and molecular docking analysis indicated that the protective effect of FA might be related to the regulation of targets tumor necrosis factor (TNF), matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2 (MMP2), and phosphatidylinositol 3-kinase (PI3K). PCR results confirmed that FA could reverse the progressive alterations of genes involving in extracellular matrix remolding and PI3K/AKT-mediated apoptosis signaling pathway.. Our results indicated that FA could mitigate APAP-induced liver injury through modulating the remolding of extracellular matrix and PI3K/AKT-mediated apoptosis.

Topics: Acetaminophen; Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cytoprotection; Extracellular Matrix; Fruit; Glutathione; Glycosides; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Protective Agents; Protein Interaction Maps; Proto-Oncogene Proteins c-akt; Zebrafish

Forsythiaside A, an active constituent isolated from air-dried fruits of Forsythia suspensa, has been reported to have multiple pharmacological activities including anti-inflammatory, anti-oxidant, and antioxidant activities. In the present study, the hepatoprotective effect of forsythiaside A was investigated in lipopolysaccharide (LPS)/d-galactosamine (GalN)-induced acute liver injury in mice. Mice acute liver injury model was induced by LPS (50μg/kg)/GalN (800mg/kg). Forsythiaside A was administrated 1h prior to LPS/GalN exposure. The results showed that forsythiaside A attenuated hepatic pathological damage, malondialdehyde (MDA) content, and serum ALT, and AST levels induced by LPS/GalN. Moreover, forsythiaside A inhibited NF-κB activation, serum TNF-α and hepatic TNF-α levels induced by LPS/GalN. Furthermore, we found that forsythiaside A up-regulated the expression of Nrf2 and heme oxygenase-1. Our results showed that forsythiaside A protected against LPS/GalN-induced liver injury through activation of Nrf2 and inhibition of NF-κB activation.

Topics: Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Forsythia; Fruit; Galactosamine; Glycosides; Lipid Peroxidation; Lipopolysaccharides; Liver Function Tests; Male; Mice, Inbred BALB C; NF-kappa B; Protective Agents; Tumor Necrosis Factor-alpha