Inhibitory effects of nodakenin on inflammation and cell death in lipopolysaccharide-induced liver injury mice

Phytomedicine. 2021 Jan:81:153411. doi: 10.1016/j.phymed.2020.153411. Epub 2020 Nov 20.

Abstract

Background: Nodakenin, a coumarin glucoside isolated from the roots of Angelica biserrata, has been reported to have anti-inflammatory, antibacterial, anticancer effects. However, despite these studies, the potential liver protective effects of nodakenin in inflammatory liver injury models have not been reported.

Methods: A mouse model of inflammatory liver injury was induced by injection of lipopolysaccharide (LPS) (15 mg/kg, intraperitoneally (i.p)). Liver tissue AST, ALT, ROS, T-GSH and T-SOD were analyzed by ELISA. The concentrations of TNF-α, IL-6, and IL-1β in serum of LPS-induced inflammatory liver injury mice were analyzed. The mRNA expression levels of GPx1, catalase, SOD1, SOD2, TNF-α, IL-6, IL-1β, iNOS and COX-2 were analyzed using real-time PCR. The expressions of MAPK, IRF3, NF-κB, Nrf2, HO-1, caspase-3 and caspase-7 were analyzed using western blotting. Liver tissue was stained with IHC to confirm NF-κB, Nrf-2, HO-1, caspase-3, Bax, and Bcl2. Tunnel analysis was performed to confirm the fragmented nuclear DNA characteristics of apoptosis.

Results: The administration of nodakenin (10 and 30 mg/kg) reduced serum aminotransferase levels compared to LPS-induced liver damage and significantly improved the oxidative state of liver tissue and pathological damage. Moreover, inhibited the phosphorylation of transforming growth factor beta (TGF-β)-activated kinase (TAK)-1 in LPS-induced inflammatory liver injury model, and significantly inhibited the transcriptional of nuclear factor-kappa B (NF-kB) and the secretion of pro-inflammatory mediators. In addition nodakenin pre-treatment also attenuated hepatocyte death by regulating apoptosis-related mitochondrial proteins, such as cysteinyl aspartate specific proteinase 3 (caspase 3), poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax).

Conclusion: Our findings suggest that nodakenin has anti-inflammatory, anti-oxidant and anti-apoptotic activity and may be an adjunctive prevention agent for liver injury.

Keywords: Apoptosis; Inflammation; Lipopolysaccharide; Liver injury; Nodakenin; Oxidative stress.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Chemical and Drug Induced Liver Injury / drug therapy*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Coumarins / pharmacology*
  • Cytokines / blood
  • Cytokines / genetics
  • Enzymes / metabolism
  • Glucosides / pharmacology*
  • Hepatitis, Animal / drug therapy*
  • Hepatitis, Animal / metabolism
  • Hepatitis, Animal / pathology
  • Lipopolysaccharides / toxicity*
  • Male
  • Mice
  • Mice, Inbred ICR
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Protective Agents / pharmacology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antioxidants
  • Coumarins
  • Cytokines
  • Enzymes
  • Glucosides
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, mouse
  • Protective Agents
  • nodakenin