Dihydronortanshinone, a natural product, alleviates LPS-induced inflammatory response through NF-κB, mitochondrial ROS, and MAPK pathways

Toxicol Appl Pharmacol. 2018 Sep 15:355:1-8. doi: 10.1016/j.taap.2018.06.007. Epub 2018 Jun 12.

Abstract

Inflammation is considered to be the common pathophysiological basis for a series of diseases. Documented data showed the anti-inflammatory effects of Salvia miltiorrhiza Bunge (Danshen), a traditional herb. The pharmacological activities of dihydronortanshinone (DNT), a tanshinone isolated from Danshen, remain unknown. In this study, the anti-inflammatory effects and underlying mechanisms of DNT were investigated with a lipopolysaccharide (LPS)-induced RAW264.7 macrophage model. DNT significantly suppressed LPS-induced inflammatory mediators such as nitrite oxide (NO), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS). LPS-induced reactive oxygen species (ROS) generation was inhibited by DNT, rotenone (Rot), thenoyltrifluoroacetone (TTFA), and antimycin A (AA). Furthermore, DNT inhibited LPS-induced NF-κBp65 phosphorylation, nuclear translocation, as well as JNK1/2 and p38MAPK phosphorylation. In addition, DNT interrupted Toll-like receptor 4 (TLR4) dimerization and molecular docking results suggested that it was buried in the pocket of TLR4-MD2 complex. In conclusion, DNT inhibited LPS-induced inflammation mainly through NF-κB, mitochondrial ROS, and MAPK pathways possibly mediated by interfering LPS-TLR4-MD2 complex.

Keywords: Dihydronortanshinone; Inflammation; LPS; Macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cytokines / metabolism
  • Diterpenes / antagonists & inhibitors
  • Diterpenes / pharmacology*
  • Inflammation / chemically induced
  • Inflammation / prevention & control*
  • Lipopolysaccharides
  • MAP Kinase Signaling System / drug effects
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitogen-Activated Protein Kinases / drug effects*
  • NF-kappa B / drug effects*
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects*
  • Toll-Like Receptor 4 / biosynthesis

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Diterpenes
  • Lipopolysaccharides
  • NF-kappa B
  • Reactive Oxygen Species
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Mitogen-Activated Protein Kinases