Regulation of the redox signaling and inflammation by Terminalia myriocarpa leaves and the predictive interactions of it's major metabolites with iNOS and NF-ĸB

J Ethnopharmacol. 2021 Nov 15:280:114459. doi: 10.1016/j.jep.2021.114459. Epub 2021 Jul 31.

Abstract

Ethnopharmacological relevance: The present study was designed to investigate the regulation of the redox signaling and inflammation by ethanolic leaf extract of Terminalia myriocarpaVan Heurck & Müller (ETM), inspired by the reported antioxidant potential of the plant bark and the anti-edema effect of the same genus.

Materials and methods: HPLC-DAD dereplication study was conducted to detect the major polyphenolic secondary metabolites. In-vitro DPPH free radical scavenging assay, nitric oxide (NO) scavenging assay, Fe2+ ion chelating ability assay and reducing power assay were conducted to evaluate the antioxidant capacity. The molecular mechanism of anti-inflammation was investigated via assessing the NO and NF-ĸB inhibiting properties in different cell lines. In-vivo carrageenan and histamine-induced edema tests were conducted using established animal models. Pro-inflammatory proteins iNOS and NF-κB were docked against the major metabolites of ETM in the in-silico study.

Results: HPLC dereplication analysis revealed the presence of considerable amount of ellagic acid, where methyl-(S)-flavogallonate was previously reported in T. myriocarpa. Significant antioxidant activity was found in every in- vitro redox assay conducted. NO was reduced in RAW 264.7 cells, showing 83.67 ± 4.18% inhibitory activity at the highest tested concentration. TNF-α induced NF-κB was also observed to be reduced in 293/NF-кB-luc cells with an inhibitory activity of 66.23 ± 0.81% at the highest dose tested. In-vivo carrageenan-induced edema test demonstrated significant anti-inflammatory activity (p < 0.05; p < 0.01) at both doses of 250 and 500 mg/kg with 60.10% highest reduction in rat paw volume. Using same doses, histamine-induced edema test exhibited mentionable anti-inflammatory potential (p < 0.05; p < 0.01) with 67.91% highest reduction in rat paw volume. Moreover, ellagic acid and methyl-(S)-flavogallonate showed significant binding affinity with iNOS (-8.5 and -8.7 Kcal/moL, respectively) and NF-κB (-7.3 and -7.3 Kcal/moL, respectively).

Conclusion: Mentionable basis was found on behalf of the anti-inflammatory and antioxidant potentials of ETM which might be correlated with its NF-ĸB inhibiting properties.

Keywords: Anti-inflammatory; Molecular docking; NF-κB inhibition; NO production inhibition; Terminalia myriocarpa; antioxidant.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / isolation & purification
  • Anti-Inflammatory Agents / pharmacology*
  • Antioxidants / administration & dosage
  • Antioxidants / pharmacology
  • Computer Simulation
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Inflammation / drug therapy*
  • Male
  • Mice
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidation-Reduction / drug effects
  • Plant Extracts / pharmacology*
  • Plant Leaves
  • RAW 264.7 Cells
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Terminalia / chemistry*

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • NF-kappa B
  • Plant Extracts
  • Nitric Oxide
  • Nitric Oxide Synthase Type II