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Pharmacological mechanism underlying anti-inflammatory properties of two structurally divergent coumarins through the inhibition of pro-inflammatory enzymes and cytokines

Cited 18 time in Web of Science Cited 18 time in Scopus
Authors
Khan, Salman; Shehzad, Omer; Cheng, Mao-Sheng; Li, Rui-Juan; Kim, Yeong Shik
Issue Date
2015-07-29
Publisher
BioMed Central
Citation
Journal of Inflammation, 12(1):47
Keywords
Calipteryxin(3’S,4’S)-3’,4’-disenecioyloxy-3’,4’-dihydroseselinNF-κBMAPKAktSeseli recinosum
Abstract
Background
The aim of the present study is to investigate the effects of two structurally divergent coumarins, calipteryxin (1) and (3S,4S)-3,4-disenecioyloxy-3,4-dihydroseselin (2) from Seseli recinosum, in lipopolysaccharide (LPS)-stimulated murine macrophages.

Methods
The nitrite production was evaluated using Griess reagent. The protein and mRNA expression levels were investigated through Western blot and quantitative real time-PCR analyses. The NF-κB and AP-1 DNA-binding activities were assessed using an electrophoretic mobility shift assay. The docking studies were performed with Glide XP in Schrödinger suite (version 2013).

Results
The results of the present study revealed that calipteryxin (1) and (3S,4S)-3,4-disenecioyloxy-3,4-dihydroseselin (2) treatment showed potent inhibitory effects on pro-inflammatory enzymes and cytokines associated with molecular signaling pathways. Treatment with calipteryxin and (3S,4S)-3,4-disenecioyloxy-3,4-dihydroseselin also decreased the production of nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in a dose-dependent manner. Additionally, both coumarins inhibited the LPS-induced protein and mRNA expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells. To explore the potential mechanisms underlying the inhibitory activity of coumarin derivatives, the protein signaling pathways for NF-κB, mitogen-activated protein kinase (MAPK) and Akt were examined. Calipteryxin and (3S,4S)-3,4-disenecioyloxy-3,4-dihydroseselin markedly reduced the LPS-stimulated phosphorylation of IKKα/β, p-IκBα and IκBα degradation as well as the nuclear translocation of the p65 subunit of pro-inflammatory transcription factor NF-κB. In addition, calipteryxin and (3S,4S)-3,4-disenecioyloxy-3,4-dihydroseselin) considerably inhibited the LPS-induced expression of ERK, c-Jun N-terminal kinase (JNK), p38 and Akt proteins. Furthermore, both coumarins significantly inhibited c-Jun expression in the nucleus.

Conclusions
Taken together, these results support the therapeutic potential and molecular mechanism of calipteryxin and (3S,4S)-3,4-disenecioyloxy-3,4-dihydroseselin associated with inflammatory diseases.
Language
English
URI
https://hdl.handle.net/10371/109773
DOI
https://doi.org/10.1186/s12950-015-0087-y
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Journal Papers (저널논문_약학과)
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