Abstract |
Soluble epoxide hydrolase (sEH) serves as a potential target in inflammation-related diseases. Based on the bioactivity-guided separation, a new sesquiterpenoid inulajaponoid A (1) was isolated from Inula japonica with a sEH inhibitory effect, together with five known compounds, such as 1-O-acetyl-6-O-isobutyrylbritannilactone (2), 6β-hydroxytomentosin (3), 1β,8β-dihydroxyeudesma-4(15),11(13)-dien-12,6α-olide (4), (4S,6S,7S,8R)-1-O-acetyl-6-O-(3-methylvaleryloxy)-britannilactone (5), and 1-acetoxy-6α-(2-methylbutyryl)eriolanolide (6). Among them, compounds 1 and 6 were assigned as mixed and uncompetitive inhibitors, respectively. The result of immunoprecipitation (IP)-MS demonstrated the specific binding of compound 6 to sEH in the complex system, which was further confirmed by the fluorescence-based binding assay showing its equilibrium dissociation constant (Kd = 2.43 μM). The detail molecular stimulation revealed the mechanism of action of compound 6 with sEH through the hydrogen bond of amino acid residue Gln384. Furthermore, this natural sEH inhibitor (6) could suppress the MAPK/NF-κB activation to regulate inflammatory mediators, such as NO, TNF-α, and IL-6, which confirmed the anti-inflammatory effect of inhibition of sEH by 6. These findings provided a useful insight to develop sEH inhibitors upon the sesquiterpenoids.
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Authors | Juan Zhang, Fang-Yu Yang, Qi-Meng Zhu, Wen-Hao Zhang, Min Zhang, Jing Yi, Yan Wang, Hou-Li Zhang, Guo-Biao Liang, Jian-Kun Yan, Cheng-Peng Sun |
Journal | International journal of biological macromolecules
(Int J Biol Macromol)
Vol. 235
Pg. 123911
(Apr 30 2023)
ISSN: 1879-0003 [Electronic] Netherlands |
PMID | 36878397
(Publication Type: Journal Article)
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Copyright | Copyright © 2023. Published by Elsevier B.V. |
Chemical References |
- Epoxide Hydrolases
- Tumor Necrosis Factor-alpha
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Topics |
- Epoxide Hydrolases
(chemistry)
- Molecular Dynamics Simulation
- Signal Transduction
- Gene Expression Regulation
- Tumor Necrosis Factor-alpha
(metabolism)
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