• 약학회지
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• 제56권1호
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• pp.42-47
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• 2012

Soluble epoxide hydrolase (sEH) is a metabolic regulator of epoxyeicosatrienoic acids (EETs). EETs have many beneficial effects, vasodilation, anti-diabetes, anti-inflammation, cardiovascular protection, renal protection. Therefore, selective sEH inhibitors have a potential for treating these diseases. In the present study, screening methods for sEH inhibitors using PHOME ((3-phenyl-oxiranyl)-acetic acid cyano-(6-methoxynaphthalen-2-yl)-methyl ester) and 14-15-EET as substrates were established. To determine selectivity, microsomal epoxide hydrolase (mEH) inhibition assay was also developed using styrene oxide as a substrate of microsomal epoxide hydrolase. Our results obtained from 12-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid (AUDA) used as a positive sEH inhibitor and valpromide used as a positive mEH inhibitor showed that these methods are useful for discovery of drug candidates.

• 약학회지
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• 제51권5호
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• pp.291-295
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• 2007

The present study examines the effect of dominant-negative Akt on the insulin-mediated microsomal epoxide hydrolase (mEH) induction in rat hepatocytes. We also assessed the role of insulin in the expression of soluble epoxide hydrrolase (sEH). Insulin increased mEH levels and the enzyme activities, whereas sEH protein expression was unaffected by insulin. The specific PI3K inhibitors or p70 S6 kinase inhibitor ameliorated the insulin-mediated increase in mEH protein levels. Infection with adenovirus expressing dominant-negative and kinase-dead mutant of Akt1 effectively inhibited the insulin-mediated increase in mEH expression and mEH activity. These results suggest that mEH and sEH are differentially regulated by insulin and PI3K/Akt/p70S6K are active in the insulin-mediated regulation of mEH expression.

• Natural Product Sciences
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• 제21권3호
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• pp.176-184
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• 2015

In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, an extract of the dried whole plants of Euphorbia supina Rafin was found to significantly inhibit sEH activity in vitro. Phytochemical investigation of E. supina resulted in isolation of 17 compounds (1 - 17), including triterpenes (1 - 4), phenolic compounds (5 - 8), and flavonoid derivatives (9 - 17). The structures of the isolated compounds were established mainly by extensive analysis of the 1D and 2D NMR, and MS data. All of the isolated compounds were evaluated for their sEH inhibitory activity. Among the isolated phenolic compounds, 8 was identified as a significant inhibitor of sEH, with an IC₅₀ value of 15.4 ± 1.3 μM. Additionally, a kinetic analysis of isolated compounds (2, 5, 8 - 11, 13, and 17) indicated that the inhibitory effects of flavonoid derivatives 10 and 11 were of mixed-type, with inhibitory constants (K_i) ranging from 3.6 ± 0.8 to 21.8 ± 1.0 μM, whereas compounds 2, 5, 8, 9, 13, and 17 were non-competitive inhibitors with inhibition K_i values ranging from 3.3 ± 0.2 to 39.5 ± 0.0 μM.