AUDA

AUDA

Ingestion of the epoxide hydrolase inhibitor AUDA modulates immune responses of the mosquito, Culex quinquefasciatus during blood feeding.[Pubmed:27369469]

Insect Biochem Mol Biol. 2016 Sep;76:62-69.

Epoxide hydrolases (EHs) are enzymes that play roles in metabolizing xenobiotic epoxides from the environment, and in regulating lipid signaling molecules, such as juvenile hormones in insects and epoxy fatty acids in mammals. In this study we fed mosquitoes with an epoxide hydrolase inhibitor AUDA during artificial blood feeding, and we found the inhibitor increased the concentration of epoxy fatty acids in the midgut of female mosquitoes. We also observed ingestion of AUDA triggered early expression of defensin A, cecropin A and cecropin B2 at 6 h after blood feeding. The expression of cecropin B1 and gambicin were not changed more than two fold compared to controls. The changes in gene expression were transient possibly because more than 99% of the inhibitor was metabolized or excreted at 42 h after being ingested. The ingestion of AUDA also affected the growth of bacteria colonizing in the midgut, but did not affect mosquito longevity, fecundity and fertility in our laboratory conditions. When spiked into the blood, EpOMEs and DiHOMEs were as effective as the inhibitor AUDA in reducing the bacterial load in the midgut, while EETs rescued the effects of AUDA. Our data suggest that epoxy fatty acids from host blood are immune response regulators metabolized by epoxide hydrolases in the midgut of female mosquitoes, inhibition of which causes transient changes in immune responses, and affects growth of microbes in the midgut.

Increases in levels of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EETs and DHETs) in liver and heart in vivo by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in hepatic EET:DHET ratios by cotreatment with TCDD and the soluble epoxide hydrolase inhibitor AUDA.[Pubmed:24311719]

Drug Metab Dispos. 2014 Feb;42(2):294-300.

The environmental toxin and carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) binds and activates the transcription factor aryl hydrocarbon receptor (AHR), inducing CYP1 family cytochrome P450 enzymes. CYP1A2 and its avian ortholog CYP1A5 are highly active arachidonic acid epoxygenases. Epoxygenases metabolize arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs) and selected monohydroxyeicosatetraenoic acids (HETEs). EETs can be further metabolized by epoxide hydrolases to dihydroxyeicosatrienoic acids (DHETs). As P450-arachidonic acid metabolites affect vasoregulation, responses to ischemia, inflammation, and metabolic disorders, identification of their production in vivo is needed to understand their contribution to biologic effects of TCDD and other AHR activators. Here we report use of an acetonitrile-based extraction procedure that markedly increased the yield of arachidonic acid products by lipidomic analysis over a standard solid-phase extraction protocol. We show that TCDD increased all four EETs (5,6-, 8,9-, 11,12-, and 14,15-), their corresponding DHETs, and 18- and 20-HETE in liver in vivo and increased 5,6-EET, the four DHETs, and 18-HETE in heart, in a chick embryo model. As the chick embryo heart lacks arachidonic acid-metabolizing activity, the latter findings suggest that arachidonic acid metabolites may travel from their site of production to a distal organ, i.e., heart. To determine if the TCDD-arachidonic acid-metabolite profile could be altered pharmacologically, chick embryos were treated with TCDD and the soluble epoxide hydrolase inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). Cotreatment with AUDA increased hepatic EET-to-DHET ratios, indicating that the in vivo profile of P450-arachidonic acid metabolites can be modified for potential therapeutic intervention.

Therapeutic effects of the soluble epoxide hydrolase (sEH) inhibitor AUDA on atherosclerotic diseases.[Pubmed:25975094]

Pharmazie. 2015 Jan;70(1):24-8.

In this study, we aimed to detect the effects of the soluble epoxide hydrolase (sEH) inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) on atherosclerotic diseases and to explore its mechanism. The atherosclerosis animal model was constructed by ApoE-/- mice. To determine the optimal therapeutic concentration of AUDA, different concentrations of AUDA were infused into ApoE-/- mice, with controls receiving infusions of normal saline alone. Mouse body weight and serum total cholesterol, triglyceride, LDL and HDL levels were measured. The western blotting (WB) method was used to detect the expression of TLR4 and NFKB in the aortic wall of the AUDA-treated and control mice. After the animals were sacrificed, we performed Oil Red O staining of the aortic sinus atherosclerotic plaque area followed by quantitative analysis of the aortic atherosclerotic plaque size and the percentage of lumen area in the two groups of mice. The expression levels of inflammatory cytokines, adhesion molecules and chemokines in the AUDA group were significantly decreased compared to the saline-treatment group (P < 0.05). The optimal AUDA concentration was found to be 0.35 ml/mg. AUDA significantly inhibited the expression of TLR4 and NFkappaB in ApoE-/- mouse aortas and reduced the aortic sinus plaque area of the ApoE-/- mouse group (P < 0.05). In conclusion, AUDA can regulate blood lipid balance, which may be one of the mechanisms for its protective effects on the cardiovascular system.

Soluble epoxide hydrolase inhibitor, AUDA, prevents early salt-sensitive hypertension.[Pubmed:18508449]

Front Biosci. 2008 May 1;13:3480-7.

In stroke-prone spontaneously hypertensive rats (SHRSP) end-organ damage is markedly accelerated by high-salt (HS) intake. Since epoxyeicosatrienoic acids (EETs) possess vasodepressor and natriuretic activities, we examined whether a soluble epoxide hydrolase (sEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), to inhibit the metabolism of EETs, would protect against pathologic changes in SHRSP. Seven-week-old male SHRSP were treated as follows: normal salt (NS), NS + AUDA, HS and HS + AUDA. Systolic blood pressure (SBP) (205 +/- 4 v 187 +/- 7 mmHg) and proteinuria (3.7 +/- 0.2 v 2.6 +/- 0.2 mg/6 h), but not plasma EETs (11.0 +/- 0.9 v 9.7 +/- 1.1 ng/ml), were significantly increased at 9 weeks of age in HS v NS SHRSP. HS was associated with fibrinoid degeneration and hypertrophy of arterioles in the kidney and perivascular fibrosis and contraction band necrosis in the heart. AUDA ameliorated these early salt-dependent changes in saline-drinking SHRSP and increased plasma levels of EETs but did not affect water and electrolyte excretion. sEH inhibition may provide a therapeutic strategy for treating salt-sensitive hypertension and its sequelae.

AUDA (compound 43) is a potent soluble epoxide hydrolase (sEH) inhibitor with IC50s of 18 and 69 nM for the mouse and human sEH, respectively. AUDA has anti-inflammatory activity.

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