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Type 1 diabetes (T1D) is the result of autoimmune-mediated destruction of pancreatic islet β-cells by activated autoreactive inflammatory cells, effecting insulin production from β-cells. The Ca2+-independent phospholipase A2β(iPLA2β), a member of PLA2 family, hydrolyzes the sn-2 substituent from glycerophospholipid substrates to yield a free fatty acid, which can be metabolized to bioactive lipids. Our work has revealed that iPLA2βactivation shifts macrophage polarization towards an inflammatory phenotype and that inhibition of iPLA2βreduces the development of T1D. We have now identified that iPLA2βactivation induces generation of select pro-inflammatory lipids in the non-obese diabetic (NOD) mice, including prostaglandins (PGs) and DHETs that accompany T1D development. To assess the role of these lipids in T1D development, NOD mice were administered (ip) polyethylene glycol 400 (vehicle), TPPU (sEH inhibitor, 3mg/ml), or PTUPB (dual antagonist of COX2/sEH, 9mg/ml) for up to 30 weeks. Measurement of blood concentrations of TPPU and PTUPB confirmed availability of the inhibitors between dosages. As expected, over the study-period glucose tolerance was impaired in the PEG group. Whereas glucose tolerance was not improved by PTUPB, it was significantly ameliorated by TPPU. These findings suggest that sEH1 inhibition, and thus the production of DHETs, can have beneficial effects in mitigating T1D development. Because different PGs can have pro- or anti-inflammatory effects, they further suggest that inhibition of COX2 may not be as effective as it may also lead to reductions in anti-inflammatory PGs. Overall, our findings support a role for select iPLA2β-derived lipids (iDLs) in T1D development and suggest developing strategies to target iPLA2βor the generation of select iDLs to prevent onset/progression of T1D. Disclosure T. White: None. S. Ramanadham: None. B. Hammock: None. Funding University of Alabama at Birmingham, Iacocca Family Foundation; U.S. Department of Veterans Affairs (BX001792, 13F-RCS-002); National Institutes of Health (R01DK69455, R01DK110292 to S.R.), (R01HL125353), (U01HD087198), (RR031535), (R01AI139072)

Mediators of anti-hypertensive actions of docosahexaenoic acid (DHA) are largely unknown. The omega-3 epoxide of DHA, 19, 20-EDP (epoxydocosapentaenoic acid) is metabolized by soluble epoxide hydrolase (sEH), which also metabolizes the anti-inflammatory and anti-hypertensive arachidonic acid (ARA) epoxides, EETs (epoxyeicosatrienoic acids). Based in part on plasma levels of EDPs following a DHA-rich diet, we hypothesized that 19, 20-EDP contributes to the anti-hypertensive actions of DHA in angiotensin-II dependent hypertension. Treatment individually with 19, 20-EDP, and a potent sEH inhibitor (sEHI) TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea) significantly lowered blood pressure (BP) as compared to angiotensin-II infused animals. The largest reduction in BP was obtained with the combination of 19, 20-EDP and TPPU, which was more efficacious than the combination of 14, 15-EET and TPPU. Oxylipin profiling revealed that 19, 20-EDP and 14, 15-EET infusion affected mostly metabolites o...

Uncontrolled combustion due to garbage recycling is a widespread activity among slum dwellers in distressed economy countries and has been indicated as a major source of dioxin contamination. However, because of the high cost and complexity of gas chromatography/high-resolution mass spectrometry (GC-HRMS) analysis, the magnitude of the problem remains largely unknown. The present study describes a first approach toward the use of a dioxin antibody-based enzyme-linked immunosorbent assay (ELISA) as the basis for a sustainable, simple, and low-cost monitoring program to assess the toxicological impact of uncontrolled combustion in slums. A panel of 16 samples was analyzed by GC-HRMS and ELISA on split extracts. Close to 20% of the analyzed samples showed dioxin concentrations up to almost twice the guidance level for residential soil in several countries, pointing out the need for performing a large-scale monitoring program. Despite the potential for variations in dioxin congener distribution due to the mixed nature of the incinerated material, there was a good correlation between the toxic equivalents as determined by GC-HRMS and ELISA. Furthermore, an interlaboratory ELISA validation showed that the capacity to perform the dioxin ELISA was successfully transferred between laboratories. It was concluded that the ELISA method performed very well as a screening tool to prioritize samples for instrumental analysis, which allows cutting down costs significantly.

http://www.pnas.org/; International audience; Juvenile hormone (JH) is a sesquiterpenoid of vital importance for insect development, yet the molecular basis of JH signaling remains obscure, mainly because a bona fide JH receptor has not been identified. Mounting evidence points to the basic helix-loop-helix (bHLH)/Per-Arnt-Sim (PAS) domain protein Methoprene-tolerant (Met) as the best JH receptor candidate. However, details of how Met transduces the hormonal signal are missing. Here, we demonstrate that Met specifically binds JH III and its biologically active mimics, methoprene and pyriproxyfen, through its C-terminal PAS domain. Substitution of individual amino acids, predicted to form a ligand-binding pocket, with residues possessing bulkier side chains reduces JH III binding likely because of steric hindrance. Although a mutation that abolishes JH III binding does not affect a Met-Met complex that forms in the absence of methoprene, it prevents both the ligand-dependent dissociation of the Met-Met dimer and the ligand-dependent interaction of Met with its partner bHLH-PAS protein Taiman. These results show that Met can sense the JH signal through direct, specific binding, thus establishing a unique class of intracellular hormone receptors.