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Objectives: We investigated changes of renal perfusion after topical and oral diclofenac administration in healthy volunteers using functional magnetic resonance imaging (MRI) with arterial spin labelling (ASL)., Methods: Twenty-four healthy human participants (21-51 years) underwent 1.5T MRI before and 1 h after a single oral dose of diclofenac (50 mg). Twelve of 24 participants underwent an additional MRI examination following 3-day topical diclofenac administration. For renal perfusion imaging, a flow-sensitive alternating inversion-recovery TrueFISP ASL sequence was applied. Plasma concentrations of diclofenac and serum concentrations of thromboxane were determined., Key Findings: After oral diclofenac application, large interindividual differences in plasma concentrations were observed (range <3-4604 nm). Topical diclofenac application did not result in relevant systemic diclofenac levels (range 5-75 nm). MRI showed a significant reduction of renal perfusion in individuals with diclofenac levels ≥225 nm (baseline: 347 ± 7 vs diclofenac: 323 ± 8 ml/min/100 g, P < 0.01); no significant differences were observed in participants with diclofenac levels <225 nm. Diclofenac levels correlated negatively with thromboxane B2 levels pointing towards target engagement., Conclusions: Single-dose diclofenac caused a decrease in renal perfusion in participants with diclofenac levels ≥225 nm. We demonstrated that even a single dose of diclofenac can impair renal perfusion, which could be detrimental in patients with underlying chronic kidney disease or acute kidney injury., (© 2019 Royal Pharmaceutical Society.)

Eicosanoids, including prostaglandins (PGs) and thromboxanes, are broadly bioactive lipid mediators and increase colon tumorigenesis possibly through chronic inflammatory mechanisms. Epidemiological and experimental data suggest that acetylsalicylic acid (ASA) helps prevent colorectal cancer (CRC), possibly through cyclooxygenase (COX)-mediated suppression of eicosanoid, particularly PGE 2 , formation. Recent studies suggest that statins prevent CRC and improve survival after diagnosis. We identified patients on ASA and/or statin treatment undergoing routine colonoscopy and measured eicosanoid levels in colonic mucosa with targeted metabolomics technology (LC-MS/MS). ASA-treated individuals (n = 27) had significantly lower tissue eicosanoid levels of most COX-derived metabolites than untreated individuals (n = 31). In contrast, COX-derived lipid metabolites tended to be higher in patients with statin treatment (n = 7) as compared with those not receiving statins (n = 24). This effect was not discernible in subjects treated with ASA and statins (n = 11): Individuals treated with both drugs showed a pronounced suppression of COX-derived eicosanoids in colon tissue, even compared with subjects treated with ASA alone. Our data from a routine clinical setting support the hypothesis that ASA and statins could inhibit CRC development via lipid mediator modification. Further studies should directly investigate the effect of dual ASA and statin treatment on colon tumorigenesis in humans., (Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.)

Introduction: Obesity is associated with inflammation and weight reduction has been shown to influence the inflammatory process. Besides classic inflammatory markers, oxidized polyunsaturated fatty acid (PUFA) metabolites (oxylipins) are potent mediators of inflammation. Little is known about endogenous levels of oxylipins, e.g. hydroxy, epoxy and dihydroxy FA in obese subjects with persistent low-grade inflammation. We aimed to evaluate levels of inflammatory markers and blood oxylipins in obese subjects before and after weight reduction., Subjects and Methods: In the present study, 42 obese (BMI 32.7 ± 0.22 kg/m(2)) men and women were classified in groups according to high-sensitivity C-reactive protein (hsCRP) levels (no inflammation<1mg/L; low-grade inflammation ≥ 3 mg/L). Subjects underwent an intervention for eight weeks, which consisted of two phases: (1) week 1 and 2: total replacement of three meals by a formula diet and (2) six week partial formula diet (replacement of 1-2 meals). Blood samples were taken prior and post intervention for analysis of plasma protein levels of hsCRP, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Plasma Levels of free (unesterified) hydroxy, epoxy, and dihydroxy FAs as well as several prostanoids were analyzed in plasma by means of LC-MS-based targeted metabolomics., Results: At baseline subjects with low-grade inflammation (hsCRP 8.95 ± 1.39 mg/L) showed significant higher levels of IL-6 (22.7 ± 1.15 ng/L) and TNF-α (17.4 ± 0.75 ng/L) compared to subjects with no inflammation (hsCRP: 0.69 ± 0.05 mg/L; IL-6: 15.9 ± 1.18 ng/L; TNF-α: 14.6 ± 0.80 ng/L). In both group's body weight was significantly reduced (p<0.001) after intervention (no inflammation group: -7.19 ± 0.86 kg, -7.3 ± 0.89%, p<0.001; low-grade inflammation group: -6.78 ± 0.87 kg, -6.7 ± 0.81%, p<0.001). Moreover, we observed significant decreases in levels of hsCRP (4.66 ± 0.64 mg/L; p=0.006), IL-6 (6.81 ± 1.15 ng/L; p<0.001) and TNF-α (6.09 ± 0.47 ng/L; p<0.001) in subjects with low-grade inflammation. Of 60 quantified oxylipins, 11 linoleic acid (LA)-, 1 dihomo-γ-linolenic acid (DGLA)-, 7 alpha linolenic acid (ALA)-, 15 arachidonic acid (AA)-, 8 eicosapentaenoic acid (EPA)- and 18 docosahexaenoic acid (DHA)-metabolites could be detected in plasma. For most oxylipins no differences were found between the low and high hsCRP groups before and after weight reduction. Interestingly, in subjects with low- grade inflammation several AA-derived oxylipins (5-, 8-, 12-hydroxyeicosatetraenoic acids (HETE)) were significantly higher compared to subjects with no inflammation before weight reduction and significantly reduced after weight reduction., Conclusion: Even moderate weight loss in obese subjects correlates to a significant improvement in the inflammatory state, by reducing hsCRP, IL-6, TNF-α and few oxylipins. The biological consequences of these changes remain to be further investigated., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: The present study aimed to comprehensively investigate the changes in oxylipins during murine sepsis induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)., Methods: Twenty-four hours after induction of sepsis in male C57BL/6 mice by LPS or CLP, plasma and liver, lung, kidney and heart tissues were sampled. Oxylipin levels in plasma and tissue were quantified by means of LC-MS. Moreover, clinical chemistry parameters were determined in plasma and interleukin levels (MCP-1 and IL-6) were determined in kidney and liver., Results: Elevation of liver function plasma parameters at 24 h revealed that both models were successful in the induction of sepsis. LPS induced sepsis resulted in a dramatic increase of plasma PGE2 (2,100% change in comparison to control) and other cyclooxygenase metabolites, whereas this effect was less pronounced in CLP induced sepsis (97% increase of PGE2). Plasma epoxy-fatty acids (FAs) and hydroxy-FAs and most of the dihydroxy-FAs were elevated in both models of sepsis. Changes of tissue oxylipin concentrations were organ dependent. Only few changes were detected in the lung and liver tissue, epoxy-FAs were elevated in the kidney. In the heart tissue a trend towards lower levels of hydroxy-FAs and epoxy-FAs was observed., Conclusion: Both murine models of sepsis are characterized by changes of oxylipins formed in all branches of the arachidonic acid (AA) cascade. The more pronounced effects in the LPS model make this model more suitable for the investigation of the AA cascade and its pharmacological modulation in sepsis.

The derivatization followed by reductive cleavage (DFRC) method is a well-established tool to characterize the lignin composition of plant materials. However, the application of the original procedure, especially the chromatographic determination of the DFRC monomers, is problematic for low-lignin foods. To overcome these problems a modified sample cleanup and a stable-isotope dilution approach were developed and validated. To quantitate the diacetylated DFRC monomers, their corresponding hexadeuterated analogs were synthesized and used as internal standards. By using the selected-ion monitoring mode, matrix-associated interferences can be minimized resulting in higher selectivity and sensitivity. The modified method was applied to four low-lignin samples. Lignin from carrot fibers was classified as guaiacyl-rich whereas the lignins from radish, pear, and asparagus fibers where classified as balanced lignins (guaiacyl/syringyl ratio=1-2).