Bernd Spur

Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function.

Abstract The effects of dietary fish-oil fatty acids on the function of the 5-lipoxygenase pathway of peripheral-blood polymorphonuclear leukocytes and monocytes were determined in seven normal subjects who supplemented their usual diet for six weeks with daily doses of triglycerides containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid. The diet increased the eicosapentaenoic acid content in neutrophils and monocytes more than sevenfold, without changing the quantities of arachidonic acid and docosahexaenoic acid. When the neutrophils were activated, the release of [3H]arachidonic acid and its labeled metabolites was reduced by a mean of 37 per cent, and the maximum generation of three products of the 5-lipoxygenase pathway was reduced by more than 48 per cent. The ionophore-induced release of [3H]arachidonic acid and its labeled metabolites from monocytes in monolayers was reduced by a mean of 39 per cent, and the generation of leukotriene B4 by 58 per cent. The adherence of neutro...

Skin responses to intradermal histamine and leukotrienes C4, D4, and E4 in patients with chronic idiopathic urticaria and in normal subjects

Mast cell inflammatory mediators, such as histamine, and newly formed compounds, such as the leukotrienes, cause wheal and flare when they are injected intradermally into normal subjects and may therefore play a role in the formation of urticaria. The effects of intradermal injections (50 microliters) of six different concentrations of histamine (range, 3.3 x 10(-4) to 3.3 x 10(-9) mol/L) and the leukotrienes C4, D4, and E4 (range, 2 x 10(-4) to 2 x 10(-9) mol/L) have been compared in 10 normal subjects and in 10 patients with chronic idiopathic urticaria. Wheal-and-flare sizes were measured at timed intervals up to 4 hours, and area under the curve for each response over time was calculated. There were no significant differences in leukotriene-induced responses between groups. Maximum sizes of histamine-induced wheal and flare were similar in each group of subjects. There were, however, significant increases in mean areas under the response curve of histamine wheal and flare in the patients with urticaria (wheal, p less than 0.001; flare, p less than 0.001; analysis of variance). These findings demonstrate a prolongation of skin responses to histamine in patients with urticaria and suggest an impaired clearance of histamine (or other vasoactive agents released by histamine) from the skin of these patients.

The metabolism of leukotrienes in blood plasma studied by high-performance liquid chromatography

The metabolism of leukotrienes (B4, C4, D4, and E4) within human plasma was studied and a simple sample preparation is presented. It was demonstrated that leukotriene E4 and leukotriene B4 were stable during incubation at 37 degrees C using the in vitro system. In contrast, leukotriene C4 was metabolized by gamma-glutamyl transpeptidase activities into leukotriene D4 which was further metabolized by dipeptidase activities of plasma into leukotriene E4. The transition state inhibitor of gamma-glutamyl transpeptidase L-serine-borate decreased the metabolism of leukotriene C4 in plasma. Dilution of plasma demonstrated that the dipeptidase was more active compared to the gamma-glutamyl transpeptidase. The metabolizing activities of plasma were functionally characterized by fractionating the plasma proteins.

An Efficient Asymmetric Synthesis of Prostaglandin E1

An asymmetric total synthesis of Prostaglandin E1 (5) has been achieved in a two-component coupling process. The chiral hydroxycyclopentenone 6 was readily available from furan with 96% ee. The key reaction step was a kinetic enzymatic resolution followed by an in situ inversion. A catalytic asymmetric reduction of the γ-iodo vinyl ketone 19 with the Corey CBS catalyst gave the ω-side chain 7 with >96% ee. Conjugate addition using the reaction with dilithiocyanocuprate followed by mild cleavage of the silyl protective groups and enzymatic hydrolysis of the methyl ester 22 gave (–)-PGE15in high yield.

Effects of Dietary Fish Oil Lipids on Allergic and Inflammatory Diseases

Fish oil is rich in the polyunsaturated N-3 fatty acids, eicosapentaenoic (EPA) and docosahexaenoic acids (DCHA). EPA competes with arachidonic acid (AA) for metabolism by the cyclooxygenase and lipoxygenase pathways. Selective metabolites derived from EPA have reduced biological activities as compared with the AA-derived counterparts. Dietary supplementation with EPA led to incorporation of EPA into membrane phospholipids, an inhibition of 5-lipoxygenase pathway activity, and a reduction of the elaboration of platelet-activating factor. Neutrophil chemotaxis and the capacity of these cells to adhere to endothelial cells are substantially attenuated. This suggests that EPA has anti-inflammatory potential. Clinical trials in rheumatoid arthritis, psoriasis, atopic dermatitis, and bronchial asthma have shown beneficial effects. Whether the benefit obtained clinically is sufficient to replace or significantly reduce any clinical condition remains to be answered.

Synthesis of 11, 12, 14, 15-tetrahydro-leukotriene C,D,E via A

Abstract The synthesis of tetrahydro-7E,9Z-leukotriene A methyl ester and its reaction with glutathione, cysteinylglycine and cysteine providing the tetrahydro analogues of leukotriene C 4 , C 4 , E 4 .

Effective Stereoselective Total Synthesis of 16,16‐Dimethyl Prostaglandin E2

The first stereoselective synthesis of the specific EP1 receptor agonist, 16,16‐dimethyl prostaglandin E21, is described. The key intermediate 3 was obtained from the E‐allyl alcohol 6 via Sharpless epoxidation followed by stereospecific transformations to the γ‐iodo vinyl compound 3. Two component coupling of 2 and 3, using the dilithiocyanocuprate technology, gave the 1,4‐addition product. Mild desilylation and enzymatic ester cleavage produced the optically pure prostaglandin 1 in high yield.

Neue Synthese von 6-Formyl-trans- 5.6-methanohexansäuremethylester / Novel Synthesis of Methyl 6 -Formyl-trans- 5.6-methanohexanoate

Methyl 7-oxo-5-trans-heptenoate reacts with diazomethane in the presence of Pd(CH3COO)2 in high yield to the cyclopropane aldehyde 1, an important intermediate in the 5,6-methanoleukotriene synthesis.

Formation and structure determination of 5,6-epoxy-8,11,14-eicosatrienoic acid and 5-oxo-8,11,14-z-eicosatrienoic acid

Abstract The formation of 5,6-epoxy-8,11,14-z-eicosatrienoic acid and 5-oxo-8,11,14-z-eicosatrienoic acid as by-products in the synthesis of 5-hydroxy-6-E-8,11,14-z-eicosatetraenoic acid is described.

An Acute Retinal Model for Evaluating Blood Retinal Barrier Breach and Potential Drugs for Treatment.

A low-cost, easy-to-use and powerful model system is established to evaluate potential treatments that could ameliorate blood retinal barrier breach. An inflammatory factor, histamine, is demonstrated to compromise vessel integrity in the cultured retina through positive staining of IgG outside of the blood vessels. The effects of histamine itself and those of candidate drugs for potential treatments, such as lipoxin A4, are assessed using three parameters: blood vessel leakage via IgG immunostaining, activation of Müller cells via GFAP staining and change in neuronal dendrites through staining for MAP2. Furthermore, the layered organization of the retina allows a detailed analysis of the processes of Müller and ganglion cells, such as changes in width and continuity. While the data presented is with swine retinal culture, the system is applicable to multiple species. Thus, the model provides a reliable tool to investigate the early effects of compromised retinal vessel integrity on different cell types and also to evaluate potential drug candidates for treatment.