A combination of LCPUFA ameliorates airway inflammation in asthmatic mice by promoting pro-resolving effects and reducing adverse effects of EPA.

Lipid mediators derived from omega (n)-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) play key roles in bronchoconstriction, airway inflammation, and resolution processes in asthma. This study compared the effects of dietary supplementation with either a combination of LCPUFAs or eicosapentaenoic acid (EPA) alone to investigate whether the combination has superior beneficial effects on the outcome of asthmatic mice. Mice were sensitized with house dust mite (HDM) extract, and subsequently supplemented with either a combination of LCPUFAs or EPA alone in a recall asthma model. After the final HDM and LCPUFA administration, airway hyperresponsiveness (AHR), bronchoalveolar lavages, and lung histochemistry were examined. Lipid mediator profiles were determined by liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). The LCPUFA combination reduced AHR, eosinophilic inflammation, and inflammatory cytokines (IL-5, IFN-γ, and IL-6) in asthmatic mice, whereas EPA enhanced inflammation. The combination of LCPUFAs was more potent in downregulating EPA-derived LTB5 and LTC5 and in supporting DHA-derived RvD1 and RvD4 (2.22-fold and 2.58-fold higher levels) than EPA alone. Ex vivo experiments showed that LTB5 contributes to granulocytes' migration and M1-polarization in monocytes. Consequently, the LCPUFA combination ameliorated airway inflammation by inhibiting adverse effects of EPA and promoting pro-resolving effects supporting the lipid mediator-dependent resolution program.

Synthesis of protectin D1 analogs: novel pro-resolution and radiotracer agents.

Protectin D1 is a specialized pro-resolving mediator with potent pro-resolving and anti-inflammatory effects in vivo in several human disease models. Herein the preparation of the first synthetic analog of protectin D1, named 22-F-PD1, is presented together with data from in vivo investigations. This analog showed potent pro-resolving and anti-inflammatory properties. These results inspired the preparation of the radiotracer 22-[18F]F-PD1-ME that was used in a positron emission tomography proof of concept study. Altogether, the findings presented contribute to new knowledge on the biomolecular properties of protectin D1 analogs. In addition, an improved formal synthesis of the metabolite 22-OH-PD1 is reported.

Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation.

Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) is a lipid mediator (LM) that displays organ-protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-resolving murine model of Escherichia coli pneumonia, LM metabololipidomics performed on lungs obtained at baseline, 24, and 72 h after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 h post infection) enhanced clearance of E. coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo. Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11b(Hi) CD11c(Low)) and exudative macrophages (CD11b(Hi) CD11c(Hi)). AT-RvD1 increased efferocytosis by these cells ex vivo, and accelerated neutrophil clearance during pneumonia in vivo. These anti-bacterial and pro-resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic-centered approach for combatting infections.

Moderate oral supplementation with docosahexaenoic acid improves platelet function and oxidative stress in type 2 diabetic patients.

Platelets from patients with type 2 diabetes are characterised by hyperactivation and high level of oxidative stress. Docosahexaenoic acid (DHA) may have beneficial effects on platelet reactivity and redox status. We investigated whether moderate DHA supplementation, given as a triglyceride form, may correct platelet dysfunction and redox imbalance in patients with type 2 diabetes. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (n=11 post-menopausal women with type 2 diabetes) to test the effects of 400 mg/day of DHA intake for two weeks on platelet aggregation, markers of arachidonic acid metabolism, lipid peroxidation status, and lipid composition. Each two week-period was separated from the other by a six-week washout. Daily moderate dose DHA supplementation resulted in reduced platelet aggregation induced by collagen (-46.5 %, p< 0.001), and decreased platelet thromboxane B2 (-35 %, p< 0.001), urinary 11-dehydro-thromboxane B2 (-13.2 %, p< 0.001) and F2-isoprostane levels (-19.6 %, p< 0.001) associated with a significant increase of plasma and platelet vitamin E concentrations (+20 % and +11.8 %, respectively, p< 0.001). The proportions of DHA increased both in plasma lipids and in platelet phospholipids. After placebo treatment, there was no effect on any parameters tested. Our findings support a significant beneficial effect of low intake of DHA on platelet function and a favourable role in reducing oxidative stress associated with diabetes.

LDL from obese patients with the metabolic syndrome show increased lipid peroxidation and activate platelets.

AIMS/HYPOTHESIS: This study assessed oxidative stress in LDL from obese patients with the metabolic syndrome and compared it with that in LDL from type 2 diabetic patients or control volunteers. It also determined the effect on platelets of LDL from the three groups. METHODS: The profiles of lipids, fatty acids and fatty acid oxidation products were determined in LDL isolated from plasma of patients with the metabolic syndrome, patients with type 2 diabetes and volunteers (n = 10 per group). The effects of LDL from the participant groups on the platelet arachidonic acid signalling cascade and aggregation were investigated. RESULTS: Compared with LDL from control volunteers, LDL from obese metabolic syndrome and type 2 diabetic patients had lower cholesteryl ester, higher triacylglycerol and lower ethanolamine plasmalogen levels. Proportions of linoleic acid were decreased in phosphatidylcholine and cholesteryl esters in LDL from both patient groups. Among the markers of lipid peroxidation, oxidation products of linoleic acid (hydroxy-octadecadienoic acids) and malondialdehyde were increased by 59% and twofold, respectively in LDL from metabolic syndrome and type 2 diabetic patients. LDL from metabolic syndrome and type 2 diabetic patients were equally potent in activating the platelet arachidonic acid signalling cascade through increased phosphorylation of p38 mitogen-activated protein kinase and cytosolic phospholipase A(2), and through increased thromboxane B(2) formation. LDL from patients with the metabolic syndrome and type 2 diabetes potentiated platelet aggregation by threefold and 3.5-fold respectively, whereas control LDL had no activating effects on platelets. CONCLUSIONS/INTERPRETATION: The metabolic syndrome in obese patients, without or with diabetes, is associated with increased oxidative stress in LDL, which triggers platelet activation.

Functional lipidomics of oxidized products from polyunsaturated fatty acids.

Because of their high degree of unsaturation, polyunsaturated fatty acids (PUFA) in mammals, with mainly 18, 20 and 22 carbons, can easily be autooxidized, and converted into many oxidized derivatives and degradation products. This short review reports on some of those relevant to the evaluation of oxidative stress in situ. In addition, the enzyme-dependent oxygenation by both dioxygenases and monooxygenases is briefly reviewed by functional and/or metabolic categories, pointing out the structure variety and the analytical approaches.

Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life.

OBJECTIVE: To analyze the prevalence and demography of chronic daily headache (CDH) with analgesic overuse. METHODS: A population of 9,984 inhabitants aged 14 or older living in Santoña, Spain, was studied. The authors personally interviewed 4,855 subjects, using a quota sampling approach. Those with headache for > or = 10 days/month and some analgesic use were asked to fill in a diary over the course of 1 month. Then, subjects were classified into CDH with or without analgesic overuse subtypes. Quality of life (Short Form-36 Health Survey [SF-36]) was also assessed in this second interview. RESULTS: Headache for > or = 10 days/month with analgesic consumption was reported by 332 subjects. Seven had secondary headache. Seventy-four (standardized prevalence 1.41%, 95% CI 1.1 to 1.8) fulfilled criteria for CDH with analgesic overuse. Prevalence in women (2.6%, 2.0 to 3.3) was much higher than in men (0.19%, 0.006 to 0.52). Mean age was 56 years (range 19 to 82 years). As recalled by the subjects, the mean age at onset of CDH was 38 years (range 9 to 82 years), whereas the mean age at onset of CDH with frequent analgesic consumption was 45 years (range 19 to 80 years) and that of primary headache was 22 years (range 5 to 60 years). CDH subjects showed a significant decrease in each SF-36 health-related score as compared with healthy control subjects. Transformed migraine was diagnosed in 49 (prevalence 0.9%), chronic tension-type headache in 20 (0.4%), and new daily persistent headache in 5 (0.1%). Thirty-five percent of patients overused simple analgesics, 22% ergotics, 12.5% opioids, and 2.7% triptans; the remaining 27.8% were overusing different combinations. CONCLUSION: CDH with analgesic overuse is a common disorder in the general population, mainly in women in their fifties, in whom 5% meet its diagnostic criteria.

Epidemiology of chronic daily headache.

Daily or near-daily headache is a widespread problem in clinical practice. The general term of chronic daily headache (CDH) encompasses those primary headaches presenting more than 15 days per month and lasting more than 4 hours per day. CDH includes transformed migraine (TM), chronic tension-type headache (CTTH), new daily persistent headache (NDPH), and hemicrania continua (HC). Around 40% of patients attending a specialized headache clinic meet CDH diagnostic criteria, of which 80% are women. In these clinics about 60% of patients suffer from TM, 20% from CTTH, and 20% meet NDPH criteria. Most, some 80%, overuse symptomatic medications. One should be very cautious on extrapolating these numbers to the general population. CDH prevalence in the general population seems to be around 4% to 5% (up to 8% to 9% for women). Regarding the prevalence of CDH subtypes, NDPH is rare (0.1%), whereas the prevalence of TM (1.5% to 2%) and CTTH (2.5% to 3%) is clearly higher. In contrast to data from specialized clinics, only around a quarter of CDH subjects in the general population overuse analgesics; the prevalence of CDH subjects with analgesic overuse being 1.1% to 1.9% of the general population. Most of these patients with analgesic overuse are TM patients.