Emilie Mas

Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial.

Summary A dietary intervention increasing n‐3 and reducing n‐6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality of life in a chronic headache population. Abstract Omega‐3 and n‐6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single‐blinded, parallel‐group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n‐3 and n‐6 fatty acids for treatment of chronic headaches. After a 4‐week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food‐based 12‐week dietary interventions: a high n‐3 plus low n‐6 (H3‐L6) intervention, or a low n‐6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT‐6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n‐6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n‐3 and n‐6 derivatives. Fifty‐six of 67 patients completed the intervention. Both groups achieved targeted intakes of n‐3 and n‐6 fatty acids. In intention‐to‐treat analysis, the H3‐L6 intervention produced significantly greater improvement in the HIT‐6 score (−7.5 vs −2.1; P < 0.001) and the number of Headache Days per month (−8.8 vs −4.0; P = 0.02), compared to the L6 group. The H3‐L6 intervention also produced significantly greater reductions in Headache Hours per day (−4.6 vs −1.2; P = 0.01) and the n‐6 in HUFA score (−21.0 vs −4.0%; P < 0.001), and greater increases in antinociceptive n‐3 pathway markers 18‐hydroxy‐eicosapentaenoic acid (+118.4 vs +61.1%; P < 0.001) and 17‐hydroxy‐docosahexaenoic acid (+170.2 vs +27.2; P < 0.001). A dietary intervention increasing n‐3 and reducing n‐6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality‐of‐life in this population.

The omega-3 fatty acids EPA and DHA decrease plasma F2-isoprostanes: Results from two placebo-controlled interventions

Abstract Omega-3 (ω3) fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular disease. Despite these benefits, concern remains that ω3 fatty acids may increase lipid peroxidation. It has previously been shown that urinary F2-isoprostanes (F2-IsoPs) were reduced following ω3 fatty acid supplementation in humans. It is now determined whether EPA or DHA supplementation affects plasma F2-IsoPs. In two 6-week placebo-controlled interventions, Study A: overweight, dyslipidaemic men; and Study B: treated-hypertensive Type 2 diabetic, patients were randomized to 4 g daily EPA, DHA. Post-intervention plasma F2-IsoPs were significantly reduced by EPA (24% in Study A, 19% in Study B) and by DHA (14% in Study A, 23% in Study B) relative to the olive oil group. The fall in plasma F2-IsoPs was not altered in analyses that corrected for changes in plasma arachidonic acid, which was reduced with EPA and DHA supplementation. Neither F3- nor F4-IsoPs were observed in plasma in both studies. These results show that in humans, EPA and DHA reduce in vivo oxidant stress as measured in human plasma and urine.

A thromboxane effect of a hydroxytyrosol-rich olive oil wastewater extract in patients with uncomplicated type I diabetes.

Objective:To assess the antioxidant/non-antioxidant effects of a hydroxytyrosol (HT)-rich phenolic extract from olive mill wastewaters administered with a breakfast.Design, setting and subjects:Five type I diabetic patients received 25 mg of HT the first day and 12.5 mg/day the following 3 days. Blood sampling was carried out at T0 (baseline) and T4d just before the breakfast+HT administration and at time points 1, 2, 3 and 4 h after T0. Urines (24-h) were collected from T0 to T4d. Baseline HbA1c was generally inferior to 10%, glycemia was within the range 6–24 mmol/l, whereas total cholesterol, HDL-chol and triglycerides were normal.Results:The major finding was the 46% decrease in the serum TXB2 production after blood clotting at T4d. Plasma vitamin A, E, β-carotene were not changed. Vitamin C tended to increase (P=0.075). Plasma antioxidant capacity was enhanced at T0+1 h only, whereas its main determinants (albumin, bilirubin, uric acid) were not modified. Urinary 8-isoPGF2α levels were highly variable and were not affected significantly by HT administration.Conclusion:The major effect of HT accounts for an antiaggregating platelet action, leading to a possible prevention of thrombotic and microthrombotic processes.

Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment.

In May 2006, a 28-year-old woman abruptly experienced excessive daytime sleepiness (EDS) and 2 to 3 short, refreshing but irresistible naps per day. She also reported increased nighttime sleep duration of more than 3 hours. Her Epworth Sleepiness Scale score was 22, indicating severe sleepiness. She also developed clear-cut generalized and partial cataplexy provoked by laughter but also by stress with a frequency of more than 1 attack per day. A rapid but large weight gain was noted up to 6 kg within 2 weeks, without a clear change in appetite. She never experienced sleep paralysis, hypnagogic hallucinations, or mood disorders. She had no personal or familial history of a particular disease, and no treatment. She was seen by us 15 days after the first cataplexy episode to confirm the diagnosis of narcolepsy with cataplexy.1 Nighttime polysomnography results were unremarkable; a multiple sleep latency test (PSG-MSLT) indicated a mean sleep latency of 5 minutes and 2 sleep-onset REM periods. She was positive for HLA DRB1*1501 and DQB1*0602. Brain …

Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: a randomized trial.

There is mounting evidence that specific dietary polyphenols can enhance vascular health by augmenting nitric oxide. Our aim was to investigate the acute effects of chlorogenic acid, an important dietary phenolic acid present in coffee (400 mg, equivalent to 2 cups of coffee), on nitric oxide status, endothelial function, and blood pressure. Healthy men and women (n = 23) were recruited to a randomized, double-blind, placebo-controlled, crossover trial. Chlorogenic acid resulted in significantly higher plasma concentrations of chlorogenic acid (P < 0.001). Relative to control, the mean post-treatment systolic blood pressure (-2.41 mmHg, 95% CI: -0.03, -4.78; P = 0.05) and diastolic blood pressure (-1.53 mmHg, 95% CI: -0.05, -3.01; P = 0.04) were significantly lower with chlorogenic acid. Markers of nitric oxide status (P > 0.10) and the measure of endothelial function (P = 0.60) were not significantly influenced. Chlorogenic acid can lower blood pressure acutely, an effect that, if sustained, would benefit cardiovascular health.

Isoprostanes and neuroprostanes: total synthesis, biological activity and biomarkers of oxidative stress in humans.

Isoprostanes (IsoPs) and neuroprostanes (NeuroPs) are formed in vivo by a free radical non-enzymatic mechanism involving peroxidation of arachidonic acid (AA, C20:4 n-6) and docosahexaenoic acid (DHA, C22:6 n-3) respectively. This review summarises our research in the total synthesis of these lipid metabolites, as well as their biological activities and their utility as biomarkers of oxidative stress in humans.

Short-term n-3 fatty acid supplementation but not aspirin increases plasma proresolving mediators of inflammation

Resolution of inflammation is an active process involving specialized proresolving mediators (SPM) formed from the n-3 fatty acids. This study examined the effect of n-3 fatty acid supplementation and aspirin on plasma SPMs in healthy humans. Healthy volunteers (n = 21) were supplemented with n-3 fatty acids (2.4g/day) for 7 days with random assignment to take aspirin (300 mg/day) or placebo from day 5 to day 7. Blood was collected at baseline (day 0), day 5, and day 7. Plasma 18R/S-HEPE, E-series resolvins, 17R/S-HDHA, D-series resolvins, 14R/S-HDHA, and MaR-1 were measured by LC/MS/MS. At baseline concentrations of E- and D- series resolvins and the upstream precursors 18R/S-HEPE, 17R/S-HDHA ranged from 0.1nM to 0.2nM. 14R/S-HDHA was 3-fold higher than the other SPMs at baseline but MaR-1 was below the limit of detection. Supplementation with n-3 fatty acids significantly increased RvE1, 18R/S-HEPE, 17R/S-HDHA, and 14R/S-HDHA but not other SPMs. The addition of aspirin after 5 days of n-3 fatty acids did not affect concentrations of any SPM. N-3 fatty acid supplementation for 5 days results in concentrations of SPMs that are biologically active in healthy humans. Aspirin administered after n-3 fatty acids did not offer any additional benefit in elevating the levels of SPMs.

Maternal dietary omega-3 fatty acid intake increases resolvin and protectin levels in the rat placenta

Placental inflammation is associated with several pregnancy disorders. Inflammation is limited by anti-inflammatory and proresolving mechanisms, the latter partly mediated by resolvins and protectins derived from omega-3 polyunsaturated fatty acids (n-3PUFA). We examined effects of dietary n-3PUFAs on levels of resolvins, protectins, and lipoxygenase (ALOX) enzymes in the rat placenta. Rats consumed standard (Std) or high n-3PUFA (Hn3) diets from day 1 of pregnancy; tissues were collected on day 17 or 22 (term = day 23). Maternal Hn3 diet increased resolvin and protectin precursors, 18R/S-HEPE (P < 0.001), and 17R/S-HDHA (P < 0.01) at both days. Resolvins (17R-RvD1 and RvD1) increased at day 22 (P < 0.001) after Hn3 consumption, coincident with higher Alox15b and Alox5 mRNA expression, while RvD2 increased at both days (P < 0.05). Protectins, PD1, and 10S,17S-DiHDHA increased over late gestation (P < 0.001), coincident with higher Alox15 mRNA expression (P < 0.001) and further increased with Hn3 diet (P < 0.05). Maternal systemic and placental proinflammatory mediators were not suppressed by Hn3 diet; systemic IL1β, placental Il1β, and Il6 mRNA expression increased marginally with Hn3 at day 22 (P < 0.001), while Ptgs1 (Cox1) expression increased both days (P < 0.05). Our data indicate that maternal n-3PUFA supplementation enhances expression of enzymes in the n-3PUFA metabolic pathway and increases placental levels of resolvins and protectins.

Specialised pro-resolving mediators of inflammation in inflammatory arthritis

INTRODUCTION Specialised pro-resolving mediators (SPM) are derived from n-3 long chain polyunsaturated fatty acids (n-3FA). They promote resolution of inflammation and may contribute to the beneficial effects of n-3FA in patients with arthritis. This study compared SPM in knee effusions and plasma of patients with arthritis taking n-3FA, and plasma of healthy volunteers taking n-3FA. METHODS Thirty six patients taking n-3FA undergoing arthrocentesis for an inflammatory knee effusion and 36 healthy volunteers who had taken n-3FA (2.4g/day) for 4 weeks were studied. SPM in synovial fluid and plasma were measured by liquid chromatography-tandem mass spectrometry included 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of the E-series SPM (RvE1, RvE2, RvE3, 18R-RvE3), and 17-hydroxydocosahexaenoic acid (17-HDHA), the precursor of the D-series SPM (RvD1, 17R-RvD1, RvD2). Other SPM included protectin D1 (PD1), 10S,17S-dihydroxydocosahexaenoic acid (10,17S-DHDHA), maresin-1 (MaR-1) and 14-hydroxydocosahexaenoic acid (14-HDHA) derived from docosahexaenoic acid (DHA). RESULTS E- and D-series SPM and the precursors 18-HEPE and 17-HDHA were present in synovial fluid and plasma of the patients with inflammatory arthritis. Plasma SPM were negatively related to erythrocyte sedimentation rate in arthritis patients (P<0.01) and synovial fluid RvE2 was negatively associated with pain score (P=0.02). Conversion from 18-HEPE and 17-HDHA to E- and D-series SPM was greater in synovial fluid (P<0.01). Most plasma SPM in arthritis patients were elevated (P<0.05) compared with healthy volunteers, and conversion to E- and D-series SPM was greater (P<0.01). CONCLUSIONS SPM are present in chronic knee effusions and although the levels are lower than in plasma, the association between synovial fluid RvE2 and reduced pain scores suggests that synthesis of SPM at the site of inflammation is a relevant mechanism by which n-3FA alleviate the symptoms of arthritis.

Effects of maternal n-3 fatty acid supplementation on placental cytokines, pro-resolving lipid mediators and their precursors

The aim of this study was to determine whether supplementation with fish oil-derived n-3 polyunsaturated fatty acids (n-3 PUFA) during pregnancy modifies placental PUFA composition, the accumulation of specialised pro-resolving lipid mediators (SPMs, specifically resolvins (Rv), protectins (PD) and upstream precursors) and inflammatory gene expression. Placentas were collected from women (n=51) enrolled in a randomised, placebo controlled trial of n-3 PUFA supplementation from 20-week gestation. Lipids were extracted for fatty acid analysis and SPMs were quantitated by mass spectrometry. Gene expression was determined by qRT-PCR. Using multiple regression analysis, data were correlated for placental n-3 PUFA and SPM levels with PUFA levels in maternal and cord blood erythrocytes. Supplementation with n-3 PUFAs increased placental docosahexaenoic acid (DHA) levels, but not eicosapentaenoic acid (EPA) levels (P<0.05), and increased the levels of the SPM precursors 18-hydroxyeicosapentaenoic acid and 17-hydroxydocosahexaenoic acid (17-HDHA) by two- to threefold (P<0.0005). RvD1, 17R-RvD1, RvD2 and PD1 were detectable in all placentas, but concentrations were not significantly increased by n-3 PUFA supplementation. Placental DHA levels were positively associated with maternal and cord DHA levels (P<0.005), and with placental 17-HDHA concentrations (P<0.0001). Placental mRNA expression of PTGS2, IL1β, IL6 and IL10 was unaffected by n-3 PUFA supplementation, but TNFα expression was increased by 14-fold (P<0.05). We conclude that n-3 PUFA supplementation in pregnancy i) enhances placental accumulation of DHA and SPM precursors, ii) does not alter placental EPA levels, and iii) has no stimulatory effects on inflammatory gene expression. Further studies are required to ascertain the biological significance of SPMs in the placenta and the potential immunomodulatory effects of elevating placental SPM levels.