no / Chronic wounds often result from prolonged inflammation involving excessive polymorphonuclear leukocyte activity. Studies show that the omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids found in fish oils generate bioactive lipid mediators that reduce inflammation and polymorphonuclear leukocyte recruitment in numerous inflammatory disease models. The purpose of this study was to test the hypotheses that boosting plasma levels of eicosapentaenoic and docosahexaenoic acids with oral supplementation would alter lipid mediator levels in acute wound microenvironments and reduce polymorphonuclear leukocyte levels. Eighteen individuals were randomized to 28 days of either eicosapentaenoic + docosahexaenoic acid supplementation (Active Group) or placebo. After 28 days the Active Group had significantly higher plasma levels of eicosapentaenoic (p<0.001) and docosahexaenoic acid (p<0.001) than the Placebo Group and significantly lower wound fluid levels of two 15-lipoxygenase products of omega-6 polyunsaturated fatty acids, [9- hydroxyoctadecadienoic (HODE) acid (p = 0.033) and15-hydroxyeicosatrienoic acid (HETrE) (p = 0.006)], at 24 hours post wounding. The Active Group also had lower mean levels of myeloperoxidase, a leukocyte marker, at 12 hours and significantly more re-epithelialization on Day 5 post wounding. We suggest that lipid mediator profiles can be manipulated by altering polyunsaturated fatty acid intake to create a wound microenvironment more conducive to healing.

No / Eicosanoids play an integral part in homeostatic mechanisms related to skin health and structural integrity. They also mediate inflammatory events developed in response to environmental factors, such as exposure to ultraviolet radiation, and inflammatory and allergic disorders, including psoriasis and atopic dermatitis. This review article discusses biochemical aspects related to cutaneous eicosanoid metabolism, the contribution of these potent autacoids to skin inflammation and related conditions, and considers the importance of nutritional supplementation with bioactives such as omega-3 and omega-6 polyunsaturated fatty acids and plant-derived antioxidants as means of addressing skin health issues. / The Wellcome Trust and BBSRC-DRINC

Yes / The naturally-occurring omega (ω)-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) reduces colorectal adenoma (polyp) number and size in patients with familial adenomatous polyposis. The safety profile and potential cardiovascular benefits associated with ω-3 PUFAs make EPA a strong candidate for colorectal cancer (CRC) chemoprevention, alone or in combination with aspirin, which itself has recognized anti-CRC activity. Colorectal adenoma number and size are recognized as biomarkers of future CRC risk and are established as surrogate end-points in CRC chemoprevention trials. The seAFOod Polyp Prevention Trial is a randomized, double-blind, placebo-controlled, 2 × 2 factorial ‘efficacy’ study, which will determine whether EPA prevents colorectal adenomas, either alone or in combination with aspirin. Participants are 55–73 year-old patients, who have been identified as ‘high risk’ (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Exclusion criteria include the need for more than one repeat endoscopy within the three-month BCSP screening period, malignant change in an adenoma, regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs, regular use of fish oil supplements and concomitant warfarin or anti-platelet agent therapy. Patients are randomized to either EPA-free fatty acid 1 g twice daily or identical placebo AND aspirin 300 mg once daily or identical placebo, for approximately 12 months. The primary end-point is the number of participants with one or more adenomas detected at routine one-year BCSP surveillance colonoscopy. Secondary end-points include the number of adenomas (total and ‘advanced’) per patient, the location (left versus right colon) of colorectal adenomas and the number of participants re-classified as ‘intermediate risk’ for future surveillance. Exploratory end-points include levels of bioactive lipid mediators such as ω-3 PUFAs, resolvin E1 and PGE-M in plasma, urine, erythrocytes and rectal mucosa in order to gain insights into the mechanism(s) of action of EPA and aspirin, alone and in combination, as well as to discover predictive biomarkers of chemopreventive efficacy. The recruitment target is 904 patients. / Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership

No / Background Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM). Design: We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA-FFA 2 g daily in patients undergoing liver resection surgery for CRCLM. The patients took EPA-FFA (n=43) or placebo (n=45) prior to surgery. The primary end-point was the CRCLM Ki67 proliferation index (PI). Secondary end-points included safety and tolerability of EPA-FFA, tumour fatty acid content and CD31-positive vascularity. We also analysed overall survival (OS) and disease-free survival (DFS). Results The median (range) duration of EPA-FFA treatment was 30 (12–65) days. Treatment groups were well matched with no significant difference in disease burden at surgery or preoperative chemotherapy. EPA-FFA treatment was well tolerated with no excess of postoperative complications. Tumour tissue from EPA-FFA-treated patients demonstrated a 40% increase in EPA content (p=0.0008), no difference in Ki67 PI, but reduced vascularity in ‘EPA-naïve’ individuals (p=0.075). EPA-FFA also demonstrated antiangiogenic activity in vitro. In the first 18 months after CRCLM resection, EPA-FFA-treated individuals obtained OS benefit compared with placebo, although early CRC recurrence rates were similar. Conclusions EPA-FFA therapy is safe and well tolerated in patients with advanced CRC undergoing liver surgery. EPA-FFA may have antiangiogenic properties. Remarkably, limited preoperative treatment may provide postoperative OS benefit. Phase III clinical evaluation of prolonged EPA-FFA treatment in CRCLM patients is warranted. Trial Identifier: ClinicalTrials.gov NCT01070355. / The Cancer Research UK Clinical Trials Awards and Advisory Committee approved the Trial. PML and ADR were supported by Department of Health/Cancer Research UK Yorkshire Experimental Cancer Medicine Centre funding. The Trial was adopted by the UKCRN Clinical Trials Portfolio (UKCRN ID 8946) allowing West Yorkshire Comprehensive Local Research Network funding of Pharmacy costs. SLA Pharma AG funded some of the experimental work and provided EPA-FFA and placebo. SLA Pharma AG played no role in the design or execution of the Trial. Laboratory costs were also supported by the Leeds Teaching Hospitals Charitable Foundation (Rays of Hope).

yes / Background: Oral administration of purified omega-3 (ω-3) PUFAs is associated with changes to the fecal microbiome. However, it is not known whether this effect is associated with increased PUFA concentrations in the gut. Objectives: We investigated the luminal bioavailability of oral ω-3 PUFAs (daily dose 1 g EPA and 1g DHA free fatty acid equivalents as triglycerides in soft-gel capsules, twice daily) and changes to the gut microbiome, in the ileum. Methods: Ileostomy fluid (IF) and blood were obtained at baseline, after first capsule dosing (median 2 h), and at a similar time after final dosing on day 28, in 11 individuals (median age 63 y) with a temporary ileostomy. Fatty acids were measured by LC–tandem MS. The ileal microbiome was characterized by 16S rRNA PCR and Illumina sequencing. Results: There was a mean 6.0 ± 9.8-fold and 6.6 ± 9.6-fold increase in ileal EPA and DHA concentrations (primary outcome), respectively, at 28 d, which was associated with increased RBC ω-3 PUFA content (P ≤ 0.05). The first oral dose did not increase the ileal ω-3 PUFA concentration except in 4 individuals, who displayed high luminal EPA and DHA concentrations, which reduced to concentrations similar to the overall study population at day 28, suggesting physiological adaptation. Bacteroides, Clostridium, and Streptococcus were abundant bacterial genera in the ileum. Ileal microbiome variability over time and between individuals was large, with no consistent change associated with acute ω-3 PUFA dosing. However, high concentrations of EPA and DHA in IF on day 28 were associated with higher abundance of Bacteroides (r2 > 0.86, P < 0.05) and reduced abundance of other genera, including Actinomyces (r2 > 0.94, P < 0.05). Conclusions: Oral administration of ω-3 PUFAs leads to increased luminal ω-3 PUFA concentrations and changes to the microbiome, in the ileum of individuals with a temporary ileostomy.

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Studies were conducted to investigate the tissue distribution of stearoyl-CoA desaturase-1 (SCD) and the regulation of SCD1 protein expression by dietary fat, insulin, polyunsaturated fatty acids (PUFA), and linoleic acid (cis-9, cis-12 18:2). The first study examined tissue distribution of SCD1 protein in Holstein calves (n=6/diet) fed one of four milk replacer diets for a nine wk period after which they were sacrificed. Milk replacer diets varied in fat content and were formulated and administered as follows: 0.4 kg/d 20% protein, 20% fat (20:20; CON), 0.97 kg/d (28:20; HPLF), 0.97 kg/d (28:28; HPHF), or 1.46 kg/d (28:28; HPHF+). Samples of subcutaneous adipose tissue (AT), perirenal AT, omental AT, duodenum, proximal jejunum, distal jejunum, ileum, and liver were collected from calves fed the HPHF+ diet to determine SCD1 tissue distribution. Tissue homogenates were prepared and used for Western blotting. Additionally, dietary effects were analyzed on tissues expressing SCD1 protein for all 24 calves. The second study investigated the regulation of SCD1 protein expression by insulin, fatty acids increasing in degree of unsaturation, and increasing concentrations of linoleic (18:2) acid. Subcutaneous AT was collected from Smith Valley Meats in Rich Creek, VA and used to prepare explants cultured in treatment media for 24 h. Treatments consisted of insulin at 0, 7, 14, and 21 nM; stearic (18:0), oleic (18:1), linoleic (18:2), and linolenic (18:3) acids at 100 μM; and linoleic (18:2) acid at concentrations of 0, 25, 50, 75, and 100 μM. Tissue explant homogenates were used for Western blotting to detect SCD1. In the first study, we found that SCD1 protein was detectable in subcutaneous AT, perirenal AT, and omental AT; however, it was not detectable in liver or small intestine samples. Also, the HPHF+ diet increased SCD1 protein expression in subcutaneous AT and perireanl AT. In the second study, SCD1 protein expression increased linearly with insulin concentration. There was no fatty acid treatment effect, but there was a negative linear effect with increase in degree of unsaturation. Finally, there was no effect on SCD1 protein expression with linoleic acid increasing in concentration. In conclusion, results indicate that SCD1 protein expression was detected in bovine AT depots, regulated by dietary fat, insulin, and by PUFA . / Master of Science

Master of Science / Department of Animal Sciences and Industry / Joann M. Kouba / The objective of this study was to evaluate the reproductive effects of supplementing normally cycling mares with marine-derived omega-3 (n-3) fatty acids during the estrous cycle. Fifteen mares were assigned to a control diet (CONT, n=7) or a fish oil supplemented diet (FO, n=8) containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The FO mares received 18.48 g EPA/10.08 g DHA/mare/d. At the start of the trial, mares were synchronized using a progesterone and estradiol protocol. Following synchronization, mares were monitored with transrectal ultrasonography throughout the second estrous cycle. Ovarian activity, ovulation, and presence of a corpus luteum were noted. Mares were ultrasounded throughout the third estrous cycle until a 35 mm follicle was detected. Upon detection of the 35 mm follicle, hCG was administered. Within 16 hr, transvaginal ultrasound-guided follicular aspiration (TUGA) was performed on the preovulatory follicle, signifying the end of the trial. Follicular fluid was analyzed for fatty acid and hormone concentrations. Serum fatty acids were measured every 2 wk and serum hormone concentrations were analyzed during the second estrous cycle at 5 d to 1 d prior to ovulation, at ovulation, and 3 and 5 d post-ovulation. Samples were also collected prior to hCG administration and on aspiration day for hormone analysis. Serum estradiol-17β, progesterone, luteinizing hormone (LH), and insulin-like growth factor 1 (IGF-1) were measured. Fish oil supplementation increased (P < 0.01) arachidonic acid (ARA), EPA, docosapentaenoic acid (DPA), and DHA in mare serum and increased (P<0.01) EPA, DPA, and DHA in follicular fluid. No overall treatment effect was found on serum hormone concentrations during the second estrous cycle, but a decrease (P<0.05) in IGF-1 was noted in the FO group on aspiration day. Concentrations of IGF-1 were also lower (P<0.05) in follicular fluid in the FO group compared to controls. No other follicular fluid differences were observed. Supplementation resulted in a smaller diameter follicle (P<0.05, 38.0 ± 0.47 mm) on aspiration day than the CONT group (39.5 ± 0.5 mm). Dietary n-3 fatty acids modify mare serum and follicular fluid fatty acid profiles, with supplementation of EPA and DHA decreasing serum and follicular IGF-1 concentrations.