A phase IIb randomized placebo-controlled trial testing the effect of MAG-EPA long-chain omega-3 fatty acid dietary supplement on prostate cancer proliferation.

BACKGROUND: High prostate eicosapentaenoic fatty acid (EPA) levels were associated with a significant reduction of upgrading to grade group (GG) ≥ 2 prostate cancer in men under active surveillance. We aimed to evaluate the effect of MAG-EPA long-chain omega-3 fatty acid dietary supplement on prostate cancer proliferation. METHODS: A phase II double-blind randomized placebo-controlled trial was conducted in 130 men diagnosed with GG ≥ 2 prostate cancer and undergoing radical prostatectomy between 2015-2017 (Clinicaltrials.gov: NCT02333435). Participants were randomized to receive 3 g daily of either MAG-EPA (n = 65) or placebo (n = 65) for 7 weeks (range 4-10) prior to radical prostatectomy. The primary outcome was the cancer proliferation index quantified by automated image analysis of tumor nuclear Ki-67 expression using standardized prostatectomy tissue microarrays. Additional planned outcomes at surgery are reported including plasma levels of 27 inflammatory cytokines and fatty acid profiles in circulating red blood cells membranes and prostate tissue. RESULTS: Cancer proliferation index measured by Ki-67 expression was not statistically different between the intervention (3.10%) and placebo (2.85%) groups (p = 0.64). In the per protocol analyses, the adjusted estimated effect of MAG-EPA was greater but remained non-significant. Secondary outcome was the changes in plasma levels of 27 cytokines, of which only IL-7 was higher in MAG-EPA group compared to placebo (p = 0.026). Men randomized to MAG-EPA prior to surgery had four-fold higher EPA levels in prostate tissue compared to those on placebo. CONCLUSIONS: This MAG-EPA intervention did not affect the primary outcome of prostate cancer proliferation according to nuclear Ki-67 expression. More studies are needed to decipher the effects of long-chain omega-3 fatty acid dietary supplementation in men with prostate cancer.

It is thought that our diet can impact our risk of cancer and affect outcomes in patients with cancer. Omega-3 fatty acids, mostly found in fatty fish, might be beneficial by protecting against prostate cancer and its adverse outcomes. We conducted a clinical trial to test the effects of an omega-3 dietary supplement (MAG-EPA) in men with prostate cancer. We randomly allocated 130 men to receive either MAG-EPA or a placebo for 7 weeks before their prostate cancer surgery. We measured a marker of how much tumor cells were proliferating (or growing in number) at the point of surgery, which might indicate how aggressive their disease was. However, the supplement did not affect tumor cell proliferation. The supplement was therefore not beneficial in this group of patients and further studies  are needed to test and confirm the effects of MAG-EPA on prostate cancer cells.

Effects of omega-3 supplementation on psychological symptoms in men with prostate cancer: Secondary analysis of a double-blind placebo-controlled randomized trial.

BACKGROUND: In the general population, a higher omega-3 polyunsaturated fatty acids intake is associated with lower levels of several psychological symptoms, especially depression. However, the existing evidence in cancer is equivocal. METHODS: This phase IIB double-blind, placebo-controlled trial was aimed at comparing the effects of eicosapentaenoic acid monoacylglyceride (MAG-EPA) supplementation and high oleic acid sunflower oil (HOSO; placebo) on depression levels (primary outcome) and other symptoms (anxiety, fear of cancer recurrence, fatigue, insomnia, perceived cognitive impairments; secondary outcomes). Participants, recruited in a prostate cancer clinic, were randomized to MAG-EPA (3.75 g daily; n = 65) or HOSO (3.75 g daily; n = 65) for 1 year post-radical prostatectomy (RP), starting 4-10 weeks before surgery. Patients completed self-report scales at baseline (before RP) and 3, 6, 9, and 12 months after: Hospital Anxiety and Depression Scale (HADS), Fear of Cancer Recurrence Inventory (FCRI), Insomnia Severity Index (ISI), Fatigue Symptom Inventory (FSI), and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). RESULTS: Analyses showed significant reductions in HADS-depression, HADS-anxiety, FCRI, ISI, FSI-number of days, and FACT-Cog-impact scores over time. A significant group-by-time interaction was obtained on FACT-Cog-Impact scores only; yet, the temporal change was significant in HOSO patients only. CONCLUSIONS: Several symptoms significantly decreased over time, mainly within the first months of the study. However, MAG-EPA did not produce greater reductions than HOSO. Omega-3 supplementation does not seem to improve psychological symptoms of men treated with RP.

Eicosapentaenoic Acid Influences the Lipid Profile of an In Vitro Psoriatic Skin Model Produced with T Cells.

Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin's lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 PUFAs). Bioactive lipid mediators derived from arachidonic acid (AA) are involved in the inflammatory functions of T cells in psoriasis, whereas n-3 PUFAs' derivatives are anti-inflammatory metabolites. Here, we sought to evaluate the influence of a supplementation of the culture media with eicosapentaenoic acid (EPA) on the lipid profile of a psoriatic skin model produced with polarized T cells. Healthy and psoriatic skin substitutes were produced following the auto-assembly technique. Psoriatic skin substitutes produced with or without T cells presented increased epidermal and dermal linolenic acid (LA) and AA levels. N-6 PUFA lipid mediators were strongly measured in psoriatic substitutes, namely, 13-hydroxyoctadecadienoic acid (13-HODE), prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE). The added EPA elevated the amounts of EPA, n-3 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the epidermal and dermal phospholipids. The EPA supplementation balanced the production of epidermal lipid mediators, with an increase in prostaglandin E3 (PGE3), 12-hydroxyeicosapentaenoic acid (12-HEPE) and N-eicosapentaenoyl-ethanolamine (EPEA) levels. These findings show that EPA modulates the lipid composition of psoriatic skin substitutes by encouraging the return to a cutaneous homeostatic state.

Small-for-gestational-age and predictors of HOMA indices, leptin and adiponectin in infancy.

AIM: To assess whether small-for-gestational-age (SGA) - an indicator of poor fetal growth, may affect metabolic health biomarkers in infancy and explore the predictors. METHODS: This was a nested matched (1:2) prospective observational study of 65 SGA (birth weight < 10th percentile) and 130 optimal-for-gestational-age (OGA, birth weight 25th-75th percentiles, control) infants in the 3D birth cohort with subjects recruited in Canada from 1 May 2010 to 31 August 2012. The outcomes included homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-ß), circulating leptin and adiponectin concentrations at age 2 years. RESULTS: HOMA-IR, HOMA-ß, leptin and adiponectin concentrations were similar in SGA versus OGA infants. Female sex and accelerated growth in length during mid-infancy (3-12 months) were associated with higher HOMA-IR. Caucasian ethnicity and decelerated growth in weight during late infancy (12-24 months) were associated with lower HOMA-IR. Current BMI was positively associated with circulating adiponectin in SGA infants only (+13.4% [4.0%-23.7%] per BMI z score increment). CONCLUSION: Insulin resistance and secretion, circulating leptin and adiponectin levels were normal in SGA subjects in infancy at age 2 years. The novel observation in SGA-specific positive association between current BMI and circulating adiponectin suggests dysfunctional adiposity-adiponectin negative feedback loop development during infancy in SGA subjects.

Effects of Concentrated Long-Chain Omega-3 Polyunsaturated Fatty Acid Supplementation on Quality of Life after Radical Prostatectomy: A Phase II Randomized Placebo-Controlled Trial (RCT-EPA).

Prostate cancer (PCa) and associated treatments incur symptoms that may impact patients' quality of life. Studies have shown beneficial relationships between diet, especially omega-3 fatty acids, and these symptoms. Unfortunately, only few data describing the relationship between long-chain omega-3 fatty acids (LCn3) and PCa-related symptoms in patients are available. The purpose of this study was to evaluate the effects of LCn3 supplementation on PCa-specific quality of life in 130 men treated by radical prostatectomy. Men were randomized to receive a daily dose of either 3.75 g of fish oil or a placebo starting 7 weeks before surgery and for up to one-year post-surgery. Quality of life was assessed using the validated EPIC-26 and IPSS questionnaires at randomization, at surgery, and every 3 months following surgery. Between-group differences were assessed using linear mixed models. Intention-to-treat analyses showed no significant difference between the two groups. However, at 12-month follow-up, per-protocol analyses showed a significantly greater increase in the urinary irritation function score (better urinary function) (MD = 5.5, p = 0.03) for the LCn3 group compared to placebo. These results suggest that LCn3 supplementation may improve the urinary irritation function in men with PCa treated by radical prostatectomy and support to conduct of larger-scale studies.

Alpha-Linolenic Acid Modulates T Cell Incorporation in a 3D Tissue-Engineered Psoriatic Skin Model.

Psoriasis is an autoimmune skin disease with an increased number of leukocytes infiltrating the dermal and epidermal compartments compared with normal skin. N-3 polyunsaturated fatty acids (n-3 PUFAs) are frequently used in the clinic in order to attenuate the symptoms of psoriasis. For psoriatic patients, a supplementation of the diet with alpha-linolenic acid (ALA) reduces the activation of T cell signaling pathways, leading to a significant reduction in inflammatory cytokine secretion. However, the precise mechanism of action of n-3 PUFAs in psoriasis is still not understood. In the present study, we elucidated the bioaction of ALA on the adaptive immune component of psoriasis by using a psoriatic skin model produced with the addition of activated T cells. Healthy and psoriatic skin substitutes were produced according to the self-assembly method, using culture media supplemented with 10 µM of ALA. T cells were isolated from blood samples using a negative selection isolation method. ALA supplementation regulated the hyperproliferation and abnormal cell differentiation of psoriatic keratinocytes stimulated by T cells. Additionally, the exogenous ALA was correctly incorporated into the phospholipids of keratinocytes, which resulted in increased levels of ALA, eicosapentaenoic acid (EPA) and n-3 docosapentaenoic acid (n-3 DPA). The infiltration of T cells into the epidermis was reduced when ALA was added to the culture medium, and significant decreases in the levels of inflammatory cytokines and chemokines such as CXCL1, interleukin-6 (IL-6) and interleukin-8 (IL-8) were consequently measured in psoriatic substitutes supplemented with this n-3 PUFA. Altogether, our results showed that in this psoriatic skin model enriched with T cells, ALA exerted its beneficial effect by decreasing the quantities of inflammatory mediators released by T cells.

Large-for-Gestational-Age, Leptin, and Adiponectin in Infancy.

CONTEXT: Fetal overgrowth "programs" an elevated risk of obesity and type 2 diabetes in adulthood. Plausibly, adipokines may be involved in programming metabolic health. OBJECTIVE: This work aimed to evaluate whether large-for-gestational-age (LGA), an indicator of fetal overgrowth, is associated with altered circulating leptin and adiponectin levels in infancy, and assess the determinants. METHODS: In the Canadian 3D birth cohort, we studied 70 LGA (birth weight > 90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) infants matched by maternal ethnicity, smoking, and gestational age at delivery. The primary outcomes were fasting leptin, and total and high-molecular-weight (HMW) adiponectin concentrations at age 2 years. RESULTS: LGA infants had higher body mass index (BMI) than OGA infants. However, there were no significant differences in leptin, and total and HMW adiponectin concentrations. Leptin concentrations were positively associated with female sex, weight (z score) gain 0 to 24 months, current BMI, and the sum of triceps and subscapular skinfold thickness, and negatively associated with maternal age and White ethnicity. Female sex was associated with lower total and HMW adiponectin concentrations. Weight (z score) gain 0 to 24 months and current BMI were positively correlated with total and HMW adiponectin concentrations in LGA infants only. CONCLUSION: This study is the first to demonstrate that LGA does not matter for circulating leptin and adiponectin concentrations in infancy, and there may be LGA-specific positive associations between weight gain or current BMI and adiponectin concentrations in infancy, suggesting dysfunction in establishing the adiposity-adiponectin negative feedback loop in LGA individuals.

α-Linolenic acid and linoleic acid modulate the lipidome and the skin barrier of a tissue-engineered skin model.

Polyunsaturated fatty acids (PUFAs) play an important role in the establishment and the maintenance of the skin barrier function. However, the impact of their derived lipid mediators remains unclear. Skin substitutes were engineered according to the self-assembly method with a culture medium supplemented with 10 µM of both α-linolenic acid (ALA) and linoleic acid (LA). The supplementation with ALA and LA decreased testosterone absorption through a tissue-engineered reconstructed skin model, thus indicating an improved skin barrier function following supplementation. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes. Indeed, the dual supplementation increased the levels of eicosapentaenoic acid (EPA) (15-fold), docosapentaenoic acid (DPA) (3-fold), and LA (1.5-fold) in the epidermal phospholipids while it increased the levels of ALA (>20-fold), DPA (3-fold) and LA (1.5-fold) in the epidermal triglycerides. The bioactive lipid mediator profile of the skin substitutes, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols, was next analyzed using liquid chromatography-tandem mass spectrometry. The lipid supplementation further modulated bioactive lipid mediator levels of the reconstructed skin substitutes, leading to a lipid mediator profile more representative of the one found in normal human skin. These findings show that an optimized supply of PUFAs via culture media is essential for the establishment of improved barrier function in vitro. STATEMENT OF SIGNIFICANCE: Supplementation of the culture medium with 10 µM of both α-linolenic acid (ALA) and linoleic acid (LA) improved the skin barrier function of a tissue-engineered skin model. The exogenously provided fatty acids were incorporated into the phospholipid and triglyceride fractions of the skin substitutes and further modulated bioactive lipid mediator levels, including prostaglandins, hydroxy-fatty acids, N-acylethanolamines and monoacylglycerols. These findings highlight the important role of ALA and LA in skin homeostasis and show that an optimized supply of polyunsaturated fatty acids via culture media is essential for the establishment of improved barrier function in vitro.

Docosahexaenoic acid-rich algae oil supplementation on breast milk fatty acid profile of mothers who delivered prematurely: a randomized clinical trial.

Preterm infants are deficient in long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), a fatty acid (FA) associated with an increase in bronchopulmonary dysplasia (BPD). In two previous randomized control trials, DHA supplementation did not reduce the risk of BPD. We examined the breast milk FA profile, collected 14 days after birth, of mothers who delivered before 29 weeks of gestation and who were supplemented with DHA-rich algae oil or a placebo within 72 h after birth as part of the MOBYDIck trial. Milk FA were analyzed by gas chromatography. The total amount of FA (mg/mL) was similar in both groups but the supplementation increased DHA (expressed as % of total FA, mean ± SD, treatment vs placebo, 0.95 ± 0.44% vs 0.34 ± 0.20%; P < 0.0001), n-6 docosapentaenoic acid (DPA) (0.275 ± 0.14% vs 0.04 ± 0.04%; P < 0.0001) and eicosapentaenoic acid (0.08 ± 0.08% vs 0.07 ± 0.07%; P < 0.0001) while decreasing n-3 DPA (0.16 ± 0.05% vs 0.17 ± 0.06%; P < 0.05). Supplementation changed the ratio of DHA to arachidonic acid (1.76 ± 1.55% vs 0.60 ± 0.31%; P < 0.0001) and n-6 to n-3 FA (0.21 ± 0.06% vs 0.17 ± 0.04%; P < 0.0001). DHA-rich algae supplementation successfully increased the DHA content of breast milk but also included secondary changes that are closely involved with inflammation and may contribute to changing clinical outcomes.

The plasma antioxidant vitamin status of the INTAPP cohort examined: The unsuspected importance of ß-carotene and γ-tocopherol in preeclampsia.

OBJECTIVE: Examine the levels of plasma antioxidant vitamins before and during a treatment with placebo or vitamin E + C supplement to prevent preeclampsia (PE). STUDY DESIGN: Per-protocol analysis of a subset group of pregnant women (n = 295) from the International Trial of Antioxidants for the Prevention of PE (INTAPP) randomized case-control study. Normotensive receiving placebo or vitamins (n = 115 and 87 respectively) were compared to gestational hypertension (GH) without proteinuria (n = 30 and 27) and PE (n = 21 and 15). Vitamin quantification was performed at 12-18, 24-26 and 32-34 weeks of gestation. MAIN OUTCOME MEASURES: Coenzyme (Co) Q10, ß-carotene and vitamins E (α and γ forms) plasma levels. RESULTS: Vitamin E + C supplementation was found to increase the α-tocopherol levels by 40% but was associated with a 57% decrease in the γ-tocopherol isoform for all study groups (p < 0.001). The ß -carotene was lower in the PE than in the normotensive and GH groups (p < 0.001) while the level of CoQ10 remained unaffected. CONCLUSIONS: A more personalized approach that target the suboptimal levels of specific antioxidants without disturbing the α/γ-tocopherol ratio could be a more successful approach to counteract oxidative stress in PE.

Large birth size, infancy growth pattern, insulin resistance and ß-cell function.

OBJECTIVE: Large birth size programs an elevated risk of type 2 diabetes in adulthood, but data are absent concerning glucose metabolic health impact in infancy. We sought to determine whether the large birth size is associated with insulin resistance and ß-cell function in infancy and evaluate the determinants. DESIGN AND PARTICIPANTS: In the Canadian 3D birth cohort, we conducted a nested matched (1:2) study of 70 large-for-gestational-age (LGA, birth weight >90th percentile) and 140 optimal-for-gestational-age (OGA, 25th-75th percentiles) control infants. The primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-ß) at age 2-years. RESULTS: HOMA-IR and HOMA-ß were similar in LGA and OGA infants. Adjusting for maternal and infant characteristics, decelerated growth in length during early infancy (0-3 months) was associated with a 25.8% decrease (95% confidence intervals 6.7-41.0%) in HOMA-ß. During mid-infancy (3-12 months), accelerated growth in weight was associated with a 25.5% (0.35-56.9%) increase in HOMA-IR, in length with a 69.3% increase (31.4-118.0%) in HOMA-IR and a 24.5% (0.52-54.3%) increase in HOMA-ß. Decelerated growth in length during late infancy (1-2 years) was associated with a 28.4% (9.5-43.4%) decrease in HOMA-IR and a 21.2% (3.9-35.4%) decrease in HOMA-ß. Female sex was associated with higher HOMA-ß, Caucasian ethnicity with lower HOMA-IR, and maternal smoking with lower HOMA-ß. CONCLUSIONS: This study is the first to demonstrate that large birth size is not associated with insulin resistance and ß-cell function in infancy but infancy growth pattern matters. Decelerated infancy growth may be detrimental to beta-cell function.

Investigation of Omega-3 Polyunsaturated Fatty Acid Biological Activity in a Tissue-Engineered Skin Model Involving Psoriatic Cells.

Clinical studies have shown that diets enriched with omega-3 (also know as n-3) polyunsaturated fatty acids could relieve the symptoms of patients with psoriasis. However, the mechanisms involved remain poorly understood. The aim of this study was to investigate the effects of α-linolenic acid (ALA) on the proliferation and differentiation of psoriatic keratinocytes in a three-dimensional skin model. Skin models featuring healthy (healthy substitute) or psoriatic (psoriatic substitute) cells were engineered by the self-assembly method of tissue engineering using a culture medium supplemented with 10 µM ALA in comparison with the regular unsupplemented medium. ALA decreased keratinocyte proliferation and improved psoriatic substitute epidermal differentiation, as measured by decreased Ki67 staining and increased protein expression of FLG and loricrin. The added ALA was notably incorporated into the epidermal phospholipids and metabolized into long-chain n-3 polyunsaturated fatty acids, mainly eicosapentaenoic acid and n-3 docosapentaenoic acid. ALA supplementation led to increased levels of eicosapentaenoic acid derivatives (15-hydroxyeicosapentaenoic acid and 18-hydroxyeicosapentaenoic acid) as well as a decrease in levels of omega-6 (also know as n-6) polyunsaturated fatty acid lipid mediators (9-hydroxyoctadecadienoic acid, 12-hydroxyeicosatetraenoic acid, and leukotriene B4). Furthermore, the signal transduction mediators extracellular signal‒regulated kinases 1 and 2 were the kinases most activated after ALA supplementation. Taken together, these results show that ALA decreases the pathologic phenotype of psoriatic substitutes by normalizing keratinocyte proliferation and differentiation in vitro.

Cord Blood IGF-I, Proinsulin, Leptin, HMW Adiponectin, and Ghrelin in Short or Skinny Small-for-Gestational-Age Infants.

CONTEXT: Small-for-gestational-age (SGA) is an indicator of poor fetal growth "programming" an elevated risk of type 2 diabetes in adulthood. Little is known about early-life endocrine characteristics in SGA subtypes. Stunting (short) and wasting (skinny) are considered distinct SGA phenotypes in neonatal prognosis. OBJECTIVES: This work aimed to assess whether SGA infants with stunting or wasting have similar alterations in neonatal endocrine metabolic health biomarkers. METHODS: This was a nested case-control study based on the 3D (Design, Develop, and Discover) birth cohort in Canada. The study subjects were 146 SGA (birth weight < 10th percentile) and 155 optimal-for-gestational age (OGA, 25th-75th percentiles) infants. Stunting was defined as birth length less than the 10th percentile, and wasting as body mass index less than the 10th percentile for sex and gestational age, respectively. Main outcome measures included cord plasma concentrations of insulin-like growth factor I (IGF-I), proinsulin, leptin, high-molecular-weight (HMW) adiponectin, and ghrelin. RESULTS: Comparing to OGA infants adjusted for maternal and neonatal characteristics, SGA infants with either stunting only or wasting only had lower cord plasma IGF-I and leptin concentrations. HMW adiponectin concentrations were lower in SGA infants with wasting only (P = .004), but similar in SGA infants with stunting only (P = .816). Only SGA infants with both stunting and wasting had substantially lower proinsulin (P < .001) and higher ghrelin concentrations (P < .001) than OGA infants. CONCLUSION: This study is the first to demonstrate that SGA infants with wasting only are characterized by low HMW adiponectin concentrations, whereas those with stunting only are not. SGA with both stunting and wasting are characterized by low proinsulin and high ghrelin concentrations.

Oxidized LDL, insulin sensitivity and beta-cell function in newborns.

INTRODUCTION: Oxidized low-density lipoprotein (OxLDL), a biomarker of oxidative stress, itself possesses proatherogenic and proinflammatory effects. Elevated circulating OxLDL levels have been consistently associated with insulin resistance and diabetes in adults. We sought to assess whether OxLDL may be associated with insulin sensitivity and beta-cell function in early life. RESEARCH DESIGN AND METHODS: In a birth cohort study, we assessed cord plasma OxLDL concentration and OxLDL to total LDL ratio in relation to glucose to insulin ratio (an indicator of fetal insulin sensitivity), proinsulin to insulin ratio (an indicator of fetal beta-cell function), and leptin and adiponectin concentrations in 248 singleton newborns. RESULTS: Cord plasma OxLDL concentration was positively correlated with glucose to insulin ratio (r=0.24, p<0.001) and proinsulin to insulin ratio (r=0.20, p<0.001) and was not correlated with leptin or adiponectin. Adjusting for maternal and neonatal characteristics, each log unit increase in cord plasma OxLDL concentration was associated with a 25.8% (95% CI 12.8% to 40.3%) increase in glucose to insulin ratio and a 19.0% (95% CI 6.8% to 32.9%) increase in proinsulin to insulin ratio, respectively. Similar associations were observed for cord plasma OxLDL to LDL ratio in relation to cord plasma glucose to insulin ratio and proinsulin to insulin ratio. CONCLUSIONS: Higher OxLDL levels were associated with lower fetal beta-cell function (higher proinsulin to insulin ratio) but higher insulin sensitivity (higher glucose to insulin ratio). The study is the first to demonstrate that OxLDL may affect glucose metabolic health in early life in humans.

Dairy product intake modifies gut microbiota composition among hyperinsulinemic individuals.

PURPOSES: The objectives of this study were to investigate differences in gut microbiota (GM) composition after high dairy intake (HD) compared to adequate dairy intake (AD) and to correlate GM composition variations with the change in glycemic parameters in hyperinsulinemic subjects. METHODS: In this crossover study, 10 hyperinsulinemic adults were randomized to HD (≥ 4 servings/day) or AD (≤ 2 servings/day) for 6 weeks, separated by a 6-week washout period. Fasting insulin and glucose levels were measured after each intervention. Insulin resistance was calculated with the homeostasis model assessment of insulin resistance (HOMA-IR). GM was determined with 16S rRNA-based high-throughput sequencing at the end of each intervention. Paired t test, correlations and machine learning analyses were performed. RESULTS: Endpoint glycemic parameters were not different between HD and AD intake. After HD compared with AD intake, there was a decrease in the abundance of bacteria in Roseburia and Verrucomicrobia (p = 0.04 and p = 0.02, respectively) and a trend for an increase abundance in Faecalibacteria and Flavonifractor (p = 0.05 and p = 0.06, respectively). The changes in abundance of Coriobacteriia, Erysipelotrichia, and Flavonifractor were negatively correlated with the change in HOMA-IR between the AD and HD phases. Furthermore, a predictive GM signature, including Anaerotruncus, Flavonifractor, Ruminococcaceae, and Subdoligranulum, was related to HOMA-IR. CONCLUSION: Overall, these results suggest that HD modifies the abundance of specific butyrate-producing bacteria in Firmicutes and of bacteria in Verrucomicrobia in hyperinsulinemic individuals. In addition, the butyrate producing bacteria in Firmicutes phylum correlate negatively with insulin resistance.

Omega-3 Eicosapentaenoic Acid Reduces Prostate Tumor Vascularity.

The impact of omega (ω)-3 fatty acids on prostate cancer is controversial in epidemiological studies but experimental studies suggest a protective effect. However, little is known about the mechanism of action. Here, we studied the effects of purified fatty acid molecules on prostate tumor progression using the TRAMP-C2 syngeneic immunocompetent mouse model. Compared with ω-6 or ω-9-supplemented animals, we observed that late-stage prostate tumor growth was reduced with a monoacylglyceride (MAG)-conjugated form of eicosapentaenoic acid (EPA) supplementation, whereas docosahexanenoic acid (DHA) caused an early reduction. MAG-EPA significantly decreased tumor blood vessel diameter (P < 0.001). RNA sequencing analysis revealed that MAG-EPA downregulated angiogenesis- and vascular-related pathways in tumors. We also observed this tissue vascular phenotype in a clinical trial testing MAG-EPA versus a high oleic sunflower oil placebo. Using anti-CD31 IHC, we observed that MAG-EPA reduced blood vessel diameter in prostate tumor tissue (P = 0.03) but not in normal adjacent tissue. Finally, testing autocrine and paracrine effects in an avascular tumor spheroid growth assay, both exogenous MAG-EPA and endogenous ω3 reduced VEGF secretion and in vitro endothelial cell tube formation and blocked tumor spheroid growth, suggesting that ω3 molecules can directly hinder prostate cancer cell growth. Altogether, our results suggest that fatty acids regulate prostate cancer growth and that a tumor-specific microenvironment is required for the anti-vascular effect of MAG-EPA in patients with prostate cancer. IMPLICATIONS: Increasing the amount of ingested EPA omega-3 subtype for patients with prostate cancer might help to reduce prostate tumor progression by reducing tumor vascularization.

Maternal vitamin D, oxidative stress, and pre-eclampsia.

OBJECTIVE: To examine the associations between risk of pre-eclampsia and pregnancy levels of maternal 25-hydroxyvitamin D (25[OH]D) and oxidative stress biomarkers. METHODS: A nested case-control study (n = 99; 34 cases; 65 controls) within a prospective pregnancy cohort. Maternal 25(OH)D and oxidative stress markers (six isomers of F2 -isoprostanes; F2 -isoPs) were measured in plasma at 12-18 and 24-26 gestational weeks. Vitamin D deficiency was defined as 25[OH]D less than 50 nmol/L. RESULTS: Maternal vitamin D deficiency was associated with increased 8-iso-PGF2α (P = 0.037), 15(R)-PGF2α (P = 0.004), (±)5-iPF2α -VI (P = 0.026) at 12-18 weeks. Vitamin D deficiency was inversely associated with 8-iso-PGF2α (P = 0.019) and (±)5-iPF2α -VI isomer (P = 0.010) at 24-26 weeks. Both maternal vitamin D deficiency (adjusted odds ratio [aOR], 4.79; 95% confidence interval [CI], 1.67-13.75) and increased (±)5-iPF2α -VI (aOR, 2.46; 95% CI, 1.16-5.22) at 24-26 weeks were associated with risk of pre-eclampsia. However, the interaction test between 25(OH)D and (±)5-iPF2α -VI was not significant (P = 0.143). CONCLUSION: Plasma 25(OH)D below 50 nmol/L was associated with increased oxidative stress levels during pregnancy as measured by two F2 -isoP isomers, including the well-studied marker 8-iso-PGF2α . Whether vitamin D-induced oxidative stress mediates the risk of pre-eclampsia warrants future study.

Long chain omega-3 fatty acids and their oxidized metabolites are associated with reduced prostate tumor growth.

INTRODUCTION: Cancer has been associated with increased oxidative stress and deregulation of bioactive oxylipins derived from long-chain polyunsaturated fatty acids (LC-PUFA) like arachidonic acid (AA). There is a debate whether ω-3 LC-PUFA could promote or prevent prostate tumor growth through immune modulation and reduction of oxidative stress. Our aim was to study the association between enzymatically or non-enzymatically produced oxidized-LC-PUFA metabolites and tumor growth in an immune-competent eugonadal and castrated C57BL/6 male mice injected with TRAMP-C2 prostate tumor cells, fed with ω-3 or ω-6 LC-PUFA-rich diets. MATERIALS AND METHODS: Tumor fatty acids were profiled by gas chromatography and 26 metabolites derived from either AA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were assessed by liquid chromatography-mass spectrometry. RESULTS: The enriched ω-3 diet did not reduce oxidative stress overall in tumors but favored the formation of ω-3 rather than ω-6 derived isoprostanoids. We discovered that EPA and its oxidized-derivatives like F3-isoprostanes and prostaglandin (PG)F3α, were inversely correlated with tumor volume (spearman correlations and T-test, p<0.05). In contrast, F2-isoprostanes, adrenic acid, docosapentaenoic acid (DPAω-6) and PGE2 were positively correlated with tumor volume. Interestingly, F4-neuroprostanes, PGD2, PGF2α, and thromboxane were specifically increased in TRAMP-C2 tumors of castrated mice compared to those of eugonadal mice. DISCUSSION: Decreasing tumor growth under ω-3 diet could be attributed in part to increased levels of EPA and its oxidized-derivatives, a reduced level of pro-angiogenic PGE2 and increased levels of F4-neuroprostanes and resolvins content in tumors, suspected of having anti-proliferative and anti-inflammatory effects.

Effect of Maternal Docosahexaenoic Acid Supplementation on Bronchopulmonary Dysplasia-Free Survival in Breastfed Preterm Infants: A Randomized Clinical Trial.

Importance: Maternal docosahexaenoic acid (DHA) supplementation may prevent bronchopulmonary dysplasia, but evidence remains inconclusive. Objective: To determine whether maternal DHA supplementation during the neonatal period improves bronchopulmonary dysplasia-free survival in breastfed infants born before 29 weeks of gestation. Design, Setting, and Participants: Superiority, placebo-controlled randomized clinical trial at 16 Canadian neonatal intensive care units (June 2015-April 2018 with last infant follow-up in July 2018). Lactating women who delivered before 29 weeks of gestation were enrolled within 72 hours of delivery. The trial intended to enroll 800 mothers, but was stopped earlier. Interventions: There were 232 mothers (273 infants) assigned to oral capsules providing 1.2 g/d of DHA from randomization to 36 weeks' postmenstrual age and 229 mothers (255 infants) assigned to placebo capsules. Main Outcomes and Measures: The primary outcome was bronchopulmonary dysplasia-free survival in infants at 36 weeks' postmenstrual age. There were 22 secondary outcomes, including mortality and bronchopulmonary dysplasia. Results: Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study. Among 461 mothers and their 528 infants (mean gestational age, 26.6 weeks [SD, 1.6 weeks]; 253 [47.9%] females), 375 mothers (81.3%) and 523 infants (99.1%) completed the trial. Overall, 147 of 268 infants (54.9%) in the DHA group vs 157 of 255 infants (61.6%) in the placebo group survived without bronchopulmonary dysplasia (absolute difference, -5.0% [95% CI, -11.6% to 2.6%]; relative risk, 0.91 [95% CI, 0.80 to 1.04], P = .18). Mortality occurred in 6.0% of infants in the DHA group vs 10.2% of infants in the placebo group (absolute difference, -3.9% [95% CI, -6.8% to 1.4%]; relative risk, 0.61 [95% CI, 0.33 to 1.13], P = .12). Bronchopulmonary dysplasia occurred in 41.7% of surviving infants in the DHA group vs 31.4% in the placebo group (absolute difference, 11.5% [95% CI, 2.3% to 23.2%]; relative risk, 1.36 [95% CI, 1.07 to 1.73], P = .01). Of 22 prespecified secondary outcomes, 19 were not significantly different. Conclusions and Relevance: Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia-free survival at 36 weeks' postmenstrual age compared with placebo. Study interpretation is limited by early trial termination. Trial Registration: ClinicalTrials.gov Identifier: NCT02371460.