Omega-3 fatty acids for inflamed depression - A match/mismatch study.

Despite decades of research on the pathophysiology of depression, the development of new therapeutic interventions has been slow, and no biomarkers of treatment response have been clinically implemented. Several lines of evidence suggest that the clinical and biological heterogeneity among patients with major depressive disorder (MDD) has hampered progress in this field. MDD with low-grade inflammation - "inflamed depression" - is a subtype of depression that may be associated with a superior antidepressant treatment response to anti-inflammatory compounds. Omega-3 fatty acid eicosapentaenoic acid (EPA) has anti-inflammatory properties, and preliminary data suggest that it may be particularly efficacious in inflamed depression. In this study we tested the hypothesis that add-on EPA has greater antidepressant efficacy in MDD patients with high baseline high-sensitivity C-reactive protein (hs-CRP) compared to MDD patients with low hs-CRP. All subjects received 2.2 g EPA, 400 mg docosahexaenoic acid and 800 mg of other fatty acids daily for 8 weeks, added to stable ongoing antidepressant treatment. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAMD-17). Patients and raters were blind to baseline hs-CRP status. In an intention-to-treat analysis including all subjects with at least one post baseline visit (n = 101), ahs-CRPcut-off of ≥1 mg/L, but not ≥3 mg/L, was associated with a greater improvement in HAMD-17 total score. In addition to a general antidepressant effect among patients with hs-CRP ≥ 1 mg/L, adjuvant EPA treatment improved symptoms putatively related to inflamed depression such as fatigue and sleep difficulties. This adds to the mounting evidence that delineation of MDD subgroups based on inflammation may be clinically relevant to predict treatment response to anti-inflammatory interventions.

N-3 PUFA supplementation alleviates anxiety symptoms by manipulating erythrocyte fatty acid levels in depression.

PURPOSE: Major depressive disorder (MDD) is frequently accompanied by the symptoms of clinical anxiety. Since our previous research has found that n-3 PUFA supplementation alleviates anxiety in MDD, this study was aimed to further explore whether n-3 PUFA supplementation improves anxiety symptoms in depression by directly manipulating fatty acid levels. METHODS: A secondary analysis of biomarker data (erythrocyte fatty acid composition) collected as part of the randomized clinical trial which investigated the adjunctive effect of n-3 PUFAs was conducted on 72 venlafaxine-treated outpatients with first-diagnosed, drug-naïve depression. All participants with longitudinal biomarker data were included in the association analysis to determine how n-3 PUFA supplementation influences fatty acid composition and alleviates anxiety symptoms in depression. RESULTS: Decreases of the C20:3n6 were found in all participants at both follow-up time points (χ2 = 96.36, p = 0.000). The n-3 index (χ2 = 10.59, p = 0.001), EPA (χ2 = 24.31, p = 0.000), and C22:5n3/C20:5n3 ratio (χ2 = 10.71, p = 0.001) were increased, while C22:4n6 (χ2 = 7.703, p = 0.006) was decreased in n-3 PUFA group compared to the placebo group. The improvement in anxiety symptoms positively correlates with the extent of reduction of C16:0, C18:0, and total fatty acid levels as well as D5 desaturase activity (p < 0.05). CONCLUSION: These data suggest that the anxiolytic effect exerted by n-3 PUFAs in first-diagnosed, drug-naïve depression is manipulated by erythrocyte fatty acid levels. Saturated fatty acid levels have an important role in predicting the severity of anxiety symptoms.

Association between fish and shellfish consumption, n-3 polyunsaturated fatty acids, and gastric cancer risk: the Japan Public Health Center-based Prospective Study.

PURPOSE: Fish and shellfish consumption is suggested to be a cancer-protective factor. However, studies investigating this association for gastric cancer, especially considering Helicobacter pylori (H. pylori) and atrophic gastritis (AG), are limited. We investigated gastric cancer risk associated with fish, shellfish, and n-3 polyunsaturated fatty acids (n-3 PUFAs) consumption among Japanese adults. METHODS: 90,504 subjects enrolled in the Japan Public Health Center-based Prospective Study (JPHC Study) were followed until December 2013. Dietary intake data were collected using a food frequency questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for gastric cancer risk associated with fish and shellfish consumption and marine n-3 PUFAs (sum of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA)) using Cox proportional hazards models. Among those with avaliable data, we conducted a subgroup analysis taking H. pylori infection and AG status  into consideration. RESULTS: There were 2,701 gastric cancer cases during an average of 15 years of follow-up. We observed an increased gastric cancer risk for salted fish consumption for men [HR for fifth quintile versus first quintile 1.43 (95% CI 1.18-1.75)] and for women [HR 1.33 (95% CI 1.00-1.77)]. We observed a weak risk reduction trend for women as the intake of marine n-3 PUFAs increased (p-trend:0.07). When we included H. pylori infection and atrophic gastritis status in the analysis, the associations diminished. CONCLUSION: Our results suggest that salted fish increases gastric cancer risk for men and women, while marine n-3 PUFAs marginally decreases this risk among women in Japan.

Dietary polyunsaturated fatty acids intake is negatively associated with hyperuricemia: The National Health and Nutrition Examination Survey 2003-2015.

BACKGROUND AND AIMS: The objective of this research was to explore the associations between dietary PUFAs intake and hyperuricemia risk. METHODS AND RESULTS: Based on the National Health and Nutrition Examination Survey (NHANES) 2003-2015, all eligible individuals were divided into hyperuricemia and non-hyperuricemia groups based on diagnostic criteria for hyperuricemia (serum uric acid >420 µmol/L for men and >360 µmol/L for women). Multivariate-adjusted logistic regression was employed to explore the relationship between dietary PUFAs intake and hyperuricemia risk. Total PUFAs and their subtypes were modeled to isocalorically replace saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Higher intake of n-3 PUFAs, n-6 PUFAs, linoleic acid (LA), alpha-linoleic acid (ALA), and non-marine PUFAs intake correlated with decreased hyperuricemia risk, with adjusted odds ratio (OR) and 95% confidence interval (95%CIs) were 0.77 (0.63, 0.93), 0.75 (0.61, 0.92), 0.75 (0.61, 0.91), 0.69 (0.55, 0.87), and 0.73 (0.59, 0.91), respectively. Replacing 5% of total energy intake from SFAs with isocaloric PUFAs was associated with decreased odds of hyperuricemia in men (0.69 (0.57, 0.84)) and in individuals (0.81 (0.71, 0.92)). Similar trends were observed in the substitution of SFAs with non-marine PUFAs in men (0.87 (0.80, 0.94)) and in all individuals (0.92 (0.88, 0.98)). Sensitivity analyses exhibited consistent results with primary analyses. CONCLUSION: Higher dietary intake of n-3 PUFAs, n-6 PUFAs, LA, ALA, and non-marine PUFAs was associated with decreased hyperuricemia risk. These results support the recommendation to substitute SFAs with PUFAs in diet.

Optimization of concentrations of different n-3PUFAs on antioxidant capacity in mouse hepatocytes.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), mainly including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), possess antioxidant properties and play a crucial role in growth and development. However, the combined effects of ALA, EPA, and DHA at different concentrations have rarely been reported. This work explored the effects of EPA, ALA, and DHA on the viability and antioxidant capacity of mouse hepatocytes, with the objective of enhancing the antioxidant capacity. Within the appropriate concentration range, cell viability and the activity of glutathione S-transferase, superoxide dismutase, and catalase were increased, while the oxidation products of malondialdehyde and the level of intracellular reactive oxygen species were obviously reduced. Thus, oxidative stress was relieved, and cellular antioxidant levels were improved. Finally, response surface optimization was carried out for EPA, ALA, and DHA, and the model was established. The antioxidant capacity of the cells was highest at EPA, ALA, and DHA concentrations of 145.46, 405.05, and 551.52 µM, respectively. These findings lay the foundation for further exploration of the interactive mechanisms of n-3 PUFAs in the body, as well as their applications in nutraceutical food.

The association between n-3 polyunsaturated fatty acid intakes and asthma in US children and adolescents: A cross-sectional study from NHANES.

BACKGROUND: Asthma is an inflammatory disease. The potential of n-3 polyunsaturated fatty acids (PUFAs) to alleviate asthma symptoms through their anti-inflammatory effects and immune modulation has been explored. However, the precise role of dietary n-3 PUFAs in childhood and adolescent asthma remains unclear. OBJECTIVE: This study aimed to evaluate the association between dietary n-3 PUFAs intake and asthma in children and adolescents in the United States. METHODS: We conducted a cross-sectional analysis of 8543 children and adolescents from the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2020 by adjusting for covariates and using multivariate logistic regression, restricted cubic spline, threshold effects, and subgroup analyses. RESULTS: Among 8354 participants, 1456 (16.5%) self-reported diagnosis of asthma by a healthcare provider. After adjusting for potential confounding factors, compared with individuals in the lowest n-3 PUFA consumption group (T1, <26.07 mg/kg/day), the adjusted odds ratio (OR) for asthma was 0.71 (95% CI: 0.6-0.84, p < .001) in the second group (T2, 26.07-48.93 mg/kg/day) and 0.58 (95% CI: 0.47-0.73, p < .001) in the third group (T3, >48.93 mg/kg/day). Furthermore, a nonlinear (L-shaped) relationship was observed between n-3 PUFA intake and asthma (p = .009), with subgroup and sensitivity analyses confirming the stability of the results. In the threshold analysis, a critical turning point was observed at approximately 59.0 mg/kg/day (OR = 0.984, 95% CI: 0.977-0.991, p < .001). CONCLUSION: Dietary intake of n-3 PUFAs exhibited an L-shaped relationship with asthma in children and adolescents in the United States, with a critical turning point observed at approximately 59.0 mg/kg/day.

Omega-3 Polyunsaturated Fatty Acid Eicosapentaenoic Acid or Docosahexaenoic Acid Improved Ageing-Associated Cognitive Decline by Regulating Glial Polarization.

Neuroinflammation induced by microglial and astrocyte polarizations may contribute to neurodegeneration and cognitive impairment. Omega (n)-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory and neuroprotective effects, but conflicting results were reported after different n-3 PUFA treatments. This study examined both the change in glial polarizations in ageing rats and the differential effects of two omega-3 PUFAs. The results showed that both PUFAs improved spatial memory in ageing rats, with docosahexaenoic acid (DHA) being more effective than eicosapentaenoic acid (EPA). The imbalance between microglial M1/M2 polarizations, such as up-regulating ionized calcium binding adaptor molecule 1 (IBA1) and down-regulating CD206 and arginase-1 (ARG-1) was reversed in the hippocampus by both n-3 PUFAs, while the DHA effect on CD206 was stronger. Astrocyte A1 polarization presented increasing S100B and C3 but decreasing A2 parameter S100A10 in the ageing brain, which were restored by both PUFAs, while DHA was more effective on S100A10 than EPA. Consistent with microglial M1 activation, the concentration of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were significantly increased, which were attenuated by DHA, while EPA only suppressed IL-6. In correlation with astrocyte changes, brain-derived neurotrophic factor precursor was increased in ageing rats, which was more powerfully down-regulated by DHA than EPA. In summary, enhanced microglial M1 and astrocytic A1 polarizations may contribute to increased brain pro-inflammatory cytokines, while DHA was more powerful than EPA to alleviate ageing-associated neuroimmunological changes, thereby better-improving memory impairment.

Supplementation of n-3 PUFAs in Adulthood Attenuated Susceptibility to Pentylenetetrazol Induced Epilepsy in Mice Fed with n-3 PUFAs Deficient Diet in Early Life.

The growth and development of the fetus and newborn throughout pregnancy and lactation are directly related to the nutritional status of the mother, which has a significant impact on the health of the offspring. The purpose of this experiment was to investigate the susceptibility of n-3 polyunsaturated fatty acid deficiency in early life to seizures in adulthood. The n-3 PUFAs-deficient mice's offspring were established and then fed with α-LNA diet, DHA-enriched ethyl ester, and DHA-enriched phospholipid-containing diets for 17 days at the age of eight weeks. During this period, animals received intraperitoneal injections of 35 mg/kg of pentylenetetrazol (PTZ) every other day for eight days. The results showed that dietary n-3 PUFA-deficiency in early life could aggravate PTZ-induced epileptic seizures and brain disorders. Notably, nutritional supplementation with n-3 PUFAs in adulthood for 17 days could significantly recover the brain n-3 fatty acid and alleviate the epilepsy susceptibility as well as raise seizure threshold to different levels by mediating the neurotransmitter disturbance and mitochondria-dependent apoptosis, demyelination, and neuroinflammation status of the hippocampus. DHA-enriched phospholipid possessed a superior effect on alleviating the seizure compared to α-LNA and DHA-enriched ethyl ester. Dietary n-3 PUFA deficiency in early life increases the susceptibility to PTZ-induced epilepsy in adult offspring, and nutritional supplementation with n-3 PUFAs enhances the tolerance to the epileptic seizure.

The Role of Marine n-3 Polyunsaturated Fatty Acids in Inflammatory-Based Disease: The Case of Rheumatoid Arthritis.

Inflammation is a conserved process that involves the activation of immune and non-immune cells aimed at protecting the host from bacteria, viruses, toxins and injury. However, unresolved inflammation and the permanent release of pro-inflammatory mediators are responsible for the promotion of a condition called "low-grade systemic chronic inflammation", which is characterized by tissue and organ damage, metabolic changes and an increased susceptibility to non-communicable diseases. Several studies have demonstrated that different dietary components may influence modifiable risk factors for diverse chronic human pathologies. Marine n-3 polyunsaturated fatty acids (n-3 PUFAs), mainly eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are well-recognized anti-inflammatory and immunomodulatory agents that are able to influence many aspects of the inflammatory process. The aim of this article is to review the recent literature that relates to the modulation of human disease, such as rheumatoid arthritis, by n-3 PUFAs.

Impact of n-3 polyunsaturated fatty acid intake in pregnancy on maternal health and birth outcomes: systematic review and meta-analysis from randomized controlled trails.

BACKGROUND: Maternal omega-3 consumption during pregnancy has been positively linked with a positive impact on maternal health and fetal growth. However, the results of individual studies are inconsistent and conflicting. OBJECTIVE: Examine the effect of supplementation with DHA, and/or EPA, and/or ALA throughout pregnancy on offspring's growth and pregnancy outcomes. DESIGN: A systematic review and meta-analysis. POPULATION: Pregnant women. METHODS: According to (PRISMA) statement and the Cochrane Handbook guidelines. Human trials (RCT or quasi-RCT) which involved oral omega-3 supplementation at least twice a week during pregnancy were included and comparing it with control groups with no supplementation or placebo administration. Data were extracted and directed using RevMan software. Fifty-nine randomized controlled trials were eligible for inclusion in the meta-analysis. Performed in MEDLINE, PubMed, Scopus, Google Scholar, and the Cochrane Library comparing omega 3 with control groups, from 1990 to 2020. THE MAIN OUTCOME MEASURES: The primary outcome measures were pregnancy-induced hypertension, preeclampsia, gestational duration, preterm birth, early preterm birth, birth weight, low birth weight, neonatal length, and head circumference. The secondary outcomes were neonatal intensive care unit, infant death, prenatal death, and cesarean section. RESULTS: In 24 comparisons (21,919 women) n-3 fatty acids played a protective role against the risk of preeclampsia (RR = 0.84, 95% CI 0.74-0.96 p = 0.008; I2 = 24%). In 46 comparisons (16,254 women) n-3 fatty acids were associated with a significantly greater duration of pregnancy (MD = 1.35, 95% CI 0.65-2.05, p = 0.0002; I2 = 59%). 27 comparisons (15,510 women) was accompanied by a significant decrease in pre-term birth less than 37 weeks (RR = 0.86, 95% CI 0.77-0.95, p = 0.005; I2 = 0%). 12 comparisons (11,774 women) was accompanied by a significant decrease in early pre-term birth less than 34 weeks (RR = 0.77, 95% CI 0.63-0.95, p = 0.01; I2 = 40%). 38 comparisons (16,505 infants) had a significant increase in birth weight (MD = 49.19, 95% CI 28.47-69.91, p < 0.00001; I2 = 100%). Finally, 14 comparisons (8,449 infants) had a borderline significance in increase in low birth weight (RR = 0.88, 95% CI 0.78-1.00, p = 0.05; I2 = 28%). CONCLUSIONS: Supplementation with omega-3 in prgnancy can prevent preeclampsia, increase gestational duration, increase birth weight and decrease the risk of low birth weight and preterm birth.

Identification of Optimal Reference Genes for qRT-PCR Normalization for Physical Activity Intervention and Omega-3 Fatty Acids Supplementation in Humans.

The quantitative polymerase chain reaction (qRT-PCR) technique gives promising opportunities to detect and quantify RNA targets and is commonly used in many research fields. This study aimed to identify suitable reference genes for physical exercise and omega-3 fatty acids supplementation intervention. Forty healthy, physically active men were exposed to a 12-week eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation and standardized endurance training protocol. Blood samples were collected before and after the intervention and mRNA levels of six potential reference genes were tested in the leukocytes of 18 eligible participants using the qRT-PCR method: GAPDH (Glyceraldehyde-3-phosphate dehydrogenase), ACTB (Beta actin), TUBB (Tubulin Beta Class I), RPS18 (Ribosomal Protein S18), UBE2D2 (Ubiquitin-conjugating enzyme E2 D2), and HPRT1 (Hypoxanthine Phosphoribosyltransferase 1). The raw quantification cycle (Cq) values were then analyzed using RefFinder, an online tool that incorporates four different algorithms: NormFinder, geNorm, BestKeeper, and the comparative delta-Ct method. Delta-Ct, NormFinder, BestKeeper, and RefFinder comprehensive ranking have found GAPDH to be the most stably expressed gene. geNorm has identified TUBB and HPRT as the most stable genes. All algorithms have found ACTB to be the least stably expressed gene. A combination of the three most stably expressed genes, namely GAPDH, TUBB, and HPRT, is suggested for obtaining the most reliable results.

Beneficial effects of an endogenous enrichment in n3-PUFAs on Wnt signaling are associated with attenuation of alcohol-mediated liver disease in mice.

Alcohol-associated liver disease (ALD) is a major human health issue for which there are limited treatment options. Experimental evidence suggests that nutrition plays an important role in ALD pathogenesis, and specific dietary fatty acids, for example, n6 or n3-PUFAs, may exacerbate or attenuate ALD, respectively. The purpose of the current study was to determine whether the beneficial effects of n3-PUFA enrichment in ALD were mediated, in part, by improvement in Wnt signaling. Wild-type (WT) and fat-1 transgenic mice (that endogenously convert n6-PUFAs to n3) were fed ethanol (EtOH) for 6 weeks followed by a single LPS challenge. fat-1 mice had less severe liver damage than WT littermates as evidenced by reduced plasma alanine aminotransferase, hepatic steatosis, liver tissue neutrophil infiltration, and pro-inflammatory cytokine expression. WT mice had a greater downregulation of Axin2, a key gene in the Wnt pathway, than fat-1 mice in response to EtOH and LPS. Further, there were significant differences between WT and fat-1 EtOH+LPS-challenged mice in the expression of five additional genes linked to the Wnt signaling pathway, including Apc, Fosl1/Fra-1, Mapk8/Jnk-1, Porcn, and Nkd1. Compared to WT, primary hepatocytes isolated from fat-1 mice exhibited more effective Wnt signaling and were more resistant to EtOH-, palmitic acid-, or TNFα-induced cell death. Further, we demonstrated that the n3-PUFA-derived lipid mediators, resolvins D1 and E1, can regulate hepatocyte expression of several Wnt-related genes that were differentially expressed between WT and fat-1 mice. These data demonstrate a novel mechanism by which n3-PUFAs can ameliorate ALD.

Omega-3 fatty acids and blood-based biomarkers in Alzheimer's disease and mild cognitive impairment: A randomized placebo-controlled trial.

BACKGROUND: Increased serum levels of pro-inflammatory biomarkers are consistently associated with cognitive decline. The omega-3 unsaturated fatty acids (n-3 PUFAs) had been linked to slowing cognitive decline due to their potential anti-inflammatory effects. To our knowledge, the different regiments of pure DHA, pure EPA, and their combination on various associated symptoms of dementia, including a mild form of cognitive impairment (MCI) and Alzheimer's disease (AD), have never been studied. METHODS: This multisite, randomized, double-blind, placebo-controlled trial was conducted at two veteran's retirement centers and one medical center in central Taiwan between 2013 and 2015. 163 MCI or AD patients were randomly assigned to placebo (n = 40), docosahexaenoic acid (DHA, 0.7 g/day, n = 41), eicosapentaenoic acid (EPA, 1.6 g/day, n = 40), or EPA (0.8 g/day) + DHA (0.35 g/day) (n = 42) group for 24 months. The results were measured as the cognitive and functional abilities, biochemical, and inflammatory cytokines profiles. Chi-square tests, two-sample t-test, ANOVA, and linear mixedeffects models were conducted with p < 0.05. RESULTS: 131 (80%) participants had completed the trial with all cognitive, functional, and mood status assessments. The statistically significant difference between the placebo and treatment groups was not determined, concerning the changes in cognitive, functional, and mood status scores, the biochemical profiles, and inflammatory cytokines levels. However, EPA was found to reduce the C-C motif ligands 4 (CCL4) level (p < 0.001). Additionally, EPA could reduce the constructional praxis (p < 0.05) and spoken language ability scores (p < 0.01), and DHA also reduced the spoken language ability score (p < 0.05). CONCLUSION: Overall, n-3 PUFAs supplements did not reduce cognitive, functional, and depressive symptom outcomes, but spoken language ability and constructional praxis subitems of ADAS-cog. These findings show that attention to clinical heterogeneity in dementia is crucial when studying nutrients interventions, such as n-3 PUFAs. In addition, with small effect size CCL4 is a better indicator than other inflammatory cytokines for EPA treatment response.

Blood-Brain Barrier Disruption Mediated by FFA1 Receptor-Evidence Using Miniscope.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), obtained from diet and dietary supplements, have been tested in clinical trials for the prevention or treatment of several diseases. n-3 PUFAs exert their effects by activation of free fatty acid (FFA) receptors. FFA1 receptor, expressed in the pancreas and brain, is activated by medium- to long-chain fatty acids. Despite some beneficial effects on cognition, the effects of n-3 PUFAs on the blood-brain barrier (BBB) are not clearly understood. We examined the effects of FFA1 activation on BBB permeability in vitro, using rat brain microvascular endothelial cells (RBMVEC), and in vivo, by assessing Evans Blue extravasation and by performing live imaging of brain microcirculation in adult rats. AMG837, a synthetic FFA1 agonist, produced a dose-dependent decrease in RBMVEC monolayer resistance assessed with Electric Cell-Substrate Impedance Sensing (ECIS); the effect was attenuated by the FFA1 antagonist, GW1100. Immunofluorescence studies revealed that AMG837 produced a disruption in tight and adherens junction proteins. AMG837 increased Evans Blue content in the rat brain in a dose-dependent manner. Live imaging studies of rat brain microcirculation with miniaturized fluorescence microscopy (miniscope) showed that AMG837 increased extravasation of sodium fluorescein. Taken together, our results demonstrate that FFA1 receptor activation reduced RBMVEC barrier function and produced a transient increase in BBB permeability.

High Endogenously Synthesized N-3 Polyunsaturated Fatty Acids in Fat-1 Mice Attenuate High-Fat Diet-Induced Insulin Resistance by Inhibiting NLRP3 Inflammasome Activation via Akt/GSK-3ß/TXNIP Pathway.

High-fat (HF) diets and low-grade chronic inflammation contribute to the development of insulin resistance and type 2 diabetes (T2D), whereas n-3 polyunsaturated fatty acids (PUFAs), due to their anti-inflammatory effects, protect against insulin resistance. Interleukin (IL)-1ß is implicated in insulin resistance, yet how n-3 PUFAs modulate IL-1ß secretion and attenuate HF diet-induced insulin resistance remains elusive. In this study, a HF diet activated NLRP3 inflammasome via inducing reactive oxygen species (ROS) generation and promoted IL-1ß production primarily from adipose tissue preadipocytes, but not from adipocytes and induced insulin resistance in wild type (WT) mice. Interestingly, endogenous synthesized n-3 polyunsaturated fatty acids (PUFAs) reversed this process in HF diet-fed fat-1 transgenic mice although the HF diet induced higher weight gain in fat-1 mice, compared with the control diet. Mechanistically, palmitic acid (PA), the main saturated fatty acid in an HF diet inactivated AMPK and led to decreased GSK-3ß phosphorylation, at least partially through reducing Akt activity, which ultimately blocked the Nrf2/Trx1 antioxidant pathway and induced TXNIP cytoplasm translocation and NLRP3 inflammasome activation, whereas docosahexaenoic acid (DHA), the most abundant n-3 PUFA in fat-1 adipose tissue, reversed this process via inducing Akt activation. Our GSK-3ß shRNA knockdown study further revealed that GSK-3ß played a pivot role between the upstream AMPK/Akt pathway and downstream Nrf2/Trx1/TXNIP pathway. Given that NLRP3 inflammasome is implicated in the development of most inflammatory diseases, our results suggest the potential of n-3 PUFAs in the prevention or adjuvant treatment of NLRP3 inflammasome-driven diseases.

Inflammatory Depression-Mechanisms and Non-Pharmacological Interventions.

Treatment of depression is hampered by the failure to identify distinct symptom profiles with distinct pathophysiologies that differentially respond to distinct treatments. We posit that inflammatory depression is a meaningful depression subtype associated with specific symptoms and biological abnormalities. We review several upstream, potentially causative, mechanisms driving low-grade inflammation in this subtype of depression. We also discuss downstream mechanisms mediating the link between inflammation and symptoms of depression, including alterations in dopaminergic neurotransmission and tryptophan metabolism. Finally, we review evidence for several non-pharmacological interventions for inflammatory depression, including probiotics, omega-3 fatty acids, and physical exercise interventions. While some evidence suggests that these interventions may be efficacious in inflammatory depression, future clinical trials should consider enriching patient populations for inflammatory markers, or stratify patients by inflammatory status, to confirm or refute this hypothesis.

Cardiovascular and cancer mortality in relation to dietary polychlorinated biphenyls and marine polyunsaturated fatty acids: a nutritional-toxicological aspect of fish consumption.

BACKGROUND: Co-exposure to environmental contaminants present in fish could mitigate the beneficial effects of fish consumption and possibly explain the lack of association observed for mortality in some geographical regions. OBJECTIVE: To assess the independent associations of dietary exposure to polychlorinated biphenyls (PCBs) and long-chain omega-3 fish fatty acids intake with cardiovascular and cancer mortality. METHODS: We used the prospective population-based Swedish Mammography Cohort and the Cohort of Swedish Men comprising 32 952 women and 36 545 men, free from cancer, cardiovascular disease and diabetes at baseline in 1998. Validated estimates of dietary PCBs and long-chain omega-3 fish fatty acids [i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] intake were obtained via a food frequency questionnaire at baseline. Information on death was ascertained through register linkage. RESULTS: During a mean follow-up of 15.5 years, we ascertained 16 776 deaths. We observed for cardiovascular mortality, comparing extreme quintiles in multivariable models mutually adjusted for PCBs and EPA-DHA, dose-dependent associations for dietary PCB exposure, hazard ratio (HR) 1.31 (CI 95%: 1.08 to 1.57; P-trend 0.005) and for dietary EPA-DHA intake, HR 0.79 (CI 95%: 0.66 to 0.95; P-trend 0.041). For cancer mortality, no clear associations were discerned. CONCLUSION: The beneficial effect of fish consumption on the cardiovascular system seems compromised by co-exposure to PCBs - one likely explanation for the inconsistent associations observed between fish consumption and mortality.

Rapeseed oil fortified with micronutrients improves cognitive alterations associated with metabolic syndrome.

Metabolic syndrome represents a major risk factor for severe comorbidities such as cardiovascular diseases or diabetes. It is also associated with an increased prevalence of emotional and cognitive alterations that in turn aggravate the disease and related outcomes. Identifying therapeutic strategies able to improve those alterations is therefore a major socioeconomical and public health challenge. We previously reported that both hippocampal inflammatory processes and neuronal plasticity contribute to the development of emotional and cognitive alterations in db/db mice, an experimental model of metabolic syndrome that displays most of the classical features of the syndrome. In that context, nutritional interventions with known impact on those neurobiological processes appear as a promising alternative to limit the development of neurobiological comorbidities of metabolic syndrome. We therefore tested here whether n-3 polyunsaturated fatty acids (n-3 PUFAs) associated with a cocktail of antioxidants can protect against the development of behavioral alterations that accompany the metabolic syndrome. Thus, this study aimed: 1) to evaluate if a diet supplemented with the plant-derived n-3 PUFA α-linolenic acid (ALA) and antioxidants (provided by n-3 PUFAs-rich rapeseed oil fortified with a mix of naturally constituting antioxidant micronutrients, including coenzyme Q10, tocopherol, and the phenolic compound canolol) improved behavioral alterations in db/db mice, and 2) to decipher the biological mechanisms underlying this behavioral effect. Although the supplemented diet did not improve anxiety-like behavior and inflammatory abnormalities, it reversed hippocampus-dependent spatial memory deficits displayed by db/db mice in a water maze task. It concomitantly changed subunit composition of glutamatergic AMPA and NMDA receptors in the hippocampus that has been shown to modulate synaptic function related to spatial memory. These data suggest that changes in local neuronal plasticity may underlie cognitive improvements in db/db mice fed the supplemented diet. The current findings might therefore provide valuable data for introducing new nutritional strategies for the treatment of behavioral complications associated with MetS.

Variation in Lipid Components from 15 Species of Tropical and Temperate Seaweeds.

The present study describes the variation in lipid components from 15 species of seaweeds belonging to the Chlorophyta, Ochrophyta, and Rhodophyta phyla collected in tropical (Indonesia) and temperate (Japan) areas. Analyses were performed of multiple components, including chlorophylls, carotenoids, n-3 and n-6 polyunsaturated fatty acids (PUFAs), and alpha tocopherol (α-Toc). Chlorophyll (Chl) and carotenoid contents varied among phyla, but not with the sampling location. Chl a and b were the major chlorophylls in Chlorophyta. Chl a and Chl c were the main chlorophylls in Ochrophyta, while Chl a was the dominant chlorophylls in Rhodophyta. ß-Carotene and fucoxanthin were detected as major seaweed carotenoids. The former was present in all species in a variety of ranges, while the latter was mainly found in Ochrophyta and in small quantities in Rhodophyta, but not in Chlorophyta. The total lipids (TL) content and fatty acids composition were strongly affected by sampling location. The TL and n-3 PUFAs levels tended to be higher in temperate seaweeds compared with those in tropical seaweeds. The major n-3 PUFAs in different phyla, namely, eicosapentaenoic acid (EPA) and stearidonic acid (SDA) in Ochrophyta, α-linolenic acid (ALA) and SDA in Chlorophyta, and EPA in Rhodophyta, accumulated in temperate seaweeds. Chlorophylls, their derivatives, and carotenoids are known to have health benefits, such as antioxidant activities, while n-3 PUFAs are known to be essential nutrients that positively influence human nutrition and health. Therefore, seaweed lipids could be used as a source of ingredients with health benefits for functional foods and nutraceuticals.

The protective role of endogenous n-3 polyunsaturated fatty acids in Tau Alzheimer's disease mouse model.

OBJECTIVES: The role of n-3 polyunsaturated fatty acid (PUFA) as the main docosahexaenoic acid (DHA) in Alzheimer's disease (AD) remains controversial. Our study aimed to provide detailed information about the role of endogenous n-3 PUFAs in AD. METHODS: Here, we generated a fat-1/tau transgenic mouse AD model by crossing female tau mice with male fat-1 mice to exclude confounding variables associated with the benefit of a DHA diet in these AD mice models. PUFAs presented in these AD models were detected by gas chromatography, and the role of endogenous n-3 PUFAs was assessed by lifespan survival assay, behavioral, pathologic, and molecular biology testing as well as imaging of cerebral vasculature. RESULTS: Endogenous n-3 PUFAs were shown to improve the memory and learning ability of AD mice. One possible reason for this improvement is the reduced formation of neurotrophic factors (NFTs) and Aß amyloid plaques which usually damage hippocampal neurons. Additionally, endogenous n-3 PUFAs were demonstrated to protect cerebral vascular of AD mice, thereby increasing brain metabolism. Besides, endogenous n-3 PUFAs were observed to extend of the overall survival of tau mouse models. CONCLUSION: Endogenous n-3 PUFAs delayed the onset of Alzheimer's disease caused by tau protein dysfunction, alleviating related symptoms and significantly prolonging survival in vivo.