Maresin1 improves hippocampal neuroinflammation and cognitive function in septic rats by activating the SLC7A11 / GPX4 ferroptosis signaling pathway.

Sepsis-associated encephalopathy (SAE) is a prevalent complication of sepsis, with hippocampal neuroinflammation playing a crucial role in SAE-induced cognitive impairment. Maresin1 (MaR1), a bioactive docosahexaenoic acid (DHA) metabolite, demonstrates comprehensive anti-inflammatory and neuroprotective attributes. Yet, its protective efficacy against SAE-induced cognitive decline remains unexplored. In this investigation, we implemented a rat SAE model via cecal ligation and puncture (CLP), while lipopolysaccharide (LPS) stimulation of HT22 cells simulated an in vitro SAE model; both models were pre-treated with MaR1. We evaluated rat learning and memory using a water maze, assessed hippocampal neuron damage via Nissl and FJC staining, and observed mitochondrial alterations through TEM. In vivo and in vitro assays gauged levels of Fe2+, MDA, GSH, and SOD. Additionally, Iba1 expression in the hippocampus was examined via immunofluorescence, while SLC7A11 and GPX4 protein expression levels were determined using western blot. Our findings indicated CLP-induced learning and memory impairment in rats, along with heightened ROS, Fe2+, and MDA levels in hippocampal neurons, diminished GSH and SOD levels, and down-regulated ferroptosis-related proteins (GPX4 and SLC7A11). Remarkably, MaR1 treatment attenuated these adverse effects. In LPS-stimulated HT22 cells, MaR1 lowered lipid ROS and bolstered mitochondrial membrane potential. Nonetheless, the ferroptosis inducer Erastin reversed MaR1's protective effects. Transwell experiments further showed MaR1's potential to inhibit microglia activation triggered by ferroptosis in HT22 cells. Consequently, MaR1 may mitigate hippocampal neuroinflammation via activating the SLC7A11/GPX4 ferroptosis signaling pathway, thus ameliorating SAE-related cognitive impairment.

The effect of omega-3 fatty acid supplementation on weight loss and cognitive function in overweight or obese individuals on weight-loss diet / El efecto de la suplementación con ácidos grasos omega-3 sobre la pérdida de peso y las funciones cognitivas en personas con sobrepeso u obesidad en dieta para adelgazar

Objective: omega-3 polyunsaturated fatty acids (PUFAs) are important nutrients that play role in obesity, body lipids, inflammation, and neural function. There is controversy in studies on the effect of omega-3 PUFA supplementation on weight loss and cognitive function. The aim of this study was to investigate the effect of omega-3 PUFA supplementation on weight loss and cognitive function in obese or overweight adults on a weight loss diet.Methods:40 adult volunteers aged 30-60 years, with body mass index (BMI) between 27.0 and 35.0 kg/m2, were randomly allocated into two groups. All subjects were involved in a weight loss diet program. The subjects in the omega-3 group (n = 20) also received daily supplementation with 1020 mg of omega-3 PUFAs (580 mg eicosapentaenoic acid (EPA), 390 mg docosahexaenoic acid (DHA), 50 mg other omega-3 PUFAs) for 12 weeks. Anthropometric measurements and body composition analysis were obtained at onset and at weeks 4, 8, and 12 of the study. The Montreal Cognitive Assessment (MoCA) test was used for evaluating cognitive functions at diet onset and at the end of week 12.Results:significant decreases were observed in weight, waist, and BMI in both groups. Abdominal fat mass and percentage decreased more in the omega-3 group than in the control group (p ≤ 0.05). MoCA scores increased in both groups within time, without statistical significance between groups.Conclusion:omega-3 PUFA supplementation augmented the reduction of abdominal fat mass and percentage in overweight or obese individuals on a weight loss diet. Further studies are required to identify the relationship and mechanisms of action of omega-3 PUFA supplementation on cognitive performance and weight loss. (AU)

Objetivo: los ácidos grasos poliinsaturados (AGPI) omega-3 son nutrientes importantes que intervienen en la obesidad, los lípidos corporales, la inflamación y las funciones neuronales. Existe controversia en los estudios sobre el efecto de la suplementación con AGPI omega-3 sobre la pérdida de peso y las funciones cognitivas. El objetivo de este estudio fue investigar el efecto de la suplementación con ácidos grasos poliinsaturados omega-3 sobre la pérdida de peso y la función cognitiva en adultos obesos o con sobrepeso que siguen una dieta para adelgazar.Métodos:40 voluntarios adultos de entre 30 y 60 años, con índice de masa corporal (IMC) entre 27,0 y 35,0 kg/m2, fueron distribuidos aleatoriamente en dos grupos. Todos los sujetos participaron en un programa de dieta para adelgazar. Los sujetos del grupo con omega-3 (n = 20) también recibieron suplementos diarios de 1020 mg de AGPI omega-3 (580 mg de ácido eicosapentaenoico (AEP), 390 mg de ácido docosahexaenoico (ADH), 50 mg de otros AGPI omega-3) durante 12 semanas. Las mediciones antropométricas y el análisis de la composición corporal se obtuvieron al inicio y a las 4, 8 y 12 semanas del estudio. La prueba de la “Evaluación Cognitiva de Montreal” (MoCA) se utilizó para evaluar las funciones cognitivas al inicio de la dieta y al final de la semana 12.Resultados:se observaron disminuciones significativas en el tiempo en el peso, la cintura y el IMC en ambos grupos. La masa y el porcentaje de grasa abdominal disminuyeron más en el grupo con omega-3 que en el de control (p ≤ 0,05). Las puntuaciones MoCA aumentaron en ambos grupos en el tiempo, sin significación estadística entre los grupos.Conclusión:la suplementación con ácidos grasos poliinsaturados omega-3 aumentó la reducción de la masa y el porcentaje de grasa abdominal en personas con sobrepeso u obesidad que siguieron una dieta para adelgazar. Se necesitan más estudios para identificar la ... (AU)

Dietary omega-3 LCPUFA intake in the prevention of neovascular age-related macular degeneration: a systematic review and meta-analysis / La ingesta de AGPICL omega-3 en la prevención de la degeneración macular neovascular relacionada con la edad: revisión sistemática y metaanálisis

Purpose: to evaluate the protective effect of omega-3 long-chain unsaturated fatty acids on the progression of wet age-related macular degeneration (wAMD). Methods: this meta-analysis was designed, implemented, and analyzed in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol and is reported following PRISMA guidelines. Results: in this study we included 5 observational trials, including 2 cross-sectional studies, 2 case-control studies, and 1 confrontation study. These tests are conducted in the U.S., Europe and Japan, and are of high quality. In general, people with high dietary long-chain omega-3 polyunsaturated fatty acids (omega-3 LCPUFAs) have a lower risk of progression to advanced age-related macular degeneration (AMD) (effect size, ES: 0.51, 95 % CI [0.34, 0.75], I2 = 70 %, p = 0.01). When assessing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake and wAMD risk a total of the three above studies were included, which also produced similar results. Conclusions: the highest DHA consumption reduced the risk of disease by 39 % (effect size: 0.61, 95 % CI [0.50, 0.74], I2 = 14 %, p = 0.31); compared with the lowest EPA consumption, the highest EPA consumption reduced the risk of wAMD by 32 % (ES: 0.68, 95 % CI [0.57, 0.82], I2 = 39 %, p = 0.20) (AU)

Propósito: evaluar el efecto protector de los AGPICL omega-3 sobre la degeneración macular húmeda asociada a la edad (DMAE). Métodos: este metaanálisis fue diseñado, implementado y analizado de acuerdo con el protocolo de Metaanálisis de Estudios Observacionales en Epidemiología (MOOSE) y se informa siguiendo las directrices de PRISMA. Resultados: en este estudio se incluyeron 5 ensayos observacionales, entre ellos 2 estudios transversales, 2 estudios de casos y controles y 1 estudio de confrontación. Estos ensayos se realizan en Estados Unidos, Europa y Japón y son de alta calidad. En general, las personas con una dieta alta en ácidos grasos poliinsaturados de cadena larga (AGPICL omega-3) tienen un menor riesgo de progresión hacia la degeneración macular avanzada relacionada con la edad (DMAE) (tamaño del efecto, ES: 0,51, IC 95 % [0,34, 0,75], I2 = 70 %, p = 0,01). Al evaluar la ingesta de ácido docosahexaenoico (DHA) y ácido eicosapentaenoico (EPA) y el riesgo de DMAE se incluyeron en total tres de los estudios anteriores, que también arrojaron resultados similares. Conclusiones: el mayor consumo de DHA redujo el riesgo de enfermedad en un 39 % (tamaño del efecto: 0,61, IC del 95 % [0,50, 0,74], I2 = 14 %, p = 0,31); en comparación con el menor consumo de EPA, el mayor consumo de EPA redujo el riesgo de wAMD en un 32 % (ES: 0,68, IC del 95 % [0,57, 0,82], I2 = 39 %, p = 0,20) (AU)

Identification of Resolvin D1 and Protectin D1 as Potential Therapeutic Agents for Treating Kidney Stones.

Intrarenal calcium oxalate (CaOx) crystals induce renal tubular epithelial cell (TEC) inflammatory and oxidative injury. This study is aimed at exploring potential therapeutic lipid components in kidney stones because lipids are involved in the development of several diseases and indicate the risk of kidney stones. Serum specimens were collected from 35 kidney stone patients and 35 normal controls. The lipid components in serum were measured, and differences were analyzed. The documented biological importance was comprehensively reviewed to identify lipids that differed significantly between the two groups to find potential agents associated with kidney stones. CaOx nephrocalcinosis mouse model was established to examine the therapeutic effects of specific lipids on CaOx deposition and CaOx-induced oxidative renal injury. Several lipids with significantly different levels were present in the serum of patients with stones and normal controls. Resolvin D1 (RvD1) (4.93-fold change, P < 0.001) and protectin D1 (PD1) (5.06-fold change, P < 0.001) were significantly decreased in the serum of patients with kidney stones, and an integrative review suggested that these factors might be associated with inflammatory responses, which is a crucial mechanism associated with stone damage. The administration of RvD1 and PD1 significantly inhibited kidney CaOx deposition and suppressed CaOx-induced renal tubular cell inflammatory injury and necrosis in a CaOx nephrocalcinosis mouse model. Furthermore, RvD1 and PD1 facilitated the expression of the oxidative indicator superoxide dismutase 2 (SOD2), inhibited NADPH oxidase 2 (NOX2) expression, and diminished intracellular reactive oxygen species (ROS) levels. This study preliminarily elucidated the role of lipids in kidney stones. The inhibitory effects of RvD1 and PD1 on oxidative damage induced by CaOx deposition provide a promising perspective for kidney stone treatment strategies.

Effects of fatty acid metabolites on nocturia.

Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; however, the reason remains unknown. Here, we investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. WT and Clock mutant (ClockΔ19/Δ19) mice, a model for nocturia with circadian rhythm disorder, were used. Levels of serum PEA, 9-HODE, and 4-HDoHEl were measured every 8 h using LC/MS. Voiding pattern was recorded using metabolic cages after administration of PEA, 9-HODE, and 4-HDoHE to WT mice. Levels of serum PEA and 9-HODE fluctuated with circadian rhythm in WT mice, which were lower during the light phase. In contrast, circadian PEA and 9-HODE level deteriorated or retreated in ClockΔ19/Δ19 mice. Levels of serum PEA, 9-HODE, and 4-HDoHE were higher in ClockΔ19/Δ19 than in WT mice. Voiding frequency increased in PEA- and 4-HDoHE-administered mice. Bladder capacity decreased in PEA-administered mice. The changes of these bladder functions in mice were similar to those in elderly humans with nocturia. These findings highlighted the novel effect of lipids on the pathology of nocturia. These may be used for development of biomarkers and better therapies for nocturia.

Oxidative damage in Nile tilapia, Oreochromis niloticus, is mainly induced by water temperature variation rather than Aurantiochytrium sp. meal dietary supplementation.

We investigated whether dietary supplementation with Aurantiochytrium sp. meal, a DHA-rich source (docosahexaenoic acid, 22: 6 n-3), fed during long-term exposure to cold-suboptimal temperature (22 °C, P1), followed by short-term exposure to higher temperatures (28 °C, P2, and 33 °C, P3), would promote oxidative damage in Nile tilapia (Oreochromis niloticus). Two supplementation levels were tested: 1.0 g 100 g-1 (D1) and 4.0 g 100 g-1 (D4). A control diet, without the additive (D0, 0 g 100 g-1), and a positive control diet supplemented with cod liver oil (CLO) were also tested. The concentrations of DHA and total n-3 PUFAs in the CLO diet were similar to those found in diets D1 and D4, respectively. The parameters analyzed included hemoglobin (Hb), the antioxidant enzymes catalase, glutathione peroxidase, total glutathione, non-protein thiols, and the oxidative markers protein carbonyl and erythrocyte DNA damage. Nile tilapia did not present differences in Hb content, regardless of diet composition, but the temperature increase (P1 to P2) led to a higher Hb content. Likewise, the temperature increases promoted alterations in all antioxidant enzymes. The dietary supplementation with 1.0 g 100 g-1 Aurantiochytrium sp. meal after P1 caused minor DNA damage in Nile tilapia, demonstrating that the additive can safely be included in winter diets, despite its high DHA concentration.

Omega-3 fatty acid, carotenoid and vitamin E supplementation improves working memory in older adults: A randomised clinical trial.

BACKGROUND & AIMS: Accumulating evidence suggests that omega-3 fatty acids (ω-3FAs), carotenoids and vitamin E can improve cognitive performance. However, their collective impact on cognition has not yet been investigated in healthy individuals. This study investigated the combined effect of ω-3FA, carotenoid and vitamin E supplementation on the cognitive performance of older adults. METHODS: Cognitively healthy individuals aged ≥65 years consumed daily 1 g fish oil (of which 430 mg docosahexaenoic acid, 90 mg eicosapentaenoic acid), 22 mg carotenoids (10 mg lutein, 10 mg meso-zeaxanthin, 2 mg zeaxanthin) and 15 mg vitamin E or placebo for 24 months in a double-blind, placebo-controlled, randomised clinical trial. RESULTS: Following 24-month supplementation, individuals in the active group (n = 30; aged 69.03 ± 4.41 years; 56.7% female) recorded significantly fewer errors in working memory tasks than individuals receiving placebo (n = 30; aged 69.77 ± 3.74 years; 70% female) (point estimate effect sizes ranged 0.090-0.105). Interestingly, as the cognitive load of the working memory tasks increased, the active group outperformed the placebo group. Statistically significant improvements in tissue carotenoid concentrations, serum xanthophyll carotenoid concentrations and plasma ω-3FA concentrations were also observed in the active group versus placebo (point estimate effect sizes ranged 0.078-0.589). Moreover, the magnitude of change of carotenoid concentrations in tissue, and ω-3FA and carotenoid concentrations in blood were related to the magnitude of change in working memory performance. CONCLUSION: These results support a biologically plausible rationale whereby these nutrients work synergistically, and in a dose-dependent manner, to improve working memory in cognitively healthy older adults. Increasing nutritional intake of carotenoids and ω-3FAs may prove beneficial in reducing cognitive decline and dementia risk in later life. STUDY ID NUMBER: ISRCTN10431469; https://doi.org/10.1186/ISRCTN10431469.

Preserving Brain LPC-DHA by Plasma Supplementation Attenuates Brain Injury after Cardiac Arrest.

OBJECTIVE: Cardiac arrest (CA) is a major health burden with brain damage being a significant contributor to mortality. We found lysophosphatidylcholine (LPC), including a species containing docosahexaenoic acid (LPC-DHA), was significantly decreased in plasma post-CA, supplementation of which significantly improved neurological outcomes. The aim of this study is to understand the protective role of LPC-DHA supplementation on the brain post-CA. METHODS: We first evaluated associations between the plasma level of LPC-DHA and neurological injury and outcomes of human patients with CA. We then utilized a rat CA model and cell cultures to investigate therapeutic and mechanistic aspects of plasma LPC-DHA supplementation. RESULTS: We found that decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of the difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased levels of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocytes, and expression of various inflammatory and mitochondrial dynamics genes. We also observed deceased severity of metabolic alterations with LPC-DHA supplementation using untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures. INTERPRETATION: The observed neuroprotection accompanied with normalized brain LPC-DHA level by plasma supplementation implicate the importance of preventing the decrease of brain LPC-DHA post-CA for attenuating brain injury. Furthermore, the data supports the causative role of decreased plasma LPC-DHA for brain damage after CA. ANN NEUROL 2022;91:389-403.

The effects of fish oil plus vitamin D3 intervention on non-alcoholic fatty liver disease: a randomized controlled trial.

PURPOSE: The present study aimed to investigate fish oil plus vitamin D3 (FO + D) supplementation on biomarkers of non-alcoholic fatty liver disease (NAFLD). METHODS: In a 3-month randomized controlled trial, 111 subjects with NAFLD, aged 56.0 ± 15.9 y, were randomized into FO + D group (n = 37), fish oil group (FO, n = 37) or corn oil group (CO, n = 37). The subjects consumed the following capsules (3 g/day), which provided 2.34 g/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) + 1680 IU vitamin D3 (FO + D group), or 2.34 g/day of EPA + DHA (FO group), or 1.70 g/d linoleic acid (CO group). RESULTS: Using multivariable-adjusted general linear model, there were significant net reductions in serum alanine aminotransferase (ALT), and triacylglycerol (TAG) and TNF-α levels in the FO + D and FO groups, compared with the control group (P < 0.05). The supplemental FO + D also showed significant reductions in insulin (- 1.58 ± 2.00 mU/L vs. - 0.63 ± 1.55 mU/L, P = 0.050) and IL-1ß (- 6.92 ± 7.29 ng/L vs. 1.06 ± 5.83 ng/L, P < 0.001) in comparison with control group. Although there were no significant differences between FO + D and FO groups regarding biochemical parameters, supplemental FO + D showed decreases in ALT (from 26.2 ± 13.5 U/L to 21.4 ± 9.6 U/L, P = 0.007), aspartate aminotransferase (AST, from 22.5 ± 7.0 U/L to 20.2 ± 4.0 U/L, P = 0.029), HOMA-IR (from 3.69 ± 1.22 to 3.38 ± 1.10, P = 0.047), and TNF-α (from 0.43 ± 0.38 ng/L to 0.25 ± 0.42 ng/L, P < 0.001) levels following the intervention. CONCLUSION: The present study demonstrated that groups supplemented with FO + D and FO had similar beneficial effects on biomarkers of hepatocellular damage and plasma TAG levels in subjects with NAFLD, while in the FO + D group, there were some suggestive additional benefits compared with FO group on insulin levels and inflammation. TRIAL REGISTRATION: ChiCTR1900024866.

Fatty acid compositions of immature and mature testis are differently responsive to dietary docosahexasenoic acid during development in rats exposed to prenatal ethanol.

BACKGROUND: Ethanol (EtOH) exposure impairs, but docosahexaenoic acid (DHA) supports testis functions. This study investigated whether dietary DHA and prenatal EtOH exposure affected fatty acid profiles equally in immature and mature testis during developmental stages. METHODS: Female rats were exposed to ± EtOH (3g/kg BW, twice a day via gavage) throughout pregnancy, while consuming a diet supplemented ± DHA (1.4%, w/w). Pups were continued on their mother's diet after weaning with testes collected for fatty acid analysis at different stages of reproductive development, at gestational day 20 (GD20) and postnatal day (PD) 4, 21, 49, and 90, to present fetal, neonatal, weaning, prepubertal and adult stages, respectively. RESULTS: Regardless of EtOH exposure, dietary DHA significantly increased in testis DHA at all ages, with testis at weaning and prepuberty being more responsive to the diet (p<0.0002). Immature testis at GD20 and PD4 contained more DHA than n-6 docosapentaenoic acid (n-6 DPA) compared to mature testis while being well responsive to the maternal DHA diet through gestation and lactation. The level of n-6 very long chain fatty acids and (VLCFA) and n-6 DPA, distinctively increased from weaning and prepuberty, respectively, and were not reduced by the DHA diet at prepuberty and adulthood. Prenatal EtOH minimally affected testis fatty acids during development. CONCLUSION: Immature and mature testis responds differently to dietary DHA. The age around sexual maturity might be a critical time for dietary intervention as testis was more responsive to diet at this time point. The increase in DPA and n-6 VLCFA in matured testis while not affected by dietary DHA, indicates their critical roles in male reproductive function in rodents.

Visualization of dietary docosahexaenoic acid in whole-body zebrafish using matrix-assisted laser desorption/ionization mass spectrometry imaging.

Zebrafish models have been developed for several studies involving lipid metabolism and lipid-related diseases. In the present study, the migration of dietary docosahexaenoic acid (DHA) in whole-body zebrafish was estimated by stable-isotope tracer and matrix-assisted laser desorption/ionization mass spectrometry imaging. Administration of 1-13C-2,2-D2-labeled DHA ((+3)DHA) ethyl ester to male zebrafish was conducted to evaluate its accumulation, migration, and distribution in the body. The (+3)DHA content in the body of zebrafish after administering (+3)DHA for 10 and 15 d was significantly higher than that in the control group. (+3)DHA was observed as a constituent of phosphatidylcholine (PC) in the intestine of zebrafish that were administered (+3)DHA for 5 and 10 d. (+3)DHA-containing PC tended to accumulate in the intestines of zebrafish administered (+3)DHA for 1 d, indicating that recombination of (+3)DHA from ethyl ester to PC occurs quickly at intestine. After administration for 15 d, (+3)DHA-containing PC accumulated in the intestine, liver, and muscle of whole-body zebrafish. In contrast, (+3)DHA-containing PC was not detected in the brain. These results showed that dietary DHA is initially constructed into PC as a structural component of intestinal cell membranes and gradually migrates into peripheral tissues such as muscle.

Prenatal docosahexaenoic acid supplementation has long-term effects on childhood behavioral and brain responses during performance on an inhibitory task.

Introduction: Offsprings from a prenatal docosahexaenoic acid (DHA) supplementation trial, in which pregnant women were assigned to placebo or 600mg DHA/day, were followed to determine the effect of prenatal DHA supplementation on the behavior and brain function at 5.5 years (n=81 placebo, n=86 supplemented).Methods: Event-related potentials (ERP) were recorded during a visual task requiring a button press (Go) to frequent target stimuli and response inhibition to the rare stimuli (No-Go). Univariate ANOVAs were used to test differences between group and sex for behavioral measures. ERP differences were tested using a three-way mixed-design multivariate analysis of variance (MANOVA).Results: There was a significant sex × group interaction for hit rate and errors of omission; there was no difference between males and females in the placebo group, but DHA males outperformed DHA females. Males overall and the placebo group made more errors requiring response inhibition; DHA females were significantly better than placebo females and DHA males. ERP P2 amplitude was larger in the DHA group. A significant N2 amplitude condition effect was observed in females and DHA group males, but not in placebo group males.Discussion: Prenatal DHA supplementation improved inhibitory performance overall, especially for females in the DHA group, possibly accounting for their conservative behavior during Go trials. Development of brain regions responsible for visual processing may be sensitive to maternal DHA status, evidenced by greater P2 amplitude. Males may benefit more from maternal DHA supplementation, indicated by the N2 condition effect seen only in males in the DHA group.

Omacor Protects Normotensive and Hypertensive Rats Exposed to Continuous Light from Increased Risk to Malignant Cardiac Arrhythmias.

Light pollution disturbs circadian rhythm, and this can also be deleterious to the heart by increased susceptibility to arrhythmias. Herein, we investigated if rats exposed to continuous light had altered myocardial gene transcripts and/or protein expression which affects arrhythmogenesis. We then assessed if Omacor® supplementation benefitted affected rats. Male and female spontaneously hypertensive (SHR) and normotensive Wistar rats (WR) were housed under standard 12 h/12 h light/dark cycles or exposed to 6-weeks continuous 300 lux light for 24 h. Half the rats were then treated with 200 mg/100 g b.w. Omacor®. Continuous light resulted in higher male rat vulnerability to malignant ventricular fibrillation (VF). This was linked with myocardial connexin-43 (Cx43) down-regulation and deteriorated intercellular electrical coupling, due in part to increased pro-inflammatory NF-κB and iNOS transcripts and decreased sarcoplasmic reticulum Ca2+ATPase transcripts. Omacor® treatment increased the electrical threshold to induce the VF linked with amelioration of myocardial Cx43 mRNA and Cx43 protein levels and the suppression of NF-κB and iNOS. This indicates that rat exposure to continuous light results in deleterious cardiac alterations jeopardizing intercellular Cx43 channel-mediated electrical communication, thereby increasing the risk of malignant arrhythmias. The adverse effects were attenuated by treatment with Omacor®, thus supporting its potential benefit and the relevance of monitoring omega-3 index in human populations at risk.

DHA Supplementation of Obese Rats throughout Pregnancy and Lactation Modifies Milk Composition and Anxiety Behavior of Offspring.

We investigated if supplementing obese mothers (MO) with docosahexaenoic acid (DHA) improves milk long-chain polyunsaturated fatty acid (LCPUFA) composition and offspring anxiety behavior. From weaning throughout pregnancy and lactation, female Wistar rats ate chow (C) or a high-fat diet (MO). One month before mating and through lactation, half the mothers received 400 mg DHA kg-1 d-1 orally (C+DHA or MO+DHA). Offspring ate C after weaning. Maternal weight, total body fat, milk hormones, and milk nutrient composition were determined. Pups' milk nutrient intake was evaluated, and behavioral anxiety tests were conducted. MO exhibited increased weight and total fat, and higher milk corticosterone, leptin, linoleic, and arachidonic acid (AA) concentrations, and less DHA content. MO male and female offspring had higher ω-6/ ω-3 milk consumption ratios. In the elevated plus maze, female but not male MO offspring exhibited more anxiety. MO+DHA mothers exhibited lower weight, total fat, milk leptin, and AA concentrations, and enhanced milk DHA. MO+DHA offspring had a lower ω-6/ω-3 milk intake ratio and reduced anxiety vs. MO. DHA content was greater in C+DHA milk vs. C. Supplementing MO mothers with DHA improves milk composition, especially LCPUFA content and ω-6/ω-3 ratio reducing offspring anxiety in a sex-dependent manner.

Higher-Dose DHA Supplementation Modulates Immune Responses in Pregnancy and Is Associated with Decreased Preterm Birth.

Pregnancy and parturition involve extensive changes in the maternal immune system. In our randomized, multi-site, double-blind superiority trial using a Bayesian adaptive design, we demonstrated that 1000 mg/day of docosahexaenoic acid (DHA) was superior to 200 mg/day in preventing both early preterm birth (less than 34 weeks' gestation) and preterm birth (less than 37 weeks' gestation). The goal of this secondary study is to compare the effects of 1000 mg/day versus 200 mg/day on maternal inflammation, a possible mechanism by which DHA may prevent preterm birth. Maternal blood samples were collected at enrollment (12-20 weeks' gestation) and at delivery. Red blood cell DHA levels were measured by gas chromatography, and plasma concentrations of sRAGE, IL-6, IL-1ß, TNFα, and INFγ were measured by ELISA. Data were analyzed for associations with the DHA dose, gestational age at birth, and preterm birth (<37 weeks). Higher baseline and lower delivery levels of maternal sRAGE were associated with a greater probability of longer gestation and delivery at term gestation. Higher-dose DHA supplementation increased the probability of a smaller decrease in delivery sRAGE levels. Higher IL-6 concentrations at delivery were associated with the probability of delivering after 37 weeks, and higher-dose DHA supplementation increased the probability of greater increases in IL-6 concentrations between enrollment and delivery. These data provide a proposed mechanistic explanation of how a higher dose of DHA during pregnancy provides immunomodulatory regulation in the initiation of parturition by influencing sRAGE and IL-6 levels, which may explain its ability to reduce the risk of preterm birth.

Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation.

Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is derivative of ω-3 docosahexaenoic acid (DHA), which has been shown to have pro-resolutive and anti-inflammatory effects. We tested the hypothesis that the application of MaR1 could prevent the development of fibrosis in an animal model of chronic hepatic damage. Sprague-Dawley rats were induced with liver fibrosis by injections of diethylnitrosamine (DEN) and treated with or without MaR1 for four weeks. In the MaR1-treated animals, levels of AST and ALT were normalized in comparison with DEN alone, the hepatic architecture was improved, and inflammation and necrotic areas were reduced. Cell proliferation, assessed by the mitotic activity index and the expression of Ki-67, was increased in the MaR1-treated group. MaR1 attenuated liver fibrosis and oxidative stress was induced by DEN. Plasma levels of the pro-inflammatory mediators TNF-α and IL-1ß were reduced in MaR1-treated animals, whereas the levels of IL-10, an anti-inflammatory cytokine, increased. Interestingly, MaR1 inhibited the translocation of the p65 subunit of NF-κB, while increasing the activation of Nrf2, a key regulator of the antioxidant response. Finally, MaR1 treatment reduced the levels of the pro-fibrotic mediator TGF-ß and its receptor, while normalizing the hepatic levels of IGF-1, a proliferative agent. Taken together, these results suggest that MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and decreasing oxidative stress and inflammation. These results open the possibility of MaR1 as a potential therapeutic agent in fibrosis and other liver pathologies.

New Insights into Depressive Disorder with Respect to Low-Grade Inflammation and Fish Oil Intake.

Unipolar depression has been recognized as one of the major diseases by the World Health Organization in the 21st century. The etiology of depression is complicated and includes genetic factors, stress, aging, and special physical status (pregnancy, metabolic syndrome, and trauma). Numerous animal and human studies have demonstrated that n-3 polyunsaturated fatty acids (n-3 PUFAs) are highly correlated to cognition and depression. These nutritional antidepressants, including EPA and DHA, have a range of neurobiological activities contributing to their potential antidepressant effects. Our preclinical and clinical studies have indicated that n-3 PUFA supplementation in addition to standard antidepressant medications may provide synergistic neuroprotective and antioxidant/inflammatory effects. To translate our preliminary findings into clinical application, this paper reviews the existing evidence on the antidepressant effects of n-3 PUFAs and the potential underlying mechanisms, which include modulation of chronic lowgrade inflammation and the corresponding changes in peripheral blood immune biomarkers.

Intake of Docosahexaenoic Acid-Enriched Milk Beverage Prevents Age-Related Cognitive Decline and Decreases Serum Bone Resorption Marker Levels.

The pathogenic mechanism of dementia is still unknown, and the fundamental treatment remains to be established. Thus, there is growing interest in preventing dementia through diet. One of the functional ingredients attracting attention is docosahexaenoic acid. We conducted a 12-month, randomized, double-blind, placebo-controlled clinical trial in healthy elderly Japanese individuals with a Mini-Mental State Examination score of 28 or higher at baseline using a docosahexaenoic acid-enriched milk beverage containing 297 mg docosahexaenoic acid and 137 mg eicosapentaenoic acid. Consumption of a docosahexaenoic acid-enriched milk beverage increased the fatty acid levels of docosahexaenoic acid and eicosapentaenoic acid in erythrocyte membranes, which was the primary outcome of this study. Moreover, intake of this beverage prevented age-related cognitive decline and decreased serum bone resorption marker levels. Our data demonstrate that, even at a low dose, long-term daily intake of docosahexaenoic acid prevents dementia and may show beneficial effect on bone health.

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease.

BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. In 30% of cases, after years of infection and in the absence of treatment, the disease progresses from an acute asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapeutic agent to regulate the pro-inflammatory state during the early chronic phase of Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 µg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 µg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the early chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue. CONCLUSIONS/SIGNIFICANCE: AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during early chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

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.