Vegetable omega-3 and omega-6 fatty acids differentially modulate the antiviral and antibacterial immune responses of Atlantic salmon.

The immunomodulatory effects of omega-3 and omega-6 fatty acids are a crucial subject of investigation for sustainable fish aquaculture, as fish oil is increasingly replaced by terrestrial vegetable oils in aquafeeds. Unlike previous research focusing on fish oil replacement with vegetable alternatives, our study explored how the omega-6 to omega-3 polyunsaturated fatty acid (PUFA) ratio in low-fish oil aquafeeds influences Atlantic salmon's antiviral and antibacterial immune responses. Atlantic salmon were fed aquafeeds rich in soy oil (high in omega-6) or linseed oil (high in omega-3) for 12 weeks and then challenged with bacterial (formalin-killed Aeromonas salmonicida) or viral-like (polyriboinosinic polyribocytidylic acid) antigens. The head kidneys of salmon fed high dietary omega-3 levels exhibited a more anti-inflammatory fatty acid profile and a restrained induction of pro-inflammatory and neutrophil-related genes during the immune challenges. The high-omega-3 diet also promoted a higher expression of genes associated with the interferon-mediated signaling pathway, potentially enhancing antiviral immunity. This research highlights the capacity of vegetable oils with different omega-6 to omega-3 PUFA ratios to modulate specific components of fish immune responses, offering insights for future research on the intricate lipid nutrition-immunity interplay and the development of novel sustainable low-fish oil clinical aquaculture feeds.

Differential Effects of n-3 and n-6 Polyunsaturated Fatty Acids on Placental and Embryonic Growth and Development in Diabetic Pregnant Mice.

The present study aimed to investigate the differential effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) on placental and embryonic development. Pregnant mice were assigned to five groups: healthy control (HC), diabetes mellitus control (DMC), diabetes + low-dose n-3 PUFA (Ln-3), diabetes + high-dose n-3 PUFA (Hn-3), and diabetes + n-6 PUFA (n-6). On E12.5d, the Hn-3 group, but not the n-6 group, had a higher placenta weight. The weight ratio of embryo to placenta in the n-6 group was significantly lower than in the Hn-3 group but higher than in the DMC group. The Hn-3 group had significantly higher protein levels of VEGF, IGF-1, and IGFBP3, while the n-6 group had lower VEGF than the DMC group. Compared with the DMC group, embryonic Cer-16:0 was significantly higher in the Hn-3 group, while embryonic PC (36:6), PC (38:7), and PE (40:7) were significantly lower in the n-6 group. The embryo and placenta weights were positively correlated with placental VEGF, IGFBP3, and embryonic Cer-16:0, and they were negatively correlated with embryonic PC (36:6) and PE (40:7). The weight ratio of embryo to placenta was negatively correlated with embryonic PC (36:6). In addition, embryonic Cer-16:0 was positively correlated with placental VEGF and IGFBP3. In conclusion, n-3 PUFA and n-6 PUFA improved placental and embryonic growth through different mechanisms.

Differential Interventional Effects of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on High Fat Diet-Induced Obesity and Hepatic Pathology.

Current Dietary Guidelines for Americans recommend replacing saturated fat (SFA) intake with polyunsaturated fatty acids (PUFAs) and monosaturated fatty acids (MUFAs) but do not specify the type of PUFAs, which consist of two functionally distinct classes: omega-6 (n-6) and omega-3 (n-3) PUFAs. Given that modern Western diets are already rich in n-6 PUFAs and the risk of chronic disease remains high today, we hypothesized that increased intake of n-3 PUFAs, rather than n-6 PUFAs, would be a beneficial intervention against obesity and related liver diseases caused by high-fat diets. To test this hypothesis, we fed C57BL/6J mice with a high-fat diet (HF) for 10 weeks to induce obesity, then divided the obese mice into three groups and continued feeding for another 10 weeks with one of the following three diets: HF, HF+n-6 (substituted half of SFA with n-6 PUFAs), and HF+n-3 (substituted half of SFA with n-3 PUFAs), followed by assessment of body weight, fat mass, insulin sensitivity, hepatic pathology, and lipogenesis. Interestingly, we found that the HF+n-6 group, like the HF group, had a continuous increase in body weight and fat mass, while the HF+n-3 group had a significant decrease in body weight and fat mass, although all groups had the same calorie intake. Accordingly, insulin resistance and fatty liver pathology (steatosis and fat levels) were evident in the HF+n-6 and HF groups but barely seen in the HF+n-3 group. Furthermore, the expression of lipogenesis-related genes in the liver was upregulated in the HF+n-6 group but downregulated in the HF+n-3 group. Our findings demonstrate that n-6 PUFAs and n-3 PUFAs have differential effects on obesity and fatty liver disease and highlight the importance of increasing n-3 PUFAs and reducing n-6 PUFAs (balancing the n-6/n-3 ratio) in clinical interventions and dietary guidelines for the management of obesity and related diseases.

Crystalline silica-induced proinflammatory eicosanoid storm in novel alveolar macrophage model quelled by docosahexaenoic acid supplementation.

Introduction: Phagocytosis of inhaled crystalline silica (cSiO2) particles by tissue-resident alveolar macrophages (AMs) initiates generation of proinflammatory eicosanoids derived from the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (ARA) that contribute to chronic inflammatory disease in the lung. While supplementation with the ω-3 PUFA docosahexaenoic acid (DHA) may influence injurious cSiO2-triggered oxylipin responses, in vitro investigation of this hypothesis in physiologically relevant AMs is challenging due to their short-lived nature and low recovery numbers from mouse lungs. To overcome these challenges, we employed fetal liver-derived alveolar-like macrophages (FLAMs), a self-renewing surrogate that is phenotypically representative of primary lung AMs, to discern how DHA influences cSiO2-induced eicosanoids. Methods: We first compared how delivery of 25 µM DHA as ethanolic suspensions or as bovine serum albumin (BSA) complexes to C57BL/6 FLAMs impacts phospholipid fatty acid content. We subsequently treated FLAMs with 25 µM ethanolic DHA or ethanol vehicle (VEH) for 24 h, with or without LPS priming for 2 h, and with or without cSiO2 for 1.5 or 4 h and then measured oxylipin production by LC-MS lipidomics targeting for 156 oxylipins. Results were further related to concurrent proinflammatory cytokine production and cell death induction. Results: DHA delivery as ethanolic suspensions or BSA complexes were similarly effective at increasing ω-3 PUFA content of phospholipids while decreasing the ω-6 PUFA arachidonic acid (ARA) and the ω-9 monounsaturated fatty acid oleic acid. cSiO2 time-dependently elicited myriad ARA-derived eicosanoids consisting of prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acids in unprimed and LPS-primed FLAMs. This cSiO2-induced eicosanoid storm was dramatically suppressed in DHA-supplemented FLAMs which instead produced potentially pro-resolving DHA-derived docosanoids. cSiO2 elicited marked IL-1α, IL-1ß, and TNF-α release after 1.5 and 4 h of cSiO2 exposure in LPS-primed FLAMs which was significantly inhibited by DHA. DHA did not affect cSiO2-triggered death induction in unprimed FLAMs but modestly enhanced it in LPS-primed FLAMs. Discussion: FLAMs are amenable to lipidome modulation by DHA which suppresses cSiO2-triggered production of ARA-derived eicosanoids and proinflammatory cytokines. FLAMs are a potential in vitro alternative to primary AMs for investigating interventions against early toxicant-triggered inflammation in the lung.

Adverse effects of gestational ω-3 and ω-6 polyunsaturated fatty acid imbalance on the programming of fetal brain development.

Obesity is a key medical challenge of our time. The increasing number of children born to overweight or obese women is alarming. During pregnancy, the circulation of the mother and her fetus interact to maintain the uninterrupted availability of essential nutrients for fetal organ development. In doing so, the mother's dietary preference determines the amount and composition of nutrients reaching the fetus. In particular, the availability of polyunsaturated fatty acids (PUFAs), chiefly their ω-3 and ω-6 subclasses, can change when pregnant women choose a specific diet. Here, we provide a succinct overview of PUFA biochemistry, including exchange routes between ω-3 and ω-6 PUFAs, the phenotypes, and probable neurodevelopmental disease associations of offspring born to mothers consuming specific PUFAs, and their mechanistic study in experimental models to typify signaling pathways, transcriptional, and epigenetic mechanisms by which PUFAs can imprint long-lasting modifications to brain structure and function. We emphasize that the ratio, rather than the amount of individual ω-3 or ω-6 PUFAs, might underpin physiologically correct cellular differentiation programs, be these for neurons or glia, during pregnancy. Thereupon, the PUFA-driven programming of the brain is contextualized for childhood obesity, metabolic, and endocrine illnesses.

Study of anti-tumorigenic actions of essential fatty acids in a murine mammary gland adenocarcinoma by micro-XRF.

In the present work, a statistical experiment based on the microscopy X-ray fluorescence technique was developed to evaluate the effect of diets rich in ω-3 and ω-6 polyunsaturated fatty acids on tumour tissues. Relative variations on the local content of P, S, Ca, Fe, Cu and Zn were analysed in the experiment. Neoplastic tissues were obtained from mammary gland adenocarcinomas inoculated in mice belonging to three different dietary groups: normal, rich in ω-3 and in ω-6 polyunsaturated fatty acids. Slices of 30 microns thick sections of these samples were scanned in the air atmosphere in areas of 5 mm × 5 mm with a spatial resolution of 50 microns using synchrotron radiation. Principal component analysis was employed to analyse the correlation between the X-ray fluorescence signals of P, S, Ca, Fe, Cu and Zn. The subsequent application of the K-means clustering was used for the automatic segmentation of the image scans. By comparison with conventional histological analysis, the clusters were positively identified as tumour parenchyma, transition and necrotic region. The calculation of the mean content of P, S, Ca, Fe, Cu, and Zn in these regions showed that dietary polyunsaturated fatty acids modify elemental content of tumour parenchyma, suggesting its involvement in the antitumour effects of chia oil and protumour effects of safflower oil.

Exploring the role of polyunsaturated fatty acid ratios in modulating neuroinflammation in LPS-induced microglia: A comprehensive in vitro analysis.

The study investigated the effect of different omega (ω)- 3 and omega (ω)- 6 polyunsaturated fatty acid (PUFA) ratios on cytokine secretion, cell viability, and microglial cell shape in lipopolysaccharide (LPS)-induced microglia. The addition of PUFAs at different ratios, especially ω-3 and ratios of 7/1 and 2/1 ω-6/ω-3, resulted in a significant increase in the ameboid form of microglial cells, as well as more branching of their distal branches. Microglial cells were treated with varying ratios of PUFAs, and their cytokine secretion was measured. The results showed that all PUFA ratios had lower tumor necrosis factor (TNF)-α secretion than the control group, higher interleukin (IL)- 4 secretion in the ω-6 group, and less IL-10 secretion most down IL-6 secretion in the 7/1 ratio group. The study suggests that determining the appropriate ω-6/ω-3 consumption ratio, especially the 7/1 and 2/1 ratios, may help manage neuroinflammation, develop dietary models in immune-mediated neurodegenerative diseases, and open up new treatment possibilities.

Dietary n-3 and n-6 polyunsaturated fatty acids differentially modulate the adiponectin and leptinmediated major signaling pathways in visceral and subcutaneous white adipose tissue in high fat diet induced obesity in Wistar rats.

Obesity is a chronic metabolic disease that involves excessive accumulation of fat in white adipose tissue (WAT). Apart from storing excess fats, WAT also serves as an important endocrine organ secreting adipocytokines such as adiponectin and leptin. Adiponectin and leptin bind to their transmembrane receptors adiponectin receptor 1 (AdipoR1)/adiponectin receptor 2 (AdipoR2) and Ob-R, respectively, and mediate their effect on metabolism by regulating multiple downstream targets. Dietary fat is considered the main culprit behind obesity development. Numerous preclinical studies have highlighted role of essential polyunsaturated fatty acids (PUFAs), particularly n-3 PUFAs, in prevention of obesity. Despite emerging data, there still is no clear understanding of the mechanism of action of n-3 PUFAs and n-6 PUFAs on adipose tissue function in two functionally and anatomically different depots of WAT: visceral and subcutaneous. We designed this study using a high fat diet (HFD) fed rodent model of obesity to test our hypothesis that n-3 and n-6 PUFAs possibly differentially modulate adipokine secretion and downstream metabolic pathways such as peroxisome proliferator-activated receptor-γ (PPAR-γ), protein kinase B (AKT)-forkhead box O1 (FOXO1), and Janus kinase-signal transducer and activator of transcription in obesity. The results of the current study showed that n-3 PUFAs upregulate the expression of AdipoR1/R2 and ameliorate the effects of HFD by modulating adipogenesis via PPAR-γ and by improving glucose tolerance and lipid metabolism via AKT-FOXO1 axis in fish oil fed rats. However, n-6 PUFAs did not show any remarkable change compared with HFD fed animals. Our study highlights that n-3 PUFAs modulate expression of various targets in adiponectin and leptin signaling cascade, bringing about an overall reduction in obesity and improvement in adipose tissue function in HFD induced obesity.

Essential lipid autacoids rewire mitochondrial energy efficiency in metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIM: Injury to hepatocyte mitochondria is common in metabolic dysfunction-associated fatty liver disease. Here, we investigated whether changes in the content of essential fatty acid-derived lipid autacoids affect hepatocyte mitochondrial bioenergetics and metabolic efficiency. APPROACH AND RESULTS: The study was performed in transgenic mice for the fat-1 gene, which allows the endogenous replacement of the membrane omega-6-polyunsaturated fatty acid (PUFA) composition by omega-3-PUFA. Transmission electron microscopy revealed that hepatocyte mitochondria of fat-1 mice had more abundant intact cristae and higher mitochondrial aspect ratio. Fat-1 mice had increased expression of oxidative phosphorylation complexes I and II and translocases of both inner (translocase of inner mitochondrial membrane 44) and outer (translocase of the outer membrane 20) mitochondrial membranes. Fat-1 mice also showed increased mitofusin-2 and reduced dynamin-like protein 1 phosphorylation, which mediate mitochondrial fusion and fission, respectively. Mitochondria of fat-1 mice exhibited enhanced oxygen consumption rate, fatty acid ß-oxidation, and energy substrate utilization as determined by high-resolution respirometry, [1- 14 C]-oleate oxidation and nicotinamide adenine dinucleotide hydride/dihydroflavine-adenine dinucleotide production, respectively. Untargeted lipidomics identified a rich hepatic omega-3-PUFA composition and a specific docosahexaenoic acid (DHA)-enriched lipid fingerprint in fat-1 mice. Targeted lipidomics uncovered a higher content of DHA-derived lipid autacoids, namely resolvin D1 and maresin 1, which rescued hepatocytes from TNFα-induced mitochondrial dysfunction, and unblocked the tricarboxylic acid cycle flux and metabolic utilization of long-chain acyl-carnitines, amino acids, and carbohydrates. Importantly, fat-1 mice were protected against mitochondrial injury induced by obesogenic and fibrogenic insults. CONCLUSION: Our data uncover the importance of a lipid membrane composition rich in DHA and its lipid autacoid derivatives to have optimal hepatic mitochondrial and metabolic efficiency.

Supplementation with omega-3 or omega-6 fatty acids attenuates platelet reactivity in postmenopausal women.

Postmenopausal women are at increased risk for a cardiovascular event due to platelet hyperactivity. There is evidence suggesting that ω-3 polyunsaturated fatty acids (PUFAs) and ω-6 PUFAs have cardioprotective effects in these women. However, a mechanistic understanding of how these fatty acids regulate platelet function is unknown. In this study, we supplemented postmenopausal women with fish oil (ω-3 fatty acids) or evening primrose oil (ω-6 fatty acids) and investigated the effects on their platelet activity. The effects of fatty acid supplementation on platelet aggregation, dense granule secretion, and activation of integrin αIIbß3 at basal levels and in response to agonist were tested in postmenopausal women following a supplementation and washout period. Supplementation with fish oil or primrose oil attenuated the thrombin receptor PAR4-induced platelet aggregation. Supplementation with ω-3 or ω-6 fatty acids decreased platelet dense granule secretion and attenuated basal levels of integrin αIIbß3 activation. Interestingly, after the washout period following supplementation with primrose oil, platelet aggregation was similarly attenuated. Additionally, for either treatment, the observed protective effects post-supplementation on platelet dense granule secretion and basal levels of integrin activation were sustained after the washout period, suggesting a long-term shift in platelet reactivity due to fatty acid supplementation. These findings begin to elucidate the underlying mechanistic effects of ω-3 and ω-6 fatty acids on platelet reactivity in postmenopausal women. Hence, this study supports the beneficial effects of fish oil or primrose oil supplementation as a therapeutic intervention to reduce the risk of thrombotic events in postmenopausal women. https://clinicaltrials.gov/ct2/show/NCT02629497.

Omega-6 Polyunsaturated Fatty Acids Enhance Tumor Aggressiveness in Experimental Lung Cancer Model: Important Role of Oxylipins.

Lung cancer is currently the leading cause of cancer death worldwide; it is often diagnosed at an advanced stage and bears poor prognosis. It has been shown that diet is an important environmental factor that contributes to the risk and mortality of several types of cancers. Intake of ω-3 and ω-6 PUFAs plays an important role in cancer risk and progression. Current Western populations have high consumption of ω-6 PUFAs with a ratio of ω-6/ω-3 PUFAs at 15:1 to 16.7:1 This high consumption of ω-6 PUFAs is related to increased cancer risk and progression. However, whether a diet rich in ω-6 PUFAs can contribute to tumor aggressiveness has not been well investigated. We used a murine model of pulmonary squamous cell carcinoma to study the aggressiveness of tumors in mice fed with a diet rich in ω-6 PUFAs and its relationship with oxylipins. Our results shown that the mice fed a diet rich in ω-6 showed a marked increase in proliferation, angiogenesis and pro-inflammatory markers and decreased expression of pro-apoptotic proteins in their tumors. Oxylipin profiling revealed an upregulation of various pro-tumoral oxylipins including PGs, HETEs, DiHETrEs and HODEs. These results demonstrate for the first time that high intake of ω-6 PUFAs in the diet enhances the malignancy of tumor cells by histological changes on tumor dedifferentiation and increases cell proliferation, angiogenesis, pro-inflammatory oxylipins and molecular aggressiveness targets such as NF-κB p65, YY1, COX-2 and TGF-ß.

Decreased Tissue Omega-6/Omega-3 Fatty Acid Ratio Prevents Chemotherapy-Induced Gastrointestinal Toxicity Associated with Alterations of Gut Microbiome.

Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial ß-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host-microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.

Interaction between ω-6 fatty acids intake and blood cadmium on the risk of low cognitive performance in older adults from National Health and Nutrition Examination Survey (NHANES) 2011-2014.

BACKGROUND: Identifying preventable diets and environmental exposure is essential to ensuring the health of the aging population. This study evaluated the interaction effect between blood cadmium and ω-6 fatty acids intake on low cognitive performance in Americans. METHOD: The data of this cross-sectional study were obtained from the 2011-2012 and 2013-2014 National Health and Nutritional Examination Survey (NHANES). Cognitive performance was measured by the Consortium to Establish a Registry for Alzheimer's Disease test, Animal Fluency Test, and Digit Symbol Substitution Test. Multivariate logistic regression models were used. RESULTS: A total of 1,918 individuals were included, with 467 (24.35%) low cognitive performance. Compared with participants with normal-level blood cadmium, those with high-level blood cadmium had a higher risk of low cognitive performance [odds ratio (OR) was 1.558 with 95% confidence interval (CI): 1.144-2.123]. Low-level ω-6 fatty acids intake was positively associated with low cognitive performance [OR = 1.633 (95%CI: 1.094-2.436)] compared with normal-level intake. Moreover, there was a significant interaction between low-level ω-6 fatty acids intake and high-level blood cadmium on the risk of low cognitive performance (relative excess risk due to interaction: 0.570, 95%CI: 0.208-0.932; the attributable proportion of interaction: 0.219, 95%CI: 0.102-0.336; synergy index: 1.552, 95%CI: 1.189-2.027). CONCLUSIONS: There was a synergistic interaction between low-level ω-6 fatty acids intake and high-level blood cadmium on low cognitive performance. Low-level ω-6 fatty acids intake may amplify the adverse effects of long-term exposure to cadmium on cognitive performance. This may have a certain significance for the prevention of cognitive decline in the elderly.

Synergistic hepatoprotective effects of ω-3 and ω-6 fatty acids from Indian flax and sesame seed oils against CCl4-induced oxidative stress-mediated liver damage in rats.

Flaxseed (FS) and sesame seed (SS) are traditional and functional foods in traditional Indian medicine for treating various disorders. The present study investigated the hepatoprotective effects of bioactive-fatty acids (FAs) from FS and SS against carbon tetrachloride (CCl4)-induced hepatic damage in rats. Pre and post-treatments for 28 consecutive days significantly increased the activities of in vivo antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and peroxidase (POX), whereas, lipid peroxidation (LPO) activity was markedly decreased in a dose-dependent manner in liver and kidneys. A significant reduction was observed in the hematological parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin in the serum of post-treated animals compared to the negative control. The results were confirmed histopathologically. The results suggested that the ω-3 and ω-6 FAs from flaxseed oil (FSO) and sesame seed oil (SSO), respectively, showed potential synergistic hepatoprotective and antioxidant effects that were mediated mainly by ω-3 and ω-6 FAs present in the respective seed oils.

Susceptibility of Female Mice to the Dietary Omega-3/Omega-6 Fatty-Acid Ratio: Effects on Adult Hippocampal Neurogenesis and Glia.

Maternal intake of omega-3 (n-3 PUFAs) and omega-6 (n-6 PUFAs) polyunsaturated fatty acids impacts hippocampal neurogenesis during development, an effect that may extend to adulthood by altering adult hippocampal neurogenesis (AHN). The n-3 PUFAs and n-6 PUFAs are precursors of inflammatory regulators that potentially affect AHN and glia. Additionally, n-3 PUFA dietary supplementation may present a sexually dimorphic action in the brain. Therefore, we postulated that dietary n-6/n-3 PUFA balance shapes the adult DG in a sex-dependent manner influencing AHN and glia. We test our hypothesis by feeding adult female and male mice with n-3 PUFA balanced or deficient diets. To analyze the immunomodulatory potential of the diets, we injected mice with the bacterial endotoxin lipopolysaccharide (LPS). LPS reduced neuroblast number, and its effect was exacerbated by the n-3 PUFA-deficient diet. The n-3 PUFA-deficient diet reduced the DG volume, AHN, microglia number, and surveilled volume. The diet effect on most mature neuroblasts was exclusively significant in female mice. Colocalization and multivariate analysis revealed an association between microglia and AHN, as well as the sexual dimorphic effect of diet. Our study reveals that female mice are more susceptible than males to the effect of dietary n-6/n-3 PUFA ratio on AHN and microglia.

Altered Plasma Fatty Acids Associate with Gut Microbial Composition in Common Variable Immunodeficiency.

PURPOSE: Fatty acid (FA) abnormalities are found in various inflammatory disorders and have been related to disturbed gut microbiota. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with altered gut microbial composition. We hypothesized that there is an altered FA profile in CVID patients, related to gut microbial dysbiosis. METHODS: Plasma FAs were measured in 39 CVID patients and 30 healthy controls. Gut microbial profile, a food frequency questionnaire, and the effect of the oral antibiotic rifaximin were investigated in CVID patients. RESULTS: The n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) (1.4 [1.0-1.8] vs. 1.9 [1.2-2.5], median (IQR), P < 0.05), and docosahexaenoic acid (DHA) (3.2 [2.4-3.9] vs. 3.5 [2.9-4.3], P < 0.05), all values expressed as weight percent of total plasma FAs, were reduced in CVID compared to controls. Also, n-6 PUFAs (34.3 ± 3.4 vs. 37.1 ± 2.8, mean ± SD, P < 0.001) and linoleic acid (LA) (24.5 ± 3.3 vs. 28.1 ± 2.7, P < 0.0001) and the FA anti-inflammatory index (98.9 [82.1-119.4] vs. 117.0 [88.7-153.1], median (IQR), P < 0.05) were reduced in CVID. The microbial alpha diversity was positively associated with plasma n-6 PUFAs (r = 0.41, P < 0.001) and LA (r = 0.51, P < 0.001), but not n-3 PUFAs (P = 0.78). Moreover, a 2-week course of rifaximin significantly reduced the proportion of n-6 PUFAs (P = 0.04, UNIANOVA). Serum immunoglobulin G (IgG) levels correlated with plasma n-3 PUFAs (rho = 0.36, P = 0.03) and DHA (rho = 0.41, P = 0.009). CONCLUSION: We found a potentially unfavorable FA profile in CVID, related to low IgG levels. High plasma n-6 PUFAs were related to increased gut microbial diversity and altered by rifaximin therapy.

The Effects of Specific Omega-3 and Omega-6 Polyunsaturated Fatty Acids and Antioxidant Vitamins on Gait and Functional Capacity Parameters in Patients with Relapsing-Remitting Multiple Sclerosis.

Patients with multiple sclerosis (MS) are characterized by, among other symptoms, impaired functional capacity and walking difficulties. Polyunsaturated fatty acids (PUFAs) have been found to improve MS patients' clinical outcomes; however, their effect on other parameters associated with daily living activities need further investigation. The current study aimed to examine the effect of a 24-month supplementation with a cocktail dietary supplement formula, the NeuroaspisTM PLP10, containing specific omega-3 and omega-6 PUFAs and specific antioxidant vitamins on gait and functional capacity parameters of patients with MS. Fifty-one relapsing-remitting MS (RRMS) patients with low disability scores (age: 38.4 ± 7.1 years; 30 female) were randomized 1:1 to receive either a 20 mL daily dose of the dietary formula containing a mixture of omega-3 and omega-6 PUFAs (12,150 mg), vitamin A (0.6 mg), vitamin E (22 mg), and γ-tocopherol (760 mg), the OMEGA group (n = 27; age: 39 ± 8.3 years), or 20 mL placebo containing virgin olive oil, the placebo group (n = 24; age: 37.8 ± 5.3 years). The mean ± SD (standard deviation) Expanded Disability Status Scale (EDSS) score for the placebo group was 2.36 and for the OMEGA group 2.22. All enrolled patients in the study were on Interferon-ß treatment. Spatiotemporal gait parameters and gait deviation index (GDI) were assessed using a motion capture system. Functional capacity was examined using various functional tests such as the six-minute walk test (6MWT), two sit-to-stand tests (STS-5 and STS-60), and the Timed Up and Go test (TUG). Isometric handgrip strength was assessed by a dynamometer. Leg strength was assessed using an isokinetic dynamometer. All assessments were performed at baseline and at 12 and 24 months of supplementation. A total of 36 patients completed the study (18 from each group). Six patients from the placebo group and 9 patients from the OMEGA group dropped out from the study or were lost to follow-up. The dietary supplement significantly improved the single support time and the step and stride time (p < 0.05), both spatiotemporal gait parameters. In addition, while GDI of the placebo group decreased by about 10% at 24 months, it increased by about 4% in the OMEGA group (p < 0.05). Moreover, performance in the STS-60 test improved in the OMEGA group (p < 0.05) and there was a tendency for improvement in the 6MWT and TUG tests. Long-term supplementation with high dosages of omega-3 and omega-6 PUFAs (compared to previous published clinical studies using PUFAs) and specific antioxidant vitamins improved some functional capacity and gait parameters in RRMS patients.

Omega-3 and omega-6 fatty acids have distinct effects on endothelial fatty acid content and nitric oxide bioavailability.

Treatment with high dose icosapent ethyl (IPE), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA), significantly reduced ischemic events in patients with either cardiovascular disease (CV) or diabetes plus other risk factors (REDUCE-IT) but the mechanism is not well understood.  We compared the effects of EPA, docosahexaenoic acid (DHA), and the omega-6 fatty acid arachidonic acid (AA) on bioavailability of nitric oxide (NO) and fatty acid composition. Human umbilical vein endothelial cells (HUVECs) were pretreated with EPA, DHA, or AA (10 µM). Cells were stimulated with calcium ionophore and NO and peroxynitrite (ONOO-) were measured using porphyrinic nanosensors. Levels of EPA, DHA, AA and other fatty acids were measured by gas chromatography (GC). EPA treatment caused the greatest NO release (18%, p < 0.001) and reduction in ONOO- (13%, p < 0.05) compared to control; the [NO]/[ ONOO-] ratio increased by 35% (p < 0.001). DHA treatment increased NO levels by 12% (p < 0.01) but had no effect on ONOO- release. AA did not affect either NO or ONOO- release.  Fatty acid treatments increased their respective levels in endothelial cells.  EPA levels increased 10-fold to 4.59 mg/g protein (p < 0.001) with EPA treatment and the EPA/AA ratio increased by 10-fold (p < 0.001) compared to vehicle.  Only EPA increased docosapentaenoic acid (DPA, omega-3) levels by 2-fold (p < 0.001). AA alone decreased the EPA/AA ratio 4-fold (p<0.001). These findings support a preferential benefit of EPA on endothelial function and omega-3 fatty acid content.

The effects of the esterified Quercetin with omega3 and omega6 fatty acids on viability, nanomechanical properties, and BAX/BCL-2 gene expression in MCF-7 cells.

Quercetin is one of the major flavonoids and it appears to have cytotoxic effects on various cancer cells through regulating the apoptosis pathway genes such as BAX and BCL2. Combination of Quercetin (Q) with other compounds can increase its effectiveness. In the present study, the effects of the Quercetin and its esterified derivatives on viability, nanomechanical properties of cells, and BAX/BCL-2 gene expression were investigated. Using the MTT and flow cytometry assays, the cytotoxic potential, apoptosis, and necrosis were investigated. The AFM assay was performed to find the nanomechanical properties of cells as the elastic modulus value and cellular adhesion forces. The BAX/BCL2 gene expression was investigated through the Real-Time PCR. The results showed that the esterification of Quercetin with linoleic acid (Q-LA) and α-linolenic acid (Q-ALA) increased the cytotoxic potential of Q. The elastic modulus value and cellular adhesion forces were increased using the esterified derivatives and the highest ratio of BAX/BCL2 gene expression was observed in Q-LA. Esterified Quercetin derivatives have a higher cytotoxic effect than the un-esterified form in a dose-dependent manner. Esterified derivatives caused the nanomechanical changes and pores formation on the cytoplasmic membrane. One of the internal apoptosis pathway regulation mechanisms of these compounds is increasing the BAX/BCL2 gene expression ratio.

Chronic nutritional restriction of omega-3 fatty acids induces a pro-inflammatory profile during the development of the rat visual system.

Modern western diets have been associated with a reduced proportion of dietary omega-3 fatty acids leading to decreased levels of DHA (docosahexaenoic acid) in the brain. Low DHA content has been associated with altered development of visual acuity in infants and also with an altered time course of synapse elimination and plasticity in subcortical visual nuclei in rodents. Microglia has an active role in normal developmental processes such as circuitry refinement and plasticity, and its activation status can be modulated by omega-3 (ω3) and omega-6 (ω6) essential fatty acids. In the present study, we investigated the impact of dietary restriction of DHA (ω3-), through the chronic administration of a coconut-based diet as the only fat source. This dietary protocol resulted in a reduction in DHA content in the retina and superior colliculus (SC) and in a neuroinflammatory outcome during the development of the rodent visual system. The ω3- group showed changes in microglial morphology in the retina and SC and a corresponding altered pattern of pro-inflammatory cytokine expression. Early and late fish oil protocols supplementation were able to restore DHA levels. The early supplementation also decreased neuroinflammatory markers in the visual system. The present study indicates that a chronic dietary restriction of omega-3 fatty acids and the resulting deficits in DHA content, commonly observed in Western diets, interferes with the microglial profile leading to an inflamed microenvironment which may underlie a disruption of synapse elimination, altered topographical organization, abnormal plasticity, and duration of critical periods during brain development.