Polyunsaturated Fatty Acids In Treatment Research Articles

Abstract PO5-14-01: Weight loss and omega-3 polyunsaturated fatty acid intervention in overweight and obese peri- and postmenopausal women with increased breast cancer risk modifies the gut microbiome and is associated with circulating biomarkers

Abstract Background: Obesity-associated gut microbiome dysbiosis is thought to increase risk for postmenopausal breast cancer through alteration of estrogen metabolism and an increase in pro-inflammatory microbe abundance. Many studies have reported an increase in the Firmicutes/Bacteroidetes phyla ratio as a biomarker of obesity and is associated with adverse metabolic outcomes. Marine omega-3 eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids are thought to have favorable metabolic and inflammation resolving properties resulting in reduced risk for several epithelial cancers. One possible mechanism is the effect of EPA and DHA on the gut microbiome. We assessed the effect of weight loss and/or omega-3 supplementation on the gut microbiome and circulating molecular breast cancer risk factors. Methods: 46 peri/postmenopausal overweight and obese women at increased risk for breast cancer were enrolled into a weight-loss intervention and after 2 weeks randomized to 3.25 g/day combined EPA and DHA or placebo (PMC8416797). Fecal samples were collected at 0, 2-weeks and 6-months, with matched fecal samples for all timepoints available for 26 patients. Fecal samples at 6-months were available for 34 patients. 12M read depth metagenomic sequencing was performed on DNA isolated from feces to determine shifts in the gut microbiome. Fasting and non-fasting blood was also collected for circulating biomarker analysis. Body composition by DXA scan were also performed at baseline and 6-month time points. Results: Mean baseline BMI was 32 kg/m2. There was no significant difference between arms in age, baseline BMI, % body fat, or baseline Firmicutes/Bacteroidetes ratio. We identified gut microbiota species (A. hadrus and P. faecium) that correlated with metabolic parameters (% body fat, adiponectin/leptin ratio, and fasting insulin), species (P. dorei and B. ovatus) that correlated with estradiol levels, and mucin-degrading species (D. formicigenerans and R. gnavus) whose abundance correlated with inflammation (as measured by circulating monocyte-chemoattractant protein 1 (MCP-1)). Median 6-month weight change for all randomized subjects was -10% from baseline. Favorable change in the Firmicutes/Bacteroidetes ratio was associated both with the degree of weight loss and with omega-3 supplementation, although significant species modification differed between weight loss and omega-3 PUFA groups. Women with both >10% weight loss and omega-3 supplementation had a significantly reduced Firmicutes abundance and lower Firmicute/Bacteroidetes ratio than other groups. Species abundance shifts appear to differ between weight loss and omega-3 supplementation with 3 species modified by weight loss and 12 species shifted by omega-3 PUFA administration. Omega-3 PUFA supplementation significantly reduced proportional abundance of Dorea formicigenerans, which was a microbe associated with inflammation. Conclusions: Omega-3 supplementation at 3.25 g/day compared to placebo had a greater net effect on changing the gut microbiome in overweight and obese women at increased risk for breast cancer undergoing a weight loss intervention. Change in the gut microbiome may serve as a useful response biomarker in Phase II prevention trials of omega-3 fatty acid and weight loss. Citation Format: Katherine L. Cook, Erin Giles, Amy Kreutzjans, Shahid Umar, Christie Befort, Bruce Kimler, Stephen Hursting, Carol Fabian. Weight loss and omega-3 polyunsaturated fatty acid intervention in overweight and obese peri- and postmenopausal women with increased breast cancer risk modifies the gut microbiome and is associated with circulating biomarkers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-01.

Effects of polyunsaturated fatty acids on interleukin-6 and brain-derived neurotrophic factor in monosodium glutamate-induced depression male rats

Background: Depression is the most common psychiatric disorder affecting around 5% of the population worldwide. It leads to morbidity and affects quality of life. Monosodium glutamate (MSG) popularly called a tastemaker is used as a food additive in fast food and other processed foods. MSG has been implicated in causing depression. Since many adolescents and children are being habituated to fast foods, the current study is to evaluate the effects of polyunsaturated fatty acids (PUFAs) supplementation on plasma concentration of brain-derived neurotrophic factor (BDNF) and IL-6 which are important biochemical and immunological markers found in depression. Aims and Objectives: The aim of the current study was to assess the effect of supplementation of PUFA on MSG-induced depression in Wistar albino rats. Materials and Methods: The present prospective interventional study was conducted on 3-month-old, 24 male Wistar albino rats (weighing 200–300 g) for 21 days. The study group was divided into four equal groups among which 1st group that is control received distilled water with carboxymethylcellulose (CMC), the 2nd group positive control group received 500 mg of MSG along with CMC, the 3rd group normal control with PUFA received PUFA dissolved in CMC and the 4th group was positive control with PUFA received MSG dissolved in CMC and PUFA intervention was introduced from the 7th day. The study period was for 21 days and the 22nd day was an acclimatization day. The parameters in the blood samples of the rats were tested on the 23rd day using an ELISA kit and results were analyzed using Tukey’s post hoc test among the various groups and it was taken as statistically significant when the P < 0.05. Results: Among the groups, IL-6 levels raised and BDNF levels dropped in plasma of MSG-induced depressed rats. In PUFA-treated MSG-induced depressed rats, the plasma level of IL-6 was reduced and there was a significant rise in BDNF levels. Conclusion: PUFA supplementation is effective in treating MSG-induced depression in rats.

Omega Fatty Acid Ratios and Neurodegeneration in a Healthy Environment

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis pose substantial public health challenges. While genetics play a primary role, recent research emphasizes the impact of environmental factors, particularly diet and lifestyle. This study investigates the initiating effects of Omega (ω)-3 and Omega (ω)-6 fatty acids on neuroinflammation, potentially contributing to these diseases. Using BV-2 microglial cells, we explored the influence of different fatty acid compositions and ratios on cell viability, cytokine production, morphological changes, and lipid peroxidation. Notably, a 2/1 ω-6:ω-3 ratio led to decreased cell viability. Fatty acid compositions influenced cytokine secretion, with reduced TNF-α suggesting anti-inflammatory effects. IL-17 increased, while IL-4 and IL-10 decreased in the 15/1 ω-6:ω-3 ratio, indicating complex cytokine interactions. This study found that polyunsaturated fatty acids interventions induced microglial activation, altering cell morphology even without immunostimulants. These findings demonstrate the intricate nature of fatty acid interactions with microglial cells and their potential implications for neuroinflammation. Further research is needed to clarify mechanisms and their relevance to neurodegenerative diseases, informing possible therapeutic strategies.

Dousing the flame: reviewing the mechanisms of inflammatory programming during stress-induced intrauterine growth restriction and the potential for ω-3 polyunsaturated fatty acid intervention.

Intrauterine growth restriction (IUGR) arises when maternal stressors coincide with peak placental development, leading to placental insufficiency. When the expanding nutrient demands of the growing fetus subsequently exceed the capacity of the stunted placenta, fetal hypoxemia and hypoglycemia result. Poor fetal nutrient status stimulates greater release of inflammatory cytokines and catecholamines, which in turn lead to thrifty growth and metabolic programming that benefits fetal survival but is maladaptive after birth. Specifically, some IUGR fetal tissues develop enriched expression of inflammatory cytokine receptors and other signaling cascade components, which increases inflammatory sensitivity even when circulating inflammatory cytokines are no longer elevated after birth. Recent evidence indicates that greater inflammatory tone contributes to deficits in skeletal muscle growth and metabolism that are characteristic of IUGR offspring. These deficits underlie the metabolic dysfunction that markedly increases risk for metabolic diseases in IUGR-born individuals. The same programming mechanisms yield reduced metabolic efficiency, poor body composition, and inferior carcass quality in IUGR-born livestock. The ω-3 polyunsaturated fatty acids (PUFA) are diet-derived nutraceuticals with anti-inflammatory effects that have been used to improve conditions of chronic systemic inflammation, including intrauterine stress. In this review, we highlight the role of sustained systemic inflammation in the development of IUGR pathologies. We then discuss the potential for ω-3 PUFA supplementation to improve inflammation-mediated growth and metabolic deficits in IUGR offspring, along with potential barriers that must be considered when developing a supplementation strategy.

Long-chain omega-3 polyunsaturated fatty acids are reduced in neonates with substantial brain injury undergoing therapeutic hypothermia after hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Although therapeutic hypothermia is an effective treatment, substantial chronic neurological impairment often persists. The long-chain omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, offer therapeutic potential in the post-acute phase. To understand how PUFAs are affected by HIE and therapeutic hypothermia we quantified for the first time the effects of HIE and therapeutic hypothermia on blood PUFA levels and lipid peroxidation. In a cross-sectional approach, blood samples from newborns with moderate to severe HIE, who underwent therapeutic hypothermia (sHIE group) were compared to samples from newborns with mild HIE, who did not receive therapeutic hypothermia, and controls. The sHIE group was stratified into cerebral MRI predictive of good (n = 10), or poor outcomes (n = 10; nine developed cerebral palsy). Cell pellets were analyzed for fatty acid content, and plasma for lipid peroxidation products, thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal. Omega-3 Index (% DHA + EPA) was similar between control and HIE groups; however, with therapeutic hypothermia there were significantly lower levels in poor vs. good prognosis sHIE groups. Estimated Δ-6 desaturase activity was significantly lower in sHIE compared to mild HIE and control groups, and linoleic acid significantly increased in the sHIE group with good prognosis. Reduced long-chain omega-3 PUFAs was associated with poor outcome after HIE and therapeutic hypothermia, potentially due to decreased biosynthesis and tissue incorporation. We speculate a potential role for long-chain omega-3 PUFA interventions in addition to existing treatments to improve neurologic outcomes in sHIE.

N-3 Polyunsaturated Fatty Acid Supplementation Affects Oxidative Stress Marker Levels in Patients with Type II Intestinal Failure: A Randomized Double Blind Trial.

Type II intestinal failure (IF-II) is a condition in which the gastrointestinal tract is compromised. Liver complications may occur because of the pathology and/or prolonged use of parenteral nutrition (PN); oxidative stress has been implicated as one of the causes. Lipid emulsions containing n-3 polyunsaturated fatty acids (PUFAs) have been proposed for the treatment. We aimed to evaluate the effect of 7-day n-3 PUFA supplementation on oxidative stress in IF-II patients receiving PN. This was a randomized, controlled, double-blinded, pilot trial of adult patients with IF-II, receiving either conventional PN (control) or PN enriched with n-3 PUFAs (intervention). Twenty patients were included (14 men, 49 ± 16.9 years), with the ANCOVA analysis the glucose (p = 0.003), and direct bilirubin (p = 0.001) levels reduced; whereas the high-density lipoprotein cholesterol (HDL-C) increased (p = 0.017). In the random-effect linear regression analysis, a reduction (p < 0.0001) in the malondialdehyde (MDA) level was found in the intervention group when the covariables age, HDL-C level, and alanine aminotransferase activity were considered. After 1 week of PN supplementation with n-3 PUFAs, the marker levels of some oxidative stress, blood lipids, and hepatic biomarkers improved in patients with IF-II.

Reduced gut microbial diversity in familial hypercholesterolemia with no effect of omega-3 polyunsaturated fatty acids intervention – a pilot trial

Individuals with familial hypercholesterolemia (FH) undergo an aggressive treatment with cholesterol-lowering drugs to prevent coronary heart disease. Recent evidence suggests an interplay between the gut microbiota, blood lipid levels and lipid-lowering drugs, but this has yet to be studied in individuals with FH. The objective of the study was to characterize the gut microbiota of individuals with familial hypercholesterolemia and examine if effects of omega-3 polyunsaturated fatty acids (PUFAs) on blood lipids act through modification of the gut microbiome. The gut microbiota composition of individuals with FH (N = 21) and healthy controls (N = 144) was analyzed by extracting DNA from stool samples and sequencing of the V3–V4 region of the 16S rRNA gene. A subgroup (n = 15) of the participants received omega-3 polyunsaturated fatty acids (PUFAs) supplementation or placebo in a crossover manner, and the effect of PUFAs on the gut microbiota was also investigated. Individuals with FH had a different gut microbiota composition compared to healthy controls, characterized by reduced richness (p = .001) and reduction of several genera belonging to Clostridia and Coriobacteriia. Patients using ezetimibe in addition to statins appeared to have lower richness compared to those only using statins (p = .01). Intervention with omega-3 PUFAs had negligible impact on the microbiota composition. Positive effects on blood lipids after intervention with omega-3 PUFA were not associated with baseline gut microbiota composition or gut microbial changes during treatment. Further, patients with FH have an altered gut microbiota compared to healthy controls, possibly driven by the use of ezetimibe.

The Blood Immune Cell Count, Immunoglobulin, Inflammatory Factor, and Milk Trace Element in Transition Cows and Calves Were Altered by Increasing the Dietary n-3 or n-6 Polyunsaturated Fatty Acid Levels.

Transition dairy cows experience sudden changes in both metabolic and immune functions, which lead to many diseases in postpartum cows. Therefore, it is crucial to monitor and guarantee the nutritional and healthy status of transition cows. The objective of this study was to determine the effect of diet enriched in n-3 or n-6 polyunsaturated fatty acid (PUFA) on colostrum composition and blood immune index of multiparous Holstein cows and neonatal calves during the transition period. Forty-five multiparous Holstein dairy cows at 240 days of pregnancy were randomly assigned to receive 1 of 3 isoenergetic and isoprotein diets: 1) CON, hydrogenated fatty acid (control), 1% of hydrogenated fatty acid [diet dry matter (DM) basis] during prepartum and postpartum, respectively; 2) HN3, 3.5% of extruding flaxseed (diet DM basis, n-3 PUFA source); 3) HN6, 8% of extruding soybeans (diet DM basis, C18:2n-6 PUFA source). Diets containing n-3 and n-6 PUFA sources decreased colostrum immunoglobulin G (IgG) concentration but did not significantly change the colostrum IgG yield compared with those with CON. The commercial milk yield (from 14 to 28 days after calving) was higher in the HN3 and HN6 than that in the CON. Furthermore, the n-3 PUFA source increased neutrophil cell counts in blood during the prepartum period and increased neutrophil percentage during the postpartum period when compared with those with control treatment. Diets containing supplemental n-3 PUFA decreased the serum concentration of interleukin (IL)-1β in maternal cows compared with those in control and n-6 PUFA during prepartum and postpartum. In addition, the neonatal calf serum concentration of tumor necrosis factor (TNF) was decreased in HN3 compared with that in the HN6 treatment. The diet with the n-3 PUFA source could potentially increase the capacity of neutrophils to defend against pathogens in maternal cows by increasing the neutrophil numbers and percentage during the transition period. Meanwhile, the diet with n-3 PUFA source could decrease the pro-inflammatary cytokine IL-1β of maternal cows during the transition period and decline the content of pro-inflammatary cytokine TNF of neonatal calves. It suggested that the highest milk production in n-3 PUFA treatment may partially be due to these beneficial alterations.

Long-Term Effect of PNPLA3 on the Aggravation of Nonalcoholic Fatty Liver Disease in a Biopsy-Proven Cohort

The PNPLA3 rs738409 G allele increases the risk of not only nonalcoholic fatty liver disease (NAFLD) but also nonalcoholic steatohepatitis (NASH) or fibrosis.1 It also affects the prognosis of patients with NAFLD in specific conditions. After liver transplantation, patients with NAFLD carrying the rs738409 GG genotype have a higher risk of graft steatosis2 or development of hepatocellular carcinoma.3 In addition, rs738409 modifies the effects of medical intervention: patients with NAFLD carrying the GG genotype showed a lower effect of omega-3 polyunsaturated fatty acid treatment on the reduction of liver fat;4 in contrast, they were more sensitive to the beneficial effects of lifestyle modifications.5,6.

Adjunct n-3 Long-Chain Polyunsaturated Fatty Acid Treatment in Tuberculosis Reduces Inflammation and Improves Anemia of Infection More in C3HeB/FeJ Mice With Low n-3 Fatty Acid Status Than Sufficient n-3 Fatty Acid Status.

Populations at risk for tuberculosis (TB) may have a low n-3 polyunsaturated fatty acid (PUFA) status. Our research previously showed that post-infection supplementation of n-3 long-chain PUFA (LCPUFA) in TB without TB medication was beneficial in n-3 PUFA sufficient but not in low-status C3HeB/FeJ mice. In this study, we investigated the effect of n-3 LCPUFA adjunct to TB medication in TB mice with a low compared to a sufficient n-3 PUFA status. Mice were conditioned on an n-3 PUFA-deficient (n-3FAD) or n-3 PUFA-sufficient (n-3FAS) diet for 6 weeks before TB infection. Post-infection at 2 weeks, both groups were switched to an n-3 LCPUFA [eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)] supplemented diet and euthanized at 4- and 14- days post-treatment. Iron and anemia status, bacterial loads, lung pathology, lung cytokines/chemokines, and lung lipid mediators were measured. Following 14 days of treatment, hemoglobin (Hb) was higher in the n-3FAD than the untreated n-3FAS group (p = 0.022), whereas the n-3FAS (drug) treated control and n-3FAS groups were not. Pro-inflammatory lung cytokines; interleukin-6 (IL-6) (p = 0.011), IL-1α (p = 0.039), MCP1 (p = 0.003), MIP1- α (p = 0.043), and RANTES (p = 0.034); were lower, and the anti-inflammatory cytokine IL-4 (p = 0.002) and growth factor GMCSF (p = 0.007) were higher in the n-3FAD compared with the n-3FAS mice after 14 days. These results suggest that n-3 LCPUFA therapy in TB-infected mice, in combination with TB medication, may improve anemia of infection more in low n-3 fatty acid status than sufficient status mice. Furthermore, the low n-3 fatty acid status TB mice supplemented with n-3 LCPUFA showed comparatively lower cytokine-mediated inflammation despite presenting with lower pro-resolving lipid mediators.

Beneficial effects of Omega-3 polyunsaturated fatty acids in treatment of non-alcoholic fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) is sickness with different causes and it is the most hepatic illness. The objective of this work is to investigate the bimolecular changes in a model of high fat diet induced- NAFLD in rats. Also, the hypolipidemic, antioxidant and anti-inflammatory effects of omega-3 were clarify via evaluation of some biochemical and molecular parameters in the liver tissue of rats.Twenty one adult white albino rats were divided into three groups. Group I (Normal control): received no drugs and fed balanced diet, Group II (NAFLD- induced group): rats fed high fat diet for 8 weeks followed by normal basal ration for additional 8 weeks. Group III (NAFLD + omega-3): rats administrated omega-3 (300 mg/kg b.wt/day), orally for 8 weeks post-induction of NAFLD. The obtained results showed a significant increase in serum Total cholesterol and Triacylglycerols (TAG) concentrations, L-MDA and TAC in liver tissuewith significant up-regulation in CPT-1α, FAS, SREBP-1c, PPAR-α, Nrf2 and TAK1gene expression in NAFLD-induced rats. Treatment with Omega-3 to NAFLD induced rats potentially improved molecular hepatic cell function and oxidative alterations related to NAFLD near its normal ranges. Meanwhile, histo-pathological findings supported that Omeg-3 markedly attenuates harmful effects of NAFLD and protected liver cell. On conclusion, Omega-3 plays an important role as potent anti-oxidant, anti-obesity, anti-inflammatory via inhibition of hepatic steatosis and oxidative stress singling.

The efficacy of probiotics and/or n-3 long-chain polyunsaturated fatty acids intervention on maternal prenatal and postnatal depressive and anxiety symptoms among overweight and obese women

BackgroundMaternal depression and anxiety may endanger well-being of both mother and child. We investigated the efficacy of probiotics and/or fish oil (FO) in modifying pre- and postnatal depressive and anxiety symptoms. Symptom trajectories were identified and the influence of lifestyle factors on symptoms was evaluated. MethodsOverweight women (n = 439) were randomized to intervention groups (probiotics+FO, probiotics+placebo, FO+placebo, placebo+placebo) from early pregnancy until six months postpartum, and assessed for depressive and anxiety symptoms with Edinburgh Postnatal Depression Scale (EPDS) and Anxiety subscale of Symptoms Checklist (SCL-90) at early and late pregnancy and three, six and 12 months postpartum. Latent growth mixture modeling was used to model the symptom courses. Dietary quality and physical activity were assessed with validated indices. ResultsSymptom scores were generally low. Statistically significant intervention effect was seen during pregnancy (p = 0.017): EPDS scores increased (by 1.11 points) in the FO+probiotics group and decreased (by 0.85 points) in the FO+placebo group. At 12 months postpartum, FO+placebo group had lower EPDS scores compared to probiotics+placebo group (p = 0.039). No differences in SCL scores were seen in response to the intervention. Irrespective of the intervention, three depressive and two anxiety symptoms trajectories were identified. Dietary quality correlated negatively with depressive symptoms in early pregnancy and six months postpartum and with anxiety symptoms in early pregnancy. Perinatal events including mother-reported colic were related to symptoms. LimitationsSecondary outcomes of the primary trial. ConclusionsIntervention had a modest impact on depressive symptoms. Diet and obstetric events were associated with depressive and anxiety symptoms.

Omega-3 Polyunsaturated Fatty Acid Intervention Against Established Autoimmunity in a Murine Model of Toxicant-Triggered Lupus.

Workplace exposure to respirable crystalline silica dust (cSiO2) has been etiologically linked to the development of lupus and other human autoimmune diseases. Lupus triggering can be recapitulated in female NZBWF1 mice by four weekly intranasal instillations with 1 mg cSiO2. This elicits inflammatory/autoimmune gene expression and ectopic lymphoid structure (ELS) development in the lung within 1 week, ultimately driving early onset of systemic autoimmunity and glomerulonephritis. Intriguingly, dietary supplementation with docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid (PUFA) found in fish oil, beginning 2 week prior to cSiO2 challenge, prevented inflammation and autoimmune flaring in this novel model. However, it is not yet known how ω-3 PUFA intervention influences established autoimmunity in this murine model of toxicant-triggered lupus. Here we tested the hypothesis that DHA intervention after cSiO2-initiated intrapulmonary autoimmunity will suppress lupus progression in the NZBWF1 mouse. Six-week old NZWBF1 female mice were fed purified isocaloric diet for 2 weeks and then intranasally instilled with 1 mg cSiO2 or saline vehicle weekly for 4 consecutive weeks. One week after the final instillation, which marks onset of ELS formation, mice were fed diets supplemented with 0, 4, or 10 g/kg DHA. One cohort of mice (n = 8/group) was terminated 13 weeks after the last cSiO2 instillation and assessed for autoimmune hallmarks. A second cohort of mice (n = 8/group) remained on experimental diets and was monitored for proteinuria and moribund criteria to ascertain progression of glomerulonephritis and survival, respectively. DHA consumption dose-dependently increased ω-3 PUFA content in the plasma, lung, and kidney at the expense of the ω-6 PUFA arachidonic acid. Dietary intervention with high but not low DHA after cSiO2 treatment suppressed or delayed: (i) recruitment of T cells and B cells to the lung, (ii) development of pulmonary ELS, (iii) elevation of a wide spectrum of plasma autoantibodies associated with lupus and other autoimmune diseases, (iv) initiation and progression of glomerulonephritis, and (v) onset of the moribund state. Taken together, these preclinical findings suggest that DHA supplementation at a human caloric equivalent of 5 g/d was an effective therapeutic regimen for slowing progression of established autoimmunity triggered by the environmental toxicant cSiO2.

The effects of low-ratio n-6/n-3 PUFA on biomarkers of inflammation: a systematic review and meta-analysis.

The purpose of the systematic review and meta-analysis was to determine if low-ratio n-6/n-3 long-chain polyunsaturated fatty acid (PUFA) supplementation affects serum inflammation markers based on the current studies. PubMed, Embase and The Cochrane library databases were systematically searched to find randomized controlled trials (RCTs) on the effect of low-ratio n-6/n-3 PUFA intervention on inflammation markers up to July 2020. Data were pooled using standardized mean difference (SMD) and 95% confidence intervals (95% CI), with P value ≦ 0.05 as statistical significance. Thirty-one RCTs were included in the meta-analysis. The analysis indicated that increasing low-ratio n-6/n-3 PUFA supplementation decreased the level of tumor necrosis factor-α (TNF-α) (SMD = -0.270; 95% CI: -0.433, -0.106; P = 0.001) and interleukin 6 (IL-6) (SMD = -0.153; 95% CI: -0.260, -0.045; P = 0.005). There were no significant effects on C-reactive protein (CRP) (SMD = -0.027; 95% CI: -0.189: 0.135; P = 0.741). Subgroup analysis indicated that there was a significant reduction in TNF-α serum concentration in subjects from Asia (SMD: -0.367; 95% CI: -0.579, -0.155; P = 0.001) and in subjects with diseases (SMD: -0.281; 95% CI: -0.436, -0.127; P < 0.001). In the subgroup of the n-6/n-3 ratio ≦5, low-ratio n-6/n-3 PUFA supplementation could decrease the level of TNF-α (SMD: -0.335; 95% CI: -0.552, -0.119; P = 0.002). Serum IL-6 decreased significantly in patients from the Europe subgroup (SMD: -0.451; 95% CI: -0.688, -0.214; P < 0.001), but not in Asia (SMD: -0.034; 95% CI: -0.226, 0.157; P = 0.724), North America (SMD: -0.115; 95% CI: -0.274, 0.044; P = 0.157) and Oceania (SMD: 0.142; 95% CI: -0.557, 0.842; P = 0.690). Low-ratio n-6/n-3 PUFA supplementation could decrease significantly the concentration of serum TNF-α and IL-6, but not decrease CRP concentration.

A 16-week randomized placebo-controlled trial investigating the effects of omega-3 polyunsaturated fatty acid treatment on white matter microstructure in recent-onset psychosis patients concurrently treated with risperidone

We examined the impact of treatment with fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids (n-3 PUFA), on white matter in 37 recent-onset psychosis patients receiving risperidone in a double-blind placebo-controlled randomized clinical trial. Patients were scanned at baseline and randomly assigned to receive 16-weeks of treatment with risperidone + FO or risperidone + placebo. Eighteen patients received follow-up MRIs (FO, n = 10/Placebo, n = 8). Erythrocyte levels of n-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA) were obtained at both time points. We employed Free Water Imaging metrics representing the extracellular free water fraction (FW) and fractional anisotropy of the tissue (FA-t). Analyses were conducted using Tract-Based-Spatial-Statistics and nonparametric permutation-based tests with family-wise error correction. There were significant positive correlations of FA-t with DHA and DPA among all patients at baseline. Patients treated with risperidone + placebo demonstrated reductions in FA-t and increases in FW, whereas patients treated with risperidone + FO exhibited no significant changes in FW and FA-t reductions were largely attenuated. The correlations of DPA and DHA with baseline FA-t support the hypothesis that n-3 PUFA intake or biosynthesis are associated with white matter abnormalities in psychosis. Adjuvant FO treatment may partially mitigate against white matter alterations observed in recent-onset psychosis patients following risperidone treatment.

P0326EFFECT OF PRAVASTATIN ON ERYTHROCYTE MEMBRANE FATTY ACID CONTENTS IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Treatment with statin has been decreased the risk of cardiovascular events in patients with chronic kidney disease (CKD). Erythrocyte membrane oleic acid contents are significantly higher in patients with acute coronary syndrome than control subjects. Still, there is no report about the effect of statin on erythrocyte membrane fatty acid (FA) including oleic acid. The aim of this study was to evaluate the effect of pravastatin on the erythrocyte membrane FA in patients with CKD. Method Sixty two CKD patients were enrolled in this single arm randomized clinical trial and this trial was conducted at two centers from Jan 2017 to March 2019 (NCT02992548). Pravastatin with dose of 20mg was initially treated for 24 weeks. Pravastatin dose was increased to 40mg after 12 weeks, if it is necessary to control dyslipidemia. The primary outcome of this study was the change of erythrocyte membrane FA including oleic acid after pravastatin treatment for 24 weeks. We checked total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol and adiponectin for secondary outcome at baseline and after 24 weeks. Erythrocyte membrane FA contents were measured by gas chromatography at baseline and after 24 weeks. Results Forty-five patients finished this study (age: 59.2±12.4 years, male: 42.2%, diabetes: 48.9%). There was no adverse effect related with pravastatin. Baseline serum creatinine was 1.5±0.7 mg/dL and estimated glomerular filtration rate was 54.2±27.3 ml/min/1.73 m2. Compared to baseline, total cholesterol (223.1±50.8 mg/dL vs. 168.4±32.5 mg/dL), LDL-cholesterol (149.1±35.3mg/dL vs. 100.1±25.4 mg/dL) and C-reactive protein were significantly decreased after pravastatin treatment. There were no significant changes in triglyceride, HDL-cholesterol, serum creatinine, amounts of proteinuria and adiponectin levels. Saturated FA, oleic acid and arachidonic acid contents of erythrocyte membrane were significantly increased after pravastatin treatment compared to baseline levels. Polyunsaturated FA (PUFA) and linoleic acid were significantly decreased after pravastatin treatment compared to baseline. Decreased tendency of eicosapentaenoic acid and omega-3 index were found after pravastatin treatment. Conclusion Linoleic acid or omega-3 FA supplementations may be necessary to recover erythrocyte membrane FA changes, when pravastatin is used for dyslipidemia treatment in CKD patients. Further study for reducing cardiovascular events are necessary by using combined PUFA and pravastatin treatment.

The Efficacy of Polyunsaturated Fatty Acids as Protectors against Calcium Oxalate Renal Stone Formation: A Review.

In the pathogenesis of hypercalciuria and hyperoxaluria, n-6 polyunsaturated fatty acids (PUFAs) have been implicated by virtue of their metabolic links with arachidonic acid (AA) and prostaglandin PGE2. Studies have also shown that n-3 PUFAs, particularly those in fish oil—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—can serve as competitive substrates for AA in the n-6 series and can be incorporated into cell membrane phospholipids in the latter’s place, thereby reducing urinary excretions of calcium and oxalate. The present review interrogates several different types of study which address the question of the potential roles played by dietary PUFAs in modulating stone formation. Included among these are human trials that have investigated the effects of dietary PUFA interventions. We identified 16 such trials. Besides fish oil (EPA+DHA), other supplements such as evening primrose oil containing n-6 FAs linoleic acid (LA) and γ-linolenic acid (GLA) were tested. Urinary excretion of calcium or oxalate or both decreased in most trials. However, these decreases were most prominent in the fish oil trials. We recommend the administration of fish oil containing EPA and DHA in the management of calcium oxalate urolithiasis.

Effect of High-Dose vs Standard-Dose Vitamin D Supplementation in Pregnancy on Bone Mineralization in Offspring Until Age 6 Years

Studies suggest an association between maternal vitamin D status during pregnancy and offspring anthropometry and bone mineralization, but investigations are few and with mixed results. To investigate the effect of a high dose vs standard dose of vitamin D supplementation in pregnancy on anthropometric and bone outcomes until age 6 years in the offspring. A prespecified analysis of a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort that included 623 pregnant mothers and their 584 children. Data were analyzed between January 2019 and September 2019. Vitamin D supplementation of 2800 IU/d (high-dose) vs 400 IU/d (standard-dose) from pregnancy week 24 until 1 week after birth. Longitudinal anthropometry assessments including length/height, weight, and body mass index until age 6 years and bone mineral content (BMC) and bone mineral density (BMD) at age 3 years and 6 years from dual-energy radiography absorptiometry scans. At age 6 years, 517 children (89%) completed the clinical follow-up. All participants were Danish and white; 261 were boys and 256 were girls. A mixed-effects model analysis of dual-energy radiography absorptiometry scan outcomes from ages 3 years and 6 years showed that children in the vitamin D vs placebo group had higher whole-body BMC: mean difference adjusted (aMD) for age, sex, height, and weight was 11.5 g (95% CI, 2.3-20.7; P = .01); higher whole-body-less-head BMC aMD was 7.5 g (95% CI, 1.5-13.5; P = .01); and higher head BMD aMD was 0.023 g/cm2 (95% CI, 0.003-0.004; P = .03). The largest effect was in children from vitamin D-insufficient mothers (<30 ng/mL; to convert to nanomoles per liter, multiply by 2.496) and among winter births. In a post hoc analysis, we found borderline lower incidence of fractures in the vitamin D group (n = 23 vs n = 36; incidence rate ratio, 0.62 [95% CI, 0.37-1.05]; P = .08), but no differences in any anthropometric outcomes. Adjustment for a concomitant ω-3 polyunsaturated fatty acids intervention did not change the results. High-dose vitamin D supplementation in pregnancy improved offspring bone mineralization through age 6 years compared with the standard dose, suggesting an increased recommended gestational intake, which may influence peak bone mass, fracture risk, and risk of osteoporosis later in life. We found no supplementation effect on anthropometric outcomes. ClinicalTrials.gov Identifier: NCT00856947.

Angiopoietin-1 protects 3T3-L1 preadipocytes from saturated fatty acid–induced cell death

Cross talk between endothelial cells and adipocytes is vital to adipocyte functions, but little is known about the mechanisms or factors controlling the process. Angiogenesis is a critical component linking the endothelium to healthy adipogenesis, yet it is not known if or how it is involved in adipocyte physiology. Therefore, the purpose of this study was to determine the effect of angiopoietin-1 (Ang-1) and -2 (Ang-2) as well as their receptor, Tie-2, on adipocyte physiology. 3T3-L1 pre- and mature adipocytes were found to express Ang-1, Ang-2, and Tie-2, which decrease upon polyunsaturated fatty acid treatment. Furthermore, 3T3-L1 cells treated with recombinant Ang-1 or Ang-2 increased expression of the antiapoptotic gene Bcl-x and decreased expression of the proapoptotic gene Casp-8. Next, preadipocytes were treated with saturated fatty acids (SFAs) to induce cell stress. SFA-mediated splicing of X-box-binding protein-1 was reduced by co-treatment with Ang-1, and cell viability was improved in the presence of SFAs + Ang-1. Taken together, these results indicate that Ang-1 may protect preadipocytes from SFA-induced apoptosis and endoplasmic reticulum stress.

Marine-derived fatty acids therapy for stroke: a systematic review

AbstractWith stroke burden increasing rapidly in recent years, the need for therapies that mitigate the acute insult persists(1). Experimental stroke evidence has shown a neuroprotective effect of marine-derived n-3 polyunsaturated fatty acids (PUFAs), resulting in improved functional outcomes(2). However, evidence in humans remains unclear. Therefore, we conducted a systematic review(3) to evaluate the effects of marine-derived n-3 PUFAs on functional outcomes and dependence after stroke. Secondary outcomes included vascular-related death, recurrence, and adverse events.We searched the Cochrane Stroke Group trials register and the following databases: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL EBSCO, and Web of Science (SCI-EXPANDED, CPCI-S, and BIOSIS). We also hand-searched relevant sources and used the Science Citation Index Reference Search. We included randomised controlled trials (RCTs) assessing marine-derived n-3 PUFAs intervention in people with history of stroke and/or transient ischaemic attack. Two authors independently selected trials, extracted data, assessed risk of bias, and evaluated the quality of the evidence. We contacted study authors for clarification and conducted random effects meta-analysis or narrative synthesis, as appropriate. We divided studies by follow-up length (up to three months and more than three months).Twenty-nine RCTs were included. Of these, nine studies (3,339 participants) provided outcome data with only one study assessing acute stroke (subarachnoid haemorrhage). Doses of marine-derived n-3 PUFAs ranged from 400 to 3,300 mg per day. Functionality was assessed only in two small studies, one in each follow-up category. These trials reported a trend in improvement (RR 0.78, 95% CI 0.36 to 1.68, 40 participants; and mean difference 7.09, 95% CI -5.16 to 19.34, 52 participants; respectively). However, due to imprecision and small sample size, the quality of the evidence was very low. No studies reported on acute ischaemic stroke.Our results show that, currently, evidence on the effect of marine-derived n-3 PUFAs on functional outcomes of stroke is limited and of very low quality. Therefore, more RCTs are needed, especially in the acute phase, to determine whether such intervention could improve stroke outcomes.This abstract is based on a post-peer review version of a Cochrane Review. Upon completion and approval, the final version is expected to be published in the Cochrane Database of Systematic Reviews.