Long-chain Polyunsaturated Fatty Acid Supplementation Research Articles

Age-Dependent Changes in Nrf2/Keap1 and Target Antioxidant Protein Expression Correlate to Lipoxidative Adducts, and Are Modulated by Dietary N-3 LCPUFA in the Hippocampus of Mice.

The brain has a high metabolism rate that may generate reactive oxygen and nitrogen species. Consequently, nerve cells require highly efficient antioxidant defenses in order to prevent a condition of deleterious oxidative stress. This is particularly relevant in the hippocampus, a highly complex cerebral area involved in processing superior cognitive functions. Most current evidence points to hippocampal oxidative damage as a causal effect for neurodegenerative disorders, especially Alzheimer's disease. Nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) is a master key for the transcriptional regulation of antioxidant and detoxifying systems. It is ubiquitously expressed in brain areas, mainly supporting glial cells. In the present study, we have analyzed the relationships between Nrf2 and Keap1 isoforms in hippocampal tissue in response to aging and dietary long-chain polyunsaturated fatty acids (LCPUFA) supplementation. The possible involvement of lipoxidative and nitrosative by-products in the dynamics of the Nrf2/Keap1 complex was examined though determination of protein adducts, namely malondialdehyde (MDA), 4-hydroxynonenal (HNE), and 3-nitro-tyrosine (NTyr) under basal conditions. The results were correlated to the expression of target proteins heme-oxygenase-1 (HO-1) and glutathione peroxidase 4 (GPx4), whose expressions are known to be regulated by Nrf2/Keap1 signaling activation. All variables in this study were obtained simultaneously from the same preparations, allowing multivariate approaches. The results demonstrate a complex modification of the protein expression patterns together with the formation of adducts in response to aging and diet supplementation. Both parameters exhibited a strong interaction. Noticeably, LCPUFA supplementation to aged animals restored the Nrf2/Keap1/target protein patterns to the status observed in young animals, therefore driving a "rejuvenation" of hippocampal antioxidant defense.

The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk.

Long-chain polyunsaturated fatty acids (LC-PUFAs) are obtained from diet or derived from essential shorter-chain fatty acids, and are crucial for brain development and functioning. Fundamentally, LC-PUFAs' neurobiological effects derive from their physicochemical characteristics, including length and double bond configuration, which differentiate LC-PUFA species and give rise to functional differences between n(omega)-3 and n-6 LC-PUFAs. LC-PUFA imbalances are implicated in psychiatric disorders, including major depression and suicide risk. Dietary intake and genetic variants in enzymes involved in biosynthesis of LC-PUFAs from shorter chain fatty acids influence LC-PUFA status. Domains impacted by LC-PUFAs include 1) cell signaling, 2) inflammation, and 3) bioenergetics. 1) As major constituents of lipid bilayers, LC-PUFAs are determinants of cell membrane properties of viscosity and order, affecting lipid rafts, which play a role in regulation of membrane-bound proteins involved in cell-cell signaling, including monoaminergic receptors and transporters. 2) The n-3:n-6 LC-PUFA balance profoundly influences inflammation. Generally, metabolic products of n-6 LC-PUFAs (eicosanoids) are pro-inflammatory, while those of n-3 LC-PUFAs (docosanoids) participate in the resolution of inflammation. Additionally, n-3 LC-PUFAs suppress microglial activation and the ensuing proinflammatory cascade. 3) N-3 LC-PUFAs in the inner mitochondrial membrane affect oxidative stress, suppressing production of and scavenging reactive oxygen species (ROS), with neuroprotective benefits. Until now, this wealth of knowledge about LC-PUFA biomechanisms has not been adequately tapped to develop translational studies of LC-PUFA clinical effects in humans. Future studies integrating neurobiological mechanisms with clinical outcomes may suggest ways to identify depressed individuals most likely to respond to n-3 LC-PUFA supplementation, and mechanistic research may generate new treatment strategies.

Lung function in preterm infants at 3 months corrected age after neonatal LC-PUFA supplementation.

To test the hypothesis that long-chain polyunsaturated fatty acid (LC-PUFA) supplementation improves lung function at 3 months corrected age (CA) compared with standard treatment in very preterm infants. We also aimed to investigate the association between bronchopulmonary dysplasia (BPD), longitudinal growth, and lung function at 3 months CA. A secondary analysis from the ImNuT trial, in which 121 infants with gestational age <29 weeks were randomized to a daily supplement with arachidonic acid (ARA) and docosahexaenoic acid (DHA) (ARA:DHA group) or MCT-oil (control group) from birth up to 36 weeks postmenstrual age (PMA). Lung function was assessed at 3 months CA by tidal flow volume loops and the outcomes were the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) and tidal volume (VT ) per body weight (mL/kg). Thirty-nine infants in the ARA:DHA group versus 51 in the control group had a successful lung function test. There was no mean difference (MD) in tPTEF /tE ratio (MD: 0.01, 95% confidence interval [CI]: -0.04 to 0.05; p = .77) or VT (MD: 0.09 mL/kg, 95% CI: -0.79 to 0.62; p = .81) between the study groups. The multivariable regression model showed that BPD was associated with tPTEF /tE ratio ≤ 0.25 (p = .03) and that an increase in z score for length after 36 weeks PMA correlated positively with VT (mL/kg) (p = .03). Neonatal LC-PUFA supplementation did not improve lung function at 3 months CA in very preterm infants. BPD was independently associated with reduced lung function, while improved linear growth correlated with higher tidal volumes.

Lipid Aldehydes 4-Hydroxynonenal and 4-Hydroxyhexenal Exposure Differentially Impact Lipogenic Pathways in Human Placenta.

Long chain polyunsaturated fatty acids (LCPUFAs), such as the omega-6 (n-6) arachidonic acid (AA) and n-3 docosahexanoic acid (DHA), have a vital role in normal fetal development and placental function. Optimal supply of these LCPUFAs to the fetus is critical for improving birth outcomes and preventing programming of metabolic diseases in later life. Although not explicitly required/recommended, many pregnant women take n-3 LCPUFA supplements. Oxidative stress can cause these LCPUFAs to undergo lipid peroxidation, creating toxic compounds called lipid aldehydes. These by-products can lead to an inflammatory state and negatively impact tissue function, though little is known about their effects on the placenta. Placental exposure to two major lipid aldehydes, 4-hydroxynonenal (4-HNE) and 4-hydroxyhexenal (4-HHE), caused by peroxidation of the AA and DHA, respectively, was examined in the context of lipid metabolism. We assessed the impact of exposure to 25 μM, 50 μM and 100 μM of 4-HNE or 4-HHE on 40 lipid metabolism genes in full-term human placenta. 4-HNE increased gene expression associated with lipogenesis and lipid uptake (ACC, FASN, ACAT1, FATP4), and 4-HHE decreased gene expression associated with lipogenesis and lipid uptake (SREBP1, SREBP2, LDLR, SCD1, MFSD2a). These results demonstrate that these lipid aldehydes differentially affect expression of placental FA metabolism genes in the human placenta and may have implications for the impact of LCPUFA supplementation in environments of oxidative stress.

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

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

EBNEO commentary: Maternal high-dose DHA supplementation and neurodevelopment in infants born before 29 weeks' gestation.

This was a planned follow-up study of the Canadian multicentre, randomised, double-blind, placebo-controlled superiority trial, Maternal Omega-3 Supplementation to Reduce Bronchopulmonary Dysplasia in Very Preterm Infants (MOBYDIck). Enrolment in the primary study occurred from 2015 to 2018. A total of 457 infants were included in the final analysis.1, 2 At 18–22 months' corrected age, neurodevelopmental outcomes as assessed by Bayley-III cognitive, language, and motor composite scores were not statistically significant between the treatment and placebo groups.1 The rates of death before 18–22 months' corrected age, cerebral palsy, hearing impairment and visual impairment were also not statistically significant between the two groups.1 Some aspects may bias study results towards the null. First, approximately half the infants in both groups received intravenous docosahexaenoic acid (DHA). This was on average for 21–23 days, in the form of DHA-rich lipids. Second, there may have been additional enteral DHA supplementation in both groups. At 6 weeks postmenstrual age, infants received a median of 130–133 mL/kg/day of expressed breast milk.1 This suggests that many infants at this age were receiving supplemental nutrition, such as donor breast milk or formula. Formula frequently contains DHA.3 The use of fortifier, which also contains DHA, was not commented on.4 The total fatty acid levels in breast milk at 14 days post-delivery were, on average, similar between the groups. In the treatment group DHA composed on average 0.97% of total fatty acids in breast milk at 14 days post-delivery, and in the placebo group, 0.35%.1 The authors note the hypothesis that sole DHA supplementation may cause an imbalance between the long-chain polyunsaturated fatty acids (LCPUFAs), potentially negating the benefits of high-dose DHA supplementation.1 Indeed, expert consensus statements recommend that preterm infants are supplemented with multiple LCPUFAs, such as DHA and arachidonic acid.4, 5 Due to the lower frequency of severe intraventricular haemorrhage (IVH) in the DHA group, a post hoc sensitivity analysis excluding participants with severe IVH was completed. This did not change the primary findings. Subgroup analysis found that for neonates born <27 weeks' gestation, those in the treatment group had a higher language score (mean difference 5.06, 95% CI 0.08–10.03; p = 0.05). This analysis was not adjusted for the imbalance in frequency of IVH.1 Further study limitations are well documented by the authors. This includes a suboptimal sample size limiting study interpretation, as enrolment for the MOBYDIck trial was terminated early due to concern that DHA was associated with bronchopulmonary dysplasia.1 Additionally, the sample size was chosen for the primary outcome of the MOBYDIck trial, and therefore has limited ability to detect differences in the primary outcome of this study. Despite the theoretical benefit of LCPUFA supplementation for preterm infants, several randomised controlled trials and a Cochrane systematic review have found little, if any, clinical neurodevelopmental effect.4, 6-9 This study is important as there is limited data on very preterm and extremely preterm infants. Based on this trial, maternal supplementation with high-dose DHA in breastfed infants born before 29 weeks' gestational age does not improve neurodevelopmental outcomes at 18–22 months' corrected age. URL LINK: https://ebneo.org/ebneo-commentary-maternal-dha-and-nd DV wrote the initial draft with AK providing key input. All authors revised the paper for critical scientific content. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. AK receives funding from the Australian National Health and Medical Research Council (NHMRC) (APP1161379). The contents of this paper are solely the responsibility of the individual authors and do not reflect the views of the NHMRC. The authors have no conflicts of interest to declare.

Effects of n-3 polyunsaturated fatty acid supplementation on quadriceps weakness immediately after total knee arthroplasty: a pilot, randomized, open-label clinical trial.

[Purpose] Severe quadriceps weakness immediately after total knee arthroplasty can be problematic. The n-3 long-chain polyunsaturated fatty acids have antioxidant and anti-inflammatory effects against ischemia-reperfusion injury, whereas n-6 long-chain polyunsaturated fatty acids exert pro-inflammatory effects, thereby promoting ischemia-reperfusion injury. [Participants and Methods] We explored the efficacy of preoperative n-3 long-chain polyunsaturated fatty acid supplementation against early quadriceps weakness among 20 patients scheduled for total knee arthroplasty (intervention group, n=10; control group, n=10). The intervention group received 645 mg of eicosapentaenoic acid) and 215 mg of docosahexaenoic acid daily for 30 days preoperatively. Serum eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were measured preoperatively. We compared serum derivatives of reactive oxygen metabolites as oxidative stress biomarkers, knee circumference, thigh volume, knee pain during the quadriceps strength test, and quadriceps strength preoperatively and 4 days postoperatively to quantify the change. [Results] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation significantly increased the (eicosapentaenoic acid+docosahexaenoic acid)/arachidonic acid ratio in the intervention group. A significantly lower increase in quadriceps weakness was exhibited in the intervention group than in the control group. However, changes in oxidative stress, knee/thigh swelling, and knee pain during strength testing did not significantly differ between the two groups. [Conclusion] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation exhibited beneficial effects on quadriceps weakness immediately after total knee arthroplasty.

Maternal omega-3 LC-PUFA supplementation programs an improved bone mass in the offspring with a more pronounced effect in females than males at adulthood

Early balanced nutrition is vital in achieving optimal skeletal mass and its maintenance. Although a lower omega-6 (n-6): omega-3 (n-3) long-chain polyunsaturated fatty acid (LC-PUFA) ratio is strongly linked with bone health, its maternal effect in the programming of the offspring's skeleton remains to be elucidated. Plugged C57BL/6 mice were fed either n-3 LC-PUFA Enriched Diet (LED) or a control diet (C) throughout their gestation and lactation. Offspring born to both the groups were weaned onto C till 6, 12, and 24 weeks of their age. Offspring's skeleton metabolism and serum fatty acid composition was studied. In humans, seventy-five mother-female newborns pairs from term gestation were tested for their maternal LC-PUFA status relationships to venous cord blood bone biomarkers. Offspring of maternal LED supplemented mice exhibited a superior bone phenotype over C, more prominent in females than males. A lower serum n-6/n-3 LC-PUFA in the LED group offspring was strongly associated with blood biomarkers of bone metabolism. Sexual dimorphism evidenced had a strong correlation between offspring's LC-PUFA levels and bone turnover markers in serum. A higher potential for osteoblastic differentiation in both LED offspring genders and reduced osteoclastogenesis in females was cell-autonomous effect. The human cross-sectional study also showed a positive correlation between maternal n-3 PUFA and cord blood markers of bone formation in female newborns at birth. Maternal dietary n-6/ n-3 fat quality determines offspring's bone growth and development. Our data suggest that the skeleton of female offspring is likely to be more sensitive to this early exposure.

Long-chain polyunsaturated fatty acid supplementation increases levels in red blood cells and reduces the prevalence and severity of squamous gastric ulcers in exercised Thoroughbreds.

To assess the relationship between plasma and RBC fatty acid composition and incidence and severity of squamous gastric ulcers when altered by short-chain (SC) or long-chain (LC) polyunsaturated fatty acid (PUFA) supplementation. 13 fit Thoroughbred horses in training. Horses were evaluated by gastroscopy for squamous ulcer score, gastric pH, and blood fatty acid composition prior to supplementation (UNSUPP) and after 3 months of supplementation with a corn-flax oil blend of alpha-linolenic acid and linoleic acid (SC-PUFA) or a gamma-linolenic acid (GLA)-fish oil blend of GLA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA; LC-PUFA) in a crossover design. Prior to gastroscopy and blood collection, horses performed a 4,600-m standardized exercise test on the racetrack as a stressor. Three months of supplementation with LC-PUFAs increased RBC levels of GLA, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), EPA, and DHA, and reduced severe ulcer prevalence (38% UNSUPP vs 8% LC-PUFA with a severe ulcer score of grade 3 to 4). Short-chain PUFA supplementation did not effectively elevate RBC GLA, DGLA, AA, EPA, or DHA and severe ulcer incidence was not different (38% UNSUPP vs 23% SC-PUFA with a severe ulcer score of grade 3 to 4). Lower levels of RBC GLA, DGLA, AA, and EPA correlated with severe squamous gastric ulceration (grade 3 to 4). Equine gastric ulcer syndrome is prevalent in high-performance horses and is a concern to owners and trainers. Long-chain PUFA supplementation increased levels of GLA, DGLA, AA, EPA, and DHA, unlike SC-PUFA supplementation, and was associated positively with prevention or resolution of severe squamous gastric ulceration. Further studies are needed to evaluate different management styles and exercise intensities.

Effects of n-3 long-chain polyunsaturated fatty acid supplementation on the omega-3 index, and exercise performance among Malaysian football players: a randomised controlled trial

PurposeThe present randomised controlled trial aimed to assess the effects of 8-week supplementation of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) on the n-3 index and performance of professional male football players.Design/methodology/approachA total of 27 professional male football players were randomly assigned into 2 groups: placebo (n = 14) and n-3 LCPUFA (n = 13). n-3 LCPUFA supplements containing 1.5 g eicosapentaenoic acid (EPA) and 600 mg docosahexaenoic acid (DHA) were administered as 6 capsules (four in the morning and two in the evening, 30 min after a meal). Anthropometry, body composition, dried-blood spot n-3 LCPUFA levels, exercise performance and dietary intake of football players were measured at week 0, week 4 and week 8.Findingsn-3 LCPUFA supplementation improved blood levels of EPA and DHA levels, omega-3 index vs placebo (p time*group = 0.010, 0.041 and 0.018, respectively). n-3 LCPUFA supplemented group had significantly higher aerobic capacity than placebo participants, at week 8 (p group = 0.021).Originality/valueThis study shows the effect of n-3 LCPUFA supplementation in Malaysian professional male football players involved in team sports having low dietary intakes of n-3 LCPUFA.

The Effect of Dietary Supplementations on Delaying the Progression of Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

Purpose: Age-related macular degeneration (AMD) is a neurodegenerative ophthalmic disease. The purpose of this systematic review (SR) and meta-analysis was to evaluate if dietary supplementation alone or in combinations might delay the progression of any of the stages of AMD. Methods: A SR and meta-analysis identifying cohort studies and randomized controlled trials (RCTs) evaluating the effect of supplements in patients diagnosed with AMD. PubMed, Scopus, Web of Science, CINAHL, and Cochrane were searched through 8th October 2021. Results: Twenty studies, examining 5634 participants ranging from 55 to 80 years, were included in the SR. Eight studies were selected for meta-analysis (414 and 216 subjects in the intervention and control groups). Lutein and zeaxanthin plus n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) supplementation showed significant improvements in best-corrected visual acuity (BCVA) (SMD: −1.99, 95% CI: −3.33, −0.65) compared to the control group. Multifocal electroretinogram results (mfERG) were significantly improved overall (SMD: 4.59, 95% CI: 1.75, 7.43) after lutein plus zeaxanthin supplementation. Conclusions: Combinations of lutein and zeaxanthin with n-3 LC-PUFA might be beneficial in preventing AMD progression and deterioration of visual function. Our results encourage initiating further studies with combinations of n-3 LC-PUFA, lutein, and zeaxanthin especially in early AMD patients.

The Fish Oil to Reduce Tobacco Use iN Expectant mothers (FORTUNE) feasibility trial

Three small clinical trials have suggested that supplementation with n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) found in fish oils may reduce nicotine cravings and at higher doses reduce cigarette consumption. Pregnant women who smoke have fewer pharmacologic options to aid them with smoking cessation. Although n-3 long-chain polyunsaturated fatty acid supplementation has been studied in pregnancy, few studies have evaluated doses of ≥4 g per day, and no previous studies have selectively enrolled pregnant women who smoke. High-dose n-3 long-chain polyunsaturated fatty acids may aid cessation but could be poorly tolerated in pregnant women who smoke because of gastrointestinal side effects. We conducted a feasibility trial to determine the tolerability of high-dose n-3 long-chain polyunsaturated fatty acid supplementation in pregnant women who smoked. We hypothesized that n-3 long-chain polyunsaturated fatty acid doses of 4.2 g a day would be well-tolerated relative to an olive oil placebo. We assessed red blood cell phospholipid membrane concentrations at baseline and end of therapy (4 weeks) and piloted outcomes for a future efficacy trial of n-3 long-chain polyunsaturated fatty acid supplementation for smoking cessation in pregnancy. We recruited 28 pregnant women between the gestational ages of 6 and 36 weeks who reported daily cigarette smoking and were motivated to quit to participate in a double-blind placebo-controlled randomized feasibility trial of 4.2 g per day of n-3 long-chain polyunsaturated fatty acid supplementation. Participants reported cigarettes per day, completed the Fagerström Test for Cigarette Dependence, and provided blood, urine, and exhaled CO samples. We used repeated-measures analysis of variance to pilot analyses of changes in cigarettes per day and Fagerström Test for Cigarette Dependence scores. At baseline, red blood cell membrane eicosapentaenoic acid concentrations were negatively correlated with cigarettes per day (r=-0.44; P=.04). By 4 weeks, circulating n-3 long-chain polyunsaturated fatty acid levels increased by 18% in the n-3 long-chain polyunsaturated fatty acid supplementation arm vs a decrease of 3% in the placebo arm. Occurrence of gastrointestinal side effects such as burping, heartburn, diarrhea, abdominal pain, or nausea did not differ statistically between study arms. At 4 weeks, participants allocated to the n-3 long-chain polyunsaturated fatty acids arm reported a median of 3 cigarettes per day (interquartile range, 1-8) vs 7 cigarettes per day (interquartile range, 1-14) in the placebo arm, which was not statistically significant (P=.99). Participants allocated to the n-3 long-chain polyunsaturated fatty acids arm had a decrease of 1 (interquartile range, 0-1) on the Fagerström Test for Cigarette Dependence score vs 0 (interquartile range, 0-0) for placebo (P=.46). High-dose n-3 long-chain polyunsaturated fatty acids may be tolerated in pregnant women who smoke; however, there was a high level of participant dropout, with more participants allocated to the fish oil arm becoming lost to follow-up. These results will inform the design of a future large-scale randomized controlled trial to test the impact of fish oil supplements on smoking cessation in pregnancy.

Effects of Dietary n-3 LCPUFA Supplementation on the Hippocampus of Aging Female Mice: Impact on Memory, Lipid Raft-Associated Glutamatergic Receptors and Neuroinflammation.

Long-chain polyunsaturated fatty acids (LCPUFA), essential molecules whose precursors must be dietary supplied, are highly represented in the brain contributing to numerous neuronal processes. Recent findings have demonstrated that LCPUFA are represented in lipid raft microstructures, where they favor molecular interactions of signaling complexes underlying neuronal functionality. During aging, the brain lipid composition changes affecting the lipid rafts’ integrity and protein signaling, which may induce memory detriment. We investigated the effect of a n-3 LCPUFA-enriched diet on the cognitive function of 6- and 15-months-old female mice. Likewise, we explored the impact of dietary n-3 LCPUFAs on hippocampal lipid rafts, and their potential correlation with aging-induced neuroinflammation. Our results demonstrate that n-3 LCPUFA supplementation improves spatial and recognition memory and restores the expression of glutamate and estrogen receptors in the hippocampal lipid rafts of aged mice to similar profiles than young ones. Additionally, the n-3 LCPUFA-enriched diet stabilized the lipid composition of the old mice’s hippocampal lipid rafts to the levels of young ones and reduced the aged-induced neuroinflammatory markers. Hence, we propose that n-3 LCPUFA supplementation leads to beneficial cognitive performance by “rejuvenating” the lipid raft microenvironment that stabilizes the integrity and interactions of memory protein players embedded in these microdomains.

Effect of Enteral Long-Chain Polyunsaturated Fatty Acids on Retinopathy of Prematurity: A Systematic Review and Meta-Analysis

Background: Long-chain polyunsaturated fatty acids (LCPUFA) are critical for the maturation of the brain and retina. Retinopathy of prematurity (ROP) is a preventable cause of blindness in preterm infants. LCPUFA have anti-inflammatory, antioxidant, and antiangiogenesis effects. Supplementation of enteral LCPUFA might mitigate the incidence of ROP in these infants. Available limited randomized studies showed promising results. We aimed to assess the effect of enteral supplementation of LCPUFA on ROP in preterm infants. Methods: We followed PRISMA guidelines and searched MEDLINE, Cumulative Index of Nursing and Allied Health Literature, Embase, and Cochrane Registry from 1990 to 2021 for the studies that examined the effects of enteral LCPUFA and ROP in preterm infants. We included the studies that satisfied the predefined inclusion criteria. RevMan 5.3 software derived the forest plot of pooled relative risk. We assessed the quality of all the included studies using GRADE recommendations. Results: Nine studies were eligible for the meta-analysis involving 2,482 infants. Of the nine RCTs, six studies provided LCPUFA (DHA/AA) as a separate intervention in different concentrations, and three studies provided formula milk enriched with LCPUFA. In addition, five studies recruited infants below 32 weeks of gestational age. Supplementation of LCPUFA did not reduce the incidence of severe ROP (RR 0.71, 95% CI: 0.50–1.01, 5 studies, 1,822 infants) with very low CoE or any ROP (RR 0.95, 95% CI: 0.73–1.12, 6 studies, 1,177 infants) with very low CoE or ROP requiring treatment (RR 0.92, 95% CI: 0.62–1.38, 4 studies, 1,395 infants) with very low CoE. Regarding safety outcomes, enteral LCPUFA did not increase the risk of necrotizing enterocolitis or mortality. Discussion/Conclusion: Supplementation of enteral LCPUFA to preterm infants did not reduce ROP incidence; however, there was a trend toward benefit in mitigating severe form of ROP. More well-designed, large, randomized controlled studies are warranted.

Hyperandrogenism diminishes maternal-fetal fatty acid transport by increasing FABP4-mediated placental lipid accumulation†.

Long-chain polyunsaturated fatty acids (LCPUFAs) are critical for fetal brain development. Infants born to preeclamptic mothers or those born growth restricted due to placental insufficiency have reduced LCPUFA and are at higher risk for developing neurodevelopmental disorders. Since plasma levels of testosterone (T) and fatty acid-binding protein 4 (FABP4) are elevated in preeclampsia, we hypothesized that elevated T induces the expression of FABP4 in the placenta leading to compromised transplacental transport of LCPUFAs. Increased maternal T in pregnant rats significantly decreased n-3 and n-6 LCPUFA levels in maternal and fetal circulation, but increased their placental accumulation. Dietary LCPUFAs supplementation in T dams increased LCPUFA levels in the maternal circulation and further augmented placental storage, while failing to increase fetal levels. The placenta in T dams exhibited increased FABP4 mRNA and protein levels. In vitro, T dose-dependently upregulated FABP4 transcription in trophoblasts. Testosterone stimulated androgen receptor (AR) recruitment to the androgen response element and trans-activated FABP4 promoter activity, both of which were abolished by AR antagonist. Testosterone in pregnant rats and cultured trophoblasts significantly reduced transplacental transport of C14-docosahexaenoic acid (DHA) and increased C14-DHA accumulation in the placenta. Importantly, FABP4 overexpression by itself in pregnant rats and trophoblasts increased transplacental transport of C14-DHA with no significant placental accumulation. Testosterone exposure, in contrast, inhibited this FABP4-mediated effect by promoting C14-DHA placental accumulation.

Maternal and Neonatal Polyunsaturated Fatty Acid Intake and Risk of Neurodevelopmental Impairment in Premature Infants.

The N3 and N6 long chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are essential for proper neurodevelopment in early life. These fatty acids are passed from mother to infant via the placenta, accreting into fetal tissues such as brain and adipose tissue. Placental transfer of LCPUFA is highest in the final trimester, but this transfer is abruptly severed with premature birth. As such, efforts have been made to supplement the post-natal feed of premature infants with LCPUFA to improve neurodevelopmental outcomes. This narrative review analyzes the current body of evidence pertinent to neurodevelopmental outcomes after LCPUFA supplementation in prematurely born infants, which was identified via the reference lists of systematic and narrative reviews and PubMed search engine results. This review finds that, while the evidence is weakened by heterogeneity, it may be seen that feed comprising 0.3% DHA and 0.6% AA is associated with more positive neurodevelopmental outcomes than LCPUFA-deplete feed. While no new RCTs have been performed since the most recent Cochrane meta-analysis in 2016, this narrative review provides a wider commentary; the wider effects of LCPUFA supplementation in prematurely born infants, the physiology of LCPUFA accretion into preterm tissues, and the physiological effects of LCPUFA that affect neurodevelopment. We also discuss the roles of maternal LCPUFA status as a modifiable factor affecting the risk of preterm birth and infant neurodevelopmental outcomes. To better understand the role of LCPUFAs in infant neurodevelopment, future study designs must consider absolute and relative availabilities of all LCPUFA species and incorporate the LCPUFA status of both mother and infant in pre- and postnatal periods.

Immune responses and acute inflammation in common carp Cyprinus carpio injected by E.coli lipopolysaccharide (LPS) as affected by dietary oils

Eicosanoids, resolvins, and lipoxins formed from long-chain polyunsaturated fatty acids (LC-PUFAs) are the main lipid mediators in the inflammatory processes explaining the influence of dietary lipid sources on the immune system. The current study aimed to determine the effects of dietary plant oils instead of fish oil or LC-PUFA supplementation in these oils on fish immune and inflammatory responses under normal and LPS-stimulated conditions. Six iso-nitrogenous (ranging from 30.4 to 31.1%) and iso-lipidic (from 11.2 to 11.6%) diets were formulated using three oil sources: cod liver oil (CLO, as fish oil control); linseed oil (LO, rich in α-linolenic acid, ALA); sesame oil (SO, rich in linoleic acid, LA); a blend of LO and SO (SLO, v:v 1:1); and two pure plant oil diets supplemented with docosahexaenoic acid, DHA (SO + DHA, SOD) or arachidonic acid, ARA (LO + ARA, LOA). Fish were fed the experimental diets to satiation for 42 days. On day 43, they were injected with E.coli lipopolysaccharide (LPS) at 100 μg/fish. Fish plasma and tissues such as head kidney and liver were collected on day 42 and one day after LPS injection (day 44) for humoral immune variables and gene expression analyses, respectively. After 42 days of feeding, no influences of dietary oils were found on fish survival, growth, feed utilization, and humoral immune responses. On the other hand, LPS injection significantly stimulated immune responses and induced an acute inflammation in common carp through an increase of the complement activity and the up-regulation of genes involved in the innate immune system (c2), pro-inflammatory response (tlr-4, tnf-α, il-1, il-6, il-8, and cxc), eicosanoid metabolism (pla2, cox-1, 5-lox, and pge2), and anti-inflammatory response (tgf-β1 and nf-fki). Further, the expression of hsp70 was stimulated by LPS injection. The effects of dietary oil sources were observed after LPS injection, with a significant modification in the expression of almost all candidate genes. The highest pro-inflammatory responses induced by LPS were observed in CLO-fed fish while the mixture of plant oils (SLO) and LC-PUFA-supplemented diets induced significantly higher modulations in anti-inflammatory responses (il-10 and nf-kbi), general stress status (hsp70), and cytoprotection (gpx-1) compared to fish oil control and other pure plant oil groups. In conclusion, the immune response of common carp has been modified by the dietary fat sources. The fish oil-based diet supported an increase of the pro-inflammatory responses while the mixture of plant oil or LC-PUFA supplemented diets improved the anti-inflammatory responses and cytoprotection.

Effect of nutritional intervention on nutritional status among children with disorders of amino acid and nitrogen metabolism (AANMDs): A scoping review.

Disorders of amino acid and nitrogen metabolism (AANMDs) occur due to an enzyme deficiency in a normal biochemical pathway. Nutritional intervention is recognized as the mainstay of treatment for children diagnosed with AANMD. Hence, this scoping review aimed to identify the nutritional interventions available in managing AANMD disorders and their effects on nutritional status. A systematic search using PRISMA Extension for Scoping Reviews (PRISMA-ScR) method was conducted across 4 databases: PubMed, ScienceDirect (Elsevier), EBSCOhost and Cochrane Central Register of Controlled Trials (CENTRAL). Inclusion criteria for the study to be selected are: subjects aged less than 18-year-old, article published in English, utilized an experimental design and published within the past 20 years. A total of 22 articles were included in this review. The majority of the subjects are boys (55.6%) and employed a randomized controlled trial (RCT) study design (45.4%). Nutritional interventions were categorized into 4 categories which are: "protein substitute" (n = 5), "protein substitute with modified composition" (n = 6), "nutrient supplementation (n=8)", and "distribution and dosage of protein substitute (n = 3)". The most frequently assessed outcomes were biochemical parameters that gauge the effectiveness of metabolic control (68.2%). Overall, "protein substitute enriched with inhibitive amino acids", "long-chain polyunsaturated fatty acids supplementation", and "evenly distributed protein substitute" demonstrated beneficial effects towards the nutritional status, especially in terms of biochemical parameters. In summary, nutritional intervention plays a significant role in improving the nutritional status of AANMD patients. Further investigations of nutritional intervention among AANMD children using a meta-analysis approach are necessary for better comprehension of their impact in management of AANMD disorders.

Translating n-3 polyunsaturated fatty acid status from whole blood to plasma and red blood cells during pregnancy: Translating n-3 status across blood fractions in pregnancy

Women with low n-3 (omega-3) status in pregnancy can reduce their risk of early preterm birth (<34 weeks’ gestation) through n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation. As investigators measure fatty acid status in different blood fractions, equations are needed to compare results across studies. Similarly, derived cut-points for defining low and replete n-3 status are needed to assist clinical interpretation during early pregnancy. Our aims were to develop equations to convert the percentage of total n-3 fatty acids, EPA+DHA and DHA between whole blood, plasma and red blood cells (RBC), and to derive cut-points for defining low and replete total n-3 fatty acid status in plasma and RBC from those already established in whole blood. Using blood samples from 457 pregnant women in a multicentre randomised controlled trial, equations for these interconversions were developed using simple linear regression models. Measures of n-3 fatty acid status in whole blood and plasma were strongly related (R2 > 0.85), while more moderate relationships were observed between measures in whole blood and RBC (R2 0.55 – 0.71), or plasma and RBC (R2 0.55 – 0.63). Using the conversion equations, established cut-points for low and replete n-3 status in whole blood (<4.2% and >4.9% of total fatty acids) converted to <3.7% and >4.3% of plasma total fatty acids, and to <7.3% and >8.1% of RBC total fatty acids. Agreement to define low and replete n-3 status was better between whole blood and plasma, rather than between whole blood and RBC. Our data also show that total n-3 fatty acids in plasma and serum are interchangeable. We conclude that either whole blood or plasma total n-3 fatty acids can be used to define low status in pregnancy and identify women who will most benefit from n-3 LCPUFA supplementation to reduce their risk of early birth. Further research is needed to determine the clinical utility of other fatty acid measures in various blood lipid fractions.

Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study

Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.