Prostaglandins, leukotrienes, and essential fatty acids最新文献

Linoleic acid (LA, omega-6), an essential polyunsaturated fatty acid, is supplied by vegetable oils such as corn, sunflower and soybean. Supplementary LA in infants and children is required for normal growth and brain development, but has also been reported to induce brain inflammation and neurodegenerative diseases. This controversial role of LA development requires further investigation. Our study utilized Caenorhabditis elegans (C. elegans) as a model to clarify the role of LA in regulating neurobehavioral development. A mere supplementary quantity of LA in C. elegans larval stage affected the worm's locomotive ability, intracellular ROS accumulation and lifespan. We found that more serotonergic neurons were activated by supplementing LA above 10 μM thereby promoting locomotive ability with upregulation of serotonin-related genes. Supplementation with LA above 10 μM also inhibited the expression of mtl-1, mtl-2 and ctl-3 to accelerate oxidative stress and attenuate lifespan in nematodes; however, enhancement of stress-related genes such as sod-1, sod-3, mtl-1, mtl-2 and cyp-35A2 by supplementary LA under 1 μM decreased oxidative stress and increased the worm's lifespan. In conclusion, our study reveals that supplementary LA possesses both pros and cons in worm physiology and provides new suggestions for LA intake administration in childhood.

Phospholipase A₂ (PLA₂) enzymes cleave cell membrane phospholipids and release polyunsaturated fatty acids (PUFA), which can be converted into oxylipins. However, little is known about PLA₂ preference for PUFA, and even less is known about how this further impacts oxylipin formation. Therefore, we investigated the role of different PLA₂ groups in PUFA release and oxylipin formation in rat hearts. Sprague-Dawley rat heart homogenates were incubated without or with varespladib (VAR), methyl arachidonyl fluorophosphonate (MAFP) or EDTA. Free PUFA and oxylipins were determined by HPLC-MS/MS, and isoform expressions by RT-qPCR. Inhibition of sPLA₂ IIA and/or V by VAR reduced the release of ARA and DHA, but only DHA oxylipins were inhibited. MAFP reduced the release of ARA, DHA, ALA, and EPA, and the formation of ARA, LA, DGLA, DHA, ALA, and EPA oxylipins. Interestingly, cyclooxygenase and 12-lipoxygenase oxylipins were not inhibited. mRNA expression levels of sPLA₂ and iPLA₂ isoforms were highest whereas levels of cPLA₂ were low, consistent with activity. In conclusion, sPLA₂ enzymes lead to the formation of DHA oxylipins, while iPLA₂ is likely responsible for the formation of most other oxylipins in healthy rat hearts. Oxylipin formation cannot be implied from PUFA release, thus, both should be evaluated in PLA₂ activity studies.

The olfactory mucosa (OM) and olfactory bulb (OB) are neuronal tissues that contribute to the early processing of olfactory information. They contain significant amounts of n-3 and n-6 polyunsaturated fatty acids (PUFAs), which are crucial for neuronal tissue development. In this study, we evaluated the impact of feeding mice diets that are either deficient in α-linolenic acid (ALA) or supplemented with n-3 long-chain PUFAs from gestation to adolescence on the phospholipid and ganglioside composition of these tissues. Both diets modified the levels of some phospholipid classes, notably the phosphatidylserine and phosphatidylethanolamine levels. In addition, the low-ALA diet enriched n-6 PUFAs in the main phospholipid classes of both tissues, while the diet supplemented with n-3 PUFAs enhanced the n-3 PUFA-containing phospholipid species level, mainly in OM. The diets also modulated the levels and profiles of several ganglioside classes in OM and OB. These modifications may have repercussions on the olfactory sensitivity.

Long-chain polyunsaturated fatty acids (LCPUFA) are important for brain development and functioning and with that, possibly school performance. Several cross-sectional studies have shown significant positive associations between fish consumption, an important source of LCPUFA and school grades in adolescents. The effect of LCPUFA supplementation on school grades in adolescents has not been investigated yet. The goal of the current study was to investigate (I) the associations between the Omega-3 Index (O3I) at baseline and after 12 months respectively and school grades and (II) the effect of one year krill oil supplementation (source of LCPUFA) on school grades in adolescents with a low O3I at baseline. A double-blind randomised placebo-controlled trial with repeated measurements was executed. Participants received either 400 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day for the first three months in Cohort 1 and the nine months thereafter 800 mg EPA + DHA per day, Cohort 2 started immediately with 800 mg EPA + DHA per day,or a placebo. The O3I was monitored with a finger prick at baseline, three, six and twelve months. Subject grades for English, Dutch and math were collected, a standardised mathematics test was executed at baseline and at 12 months. Data was analysed with (I) explorative linear regressions to investigate associations at baseline and follow-up and (II) mixed model analyses separately for each of the subject grades and the standardised mathematics test to investigate the effect of supplementation after 12 months. The krill oil group had a small significant increase in the mean O3I at all time points. However, very few participants achieved the intended target O3I range of 8–11%. At baseline a significant association between baseline O3I and English grade was show, additionally a trend for an association with Dutch grade was shown. After 12 months no significant associations were found. Additionally, there was no significant effect of krill oil supplementation on subject grades or standardised mathematics test score. In this study, no significant effect of krill oil supplementation on subject grades or standardised mathematics test performance was found. However, as many participants dropped out and/or were non-adherent, results should be interpreted with caution.

Maternal n-3 PUFA (omega-3) deficiency can affect brain development in utero and postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal hippocampus remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, the expression of fatty acid desaturases, elongases, free fatty acids signaling receptors, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent (∼31 fold), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus. Increasing dietary LA to ALA (50:1) elevated the ARA to DHA ratio by ∼8 fold in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by ∼15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient mice exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression in hippocampus (p<0.05). Maternal n-3 PUFA deficiency affects the hippocampal expression of key neurogenesis genes in the offspring with concomitant expression of desaturase and elongase genes, suggesting the importance of dietary n-3 PUFA for neurodevelopment.

Polyunsaturated fatty acids (PUFAs) have received attention for their anti-inflammatory and antioxidant properties. Preclinical studies have investigated the efficacy of PUFAs in animal models of spinal cord injury (SCI) to determine if these properties can translate to neuroprotection and locomotor recovery. Findings from such studies have been promising, suggesting PUFAs as potential treatments against the neurological dysfunction induced by SCI. This systematic review and meta-analysis sought to investigate the efficacy of PUFAs for promoting locomotor recovery in animal models of SCI. PubMed, Web of Science and Embase (Ovid) were searched for relevant papers and those that examined the restorative effects of PUFAs on locomotor recovery in preclinical SCI models were included in our analysis. A random effects meta-analysis (restricted maximum likelihood estimator) was employed. A total of 28 studies were included and the results showed the claim that PUFAs have a beneficial therapeutic effect for promoting locomotor recovery (SMD = 1.037, 95% CI = 0.809–1.2644, p = <0.001) and cell survival (SMD = 1.101, 95% CI = 0.889–1.313, p = <0.001) in animal models of SCI. No significant differences for the secondary outcomes of neuropathic pain and lesion volume. Moderate asymmetry was observed in the funnel plots for locomotor recovery, cell survival and neuropathic pain measures, suggesting publication bias. Trim-and-fill analysis estimated 13, 3, 0 and 4 missing studies for locomotor recovery, cell survival, neuropathic pain, and lesion volume, respectively. A modified CAMARADES checklist was also used to assess risk of bias, showing that the median score for all included papers was 4 out of a possible 7.

Perinatal depression can negatively affect the health of the mother and her offspring. N-3 polyunsaturated fatty acids (PUFA) may play a role in the aetiology of depression. Therefore, we investigated the association of n-3 PUFA status during early pregnancy with perinatal depression among women living in urban Johannesburg, South Africa. For this prospective analysis, we analysed red blood cell (RBC) total phospholipid fatty acid (FA) composition (% of total FA) of 242 pregnant women at $<$18 weeks’ gestation. We used the Edinburgh Postnatal Depression Scale (EPDS) to identify women at risk for depression (EPDS score $\ge$9) at $<$18, 22 and 36 weeks’ gestation, and at 6 and 12 months postpartum. RBC EPA status was negatively ($\beta$=-0.22, $p<0.05$), and the AA/EPA ratio positively ($\beta$=0.24, $p<0.05$) associated with EPDS scores at 12 months postpartum. Higher RBC DHA and n-3 index were further associated with lower odds (OR=0.56 [95% CI: 0.32-0.91]; OR=0.63 [95% CI: 0.39-0.94]), while higher n-6/n-3 PUFA and AA/EPA ratios early in pregnancy were associated with higher odds for depression at 12 months postpartum ((OR=2.34 [95% CI: 1.12-4.97]; OR=1.02 [95% CI: 1.00-1.05]). Our results suggest that women with a higher RBC n-3 PUFA status during early pregnancy may be at lower risk for depression at 12 months postpartum.

Prohibitins (PHB1 and PHB2) are ubiquitously expressed proteins which play critical roles in multiple biological processes, and together form the ring-like PHB complex found in phospholipid-rich cellular compartments including lipid rafts. Recent studies have implicated PHB1 as a mediator of fatty acid transport as well as a membrane scaffold mediating B lymphocyte and mast cell signal transduction. However, the specific role of PHBs in the macrophage have not been characterized, including their role in fatty acid uptake and lipid raft-mediated inflammatory signaling. We hypothesized that the PHB complex regulates macrophage inflammatory signaling through the formation of lipid rafts. To evaluate our hypothesis, RAW 264.7 macrophages were transduced with shRNA against PHB1, PHB2, or scrambled control (Scr), and then stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-α), which activate lipid raft-dependent receptor signaling (CD14/TLR4 and TNFR1, respectively). PHB1 knockdown was lethal, whereas PHB2 knockdown (PHB2kd), which also resulted in decreased PHB1 expression, led to attenuated nuclear factor-kappa-B (NF-κB) activation and subsequent cytokine and chemokine production. PHB2kd macrophages also had decreased cell surface TNFR1, CD14, TLR4, and lipid raft marker ganglioside GM1 at baseline and post-stimuli. Post-LPS, PHB2kd macrophages did not increase the concentration of cellular saturated, monounsaturated, and polyunsaturated fatty acids. This was accompanied by decreased lipid raft formation and modified plasma membrane molecular packing, further supporting the PHB complex's importance in lipid raft formation. Taken together, these data suggest a critical role for PHBs in regulating macrophage inflammatory signaling via maintenance of fatty acid composition and lipid raft structure.

Summary

Prohibitins are proteins found in phospholipid-rich cellular compartments, including lipid rafts, that play important roles in signaling, transcription, and multiple other cell functions. Macrophages are key cells in the innate immune response and the presence of membrane lipid rafts is integral to signal transduction, but the role of prohibitins in macrophage lipid rafts and associated signaling is unknown. To address this question, prohibitin knockdown macrophages were generated and responses to lipopolysaccharide and tumor necrosis factor-alpha, which act through lipid raft-dependent receptors, were analyzed. Prohibitin knockdown macrophages had significantly decreased cytokine and chemokine production, transcription factor activation, receptor expression, lipid raft assembly and membrane packing, and altered fatty acid remodeling. These data indicate a novel role for prohibitins in macrophage inflammatory signaling through regulation of fatty acid composition and lipid raft formation.

Maternal obesity and the imbalance in linoleic acid (C18:2 n-6, LA) and alpha-linolenic acid (C18:3 n-3, ALA) levels are related with hepatic disturbances in the offspring. However, whether these alterations are present during fetal life is not well understood. Obese and normal weight pregnant women were recruited to determine fatty acids (FAs) consumption, FAs profile (in maternal erythrocytes, placenta and neonatal very low-density lipoproteins VLDL) and biomarkers of fetal liver function, such as gamma-glutamyl transferase (GGT), alpha-fetoprotein (AFP) and albumin, in umbilical cord blood. Stearic acid (C18:0, ST) was lower, and total n-3 FAs tended to be lower in umbilical cord VLDLs of obese women compared to controls. Independently of maternal obesity, GGT levels in umbilical cord blood was positively correlated with the LA content and negatively correlated with the ALA content in maternal erythrocytes. We conclude that maternal obesity and its imbalance of LA and ALA are associated with changes in biomarkers of fetal liver function.

Fatty acids (FA) play a key role in infant growth and development. The aim of this study was to study the temporal evolution of FA from 3 or 4 weeks to 4 months postpartum in human milk (HM) from Filipino mothers. Mid-morning HM samples (n = 41) were collected after full expression from a single breast and FA were assessed using gas-liquid chromatography coupled to flame ionization detector. The total FA content remained relatively constant over the study period. The most abundant FA in HM were oleic acid (OA), palmitic acid (PA) and linoleic acid (LA), a trend similarly reported in HM from European and Chinese mothers. The former two were unchanged over the course of lactation while there was a slight increase in LA content over time. Similarly, the saturated fatty acid (SFA) and monounsaturated FA (MUFA) contents did not vary over the first four months of lactation. The SFA content was much higher than that reported in HM from Europe and China, mainly driven by PA, lauric and myristic acids. The MUFA content on the other hand, while comparable to that reported in HM from Chinese populations was lower than that reported in Europe. There was a small increase in the polyunsaturated FA (PUFA) content over the study duration. The levels of essential FA, linoleic acid (LA) and α-linolenic acid (ALA) were found to be much lower than that reported in other populations. The concentrations of arachidonic acid (AA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) remained stable over the study duration. AA and DHA in HM from Filipino mothers were comparable to global averages, however in case of the latter the concentration was found to be lower than in previous reports. DHA is of great clinical significance as it plays a key role in infant growth and development. In our study, we observed a wide inter- and intra-individual variability in the levels of DHA in HM, presumably reflecting diverse intakes of DHA rich foods and bioconversion in vivo. Personalized recommendations may help achieve recommended levels of DHA amongst population with levels below global averages. This may help achieve HM sufficiency and therefore be linked to clinical benefits for the mother and the baby.

Summary

This study details the temporal evolution of human milk (HM) fatty acids (FA) in Filipino mothers up to four months postpartum. The total FA content remained relatively constant over the study period. The most abundant FA were oleic, palmitic and linoleic acids. HM from Filipino mothers had relatively higher saturated FA content driven by palmitic, lauric and myristic acids, while the levels of essential FA, linoleic and α-linoleic acids were lower compared to other populations. Similarly, the concentration of monounsaturated FA were also lower than that reported in HM from European mothers. Arachidonic acid and docosahexaenoic acid (DHA) concentrations were comparable to global averages however the HM DHA levels were seen