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Abstract

Inflammation is a normal process that is part of host defense and tissue healing. However, excessive or unresolved inflammation can lead to uncontrolled tissue damage, pathology and disease. In humans on a Western diet, the omega-6 polyunsaturated fatty acid arachidonic acid (ARA) makes a significant contribution to the fatty acids present in the membrane phospholipids of cells involved in inflammation. ARA is a precursor to a number of potent pro-inflammatory mediators including well described prostaglandins and leukotrienes, which has led to the development of anti-inflammatory pharmaceuticals that target the ARA pathway to successfully control inflammation. Hence, it is commonly believed that increasing dietary intake of the omega-6 fatty acids ARA or its precursor linoleic acid (LA) will increase inflammation. However, studies in healthy human adults have found that increased intake of ARA or LA does not increase the concentrations of many inflammatory markers. Epidemiological studies have even suggested that ARA and LA may be linked to reduced inflammation. Contrastingly, there is also evidence that a high omega-6 fatty acid diet inhibits the anti-inflammatory and inflammation-resolving effect of the omega-3 fatty acids. Thus, the interaction of omega-3 and omega-6 fatty acids and their lipid mediators in the context of inflammation is complex and still not properly understood.

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... Important details that may potentially explain such mismatch (e.g., sex distribution [30], dose of EPA + DHA [33,36,58], type [59][60][61], duration [62][63][64], and timing of the supplementation [63,64]) remain largely unexplored [44]. In addition, when investigating Ω-3 PUFAs, other oils such as corn or olive oil are used as a placebo that may influence the study outcomes [59,65]. As an inert placebo seems unfeasible, this present review also included a study [54] without a placebo provided to the RT group, while accounting for this in the sensitivity analysis. ...
... Factors like intake vs. uptake, diet, protein intake, placebo type, Ω-3 PUFA forms, and timing may also affect outcomes. For example, using corn or olive oil as placebos might alter the net effect of Ω-3 PUFAs [59,65]. To enhance bioavailability, formulations with equal EPA and DHA ratios [106,107], low oxidation rates [108][109][110][111][112][113], and high levels of polyphenols [59], as well as ingestion with high-fat foods, may be beneficial [114]. ...
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Age-related declines in muscle mass, neuromuscular, and physical function can be mitigated by resistance training (RT). Omega-3 polyunsaturated fatty acids (Ω-3 PUFAs) supplementation has shown benefits in older adults. However, it remains unclear if combining Ω-3 PUFAs with RT is more effective than RT alone or with placebo. This systematic review and meta-analysis examined the effects in randomized controlled trials (RCTs) of Ω-3 PUFAs combined with RT compared to RT alone or placebo on muscle mass and function in healthy older adults (≥65 y). Databases such as PubMed, Embase, SPORTDiscus, and Web of Science were searched on 11 April 2024. No restriction on language or publication date was implemented. Mean differences (MDs) or standardized mean differences (SMDs) with 95% confidence intervals and pooled effects were calculated. Nine studies (n = 286, 54% men) met the inclusion criteria. The meta-analysis found no significant effect of Ω-3 PUFAs on muscle mass or neuromuscular function but a large effect on chair-rise performance. Potential impact of Ω-3 PUFAs dose, duration, or sex were not observed. Most studies had varying levels of bias, and none met recommended quality standards for investigating Ω-3 PUFAs, but findings suggest no clear advantage of combining Ω-3 PUFAs with RT.
... ω6 PUFAs are metabolized into arachidonic acid, which is converted into potent eicosanoids. 35 Eicosanoids are a class of proinflammatory mediators, which includes leukotrienes and prostaglandins. Both leukotrienes and prostaglandins promote the production of inflammatory mediators and collagenase in cartilage, which contribute to OA progression. ...
... Both leukotrienes and prostaglandins promote the production of inflammatory mediators and collagenase in cartilage, which contribute to OA progression. 36 While all ω6 PUFAs are converted to potent proinflammatory eicosanoids such as PGE2 and LTB4, 35 ω3 PUFAs EPA and DHA have distinct metabolic pathways. 37 EPA is metabolized into weak eicosanoids and resolvins, while DHA is primarily converted into resolvins, protectins, and maresins, 37 which have mixed pro-and antiinflammatory effects. ...
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Osteoarthritis (OA) is characterized by articular cartilage degeneration, leading to pain and loss of joint function. Recent studies have demonstrated that omega‐3 (ω3) polyunsaturated fatty acid (PUFA) supplementation can decrease injury‐induced OA progression in mice fed a high‐fat diet. Furthermore, PUFAs have been shown to influence the mechanical properties of chondrocyte membranes, suggesting that alterations in mechanosensitive ion channel signaling could contribute to the mechanism by which ω3 PUFAs decreased OA pathogenesis. Here, we hypothesized that PUFAs may alter mechanical signaling through PIEZO1 (activated by changes in membrane tension) and TRPV4 (activated by physiologic mechano‐osmotic signals), as these mechanosensitive cation channels have been shown to influence OA progression. Our results demonstrated that PUFAs reduced chondrocyte sensitivity to single‐cell mechanical compression and to pharmacologic agonists of PIEZO1 and TRPV4, with ω3 PUFAs having the most significant effects overall. We also found that supplementation with ω6 PUFA linoleic acid (LA) altered the biophysical properties of chondrocytes, as evidenced by increased intracellular lipid droplet formation and more rapid membrane rupture in response to hypo‐osmotic shock, suggesting that LA increases chondrocyte membrane susceptibility to damage. Our findings underscore the differential impacts of specific PUFAs on chondrocyte signaling and membrane properties and provide important considerations in the development of nutritional interventions to prevent or treat OA.
... However, recent studies in healthy adults have shown that increased dietary intake of LA does not elevate concentrations of inflammatory markers. Furthermore, epidemiological studies suggest that LA may be associated with reduced inflammation [66]. Several studies have investigated the anti-inflammatory effects of LA in both cultured cells and murine models. ...
... The ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are considered as anti-inflammatory. However, LA has been shown to inhibit the conversion from α-linolenic acid (ALA) to EPA, as they compete for the same elongases and desaturases involved in the biosynthesis of PUFAs [66,74]. Thus, a high intake of LA potentially creates a more inflammatory environment. ...
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Lipids are intimately associated with skin condition. This review aims to discuss the function of linoleic acid (LA, 18:2, ω-6), an essential fatty acid, in skin health and hair growth. In skin, LA can be metabolized into ω-6 unsaturated fatty acid, oxidized derivatives and incorporated into complex lipid molecules, including ω-hydroxy-ceramides. Previous research has revealed that skin diseases including acne, atopic dermatitis and psoriasis are associated with disordered LA metabolism. Studies based on animal or skin cell models suggest that LA or LA-rich vegetable oils, topically applied, exhibit diverse biological activities, including the repair of the skin barrier, the promotion of wound healing, skin whitening, photoprotection, anti-inflammatory effects and the stimulation of hair growth. Moreover, the underlying mechanisms of LA’s beneficial effects on skin are summarized. Further research on the correlation of LA metabolism and skin disorders, a deeper exploration of the mechanisms underlying the function of LA in skin management and more investigations of its clinical application are required to enhance the understanding and utilization of LA in cosmetics and pharmaceuticals.
... Several trials and a large narrative review have already addressed these research questions [32]. Omega-3 fatty acids are thought to have anti-inflammatory properties, whereas omega-6 fatty acids are thought to be pro-inflammatory [32,33]. Maes et al. demonstrated a negative correlation between a low omega-3:omega-6 ratio and fatigue severity in patients with chronic fatigue syndrome [34]. ...
... Participants with PASC had a significantly longer sleep duration of 49 min per night. Patients with fatigue often report sleep disturbances and insomnia as one of the key symptoms of chronic fatigue syndrome [33]. It has been established that sleep disturbance occurs in patients with both mild, moderate, and severe symptoms [14]. ...
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Background/Objectives: A significant number of patients experience prolonged symptoms following COVID-19 in particular cases of fatigue. Yet, pathomechanisms of COVID-19-related fatigue remain unclear. Methods: This study investigated patients after confirmed SARS-CoV-2 infection (PC) with relevant fatigue according to the Fatigue Assessment Scale (≥22 points) to rule out malnutrition as a driving factor for fatigue and to evaluate daily activity and sleep characteristics. Dietary behavior was recorded through food diaries and physical activity by self-reported (questionnaires) and objective (activity tracker) outcomes. Data were collected over a 7-day period and compared with a healthy control group (HC). A subgroup analysis of patients with fatigue and severe fatigue, as well as a sex-specific analysis, were included. Results: No significant differences in dietary intake were observed, but an indication toward a healthier Mediterranean diet in PC patients with a median Mediterranean Diet Score of 4 (IQR 3, 5) in HC vs. 5 (IQR 3, 6) in PC (p = 0.24). There were also no differences in physical activity, either by objective or subjective measures. However, the median sleep duration was 49 min longer in PC patients (p = 0.003). Conclusions: In conclusion, malnutrition did not significantly contribute to fatigue, yet patients with COVID-19-related fatigue showed increased sleep duration. As sleep characteristics play a crucial role in mental and physical wellbeing, the association of sleep, physical activity, and fatigue should be evaluated in further studies.
... Additionally, linoleic acid regulates sebum production and combats comedogenesis, addressing acne and textural irregularities, thus contributing significantly to overall skin health and appearance. Furthermore, linoleic acid has been reported to exhibit anti-tyrosinase activity, making it a valuable compound for reducing hyperpigmentation and promoting a more even skin tone, further enhancing its role in cosmeceutical applications [52][53][54][55]. ...
Article
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The cosmeceutical industry has increasingly turned its attention to marine macroalgae, recognizing their significant bioactive potential as sources of natural compounds for skincare applications. A growing number of products now incorporate extracts or isolated compounds from various macroalgae species. However, many species remain underexplored, highlighting a valuable opportunity for further research. Among these, Caulerpa prolifera (Forsskål) J.V. Lamouroux has emerged as a promising candidate for cosmeceutical applications. This study provides the most comprehensive phytochemical assessment of C. prolifera to date, revealing its potential as a source of bioactive extracts and compounds. The analysis identified key components of its lipophilic profile, predominantly saturated and unsaturated fatty acids, alongside di-(2-ethylhexyl) phthalate—an endocrine disruptor potentially biosynthesized or bioaccumulated by the algae. While the crude extract exhibited moderate tyrosinase inhibitory activity, its overall antioxidant capacity was limited. Fractionation of the extract, however, yielded subfractions with distinct bioactivities linked to changes in chemical composition. Notably, enhanced inhibitory activities against elastase and collagenase were observed in subfractions enriched with 1-octadecanol and only traces of phthalate. Conversely, antioxidant activity diminished with the loss of specific compounds such as β-sitosterol, erucic acid, nervonic acid, and lignoceric acid. This work advances the understanding of the relationship between the chemical composition of C. prolifera and its bioactivities, emphasizing its potential as a source of cosmeceutical ingredients, leading to a more comprehensive valorization of this macroalga.
... AA is one of the most widely distributed polyunsaturated fatty acids in vivo [24,25]. The cyclooxygenase (COX) pathway represents one of its primary metabolic routes. ...
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Background The impact of a high-salt (HS) diet on metabolic disturbances in individuals with coronary heart disease remains unclear. The arachidonic acid (AA) metabolic pathway is closely linked to the development of cardiometabolic diseases and atherosclerotic cardiovascular diseases. Furthermore, endoplasmic reticulum stress (ERS) has emerged as a major contributor to cardiometabolic diseases. AA-related inflammation and ERS are hypothesized to play a role in HS diet-induced coronary remodeling. Methods Rats were subjected to an HS diet for 4 weeks, and the serum concentration of AA was measured via enzyme-linked immunosorbent assay. Immunofluorescence staining and vascular tension measurements were conducted on coronary arteries. In addition, AA-stimulated coronary artery smooth muscle cells (CASMCs) were treated with ERS inhibitors to explore the underlying pathway involved. Results Increased susceptibility to myocardial infarction in the HS diet-fed rats was accompanied by increased serum AA concentrations and increased expression of the key AA metabolic enzyme cyclooxygenase-2 (COX-2). AA incubation weakened the contraction of denuded coronary arteries, reduced the expression of contraction markers, and increased the fluorescence intensity of synthetic and ERS response markers in coronary arteries. Further investigation of CASMCs revealed that AA-induced phenotypic transformation was mediated via the ERS pathway. Conclusions ERS and AA were found to be stimulated in CASMCs following an HS diet. AA triggers an ERS response through COX-2 catalysis, and the downstream inositol requiring enzyme 1 - X-box binding protein-1 - osteopontin pathway may contribute to the AA-induced phenotypic transformation of CASMCs, resulting in dysfunctional coronary tension. This study may provide potential therapeutic targets for cardiovascular diseases associated with excessive AA-derived ERS.
... Since lipid mediators controlling inflammation are produced from PUFA precursors that phospholipases have cleaved from membrane phospholipids, the membrane PUFA contents modulate inflammation [56]. The PUFAs of the RWPE1 cells were identified to contain 20:4n-6, which is a precursor of pro-inflammatory lipid mediators [57], and 20:3n-9, which has also been proposed to be a lipid mediator precursor but with poorly known effects [58]. Thus, the increased supply of the PUFA precursors for the production of proinflammatory lipid mediators may have contributed to the upregulation of inflammatory response genes in the ANO7-expressing RWPE1 cells in this study. ...
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Background Prostate cancer (PrCa) is a significant health concern, ranking as the second most common cancer in males globally. Genetic factors contribute substantially to PrCa risk, with up to 57% of the risk being attributed to genetic determinants. A major challenge in managing PrCa is the early identification of aggressive cases for targeted treatment, while avoiding unnecessary interventions in slow-progressing cases. Therefore, there is a critical need for genetic biomarkers that can distinguish between aggressive and non-aggressive PrCa cases. Previous research, including our own, has shown that germline variants in ANO7 are associated with aggressive PrCa. However, the function of ANO7 in the prostate remains unknown. Methods We performed RNA-sequencing (RNA-seq) on RWPE1 cells engineered to express ANO7 protein, alongside the analysis of a single-cell RNA-sequencing (scRNA-seq) dataset and RNA-seq from prostate tissues. Differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted to identify key pathways. Additionally, we assessed oxidative phosphorylation (OXPHOS), glycolysis, and targeted metabolomics. Image analysis of mitochondrial morphology and lipidomics were also performed to provide further insight into the functional role of ANO7 in prostate cells. Results ANO7 expression resulted in the downregulation of metabolic pathways, particularly genes associated with the MYC pathway and oxidative phosphorylation (OXPHOS) in both prostate tissue and ANO7-expressing cells. Measurements of OXPHOS and glycolysis in the ANO7-expressing cells revealed a metabolic shift towards glycolysis. Targeted metabolomics showed reduced levels of the amino acid aspartate, indicating disrupted mitochondrial function in the ANO7-expressing cells. Image analysis demonstrated altered mitochondrial morphology in these cells. Additionally, ANO7 downregulated genes involved in fatty acid metabolism and induced changes in lipid composition of the cells, characterized by longer acyl chain lengths and increased unsaturation, suggesting a role for ANO7 in regulating lipid metabolism in the prostate. Conclusions This study provides new insights into the function of ANO7 in prostate cells, highlighting its involvement in metabolic pathways, particularly OXPHOS and lipid metabolism. The findings suggest that ANO7 may act as a key regulator of cellular lipid metabolism and mitochondrial function in the prostate, shedding light on a previously unknown aspect of ANO7’s biology.
... Despite the importance of Omega-3 PUFA intake, the importance of Omega-6 intake has not received much attention so far. Unlike Omega-3 PUFA, Omega-6 PUFA is known to induce inflammation and obesity [32,33]. Especially, a high ratio of Omega-6/3 PUFA intake is known to affect various diseases, including obesity and various cardiovascular diseases, as well as stress [30,34,35], but its impact on preventing sarcopenia, including muscle loss, has not been reported. ...
... Long-chain ω-3 PUFAs fulfill crucial structural and functional roles in the body, notably in the human brain [74], and low ω-6:ω-3 PUFAs ratio is important for proper brain development in young ages [31]. In contrast, ω-6 PUFAs are pro-inflammatory [75], with higher intakes being linked to increased incidence of obesity and metabolic diseases [76]. One efficient way to restore a balanced ω-3:ω-6 PUFAs ratio is to use DHA supplementation in the WD and new nutritional methods include the use of ω-3 enriched diets [77] as complementary approaches to pharmacological treatments against obesity and obesity-related health risks. ...
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Background/Objective Obesity is a devastating worldwide metabolic disease, with the highest prevalence in children and adolescents. Obesity impacts neuronal function but the fate of functional hyperemia, a vital mechanism making possible cerebral blood supply to active brain areas, is unknown in organisms fed a high-caloric Western Diet (WD) since adolescence. Subjects/Methods We mapped changes in cerebral blood volume (CBV) in the somatosensory cortex in response to whisker stimulation in adolescent, adult, and middle-aged mice fed a WD since adolescence. To this aim, we used non-invasive and high-resolution functional ultrasound imaging (fUS). Results We efficiently mimicked the metabolic syndrome of adolescents in young mice with early weight gain, dysfunctional glucose homeostasis, and insulinemia. Functional hyperemia is compromised as early as 3 weeks of WD and remains impaired after that in adolescent mice. These findings highlight the cerebrovascular vulnerability to WD during adolescence. In WD, ω-6:ω-3 polyunsaturated fatty acids (PUFAs) ratio is unbalanced towards proinflammatory ω-6. A balanced ω-6:ω-3 PUFAs ratio in WD achieved by docosahexaenoic acid supplementation efficiently restores glucose homeostasis and functional hyperemia in adults. Conclusions WD triggers a rapid impairment in cerebrovascular activity in adolescence, which is maintained at older ages, and can be rescued by a PUFA-based nutraceutical approach.
... The balance between ω-3 and ω-6 PUFAs is crucial for maintaining homeostasis in the body [52,53]. Excessive levels of ω-6 PUFAs, such as arachidonic acid (AA), can produce pro-inflammatory eicosanoids [54,55]. These substances contribute to thrombus and atheroma formation [56], allergic reactions [57], inflammatory disorders [58], excessive cell proliferation [59], and a hyperactive endocannabinoid system [60], which may increase appetite and food intake, potentially leading to weight gain and obesity. ...
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Background/Objectives: Cashew nutshell liquid (CNSL) is obtained during the industrial processing of cashew nuts. It contains anacardic acid (2-hydroxy-6-n-pentadecylbenzoic acid) and cardanol (3-n-pentadecylphenol). Therefore, CNSL provides a rich source of phenolic lipids serving as natural antioxidants or precursors for industrial uses. Here, we have analyzed in detail a commercial sample of cardanol by nuclear magnetic resonance (NMR) spectroscopy and its biological activities in the human keratinocyte cell line (HaCaT cells). Methods: The cytotoxic effects, genotoxicity, cell proliferation, and healing properties on HaCaT cells were studied using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, comet assay, proliferation assay, and scratch assay, respectively. Additionally, the modulatory effect of cardanol on the cellular fatty acid profile of HaCaT cells was analyzed by gas chromatography. Results: NMR showed the structure of cardanol as a mixture of the 8′-monoene (42%), the 8′,11′-diene (22%), and the 8′,11′,14′-triene (36%) for the pentadecyl side chain with all double bonds in Z configuration. The cytotoxic effects on HaCaT cells only occurred at high concentrations of cardanol (>10 µg/mL), which caused significant reductions in cell viability. Using the comet assay, a dose-dependent increase in DNA damage was found at concentrations above 10 µg/mL. Scratch assays revealed that cardanol achieved 99% wound closure of HaCaT cells treated with 1 µg/mL cardanol after 48 h. Cardanol at 1 and 0.1 µg/mL significantly enhanced HaCaT cell proliferation and promoted migration, contributing to accelerated wound healing processes. As shown by gas chromatography, 1 µg/mL cardanol increased the total amount of polyunsaturated fatty acids (PUFA), including ω-3, ω-6, and ω-9 fatty acids. Conclusions: Together, these findings suggest that concentrations of <10 µg/mL cardanol are safe and exhibit beneficial biological activities, particularly wound-healing effects on HaCaT cells. Further studies are necessary to explore additional potential applications of cardanol, to refine its formulations for clinical use, and to ensure its safety and action in other target cells and species.
... In the 1 H NMR spectra of the CDCl 3 fraction, fatty acid (FA) signals were mainly identified ( Figure 2). Fatty acids play a multifaceted role in cancer progression by affecting energy metabolism, cellular structure, inflammatory processes, and key signaling pathways [35][36][37][38]. The reprogramming of lipid metabolism in cancer cells allows them to thrive in the challenging tumor microenvironment [39,40]. ...
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Metabolomics is a powerful tool that can be used to identify different stages in cancer development. In this study, the metabolomic profile of Lewis lung carcinoma (LLC) was characterized in C57BL/6 mice bearing LLC tumors. Magnetic resonance spectroscopy (nuclear magnetic resonance—NMR) was applied using a 400 MHz 1H NMR spectrometer. Two types of metabolites (polar and non-polar) were identified on LLC based on the analysis of methanol/water and chloroform extracts collected from lung cancer samples in mice. The investigated metabolomics show that the neoplastic processes of growing LLC on mice may affect carbohydrate; alanine and glutamate; leucine and isoleucine; lysine; creatine; and choline metabolism, whereas hypoxia states were identified due to elevated lactate in lung cancer tissues. The metabolomic profile of Lewis lung carcinoma could be considered to be a valuable biomarker in translational lung cancer research.
... The correlations in the interaction networks were significant ( To explore the specific relationships and internal mechanisms between microorganisms and metabolites, lipid metabolism pathways were integrated and analyzed (Fig. 6C). Ligninoleic acid, alpha-ligninolenic acid, stearidonic acid, and arachidonic acid are the main long-chain fatty acids involved in lipid metabolism and are the primary components of animal and plant oils (Calder, 2015;Fritsche, 2015;He et al., 2020;Innes and Calder, 2018). Microorganisms degrade long-chain fatty acids into medium-chain fatty acids and small-molecule lipids using a series of enzymes. ...
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Food waste is particularly common type of organic solid waste in urban and rural regions. This study revealed the effects of sheep manure addition on physicochemical properties, oil and lignocellulose degeneration, bacterial community succession, and metabolic functions using pilot-scale food waste composting treatments without (FC) and with (FS) sheep manure. The sheep manure increased the reduction rates of oil, cellulose, hemicellulose, and lignin by 63.90%, 47.25%, 66.15%, and 31.05%, respectively, and increased the GI value by 22.12%. Microbial and metabolite dynamics analyses revealed that sheep manure addition enhanced the composting temperature, NO3-N, and available phosphorus (P), which are key environmental conditions, and enhanced the proliferation of the bacteria decomposing oil and lignocellulose. Overall, sheep manure addition enriched functional bacteria and strengthened key metabolic pathways during the thermophilic stage, thus accelerating the degradation of oil and lignocellulose and promoting compost maturity.
... They have a pleiotropic effect (beneficial or deleterious), and so it is impossible to identify a clear answer. As mentioned earlier, prostaglandin and thromboxane are produced from AA (omega-6 (ω-6) polyunsaturated fatty acid), which may suggest that eating foods high in ω-6 fatty acids may induce or inhibit inflammatory processes [52]. ...
... Besides, omega-3 fatty acids (α-linoleic acid) not only play a role in preventing the production of pro-inflammatory factors, but also in inhibiting the formation of omega-6 fatty acids. Omega-6 fatty acids are potent precursors for inflammatory mediators, even though they are still constituent components of membrane phospholipids [37,38]. These inflammatory substances are increased in people who suffer from insomnia or poor sleep quality, by increasing the systemic markers of inflammation, such as C-reactive protein and interleukin-6 [39]. ...
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The Thai herbal Yahom 20 formula (YHF20), is traditionally used for dizziness and fainting and off-label use for sleep aid, with inadequate substantial evidence afterward. This study’s primary objective is to employ metabolomics to investigate YHF20's effects, comparing it with lorazepam and a placebo in healthy volunteers. Phytochemical and metabolite profiling were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LC/MS Q-ToF, respectively, on plasma samples from 90 healthy participants aged 20 to 60 years. These participants were randomized into three groups: YHF20 (n=30), Lorazepam (n=30), and Placebo (n=30). Principal Component Analysis (PCA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) were then conducted to identify differential metabolites and pathways. Six phytochemicals, including ellagic acid, glycyrrhizic acid, (E)-ferulic acid hexacosyl ester, 6-aldehydo-7-methoxy-isoophiopogonone B, melianol, and myristic acid were identified in YHF20. Despite PCA showing no significant overall metabolite profile differences among the groups, OPLS-DA pinpointed eight YHF20-associated metabolites, such as DHA ethyl ester, α-linolenic acid, (9Z)-9-octadecenamide, ricinoleic acid methyl ester, idazoxan, 13-HPODE, 12,13-DiHODE, and myristoleic acid, implying at anti-inflammatory pathway involvement, especially in α-linoleic and linoleic acid metabolism. No direct impact on sleep-related metabolites was found, the anti-inflammatory effects suggested by YHF20 could indirectly improve sleep quality by mitigating inflammation, a common sleep disruptor. These results highlight YHF20's potential for enhancing life quality through anti-inflammatory mechanisms. They offer a scientific basis for its traditional and anecdotal uses and suggest a novel approach to sleep quality improvement not previously documented.
... Importantly, w-3 PUFAs can interfere with the above AA-driven proinflammatory pathways (10) and have been proposed as non-steroidal treatments in human discogenic pain, neuropathic pain, and inflammatory joint pain (15)(16)(17). LA is found in plant oils (e.g., soybean, corn, and peanut) and considered to be an essential FA (18). The w-3 PUFA alinolenic acid (ALA), another essential FA, is found in certain nuts, seeds, and seed oils, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), products of ALA elongation by certain microalgae, are bioconcentrated in oily fish such as salmon and herring. ...
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Introduction Despite progress in systemic lupus erythematosus (SLE) treatment, challenges persist in medication adherence due to side effects and costs. Precision nutrition, particularly adjusting fatty acid intake, offers a cost-effective strategy for enhancing SLE management. Prior research, including our own, indicates that increased consumption of omega-3 polyunsaturated fatty acids (PUFAs) correlates with improved outcomes in SLE patients. Here we build upon these findings by investigating associations between serum fatty acids—grouped as PUFAs, monounsaturated fatty acids (MUFAs), and saturated fatty acids (SFAs)—and lupus activity, pain, and sleep disturbance. Methods Using data from 418 participants with SLE in the Michigan Lupus Epidemiology and Surveillance (MILES) Cohort, we examined associations between serum levels of 25 fatty acids determined by GC-MS and patient-reported outcomes. Disease activity, pain, and sleep quality were assessed using standardized questionnaires. Generalized additive models and partial residual plots were utilized to examine the linearity of fatty acid effects. Variable selection was performed using Least Absolute Shrinkage and Selection Operator (LASSO), followed by multiple linear regression adjusting for sociodemographic factors. Results Findings indicated favorable associations between ω-3 PUFAs—and, to a lesser extent, ω-6 PUFAs—and patient-reported outcomes, while MUFAs and SFAs showed unfavorable associations. Docosahexaenoic acid (DHA), an omega-3 PUFA, exhibited the most robust favorable associations across all outcomes. Additionally, the omega-3 α-linolenic acid (ALA) was linked to reduced pain, whereas eicosapentaenoic acid (EPA), another omega-3, was associated with worsened disease activity and pain. Among omega-6 PUFAs, dihomo-γ-linolenic acid (DGLA) was favorably associated with disease activity, while the omega-9 PUFA Mead acid was linked to increased pain. Discussion These findings underscore the prospect that increased tissue levels of long-chain omega-3 PUFAs, particularly DHA, are favorably associated with SLE outcomes. Although further research is needed to establish causal relationships, existing evidence supports the role of omega-3 PUFAs in managing cardiovascular and chronic kidney disease, common SLE comorbidities. Most study participants exhibited low omega-3 PUFA status, suggesting substantial potential for improvement through targeted dietary interventions and supplementation. This study supports a potential role for precision nutrition in comprehensive SLE management, considering the impact of PUFAs, SFAs and MUFAs.
... Maintaining a balance between omega-6 and omega-3 PUFAs is critical for optimal brain function, as these PUFAs have distinct roles. Omega-3 PUFAs (EPA, DPA, and DHA) are recognized for their anti-inflammatory properties, while omega-6 PUFAs (ARA) are associated with pro-inflammatory processes [33][34][35][36][37] . The antagonistic relationship between DHA and ARA suggests that DHA's modulation of ARA metabolism may mitigate symptoms of such disorders. ...
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Williams Syndrome (WS) is a rare neurodevelopmental disorder with a prevalence of 1 in 7500 to 1 in 20,000 individuals, caused by a microdeletion in chromosome 7q11.23. Despite its distinctive clinical features, the underlying metabolic alterations remain largely unexplored. This study employs targeted metabolomics to investigate the metabolic characteristics of children with WS. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified significant dysregulation of 15 metabolites, with 11 upregulated and 4 downregulated. Notably, amino acids such as alanine, proline, and arginine were significantly elevated. Fatty acid metabolism showed pronounced upregulation of long-chain saturated fatty acids (C18:0, C20:0, C22:0, C24:0, C26:0, and C28:0) and downregulation of long-chain unsaturated fatty acids (C18:2 LA, C22:6 DHA, C16:1 PLA, and t-C18:1 EA), except for upregulated nervonic acid (C24:1) and arachidonic acid (C20:4). Metabolic pathway analysis highlighted disruptions in arginine synthesis, arginine/proline metabolism, alanine, aspartate and glutamate metabolism, biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and arachidonic acid metabolism. This study provides the first comprehensive analysis of amino acid and fatty acid metabolism in children with WS, offering insights into the disorder’s complex metabolic landscape. Further validation in larger cohorts is essential to confirm these findings and their potential as biomarkers and therapeutic targets. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-83146-4.
... Omega-6 PUFA, particularly arachidonic acid (AA), are highly abundant in cell membranes involved in inflammation. Omega-6-enriched dietary intake has been associated with inflammation, mainly because AA is a precursor of pro-inflammatory lipid mediators [45]. Dietary linoleic acid substantially upregulates cyclooxygenase-2, which converts AA to proinflammatory eicosanoids [46]. ...
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Background Excessive intake of fatty acids is a key factor contributing to metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effects of saturated fatty acids (SFA) and unsaturated fatty acids (UFA) on the development of MASLD are uncertain. Therefore, we conducted two-sample Mendelian randomization studies and animal experiments to explore the effects of SFA, monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) on the risk of developing MASLD. Methods The genetic summary data of exposures and outcome were retrieved from genome-wide association studies (GWASs) and used for five Mendelian randomization methods. A comprehensive sensitivity analysis was performed to verify the robustness of the results. Mice were subjected to different diets followed by assessment of severity of steatosis based on a histological score and determination of hepatic triglyceride levels to investigate the relationships between SFA, MUFA, PUFA and MASLD. Results The Mendelian randomization results showed that MUFA (odds ratio: 1.441, 95% confidence interval: 1.078–1.927, P = 0.014) was causally associated with the incidence of MASLD. SFA and PUFA were not causally associated with the incidence of MASLD. Sensitivity analysis did not identify any significant bias in the results. The animal experiment results showed that a MUFA-enriched diet significantly contributed to the development of hepatic steatosis (P < 0.001). Conclusion SFA and PUFA did not have a significant causal effect on MASLD, but MUFA intake is a risk factor for MASLD. A MUFA-enriched diet increased the incidence of macrovesicular steatosis and the hepatic triglyceride levels. Therefore, replacing MUFA intake with a moderate intake of PUFA might help reduce the risk of MASLD. Graphical Abstract
... The DHA and EPA is really important in the human diet such as proper fetal and infant development (Carver et al.,2001;Ramakrishnan et al., 2010), cardiovascular function (Kromhout et al., 2010;Bernasconi et al., 2021), Alzheimer's disease (Quinn et al., 2010), immune response (Krauss-Etschmann et al., 2008), cognitive function (Titova et al., 2013) eye health (Cortina &Bazan, 2011) andprebiotics (Fu et al., 2021). The omega-6 linoleic acids are also the major precursor of the eicosanoids, including thromboxane, prostaglandins, prostacyclin, anandamides, and leukotrienes which regulate a wide range of physiological processes (Innes & Calder, 2018). Arachidonic acid (ARA) is a crucial component of cell structure and is required for growth and development as well as in the event of severe or pervasive cell injury (Tallima & Ridi, 2018). ...
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Puffer fish oil extracted from Xenopterus naritus represents a beneficial source of bioactive compounds with health-promoting properties. Despite the known benefits of puffer fish oil, there is a lack of detailed information on its fatty acid composition. This study aimed to fill this gap by investigating the fatty acid profiles of puffer fish oil extracted from the liver and muscle tissues. The oil was extracted using the solvent Bligh & Dyer method, and the samples were derivatized into fatty acid methyl esters (FAME) before being analyzed via Shimadzu QP2010 Plus gas chromatography-mass spectrometry (GC-MS). This analysis highlighted the prevalence of omega-3 fatty acids, particularly Docosahexaenoic acid (DHA) (8.28 ± 0.08% in liver, 6.15 ± 0.33% in muscle oil) and Eicosapentaenoic acid (EPA) (3.29 ± 0.12% in liver and 2.16 ± 0.06% in muscle oil), along with the abundance of omega-6 and omega-9 fatty acids, including arachidonic and oleic acid. Additionally, the antimicrobial properties of these fish oils were assessed against Gram-negative and Gram-positive bacteria using the Minimum Inhibitory Concentration (MIC) method, revealing promising inhibitory effects, with liver oil demonstrating greater efficacy. These findings suggest that puffer fish oil is rich in beneficial fatty acids and possesses antimicrobial properties that could find applications in food preservation, medicine, and agriculture, thereby offering a fresh perspective on the functional and nutritional value of Xenopterus naritus.
... Emerging findings indicate that LA could potentially exert inhibitory effects on the inflammatory response (Burns et al., 2018;Innes and Calder, 2018;Marangoni et al., 2020). A prior investigation has exhibited the regulatory impact of LA on the signaling pathway linked to inflammation in macrophages when exposed to LPS (Qian et al., 2015). ...
... Two polyunsaturated fats are highlighted in the literature: essential fatty acids omega-3 and omega-6. Omega-6 fatty acids are pro-inflammatory, while omega-3 fatty acids are anti-inflammatory (179). ...
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Background/Objectives Schizophrenia is a complex mental disorder influenced by genetic and environmental factors, including dietary habits. Oxidative stress and inflammation play a crucial role in the pathophysiology of schizophrenia. Emerging research suggests that diet may affect schizophrenia through different biological mechanisms beyond oxidative stress and inflammation. In particular, epigenetic changes may alter the expression of genes related to neurodevelopment and neurotransmitter systems, while neuroplasticity plays a crucial role in brain adaptation and resilience to psychiatric disorders. Methods The literature search included the main available databases (Science Direct, PubMed and Google Scholar), considering the English language, and our screening was performed based on several words such as “schizophrenia”, “diet”, “nutrients”, “obesity”, “oxidative stress”, “inflammation”, “antioxidants” and “prenatal nutritional deficiency”. The review focused specifically on studies examining the relevance of diet in schizophrenia, as well as prenatal nutritional deficiency, obesity, oxidative stress, and inflammation associated with this disorder. Results Following a review of the literature, it was found that nutritional deficiencies, including lack of omega-3 fatty acids, vitamins D, and B, during the prenatal and postnatal periods can have a negative impact on neurodevelopment and increase the risk of schizophrenia. Patients with schizophrenia have imbalances in antioxidant enzymes, such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and reduced levels of antioxidants (vitamin E, vitamin C). These biochemical changes lead to an increase in markers of oxidative stress, including malondialdehyde (MDA). In addition, cytokine-mediated inflammation, microglial activation, and intestinal dysbiosis are associated with the onset of schizophrenia and the severity of schizophrenia symptoms. Currently, there is no universally accepted dietary regimen for control. However, various diets and nutritional methods are being researched and applied to alleviate the symptoms of schizophrenia and improve the overall health of patients, including the Mediterranean diet, the ketogenic diet, the gluten-free diet, and the DASH (Dietary Approaches to Stop Hypertension) diet. Conclusion A healthy diet, rich in anti-inflammatory nutrients and antioxidants, may help manage schizophrenia by reducing oxidative stress, preventing complications, and improving quality of life. Omega-3 fatty acids, vitamin D, and B vitamins are particularly important for brain development and function. In this review, we aim to analyze the literature on the influence of diet on schizophrenia, focusing on the role of prenatal nutritional deficiencies, obesity, oxidative stress, and inflammation.
... For instance, numerous studies have highlighted the activities of antitumor and anti-inflammation of traditional Chinese medicine (TCM), demonstrating that various TCM monomers, extracts, and compounds effectively inhibit cancer development and yield positive therapeutic effects. 9,10 Given the known effect of arachidonic acid (AA) metabolites on regulating inflammation, 11 that on tumor development and progression has also been examined. The results showed that many AA metabolites have been closely related to tumor genesis and progression. ...
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In the process of cancer transformation, arachidonic acid (AA) serves as an important metabolic pathway, contributing to the production of carcinogens by participating in the enzyme metabolic processes, like phospholipase A2, cyclooxygenases, cytochrome P450, and lipoxygenases. Chemopreventive drugs for various cancers have been developed from natural products that inhibit the AA pathway. Moreover, different monomers and components of traditional Chinese medicine (TCM) are widely suggested to be effective on preventing and treating cancer chemically. The present work focused on analyzed different therapeutic methods for natural ingredients from TCM, targeting the metabolic pathways of three enzymes within the AA pathway. Additionally, we summarized the substantial effect of TCM in effectively inhibiting tumors by regulating this pathway.
... Although the effects of LA and its derivatives on inflammation were less studied, recent studies have demonstrated that its oxidative metabolites contributed to inflammatory pain in essence (28). LA is an essential fatty acid that can be oxidized by endogenous enzymes and reactive oxygen species in the circulation to synthesize a series of oxidative derivatives that play key roles in regulating inflammation (29). For example, LA is metabolized by LOX into hydroxy-octadecene dienoic acid (HODEs) derivatives (such as 9and 13-HODE) and is further converted into oxygen-HODE (such as 9-oxygen-HODE and 13-oxygen-HODE) and epoxy-HODE, which play a role in inflammation (30). ...
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Introduction Dermatomyositis (DM) is an idiopathic inflammatory myopathy. Because of clinical heterogeneity, the metabolite profile of DM patients with different myositis-specific autoantibodies (MSAs) remains elusive. This study aimed to explore the metabolomics characteristics of the serum in DM with different MSAs, low or high disease activity, and interstitial lung disease. Methods Untargeted metabolomics profiling was performed in the serum of a discovery cohort (n=96) and a validation cohort (n=40), consisting of DM patients with MSAs, low or high disease activity, and/or interstitial lung disease (DM-ILD) compared to age- and gender-matched healthy controls (HCs). Results The lipid profile in DM was found to be abnormal, especially dysregulated glycerophospholipid metabolism and fatty acid oxidation, which might affect the pathogenesis of DM by disrupting the balance of Th17 and Treg. We identified potential biomarkers of DM that can distinguish between low or high disease activity and reflect lung involvement. Two metabolite combinations including pro-leu, FA 14:0;O can distinguish high disease activity DM from low disease activity DM and HCs, and five including indole-3-lactic acid, dihydrosphingosine, SM 32:1;O2, NAE 17:1, and cholic acid can distinguish DM-ILD from DM without ILD (DM-nonILD). DM with different MSAs had unique metabolic characteristics, which can distinguish between MDA5+DM, Jo-1+DM, and TIF1-γ+DM, and from the antibody-negative groups. The sphingosine metabolism has been found to play an important role in MDA5+DM, which was associated with the occurrence of ILD. Discussion Altered metabolic profiles of dermatomyositis were associated with different myositisspecific autoantibodies, disease activity, and interstitial lung disease, which can help in the early diagnosis, prognosis, or selection of new therapeutic targets for DM.
... Moreover, the impact of omega-3 and omega-6 PUFAs in maintaining LTL might be multifaceted and intertwined, as oxidative stress and inflammation are two closely related and interdependent pathophysiological processes that can both be activated or inhibited by these PUFAs [62]. However, the interaction between omega-3 and omega-6 PUFAs in the backdrop of inflammation and oxidative stress is intricate, and currently, it is poorly understood [63]. ...
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Background polyunsaturated fatty acids (PUFAs) are a category of fatty acids that contain omega-3 and omega-6 fatty acids, which constitute a substantial portion of the Western diet and are vital for maintaining human wellness. The extent to which circulating PUFAs influence the effects of BMI on leukocyte telomere length (LTL) is unknown. Additionally, the impact of circulating PUFA on LTL remains controversial in observational studies. Methods Using publicly accessible datasets, a genome-wide association study (GWAS) was carried out to determine genetic association estimates for BMI, circulating PUFAs, and LTL. The circulating PUFAs considered were omega-3 PUFAs (i.e., docosahexaenoic acid (DHA) and total omega-3 PUFAs) and omega-6 PUFAs (i.e., linoleic acid (LA) and total omega-6 PUFAs). Two-sample Mendelian randomization (MR) was used to investigate the causal relationships between BMI and PUFA with LTL. Additionally, we examined whether certain PUFA mediate the impact of BMI on LTL. Results None of the evidence supported a causal effect of genetically predicted DHA and total omega-3 PUFA on LTL (DHA: β = 0.001, 95% CI: −0.023 to 0.026, p = 0.926; total omega-3 PUFA: β = 0.008, 95% CI: −0.013 to 0.029, p = 0.466). After conducting sensitivity analyses to account for various models of horizontal pleiotropy, the causal association between higher levels of LA and longer LTL persisted (β = 0.034, 95% CI 0.016 to 0.052, p < 0.001). Adjusting for LA in genetics reduced the effect of BMI on LTL from β = -0.039 (95% CI: -0.058 to -0.020, p < 0.001) to -0.034 (95% CI: -0.054 to -0.014, p < 0.001). Conclusions This MR study indicates that an increase in genetically predicted circulating LA levels is associated with longer LTL. Additionally, it appears that circulating LA levels play a role in mediating some of the impact that BMI has on LTL.
... Linolenic acid (omega 3) is powerful when it comes to reducing colorectal cancer (Szachowicz-Petelska et al., 2007), and the development of inflammatory bowel disease (Hassan et al., 2010). In addition, linoleic acid (omega 6) may increase process of inflammation in human body ( Innes & Calder, 2018), and also reduce the risk of cardiometabolic disease development (Belury, 2023). Some recent scientific papers in which SFE oils isolation was the goal are shown in Table 14.1, as well as other groups of discussed bioactives in this chapter. ...
... Although several researches have demonstrated that higher omega-6 PUFA levels have potentially detrimental effects on the risks of depressive disorder and anxiety, their proinflammatory traits are still controversial [42]. Omega-6 PUFAs produce not only proinflammatory eicosanoids but also lipid mediators that play important roles in inflammation resolution [43]. The results from our study showed that high plasma omega-6 PUFA and LA levels were significantly associated with lower risks of depressive disorder and anxiety disorder. ...
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Background: Polyunsaturated fatty acids (PUFAs) are promising nutrients for the prevention and management of psychiatric disorders. Both animal experiments and cohort studies have demonstrated the antidepressant effects of PUFAs, especially omega-3 PUFAs. However, inconsistent reports about specific types of PUFAs, such as the omega-3 and omega-6 PUFAs, still exist. Objectives: To assess the effects of specific PUFAs on mental disorders and related symptoms and explore the potential mechanisms involving white matter microstructure. Methods: Leveraging 102,252 residents from the UK Biobank, the effects of five PUFA measures on depressive disorder and anxiety disorder were explored through Cox regression models with full adjustment for possible confounders. Furthermore, the effects on related psychiatric symptoms and brain white matter microstructures were also estimated using logistic regression models and multiple linear regression models, respectively. Results: In this study, plasma levels of five PUFAs measured in quartile 4 were associated with lower risks of incident depressive disorder compared with the lowest quartile, with hazard ratios of 0.80 [95% confidence interval] = [0.71, 0.90] for total PUFAs, 0.86 [0.76, 0.97] for omega-3 PUFAs, 0.80 [0.71, 0.91] for docosahexaenoic acid, 0.79 [0.70, 0.89] for omega-6 PUFAs, and 0.77 [0.69, 0.87] for linoleic acid. Similar associations were observed between PUFAs and the incident risk of anxiety disorder. In addition, high plasma PUFA levels were also related to lower risks of occurrence of several adverse psychological symptoms, especially omega-3 PUFAs and DHA. Among the included participants, 8780 individuals with brain imaging information were included in further neuroimaging analyses, and significant associations with white matter microstructures were observed. Conclusions: Thus, this study provides population-based evidence to support the value of interventions to target PUFAs (specifically omega-3 PUFAs) for the prevention and improvement of mental health.
... DHA is an omega-3 polyunsaturated fatty acid that is essential for the brain, maintaining the growth of nervous system cells and promoting intellectual development in infants and young children [1]. The human body cannot synthesize DHA on its own, and most of it needs to be obtained through food [2]. When breastfeeding is not possible, DHA supplementation through food becomes necessary [3]. ...
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Commercial DHA-rich algal oil has some issues, such as an unpleasant odor and susceptibility to oxidation. The main fishy odor compounds in commercial DHA-rich algal oil powder and DHA-rich algal oil microcapsules are hexanal and (E, E)-2,4-heptadienal. To address this issue, a microencapsulation process was designed for DHA-rich algal oil using infant rice powder (IRP), maltodextrin (MD), and whey protein concentrate (WPC) as wall materials, with sodium starch octenyl succinate (SSOS) and monoacylglycerol (MAC) as emulsifiers. The spray-drying method was used for microencapsulation. The experimental data showed that microcapsules with wall materials in a ratio of IRP/MD/WPC = 1:3:1 and an emulsifier content of 3.5% (SSOS and MAC) had the highest encapsulation efficiency (85.20 ± 6.03%) and the lowest aldehyde content (65.38 ± 3.23%). This microcapsule showed a good appearance and better oxidation stability compared with the crude oil, with a water content and average particle size of 1.69 ± 0.57% and 631.60 ± 23.19 nm, respectively. The results indicated that DHA-rich algal oil microcapsules prepared with infant rice powder had a lower fishy odor and better sensory acceptability compared to commercial DHA-rich algal oil powder.
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Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance and beta cell dysfunction, resulting in hyperglycemia. Olive oil, a cornerstone of the Mediterranean diet, has attracted considerable attention due to its potential health benefits, including reducing the risk of developing T2DM. This literature review aims to critically examine and synthesize existing research regarding the impact of olive oil on the expression of genes relevant to T2DM. This paper also seeks to provide an immunological and genetic perspective on the signaling pathways of the main components of extra virgin olive oil. Key bioactive components of olive oil, such as oleic acid and phenolic compounds, were identified as modulators of insulin signaling. These compounds enhanced the insulin signaling pathway, improved lipid metabolism, and reduced oxidative stress by decreasing reactive oxygen species (ROS) production. Additionally, they were shown to alleviate inflammation by inhibiting the NF-κB pathway and downregulating pro-inflammatory cytokines and enzymes. Furthermore, these bioactive compounds were observed to mitigate endoplasmic reticulum (ER) stress by downregulating stress markers, thereby protecting beta cells from apoptosis and preserving their function. In summary, olive oil, particularly its bioactive constituents, has been demonstrated to enhance insulin sensitivity, protect beta cell function, and reduce inflammation and oxidative stress by modulating key genes involved in these processes. These findings underscore olive oil’s therapeutic potential in managing T2DM. However, further research, including well-designed human clinical trials, is required to fully elucidate the role of olive oil in personalized nutrition strategies for the prevention and treatment of T2DM.
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Essential polyunsaturated fatty acids (PUFAs) of the n-3 and n-6 classes are crucial for maintaining many physiological functions of the human body. It has previously been suggested that the beneficial...
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Asthma, is a common, significant and diverse condition marked by persistent airway inflammation, with a major impact on human health worldwide. The predisposing factors for asthma are complex and widespread. The beneficial effects of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) in asthma have increasingly attracted attention recently. In asthma therapy, n-3 PUFAs may reduce asthma risk by controlling on levels of inflammatory cytokines and regulating recruitment of inflammatory cells in asthma. The specialized pro-resolving mediators (SPMs) derived from n-3 PUFAs, including the E- and D-series resolvins, protectins, and maresins, were discovered in inflammatory exudates and their biosynthesis by lipoxygenase mediated pathways elucidated., SPMs alleviated T-helper (Th)1/Th17 and type 2 cytokine immune imbalance, and regulated macrophage polarization and recruitment of inflammatory cells in asthma via specific receptors such as formyl peptide receptor 2 (ALX/FPR2) and G protein-coupled receptor 32. In conclusion, the further study of n-3 PUFAs and their derived SPMs may lead to novel anti-inflammatory asthma treatments.
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Ferroptosis is an iron-dependent form of cell death, which is characterized by the uncontrolled and overwhelming peroxidation of cell membrane lipids. Ferroptosis has been implicated in the progression of various pathologies, including steatotic liver, heart failure, neurodegenerative diseases, and diabetes. Targeted inhibition of ferroptosis provides a promising strategy to treat ferroptosis-related diseases. Multivitamins, including vitamins A, B, C, D, E, and K, have shown a good ability to inhibit ferroptosis. For example, vitamin A significantly upregulated the expression of several key ferroptotic gatekeepers genes through nuclear retinoic acid receptors and retinoic X receptors (RAR/RXR). Vitamin B6 could compensate for the impaired glutathione (GSH) levels and restore Glutathione peroxidase 4 (GPX4) expression in cells, ultimately inhibiting ferroptosis. Vitamin D could up-regulate the expression of several anti-ferroptosis proteins by activating vitamin D receptors. Vitamin E and hydroquinone vitamin K (VKH2) can directly inhibit the propagation of lipid peroxidation, thereby inhibiting ferroptosis. In this review, we summarize the currently understood mechanisms by which vitamins inhibit ferroptosis to provide reference information for future research on the development of ferroptosis inhibitors.
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Mood disorders include a set of psychiatric manifestations of increasing prevalence in our society, being mainly represented by major depressive disorder (MDD) and bipolar disorder (BD). The etiopathogenesis of mood disorders is extremely complex, with a wide spectrum of biological, psychological, and sociocultural factors being responsible for their appearance and development. In this sense, immune system dysfunction represents a key mechanism in the onset and pathophysiology of mood disorders, worsening mainly the central nervous system (neuroinflammation) and the periphery of the body (systemic inflammation). However, these alterations cannot be understood separately, but as part of a complex picture in which different factors and systems interact with each other. Psychoneuroimmunoendocrinology (PNIE) is the area responsible for studying the relationship between these elements and the impact of mind–body integration, placing the immune system as part of a whole. Thus, the dysfunction of the immune system is capable of influencing and activating different mechanisms that promote disruption of the psyche, damage to the nervous system, alterations to the endocrine and metabolic systems, and disruption of the microbiota and intestinal ecosystem, as well as of other organs and, in turn, all these mechanisms are responsible for inducing and enhancing the immune dysfunction. Similarly, the clinical approach to these patients is usually multidisciplinary, and the therapeutic arsenal includes different pharmacological (for example, antidepressants, antipsychotics, and lithium) and non-pharmacological (i.e., psychotherapy, lifestyle, and electroconvulsive therapy) treatments. These interventions also modulate the immune system and other elements of the PNIE in these patients, which may be interesting to understand the therapeutic success or failure of these approaches. In this sense, this review aims to delve into the relationship between immune dysfunction and mood disorders and their integration in the complex context of PNIE. Likewise, an attempt will be made to explore the effects on the immune system of different strategies available in the clinical approach to these patients, in order to identify the mechanisms described and their possible uses as biomarkers.
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The octadecanoids are a broad class of lipids consisting of the oxygenated products of 18-carbon fatty acids. Originally referring to production of the phytohormone jasmonic acid, the octadecanoid pathway has been expanded to include products of all 18-carbon fatty acids. Octadecanoids are formed biosynthetically in mammals via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) activity, as well as nonenzymatically by photo- and autoxidation mechanisms. While octadecanoids are well-known mediators in plants, their role in the regulation of mammalian biological processes has been generally neglected. However, there have been significant advancements in recognizing the importance of these compounds in mammals and their involvement in the mediation of inflammation, nociception, and cell proliferation, as well as in immuno- and tissue modulation, coagulation processes, hormone regulation, and skin barrier formation. More recently, the gut microbiome has been shown to be a significant source of octadecanoid biosynthesis, providing additional biosynthetic routes including hydratase activity (e.g., CLA-HY, FA-HY1, FA-HY2). In this review, we summarize the current field of octadecanoids, propose standardized nomenclature, provide details of octadecanoid preparation and measurement, summarize the phase-I metabolic pathway of octadecanoid formation in mammals, bacteria, and fungi, and describe their biological activity in relation to mammalian pathophysiology as well as their potential use as biomarkers of health and disease.
Chapter
Globally, cancer ranks among the most prevalent problems that impact the health of society. Several factors contribute to cancer’s onset and development, including genetics and environmental variables both inside and outside the body. In the prevention and treatment of various cancers, nutrition and diet play an important role. It is well known that the type of diet and nutrition we consume can have a major impact may profoundly impact on the possibility of cancer since numerous dietary elements, like the consumption of vegetables, fruit, dietary fiber, and alcohol, may significantly impact the prevalence of cancer. Multiple investigations have demonstrated the potential of appropriate eating patterns to either prevent cancer or slow the growth of tumors in cancer patients. Consuming a balanced diet packed with macronutrients and micronutrients to prevent and treat cancer. This chapter briefly focuses on the role of macronutrients and micronutrients in preventing cancer. Moreover, we summarized the various studies assessing the contribution of micro- and macronutrients in cancer prevention.
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Objective: Chronic lung disease (CLD) is a complication of prematurity. Studies examining the effects of long-chain polyunsaturated fatty acids (LC-PUFAs) on CLD are conflicting. This study investigated LC-PUFAs in the red blood cell membrane (RBCM) in preterm infants. Study design: This prospective observational study included infants with gestational age <32 weeks or birth weight <2 kg and at least one LC-PUFA measurement in the first month of life. Subjects without CLD (CON group) were compared to those with CLD (CLD group) and then by CLD severity. Results: Seventy infants were included (CON n=29; CLD n=41). Twenty six infants had Grade 1 CLD; 12 had Grade 2 CLD; 3 had Grade 3 CLD. When the CLD group was compared to the CON group, the overall mean (95% confidence interval) RBCM% for linoleic acid (LA) was similar (CLD vs. CON 12.5% [11.7% - 13.4%] vs. 11.2% [10.2 - 12.3%] p=0.06) but the overall mean arachidonic acid (ARA) was lower (17.6% [17.1% - 18.0%] vs. 18.6% [18.1% - 19.2%], p<0.01). During weeks 1-4, LA% was similar, while ARA% was lower in weeks 2 and 3 (18.8% ± 2.2% vs. 20.0% ± 1.5%, p=0.05, 16.8% ± 2.0% vs. 18.3% ± 1.6%, p=0.01). A similar trend was noted when groups were compared by CLD severity. The CLD group had a higher overall mean ∝-linolenic acid (ALA) compared to the CON group (0.4% [0.3% - 0.4%] vs. 0.2% [0.2 % - 0.3%], p<0.01) but no difference in docosahexaenoic acid (DHA) (3.8% [3.4% - 4.1%] vs. 3.8% [3.4% - 4.3%], p=0.80). During weeks 1-4, ALA% was higher during week 1 only (0.4% ± 0.3% vs. 0.2% ± 0.1%, p<0.01), and DHA% was similar for weeks 1-4. Results were similar when groups were compared by CLD severity. Conclusions: In this study, low ARA status was associated with CLD.
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Background: Polar lipids from dairy are novel sources of energy that may replace other dietary lipids and impact plasma lipidomic profiles in piglets. This study evaluated the impact of feeding diets rich in polar lipids on the plasma lipidome of piglets during the weaning period. Material and Methods: Weaned male piglets (n = 240; 21 days of age; 6.3 ± 0.5 kg of BW) were blocked by initial weight and distributed into 48 pens of five animals each in a complete randomized block design with a 2 × 3 factorial arrangement of treatments as follows: a plant-based diet rich in neutral lipids from soybeans (24 pens; SD) or a polar lipid-rich diet by-product of cheese making (24 pens; PD) from weaning until the 21st day of the nursery phase. Within each diet group, animals received one of three milk replacers (MR; 0.5 L/d/animal) for the first 7 days after weaning: (1) commercial MR containing animal and coconut lipids (CO); (2) polar lipid-based MR (PO); or (3) soybean lipids-based MR (SO). Results: The PD diet group increased the plasma concentrations of sphingolipids, phospholipids, and cholesterol esters, but did not impact the concentrations of glycerolipids (GLs). Both the PO and CO milk replacers increased the plasma concentrations of ceramide, acyl-chain phosphatidyl choline, and cholesterol esters. The plasma concentrations of GLs containing 18-carbon fatty acids such as 18:0, 18:1, 18:2, and 18:3, were higher in SD, whereas GLs containing 16:0 and 20:3 were higher in PD. Conclusions: In summary, the diet lipid type significantly modulated the plasma lipid composition in piglets 7 days after weaning. The dietary inclusion of polar lipids in diets for growing pigs can modulate the plasma lipidomic profile, relative to plant-based diets rich in soybean lipids. Cost may be a major consideration when using these lipids in pig diets. Their health benefits need to be further characterized in other models of stress and inflammation.
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Bioactive lipid mediators (LMs) have been implicated in Alzheimer’s disease (AD), but their involvement in disease pathogenesis is poorly understood. Using targeted liquid chromatography-tandem mass spectrometry on human AD and non-neurological control brain tissue, we identified a differential activation of arachidonic acid (AA) metabolism in the occipital and temporal cortex of AD subjects. The cyclooxygenase (COX)-1/2 pathway was activated in the occipital cortex and associated with increased expression of neuronal COX-2. Contrarily, in the temporal cortex the lipoxygenases (LOX) pathways, mainly 5-LOX, were activated. Association analysis revealed a positive correlation between 5-LOX-derived LMs and microglia activation. In line, the expression of 5-LOX and its activating protein (FLAP) was increased in disease-associated microglia near amyloid plaques in AD brains. We propose that the latter process is partially mediated by transforming growth factor-β1 and can be abrogated by FLAP inhibition. Our results indicate a differential response in AD brains associated with an AA-derived LM profile, driven by distinct LM biosynthetic pathways. These findings advance our understanding of the role of LMs in the pathophysiology of AD and provide new therapeutic targets to combat disease progression.
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In 1970, the central role of lipids in energy storage and metabolism was well accepted and the structural role of amphipathic lipids as the backbone of biological membranes was assumed. At the time, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable time and effort until scientists accepted that lipids, too, contain specific and unique information and play a central role in cell signaling. Futhermore, it remained to be recognized that the enzymes that act on lipid substrates residing in or on membranes and micelles have important signaling roles and display unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of "surface dilution kinetics" for describing the mechanism of enzymes acting on lipid substrates and the demonstration that phospholipase A2 (PLA2) contains allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are information-containing signaling molecules and that PLA2 regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine.
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Background/aim: For international recommendations on docosahexaenoic acid (DHA) and arachidonic acid (ARA) dietary intake to be valid, there needs to be a greater understanding of dietary patterns across both the developed and developing world. The aim of this investigation was to provide a global overview of dietary intake of DHA and ARA. Methods: Food balance sheets from the Food and Agriculture Organisation Statistics Division and fatty acid composition data from Australian food composition tables in Nutrient Tables 2010 were utilised to generate median per capita intake estimates for DHA and ARA in 175 countries worldwide. Results: Estimated dietary intake per capita for DHA and ARA in 47 developed and 128 developing countries demonstrated that 48% of the 175 countries have an ARA intake of <150 mg/day and 64% have a dietary DHA intake of <200 mg/day. There was a direct relationship between dietary ARA and DHA intake and the per capita gross national income of the country. Regional analysis showed the lowest ARA and DHA dietary intake in Sub-Saharan Africa and Central and Southern Asian populations. Conclusions: This study demonstrates there are many populations worldwide that have ARA and DHA intake that do not reflect current international recommendations, and the public health consequences of this global inadequacy need to be urgently considered.
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Background: Supplementation of the diet with fish oil, which is rich in the long-chain n−3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is reported to decrease several markers of immune function. However, whether EPA, DHA, or a combination of the 2 exerts these immunomodulatory effects is unclear. Objective: The objective of the study was to determine the effects of supplementation with an EPA-rich or DHA-rich oil on a range of immune outcomes representing key functions of human neutrophils, monocytes, and lymphocytes in healthy humans. Design: In a placebo-controlled, double-blind, parallel study, 42 healthy subjects were randomly allocated to receive supplementation with either placebo (olive oil), EPA (4.7 g/d), or DHA (4.9 g/d) for 4 wk. Blood samples were taken before and after supplementation. Results: The fatty acid composition of plasma phospholipids and neutrophils was dramatically altered by supplementation with EPA or DHA, and the effects of EPA differed notably from those of DHA. DHA supplementation decreased T lymphocyte activation, as assessed by expression of CD69, whereas EPA supplementation had no significant effect. Neither the EPA-rich oil nor the DHA-rich oil had any significant effect on monocyte or neutrophil phagocytosis or on cytokine production or adhesion molecule expression by peripheral blood mononuclear cells. Conclusions: Supplementation with DHA, but not with EPA, suppresses T lymphocyte activation, as assessed by expression of CD69. EPA alone does not, therefore, influence CD69 expression. No other marker of immune function assessed in this study was significantly affected by either EPA or DHA.
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Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are increased in plasma lipids and blood cell membranes in response to supplementation. Whilst arachidonic acid (AA) is correspondingly decreased, the effect on other fatty acids (FA) is less well described and there may be site-specific differences. In response to 12 months EPA + DHA supplementation in doses equivalent to 0-4 portions of oily fish/week (1 portion: 3.27 g EPA+DHA) multinomial regression analysis was used to identify important FA changes for plasma phosphatidylcholine (PC), cholesteryl ester (CE) and triglyceride (TAG) and for blood mononuclear cells (MNC), red blood cells (RBC) and platelets (PLAT). Dose-dependent increases in EPA + DHA were matched by decreases in several n-6 polyunsaturated fatty acids (PUFA) in PC, CE, RBC and PLAT, but were predominantly compensated for by oleic acid in TAG. Changes were observed for all FA classes in MNC. Consequently the n-6:n-3 PUFA ratio was reduced in a dose-dependent manner in all pools after 12 months (37%-64% of placebo in the four portions group). We conclude that the profile of the FA decreased in exchange for the increase in EPA + DHA following supplementation differs by FA pool with implications for understanding the impact of n-3 PUFA on blood lipid and blood cell biology.
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To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation.
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Ulcerative colitis (UC) is a relapsing inflammatory disorder of unconfirmed aetiology, variable severity and clinical course, characterised by progressive histological inflammation and with elevation of eicosanoids which have a known pathophysiological role in inflammation. Therapeutic interventions targetting eicosanoids (5-aminosalicylates (ASA)) are effective first line and adjunctive treatments in mild-moderate UC for achieving and sustaining clinical remission. However, the variable clinical response to 5-ASA and frequent deterioration in response to cyclo-oxygenase (COX) inhibitors, has prompted an in depth simultaneous evaluation of multiple lipid mediators (including eicosanoids) within the inflammatory milieu in UC. We hypothesised that severity of inflammation is associated with alteration of lipid mediators, in relapsing UC. Study was case-control design. Mucosal lipid mediators were determined by LC-MS/MS lipidomics analysis on mucosal biopsies taken from patients attending outpatients with relapsing UC. Univariate and multivariate statistical analyses were used to investigate the association of mucosal lipid mediators, with the disease state and severity graded histologically. Levels of PGE2, PGD2, TXB2, 5-HETE, 11-HETE, 12-HETE and 15-HETE are significantly elevated in inflamed mucosa and correlate with severity of inflammation, determined using validated histological scoring systems. Our approach of capturing inflammatory mediator signature at different stages of UC by combining comprehensive lipidomics analysis and computational modelling could be used to classify and predict mild-moderate inflammation; however, predictive index is diminished in severe inflammation. This new technical approach could be developed to tailor drug treatments to patients with active UC, based on the mucosal lipid mediator profile.
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Resolution of inflammation is now held to be an active process where autacoids promote homeostasis. Using functional-metabololipidomics and in vivo systems, herein we report that endogenous n-3 docosapentaenoic (DPA) acid is converted during inflammation-resolution in mice and by human leukocytes to novel n-3 products congenerous to D-series resolvins (Rv), protectins (PD) and maresins (MaR), termed specialized pro-resolving mediators (SPM). The new n-3 DPA structures include 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1n-3 DPA), 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1n-3 DPA) and related bioactive products. Each n-3 DPA-SPM displayed protective actions from second organ injury and reduced systemic inflammation in ischemia-reperfusion. The n-3 DPA-SPM, including RvD1n-3 DPA and MaR1n-3 DPA, each exerted potent leukocyte directed actions in vivo. With human leukocytes each n-3 DPA-SPM reduced neutrophil chemotaxis, adhesion and enhanced macrophage phagocytosis. Together, these findings demonstrate that n-3 DPA is converted to novel immunoresolvents with actions comparable to resolvins and are likely produced in humans when n-3 DPA is elevated.
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The majority of evidence suggests that n-6 polyunsaturated fatty acids, including linoleic acid (LA), reduce the risk of cardiovascular disease as reflected by current dietary recommendations. However, concern has been expressed that a high intake of dietary n-6 polyunsaturated fatty acid contributes to excess chronic inflammation, primarily by prompting the synthesis of proinflammatory eicosanoids derived from arachidonic acid and/or inhibiting the synthesis of anti-inflammatory eicosanoids from eicosapentaenoic and/or docosahexaenoic acids. A systematic review of randomized controlled trials that permitted the assessment of dietary LA on biologic markers of chronic inflammation among healthy noninfant populations was conducted to examine this concern. A search of the English- and non-English-language literature using MEDLINE, the Cochrane Controlled Trials Register, and EMBASE was conducted to identify relevant articles. Fifteen studies (eight parallel and seven crossover) met inclusion criteria. None of the studies reported significant findings for a wide variety of inflammatory markers, including C-reactive protein, fibrinogen, plasminogen activator inhibitor type 1, cytokines, soluble vascular adhesion molecules, or tumor necrosis factor-α. The only significant outcome measures reported for higher LA intakes were greater excretion of prostaglandin E2 and lower excretion of 2,3-dinor-thromboxane B(2) in one study and higher excretion of tetranorprostanedioic acid in another. However, the authors of those studies both observed that these effects were not an indication of increased inflammation. We conclude that virtually no evidence is available from randomized, controlled intervention studies among healthy, noninfant human beings to show that addition of LA to the diet increases the concentration of inflammatory markers.
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Low-grade inflammation is a characteristic of the obese state, and adipose tissue releases many inflammatory mediators. The source of these mediators within adipose tissue is not clear, but infiltrating macrophages seem to be especially important, although adipocytes themselves play a role. Obese people have higher circulating concentrations of many inflammatory markers than lean people do, and these are believed to play a role in causing insulin resistance and other metabolic disturbances. Blood concentrations of inflammatory markers are lowered following weight loss. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation, and this is exaggerated by a high meal content of advanced glycation end products (AGE) and partly ablated by inclusion of certain antioxidants or antioxidant-containing foods within the meal. Healthy eating patterns are associated with lower circulating concentrations of inflammatory markers. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation. AGE are associated with enhanced oxidative stress and inflammation. SFA and trans-MUFA are pro-inflammatory, while PUFA, especially long-chain n-3 PUFA, are anti-inflammatory. Hyperglycaemia induces both postprandial and chronic low-grade inflammation. Vitamin C, vitamin E and carotenoids decrease the circulating concentrations of inflammatory markers. Potential mechanisms are described and research gaps, which limit our understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identified.
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The importance of arachidonic acid (ARA) among the elderly has recently gained increased attention. The effects of ARA supplementation in the elderly are not fully understood, although ARA is considered to be associated with various diseases. We investigate whether ARA supplementation to Japanese elderly subjects affects clinical parameters involved in cardiovascular, inflammatory, and allergic diseases. We also examine the levels of ARA metabolites such as prostanoids during intervention. We conducted a randomized, double-blind and placebo-controlled parallel group intervention trial. ARA-enriched oil (240 or 720 mg ARA per day) or placebo was administered to Japanese healthy men and women aged 55-70 years for 4 weeks followed by a 4-week washout period. The fatty acid contents of plasma phospholipids, clinical parameters, and ARA metabolites were determined at baseline, 2, 4, and 8 weeks. The ARA content in plasma phospholipids in the ARA-administrated groups increased dose-dependently and was almost the same at 2 weeks and at 4 weeks. The elevated ARA content decreased to nearly baseline during a 4-week washout period. During the supplementation and washout periods, no changes were observed in eicosapentaenoic acid and docosahexaenoic acid contents. There were no changes in clinical blood parameters related to cardiovascular, inflammatory and allergic diseases. ARA supplementation did not alter the level of ARA metabolites such as urinary 11-dehydro thromboxane B2, 2,3-dinor-6-keto prostaglandin (PG) F1α and 9,15-dioxo-11α-hydroxy-13,14-dihydro-2,3,4,5-tetranor-prostan-1,20-dioic acid (tetranor-PGEM), and plasma PGE2 and lipoxin A4. ARA in plasma phospholipids was not correlated with ARA metabolite levels in the blood or urine. These results indicate that ARA supplementation, even at a relatively high dose, does not increase ARA metabolites, and suggest that it does not induce cardiovascular, inflammatory or allergic diseases in Japanese elderly individuals.
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High saturated fat intake is an established risk factor for several chronic diseases. The objective of the present study is to report dietary intakes and main food sources of fat and fatty acids (FA) from the first year of the National Diet and Nutrition Survey (NDNS) rolling programme in the UK. Dietary data were collected using 4 d estimated food diaries (n 896) and compared with dietary reference values (DRV) and previous NDNS results. Total fat provided 34-36 % food energy (FE) across all age groups, which was similar to previous surveys for adults. Men (19-64 years) and older girls (11-18 years) had mean intakes just above the DRV, while all other groups had mean total fat intakes of < 35 % FE. SFA intakes were lower compared with previous surveys, ranging from 13 to 15 % FE, but still above the DRV. Mean MUFA intakes were 12·5 % FE for adults and children aged 4-18 years and all were below the DRV. Mean n-3 PUFA intake represented 0·7-1·1 % FE. Compared with previous survey data, the direction of change for n-3 PUFA was upwards for all age groups, although the differences in absolute terms were very small. Trans-FA intakes were lower than in previous NDNS and were less than 2 g/d for all age groups, representing 0·8 % FE and lower than the DRV in all age groups. In conclusion, dietary intake of fat and FA is moving towards recommended levels for the UK population. However, there remains room for considerable further improvement.
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Increasing intakes of long-chain n-3 polyunsaturated fatty acids (PUFAs) can decrease markers of immunity. However, dose- and age-related responses have not been identified. The objective was to determine the effects of different amounts of eicosapentaenoic acid (EPA) on innate immune outcomes in young and older males. In a controlled, double-blind study, healthy young and older men consumed 1 of 4 supplements provided as capsules: placebo (corn oil) or different amounts of an oil providing 1.35, 2.7, or 4.05 g EPA/d for 12 wk. Blood samples were collected at baseline and after 12 wk. EPA was incorporated in a linear dose-response fashion into plasma and mononuclear cell (MNC) phospholipids; incorporation was greater in the older men. EPA treatment did not alter neutrophil or monocyte phagocytosis, monocyte respiratory burst, or the production of inflammatory cytokines by MNCs in the young or older men. EPA treatment caused a dose-dependent decrease in neutrophil respiratory burst only in the older men. Increased incorporation of EPA into plasma or MNC phospholipids was associated with decreased production of prostaglandin E2 by MNCs from both young and older men. Older subjects incorporate EPA into plasma and MNC phospholipids more readily than do younger subjects. Other than prostaglandin E2 production, innate immune responses in young subjects are not affected by an EPA intake of < or =4.05 g/d. Older subjects are more sensitive to the immunologic effects of EPA, and the neutrophil respiratory burst is lower at higher EPA intakes.
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Linoleic acid, with a DRI of 12-17 g/d, is the most highly consumed polyunsaturated fatty acid in the Western diet and is found in virtually all commonly consumed foods. The concern with dietary linoleic acid, being the metabolic precursor of arachidonic acid, is its consumption may enrich tissues with arachidonic acid and contribute to chronic and overproduction of bioactive eicosanoids. However, no systematic review of human trials regarding linoleic acid consumption and subsequent changes in tissue levels of arachidonic acid has been undertaken. In this study, we reviewed the human literature that reported changes in dietary linoleic acid and its subsequent impact on changing tissue arachidonic acid in erythrocytes and plasma/serum phospholipids. We identified, reviewed, and evaluated all peer-reviewed published literature presenting data outlining changes in dietary linoleic acid in adult human clinical trials that reported changes in phospholipid fatty acid composition (specifically arachidonic acid) in plasma/serum and erythrocytes within the parameters of our inclusion/exclusion criteria. Decreasing dietary linoleic acid by up to 90% was not significantly correlated with changes in arachidonic acid levels in the phospholipid pool of plasma/serum (p = 0.39). Similarly, when dietary linoleic acid levels were increased up to six fold, no significant correlations with arachidonic acid levels were observed (p = 0.72). However, there was a positive relationship between dietary gamma-linolenic acid and dietary arachidonic acid on changes in arachidonic levels in plasma/serum phospholipids. Our results do not support the concept that modifying current intakes of dietary linoleic acid has an effect on changing levels of arachidonic acid in plasma/serum or erythrocytes in adults consuming Western-type diets.
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The consumption of omega-3 (n-3) and omega-6 (n-6) essential fatty acids in Western diets is thought to have changed markedly during the 20th century. We sought to quantify changes in the apparent consumption of essential fatty acids in the United States from 1909 to 1999. We calculated the estimated per capita consumption of food commodities and availability of essential fatty acids from 373 food commodities by using economic disappearance data for each year from 1909 to 1999. Nutrient compositions for 1909 were modeled by using current foods (1909-C) and foods produced by traditional early 20th century practices (1909-T). The estimated per capita consumption of soybean oil increased >1000-fold from 1909 to 1999. The availability of linoleic acid (LA) increased from 2.79% to 7.21% of energy (P < 0.000001), whereas the availability of α-linolenic acid (ALA) increased from 0.39% to 0.72% of energy by using 1909-C modeling. By using 1909-T modeling, LA was 2.23% of energy, and ALA was 0.35% of energy. The ratio of LA to ALA increased from 6.4 in 1909 to 10.0 in 1999. The 1909-T but not the 1909-C data showed substantial declines in dietary availability (percentage of energy) of n-6 arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Predicted net effects of these dietary changes included declines in tissue n--3 highly unsaturated fatty acid status (36.81%, 1909-T; 31.28%, 1909-C; 22.95%, 1999) and declines in the estimated omega-3 index (8.28, 1909-T; 6.51, 1909-C; 3.84, 1999). The apparent increased consumption of LA, which was primarily from soybean oil, has likely decreased tissue concentrations of EPA and DHA during the 20th century.
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Inflammation is a stereotypical physiological response to infections and tissue injury; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites. Acute inflammatory reactions are usually self-limiting and resolve rapidly, due to the involvement of negative feedback mechanisms. Thus, regulated inflammatory responses are essential to remain healthy and maintain homeostasis. However, inflammatory responses that fail to regulate themselves can become chronic and contribute to the perpetuation and progression of disease. Characteristics typical of chronic inflammatory responses underlying the pathophysiology of several disorders include loss of barrier function, responsiveness to a normally benign stimulus, infiltration of inflammatory cells into compartments where they are not normally found in such high numbers, and overproduction of oxidants, cytokines, chemokines, eicosanoids and matrix metalloproteinases. The levels of these mediators amplify the inflammatory response, are destructive and contribute to the clinical symptoms. Various dietary components including long chain omega-3 fatty acids, antioxidant vitamins, plant flavonoids, prebiotics and probiotics have the potential to modulate predisposition to chronic inflammatory conditions and may have a role in their therapy. These components act through a variety of mechanisms including decreasing inflammatory mediator production through effects on cell signaling and gene expression (omega-3 fatty acids, vitamin E, plant flavonoids), reducing the production of damaging oxidants (vitamin E and other antioxidants), and promoting gut barrier function and anti-inflammatory responses (prebiotics and probiotics). However, in general really strong evidence of benefit to human health through anti-inflammatory actions is lacking for most of these dietary components. Thus, further studies addressing efficacy in humans linked to studies providing greater understanding of the mechanisms of action involved are required.
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Cyclooxygenase (COX), or prostaglandin (PG) H synthase, plays a role in inflammatory diseases, but very limited data exist on the regulation of COX in vivo. We, therefore, studied the in vivo expression of COX in synovia from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), as well as joints of rats with streptococcal cell wall (SCW) and adjuvant arthritis. Extensive and intense intracellular COX immunostaining, which correlated with the extent and intensity of mononuclear cell infiltration, was observed in cells throughout RA synovia. Significantly less or equivocal staining was noted in OA and normal human synovia. Similarly, COX immunostaining was equivocal in the joints of normal and arthritis-resistant F344/N rats. In contrast, high level expression developed rapidly in euthymic female Lewis (LEW/N) rats throughout the hindlimb joints and overlying tissues including skin, preceding or paralleling clinically apparent experimental arthritis. COX was expressed in the joints of athymic LEW.rnu/rnu rats 2-4 d after injection of SCW or adjuvant but was not sustained. Physiological doses of antiinflammatory glucocorticoids, but not progesterone, suppressed both arthritis and COX expression in LEW/N rats. These observations suggest that, in vivo, (a) COX expression is upregulated in inflammatory joint diseases, (b) the level of expression is genetically controlled and is a biochemical correlate of disease severity, (c) sustained high level up-regulation is T cell dependent, and (d) expression is down-regulated by antiinflammatory glucocorticoids.
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Earlier studies demonstrated that dietary omega-3 polyunsaturated fatty acid (PUFA) supplementation attenuates the chemotactic response of neutrophils and the generation of leukotriene (LT) B4 by neutrophils stimulated with calcium ionophore; however, the mechanisms and relationship of these effects were not examined. Neutrophils and monocytes from eight healthy individuals were examined before and after 3 and 10 wk of dietary supplementation with 20 g SuperEPA daily, which provides 9.4 g eicosapentaenoic acid (EPA) and 5 g docosahexaenoic acid. The maximal neutrophil chemotactic response to LTB4, assessed in Boyden microchambers, decreased by 69% after 3 wk and by 93% after 10 wk from prediet values. The formation of [3H]inositol tris-phosphate (IP3) by [3H]inositol-labeled neutrophils stimulated by LTB4 decreased by 71% after 3 wk (0.033 +/- 0.013% [3H] release, mean +/- SEM) and by 90% after 10 wk (0.011 +/- 0.011%) from predict values (0.114 +/- 0.030%) as quantitated by beta-scintillation counting after resolution on HPLC. LTB4-stimulated neutrophil chemotaxis and IP3 formation correlated significantly (P < 0.0001); each response correlated closely and negatively with the EPA content of the neutrophil phosphatidylinositol (PI) pool (P = 0.0003 and P = 0.0005, respectively). Neither the affinities and densities of the high and low affinity LTB4 receptors on neutrophils nor LTB4-mediated diglyceride formation changed appreciably during the study. Similar results were observed in neutrophils activated with platelet-activating factor (PAF). The summed formation of LTB4 plus LTB5 was selectively inhibited in calcium ionophore-stimulated neutrophils and was also inhibited in zymosan-stimulated neutrophils. The inhibition of the summed formation of LTB4 plus LTB5 in calcium ionophore-stimulated neutrophils and in zymosan-stimulated neutrophils did not correlate significantly with the EPA content of the PI pool. The data indicate that dietary omega-3 PUFA supplementation inhibits the autoamplification of the neutrophil inflammatory response by decreasing LTB4 formation through the inactivation of the LTA epoxide hydrolase and independently by inhibiting LTB4- (and PAF) stimulated chemotaxis by attenuating the formation of IP3 by the PI-selective phospholipase C. This is the initial demonstration that dietary omega-3 PUFA supplementation can suppress signal transduction at the level of the PI-specific phospholipase C in humans.
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To understand the in vivo metabolism of dietary gamma-linolenic acid (GLA), we supplemented the diets of 29 volunteers with GLA in doses of 1.5-6.0 g/d. Twenty-four subjects ate controlled eucaloric diets consisting of 25% fat; the remaining subjects maintained their typical Western diets. GLA and dihomo-gamma-linolenic acid (DGLA) increased in serum lipids of subjects supplemented with 3.0 and 6.0 g/d; serum arachidonic acid increased in all subjects. GLA supplementation with 3.0 and 6.0 g/d also resulted in an enrichment of DGLA in neutrophil phospholipids but no change in GLA or AA levels. Before supplementation, DGLA was associated primarily with phosphatidylethanolamine (PE) of neutrophil glycerolipids, and DGLA increased significantly in PE and neutral lipids after GLA supplementation. Extending the supplementation to 12 wk did not consistently change the magnitude of increase in either serum or neutrophil lipids in subjects receiving 3.0 g/d. After GLA supplementation, A23187-stimulated neutrophils released significantly more DGLA, but AA release did not change. Neutrophils obtained from subjects after 3 wk of supplementation with 3.0 g/d GLA synthesized less leukotriene B4 (P < 0.05) and platelet-activating factor. Together, these data reveal that DGLA, the elongase product of GLA, but not AA accumulates in neutrophil glycerolipids after GLA supplementation. The increase in DGLA relative to AA within inflammatory cells such as the neutrophil may attenuate the biosynthesis of AA metabolites and may represent a mechanism by which dietary GLA exerts an anti-inflammatory effect.
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Leukotrienes (LTs) and prostaglandins (PGs) amplify acute inflammation, whereas lipoxins (LXs) have unique anti-inflammatory actions. Temporal analyses of these eicosanoids in clinical and experimental exudates showed early coordinate appearance of LT and PG with polymorphonuclear neutrophil (PMN) recruitment. This was followed by LX biosynthesis, which was concurrent with spontaneous resolution. Human peripheral blood PMNs exposed to PGE2 (as in exudates) switched eicosanoid biosynthesis from predominantly LTB4 and 5-lipoxygenase (5-LO)-initiated pathways to LXA4, a 15-LO product that "stopped" PMN infiltration. These results indicate that first-phase eicosanoids promote a shift to anti-inflammatory lipids: functionally distinct lipid-mediator profiles switch during acute exudate formation to "reprogram" the exudate PMNs to promote resolution.
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Animal and human studies have shown that greatly increasing the amounts of flax seed oil [rich in the (n-3) polyunsaturated fatty acid (PUFA) alpha-linolenic acid (ALNA)] or fish oil [FO; rich in the long chain (n-3) PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] in the diet can decrease mitogen-stimulated lymphocyte proliferation. The objective of this study was to determine the effect of dietary supplementation with moderate levels of ALNA, gamma-linolenic acid (GLA), arachidonic acid (ARA), DHA or FO on the proliferation of mitogen-stimulated human peripheral blood mononuclear cells (PBMC) and on the production of cytokines by those cells. The study was randomized, placebo-controlled, double-blinded and parallel. Healthy subjects ages 55-75 y consumed nine capsules/d for 12 wk; the capsules contained placebo oil (an 80:20 mix of palm and sunflower seed oils) or blends of placebo oil with oils rich in ALNA, GLA, ARA or DHA or FO. Subjects in these groups consumed 2 g of ALNA or 770 mg of GLA or 680 mg of ARA or 720 mg of DHA or 1 g of EPA plus DHA (720 mg of EPA + 280 mg of DHA) daily from the capsules. Total fat intake from the capsules was 4 g/d. The fatty acid composition of PBMC phospholipids was significantly changed in the GLA, ARA, DHA and FO groups. Lymphocyte proliferation was not significantly affected by the placebo, ALNA, ARA or DHA treatments. GLA and FO caused a significant decrease (up to 65%) in lymphocyte proliferation. This decrease was partly reversed by 4 wk after stopping the supplementation. None of the treatments affected the production of interleukin-2 or interferon-gamma by PBMC and none of the treatments affected the number or proportion of T or B lymphocytes, helper or cytotoxic T lymphocytes or memory helper T lymphocytes in the circulation. We conclude that a moderate level GLA or EPA but not of other (n-6) or (n-3) PUFA can decrease lymphocyte proliferation but not production of interleukin-2 or interferon-gamma.
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The anti-inflammatory eicosanoid lipoxin A(4) (LXA(4)), aspirin-triggered 15-epi-LXA(4), and their stable analogs down-regulate IL-8 secretion and subsequent recruitment of neutrophils by intestinal epithelia. In an effort to elucidate the mechanism by which these lipid mediators modulate cellular proinflammatory programs, we surveyed global epithelial gene expression using cDNA microarrays. LXA(4) analog alone did not significantly affect expression of any of the >7000 genes analyzed. However, LXA(4) analog pretreatment attenuated induction of approximately 50% of the 125 genes up-regulated in response to the gastroenteritis-causing pathogen Salmonella typhimurium. A major subset of genes whose induction was reduced by LXA(4) analog pretreatment is regulated by NF-kappaB, suggesting that LXA(4) analog was influencing the activity of this transcription factor. Nanomolar concentrations of LXA(4) analog reduced NF-kappaB-mediated transcriptional activation in a LXA(4) receptor-dependent manner and inhibited induced degradation of IkappaBalpha. LXA(4) analog did not affect earlier stimulus-induced signaling events that lead to IkappaBalpha degradation, such as S. typhimurium-induced epithelial Ca(2+) mobilization or TNF-alpha-induced phosphorylation of IkappaBalpha. To establish the in vivo relevance of these findings, we examined whether LXA(4) analogs could affect intestinal inflammation in vivo using the mouse model of DSS-induced inflammatory colitis. Oral administration of LXA(4) analog (15-epi-16-para-fluoro-phenoxy-LXA(4), 10 microg/day) significantly reduced the weight loss, hematochezia, and mortality that characterize DSS colitis. Thus, LXA(4) analog-mediated down-regulation of proinflammatory gene expression via inhibition of the NF-kappaB pathway can be therapeutic for diseases characterized by mucosal inflammation.
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Patients with rheumatoid arthritis (RA) improve on a vegetarian diet or supplementation with fish oil. We investigated the effects of both dietary measures, alone and in combination, on inflammation, fatty acid composition of erythrocyte lipids, eicosanoids, and cytokine biosynthesis in patients with RA. Sixty-eight patients with definitive RA were matched into two groups of 34 subjects each. One group was observed for 8 months on a normal western diet (WD) and the other on an anti-inflammatory diet (AID) providing an arachidonic acid intake of less than 90 mg/day. Patients in both groups were allocated to receive placebo or fish oil capsules (30 mg/kg body weight) for 3 months in a double-blind crossover study with a 2-month washout period between treatments. Clinical examination and routine laboratory findings were evaluated every month, and erythrocyte fatty acids, eicosanoids, and cytokines were evaluated before and after each 3-month experimental period. Sixty patients completed the study. In AID patients, but not in WD patients, the numbers of tender and swollen joints decreased by 14% during placebo treatment. In AID patients, as compared to WD patients, fish oil led to a significant reduction in the numbers of tender (28% vs 11%) and swollen (34% vs 22%) joints (P<0.01). Compared to baseline levels, higher enrichment of eicosapentaenoic acid in erythrocyte lipids (244% vs 217%) and lower formation of leukotriene B(4) (34% vs 8%, P>0.01), 11-dehydro-thromboxane B(2) (15% vs 10%, P<0.05), and prostaglandin metabolites (21% vs 16%, P<0.003) were found in AID patients, especially when fish oil was given during months 6-8 of the experiment. A diet low in arachidonic acid ameliorates clinical signs of inflammation in patients with RA and augments the beneficial effect of fish oil supplementation.
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Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.
Article
Objectives: Pain is a significant problem in rheumatoid arthritis (RA) and is associated with prostaglandins derived from the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid. The ω-3 PUFAs eicosapentaenoic acid and docosahexaenoic acid have been shown to reduce inflammation, with some studies showing clinical improvements in RA. The aim of this systematic review was to investigate the effect of ω-3 PUFAs on arthritic pain. Method: A systematic literature review of ω-3 PUFAs and pain associated with RA was performed up to December 2015. Randomized controlled trials (RCTs) investigating the effect of ω-3 PUFAs (>2 g/d) on patient or physician assessment of pain, or assessment by both patient and physician, were included. The Cochrane Collaboration's tool for assessing risk for bias was employed. Data for outcomes of interest were extracted and collated for interpretation. Results: Eighteen RCTs published between 1985 and 2013 involving 1143 patients were included. Dosage of ω-3 PUFAs used was 2.1 to 9.1 g/d, with study durations of 12 to 52 wk. Ten studies supported the hypothesis that there is a reduction in patient or physician assessment of pain associated with RA after intake of ω-3 PUFAs. Eight studies found no statistically significant effect of ω-3 PUFAs on arthritic pain. Conclusions: ω-3 PUFAs may have a therapeutic role in decreasing pain associated with RA, with doses of 3 to 6 g/d appearing to have a greater effect. Due to the limitations identified in the RCTs included in this review, more research is needed to investigate ω-3 PUFAs in larger populations and over extended periods of time.
Article
Alpha-linolenic acid (ALA) is an essential fatty acid and the substrate for the synthesis of longer-chain, more unsaturated ω-3 fatty acids, eicosapentaenoic acid (EPA), docosapentaenoic acid and docosahexaenoic acid (DHA). EPA and DHA are associated with human health benefits. The primary source of EPA and DHA is seafood. There is a need for sustainable sources of biologically active ω-3 fatty acids. Certain plants contain high concentrations of ALA and stearidonic acid (SDA). Here we review the literature on the metabolism of ALA and SDA in humans, the impact of increased ALA and SDA consumption on concentrations of EPA and DHA in blood and cell lipid pools, and the extent to which ALA and SDA might have health benefits. Although it is generally considered that humans have limited capacity for conversion of ALA to EPA and DHA, sex differences in conversion to DHA have been identified. If conversion of ALA to EPA and DHA is limited, then ALA may have a smaller health benefit than EPA and DHA. SDA is more readily converted to EPA and appears to offer better potential for health improvement than ALA. However, conversion of both ALA and SDA to DHA is limited in most humans.
Article
Gamma-linolenic acid (GLA, 18:3n-6) is an omega-6 (n-6), 18 carbon (18C-) polyunsaturated fatty acid (PUFA) found in human milk and several botanical seed oils and is typically consumed as part of a dietary supplement. While there have been numerous in vitro and in vivo animal models which illustrate that GLA-supplemented diets attenuate inflammatory responses, clinical studies utilizing GLA or GLA in combination with omega-3 (n-3) PUFAs have been much less conclusive. A central premise of this review is that there are critical metabolic and genetic factors that affect the conversion of GLA to dihommo-gamma linolenic acid (DGLA, 20:3n-6) and arachidonic acid (AA, 20:4n-6), which consequently affects the balance of DGLA- and AA- derived metabolites. As a result, these factors impact the clinical effectiveness of GLA or GLA/n-3 PUFA supplementations in treating inflammatory conditions. Specifically, these factors include: 1) the capacity for different human cells and tissues to convert GLA to DGLA and AA and to metabolize DGLA and AA to bioactive metabolites; 2) the opposing effects of DGLA and AA metabolites on inflammatory processes and diseases; and 3) the impact of genetic variations within the fatty acid desaturase (FADS) gene cluster, in particular, on AA/DGLA ratios and bioactive metabolites. We postulate that these factors influence the heterogeneity of results observed in GLA supplement-based clinical trials and suggest that "one-size fits all" approaches utilizing PUFA-based supplements may no longer be appropriate for the prevention and treatment of complex human diseases.
Article
Linoleic acid (LA) is a major constituent of low-density lipoproteins. An essential fatty acid, LA is a polyunsaturated fatty acid, which is oxidised by endogenous enzymes and reactive oxygen species in the circulation. Increased levels of low-density lipoproteins coupled with oxidative stress and lack of antioxidants drive the oxidative processes. This results in synthesis of a range of oxidised derivatives, which play a vital role in regulation of inflammatory processes. The derivatives of LA include, hydroxyoctadecadienoic acids, oxo- octadecadienoic acids, epoxy octadecadecenoic acid and epoxy-keto-octadecenoic acids. In this review, we examine the role of LA derivatives and their actions on regulation of inflammation relevant to metabolic processes associated with atherogenesis and cancer. The processes affected by LA derivatives include, alteration of airway smooth muscles and vascular wall, affecting sensitivity to pain, and regulating endogenous steroid hormones associated with metabolic syndrome. LA derivatives alter cell adhesion molecules, this initial step, is pivotal in regulating inflammatory processes involving transcription factor peroxisome proliferator-activated receptor pathways, thus, leading to alteration of metabolic processes. The derivatives are known to elicit pleiotropic effects that are either beneficial or detrimental in nature hence making it difficult to determine the exact role of these derivatives in the progress of an assumed target disorder. The key may lie in understanding the role of these derivatives at various stages of development of a disorder. Novel pharmacological approaches in altering the synthesis or introduction of synthesised LA derivatives could possibly help drive processes that could regulate inflammation in a beneficial manner.
Article
Inflammation is a condition which contributes to a range of human diseases. It involves a multitude of cell types, chemical mediators, and interactions. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of marine n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor peroxisome proliferator activated receptor γ and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked, although the full extent of this is not yet elucidated. Animal experiments demonstrate benefit from marine n-3 fatty acids in models of rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in RA demonstrate benefit, but clinical trials of fish oil in IBD and asthma are inconsistent with no overall clear evidence of efficacy. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance."
Article
Omega-3 and n-6 fatty acids are biosynthetic precursors to lipid mediators with anti-nociceptive and pro-nociceptive properties. We conducted a randomized, single-blinded, parallel-group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n-3 and n-6 fatty acids for treatment of chronic headaches. After a 4-week pre-intervention phase, ambulatory patients with Chronic Daily Headache undergoing usual care were randomized to one of two intensive, food-based 12-week dietary interventions: a high n-3 plus low n-6 (H3-L6) intervention, or a low n-6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT-6, primary clinical outcome), Headache Days per month and Headache Hours per day. Biochemical outcomes included the erythrocyte n-6 in HUFA score (primary biochemical outcome) and bioactive n-3 and n-6 derivatives. Fifty-six of sixty-seven patients completed the intervention. Both groups achieved targeted intakes of n-3 and n-6 fatty acids. In intention-to-treat analysis, the H3-L6 intervention produced significantly greater improvement in the HIT-6 score (-7.5 vs. -2.1; p<0.001) and the number of Headache Days per month (-8.8 vs. -4.0; p=0.02), compared to the L6 group. The H3-L6 intervention also produced significantly greater reductions in Headache Hours per day (-4.6 vs. -1.2; p=0.01) and the n-6 in HUFA score (-21.0 vs. -4.0%; <0.001), and greater increases in anti-nociceptive n-3 pathway markers 18-hydroxy-eicosapentaenoic acid (+118.4 vs. +61.1%; p<0.001) and 17-hydroxy-docosahexaenoic acid (+170.2 vs. +27.2; p<0.001). A dietary intervention increasing n-3 and reducing n-6 fatty acids reduced headache pain, altered anti-nociceptive lipid mediators, and improved quality-of-life in this population.
Article
Lipid mediators are appreciated for their roles in leukocyte traffic required in host defense. With identification of novel resolution phase mediators, resolvins, protectins and maresins, these three families and their aspirin-triggered forms, given their potent stereoselective actions with human cells and animal disease models, are coined specialized pro-resolving mediators (SPM). Stereochemistries of key SPM are established and several groups reported organic synthesis. Given increased availability, this two-year-review period expands their potent pro-resolving and non-redundant actions. Collectively, they support the concept that return of acute inflammation involves active biosynthesis and SPM signaling toward homeostasis.
Article
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T cell reactivity. In parallel, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving resolvins and protectins. Mechanisms underlying the anti-inflammatory actions of n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor NR1C3 (i.e. peroxisome proliferator activated receptor γ?, and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked. In adult humans, an EPA plus DHA intake greater than 2 g per day seems to be required to elicit anti-inflammatory actions, but few dose finding studies have been performed. Animal models demonstrate benefit from n-3 fatty acids in rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta-analyses of the data. Clinical trails of fish oil in patients with IBD and asthma are inconsistent with no overall clear evidence of efficacy.
Article
Although essential to host defense, neutrophils are also involved in numerous inflammatory disorders including rheumatoid arthritis. Dietary supplementation with relatively large amounts of fish oil [containing >2.6 g eicosapentaenoic acid (EPA) plus 1.4 g docosahexaenoic acid (DHA) per day] can attenuate neutrophil functions such as chemotaxis and superoxide radical production. In this study, the effects of more moderate supplementation with fish oil on neutrophil lipid composition and function were investigated. The rationale for using lower supplementary doses of fish oil was to avoid adverse gastrointestinal problems, which have been observed at high supplementary concentrations of fish oil. Healthy male volunteers aged <40 yr were randomly assigned to consume one of six dietary supplements daily for 12 wk (n=8 per treatment group). The dietary supplements included four different concentrations of fish oil (the most concentrated fish oil provided 0.58 g EPA plus 1.67 g DHA per day), linseed oil, and a placebo oil. The percentages of EPA and DHA increased (both P<0.05) in neutrophil phospholipids in a dose-dependent manner after 4 wk of supplementation with the three most concentrated fish oil supplements. No further increases in EPA or DHA levels were observed after 4 wk. The percentage of arachidonic acid in neutrophil phospholipids decreased (P<0.05) after 12 wk supplementation with the linseed oil supplement or the two most concentrated fish oil supplements. There were no significant changes in N-formyl-met-leu-phe-induced chemotaxis and superoxide radical production following the dietary supplementations. In conclusion, low-to-moderate amounts of dietary fish oil can be used to manipulate neutrophil fatty acid composition. However, this may not be accompanied by modulation of neutrophil functions such as chemotaxis and superoxide radical production.