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      Application of metabolomics part II: Focus on fatty acids and their metabolites in healthy adults

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          Fatty acids (FAs) play critical roles in health and disease. The detection of FA imbalances through metabolomics can provide an overview of an individual’s health status, particularly as regards chronic inflammatory disorders. In this study, we aimed to establish sensitive reference value ranges for targeted plasma FAs in a well-defined population of healthy adults. Plasma samples were collected from 159 participants admitted as outpatients. A total of 24 FAs were analyzed using gas chromatography-mass spectrometry, and physiological values and 95% reference intervals were calculated using an approximate method of analysis. The differences among the age groups for the relative levels of stearic acid (P=0.005), the omega-6/omega-3 ratio (P=0.027), the arachidonic acid/eicosapentaenoic acid ratio (P<0.001) and the linoleic acid-produced dihomo-gamma-linolenic acid (P=0.046) were statistically significant. The majority of relative FA levels were higher in males than in females. The levels of myristic acid (P=0.0170) and docosahexaenoic acid (P=0.033) were signifi-cantly different between the sexes. The reference values for the FAs examined in this study represent a baseline for further studies examining the reproducibility of this methodology and sensitivities for nutrient deficiency detection and investigating the biochemical background of pathological conditions. The application of these values to clinical practice will allow for the discrimination between health and disease and contribute to early prevention and treatment.

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          Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers.

          Persons with high intake of polyunsaturated fatty acids (PUFAs) have lower cardiovascular morbidity and mortality. The protective effect of PUFAs is mediated by multiple mechanisms, including their antiinflammatory properties. The association of physiological PUFA levels with pro- and antiinflammatory markers has not been established. In 1123 persons (aged 20-98 yr), we examined the relationship between relative concentration of fatty acids in fasting plasma and level of inflammatory markers. Adjusting for age, sex, and major confounders, lower arachidonic and docosahexaenoic acids were associated with significantly higher IL-6 and IL-1ra and significantly lower TGFbeta. Lower alpha-linolenic acid was associated with higher C-reactive protein and IL-1ra, and lower eicosapentaenoic acid was associated with higher IL-6 and lower TGFbeta. Lower docosahexaenoic acid was strongly associated with lower IL-10. Total n-3 fatty acids were associated with lower IL-6 (P = 0.005), IL-1ra (P = 0.004), and TNFalpha (P = 0.040) and higher soluble IL-6r (P < 0.001), IL-10 (P = 0.024), and TGFbeta (P = 0.0012). Lower n-6 fatty acid levels were significantly associated with higher IL-1ra (P = 0.026) and lower TGFbeta (P = 0.014). The n-6 to n-3 ratio was a strong, negative correlate of IL-10. Findings were similar in participants free of cardiovascular diseases and after excluding lipids from covariates. In this community-based sample, PUFAs, and especially total n-3 fatty acids, were independently associated with lower levels of proinflammatory markers (IL-6, IL-1ra, TNFalpha, C-reactive protein) and higher levels of antiinflammatory markers (soluble IL-6r, IL-10, TGFbeta) independent of confounders. Our findings support the notion that n-3 fatty acids may be beneficial in patients affected by diseases characterized by active inflammation.
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            Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis.

            Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. The n-6 polyunsaturated fatty acid (PUFA) arachidonic acid (ARA) is the precursor of inflammatory eicosanoids which are involved in RA. Some therapies used in RA target ARA metabolism. Marine n-3 PUFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) found in oily fish and fish oils decrease the ARA content of cells involved in immune responses and decrease the production of inflammatory eicosanoids from ARA. EPA gives rise to eicosanoid mediators that are less inflammatory than those produced from ARA and both EPA and DHA give rise to resolvins that are anti-inflammatory and inflammation resolving, although little is known about these latter mediators in RA. Marine n-3 PUFAs can affect other aspects of immunity and inflammation relevant to RA, including dendritic cell and T cell function and production of inflammatory cytokines and reactive oxygen species, although findings for these outcomes are not consistent. Fish oil has been shown to slow the development of arthritis in animal models and to reduce disease severity. A number of randomised controlled trials of marine n-3 PUFAs have been performed in patients with RA. A systematic review included 23 studies. Evidence is seen for a fairly consistent, but modest, benefit of marine n-3 PUFAs on joint swelling and pain, duration of morning stiffness, global assessments of pain and disease activity, and use of non-steroidal anti-inflammatory drugs.
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              Inflammatory disease processes and interactions with nutrition.

              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.

                Author and article information

                Int J Mol Med
                Int. J. Mol. Med
                International Journal of Molecular Medicine
                D.A. Spandidos
                January 2019
                14 November 2018
                14 November 2018
                : 43
                : 1
                : 233-242
                [1 ]Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, 71003 Heraklion
                [2 ]Metabolomic Medicine Clinic, 10674 Athens, Greece
                [3 ]European Institute of Nutritional Medicine, E.I.Nu.M, 00198 Rome, Italy
                [4 ]Toxplus Spin-Off S.A., 71601 Heraklion
                [5 ]Laboratory of Anatomy-Histology-Embryology and
                [6 ]Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
                Author notes
                Correspondence to: Professor Aristides Tsatsakis, Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, P.O. Box 1393, 71003 Heraklion, Greece, E-mail: toxlab.uoc@

                Contributed equally

                Copyright: © Tsoukalas et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.


                metabolism, fatty acids, adults, metabolomic, reference values


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