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Omega-3 Fatty Acids in Health and Disease

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (20 November 2015) | Viewed by 197026

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Special Issue Editors

Prof. Dr. Lindsay Brown

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Guest Editor

School of Pharmacy and Medical Science, Griffith University, Southport, QLD 4222, Australia
Interests: Functional foods, rat models of chronic human diseases, obesity, hypertension, diabetes, osteoarthritis, anthocyanins, polyphenols, prebiotics, microalgae, macroalgae, tropical fruits
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Bernhard Rauch

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Stiftung IHF Institut für Herzinfarktforschung Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen am Rhein, Germany
Interests: cardiology in general; cardiovascular prevention; cardiac rehabilitation (specialized); cardiovascular pharmacology of any kind; psychosocial interactions; meta-analyses; hyperlipidemia; hypertension; nutrition; exercise

Dr. Hemant Poudyal

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Guest Editor

Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine and The Hakubi, Center for Advanced Research, Kyoto University, Kyoto, Japan
Interests: endocrinology; nutrition; obesity; diabetes; gut; heart; intestine; incretins; cardiovascular remodeling

Special Issue Information

Dear Colleagues,

The role of the major dietary omega-3 fatty acids (alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid) in human health has generated controversy. The effects of omega-3 fatty acids on cardiometabolic risk factors, such as obesity, insulin resistance, and dyslipidaemia (especially hypertriglyceridaemia) are widely reported in scientific journals, as well as in the mass media. In addition, omega-3 fatty acids are precursors of bioactive metabolites, such as eicosanoids, lipoxins, resolvins, protectins, maresins, and nitrolipids; these metabolites play an important role in physiological processes, such as the regulation of cardiovascular function, the resolution of inflammation, and neuroprotection. Finally, omega-3 fatty acids interfere with cardiac electrophysiology via a variety of mechanisms, thereby potentially mediating cardiac arrhythmias.

This Special Issue of the Journal of Clinical Medicine will emphasize the mechanisms underlying the responses of omega-3 fatty acids with regard to the following important aspects of human health and disease:

Memory and healthy aging
Metabolic syndrome risk factors
Cardiovascular disease
Neurodegenerative disease
Bone health
Cancer
Inflammation
Nutrigenomics and nutrigenetics

Prof. Dr. Lindsay Brown
Prof. Dr. Bernhard Rauch
Dr. Hemant Poudyal
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

diabetes
dyslipidaemia
obesity
cardiovascular disease
cardiac arrhythmias
schizophrenia
Alzheimer’s disease
depression
rheumatoid arthritis
inflammation
cancer

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Published Papers (14 papers)

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Research

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926 KiB

Open AccessArticle

Up-Regulation of Mitochondrial Antioxidant Superoxide Dismutase Underpins Persistent Cardiac Nutritional-Preconditioning by Long Chain n-3 Polyunsaturated Fatty Acids in the Rat

by Grace G. Abdukeyum, Alice J. Owen, Theresa A. Larkin and Peter L. McLennan

J. Clin. Med. 2016, 5(3), 32; https://doi.org/10.3390/jcm5030032 - 4 Mar 2016

Cited by 19 | Viewed by 7113

Abstract

Reactive oxygen species paradoxically underpin both ischaemia/reperfusion (I/R) damage and ischaemic preconditioning (IPC) cardioprotection. Long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFA) are highly susceptible to peroxidation, but are paradoxically cardioprotective. This study tested the hypothesis that LCn-3 PUFA cardioprotection is underpinned by peroxidation, upregulating antioxidant activity to reduce I/R-induced lipid oxidation, and the mechanisms of this nutritional preconditioning contrast to mechanisms of IPC. Rats were fed: fish oil (LCn-3 PUFA); sunflower seed oil (n-6 PUFA); or beef tallow (saturated fat, SF) enriched diets for six weeks. Isolated hearts were subject to: 180 min normoxic perfusion; a 30 min coronary occlusion ischaemia protocol then 120 min normoxic reperfusion; or a 3 × 5 min global IPC protocol, 30 min ischaemia, then reperfusion. Dietary LCn-3 PUFA raised basal: membrane docosahexaenoic acid (22:6n-3 DHA); fatty acid peroxidisability index; concentrations of lipid oxidation products; and superoxide dismutase (MnSOD) activity (but not CuZnSOD or glutathione peroxidase). Infarct size correlated inversely with basal MnSOD activity (r² = 0.85) in the ischaemia protocol and positively with I/R-induced lipid oxidation (lipid hydroperoxides (LPO), r² = 0.475; malondialdehyde (MDA), r² = 0.583) across ischaemia and IPC protocols. While both dietary fish oil and IPC infarct-reduction were associated with reduced I/R-induced lipid oxidation, fish oil produced nutritional preconditioning by prior LCn-3 PUFA incorporation and increased peroxidisability leading to up-regulated mitochondrial SOD antioxidant activity. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease)

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Mechanisms Involved in the Improvement of Lipotoxicity and Impaired Lipid Metabolism by Dietary α-Linolenic Acid Rich Salvia hispanica L (Salba) Seed in the Heart of Dyslipemic Insulin-Resistant Rats

by Agustina Creus, María R. Ferreira, María E. Oliva and Yolanda B. Lombardo

J. Clin. Med. 2016, 5(2), 18; https://doi.org/10.3390/jcm5020018 - 28 Jan 2016

Cited by 38 | Viewed by 7511

Abstract

This study explores the mechanisms underlying the altered lipid metabolism in the heart of dyslipemic insulin-resistant (IR) rats fed a sucrose-rich diet (SRD) and investigates if chia seeds (rich in α-linolenic acid 18:3, n-3 ALA) improve/reverse cardiac lipotoxicity. Wistar rats received an SRD-diet for three months. Half of the animals continued with the SRD up to month 6. The other half was fed an SRD in which the fat source, corn oil (CO), was replaced by chia seeds from month 3 to 6 (SRD+chia). A reference group consumed a control diet (CD) all the time. Triglyceride, long-chain acyl CoA (LC ACoA) and diacylglycerol (DAG) contents, pyruvate dehydrogenase complex (PDHc) and muscle-type carnitine palmitoyltransferase 1 (M-CPT1) activities and protein mass levels of M-CPT1, membrane fatty acid transporter (FAT/CD36), peroxisome proliferator activated receptor α (PPARα) and uncoupling protein 2 (UCP2) were analyzed. Results show that: (a) the hearts of SRD-fed rats display lipotoxicity suggesting impaired myocardial lipid utilization; (b) Compared with the SRD group, dietary chia normalizes blood pressure; reverses/improves heart lipotoxicity, glucose oxidation, the increased protein mass level of FAT/CD36, and the impaired insulin stimulated FAT/CD36 translocation to the plasma membrane. The enhanced M-CPT1 activity is markedly reduced without similar changes in protein mass. PPARα slightly decreases, while the UCP2 protein level remains unchanged in all groups. Normalization of dyslipidemia and IR by chia reduces plasma fatty acids (FAs) availability, suggesting that a different milieu prevents the robust translocation of FAT/CD36. This could reduce the influx of FAs, decreasing the elevated M-CPT1 activity and lipid storage and improving glucose oxidation in cardiac muscles of SRD-fed rats. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease)

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2933 KiB

Open AccessFeature PaperArticle

Eicosopentaneoic Acid and Other Free Fatty Acid Receptor Agonists Inhibit Lysophosphatidic Acid- and Epidermal Growth Factor-Induced Proliferation of Human Breast Cancer Cells

by Mandi M. Hopkins, Zhihong Zhang, Ze Liu and Kathryn E. Meier

J. Clin. Med. 2016, 5(2), 16; https://doi.org/10.3390/jcm5020016 - 26 Jan 2016

Cited by 46 | Viewed by 7971

Abstract

Many key actions of ω-3 (n-3) fatty acids have recently been shown to be mediated by two G protein-coupled receptors (GPCRs) in the free fatty acid receptor (FFAR) family, FFA1 (GPR40) and FFA4 (GPR120). n-3 Fatty acids inhibit proliferation of human breast cancer cells in culture and in animals. In the current study, the roles of FFA1 and FFA4 were investigated. In addition, the role of cross-talk between GPCRs activated by lysophosphatidic acid (LPA), and the tyrosine kinase receptor activated by epidermal growth factor (EGF), was examined. In MCF-7 and MDA-MB-231 human breast cancer cell lines, both LPA and EGF stimulated proliferation, Erk activation, Akt activation, and CCN1 induction. LPA antagonists blocked effects of LPA and EGF on proliferation in MCF-7 and MDA-MB-231, and on cell migration in MCF-7. The n-3 fatty acid eicosopentaneoic acid inhibited LPA- and EGF-induced proliferation in both cell lines. Two synthetic FFAR agonists, GW9508 and TUG-891, likewise inhibited LPA- and EGF-induced proliferation. The data suggest a major role for FFA1, which was expressed by both cell lines. The results indicate that n-3 fatty acids inhibit breast cancer cell proliferation via FFARs, and suggest a mechanism involving negative cross-talk between FFARS, LPA receptors, and EGF receptor. Full article

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Review

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292 KiB

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Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data

by Paola Bozzatello, Elena Brignolo, Elisa De Grandi and Silvio Bellino

J. Clin. Med. 2016, 5(8), 67; https://doi.org/10.3390/jcm5080067 - 27 Jul 2016

Cited by 135 | Viewed by 68434

Abstract

A new application for omega-3 fatty acids has recently emerged, concerning the treatment of several mental disorders. This indication is supported by data of neurobiological research, as highly unsaturated fatty acids (HUFAs) are highly concentrated in neural phospholipids and are important components of the neuronal cell membrane. They modulate the mechanisms of brain cell signaling, including the dopaminergic and serotonergic pathways. The aim of this review is to provide a complete and updated account of the empirical evidence of the efficacy and safety that are currently available for omega-3 fatty acids in the treatment of psychiatric disorders. The main evidence for the effectiveness of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been obtained in mood disorders, in particular in the treatment of depressive symptoms in unipolar and bipolar depression. There is some evidence to support the use of omega-3 fatty acids in the treatment of conditions characterized by a high level of impulsivity and aggression and borderline personality disorders. In patients with attention deficit hyperactivity disorder, small-to-modest effects of omega-3 HUFAs have been found. The most promising results have been reported by studies using high doses of EPA or the association of omega-3 and omega-6 fatty acids. In schizophrenia, current data are not conclusive and do not allow us either to refuse or support the indication of omega-3 fatty acids. For the remaining psychiatric disturbances, including autism spectrum disorders, anxiety disorders, obsessive-compulsive disorder, eating disorders and substance use disorder, the data are too scarce to draw any conclusion. Concerning tolerability, several studies concluded that omega-3 can be considered safe and well tolerated at doses up to 5 g/day. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease)

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Open AccessReview

Is there A Role for Alpha-Linolenic Acid in the Fetal Programming of Health?

by Alicia I. Leikin-Frenkel

J. Clin. Med. 2016, 5(4), 40; https://doi.org/10.3390/jcm5040040 - 23 Mar 2016

Cited by 13 | Viewed by 8805

Abstract

The role of ω3 alpha linolenic acid (ALA) in the maternal diet during pregnancy and lactation, and its effect on the prevention of disease and programming of health in offspring, is largely unknown. Compared to ALA, ω3 docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids have been more widely researched due to their direct implication in fetal neural development. In this literature search we found that ALA, the essential ω3 fatty acid and metabolic precursor of DHA and EPA has been, paradoxically, almost unexplored. In light of new and evolving findings, this review proposes that ALA may have an intrinsic role, beyond the role as metabolic parent of DHA and EPA, during fetal development as a regulator of gene programming for the prevention of metabolic disease and promotion of health in offspring. Full article

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Omega-3 Fatty Acids in Modern Parenteral Nutrition: A Review of the Current Evidence

by Stanislaw Klek

J. Clin. Med. 2016, 5(3), 34; https://doi.org/10.3390/jcm5030034 - 7 Mar 2016

Cited by 71 | Viewed by 10033

Abstract

Intravenous lipid emulsions are an essential component of parenteral nutrition regimens. Originally employed as an efficient non-glucose energy source to reduce the adverse effects of high glucose intake and provide essential fatty acids, lipid emulsions have assumed a larger therapeutic role due to research demonstrating the effects of omega-3 and omega-6 polyunsaturated fatty acids (PUFA) on key metabolic functions, including inflammatory and immune response, coagulation, and cell signaling. Indeed, emerging evidence suggests that the effects of omega-3 PUFA on inflammation and immune response result in meaningful therapeutic benefits in surgical, cancer, and critically ill patients as well as patients requiring long-term parenteral nutrition. The present review provides an overview of the mechanisms of action through which omega-3 and omega-6 PUFA modulate the immune-inflammatory response and summarizes the current body of evidence regarding the clinical and pharmacoeconomic benefits of intravenous n-3 fatty acid-containing lipid emulsions in patients requiring parenteral nutrition. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease)

1879 KiB

Open AccessReview

Cancer Risk and Eicosanoid Production: Interaction between the Protective Effect of Long Chain Omega-3 Polyunsaturated Fatty Acid Intake and Genotype

by Georgia Lenihan-Geels, Karen S. Bishop and Lynnette R. Ferguson

J. Clin. Med. 2016, 5(2), 25; https://doi.org/10.3390/jcm5020025 - 15 Feb 2016

Cited by 19 | Viewed by 9200

Abstract

Dietary inclusion of fish and fish supplements as a means to improve cancer prognosis and prevent tumour growth is largely controversial. Long chain omega-3 polyunsaturated fatty acids (LCn-3 PUFA), eicosapentaenoic acid and docosahexaenoic acid, may modulate the production of inflammatory eicosanoids, thereby influencing local inflammatory status, which is important in cancer development. Although in vitro studies have demonstrated inhibition of tumour cell growth and proliferation by LCn-3 PUFA, results from human studies have been mainly inconsistent. Genes involved in the desaturation of fatty acids, as well as the genes encoding enzymes responsible for eicosanoid production, are known to be implicated in tumour development. This review discusses the current evidence for an interaction between genetic polymorphisms and dietary LCn-3 PUFA in the risk for breast, prostate and colorectal cancers, in regards to inflammation and eicosanoid synthesis. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease)

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Open AccessReview

Potential Benefits of Omega-3 Fatty Acids in Non-Melanoma Skin Cancer

by Homer S. Black and Lesley E. Rhodes

J. Clin. Med. 2016, 5(2), 23; https://doi.org/10.3390/jcm5020023 - 4 Feb 2016

Cited by 27 | Viewed by 12875

Abstract

Considerable circumstantial evidence has accrued from both experimental animal and human clinical studies that support a role for omega-3 fatty acids (FA) in the prevention of non-melanoma skin cancer (NMSC). Direct evidence from animal studies has shown that omega-3 FA inhibit ultraviolet radiation (UVR) induced carcinogenic expression. In contrast, increasing levels of dietary omega-6 FA increase UVR carcinogenic expression, with respect to a shorter tumor latent period and increased tumor multiplicity. Both omega-6 and omega-3 FA are essential FA, necessary for normal growth and maintenance of health and although these two classes of FA exhibit only minor structural differences, these differences cause them to act significantly differently in the body. Omega-6 and omega-3 FA, metabolized through the lipoxygenase (LOX) and cyclooxygenase (COX) pathways, lead to differential metabolites that are influential in inflammatory and immune responses involved in carcinogenesis. Clinical studies have shown that omega-3 FA ingestion protects against UVR-induced genotoxicity, raises the UVR-mediated erythema threshold, reduces the level of pro-inflammatory and immunosuppressive prostaglandin E2 (PGE₂) in UVR-irradiated human skin, and appears to protect human skin from UVR-induced immune-suppression. Thus, there is considerable evidence that omega-3 FA supplementation might be beneficial in reducing the occurrence of NMSC, especially in those individuals who are at highest risk. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease)

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Open AccessReview

Using Caenorhabditis elegans to Uncover Conserved Functions of Omega-3 and Omega-6 Fatty Acids

by Jennifer L. Watts

J. Clin. Med. 2016, 5(2), 19; https://doi.org/10.3390/jcm5020019 - 2 Feb 2016

Cited by 43 | Viewed by 11526

Abstract

The nematode Caenorhabditis elegans is a powerful model organism to study functions of polyunsaturated fatty acids. The ability to alter fatty acid composition with genetic manipulation and dietary supplementation permits the dissection of the roles of omega-3 and omega-6 fatty acids in many biological process including reproduction, aging and neurobiology. Studies in C. elegans to date have mostly identified overlapping functions of 20-carbon omega-6 and omega-3 fatty acids in reproduction and in neurons, however, specific roles for either omega-3 or omega-6 fatty acids are beginning to emerge. Recent findings with importance to human health include the identification of a conserved Cox-independent prostaglandin synthesis pathway, critical functions for cytochrome P450 derivatives of polyunsaturated fatty acids, the requirements for omega-6 and omega-3 fatty acids in sensory neurons, and the importance of fatty acid desaturation for long lifespan. Furthermore, the ability of C. elegans to interconvert omega-6 to omega-3 fatty acids using the FAT-1 omega-3 desaturase has been exploited in mammalian studies and biotechnology approaches to generate mammals capable of exogenous generation of omega-3 fatty acids. Full article

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Omega-3 Fatty Acids and Cancer Cell Cytotoxicity: Implications for Multi-Targeted Cancer Therapy

by Donatella D’Eliseo and Francesca Velotti

J. Clin. Med. 2016, 5(2), 15; https://doi.org/10.3390/jcm5020015 - 26 Jan 2016

Cited by 251 | Viewed by 18294

Abstract

Cancer is a major disease worldwide. Despite progress in cancer therapy, conventional cytotoxic therapies lead to unsatisfactory long-term survival, mainly related to development of drug resistance by tumor cells and toxicity towards normal cells. n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can exert anti-neoplastic activity by inducing apoptotic cell death in human cancer cells either alone or in combination with conventional therapies. Indeed, n-3 PUFAs potentially increase the sensitivity of tumor cells to conventional therapies, possibly improving their efficacy especially against cancers resistant to treatment. Moreover, in contrast to traditional therapies, n-3 PUFAs appear to cause selective cytotoxicity towards cancer cells with little or no toxicity on normal cells. This review focuses on studies investigating the cytotoxic activity of n-3 PUFAs against cancer cells via apoptosis, analyzing the molecular mechanisms underlying this effective and selective activity. Here, we highlight the multiple molecules potentially targeted by n-3 PUFAs to trigger cancer cell apoptosis. This analysis can allow a better comprehension of the potential cytotoxic therapeutic role of n-3 PUFAs against cancer, providing specific information and support to design future pre-clinical and clinical studies for a better use of n-3 PUFAs in cancer therapy, mainly combinational therapy. Full article

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Open AccessReview

The Effect of Marine Derived n-3 Fatty Acids on Adipose Tissue Metabolism and Function

by Marijana Todorčević and Leanne Hodson

J. Clin. Med. 2016, 5(1), 3; https://doi.org/10.3390/jcm5010003 - 31 Dec 2015

Cited by 65 | Viewed by 8279

Abstract

Adipose tissue function is key determinant of metabolic health, with specific nutrients being suggested to play a role in tissue metabolism. One such group of nutrients are the n-3 fatty acids, specifically eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Results from studies where human, animal and cellular models have been utilised to investigate the effects of EPA and/or DHA on white adipose tissue/adipocytes suggest anti-obesity and anti-inflammatory effects. We review here evidence for these effects, specifically focusing on studies that provide some insight into metabolic pathways or processes. Of note, limited work has been undertaken investigating the effects of EPA and DHA on white adipose tissue in humans whilst more work has been undertaken using animal and cellular models. Taken together it would appear that EPA and DHA have a positive effect on lowering lipogenesis, increasing lipolysis and decreasing inflammation, all of which would be beneficial for adipose tissue biology. What remains to be elucidated is the duration and dose required to see a favourable effect of EPA and DHA in vivo in humans, across a range of adiposity. Full article

(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease)

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Open AccessReview

Pork as a Source of Omega-3 (n-3) Fatty Acids

by Michael E.R. Dugan, Payam Vahmani, Tyler D. Turner, Cletos Mapiye, Manuel Juárez, Nuria Prieto, Angela D. Beaulieu, Ruurd T. Zijlstra, John F. Patience and Jennifer L. Aalhus

J. Clin. Med. 2015, 4(12), 1999-2011; https://doi.org/10.3390/jcm4121956 - 16 Dec 2015

Cited by 87 | Viewed by 11352

Abstract

Pork is the most widely eaten meat in the world, but typical feeding practices give it a high omega-6 (n-6) to omega-3 (n-3) fatty acid ratio and make it a poor source of n-3 fatty acids. Feeding pigs n-3 fatty acids can increase their contents in pork, and in countries where label claims are permitted, claims can be met with limited feeding of n-3 fatty acid enrich feedstuffs, provided contributions of both fat and muscle are included in pork servings. Pork enriched with n-3 fatty acids is, however, not widely available. Producing and marketing n-3 fatty acid enriched pork requires regulatory approval, development costs, quality control costs, may increase production costs, and enriched pork has to be tracked to retail and sold for a premium. Mandatory labelling of the n-6/n-3 ratio and the n-3 fatty acid content of pork may help drive production of n-3 fatty acid enriched pork, and open the door to population-based disease prevention polices (i.e., food tax to provide incentives to improve production practices). A shift from the status-quo, however, will require stronger signals along the value chain indicating production of n-3 fatty acid enriched pork is an industry priority. Full article

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Lipidomics to Assess Omega 3 Bioactivity

by Francesco Visioli

J. Clin. Med. 2015, 4(9), 1753-1760; https://doi.org/10.3390/jcm4091753 - 7 Sep 2015

Cited by 5 | Viewed by 5455

Abstract

How can we resolve the conflict between the strong epidemiological evidence pointing to the usefulness of fish—and, thus, omega 3—consumption with the debacle of supplementation trials? One potential explanation is that the null results obtained thus far are the consequences of ill-contrived investigations that do not allow us to conclude on the effects (or lack thereof) of omega 3 fatty acid supplementation. One potential solution is through the use of lipidomics, which should prove very useful to screen suitable patients and to correlate plasma (or red blood cells, or whole blood, or phospholipid) fatty acid profile with outcomes. This has never been done in omega 3 trials. The wise use of lipidomics should be essential part of future omega 3 trials and would help in untangling this current riddle. Full article

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Open AccessComment

Comments on Bozzatello et al. Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. J. Clin. Med. 2016, 5, 67

by Gregor Berger

J. Clin. Med. 2016, 5(8), 69; https://doi.org/10.3390/jcm5080069 - 3 Aug 2016

Cited by 4 | Viewed by 6314

Abstract

Paola Bozzatello et al. [1] have done a comprehensive qualitative review of the potential use of long-chain polyunsaturated fatty acids in the prevention and treatment of mental disorders.[...] Full article

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