Supportive Statements out of Bibliography
- “We confirmed the anti-inflammatory nature of DHA- and DPA-derived EFOX by showing that they can act as peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and inhibit pro-inflammatory cytokine and nitric oxide production, all within biological concentration ranges. These data support the idea that EFOX are signaling mediators that transduce the beneficial clinical effects of omega-3 fatty acids, COX-2 and aspirin.”
- “The reduced production of these proinflammatory eicosanoids, and the decrease of some cytokines with an immunohenancing effect as a consequence of n-3 PUFA supplementation, could modulate some immune functions which have been demonstrated to be altered in MSP.”
- “Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPARγ:RXR heterodimers”
- “High DHA consumption is associated with reduced Alzheimer’s disease (AD) risk. Reduction of dietary n-3 PFA in an Alzheimer’s Disease (AD) mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. n-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.” 
- “Exposure of bone marrow-derived DC to DHA resulted in the maintenance of an immature phenotype and drastic reduction in proinflammatory cytokine release. DHA inhibited the expression and secretion of the IL-12 cytokine family members (IL-12p70, IL-23 and IL-27), which play essential roles in the differentiation of the proinflammatory Th1/Th17 effector cells. The effect of DHA on IL-12 expression was mediated through activation of PPARgamma and inhibition of NFkappaB. Inhibition of IL-12 and IL-23 expression was also evident in splenic DC from mice fed a DHA-enriched diet, suggesting that dietary DHA acts as an anti-inflammatory agent in vivo.”
- “Salmon fillets rich in marine n-3 polyunsaturated fatty acids (PUFAs):-After 5 weeks of cuprizone treatment, the mice given salmon-cuprizone had significantly less hyperintense lesion volume on brain magnetic resonance imaging (MRI) than the two other groups (P<0.0005). After 6 weeks of cuprizone treatment, the salmon-cuprizone group had less demyelination in the corpus callosum, as measured with luxol fast blue (LFB) (P<0.0005) and anti-proteolipid protein (PLP) (P=0.014). The salmon-cuprizone group also had enhanced remyelination.” 
- “The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have neuroprotective effects in the aged brain and are endogenous ligands of RXR and PPAR. Overall, DHA supplementation appeared to increase receptor expression compared with the untreated old group. These observations illustrate additional mechanisms that might underlie the neuroprotective effects of omega-3 fatty acids in ageing.”
- “Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitis.”
- “Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease; data suggest that a high n-3 PUFA dietary intake exerts neuroprotective actions in an animal model of Parkinsonism.”
- “Omega-3 FA significantly decreased metalloproteinase-9 (MMP-9) levels in RRMS and may act as an immune-modulator that has potential therapeutic benefit in MS patients.”
- “DHA-derived Neuro protectin D1 regulation targets upstream events of brain cell apoptosis, as well as neuro-inflammatory signaling, promoting and maintaining cellular homeostasis, and restoring neural and retinal cell integrity.”
- “Fatty acids (FAs) have been shown to alter leucocyte function and thus to modulate inflammatory and immune responses.”
- “A high intake of PUFAs and vitamin E is associated with a 50-60% decreased risk of developing ALS, and these nutrients appear to act synergistically.”
- “The treatment with both omega-3 PUFA and fish oil dose-dependently inhibited the LPS-induced production of MMP-9. Our results suggest that a low fat diet supplemented with omega-3 PUFA may become recommended for the well being of MS patients under therapy.”
- “Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.”
- “Now that we know the molecular mechanisms by which dietary factors and exercise affect the inflammatory status in MS, we can expect that a nutritional intervention with anti-inflammatory food and dietary supplements can alleviate possible side effects of immune-modulatory drugs and the symptoms of chronic fatigue syndrome and thus favor patient wellness.”
 Groeger AL1, Cipollina C, Cole MP, Woodcock SR, Bonacci G, Rudolph TK, Rudolph V, Freeman BA, Schopfer FJ. Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. Nat Chem Biol. 2010; 6(6):433-41.
 Gallai V1, Sarchielli P, Trequattrini A, Franceschini M, Floridi A, Firenze C, Alberti A, Di Benedetto D, Stragliotto E. Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol. 1995 Feb;56(2):143-53.
 Fernando Zapata-Gonzalez, Felix Rueda, Jordi Petriz, Pere Domingo, Francesc Villarroya, Julieta Diaz-Delfin, Maria A. de Madariaga and Joan C. Domingo. Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPARγ:RXR heterodimers: comparison with other polyunsaturated fatty acids. Journal of Leukocyte Biology vol. 84 no. 4 1172-1182
 Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N Jr, Ashe KH, Frautschy SA, Cole GM. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron. 2004 Sep 2;43(5):633-45.
 Kong W, Yen JH, Vassiliou E, Adhikary S, Toscano MG, Ganea D. Docosahexaenoic acid prevents dendritic cell maturation and in vitro and in vivo expression of the IL-12 cytokine family. Lipids Health Dis. 2010 Feb 1;9:12.
Torkildsen Ø1, Brunborg LA, Thorsen F, Mørk SJ, Stangel M, Myhr KM, Bø L. Effects of dietary intervention on MRI activity, de- and remyelination in the cuprizone model for demyelination. Exp Neurol. 2009 Jan;215(1):160-6.
 Dyall SC, Michael GJ, Michael-Titus AT. Omega-3 fatty acids reverse age-related decreases in nuclear receptors and increase neurogenesis in old rats. J Neurosci Res. 2010 Aug 1;88(10):2091-102.
 Kong W, Yen JH, Ganea D. Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitis. Brain Behav Immun. 2011 Jul;25(5):872-82.
Bousquet M, Saint-Pierre M, Julien C, Salem N Jr, Cicchetti F, Calon F. Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease. FASEB J. 2008 Apr;22(4):1213-25.
Shinto L, Marracci G, Baldauf-Wagner S, Strehlow A, Yadav V, Stuber L, Bourdette D. Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis. Prostaglandins Leukot Essent Fatty Acids. 2009 Feb-Mar;80(2-3):131-6.
Palacios-Pelaez R1, Lukiw WJ, Bazan NG. Omega-3 essential fatty acids modulate initiation and progression of neurodegenerative disease. Mol Neurobiol. 2010 Jun;41(2-3):367-74.
 Martins de Lima T1, Gorjão R, Hatanaka E, Cury-Boaventura MF, Portioli Silva EP, Procopio J, Curi R. Mechanisms by which fatty acids regulate leucocyte function. Clin Sci (Lond). 2007 Jul;113(2):65-77.
 Veldink JH1, Kalmijn S, Groeneveld GJ, Wunderink W, Koster A, de Vries JH, van der Luyt J, Wokke JH, Van den Berg LH. Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2007 Apr;78(4):367-71.
 Liuzzi GM1, Latronico T, Rossano R, Viggiani S, Fasano A, Riccio P.Inhibitory effect of polyunsaturated fatty acids on MMP-9 release from microglial cells–implications for complementary multiple sclerosis treatment. Neurochem Res. 2007 Dec;32(12):2184-93. Epub 2007 Jul 11.
 van Meeteren ME, Teunissen CE, Dijkstra CD, van Tol EA. Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005; 59(12):1347-61.
 Paolo Riccio and Rocco Rossano. Nutrition Facts in Multiple Sclerosis. ASN Neuro. 2015 Feb; 7(1): 1759091414568185.
Other Related Supportive Bibliography
Ahn AC, Tewari M, Poon CS, et al. The clinical applications of a systems approach. PLoS Med 2006;3: e209.
Alessandri JM, Poumes-Ballihaut C, Langelier B, Perruchot MH, Raguenez G, Lavialle M & Guesnet P (2003). Incorporation of docosahexaenoic acid into nerve membrane phospholipids: bridging the gap between animals and cultured cells. Am. J. Clin. Nutr. 78, 702–710.
Annpey Pong, MS et.al. (1997). Drug Information Journal, Vol. 31, pp. 1167–1174.
Annpey Pong, MS, Statistical/Practical issues in clinical trials. Research Statistician, Biostatistics Berlex Laboratories, Inc., Montville, New Jersey
Artemis P. Simopoulos (2002). Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases. Journal of the American College of Nutrition, Vol. 21, No. 6, 495–505
Auffray C, Chen Z, Hood L. Systems medicine: the future of medical genomics and healthcare. Genome Med 2009;1:2.
Baranzini SE, Oksenberg JR, Hauser SL. New insights into the genetics of multiple sclerosis. J Rehabil Res Dev 2002;39:201–10.
Barkhof F, Filippi M, Miller DH, et al. (1997). Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain; 120: 2059–69.
Barnett MH & Prineas JW (2004): Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol. 55, 458–468.
Barnett MH & Prineas JW. (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion; Ann. Neurol. 55, 458–468.
Bates D et al. (1978) Polyunsaturated fatty acids in treatment of acute remitting multiple sclerosis. Br Med J 2: 1390–1391
Bates D, Cartlidge NE, French JM, Jackson MJ, Nightingale S, Shaw DA, Smith S, Woo E, Hawkins SA, Millar JH,
Belin J, Conroy DM, Gill SK, Sidey M, Smith AD, Thompson RH, Zilkha K, Gale M & Sinclair HM (1989): A double-blind controlled trial of long chain n-3 polyunsaturated fatty acids in the treatment of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 52, 18–22.
Beck RW, Cleary PA, Anderson MM Jr, et al. (1992). A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis: the Optic Neuritis Study Group. N Engl J Med; 326: 581–88.
Beharka, A.A., Wu, D., Han, S.N. and Meydani, S.N. (1997) Macrophage prostaglandin production contributes to the age-associated decrease in T cell function which is reversed by the dietary antioxidant vitamin E. Mechanisms of Ageing and Development 93, 59-77.
Belisle, S.E., Hamer, D.H., Leka, L.S., Dallal, G.E., Delgado-Lista, J., et al. (2010) IL-2 and IL-10 gene polymorphisms are associated with respiratory tract infection and may modulate the effect of vitamin E on lower respiratory tract infections in elderly nursing home residents. American Journal of Clinical Nutrition 92, 106-114.
Belisle, S.E., Leka, L.S., Delgado-Lista, J., Jacques, P.F., Ordovas, J.M., et al. (2009) Polymorphisms at cytokine genes may determine the effect of vitamin E on cytokine production in the elderly. The Journal of Nutrition 139, 1855-1860.