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Autoimmunity and Immune Pathological Aspects of Virus Disease
Published in Irun R. Cohen, Perspectives on Autoimmunity, 2020
H. Wege, R. Dörries, P. Massa, R. Watanabe
Increasing evidence supports the hypothesis that important immunological functions are mediated by astrocytes. A glia maturation factor and other mediators stimulate the secretion of interleukin-1 from cultured astrocytes.12 This lymphokine in turn can activate T-lymphocytes. It is conceivable that cellular destruction or virus infection of brain cells could induce the release of glia maturation factors. Furthermore, cultured astrocytes can also present myelin basic protein (MBP) in the context of immune region-associated antigens (la in particular).13 These functions are normally performed by macrophages and resident dendritic cells. Activated T-lymphocytes release a variety of regulatory factors including γ-interferon which — among other functions — enhances and induces expression of la antigens. These surface glycoproteins are indeed inducible — at least under culture conditions — in a subpopulation of astrocytes following exposure γ-interferon.14,15 An additional function may possibly be mediated by microglia cells. Microglia cells are monocytes which bear Fc-receptors and can be considered as resident brain macrophages. Finally, impairment of oligodendrocyte functions can result in a breakdown of certain lipoids (e.g., plasmalogens). Among released metabolites are arachidonic and adrenic acid.16 Futher processing leads to the synthesis of prostaglandins, which are mediators of inflammation.
Genetic Determinants of Nutrient Processing
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Although this chromosomal region has been linked to multiple common diseases, including type 1 diabetes [59], osteoarthritis [60], bipolar disease [61], and asthma [62], the first study to examine the role of genetic variation on desaturase activity and its impact on fatty acid composition was a candidate gene study performed by Schaeffer et al. [63]. Using a population-based sample of 727 randomly selected, mainly Caucasian, participants, variants within the FADS gene cluster were found to be strongly associated with a subset of the n-6 and n-3 fatty acids—that is, the minor alleles were associated with increased levels of linoleic acid, eicosadienoic acid, dihomo-γ-linolenic acid, and α-linolenic acid, and decreased levels of γ-linolenic acid, arachidonic acid, adrenic acid, eicosapentaenoic acid, and docosapentaenoic acid. These findings were replicated and extended by Rzehak et al. [64], with evidence of association in erythrocyte membranes. Extension of genetic studies to genome-wide approaches (i.e., GWAS) likewise identified association of a variant in FADS1, rs174548, with several plasma glycerophospholipid concentrations, explaining up to 10% of the variance in certain species (e.g., arachidonic acid levels were significantly decreased among minor allele carriers) [65]. This observation was followed and corroborated in a larger study focused on identifying the genetic contributors of plasma polyunsaturated fatty acid concentrations wherein a significant association was also found near FADS1 at rs174537 with arachidonic acid, which accounted for 18.6% of the additive variance in arachidonic acid concentrations [66]. Variants in this region are highly correlated, suggesting that any one of the associated variants could be the causal.
Omega-3 and Omega-6 Fatty Acids*
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
William S. Harris, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Whether in reference to dietary FA intakes or blood-based biomarker FA levels, there are many ways to express what is sometimes called “omega status.” Our bias over the last 12 years has been to use the Omega-3 Index (erythrocyte EPA+DHA, expressed as a percent of total FAs) (Harris and von Schacky, 2004; von Schacky, 2014). This marker has gained widespread use in the FA research community owing to its ease of analysis, intuitive meaning, low within-person variability (Harris and Thomas, 2010), insensitivity to acute omega-3 FA loads (Harris et al., 2013), strong correlation with cardiac EPA+DHA levels (Harris et al., 2004), responsiveness to omega-3 supplementation (Flock et al., 2013), and utility as both a biomarker and risk factor for CHD (Harris, 2009). An alternate expression of “omega status” is the omega-6/omega-3 ratio. This pools all omega-6 FAs and all omega-3 FAs, regardless of chain length or double bond number, and then divides the former by the latter. In the author’s opinion, this metric is of little to no use for reasons previously outlined (Harris, 2006). Among the theoretical weaknesses of this ratio are (1) the failure to distinguish among the specific FA species within each class, effectively allowing ALA to “count” as equivalent metabolically to EPA, DPA, and DHA, and LA as equivalent to AA (or gamma-linolenic or adrenic acid); (2) the imprecision that arises from the fact that a virtually endless array of FA levels can all produce the same ratio; (3) the implicit presumption that the omega-6 FAs are “bad” and the omega-3 FAs are “good”; and (4) that lowering a “high” ratio (which is presumably bad) can be accomplished in five ways, at least one of which involves actually lowering omega-3 levels. In a workshop sponsored by the UK Food Standards Agency that addressed the utility of the omega-6/omega-3 ratio, the panel concluded, “On the basis of this review of the experimental evidence and on theoretical grounds, it was concluded that the n-6:n-3 FA ratio is not a useful concept and that it distracts attention away from increasing absolute intakes of long-chain n-3 FAs which have been shown to have beneficial effects on cardiovascular health” (Stanley et al., 2007).
The design and discovery of phospholipase A2 inhibitors for the treatment of inflammatory diseases
Published in Expert Opinion on Drug Discovery, 2021
Charikleia S. Batsika, Anna-Dimitra D. Gerogiannopoulou, Christiana Mantzourani, Sofia Vasilakaki, George Kokotos
Furthermore, lipidomic approaches may unravel the effect of a small-molecule inhibitor on a full set of lipids ex vivo or in vivo. For example, most recently, an LC-HRMS method allowed the exploration of the effect of a 2-oxoester inhibitor of GIVA cPLA2 on the fatty acid profile in a SH-SY5Y cellular model [135]. Instead of studying the effect of the inhibitor only on the generation of AA, a full set of cellular free fatty acids was explored, highlighting additional remarkable changes of the adrenic acid levels. These studies recommend that changes in the levels of free fatty acids, and especially AA and adrenic acid, may contribute to the formation of α-synuclein conformers, which are more susceptible to proteasomal degradation. Thus, the interactions of fatty acids with α-synuclein may be a crucial determinant of the fate of α-synuclein in the cell interior and, as a consequence, GIVA cPLA2 inhibitors might reduce the intracellular, potentially pathological, α-synuclein burden [135]. In general, research studies in previous years usually monitored the effect of a PLA2 inhibitor on the production of AA or an eicosanoid, such as PGE2 or LTB4. It would be really advantageous if someone monitors the simultaneous alterations of a full set of fatty acids and/or a full set of bioactive eicosanoids. Functional lipidomics studies may unravel novel medicinal targets and identify lipid metabolites that are unrecognized so far.
Maternal dietary n-6 polyunsaturated fatty acid deprivation does not exacerbate post-weaning reductions in arachidonic acid and its mediators in the mouse hippocampus
Published in Nutritional Neuroscience, 2019
Shoug M. Alashmali, Alex P. Kitson, Lin Lin, R. J. Scott Lacombe, Richard P. Bazinet
Table 2 presents the concentrations of esterified fatty acids from the hippocampus total PL of both maternal and offspring exposures to deprived and adequate n-6 PUFA diet. There was about 30% less ARA in the AD and DD versus DA and AA groups (diet effect: P < 0.05), independent of maternal exposure. This was accompanied by ∼40% lower concentration of adrenic acid (22:4n-6) in AD and DD groups (1155 ± 150 versus 2027 ± 346 nmol/g, diet effect: P < 0.05). Hippocampal LA content had a significant effect (P < 0.05), with lower concentrations in the AD and DD groups. Docosapentaenoic acid n-6 (22:5n-6; DPAn-6) concentration was reduced in the DD group compared to the other groups (interaction effect: P < 0.05). Conversely, there was a 38% higher concentration of eicosadonoic acid (20:2n-6; diet effect: P < 0.05) and 53% docosapentaenoic acid n-3 (22:5n-3; DPAn-3) in the AD and DD groups (diet effect: P < 0.05). Interestingly, ALA was 40% lower in the AD and DD groups (diet effect: P < 0.05). However, DHA did not show any statistical changes among all groups.