Cholesterol crystalline domains characterize atherosclerotic membranes, altering vascular signaling and function. Omega-3 fatty acids reduce membrane lipid peroxidation and subsequent cholesterol domain formation. We evaluated non-peroxidation-mediated effects of eicosapentaenoic acid (EPA), other TG-lowering agents, docosahexaenoic acid (DHA), and other long-chain fatty acids on membrane fluidity, bilayer width, and cholesterol domain formation in model membranes. In membranes prepared at 1.5:1 cholesterol-to-phospholipid (C/P) mole ratio (creating pre-existing domains), EPA, glycyrrhizin, arachidonic acid, and alpha linolenic acid promoted the greatest reductions in cholesterol domains (by 65.5%, 54.9%, 46.8%, and 45.2%, respectively) compared to controls; other treatments had modest effects. EPA effects on cholesterol domain formation were dose-dependent. In membranes with 1:1 C/P (predisposing domain formation), DHA, but not EPA, dose-dependently increased membrane fluidity. DHA also induced cholesterol domain formation without affecting temperature-induced changes in-bilayer unit cell periodicity relative to controls (d-space; 57Å-55Å over 15-30°C). Together, these data suggest simultaneous formation of distinct cholesterol-rich ordered domains and cholesterol-poor disordered domains in the presence of DHA. By contrast, EPA had no effect on cholesterol domain formation and produced larger d-space values relative to controls (60Å-57Å; p<0.05) over the same temperature range, suggesting a more uniform maintenance of lipid dynamics despite the presence of cholesterol. These data indicate that EPA and DHA had different effects on membrane bilayer width, membrane fluidity, and cholesterol crystalline domain formation; suggesting omega-3 fatty acids with differing chain length or unsaturation may differentially influence membrane lipid dynamics and structural organization as a result of distinct phospholipid/sterol interactions.

Until recently, studies of natural killer (NK) cells in infection have focused almost entirely on their role in viral infections. However, there is an increasing awareness of the potential for NK cells to contribute to the control of a wider range of pathogens, including intracellular parasites such as Plasmodium spp. Given the high prevalence of parasitic diseases in the developing world and the devastating effects these pathogens have on large numbers of vulnerable people, investigating interactions between NK cells and parasitized host cells presents the opportunity to reveal novel immunological mechanisms with the potential to aid efforts to eradicate these diseases. The capacity of NK cells to produce inflammatory cytokines early after malaria infection, as well as a possible role in direct cytotoxic killing of malaria-infected cells, suggests a beneficial impact of NK cells in this disease. However, NK cells may also contribute to overproduction of pro-inflammatory cytokines and the consequent immunopathology. As comparatively little is known about the role of NK cells later in the course of infection, and growing evidence suggests that heterogeneity in NK cell responses to malaria may be influenced by KIR/HLA interactions, a better understanding of the mechanisms by which NK cells might directly interact with parasitized cells may reveal a new role for these cells in the course of malaria infection.

No abstract

Widely available fish oil dietary supplements (DS) may contain fats and oxidized lipids in addition to the beneficial omega-3 fatty acids (OM3FAs) for which they are purchased. Little is known about the potential biological effects of these oxidized lipids. The objective of this study was to assess the fatty acid content, oxidation products, and biological effects of leading fish oil DS available in the United States. Three top-selling fish oil DS in the US were included in this analysis. Fatty acid composition was measured using gas chromatography. Lipid oxidation (primary and secondary products) was measured by spectroscopy in both DS and a prescription OM3FA product. OM3FAs were also isolated and concentrated from DS and were tested for the ability to inhibit copper-induced oxidation of human small dense low-density lipoprotein particles (sdLDL) in vitro. Fish oil DS were found to contain more than 30 different fatty acids, including 10 to 14 different saturated species comprising up to 36% of the total fatty acid content. Levels of OM3FAs also varied widely among DS (33%-79%). Primary (peroxide), secondary (anisidine), and total oxidation products exceeded maximum levels established by international standards of quality in the DS but not the prescription OM3FA product. Oxidation of sdLDL was inhibited by >95% (P < 0.001) with non-oxidized forms of OM3FA but not with OM3FAs isolated from DS, which were a mixture of oxidized and non-oxidized OM3FAs. These data indicate that levels of saturated fat and oxidized OM3FAs found in common DS may interfere with their intended/potential biological benefits.

The endothelium exerts many vasoprotective effects that are largely mediated by release of nitric oxide (NO). Endothelial dysfunction represents an early but reversible step in atherosclerosis and is characterized by a reduction in the bioavailability of NO. Previous studies have shown that eicosapentaenoic acid (EPA), an omega-3 fatty acid (O3FA), and statins individually improve endothelial cell function, but their effects in combination have not been tested. Through a series of in vitro experiments, this study evaluated the effects of a combined treatment of EPA and the active metabolite of atorvastatin (ATM) on endothelial cell function under conditions of oxidative stress. Specifically, the comparative and time-dependent effects of these agents on endothelial dysfunction were examined by measuring the levels of NO and peroxynitrite (ONOO) released from human umbilical vein endothelial cells (HUVECs). The data suggest that combined treatment with EPA and ATM is beneficial to endothelial function and was unique to EPA and ATM since similar improvements could not be recapitulated by substituting another O3FA docosahexaenoic acid (DHA) or other TG-lowering agents such as fenofibrate, niacin, or gemfibrozil. Comparable beneficial effects were observed when HUVECs were pretreated with EPA and ATM before exposure to oxidative stress. Interestingly, the kinetics of EPA-based protection of endothelial function in response to oxidation were found to be significantly different than those of DHA. Lastly, the beneficial effects on endothelial function generated by combined treatment of EPA and ATM were reproduced when this study was expanded to an ex vivo model utilizing rat glomerular endothelial cells. Taken together, these findings suggest that a combined treatment of EPA and ATM can inhibit endothelial dysfunction that occurs in response to conditions such as hyperglycemia, oxidative stress, and dyslipidemia.