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Cholesterol Reduces Partitioning of Antifungal Drug Itraconazole into Lipid Bilayers.
Poojari, C, Zak, A, Dzieciuch-Rojek, M, Bunker, A, Kepczynski, M, Róg, T
The journal of physical chemistry. B. 2020;(11):2139-2148
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Abstract
Cholesterol plays a crucial role in modulating the physicochemical properties of biomembranes, both increasing mechanical strength and decreasing permeability. Cholesterol is also a common component of vesicle-based delivery systems, including liposome-based drug delivery systems (LDSs). However, its effect on the partitioning of drug molecules to lipid membranes is very poorly recognized. Herein, we performed a combined experimental/computational study of the potential for the use of the LDS formulation for the delivery of the antifungal drug itraconazole (ITZ). We consider the addition of cholesterol to the lipid membrane. Since ITZ is only weakly soluble in water, its bioavailability is limited. Use of an LDS has thus been proposed. We studied lipid membranes composed of cholesterol, 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), and ITZ using a combination of computational molecular dynamics (MD) simulations of lipid bilayers and Brewster angle microscopy (BAM) experiments of monolayers. Both experimental and computational results show separation of cholesterol and ITZ. Cholesterol has a strong preference to orient parallel to the bilayer normal. However, ITZ, a long and relatively rigid molecule with weakly hydrophilic groups along the backbone, predominantly locates below the interface between the hydrocarbon chain region and the polar region of the membrane, with its backbone oriented parallel to the membrane surface; the orthogonal orientation in the membrane could be the cause of the observed separation. In addition, fluorescence measurements demonstrated that the affinity of ITZ for the lipid membrane is decreased by the presence of cholesterol, which is thus probably not a suitable formulation component of an LDS designed for ITZ delivery.
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Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study.
Souza, PR, Marques, RM, Gomez, EA, Colas, RA, De Matteis, R, Zak, A, Patel, M, Collier, DJ, Dalli, J
Circulation research. 2020;126(1):75-90
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Plain language summary
Specialized pro-resolving mediators (SPM) are derived from essential fatty acids and promote resolution of inflammation. The main aim of this study was to establish the relationship(s) between supplement dose, peripheral blood SPM concentrations, and cellular responses using a novel enriched marine oil preparation. This study is a double-blind, randomized, crossover, dose escalation placebo-controlled study in healthy volunteers. Participants (n=22) were randomised to one of eight groups. Results show supplementation with refined marine oils lead to a rapid upregulation of peripheral blood SPM concentrations and reprograming of peripheral blood cell responses to sterile and infectious stimuli, changes that were found to persist after SPM concentrations returned to baseline. Authors conclude that enriched marine oil supplementation leads to a dose-and time-dependent increase of plasma SPM concentrations.
Abstract
RATIONALE Specialized pro-resolving mediators (SPM-lipoxins, resolvins, protectins, and maresins) are produced via the enzymatic conversion of essential fatty acids, including the omega-3 fatty acids docosahexaenoic acid and n-3 docosapentaenoic acid. These mediators exert potent leukocyte directed actions and control vascular inflammation. Supplementation of animals and humans with essential fatty acids, in particular omega-3 fatty acids, exerts protective actions reducing vascular and systemic inflammation. Of note, the mechanism(s) activated by these supplements in exerting their protective actions remain poorly understood. OBJECTIVE Given that essential fatty acids are precursors in the biosynthesises of SPM, the aim of the present study was to establish the relationship between supplementation and peripheral SPM concentrations. We also investigated the relationship between changes in plasma SPM concentrations and peripheral blood platelet and leukocyte responses. METHODS AND RESULTS Healthy volunteers were enrolled in a double-blinded, placebo-controlled, crossover study, and peripheral blood was collected at baseline, 2, 4, 6, and 24 hours post administration of placebo or one of 3 doses of an enriched marine oil supplement. Assessment of plasma SPM concentrations using lipid mediator profiling demonstrated a time- and dose-dependent increase in peripheral blood SPM concentration. Supplementation also led to a regulation of peripheral blood cell responses. Here we found a dose-dependent increase in neutrophil and monocyte phagocytosis of bacteria and a decrease in the diurnal activation of leukocytes and platelets, as measured by a reduction in adhesion molecule expression. In addition, transcriptomic analysis of peripheral blood cells demonstrated a marked change in transcript levels of immune and metabolic genes 24 hours post supplementation when compared with placebo. CONCLUSIONS Together, these findings demonstrate that supplementation with an enriched marine oil leads to an increase in peripheral blood SPM concentrations and reprograms peripheral blood cells, indicating a role for SPM in mediating the immune-directed actions of this supplement. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT03347006.
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N-3 polyunsaturated fatty acids in the treatment of atherogenic dyslipidemia.
Vecka, M, Dušejovská, M, Stankova, B, Zeman, M, Vavrova, L, Kodydkova, J, Slaby, A, Zak, A
Neuro endocrinology letters. 2012;:87-92
Abstract
BACKGROUND Atherogenic dyslipidemia contributes substantially to the residual cardiovascular risk. The aim of this study was to examine the effects of therapeutic doses of n-3 polyunsaturated fatty acids on the three major lipid abnormalities of atherogenic dyslipidemia, i.e. hypertriacylglycerolemia, low HDL cholesterol, and increased levels of small dense LDL particles, as well as on some new risk factors. MATERIALS AND METHODS A total of 60 hypertriacylglycerolemic patients were included in the study. Group S consisted of 36 patients who were already treated with statins, Group N of 24 patients not yet treated. Each patient was examined after six weeks on placebo and six weeks of treatment with n-3 PUFA (eicosapentaenoic and docosahexaenoic acid ethyl esters, 3.0 g/d). RESULTS Treatment with n-3 PUFA caused a decrease in plasma triacylglycerols (28%, p<0.001), and VLDL (-27%, p<0.001), an increase in HDL-C (+4%, p<0.01), and a decrease in sdLDL cholesterol (-16%, p<0.05). These changes were accompanied by a decrease in microalbuminuria (-30%, p<0.05), as well as in several parameters of oxidative stress. Analysis of the fatty acids composition of plasma phospholipids showed a significant increase in all n-3 PUFAs examined, accompanied by a decrease in n-6 PUFAs, as well as in monounsaturated acids. No significant differences in the effects of n-3 PUFA were found between the Groups S and N. CONCLUSION Our results support the opinion that hypertriacylglycerolemic patients benefit from the treatment with n-3 PUFA which improves several important metabolic factors of cardiovascular risk.