Rafat A. Siddiqui

Thrombosis and immune dysfunction are two important complications that result from the administration of parenteral nutrition. Endothelial cells within the vasculature are crucial components necessary for maintenance of normal coagulation and immune function. We compared the effects of three commercial lipid emulsions (LEs; Intralipid®, ClinOleic® [or Clinolipid®], and Omegaven®) differing in the levels of omega-6 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, omega-9 monounsaturated fatty acids, and saturated fatty acids upon endothelial cell fatty acid composition using Gas chromatography, endothelial cell integrity by assessing measurement of apoptosis and necrosis using flow cytometry, endothelial cell inflammatory activation by assessing the induction of ICAM-1 by lipopolysaccharide [LPS]), and transcription factor activation (phosphorylation of NF-κB) using western blot analysis. Gas chromatographic analysis confirmed cellular uptake of the fatty acids within the LEs; furthermore, these fatty acid changes reflected the composition of the oils and egg phosphatides used in the manufacturing of these emulsions. However, the kinetics of fatty acid uptake and processing differed between LEs. Fish oil LE negatively impacted cell viability by doubling the percentage of apoptotic and necrotic cell populations quantified by flow cytometry using Annexin V/Fluorescein and propidium iodide. The soybean oil LE did not alter cell viability, while the olive oil-predominate emulsion improved cell viability. All LEs were capable of suppressing LPS-induced ICAM-1 expression; however, the fish oil LE was more potent than the other emulsions. Fish oil LE supplementation of cells also suppressed LPS-induced phosphorylation of NF-κB, while the soybean oil and olive predominant LE had no effect upon NF-κB phosphorylation. Lipid emulsions are readily incorporated and stored in the form of triacylglycerols. Soybean oil-based, olive oil-predominant and fish-oil based LEs differentially affected endothelial cell integrity. Importantly, these three LEs were capable of suppressing endothelial cell inflammatory response despite their fatty acid content.

Background: Tocopherols and tocotrienols possess vitamin E activity and function as the major lipid‐soluble antioxidants in the human body. Commercial lipid emulsions are composed of different oils and supply different amounts of vitamin E. The objective of this study was to measure all 8 vitamin E homologs within 4 different commercial lipid emulsions and evaluate their distribution in guinea pig tissues. Materials and Methods: The distribution of vitamin E homologs within plasma and guinea pig tissues was determined using a high‐performance liquid chromatography (HPLC) system. Lipid hydroperoxides in lipid emulsions were determined using a commercial kit (Cayman Chemical Company, Ann Arbor, MI), and malondialdehyde tissue levels were determined using an HPLC system. Results: The lipid emulsions contained variable amounts of tocopherols, which were significantly different between emulsions. Tocotrienols were present at very low concentrations (≤0.3%). We found no correlation between the amount of vitamin E present in the lipid emulsions and lipid peroxidation. Hydroperoxides were the lowest with an olive oil–based emulsion and highest with a fish oil emulsion. The predominant vitamin E homolog in guinea pig tissues was α‐tocopherol. No tissues had detectable levels of tocotrienols. Vitamin E levels (primarily α‐tocopherol and γ‐tocopherol) were highly variable among organ tissues. Plasma levels were a poor reflection of most tissue levels. Conclusion: Vitamin E levels within different lipid emulsions and plasma/tissues are highly variable, and no one tissue or plasma sample serves as a good proxy for levels in other tissues. All study emulsions were well tolerated and did not significantly increase systemic lipid peroxidation.

Parenteral lipid emulsions, which are made of oils from plant and fish sources, contain different types of tocopherols and tocotrienols (vitamin E homologs). The amount and types of vitamin E homologs in various lipid emulsions vary considerably and are not completely known. The objective of this analysis was to develop a quantitative method to determine levels of all vitamin E homologs in various lipid emulsions. An HPLC system was used to measure vitamin E homologs using a Pinnacle DB Silica normal phase column and an isocratic, n‐hexane:1,4 dioxane (98:2) mobile phase. An optimized protocol was used to report vitamin E homolog concentrations in soybean oil‐based (Intralipid®, Ivelip®, Lipofundin^® N, Liposyn^® III, and Liposyn^® II), medium‐ and long‐chain fatty acid‐based (Lipofundin^® , MCT and Structolipid®), olive oil‐based (ClinOleic®), and fish oil‐based (Omegaven®) and mixture of these oils‐based (SMOFlipid®, Lipidem®) commercial parenteral lipid emulsions. Total content of all vitamin E homologs varied greatly between different emulsions, ranging from 57.9 to 383.9 µg/mL. Tocopherols (α, β, γ, δ) were the predominant vitamin E homologs for all emulsions, with tocotrienol content < 0.3%. In all of the soybean emulsions, except for Lipofundin® N, the predominant vitamin E homolog was γ‐tocopherol, which ranged from 57–156 µg/mL. ClinOleic® predominantly contained α‐tocopherol (32 µg/mL), whereas α‐tocopherol content in Omegaven® was higher than most of the other lipid emulsions (230 µg/mL).Practical applications: The information on the types and quantity of vitamin E homologs in various lipid emulsions will be extremely useful to physicians and healthcare personnel in selecting appropriate lipid emulsions that are exclusively used in patients with inadequate gastrointestinal function, including hospitalized and critically ill patients. Some emulsions may require vitamin E supplementation in order to meet minimal human requirements.Vitamin E homologs (tocopherols and tocotrienols) contain a chromanol ring and a hydrophobic side chain.

Lipid emulsions are made by mixing vegetable and/or fish oils with egg yolk and contain different types and amounts of fatty acids and sterols. This study assessed the effects of oral diet, soybean oil (SO)‐, fish oil (FO)‐, a mixture of olive and soybean oil (OOSO)‐, and a mixture of fish, olive, coconut, and soybean oil (FOCS)‐based emulsions on plasma triacylglycerols and plasma and tissue fatty acid and sterol content following acute and chronic intravenous administration in the guinea pig. Upon acute administration, peak triacylglycerols were highest with SO and lowest with OOSO. Upon chronic administration, the plasma triglyceride levels did not increase in any group over that of the controls. Fatty acid levels varied greatly between organs of animals on the control diets and organs of animals following acute or chronic lipid administration. Squalene levels increased in plasma following acute administration of OOSO, but plasma squalene levels were similar to control in all emulsion groups following chronic administration. Total plasma phytosterol levels were increased in the SO, OOSO, and FOCS groups following both acute and chronic infusions, whereas phytosterols were not increased following FO infusion. Total phytosterol levels were higher in liver, lung, kidney and adipose tissue following SO and OOSO. Levels were not increased in tissues after FO and FOCS infusion. These results indicate that fatty acid and sterol contents vary greatly among organs and that no one tissue reflects the fatty acid or sterol composition of other tissues, suggesting that different organs regulate these compounds differently.

The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice.

Parenteral nutrition lipid emulsions made from various plant oils contain steroidal compounds, called phytosterols. During parenteral administration of lipid emulsions, phytosterols can reach levels in the blood that are many fold higher than during enteral administration. The elevated phytosterol levels have been associated with the development of liver dysfunction and the rare development of liver failure. There is limited information available in the literature related to phytosterol concentrations in lipid emulsions. The objective of the current study was to validate an assay for steroidal compounds found in lipid emulsions and to compare their concentrations in the most commonly used parenteral nutrition lipid emulsions: Liposyn^® II, Liposyn^® III, Lipofundin^® MCT, Lipofundin^® N, Structolipid^®, Intralipid^®, Ivelip^® and ClinOleic^®. Our data demonstrates that concentrations of the various steroidal compounds varied greatly between the eight lipid emulsions, with the olive oil-based lipid emulsion containing the lowest levels of phytosterols and cholesterol, and the highest concentration of squalene. The clinical impression of greater incidences of liver dysfunction with soybean versus MCT/LCT and olive/soy lipid emulsions may be reflective of the levels of phytosterols in these emulsions. This information may help guide future studies and clinical care of patients with lipid emulsion-associated liver dysfunction.

Epidemiological data have shown an association of the intake of industrial produced trans fatty acids (TFA) and sudden cardiac death. The present study examines the impact of elaidic acid (t18:1n‐9) and linoelaidic acid (t18:2n‐6) on the human aortic endothelial cell functional response. Trans fatty acids predominately incorporated into the phospholipid component while only a minute fraction of the total fatty acids (FA) incorporated into triacylglycerol. Trans fatty acids incorporated into the plasma membranes at the expense of the saturated‐FA, stearic, palmitic, and to a lesser extent, myristic acid. Both t18:1n‐9 and t18:2n‐6 induced a pro‐inflammatory response by elevating surface expression of intercellular adhesion molecule‐1 (ICAM‐1). Neither oleic nor linoleic evoked a pro‐inflammatory phenotype under the maximal 50 µM treatments. Both TFA and stearic acid increased phosphorylation of the ICAM‐1 transcriptional regulator, nuclear factor‐κβ (NF‐κβ), while oleic and linoleic acids did not appear to alter the phosphorylation status. Elaidic acid minimally affected endothelial cell growth, whereas linoelaidic acid completely inhibited growth at 100 µM and imparted limited cytotoxicity up to 300 µM. Stearic acid induced cytotoxicity at concentrations above 75 µM, while oleic and linoleic acids evoked gradual dose‐dependent growth inhibition with cytotoxicity occurring only at linoleic acid concentrations greater than 200 µM. In conclusion, t18:1n‐9 and t18:2n‐6 fatty acids effectively incorporated into the phospholipid component of endothelial cells and subsequently induce a pro‐inflammatory phenotype.

Epidemiological studies have linked fish oil consumption to a decreased incidence of cancer. The anticancer effects of fish oil are mostly attributed to its content of omega‐3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, DHA, because of its unique effect of altering membrane composition, is often regarded as the major omega‐3 fatty acid involved in anticancer activity. Although use of DHA as an anticancer drug to prevent or treat human cancer in clinical settings has not yet been well established, recent studies suggest that DHA can be very effective as an adjuvant with other anticancer agents. In this article, we present studies that show the role of DHA in improving anticancer drug efficacy. Several in vitro and animal studies suggest that combining DHA with other anticancer agents often improves efficacy of anticancer drugs and also reduces therapy‐associated side effects. Incorporation of DHA in cellular membranes improves drug uptake, whereas increased lipid peroxidation is another mechanism for DHA‐mediated enhanced efficacy of anticancer drugs. In addition, several intracellular targets including cyclooxygenase‐2, nuclear factor kappa B, peroxisome proliferator‐activated receptor gamma, mitogen‐activated protein kinase, AKT, and BCL‐2/BAX are found to play an important role in DHA‐mediated additive or synergistic interaction with anticancer drugs. The data suggest that DHA is a safe, natural compound that can greatly improve the anticancer properties of anticancer drugs. Use of DHA with anticancer treatments provides an avenue to therapeutic improvement that involves less risk or side effects for patients and reduced regulatory burden for implementation.