linoleic-acid and 7-ketocholesterol

Atherosclerosis, macular degeneration, and neurodegenerative diseases such as Alzheimer's disease, are associated with the intracellular accumulation of substances that impair cellular function and viability. Reversing this accumulation may be a valuable therapy, but the accumulating substances resist normal cellular catabolism. On the other hand, these substances are naturally degraded in the soil and water by microorganisms. Thus, we propose the concept of "medical bioremediation," which derives from the successful field of in situ environmental bioremediation of petroleum hydrocarbons. In environmental bioremediation, communities of microorganisms mineralize hydrophobic organics using a series of enzymes. In medical bioremediation, we hope to utilize one or several microbial enzymes to degrade the intracellular accumulators enough that they can be cleared from the affected cells. Here, we present preliminary, but promising results for the bacterial biodegradation of 7-ketocholesterol, the main accumulator of foam cells associated with atherosclerosis. In particular, we report on the isolation of several Nocardia strains able to biodegrade 7-ketocholesterol and as an ester of 7-ketocholoesterol. We also outline key intermediates in the biodegradation pathway, a key step towards identifying the key enzymes that may lead to a therapy.

Topics: Atherosclerosis; Biodegradation, Environmental; Foam Cells; Genetic Engineering; Hydrocarbons; Ketocholesterols; Linoleic Acid; Longevity; Lysosomes; Metabolism; Models, Chemical; Nocardia; Petroleum

Topics: Acyl-CoA Oxidase; Adolescent; Adrenoleukodystrophy; Adult; alpha-Tocopherol; Animals; Apoptosis; ATP-Binding Cassette Transporters; Brain; Case-Control Studies; Catalase; Cell Survival; Child; Disease Progression; Docosahexaenoic Acids; Glutathione; Humans; Hydrogen Peroxide; Ketocholesterols; Linoleic Acid; Male; Membrane Proteins; Mice; Microglia; Middle Aged; Oxidative Stress; Peroxisomes; Reactive Oxygen Species; Repressor Proteins; Young Adult

Oxidized low-density lipoprotein (ox-LDL) causes atherosclerosis and endothelial dysfunction. No study up to the present date has examined the relative contribution of all the oxidized components in ox-LDL to inhibition on vascular function. Our aim was to investigate the effects of individual oxidized components at concentrations similar to those in ox-LDL on the impairment of endothelium-dependent relaxation in rat aorta.. Rat thoracic aorta was pre-treated with lysophosphatidylcholine (LPC), cholesterol oxidized products (COPs), oxidized linoleic acid (ox-18:2) and oxidized linolenic acid (ox-18:3) at concentrations similar to those in human ox-LDL. Ox-LDL as a whole caused 61% inhibition while LPC, COPs and ox-18:2 at concentrations similar to those in ox-LDL caused 12%, 24% and 19% inhibition, respectively, on endothelium-dependent relaxation, suggesting that COPs produced the most adverse effect followed by ox-18:2 and LPC in an additional way. Three COPs including 7-ketocholesterol, 7α-hydroxycholesterol and 7β-hydroxycholesterol showed inhibition on endothelium-dependent relaxation with E(max) being reduced to 79-87% compared with the control E(max) (95%). At Western blot analysis phosphorylation of eNOS at Ser1177 site and total eNOS were not altered by ox-LDL treatment, indicating that ox-LDL did not affect nitric oxide (NO) synthesis capacity. Ox-LDL might react directly with NO and lower NO bioavailability.. The present study demonstrated the relative contribution of individual oxidized components in ox-LDL in the inhibition of endothelium-dependent relaxation in rat aorta. This inhibitory effect could be caused by the reduction of NO bioactivity.

Topics: alpha-Linolenic Acid; Animals; Aorta, Thoracic; Cholesterol; Endothelium, Vascular; Humans; Hydroxycholesterols; In Vitro Techniques; Isomerism; Ketocholesterols; Linoleic Acid; Lipoproteins, LDL; Lysophosphatidylcholines; Male; Nitric Oxide Synthase Type III; Osmolar Concentration; Oxidation-Reduction; Phosphorylation; Rats; Rats, Sprague-Dawley; Vasodilation

Complex polyphenols present in extravirgin olive oil are not directly absorbed, but undergo gastrointestinal biotransformation, increasing the relative amount of tyrosol (TYR) and hydroxytyrosol (HT) entering the small and large intestine. We investigated the capacity of TYR and HT to inhibit the insult of dietary lipid hydroperoxydes on the intestinal mucosa, using cultures of Caco-2, a cell line with enterocyte-like features, and studying the effect of tert-butyl hydroperoxide (TBH) treatment on specific cell membrane lipid targets. The effect of homovanillic alcohol (HVA), metabolite of HT in humans and detected as metabolite of HT in Caco-2 cells, was also evaluated. Exposure to TBH induced a significant increase of the level of MDA, the formation of fatty acid hydroperoxides and 7-ketocholesterol and the loss of α-tocopherol. Pretreatment with both HT and HVA protected Caco-2 cells from oxidative damage: there was no significant detection of oxidation products and the level of α-tocopherol was preserved. Noteworthy, TYR also exerted a protective action against fatty acids degradation. In vitro trials, where the simple phenols were tested during linoleic acid and cholesterol oxidation, gave evidence of a direct scavenging of peroxyl radicals and suggested a hydrogen atom-donating activity.

Topics: alpha-Tocopherol; Antioxidants; Caco-2 Cells; Cell Survival; Cholesterol; Fatty Acids; Free Radical Scavengers; Humans; Ketocholesterols; Linoleic Acid; Lipid Peroxidation; Malondialdehyde; Olive Oil; Oxidation-Reduction; Phenols; Phenylethyl Alcohol; Plant Oils

The activity of a single IP administration (15 or 30 mg/Kg body weight) of vanillyl nonanoate, a simplified analog of capsiate, on ferric nitrilotriacetate (Fe-NTA)-mediated oxidative damage was investigated. A sub-lethal dose of Fe-NTA (15 mg Fe/Kg body weight) was administered IP to rats; animals were sacrificed, and kidney and plasma were collected 1 h after injection. In response to the Fe-NTA administration, a reduction of the levels of total lipids, total unsaturated fatty acids and cholesterol was observed, accompanied by a rise in the concentrations of malondialdehyde (MDA), conjugated dienes fatty acids hydroperoxides and 7-ketocholesterol in plasma and kidney 1 h after administration. A pre-treatment with synthetic capsiate (SCPT) showed remarkable protective effect on the reduction of the levels of total lipids, total unsaturated fatty acids and cholesterol, and the cellular antioxidant vitamin E, inhibiting the increase of MDA, conjugated dienes fatty acids hydroperoxides and 7-ketocholesterol in the plasma and kidney. The protective effect of SCPT and two analogues (vanillyl alcohol and vanillin) during the linoleic acid and cholesterol oxidation was investigated in in vitro systems, providing evidence of definite structure-activity relationships.

Topics: Analysis of Variance; Animals; Antioxidants; Body Weight; Capsaicin; Cholesterol; Chromatography, High Pressure Liquid; Fatty Acids; Ferric Compounds; Hydrogen Peroxide; Ketocholesterols; Kidney; Linoleic Acid; Lipid Peroxidation; Lipids; Malondialdehyde; Models, Chemical; Models, Statistical; Mutagens; Nitrilotriacetic Acid; Oxidative Stress; Oxygen; Rats; Rats, Wistar; Structure-Activity Relationship; Time Factors; Vanillic Acid