linoleic-acid and 4-hydroxy-2-nonenal

An increasing body of evidence from animal models, human specimens and cell lines points to reactive oxygen species as likely involved in the pathways, which convey both extracellular and intracellular signals to the nucleus, under a variety of pathophysiological conditions. Indeed, reactive oxygen species (ROS), in a concentration compatible with that detectable in human pathophysiology, appear able to modulate a number of kinases and phosphatases, redox sensitive transcription factors and genes. This type of cell signalling consistently implies the additional involvement of other bioactive molecules that stem from ROS reaction with cell membrane lipids. The present review aims to comprehensively report on the most recent knowledge about the potential role of ROS and oxidised lipids in signal transduction processes in the major events of cell and tissue pathophysiology. Among the lipid oxidation products of ROS-dependent reactivity, which appear as candidates for a signalling role, there are molecules generated by oxidation of cholesterol, polyunsaturated fatty acids and phospholipids, as well as lysophosphatidic acid and lysophospholipids, platelet activating factor-like lipids, isoprostanes, sphingolipids and ceramide.

Topics: Aldehydes; Animals; Arachidonic Acid; Cell Communication; Growth Substances; Humans; Isoprostanes; Linoleic Acid; Lipid Metabolism; Lysophospholipids; Oxidation-Reduction; Oxidative Stress; Platelet Activating Factor; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Reactive Oxygen Species; Signal Transduction; Transcription Factors

Angiotensin (Ang) II is a major bioactive peptide of the renin/angiotensin system and is involved in various cardiovascular functions and diseases. Ang II type 1 (AT

Topics: Aldehydes; Angiotensin II; Ascorbic Acid; Carbon Isotopes; Cell Line; Copper Sulfate; Endothelial Cells; Humans; Isotope Labeling; Linoleic Acid; Lipid Peroxidation; Oxidative Stress; Receptor, Angiotensin, Type 1

Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA).. Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R (2)=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only.. Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts.

Topics: Aged; Aldehydes; Case-Control Studies; Cholesterol, HDL; Fatty Acids, Unsaturated; Female; Heart Failure; Humans; Linoleic Acid; Lipid Peroxidation; Male; Middle Aged

Animal and epidemiological studies confirm an impact of the fatty-acid composition in the diet on cancer development. We investigated the role of supplementation of the diet of female F344-rats with sunflower, rapeseed, olive or coconut oil on the formation of the promutagenic, exocyclic 1,N2-propanodeoxyguanosine adduct of the main lipid peroxidation product 4-hydroxy-2-nonenal in the mucosa of the glandular stomach, the small intestine, the colon, the whole kidney and the lung. This adduct is considered as the predominant DNA adduct arising from lipid peroxidation. The correlations between adduct levels and the different fatty acids were not uniform for all organs. No clear relationships between fatty acids and adduct levels were found in the colon. Significant positive correlations were observed between linoleic acid, total polyunsaturated fatty acids (PUFAs), vitamin E and DNA adduct levels in the small intestine and in the kidney. The results indicate an increasing effect on cancer risk in these organs as a result of high intake of linoleic acid. Inverse relationships between linoleic acid, PUFA and vitamin E intake and adduct levels were found in the glandular stomach and the lung. We could not confirm a chemopreventive effect of linolenic acid (C-18 omega-3 PUFA) on the formation of adducts in our animal study, as was shown in white blood cells of women in a previous study. A tendency towards a decrease in adduct levels was seen with monounsaturated fatty acids (MUFAs) in all organs except the lung. Saturated fatty acids showed a significant positive correlation with adduct levels in the mucosa of the glandular stomach and a significant inverse correlation in the small intestine. Saturated fatty acids are not considered to directly influence lipid peroxidation to a major extent.

Topics: Aldehydes; Animals; Brassica rapa; Coconut Oil; Colon; Deoxyguanosine; DNA Adducts; Female; Gastric Mucosa; Helianthus; Intestine, Small; Kidney; Linoleic Acid; Lipid Peroxidation; Lung; Olive Oil; Plant Oils; Rats; Rats, Inbred F344; Vitamin E

Oxidative stress-induced lipid peroxidation leads to the formation of cytotoxic and genotoxic 2-alkenals, such as 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE). Lipid-derived reactive aldehydes are subject to phase-2 metabolism and are predominantly found as mercapturic acid (MA) conjugates in urine. This study shows evidence for the in vivo formation of ONE and its phase-1 metabolites, 4-oxo-2-nonen-1-ol (ONO) and 4-oxo-2-nonenoic acid (ONA). We have detected the MA conjugates of HNE, 1,4-dihydroxy-2-nonene (DHN), 4-hydroxy-2-nonenoic acid (HNA), the lactone of HNA, ONE, ONO, and ONA in rat urine by liquid chromatography-tandem mass spectrometry comparison with synthetic standards prepared in our laboratory. CCl(4) treatment of rats, a widely accepted animal model of acute oxidative stress, resulted in a significant increase in the urinary levels of DHN-MA, HNA-MA lactone, ONE-MA, and ONA-MA. Our data suggest that conjugates of HNE and ONE metabolites have value as markers of in vivo oxidative stress and lipid peroxidation.

Topics: Acetylcysteine; Aldehydes; Animals; Biomarkers; Carbon Tetrachloride; Chromatography, Liquid; Lactones; Linoleic Acid; Lipid Peroxidation; Mass Spectrometry; Models, Chemical; Oxidative Stress; Rats; Rats, Inbred F344

Substantial work has been carried out to elucidate the nature of protein modification by 4-hydroxy-2-nonenal (HNE) and its relatives. Its keto cousin, 4-oxo-2-nonenal (ONE), which arises from linoleic acid oxidation independently of HNE, was previously reported to form Michael adducts with His and Cys that can subsequently, in part, condense with Lys residues to give imidazolylpyrrole cross-links. Despite mass spectrometric evidence also for ONE-Lys Michael adducts, the latter do not accumulate in solution. A long-lived adduct that has the same mass as the ONE Lys Michael adduct is suggested instead to be the isomeric 4-ketoamide that arises, along with other adducts, from the reversibly-formed ONE Lys Schiff base. The Lys-ketoamide and His-Lys imidazolylpyrrole cross-links appear to be unusually prominent markers of stable protein modification by ONE.

Topics: Aldehydes; Kinetics; Linoleic Acid; Mass Spectrometry; Models, Molecular; Molecular Conformation; Proteins; Schiff Bases

Increasing evidence indicates the involvement of immune reactions in the pathogenesis of alcoholic liver disease. We have investigated whether ethanol-induced oxidative stress might contribute to immune response in alcoholics. Antibodies against human serum albumin modified by reaction with malondialdehyde (MDA), 4-hydroxynonenal (HNE), 2-hexenal, acrolein, methylglyoxal, and oxidized arachidonic and linoleic acids were measured by ELISA in 78 patients with alcoholic cirrhosis and/or hepatitis, 50 patients with nonalcoholic cirrhosis, 23 heavy drinkers with fatty liver, and 80 controls. Titers of IgG-recognizing epitopes derived from MDA, HNE, and oxidized fatty acids were significantly higher in alcoholic as compared to nonalcoholic cirrhotics or healthy controls. No differences were instead observed in the titers of IgG-recognizing acrolein-, 2-hexenal-, and methylglyoxal-modified albumin. Alcoholics showing high IgG titers to one adduct tended to have high titers to all the others. However, competition experiments showed that the antigens recognized were structurally unrelated. Anti-MDA and anti-HNE antibodies were significantly higher in cirrhotics with more severe disease as well as in heavy drinkers with cirrhosis or extensive fibrosis than in those with fatty liver only. We conclude that antigens derived from lipid peroxidation contribute to the development of immune responses associated with alcoholic liver disease.

Topics: Acrolein; Adult; Aged; Aldehydes; Arachidonic Acid; Ethanol; Female; Humans; Immunoglobulin G; Linoleic Acid; Lipid Peroxidation; Liver Diseases, Alcoholic; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Oxidative Stress; Serum Albumin

The oxidation of linoleic acid by soybean lipoxygenase-1 (LOX-1) was inhibited in a time-dependent manner by 4-hydroxy-2(E)-nonenal (HNE). Kinetic analysis indicated the effect was due to slow-binding inhibition conforming to an affinity labeling mechanism-based inhibition. After 25 min of preincubation of LOX-1 with and without HNE, Lineweaver-Burk reciprocal plots indicated mixed noncompetitive/competitive inhibition. Low concentrations of HNE influenced the electron paramagnetic resonance (EPR) signal of 13(S)-hydroperoxy-9(Z), 11 (E)-octadecadienoic acid (13-HPODE)-generated Fe3+-LOX-1 slightly, but higher concentrations completely eliminated the EPR signal indicating an active site hindered from access by 13-HPODE. HNE may compete for the active site of LOX-1 because its precursor, 4-hydroperoxy-(2E)-nonenal, is a product of LOX-1 oxidation of (3Z)-nonenal. Also, it was an attractive hypothesis to suggest that HNE may disrupt the active site by forming a Michael adduct with one or more of the three histidines that ligate the iron active site of LOX-1.

Topics: Aldehydes; Buffers; Catalytic Domain; Cysteine Proteinase Inhibitors; Electron Spin Resonance Spectroscopy; Enzyme Activation; Histidine; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Lipoxygenase; Lipoxygenase Inhibitors

Peroxynitrite-mediated linoleic acid oxidation and tyrosine nitration were analysed in the presence of synthetic model neuromelanins: dopamine (DA) -melanin, cysteinyldopamine (CysDA) -melanin and various DA/CysDA copolymers. The presence of melanin significantly decreased the amount of 3-nitrotyrosine formed. This inhibitory effect depended on the type and concentration of melanin polymer. It was found that incorporation of CysDA-derived units into melanin attenuated its protective effect on tyrosine nitration induced by peroxynitrite. In the presence of bicarbonate, the melanins also inhibited 3-nitrotyrosine formation in a concentration dependent manner, although the extent of inhibition was lower than in the absence of bicarbonate. The tested melanins inhibited peroxynitrite-induced formation of linoleic acid hydroperoxides, both in the absence and in the presence of bicarbonate. In the presence of bicarbonate, among the oxidation products appeared 4-hydroxynonenal (HNE). CysDA-melanin inhibited the formation of HNE, while DA-melanin did not affect the aldehyde level. The results of the presented study suggest that neuromelanin can act as a natural scavenger of peroxynitrite.

Topics: Aldehydes; Chromatography, High Pressure Liquid; Cross-Linking Reagents; Dose-Response Relationship, Drug; Hydrogen Peroxide; Linoleic Acid; Melanins; Nitrogen; Oxygen; Peroxynitrous Acid; Tyrosine

Macrophage death, believed to be an important event in the pathogenesis of human atherosclerosis, can be induced by oxidised low-density lipoprotein (LDL) in vitro. Supplementation of the culture medium with 5 mM GSH significantly protected human monocyte-macrophages in vitro against the toxicity of copper-oxidised LDL. Oxidation products of LDL include the aldehyde 4-hydroxynonenal (HNE). We present evidence that conjugation of HNE by GSH contributes to this protection. In the absence of cells, HPLC analysis showed there were marked reductions in the levels of both pure HNE and HNE in copper-oxidised LDL in the presence of GSH. However, GSH did not reverse protein modification, as judged by agarose gel electrophoresis, nor did it influence the depletion of polyunsaturated fatty acids, which were assessed using gas chromatography. The possible implications for human atherosclerosis are discussed.

Topics: Aldehydes; Arachidonic Acid; Cell Death; Cell Membrane Permeability; Chromatography, High Pressure Liquid; Copper; Dose-Response Relationship, Drug; Electrophoresis; Fatty Acids, Unsaturated; Glutathione; Humans; Hydroxycholesterols; Linoleic Acid; Lipoproteins, LDL; Macrophages; Monocytes; Oxidants; Oxidation-Reduction

4-Hydroxy-trans-2-nonenal (HNE) and omega 6 fatty acids contents were analyzed in pork and beef. The HNE contents in beef (n = 4) and pork (n = 7) were 14.0-150 nmol/g and 1.0-152 nmol/g, respectively. Furthermore, a linear correlation between the content of HNE and the content of total omega 6 fatty acids, linoleic acid, or arachidonic acid was observed in pork.

Topics: Aldehydes; Animals; Arachidonic Acid; Cattle; Chromatography, High Pressure Liquid; Dietary Fats, Unsaturated; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Meat; Swine

Gas chromatograph-mass spectrometry has been applied to the analysis of plasma linoleic acid and one of its oxidation products, 4-hydroxy-2-nonenal (HNE), in adult patients with the acute respiratory distress syndrome (ARDS). Peak areas of total ion chromatograms showed there to be negative correlations between loss of linoleic acid and formation of HNE (measured by selective ion monitoring) in 7 out 10 patients studied. When HNE was quantitated by selective ion monitoring, with reference to a pure standard of HNE and an internal standard of nonanoic acid, ARDS patients showed significantly increased levels of HNE (0.412 +/- 0.023 nmol/ml) compared with normal healthy controls (0.205 +/- 0.018 nmol/ml).

Topics: Adult; Aldehydes; Free Radicals; Gas Chromatography-Mass Spectrometry; Humans; Linoleic Acid; Linoleic Acids; Regression Analysis; Respiratory Distress Syndrome

Malonaldehyde (MA) and 4-hydroxynonenal (4-HN) formed upon oxidation with Fe2+/H2O2 from arachidonic acid and linoleic acid, and their ethyl esters were analyzed by gas chromatography (GC). The MA and 4-HN produced were reacted with N-methylhydrazine (NMH) to give 1-methylpyrazole and 5(1'-hydroxyhexyl)-1-methyl-2-pyrazoline, respectively. The derivatives were analyzed by GC on a fused silica capillary column using a nitrogen-phosphorus detector. With arachidonic acid, more MA and 4-HN were formed from the ester (88 nmol/mg and 23 nmol/mg, respectively) than from the free acid (25 nmol/mg and 9 nmol/mg, respectively). In contrast, with linoleic acid, more MA and 4-HN were produced from the free acid (53 nmol/mg and 13 nmol/mg, respectively) than from the ester (39 nm/mg and 8 nmol/mg, respectively).

Topics: Aldehydes; Arachidonic Acid; Arachidonic Acids; Chromatography, Gas; Hydrogen Peroxide; Iron; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Malondialdehyde; Models, Biological; Molecular Structure

Peroxidation of lipids produces carbonyl compounds; some of these, e.g., malonaldehyde and 4-hydroxynonenal, are genotoxic because of their reactivity with biological nucleophiles. Analysis of the reactive carbonyl compounds is often difficult. The methylhydrazine method developed for malonaldehyde analysis was applied to simultaneously measure the products formed from linoleic acid, linolenic acid, arachidonic acid, and squalene upon ultraviolet-irradiation (UV-irradiation). The photoreaction products, saturated monocarbonyl, alpha,beta-unsaturated carbonyls, and beta-dicarbonyls, were derivatized with methylhydrazine to give hydrazones, pyrazolines, and pyrazoles, respectively. The derivatives were analyzed by gas chromatography and gas chromatography-mass spectrometry. Lipid peroxidation products identified included formaldehyde, acetaldehyde, acrolein, malonaldehyde, n-hexanal, and 4-hydroxy-2-nonenal. Malonaldehyde levels formed upon 4 hr of irradiation were 0.06 micrograms/mg from squalene, 2.4 micrograms/mg from linolenic acid, and 5.7 micrograms/mg from arachidonic acid. Significant levels of acrolein (2.5 micrograms/mg) and 4-hydroxy-2-nonenal (0.17 micrograms/mg) were also produced from arachidonic acid upon 4 hr irradiation.

Topics: Acetaldehyde; Acrolein; Aldehydes; Arachidonic Acid; Arachidonic Acids; Chromatography, Gas; Formaldehyde; Gas Chromatography-Mass Spectrometry; Linoleic Acid; Linoleic Acids; Linolenic Acids; Lipid Peroxidation; Lipids; Malondialdehyde; Monomethylhydrazine; Squalene; Ultraviolet Rays

Both 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and carbon tetrachloride (CCl4) have conspicuous effects on lipid metabolism in rat liver. Although it is generally accepted that CCl4 administration leads to hepatic lipid peroxidation in vivo, conflicting reports from different laboratories make it unclear whether or not lipid peroxidation is involved in the mechanism of toxicity of TCDD. The present study involved pretreating F344 rats with CCl4 or TCDD, then at predetermined times thereafter, giving [U-14C]linoleic acid. A variety of compound classes were monitored in extracts of liver taken 30 min after the label was given. A previously unreported effect of CCl4 was a conspicuous increase in turnover of 1,2-diglycerides. That CCl4 did cause lipid peroxidation was evident from the presence of allylic hydroxyacids not seen in vehicle-treated controls, greatly increased radioactivity in protein-bound material, and decreased levels of arachidonate without decreased synthesis from linolate. Where effects of TCDD pretreatment could be seen, they were much less than the corresponding effects of CCl4. No allylic hydroxyacids were detected in livers of TCDD-treated rats. The concentration of arachidonate was not reduced, and elongation of linolate was not stimulated, indicating that TCDD did not cause extensive-but-repaired peroxidation. It is concluded that while TCDD may slightly increase hepatic lipid peroxidation in rats in vivo, the extent of such stimulation appears to be too slight to account for the toxicity of TCDD.

Topics: Aldehydes; Animals; Arachidonic Acid; Arachidonic Acids; Carbon Radioisotopes; Carbon Tetrachloride; Chromatography, Thin Layer; Dioxins; Fatty Acids; Female; Gas Chromatography-Mass Spectrometry; Kinetics; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Liver; Oxidation-Reduction; Polychlorinated Dibenzodioxins; Rats; Rats, Inbred F344