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PubMed2006

Canine myocilin is associated with lipid modified by palmitic acid.

PURPOSE: Myocilin, the product of the GLC1A locus in humans, has been associated with primary open angle glaucoma (POAG). Mutations in myocilin exon 3 correlate with age of onset and severity of POAG. Myocilin has been under investigation in experimentally induced glaucoma in rats, mice, and monkeys, however no animal model of inherited POAG exists except in beagles. Our aim was to determine whether canine myocilin more closely resembles human myocilin than does myocilin from other species. METHODS: Canine myocilin was cloned and sequenced from beagle ocular tissues and Madin-Darby Canine Kidney (MDCK) cells, a well characterized canine cell line. Immunohistochemistry was performed on beagle tissues and cultured canine ocular primary cells. RT-PCR was employed to analyze genes expressed by tissues and cells. Myocilin protein synthesized by MDCK and canine optic nerve head cells (ONH) was analyzed by metabolic radioisotope labeling. Immunoprecipitation, enzymatic digestion, and Triton X-114 phase separation were performed to determine the carbohydrate content and the hydrophobicity of canine myocilin, respectively. RESULTS: Canine ONH astrocytes cultured from a beagle eye expressed myocilin and markers of type 1B astrocytes observed also in human ONH cells in culture. The sequence of canine myocilin showed close similarity with the human sequence but lacked the additional upstream coding region found only in human and rat. Myocilin was labeled with (3)H palmitic acid. This label co-eluted with (35)S label in hydroxylapatite chromatography despite purification by phase separation in Triton X-114, immunoprecipitation with myocilin-specific sera, and denaturing conditions of heat, SDS, and reducing agent. CONCLUSIONS: Canine myocilin revealed no striking sequence differences from myocilin of other species. Mutations in myocilin of glaucomatous beagles may suggest a similar pattern of involvement in inherited POAG. This represents the first report of lipid associated with the myocilin protein. Many lipid-modified proteins reside in lipid rafts. This modification of myocilin with lipids supports the unusual secretion properties and may suggest a function of myocilin in sorting, cell signaling and communication between the extracellular matrix and the cell membranes.

Amino Acid Sequence↗
PubMedDate not supplied

[Effect of the state of the lipid phase of the membrane on the effectiveness of photochemical modification of erythrocyte acetylcholinesterase].

Modification of the lipid phase structure of the erythrocyte membrane by phospholipases A2, C and D as well as the partial depletion of cholesterol was shown to be accompanied by the change of the acetylcholinesterase (AChE) UV-sensitivity. The ability of UV-light to change the catalytic properties (Km) of the membrane-bound AChE not observed for free AChE (constant value of Km) and known as the phenomenon of photochemical allotopy, is retained in the cholesterol depleted membranes and disappears after an enzymatic treatment of the membranes by phospholipases. The possible non-photochemical influence of the membrane lipid phase in response to UV-damage of membrane-bound AChE is discussed.

Acetylcholinesterase↗
PubMed1997

Lipid peroxidation and changes in the ubiquinone content and the respiratory chain enzymes of submitochondrial particles.

The relationship between, lipid peroxidation induced by ascorbate and adenosine ADP/Fe3+, and its effect on the respiratory chain activities of beef heart submitochondrial particles has been investigated. Lipid peroxidation, measured as thiobarbituric acid reactive substance formation, resulted in an inhibition of the NADH and succinate oxidase activities. Examination of several partial reactions of the respiratory chain revealed inactivation primarily of those involving endogenous ubiquinone, i.e., NADH- and succinate-ubiquinone1 and cytochrome c reductases. Ubiquinol-cytochrome c reductase, measured with reduced ubiquinone2 as electron donor, was unaffected. The amount of NADH- or succinate-reducible cytochrome b in the presence of cyanide was strongly decreased, but could be recovered by the addition of antimycin. There occurred a substantial decrease of the ubiquinone content in the course of lipid peroxidation, with a linear relationship between this decrease and the NADH and succinate oxidase activities. The results are consistent with the conclusion that the ubiquinone pool undergoes an oxidative modification during lipid peroxidation, to a form that can no longer function as a component of the respiratory chain. Lipid peroxidation also led to a partial inhibition of the succinate dehydrogenase and cytochrome c oxidase activities and a minor decrease of the cytochrome c and cytochrome a contents. Reduction of endogenous ubiquinone prevented lipid peroxidation as well as the concomitant modification of ubiquinone and inactivation of the respiratory chain. These observations suggest that the destruction of ubiquinone through lipid peroxidation is the primary cause of inactivation of the respiratory chain, and emphasize the antioxidant role of ubiquinol in preventing these effects. The possible implications of these findings for regulation of the cellular turnover of ubiquinone by the prevailing oxidative stress are discussed.

Adenosine Diphosphate↗
PubMedDate not supplied

[Interrelationship between structural and functional modifications in the membranes of the sarcoplasmic reticulum following lipid peroxidation].

Structural and functional modifications of sarcoplasmic reticulum membranes from skeletal muscles by molecular oxygen was studied. Lipid peroxidation (accumulation of 5-10 nmoles hydroperoxides/mg lipids) results in membrane permeability increase for Ca2+-ions whereas the activity of Ca2+-dependant ATPase preserved unchanged. In the temperature range 5-30 degrees C decrease of solubilization parameter alpha (for nitroxide radical 2,2,6,6-tetramethylpiperidin-1-oxyl) was registered while alpha reached the control values at temperatures higher than 30 degrees C. Further increase in lipoperoxide content (more than 20 nmoles/mg lipids) lead to inhibition of Ca2+dependant ATPase. In this case alpha was lower than in intack membranes in the whole temperature interval investigated. The loss of Ca2+-accumulating capacity is explained on the basis of peroxide clusters formation in lipid bilayer regions of sarcoplasmic membrane. One of the mechanisms of Ca2+-dependant ATPase inhibition after lipid peroxidation is the deficiency of polyunsaturated fatty acyls in microenvironment of the enzyme.

Adenosine Triphosphatases↗
PubMed1998

[Hyperalphalipoproteinemias and medical advise in primary care. Changes of the lipid pattern].

OBJECTIVE: To analyse the modifications in the lipid pattern experienced in the observance of patients with Hyperalpha-lipoproteinaemia (HAL). DESIGN: A prospective follow-up study. SETTING: La Orden Primary Care Centre, Huelva. PATIENTS: 120 diagnosed with HAL (cHDL higher than the 90 percentile of their same age and sex group from a reference population with cLDL and Triglycerides less than 150 and 200 mg/dl, respectively) and observed for 2.5 +/- 1.5 years. MEASUREMENTS AND RESULTS: Blood pressure, weight, size, cholesterol, cHDL, cLDL, Triglycerides, Glucaemia and Uric acid were determined. The modifications in the diagnosis of HAL, and changes in averages and percentages of several variables, were calculated. Out of 95 people (79.1%) (Age: 42.6 +/- 16), HAL was confirmed in 42.1% (CI, 24.8-59.4) and Hypercholesterolaemia 11a in 20%. There was no lipid disorder in 37.9%. CONCLUSIONS: HAL at a high rate was not confirmed. After HAL is diagnosed, we must be cautious in our advice on cardiovascular protection, as it could be secondary or be modified over time.

Adult↗
PubMed1993

Spermine accelerates iron-induced lipid peroxidation in mitochondria by modification of membrane surface charge.

The polyamine spermine was found to make the mitochondrial membrane more susceptible to lipid peroxidation induced by adenosine 5'-diphosphate (ADP)/Fe2+. It shortened the lag time before induction of peroxidation, but did not affect the rate of lipid peroxidation. It had no effect on lipid peroxidation of electrically neutral egg yolk phosphatidylcholine liposomes, but had an effect on lipid peroxidation of negatively charged liposomes consisting of egg yolk phosphatidylcholine and bovine heart cardiolipin similar to that on peroxidation in mitochondria. Spermine decreased the negative zeta-potential of these negatively charged liposomes consisting of phosphatidylcholine and cardiolipin. These results suggest that the hydrophilic polycation spermine reduces the negative charge on the surface of mitochondrial membrane, possibly by its interaction with negatively charged polar heads of phospholipids, and that this neutralization of the surface charge renders the mitochondrial membrane more susceptible to induction of lipid peroxidation induced by ADP/Fe2+.

Adenosine Diphosphate↗
PubMed2004

Oxidative modification of low-density lipoprotein: lipid peroxidation by myeloperoxidase in the presence of nitrite.

Oxidative modification of low-density lipoprotein (LDL) is a pivotal process in early atherogenesis and can be brought about by myeloperoxidase (MPO), which is capable of reacting with nitrite, a NO metabolite. We studied MPO-mediated formation of conjugated dienes in isolated human LDL in dependence on the concentrations of nitrite and chloride. This reaction was strongly stimulated by low concentrations (5-50 microM) of nitrite which corresponds to the reported concentration in the arterial vessel wall. Under these conditions no protein tyrosine nitration occurred; this reaction required much higher nitrite concentrations (100 microM-1 mM). Chloride neither supported lipid peroxidation alone nor was its presence mandatory for the effect of nitrite. We propose a prominent role of lipid peroxidation for the proatherogenic action of the MPO/nitrite system, whereas peroxynitrite may be competent for protein tyrosine nitration of LDL. Monomeric and oligomeric flavan-3-ols present in cocoa products effectively counteracted, at micromolar concentrations, the MPO/nitrite-mediated lipid peroxidation of LDL. Flavan-3-ols also suppressed protein tyrosine nitration induced by MPO/nitrite or peroxynitrite as well as Cu2+-mediated lipid peroxidation of LDL. This multi-site protection by (-)-epicatechin or other flavan-3-ols against proatherogenic modification of LDL may contribute to the purported beneficial effects of dietary flavan-3-ols for the cardiovascular system.

Dose-Response Relationship, Drug↗
PubMed2003

A novel lipid hydroperoxide-derived cyclic covalent modification to histone H4.

Previous studies have established that 4-hydroxy-2-nonenal is a lipid hydroperoxide-derived aldehydic bifunctional electrophile that reacts with DNA and proteins. However, it has now been recognized that 4-oxo-2-nonenal is also a major product of lipid hydroperoxide decomposition. Furthermore, 4-oxo-2-nonenal is more reactive than 4-hydroxy-2-nonenal toward the DNA-bases 2'-deoxyguanosine, 2'-deoxyadenosine, and 2'-deoxycytidine and proteins. The formation of 4-oxo-2-nonenal can be induced through vitamin C-mediated or transition metal ion-mediated homolytic decomposition of polyunsaturated omega-3 lipid hydroperoxides such as 13(S)-hydroperoxyoctadecadienoic acid. We have discovered that synthetic 4-oxo-nonenal or 4-oxo-2-nonenal-generated from 13(S)-hydroperoxyoctadecadienoic acid recognizes the specific amino acid motifs of His75, Ala76, and Lys77 in bovine histone H4. Reaction of the histidine and lysine residues with 4-oxo-2-nonenal results in the formation of a novel cyclic structure within the protein. The cyclic structure incorporates the histidine imidazole ring and a newly formed pyrrole derived from the lysine. The cyclic imidazole-pyrrole derivative that is formed from the small Nalpha-acetyl-His-Ala-Lys peptide exists as a mixture of two atropisomers that inter-convert upon heating. Such lipid hydroperoxide-derived modifications could potentially modulate transcriptional activation in vivo. Furthermore, the ability to synthesize cyclic peptides using 4-oxo-2-nonenal will facilitate the preparation of novel structural analogs with potential biological activity.

Aldehydes↗
PubMed2000

Inhibitory effects of astragali radix, crude drug in Oriental medicines on lipid peroxidation and protein oxidative modification of mouse brain homogenate by copper.

Astragali Radix, the root of Astragalus membranaceus Bunge, is a crude drug used widely in Oriental medicines. It is a major component of Ougi-Keishi-gomotsu-to, a traditional herbal medicine, used for neurop patients with abnormal sensations and neuropathic pain of the legs. It was shown to have inhibitory effects on lipid peroxidation and protein oxidative modification by copper. The effects were similar to and stronger than those of mannitol and superoxide dismutase as free radical scavengers. These results demonstrated that Astragali Radix has inhibitory effects on oxidative stress induced by metal.

Animals↗
PubMed1989

Pyrene-labeled lipids: versatile probes of membrane dynamics in vitro and in living cells.

Pyrene-labeled analogs of fatty acids have been studied as probes of lipid metabolism in vitro and in cultured cells. Procedures for the synthesis of complex pyrenyl lipids and the analytical methods for their separation and quantification are described. Pyrenyl-lipids have been used to quantify the relationship between lipid structure and the rates of spontaneous lipid transfer. Modifications of these methods have also been used to monitor protein-mediated lipid transfer, lipolysis and lipid translocation across bilayer membranes. According to several criteria, pyrene dodecanoic acid has been identified as a good analog of some naturally occurring fatty acids. Digital imaging microscopy has been used to monitor the rate of accumulation of pyrenyl lipids in living cells.

Animals↗
PubMed2003

Withania somnifera (Ashwagandha) attenuates antioxidant defense in aged spinal cord and inhibits copper induced lipid peroxidation and protein oxidative modifications.

Withania somnifera is classified in Ayurveda, the ancient Indian system of medicine, as a rasayana, a group of plant-derived drugs which promote physical and mental health, augment resistance of the body against disease and diverse adverse environmental factors, revitalize the body in debilitated conditions and increase longevity. We investigated the effects of Withania somnifera on copper-induced lipid peroxidation and antioxidant enzymes in aging spinal cord of Wistar rats. The activity of glutathione peroxidase (GPx) decreased significantly in the spinal cord from adult to aged mice. Treatment with Withania somnifera successfully attenuated GPx activity and inhibited lipid peroxidation in a dose dependent manner. Withania somnifera inhibited both the lipid peroxidation and protein oxidative modification induced by copper. These effects were similar to those of superoxide dismutase and mannitol. The results indicate the therapeutic potential of Withania somnifera in aging and copper-induced pathophysiological conditions.

Aging↗
PubMed2003

Advanced glycation endproducts cause lipid peroxidation in the human neuronal cell line SH-SY5Y.

Advanced glycation endproducts (AGEs), sugar-derived protein modifications and lipid peroxidation products are prominent features of Alzheimer's disease. AGEs accumulate on beta-amyloid plaques during the course of the disease and can exert chronic oxidative stress via receptor-mediated mechanisms. Lipid peroxidation products such as hydroxynonenal, further markers of oxidative stress, are also increased in Alzheimer's diesease. In this study we present evidence for a direct biochemical link between AGEs and lipid peroxidation. Our results show that AGEs induce lipid peroxidation in a neuronal cell line in a dose-dependant manner, and that blocking the specific AGE-receptor RAGE, as well as using different antioxidants (alpha-lipoic acid, N-acetylcysteine, 17 beta-estradiol or aminoguanidine) can reduce the AGE-mediated formation of lipid peroxidation products. Thus, both RAGE antagonists and scavengers of oxygen free radicals could be useful in protecting brain tissue from lipid peroxidation and its pathophysilogical consequences that occur in Alzheimer's disease.

Acetylcysteine↗
PubMed1977

Modification of fatty acid composition of rat heart lipids by feeding cod liver oil.

Modification of the fatty acid composition of cardiac phospholipids and neutral lipids was studied in rats fed a diet containing 10% cod liver oil. The results reflect the dynamic state of esterified fatty acids in neutral lipids and phospholipids of heart muscle. In cardiac neutral lipids there was a moderate but significant increase in exogenous fatty acids, 20:1(n--9), 22:1(n--11), 20:5(n--3) and 22:6(n--3), in animals fed cod liver oil, and a relative decrease in endogenous fatty acids, 16:0, 18:2(n--6 and 20:4(n--6). Increased dietary availability of 22: 6(n--3) resulted in a major increase in the content of this fatty acid in phospholipids and replacement of 18:2(n--6) and 20:4(n--6). The 22:6(n--3) was able to replace one third of 18:2(n--6): further increase in 22: 6n--3) was accompanied by a decrease in 18:0. An inverse relationship between (n--6) and (n--3) polyene fatty acids in cardiac phospholipids suggests a replacement of (n--6) acids by (n--3) fatty acids.

Animals↗
PubMed2000

Issues in managing hyperlipidaemia.

BACKGROUND: The relationship of plasma cholesterol to human coronary artery disease was established with the Framingham study in 1960 and an elevated plasma cholesterol is now considered the major modifiable risk factor for developing coronary artery disease. Recent studies, including the Australian LIPID study, have changed what we consider to be acceptable cholesterol levels. OBJECTIVE: To discuss the role of serum cholesterol levels, dietary modification and lipid lowering drug treatments in overall cardiovascular risk management. DISCUSSION: The current challenges in lipid management are to find ways to increase adherence to medication and deciding how far cholesterol should be lowered. Treatment of a particular patient depends not just on their serum cholesterol but on their overall cardiovascular risk. Diet has cardioprotective effects separate from modification of serum cholesterol levels and this may be true of some lipid lowering treatments.

Coronary Disease↗
PubMed1990

[The effect of changes in the lipid composition of membranes on the functional activity of platelets].

The phospholipid and fatty acid composition as well as the effect of platelet lipid composition modifications on the functional parameters of platelets were studied in blood sera from healthy donors and from patients with ischemic heart disease (IHD). It was found that the content of cholesterol and phospholipid hydrolysis products in IHD patients was increased. Reconstitution of the lipid composition of donor platelets by lysophosphatidylcholines, phosphatidic acid, fatty acids and cholesterol led to the increase of the platelet functional activity. It is suggested that the increased adsorption of Ca2+ on platelet surface is due to alterations in the platelet lipid composition in IHD and after modifications.

Blood Platelets↗
PubMed1992

The role of lipid peroxidation and antioxidants in oxidative modification of LDL.

The purpose of this study is to provide a comprehensive survey on the compositional properties of LDL (e.g., lipid classes, fatty acids, antioxidants) relevant for its susceptibility to oxidation, on the mechanism and kinetics of LDL oxidation, and on the chemical and physico-chemical properties of LDL oxidized by exposure to copper ions. Studies on the occurrence of oxidized LDL in plasma, arteries, and plaques of humans and experimental animals are discussed with particular focus on the use of poly- and monoclonal antibodies for immunochemical demonstration of apolipoprotein B modifications characteristic for lipid peroxidation. Apart from uptake of oxidized LDL by macrophages, studies describing biological effects of heavily or minimally oxidized LDL are only briefly addressed, since several reviews dealing with this subject were recently published. This article is concluded with a section on the role of natural and synthetic antioxidants in protecting LDL against oxidation, as well as some previously unpublished material from our laboratories.

Animals↗
PubMed1987

Variations in lipoproteins during aminoglutethimide therapy.

Plasma lipids, apolipoproteins, and gamma-glutamyl-transpeptidase (GGT) were measured in 28 patients receiving aminoglutethimide (500 mg) and hydrocortisone (30 or 40 mg) for advanced breast cancer. A rise in cholesterol (CHOL), LDL-CHOL, apoprotein B, apoprotein CIII, and GGT was observed after 45 days. When the patients were divided in two groups according to lipid basal plasma levels, those with high CHOL and triglyceride did not experience any modification of lipid parameters (only GGT were elevated). Conversely normolipidaemic patients experienced an increase in CHOL, triglycerides, LDL-CHOL, apoproteins B and CIII, and GGT.

Aminoglutethimide↗
PubMed1995

Amiodarone induced lipidosis similar to Niemann-Pick C disease. Biochemical and morphological study.

Amiodarone is effective in the treatment of supraventricular and ventricular cardiac arrhythmia, however a high incidence of toxic side effects has been observed in various organs and tissues during chronic treatment. Ultrastructural observation of affected tissues reveals myelinoid inclusion bodies. The exact pathogenetic mechanism of these changes is still unknown. In this study we investigated the biochemical effects of this drug on lysosomal hydrolases and the alterations induced in subcellular organelles of fibroblasts cultured for 24 h with different concentrations of amiodarone in the medium. Of the enzyme activities assayed, we only observed a significant reduction in sphingomyelinase. Ultrastructural observation of fibroblasts showed swollen lysosomes and a few onionoid inclusion bodies at lower concentrations of the drug; at higher concentrations the lysosomal system was severely impaired. Cytochemical staining of unesterified cholesterol with filipin showed accumulation of cholesterol. We conclude that chronic amiodarone treatment in experimental conditions induces inhibition in sphingomyelinase activity through interaction with membrane lipids and modification of bilayer structure. Higher concentrations of the drug impair cholesterol transport and induce lipid accumulation. These results may be useful for understanding the pathogenesis of induced lipidosis in patients in chronic treatment with amiodarone.

Amiodarone↗