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PubMed2002

Modulation of endothelial permeability by 1-O-alkylglycerols.

Regulation of endothelial barrier function often occurs through signalling involving phospholipase C activation which produces diacylglycerol (DAG), a lipidic second messenger activator of protein kinase C (PKC). Therefore, modification of lipidic composition of endothelial cell membranes might modify DAG production and, as a result, alter regulation of endothelial permeability. We investigated the in vitro effects of natural 1-O-alkylglycerols on porcine aortic endothelial cell permeability to dye-labelled albumin. [3H]-1-O-alkylglycerols (10 microm) were substantially incorporated into phosphatidylcholine (6.6%) and phosphatidylethanolamine (4.4%). Stimulation of endothelial cell monolayer with phorbol-myristate-acetate or with the calcium ionophore A23187 resulted in a raise in permeability to albumin. Pre-treatment with 1-O-alkylglycerols (10 microm, 24 h) had no effect on basal albumin permeability but totally inhibited the effect of phorbol-myristate-acetate, and brought the permeability of A23187-stimulated endothelial cell monolayers below control. After incubation of cells with [3H]-1-O-alkylglycerols (10 microm, 24 h), we detected the production of the analogue of DAG, and PKC inhibitor, [3H]-1-O-alkyl-2-acyl-glycerol, in resting cells. This production was increased by 58% under A23187 stimulation while phorbol-myristate-acetate had no effect. Our data demonstrate that natural 1-O-alkylglycerols modify endothelial permeability, and suggest that this effect could be mediated through alteration of lipidic signalling.

Albumins↗

PubMed2003

[LDL-receptors expression on peripheral blood monocytes in various clinical types of atherosclerosis, depending on LDL concentration in serum].

In our studies an attempt was undertaken to establish whether there is a relationship between total cholesterol and LDL fraction concentrations and LDL receptors expression on monocytes in various clinical types of atherosclerosis and in subjects without clinical manifestations of this disease before and after 40 years of age. The study included 77 subjects divided into 4 groups: I--after myocardial infarction, II--after cerebral ischaemic stroke, III--with obliterative atheromatosis of the lower limbs, and control group IV without clinical symptoms of atheromatosis: a) subjects below 40 years of age b) over 40 years of age. Receptor expression on monocytes was tested with LDL Receptor Test (Orpegen Pharma, Heidelberg, Germany) using flow fluorometry method (FAC Scan, Backton Dickinson, San Jose, USA). The value of LDL receptors expression was calculated based on the difference of mean fluorescence intensity of monocytes incubated in low-lipid (LPDS) and autologous sera. It has been demonstrated that particular types of atheromatosis vary in the value of total cholesterol and LDL fraction concentrations. The highest concentrations of these lipid fractions were observes in ischaemic heart disease and only in this group they correlated with the value of LDL receptors expression on monocytes. This observation suggests that various clinical types of atheromathosis may differ pathogenically and lesions in the vessels may be the consequence of cholesterol transport defect or of lipid molecule modification; they not necessarily depend on the value of absolute lipid concentration in blood.

Adult↗

PubMed2005

Increased plasma malondialdehyde and protein carbonyl levels and lymphocyte DNA damage in patients with angiographically defined coronary artery disease.

We investigated the oxidative modifications of lipids, proteins and DNA, three potential molecular targets of oxidative stress, in 30 patients with angiographically defined coronary artery disease (CAD) and 30 healthy control subjects. In addition, we examined relationships between these oxidative modifications and the severity of vascular lesions in patients with CAD. Malondialdehyde (MDA) and protein carbonyl (PC) levels, as well as ferric reducing antioxidant power (FRAP), were measured in the plasma. DNA damage was evaluated as single strand breaks (SSBs), formamidopyrimidine glycosylase (Fpg) and endonuclease III (E-III)-sensitive sites by the comet assay in DNA isolated from lymphocytes. MDA and PC levels increased, but FRAP values decreased, in patients as compared to controls. However, these values did not vary with the number of affected coronary vessels and were not correlated with Duke score, a parameter of the severity of vascular lesions in patients with CAD. We also found that lymphocyte DNA damage (SSBs, Fpg and E-III sites) were increased in patients. Although there were no significant differences in SSBs values in patients grouped according to affected vessel number, Fpg and E-III sites increased. We also detected significant correlations between Duke scores and SSBs and Fpg sites. Serum cholesterol, triglyceride and LDL-cholesterol levels were found to increase, but HDL-cholesterol levels decreased in CAD patients, but these lipids were not correlated with Duke scores. The results of this study reinforce the presence of increased combined oxidative modifications in lipid, protein and DNA in patients with CAD. However, lymphocyte DNA damage seems to be a more reliable assay than MDA and PC determinations to detect the severity of vascular lesions in patients.

Adult↗

PubMed1984

Elasticity, strength and stability of bilayer lipid membranes and their changes due to phospholipid modification.

Elasticity measurements of bilayer lipid membranes (BLM) based on registration of the third harmonic of the membrane current during the application of a periodic tension to the membrane was used to study the effects of lipid peroxidation (LPO) and phospholipase A on BLM. LPO resulted in decreased values of the Young modulus for BLM, while some products of LPO and phospholipid hydrolysis (linolenic acid) were able to increase drastically the modulus. The presence of individual products of LPO and phospholipid hydrolysis in BLM produced non-additive effects on the elasticity, strength and stability of BLM. Lysolecithine strongly affected both the strength and stability of BLM. without changing its elasticity modulus. It was found that the lower the rate of structural changes in lecithine BLM, the longer its lifetime. Membranes having a heterogeneous polar composition form more stable BLM as compared to chemically homogeneous membranes.

Animals↗

PubMed1987

Action of iturin A, an antifungal antibiotic from Bacillus subtilis, on the yeast Saccharomyces cerevisiae: modifications of membrane permeability and lipid composition.

The action of iturin A on non-growing cells of Saccharomyces cerevisiae was tested. This antibiotic gave important modifications in the membrane permeability which permitted nucleotides, proteins, polysaccharides and lipids to escape from cells. The lipid content of cells was strongly disturbed; the level of phospholipids, essentially phosphatidylcholine, decreased while the level of fatty acids increased. A part of these fatty acids were extruded from yeast cells. The role of iturin A in these modifications was discussed.

Anti-Bacterial Agents↗

PubMed2006

Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis -induced inflammation and virulence.

Recent studies have shown that fine structural modifications of Mycobacterium tuberculosis cell envelope lipids mediate host cell immune activation during infection. One such alteration in lipid structure is cis-cyclopropane modification of the mycolic acids on trehalose dimycolate (TDM) mediated by proximal cyclopropane synthase of alpha mycolates (pcaA), a proinflammatory lipid modification during early infection. Here we examine the pathogenetic role and immunomodulatory function of mycolic acid cyclopropane stereochemistry by characterizing an M. tuberculosis cyclopropane-mycolic acid synthase 2 (cmaA2) null mutant (Delta cmaA2) that lacks trans-cyclopropanation of mycolic acids. Although titers of WT and Delta cmaA2 organisms were identical during mouse infection, Delta cmaA2 bacteria were hypervirulent while inducing larger granulomas than WT M. tuberculosis. The hypervirulence of the Delta cmaA2 strain depended on host TNF-alpha and IFN-gamma. Loss of trans-cyclopropanation enhanced M. tuberculosis-induced macrophage inflammatory responses, a phenotype that was transferable with petroleum ether extractable lipids. Finally, purified TDM lacking trans-cyclopropane rings was 5-fold more potent in stimulating macrophages. These results establish cmaA2-dependent trans-cyclopropanation of TDM as a suppressor of M. tuberculosis-induced inflammation and virulence. In addition, cyclopropane stereochemistries on mycolic acids interact directly with host cells to both positively and negatively influence host innate immune activation.

Animals↗

PubMedDate not supplied

[Study of P-glycoprotein effect on the lipid monolayer properties by the Langmuir-Blodgett technique].

Expression of the P-glycoprotein (Pgp) is proved to be one of the main reasons for the development of the multidrug resistance (MDR) phenotype by cancer cells. The effect of Pgp on the properties of lipid monolayers was studied using membrane fractions of sensitive and Pgp over-expressing multidrug resistance cancer cells containing 11, 24 or 32% of Pgp relative to the total content of membrane proteins. The effect of the Pgp membrane concentration on the properties of monolayers prepared from the membrane fractions was analyzed by the Langmuir-Blodgett method. The subphase composition was found to play a critical role in the stability of monolayers at any Pgp concentration. The optimal subphase comprised 10 mM tris-HCl buffer, pH 6.5, which made it possible to create very stable monolayer films with the pressure of collapse of about 30-40 mN/m. Monolayers prepared from membrane fractions of sensitive cells and cells containing the maximum (32%) amount of Pgp were found to be much more stable compared with fractions comprising 11 or 24% of Pgp. The analysis of monolayer compression dynamics revealed three distinct stages: (1) the self-organization of lipid molecules, which is characterized by an abrupt change of surface potential; (2) the compression of Pgp molecules at the constant potential of monolayers; and (3) the compression of lipid molecules, which is characterized by a quasilinear increase of both pressure and surface potential. It was shown that the specific surface areas of monolayers formed from sensitive and Pgp-enriched membranes containing 11 or 24% of Pgp are very similar, whereas the surface area of the monolayer formed from membranes containing 32% of Pgp is nearly 1.5-fold greater. This fact may reflect the effect of the threshold rearrangement of the structure of lipid molecules or cooperative modifications of lipid-Pgp interactions induced by the increase in the Pgp content from 24 to 32%. The effect of verapamil, a well-known Pgp modulator, on the properties of monolayers was studied. It was show that verapamil is able to induce changes of the surface of Pgp-containing monolayers, and these modifications are maximal at the Pgp:verapamil 1:1 molar ratio. The data present the first experimental evidence for the possible intervention of Pgp modulator into the processes of lipid-lipid or lipid-Pgp cooperative interactions within Pgp-enriched membranes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Incorporation of exogenous lipids modulates insulin signaling in the hepatoma cell line, HepG2.

The lipid content of cultured cells can be experimentally modified by supplementing the culture medium with specific lipids or by the use of phospholipases. In the case of the insulin receptor, these methods have contributed to a better understanding of lipid disorder-related diseases. Previously, our laboratory demonstrated that experimental modification of the cellular lipid composition of an insulin-sensitive rat hepatoma cell line (ZHC) resulted in an alteration in insulin receptor binding and biological action (Bruneau et al., Biochim. Biophys. Acta 928 (1987) 287-296/297-304). In this paper, we have examined the effects of lipid modification in another hepatoma cell line, HepG2. Exogenous linoleic acid (LA, n-6), eicosapentaenoic acid (EPA, n-3) or hemisuccinate of cholesterol (CHS) was added to HepG2 cells, to create a cellular model in which membrane composition was modified. In this model, we have shown that: (1) lipids were incorporated in treated HepG2 cells, but redistributed differently when compared to treated ZHC cells; (2) that insulin signaling events, such as insulin receptor autophosphorylation and the phosphorylation of the major insulin receptor substrate (IRS-1) were altered in response to the addition of membrane lipids or cholesterol derived components; and (3) different lipids affected insulin receptor signaling differently. We have also shown that the loss of insulin receptor autophosphorylation in CHS-treated cells can be correlated with a decreased sensitivity to insulin. Overall, the results suggest that the lipid environment of the insulin receptor may play an important role in insulin signal transduction.

Animals↗

PubMed1993

Histological findings and evidence of lipid conjugated dienes and malonyldialdehyde in human fetal aortas.

Recent evidence strongly suggests that peroxidative modification of lipids may play a significant role in atherogenesis. In our present research, we investigated if the oxidative stress mediated by oxygen free radicals was a pathophysiologic condition that occurred in the early stages of human development. Thus the aim of this research was to examine lipid peroxidation in human fetal aortas. Human fetal aortas and proximal iliac arteries (n = 8) were obtained from fetuses aged 7 +/- 2 months, immediately after autopsy. Lipids from the initial fatty streak lesions (LFS) and the vessels uninvolved (LUV) were extracted by the chloroform/methanol method. Lipid peroxidation levels were measured by two different methods: determination of lipid conjugate dienes (the spectrum trend was recorded from 320 to 200 nm with a spectrophotometer) and malonyldialdehyde (MDA) content (TBA method). We observed that lipid conjugated dienes were present in LFS, but not in LUV, with a characteristic absorption peak at 233 nm. In addition, MDA levels were significantly higher when the LFS = 3.85 +/- 0.91 nmol than when the LUV = 0.41 +/- 0.12 nmol (p < 0.001 versus LUV). The presence of lipid peroxidation in our samples could be mediated by free radical production in the first stages of human development. Thus these data suggest that LFS peroxidation mediated by free radicals occurs in the vascular circulation in the early stages of human development. This could influence the progression of vascular damage and atherosclerotic disease.

Aorta↗

PubMed1986

Role of risk factor management in progression and regression of coronary and femoral artery atherosclerosis.

The results of 3 recently completed studies usher in a new era in the treatment of coronary atherosclerosis and its sequelae. In aggregate, these results show that reductions in low density lipoprotein (LDL) cholesterol or reductions in the ratio of total to high density lipoprotein (HDL) cholesterol by either diet or drugs or both are effective in primary and secondary prevention of coronary artery disease (CAD). In the Lipid Research Clinics' Coronary Primary Prevention Trial, reducing levels of LDL cholesterol, regardless of whether the primary intervention was diet or drug, correlated with a reduction in CAD events. In the National Heart, Lung, and Blood Institute's Type II Coronary Intervention Study, CAD progression at 5 years was inversely related to a change in the ratio of HDL cholesterol to total cholesterol. In the Leiden Intervention Trial, cessation of coronary artery atherosclerotic lesion growth correlated with the ratio of total cholesterol to HDL cholesterol. Several trials now under way will test the effects of much more substantial reductions of LDL cholesterol (up to 50%) and increments in HDL cholesterol (up to 25%) on interrupting the progression or inducing the regression of coronary artery atherosclerosis. Even small reductions in the progression of coronary artery lesions or induction of their regression should produce major reductions in morbidity and mortality from CAD. The importance of secondary prevention also extends to patients after coronary artery bypass surgery, because the likelihood of graft occlusion is likewise related to the patient's lipid profile. Further, the importance of primary prevention of atherosclerosis through modification of lipids and lipoprotein cholesterol in the first-degree relatives of young victims of atherosclerosis cannot be overemphasized.

Arteriosclerosis↗

PubMed2026

Comparative analysis of lipopolysaccharide lipid A structure and its biosynthetic genes in the plant-associated bacteria Brucella cytisi and Brucella lupini.

The genus Brucella comprises important human and animal pathogens, as well as numerous environmental and symbiotic species. Lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, plays a crucial role in bacterial physiology and host interactions. In this study, the structures of lipid A, the hydrophobic anchor of lipopolysaccharide, isolated from two plant-associated strains, Brucella cytisi ESC1ᵀ and Brucella lupini LUP21ᵀ, were presented. Lipid A preparations were structurally characterized using chemical methods, MALDI-TOF mass spectrometry, and nuclear magnetic resonance spectroscopy. The obtained results indicated that both lipid A molecules have almost identical structures. Their sugar backbones consist exclusively of 2,3-diamino-2,3-dideoxy-d-glucose (d-GlcpN3N). Phosphate residues were connected to distal and proximal GlcpN3N in approximately half of the lipid A molecules. Fatty acid analysis revealed the presence of C14:0 (3-OH), C16:0 (3-OH), and traces of C18:0 (3-OH). All of these were primary fatty substituents of the sugar backbone and were amide-linked residues. Lactobacillic acid C19:0cyc and 27-hydroxyoctacosanoic acid (C28:0 (27-OH)) were found as ester-linked secondary acyl residues. In turn, C28:0 (27-OH) was partly esterified by a 3-hydroxybutyroyl residue. Two unsubstituted 3-hydroxyfatty acids were linked exclusively to the proximal d-GlcpN3N residue. It was pointed out that sequences of putative genes encoding enzymes required for lipid A biosynthesis and genes encoding specific enzymes involved in structural modifications of lipid A occurring in the genomes of both bacterial species are almost identical. The high sequence similarity of these proteins reflects the observed similarities in the lipid A structures in both investigated Brucella species.

Brucella↗

PubMed1989

Prevention of platelet aggregation by dietary polyunsaturated fatty acids in the biodegradable polyurethane vascular prosthesis: an experimental model in pigs.

A 6-7 cm long degradable polyurethane vascular prosthesis was implanted in the infrarenal aorta of 25 young growing pigs, sacrificed from day 30 to 365 to study the processes of degradation and tissue growth, the characteristics of prosthetic substitutes and the incidence of thrombosis. Ten animals were used as controls and 15 were fed with cod liver oil (25 ml twice daily). Aortography performed at day 30, 60 and 90 showed 100% thrombosed implants in the controls, while in the lipid diet fed animals there was 100% patency. At graft retrieval, there were 7 patent grafts out of 9 in the cod liver oil fed animals. Laboratory tests indicated that the lipid diet rich in n-3 polyunsaturated fatty acids induces significant modifications of lipid metabolism preventing platelet aggregation. These data correlate well with findings of the morphological studies showing that all patent prostheses are lined with tissues similar to the endothelium of the native aorta with a mid layer made of circular and longitudinal smooth muscle cells well differentiated at day 180. These data show that the essential polyunsaturated fatty acid rich diet is able to prevent thrombosis of the biodegradable polyurethane vascular prosthesis. The combination of a synthetic material and the lipid diet experimental model, makes it possible to assess the long-term tissue-synthetic material interaction and the process of tissue growth.

Animals↗

PubMed1999

Inhibitory effects of Ougi-keishi-gomotsu-to, a traditional herbal medicine, on lipid peroxidation and protein oxidative modification of mouse brain homogenate induced by copper.

Ougi-Keishi-gomotsu-to a traditional herbal medicine, is used clinically for patients with abnormal sensations and pain in the legs in neuropathy. It was shown to have inhibitory effects on lipid peroxidation and protein oxidative modification of brain homogenate induced by copper. Its effect was stronger than those of mannitol and alpha-tocopherol as free radical scavenger and antioxidant. These results demonstrated that Ougi-kelshi-gomotsu-to has antioxidative effects on neuron injury derived from oxidative stress induced by metal.

Animals↗

PubMed2006

Synthesis and evaluation of acyl protein thioesterase 1 (APT1) inhibitors.

Lipid-modified proteins play decisive roles in important biological processes such as signal transduction, organisation of the cytoskeleton and vesicular transport. Lipidation of these proteins is essential for correct biological function. Among the modifications with lipids, prenylation and myristoylation are well understood. However, the machinery of palmitoylation is still under investigation. Recently, an enzyme, acyl protein thioesterase 1 (APT1), that may play a regulatory role in the palmitoylation cycle of H-Ras and G-protein alpha subunits, was purified. Motivated by this work, several inhibitors of APT1 were designed, synthesized and biologically evaluated leading to highly active compounds.

Drug Design↗

PubMed2002

Ultrasound extraction and thin layer chromatography-flame ionization detection analysis of the lipid fraction in marine mucilage samples.

This paper reports an analytical procedure based on ultrasound to extract lipids in marine mucilage samples. The experimental conditions of the ultrasound procedure (solvent and time) were identified by a FT-IR study performed on different standard samples of lipids and of a standard humic sample, before and after the sonication treatment. This study showed that diethyl ether was a more suitable solvent than methanol for the ultrasonic extraction of lipids from environmental samples because it allowed to minimize the possible oxidative modifications of lipids due to the acoustic cavitation phenomena. The optimized conditions were applied to the extraction of total lipid amount in marine mucilage samples and TLC-flame ionization detection analysis was used to identify the relevant lipid sub-fractions present in samples.

Chromatography, Thin Layer↗

PubMed1979

Lipid composition of Staphylococcus aureus and its derived L-forms.

Two strains of Staphylococcus aureus (Newman and Tazaki) and their derived L-forms were cultured in serum-containing broth and the differences in their lipid compositions were analyzed. Cardiolipin accounted for more than 50% of the total phospholipid phosphorus in L-forms, but for less than 25% in parent bacteria. The cardiolipin content of L-forms was very high through all growth phases, although it increased gradually as growth proceeded. Significant amounts of cholesterol and its esters were present in parent strains and L-forms, all of which incorporated serum cholesterol into the cell membrane. On the other hand, they could be detected in the L-forms but not in the parent strains when they were cultured in serum-free broth. To examine the ability of L-forms to synthesize cholesterol, the cholesterol content of L-forms cultured in serum-free broth was compared with that of the medium. The results indicated that staphylococcal L-forms could synthesize cholesterol and its esters. These differences in lipid composition suggested that modification of membrane lipids may occur as an adaptational change in response to the disappearance of the cell wall.

Cardiolipins↗

PubMed2003

Effect of steroids on intestinal lipid uptake in rats is enhanced by a saturated fatty acid diet. Cell and molecular biology collaborative network in gastrointestinal physiology.

Glucocorticosteroids enhance sugar digestive and absorptive functions of the intestine, but their effect on lipid uptake is unknown. Modifications in dietary lipids alter the nutrient transport properties of the intestine. The influence of 4 weeks' treatment with budesonide (BUD), prednisone (PRED), or control vehicle in weanling rats fed either an isocaloric semisynthetic saturated fatty acid diet (SFA) or a polyunsaturated fatty acid diet (PUFA), on the uptake of lipids was assessed using everted gut rings. PRED and BUD increased the uptake of several fatty acids, and this was higher when the animals were fed SFA rather than PUFA. Changes in expression of the mRNAs for L-FABP (liver fatty acid binding protein) and ILBP (ileal lipid binding protein) did not explain these alterations in lipid uptake. Dietary lipid signalling of this adaptive response may involve proglucagon, c-jun, TNF-alpha and IL-10, whereas steroid signalling may involve proglucagon. In summary, steroids increase the absorption of lipids by a process which can be enhanced by the substitution of saturated for polyunsaturated lipids in the diet, and which is not explained by alterations in the expression of the mRNAs of L-FABP or ILBP.

Adaptation, Biological↗

PubMed2004

Increased susceptibility to plasma lipid peroxidation in Alzheimer disease patients.

Oxidative stress, linked to Abeta-lipid interactions, plays a pathogenetic role in Alzheimer's disease. We investigated modifications of lipid peroxidation products in plasma of 52 AD patients, 42 healthy controls and 16 patients with amyotrophic lateral sclerosis, a neurodegenerative disease where oxidative stress also plays a pathogenetic role. Final lipid peroxidation products were measured in plasma by thiobarbituric acid reactive substances (TBARS) assay before and after ex vivo oxidative stress catalysed by copper. There were no significant changes at basal conditions, but after copper-induced oxidation TBARS levels were higher in AD patients (19.0 microM +/- 2.2) versus both controls (5.2 microM +/- 0.8, p<0.001) and ALS patients (7.6 microM +/- 2.1, p<0.01). Stimulated TBARS levels were significantly higher in mild and moderate AD (p<0.0001) with respect to controls, but not in severe AD patients, with a significant inverse correlation between disease severity and lipid peroxidation (p<0.005, r2=0.21). Treatment of a subgroup (13) of mild and moderate AD patients with vitamin C and E for three months decreased plasma lipoperoxidation susceptibility by 60%. Thus, oxidative stress, expressed as ex vivo susceptibility to lipid peroxidation, appears to be an early phenomenon, probably related to AD pathogenetic mechanisms.

Aged↗