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PubMed2006

Interactions between flavonoids and hemoglobin in lecithin liposomes.

In this paper, the binding of flavonoids (quercetin and rutin) to hemoglobin (Hb) have been investigated by fluorescence, absorption spectroscopy and circular dichroism (CD) spectroscopy. The binding parameters and binding mode between flavonoids and Hb are determined and the results of CD and synchronous fluorescence spectra indicate a conformational change of Hb with addition of flavonoids. The effects of lecithin liposomes on the binding parameter of quercetin and rutin to Hb are also studied. When incorporated into liposome, flavonoids can reduce the fluorescence of tryptophanyl residues of Hb to a lesser extent. The difference of the structure characteristics between quercetin and rutin has a significant effect on their binding affinity for Hb.

Circular Dichroism↗

PubMed2005

QSPR modeling of pseudoternary microemulsions formulated employing lecithin surfactants: application of data mining, molecular and statistical modeling.

Data mining, computer aided molecular modeling, descriptor calculation, genetic algorithm and multiple linear regression analysis techniques were combined together to generate predictive quantitative structure property relationship (QSPR) models explaining the formation of lecithin-based W/O microemulsions. Ninety-four microemulsion phase diagrams were collected from five different references published over the past few years. Computer-based molecular modeling techniques were then applied on the components of the collected microemulsion systems to generate corresponding plausible three-dimensional (3D) structures. The resulting 3D models were utilized to calculate a group of molecular physicochemical descriptors. Thereafter, genetic algorithm and backward stepwise regression analysis were separately assessed as means for selecting optimal descriptor sets for statistical modeling. The selected descriptors were correlated with microemulsion existence areas employing multiple linear regression analysis. The resulting W/O models were statistically validated and found to be of significant predictive power. The models allowed better understanding of the process of microemulsion formation. Unfortunately, all QSPR modeling efforts directed towards O/W microemulsions failed completely.

Emulsions↗

PubMed2005

A lecithin-based microemulsion of rh-insulin with aprotinin for oral administration: Investigation of hypoglycemic effects in non-diabetic and STZ-induced diabetic rats.

The aim of this study was to develop a microemulsion formulation providing an improved efficacy of orally administered insulin. The microemulsions were prepared using Labrafil M 1944 CS, Phospholipon 90 G (lecithin), absolute alcohol and bi-distilled water. The microemulsions of recombinant human (rh)-insulin and aqueous solution (200 IU/kg) were administered intragastrically by a canulla to diabetic and non-diabetic rats. Aprotinin (2500 KIU/g) was added as the enzyme inhibitor to the formulation. Upon the administration of intragastric rh-insulin solution (IS) to non-diabetic rats, the plasma glucose and insulin levels were not changed significantly. Therefore, the hypoglycemic effect caused by subcutaneous rh-insulin solution (SC), microemulsion containing rh-insulin (IME) and microemulsion containing rh-insulin and aprotinin (IMEA) were analyzed in diabetic rats. The area above the plasma glucose levels time curves (AAC), minimum glucose concentration (Cmin) and time to Cmin (tmin) were derived from the plasma glucose profiles. IME and IMEA caused approximately 30% decrease in plasma glucose levels. The decrease in the plasma glucose levels continued after the 90th min. The highest AAC value was obtained when IMEA was administered to rats. The maximum plasma insulin concentration (Cmax), time to reach Cmax (tmax), terminal half-life (t(1/2)), area under the plasma concentration-time curve (AUC), mean residence time (MRT) and elimination rate constant (k(el)) values were also calculated. It was observed that t(1/2) values varied between 0.53 and 1.31h. No significant difference could be found between the pharmacokinetic parameters of the IME and IMEA administered groups. Addition of aprotinin to the microemulsion containing rh-insulin increased bioavailability when compared to those not containing it, although the difference is not significant.

Administration, Oral↗

PubMed2006

Partitioning of parabens between phases of submicron emulsions stabilized with egg lecithin.

Partitioning of methyl and propyl parabens (methyl and propyl hydroxybenzoate, paraben M and P) between the major phases in the parenteral submicron emulsions was studied. The investigated emulsions contained 10% or 20% soya-bean oil, 1.2% or 2.4% egg lecithin, 0.18% or 0.36% paraben M and 0.02% or 0.04% paraben P. The aqueous phase was obtained by ultracentrifugation, and subsequently, it was subjected to ultrafiltration, which procedure allowed to distinguish between the fractions of free preservatives (Fw) and incorporated in the liposomal or micellar region (Flm). The fractions present in the oily phase and in the interface were calculated. Depending on the formulation, Fw was 17-31% and 2.3-6.0% for paraben M and P, respectively. The Flm values were in a very narrow range, i.e. 3.0-6.0% for both preservatives. Substantial accumulation, i.e. 38-58% was found in the interface and the partitioning into this region was related to the oil/lecithin ratio rather than to lipophilicity of the preservative.

Chemistry, Pharmaceutical↗

PubMed2006

Interactions of alpha-tocopherol with biomembrane models: binding to dry lecithin reversed micelles.

The state of alpha-tocopherol (Vitamin E) in solutions of dry lecithin reversed micelles dispersed in an apolar medium has been investigated as a function of the Vitamin E to surfactant molar ratio (RVE) at fixed surfactant concentration by FT-IR, 1H NMR and SAXS with the aim to emphasize the role played by anisotropic intermolecular interactions and confinement effects as driving forces of its partitioning between apolar bulk solvent and polar nanodomains and of mutual Vitamin E/reversed micelle effects. It has been found that its binding strength to reversed micelles, triggered by steric and orientational constrains, is mainly regulated by specific interactions between the hydrophilic groups both of Vitamin E and surfactant. Moreover, the RVE dependence of the Vitamin E distribution constant and of the micellar size suggest that the inclusion of increasing amounts of Vitamin E in reversed micelles involves substantial changes in the structural and dynamical properties of the micellar aggregates. The occurrence of mutual effects and the partitioning of Vitamin E between hydrophilic/hydrophobic interfaces and apolar domains allow to infer some important biological implications concerning the capacity of Vitamin E to scavenge free radicals arising from hydrophilic and/or hydrophobic domains, possible variations of its local reactivity respect to that observed in bulk as well as its significant influence on the stability of biomembranes.

Carbon Tetrachloride↗

PubMed2005

Effect of lecithin-bound iodine on the patients with bronchial asthma.

Lecithin-bound iodine (LBI), which has been reported to be a potential candidate for one of the therapeutic modalities for children with bronchial asthma based on the in-vitro study, was also found to be effective in relieving the symptoms of patients with childhood asthma. In addition to the in-vitro effect of downregulation and upregulation of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), respectively, the clinical effect of LBI was highlighted through the concomitant upregulation of IFN-gamma production by the patients' lymphocytes, which were treated with LBI for 8 weeks. Therefore, LBI may reduce the signs of bronchial asthma by upregulating the synthesis of IFN-gamma that is a representative Th1 cytokine.

Asthma↗

PubMed2006

Response surface methodology for the evaluation of glucose-6-phosphate dehydrogenase enrichment process by soybean lecithin reversed micelles.

Glucose-6-phosphate dehydrogenase (G6PD) present in Saccahromyces cerevisiae is an enzyme of the pentose pathway. An effective enrichment of this intracellular enzyme can be achieved with the reversed micellar methodology. In this work, this methodology was employed with soybean lecithin, a biocompatible surfactant. A factorial design was used to evaluate the influence of pH (A) and extraction runs (B) on the G6PD purification factor. After statistical analysis and process optimization, a mathematical model representing G6PD enrichment was obtained: Y=4.89-0.83A+0.092B+0.27AB-1.37B2 with an enzyme purification factor of about 5.2.

Algorithms↗

PubMed2004

Characterization of lecithin:cholesterol acyltransferase expressed in a human lung cell line.

Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme for the transfer of mammalian cholesterol from peripheral tissues to the liver. In patients deficient in LCAT, serum cholesterol levels rise and can lead to corneal opacity, proteinuria, anemia, and kidney failure. As early as 1968, relatively low volume transfusion of normal plasma was shown to temporarily correct the abnormal lipoprotein profiles in LCAT-deficient patients. However, despite the cloning, study, and extensive expression of LCAT in mammalian cell lines, there is still no viable, clinical therapy for LCAT deficiency. The current study was initiated to provide a source of recombinant human LCAT for enzyme replacement therapy. Accordingly, human LCAT has been cloned and expressed for the first time in a human cell line. The recombinant LCAT secreted by these cells was purified by phenyl-Sepharose chromatography, analyzed to determine the nature of its glycosylation, and tested for its enzymatic properties. The activity and basic kinetic parameters for the enzyme were determined using both a fluorescent water-soluble substrate and a macromolecular (proteoliposome) substrate. The enzymatic properties and the carbohydrate components of the recombinant LCAT were all sufficiently similar to those of the circulating human plasma enzyme, suggesting that this source of LCAT may be appropriate for use in some form of enzyme replacement therapy.

Anemia↗

PubMed2004

Lecithinized copper,zinc-superoxide dismutase as a protector against doxorubicin-induced cardiotoxicity in mice.

Production of superoxide radicals from doxorubicin is widely accepted to be the cause of the cardiotoxicity induced by this antitumor agent. Pretreatment with superoxide dismutase could improve the therapeutic application. Aim of the present study was to determine whether lecithinized superoxide dismutase (PC-SOD) can serve as a cardioprotective drug during doxorubicin treatment. The protective potential of PC-SOD on doxorubicin-induced cardiotoxicity was investigated in BALB/c mice. The possible influence of PC-SOD on the antitumor activity of doxorubicin was investigated in vitro as well as in vivo. Mice were treated intravenously with doxorubicin (4 mg x kg(-1)) or doxorubicin and PC-SOD (5000, 20000 or 80000 U x kg(-1)) weekly x 6 and appropriate controls were included. Cardiotoxicity was monitored for 8 weeks by ECG measurement. The influence of PC-SOD on the antitumor activity of doxorubicin was evaluated in three human malignant cell lines. Nude mice bearing OVCAR-3 human ovarian cancer xenografts were treated intravenously with doxorubicin (8 mg x kg(-1)) alone or preceded by PC-SOD 20000 or 80000 U x kg(-1) weekly x 2 and appropriate controls were included. PC-SOD prevented doxorubicin-induced cardiotoxicity already at 5000 U x kg(-1) whereas 20000 and 80000 U x kg(-1) were equally protective. No toxicity was observed in mice treated with PC-SOD. PC-SOD did not interfere with the antiproliferative effects of doxorubicin in vitro. In vivo, PC-SOD had no negative effect on the inhibition of xenograft growth induced by doxorubicin. It can be concluded that PC-SOD protects the heart, but not the tumor against doxorubicin. These data suggest that PC-SOD may be a suitable cardioprotector during doxorubicin treatment.

Animals↗

PubMed2003

Lecithin-bound superoxide dismutase in the treatment of noninfectious corneal ulcers.

PURPOSE: To evaluate the effects of a lipophilic analog of superoxide dismutase in the treatment of persistent epithelial defects of the cornea. DESIGN: Interventional case series. METHODS: Nineteen eyes of 19 patients with noninfectious corneal ulcers were enrolled. Patient profiles consisted of seven cases with Mooren-type peripheral ulcers, three cases with chemical or thermal burns, two cases with vernal keratoconjunctivitis, four cases with cicatricial keratoconjunctivitis, and three cases with sterile ulcers after corneal surgery. Patients consisted of 11 men and 8 women, with a mean age of 51.5 +/- 17.9 years (range, 14-77). Only patients who did not respond to conventional therapy were recruited for the study. Lecithinated superoxide dismutase was applied for 2 weeks, and sketches and/or fluorescein slit micrographs were recorded before and at the end of the study. The main outcome measure was decrease in ulcer size. RESULTS: As a group, the average ulcer size relative to the entire cornea decreased from 18.2 +/- 15.1% to 10.0 +/- 15.0% after 2 weeks (P <.05). A dramatic effect (>90% decrease in ulcer size) was observed in eight cases (100% in six cases), whereas no apparent change was found (<30% decrease in ulcer size) in five cases. The presence of polymorphonucleocytes within the ulcerated tissue was confirmed by brush cytology. CONCLUSION: Lecinthinated superoxide dismutase was effective in decreasing persistent epithelial defect size in a subset of patients with sterile corneal ulcers refractive to conventional therapy. A large-scale clinical investigation is merited.

Adolescent↗

PubMed1997

Analysis of human lecithin-cholesterol acyltransferase activity by carboxyl-terminal truncation.

Lecithin-cholesterol acyltransferase (LCAT) is a key enzyme in reverse cholesterol transport and catalyzes the esterification of cholesterol in human plasma. Human LCAT is a glycosylated protein, containing 416 amino acids and a proline-rich region at the C-terminus. To address the function of the C-terminal region of LCAT as well as that of the proline-rich region, we constructed and expressed LCAT mutants with C-terminal truncations at different positions. The expression of wild-type LCAT in COS-1 cells resulted in an enzymatically active protein that was secreted by the cells. The mutants lacking the proline-rich region at the C-terminus were expressed and secreted at levels comparable to those of wild-type (approximately 50% of wild-type concentrations in cell media). The proline-deletion mutants were similar to wild-type LCAT in terms of phospholipase or transferase activities with various interfacial substrates, including reconstituted HDL, proteoliposomes, LDL, and micelles of platelet activating factor. Thus, the binding of LCAT to the diverse interfaces is not affected by the removal of its C-terminal region. Also, the activation by apolipoproteins and access of water-insoluble substrates to the active site are not significantly affected by the deletion of the proline-rich region. However, deletions of the proline-rich region, including the five amino acids nearest to the C-terminus, resulted in approximately an 8-fold increase in the specific activity of LCAT towards the water-soluble substrate, p-nitrophenylbutyrate. This suggests that the C-terminal proline-rich region may interfere with the access of this water-soluble substrate to the active site of LCAT, and may form part of a protective covering of the active site of LCAT while in solution. Further deletions at the C-terminus, beyond the proline-rich region, impaired the secretion of the enzyme, implying that this region may play a critical role in either the secretion or folding of LCAT in COS-1 cells.

Amino Acid Sequence↗

PubMed1997

Cloning and in vitro expression of rat lecithin:cholesterol acyltransferase.

Rat lecithin:cholesterol acyltransferase (LCAT) cDNA was obtained by reverse transcriptase/polymerase chain reaction amplification of rat liver total RNA. A consensus sequence was derived from four independent clones from two strains of rats. In vitro expression of rat LCAT cDNA in COS cells resulted in secreted enzyme protein with the same fatty acyl specificity for phospholipase A2 activity and cholesterol esterification as rat plasma LCAT, but different from that of recombinant or human plasma LCAT.

Animals↗

PubMed1998

Protein lipid interaction in bile: effects of biliary proteins on the stability of cholesterol-lecithin vesicles.

The nucleation of cholesterol crystals is an obligatory precursor to cholesterol gallstone formation. Nucleation, in turn, is believed to be preceded by aggregation and fusion of cholesterol-rich vesicles. We have investigated the effects of two putative pro-nucleating proteins, a concanavalin A-binding protein fraction and a calcium-binding protein, on the stability of sonicated small unilamellar cholesterol-lecithin vesicles. Vesicle aggregation is followed by monitoring absorbance, and upon addition of the concanavalin A-binding protein fraction the absorbance of a vesicle dispersion increases continuously with time. Vesicle fusion is probed by a fluorescence contents-mixing assay. Vesicles apparently fuse slowly after the addition of the concanavalin A-binding protein, although inner filter effects confound the quantitative measurement of fusion rates. The rates of change of absorbance and fluorescence increase with the concentration of the protein, and the second-order dimerization rate constant increases with both the protein concentration and the cholesterol content of the vesicles. On the other hand, the calcium-binding protein has no effect on the stability of the vesicle dispersion. This protein may therefore affect cholesterol crystal formation not by promoting the nucleation process, but by enhancing crystal growth and packaging. Our results demonstrate that biliary proteins can destabilize lipid vesicles and that different proteins play different roles in the mechanism of cholesterol gallstone formation.

Bile↗

PubMed1998

Effect of the surface lipid composition of reconstituted LPA-I on apolipoprotein A-I structure and lecithin: cholesterol acyltransferase activity.

Characterization of the factors that regulate plasma cholesterol esterification shows that the increased activity of lecithin:cholesterol acyltransferase (LCAT) in the plasma of hyperlipidemic subjects is due to enhanced interactions with a preferred substrate. The details of how the physical properties of high density lipoproteins (HDL) may affect their ability to stimulate cholesterol esterification by LCAT have been investigated in homogeneous reconstituted HDL particles containing two molecules of apolipoprotein (apo) A-I (Lp2A-I) and palmitoyl-oleoyl phosphatidylcholine (POPC). Increasing the POPC or sphingomyelin (SPH) content in an Lp2A-I complex increases particle size and stability but decreases the negative surface charge of apoA-I. Increasing Lp2A-I POPC or SPH content also significantly inhibits cholesterol esterification by LCAT. Increase in the maximum rate of CE production (Vmax) by LCAT is directly related to an increased negative charge on the different Lp2A-I particles and to a reduced amount and stability of amphipathic alpha-helices in apoA-I. In contrast, increasing the Lp2A-I complex negative charge directly by addition of a charged lipid, phosphatidylinositol (PI), has minimal effect on apoA-I conformation and LCAT activation. While variations in Lp2A-I PI content have little effect on the interfacial binding of LCAT, increasing POPC content appears to directly increase the binding affinity of LCAT for the different Lp2A-I particles. These results show that LCAT is stimulated by an apoA-I conformation-dependent increase in negative charge but is less sensitive to electrostatic changes in the lipid interface of discoidal Lp2A-I. The activation of LCAT appears to be dependent on the exposure of both central (residues 98-132) and N-terminal (residues 2-8) domains in apoA-I. A strong relationship between the immunoreactivity of two specific mAbs, 4H1 and A11, and LCAT reactivity suggests that the N-terminus of apoA-I may interact with a central domain in a manner that may regulate the accessibility of LCAT to the edge of the disc. This indicates that the conformation and charge of apoA-I are sensitive to the surface-lipid composition of HDL particles and play a central role in regulating LCAT activation. Since alterations in the surface lipid composition of HDL particles from hyperlipidemic subjects also modify the charge and structure of these particles, this may stimulate the rates of cholesterol esterification by making these lipoproteins preferred LCAT substrates.

Apolipoprotein A-I↗

PubMed1999

Reduced lecithin:retinol acyl transferase activity in cultured squamous cell carcinoma lines results in increased substrate-driven retinoic acid synthesis.

The uptake and metabolism of retinol was compared in squamous cell carcinoma lines, SCC12b and SCC13, and in normal human keratinocytes (NHK). Long chain fatty acid esters of retinol and 3,4-didehydroretinol were the predominant metabolites formed in both cell types. Lesser amounts of unesterified retinol, 3,4-didehydroretinol, and their respective active acid forms were also observed. Despite a qualitatively similar retinoid composition, there were significant quantitative differences between cell types. Most notable was that SCC formed only about one-fourth the retinoid ester as did normal cells. In parallel with this, unesterified retinol and retinoic acid concentrations in SCC were significantly elevated over those in normal cells. This altered pattern of retinoid metabolites in SCC was found to be due to very low lecithin:retinol acyltransferase (LRAT) activity. SCC exhibited less than one-tenth the LRAT activity of normal cells. Acyl-coenzyme A:retinol acyltransferase (ARAT) and retinyl ester hydrolase activities were not different between cell types. Challenging cells with increasing medium retinol concentrations resulted in dose-dependent increases in retinol and retinoic acid within SCC. In contrast, retinol and retinoic acid concentrations in similarly challenged normal cells remained relatively low across a wide retinol concentration range. This was accomplished by the storage of retinol, via LRAT activity, as retinyl ester. Consistent with increased substrate-driven retinoic acid synthesis in SCC, the expression of transglutaminase 1 was suppressed to a greater extent in the SCCs than in NHK, when cells were exposed to equivalent medium concentrations of retinol. The data demonstrate a central role of LRAT in regulating retinoic acid synthesis via its capacity to modulate cellular levels of substrate retinol.

Acyltransferases↗

PubMed1991

Functional analysis of the human lecithin cholesterol acyl transferase gene promoter.

In this report cis-acting sequences that direct transcription of the lecithin choleterol acyl transferase (LCAT) gene were identified. To assay the promoter activity, fragments from the 5' flanking region were fused upstream to the cloramphenicol acetyl transferase gene and transfected into Hep3B and HeLa cells. The gene sequences were active in both cell lines. A minimal promoter comprising only 71 bp is still fully active and contains a TATA box, a LFAI motif and two Sp1 binding sites. The activity of the promoter was entirely dependent on the Sp1 sites.

Base Sequence↗

PubMed2003

Kinetics of the micelle-to-vesicle transition: aqueous lecithin-bile salt mixtures.

Important routes to lipid vesicles (liposomes) are detergent removal techniques, such as dialysis or dilution. Although they are widely applied, there has been only limited understanding about the structural evolution during the formation of vesicles and the parameters that determine their properties. We use time-resolved static and dynamic light scattering to study vesicle formation in aqueous lecithin-bile salt mixtures. The kinetic rates and vesicle sizes are found to strongly depend on total amphiphile concentration and, even more pronounced, on ionic strength. The observed trends contradict equilibrium calculations, but are in agreement with a kinetic model that we present. This model identifies the key kinetic steps during vesicle formation: rapid formation of disk-like intermediate micelles, growth of these metastable micelles, and their closure to form vesicles once line tension dominates bending energy. A comparison of the rates of growth and closure provides a kinetic criterion for the critical size at which disks close and thus for the vesicle size. The model suggests that liposomes are nonequilibrium, kinetically trapped structures of very long lifetime. Their properties are hence controlled by kinetics rather than thermodynamics.

Animals↗

PubMed1974

Coexistence of rigid crystalline and liquid crystalline phases in lecithin-water mixtures.

X-ray diffraction measurements show that the beta'-crystalline to liquid crystalline transitions of dipalmitoyl lecithin-water mixtures take place over temperature ranges of several degrees, and by the gradual disappearance of one crystalline state accompanied by the gradual appearance of the other. The narrowness of the low angle X-ray lines indicates that the two crystalline states exist in separate phases. At a given temperature, the liquid crystalline phase has the greater water content. The bilayers of the liquid crystalline phase are thinner than those of the beta'-crystalline phase while the distances between bilayers are essentially equal in the two phases.

Crystallization↗