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At least 145 records · Page 8Linked to original sources

PubMed2005

Multicomponent complex formation between vinpocetine, cyclodextrins, tartaric acid and water-soluble polymers monitored by NMR and solubility studies.

This work deals with multicomponent complex formation of vinpocetine (VP) with beta-cyclodextrin (betaCD), sulfobutyl ether beta-cyclodextrin (SBEbetaCD) and tartaric acid (TA), in the presence or absence of water-soluble polymers, in aqueous solution. Complexation was monitored by phase-solubility and proton nuclear magnetic resonance ((1)H NMR) studies. TA demonstrated a synergistic effect on VP solubility, and in the complexation efficiency of betaCD and SBEbetaCD. Additionally, water-soluble polymers increased even more the complexation efficiency of the CDs that was reflected by a 2.1-2.5 increase on K(C) values for VP-CD-TA-polymer multicomponent complexes. SBEbetaCD was more effective in VP solubilization, as K(C) values of VP-SBEbetaCD-TA multicomponent complexes were notably higher than in corresponding betaCD complexes. The large chemical shift displacements from protons located in the interior of the hydrophobic CD cavities (i.e., H-3 and H-5) coupled with significant chemical shift displacements of VP aromatic protons suggested that this moiety was included in the cavity of both betaCD and SBEbetaCD. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out in order to obtain information about the multicomponent complex geometry in solution. Inspection of ROESY spectra allowed the establishment of spatial proximities between all aromatic protons of VP and the internal protons of the CDs, confirming that the aromatic moiety of VP is included in CD cavities being deeply inserted in SBEbetaCD multicomponent complexes, since additional interactions with the sulfobutyl side chains were evidenced.

Chemistry, Pharmaceutical↗

PubMed1998

The metalloproteinase-mediated pathway is essential for generation of soluble HLA class I proteins by activated cells in vitro: proposed mechanism for soluble HLA release in transplant rejection.

We and others have found donor-derived soluble beta2m-associated HLA class I proteins (sHLA/beta2m) in the serum of allograft recipients with acute and chronic rejection. Whether appearance of sHLA/beta2m and upregulated expression of donor cell-bound HLA/beta2m during allograft rejection are related events is unknown. Activation-induced upregulation of in vitro HLA/beta2m expression correlates with the surface expression of another form of HLA class I, namely beta2m-free HLA heavy chains (beta2m-free HC). We have shown that beta2m-free HC, but not beta2m-associated HC, are then cleaved by a specific membrane-bound metalloproteinase and released into supernatants as soluble 36 kDa proteins. We show now that activated peripheral blood lymphocytes produce predominantly the 36 kDa form of sHLA proteins which is present in supernatants as both beta2m-free HC and sHLA/beta2m. Importantly, the metalloprotease inhibitor BB-94 blocked not only the release of soluble beta2m-free HC, but also the appearance of sHLA/beta2m in cell supernatants. Low levels of 36 kDa beta2m-free HC were also present in human plasma of healthy donors. These data suggest an important role for the HLA class I-specific metalloproteinase in vivo in healthy individuals and during allograft rejection in the generation of soluble beta2m-free and beta2m-associated HLA proteins.

Cell-Free System↗

PubMed1998

Stability of water-soluble and lipid-soluble paramagnetic probes in Bacillus subtilis.

Batch cultures of the Gram-positive bacterium Bacillus subtilis PB19 have been investigated for their metabolic action to electron spin resonance (ESR) probes. Five- and six-membered water-soluble and lipid-soluble nitroxides have been used, which were reduced most probably to the corresponding hydroxylamine derivatives. The reduction was followed by the ESR signal intensity and found to be dependent on chemical structure and stability, lipophilic/hydrophilic character, charge, concentration, and temperature. Water-soluble nitroxides did not show apparent toxicity towards B. subtilis, in contrast with n-DXSA (n=5, 12, 16) which were found to be strongly cytotoxic. The cytotoxicity depended on the position of the doxyl unit along the hydrocarbon chain. The hydrophilic nitroxides were reduced at a much slower rate relative to the lipophilic ones. Membrane diffusion was suggested to be a slower process relative to chemical reduction for water-soluble nitroxides. The lipophilic nitroxides were solubilized into the membrane where they were rapidly reduced with a reduction maximum at 303-310 K, which is the optimal growth temperature of B. subtilis, while an inactivation at higher temperatures was observed. Both toxicity and reduction rates of nitroxides strongly indicated that the reduction was an enzyme-mediated process taking place near the outer surface of the periplasmic membrane.

Bacillus subtilis↗

PubMed2003

The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action.

Regulation of the activity of the proinflammatory cytokine IL-1 is complex, involving transcriptional and translational control, precursor processing, a receptor antagonist (IL-1ra), and a decoy receptor. Here we report that the soluble form of the IL-1 receptor accessory protein (AcP) increases the affinity of binding of human IL-1alpha and IL-1beta to the soluble human type II IL-1 receptor by approximately 100-fold, while leaving unaltered the low binding affinity of IL-1ra. Soluble AcP is present in normal human serum at an average concentration greater than 300 ng/ml. These findings suggest that the soluble form of IL-1R AcP contributes to the antagonism of IL-1 action by the type II decoy receptor, adding another layer of complexity to the regulation of IL-1 action.

Alternative Splicing↗

PubMed1998

Interaction between soluble P-selectin and soluble P-selectin glycoprotein ligand 1: equilibrium binding analysis.

Leukocyte rolling in the vasculature is mediated by the interaction of endothelial P-selectin and leukocyte P-selectin glycoprotein ligand 1 (PSGL-1). Since cell-cell interaction mediated by P-selectin and PSGL-1 is cooperative and complex, we have developed a model system to examine the binding of P-selectin to PSGL-1 in a soluble system. Equilibrium binding analyses were performed with truncated forms of soluble human P-selectin and dimeric PSGL-1, both lacking the transmembrane domain and both produced in Chinese hamster ovary (CHO) cells. Soluble PSGL-1 (sPSGL-1), which contains no tryptophan residues and exhibits no intrinsic fluorescence, was harvested from CHO cells cotransfected with either fucosyltransferase III (sPSGL-1/Fuc-TIII) or fucosyltransferase VII (sPSGL-1/Fuc-TVII). Both fucosylation isoforms of sPSGL-1 bound to sP-selectin. The interaction of sP-selectin and sPSGL-1 was studied by monitoring changes in the intrinsic fluorescence of sP-selectin upon binding to sPSGL-1. Binding of sPSGL-1 to sP-selectin in the presence of calcium caused an increase in tryptophan fluorescence that could be reversed by the addition of ethylenediaminetetraacetic acid (EDTA). The fluorescence enhancement of sP-selectin by sPSGL-1 was used to generate binding isotherms, and these data were fitted to a bimolecular binding model. The binding constant, Kd, for the binding of sPSGL-1/Fuc-TIII and sPSGL-1/Fuc-TVII to sP-selectin was 3 +/- 2 nM and 80 +/- 44 nM, respectively. Monomeric sP-selectin bound to dimeric sPSGL-1 with a 2:1 stoichiometry. In a system in which both protein species are soluble and lack transmembrane domains, these results indicate high-affinity interaction between P-selectin and PSGL-1. Furthermore, the fucosylation pattern of PSGL-1 can affect its affinity for P-selectin. These binding constants can be used to explore models of cell adhesion in flow systems.

Alkylation↗

PubMed2005

Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility.

Soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. 1,3-Disubstituted ureas with a polar group located on the fifth atom from the carbonyl group of urea function are active inhibitors of sEH both in vitro and in vivo. However, their limited solubility in water and relatively high melting point lead to difficulties in formulating the compounds and poor in vivo efficacy. To improve these physical properties, the effect of structural modification of the urea pharmacophore on the inhibition potencies, water solubilities, octanol/water partition coefficients (log P), and melting points of a series of compounds was evaluated. For murine sEH, no loss of inhibition potency was observed when the urea pharmacophore was modified to an amide function, while for human sEH 2.5-fold decreased inhibition was obtained in the amide compounds. In addition, a NH group on the right side of carbonyl group of the amide pharmacophore substituted with an adamantyl group (such as compound 14) and a methylene carbon present between the adamantyl and amide groups were essential to produce potent inhibition of sEH. The resulting amide inhibitors have 10-30-fold better solubility and lower melting point than the corresponding urea compounds. These findings will facilitate synthesis of sEH inhibitors that are easier to formulate and more bioavailable.

1-Octanol↗

PubMed1997

Effect of soluble or partly soluble dietary fibres supplementation on absorption and balance of calcium, magnesium, iron and zinc in healthy young men.

OBJECTIVES: This study is aimed at investigating the effect of feeding a soluble or partly soluble fibre rich-diet on the apparent absorption and balance of calcium, magnesium, iron and zinc in healthy young men, by using a chemical balance technique. STUDY DESIGN: Nine healthy young men were given a control diet or the same diet complemented with either inulin (soluble) or sugar beet fibre (partly soluble) during 28 d periods according to a 3 x 3 latin square design with three repetitions. During the 20 d adaptation period to fibre ingestion, experimental fibres were incorporated into bread (60%) and liquid foods (40%) up to a maximum of 40 g/d. Ca, Mg, Fe and Zn were measured in diets and in a 8 d urine and faecal composites to assess mineral absorption and balance. RESULTS: The dietary mineral intake provided (mg/d) 859 +/- 196 of Ca; 311 +/- 43 of Mg; 11.6 +/- 1.7 of Fe; and 11.1 +/- 1.6 of Zn from the control diet. The apparent absorption of minerals from the control diet was (%) Ca: 21.3 +/- 12.5; Mg: 46.3 +/- 10.9; Fe: 21.8 +/- 12.3 and Zn: 14.0 +/- 14.5 (mean +/- s.d.). Ingestion of inulin significantly increased the apparent absorption and the balance of Ca. Sugar beet fibre ingestion resulted in a significant increase in Ca intake and balance, without modification its apparent absorption. Apparent absorption and balance of Mg, Fe and Zn were not significantly altered by the ingestion of either experimental fibre. CONCLUSIONS: Addition of the two experimental fibres (inulin or sugar beet fibre) to normal mixed diets can improve Ca balance without adverse effects on other mineral retention. SPONSORSHIP: This project was supported by the French Ministry of Agriculture, Fisheries and Foods (programme Aliment #2002-Aliment Demain; No. 906335). The authors acknowledge the société Agro Industries, Recherche et Developpement (Mr R. De Baynast) who supplied them with the experimental fibres.

Absorption↗

PubMed2001

Differential activation of TRAIL-R1 and -2 by soluble and membrane TRAIL allows selective surface antigen-directed activation of TRAIL-R2 by a soluble TRAIL derivative.

TNF-related apoptosis-inducing ligand (TRAIL) is a typical member of the tumor necrosis factor (TNF) ligand family that is expressed as a type II membrane protein (memTRAIL) and signals apoptosis via the death domain-containing receptors TRAIL-R1 and -2. Soluble recombinant derivatives of TRAIL (sTRAIL) are considered as novel tumors therapeutics because of their selective apoptosis inducing activity in a variety of human tumors but not in normal cells. Using antagonistic antigen-binding fragment (Fab) preparations of TRAIL-R1- and TRAIL-R2-specific antibodies, we demonstrate in this study that TRAIL-R1 becomes activated by both the soluble and the membrane-bound form of the ligand, whereas TRAIL-R2 becomes only activated by memTRAIL or soluble TRAIL secondarily cross-linked by antibodies. Furthermore, we show that the restricted signal capacity of sTRAIL can be readily converted into a fully signal competent memTRAIL-like molecule, i.e. a TRAIL-R2 stimulating ligand, by genetic fusion to an antibody derivative that allows antigen-dependent 'immobilization' of the fusion protein to cell surfaces. We conclude that antibody targeting-dependent activation can be used to design selective therapeutics derived of those ligands of the TNF family that are biologically inactive in their soluble form.

Animals↗

PubMed1996

Co-expression of the alpha subunit of human prolyl 4-hydroxylase with BiP polypeptide in insect cells leads to the formation of soluble and insoluble complexes. Soluble alpha-subunit-BiP complexes have no prolyl 4-hydroxylase activity.

Prolyl 4-hydroxylase (EC 1.14.11.2) catalyses the post-translational formation of 4-hydroxyproline in collagens. The vertebrate enzymes are alpha2beta2 tetramers, their beta subunit being identical to protein disulphide isomerase (PDI). The function of the PDI-beta subunit in prolyl 4-hydroxylases is not fully understood, but it seems to be that of keeping the highly insoluble alpha subunits in solution. We report here that expression of the alpha subunit of human type I prolyl 4-hydroxylase in insect cells together with BiP polypeptide leads to the formation of both soluble and insoluble alpha-subunit-BiP complexes. Formation of the soluble complexes was evident from (1) a marked increase in the amount of the alpha subunit in the soluble fraction of the cell homogenates when expressed together with BiP, (2) immunoprecipitation experiments and (3) demonstration of the presence of some of the complexes by polyacrylamide gel electrophoresis under non-denaturing conditions. Formation of the insoluble complexes was suggested by an increase in the amount of BiP in the insoluble fraction when expressed together with the alpha subunit. Nevertheless the soluble alpha-subunit-BiP complexes had no prolyl 4-hydroxylase activity. This indicates that the function of the PDI-beta subunit in the prolyl 4-hydroxylase tetramer is not only that of keeping the alpha subunits in solution but appears to be more specific, probably that of keeping them in a catalytically active, non-aggregated conformation.

Amino Acid Sequence↗

PubMed1999

Soluble Fas and soluble Fas ligand proteins in human milk: possible significance in the development of immunological tolerance.

Human milk contains a complex uncharacterized, immune system able to exert actions both locally and systemically. This study reports the results of an ELISA-based quantitation of soluble Fas and soluble Fas ligand in human milk which may modulate the Fas/FasL system that is critical for the expression of immune tolerance and apoptosis. Production of Fas/FasL mRNAs by milk cells was also examined using RT-PCR. Fas is ubiquitously expressed in various cells and when bound by its ligand FasL, present predominantly on activated T- and NK cells, Fas-expressing cells are killed. A large amount of soluble Fas (1746-4320 pg/ml) is detected in colostrum, transitional milk and the mature milk of mothers delivering prematurely or at full-term, whereas FasL is present only in the range 123-310 pg/ml. Milk cells are positive for Fas mRNA, but negative for FasL mRNA. An excess of soluble Fas in human milk may bind to FasL preventing apoptosis and preserving epithelial barriers, and may represent an additional new mechanism whereby human milk favours immune tolerance and normal gastrointestinal development.

Colostrum↗

PubMed1998

Soluble CD21 (sCD21) forms biologically active complexes with CD23: sCD21 is present in normal plasma as a complex with trimeric CD23 and inhibits soluble CD23-induced IgE synthesis by B cells.

A soluble form of CD21 (sCD21) of 135 kDa is spontaneously released by human B and T lymphocytes upon shedding of the extracellular domain of the molecule. By Western blotting, we have now identified two forms of sCD21 of Mr 135 and 90 kDa in normal human serum. We further demonstrate that sCD21 circulates in a complexed form with cleavage fragments of C3 and CD23, two previously identified ligands of the membrane CD21 receptor. The CD23 molecule was in the form of a trimer in the soluble complex purified from plasma by affinity chromatography on anti-CD21 Sepharose. The serum sCD21 complex was also found to contain IgE. The presence of IgE and of CD21 in a soluble complex that contains trimeric CD23 as the only form of soluble CD23 (sCD23) is in agreement with a model in which two of the three lectin heads of CD23 bind to the Cepsilon3 domain of IgE, thus leaving one of the heads available for interaction with CD21. We further demonstrate that sCD21 inhibits sCD23-induced IgE synthesis by IL-4-stimulated B cells. The results indicate that sCD21 in plasma retains the ligand-binding properties of the membrane CD21 receptor and exhibits immunoregulatory properties that may be relevant to allergic and inflammatory disorders.

B-Lymphocytes↗

PubMed2002

Effects of severe, uncontrolled hypertension on endothelial activation: soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and von Willebrand factor.

OBJECTIVES: The molecular mechanisms whereby severe, uncontrolled hypertension (SHT) is translated into acute vascular target organ dysfunction have not been completely defined. We sought to determine whether SHT is associated with pressure-dependent endothelial activation as assessed by soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and von Willebrand Factor (vWF). METHODS: We determined sVCAM-1, sICAM-1 and vWF in three groups: (i) untreated patients referred specifically for treatment of SHT [diastolic blood pressure (DBP) > or = 120 mm Hg; n = 24]; (ii) untreated patients with established mild hypertension (MHT; DBP 95-100 mmHg; n = 19); and (iii) normotensive volunteers (DBP < or = 90; n = 16). RESULTS: By analysis of variance, sVCAM-1 (P = 0.002), sICAM-1 (P = 0.02) and vWF (P = 0.009) were greater in SHT and MHT than in normotensives but did not differ between SHT and MHT. We observed a significant positive correlation between blood pressure and soluble activation markers at lower blood pressures (normotensives and MHT considered together) that was not present in SHT. CONCLUSIONS: Even mild elevation of blood pressure may be sufficient to activate the expression of adhesion molecules. Mechanisms other than the endothelial expression of adhesion molecules may be important in mediating the accelerated target organ injury produced by SHT in humans. Concentrations of soluble adhesion molecules and vWF may depend more strongly upon factors in the hypertensive microenvironment other than the absolute level of blood pressure.

Adult↗

PubMed1985

Proteolytic digestion patterns of "soluble" and "detergent-soluble" bovine caudate nucleus acetylcholinesterases.

The structures of purified "soluble" and "detergent-soluble" bovine caudate nucleus acetylcholinesterases were compared by peptide mapping on polyacrylamide gels. The digestion products generated from the two acetylcholinesterases on proteolysis by a given protease (Staphylococcus aureus V8 protease, alpha-chymotrypsin, or papain) are remarkably similar as judged from the electrophoretic band patterns. We conclude that the "soluble" and "detergent-soluble" acetylcholinesterases from bovine caudate nucleus share a common evolutionary origin.

Acetylcholinesterase↗

PubMed1985

Molecular forms of acetylcholinesterase from human caudate nucleus: comparison of salt-soluble and detergent-soluble tetrameric enzyme species.

Extraction of human caudate nucleus under high-ionic-strength conditions solubilized 20-30% of total acetylcholinesterase (AChE) activity. Density gradient centrifugation revealed monomeric (5.0 S) and tetrameric (11.0 S) enzyme species. The purified, tetrameric salt-soluble (SS) AChE sedimented at 10.6 S and did not bind detergents. It showed an immunochemical reaction of identity with the detergent-soluble (DS) AChE species from human caudate nucleus and human erythrocytes, but did not cross-react with antibodies raised against human serum cholinesterase. The remaining activity was solubilized under low-ionic-strength conditions in the presence of 1.0% Triton X-100. The purified tetrameric, DS-AChE sedimented at 10.0 S as detergent-protein mixed micelle and on extensive removal of the detergent this enzyme formed defined aggregates by self-micellarization. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions revealed that the salt-soluble and detergent-soluble tetrameric enzyme species both contained a heavy and a light dimer; under reducing conditions mainly one band corresponding to the light subunit was seen. Molecular weights of 300,000 dalton and 280,000 dalton were calculated for SS-AChE and DS-AChE, respectively. Limited digestion of DS-AChE with proteinase K led to isolation of an enzyme that no longer bound detergents and lacked the intersubunit disulfide bridges.

Acetylcholinesterase↗

PubMed1975

Improvement of solubility and dissolution rate of poorly water-soluble salicylic acid by a spray-drying technique.

Spray drying techniques have been applied to improve the solubility and dissolution rate of poorly water-soluble salicylic acid. Spray drying of the acid dispersed in acacia solutions resulted in as much as a 50% improvement in the solubility of the product. Solubility improvement was closely related not only to the concentration of acacia but also the amount of amorphous material in the spray-dried products. The heat of solution was inversely related to these parameters. The dissolution rate of spray-dried product was almost instantaneous being about 60 times faster than that of the original powder. A great improvement in the wettability of the spray-dried material seemed to be mainly responsible for the increase of dissolution rate.

Diffusion↗

PubMed1983

Soluble luteinizing hormone/human chorionic gonadotropin receptors of the rat ovary: comparative studies of water- and detergent-soluble receptors.

The water-soluble LH-hCG receptors of the luteinized rat ovary have the properties of glycoproteins and can be separated into four fractions by chromatography on Sepharose-Concanavalin A. Polyacrylamide gel electrophoresis of these fractions demonstrates a broad similarity of molecular compositions. However, the chromatographic fractions had different quantities of the individual receptor species (mol wt, 165,000, 81,000, 24,000, 48,000, and 12,000). While all receptor species declined in the desensitized ovaries the losses of the 24.000 and 12,000 mol wt species were most prominent. Analysis of detergent extracts demonstrated that water-soluble and detergent-soluble LH/hCG receptors have comparable molecular compositions and resolved similarly during chromatography on Sepharose-Concanavalin A. These results have also indicated that lectin affinity chromatography is a powerful tool for the initial purification step of water-soluble or detergent-extracted ovarian LH/hCG receptors.

Animals↗

PubMed1989

Enhancement of the dissolution rates of poorly water-soluble drugs by water-soluble gelatin.

The dissolution behavior of several acidic and basic drugs from kneaded mixtures with water-soluble gelatin have been studied in comparison with that of the drug alone. The results revealed a significant increase of dissolution rate of drugs from kneaded mixtures. The water-soluble gelatin showed little interaction with any of the drugs in solution or in the solid state. Interestingly, the contact angle of the kneaded mixture was remarkably decreased compared with that of the drug powder and was found to be almost the same as that of water-soluble gelatin powder. Thus, the enhanced dissolution rate of the drug caused by water-soluble gelatin was explained by the improvement of wettability of the drug by water.

Chemistry, Pharmaceutical↗

PubMed2001

[Crystalline molecular complexes generated between surfactants and various additive compounds: an attempt to modify sparingly water soluble drugs to easily water soluble drugs].

It has been established that ionic surfactants, whether cationic or anionic, provide crystalline molecular complexes stably with various aromatic compounds as additives. Among various additives phenolic compounds are especially favorable for both surfactant species. Other than these additives, cationic surfactants easily provide crystalline molecular complexes with basic materials and even with non-polar substances such as biphenyl and phenanthrene. The isolated surfactant molecular complexes were analyzed by X-ray. To date the number of the obtained surfactant molecular complexes exceeds two hundred species or more and thirty or more of them were structurally analyzed. These surfactant molecular complexes were shown to be novel surfactant species different from their mother species, supplied with enhanced solubility to the complex additives. We applied these characteristics to sparingly water soluble drugs as the complex additive to modify them into easily water soluble drugs. The obtained complex drugs revealed an improved behavior in solubility and dissolution rate compared with pure drugs.

Crystallization↗