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At least 1,279 records · Page 71Linked to original sources
PubMed2004

The monotopic membrane protein human oxidosqualene cyclase is active as monomer.

The monotopic integral membrane protein 2,3-oxidosqualene cyclase (OSC) catalyzes the formation of lanosterol the first sterol precursor of cholesterol in mammals. Therefore, it is an important target for the development of new hypocholesterolemic drugs. Here, we report the overexpression and purification of functional human OSC (hOSC) in Pichia pastoris. The obtained IC(50) for the reference inhibitor Ro 48-8071 is nearly identical for the recombinant hOSC compared to OSC from human liver microsomes. The correlation of analytical ultracentrifugation data and activity measurements showed the highest enzymatic activity for the monomeric hOSC indicating that this would be the natural form. Furthermore, these data helped us to identify the detergent for a successful crystallization of the protein. The availability of this active recombinant human membrane protein is a very important step on the way to a more detailed functional and structural characterization of OSCs.

Benzophenones↗
PubMed2006

Novel membranes and surface modification able to activate specific cellular responses.

The design of new polymeric biomaterials together with new strategies to modify membrane surface are crucial to optimise cell-biomaterial interactions in vivo and in vitro biohybrid systems. In this study we report on the novel semipermeable membranes synthesised from a polymeric blend of modified polyetheretherketone and polyurethane able to support the long-term maintenance and differentiation of human liver cells and on the surface modification of polyethersulfone membranes by plasma polymerisation of acrylic acid monomers and by immobilization of arginine-glycine-aspartic acid (RGD) peptide through a hydrophilic "spacer arm" molecule. The performance of the modified and unmodified membranes was tested by evaluation of the liver function expression of primary human hepatocytes in terms of albumin production, protein secretion and drug biotransformation.

Benzophenones↗
PubMed2004

New modified polyetheretherketone membrane for liver cell culture in biohybrid systems: adhesion and specific functions of isolated hepatocytes.

There has been growing interest in innovative materials with physico-chemical properties that provide improved blood/cell compatibility. We propose new polymeric membranes made of modified polyetheretherketone (PEEK-WC) as materials with potential for use in biohybrid devices. PEEK-WC exhibits high chemical, thermal stability and mechanical resistance. Owing to its lack of crystallinity this polymer can be used for preparing membranes with cheap and flexible methods. We compared the properties of PEEK-WC membranes to polyurethane membranes prepared using the same phase inverse technique and commercial membranes. The physico-chemical properties of the membranes were characterised by contact angle measurements. The different parameters acid (gamma+), base (gamma-) and Lifshitz-van der Waals (gammaLW) of the surface free energy were calculated according to Good-van Oss's model. We evaluated the cytocompatibility of PEEK-WC membranes by culturing hepatocytes isolated from rat liver. Cell adhesion and metabolic behaviour in terms of ammonia elimination, urea synthesis and protein synthesis were evaluated during the first days of culture. Liver cells adhered and formed three-dimensional aggregates on the most tested membranes. PEEK-WC membranes promoted hepatocyte adhesion most effectively. Urea synthesis, ammonia elimination and protein synthesis improved significantly when cells adhered to PEEK-WC membrane. The considerable metabolic activities of cells cultured on this membrane confirmed the good structural and physico-chemical properties of the PEEK-WC membrane that could be a promising biomaterial for cell culture in biohybrid devices.

Animals↗
PubMed2004

Feasibility of knitted carbon/PEEK composites for orthopedic bone plates.

This paper focuses on fabrication and characterization of knitted carbon/PEEK fabric composites for orthopedic bone plate application. Bending performance of the knitted carbon/PEEK composite bone plates was investigated with respect to two principal knitting directions (wale- and course-directions). As a result, the wale-direction knitted composite bone plates had much scattering in bending stiffness and maximum bending moment although they exhibited the same bending behavior as that of the course-direction specimens. In comparison with our previously developed braided composite bone plates, the knitted composite bone plates had 55-59% bending stiffness, 40-63% yield bending moment, and 54-77% maximum bending moment. However, the knitted composite bone plates showed higher deformability. Based on the results of the braided composite bone plates, it is considered that the knitted composite plate with 3.2mm thickness can be suitable for forearm or humerus treatment especially when damaged bones need higher deformation to encourage bone ossification.

Benzophenones↗
PubMed2004

Influence of interphase layer on the overall elasto-plastic behaviors of HA/PEEK biocomposite.

A three-dimensional finite element unit cell model has been designed and constructed for studying mechanical properties of hydroxyapatite (HA) reinforced polyetheretherketone (PEEK) biocomposite. The model consists of an elastic-brittle HA spherical particle, an elasto-plastic matrix and an interphase layer between the particle and the matrix. The interphase layers with four different kinds of material behaviors have been taken into consideration to examine their effects on the overall properties of the composite. The damage evolution in the matrix and the interphase layer, and the interface failure, were also taken into account. Some other factors, such as mesh sensitivity, loading velocity and mass scale scheme, were also discussed in this investigation. A general-purpose finite element software package, ABAQUS, incorporated with a user-defined material subroutine, was used to perform the analysis. The predicted results were compared with the experimental data obtained from existing literatures. The results predicted by using the cell model with consideration of the matrix degradation and the effects of the damage and failure on the interphase layer are in good agreement with the experimental ones. Hence, the suitability of our proposed cell model incorporated with an appropriate type of the interphase layer for modeling the mechanical properties of the particulate biocomposite could be verified.

Benzophenones↗
PubMed2005

In vitro apatite formation and its growth kinetics on hydroxyapatite/polyetheretherketone biocomposites.

The formation of biologically equivalent carbonate-containing apatite on the surface of synthetic hydroxyapatite (HA) is an important step leading to good bone healing. In this study, HA-reinforced polyetheretherketone (PEEK) composites were prepared by homogeneous mixing of HA and PEEK powders, compaction, and pressureless sintering. The bioactivity of HA/PEEK composite with 10, 20, 30 and 40 vol% HA was evaluated by immersing the composite disks in the simulated body fluid (SBF) for up to 4 weeks. The surface of composite with 40 vol% HA was covered by a layer of bone-like apatite just after 3 days of immersion, while 10 vol% HA was covered only after 28 days. This apatite layer was characterized by SEM, thin film X-ray diffractometer, attenuated total reflectance-Fourier transform infrared spectrometer (FTIR)/FTIR. Introducing a concept called apatite-forming capacity of SBF, growth kinetics of the apatite layer on the surface of the composite disks was carried out. The growth rate constant increased with HA volume fraction of the composite, suggesting that the bioactivity of the HA/PEEK composite increases with increasing HA volume fraction in the composite.

Apatites↗
PubMed2005

Effect of isoliquiritigenin on viability and differentiated functions of human hepatocytes maintained on PEEK-WC-polyurethane membranes.

In this study, we tested the ability of microporous membranes synthesised from a polymeric blend of modified polyetheretherketone (PEEK-WC) and polyurethane (PU) to support long-term maintenance and differentiation of human liver cells. The effect of isoliquiritigenin (ISL), which is a component of liquorice extract, exhibiting growth stimulatory and antiproliferative dose-dependent effect was investigated by comparing cultures treated with ISL with those untreated. To this purpose, flat-sheet membranes were prepared by a blend of PEEK-WC and PU polymers by phase inverse technique. The morphological and physico-chemical properties were characterised, respectively, by scanning electron microscopy and water contact angle measurements. Human hepatocytes cultured on PEEK-WC-PU membranes were constant up to 1 month albumin production and urea synthesis as well as the synthesis of total proteins. The liver-specific functions were expressed at high levels when cells were cultured on membranes with respect to collagen. Also the biotransformation functions were maintained for all culture periods: the ISL elimination rate increased during the culture time and high values were measured up to 22 days. Thereafter, a decrease was observed. ISL stimulated the proliferation of hepatocytes cultured on both substrata but did not affect their liver-specific functions. Hepatocytes cultured on PEEK-WC-PU membranes responded very well to ISL and expressed high levels of P450 cytochrome. These results demonstrated that long-term maintenance of human liver differentiation can be achieved on PEEK-WC-PU membranes. The incubation with ISL at the investigated concentration could stimulate the proliferation of human hepatocytes in biohybrid systems.

Benzophenones↗
PubMed2005

Polyetheretherketone as a biomaterial for spinal applications.

Threaded lumbar interbody spinal fusion devices (TIBFD) made from titanium have been reported to be 90% effective for single-level lumbar interbody fusion, although radiographic determination of fusion has been intensely debated in the literature. Using blinded radiographic, biomechanic, histologic, and statistical measures, we evaluated a radiolucent polyetheretherketone (PEEK)-threaded interbody fusion device packed with autograft or rhBMP-2 on an absorbable collagen sponge in 13 sheep at 6 months. Radiographic fusion, increased spinal level biomechanical stiffness, and histologic fusion were demonstrated for the PEEK cages filled with autograft or rhBMP-2 on a collagen sponge. No device degradation or wear debris was observed. Only mild chronic inflammation consisting of a few macrophages was observed in peri-implant tissues. Based on these results, the polymeric biomaterial PEEK may be a useful biomaterial for interbody fusion cages due to the polymer's increased radiolucency and decreased stiffness.

Animals↗
PubMed2006

Processing and tensile properties of hydroxyapatite-whisker-reinforced polyetheretherketone.

Polyetheretherketone (PEEK) was reinforced with 0-50 vol% hydroxyapatite (HA) whiskers using a novel powder processing and compression molding technique which enabled uniform mixing at high whisker content. Texture analysis showed that viscous flow during compression molding produced a preferred orientation of whiskers along the specimen tensile axis. Consequently, the elastic modulus or ultimate tensile strength of HA-whisker-reinforced PEEK was able to be tailored to mimic human cortical bone. PEEK reinforced with 40 and 50 vol% HA whiskers exhibited elastic moduli of 17 and 23 GPa, respectively. Elastic constants were measured using ultrasonic wave propagation and revealed an orthotropic anisotropy also similar to that measured in human cortical bone. PEEK reinforced with 10 and 20 vol% HA whiskers exhibited an ultimate tensile strength of 90 and 75 MPa, respectively. Tensile specimen fracture surfaces showed evidence of brittle failure in both reinforced and un-reinforced PEEK. Whisker pullout was observed with PEEK adhered to HA whiskers, suggesting a relatively strong interface between the PEEK matrix and HA whisker reinforcements.

Benzophenones↗
PubMed2006

3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold.

With annual death tolls in the millions and emerging resistance to existing drugs, novel therapies are needed against malaria. Wiesner et al. recently developed a novel class of antimalarials derived from farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold. The compounds displayed a wide range of activity, including submicromolar, against the multi-drug resistant Plasmodium falciparum strain Dd2. In order to investigate quantitatively the local physicochemical properties involved in the interaction between drug and biotarget, we used the 3D-QSAR methods CoMFA and CoMSIA to study some of the series, including the screened lead compound 2,5-bis-acylaminobenzophenone, 28 cinnamic acid derivatives, 29 N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides, and 34 N-(4-substituted-amino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides. We found that steric, electrostatic, and hydrophobic properties of substituent groups play key roles in the bioactivity of the series of compounds, while hydrogen bonding interactions show no obvious impact. We built several highly predictive 3D-QSAR models, including a CoMSIA one composed of steric, electrostatic, and hydrophobic fields, with r(2)=0.94, q(2)=0.63, and r(pred)(2)=0.63. The results provide insight for optimization of this class of antimalarials for better activity and may prove helpful for further lead optimization.

Animals↗
PubMed2004

Parallel synthesis of DAPT derivatives and their gamma-secretase-inhibitory activity.

Parallel synthesis of the C-terminal-modified DAPT (1) derivatives was accomplished utilizing our novel resin 7. Condensation reaction of the N-acylamino acid 10 with the amines 11a-o proceeded smoothly to give the corresponding amides 6a-o without any epimerization. Among the analogues, the benzophenonemethyl amide derivative 6o showed 30 times more potent activity than the original DAPT (1).

Amides↗
PubMed2004

Effects of ZD6169, a K ATP channel opener, on neurally-mediated plasma extravasation in the rat urinary bladder induced by chemical or electrical stimulation of nerves.

The effects of oral administration of ZD6169, a potassium channel opener, on neurally mediated plasma extravasation in the urinary bladder and urethra were examined in urethane-anesthetized rats. Plasma extravasation was evaluated by measuring the tissue concentration of Evans blue, administered intravenously (50 mg/kg) 15 min prior to removal of tissues. Plasma extravasation was induced by three different stimuli: intravesical administration of either 0.25% acetic acid or 100 microM capsaicin or electrical stimulation of the pelvic nerve on one side (50 V, 10 s trains, 30 Hz intra-train frequency at 1 min intervals for 40 min). ZD6169 (5 mg/kg), administered orally 5 h prior to stimulation, significantly reduced the capsaicin-induced (50% decrease, p<0.05) or the electrical stimulation-induced (58% decrease, p<0.05) plasma extravasation in the bladder, but did not prevent the plasma extravasation in the bladder or urethra induced by intravesical infusion of 0.25% acetic acid. Administration of a K(ATP) channel blocker, glibenclamide (20 mg/kg, iv) 45 min prior to ZD6169 administration blocked the effects of ZD6169 on the electrical stimulation-induced plasma extravasation in the bladder and reduced the effects of ZD6169 on capsaicin-induced plasma extravasation. These findings indicate that ZD6169 (and/or a metabolite) can reduce neurogenic plasma extravasation in the bladder and are consistent with other studies indicating that ZD6169 can activate K(ATP) channels in C-fiber bladder afferents and suppress afferent activity.

Acetic Acid↗
PubMed2006

Analysis of estrogens in environmental waters using polymer monolith in-polyether ether ketone tube solid-phase microextraction combined with high-performance liquid chromatography.

A simple, rapid and sensitive on-line method for simultaneous determination of four endocrine disruptors (17beta-estradiol, estriol, bisphenol A and 17alpha-ethinylestradiol) in environmental waters was developed by coupling in-tube solid-phase microextraction (SPME) to high-performance liquid chromatography (HPLC) with fluorescence detection (FLD). A poly(acrylamide-vinylpyridine-N,N'-methylene bisacrylamide) monolith, synthesized inside a polyether ether ketone (PEEK) tube, was selected as the extraction medium. To achieve optimum extraction performance, several parameters were investigated, including extraction flow-rate, extraction time, and pH value, inorganic salt and organic solvent content of the sample matrix. By simply filtered with nylon membrane filter and adjusting the pH of samples to 6.0 with phosphoric acid, the sample solution then could be directly injected into the device for extraction. Low detection limits (S/N=3) and quantification limits (S/N=10) of the proposed method were achieved in the range of 0.006-0.10 ng/mL and 0.02-0.35 ng/mL from spiked lake waters, respectively. The calibration curves of four endocrine disruptors showed good linearity ranging from quantification limits to 50 ng/mL with a linear coefficient R(2) value above 0.9913. Good method reproducibility was also found by intra- and inter-day precisions, yielding the RSDs less than 12 and 9.8%, respectively. Finally, the proposed method was successfully applied to the determination of these compounds in several environmental waters.

Benzophenones↗
PubMed2006

Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs: a case/noncase analysis of spontaneous reports.

BACKGROUND: Hepatic adverse events associated with the use of nonaspirin drugs and NSAIDs are uncommon, but the widespread use of these drugs may impact public health. OBJECTIVE: We conducted a case/noncase analysis of spontaneous reports to compare the hepatic safety profile of cyclooxygenase (COX)-2 selective inhibitors with that of nonselective NSAIDs. METHODS: This case/noncase analysis was conducted using the US Food and Drug Administration Freedom of Information (FDA/FOI) database (through quarter 1, 2003) and the World Health Organization Uppsala Monitoring Centre (WHO/UMC) database (through quarter 3, 2003). Council for International Organizations of Medical Sciences and WHO Adverse Reaction Terminology preferred terms were used to classify hepatic disorders with broad and specific case definitions. After reports involving established hepatotoxic drugs (bromfenac, nimesulide, sulindac) were excluded, the proportion of reports (PRs) of each case definition was calculated for each NSAID. Crude and adjusted reporting odds ratios (RORs) were used to compare the overall proportions of hepatic disorders and hepatic failure of celecoxib and rofecoxib versus nonselective NSAIDs. RESULTS: A total of 158,539 and 185,253 reports of NSAIDs were identified in the FDA/FOI and WHO/UMC databases and 25% and 16%, respectively, involved other hepatotoxic drugs. The PRs of hepatic disorders for all COX-2 selective inhibitors and non-selective NSAIDs were 3.0% in the FDA/FOI database and 2.7% in the WHO/UMC database. In the FDA/FOI and WHO/UMC databases, respectively, mmesulide (16.7% and 14.4%), bromfenac (12.0% and 20.7%), diclofenac (8.1% and 4.7%), and sulindac (6.1 % and 9.9%) were reported to be associated with higher proportions of overall hepatic disorders compared with those of other NSAIDs. Crude and adjusted RORs for the prevalences of overall hepatic disorders and hepatic failure with celecoxib and rofecoxib versus the other NSAIDs were <1 (indicating that the proportion was not higher than that of the comparator) in both databases. The interpretation of the results was unchanged when bromfenac, nimesulide, and sulindac were excluded from the analysis. CONCLUSIONS: In this case/noncase analysis, bromfenac, nimesulide, sulindac, and diclofenac had higher proportions of reports of hepatic disorders compared with those of other NSAIDs in the FDA/FOI and WHO/UMC databases. The analysis did not raise a safety concern for celecoxib or rofecoxib versus NSAIDs for overall hepatic disorders and hepatic failure.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Umbelliferone aminoalkyl derivatives, a new class of squalene-hopene cyclase inhibitors.

The synthesis is described of several aminoalkyl derivatives of coumarin, obtained in good yields under microwave or high-intensity ultrasound irradiation. These compounds proved uniformly active as inhibitors of squalene-hopene cyclase (SHC) from Alicyclobacillus acidocaldarius. Their design stemmed from our recent finding that the umbelliferone nucleus acquires inhibitory properties towards SHC when functionalized with a suitable chain such as the omega-epoxyfarnesyl group. Under our experimental conditions the most active ones, such as 7-(4'-allylmethylamino-but-2-ynyloxy)chromen-2-one (IC(50) 0.75 mM), approached the potency of anticholesteremic drug Ro 48-8071 (IC(50) 0.35 mM), an effective inhibitor of both squalene- and oxidosqualene-cyclases (OSC). Tests are in progress to determine their efficacy on different eukaryotic OSCs.

Animals↗
PubMed2005

A solid-phase approach to DDB derivatives.

Since the discovery of 2,2'-dimethoxycarbonyl-4,4-dimethoxy-5,6,5',6'-biomethylenedioxy-biphenyl (DDB) as a potent anti-HBV agent, we have studied the structure-activity relationships of 4,4'-dimethoxy-5,6,5',6'-dimethenedioxy-2-alkyloxycarbonyl-2'-(4-substituted benzyl piperazin-1-yl)carbonyl-biphenyl as anti-HBV agents. Therefore, it is rational to extend this study to the 3,3'-disustituted-4,4'-dimethoxy-5,6,5',6'-dimethenedioxy-2-alkyloxycarbonyl-2'-Serine derivatives. Thus, in an attempt to develop an efficient method for the preparation of a large number of DDB derivatives, the reaction between a DDB acid chloride and serine derivatives on solid support was studied. The structure of resulted compounds was confirmed by LC-MS and (1)H NMR analysis. Compounds 2a, 2d, 2f, 2j showed in vitro anti-HBV activity without significant toxicity up to 100 microM.

Benzophenones↗
PubMed2005

Synthesis and antimicrobial study of novel heterocyclic compounds from hydroxybenzophenones.

The triazolothiadiazine analogues 6a-e were obtained via a multistep synthesis sequences beginning with the hydroxybenzophenones 1a-e. Hydroxybenzophenones on reaction with ethyl chloroacetate affords ethyl (2-aroylaryloxy)acetates 2a-e which on treatment with hydrazine hydrate yields 2-(2-aroylaryloxy)acetohydrazides 3a-e. Intramolecular cyclization of 3a-e with carbon disulfide affords 5-(2-aroylaryloxy)methyl-1,3,4-oxadiazole-2-(3H)thiones 4a-e, which on treatment with hydrazine hydrate yields 4-amino-5-(2-aroyl aryloxy)methyl-1,2,4-triazole-3-(2H)thiones 5a-e. Condensation of 5a-e with alpha-halocarbonyl compound results in 3-(2-aroylaryloxy)methyl-6-phenyl-1,2,4-triazolo[3,4-b][1,3,4] thiadiazine 6a-e analogues. The compounds 4a-e, 5a-e and 6a-e were tested against variety of fungal and bacterial strains in comparison to fluconazole and chloramphenicol, respectively.

Anti-Infective Agents↗
PubMed2004

Characterization of human urinary bladder KATP channels containing SUR2B splice variants expressed in L-cells.

The molecular properties of the sulfonylurea receptor 2 (SUR2) subunits of K(ATP) channels expressed in urinary bladder were assessed by polymerase chain reaction (PCR). This showed that SUR2B exon 17- mRNA (72%) was predominant over the SUR2B exon 17+ splice variant (28%). The pharmacological properties of both of these isoforms stably expressed in mouse Ltk(-)cells (L-cells) with K(IR) 6.2 were determined by measuring changes in membrane potential responses evoked by K(+) channel openers using bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC(4)(3)) fluorescence. The rank order potency of a variety of structurally distinct K(+) channel openers was found to be the same in both stable cell lines and compared well with guinea pig bladder cells. The potency of these compounds in the SUR2B exon 17- cells more closely resembled the potency measured in guinea pig bladder unlike the cell line containing the SUR2B exon 17+ subtype. Analysis of the displacement of [125I]A-312110 binding with the same K(+) channel openers to the SUR2B exon 17- cells showed excellent correlation to those measured in guinea pig bladder. This study supports the notion that K(ATP) channels containing SUR2B exon 17- represent a major splice variant expressed in urinary bladder smooth muscle.

ATP-Binding Cassette Transporters↗