Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CHAG, that is, porous hydroxyapatite hydrothermally converted from the calcium carbonate exoskeleton of a coral (genus Goniopora), has been shown to be effective as a scaffold for bone ingrowth. The large pores in the material, however, resulted in low compressive strengths. Compressive testing was performed to assess the changes in mechanical properties by coating the internal surfaces of CHAG with DL-PLA. Plugs of CHAG with thick (3:1 chloroform to DL-PLA by weight), medium (10:1), and thin (30:1) coatings as well as uncoated CHAG were then implanted transcortically in the proximal third of the diaphysis of rabbit tibiae to assess the in vivo response. The mechanical tests demonstrated significantly improved compressive strength, stiffness, and energy absorption for coated specimens compared with uncoated specimens. Coated specimens were not significantly different from canine tibial cancellous bone in strength and stiffness although they achieved only 36% of the energy absorption capacity. Specimens from rabbit tibiae were harvested at 3, 12, and 24 weeks for interface shear strength determination and contralaterally for histological and histomorphometric assessment. At 12 weeks, uncoated CHAG plugs developed an average ultimate interface shear stress of 26.7 MPa compared with 17 MPa for specimens with 30:1 coatings and 8 MPa for specimens with 10:1 and 3:1 coatings. At 24 weeks, there were no significant differences in shear stress between any of the specimens. Histomorphometric assessments showed that the ratio of area fraction of new bone to area fraction of new bone and void space increased from 68-70% for specimens with 3:1 and 10:1 coatings at 3 weeks to 85.5-89.5% at 24 weeks. In comparison, uncoated and 30:1 specimens had area fraction ratios of about 82% at 3 weeks and 93% at 24 weeks. Histologic sections demonstrated direct apposition of new bone to both the coating and the hydroxyapatite as well as degradation of the coating.
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PMID:Mechanical and bone ingrowth properties of a polymer-coated, porous, synthetic, coralline hydroxyapatite bone-graft material. 289 22

In rats, fibrinolytic activity and acidosis increased rapidly after death. Postmortem fibrinolysis and the pH, base excess (BE), and [HCO3-] levels were affected by the method of sacrifice: the lower the pH, BE, and [HCO3-] levels, the higher the fibrinolytic activity. Conversely, in experiments using the vascular perfusion technique, low pH, BE, and [HCO3-] levels of the perfusate induced abundant release of plasminogen activator from the vascular wall.
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PMID:Fluidity of cadaveric blood after sudden death: Part III. Acid-base balance and fibrinolysis. 372 18

Tyrosine-derived polycarbonates are a new class of degradable polymers developed for orthopedic applications. In this study the long-term (48 week) in vivo degradation kinetics and host bone response to poly(DTE carbonate) and poly(DTH carbonate) were investigated using a canine bone chamber model. Poly(L-lactic acid) (PLA) served as a control material. Two chambers of each test material were retrieved at 6-, 12-, 24-, and 48-week time points. Tyrosine-derived polycarbonates were found to exhibit degradation kinetics comparable to PLA. Each test material lost approximately 50% of its initial molecular weight (Mw) over the 48-week test period. Poly(DTE carbonate) and poly(DTH carbonate) test chambers were characterized by sustained bone ingrowth throughout the 48 weeks. In contrast, bone ingrowth into the PLA chambers peaked at 24 weeks and dropped by half at the 48-week time point. A fibrous tissue layer was found surrounding the PLA implants at all time points. This fibrous tissue layer was notably absent at the interface between bone and the tyrosine-derived polycarbonates. Histologic sections revealed intimate contact between bone and tyrosine-derived polycarbonates. From a degradation-biocompatibility perspective, the tyrosine-derived polycarbonates appear to be comparable, if not superior, to PLA in this canine bone chamber model.
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PMID:Canine bone response to tyrosine-derived polycarbonates and poly(L-lactic acid). 873 Nov 47

A degradable L-PLA/calcium carbonate composite made of interconnecting phases was examined. This structure was used both to slow the degradation rate and to reduce the brittleness of the ceramic. Both in vitro and in vivo degradation studies were performed. Samples were incubated in buffered saline or placed in the dorsum of rats for 0, 1, or 4 weeks. Mechanical testing was performed on both groups, volume fraction of each component was determined for in vitro samples, and histology was performed on in vivo samples. Failure load, tensile strength, and elastic modulus significantly decreased during the 1st week for both groups. Continued decreases were seen at 4 weeks for in vitro samples but not for in vivo. Failure strain and tensile strength decreased only for in vitro specimens. PLA fraction significantly decreased during the 1st week and then stabilized. Histology showed that tissue ingrowth occurred at 4 weeks. The decrease in mechanical properties was probably a result of the decreased PLA fraction. The stabilization and even a slight increase in tensile strength and failure strain in the in vivo samples was probably due to the tissue ingrowth forming an implant-tissue composite.
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PMID:Analysis of a biodegradable composite for bone healing. 889 47

A library of compounds were prepared by reacting 2-(bromomethyl)-1, 2-benzisothiazol-3(2H)-one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a tertiary amine base. From this library, (1,1-dioxido-3-oxo-1, 2-benzisothiazol-2(3H)-yl)methyl N-[(phenylmethoxy)carbonyl]-beta-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 microM). Extension of the side chain of 7b by two carbons gave (1, 1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 5-[[(phenylmethoxy)carbonyl]amino]pentanoate (7d) which was an 8-fold more potent inhibitor (IC50 = 0.1 microM). Further modification of this series produced benzoic acid derivative (1, 1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 4-[[(phenylmethoxy)carbonyl]amino]benzoate (7n) which is the most potent inhibitor identified in this series (IC50 = 0.064 microM). These compounds exhibit time-dependent inhibition consistent with mechanism-based inhibition. For 7b, the initial enzyme velocity is not a saturable function of the inhibitor concentration and the initial Ki could not be determined (Ki > 10 microM). The steady-state rate constant, Ki, was determined to be 396 nM. On the other hand, compounds 7d and 7n are time-dependent inhibitors with a saturable initial complex. From these studies, an initial rate constant, Ki, for 7d and 7n was found to be 345 and 465 nM, respectively. The steady-state inhibition constants, Ki, for 7d and 7n were calculated to be 60 and 52 nM, respectively. Compound 7n is a 13-fold more potent inhibitor than 7b, and these kinetic studies indicate that the increase in inhibitory activity is due to an increase in initial affinity toward the enzyme and not an increase in chemical reactivity. These inhibitors generally show high selectivity for tryptase, being 40-fold weaker inhibitors of elastase, being 100-fold weaker against trypsin, and showing no inhibition against thrombin. These compounds are not inhibitors of thrombin, plasmin t-PA, urokinase, and factor Xa (IC50 > 33 microM). In the delayed-type hypersensitivity (DTH) mouse model, a model of skin inflammation, a 5% solution of 7d reduced edema by 69% compared to control animals.
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PMID:1,2-Benzisothiazol-3-one 1,1-dioxide inhibitors of human mast cell tryptase. 982 54

The effect of polymer chemistry on adhesion, proliferation, and morphology of human articular cartilage (HAC) chondrocytes was evaluated on synthetic degradable polymer films and tissue culture polystyrene (TCPS) as a control. Two-dimensional surfaces of poly(glycolide) (PGA), poly(L-lactide) (L-PLA), poly(D,L-lactide) (D,L-PLA), 85:15 poly(D,L-lactide-co-glycolide) (D,L-PLGA), poly(epsilon-caprolactone) (PCL), 90:10 (D,L-lactide-co-caprolactone) (D,L-PLCL), 9:91 D,L-PLCL, 40:60 L-PLCL, 67:33 poly(glycolide-co-trimethylene carbonate) (PGTMC), and poly(dioxanone) (PDO) were made by spin-casting into uniform thin films. Adhesion kinetics were studied using TCPS and PCL films and revealed that the rate of chondrocyte adhesion began to level off after 6 h. Degree of HAC chondrocyte adhesion was studied on all the substrates after 8 h, and ranged from 47 to 145% of the attachment found on TCPS. The greatest number of chondrocytes attached to PGA and 67:33 PGTMC polymer films, and attachment to PCL and L-PLA films was statistically lower than that found on PGA (p < 0.05). There was no correlation between amount of chondrocyte attachment to the substrates and the substrates' water contact angle. Chondrocytes proliferated equally well on all the substrates resulting in equivalent cell numbers on all the substrates at both day 4 and day 7 of the culture. However, these total cell numbers were reached as a result of a 88- and 42-fold expansion on PDO and PLA, respectively, which was significantly higher than the 11-fold expansion found on TCPS (p < 0.05). The greater fold expansion of the cells on PDO and L-PLA films may be attributed to the availability of space for cells to grow, since their numbers at the start of culture were fewer following the 8 h attachment period. This suggests that regardless of initial seeding density on these degradable polymer substrates (i.e., if some minimum number of cells are able to attach), they will eventually populate the surfaces of all these polymers given sufficient space and time.
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PMID:Human articular chondrocyte adhesion and proliferation on synthetic biodegradable polymer films. 1061 31

The preparation, characterisation and drug release behaviour of ibuprofen loaded poly(D,L-lactic acid) (PLA) microspheres are described. Depending on the gelatin concentration in the aqueous external solution (1, 0.5, 0.1% w/v), microspheres with three different sizes (2.2, 4.1, 7.5 micrometer) were obtained. The properties of microspheres washed with water (Untreated microspheres) (Un-Ms) were compared to those of the microspheres washed with a sodium carbonate solution in order to remove the surface drug (treated microspheres) (T-Ms). The results indicate that the removal of the surface drug did not induce any change in the size of the microspheres whereas the morphology of the smallest T-Ms appeared to be modified. The release profiles of both Un-Ms and T-Ms resulted in biphasic patterns. The initial burst effect (first release phase) of the T-Ms was lower than that of the Un-Ms. The rate of the second release phase did not change for the microspheres with the biggest size but increased for the smallest microspheres probably owing to the modification of the matrix porosity.
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PMID:Surface drug removal from ibuprofen-loaded PLA microspheres. 1067 2

Previously, we obtained a protein that has considerable amino acid sequence homology with secretory phospholipase A(2) (PLA(2)) from a bullfrog pituitary fraction obtained during the purification of thyrotropin (TSH). Subsequently, partial amino acid sequence (N-terminal 45 amino acid residues) analysis revealed this protein to be identical to the N-terminal amino acid sequence of otoconin-22, the major protein of aragonitic otoconia in the Xenopus saccule. In this study we developed an antibody against the N-terminal peptide of the bullfrog protein and applied it for immunocytochemical study of the pituitary and its surrounding tissue. Western blotting analysis showed that this antibody recognizes a 20.4-kD protein that has a molecular mass close to that of otoconin-22. Immunohistochemical reaction with the antibody was not found in any anterior pituitary cells but was intense in the monolayer epithelial cells of the endolymphatic sac surrounding the pituitary gland, which is a major storage site of calcium carbonate in amphibians. An electron microscopic study revealed that the cuboidal cells in the endolymphatic sac contained large, polymorphic secretory granules in their apical cytoplasm. Immunogold particles indicating the presence of a PLA(2)-like protein were observed predominately in these secretory granules. These findings support the view that this PLA(2)-like protein obtained during purification of TSH was derived from the endolymphatic sac adhering to the pituitary and that this protein is a bullfrog otoconin. (J Histochem Cytochem 49:631-637, 2001)
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PMID:Immunocytochemical localization of secretory phospholipase A(2)-like protein in the pituitary gland and surrounding tissue of the bullfrog, Rana catesbeiana. 1130 1

Future surgical strategies to restore neurological function in peripheral nerve loss may involve replacement of nerve tissue with cultured Schwann cells using biodegradable guiding implants. Random copolymers of trimethylene carbonate and epsilon caprolactone (P(epsilonCL-TMC), 50: 50) have been synthesized by ring opening polymerization using rare earth alkoxides as initiator. Their potential use as nerve guide repairs has been assessed through indirect and direct in vitro biocompatibility tests and in vivo soft tissue response to EDI subclass macrophages. In vitro, we exposed monolayers of human skin fibroblasts and an established continuous cell line (Hela) to liquid extracts (either pure or diluted in the culture medium) of epsilonCL-TMC copolymer including positive (phenol) and negative controls. Then, colorimetric assays (Neutral red and MTT) were performed. The extracts of epsilonCL-TMC induced no significant cytotoxic effect. We also exposed in vitro Schwann cells to pieces of P(epsilonCL-TMC) and P(LA-GA) copolymers. We evaluated cell attachment at 1 and 3 h by measuring the activity of the lysosomal enzyme (N-acetyl-beta-hexosaminidase) and cell proliferation at 1, 3, 6 and 9 days by measuring the cell metabolic activity (MTT assay). Values for attachment slightly decreased between 1 and 3 h but were significantly higher than on agars (negative control). Cells plated on epsilonCL-TMC showed a rate of proliferation comparable with that of normalized controls and higher than on PGA-PLA at day 9. Finally, we evaluated in vivo the soft tissue response after implantation of cylindrical tubes of P(epsilonCL-TMC) and P(LA-GA) copolymers with an immunohistochemistry staining procedure for the newly recruited ED1 macrophages. An image analysis system automatically measured the optical density of labelled positive ED1 cells at 9, 21 and 60 days after implantation. epsilonCL-TMC copolymer showed a mild soft tissue reaction with no adverse chronic inflammatory reaction. These data allowed us to consider this conduit as a potential effective substitute in nerve repair. El sevier Science Ltd. All rights reserved.
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PMID:Study of a (trimethylenecarbonate-co-epsilon-caprolactone) polymer--part 2: in vitro cytocompatibility analysis and in vivo ED1 cell response of a new nerve guide. 1157 69

Photoreactive phenylazide-end-capped liquid copolymers were prepared by ring-opening copolymerization of epsilon-caprolactone (CL) and trimethylene carbonate (TMC) at an equimolar monomer feed ratio in the presence of a polyol, namely, a low-molecular-weight alcohol (di-, tri-, and tetraol) or poly(ethylene glycol) (PEG) as an initiator and tin(II) 2-ethylhexanoate as a catalyst, followed subsequently by phenylazide derivatization at their hydroxyl terminus. These tri- and tetrabranched liquid copolymers (precursors) with a molecular weight from approximately 2500 to 7000 g/mol were cross-linked to yield insoluble solids by ultraviolet (UV) light irradiation. The photocuring rate increased with increasing functionality of phenylazide and UV intensity and decreasing thickness of the liquid film of precursors. The photo-cross-linkability of phenylazide-derivatized liquid copolymers was found to be higher than that of the corresponding coumarin-derivatized liquid copolymers. Poly(lactide) (PLA) films surface-layered with photocured copolymers were prepared by coating surfaces with phenylazide-derivatized copolymers and their subsequent photoirradiation. Endothelial cells adhered well on the nontreated PLA and low-molecular-weight alcohol-based copolymer-layered and photocured films. Little cell adhesion was observed on the hydrolytically surface-eroded PLA film and the PEG-based copolymer-layered film. When a phenylazide-derivatized hexapeptide with the cell-adhesion tripeptidyl sequence, Arg-Gly-Asp (RGD), common to cell adhesive proteins, was photoimmobilized on these surfaces, the surfaces became cell adhesive. Microarchitectured surfaces, which were prepared by sequential procedures of surface coating and photocuring using a photomask with lattice windows, produced regionally differentiated cell adhesiveness.
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PMID:Liquid, phenylazide-end-capped copolymers of epsilon-caprolactone and trimethylene carbonate: preparation, photocuring characteristics, and surface layering. 1209 9


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