Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) has an important function in renal vascular ontogenesis and is constitutively expressed in podocytes of the adult kidney. The ability of VEGF to be chemotactic for monocytes and to increase the activity of collagenase and plasminogen activator may have implications for renal development and renal disease. In humans, the cellular actions of VEGF depend on binding to two specific receptors: Flt-1 and KDR. The aims of this study were: (1) to localize VEGF receptor proteins in human renal ontogenesis; (2) to quantify VEGF binding in human fetal and adult kidney; and (3) to dissect the binding into its two known components: the KDR and Flt-1 receptors. The latter aim was achieved by competitive binding of VEGF and placenta growth factor-2, which only binds to Flt-1. Quantification of 125I-VEGF binding sites was performed by autoradiography and computerized densitometry. By double-label immunohistochemistry, VEGF receptor proteins were localized solely to endothelial cells of preglomerular vessels, glomeruli, and postglomerular vessels. In developing glomeruli, VEGF receptor protein appeared as soon as endothelial cells were positive for von Willebrand factor. Specific 125I-VEGF binding could be localized to renal arteries and veins, glomeruli, and the tubulointerstitial capillary network in different developmental stages. Affinity (Kd) of adult (aK) and fetal (fK) kidneys was: Kd: glomeruli 38.6 +/- 11.2 (aK, n = 5), 36.3 +/- 7.1 (fK, n = 5); cortical tubulointerstitium 19.4 +/- 2.6 (aK, n = 5), 11.6 +/- 7.0 (fK, n = 5) pmol. Placenta growth factor-2 displaced VEGF binding in all renal structures by approximately 60%. VEGF receptor proteins thus were found only in renal endothelial cells. A coexpression of both VEGF binding sites could be shown, with Flt-1 demonstrating the most abundant VEGF receptor binding sites in the kidney. These studies support the hypothesis of a function for VEGF in adult kidney that is independent of angiogenesis.
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PMID:Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: localization and [125I]VEGF binding sites. 962 Dec 86

Isradipine, an antihypertensive agent, was encapsulated by the nanoprecipitation method using polymers including poly(epsilon-caprolactone), poly(D,L-lactide) and poly(d, L-lactide-co-glycolide). In vitro scanning electron microscopy and differential scanning calorimetry were used to characterize the nanoparticles. The average diameters of the nanoparticles ranged from 110 nm to 208 nm. PCL nanoparticles were larger than nanoparticles prepared with the other polymers. The zeta potential of the nanoparticles was negative, with values of about -25 mV which promoted good stabilization of the particles. The amorphous state of PLA and PLAGA non-loaded nanoparticles and the semi-crystalline state of PCL were demonstrated with X-ray diffraction and differential scanning calorimetry. For all nanoparticles, isradipine was found to be totally amorphous in the polymer which suggested that the drug was molecularly dispersed in the matrix. The colloidal suspensions displayed a sustained release profile in comparison with the drug release profile of isradipine in a PEG solution. Results from this investigation suggest that these nanospheres will be a good candidate delivery system for oral administration, to reduce the initial hypotensive peak and to prolong the antihypertensive effect of the drug.
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PMID:Preparation and characterization of nanoparticles containing an antihypertensive agent. 979 32

Heparin-binding growth factors have been implicated in central nervous system development, regeneration and pathology. To assess the expression pattern and possible function in multiple sclerosis, the heparin-binding growth factors pleiotrophin (PTN), midkine (MK), basic fibroblast growth factor (FGF-2) and one of its receptors (FGFR1/flg) mRNA and protein levels were examined in an experimental autoimmune encephalomyelitis (EAE) model in the Lewis rat. We assessed the time course of expression of PTN, MK and FGF-2 during EAE and determined the cellular origin of FGF-2 and FGFR1 in normal spinal cord and during inflammatory demyelination. Basal expression of PTN and MK mRNAs in normal spinal cords was significantly upregulated after induction of EAE. MK expression was upregulated two to threefold correlating with disease progression, whereas PTN expression reached peak levels threefold above basal levels during the clinical recovery period. FGF-2 mRNA expression was low in normal spinal cord and dramatically increased in correlation with progressive demyelination. FGF-2 was confined to neurons in normal tissue and shifted dramatically to microglia, paralleling their activation during EAE. Double immunohistochemistry revealed colocalization of FGF-2 to activated microglia/macrophages with strongest expression in the macrophage-rich perivascular core area and microglial expression at the edges of white and gray matter perivascular regions. FGFR1, like its ligand, was induced in activated macrophages/microglia. Growth factor expression in demyelinating diseases could serve several functions, e.g., to modulate the activity of microglia/macrophage in an autocrine fashion, to induce the expression of other factors like insulin-like growth factor 1 or plasminogen activator, which can effect regeneration or degeneration, respectively, and finally to stimulate directly localized proliferation and/or regeneration of oligodendrocytes within the lesion area.
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PMID:Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: temporally distinct expression of midkine and pleiotrophin. 981 19

Several formulations of poly(epsilon-caprolactone) (PCL), poly(lactic acid) (PLA), and poly(lactic-co-glycolic acid) (PLGA) nanocapsules containing phenylbutazone were prepared according to the interfacial deposition technique. These formulations differed in the type of polymer used to form the shell of the nanocapsules. Analysis of particle size distribution and encapsulation efficiency of the nanocapsules revealed that the type and molecular weight of polyester used were the main factors influencing these properties. PLA had the highest encapsulation efficiency with the best reproducibility. From in vitro release studies, a small amount of drug release was observed at pH 7.4. However, in the gastric medium, an important burst effect occurred and was highest with the PLGAs and lowest with PCL, suggesting that drug release from these systems is affected by the type of polymer and the environmental conditions. The two formulations of phenylbutazone-loaded nanocapsules should be evaluated based on PCL and PLA in vivo in order to determine to what extent they are able to reduce the local side effects of this drug.
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PMID:Entrapment efficiency and initial release of phenylbutazone from nanocapsules prepared from different polyesters. 987 42

Bioabsorbable polymer implants may provide a viable alternative to metal implants for internal fracture fixation. One of the potential difficulties with absorbable implants is the possible toxicity of the polymeric degradation products especially if they accumulate and become concentrated. Accordingly, material evaluation must involve dose-response toxicity data as well as mechanical properties and degradation rates. In this study the toxicity and rates of degradation for six polymers were determined, along with the toxicity of their degradation product components. The polymers studied were poly(glycolic acid) (PGA), two samples of poly(L-lactic acid) (PLA) having different molecular weights, poly(ortho ester) (POE), poly(epsilon-caprolactone) (PCL), and poly(hydroxy butyrate valerate) (5% valerate) (PHBV). Polymeric specimens were incubated at 37 degrees C in 0.05 M Tris buffer (pH 7.4 at 37 degrees C) and sterile deionized water. The solutions were not changed during the incubation intervals, providing a worst-case model of the effects of accumulation of degradation products. The pH and acute toxicity of the incubation solutions and the mass loss and logarithmic viscosity number of the polymer samples were measured at 10 days, 4, 8, 12, and 16 weeks. Toxicity was measured using a bioluminescent bacteria, acute toxicity assay system. The acute toxicity of pure PGA, PLA, POE, and PCL degradation product components was also determined. Degradation products for PHBV were not tested. PGA incubation solutions were toxic at 10 days and at all following intervals. The lower molecular weight PLA incubation solutions were not toxic in buffer but were toxic by 4 weeks in water.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Six bioabsorbable polymers: in vitro acute toxicity of accumulated degradation products. 1014 75

Fibroblast growth factor 7 (FGF7/KGF) is synthesized exclusively by fibroblasts in normal tissues; it acts as a potent mitogen on epithelial cells, through interaction with the FGF7-specific receptor FGFR2/IIIb. To examine the importance of this growth factor both to prostate physiology and to prostate-cancer progression, we have tested the exogenous effect of FGF7. Thus, by mimicking the paracrine pathway (on proliferation, growth in soft agar and invasion) on the human prostatic epithelial cell line PNT1A positively checked for FGFR2/IIIb expression, FGF7 significantly enhanced cell proliferation at an optimal concentration of 7.5 x 10(-11) M, but no significant invasion or growth in soft agar were observed. To confirm FGF7 properties on human prostatic epithelial cells, we constitutively expressed FGF7 by transfecting PNT1A cells with FGF7-cDNA. The FGF7-transfected clones, PNT1A/ FGF7-T5 and PNT1A/FGF7-T6, were stable and expressed FGF7. Analysis of the FGF7-autocrine loop on the non-tumorigenic epithelial cells PNT1A showed acquired invasive potential in in vitro extracellular-matrix migration assays, specifically inhibited by an FGF7-neutralizing antibody, and over-expressed factors implicated in the migration process: the metalloproteinase MMP-1 and the plasminogen activator uPA. Taken together, these results demonstrate a role for FGF7 in triggering invasion of human prostatic epithelial cells. Furthermore, these FGF7-transfected clones exhibited functional and physiological differences from the original PNT1A cell line: anchorage-independent growth, growth in serum-free media and increased proliferation. These data confirm the oncogenic function of FGF7 in prostate progression potentially acting through paracrine and/or autocrine regulatory pathways.
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PMID:FGF7/KGF triggers cell transformation and invasion on immortalised human prostatic epithelial PNT1A cells. 1038 58

The goal of this research was to evaluate the in vitro stability of fibrin coatings on polymeric materials in the presence of plasmin. Factor XIIIa-crosslinked and noncrosslinked fibrin layers were coated on three different polyurethane substrates: Corethane, Tegaderm, and a biodegradable polyurethane, PCL/HDI/Phe. Degradation assays indicated that crosslinking the fibrin coatings enhanced the stability of the coatings on both Tegaderm and PCL/HDI/Phe; however, the persistence of the coating on the woven Corethane was not influenced by crosslinking. Degradation assay results also showed that the fibrin coating on the Corethane was significantly less stable than the fibrin coatings on the Tegaderm and PCL/HDI/Phe films. The chromogenic substrate assay data showed crosslinking did not affect the specific plasmin activity on the coatings; therefore, the increased stability resulting from crosslinking was not achieved through a reduction of fibrinolysis. The plasmin activity on the coated Corethane samples was much greater than that on either of the coated flat wound dressing materials. The large surface area of Corethane, a porous woven vascular graft material, may have had a direct influence on the fibrinolysis of its coatings by providing a large number of tissue-type plasminogen activator (tPA) binding sites. A thin, crosslinked, fibrin-coated polyurethane provides a theoretically attractive biomaterial for use in a wound dressing application and should be subject to ongoing research.
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PMID:Plasmin degradation of fibrin coatings on synthetic polymer substrates. 1039 86

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

We have previously reported a constitutively activated form of the Flt-1 kinase (BCR-FLTm) molecularly engineered based on the structural backbone of the activated tyrosine kinase BCR-ABL. Here we show that it can induce not only growth stimulation but also tubulogenic differentiation of non-tubulogenic NP31 (non parenchymal) sinusoidal endothelial cells of rat liver in basement membrane matrix. Tubules formed in vitro were accompanied by fenestration structures and allowed circulation when transplanted into syngeneic animals. This biological response was not observed in other activated forms of kinases constructed in a similar fashion, which include Trk (BCR-TRK), KDR (BCR-KDR), and the parental BCR-ABL. Interestingly, formation of fine tubules was accomplished with lower but not higher expression levels of BCR-FLTm. Compared to NP cells in primary culture NP31 is deficient in expression of alpha1 integrin subunit, which was restored by expression of BCR-FLTm that had tubulogenic ability. Matrix-induced tyrosine phosphorylation of an adaptor protein Shc with recruitment of Grb-2 was observed even when tubulogenesis was nearly completed at G1 stage of the cell cycle in 2-3 weeks. Activation of matrix metalloproteinase 2 (MMP-2) and expression of urokinase type plasminogen activator (uPA) was observed with cellular invasion into matrix at the depth of 200-300 microm. Inhibitors for MAP kinase activator MEK1 and for serine proteases showed deleterious effects on the tubulogenesis. We suppose that matrix ligand-induced integrin signals cooperate with a low level of Flt-1 kinase activity to promote tubulogenic behaviors of endothelial cells in this system.
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PMID:An oncogenic form of the Flt-1 kinase has a tubulogenic potential in a sinusoidal endothelial cell line. 1072 21

Polyester blending of poly(epsilon-caprolactone) (PCL) with poly(D, L-lactide) (PLA) and their random copolymers (R(CL/LA)) was found to be a convenient approach to regulate the degradation and drug release behaviors of the polyesters. The blend composition and compatibility both affected its degradation and drug release behavior. A DSC study showed that PCL was compatible with 50:50 poly(CL-CO-D,L-LA) (R(50/50)) but incompatible with 25:75 poly(CL-CO-LA) (R(25/75)) and PLA homopolymer. The hydrolysis experiments indicated that with the same CL/LA segment proportion, compatible blends (PCL/R(50/50)) had higher water content and faster weight loss than incompatible blends (PCL/PLA, PCL/R(25/75)). In the compatible blends the PCL degradation rate was increased while that of R(50/50) was decreased. The controlled release kinetics, diffusion constants, and permeation coefficients of the polymer blends were measured by using northindrone (NTD) as a model. The NTD release rates from the polyester blends increased as the CL unit fraction increased but decreased with increasing the LA unit fraction in the blends. With the same CL/LA unit ratios, the NTD release rate from the compatible blend was slower than that from the incompatible blend. The NTD release from the polyester blend was controlled by the diffusion process in the early stage, but the degradation-caused NTD release was later involved. By tailoring the blend composition to such an extent that the degradation-caused release compensated the decline of the diffusion-caused release, a zero-order NTD release was achieved.
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PMID:Regulation of biodegradability and drug release behavior of aliphatic polyesters by blending. 1075 11


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