Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Proliferation of vascular smooth muscle cells (VSMC) contributes to the pathogenesis of atherosclerosis, and glycated serum albumin (GSA, Amadori adduct of albumin) might be a mitogen for VSMC proliferation, which may further be associated with diabetic vascular complications. In this study, we investigated the involvement of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and protein kinase C (PKC), in GSA-stimulated mitogenesis, as well as the functional relationship between these factors. VSMC stimulation with GSA resulted in a marked activation of ERK. The MAPK kinase (MEK) inhibitor, PD98059, blocked GSA-stimulated MAPK activation and resulted in an inhibition of GSA-stimulated VSMC proliferation. GSA also increased PKC activity in VSMC in a dose-dependent manner. The inhibition of PKC by the PKC inhibitors, GF109203X and Rottlerin (PKCdelta specific inhibitor), as well as PKC downregulation by phorbol 12-myristate 13-acetate (PMA), inhibited GSA-induced cell proliferation and blocked ERK activation. This indicates that phorbol ester-sensitive PKC isoforms including PKCdelta are involved in MAPK activation. Thus, we show that the MAPK cascade is required for GSA-induced proliferation, and that phorbol ester-sensitive PKC isoforms contribute to cell activation and proliferation in GSA-stimulated VSMC.
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PMID:Glycated serum albumin-induced vascular smooth muscle cell proliferation through activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by protein kinase C. 1123 43

This study was designed to systematically investigate the characteristics of bovine serum albumin (BSA) loaded poly(epsilon-caprolactine) (PCL) microparticles based on a 2(4) factorial experiment. The influences of polyvinyl pyrrolidone (PVP) concentration, BSA/PCL ratio, w/o/o/o ratio, and PEG/PCL ratio on the surface morphology, particle size, as well as the yield of microparticles, encapsulation efficiency of BSA, and in vitro release properties were evaluated. The microparticles were prepared by the w/o/o/o solvent evaporation method. The structure of BSA retained its integrity using this technique. The mean particle sizes of BSA-loded microparticles were in the range of 20-50 microm, and a highly porous morphology existed in these microparticles, irrespective of the formulations. The production yields of microparticles were in the range of 52.1-89.0%, and the encapsulation efficiencies were in the range of 13.8-68.3%. The burst release of BSA was in the range of 6.9-69.0%. The volume ration of the multi-phases significantly affected the encapsulation efficiency of BSA in PCL microparticles, and the initial amount of BSA encapsulated by PCL in terms of BSA/PCL ratio significantly affected the amount of BSA released at the end of 14 days (p < 0.05).
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PMID:Characterization of protein-loaded poly(epsilon-caprolactone) microparticles based on a factorial design. 1125 35

The selective accumulation of eosinophils in tissue is a characteristic feature of allergic diseases where there is a predominance of lymphocytes expressing a Th2 phenotype. In an attempt to define factors determining specific eosinophil accumulation in vivo, we have used a radiolabeled technique to assess the occurrence and the mechanisms underlying (111)In-eosinophil recruitment into Th1- and Th2-predominant, delayed-type hypersensitivity (DTH) reactions. Eosinophils were purified from the blood of IL-5 transgenic mice, labeled with (111)In and injected into nontransgenic CBA/Ca mice. Th1- and Th2-predominant, DTH reactions were induced in mice by immunization with methylated bovine serum albumin (MBSA) in Freund's complete adjuvant or with Schistosoma mansoni eggs, respectively. In these animals, (111)In-eosinophils were recruited in skin sites in an antigen-, time-, and concentration-dependent manner. Depletion of CD4+ lymphocytes abrogated (111)In-eosinophil recruitment in both reactions. Pretreatment of animals with anti-IFN-gamma mAb abrogated (111)In-eosinophil recruitment in MBSA-immunized and -challenged animals, whereas anti-IL-4 inhibited (111)In-eosinophil recruitment in both models. Local pretreatment with an anti-eotaxin polyclonal antibody inhibited the MBSA and SEA reactions by 51% and 39%, respectively. These results demonstrate that, although eosinophilia is not a feature of Th1-predominant, DTH reactions, these reactions produce the necessary chemoattractants and express the necessary cell adhesion molecules for eosinophil migration. The control of the circulating levels of eosinophils appears to be a most important strategy in determining tissue eosinophilia.
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PMID:Eosinophil recruitment into sites of delayed-type hypersensitivity reactions in mice. 1126 81

This study was systematically designed to compare bovine serum albumin (BSA) loaded poly(epsilon-caprolactone) (PCL) microparticles based on a 2(3) factorial experiment. The microparticles were prepared by the holt-melt technique without using an organic solvent for polymer solubilization. The influence of the particle size of protein, protein/polymer ratio, and hydrophilic PEG on the surface morphology, particle size as well as the yield of PCL microparticles, encapsulation efficiency of BSA, and in vitro release properties were investigated. The structure of BSA remained its integrity using this technique. The mean particle size of BSA-loaded microparticles were in the range of 12.7 +/- 0.1-16.9 +/- 0.8 microm, and all of the particles were smooth on the surface. The production yield of microparticles and the encapsulation efficiencies were high, and the values were in the range of 94.8 +/- 1.6%-98.1 +/- 1.0% and 94.9 +/- 9.6%-98.6 + 0.3%, respectively. The burst release of BSA was in the range of 8.2 +/- 0.4%-61.0 +/- 0.8%, which strongly depended on the formulation. None of three variables affected the yield of microparticles prepared from eight formulations (p > 0.05). However, the particle size of BSA significantly affected the size and the burst release as well as the cumulative release of protein in these microparticles (p < 0.05). The initial loading of BSA in terms of BSA/PCL ratio and the amount of PEG blended with PCL significantly affected all of the properties, except the yield (p < 0.05). The smaller the particle size of the BSA, the smaller the size of the resulting microparticles. Since the total surface area of the small particles was larger than that of the large particles, this accounted for the high burst release of protein from the microparticles encapsulating triturated-BSA.
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PMID:Comparison of protein loaded poly(epsilon-caprolactone) microparticles prepared by the hot-melt technique. 1150 64

Dendritic cells (DC) with the potential to induce anti-tumour immunity represent one of the promising candidates for cancer vaccines. Efficiency of ex vivo DC generation depends on culture conditions, especially protein components in the plasma or serum used. Using human serum albumin (HSA), we devised a constant and reproducible culture method for DC generation from peripheral blood CD14+ cells. The number of DC obtained with 2% HSA-supplemented cultures containing granulocyte-macrophage colony-stimulating factor and interleukin 4 were consistently higher than in cultures with various concentrations of autologous plasma or serum. The concentrations and time points tested for plasma or serum considerably affected the number of DC recovered. DC prepared with HSA acquired the ability to uptake dextran, and expressed high levels of major histocompatibility (MHC) and co-stimulatory molecules similar to DC cultured with autologous plasma or serum. Although DC cultured with autologous plasma or serum consisted of CD1a+ and CD1a- populations, DC differentiated in the presence of HSA expressed CD1a. DC obtained with HSA primed and induced immunogenic peptide-specific cytotoxic T lymphocytes against a tumour rejection antigen, HER2. These findings suggest that our method for preparation of DC with HSA should prove valuable in DC generation for immunotherapy.
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PMID:Efficient ex vivo generation of dendritic cells from CD14+ blood monocytes in the presence of human serum albumin for use in clinical vaccine trials. 1155 98

The protein release profiles and the morphology of poly(D,L-lactide-co-glycolide) (PLG) and poly(epsilon-caprolactone) (PCL) microcapsules were investigated. The microcapsules were prepared by the (oil(1)-in-oil2)-in-water emulsion solvent evaporation method using bovine serum albumin (BSA) as a model protein. The internal and external morphologies of the microcapsules were examined using a light microscope, scanning electron microscope and a laser scanning confocal microscope. A Coulter counter was used to determine particle size and particle size distribution. Protein quantitation and molecular integrity were performed by the bicinchoninic acid protein assay micro-method and SDS-PAGE, respectively. Microcapsules with a polymeric wall surrounding an oily core containing the protein were formed. The encapsulation efficiency (39-96%) for PLG and (13-90%) for PCL increased with polymer molecular weight and particle volume mean diameter (Vmd). Vmd ranged from 87-128 to 42-157 microm for PLG and PCL, respectively. The protein release profile for PLG microcapsules was either continuous or irregularly pulsatile depending on particle morphology and was completed after cavity breakdown. However, that of PCL microcapsules was essentially irregularly pulsatile and was completed after a longer period of time without cavity breakdown but with significant swelling. There was no detectable cleavage of the protein during 6 months storage of PLG and PCL microcapsules at 4 degrees C. Furthermore, insignificant degradation of protein occurred during in vitro release from PCL microcapsules. In contrast, significant degradation occurred in PLG microcapsules. This approach to microencapsulation of a protein may be promising for the controlled delivery of protein vaccines, and the oil core may enhance the immunogenicity of some weak subunit vaccine candidates.
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PMID:Protein release profiles and morphology of biodegradable microcapsules containing an oily core. 1157 45

A method is described to amplify the delivery of 111In to human breast cancer cells utilizing a novel human serum albumin-human EGF (HSA-hEGF) bioconjugate substituted preferentially in the HSA domain with multiple DTPA metal chelators for 111In. 111In-DTPA-HSA-hEGF exhibited a lower receptor-binding affinity than 111In-DTPA-hEGF but was rapidly and specifically bound, internalized and translocated to the nucleus in EGFR-positive MDA-MB-468 breast cancer cells. 111In-DTPA-HSA-hEGF was cytotoxic in vitro mainly through the emission of short-range Auger electrons and partially through the effects of the hEGF moiety to MDA-MB-468 cells overexpressing EGFR (1-2 x 10(6) receptors/cell) but not towards MCF-7 breast cancer cells with a 100-fold lower level of EGFR on their surface. The cytotoxicity in vitro against MDA-MB-468 cells of 111In-DTPA-HSA-hEGF substituted with nine DTPA chelators was enhanced 4-fold compared to 111In-DTPA-hEGF monosubstituted with DTPA. Studies are planned to further evaluate 111In-DTPA-HSA-hEGF in vivo as a new imaging and targeted radiotherapeutic agent for breast cancer.
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PMID:Amplified delivery of indium-111 to EGFR-positive human breast cancer cells. 1171 8

The biochemical and toxicological effects of occupational and dietary exposure of humans to cyanide poisoning from large-scale cassava processing and ingestion of cassava foods were investigated using spectrophotometric and enzymatic methods. Analysis of urinary and serum thiocyanate (cyanide metabolite) from workers in cassava processing industries, who were 'frequent' [those who eat cassava food(s) at least once a day] and 'infrequent' [those who eat cassava food(s) only occasionally] consumers of cassava-based diets, was carried out with the aid of questionnaries. The mean urinary thiocyanate level of the cassava processors (mean+/-S.D.; 153.50+/-25.21 micromo1/l) was 2.2 and 2.6 times higher than that of frequent (70.1+/-21.8 micromo1/l) and infrequent (mean+/-S.D.; 59.30+/-17.0 micromo1/l) cassava consumers, respectively. The mean serum thiocyanate levels rose to 126.73+/-12.4 micromo1/l for the former and 68.4+/-18.3 and 54.7+/-13.2 micromo1/l, respectively, for the latter. An increase in plasma activity by 10% above normal of aspartate aminotransferase (AST) was observed in 40% of the cassava processors, whereas it was within normal range in all consumers. The activities of alanine aminotransferase (ALT) and alkaline phosphatase (ALK.PHOS) were within the normal value in all cases studied. The blood glucose level of 50% of the cassava processors was 100 mg/ml or above while that of the consumers was in the range of 68-85 mg/100 ml. The total protein, serum albumin and creatinine levels were in the range for normal values for the processors and consumers. The health implications of these findings are discussed.
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PMID:Occupational and dietary exposures of humans to cyanide poisoning from large-scale cassava processing and ingestion of cassava foods. 1206 22

Dach1 is a mouse homologue of the Drosophila dachshund gene, which is a key regulator of cell fate determination during eye, leg, and brain development in the fly. We have investigated the expression and growth factor regulation of Dach1 during pre- and postnatal skeletal development in the mouse limb to understand better the function of Dach1. Dach1 was expressed in the distal mesenchyme of the early embryonic mouse limb bud and subsequently became restricted to the tips of digital cartilages. Dach1 protein was localized to postmitotic, prehypertrophic, and early hypertrophic chondrocytes during the initiation of ossification centers, but Dach1 was not expressed in growth plates that exhibited extensive ossification. Dach1 colocalized with Runx2/Cbfa1 in chondrocytes but not in the forming bone collar or primary spongiosa. Dach1 also colocalized with cyclin-dependent kinase inhibitors p27 (Kip1) and p57 (Kip2) in chondrocytes of the growth plate and in the epiphysis before the formation of the secondary ossification center. Because fibroblast growth factors (FGF), bone morphogenetic proteins (BMP), and hedgehog molecules (Hh) regulate skeletal patterning of the limb bud and chondrocyte maturation in developing endochondral bones, we investigated the regulation of Dach1 by these growth and differentiation factors. Expression of Dach1 in 11 days postcoitus mouse limb buds in organ culture was up-regulated by implanting beads soaked in FGF1, 2, 8, or 9 but not FGF10. BMP4-soaked beads down-regulated Dach1 expression, whereas Shh and bovine serum albumin had no effect. Furthermore, FGF4 or 8 could substitute for the apical ectodermal ridge in maintaining Dach1 expression in the limb buds. Immunolocalization of FGFR2 and FGFR3 revealed overlap with Dach1 expression during skeletal patterning and chondrocyte maturation. We conclude that Dach1 is a target gene of FGF signaling during limb skeletal development, and Dach1 may function as an intermediary in the FGF signaling pathway regulating cell proliferation or differentiation.
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PMID:Fibroblast growth factor signaling regulates Dach1 expression during skeletal development. 1220 18

Most low-molecular-weight drugs are short-lived species in the circulatory system, being rapidly eliminated by glomerular filtration in the kidney. However, binding to human serum albumin (HSA) can slow clearance and prolong lifetime profile in vivo. In this study, we have engineered a gentamicin derivative with affinity to albumin by linking three (2-sulfo)-9-fluorenylmethoxycarbonyl (FMS) to three amino groups of gentamicin C(1). FMS(3)-gentamicin associates with HSA with a K(a) value of (1.31 +/- 0.2) x 10(5) M(-1). It has less than 1% the antibacterial potency of native gentamicin. Upon incubation at pH 8.5 and 37 degrees C, the FMS moieties from FMS(3)-gentamicin undergo slow hydrolysis (t(1/2) = 8.0 +/- 0.2 h), leading to a linear regeneration of the antibacterial potency with a t(1/2) value of 11 +/- 0.7 h. FMS(3)-gentamicin is a long-lived species in the rat circulatory system. Following a single subcutaneous or intravenous administration, it maintains a prolonged pharmacokinetic profile with a peak and a "through" concentration of immuno/antibacterial active gentamicin exceeding 4-5 times the duration obtained by administered native gentamicin. To sum up, an approach aimed at elongating the lifetime of low-molecular-weight drugs in vivo has been examined here with gentamicin. Two to three FMS per mole of compound are to be introduced to obtain an albumin associating affinity of K(d) = 7.6-9.2 microM and, hence, to significantly extend the drug's lifetime in situ following administration. By use of this technology, the loss of pharmacological potency with derivatization is of no consequence, since FMS moieties are hydrolyzed and activity is generated at physiological conditions.
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PMID:N-[(2-Sulfo)-9-fluorenylmethoxycarbonyl](3)-gentamicin C(1) is a long-acting prodrug derivative. 1221 67


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