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)

To determine whether Insulin-like growth factor (IGF-I) treatment represents a potential means of enhancing the survival of cardiac muscle cells from adriamycin (ADR)-induced cell death, the present study examined the ability of IGF-I to prevent cell death. The study was performed utilising the embryonic, rat, cardiac muscle cell line, H9C2. Incubating cardiac muscle cells in the presence of adriamycin increased cell death, as determined by MTT assay and annexin V-positive cell number. The addition of 100 ng/mL IGF-I, in the presence of adriamycin, decreased apoptosis. The effect of IGF-I on phosphorylation of PI, a substrate of phosphatidylinositol 3-kinase (PI 3-kinase) or protein kinase B (AKT), was also examined in H9C2 cardiac muscle cells. IGF-I increased the phosphorylation of ERK 1 and 2 and PKC zeta kinase. The use of inhibitors of PI 3-kinase (LY 294002), in the cell death assay, demonstrated partial abrogation of the protective effect of IGF-I. The MEK1 inhibitor-PD098059 and the PKC inhibitor-chelerythrine exhibited no effect on IGF-1-induced cell protection. In the regulatory subunit of PI3K-p85- dominant, negative plasmid-transfected cells, the IGF-1-induced protective effect was reversed. This data demonstrates that IGF-I protects cardiac muscle cells from ADR-induced cell death. Although IGF-I activates several signaling pathways that contribute to its protective effect in other cell types, only activation of PI 3-kinase contributes to this effect in H9C2 cardiac muscle cells.
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PMID:Signal transduction of the protective effect of insulin like growth factor-1 on adriamycin-induced apoptosis in cardiac muscle cells. 1508 39

Hypercholesterolaemia contributes to atherosclerosis and coronary artery diseases by inducing endothelial cell injury and dysfunction. Recent studies have provided increasing evidence that EPCs (endothelial progenitor cells) participate in ongoing endothelial repair and postnatal neovascularization. However, the changes in EPCs in patients with hypercholesterolaemia have not been elucidated to date. Therefore we investigated the number and functional activity of EPCs in patients with hypercholesterolemia. Total MNCs (mononuclear cells) were isolated from 20 patients with hypercholesterolaemia and 20 matched control subjects. EPCs were characterized as adherent cells double-positive for DiI-LDL (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanide percholate-labelled low-density lipoprotein) uptake and lectin binding by direct fluorescent staining under a laser scanning confocal microscope, and were characterized further by demonstrating the expression of KDR (kinase insert domain-containing receptor), CD34 and AC133 by flow cytometry. Proliferation, migration and in vitro vasculogenesis activity of EPCs were assayed using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay, modified Boyden chamber assay and an in vitro vasculogenesis kit respectively. EPC adhesion assay was performed by replating cells on fibronectin-coated dishes and then counting the adherent cells. As a result, the number of EPCs was significantly reduced in patients with hypercholes-terolaemia compared with that in control subjects (41.8 +/- 8.7 compared with 64.5 +/- 16.6 EPCs/x 200 field respectively; P < 0.05). The number of EPCs was inversely correlated with total cholesterol (r = -0.659, P < 0.001) and LDL-cholesterol (r = -0.611, P < 0.001) levels. In addition, the functional activities of isolated EPCs, such as proliferative, migratory, adhesive and in vitro vasculogenesis capacity, were also impaired. In conclusion, the results of the present study may state a novel pathophysiological mechanism of hypercholesterolaemia: the reduction of EPCs with decreased functional activity.
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PMID:Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia. 2095 66

Biodegradable and biocompatible materials are the basis for tissue engineering. As an initial step for developing vascular grafts, the in vitro biocompatibility of poly(epsilon-caprolactone) (PCL), recently suggested for several clinical applications, was evaluated in this study using L929 mouse fibroblasts. Different cellular aspects were analyzed in order to know the cell viability during cell culture on PCL films: adhesion, proliferation, morphology, LDH release and mitochondrial function. Since topography and other surface characteristics of materials play an essential part in cell adhesion, PCL membranes with either smooth or rough surface were prepared, characterized and used to carry out cell cultures. During short culture times, PCL produced a significant stimulation of mitochondrial activity evaluated by reduction of the MTT reagent. The results provide evidences of good adhesion, growth, viability, morphology and mitochondrial activity of cells on PCL films. Therefore, it can be concluded that PCL is a suitable and biocompatible material as a scaffold for vascular graft development.
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PMID:In vitro biocompatibility assessment of poly(epsilon-caprolactone) films using L929 mouse fibroblasts. 1515 76

We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and ionizing radiation on the proliferation and survival of nonestablished human glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN and p53 molecules, activated ERBB1VIII, overexpressing wild type ERBB1 or without receptor overexpression were selected. In MTT assays, GST-MDA-7 caused a dose-dependent reduction in the proliferation of nonestablished glioma cells; however only at higher concentrations did GST-MDA-7 reduce cell viability. The anti-proliferative and cytotoxic effects of GST-MDA-7 were enhanced by radiation in a greater than additive fashion that correlated with JNK1/2/3 activation. The reduction in cell growth and enhancement in cell killing by the combination of GST-MDA-7 and radiation were blocked by an ROS scavenger, N-acetyl cysteine (NAC), a JNK1/2/3 inhibitor SP600125, a pan-caspase inhibitor (zVAD) and by an inhibitor of caspase 9 (LEHD), but not by an inhibitor of caspase 8 (IETD). Low concentrations of either GST-MDA-7 or radiation reduced clonogenic survival, however colony formation ability was significantly further decreased when the two treatments were combined, which was also blocked by inhibition of caspase 9 function. In general agreement with activation of the intrinsic caspase pathway, cell death correlated with reduced BCL-XL expression and with increased levels of the pro-apoptotic proteins BAD and BAX. Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and inhibition of ERK1/2 activity. In contrast, incubation with NAC blocked JNK1/2/3 activation and cell killing, but not the increases in BAD and BAX expression. These findings argue that after combination treatment JNK1/2/3 activation is a primary pro-apoptotic event and loss of BCL-XL expression and ERK1/2 activity are secondary caspase-dependent processes. This data also argues that GST- MDA-7 induces two parallel pro-apoptotic pathways via ROS-dependent and -independent mechanisms. Infection of primary human astrocytes with a recombinant adenovirus to express MDA-7, Ad.mda-7, but not infection with either Ad.cmv or Ad.mda-7SP- lacking MDA-7 secretion, resulted in the suppression of GBM cell colony formation in soft agar overlay assays, an effect that was enhanced in a greater than additive fashion by radiation. Collectively, our findings demonstrate that MDA-7 reduces proliferation and enhances the radiosensitivity of nonestablished human GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs independently of basal EGFR/ERK1/2/AKT activity or the functions of PTEN and p53.
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PMID:MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. 1532 89

Pancreatic cancer is a devastating malignancy, characterized by low responsiveness to conventional chemotherapies. Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has shown clinical activity against EGFR-expressing tumors. Since pancreatic cancers frequently overexpress EGFR (ErbB-1) and its ligands, our aim was to investigate the potential role of gefitinib in this disease. The GI50 of gefitinib as well as the effects of gefitinib on growth factor actions in pancreatic cancer cell lines were analyzed using MTT assays. FACS analysis using Annexin and propidium iodide (PI) staining were performed to study cell cycle, apoptosis and cell death. Western blot analysis was carried out to investigate expression levels of the 4 members of the ErbB family of receptors in pancreatic cancer cell lines, as well as MAP kinase and EGFR phosphorylation. Soft agar assays were used to measure colony formations. Invasiveness of cancer cells was analyzed using Matrigel-coated filters. gefitinib inhibited cell proliferation of pancreatic cancer cell lines with GI50 concentrations ranging from 2.5 to over 10 micro M. Gefitinib completely inhibited EGF-induced cell proliferation, but did not significantly influence insulin-like growth factor (IGF)-induced mitogenesis. Gefitinib also completely abolished EGF-induced phosphorylation of EGFR and MAP kinase. Furthermore, gefitinib inhibited basal and EGF-induced anchorage-independent cell growth and invasion. Our data demonstrate that gefitinib inhibits pancreatic cancer cell growth through EGFR-dependent pathways. Gefitinib also inhibits anchorage-independent growth and invasiveness, suggesting that gefitinib may offer a new approach for the treatment of pancreatic cancer.
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PMID:Gefitinib ('Iressa', ZD1839), a selective epidermal growth factor receptor tyrosine kinase inhibitor, inhibits pancreatic cancer cell growth, invasion, and colony formation. 1520 7

The aim of the present study was to investigate whether fluvastatin augments the number of endothelial progenitor cells (EPCs), and promotes EPCs proliferation, migration and adhesion. Total mononuclear cells (MNCs) were isolated from peripheral blood by Ficoll density gradient centrifugation. The cells were then plated on fibronectin-coated culture dishes. After being cultured for 7 d, the attached cells were stimulated with fluvastatin (final concentrations: 0.01, 0.1, 1, 10 micromol/L), simvastatin (1 micromol/L) or a vehicle for the respective time points (6, 12, 24 and 48 h). EPCs were characterized as adherent cells double positive for DiLDL-uptake and lectin binding by direct fluorescent staining under a laser scanning confocal microscope. EPCs were further documented by demonstrating the expression of KDR, VEGFR-2 and AC133 with flow cytometry. EPCs proliferation, migration and in vitro vasculogenesis activity were assayed by MTT assay, modified Boyden chamber assay and in vitro vasculogenesis kit, respectively. EPCs adhesion assay was performed by replating it on fibronectin-coated dishes, and the adherent cells were then counted. In addition, we also studied EPCs culture assay of peripheral blood from fluvastatin-treated animals in vivo. Incubation of isolated human MNCs with fluvastatin dose- and time-dependently increased the number of EPCs, while reached the maximum 24 h after the administration at 1 micromol/L, (2.5-fold increase, P<0.05). Moreover, treatment of rats with fluvastatins elevated the number of EPCs (3-fold increase, P<0.05), thus extending the in vitro data. In addition, fluvastatin also promoted EPC proliferation, migration, adhesion and in vitro vasculogenesis in a concentration-dependent manner. The effects of fluvastatin on EPCs were compared with those of simvastatin at the same concentration (1 micromol/L), with a result of no statistical difference. The results of the present study define a novel mechanism of the action of statins: the augmentation of EPCs with enhanced functional activity.
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PMID:Statins contribute to enhancement of the number and the function of endothelial progenitor cells from peripheral blood. 1522 50

Gastrodia elata (G. elata) is a traditional Chinese herbal medicine for treating headaches, dizziness, tetanus, and epilepsy. In this study, differential methanol (MeOH) extracts of G. elata were found to prevent serum-deprived rat pheochromocytoma (PC12) cell apoptosis by the MTT assay and Hoechst staining. A serine/threonine kinase inhibitor attenuated this protection. G. elata resulted in phosphorylation and dephosphorylation of ERK1/2 and JNK1/2-p38 MAPKs (members of the serine/threonine kinase family), respectively, as revealed by Western blot analysis. An upstream ERK inhibitor attenuated G. elata-induced ERK phosphorylation but not protective effect. Although JNK and p38 inhibitors attenuated their related enzyme activities during serum deprivation, only JNK inhibitor prevented serum-deprived apoptosis. Thus, G. elata prevents serum-deprived apoptosis through activation of the serine/threonine kinase-dependent pathway and suppression of JNK activity.
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PMID:Gastrodia elata prevents rat pheochromocytoma cells from serum-deprived apoptosis: the role of the MAPK family. 1526 68

Gefitinib ("Iressa", ZD1839) is a selective epidermal growth factor receptor-tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. However, in vitro and in vivo studies concerning cell growth after withdrawal of gefitinib are limited. To determine whether cancer cells would resume proliferation upon removal of gefitinib, an in vitro study was undertaken using 4 human non-small cell lung cancer cell lines. With immunocytochemical staining and Western blot analysis, we confirmed positive expression of EGFR in these cell lines. We next evaluated growth inhibition before and after withdrawal of gefitinib. After incubation with 0-100 microM gefitinib for 24 h, medium containing gefitinib was removed, followed by addition of fresh growth medium to cell cultures. MTT assays were performed daily over a 6-day time course. Even at very low levels of gefitinib (<1 microM), these 4 TKB cells had 1-10% growth inhibition, respectively. With these levels of gefitinib, continued inhibitory effects after withdrawal of getitinib were observed in 3 of the 4 cell lines. Furthermore, none of the 4 cell lines, including the cell line which had abolished growth inhibition, showed accelerated re-growth rate after the withdrawal of gefitinib even in these exposure conditions. Based on our in vitro experiments, additional in vivo studies, which can compare the pre- and post-treatment growth rate, will be necessary to help better understand the mechanisms behind cell growth recovery after temporary gefitinib treatment.
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PMID:Cell growth after withdrawal of gefitinib ("Iressa", ZD1839) in human lung cancer cells. 1528 46

In order to develop scaffolds with improved biocompatibility for cell culture, hybrid scaffolds were fabricated by modifying poly(epsilon-caprolactone) (PCL) with silk fibroin (SF) in a porous structure. Scanning electronic microscopy revealed that the morphology of the PCL-SF hybrid scaffold was affected by the concentration of the SF solution. Availability of SF on the surface and the conformational transition induced by methanol treatment were proved by attenuated total reflection Fourier transformed infrared spectroscopy (ATR-FTIR), and wettability of the hybrid scaffold was greatly improved. To evaluate scaffold biocompatibility, human fibroblasts were cultured on the hybrid scaffold with the unmodified PCL scaffold as control. An MTT assay indicated that although fewer cells were initially held on the hybrid scaffold after one day of culture, comparable cell numbers were achieved after four days and significantly more cells proliferated on the hybrid after seven days. The cell morphology also indicated that the PCL-SF hybrid scaffold was favorable for cell culture. This study suggests that surface modification with SF would be an effective way to improve the biocompatibility of PCL, facilitating its application in practical tissue engineering.
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PMID:Silk fibroin modified porous poly(epsilon-caprolactone) scaffold for human fibroblast culture in vitro. 1534 34

Brain ischemia brings about hypoxic insults. Hypoxia is one of the major pathological factors inducing neuronal injury and central nervous system infection. We studied the involvement of mitogen-activated protein (MAP) kinase in hypoxia-induced apoptosis using cobalt chloride in C6 glioma cells. In vitro cytotoxicity of cobalt chloride was tested by MTT assay. Its IC(50) value was 400 microM. The DNA fragment became evident after incubation of the cells with 300 microM cobalt chloride for 24 h. We also evidenced nuclear cleavage with morphological changes of the cells undergoing apoptosis with electron microscopy. Next, we examined the signal pathway of cobalt chloride-induced apoptosis in C6 cells. The activation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) started to increase at 1 h and was activated further at 6 h after treatment of 400 M cobalt chloride. In addition, pretreatment of PD98059 inhibited cobalt chloride-induced apoptotic cell morphology in Electron Microscopy. These results suggest that cobalt chloride is able to induce the apoptotic activity in C6 glioma cells, and its apoptotic mechanism may be associated with signal transduction via MAP kinase (ERK 1/2).
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PMID:Cobalt chloride-induced apoptosis and extracellular signal-regulated protein kinase 1/2 activation in rat C6 glioma cells. 1546 37


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