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)

Surgical reconstruction is generally recommended for PCL and associated ligament injuries. A variety of graft choices exist for PCL reconstruction surgery. This study evaluated the initial fixation strength of three grafts using in PCL reconstruction in a porcine model. Twenty fresh porcine knees were harvested and randomly assigned to four groups: bone-patellar tendon-bone graft, quadruple tendons graft, Achilles tendon graft, and normal PCL. After reconstruction the knee was tested on an MTS testing machine by translating the tibia posteriorly until failure at 30 degrees of flexion, neutral rotation, and anatomical vertical alignment. Biomechanical parameters including maximal failure load, stiffness, and failure modes, were analyzed and compared. In the maximal failure load, the four-strand tendon group was significantly greater than the other two grafts. However, it had greatest translation. There were no significant differences between the three grafts in stiffness. All three of these commonly used grafts had weaker initial fixation strength and stiffness than normal PCL. Graft failure occurred mainly at the tendon-bone junction and tendon-suture sites. The Patellar tendon group had significantly least translation during continuing loading.
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PMID:Fixation strength of three different graft types used in posterior cruciate ligament reconstruction. 1458 92

The ideal dermal matrix should be able to provide the right biological and physical environment to ensure homogenous cell and extracellular matrix (ECM) distribution, as well as the right size and morphology of the neo-tissue required. Four natural and synthetic 3D matrices were evaluated in vitro as dermal matrices, namely (1) equine collagen foam, TissuFleece, (2) acellular dermal replacement, Alloderm, (3) knitted poly(lactic-co-glycolic acid) (10:90)-poly(-caprolactone) (PLGA-PCL) mesh, (4) chitosan scaffold. Human dermal fibroblasts were cultured on the specimens over 3 weeks. Cell morphology, distribution and viability were assessed by electron microscopy, histology and confocal laser microscopy. Metabolic activity and DNA synthesis were analysed via MTS metabolic assay and [(3)H]-thymidine uptake, while ECM protein expression was determined by immunohistochemistry. TissuFleece, Alloderm and PLGA-PCL mesh supported cell attachment, proliferation and neo-tissue formation. However, TissuFleece contracted to 10% of the original size while Alloderm supported cell proliferation predominantly on the surface of the material. PLGA-PCL mesh promoted more homogenous cell distribution and tissue formation. Chitosan scaffolds did not support cell attachment and proliferation. These results demonstrated that physical characteristics including porosity and mechanical stability to withstand cell contraction forces are important in determining the success of a dermal matrix material.
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PMID:In vitro characterization of natural and synthetic dermal matrices cultured with human dermal fibroblasts. 1496 59

Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30-50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15-60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.
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PMID:Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. 1507 90

HER2 is the target of a new treatment for metastatic breast cancer using the humanized monoclonal antibody (MAb) trastuzumb (Herceptin). A novel alpha-particle emitting (213)Bi-Herceptin construct, targeting the HER2 extracellular domain on breast cancer cells, was produced by chelation and characterized in vitro in this study. We used Western blot and flow cytometry analysis to examine the expression of HER2 in a panel of established human metastatic breast cancer cell lines (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) MTS assay to evaluate the cytotoxicity and the TUNEL assay to analyze cellular apoptosis. Our results demonstrate that the human breast cancer cell lines BT-474 and SK-BR-3 express high levels of HER2 protein while MDA-231 expresses low levels of HER2. (213)Bi-Herceptin alpha conjugate (AC) was specifically cytotoxic to these cell lines in a HER2 level-dependent fashion, resulting in the cellular death through apoptosis. These results suggest that (231)Bi-Herceptin AC could be a novel agent for the treatment of breast cancer cell clusters or micro-metastases with high levels of HER2 expression.
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PMID:Cytotoxicity of breast cancer cells overexpressing HER2/neu by 213Bi-Herceptin radioimmunoconjugate. 1567 Aug 95

Bacterial superantigens (SAg) are the most potent activators of human T lymphocytes and recombinant immunotoxin using bacterial SAg shows promising clinical values. To engineer superantigen for immunotherapy of hepatocellular carcinoma, we genetically fused the superantigen staphylococcus enterotoxin A (SEA(D(227)A)) to the single-chain disulfide-stabilized Fv (scdsFv) of anti-hepatoma monoclonal antibody HAb25 through a short peptide GGGSGGS. We expressed this recombinant protein in Escherichia coli and extract it from inclusion bodies. We found purified scdsFv-targeted SAg contains equivalent binding affinity with disulfide-stabilized Fv (dsFv) targeted SAg and single-chain Fvs (scFv) targeted SAg, but more stable and more suitable for large scale production. The MTS(3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoliu m, inner salt) assay shows that the scdsFv-targeted SAg also shares the ability to activate a large number of T lymphocytes and has cytotoxic activity on human hepatoma cell line SMMC-7721. Therefore, this novel generation of recombinant immunotoxins using scdsFv has a high potential in hepato cancer treatment and the same strategy may also be applied to other cancer treatments.
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PMID:Improved stability and yield of Fv targeted superantigen by introducing both linker and disulfide bond into the targeting moiety. 1592 40

In last couple of decades the use of natural compounds like flavonoids as chemopreventive agents has gained much attention. Our current study focuses on identifying chemopreventive flavonoids and their mechanism of action on human prostate cancer cells. Human prostate cancer cells (PC3), stably transfected with activator protein 1 (AP-1) luciferase reporter gene were treated with four main classes of flavonoids namely flavonols, flavones, flavonones, and isoflavones. The maximum AP-1 luciferase induction of about 3 fold over control was observed with 20 microM concentrations of quercetin, chrysin and genistein and 50 microM concentration of kaempferol. At higher concentrations, most of the flavonoids demonstrated inhibition of AP-1 activity. The MTS assay for cell viability at 24 h showed that even at a very high concentration (500 microM), cell death was minimal for most of the flavonoids. To determine the role of MAPK pathway in the induction of AP-1 by flavonoids, Western blot of phospho MAPK proteins was performed. Four out of the eight flavonoids namely kaempferol, apigenin, genistein and naringenin were used for the Western Blot analysis. Induction of phospho-JNK and phospho-ERK activity was observed after two hour incubation of PC3-AP1 cells with flavonoids. However no induction of phospho-p38 activity was observed. Furthermore, pretreating the cells with specific inhibitors of JNK reduced the AP-1 luciferase activity that was induced by genistein while pretreatment with MEK inhibitor reduced the AP-1 luciferase activity induced by kaempferol. The pharmacological inhibitors did not affect the AP-1 luciferase activity induced by apigenin and naringenin. These results suggest the possible involvement of JNK pathway in genistein induced AP-1 activity while the ERK pathway seems to play an important role in kaempferol induced AP-1 activity.
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PMID:Modulation of activator protein-1 (AP-1) and MAPK pathway by flavonoids in human prostate cancer PC3 cells. 1696 58

Dopamine D2 receptor (D2R) knockout (KO) female mice develop chronic hyperprolactinemia and pituitary hyperplasia. Our objective was to study the expression of the mitogen fibroblast growth factor (FGF2) and its receptor, FGFR1, comparatively in pituitaries from KO and wild-type (WT) female mice. We also evaluated FGF2 subcellular localization and FGF2 effects on pituitary function. FGF2-induced prolactin release showed a similar response pattern in both genotypes, even though basal and FGF2-stimulated release was higher in KO. FGF2 stimulated pituitary cellular proliferation (MTS assay and [(3)H]thymidine incorporation), with no differences between genotypes. FGF2 concentration (measured by ELISA) in whole pituitaries or cultured cells was lower in KO (P < 0.00001 and 0.00014). Immunofluorescence histochemistry showed less FGF2 in pituitaries from KO females and revealed a distinct FGF2 localization pattern between genotypes, being predominantly nuclear in KO and cytosolic in WT pituitaries. Finally, FGF2 could not be detected in the conditioned media from pituitary cultures of both genotypes. FGFR1 levels (Western blot and immunohistochemistry) were higher in pituitaries of KO. Basal concentration of phosphorylated ERKs was lower in KO cells (P = 0.018). However, when stimulated with FGF2, a significantly higher increment of ERK phosphorylation was evidenced in KO cells (P < or = 0.02). We conclude that disruption of the D2R caused an overall decrease in pituitary FGF2 levels, with an increased distribution in the nucleus, and increased FGFR1 levels. These results are important in the search for reliable prognostic indicators for patients with pituitary dopamine-resistant prolactinomas, which will make tumor-specific therapy possible.
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PMID:Fibroblast growth factor-2 in hyperplastic pituitaries of D2R knockout female mice. 1784 35

Tyroserleutide (YSL), extracted from spleen of pigs, is a tripeptide that has shown therapeutic efficacy in an experimental BEL-7402 human hepatocarcinoma model. The hollow fiber assay (HFA) is a solid tumor model for large-scale screening of potential anticancer compounds that minimizes expenditures of materials, time, and money. Tumor cells are cultivated within biocompatible, semipermeable hollow fibers, which are implanted in immunosuppressed mice. In this study, the HFA was used to investigate the therapeutic efficacy of YSL for human hepatocarcinoma. In vitro effects of YSL on human hepatocarcinoma cell lines BEL-7402, SMMC-7721, Hep3B, HepG2, and SK-HEP-1 were assayed by the MTS method. In vivo effects of YSL on the five human hepatocarcinoma cell lines were assayed by HFA. Mice implanted with tumor cells in hollow fibers were treated with YSL, and the effects of YSL on tumor cell populations were assessed by MTT assay. YSL significantly inhibited the proliferation of the five human hepatocarcinoma, both in vitro and in vivo (P < 0.05). The HFA is a rapid, accurate, and economical method for evaluating the inhibitory effects of drugs on different tumor cells in vivo. These results support the clinical application of YSL for treatment of human hepatocarcinoma.
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PMID:Evaluation of the therapeutic efficacy of tripeptide tyroserleutide (YSL) for human hepatocarcinoma by in vivo hollow fiber assay. 1826 78

Nerve tissue engineering is one of the most promising methods to restore nerve systems in human health care. Scaffold design has pivotal role in nerve tissue engineering. Polymer blending is one of the most effective methods for providing new, desirable biocomposites for tissue-engineering applications. Random and aligned PCL/gelatin biocomposite scaffolds were fabricated by varying the ratios of PCL and gelatin concentrations. Chemical and mechanical properties of PCL/gelatin nanofibrous scaffolds were measured by FTIR, porometry, contact angle and tensile measurements, while the in vitro biodegradability of the different nanofibrous scaffolds were evaluated too. PCL/gelatin 70:30 nanofiber was found to exhibit the most balanced properties to meet all the required specifications for nerve tissue and was used for in vitro culture of nerve stem cells (C17.2 cells). MTS assay and SEM results showed that the biocomposite of PCL/gelatin 70:30 nanofibrous scaffolds enhanced the nerve differentiation and proliferation compared to PCL nanofibrous scaffolds and acted as a positive cue to support neurite outgrowth. It was found that the direction of nerve cell elongation and neurite outgrowth on aligned nanofibrous scaffolds is parallel to the direction of fibers. PCL/gelatin 70:30 nanofibrous scaffolds proved to be a promising biomaterial suitable for nerve regeneration.
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PMID:Electrospun poly(epsilon-caprolactone)/gelatin nanofibrous scaffolds for nerve tissue engineering. 1875 94

Smoking is an independent prognostic factor of lung adenocarcinoma. Benzo[a]pyrene (B[a]P) is one of the strongest carcinogens and it is present in both the environment and cigarette smoke. In this study, the effect of B[a]P on the proliferative activity of lung adenocarcinoma cells was investigated. A lung adenocarcinoma cell line, A549, was cultured with B[a]P for various periods, and its proliferative activity was examined by an MTS assay. To investigate the intracellular events related to the proliferative activity, the gene expression profile was investigated by a microarray analysis and a quantitative RT-PCR, and the protein expression and activation status of Akt, ERK 1/2 and the epidermal growth factor receptor (EGFR) were examined by a western blot analysis. Following the culture with B[a]P for 24 weeks, the serum-independent proliferative activity was increased. A microarray analysis revealed that a reversible upregulation of the EGFR and epiregulin genes was recognized in the B[a]P treated cells, in which the overexpression of the phosphorylated EGFR protein was also recognized. The EGFR tyrosine kinase inhibitor reduced the cellular proliferation and the level of phosphorylation of ERK1/2, which is a downstream signal of the EGFR, in the B[a]P-treated A549 cells. Moreover, the B[a]P treatment increased the mRNA expressions of the ligands for EGFR such as amphiregulin and epiregulin. B[a]P increases the proliferative potential of lung adenocarcinoma cells through the EGFR signaling pathway.
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PMID:Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway. 1918 43


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