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)

During hematopoietic differentiation of human embryonic stem cells (hESCs), early hematopoietic progenitors arise along with endothelial cells within the CD34(+) population. Although hESC-derived hematopoietic progenitors have been previously identified by functional assays, their phenotype has not been defined. Here, using hESC differentiation in coculture with OP9 stromal cells, we demonstrate that early progenitors committed to hematopoietic development could be identified by surface expression of leukosialin (CD43). CD43 was detected on all types of emerging clonogenic progenitors before expression of CD45, persisted on differentiating hematopoietic cells, and reliably separated the hematopoietic CD34(+) population from CD34(+)CD43(-)CD31(+)KDR(+) endothelial and CD34(+)CD43(-)CD31(-)KDR(-) mesenchymal cells. Furthermore, we demonstrated that the first-appearing CD34(+)CD43(+)CD235a(+)CD41a(+/-)CD45(-) cells represent precommitted erythro-megakaryocytic progenitors. Multipotent lymphohematopoietic progenitors were generated later as CD34(+)CD43(+)CD41a(-)CD235a(-)CD45(-) cells. These cells were negative for lineage-specific markers (Lin(-)), expressed KDR, VE-cadherin, and CD105 endothelial proteins, and expressed GATA-2, GATA-3, RUNX1, C-MYB transcription factors that typify initial stages of definitive hematopoiesis originating from endothelial-like precursors. Acquisition of CD45 expression by CD34(+)CD43(+)CD45(-)Lin(-) cells was associated with progressive myeloid commitment and a decrease of B-lymphoid potential. CD34(+)CD43(+)CD45(+)Lin(-) cells were largely devoid of VE-cadherin and KDR expression and had a distinct FLT3(high)GATA3(low)RUNX1(low)PU1(high)MPO(high)IL7RA(high) gene expression profile.
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PMID:Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures. 1675 88

Inflammatory bowel diseases are associated with reduced colonic contractility and induction of cyclooxygenase-2. In this study a possible role of cyclooxygenase-2 in and the underlying mechanism of the reduced contractility were investigated in experimental colitis. The effects of meloxicam, a cyclooxygenase-2 selective inhibitor were examined on colonic contractility and MAP kinase p38 and ERK(1/2) expression. Colitis was induced in Sprague-Dawley male rats by intra-colonic instillation of trinitrobenzenesulphonic acid (TNBS; 40 mg/rat in 50 ethanol). The animals were divided into three groups. Group 1 (n=9) received meloxicam (3 mg/kg-day) gavage 1 h before and 1 day (Group 2) after induction of colitis. Group 3 (n=9) received phosphate buffered saline (PBS) in a similar manner and served as colitic control. The non colitic control animals received meloxicam in a similar manner. The animals were sacrificed after 5 days of treatment, colon was cleaned with PBS and colonic smooth muscle was obtained which was used in this study. Meloxicam treatment given 1 h before or 1 day after administration of colitis restored the reduced colonic contractility without affecting the sensitivity to carbachol. The levels of colonic smooth muscle IL-1beta mRNA, PGE(2), ERK(1/2), p38, malondialdehyde, myeloperoxidase activity and colonic mass were increased, whereas the body weight was decreased due to TNBS. The changes except colonic muscle mass and p38 expression were reversed by meloxicam treatment. These findings indicate that restoration of reduced colonic contractility by meloxicam is mediated by ERK(1/2), and that ERK(1/2) may serve as an important anti inflammatory target for treatment of colitis.
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PMID:Mechanism underlying the reversal of contractility dysfunction in experimental colitis by cyclooxygenase-2 inhibition. 1683 10

We established a leukemia cell line derived from therapy-related acute myeloid leukemia with the t(11;19) by xenotransplantation into the NOD/SCID mouse with IL-2Rgamma(c)-/- (NOG mouse). The cell line, TRL-01, could be serially transplanted from mouse to mouse and also grown in an adherence-dependent manner on a murine bone marrow stroma cell line, HESS-5. TRL-01 had the same immunophenotype as the original leukemia cells: positive for CD13, CD33, CD11a, CD18, CD29, CD49d, CD49e, CD54, CD62L, and CD117, and negative for CD3, CD4, CD8, CD19, CD34, CD41a, CD41b, CD135, and myeloperoxidase. Translocation (11;19)(q23;p13) in both the original sample and TRL-01 generated MLL-ENL chimeric transcripts joining exon 6 and exon 4, respectively, which has a novel isoform. In cultures of TRL-01, addition of GM-CSF, SCF, and G-CSF and adhesion to fibronectin-coated plates promoted transient proliferation and survival, although they did not support long-term culture. Subcutaneous injection caused a tumor to form only when HESS-5 was coinjected at the same site. These results suggest that TRL-01 is a useful cell line for studying not only the leukemia-related biology of MLL-ENL but also the intercellular association between leukemia and stroma.
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PMID:Establishment of a myeloid leukemia cell line, TRL-01, with MLL-ENL fusion gene. 1687 30

We describe here the first case of 8p11 myeloproliferative syndrome (EMS) with t(8;9)(p11;q33), who unusually demonstrated B-lymphoblastic/monoblastic biphenotypic transformation. A 57-year-old woman was admitted because of leukocytosis and diagnosed as EMS. Bone marrow was infiltrated with myeloperoxidase (MPO)-, CD10+, CD19+, CD20+, CD34+, HLA-DR+ small lymphoblasts and MPO+, CD2+, CD4+, CD13+, CD14+, CD33+, HLA-DR+ large monoblasts. The karyotype was 46,XX,t(8;9)(p11;q33)[20] and the CEP1/FGFR1 fusion transcript between CEP1 exon 38 and FGFR1 exon 9 was detected. This case clearly indicates that the blastic transformation in EMS with t(8;9) could arise in the stem cells, which differentiate into not only myelomonocytic but also B-lymphocytic lineages.
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PMID:A biphenotypic transformation of 8p11 myeloproliferative syndrome with CEP1/FGFR1 fusion gene. 1687 8

Lipopolysaccharide (LPS) induces acute lung injury (ALI) via Toll-like receptor 4 (TLR4)-mediated MAPK activation. The lipid A fraction of LPS is considered to be the active moiety, but whether the lipid A-TLR4 interaction accounts completely for ALI-associated MAPK activation in vivo has not been determined. The lipid A fraction of LPS induces a discrete MAPK activation pattern in murine ALI. Mice (C57BL/6J, C3H/HeJ) were treated with intratracheal instillations of purified lipid A or LPS (10, 30, and 100 microg per mouse) or vehicle. ALI was assessed by histology. Chromogenic myeloperoxidase (MPO) activity was measured in lung homogenates. MAPK expression was quantified by immunoblotting. In vitro ERK inhibitor studies using thioglycollate-elicited macrophages were also performed. MPO increased in a dose- and time-responsive fashion. Notably, MPO was 2.4-fold greater after lipid A compared with LPS and vehicle at 6 h after instillation (lipid A, 0.88 +/- 0.25 vs. LPS, 0.37 +/- 0.21 optical density units.min(-1).mg(-1); P < 0.05). However, ALI scores were comparable at 6 and 24 h between LPS and lipid A. MPO was also comparable in vehicle-treated or C3H/HeJ mice treated with LPS or lipid A at 6 and 24 h. Phospho-ERK activation was pronounced at 6 and 24 h after lipid A but not LPS treatment. In vitro studies confirmed the relationship between phospho-ERK activation and cytokine expression in macrophage stimulated with either LPS or lipid A. Compared with whole LPS, the lipid A fraction is associated with amplified whole lung MPO and ERK activation 6 h after intratracheal instillation in mice.
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PMID:Lipid A fraction of LPS induces a discrete MAPK activation in acute lung injury. 1749 62

An endocrine disruptor, para-nonylphenol (NP), caused a dose-dependent stimulatory effect on the generation of reactive oxygen species (ROS) in human whole blood from 50 to 1000 microM, which was measured by chemiluminescence generation. ROS-scavenging enzymes such as catalase and superoxide dismutase, and the lipophilic antioxidative agents, alpha-tocopherol and beta-carotene, showed preventive effects on NP-induced ROS generation. To analyze the biochemical mechanism of NP-induced ROS generation in human blood, we investigated the effects of different types of metabolic inhibitors on the activation pathways of ROS generation. An NADPH-dependent oxidase inhibitor, diphenyl iodonium chloride (DPI), and a myeloperoxidase inhibitor, sodium azide (NaN3), showed remarkable inhibitory effects on ROS generation induced by NP, but an inhibitor against mitochondrial respiratory function, potassium cyanide (KCN), did not exhibit a significant effect. Furthermore, a phosphatidylinositol-3 (PI3) kinase inhibitor, wortmannin, and a tyrosine kinase inhibitor, protein phosphorylation inhibitor 1 (PP1), caused a strong suppression of NP-induced ROS generation. Selective protein kinase C inhibitor, Ro-32-0432, p38 MAP kinase inhibitor, SB-203580, and ERK MAP kinase inhibitor, PD 98059, showed significant suppressive effects on NP-induced ROS generation. In addition, when human blood was exposed to lower concentrations (5-50 microM) of NP, they did not cause the significant ROS generation by themselves, but the priming and synergistic effects of NP were detected by the addition of secondary stimulants, opsonized zymosan (OZ) or phorbol myristate acetate (PMA). The analysis of the priming and synergistic effects of NP on OZ- or PMA-dependent ROS generation by antioxidative substances and metabolic inhibitors showed similar results compared with those of human blood treated with NP alone. These results suggest that NP causes an enhancing effect by itself, or priming and synergistic effects on ROS generation in human blood with other inflammatory stimulants through the activation of signal transduction pathways such as protein kinase cascades.
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PMID:Potentiating effect of an endocrine disruptor, paranonylphenol, on the generation of reactive oxygen species (ROS) in human venous blood -- association with the activation of signal transduction pathway. 1790 2

Exposure to asbestos fibers is a major risk factor for malignant pleural mesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on alpha1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes.
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PMID:Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases. 1842 Apr 50

Previous studies have demonstrated that heterotrimeric guanine nucleotide-binding regulatory (Gi) protein-deficient mice exhibit augmented inflammatory responses to lipopolysaccharide (LPS). These findings suggest that Gi protein agonists will suppress LPS-induced inflammatory gene expression. Lysophosphatidic acid (LPA) activates G protein-coupled receptors leading to Gi protein activation. We hypothesized that LPA will inhibit LPS-induced inflammatory responses through activation of Gi-coupled anti-inflammatory signaling pathways. We examined the anti-inflammatory effect of LPA on LPS responses both in vivo and in vitro in CD-1 mice. The mice were injected intravenously with LPA (10 mg/kg) followed by intraperitoneal injection of LPS (75 mg/kg for survival and 25 mg/kg for other studies). LPA significantly increased the mice survival to endotoxemia (P < 0.05). LPA injection reduced LPS-induced plasma TNF-alpha production (69 +/- 6%, P < 0.05) and myeloperoxidase (MPO) activity in lung (33 +/- 9%, P < 0.05) as compared to vehicle injection. LPS-induced plasma IL-6 was unchanged by LPA. In vitro studies with peritoneal macrophages paralleled results from in vivo studies. LPA (1 and 10 microM) significantly inhibited LPS-induced TNFalpha production (61 +/- 9% and 72 +/- 9%, respectively, P < 0.05) but not IL-6. We further demonstrated that the anti-inflammatory effect of LPA was reversed by ERK 1/2 and phosphatase inhibitors, suggesting that ERK 1/2 pathway and serine/threonine phosphatases are involved. Inhibition of phosphatidylinositol 3 (PI3) kinase signaling pathways also partially reversed the LPA anti-inflammatory response. However, LPA did not alter NFkappaB and peroxisome proliferator-activated receptor gamma (PPARgamma) activation. Inhibitors of PPARgamma did not alter LPA-induced inhibition of LPS signaling. These studies demonstrate that LPA has significant anti-inflammatory activities involving activation of ERK 1/2, serine/threonine phosphatases, and PI3 kinase signaling pathways.
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PMID:Lysophosphatidic acid inhibits bacterial endotoxin-induced pro-inflammatory response: potential anti-inflammatory signaling pathways. 1843 64

Human metabolism of benzene involves pathways coded for by polymorphic genes. To determine whether the genotype at these loci might influence susceptibility to the adverse effects of benzene exposure, 208 Bulgarian petrochemical workers and controls, whose exposure to benzene was determined by active personal sampling, were studied. The frequency of DNA single-strand breaks (DNA-SSB) was determined by alkaline elution, and genotype analysis was performed for five metabolic loci. Individuals carrying the NAD(P)H:quinone oxidoreductase 1 (NQO1) variant had significantly twofold increased DNA-SSB levels compared to wild-type individuals. The same result was observed for subjects with microsomal epoxide hydrolase (EPHX) genotypes that predict the fast catalytic phenotype. Deletion of the glutathione S-transferase T1 (GSTT1) gene also showed a consistent quantitative 35-40% rise in DNA-SSB levels. Neither glutathione S-transferase M1 (GSTM1) nor myeloperoxidase (MPO) genetic variants exerted any effect on DNA-SSB levels. Combinations of two genetic polymorphisms showed the same effects on DNA-SSB as expected from the data on single genotypes. The three locus genotype predicted to produce the highest level of toxicity, based on metabolic pathways, produced a significant 5.5-fold higher level of DNA-SSB than did the genotype predicted to yield the least genotoxicity.
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PMID:Genetic susceptibility to benzene toxicity in humans. 1883 23

The innate immune response to enteropathogenic bacteria includes chemokine-induced polymorphonuclear neutrophil (PMN) migration across mucosal epithelia leading to bacterial clearance and resolution of infection. Among these bacteria, diffusely adherent Escherichia coli expressing Afa/Dr fimbriae (Afa/Dr DAEC), causing childhood diarrhea, can promote IL-8-dependent PMN transmigration across cultured intestinal epithelial cell monolayers via MAPK pathway activation. However, interactions between PMN and Afa/Dr DAEC are poorly documented and constitute the aim of the present study. Using the human PLB-985 cell line differentiated into fully mature PMN, we described the coordinated response to various E. coli. The rapid and strong release of reactive oxygen species and preformed intragranular mediators (myeloperoxidase and IL-8) is followed by a later TNF-alpha, IL-1beta, and IL-8 synthesis. The use of wild-type (IH11128, C1845, LF82), control (AAEC185), and recombinant (AAEC185 bearing Dr or F1845 fimbriae, AdLF82, or type 1 pili) bacterial strains allowed us to demonstrate that late IL-8 hyperproduction is triggered by type 1 pili but not by Dr or F1845 fimbriae; MAPKs (p38, ERK, Src) and NF-kappaB activations are implicated in this response. Thus, in the course of Afa/Dr DAEC intestinal infection, epithelium- and neutrophil-derived IL-8 could, at least in part, control the flow of neutrophils through the lamina propria. Afa/Dr DAEC-induced IL-8 hyperproduction by PMN might thus be important for inducing and perpetuating local inflammation, and this self-amplifying loop might play a role in the pathogenesis of inflammatory bowel diseases such as Crohn's disease.
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PMID:Escherichia coli type 1 pili trigger late IL-8 production by neutrophil-like differentiated PLB-985 cells through a Src family kinase- and MAPK-dependent mechanism. 1901 76


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