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)

Endothelial cells facilitate sepsis-induced neutrophil adherence through the production of adhesion molecules and proinflammatory cytokines. The production of these factors requires coordinated intracellular inflammatory signaling. Recently, patients prone to sepsis-induced complications have been shown to have derangements in intracellular calcium and potentially calcium/calmodulin-dependent protein kinase (CaMK) activity, but the impact of these impairments is unknown. Human umbilical vein endothelial vein endothelial cells (HUVECs) were exposed to lipopolysaccharide (LPS) for various periods of time. Select HUVECs were pretreated with an inhibitor of CaMK II, KN62. Total cellular and nuclear proteins were extracted and analyzed for various components of the Toll-mediated signal cascade. Neutrophil adhesion was assayed fluorometrically using calcein-labeled neutrophils on treated HUVECs. LPS stimulation led to mitogen-activated protein kinase activation and translocation of activator protein-1 (AP-1) and nuclear factor (NF)-kappaB. CaMK blockade inhibited LPS induced ERK 1/2 and JNK but enhanced p38 activity. This selective MAPK inhibition was associated with a reduction in AP-1 activity, with no affect on NF-kappaB activity. Associated with this altered cell signaling was increased ICAM-1 production and enhanced neutrophil adhesion. Altered CaMK activity resulted in dysregulated mitogen-activated protein kinase signaling, demonstrated by reduced ERK 1/2 and JNK activity but enhanced p38 activity. This altered signaling is associated with reduced AP-1 activation and unaffected NF-kappaB activation. Neutrophil adhesion, however, is enhanced presumably through increased ICAM-1 production. Therefore, CaMK inhibition of endothelial cells, characteristic of sustained increases in intracellular calcium, appears to result in a dysregulated proadhesive phenotype.
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PMID:Modulation of endotoxin-induced endothelial function by calcium/calmodulin-dependent protein kinase. 1286 64

Experimentally and clinically, stroke is followed by both acute and prolonged inflammatory responses characterized by the production of inflammatory cytokines and leukocyte infiltration into the brain. A debate on whether inflammation after stroke is neurotoxic or participates in brain repair remains unresolved. However, the need to pharmacologically control inflammatory amplification has been commonly acknowledged. The principal challenge of devising successful anti-inflammatory strategies for stroke is to understand molecular and temporal interplay of inflammatory and cell-death-inducing processes triggered by cerebral ischemia in both parenchymal and vascular brain cells. This article will review a number of experimental and clinically tested approaches to reduce brain inflammation and damage after stroke (e.g., anti-neutrophil, anti-ICAM-1, anti-cytokine strategies) and will suggest potential pathways where novel therapeutic targets may emerge, including transcriptional regulators of inflammatory gene expression (e.g., NF-kappaB, proteasome) and signaling pathways (e.g., ICE-cascade, MAPK/MKK/ERK cascade) linked to both inflammation and neuronal cell death. Finally, we will discuss applications of functional genomics technologies in the discovery of stroke diagnostics and therapies.
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PMID:Current and future therapeutic strategies to target inflammation in stroke. 1456 Nov 97

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

The autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymic medullary epithelial cells and in the cells of the monocyte-dendritic lineage both in the thymus and in the secondary lymphoid organs. Mutations in the AIRE gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a recessively inherited disease characterized by loss of immunological self-tolerance to multiple endocrine organs. Recent mouse knockout studies suggest that AIRE is responsible for ectopic expression of peripheral self-antigens in the thymus. In the present study, we detected an increased level of endogenous AIRE expression during the differentiation process of the human monocyte derived dendritic cells (MoDCs). We subsequently identified candidates for AIRE-regulated genes by using cDNA microarray technology to analyse the changes in the gene expression profile brought about by overexpressing the AIRE protein in the monocytic U937 cells. The changes observed resembled those previously reported to occur during the maturation of DCs, including up-regulation of the CCL22, CD25, ICAM-1 and RelB genes. In contrast, increased expression of the steroidogenic enzymes P450c17, P450c21 and P450scc, the major autoantigens in APECED, was not found either in our cell model or in the dendritic cell cultures. We also identified the ERK signal transduction pathway as a candidate for mediating the signal that results in the altered expression profile. Our findings suggest that the role of AIRE in the DCs differs from its function in the thymus.
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PMID:Autoimmune regulator induced changes in the gene expression profile of human monocyte-dendritic cell-lineage. 1548 54

Isoprostanes, produced in vivo by non-enzymatic free-radical-induced lipid peroxidation, are markers of oxidative stress. Elevated serum and urine levels of 8-iso-PGF2alpha have been reported in a variety of diseases, many of which are characterized by early perivascular inflammatory infiltrates. It has been suggested that, in addition to being markers of oxidative stress, isoprostanes may have pathogenic functions. In this study, we investigated the potential role of 8-iso-PGF2alpha in inflammation, focusing on its effects on adhesion of monocytes to microvascular endothelial cells, an early event in the inflammatory response. In monocyte adhesion assays, 8-iso-PGF2alpha (>10(-8) M) suppressed both basal and TNF-alpha-induced monocyte adhesion to quiescent or proliferating human dermal (HMEC) and rat renal microvascular endothelial cells. In contrast, 8-iso-PGF2alpha stimulated monocyte adhesion to human umbilical vein endothelial cells (HUVEC) as also reported by others. 8-Iso-PGF2alpha had no effect on the viability (Trypan Blue exclusion) of U937 monocytes or HMEC. 8-Iso-PGF2alpha also had no effect on HMEC surface expression of ICAM-1 or VCAM-1. Exposure of HMEC to 8-iso-PGF2alpha for 1-2 h was sufficient to reduce monocyte adhesion to the cell surface, and this effect was independent of de novo protein synthesis by HMEC. The effect of 8-iso-PGF2alpha was mimicked by a thromboxane receptor (TP) agonist (U46619) and blocked by a TP antagonist (SQ29548), indicating a TP-mediated process. Signal transduction pathway inhibitors (SB203580, curcumin, and PD98059) implicated p38 and JNK, but not ERK, in 8-iso-PGF2alpha-induced suppression of monocyte adhesion. In addition to a direct effect, conditioned medium (CM) transfer experiments suggest that 8-iso-PGF2alpha induces a secondary mediator, which also suppresses monocyte adhesion but via an alternative mechanism initiated between 3-4 h, which is TP-independent, requires new protein synthesis, and is primarily dependent on activation of p38. The data show that 8-iso-PGF2alpha can suppress the attachment of monocytes to HMECs via two independent pathways, indicating a potential anti-inflammatory effect of 8-iso-PGF2alpha in the microvasculature.
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PMID:The isoprostane 8-iso-PGF2alpha suppresses monocyte adhesion to human microvascular endothelial cells via two independent mechanisms. 1564 Feb 82

The purpose of this study was to characterize the pattern of cytokine gene expression by human corneal epithelial cells (HCEC) in response to interleukin-1 (IL-1). Primary cultured HCEC (P-HCEC) or SV40 transformed HCEC (SV40-HCEC) were treated for 6 hr with serum-free growth-media alone or with recombinant human IL-1beta or IL-1alpha (10 ng ml(-1)). 33P labeled cDNA was generated from total RNA, then hybridized to a human cytokine expression array. An autoradiograph was generated for each experimental condition and results analysed semi-quantitatively. Reverse transcription polymerase chain reaction (RT-PCR) was performed to detect mRNA for IL-8, growth related oncogene-beta (GRO-beta), intercellular adhesion molecule (ICAM)-1 and Ephrin A5. P-HCEC and SV40-HCEC demonstrated comparable cytokine profiles. For P-HCEC (n=2) the expression of 35 genes was upregulated or only detectable following IL-1beta treatment whereas the expression of nine genes was downregulated or undetectable after IL-1beta treatment. In SV40-HCEC (n=3), the expression of 48 genes was upregulated or only detectable following IL-1beta treatment and the expression of 10 genes was downregulated or undetectable after IL-1beta treatment. Some genes that demonstrated increased expression included cadherin-5, ICAM-1, GRO-alpha, GRO-beta, GRO-gamma, Activin A (bA subunit), tumor necrosis factor-alpha, IL-6, and IL-8. Genes that showed decreased expression included the chemokine receptor-CXCR-4, ciliary neurotrophic factor (CNTF), c-kit ligand, Ephrin A5, G-protein coupled receptor RDC-1 and FGF family FGFR2. Bayesian analysis of the SV40-HCEC data (n=3) revealed the expression of 15 genes that were significantly (p<0.05) differentially regulated. Within these 15 genes, the expression of chemokines (GRO-alpha, GRO-beta, IL-8), fibroblast growth factor 13 and the cytokine IL-6 were the most upregulated, while ephrin A5 and chemokine receptor-4 were the most downregulated. IL-1alpha treatment (n=1 P-HCEC; n=1 SV40-HCEC) produced results very similar to IL-1beta treatment. RT-PCR revealed differential regulation of IL-8, GRO-beta, ICAM-1 and ephrin A5 in accordance with gene array data. In conclusion, the data demonstrate that IL-1 treatment of HCEC differentially regulates the expression of other cytokine and related genes, thus adding to the body of evidence that IL-1 is a major mediator of ocular surface inflammatory reactions. Since the expression of a large number of genes can be studied simultaneously, gene array studies such as these offers the advantage of understanding global changes in response to a specific stimulus. Thus our study provides insight in to the ocular surface response in conditions of inflammation and corneal wound healing where the levels of IL-1 are known to be increased.
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PMID:The effect of interleukin-1 on cytokine gene expression by human corneal epithelial cells. 1567 Jul 96

We investigated whether lipid peroxidation might influence activation of the mitogen activated protein kinase (MAPK) extracellular regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) in neointimal hyperplasia induced by flow interruption of carotid artery in mice. C57/BL6 mice were subjected to a complete ligation of the left common carotid artery or to a sham ligation. Animals were randomized to receive either IRFI-042, a Vitamin E-like inhibitor of lipid peroxidation (20 mg/kg/i.p., immediately after artery occlusion) or its vehicle (1 ml/kg of a NaCl-DMSO solution). The extent of lipid peroxidation (investigated by the means of conjugated dienes levels) and JNK and ERK activation were evaluated by Western blot analysis after blood flow interruption. ICAM-1 expression in injured arteries was investigated 4 days after artery ligation by the means of reverse transcriptase polymerase chain reaction (RT-PCR) and quantification of the ICAM-1 protein levels. Morphometric analysis of the structural alteration caused by the disruption of the arterial blood flow was performed 4 weeks after surgery. Flow interruption in the carotid artery resulted at 10 min, following occlusion in a marked increase in conjugated dienes tissue levels (5.8+/-0.44 DeltaABS/mg protein), caused at 30 min after occlusion peak increase in both ERK1/2 (45+/-8 integrated intensity) and JNK (38+/-6 integrated intensity) activities, enhanced ICAM-1 expression (1.5+/-0.45 relative amount of ICAM-1 mRNA) and ICAM-1 protein levels (55+/-12 pg/mg protein) and produced a marked neointimal hyperplasia (mean intimal area=101+/-14 microm2). Injured arteries harvested from IRFI-042-treated mice had reduced conjugated dienes tissue levels (2.9+/-0.5 DeltaABS/mg protein), attenuated ERK1/2 (19+/-6 integrated intensity) and JNK (2.9+/-0.5 integrated intensity) activities, blunted ICAM-1 expression (0.38+/-0.1 relative amount of ICAM-1 mRNA) and protein levels (26+/-8 pg/mg protein) and decreased neointimal hyperplasia (mean intimal area=4.5+/-1.5 microm2). Our data indicate that ERK1/2 and JNK kinases play a crucial role in neointimal hyperplasia induced by flow cessation in the mouse carotid artery. Furthermore, the present data suggest that lipid peroxidation triggers ERK and JNK activation.
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PMID:Lipid peroxidation triggers both c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) activation and neointimal hyperplasia induced by cessation of blood flow in the mouse carotid artery. 1569 37

To explore the difference of biological characteristics between two subpopulations of adult bone marrow mesenchymal stem cells (MSC), this study was designed to observe the morphological feature and immunophenotype of the adult MSC in the ex vivo culture, the mononuclear cells isolated from normal adult bone marrow were cultured in DMEM with 10% fetal bovine serum. Cell morphology, immunophenotype and cell cycle of two different subgroups were investigated. Cells from 80% confluence were passed through a 10 microm filter, then the fillered cells were cultured in the semisolid methylcellulose medium. The results showed that (1) two different subpopulations were observed in the ex vivo culture. The fibro-like cell was called mature MSC (mMSC) and the smaller round cell was defined rapidly as MSC self-renewing cells (RS cells); (2) the average proportion of cells in G(0)/G(1) of RS cells was approximately 99%, but that of mMSCs was 90%; (3) both of the two populations were negative on the lineage-committed antigen (such as CD34, CD45, CD3, CD19, CD33, HLA-DR, CD38), while positive on the expression of CD90, CD105, C166, CD29, CD44, CD49e, CD54, CD13. However, the expression of these antigens on RS cells was weaker than that on mMSC, but CD117 and KDR were higher expressed when compared with the mMSC; (4) after 4 to 5 week semisolid culture, no hematopoietic progenitor cell colonies were observed. It is concluded that adult MSCs are heterogeneous in that distinct morphological populations exist. The RS cells appear to be the more primitive with greater potential for self-renewal and multilineage differentiation.
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PMID:[Comparative study on various subpopulations in mesenchymal stem cells of adult bone marrow]. 1574 36

Mesenchymal stem cells (MSC) can be isolated from many sites adults and the fetus. Cells with osteoblastic, chondrogenic, leiomiogenic and stromogenic potentials have been obtained from the bovine artery wall, and we now show that MSC can be isolated also from the adult human vein wall. Cells detached from internal surface of the saphenous vein are cultured in vitro for 2-3 weeks and replated weekly. The culture forms a semi-confluent layer of spindle-shaped cells that are CD13(+), CD29(+), CD44(+), CD34(-), CD45(-), CD14(-), CD133(-), CD31(-), CD33(-), CD54(+), CD106(-), CD90(+), KDR(-), cadherin-5-, HLA class I(+) and HLA-DR- and differentiate in vitro into osteoblasts, chondrocytes and adipocytes. Gene expression, when compared with seven other normal tissues, shows strong similarity with MSC obtained from other sources. Three genes more expressed in saphenous MSC than in the other two MSC are related to angiogenesis, and the expression of two of them is shared by endothelial cells. These results demonstrate that the human vein wall contains mesenchymal cells with morphologic features, immunophenotypic markers, gene expression profile and differentiation potential that are similar to MSC obtained from the bone marrow and from the umbilical vein.
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PMID:Mesenchymal stem cells can be obtained from the human saphena vein. 1601 99

Kaposi's sarcoma-associated herpesvirus (KSHV) in vitro target cell infection is characterized by the expression of the latency-associated genes ORF 73 (LANA-1), ORF 72, and K13 and by the transient expression of a very limited number of lytic genes such as lytic cycle switch gene ORF 50 (RTA) and the immediate early (IE) lytic K5, K8, and v-IRF2 genes. During the early stages of infection, several overlapping multistep complex events precede the initiation of viral gene expression. KSHV envelope glycoprotein gB induces the FAK-Src-PI3K-RhoGTPase (where FAK is focal adhesion kinase) signaling pathway. As early as 5 min postinfection (p.i.), KSHV induced the extracellular signal-regulated kinase 1 and 2 (ERK1/2) via the PI3K-PKCzeta-MEK pathway. In addition, KSHV modulated the transcription of several host genes of primary human dermal microvascular endothelial cells (HMVEC-d) and fibroblast (HFF) cells by 2 h and 4 h p.i. Neutralization of virus entry and infection by PI-3K and other cellular tyrosine kinase inhibitors suggested a critical role for signaling molecules in KSHV infection of target cells. Here we investigated the induction of ERK1/2 by KSHV and KSHV envelope glycoproteins gB and gpK8.1A and the role of induced ERK in viral and host gene expression. Early during infection, significant ERK1/2 induction was observed even with low multiplicity of infection of live and UV-inactivated KSHV in serum-starved cells as well as in the presence of serum. Entry of UV-inactivated virus and the absence of viral gene expression suggested that ERK1/2 induction is mediated by the initial signal cascade induced by KSHV binding and entry. Purified soluble gpK8.1A induced the MEK1/2 dependent ERK1/2 but not ERK5 and p38 mitogen-activated protein kinase (MAPK) in HMVEC-d and HFF. Moderate ERK induction with soluble gB was seen only in HMVEC-d. Preincubation of gpK8.1A with heparin or anti-gpK8.1A antibodies inhibited the ERK induction. U0126, a selective inhibitor for MEK/ERK blocked the gpK8.1A- and KSHV-induced ERK activation. ERK1/2 inhibition did not block viral DNA internalization and had no significant effect on nuclear delivery of KSHV DNA during de novo infection. Analyses of viral gene expression by quantitative real-time reverse transcriptase PCR revealed that pretreatment of cells with U0126 for 1 h and during the 2-h infection with KSHV significantly inhibited the expression of ORF 73, ORF 50 (RTA), and the IE-K8 and v-IRF2 genes. However, the expression of lytic IE-K5 gene was not affected significantly. Expression of ORF 73 in BCBL-1 cells was also significantly inhibited by preincubation with U0126. Inhibition of ERK1/2 also inhibited the transcription of some of the vital host genes such as DUSP5 (dual specificity phosphatase 5), ICAM-1 (intercellular adhesion molecule 1), heparin binding epidermal growth factor, and vascular endothelial growth factor that were up-regulated early during KSHV infection. Several MAPK-regulated host transcription factors such as c-Jun, STAT1alpha, MEF2, c-Myc, ATF-2 and c-Fos were induced early during infection, and ERK inhibition significantly blocked the c-Fos, c-Jun, c-Myc, and STAT1alpha activation in the infected cells. AP1 transcription factors binding to the RTA promoter in electrophoretic mobility shift assays were readily detected in the infected cell nuclear extracts which were significantly reduced by ERK inhibition. Together, these results suggest that very early during de novo infection, KSHV induces the ERK1/2 to modulate the initiation of viral gene expression and host cell genes, which further supports our hypothesis that beside the conduit for viral DNA delivery into the cytoplasm, KSHV interactions with host cell receptor(s) create an appropriate intracellular environment facilitating infection.
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PMID:ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. 1605 24


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