Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent molecular characterization and sequencing of equine P-selectin (ePsel), and its glycoprotein ligand, P-selectin glycoprotein ligand-1 (PSGL-1), have provided the tools for further investigation into their role in leukocyte trafficking. Here, we report the generation of a genetically engineered chimeric protein (ePsel-IgG) in which the equine P-selectin lectin and epithelial growth factor (EGF) domains were covalently linked to the equine IgG1 heavy chain constant region. The soluble ePsel-IgG was observed to bind to equine monocytes by confocal microscopy and flow cytometry. Furthermore, equine monocytes bound to immobilized ePsel-IgG in a time course and dose dependent manner. Not only did ePsel-IgG act as an adhesion molecule, it was also found to activate ERK1/2 kinase and induce IL-8 mRNA expression in equine monocytes. That all of the aforementioned ePsel-IgG-induced cell binding and cell signaling were abolished by the addition of EDTA, suggested that ePsel-IgG chimera mediated events occurred via the P-selectin ligand, PSGL-1. We were able to demonstrate that 78% of equine monocytes cross-reacted with anti-human HECA-452 antibody, which recognizes the sialy-Lewis X (sLex) epitope, a well-known carbohydrate binding site on human PSGL-1. Pre-incubation of equine PBMC with neuraminidase or O-sialoglycoprotein endopeptidase (OSGP) reduced ePsel-IgG monocyte binding to 36% or 60%, respectively. Taken together, these data suggest that there might be two ligand recognition sites on P-selectin, one of which recognizes sLex and another which recognizes P-selectin ligand core protein. The ePsel-IgG chimera can be a useful as a reagent for further studies on the role of equine P-selectin and signal transduction in inflammatory events in horse.
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PMID:Cloning and functional characterization of recombinant equine P-selectin. 1730 78

The differential expression of Toll-like receptors (TLRs 1-9) and their associated proteins in murine peritoneal macrophages in vitro, on treatment with plant lectin concanavalin A (Con A) has been investigated. It is observed that there is enhanced expression of TLRs 2-9 and downstream molecules--MyD88, IRAK1, TRAF6 and IRF3 in murine peritoneal macrophages on in vitro treatment with Con A. Pretreatment of macrophages with inhibitors of JNK, p38, p42/44 and NF-kappaB, significantly decreased the Con A induced expression of TLRs. When cells are pre-treated with Con A and subsequently treated with TLR ligands--Zymosan A, PolyI:C, LPS, CpG DNA, there is enhanced production of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-12 and IFN-gamma,), nitric oxide and iNOS expression in murine peritoneal macrophages. The results suggest that treatment of macrophages with Con A renders them more susceptible to subsequent activation and induction of proinflammatory cytokines and nitric oxide production by different TLR ligands.
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PMID:Concanavalin A induced expression of Toll-like receptors in murine peritoneal macrophages in vitro. 1732 68

We studied whether the acute-phase protein alpha1-acid glycoprotein (AGP) induces rises in [Ca2+]i in neutrophils and sought to identify the corresponding AGP receptor (or receptors). We found that AGP elicited a minimal rise in [Ca2+]i in Fura-2-loaded neutrophils, and this response was markedly enhanced by pretreatment with anti-L-selectin antibodies. (The EC50 value of the AGP-induced Ca2+ response was 9 microg/ml.) Activation of phospholipase-C, Src tyrosine kinases, and PI3 kinases proved to be essential for the AGP-mediated increase in [Ca2+]i, whereas the p38 MAPK and SYK signaling pathways were not involved. Furthermore, antibodies against sialic acid binding, immunoglobulin-like lectin 5 (Siglec-5) and oligosaccharide 3'-sialyl-lactose both antagonized the AGP-induced response and caused an immediate increase in [Ca2+]i in anti-L-selectin-treated neutrophils, which indicates a signaling capacity of Siglec-5. We used modified forms of AGP (treated with mild periodate or neuraminidase) to establish the importance of sialic acid residues. The modified forms of AGP caused a much smaller rise in [Ca2+]i than did unaltered AGP. Affinity chromatography confirmed that unchanged AGP, but not neuraminidase-treated AGP, bound to Siglec-5. Our report provides the first evidence for a signaling capacity by AGP through a defined receptor. Pre-engagement of L-selectin significantly enhanced this signaling capacity.
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PMID:The acute-phase protein alpha 1-acid glycoprotein (AGP) induces rises in cytosolic Ca2+ in neutrophil granulocytes via sialic acid binding immunoglobulin-like lectins (siglecs). 1767 32

Angiotensin II (Ang II) induces angiogenesis by stimulating reactive oxygen species-dependent vascular endothelial growth factor (VEGF) expression. Ang II via type 1 receptor upregulates the expression of LOX-1, a lectin-like receptor for oxidized low-density lipoprotein. LOX-1 activation, in turn, upregulates Ang II type 1 receptor expression. We postulated that interruption of the feedback loop between Ang II and LOX-1 might attenuate Ang II-induced VEGF expression and capillary formation. In vitro experiments showed that Ang II (1 nmol/L) induced the expression of LOX-1 and VEGF and enhanced capillary formation from human coronary endothelial cells in Matrigel assay. Ang II-mediated expression of LOX-1 and VEGF, capillary formation, intracellular reactive oxygen species generation, and phosphorylation of p38 as well as p44/42 mitogen-activated protein kinases, were suppressed by anti-LOX-1 antibody, nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin and the Ang II type 1 receptor blocker losartan, but not by the Ang II type 2 receptor blocker PD123319. Expression of VEGF and capillary formation induced by Ang II were also inhibited by the p44/42 mitogen-activated protein kinase inhibitor U0126 and the p38 mitogen-activated protein kinase inhibitor SB203580. In ex vivo experiments, Ang II stimulated capillary sprouting from aortic rings from wild-type mice, and this phenomenon was significantly attenuated by pretreatment of aortic rings with anti-LOX-1 antibody, apocynin, and losartan, but not by PD123319. Importantly, Ang II-induced capillary sprouting was minimal from aortic rings from LOX-1 null mice compared with wild-type mice. These findings suggest that small concentrations of Ang II promote capillary formation by inducing the expression of VEGF via Ang II type 1 receptor/LOX-1-mediated stimulation of the reactive oxygen species-mitogen-activated protein kinase pathway.
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PMID:Angiotensin II induces capillary formation from endothelial cells via the LOX-1 dependent redox-sensitive pathway. 1789 72

Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acyl-CoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets.
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PMID:Macrophages: an elusive yet emerging therapeutic target of atherosclerosis. 1800 Sep 63

LOX-1 is a newly described lectin-like receptor for oxidized-LDL (ox-LDL), which is over-expressed in the ischemic myocardium. To examine the pathogenic role of LOX-1 in the determination of ischemia-reperfusion (I-R) injury to the heart, we developed LOX-1 knockout (KO) mice, and subjected these mice to 60 min of left coronary artery occlusion followed by 60 min of reperfusion. I-R in the LOX-1 KO mice resulted in a significant reduction in myocardial injury as well as in accumulation of inflammatory cells in the I-R myocardium and lipid peroxidation (P<0.01 vs. wild-type mice). Concomitantly, there was significant preservation of cardiac function in the LOX-1 KO mice despite I-R (P<0.01 vs. the wild-type mice). The phosphorylation of oxidative stress-sensitive mitogen-activated protein kinase (p38MAPK) and protein kinase B/Akt-1, expression of nitrotyrosine and inducible nitric oxide synthase (iNOS), and superoxide dismutase activity were enhanced during I-R in the wild-type mice. These alterations in p38MAPK, Akt-1 and iNOS were much less pronounced in the LOX-1 KO mice. The superoxide dismutase activity increased further in the LOX-1 KO mice. These observations provide compelling evidence that LOX-1 may be a key modulator of myocardial I-R injury, and its effect is mediated by pro-oxidant signals. LOX-1 may be a potential target for therapy of myocardial ischemic injury.
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PMID:LOX-1 abrogation reduces myocardial ischemia-reperfusion injury in mice. 1802 84

The amount of mucin on the ocular surface is regulated by the rate of mucin synthesis, mucin secretion, and the number of goblet cells. We have previously shown that cholinergic agonists are potent stimuli of mucin secretion. In contrast, there have been no studies on the control of goblet cell proliferation. In this study we investigate the presence of the EGF family of growth factors and their receptors in rat conjunctiva and cultured rat conjunctival goblet cells as well as their effects on activation of signaling intermediates and goblet cell proliferation. Rat conjunctival goblet cells were grown in organ culture and identified as goblet cells by their morphology and positive staining for the lectin UEA-1 and cytokeratin 7. In the rat conjunctiva, the presence of the EGF family members epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), heparin binding EGF (HB-EGF), and heregulin was determined by RT-PCR. The receptors for these ligands, EGF receptor (EGFR), erbB2, erbB3, and erbB4 were detected in both rat conjunctiva and goblet cells by Western blot analysis. Immunofluorescence microscopy of conjunctival tissue determined that EGFR was present as punctate staining in the cytoplasm of conjunctival goblet cells while ErbB2 was present in the basolateral and lateral membranes of goblet cells. ErbB3 was localized to the cytosol of rat conjunctival goblet cells. In cultured goblet cells, EGFR and ErbB2 were present in the perinuclear area of the cells. ErbB3 was widely distributed throughout the cytoplasm of the cells. ErbB4 was not detected in either the conjunctiva or goblet cells by immunofluorescence microscopy. Using a multiplex assay system we measured phosphorylation (activation) of p44/p42 mitogen-activated protein kinase (MAPK), also known as ERK, Jun N-terminal kinase (JNK), p38 MAPK and AKT (also known as protein kinase B), molecules known to be activated by EGF receptor members. EGF, TGF-alpha and HB-EGF activated the signaling intermediate proteins whereas heregulin did not. No EGF family member significantly activated AKT. Consistent with these findings, EGF, TGF-alpha and HB-EGF each stimulated goblet cell proliferation as measured by WST-1 assay or immunofluorescence microscopy using an antibody against Ki-67, a protein expressed in dividing cells. Heregulin did not cause goblet cell proliferation. We conclude that multiple members of the EGF family, EGF, TGF-alpha and HB-EGF, and heregulin are present with three of the four erbB receptor subtypes. EGF, TGF-alpha and HB-EGF all stimulated the activation of signaling intermediates and caused goblet cell proliferation.
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PMID:Presence of EGF growth factor ligands and their effects on cultured rat conjunctival goblet cell proliferation. 1815 94

The purpose of the study was to determine if OPC-12759 stimulates secretion from conjunctival goblet cells in culture and if it activates the EGF receptor (EGFR) and p44/p42 mitogen-activated protein kinase (MAPK) to cause mucin secretion. Conjunctival goblet cells were cultured from pieces of male rat conjunctiva. OPC-12759 was added at increasing concentrations and for varying times to the cultured cells. The cholinergic agonist carbachol was used as a positive control. In selected experiments an inhibitor of the EGFR, AG1478, or an inhibitor of the kinase that activates MAPK, U0126, were added before OPC-12759. Goblet cell secretion of high molecular weight glycoconjugates was measured by an enzyme-linked lectin assay using the lectin UEA-1. Activation of the EGFR and MAPK were determined with Western blotting analysis using antibodies specific to the phosphorylated and the total amounts of these proteins. We found that OPC-12759 induced goblet cell secretion in a time- and concentration-dependent manner. Inhibition of the EGFR with AG1478 blocked secretion stimulated by OPC-12759. Inhibition of MAPK with U0126 also blocked secretion stimulated by OPC-12759. OPC-12759 increased the phosphorylation of the EGFR and MAPK in a time-dependent manner. We concluded that OPC-12759 stimulates secretion from cultured conjunctival goblet cells by activating the EGFR, which then induces MAPK activity.
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PMID:Effect of OPC-12759 on EGF receptor activation, p44/p42 MAPK activity, and secretion in conjunctival goblet cells. 1829 5

The formation of foam cells is the hallmark of early atherosclerotic lesions, and the uptake of modified low-density lipoprotein (LDL) by macrophage scavenger receptors is thought to be a key process in their formation. In this study, we examined the role of lectin-like oxLDL receptor-1 (Lox-1) and NADPH oxidase 1 (Nox1) in toll-like receptor 9 (TLR9)-mediated foam cell formation. TLR9 activation of Raw264.7 cells or mouse primary peritoneal macrophages by CpG ODN treatment enhanced Lox-1 gene and protein expression. In addition, CpG ODN-induced Nox1 mRNA expression, which in turn increased foam cell formation. The inhibition of CpG ODN-induced reactive oxygen species (ROS) generation by treatment with antioxidants, as well as with knockdown of Nox1 using siRNA, suppressed the formation of foam cells. The induction of Lox-1 and Nox1 by CpG ODN was regulated via the TLR9-p38 MAPK signaling pathway. CpG ODN also increased NFkappaB activity, and a potent inhibitor of NFkappaB that significantly blocked CpG-induced Nox1 expression, suggesting that Nox1 regulation is mediated through an NFkappaB-dependent mechanism. Taken together, these results suggest that a combination of Lox-1 and Nox1 plays a key role in the TLR9-mediated formation of foam cells via the p38 MAPK pathway.
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PMID:A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation. 1881 66

Galectin-3 is a beta-galactoside-binding animal lectin having pleiotropic effects on cell growth, differentiation, and apoptosis. This lectin has been shown to be involved in phagocytosis by macrophages and in inflammation. Here we investigated an involvement of galectin-3 in the regulatory process of inflammatory bone resorption in rats with adjuvant-induced arthritis (AA rats) accompanying severe bone destruction in the ankle joints. The protein level of galectin-3 in the ankle-joint extracts was markedly augmented at week 3 after adjuvant injection, at the time when severe bone destruction was observed. Immunohistochemical analysis revealed an extremely high expression of galectin-3 in macrophages and granulocytes infiltrated in the area of severe bone destruction. To estimate the role of galectin-3 in osteoclastogenesis and osteoclastic bone resorption, recombinant galectin-3 was added to in vitro culture systems. Galectin-3 markedly inhibited the formation of osteoclasts in cultures of murine osteoclast precursor cell line as well as in rat bone marrow culture systems. This inhibition was not observed by heat-inactivated galectin-3 or by galectin-7. Although recombinant galectin-3 did not affect signaling through mitogen-activated protein kinase (MAPK) or nuclear factor-kappaB (NF-kappaB), it specifically suppressed the induction of nuclear factor of activated T-cells c1 (NFATc1). Galectin-3 significantly inhibited dentine resorption by mature osteoclasts in vitro. Furthermore, in vivo studies clearly showed a significant suppression of bone destruction and osteoclast recruitment accompanying arthritis, when galectin-3 was injected into the cavity of ankle joint of AA rats. Thus, abundant galectin-3 observed in the area of severe bone destruction may act as a negative regulator for the upregulated osteoclastogenesis accompanying inflammation to prevent excess bone destruction.
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PMID:A possible suppressive role of galectin-3 in upregulated osteoclastogenesis accompanying adjuvant-induced arthritis in rats. 1901 43


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