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)

Chondroitin sulphate proteoglycan (CSPG) inhibits axonal regeneration in the central nervous system (CNS) and its local degradation promotes repair. We postulated that the enzymatic degradation of CSPG generates reparative products. Here we show that an enzymatic degradation product of CSPG, a specific disaccharide (CSPG-DS), promoted CNS recovery by modulating both neuronal and microglial behaviour. In neurons, acting via a mechanism that involves the PKCalpha and PYK2 intracellular signalling pathways, CSPG-DS induced neurite outgrowth and protected against neuronal toxicity and axonal collapse in vitro. In microglia, via a mechanism that involves ERK1/2 and PYK2, CSPG-DS evoked a response that allowed these cells to manifest a neuroprotective phenotype ex vivo. In vivo, systemically or locally injected CSPG-DS protected neurons in mice subjected to glutamate or aggregated beta-amyloid intoxication. Our results suggest that treatment with CSPG-DS might provide a way to promote post-traumatic recovery, via multiple cellular targets.
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PMID:A disaccharide derived from chondroitin sulphate proteoglycan promotes central nervous system repair in rats and mice. 1545 76

Mushroom polysaccharides are increasingly being utilized to treat a wide variety of diseases. Phellinus linteus proteoglycan (PL) has been reported to have anti-tumor and immunomodulatory properties. However, the cellular and molecular mechanism underlying its therapeutic effect is poorly understood. In this study, we investigated whether PL induces the phenotypic and functional maturation of murine bone marrow-derived dendritic cells (DC) and the possibility that Toll-like receptors (TLRs), which are known to be involved in immune-related responses, may be the receptor(s) of PL. The expression of surface molecules, including major histocompatibility complex (MHC) class II and CD86, increased on DC that were stimulated in a dose-dependent manner with PL, in comparison with unstimulated DC. Furthermore, PL increases the production of IL-12 by DC, as well as the IL-2 secretion and proliferation of allogeneic T cells. In addition, the activities of PL on DC were significantly reduced by treating the cells with anti-TLR2 or anti-TLR4 antibody (Ab) prior to PL, suggesting that both of them are possible receptors of PL. Also, maturation of DC by PL was able to directly activate mitogen-activated protein kinases (MAPKs), such as ERK1/2 and p38, and the nuclear transcription factor NF-kappaB p65. Also, the pretreatment of DC with inhibitors of NF-kappaB p65, and ERK and p38 MAPK signal pathways inhibited PL-induced up-regulation of surface molecules, such as MHC class II and CD86, and IL-12 production. Our results demonstrated that PL stimulation could induce the phenotypic and functional maturation of DC via TLR2 and/or TLR4 mediated-NF-kappaB, ERK and p38 MAPK signal pathways.
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PMID:Proteoglycan isolated from Phellinus linteus induces toll-like receptors 2- and 4-mediated maturation of murine dendritic cells via activation of ERK, p38, and NF-kappaB. 1546 14

Tumour necrosis factor (TNF) signalling molecules are considered as promising therapeutic targets of antirheumatic therapy. Among them, mitogen-activated protein kinases are thought to be of central importance. Herein, we investigate the role in vivo of TNF-alpha signalling through c-Jun N-terminal kinase (JNK)1 in destructive arthritis. Human TNF transgenic (hTNFtg) mice, which develop inflammatory arthritis, were intercrossed with JNK1-deficient (JNK1-/-) mice. Animals (n = 35) of all four genotypes (wild-type, JNK1-/-, hTNFtg, JNK1-/-hTNFtg) were assessed for clinical and histological signs of arthritis. Clinical features of arthritis (swelling and decreased grip strength) developed equally in hTNFtg and JNK1-/-hTNFtg mice. Histological analyses revealed no differences in the quantity of synovial inflammation and bone erosions or in the cellular composition of the synovial infiltrate. Bone destruction and osteoclast formation were observed to a similar degree in hTNFtg and JNK1-/-hTNFtg animals. Moreover, cartilage damage, as indicated by proteoglycan loss in the articular cartilage, was comparable in the two strains. Intact phosphorylation of JNK and c-Jun as well as expression of JNK2 in the synovial tissue of JNK1-/-hTNFtg mice suggests that signalling through JNK2 may compensate for the deficiency in JNK1. Thus, JNK1 activation does not seem to be essential for TNF-mediated arthritis.
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PMID:JNK1 is not essential for TNF-mediated joint disease. 1564 37

TCDD exposure of multipotential C3H10T1/2 fibroblasts for 72 h altered the expression of over 1000 genes, including coordinated changes across large functionally similar gene clusters. TCDD coordinately induced 23 cell cycle-related genes similar to epidermal growth factor (EGF)-induced levels but without any affect on the major mitogenic signaling pathway (extracellular signal-regulated kinase, ERK). TCDD treatment also decreased glycolytic and ribosomal clusters. Most of these TCDD-induced changes were attenuated by the presence of EGF or an adipogenic stimulus, each added during the final 24 h. TCDD prevented 10% of EGF-induced gene responses and 40% of adipogenic responses. Over 100 other genes responded to TCDD during adipogenesis. This group of responses included complete suppression of three proliferins and stimulations of several cytokine receptors. Despite these varied secondary effects of TCDD, direct AhR activation measured by integrated AhR-responsive luciferase reporters was similar under quiescent, EGF-stimulated or adipogenic conditions. Only 23 genes were similarly induced by TCDD regardless of conditions and 10 were suppressed. These 23 genes include: 4 genes previously recognized to contain AhR response elements (cytochrome P450 (CYP) 1B1, CYP1A1, NAD(P)H quinone reductase 1 (NQO1), and aldehyde dehydrogenase 3A1); two novel oxidative genes (alcohol dehydrogenase 3 and superoxide dismutase 3); and glypican 1, a plasma membrane proteoglycan that affects cell signaling. Further experiments demonstrated that TCDD maximally induced NQO1, glypican 1 and alcohol dehydrogenase 3 by 6 h. Glypican 1 activates the actions of many growth factors and therefore may contribute to secondary effects on gene expression.
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PMID:Identification of novel TCDD-regulated genes by microarray analysis. 1566 27

Thrombin is a mitogen and chemoattractant for vascular smooth muscle cells (SMCs) and may contribute to vascular lesion formation. We have previously shown that human SMCs, when stimulated with thrombin, release basic fibroblast growth factor (bFGF), causing phosphorylation of FGF receptor-1 (FGFR-1). Treatment with bFGF-neutralizing antibodies (anti-bFGF) or heparin inhibits thrombin-induced DNA synthesis. We concluded that thrombin may stimulate entry into the cell cycle via bFGF release and FGFR-1 activation. In the present study, we demonstrate a requirement for not only FGFR-1 but also syndecan-4, a transmembrane heparan-sulfate proteoglycan. Inhibition of syndecan-4 expression using small interfering RNA (siRNA) resulted in reduced DNA synthesis by human SMCs after stimulation with thrombin (10 nmol/liter). Anti-bFGF antibody, which inhibits DNA synthesis in control cells, had no inhibitory effect when syndecan-4 expression was reduced by siRNA. Thrombin- or bFGF-induced SMC migration, determined in Boyden chamber assays, was reduced in cells treated with syndecan-4 or FGFR-1 siRNA or by anti-bFGF. Thrombin induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in a biphasic pattern. Although thrombin-mediated ERK phosphorylation at 5 min was not affected by syndecan-4 or FGFR-1 siRNA, ERK phosphorylation at later time points was reduced. We conclude that thrombin-released bFGF binds to syndecan-4 and FGFR-1, which is required for thrombin-induced mitogenesis and migration.
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PMID:Syndecan-4 is required for thrombin-induced migration and proliferation in human vascular smooth muscle cells. 1573 Nov

These studies compare actions of p38 MAPK inhibition and COX2 inhibition to modulate human arthritic chondrocyte responses to TGF-beta and FCS under basal and IL-1 activated conditions. Chondrocytes isolated from arthritic human femoral condyle cartilage obtained at total knee replacement were grown to 80% confluence. Proteoglycan synthesis and proliferation were measured with and without IL-1 activation in the presence and absence of growth factors and with and without inhibition of p38 MAPK or COX2 activity. Experiments to evaluate TIMP-1 production under these conditions were done using cartilage organ cultures. Neither p38 MAPK inhibitors nor COX2 inhibition affected basal proliferation. However both inhibitors enhanced the proliferative response to TGF-beta and FCS in IL-1 activated chondrocytes. TGF-beta stimulated proteoglycan synthesis was decreased by p38 MAPK inhibition, however COX2 inhibition restored the response to TGF-beta in IL-1 activated cells. In contrast, COX2 inhibition did not modulate TIMP-1 production while p38 MAPK inhibitors potentiated TGF-beta stimulated production of TIMP-1 in IL-1 activated cartilage. p38 MAPK inhibition and COX2 inhibition have unique and similar abilities to counteract some of the effects of IL-1 on human chondrocyte/cartilage metabolism. Both will partially restore the proliferative response to growth factors. p38 MAPK inhibition blunts TGF-beta stimulation of proteoglycan synthesis, but increases TIMP-1 synthesis. COX2 inhibition can restore the proteoglycan synthetic response to TGF-beta, but has no effect on cartilage TIMP-1 production. Use of these inhibitors to minimize cartilage damage in arthritic and mechanically stressed joints should reflect these characteristics.
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PMID:p38 MAPK and COX2 inhibition modulate human chondrocyte response to TGF-beta. 1573 62

The IGF-I (insulin-like growth factor-I) signalling pathway responsible for regulation of proteoglycan synthesis in chondrocytes has not been defined and is the focus of the present study. Chondrocytes isolated from normal human articular cartilage were stimulated with IGF-I in monolayer culture or in suspension in alginate. IGF-I activated members of both the PI3K (phosphoinositide 3-kinase) pathway and the ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) pathway. The PI3K inhibitors LY294002 and wortmannin blocked IGF-I-stimulated Akt phosphorylation without blocking ERK phosphorylation and this was associated with complete inhibition of proteoglycan synthesis. A decrease in IGF-I-stimulated proteoglycan synthesis was also observed upon inhibition of mTOR (mammalian target of rapamycin) and p70S6 kinase, both of which are downstream of Akt. The MEK (MAPK/ERK kinase) inhibitors PD98059 and U0126 blocked IGF-I-stimulated ERK phosphorylation but did not block the phosphorylation of Akt and did not decrease proteoglycan synthesis. Instead, in alginate- cultured chondrocytes, the MEK inhibitors increased IGF-I-stimulated proteoglycan synthesis when compared with cells treated with IGF-I alone. This is the first study to demonstrate that IGF-I stimulation of the PI3K signalling pathway is responsible for the ability of IGF-I to increase proteoglycan synthesis. Although IGF-I also activates the ERK/MAPK pathway, ERK activity is not required for proteoglycan synthesis and may serve as a negative regulator.
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PMID:IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. 1580 8

Stromal cell-derived factor-1 (SDF-1)/CXCL12, the ligand for CXCR4, induces signal transduction. We previously showed that CXCL12 binds to high- and low-affinity sites expressed by primary cells and cell lines, and forms complexes with CXCR4 as expected and also with a proteoglycan, syndecan-4, but does not form complexes with syndecan-1, syndecan-2, CD44 or beta-glycan. We also demonstrated the occurrence of a CXCL12-independent heteromeric complex between CXCR4 and syndecan-4. However, our data ruled out the glycosaminoglycan-dependent binding of CXCL12 to HeLa cells facilitating the binding of this chemokine to CXCR4. Here, we demonstrate that CXCL12 directly binds to syndecan-4 in a glycosaminoglycan-dependent manner. We show that upon stimulation of HeLa cells by CXCL12, CXCR4 becomes tyrosine phosphorylated as expected, while syndecan-4 (but not syndecan-1, syndecan-2 or beta-glycan) also undergoes such tyrosine phosphorylation. Moreover, tyrosine-phosphorylated syndecan-4 from CXCL12-stimulated HeLa cells physically coassociates with tyrosine phosphorylated CXCR4. Pretreatment of the cells with heparitinases I and III prevented the tyrosine phosphorylation of syndecan-4, which suggests that the heparan sulfate-dependent binding of SDF-1 to this proteoglycan is involved. Finally, by reducing syndecan-4 expression using RNA interference or by pretreating the cells with heparitinase I and III mixture, we suggest the involvement of syndecan-4 and heparan sulfate in p44/p42 mitogen-activated protein kinase and Jun N-terminal/stress-activated protein kinase activation by action of CXCL12 on HeLa cells. However, these treatments did not modify the calcium mobilization induced by CXCL12 in these cells. Therefore, syndecan-4 behaves as a CXCL12 receptor, selectively involved in some transduction pathways induced by SDF-1, and heparan sulfate plays a role in these events.
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PMID:Syndecan-4 is a signaling molecule for stromal cell-derived factor-1 (SDF-1)/ CXCL12. 1581 87

Interleukin (IL)-1beta induces the expression of matrix metalloproteinases (MMPs) implicated in cartilage resorption and joint degradation in osteoarthritis (OA). Pomegranate fruit extract (PFE) was recently shown to exert anti-inflammatory effects in different disease models. However, no studies have been undertaken to investigate whether PFE constituents protect articular cartilage. In the present studies, OA chondrocytes or cartilage explants were pretreated with PFE and then stimulated with IL-1beta at different time points in vitro. The amounts of proteoglycan released were measured by a colorimetric assay. The expression of MMPs, phosphorylation of the inhibitor of kappaBalpha (IkappaBalpha) and mitogen-activated protein kinases (MAPKs) was determined by Western immunoblotting. Expression of mRNA was quantified by real-time PCR. MAPK enzyme activity was assayed by in vitro kinase assay. Activation of nuclear factor-kappaB (NF-kappaB) was determined by electrophoretic mobility shift assay. PFE inhibited the IL-1beta-induced proteoglycan breakdown in cartilage explants in vitro. At the cellular level, PFE (6.25-25 mg/L) inhibited the IL-1beta-induced expression of MMP-1, -3, and -13 protein in the medium (P < 0.05) and this was associated with the inhibition of mRNA expression. IL-1beta-induced phosphorylation of p38-MAPK, but not that of c-Jun-N-terminal kinase or extracellular regulated kinase, was most susceptible to inhibition by low doses of PFE, and the addition of PFE blocked the activity of p38-MAPK in a kinase activity assay. PFE also inhibited the IL-1beta-induced phosphorylation of IkappaBalpha and the DNA binding activity of the transcription factor NF-kappaB in OA chondrocytes. Taken together, these novel results indicate that PFE or compounds derived from it may inhibit cartilage degradation in OA and may also be a useful nutritive supplement for maintaining joint integrity and function.
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PMID:Punica granatum L. extract inhibits IL-1beta-induced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NF-kappaB in human chondrocytes in vitro. 1614 Aug 82

Scarring is characterized by excessive synthesis and contraction of extracellular matrix. Here, we show that fibroblasts from scarred (lesional) areas of patients with the chronic fibrotic disorder diffuse scleroderma [diffuse systemic sclerosis (dSSc)] show an enhanced ability to adhere to and contract extracellular matrix, relative to fibroblasts from unscarred (nonlesional) areas of dSSc patients and dermal fibroblasts from normal, healthy individuals. The contractile abilities of normal and dSSc dermal fibroblasts were suppressed by blocking heparin sulfate-containing proteoglycan biosynthesis or antagonizing transforming growth factor-beta receptor type I [activin-linked kinase (ALK5)] or ras/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK). Compared with both normal and nonlesional fibroblasts, lesional dSSc fibroblasts overexpressed the heparin sulfate-containing proteoglycan syndecan 4. We also found that the procontractile signals from transforming growth factor (TGF)-beta were integrated through syndecan 4 and MEK/ERK because the ability of TGFbeta to induce contraction of dermal fibroblasts was prevented by MEK antagonism. TGFbeta could not induce a contractile phenotype or phosphorylate ERK in syndecan 4(-/-) dermal fibroblasts. These results suggest that integrating TGFbeta and ERK signals via syndecan 4 is essential for the contractile ability of dermal fibroblasts. We conclude that antagonizing MEK/ERK, TGFbeta1/ALK5, or syndecan 4 may alleviate scarring in chronic fibrotic disease.
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PMID:Matrix contraction by dermal fibroblasts requires transforming growth factor-beta/activin-linked kinase 5, heparan sulfate-containing proteoglycans, and MEK/ERK: insights into pathological scarring in chronic fibrotic disease. 1631 81


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