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)

Excessive mesangial cell (MC) proliferation is a hallmark of many glomerulopathies. In our recent study on cultured rat MC (Matousovic, K., J.P. Grande, C.C.S. Chini, E.N. Chini, and T.P. Dousa. 1995. J. Clin. Invest. 96:401-410) we found that inhibition of isozyme cyclic-3',5'-nucleotide phosphodiesterase (PDE) type III (PDE-III) suppressed MC mitogenesis by activating cAMP-dependent protein kinase (PKA) and by decreasing activity of mitogen-activated protein kinase (MAPK). We also found that inhibition of another PDE isozyme, PDE-IV, suppresses superoxide generation in glomeruli (Chini, C.C.S., E.N. Chini, J.M. Williams, K. Matousovic, and T.P. Dousa. 1994. Kidney Int. 46:28-36). We thus explored whether administration in vivo of the selective PDE-III antagonist, lixazinone (LX), together with the specific PDE-IV antagonist, rolipram (RP), can attenuate development of mesangioproliferative glomerulonephritis (MSGN) induced in rats by anti-rat thymocyte serum (ATS). Unlike the vehicle-treated MSGN rats, rats with MSGN treated with LX and RP did not develop proteinuria and maintained normal renal function when examined 5 d after injection of ATS. In PAS-stained kidneys from PDE-antagonists-treated MSGN-rats the morphology of glomeruli showed a reduction in cellularity compared with control rats with ATS. Compared with MSGN rats receiving vehicle, the MSGN rats receiving PDE-antagonists had less glomerular cell proliferation (PCNA delta -65%), a significantly lesser macrophage infiltration (delta -36% ED-1) and a significant reduction of alpha-smooth muscle actin expression by activated MC; in contrast, immunostaining for platelet antigens and laminin were not different. The beneficial effect of PDE inhibitors was not due to a moderate decrease (approximately -20%) in systolic blood pressure (SBP); as a similar decrease in SBP due to administration of hydralazine, a drug devoid of PDE inhibitory effect, did not reduce severity of MSGN in ATS-injected rats. We conclude that antagonists of PDE-III and PDE-IV administered in submicromolar concentrations in vivo to ATS-injected rats can decrease the activation and proliferation of MC, inhibit the macrophage accumulation, and prevent proteinuria in the acute phase of MSGN. We propose that PDE isozyme inhibitors act to block (negative "crosstalk") the mitogen-stimulated intracellular signaling pathway which controls MC proliferation due to activating of the cAMP-PKA pathway. These results suggest that antagonists of PDE-111 and IV may have a suppressive effect in acute phases or relapses of glomerulopathies associated with MC proliferations.
 ...
PMID:Suppression of mesangial proliferative glomerulonephritis development in rats by inhibitors of cAMP phosphodiesterase isozymes types III and IV. 875 33

MDCK-C7 cells dedifferentiated either by transient alkaline stress (C7F cells) or by transfection with a constitutively active mutant of the mitogen-activated protein kinase kinase MEK1 (C7caMEK1 cells) were analyzed by western blot and immunofluorescence microscopy to compare the expression of different cytokeratins, vimentin, and alpha-smooth muscle actin. Expression of all cytokeratins tested, the type II-neutral and basic cytokeratins CK5, CK7, CK8 as well as the type I-acidic keratins CK17 and CK19, was substantially reduced in dedifferentiated cell lines C7F and C7caMEK1 when compared with epithelial wild-type MDCK-C7 cells or mock-transfected MDCK-C7 cells. While vimentin expression was detected in all of the four MDCK-C7 cell lines examined, only the dedifferentiated cell lines C7F and C7caMEK1, which have been reported to express highly active ERK2, exhibited formation of alpha-smooth muscle actin-containing stress fibers. Taken together our results show that, associated with an increase in ERK2 activity, an epithelial to mesenchymal dedifferentiation occurred in both MDCK-C7F cells and caMEK1-transfected MDCK-C7 cells.
 ...
PMID:Loss of cytokeratin expression and formation of actin stress fibers in dedifferentiated MDCK-C7 cell lines. 942 7

Cardiac hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by a number of qualitative and quantitative changes in gene expression. Most forms of hypertrophy in vivo are compensatory or adaptative responses to increased workload resulting from various physiological and/or pathological etiologies. Until severe pathological alterations become apparent, myocytes show no drastic morphological changes. On the level of gene expression, upregulation of the so-called fetal genes, i.e., beta-myosin heavy chain, alpha-skeletal and alpha-smooth muscle actin, and atrial natriuretic factor (ANF) may be observed concomitant with a downregulation of alpha-myosin heavy chain and the Ca pump of sarcoplasmic reticulum. The use of primary cell culture systems for cardiomyocytes as an in vitro model for the hypertrophic reaction has identified a number of different stimuli as mediators of cardiac myocyte hypertrophy. The molecular dissection of the different intracellular signaling pathways involved herein has uncovered a number of branching points to cytosolic and nuclear targets and has identified many interactions between these pathways. The individual administration of these hypertrophic stimuli, i.e., hormones, cytokines, growth factors, vasoactive peptides, and catecholamines, to cultured cardiomyocytes, reveals that each stimulus induces a distinct phenotype as characterized by gene expression pattern and cellular morphology. Surprisingly, triiodothyronine (T3) and basic fibroblast growth factor (bFGF) effect a similar cellular phenotype although they use completely different intracellular pathways. This phenotype is characterized by drastic inhibition of myofibrillar growth and by upregulation of alpha-smooth muscle actin. On the other hand, insulin-like growth factor (IGF) I, a factor promoting muscle cell differentiation, and bFGF, an inhibitor of differentiation, cause completely different cardiomyocyte phenotypes although both are known to signal via receptor tyrosine kinases and have been shown to activate the Ras-Raf-MEK-MAP kinase pathway. However, both IGF-I and bFGF depend on T3 to bring about their typical responses, i.e., T3 is permissive for the action of these two growth factors on the expression of alpha-smooth muscle actin and cell morphology. Most of the hypertrophic stimuli are balanced under normal circumstances in vivo. When this balance is disturbed, however, a pathological heart phenotype may become dominant. Thus the knowledge of signaling pathways and cellular responses triggered by hypertrophic stimuli may be essential for the implementation of therapeutic strategies in the treatment of cardiac hypertrophy.
 ...
PMID:Various hypertrophic stimuli induce distinct phenotypes in cardiomyocytes. 942 23

Cultured mesangial cells constitutively express alpha-smooth muscle actin (alpha-SMA), a marker of cellular activation. We unexpectedly found that tyrosine kinase pp60v-src, a known activator for a wide range of signalling cascades, suppressed the alpha-SMA expression in mesangial cells. The present study was conducted to elucidate molecular events involved in this phenomenon. Transfection with a reporter plasmid revealed that the serum response element (SRE), the cis-element required for alpha-SMA expression, was constitutively active in mesangial cells. When mesangial cells were transfected with pp60v-src, activity of both SRE and the alpha-SMA promoter was down-regulated. This was associated with depressed levels of phosphorylated extracellular signal-regulated kinases (ERKs), but not c-Jun N-terminal kinase. Selective inhibition of ERKs by PD098059 abrogated constitutive SRE activity, leading to suppressed alpha-SMA expression. These results uncovered a novel potential of pp60v-src for suppression of alpha-SMA via intervention in the ERK-SRE signalling pathway.
 ...
PMID:Unexpected suppression of alpha-smooth muscle actin, the activation marker of mesangial cells, by pp60v-src tyrosine kinase. 953 47

Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early participants in inflammatory responses as well as potential targets for anti-inflammatory drugs. In this study, we show that fluticasone propionate (FP), a powerful inhaled corticosteroid (ICS), displays novel anti-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by IL-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kinase). Contrarily, in mildly or fully differentiated myofibroblastic cultures, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitutive and TGF-beta-induced expression of alpha-smooth muscle actin, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. Finally, FP displays an additional powerful anti-inflammatory effect, decreasing nuclear translocation of NF-kappaB independent of the degree of myofibroblastic differentiation. These data 1) suggest that myofibroblasts are priority targets for ICS, which is able to revert them to a normal phenotype even if they appear to be already engaged in their differentiation, and 2) may help to explain why asthma is improved by an early ICS treatment, whereas advanced asthma is more resistant to these drugs.
 ...
PMID:Novel anti-inflammatory effects of the inhaled corticosteroid fluticasone propionate during lung myofibroblastic differentiation. 1167 49

Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules. Blockade of RAGE has been reported to considerably improve liver function and accelerate regeneration after hepatectomy. The aim of this study was to investigate the cell type-specific expression of RAGE, and to examine whether transdifferentiation of hepatic stellate cells (HSC) into myofibroblasts (MFB) is associated with changes in RAGE expression. Northern blot analysis revealed that RAGE mRNA was exclusively expressed by HSC isolated from rat liver, while no transcripts were seen in hepatocytes, Kupffer cells, or sinusoidal endothelial cells. Expression of RAGE mRNA was up-regulated during transdifferentiation of HSC into MFB. Concomitantly, expression of RAGE protein was increased as confirmed by Western blotting and immunohistochemistry. As assessed by radioactive labeling, transforming growth factor beta(1) (TGF-beta(1)) induced a time-dependent 2- to 15-fold increase in the de novo synthesis of RAGE protein, which was completely abolished using PD098059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) kinase. As shown by double-immunofluorescence staining, RAGE colocalized with alpha-smooth muscle actin, and immunoelectron microscopy demonstrated the most prominent labeling for RAGE at filopodial membranes of MFB. In conclusion, this study demonstrates that expression of RAGE is restricted to rat HSC, and that expression is up-regulated during activation of HSC and transition to MFB. The preferential immunogold labeling of RAGE to focal membrane areas of filopodia of MFB is suggestive of a role of RAGE in the spreading and migration of activated HSC/MFB, major players in liver fibrogenesis.
 ...
PMID:Up-regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to myofibroblasts. 1167 65

To investigate the role of intracellular mitogen activated protein kinase (MAPKs, ERK, JNK and p38) signal pathways in IL-1beta -stimulated alpha-smooth muscle actin (alpha-SMA) expression in rat mesangial cells (rMC), alpha-SMA-promoter gene was transfected into rMC by electro-perforation method and the promoter activity was assayed after IL-1beta (10 ng/ml) stimulation. Protein expression of alpha-SMA was assayed by Western blot. The results were compared between the groups stimulated by IL-1beta with or without PD98059 and SB203580, which are thought to block ERK and p38 pathway, respectively. Dominant-negative-JNKK plasmid was co-transfected in rMC to block JNK pathway. The spatial distribution of alpha-SMA and microfilament-like structure was observed by a confocal laser scanning microscope or an electric microscope. After 6 or 24 h of incubation with IL-1beta, rMC underwent a phenotypic change, which was represented by up-regulation of alpha-SMA promoter activity and protein expression. An increase in alpha-SMA and microfilament-like structure was found around the cell nucleus. Block of JNK and/or p38 pathway greatly inhibited IL-1beta -induced alpha-SMA expression, and the block of p38 pathway also suppressed the basal level of alpha-SMA expression. In contrast, ERK pathway had no influence on the process. It is, therefore, concluded that IL-1beta -stimulated expression of alpha-SMA is due to its protein synthesis and cytoskeleton re-organization in activated rMC. Intracellular signal regulation of alpha-SMA expression seems to be mediated mainly by JNK/p38 pathways, but ERK appears to have no effect on the process.
 ...
PMID:[IL-1beta stimulates alpha-smooth muscle actin expression through JNK/p38 signal pathway in cultured rat mesangial cells]. 1207 73

Substantial experimental evidence supports the idea that the fibroblast may play a significant role in the vascular response to injury, especially under hypoxic conditions. Fibroblasts have the ability to rapidly respond to hypoxic stress and to modulate their function to adapt rapidly to local vascular needs. Fibroblasts appear to be uniquely equipped to proliferate, transdifferentiate, and migrate under hypoxic conditions. Proliferative responses to hypoxia depend on the activation of Galpha(i) and Gq kinase family members, and on the subsequent stimulation of protein kinase C and mitogen-activated protein kinase family members. Extracellular nucleotides (eg, adenosine triphosphate [ATP]) are likely to be increased in the hypoxic adventitial compartment and can act as autocrine/paracrine modifiers of the hypoxia-induced proliferative response. The proliferative effects of ATP appear to be mediated largely through G-protein-coupled P2Y receptors in fetal and neonatal fibroblasts. Hypoxia, acting through Galpha(iota)-coupled pathways, also can directly up-regulate alpha-smooth muscle actin expression in fibroblast subpopulations, suggesting that hypoxia may play a direct role in mediating the "transdifferentiation" of fibroblasts into myofibroblasts in the vessel wall. In addition, chronic hypoxia causes stable (at least in vitro) phenotypic changes in fibroblasts that appear to be associated with changes in the signaling pathways used to elicit proliferation. However, it is also becoming clear that, similar to the heterogeneity described for vascular smooth muscle cells, numerous fibroblast subtypes exist in the vessel wall, and that each may respond in unique ways to hypoxia and other stimuli and thus serve special functions in response to injury. In fact, adventitia may be considered to be compartments in which cells with "stem-cell-like" characteristics reside. Future work is needed to determine more precisely the role of the fibroblast in the wide variety of vascular complications observed in many humans diseases, and in the genes and gene products that confer unique properties to this important vascular cell.
 ...
PMID:Hypoxic activation of adventitial fibroblasts: role in vascular remodeling. 1247 10

Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Primary PSCs can be subcultured only several times because of their limited growth potential. A continuous cell line would be valuable in studying molecular mechanisms of these pancreatic disorders. The aim of this study was to establish an immortalized cell line of rat PSCs. PSCs were isolated from the pancreas of male Wistar rats, and the simian virus 40 T antigen was introduced to PSCs by retrovirus-mediated gene transfer. This procedure yielded an actively growing cell line, designated as SAM-K. This cell line has been passaged repeatedly for almost 2 years, and is thus likely immortalized. SAM-K cells retained morphological characteristics of primary PSCs, and expressed alpha-smooth muscle actin, glial fibrillary acidic protein, type I collagen, fibronectin, and prolyl hydroxylases. The level of p53 expression was very high in SAM-K cells. Proliferation of SAM-K cells was stimulated by serum and platelet-derived growth factor-BB. Interleukin-1beta (IL-1beta) activated nuclear factor-kappaB, activator protein-1, and three classes of mitogen-activated protein (MAP) kinases: extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase, and p38 MAP kinase. IL-1beta induced expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, both of which were abolished in the presence of pyrrolidine dithiocarbamate, a specific inhibitor of nuclear factor-kappaB activation. IL-1beta-induced monocyte chemoattractant protein-1 was partially inhibited by specific inhibitors of MAP kinase kinase (U0126) and of p38 MAP kinase (SB203580) whereas intercellular adhesion molecule-1 expression was not altered by the inhibitors. Thus, SAM-K would be useful for in vitro studies of cell biology and signal transduction of PSCs.
 ...
PMID:Establishment and characterization of a simian virus 40-immortalized rat pancreatic stellate cell line. 1249 15

The aim of this study was to evaluate the effect of cariporide, a selective Na(+)/H(+) exchange inhibitor, on isolated and cultured hepatic stellate cells (HSCs) and in 2 in vivo models of rat liver fibrosis. Platelet-derived growth factor (PDGF)-induced HSC proliferation, evaluated by measuring the percentage of bromodeoxyuridine-positive cells, was significantly inhibited by cariporide, with a maximal effect at 10 micromol/L. Incubation with cariporide did not inhibit PDGF-induced extracellular-regulated kinase 1/2 (ERK1/2), Akt (a downstream component of the phosphatidylinositol [PI]-3 kinase pathway), and protein kinase C (PKC) activation but reduced PDGF-induced activation of the Na(+)/H(+) exchanger, with a maximal effect at 10 micromol/L. Rats treated with dimethylnitrosamine (DMN; 10 mg/kg) for 1 and 5 weeks received a diet with or without 6 ppm cariporide. Treatment with cariporide reduced the degree of liver injury, as determined by alanine aminotransferase (ALT) values, also when administered after the induction of hepatic damage. This was associated with reduced HSC activation and proliferation and reduced collagen deposition, as determined by morphometric evaluation of alpha-smooth muscle actin (SMA)/proliferating cell nuclear antigen-positive cells and percentage of Sirius red-positive parenchyma, respectively. Moreover, cariporide was also able to reduce alpha(1)I procollagen messenger RNA (mRNA) expression. Similar effects were observed in bile duct-ligated (BDL) rats. In conclusion, selective inhibition of the Na(+)/H(+) exchanger by cariporide may represent an effective therapeutic strategy in the treatment of hepatic fibrosis.
 ...
PMID:Selective Na+/H+ exchange inhibition by cariporide reduces liver fibrosis in the rat. 1254 Jul 75


1 2 3 4 5 6 7 8 9 10 Next >>