Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the expression of interleukin-1 (IL-1) receptors and their involvement in the regulation of the serotonin transporter gene expression in human placenta. IL-1beta is an activator of the serotonin transporter gene expression in JAR human placental choriocarcinoma cells as demonstrated by an increase in the steady-state levels of the transporter mRNA and in serotonin transport activity. This activation is blocked by IL-1 receptor antagonist. Genistein also blocks the effect of IL-1beta, indicating involvement of tyrosine phosphorylation in the process. Treatment of JAR cells with IL-1beta activates mitogen-activated protein kinases and nuclear factor-kappaB. The nuclear factor-kappaB that is responsive to IL-1beta in these cells is the p65 homodimer. Northern blot analysis and reverse transcription-polymerase chain reaction revealed that JAR cells and human placenta express type I and type II IL-1 receptors. The binding sites for (125)I-IL-1beta are localized predominantly in the maternal-facing brush border membrane of the syncytiotrophoblast. These results show that IL-1 in the maternal circulation is likely to play a critical role in the regulation of the serotonin transporter gene expression in the placenta.
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PMID:Polarized distribution of interleukin-1 receptors and their role in regulation of serotonin transporter in placenta. 1068 20

We have previously reported that tranilast, an anti-allergic drug, prevented the experimental intimal thickening in the rat and mouse femoral arteries and its effect may be exerted through the inhibition of vascular smooth muscle cell proliferation. However, its inhibitory mechanism has yet to be understood. In this study, we investigated the inhibitory effect of tranilast on platelet-derived growth factor BB-homodimer (PDGF-BB) mediated signal transduction pathways in cultured human coronary artery smooth muscle cells (CASMCs). Growth responses to PDGF-BB were measured by [(3)H]-thymidine incorporation or cell counting. Activation of DNA synthesis and augmentation of cell proliferation stimulated by PDGF-BB in quiescent cultures of CASMCs were inhibited by tranilast in a concentration-dependent manner. Western blot analysis of lysates from CASMCs with an anti-activated mitogen-activated protein (MAP) kinase antibody revealed that tranilast (10 - 300 microM) inhibited MAP kinase activation by PDGF-BB in a concentration-dependent manner. Tranilast also reduced PDGF-BB-stimulated tyrosine phosphorylation of a 180 kDa band, corresponding in mass to the PDGF beta-receptor, as shown by immunoblots using an anti-phosphotyrosine antibody. Receptor-binding study with [(125)I]-PDGF-BB on CASMCs showed that tranilast (10 - 1000 microM) inhibited the specific binding of PDGF-BB to cell surface receptors in a concentration-dependent manner. Scatchard analysis revealed that pretreatment with 300 microM tranilast decreased the maximum binding capacity (B(max)) from 27.6 to 18.0 fmol 10(6) cells(-1) without affecting binding affinity (K(d) approximately 0.15 nM), indicating a non-competitive inhibition of the receptor binding. These results suggest that the suppression of human CASMC growth by tranilast might be at least partly due to blockade of PDGF-BB-receptor binding.
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PMID:Inhibitory mechanism of tranilast in human coronary artery smooth muscle cells proliferation, due to blockade of PDGF-BB-receptors. 1080 67

The trefoil peptide intestinal trefoil factor (ITF) plays a critical role in the protection of colonic mucosa and is essential to restitution after epithelial damage. These functional properties are accomplished through coordinated promotion of cell migration and inhibition of apoptosis. ITF contains a unique three-looped trefoil motif formed by intrachain disulfide bonds among six conserved cysteine residues, which is thought to contribute to its marked protease resistance. ITF also has a seventh cysteine residue, which permits homodimer formation. A series of cysteine-to-serine substitutions and a C-terminally truncated ITF were made by PCR site-directed mutagenesis. Any alteration of the trefoil motif or truncation resulted in loss of protease resistance. However, neither an intact trefoil domain nor dimerization was required to promote cell migration. This pro-restitution activity correlated with the ability of the ITF mutants to activate mitogen-activated protein (MAP) kinase independent of phosphorylation of the epidermal growth factor (EGF) receptor. In contrast, only intact ITF retained both phosphatidylinositol 3-kinase and the EGF receptor-dependent antiapoptotic effect in HCT116 and IEC-6 cells. The inability to block apoptosis correlated with a loss of trefoil peptide-induced transactivation of the EGF receptor or Akt kinase in HT-29 cells. In addition to defining structural requirements for the functional properties of ITF, these findings demonstrate that distinct intracellular signaling pathways mediate the effects of ITF on cell migration and apoptosis.
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PMID:Distinct pathways of cell migration and antiapoptotic response to epithelial injury: structure-function analysis of human intestinal trefoil factor. 1084 94

Our previous studies demonstrated that p38 mitogen-activated protein (MAP) kinase regulated the c-jun protein expression through phosphorylation of transcription factors of myocyte enhancer factors 2 (MEF2) family. There was a MEF2 binding site in the promoter of c-jun gene. Members of the MEF2 family of trans-cription factors bound as homo- and heterodimers to this MEF2 binding site. Here the potential role of the p38 and BMK1 MAP kinases in the regulation of c-jun expression induced by TNF-alpha was examined. It was shown that p38 MAP kinase up-regulated the transcription activity of MEF2A, while BMK1 MAP kinase up-regulated not only the transcription activity of MEF2A, but also MEF2D. The p38 and BMK1 MAP kinases had coordinated effect on the regulation of c-jun transcription. TNF-alpha induced the formation of MEF2A/MEF2D hete-rodimer. Over-expression of homodimer of MEF2 proteins inhibited c-jun transcription induced by TNF-alpha, while over-expression of heterodimer MEF2A/MEF2D enhanced c-jun transcription induced by TNF-alpha. Phosphorylation of MEF2A and MEF2D by p38 and BMK1 respectively appeared very important in TNF-alpha induced MEF2A/MEF2D heterodimer formation to enhance c-jun gene expression.
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PMID:Signal Transduction in TNF-alpha-induced c-jun Gene Expression. 1207 51

We investigated the effect of platelet-derived growth factor B homodimer (PDGF-BB) on inorganic phosphate (Pi) transport activity, which has been reported to be involved in the mechanism of atherosclerosis, in A-10 rat aortic vascular smooth muscle cells (VSMCs). PDGF-BB time- and dose-dependently stimulated Pi transport in A-10 cells. Using northern blot analysis, the PDGF-BB-enhanced Pi transporter (PiT) in A-10 cells was identified as Pit-1 (Glvr-1), a member of the type III Na-dependent PiT. An inhibitor of PDGF beta-receptor tyrosine kinase suppressed PDGF-BB-induced Pi transport. Both a protein kinase C (PKC) inhibitor calphostin C and PKC down regulation suppressed the stimulatory effect of PDGF-BB on Pi transport. On the other hand, inhibition of mitogen-activated protein (MAP) kinases by selective inhibitors did not affect Pi transport. Ly294002, a phosphatidylinositol (PI) 3-kinase inhibitor, partially attenuated PDGF-BB-induced Pi transport. A selective inhibitor of S(6) kinase, rapamycin, reduced this effect of PDGF-BB, while Akt kinase inhibitor did not. In summary, these results indicated that PDGF-BB is a potent and selective stimulator of Pi transport in VSMCs. The mechanism responsible for this effect is not mediated by MAP kinase, but involves activation of PKC, PI 3-kinase and S(6) kinase.
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PMID:Stimulation of Na-dependent phosphate transport by platelet-derived growth factor in rat aortic smooth muscle cells. 1513 46

Oxygen-derived free radicals have been demonstrated to contribute to the pathogenesis of myocardial dysfunction, although the underlying mechanism remains not fully understood. This study was designed to examine the role of the superoxide generator pyrogallol on cardiac contractile function and possible intervention with herbal medicines anisodamine and tetramethylpyrazine (TMP) on pyrogallol-induced cardiac contractile response. Adult rat ventricular myocytes were isolated and stimulated to contract at 0.5 Hz. Mechanical properties were evaluated using an IonOptix system including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)), and maximal velocity of shortening/relengthening (+/-dL/dt). A 10-min exposure of pyrogallol (0 to 10(-2) M) did not affect cardiac contractile mechanics. However, longer duration of pyrogallol exposure (1, 3, and 6 h) significantly shortened resting cell length, reduced PS and +/-dL/dt, and prolonged TPS and TR90 in time- and concentration-dependent manners. The pyrogallol (10(-4) M with 6-h incubation)-induced mechanical defects were prevented by the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 (1 microM) and superoxide dismutase (SOD, 500 U/mL) with the exception that pyrogallol-induced PS depression was unaffected by SOD. Interestingly, incubation of herbal antioxidants anisodamine (10(-7) M) and TMP (10(-7) M) effectively attenuated the pyrogallol-induced cardiac mechanical defects with the exception of PS unaffected by TMP. Our data demonstrate a direct inhibitory effect of pyrogallol on cardiac contraction, probably in a superoxide- and p38 MAP kinase-dependent manner. The antioxidant medicines anisodamine and TMP may be useful in the treatment of oxygen free radical-induced myocardial dysfunction.
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PMID:The oxygen radical generator pyrogallol impairs cardiomyocyte contractile function via a superoxide and p38 MAP kinase-dependent pathway: protection by anisodamine and tetramethylpyrazine. 1553 80

Indoxyl sulfate is a protein metabolite that is concentrated in the serum of patients with chronic renal insufficiency. It also is a uremic toxin that has been implicated in the progression of chronic renal disease in rodent models. We have shown previously that mesangial cell redox status is related to activation of mitogen-activated protein kinases and cell proliferation, which are factors related to glomerular damage. We used three methods to examine the ability of indoxyl sulfate to alter mesangial cell redox as a possible mechanism for its toxicity. Indoxyl sulfate increases mesangial cell reduction rate in a concentration-dependent manner as demonstrated by redox microphysiometry. Alterations occurred at concentrations as low as 100 microM, with more marked alterations occurring at higher concentrations associated with human renal failure. We demonstrated that indoxyl sulfate induces the production of intracellular reactive oxygen species (ROS) in mesangial cells (EC50 = 550 microM) by using the ROS-sensitive fluorescent dye CM-DCF. ROS generation was only partially (approximately 50%) inhibited by the NADPH oxidase inhibitor diphenylene iodinium at low (< or = 300 microM) indoxyl sulfate concentrations. Diphenylene iodinium was without effect at higher concentrations of indoxyl sulfate. We also used electron paramagnetic spin resonance spectroscopy with extracellular and intracellular spin traps to show that indoxyl sulfate increases extracellular SOD-sensitive O2-* production and intracellular hydroxyl radical production that may derive from an initial O2-* burst. These results document that indoxyl sulfate, when applied to renal mesangial cells at pathological concentrations, induces rapid and complex changes in mesangial cell redox.
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PMID:Indoxyl sulfate induces complex redox alterations in mesangial cells. 1643 74

Increased bone fragility attributed to osteopenia is a serious side effect of glucocorticoid treatment. Glucocorticoid-induced bone loss is caused primarily by hypofunction and apoptosis of osteoblasts, and secondarily by accelerated bone resorption. To explore the mechanism whereby dexamethasone (Dex) stimulates osteoclastogenesis in the coculture system, we analyzed the effect of Dex on the expression of both mouse osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL). Dex reduced OPG transcripts and OPG protein secretion by the ST2 osteoblastic cells. Since mainly the c-Jun homodimer maintains the steady-state transcription of the OPG gene, we examined the effect of Dex on c-Jun signaling in ST2 cells. Western blotting disclosed that Dex decreased the amount of phospho-c-Jun protein (p-c-Jun) and, correspondingly, the amount of the phosphorylated p46 isoform of Jun N-terminal kinase (JNK). The amount of phospho-SEK1 also decreased after Dex treatment, while the amounts of phospho-ERK and p38 remained constant. Among mitogen-activated protein (MAP) kinase inhibitors, the JNK inhibitor mimicked the inhibitory effect of Dex on OPG promoter activity. On the other hand, Dex treatment per se showed a nominal increase of RANKL gene expression. A part of Dex-mediated OPG gene suppression was achieved by the suppression of beta-catenin signaling. We speculate therefore that the bone resorptive action of Dex is mediated mainly by the inhibition of OPG by transrepressing the OPG gene through the AP-1 site, with a reduction (mediated mainly by the decrease in the p46 isoform of JNK) in the proportion of p-c-Jun in a JNK-dependent manner.
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PMID:Dexamethasone promotes osteoclastogenesis by inhibiting osteoprotegerin through multiple levels. 1751 44

Although interleukin-15 (IL-15) is a powerful immunomodulatory factor that has been proposed for cancer immunotherapy, its intratumoral expression may be correlated with tumor progression and/or poor clinical outcome. Therefore, neoplasias potentially sensitive to immunotherapy should be checked for their IL-15 expression and function before choosing immunotherapy protocols. Primary human renal cancer cells (RCC) express a novel form of membrane-bound IL-15 (mb-IL-15), which displays three major original properties: (a) It is expressed as a functional membrane homodimer of 27 kDa, (b) it is shed in the extracellular environment by the metalloproteases ADAM17 and ADAM10, and (c) its stimulation by soluble IL-15 receptor alpha (s-IL-15Ralpha) chain triggers a complex reverse signal (mitogen-activated protein kinases, FAK, pMLC) necessary and sufficient to ~induce epithelial-mesenchymal transdifferentiation (EMT), a crucial process in tumor progression whose induction is unprecedented for IL-15. In these cells, complete EMT is characterized by a dynamic reorganization of the cytoskeleton with the subsequent generation of a mesenchymal/contractile phenotype (alpha-SMA and vimentin networks) and the loss of the epithelial markers E-cadherin and ZO-1. The retrosignaling functions are, however, hindered through an unprecedented cytokine/receptor interaction of mb-IL-15 with membrane-associated IL-15Ralpha subunit that tunes its signaling potential competing with low concentrations of the s-IL-15Ralpha chain. Thus, human RCC express an IL-15/IL-15R system, which displays unique biochemical and functional properties that seem to be directly involved in renal tumoral progression.
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PMID:Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 receptor alpha chain, epithelial-to-mesenchymal transition. 1919 Mar 30

Immune complexes (ICs) improve the capacity of priming specific CD8(+) cytotoxic T cell responses of dendritic cells (DCs). ICs induce phosphorylation of mitogen-activated protein kinases (MAPK) and calcium influx, although the precise regulating mechanism still remains unclear. In the present study, we investigated the effect of a Ca2(+) channel blocker on the phosphorylation of p38 MAPK and extracellular signal-regulated kinase (ERK) in immature monocyte-derived DCs stimulated with lipopolysaccharide (LPS) or LPS-ICs, and the production of interleukin (IL)-12 family members (p40, p70, IL-23), T helper type 17 (Th17) cytokines (IL-6 and IL-23), tumour necrosis factor (TNF)-alpha and IL-10 were also investigated. In comparison with LPS stimulation, LPS-ICs stimulation enhanced p38 MAPK phosphorylation significantly, which was associated with an increase in IL-12 p40 monomer/homodimer secretion. LPS-ICs also enhanced TNF-alpha and IL-6 secretion, but suppressed IL-23 secretion. The use of azelnidipine (Aze), a long-acting L-type Ca2(+) channel blocker with a high lipid solubility, suppressed p38 MAPK phosphorylation stimulated with LPS or LPS-ICs, but surprisingly enhanced IL-12 p40 monomer/homodimer secretion stimulated with LPS-ICs. This IL-12 p40 secretion-enhancing effect was not accompanied by IL-10 or IL-23 production, but was associated with ERK phosphorylation. The use of Aze did not affect IL-12 p70 production. These results suggest that the use of Aze enhances ICs-mediated IL-12 p40 secretion without additional IL-23 secretion. Therefore, the use of Aze and ICs could be a new therapeutic approach to immunomolecular therapy, as it does not cause Th17 differentiation which induces autoimmunity or reduces anti-tumour immunity.
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PMID:Combination use of immune complexes and a Ca2(+) channel blocker azelnidipine enhances interleukin-12 p40 secretion without T helper type 17 cytokine secretion in human monocyte-derived dendritic cells. 1943 91


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