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:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuropeptide S (NPS)-NPS receptor 1 (NPSR1) pathway has recently been implicated in the pathogenesis of asthma. The purpose of this study was to identify downstream gene targets regulated by NPSR1 upon NPS stimulation. A total of 104 genes were found significantly up-regulated and 42 down-regulated by microarray analysis 6 h after NPS administration. By Gene Ontology enrichment analysis, the categories 'cell proliferation', 'morphogenesis' and 'immune response' were among the most altered. A TMM microarray database comparison suggested a common co-regulated pathway, which includes JUN/FOS oncogene homologs, early growth response genes, nuclear receptor subfamily 4 members and dual specificity phosphatases. The expression of four up-regulated genes, matrix metallopeptidase 10 (MMP10), INHBA (activin A), interleukin 8 (IL8) and EPH receptor A2 (EPHA2), exhibited a significant NPS dose-response relationship as confirmed by quantitative reverse-transcriptase-PCR and for MMP10 by immunoassay. Immunohistochemical analyses revealed that MMP10 and TIMP metallopeptidase inhibitor 3 (TIMP3) were both strongly expressed in bronchial epithelium, and macrophages and eosinophils expressed MMP10 in asthmatic sputum samples. Because remodeling of airway epithelium is a feature of chronic asthma, the up-regulation of MMP10 and TIMP3 by NPS-NPSR1 signaling may be of relevance in the pathogenesis of asthma.
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PMID:Downstream target genes of the neuropeptide S-NPSR1 pathway. 1692 87

We investigated the modulating actions of the nonselective K(+) channel blocker 4-aminopyridine (4-AP) on amyloid beta (Abeta(1-42))-induced human microglial signaling pathways and functional processes. Whole-cell patch-clamp studies showed acute application of Abeta(1-42) (5 mum) to human microglia led to rapid expression of a 4-AP-sensitive, non-inactivating outwardly rectifying K(+) current (I(K)). Intracellular application of the nonhydrolyzable analog of GTP, GTPgammaS, induced an outward K(+) current with similar properties to the Abeta(1-42)-induced I(K) including sensitivity to 4-AP (IC(50) = 5 mm). Reverse transcriptase-PCR showed a rapid expression of a delayed rectifier Kv3.1 channel in Abeta(1-42)-treated microglia. Abeta(1-42) peptide also caused a slow, progressive increase in levels of [Ca(2+)](i) (intracellular calcium) that was partially blocked by 4-AP. Chronic exposure of human microglia to Abeta(1-42) led to enhanced p38 mitogen-activated protein kinase and nuclear factor kappaB expression with factors inhibited by 4-AP. Abeta(1-42) also induced the expression and production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, the chemokine IL-8, and the enzyme cyclooxygenase-2; 4-AP was effective in reducing all of these pro-inflammatory mediators. Additionally, toxicity of supernatant from Abeta(1-42)-treated microglia on cultured rat hippocampal neurons was reduced if 4-AP was included with peptide. In vivo, injection of Abeta(1-42) into rat hippocampus induced neuronal damage and increased microglial activation. Daily administration of 1 mg/kg 4-AP was found to suppress microglial activation and exhibited neuroprotection. The overall results suggest that 4-AP modulation of an Abeta(1-42)-induced I(K) (candidate channel Kv3.1) and intracellular signaling pathways in human microglia could serve as a therapeutic strategy for neuroprotection in Alzheimer's disease pathology.
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PMID:Broad-spectrum effects of 4-aminopyridine to modulate amyloid beta1-42-induced cell signaling and functional responses in human microglia. 1709 87

To investigate the molecular effects of the periodontopathogens Fusobacterium nucleatum (FN) and Porphyromonas gingivalis (PG) on the oral epithelium, the H400 oral epithelial cell line was cultured in the presence of non-viable bacteria. Following confirmation of the presence of transcripts for the bacterial pattern recognition receptors in H400 cells, Toll-like receptors -2, -4 and -9, and components of the NF-kappaB signalling pathway, immunocytochemical analyses were performed showing that NF-kappaB was activated within 1 h of exposure to both periodontopathogens. A significantly greater number of NF-kappaB nuclear translocations were apparent following H400 cell exposure to FN as compared with PG. Gene expression analyses indicated that transcripts known to be regulated by the NF-kappaB pathway, including cytokines/chemokines TNF-alpha, IL-1beta, IL-8, MCP-1/CCL2 and GM-CSF, were up-regulated following 4 and 24 h of exposure to both periodontopathogens. In addition, H400 periodontopathogen exposure resulted in differential regulation of transcripts for several cytokeratin gene family members. Consistent with the immunocytochemical data, microarray results indicated that FN induced a greater number of gene expression changes than PG following 24 h of exposure, 609 and 409 genes, respectively. Ninety-one genes were commonly differentially expressed by both periodontopathogens and represented biological processes commonly associated with periodontitis. Gene expression analyses by reserve transcriptase-polymerase chain reaction (RT-PCR) of molecules identified from the microarray data sets, including Heme oxygenase-1, lysyl oxidase, SOD2, CCL20 and calprotectin components, confirmed their differential expression profiles induced by the two periodontopathogens. FN and PG have clearly different molecular effects on oral epithelial cells, potentially highlighting the importance of the composition of the plaque biofilm in periodontitis pathogenesis.
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PMID:Differential activation of NF-kappaB and gene expression in oral epithelial cells by periodontal pathogens. 1735 48

Hyungbangjihwangtang (HJT), a prescription of Sasang Constitutional Medicine, has been commonly used to treat diarrhea and edema of Soyangin in Korea. This study investigated the effect of HJT on lipopolysaccharide (LPS)-induced inflammatory cytokine production using peripheral blood mononuclear cells from the Soyangin. The inhibitory effect of HJT on LPS-induced inflammatory cytokine production was investigated using the enzyme-linked immunosorbent assay. Reverse transcriptase-polymerase chain reaction was used to investigate the interleukin (IL)-1beta mRNA expression. The expression level of nuclear factor (NF)-kappaB was examined by Western blot. HJT significantly inhibited the IL-1beta, IL-4, and tumor necrosis factor (TNF)-alpha production. The maximal inhibition rate of IL-1beta, IL-4, IL-6, IL-8, and TNF-alpha production by HJT was 240.0 +/- 48.8%, 78.4 +/- 24.7%, 27.6 +/- 10.6%, 20.7 +/- 59.8%, and 113.0 +/- 5.2%, respectively. HJT decreased the IL-1beta mRNA expression. HJT also inhibited the activation of NF-kappaB. These results suggest a potential role of HJT as a source of anti-inflammatory agent for inflammatory diseases.
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PMID:LPS-induced inflammatory cytokine production was inhibited by HyungbangJihwangTang through blockade of NF-kappaB in peripheral blood mononuclear cells. 1765 94

Aberrant regulation of innate immune responses and uncontrolled cytokine bursts are hallmarks of sepsis and endotoxemia. Activation of the nuclear liver X receptor (LXR) was recently demonstrated to suppress inflammatory genes. Our aim was to investigate the expression of LXR in human monocytes under normal and endotoxemic conditions and to study the influence of LXR activation on endotoxin-induced cytokine synthesis and release. Adherent human monocytes or whole blood were pretreated with a synthetic LXR agonist (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid) and subsequently challenged with LPS (from Escherichia coli) or peptidoglycan (from Staphylococcus aureus). Cytokine release was assessed by a Multiplex antibody bead kit, and cytokine mRNA levels were measured by real-time reverse-transcriptase-polymerase chain reaction. We found that LXRalpha mRNA was up-regulated in CD14+ monocytes in LPS-challenged blood, whereas LXRbeta mRNA was not altered. Addition of 3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid to monocytes suppressed the LPS-induced release of IL-1beta, IL-6, IL-8, IL-10, IL-12p40, TMF-alpha, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and monocyte chemoattractant protein 1 in a concentration-dependent manner. Surprisingly, an accompanying decrease in cytokine mRNA accumulation was not observed. The suppressed cytokine release could not be explained by a diminished transport of mRNA out of the nucleus or a decreased secretion of cytokines. We propose that LXR is a key regulator of cytokine release in LPS-challenged human monocytes, possibly by interfering with translational events.
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PMID:Liver X receptor is a key regulator of cytokine release in human monocytes. 1772 34

Histamine is an important mediator in immune responses, but it is unclear whether periodontal tissues express histamine receptors and are able to respond to histamine. We hypothesized that histamine, inflammatory cytokines, and bacterial components released in inflamed periodontal tissues may be synergistically involved in periodontitis. The present study showed that human gingival fibroblasts mainly express histamine receptor H1R, and responded to histamine to produce interleukin (IL)-8. Stimulation of gingival fibroblasts with tumor necrosis factor-alpha, IL-1alpha, and lipopolysaccharide markedly induced IL-8 production, and the IL-8 production was synergistically augmented in the presence of or pre-treatment with histamine. Selective inhibitors of mitogen-activated protein kinases (MAPKs), nuclear factor (NF)-kappaB, and phospholipase C (PLC) significantly inhibited the synergistic effect. These results indicate that histamine induces IL-8 production from gingival fibroblasts through H1R, and synergistically augments the inflammatory stimuli by amplification of the MAPK and NF-kappaB through H1R-linked PLC. Abbreviations used: HDC, histidine decarboxylase; LPS, lipopolysaccharide; IL, interleukin; TNF, tumor necrosis factor; HR, histamine receptor; PLC, phospholipase C; MAPK, mitogen-activated protein kinase; NF, nuclear factor; ERK, extracellular signal-related kinase; JNK, c-Jun N-terminal kinase; R, receptor; TLR, Toll-like receptor; alpha-MEM, alpha-minimum essential medium; FCS, fetal calf serum; RT-PCR, reverse-transcriptase polymerase chain-reaction; ELISA, enzyme-linked immunosorbent assay; SD, standard deviation; LDH, lactate dehydrogenase.
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PMID:Histamine amplifies immune response of gingival fibroblasts. 1795 1

A member of a new subfamily of G protein-coupled receptors, protease-activated receptor 2 (PAR2), is highly expressed on endothelial cells and plays an important role in inflammation. The purpose of this study was to determine the molecular mechanism used by PAR2 to induce IL-8 production and thereby mediate cell adhesion. We observed that PAR2-activating peptide (PAR2-AP) significantly increase peripheral blood mononuclear cells adhere to endothelial cells. Both PAR2-AP and the endogenous PAR2 activator trypsin caused concentration- and time-dependent increase in endothelial IL-8 production, and this effect was concentration dependently and selectively attenuated by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. Western blotting analysis showed that PAR2-AP induced phosphorylation of p38 MAPK and its upstream protein kinase MAPK kinase 3/6 (MKK3/6) in a time-dependent manner. Using reverse-transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, PAR2-AP was found to cause an increase in IL-8 mRNA expression and its transcription factor activating transcription factor 2, respectively,. As expected, these signals were suppressed by SB203580 in a concentration-dependent manner. Furthermore, introduction of dominant-negative vectors targeting p38 MAPK, MKK3, and MKK6 abolished PAR2-AP-mediated IL-8 production and cell adhesion function. In conclusion, PAR2 via p38 MAPK signaling regulates IL-8 production and thereby mediates cell adhesion.
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PMID:The p38 mitogen-activated protein kinase pathway plays a critical role in PAR2-induced endothelial IL-8 production and leukocyte adhesion. 1827 46

Rosette nanotubes (RNT) are a new class of metal-free organic nanotubes synthesized through self-assembly. Because of the wide range of potential biomedical applications associated with these materials, it is necessary to evaluate their potential in vitro toxicity. Here the cytotoxicity of a lysine-functionalized nanotube (RNT-K) in a human Calu-3 pulmonary epithelial cell line is investigated. The cells were treated with media only (control), lysine (50 mg mL(-1)), RNT-K (1, 5, and 50 microg mL(-1)), Min-U-Sil quartz microparticles (QM; 80 microg mL(-1)), and lipopolysaccharide (LPS; 1 microg mL(-1)). The supernatants were analyzed at 1, 6, and 24 h after treatment for the expression of three proinflammatory mediators: IL-8, TNF-alpha and EMAP-II. Cellular viability determined with the Trypan blue assay is significantly reduced in the QM and high-dose RNT-treated groups. TNF-alpha and EMAP-II are undetectable by enzyme-linked-immunosorbent assay (ELISA) in the supernatant of all groups. Although IL-8 concentrations do not differ between treatments, its concentrations increase with time within each of the groups. Quantitative reverse-transcriptase polymerase chain reaction (qRTPCR) of IL-8 mRNA shows increased expression in the high-dose RNT-treated groups at both 1 and 6 h, while an adhesion molecule, ICAM-1 mRNA, shows the greatest increase at 6 h in the QM-treated group. In summary, RNT-K neither reduces cell viability at moderate doses nor does it induce a time-dependent inflammatory response in pulmonary epithelial cells in vitro.
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PMID:Low inflammatory activation by self-assembling Rosette nanotubes in human Calu-3 pulmonary epithelial cells. 1853 89

The objective of this study was to examine the effects of (-)-epigallocatechin-3-gallate (EGCG) on cyclooxygenase 2 (COX-2), prostaglandin E(2) (PGE(2)), and interleukin 8 (IL-8) expression induced by IL-1beta in human synovial fibroblasts. Cells were enzymatically isolated from synovial tissue taken from patients undergoing joint replacement surgery for osteoarthritis. Reverse transcriptase-polymerase chain reaction, immunocytochemistry, and western blotting were used to assess the COX-2 gene and protein expression with the associated mechanisms. PGE(2) and IL-8 secretion into the culture medium was assayed by enzyme-linked immunosorbent assay. COX-2 upregulation in synovial fibroblasts induced by IL-1beta was significantly suppressed by EGCG in a dose-dependent manner. PGE(2) and IL-8 secretion was also induced by IL-1beta stimulation and significantly suppressed by EGCG. The mechanism was associated with the phosphorylation of IKKbeta. EGCG may inhibit the expression of inflammatory mediators, such as COX-2, PGE(2), and IL-8, induced by IL-1beta in human synovial fibroblasts. EGCG may be of value in the treatment of synovial inflammation.
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PMID:Effects of (-)-epigallocatechin-3-gallate on cyclooxygenase 2, PGE(2), and IL-8 expression induced by IL-1beta in human synovial fibroblasts. 1977 41

SKIN(2) ZK1300 is a three-dimensional human skin model consisting of multilayered dermal fibroblasts and well-differentiated epidermal keratinocyte layers, including a stratum corneum. To characterize this model better, constitutive levels of cytokine gene expression were determined. Reverse transcriptase-polymerase chain reaction (RT-PCR), followed by liquid hybridization to labelled internal probes, demonstrated that interleukin (IL)-1I, IL-1beta, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)I, granulocyte macrophage-colony stimulating factor (GM-CSF), transforming growth factor (TGFbeta1) and IL-12 p35 mRNAs were constitutively expressed whereas IL-12 p40 was not. The contribution of the dermal component of this human skin model (Model ZK1100) was further characterized by determining constitutive cytokines expressed and their modulation by phorbol 12-myristate, 13-acetate (PMA). The dermal component, consisting of multilayered human dermal fibroblasts, constitutively expressed message for IL-1I, 1L-1beta, IL-6, IL-8, TGFbeta1, GM-CSF and IL-12 p35. Message was not detected for IL-10, TNFI or IL-12 p40. PMA treatment of the multilayered dermal fibroblasts increased steady-state mRNA levels of IL-1I, IL-1beta, IL-6, IL-8, GM-CSF and TGFbeta1, but did not induce IL-10, TNFI or IL-12 p40 expression at the dose and times tested. In summary, these studies demonstrate that the SKIN(2) three-dimensional human skin cultures, and their dermal component, constitutively express mRNA for an array of inflammatory and immunomodulatory cytokines, and that PMA exposure modulates mRNA levels of the dermal cytokines.
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PMID:Cytokine mRNA expression in an in vitro human skin model, SKIN(2). 2065 Feb 32


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