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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tolerance to bacterial cell-wall components may represent an essential regulatory mechanism during bacterial infection. We have demonstrated previously that the inhibition of nuclear factor (NF)-kappaB and mitogen-activated protein kinase activation was present in bacterial lipoprotein (BLP) self-tolerance and its cross-tolerance to lipopolysaccharide (LPS). In this study, the effect of BLP-induced tolerance on the myeloid differentiation factor 88 (MyD88)-dependent upstream signaling pathway for NF-kappaB activation in vitro was examined further. When compared with nontolerant human monocytic THP-1 cells, BLP-tolerant cells had a significant reduction in tumor necrosis factor alpha (TNF-alpha) production in response to a high-dose BLP (86+/-12 vs. 6042+/-245 ng/ml, P < 0.01) or LPS (341+/-36 vs. 7882+/-318 ng/ml, P < 0.01) stimulation. The expression of Toll-like receptor 2 (TLR2) protein was down-regulated in BLP-tolerant cells, whereas no significant differences in TLR4, MyD88, interleukin-1 receptor-associated kinase 4 (IRAK-4), and TNF receptor-associated factor 6 expression were observed between nontolerant and BLP-tolerant cells, as confirmed by Western blot analysis. The IRAK-1 protein was reduced markedly in BLP-tolerant cells, although IRAK-1 mRNA expression remained unchanged as revealed by real-time reverse transcriptase-polymerase chain reaction analysis. Furthermore, decreased MyD88-IRAK immunocomplex formation, as demonstrated by immunoprecipitation, was observed in BLP-tolerant cells following a second BLP or LPS stimulation. BLP pretreatment also resulted in a marked inhibition in total and phosphorylated inhibitor of kappaB-alpha (IkappaB-alpha) expression, which was not up-regulated by subsequent BLP or LPS stimulation. These results demonstrate that in addition to the down-regulation of TLR2 expression, BLP tolerance is associated with a reduction in IRAK-1 expression, MyD88-IRAK association, and IkappaB-alpha phosphorylation. These findings further elucidate the molecular mechanisms underlying bacterial peptide tolerance.
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PMID:Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation. 1646 41

Amiodarone (AM) is a potent vasodilator and exhibits diverse cardiovascular protective effects in vivo, but their underlying mechanisms remain unsettled. We investigated the effects of AM and N-desethylamiodarone (DEA), the major metabolite of AM, on endothelial nitric oxide (NO) production using cultured human umbilical vein endothelial cells (HUVECs). The release of NO was evaluated as measured by nitrite, a stable metabolite of NO, using the Griess reaction and also measured directly by a NO-selective electrode. The expression of each nitric oxide synthase (NOS) mRNA was examined by reverse transcriptase-polymerase chain reaction (RT-PCR), and the effects of AM on eNOS mRNA expression were studied by quantitative real-time RT-PCR. AM and DEA (1-30 microM) enhanced NO production in a concentration-dependent manner. DEA was capable of producing more NO than AM. L-NAME, a nonselective NOS inhibitor, EGTA, a Ca(2+)-chelating agent, and nickel, a nonspecific Ca(2+) blocker, all inhibited AM-induced NO production. However, LY294002, an Akt pathway inhibitor and SB202190, a MAP kinase inhibitor, did not significantly suppress the production. In RT-PCR analysis, only eNOS mRNA was detected. Treatment with AM for 4 hours did not show a significant increase in the expression of eNOS mRNA. AM lower than 30 microM did not induce apoptosis, net cell loss, or LDH release from cells. The present study provides the first evidence that therapeutic concentrations of AM and DEA enhance eNOS-mediated NO production without any toxic or apoptotic effects. This mechanism may underlie the cardiovascular protective effects of AM and its metabolite observed in a clinical setting.
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PMID:Amiodarone and N-desethylamiodarone enhance endothelial nitric oxide production in human endothelial cells. 1647 44

Platelet-derived growth factor (PDGF)-BB and PDGF-DD mediate mesangial cell proliferation in vitro and in vivo. While PDGF-BB is a ligand for the PDGF alpha- and beta-receptor chains, PDGF-DD binds more selectively to the beta-chain, suggesting potential differences in the biological activities. Signal transduction and regulation of gene expression induced by PDGF-BB and -DD were compared in primary human mesangial cells (HMCs), which expressed PDGF alpha- and beta-receptor subunits. The growth factor concentrations used were chosen based on their equipotency in inducing HMCs proliferation and binding to the betabeta-receptor. Both growth factors, albeit at different concentrations induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. In addition, PDGFs led to the phosphorylation and activation of signal transducers and activators of transcription 1 (STAT1) and STAT3. HMCs proliferation induced by either PDGF-BB or -DD could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase-, Janus kinase (JAK)/STAT-, or phosphatidyl-inositol 3-kinase pathways. Using a gene chip array and subsequent verification by real-time reverse transcriptase (RT)-polymerase chain reaction, we found that in HMC genes for matrix metalloproteinase 13 (MMP-13) and MMP-14 and, to a low extent, cytochrome B5 and cathepsin L were exclusively regulated by PDGF-BB, whereas no exclusive gene regulation was detected by PDGF-DD. However, at the protein level, both MMP-13 and -14 were equally induced by PDGF-BB and -DD. PDGF-BB and -DD effect similar biological responses in HMCs albeit at different potencies. Rare apparently differential gene regulation did not result in different protein expression, suggesting that in HMCs both PDGFs exert their biological activity almost exclusively via the PDGF beta-receptor.
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PMID:Biological responses to PDGF-BB versus PDGF-DD in human mesangial cells. 1655 24

Genistein (4,5,7-trihydroxyisoflavone), a phytoestrogen with selective estrogen receptor modulator properties, has received a great deal of attention over the last few years because of its potentially preventive roles against cardiovascular diseases. However, the precise molecular mechanisms for this modulation are not fully elucidated. In this study, we investigated (both in vivo and in vitro) the relationship between genistein and the changes of angiotensin-converting enzyme (ACE) in rat aortic endothelial cells (RAECs), serum and tissue (aorta). ACE expression was assessed by the immunofluorescence and the reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Serum and tissue ACE activity was detected with a commercial kit. Genistein exhibited a concentration-dependent inhibitory effect on the expression of ACE, particularly at higher concentrations (24.70+/-1.20 at 100microM, P<0.01, and 18.22+/-0.92 at 200microM, P<0.01 compared with the control group 50.49+/-5.19). The estrogen receptor blocker tamoxifen at 100microM attenuated this effect of genistein. The extracellular signal-regulated kinase 1/2 (ERK1/2) blocker PD98059 also markedly inhibited this effect. The observations in vivo were highly consistent with the data in RAECs. These results indicate that genistein inhibits the expression of ACE via estrogen receptor and subsequently ERK1/2 signaling pathway in RAECs. Our results suggest that the down-regulation of ACE with a consequent change in the circulating levels of angiotensin II (Ang II), vasorelaxant angiotensin-(1-7) [Ang-(1-7)] and bradykinin plays an important role in cardiovascular effects of genistein through the ERK1/2 pathway.
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PMID:Effects of genistein on angiotensin-converting enzyme in rats. 1662 61

The mitogen activated protein kinases (MAPK) family pathway is conserved in evolution through the plant and animal kingdoms. These proteins have been implicated in diverse cellular processes including cell growth, proliferation, differentiation, survival and development. In this study we annotated and cloned members of the zebrafish MAPK gene-family, containing the ERK, JNK and p38 subfamilies. Their sequences were compared to orthologs of other vertebrates (human, mouse and rat) and the temporal and spatial expression levels of the zebrafish mapk genes were determined during early zebrafish development. Semi-quantitative reverse transcriptase-PCR analysis revealed that most mapk genes are expressed throughout zebrafish development. Erk2,3 and p38a were expressed at a constant level throughout zebrafish embryogenesis, whereas erk1,4,5,6,7 and p38b showed specific temporal expression patterns. The spatial expression patterns were obtained by whole mount in situ hybridization at 24 h post fertilization (hpf) and 48 hpf embryos. The expression patterns were localized in specific regions at both stages and were tightly regulated during embryogenesis. For p38b, no staining was detected at 24 and 48 hpf. However, its expression was demonstrated at blastula-stage. Together, we identified the zebrafish orthologs of the zebrafish MAPK gene family and determined their specific spatial and temporal expression and distribution patterns during zebrafish embryogenesis.
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PMID:Characterization and expression patterns of the MAPK family in zebrafish. 1677 48

Excitotoxic neuronal death occurs through the activation of NMDA and non-NMDA glutamatergic receptors in the CNS. Glutamate also induces strong activation of p38 and indeed, cell death can be prevented by inhibitors of the p38 pathway. Furthermore, intracellular signals generated by AMPA receptors activate the stress sensitive MAP kinases implicated in apoptotic neuronal death, such as JNK and p38. To investigate the relationship between these elements, we have used immunohistochemistry to analyze the expression of GluR2 in the cerebral cortex of postnatal rats (postnatal Day [PD] 8 and 14) after administering them with monosodium glutamate (MSG; 4 mg/g body weight on PD1, 3, 5, and 7). Similarly, the expression of REST, Fas-L and Bcl-2 mRNA transcripts in animals exposed to a p38 inhibitor, SB203580 (0.42 microg/g body weight, administered subcutaneously) was determined by reverse transcriptase-PCR. The enhanced GluR2-expression in the cerebral cortex at PD8 and the down regulation of this receptor at PD14 was correlated with neuronal damage induced by excitotoxicity. In addition, the enhanced expression of REST at PD8 and PD14 suggests that the induction of REST transcription contributes to glutamate-induced excitotoxic neurodegeneration, possibly by modulating GluR2 expression. Fas-L and Bcl-2 over expression at PD8 and their subsequent down regulation at PD14 also suggests that Fas-L could be the direct effector of apoptosis in the cerebral cortex. On the other hand, the presence of Bcl-2 at PD8 could attenuate certain survival signals in neurons under these neurotoxic conditions. Thus, a change in glutamate receptor composition, and enhanced Fas-L and Bcl-2 expression, coupled with activation of the p38/SAPK pathway appear to be events involved in the neuronal apoptosis induced under neurotoxic conditions.
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PMID:Neuronal cell death due to glutamate excitotocity is mediated by p38 activation in the rat cerebral cortex. 1678 74

Previous studies using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis have shown that the P2Y(14) receptor is expressed at high levels in human neutrophils. Therefore the primary aim of this study was to determine whether the P2Y(14) receptor is functionally expressed in human neutrophils. In agreement with previous studies RT-PCR analysis detected the expression of P2Y(14) receptor mRNA in human neutrophils. UDP-glucose (IC(50)=1 microM) induced a small but significant inhibition (circa 30%) of forskolin-stimulated cAMP accumulation suggesting functional coupling of endogenously expressed P2Y(14) receptors to the inhibition of adenylyl cyclase activity in human neutrophils. In contrast, the other putative P2Y(14) receptor agonists UDP-galactose and UDP-glucuronic acid (at concentrations up to 100 microM) had no significant effect, whereas 100 microM UDP-N-acetylglucosamine-induced a small but significant inhibition of forskolin-stimulated cAMP accumulation (20% inhibition). UDP-galactose, UDP-glucuronic acid and UDP-N-acetylglucosamine behaved as partial agonists by blocking UDP-glucose mediated inhibition of forskolin-induced cAMP accumulation. Treatment of neutrophils with pertussis toxin (G(i/o) blocker) abolished the inhibitory effects of UDP-glucose on forskolin-stimulated cAMP accumulation. UDP-glucose (100 microM) also induced a modest increase in extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, whereas the other sugar nucleotides had no effect on ERK1/2 activation. Finally, UDP-glucose and related sugar nucleotides had no significant effect on N-formyl-methionyl-leucyl-phenylalanine-induced elastase release from neutrophils. In summary, although we have shown that the P2Y(14) receptor is functionally expressed in human neutrophils (coupling to inhibition of forskolin-induced cAMP and ERK1/2 activation) it does not modulate neutrophil degranulation (assessed by monitoring elastase release). Clearly further studies are required in order to establish the functional role of the P2Y(14) receptor expressed in human neutrophils.
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PMID:Functional expression of the P2Y14 receptor in human neutrophils. 1682 Jan 47

Hedgehog (HH)/GLI signaling plays a critical role in epidermal development and basal cell carcinoma. Here, we provide evidence that epidermal growth factor receptor (EGFR) signaling modulates the target gene expression profile of GLI transcription factors in epidermal cells. Using expression profiling and quantitative reverse transcriptase PCR, we identified a set of 19 genes whose transcription is synergistically induced by GLI1 and parallel EGF treatment. Promoter studies of a subset of GLI/EGF-regulated genes, including the genes encoding interleukin-1 antagonist IL1R2, Jagged 2, cyclin D1, S100A7, and S100A9, suggest convergence of EGFR and HH/GLI signaling at the level of promoters of selected direct GLI target genes. Inhibition of EGFR and MEK/ERK but not of phosphatidylinositol 3-kinase/AKT abrogated synergistic activation of GLI/EGF target genes, showing that EGFR can signal via RAF/MEK/ERK to cooperate with GLI proteins in selective target gene regulation. Coexpression of the GLI/EGF target IL1R2, EGFR, and activated ERK1/2 in human anagen hair follicles argues for a cooperative role of EGFR and HH/GLI signaling in specifying the fate of outer root sheath (ORS) cells. We also show that EGF treatment neutralizes GLI-mediated induction of epidermal stem cell marker expression and provide evidence that EGFR signaling is essential for GLI-induced cell cycle progression in epidermal cells. The results suggest that EGFR signaling modulates GLI target gene profiles which may play an important regulatory role in ORS specification, hair growth, and possibly cancer.
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PMID:Selective modulation of Hedgehog/GLI target gene expression by epidermal growth factor signaling in human keratinocytes. 1688 May 36

Orthodontic tooth movement is recognized as a pro-inflammatory stressor of human periodontal ligament (hPDL) cells. However, the cell-signaling pathways linking interleukin-8 (IL-8), intercellular adhesion molecule-1 (ICAM-1), pro-inflammatory cytokines, and dexamethasone in hPDL cells have not been well elucidated. In this study, we investigated the role of mitogen-activated protein (MAP) kinases in dexamethasone- and TNF-alpha-induced IL-8 and ICAM-1 expression in hPDL cells. IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. MAP kinase activation and IkappaB degradation were determined by Western blot analysis, and ICAM-1 expression was determined by RT-PCR and FACS analysis. TNF-alpha increased IL-8 mRNA expression and protein secretion in a dose- and time-dependent manner. Dexamethasone suppressed TNF-alpha-induced IL-8 production in a dose-dependent manner. In addition, dexamethasone inhibited TNF-alpha-induced phosphorylation of p38 MAP kinase and extracellular-regulated kinases (ERKs), IkappaB degradation, and NF-kappaB activation. Selective inhibitors for ERKs and p38 attenuated TNF-alpha-induced IL-8 and ICAM-1 expression in the presence and absence of dexamethasone, indicating that MAP kinases play a role in the response of hDPL cells to TNF-alpha. Furthermore, these results suggest that inflammatory cytokine- and dexamethasone-induced IL-8 and ICAM-1, produced via a MAP kinase pathway, may serve as an important mediator of PDL immunoregulation involved in bone remodeling during orthodontic tooth movement.
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PMID:Roles of p38 and ERK MAP kinases in IL-8 expression in TNF-alpha- and dexamethasone-stimulated human periodontal ligament cells. 1694 35

A proteomic analysis of procyanidin B(2) isolated from cocoa against oxidized low-density lipoprotein-induced lipid-laden macrophage formation was performed. Of approximately 400 detected proteins, 12 were differentially expressed as a result of B(2) treatment. They were subsequently identified by liquid chromatography-electrospray ionization-tandem mass spectrometry and the SWISS-PROT database. Further reverse transcriptase-polymerase chain reaction and Western blot analysis revealed that B(2) strongly inhibited arachidonic acid inflammatory reactions, apoptosis, and their coupled mitogen-activated protein kinase and NF-kappaB pathways. To highlight proteins or genes with similar expressed patterns and similarly biological function induced by B(2) in lipid-laden macrophages, a cluster and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed. The data were mapped to multiple pathways. Further validation of the bioinformatic results revealed that activation of Wnt signaling may contribute to the cardioprotection of B(2). The differentially expressed genes and proteins mentioned above induced by B(2) are through regulating nuclear transcription factors, activating peroxisome proliferator-activated receptor-gamma and inhibiting AP-1 mRNA expressions. These in vitro data help to interpret the beneficial effects of B(2) in reducing the risk of atherosclerosis after consumption of flavonoid-rich foods. Many differentially expressed genes induced by B(2) help to uncover novel targets and may help to target disease interactions in atherosclerosis in the future.
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PMID:Inhibitory effects of procyanidin B(2) dimer on lipid-laden macrophage formation. 1695 22


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