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: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of falcarindiol on the expression of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) in rat primary astrocytes were investigated. The molecular mechanisms underlying falcarindiol that confers its effect on iNOS expression were also elucidated. Falcarindiol abrogated the LPS/IFN-gamma-mediated induction of iNOS by about 80%. Falcarindiol attenuated the induction of iNOS in a concentration-dependent manner. The inhibitory effect of falcarindiol on iNOS induction was attributable to decrease in the protein content and the mRNA level of iNOS. Treatment with 50 microM of falcarindiol for 30 min decreased LPS/IFN-gamma-induced nuclear factor-kappaB (NF-kappaB) activation by 32%. Treatment with 50 microM of falcarindiol for 60 min diminished the LPS/IFN-gamma-mediated activation of IkappaB kinase-alpha (IKK-alpha) and IKK-beta by 28.2 and 29.7%, respectively. Falcarindiol modulated the nuclear translocation of signal transducer and activator of transcription 1 (Stat1) in a time-dependent manner. Falcarindiol (50 microM) decreased the tyrosine phosphorylation of janus kinase 1 (JAK1) by 84.8% at 5 min. Falcarindiol also abrogated the tyrosine phoshorylation of JAK2 by 82.3% at 10 min.The present study demonstrates that falcarindiol attenuated the activation of IKK and JAK contributing to the blockade of activation of NF-kappaB and Stat1, thereby leading to the suppression of iNOS expression.
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PMID:Falcarindiol impairs the expression of inducible nitric oxide synthase by abrogating the activation of IKK and JAK in rat primary astrocytes. 1564 67

In macrophages and monocytes, lipopolysaccharide (LPS) triggers the production of pro-inflammatory cytokine through Toll-like receptor (TLR) 4. Although major TLR signalling pathways are mediated by serine or threonine kinases including IKK, TAK1, p38 and JNKs, a number of reports suggested that tyrosine phosphorylation of intracellular proteins is involved in LPS signalling. Here, we identified several tyrosine-phosphorylated proteins using mass spectrometric analysis in response to LPS stimulation. Among these proteins, we characterized C-terminal Src kinase (Csk), which negatively regulates Src-like kinases in RAW 264.7 cells using RNAi knockdown technology. Unexpectedly, LPS-induced CD40 activation and the secretion of pro-inflammatory cytokine such as IL-6 and TNF-alpha, was down-regulated in Csk knockdown cells. Furthermore, overall cellular tyrosine phosphorylation and TLR4-mediated activation of IkappaB-alpha, Erk and p38 but not of JNK, were also down-regulated in Csk knockdown cells. The protein expression levels of a tyrosine kinase, Fgr, were reduced in Csk knockdown cells, suggesting that Csk is a critical regulator of TLR4-mediated signalling by modifying the levels of Src-like kinases.
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PMID:Modulation of TLR signalling by the C-terminal Src kinase (Csk) in macrophages. 1577 98

Toll-like receptor-4 (TLR4) and its signaling molecule interleukin-1 receptor-associated kinase (IRAK-1) play an important role in host defense and tissue inflammation. Intriguingly, systemic administration of lipopolysaccharide (LPS), the agonist for TLR4, confers a cardio-protective effect against ischemic injury. However, the mechanisms leading to the cardiac protection remain largely unknown. The present study was designed to investigate the role of TLR4 activation by LPS in protecting cardiomyocytes (CM) against apoptosis in an in vitro model of ischemia and to explore the downstream mechanisms leading to the protective effect. Incubation with LPS led to activation of IRAK-1 and protected CMs against serum deprivation (SD)-induced apoptosis as demonstrated by DNA laddering, histone-DNA fragment enzyme-linked immunosorbent assay, and activation of caspase-3. Phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase 1/2, and IkappaB kinase beta appear to contribute to the anti-apoptotic effect of LPS since the specific inhibitors, wortmannin, PD98059, and dominant negative IKKbeta transgene expression reversed the LPS effect. To assess whether LPS improves CM function, we examined intracellular Ca(2+) transients and cell shortening in single adult rat CMs. SD for 6 h dramatically inhibited Ca(2+) transients and CM contractility. LPS at 500 ng/ml significantly improved the [Ca(2+)](i) transients and enhanced contractility in control CMs as well as in CMs subjected to SD. Importantly, transient ischemia led to rapid activation of IRAK-1 in cultured CMs and in adult rat myocardium. Adenovirus-mediated transgene expression of IRAK-1 but not its kinase-deficient mutant IRAK-1(K239S) protected CMs against SD-induced apoptosis. Taken together, these data suggest an important role of TLR4 signaling via IRAK-1 in protecting against SD-induced apoptosis.
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PMID:Lipopolysaccharide improves cardiomyocyte survival and function after serum deprivation. 1579 10

Tilianin has been shown to down-regulate TNF-alpha induced expression of vascular cell adhesion molecules in endothelial cells. In this study, we examined the anti-atherogenic effects and molecular mechanism of tilianin in vitro and in vivo. Male low-density lipoprotein receptor null mice (Ldlr-/-) fed a high cholesterol diet showed significant increases in the size of atherosclerotic lesions, as well as increased plasma levels of total cholesterol, triglycerides, and the pro-inflammatory cytokines TNF-alpha and IL-1beta, when compared with Ldlr-/- mice fed a normal diet. Mice fed the high cholesterol diet supplemented with tilianin showed significantly reduced lesion sizes and reductions in cytokine levels, without significant changes in serum cholesterol levels. Primary cultured peritoneal macrophages from Ldlr-/- mice showed increased level of TNF-alpha andIL-1beta mRNA in response to treatment with lipopolysaccharide; these increases were inhibited by co-treatment with tilianin. Moreover, tilianin inhibited NF-kappaB activation, as determined by electrophoretic mobility shift and NF-kappaB promoter assays. Upstream of NF-kappaB activation, tilianin inhibited IkappaB kinase activation and the subsequent phosphorylation and degradation of IkappaBalpha protein. These results suggest that tilianin ameliorates atherosclerosis by inhibiting the production of the NF-kappaB-dependent pro-inflammatory cytokines, TNF-alpha and IL-1beta, via the inhibition of IkappaB kinase activity.
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PMID:Inhibition of cytokine-induced IkappaB kinase activation as a mechanism contributing to the anti-atherogenic activity of tilianin in hyperlipidemic mice. 1582 72

The nuclear factor (NF)-kappaB transcriptional system is a major effector pathway involved in inflammation and innate immune responses. The flavonoid luteolin is found in various herbal extracts and has shown anti-inflammatory properties. However, the mechanism of action and impact of luteolin on innate immunity is still unknown. We report that luteolin significantly blocks lipopolysaccharide (LPS)-induced IkappaB phosphorylation/degradation, NF-kappaB transcriptional activity and intercellular adhesion molecule-1 (ICAM-1) gene expression in rat IEC-18 cells. Using chromatin immunoprecipitation, we demonstrate that LPS-induced RelA recruitment to the ICAM-1 gene promoter is significantly reduced in luteolin-treated cells. Moreover, in vitro kinase assays show that luteolin directly inhibits LPS-induced IkappaB kinase (IKK) activity in IEC-18 cells. Using bone-marrow derived dendritic cells (BMDCs) isolated from interleukin (IL)-10(-/-) mice or from recently engineered transgenic mice expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-kappaB cis-elements (cis-NF-kappaB(EGFP)), we found that luteolin blocks LPS-induced IkappaB phosphorylation and IKK activity, and decreases EGFP, IL-12 and tumour necrosis factor-alpha gene expression. Moreover, intraperitoneal administration of luteolin significantly inhibited LPS-induced EGFP expression in both peripheral blood mononuclear cells and splenocytes isolated from cis-NF-kappaB(EGFP) mice. These results indicate that luteolin blocks LPS-induced NF-kappaB signalling and proinflammatory gene expression in intestinal epithelial cells and dendritic cells. Modulation of innate immunity by natural plant products may represent an attractive strategy to prevent intestinal inflammation associated with dysregulated innate immune responses.
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PMID:The flavonoid luteolin prevents lipopolysaccharide-induced NF-kappaB signalling and gene expression by blocking IkappaB kinase activity in intestinal epithelial cells and bone-marrow derived dendritic cells. 1594 55

Peroxynitrite is a potent oxidant and nitrating species proposed as a direct effector of myocardial damage in numerous cardiac pathologies. Whether peroxynitrite also acts indirectly, by modulating cell signal transduction in the myocardium, has not been investigated. Therefore, we examined a possible role for peroxynitrite on the activation of NF-kappaB, a crucial pro-inflammatory transcription factor, in cultured H9C2 cardiomyocytes. H9C2 cells were stimulated with tumor necrosis factor-alpha or lipopolysaccharide following a brief (20-min) exposure to peroxynitrite. NF-kappaB activation (phosphorylation and degradation of its inhibitor IkappaBalpha, nuclear translocation of NF-kappaB p65, and NF-kappaB DNA binding) triggered by lipopolysaccharide or tumor necrosis factor-alpha was abrogated by peroxynitrite. Peroxynitrite also inhibited NF-kappaB in two human endothelial cell lines activated with tumor necrosis factor-alpha or interleukin-1beta. These effects were related to oxidative but not nitrative chemistry and were still being observed while nitration was suppressed by epicatechin. The mechanism of NF-kappaB inhibition by peroxynitrite was a complete blockade of phosphorylation and activation of the upstream kinase IkappaB kinase (IKK) beta, required for canonical, pro-inflammatory NF-kappaB activation. At the same time, peroxynitrite activated phosphorylation of NF-kappaB-inducing kinase and IKKalpha, considered as part of an alternative, noncanonical NF-kappaB activation pathway. Suppression of IKKbeta-dependent NF-kappaB activation translated into a marked inhibition of the transcription of NF-kappaB-dependent genes by peroxynitrite. Thus, peroxynitrite has a dual effect on NF-kappaB, inhibiting canonical IKKbeta-dependent NF-kappaB activation while activating NF-kappaB-inducing kinase and IKKalpha phosphorylation, which suggests its involvement in an alternative pathway of NF-kappaB activation. These findings offer new perspectives for the understanding of the relationships between redox stress and inflammation.
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PMID:Peroxynitrite is a potent inhibitor of NF-{kappa}B activation triggered by inflammatory stimuli in cardiac and endothelial cell lines. 1607 50

Rip1 is required for IkappaB kinase activation in response to tumor necrosis factor alpha (TNF-alpha) and has been implicated in the Toll-like receptor 3 (TLR3) response to double-stranded RNA. Cytokine production is impaired when rip1-/- cells are treated with TNF-alpha, poly(I-C), or lipopolysaccharide, implicating Rip1 in the Trif-dependent TLR3 and TLR4 pathways. To examine the role of Rip1 in the Trif-dependent TLR4 pathway, we generated rip1-/- MyD88-/- cells. Lipopolysaccharide failed to stimulate NF-kappaB activation in rip1-/-MyD88-/- cells, revealing that Rip1 is also required for the Trif-dependent TLR4-induced NF-kappaB pathway. In addition to activating NF-kappaB, TLR3/4 pathways also stimulate interferon regulatory factor 3 activation. However, we find that Rip1 expression stimulates NF-kappaB but not interferon regulatory factor 3 activity. In the TNF-alpha pathway, Rip1 interacts with the E3 ubiquitin ligase Traf2 and is modified by polyubiquitin chains. Upon TLR3 activation, Rip1 is also modified by polyubiquitin chains and is recruited to TLR3 along with Traf6 and the ubiquitin-activated kinase Tak1. These studies suggest that Rip1 uses a similar, ubiquitin-dependent mechanism to activate IkappaB kinase-beta in response to TNF-alpha and TLR3 ligands.
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PMID:Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation. 1611 77

2-Methyl-2-(2-methylpropenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (NFD-37) is a synthetic furonaphthoquinone compound. In the present study, the NFD-37 compound was found to inhibit prostaglandin (PG) E(2) production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7. NFD-37 compound exhibited a preferred inhibition on enzyme activity of cyclooxygenase (COX)-2 over COX-1. Further, NFD-37 compound attenuated LPS-induced synthesis of both mRNA and protein of COX-2, and suppressed LPS-induced COX-2 promoter activity in the macrophages, indicating that the furonaphthoquinone compound could down-regulate LPS-induced COX-2 expression at the transcription level. Even though COX-2 promoter behaves as a sophisticated biosensor for host defense, nuclear factor (NF)-kappaB activation has been evidenced to play a major mechanism for LPS-induced COX-2 expression in macrophages. NFD-37 compound exhibited a dose-dependent inhibitory effect on LPS-induced phosphorylation of inhibitory kappaBalpha (IkappaBalpha) protein, and subsequently inhibited IkappaBalpha degradation, DNA binding activity of NF-kappaB complex as well as NF-kappaB transcriptional activity in macrophages RAW 264.7. In another experiment, NFD-37 compound inhibited both COX-2 promoter activity and GST-IkappaBalpha phosphorylation elicited by an expression vector encoding IkappaB kinase beta. Taken together, NFD-37 compound inhibited enzyme activity of COX-2 but also suppressed COX-2 expression depending on NF-kappaB activation, and thus could provide an invaluable tool to investigate pharmacological potential in the excess PG-related disorders.
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PMID:Dual inhibitory effects of furonaphthoquinone compound on enzyme activity and lipopolysaccharide-induced expression of cyclooxygenase-2 in macrophages. 1612 37

Isovitexin exhibits potent antioxidant activities. In this study, the activity of nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-activated RAW264.7 macrophages after incubation with isovitexin was investigated. Isovitexin was able to reduce the production of hydrogen peroxide induced by LPS in mouse macrophage RAW264.7 cells. The cells incubated with isovitexin had markedly reduced LPS-stimulated NO production with an IC (50) value of 58.5 microM. The expression of iNOS was also inhibited when the cells were treated with isovitexin. A transient transfection experiment showed that isovitexin suppressed the iNOS promoter and NF-kappaB-dependent transcriptional activities. It was also found to inhibit IKK kinase activity and prevent the degradation of IkappaBalpha in activated RAW264.7 cells. Additionally, Western blotting analysis revealed that isovitexin prevented the translocation of NF-kappaB from the cytoplasm to the nucleus. Our results indicate that its ROS scavenger and IKK inhibitory activities also contribute to the suppression of ROS-mediated NF-kappaB activity. These results suggest that isovitexin, a food phytochemical contained in dietary rice products, might have biological significance.
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PMID:Isovitexin suppresses lipopolysaccharide-mediated inducible nitric oxide synthase through inhibition of NF-kappa B in mouse macrophages. 1614 40

A small number of mammalian signaling pathways mediate a myriad of distinct physiological responses to diverse cellular stimuli. Temporal control of the signaling module that contains IkappaB kinase (IKK), its substrate inhibitor of NF-kappaB (IkappaB), and the key inflammatory transcription factor NF-kappaB can allow for selective gene activation. We have demonstrated that different inflammatory stimuli induce distinct IKK profiles, and we examined the underlying molecular mechanisms. Although tumor necrosis factor-alpha (TNFalpha)-induced IKK activity was rapidly attenuated by negative feedback, lipopolysaccharide (LPS) signaling and LPS-specific gene expression programs were dependent on a cytokine-mediated positive feedback mechanism. Thus, the distinct biological responses to LPS and TNFalpha depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.
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PMID:Stimulus specificity of gene expression programs determined by temporal control of IKK activity. 1616 17


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