Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, experiments were performed to explore the action of quercetin, the most widely distributed flavonoids, and its major metabolite, quercetin-3'-sulfate, on lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-induced nitric oxide (NO) production in BV-2 microglia. Quercetin could suppress LPS- and IFN-gamma-induced NO production and inducible nitric oxide synthase (iNOS) gene transcription, while quercetin-3'-sulfate had no effect. LPS-induced IkappaB kinase (IKK), nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) activation, and IFN-gamma-induced NF-kappaB, signal transducer and activator of transcription-1 (STAT1) and interferon regulatory factor-1 (IRF-1) activation were reduced by quercetin. Moreover quercetin was able to induce heme oxygenase-1 expression. To address the involvement of heme oxygenase-1 induction in iNOS inhibition, heme oxygenase-1 antisense oligodeoxynucleotide was used. Quercetin-mediated inhibition of NO production and iNOS protein expression were partially reversed by heme oxygenase-1 antisense oligodeoxynucleotide, but was mimicked by hemin, a heme oxygenase-1 inducer. The involvement of signal pathways in quercetin-induced heme oxygenase-1 gene expression was associated with tyrosine kinase and mitogen-activated protein kinases activation. All these results suggest quercetin should provide therapeutic benefits for suppression of inflammatory-related neuronal injury in neurodegenerative diseases.
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PMID:Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. 1617 98

Chalcones are a group of plant-derived polyphenolic compounds that belong to the flavonoids family, and possess a wide variety of cytoprotective and modulatory functions. Chalcones exert their cytoprotective actions via activation of specific transcriptional factors and upregulation of endogenous defensive pathways, such as phase II enzymes and the stress protein heme oxygenase-1 (HO-1). In this study, we investigated the anti-inflammatory action of 2'-hydroxychalcone (2-HC) in a model of lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages and examined the role of HO-1 in this process. Our results demonstrate that 2-HC potently induces HO-1 expression and markedly reduces LPS-mediated nitrite and TNF-alpha production. These effects are accompanied by inhibition of inducible nitric oxide synthase protein expression and abolished by blockade of heme oxygenase activity with either tin protoporphyrin IX or HO-1 small interfering RNA. By using a pharmacological approach and siRNA technology, we also found that phosphatidylinositol 3-kinase is a major cellular mediator in 2-HC-induced HO-1 expression. These findings strongly suggest that 2-HC exerts anti-inflammatory actions via activation of the HO-1 pathway and help to elucidate the mechanisms underlying the potential therapeutic value of chalcones.
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PMID:Heme oxygenase-1 mediates the anti-inflammatory actions of 2'-hydroxychalcone in RAW 264.7 murine macrophages. 1629 20

The stress-inducible protein heme oxygenase-1 exerts potent antiinflammatory, antiapoptotic and cytoprotective effects in vitro and in vivo. Another important mediator of cytoprotection, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway activates many proteins involved in the maintenance of cellular homeostasis. Since activation of heme oxygenase-1 and PI3K/Akt both protect the cellular environment, we postulated that PI3K/Akt can regulate the induction of heme oxygenase-1 by proinflammatory stress. The treatment of primary murine macrophage cells (RAW 264.7) with lipopolysaccharide induced heme oxygenase-1 protein and mRNA expression, and increased the phosphorylation of Akt and p38 mitogen activated protein kinase (p38 MAPK). These cellular effects of lipopolysaccharide were markedly diminished by pre-treatment with wortmannin, a specific inhibitor of PI3K. Furthermore, lipopolysaccharide-inducible heme oxygenase expression was blocked by SB203580, a specific inhibitor of p38 MAPK. Both wortmannin and SB203580 decreased lipopolysaccharide-inducible NF-E2-related factor (Nrf2) DNA binding activity. Transfection of macrophages with dominant negative mutants of PI3K, Akt and Nrf2, as well as wortmannin treatment, significantly reduced the transcriptional activity of a minimal heme oxygenase-1 promoter luciferase construct (D33HO-1luc). We demonstrate, to our knowledge for the first time, that upon proinflammatory stimulation heme oxygenase-1 gene expression in macrophages depends on PI3K/Akt and p38 MAPK acting upstream of Nrf2-dependent promoter activation.
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PMID:Phosphatidylinositol 3-kinase/Akt pathway mediates heme oxygenase-1 regulation by lipopolysaccharide. 1630 68

Acute respiratory distress syndrome (ARDS) is a devastating disease process characterized by severe acute lung injury, inflammatory cell recruitment to the lung, upregulation of pro-inflammatory cytokines and increased oxidative stress. Epithelial cell injury, diffuse alveolar damage and surfactant dysfunction ensue leading to refractory hypoxemic respiratory failure. There are no specific effective therapies for ARDS and novel therapeutic approaches are desperately needed. In this study we assessed the role of the cytoprotective and anti-inflammatory enzyme heme oxygenase (HO)-1 in a model of nebulized endotoxin-induced acute lung injury. HO-1 null (HO-1(-/-)) mice exhibited severe physiologic lung dysfunction following lipopolysaccharide (LPS) nebulization, but had similar inflammatory responses as wild-type (WT) mice. However, a dramatic reduction in surfactant protein-B (SP-B) expression was observed in the lungs of LPS-treated HO-1(-/-) mice compared with similarly treated WT mice. Using reciprocal bone marrow transplantation (BMT) to generate HO-1-chimeric mice, we found that absence of HO-1 in the lung parenchyma, not in bone marrow-derived inflammatory cells, was responsible for enhanced SP-B downregulation and severe physiologic lung dysfunction. These findings have implications for our understanding of the pathophysiology of ARDS and may guide future therapeutic strategies.
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PMID:Absence of heme oxygenase-1 expression in the lung parenchyma exacerbates endotoxin-induced acute lung injury and decreases surfactant protein-B levels. 1630 74

Carbon monoxide (CO) arising from heme degradation, catalyzed particularly by the stress-inducible heme oxygenase-1 (HO-1), has recently been demonstrated to provide cytoprotection against cell death in macrophages stimulated with bacterial lipopolysaccharide (LPS). In the present study, we determined the effects of CO on the production of reactive oxygen species (ROS) and nitric oxide (NO) by the LPS-stimulated RAW 264.7 macrophages. In addition, effect of CO-exposure on the production of superoxide (O(2)(-)) in the phorbol myristate acetate (PMA)-stimulated PLB-985 neutrophils was determined. Production of ROS by the LPS-stimulated macrophages pretreated with 50microM [Ru(CO)(3)Cl(2)](2), a CO-releasing molecule (CORM-2), was abolished and the production of O(2)(-) by the PMA-stimulated neutrophils pretreated with the CORM-2 was decreased markedly. The CORM-2 (50microM) was not cytotoxic to both the unstimulated and LPS-stimulated macrophages when determined by employing mitochondrial reductase function test (MTT assay). In macrophages pretreated with increasing doses of CORM-2, both the LPS-derived upregulations of iNOS (NO production) and HO-1 expression (CO production) were suppressed in a dose-dependent manner. Alternatively, when the macrophages were treated with LPS and CO-donor together, the LPS-derived increase in NO production was decreased. Conversely, when the control and LPS-stimulated macrophages were treated with zinc protoporphyrin IX (ZnPP) to inhibit the HO activity blocking endogenous production of CO (basal and enhanced), macrophages died extensively. Interestingly, production of NO in the LPS-stimulated macrophages increased significantly following the ZnPP treatment. Addition of CORM-2 to the LPS-treated cells that were being treated additionally with ZnPP did not prevent the cell death. However, endogenous overproduction of CO by super-induction of HO-1 (obtained by pretreatment of macrophages with either buthionine sulfoximine or hemin) decreased the LPS-derived iNOS expression without affecting cell survival. Combined, these results indicated that enhanced HO activity is essential for the survival of LPS-stimulated macrophages. Thus, upregulation of HO-1 and overproduction of CO may allow the survival of LPS-stimulated macrophages; first, by eliminating the free heme to prevent Fenton reaction, second, by limiting the availability of free heme required for induction of NO-producing heme enzyme (i.e., iNOS), third, by limiting additional production of O(2)(-) and NO via CO-derived inhibition on the activities of heme enzymes like NADPH oxidase and iNOS, respectively. CO may allow the LPS-activated macrophages to return back to the normal quiet state insensitive to additional stimuli causing oxidative stress.
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PMID:CO from enhanced HO activity or from CORM-2 inhibits both O2- and NO production and downregulates HO-1 expression in LPS-stimulated macrophages. 1632 99

20( S)-Protopanaxadiol (PPD) is one of the metabolites of ginsenosides from Panax ginseng. In this study, we demonstrate that PPD inhibits the increase in lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression through inactivation of nuclear factor-kappaB by preventing degradation of inhibitory factor-kappaBalpha. PPD also induces heme oxygenase 1 (HO-1) expression in RAW 264.7 cells, at the mRNA and protein levels, in the presence and absence of LPS. This effect is associated with suppression of LPS-induced nitric oxide (NO) production and iNOS expression. The HO-1 inducer hemin is associated with the suppression of LPS-induced NO production in a dose-dependent manner, and the HO-1 inhibitor tin protoporphyrin attenuates the inhibitory activity of PPD on LPS-induced NO production. These results provide evidence for the role of HO-1 in the inhibition of LPS-induced NO production by PPD.
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PMID:Anti-inflammatory activity of 20(S)-protopanaxadiol: enhanced heme oxygenase 1 expression in RAW 264.7 cells. 1639 56

The effects of selective beta(2)-adrenoceptor agonists on proinflammatory cytokines and the expression of stress-inducible proteins have not yet been clarified. We investigated the effect of a higher dose (60 mg/kg intravenously) of salbutamol, a selective beta(2)-adrenoceptor agonist, on the induction of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha in plasma and the expression of protein and mRNA of metallothioein-1 (MT-1), heme oxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) in heart, lung, liver and spleen in rats. The plasma IL-6 concentration was significantly increased after administration with a maximum increase at 3 hr in a dose-dependent manner, but IL-1beta and TNF-alpha concentrations were not changed. MT-1 mRNA increased in heart, lung and liver, but not in spleen, and MT-1 protein increased in endocardium, fibroblasts of lung and periportal regions in liver. HO-1 mRNA was not changed in lung, decreased at 3 hr in liver and spleen, and increased at 6 hr in liver. Contrary to liver, HO-1 mRNA in the heart increased at 3 hr and decreased at 6 hr. HO-1 protein increased in cardiomyocytes and centrilobular regions in the liver. iNOS mRNA increased in lung, liver and spleen, but decreased in the heart, and iNOS protein increased in alveolar type II cells and hepatocytes, and decreased in necrotic cardiomyocytes. In contrast, a lower dose (6 mg/kg intravenously) of salbutamol suppressed lipopolysaccharide-induced HO-1 and iNOS mRNA. We conclude that salbutamol tissue- and dose-dependently alters the expression of stress-inducible proteins.
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PMID:Tissue- and dose-dependent alteration of stress-inducible proteins by beta2-adrenoceptor agonist, salbutamol, in rats. 1640 39

We used lipopolysaccharide (LPS) to activate microglia that play an important role in the brain immune system. LPS injected into the rat hippocampus CA1 region activated microglial cells resulting in an increased production of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in the hippocampus during the initial stage of treatment. Immunostaining for IL-1beta was increased at 6 hr after LPS injection. IL-1beta-immunopositive cells were co-localized with immunostaining for CD11b. Subacute treatment with LPS by the same route for 5 days caused long-term activation of microglia and induced learning and memory deficits in animals when examined with a step-through passive avoidance test, but histochemical analysis showed that neuronal cell death was not observed under these experimental conditions. The increased expression of the heme oxygenase-1 (HO-1) gene, an oxidative stress maker, was observed. However, the genetic expression of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, decreased during the course of LPS treatment. We found decreases in [3H]MK801 binding in the hippocampus CA1 region by LPS-treatment for 5 days. The data shows that glutamatergic transmission was attenuated in the LPS-treated rats. These results suggest that long-term activation of microglia induced by LPS results in a decrease of glutamatergic transmission that leads to learning and memory deficits without neuronal cell death. The physiologic significance of these findings is discussed.
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PMID:Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats. 1642 44

We report that the synthetic chalcone 2',4',6'-tris(methoxymethoxy) chalcone (TMMC) is an anti-inflammatory compound that reduces nitric oxide (NO) production by inhibiting of inducible NO synthase (iNOS) expression, and that TMMC decreases the degradation of the inhibitory factor kappaB, leading to inhibition of nuclear factor-kappaB translocation into the nucleus in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. We also demonstrate that TMMC by itself is a potent inducer of heme oxygenase 1 (HO-1). Inhibition of HO-1 activity or scavenging of carbon monoxide, a byproduct of heme degradation, significantly attenuated this anti-inflammatory action. Treating cells with the specific p42/44 MAPK inhibitor, PD98059, blocked the TMMC-mediated induction of HO-1 and the inhibition of LPS-stimulated expression of iNOS. TMMC also depleted intracellular GSH. Our data suggest that TMMC exerts an anti-inflammatory effect in macrophages through a mechanism that involves the induction of HO-1, which is mediated by activation of p42/44 MAPK and GSH depletion.
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PMID:Heme oxygenase 1 mediates anti-inflammatory effects of 2',4',6'-tris(methoxymethoxy) chalcone. 1648 Sep 75

This work aimed to elucidate the anti-inflammatory mechanism of the n-BuOH subfraction (PL) prepared from fruiting bodies of Phellinus linteus. PL induced heme oxygenase-1 (HO-1) of the RAW264.7 macrophages in concentration- and time-dependent manner. It suppressed induction of inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO) through down-regulation of iNOS promoter activity in lipopolysaccharide (LPS)-stimulated macrophages. Zn(II) protoporphyrin IX (ZnPP), a specific inhibitor of HO-1, partly blocked suppression by PL on iNOS promoter activity and NO production, which were elevated in LPS-stimulated macrophages. LPS was able to enhance NO production via reactive oxygen species (ROS) generation, c-Jun NH(2)-terminal kinase (JNK) and c-Jun induction. ZnPP prevented PL from down-regulating ROS generation and JNK activation in LPS-stimulated macrophages. Taken together, PL shows its anti-inflammatory activity via mediation of HO-1 in an in vitro inflammation model.
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PMID:Heme oxygenase-1 mediates the anti-inflammatory effect of mushroom Phellinus linteus in LPS-stimulated RAW264.7 macrophages. 1648 96


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