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)

The antinociceptive, anti-inflammatory, antipyretic effects along with gastric safety profile of parecoxib, a novel, potent selective cyclooxygenase-2 inhibiting prodrug, and those of ketorolac, a nonselective cyclooxygenase inhibitor, were evaluated in various animal models. Parecoxib (up to 20 mg/kg, i.v.) had no effect in two acute pain models, namely, the acetic acid-induced writhing (visceral pain) and the formalin test (tonic pain). However, ketorolac (up to 10 mg/kg, i.v.) showed marked antinociceptive effects in these models. In the models of carrageenan-provoked inflammatory hyperalgesia and inflammation, and in lipopolysaccharide-induced pyrexia, parecoxib significantly reversed all the behavioral changes and it was found to be more potent than ketorolac. Further, ketorolac (10 mg/kg, i.v.) produced visible gastric lesions with prominent petechiae and hemorrhagic streaks. However, parecoxib was without any effect on gastric mucosa. The present results showed that the cyclooxygenase-2 inhibitor, parecoxib, when administered parenterally, has potent antihyperalgesic, anti-inflammatory, antipyretic effects and has a better safety profile than with ketorolac, with sparing of cyclooxygenase-1 in the stomach in these animal models.
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PMID:Pharmacological profile of parecoxib: a novel, potent injectable selective cyclooxygenase-2 inhibitor. 1510 35

Up-regulation of prostaglandin E2 (PGE2) production in the periodontal tissue is considered to be important for periodontal tissue destruction. The purpose of the study was to demonstrate the dynamic changes of immuno-localization of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in rat periodontal tissue after topical application of lipopolysaccharide (LPS: 5 mg/ml in physiological saline) from Escherichia coli into the rat molar gingival sulcus. In the normal periodontal tissue, small numbers of junctional epithelium (JE) cells and numerous osteocytes embedded in alveolar bone constitutively expressed COX-1. The COX-1 expression was not effected by LPS application. JE cells, especially in the coronal portion of JE also expressed COX-2. LPS application induced the JE cells with consequent transient expression of COX-2 with a peak at day 1. These findings suggest that JE cells may play a critical role in first defense line against LPS challenge and PGE2 from JE cells may be responsible for the initiation of periodontal inflammation. In the deep periodontal tissue, cementoblasts and osteoblasts showed constitutive expression of COX-2, which may be induced by continuous cyclic tension force due to occlusal pressure. LPS application caused a transient up-regulation of COX-2 expression in periodontal ligament fibroblasts, cementoblasts and osteoblasts. It is suggested that the inducible production of PGE2 via COX-2 by these cells may be associated with connective tissue destruction and alveolar bone resorption.
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PMID:Immuno-localization of COX-1 and COX-2 in the rat molar periodontal tissue after topical application of lipopolysaccharide. 1527 61

Thiazolidinedione, peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has been used as an anti-diabetic drug and as an useful tool to elucidate multiple PPARgamma functions by in vitro and in vivo studies. We investigated the effects of thiazolidinediones on prostanoid production in lipopolysaccharide-stimulated cells. The high concentrations (>10 microM) of rosiglitazone and pioglitazone significantly increased lipopolysaccharide-stimulated prostanoid production such as thromboxane A2 and prostaglandin E2. However, PPARgamma antagonist could not inhibit them. In PPARgamma-deficient cells, thiazolidinediones increased prostaglandin E2 production. Thiazolidinediones increased arachidonic acid (AA) release from the cell membrane by not stimulating AA releasing process involving several phospholipase A2s but inhibiting AA reuptaking process. The expression of cyclooxygenase-1 and cyclooxygenase-2 were not affected by thiazolidinediones. In this study, we demonstrated that high concentrations of TZDs increased AA release by the inhibition of AA reuptaking process, leading to subsequent increase in the prostanoid production in a PPARgamma-independent manner. This mechanism provides useful information for the elucidation of multiple PPARgamma functions and diabetic drug therapy.
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PMID:Thiazolidinediones increase arachidonic acid release and subsequent prostanoid production in a peroxisome proliferator-activated receptor gamma-independent manner. 1528 52

Damage to intestinal epithelium limits the use of ionizing radiation (IR) in cancer therapy. Prostaglandins (PGs), generated through the action of cyclooxygenase-1 (COX-1) and COX-2 protect the intestinal stem cells from IR. In previous studies, we demonstrated that the RNA-binding protein CUGBP2 regulates the stability and translation of COX-2 mRNA by interacting with AU-rich sequences in 3' UTR. Here, we demonstrate a dynamic antagonistic relationship between CUGBP2 and COX-2. Both CUGBP2 and COX-2 are rapidly induced after IR in intestinal crypt epithelial cells in mice, but CUGBP2 protein expression is observed immediately and COX-2 protein expression is delayed. In contrast, administration of bacterial lipopolysaccharide induced COX-2 expression and PGE(2), resulting in the inhibition of CUGBP2 expression and radioprotection of the intestine. These effects were reversed by NS398, a COX-2-specific inhibitor, suggesting that lipopolysaccharide-mediated inhibition of CUGBP2 is a PG-dependent mechanism. Furthermore, CUGBP2 expression is higher in COX-1(-/-) and COX-2(-/-) mice than wild-type controls at basal conditions, which is further increased after IR.
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PMID:Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage. 1535 64

The purpose of the present study was to elucidate the effects of ethanol on expression of cyclooxygenase in alveolar macrophages. Rat alveolar macrophages were collected by bronchoalveolar lavage and stimulated by lipopolysaccharide. Lipopolysaccharide-induced cyclooxygenase-2 expression and prostaglandin E2 production were inhibited by ethanol (100-200 mM) in a concentration-dependent manner. Ethanol at 100-200 mM concentration-dependently inhibited cyclooxygenase-2 mRNA expression. Lipopolysaccharide-stimulated phosphorylation of both extracellular signal-related kinase and p38 mitogen-activated protein kinase was also significantly inhibited by ethanol (50-200 mM). Cyclooxygenase-2 expression was significantly inhibited by U0126 but was not affected by SB203580. In the presence of SB203580, lipopolysaccharide-induced cyclooxygenase-2 expression was also inhibited by ethanol (50-200 mM). On the other hand, cyclooxygenase-1 was expressed constitutively in alveolar macrophages and cyclooxygenase-1 expression was affected neither by lipopolysaccharide nor ethanol. Lipopolysaccharide-induced expression of inducible nitric oxide synthase in alveolar macrophages was not affected by ethanol at 50-200 mM. These results suggest that lipopolysaccharide-induced expression of cyclooxygenase-2 is mediated by extracellular signal-related kinase but not by p38 kinase and that ethanol selectively attenuates cyclooxygenase-2 expression mainly by inhibiting activation of extracellular signal-related kinase.
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PMID:Inhibitory action of ethanol on cyclooxygenase-2 expression through suppression of the extracellular signal-related kinase-mediated pathway in rat alveolar macrophages. 1554 77

To investigate a possible role of 8-isoprostaglandin F2alpha in inflammation, 8-isoprostaglandin F2alpha and prostaglandin E2 levels were determined by enzyme immunoassay (EIA) in carrageenan-induced air pouch model in rats. In this model, 8-isoprostaglandin F2alpha and prostaglandin E2 levels were found to be increased significantly. To evaluate whether this increase was due to the development of inflammation or solely to cyclooxygenase-2 induction, a lipopolysaccharide-induced air pouch model, in which only cyclooxygenase-2 induction occurs without inflammation, was used. In this model, 8-isoprostaglandin F2alpha was also found to be increased parallel to the increase in prostaglandin E2 level. Cyclooxygenase-dependent formation of 8-isoprostaglandin F2alpha was investigated in carrageenan-induced air pouch model by administrating nonselective cyclooxygenase inhibitor indomethacin, selective cyclooxygenase-1 inhibitor valeryl salicylate or selective cyclooxygenase-2 inhibitor SC-582368 (4-(5-(4-chlorophenyl)-3-3-trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonanmide) 1 h before carrageenan injection. All these inhibitors significantly inhibited the production of 8-isoprostaglandin F2alpha and prostaglandin E2. These findings show that 8-isoprostaglandin F2alpha can be formed in carrageenan-induced air pouch model in rats. The formation of 8-isoprostaglandin F2alpha in lipopolysaccharide-induced air pouch model and the inhibition of its production by various cyclooxygenase inhibitors provide evidence for cyclooxygenase-dependent formation of isoprostanes in this model.
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PMID:Formation of 8-isoprostaglandin F2alpha and prostaglandin E2 in carrageenan-induced air pouch model in rats. 1558 40

Extracts of the plant species Pinus sylvestris L. and Plantago lanceolata L. have been used in traditional medicine for the treatment of certain respiratory diseases, but little is known about their precise effects and mechanisms of action. In this study, we investigated the effect of these plant extracts on the production of nitric oxide (NO) and prostaglandin E(2), NO synthase (NOS) type II, cyclooxygenase-1 (COX-1) and COX-2 mRNA expression in the murine macrophage cell line J774A.1. We found that Pinus sylvestris and Plantago lanceolata extracts inhibited NO production in a concentration-dependent manner in this cell line, without obvious cytotoxic effects as tested by MTT assay. The Plantago lanceolata extract at all doses used, and the Pinus sylvestris extract at high doses, showed significant scavenging of NO radicals released by the NO donor PAPA-NONOate. Our data also show that pre-treatment with these extracts significantly inhibits inducible NOS (iNOS) mRNA production in this cell line, without affecting COX-1 mRNA expression. COX-2 mRNA levels and PGE(2) levels induced by lipopolysaccharide/interferon-gamma were not modified upon pre-treatment with the extracts. Thus, our results suggest that the anti-inflammatory properties of Pinus sylvestris and Plantago lanceolata extracts may reflect decreased NO production, possibly due to inhibitory effects on iNOS gene expression or to NO-scavenging activity.
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PMID:In-vitro anti-inflammatory activity of Pinus sylvestris and Plantago lanceolata extracts: effect on inducible NOS, COX-1, COX-2 and their products in J774A.1 murine macrophages. 1580 95

We examined the effect of Buthus martensi Karsch (BMK) extract on IL-1beta-induced production of nitrogen oxide (NO) in primary human osteoarthritis (OA) chondrocytes. The cells were treated with BMK (10 microg/ml) and IL-1beta (2 ng/ml) for different periods, and inducible nitric oxide synthase (iNOS) mRNA and protein expression were determined by real-time quantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The cytotoxicity of BMK on human OA chondrocytes was very low (IC50 > 250 microg/ml) as measured by the XTT assay method. Production of NO was determined as nitrite in culture supernatant. Human chondrocytes cotreated with BMK produced significantly less NO compared with chondrocytes stimulated with IL-1beta alone. Activation and translocation of and NF-(kappa)B DNA binding activity were determined by Western blotting and specific enzyme-linked immunosorbent assay. The inhibition of NO production correlated with the suppression of induction and expression of nuclear factor-kappaB (NF-(kappa)B) and activation protein-1 (AP-1)-dependent gene. BMK inhibited the activation and translocation of NF-(kappa)B to the nucleus, indicating that BMK inhibits the IL-1beta-induced production of NO in human chondrocytes by interfering with the activation of NF-(kappa)B through a novel mechanism. In addition, BMK reduced prostaglandin E2 (PGE2) production in mouse peritoneal macrophages stimulated with lipopolysaccharide, whereas no influence on the activity of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) or cyclooxygenase-1 (COX-1) was observed. Our data, therefore, suggest that BMK may be a therapeutically effective inhibitor of IL-1beta-induced inflammatory effects that are dependent on NF-(kappa)B activation in human OA chondrocytes. The results indicate that BMK exerts anti-inflammatory effects related to the inhibition of neutrophil functions and of NO and PGE2 production, which could be due to a decreased expression of iNOS and COX-2 through the transcription factors NF-(kappa)B and AP-1.
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PMID:Inhibitory effect of Buthus martensi Karsch extracts on interleukin-1beta-induced expression of nitric oxide (NO) synthase and production of NO in human chondrocytes and LPS-induced NO and prostaglandin E2 production in mouse peritoneal macrophages. 1596 82

Hexanic, dichloromethanic, ethanolic and aqueous extracts from Baccharis obtusifolia HBK, Baccharis latifolia (R. et P.) Pers., Baccharis pentlandii D.C. and Baccharis subulata Wedd., plants used in the traditional medicine of South America have been studied for their in vitro anti-inflammatory activity in cellular systems. Calcium ionophore A23187-stimulated mouse peritoneal macrophages were validated as a source of cyclooxygenase-1 (COX-1) (prostaglandin E2, PGE2) and 5-lipoxygenase (5-LOX) (leukotriene C4, LTC4), and mouse peritoneal macrophages stimulated with Escherichia coli lipopolysaccharide (LPS) were used for testing cyclooxygenase-2 (COX-2) (PGE2), nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha) activity. Most of the extracts tested were active in all assays.
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PMID:Anti-inflammatory activity of four Bolivian Baccharis species (Compositae). 1620 49

Tetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the dried root of hang-fang-chi (Stephania tetrandra S. Moore), is traditionally used in China for treating inflammation, hypertension and silicosis. In this study, our aim was to examine the anti-inflammatory mechanism of TET through measuring the inducible nitric oxide synthase (iNOS), cyclooxygenase-1, and -2 (COX-1 and COX-2) expression, cytokines (TNF-alpha, IL-4 and IL-8) formation, nitric oxide (NO) release and prostaglandin E2 (PGE2) generation in lipopolysaccharide (LPS)-induced human monocytic (THP-1) cells. Results showed that TET remarkably suppressed the LPS (1 microg/ml) induction of NO release and PGE2 generation. It also significantly attenuated the LPS-induced transcription of proinflammatory cytokines (TNF-alpha, IL-4 and IL-8) in a dose-dependent manner. Furthermore, TET at 100 microM significantly blocked the LPS induction of iNOS and COX-2 expression, but not the COX-1. Taken together, these results suggest that TET exerts anti-inflammatory effects probably through the suppression of COX-2 and iNOS expression.
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PMID:Tetrandrine inhibits proinflammatory cytokines, iNOS and COX-2 expression in human monocytic cells. 1720 60


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