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)

We evaluated whether therapeutic blood levels of meloxicam are associated with selective inhibition of monocyte cyclooxygenase (COX)-2 in vitro and ex vivo. Concentration-response curves for the inhibition of monocyte COX-2 and platelet COX-1 were obtained in vitro after the incubation of meloxicam with whole blood samples. Moreover, 11 healthy volunteers received placebo or 7.5 or 15 mg/day meloxicam, each treatment for 7 consecutive days, according to a randomized, double-blind, crossover design. Before dosing and 24 h after the seventh dose of each regimen, heparinized whole blood samples were incubated with lipopolysaccharide (10 microgram/ml) for 24 h at 37 degrees C, and prostaglandin E2 was measured in plasma as an index of monocyte COX-2 activity. The production of thromboxane B2 in whole blood allowed to clot at 37 degrees C for 60 min was assessed as an index of platelet COX-1 activity. The administration of placebo did not significantly affect plasma prostaglandin E2 (21. 3 +/- 7.5 versus 19.1 +/- 4 ng/ml, mean +/- S.D., n = 11) or serum thromboxane B2 (426 +/- 167 versus 425 +/- 150 ng/ml) levels. In contrast, the administration of 7.5 and 15 mg of meloxicam caused dose-dependent reductions in monocyte COX-2 activity by 51% and 70%, respectively, and in platelet COX-1 activity by 25% and 35%, respectively. Although the IC50 value of meloxicam for inhibition of COX-1 was 10-fold higher than the IC50 value of COX-2 in vitro, this biochemical selectivity was inadequate to clearly separate the effects of meloxicam on the two isozymes after oral dosing as a function of the daily dose and interindividual variation in steady-state plasma levels.
 ...
PMID:Dose-dependent inhibition of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by meloxicam in healthy subjects. 1038 87

Cyclooxygenase (COX) exists as constitutive (COX-1) and inducible (COX-2) isoforms. Nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and diclofenac inhibit both COX-1 and COX-2. The role of COX-2 in the genesis of fever in monkeys and humans was examined with use of the specific COX-2 inhibitor rofecoxib. Rofecoxib was administered to monkeys made febrile by 6 microg/kg intravenous lipopolysaccharide. Induced pyrexia was followed by oral rofecoxib (1 or 3 mg/kg), diclofenac (3 mg/kg), or vehicle. Rofecoxib and diclofenac rapidly reversed the elevated temperature (P < .05 versus vehicle for 3 mg/kg rofecoxib and diclofenac at 70 to 90 minutes after dosing). A single-dose, parallel-group, double-blind randomized trial was conducted in 94 patients with fever caused by a viral-type illness. Mean baseline temperature was similar for all groups (-38.5 degrees C). Patients received oral doses of 12.5 mg rofecoxib, 25 mg rofecoxib, 400 mg ibuprofen, or placebo and the mean +/- SE change in oral temperature at 4 hours after dosing was -0.97 degrees C +/- 0.11 degrees C, -1.19 degrees C +/- 0.09 degrees C, -1.20 degrees C +/- 0.11 degrees C, and 0.01 C +/- 0.17 C, respectively (P < .001 for active treatments versus placebo). Specific inhibition of COX-2 by rofecoxib results in antipyretic activity in monkeys and humans comparable to dual COX-1/COX-2 inhibitors such as diclofenac or ibuprofen. The data support the hypothesis that it is the COX-2 isoform that is primarily involved in the genesis of fever in humans.
 ...
PMID:Cyclooxygenase-2 inhibition by rofecoxib reverses naturally occurring fever in humans. 1039 71

Induction of the inducible cyclooxygenase isoform COX-2 is likely to be an important mechanism for increased prostaglandin production in renal inflammation. We examined the effect of lipopolysaccharide (LPS) on regional renal COX-2 expression in the rat. In the inner medulla, LPS injection (4 mg/kg ip) induced a twofold and 2.5-fold increase in the levels of COX-2 mRNA and COX-2 protein, respectively. In contrast, COX-2 expression in the renal cortex was not significantly altered. COX-2 promoter transgenic mice were created using the 2.7-kb flanking region of the rat COX-2 gene. In these animals, LPS injection induced reporter gene expression predominately in the inner medulla. The LPS receptor CD14, usually regarded as a monocyte/macrophage-specific marker, was found to be abundantly expressed in the inner medulla and in dissected inner medullary collecting duct (IMCD) cells, suggesting that it may mediate medullary COX-2 induction. CD14 was present only at low levels in cortex and cortical segments, including glomeruli. In cultured cells, it was abundant in mouse IMCD (mIMCD-K2) cells and renal medullary interstitial cells, but largely undetectable in mesangial cells and M1 cells, a cell line derived from mouse cortical collecting ducts. In the mIMCD-K2 cell line, LPS significantly induced COX-2 mRNA expression, with concomitant induction of CD14. LPS-stimulated COX-2 expression was reduced by the addition of an anti-CD14 monoclonal antibody to the culture medium. These results demonstrate that LPS selectively stimulates COX-2 expression in the renal inner medulla through a CD14-dependent mechanism.
 ...
PMID:Differential regulation of COX-2 expression in the kidney by lipopolysaccharide: role of CD14. 1040 92

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for the inhibition of COX-1-derived thromboxane B(2) synthesis after blood coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50) values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50) = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a (51)Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.
 ...
PMID:Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. 1041 62

Polymorphonuclear leukocytes (PMNs) produce arachidonic acid (AA) metabolites including thromboxane A2 (TXA2). These cells are the first line of defense against bacterial invasion, which often causes endotoxin shock. TXA2 which plays an important role in the pathogenesis of endotoxin shock is synthesized by three consecutive enzyme activation, cytosolic phospholipase A2 (cPLA2), prostaglandin H2 synthase (PHS type 1 and type 2) and TXA2 synthase. Among them, cPLA2- and PHS-2 activity is known to be transcriptionally and/or posttranscriptionally up-regulated by various bioactive substances including lipopolysaccharide (LPS), a bacterial endotoxin, in many cell types. We investigated the action of LPS on TXA2 synthesis in human PMNs. A23187-stimulated production of thromboxane B2 (TXB2, a stable metabolite of TXA2), assayed by specific radioimmunoassay (RIA), was significantly increased from 566.7+/-44.1 pg/10(6) cells to 966.7+/-44.1 pg/10(6) cells (p<0.05) after 6 h-exposure to LPS at the concentration of 100 ng/ml. Messenger RNA for PHS-2, PHS-1, TXA2 synthase and cPLA2, which was assessed by reverse transcription-polymerase chain reaction (RT-PCR), was expressed in PMNs without LPS stimulation. Although PHS-2 was putatively an inducible enzyme, abundance of mRNA for PHS-2 in PMNs without LPS stimulation was detectable. Messenger RNA abundance for PHS-2 and cPLA2, but not for PHS-1 and TXA2 synthase, was enhanced by LPS-treatment, indicating that the increased production of TXB2 was attributable to the up-regulation of cPLA2 and PHS-2. We conclude that (1) PHS-2 plays a more important role than PHS-1 in the production of TXA2 in human PMNs and (2) TXA2 synthesis in human PMNs is transcriptionally up-regulated by new induction of cPLA2 as well as PHS-2, when the cells encounter endotoxin producing bacteria.
 ...
PMID:Induction of cytosolic phospholipase A2 and prostaglandin H2 synthase-2 by lipopolysaccharide in human polymorphonuclear leukocytes. 1048 Feb 88

This study was set to investigate the mechanisms through which bacterial lipopolysaccharide (LPS) stimulates prostaglandin (PG) production in rat astrocytes. Primary cultures of rat hypothalamic astrocytes were established. Cells were treated with LPS alone or LPS plus antagonists of various pathways, and the subsequent changes in cyclo-oxygenase (COX) activity were monitored by measuring a COX end product, PGE2, released into the incubation medium. It was found that (i) LPS produced a concentration-dependent increase in PGE2 release from astrocytes. The potency of LPS was significantly increased by the addition of serum into the incubation medium; (ii) after 24 h of incubation, inducible COX (COX-2) accounts for most of the LPS-stimulated PG production, as the latter was markedly reduced by dexamethasone and the specific COX-2 inhibitor NS 398; and (iii) nuclear factor kappaB appears to play a role in the activation of COX-2 induced by LPS, since certain inhibitors of this transcription factor were able to antagonize, at least in part, the effects of LPS on PGE2 release.
 ...
PMID:Bacterial lipopolysaccharide increases prostaglandin production by rat astrocytes via inducible cyclo-oxygenase: evidence for the involvement of nuclear factor kappaB. 1049 33

Prostaglandins biosynthesis and nitric oxide production have been implicated in the process of carcinogenesis and inflammation. In this study, we investigated the effect of various flavonoids and (-)-epigallocatechin-3-gallate on the activities of inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Apigenin, genistein and kaempferol were markedly active inhibitors of transcriptional activation of COX-2, with IC(50) < 15 microM. In addition, apigenin and kaempferol were also markedly active inhibitors of transcriptional activation of iNOS, with IC(50) < 15 microM. Of those compounds tested, apigenin was the most potent inhibitor of transcriptional activation of both COX-2 and iNOS. Western and northern blot analyses demonstrated that apigenin significantly blocked protein and mRNA expression of COX-2 and iNOS in LPS-activated macrophages. Transient transfection experiments showed that LPS caused an approximately 4-fold increase in both COX-2 and iNOS promoter activities, these increments were suppressed by apigenin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that apigenin blocked the LPS-induced activation of nuclear factor-kB (NF-kB). The inhibition of NF-kB activation occurs through the prevention of inhibitor kB (IkB) degradation. Transient transfection experiments also showed that apigenin inhibited NF-kB-dependent transcriptional activity. Finally, we showed that apigenin could inhibit the IkB kinase activity induced by LPS or interferon-gamma. The results of further studies suggest that suppression of transcriptional activation of COX-2 and iNOS by apigenin might mainly be mediated through inhibition of IkB kinase activity. This study suggests that modulation of COX-2 and iNOS by apigenin and related flavonoids may be important in the prevention of carcinogenesis and inflammation.
 ...
PMID:Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. 1050 9

B/macrophage cells are biphenotypic leukocytes of unknown function that simultaneously express B lymphocyte (IgM, IgD, B220, CD5) and macrophage (phagocytosis, F4/80, Mac-1) characteristics. B/macrophage cells can be generated from purified mouse B lymphocytes incubated in fibroblast-conditioned medium. A potential role for B/macrophage cells in inflammation was shown by their ability to express prostaglandin H synthase-1 (COX-1) and prostaglandin H synthase-2 (COX-2) and by their production of prostaglandin (PG) E(2). COX-1 and COX-2 mRNA expression is not observed in the precursor B lymphocytes and is not known to be a property of B lineage cells. In contrast, COX-2 and the prostanoids PGE(2), PGF(2alpha) and PGD(2) are highly inducible in B/ macrophage cells upon stimulation with lipopolysaccharide, CD40 ligand, or via engagement of surface IgM, supporting a role for these cells in inflammation. PGD(2) and its metabolites are of interest because they activate the nuclear receptor PPARgamma that regulates lipid metabolism. The B/macrophage represents the first instance of a normal B-lineage cell capable of expressing COX-2. Importantly, B/macrophage cells were identified in vivo, providing evidence that they may play a significant role in immune responses. Since PGE(2) blunts IL-12 production, its synthesis by B/macrophage cells may shift the balance of an immune response towards Th2 and humoral immunity.
 ...
PMID:Biphenotypic B/macrophage cells express COX-1 and up-regulate COX-2 expression and prostaglandin E(2) production in response to pro-inflammatory signals. 1055 36

Phospholipase A2 (PLA2) regulates eicosanoid and platelet-activating factor production. It also plays an important role in the regulation of critical mediators in inflammatory diseases in which PLA2 activity is significantly enhanced during sepsis and multiple organ failure. Therefore, inhibitors of PLA2 activity offer themselves as target substances in the development of anti-inflammatory drugs. We identified 2 biflavonoids, bilobetin and ginkgetin, that can inhibit PLA2 activity. In experiments using 2-linol-[1-14C]PE as substrate both substances potently inhibited several kinds of type II 14-kDa PLA2 while inhibiting type I 14-kDa PLA2 to a lesser extent. We tested these PLA2 inhibitors for their ability to inhibit the production of tumor necrosis factor alpha (TNFalpha) and 2 enzymes, inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in an assay system using lipopolysaccharide (LPS)-stimulated Raw264.7 macrophages. In Raw264.7cells, bacterial LPS induced the production of COX-2 and iNOS proteins as well as TNFalpha. The inhibitors consistently inhibited the production of TNFalpha in a dose-dependent manner. Moreover, treatment of the macrophages with bilobetin and ginkgetin shut down the production of nitrite, one of the stable end products of NO released into the culture supernatant. The decrease in NO products was accompanied by a decrease in iNOS protein level as assessed by Western blot probed with specific anti-iNOS antibody. Both inhibitors also reduced the expression of COX-2 protein in the LPS-stimulated cells, which coincided with the reduction in iNOS protein. These results, therefore, suggest that these two sPLA2 inhibitors may be useful for inhibiting the production of inflammatory cytokine and NO production in inflammatory diseases.
 ...
PMID:The effects of two new antagonists of secretory PLA2 on TNF, iNOS, and COX-2 expression in activated macrophages. 1058 17

Prostaglandin E2 production by tissue-fixed macrophages (Mphi) after severe injury contributes to an enhanced susceptibility to infection and sepsis. The purpose of this study was to investigate the effect of cyclic adenosine monophosphate (cAMP) on prostaglandin (PGE2) production and cyclooxygenase II (COX-2) gene activation in LPS-stimulated macrophages (Mphi). RAW264.7 cells, a mouse Mphi cell line, were exposed to various concentrations of dibutyryl cAMP +/- lipopolysaccharide (10 microg/mL) stimulation. Total Mphi ribonucleic acid (RNA) was harvested for the determination of COX-2 messenger RNA (mRNA) with mouse complementary deoxyribonucleic acid (cDNA) by Northern blot assay. Mphi supernatant was collected for the measurement of tumor necrosis factor (TNF) by L929 bioassay and PGE2 by enzyme-linked immunosorbent assay (ELISA), respectively. Mphi NFkappaB activity was determined by electrophoretic mobility shift assays (EMSA). Dibutyryl cAMP significantly inhibited TNF production by LPS-stimulated Mphi. Dibutyryl cAMP (1 mM) alone induced PGE2 production. Dibutyryl cAMP (100 microM and 1 mM) also augmented PGE2 production by LPS-stimulated Mphi. Dibutyryl cAMP had similar effect on Mphi COX-2 mRNA expression and NFkappaB activity. Our data demonstrate that cAMP modulates Mphi TNF production and upregulates COX-2 gene and PGE2 production.
 ...
PMID:Cyclooxygenase 2 (COX-2) gene activation is regulated by cyclic adenosine monophosphate. 1063 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>