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 arachidonic acid metabolizing enzymes, the cyclooxygenases (COXs) and lipoxygenases (LOXs), have been implicated in the development of a variety of cancers and numerous new therapeutic inhibitors are currently under investigation. However, given the interdependence of the two pathways, the effect of inhibiting one pathway with relatively selective agents can only be appreciated in the in vivo situation. Clearly then, because of their potential beneficial or deleterious effects, it is important to understand the nature and levels of the resulting arachidonic acid metabolites when treating patients with relatively selective inhibitor drugs. In this study, using reference COX-2, 5-LOX and dual COX-2/5-LOX inhibitors, we devised a protocol which permitted the simultaneous quantification of eicosanoid metabolites formed during stimulation of human peripheral venous blood samples with the calcium ionophore, A23187, in the absence and presence of lipopolysaccharide (LPS). Not surprisingly, the end products of both COX and LOX pathways were affected depending on the inhibitor, or combination of inhibitors, used and the concentrations of drug tested. In conclusion, the method described permits the rapid screening of novel compounds for potentially positive and/or negative effects upon the products of arachidonic acid metabolism.
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PMID:Modification of eicosanoid profile in human blood treated by dual COX/LOX inhibitors. 1621 97

Bacterial endotoxin produces sepsis associated with alterations in body temperature (fever or hypothermia). The intraperitoneal administration of bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/mouse) led to a decrease in colonic temperature starting 1 hr after the injection. The hypothermic effect was accompanied by a significant increase in hypothalamic leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) levels. 5-lipoxygenase inhibitor, zileuton (200 and 400 mg/kg, po) administered 30 min before LPS challenge significantly prevented hypothermia. However, non-selective cyclooxygenase inhibitor, indomethacin (10, 20 mg/kg, po) did not reverse the hypothermic response. Further, pretreatment of mice with zileuton prevented LPS-stimulated increase in hypothalamic LTB4 levels and caused a relatively small increase in PGE2 levels. Indomethacin had no effect on LTB4 levels but it reduced PGE2 levels. These results suggest a possible involvement of leukotrienes in LPS-induced hypothermia and the potential protective role of 5-lipoxygenase inhibitors in endotoxemia.
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PMID:Effect of 5-lipoxygenase inhibitor against lipopolysaccharide-induced hypothermia in mice. 1635 26

The fruits of Evodia rutaecarpa Benth (Rutaceae) has long been used for inflammatory disorders and some anti-inflammatory actions of its constituents such as dehydroevodiamine, evodiamine and rutaecarpine were previously reported. Since the pharmacological data is not sufficient to clearly establish the scientific rationale of anti-inflammatory medicinal use of this plant material and the search for its active principles is limited so far, three major constituents (evodiamine, rutaecarpine, goshuyuamide II) were evaluated for their anti-inflammatory cellular action mechanisms in the present study. From the results, evodiamine and rutaecarpine were found to strongly inhibit prostaglandin E2 synthesis from lipopolysaccharide-treated RAW 264.7 cells at 1-10 microM. Evodiamine inhibited cyclooxygenase-2 induction and NF-kappaB activation, while rutaecarpine did not. On the other hand, goshuyuamide II inhibited 5-lipoxygenase from RBL-1 cells (IC50 = 6.6 microM), resulting in the reduced synthesis of leukotrienes. However, these three compounds were not inhibitory against inducible nitric oxide synthase-mediated nitric oxide production from RAW cells up to 50 micorM. These pharmacological properties may provide the additional scientific rationale for anti-inflammatory use of the fruits of E. rutaecarpa.
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PMID:Anti-inflammatory principles from the fruits of Evodia rutaecarpa and their cellular action mechanisms. 1668 Oct 34

A water extract of Panax notoginseng Buck F.H. Chen. (Arialiaceae) root (PN) is being used as a therapeutic agent to stop haemorrhages and as a tonic to promote health in Korean and Chinese medicine. The pharmacokinetic profiles of PN have not been accurately investigated. The preliminary aim was to elucidate the pharmacokinetic features of PN. First, the prevention of neutrophil functions was assessed. PN inhibited neutrophil functions, including degranulation, superoxide generation and leukotriene B4 production, without any effect on 5-lipoxygenase activity. PN reduced nitric oxide (NO) and prostaglandin (PG)E2 production in mouse peritoneal macrophages stimulated with lipopolysaccharide (LPS) while no influence on the activity of inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX-2) or cyclo-oxygenase-1 (COX-1) was observed. PN significantly reduced mouse paw oedema induced by carrageenan. The results indicate that PN exerts antiinflammatory effects related to the inhibition of neutrophil functions and NO and PGE2 production, which could be due to a decreased expression of iNOS and COX-2.
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PMID:Inhibitory effect of Panax notoginseng on nitric oxide synthase, cyclo-oxygenase-2 and neutrophil functions. 1712 37

Aspirin (ASA) inhibits cycloxygenase-1 and modifies cycloxygenase-2 (COX2) by acetylation at Ser(530), leading to a shift from production of PGH(2), the precursor of prostaglandin, to 15-R-HETE which is converted by 5-lipoxygenase to 15-epi-lipoxin A(4) (15-epi-LXA4), a potent anti-inflammatory mediator. Both atorvastatin (ATV) and pioglitazone (PIO) increase COX2 expression. ATV activates COX2 by S-nitrosylation at Cys(526) to produce 15-epi-LXA4 and 6-keto-PGF(1alpha) (the stable metabolite of PGI(2)). We assessed the effect of ASA on the myocardial production of 15-epi-LXA4 and PGI(2) after induction by lipopolysaccharide (LPS) or PIO+ATV. Sprague-Dawley rats were pretreated with: control; ASA 10 mg/kg; ASA 50 mg/kg; LPS alone; LPS+ASA 10 mg/kg; LPS+ASA 50 mg/kg; LPS+ASA 200 mg/kg; PIO (10 mg/kg/d)+ATV (10 mg/kg/d); PIO+ATV+ASA 10 mg/kg; PIO+ATV+ASA 50 mg/kg; PIO+ATV+ASA 50 mg/kg+1400 W, a specific iNOS inhibitor; or PIO+ATV+1400 W. ASA alone had no effect on myocardial 15-epi-LXA4. LPS increased 15-epi-LXA4 and 6-keto-PGF(1alpha) levels. ASA (50 mg/kg and 200 mg/kg, but not 10 mg/kg) augmented the LPS effect on 15-epi-LXA4 but attenuated the effect on 6-keto-PGF(1alpha). PIO+ATV increased 15-epi-LXA4 and 6-keto-PGF(1alpha) levels. ASA and 1400 W attenuated the effects of PIO+ATV on 15-epi-LXA4 and 6-keto-PGF(1alpha). However, when both ASA and 1400 W were administered with PIO+ATV, there was a marked increase in 15-epi-LXA4, whereas the production of 6-keto-PGF(1alpha) was attenuated. In conclusion, COX2 acetylation by ASA shifts enzyme from producing 6-keto-PGF(1alpha) to 15-epi-LXA4. In contrast, S-nitrosylation by PIO+ASA augments the production of both 15-epi-LXA4 and 6-keto-PGF(1alpha). However, when COX2 is both acetylated and S-nitrosylated, it is inactivated. We suggest potential adverse interactions among statins, thiazolidinediones, and high-dose ASA.
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PMID:Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart. 1725 75

Infusions of Indian black tea (BTI), when administered orally, produced significant inhibition of rat paw oedema, induced with carrageenin (pre and post treatment) and arachidonic acid. BTI was also found to inhibit peritoneal capillary permeability and caused a marked reduction of lipopolysaccharide induced PGE(2) generation. In these models, the observed antioedema effect was similar to that of BW755C (a dual inhibitor of cyclooxygenase and 5-lipoxygenase enzymes). BTI was found to scavenge superoxide and hydroxyl radicals, and also protected rat erythrocytes from the damaging effects of hydrogen peroxide. In chronic studies, BTI inhibited granuloma formation along with the reduction of both lipid peroxidation and hydroxyproline content (in the granuloma tissue). Significant antiarthritic activity was observed with regular administration of BTI in the Freund's adjuvant induced model of arthritis. Chronic treatment with BTI (in arthritic rats) resulted in a decrease of paw diameter and tissue lipid peroxidation, along with a restoration of GSH, catalase and superoxide dismutase levels.
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PMID:Pharmacological studies on Indian black tea (leaf variety) in acute and chronic inflammatory conditions. 1844 42

The immunomodulatory effects of an isoflavone-rich extract from the root of wooly glycine Glycine tomentella (GTE) were studied in a macrophage-like cell line from Atlantic salmon (TO cells). The TO cell line was stimulated with defined concentrations of lipopolysaccharide (LPS) from Escherichia coli (serotype O127:B8) for defined time periods to induce expression of pro-inflammatory enzymes and cytokines. Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were measured by real-time PCR methods and combined with analyses of eicosanoid production in cell extracts and evaluation of molecules of the TNF-alpha cell signaling pathway. The results showed that TNF-alpha was strongly induced by LPS, while GTE (25miicrog/ml) inhibited 67% of the TNF-alpha response when added to the cells together with LPS. Incubation of LPS in combination of GTE in TO cells caused increased intracellular prostaglandin E2 (PGE2), and reduced activation of p38 MAP kinase compared to LPS alone. GTE seemed to arrest NADPH oxidation, the coenzyme for carbonyl reductase and the prostaglandin-E2 9-reductase converting PGE2 to PGF2. We suggest that the mechanism of increased intracellular PGE2 levels following GTE treatment is caused by reduced breakdown of PGE2. GTE did not inhibit the other pro-inflammatory responses in LPS stimulated cells studied herein. IL-1beta and COX-2 showed moderately increased levels of expression likely caused by the increased PGE2.
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PMID:Isoflavone-rich extracts from wooly glycine Glycine tomentella inhibits LPS-induced TNF-alpha expression in a macrophage cell line of Atlantic salmon (Salmo salar L.). 1867 22

Acanthus ilicifolius Linn, is a perennial herb (Acanthaceae) widely found in the Sundarban mangroves and is popularly used for its wound healing effects. In the present study an attempt was made to evaluate the anti-inflammatory activity of the Acanthus ilicifolius leaves. The methanolic fraction of Acanthus ilicifolius leaf extract produced significant inhibition of rat paw oedema, when administered both prior to and after carrageenan administration, in a manner similar to BW755C a synthetic cyclooxygenase (COX) and lipoxygenase (LOX) inhibitor. The extract decreased protein exudation and leukocyte migration in the peritoneal fluid, thereby indicating its effectiveness towards inhibiting peritoneal inflammation. It also produced significant inhibition of COX (1 and 2) and 5-LOX activity. Preincubation of the extract inhibited the production of proinflammatory cytokines (TNFalpha and IL-6) in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). The methanolic fraction of the extract was also found to possess significant free radical (DPPH, ABTS, superoxide and hydroxyl radical) scavenging activity. The extract on intraperitoneal administration augmented the endogenous antioxidant status, as evident from the significant increase of ferric reducing ability of plasma (FRAP) and total peroxyl radical trapping activity of plasma (TRAP).
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PMID:Anti-inflammatory activity of Acanthus ilicifolius. 1870 26

Anti-inflammatory drugs such as ibuprofen appear to prevent the development of Parkinson's disease (PD); however, long-term use has undesirable side-effects. A new strategy for anti-inflammatory drug therapy is using a dual inhibitor of COX and lipooxygenase (LOX). Here, we compared the dopaminergic neuroprotective property of phenidone (a dual COX and LOX inhibitor) with COX or LOX inhibitors including SC-560 (a COX-1 inhibitor), aspirin (a COX-1/2 inhibitor), meloxicam (a preferential COX-2 inhibitor), caffeic acid (a 5-LOX inhibitor), and esculetin (a 5, 12-LOX inhibitor) in our lipopolysaccharide (LPS)-induced PD animal model. Our results show that COX-2 and 5-LOX play a major role in LPS-induced dopaminergic neurotoxicity, as meloxicam and phenidone attenuated LPS-induced oxidative stress and meloxicam, phenidone, and caffeic acid attenuated dopaminergic neurodegeneration, while SC-560, aspirin, and esculetin did not. In addition, phenidone was superior in attenuating LPS-induced dopaminergic neurodegeneration and microglia activation, probably as a result of dual inhibition of COX-2 and LOX. Therefore, dual inhibition of COX and LOX with phenidone represents a promising new candidate for anti-inflammatory drug therapy, and may provide a novel therapeutic approach for inflammation-related neurodegenerative diseases including PD.
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PMID:Phenidone protects the nigral dopaminergic neurons from LPS-induced neurotoxicity. 1876 Mar 29

The anti-inflammatory activity of Chungkukjang, a Korean traditional fermented soybean food (Korean-style Natto), was examined for the first time. From the results, it was found that the ethanol extract of Chungkukjang inhibited 5-lipoxygenase from A23187-treated RBL-1 cells, reducing leukoriene production (50% inhibitory concentration = 54.1 microg/mL). However, it did not greatly affect cyclooxygenase-2-catalyzed prostaglandin E(2) and inducible nitric oxide synthase-catalyzed nitric oxide production from lipopolysaccharide-treated RAW 264.7 cells at the same concentration ranges. Since leukotrienes are intimately involved in some allergic disorders, the anti-allergic activity of Chungkukjang was further examined in animal models of passive cutaneous anaphylaxis (type I hypersensitivity) and arachidonic acid-induced ear edema, two well-known in vivo models sensitive to 5-lipoxygenase inhibitors. After oral administration for 5 consecutive days, Chungkukjang significantly reduced (27.3%) passive cutaneous anaphylaxis in rats at 400 mg/kg/day. It also showed in vivo anti-inflammatory activity against arachidonic acid-induced mouse ear edema. Therefore, it is suggested that Chungkukjang may be beneficial for several allergic conditions such as asthma and atopic dermatitis.
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PMID:Anti-inflammatory activity of the ethanol extract of Chungkukjang, Korean fermented bean: 5-lipoxygenase inhibition. 1880 Sep 4


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