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)

There is an increasing body of evidence that prostanoids modulate mast cell functions and contribute to the development of allergic inflammation. The present study aimed to identify an undetermined function of prostaglandin (PG) F(2alpha) in mast cell activation and the signaling mechanism involved in it. Simultaneous quantification of prostanoids by liquid chromatography/tandem mass spectrometry revealed the constitutive release of PGF(2alpha), thromboxane B(2), and 6-keto-PGF(1alpha) from bone marrow-derived mast cells (BMMCs). Upon activation of BMMCs by lipopolysaccharide, the cytokine production in BMMCs was enhanced when the culture was supplemented with PGF(2alpha). However, F prostanoid receptor-a selective receptor for PGF(2alpha)-was not detected in BMMCs. Further investigations performed using prostanoid receptor antagonists revealed an alternative mechanism wherein the receptors for PGE species-E prostanoid receptors-mediated the PGF(2alpha) signal in BMMCs. The present study provides an insight into a novel function of PGF(2alpha), i.e., an autocrine accelerator for mast cell activation.
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PMID:Prostaglandin F(2alpha) regulates cytokine responses of mast cells through the receptors for prostaglandin E. 1819 Jul 89

Mangiferin, a naturally occurring glucosylxanthone, has potent antioxidant and anti-inflammatory properties, as demonstrated in several reports. However, very limited information is available on the effects of this natural polyphenol on microglial activation. Thus, the aim of this study was to examine whether mangiferin is able to reduce prostaglandin E(2) (PGE(2)) and 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) production by lipopolysaccharide (LPS)-activated primary rat microglia. Microglial cells were stimulated with 10ng/ml of LPS in the presence or absence of different concentrations of mangiferin (1-50 microM). After 24h incubation, culture media were collected to measure the production of PGE(2) and 8-iso-PGF(2alpha) using enzyme immunoassays. Protein levels of cyclooxygenase (COX)-1 and COX-2 were studied by immunoblotting after 24h of incubation with LPS. Mangiferin potently reduced LPS-induced PGE(2) synthesis and the formation of 8-iso-PGF(2alpha). Interestingly, mangiferin dose-dependently reduced LPS-induced COX-2 protein synthesis without modifying COX-2 transcription. This was due to a decrease in COX-2 transcript stability. However, mangiferin did not modify LPS-mediated phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), a key factor involved in enhancing COX-2 mRNA stability and COX-2 translation in primary microglia. Mangiferin had no effects on LPS-induced expression of inducible nitric oxide synthase (iNOS) or TNF-alpha production. Taken together, results from the present study indicate that mangiferin is able to limit microglial activation, in terms of attenuation of PGE(2) production, free radical formation and reduction in COX-2 synthesis induced by LPS. These data suggest that modulation of microglial activation might contribute to the mechanism of cerebral protection by mangiferin.
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PMID:Mangiferin inhibits cyclooxygenase-2 expression and prostaglandin E2 production in activated rat microglial cells. 1862 Oct 15

Escherichia coli infection of the endometrium causes uterine disease after parturition and is associated with prolonged luteal phases of the ovarian cycle in cattle. Termination of the luteal phase is initiated by prostaglandin F(2alpha) (PGF) from oxytocin-stimulated endometrial epithelial cells. Compared with normal animals, the peripheral plasma of animals with E. coli infection of the endometrium had higher concentrations of lipopolysaccharide (LPS) and prostaglandin E(2) (PGE) but not PGF. Endometrial explants accumulated predominantly PGE in the culture medium in response to LPS, and this effect was not reversed by oxytocin. Endometrial cells expressed the Toll-like receptor 4/CD14/MD-2 receptor complex necessary to detect LPS. Epithelial and stromal cells treated with LPS had higher steady-state media concentrations of PGE rather than PGF. Arachadonic acid is liberated from cell membranes by phospholipase 2 (PLA2) enzymes and converted to prostaglandins by synthase enzymes. Treatment of epithelial and stromal cells with LPS did not change the levels of PGE or PGF synthase enzymes. However, LPS stimulated increased levels of PLA2 group VI but not PLA2 group IV C immunoreactive protein in epithelial cells. Endometrial cells expressed the E prostanoid 2 and E prostanoid 4 receptors necessary to respond to PGE, which regulates inflammation as well as being luteotropic. In conclusion, LPS detection by endometrial cells stimulated the accumulation of PGE rather than PGF, providing a mechanism to explain prolonged luteal phases in animals with uterine disease, and this PGE may also be important for regulating inflammatory responses in the endometrium.
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PMID:Bacterial lipopolysaccharide induces an endocrine switch from prostaglandin F2alpha to prostaglandin E2 in bovine endometrium. 1905 17

The endothelium plays a major role in the pathogenesis of endotoxemia. Binding of endotoxin (lipopolysaccharide; LPS) to endothelium initiates a range of signalling events, including activation of p38 mitogen activated protein kinases (MAPKs) that are involved in the initiation of inflammatory responses. In the present study we have examined whether clinically relevant concentrations of LPS can activate p38 MAPK in equine endothelial cells and have investigated the role of the kinase in neutrophil adhesion and mediator release. Cultured equine digital vein endothelial cells (EDVEC) were exposed to LPS and phosphorylation of p38 MAPK was assessed by Western blotting using phospho-specific antibodies. Neutrophil adhesion was quantified by assaying myeloperoxidase and the release of prostacyclin (PGI(2)) was measured by radioimmunoassay of its stable breakdown product 6-keto-PGF(1alpha). The effects of the p38 MAPK inhibitors, SB203580 and PD169316, on neutrophil adhesion and 6-keto-PGF(1alpha) release were examined, as was the effect of an anti-E-selectin antibody on neutrophil adhesion to LPS-activated EDVEC. LPS treatment significantly increased p38 MAPK phosphorylation, which was maximal after a 1h LPS incubation using a concentration of 10(-5)g/ml (EC(50) = 2 x 10(-7)g/ml). Neutrophil adhesion to LPS-stimulated endothelial cells (maximal at 10(-6)g/ml; EC(50) = 6 x 10(-10)g/ml) was significantly inhibited in the presence of p38 MAPK inhibitors (reduced from a maximum of 33+/-6% to 13+/-4% adhesion at 10(-6)M SB203580 and to 21+/-4% adhesion at 10(-6) M PD169316), or an anti-E-selectin antibody (reduced from 17+/-1% adhesion to 6+/-1% adhesion). 6-keto-PGF(1alpha) release was increased in a concentration-dependent manner following LPS exposure (maximal at 10(-6)g/ml; EC(50) = 1 x 10(-9)g/ml), and was significantly inhibited by p38 MAPK blockade (reduced from 1.6+/-0.3 x 10(-9)g/ml to 4+/-1 x 10(-10)g/ml and 4+/-2 x 10(-10)g/ml with 10(-6) M SB203580 or 10(-6) M PD169316, respectively). This study has demonstrated that clinically relevant concentrations of LPS activate p38 MAPK in equine endothelial cells and that both neutrophil adhesion to LPS-activated EDVEC and PGI(2) release are dependent upon p38 MAPK phosphorylation. These results reveal a key role for p38 MAPK in the response of the endothelium to LPS and suggest that inhibition of this kinase may reduce inflammatory events in the endotoxemic horse.
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PMID:Endotoxin-induced activation of equine digital vein endothelial cells: role of p38 MAPK. 1910

This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t(1/2) << 1 min), whilst COX-2 binding was slowly reversible (t(1/2) = 25 min). In vivo, robenacoxib inhibited PGE2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID50 0.3 mg/kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg/kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg/kg but not at 2-30 mg/kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID50 0.40-0.48 mg/kg), LPS-induced fever (ID50 1.1 mg/kg) and Randall-Selitto pain (10 mg/kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng/mL in vitro). After intravenous dosing, clearance was 2.4 mL/min/kg and volume of distribution at steady-state was 306 mL/kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE2 or 6-keto PGF(1alpha) concentrations in the stomach and ileum at 30 mg/kg. Robenacoxib also had no relevant effects on kidney function at 30 mg/kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs.
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PMID:Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2. 1916 51

n-3 long-chain PUFA (n-3 LC-PUFA) may improve cardiovascular and inflammatory diseases. The effects of n-3 LC-PUFA-supplemented dairy products on inflammation and immunological parameters, biomarkers of oxidative stress, serum lipids, and on disease activity were determined in patients with rheumatoid arthritis (RA). Forty-five subjects (forty-three females and two males) were randomly divided into two groups in a double-blind, placebo-controlled cross-over study. Both groups received placebo or verum products consecutively for 3 months with a 2-month washout phase between the two periods. Blood samples were taken at the beginning and at the end of each period. The dairy products generally improved serum lipids by increasing HDL and lowering lipoprotein a. The n-3 LC-PUFA supplements act to lower TAG. Additionally, a decreased lipopolysaccharide-stimulated cylo-oxygenase-2 expression was found in patients who had consumed the enriched dairy products. The majority of the CD analysed were not influenced, although n-3 LC-PUFA did suppress the immune response as lymphocytes and monocytes were found to be significantly decreased. The n-3 LC-PUFA did not increase the biomarkers of oxidative stress such as 8-iso-PGF(2alpha) and 15-keto-dihydro PGF(2alpha), and DNA damage like 7,8-dihydro-8-oxo-2'-deoxyguanosine. The long-term consumption of dairy products (2 x 12 weeks) diminished the excretion of hydroxypyridinium crosslinks, and favoured the diastolic blood pressure. The consumption of moderate doses of n-3 LC-PUFA in combination with dairy products did not improve the disease activity. However, there is evidence of cardioprotective effects. Furthermore, the long-term consumption of dairy products acts against the cartilage and bone destruction in RA.
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PMID:Long-term moderate intervention with n-3 long-chain PUFA-supplemented dairy products: effects on pathophysiological biomarkers in patients with rheumatoid arthritis. 1924 35

8-iso-PGF(2alpha) isoprostane (IP) is one of the most-used markers of lipid peroxidation in experimental models and humans. After its formation, it is promptly metabolized to 2,3 dinor (DIN) in peroxisomes. Conjugated linoleic acid (CLA) is preferentially beta-oxidized in peroxisomes which may compete with IP, and thereby may affect its metabolism. In order to verify whether CLA is able to influence IP formation and/or metabolism and to explain the mechanism, we challenged rats supplemented with CLA or with triolein (as a control fatty acid), with a single dose of carbon tetrachloride (CCl(4)) or of bacterial lipopolysaccharide (LPS). The results showed that IP and its precursor arachidonic acid hydroperoxide, as well as malondialdehyde (MDA), increase significantly in the liver of rats challenged with CCl(4), irrespective of the diet, while in LPS-treated rats only nitrites in liver and isoprostane in plasma increase. On the other hand, the peroxisomal beta-oxidation products of IP, the DIN, is significantly lower in the CLA group with respect to control and triolein groups. To further investigate whether this is due to competition between CLA and IP at the cellular level, we incubated human fibroblasts from healthy subjects or patients with adrenoleukodystrophy (ALD), with CLA and/or commercially available IP. The rationale of this approach is based on the deficient peroxisomal beta-oxidation of fibroblasts from ALD patients, leading to a reduced formation of DIN. In both normal and ALD cells, the presence of CLA significantly inhibits the formation of DIN from IP. We may conclude that both in vitro and in vivo studies strongly suggest that CLA may impair IP catabolism in peroxisomes. Consequently an increase of IP, as a sole result of CLA intake, cannot be considered as a marker of lipid peroxidation.
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PMID:Impairment of 8-iso-PGF(2ALPHA) isoprostane metabolism by dietary conjugated linoleic acid (CLA). 1940 95

Isoprostanes (iPs) are prostaglandin (PG) isomers generated by free radical-catalyzed peroxidation of polyunsaturated fatty acids (PUFAs). Urinary F(2)-iPs, PGF(2alpha) isomers derived from arachidonic acid (AA) are used as indices of lipid peroxidation in vivo. We now report the characterization of two major F(3)-iPs, 5-epi-8,12-iso-iPF(3alpha)-VI and 8,12-iso-iPF(3alpha)-VI, derived from the omega-3 fatty acid, eicosapentaenoic acid (EPA). Although the potential therapeutic benefits of EPA receive much attention, a shift toward a diet rich in omega-3 PUFAs may also predispose to enhanced lipid peroxidation. Urinary 5-epi-8,12-iso-iPF(3alpha)-VI and 8,12-iso-iPF(3alpha)-VI are highly correlated and unaltered by cyclooxygenase inhibition in humans. Fish oil dose-dependently elevates urinary F(3)-iPs in mice and a shift in dietary omega-3/omega-6 PUFAs is reflected by an increasing slope [m] of the line relating urinary 8, 12-iso-iPF(3alpha)-VI and 8,12-iso-iPF(2alpha)-VI. Administration of bacterial lipopolysaccharide evokes a reversible increase in both urinary 8,12-iso-iPF(3alpha)-VI and 8,12-iso-iPF(2alpha)-VI in humans on an ad lib diet. However, while excretion of the iPs is highly correlated (R(2) median = 0.8), [m] varies by an order of magnitude, reflecting marked inter-individual variability in the relative peroxidation of omega-3 versus omega-6 substrates. Clustered analysis of F(2)- and F(3)-iPs refines assessment of the oxidant stress response to an inflammatory stimulus in vivo by integrating variability in dietary intake of omega-3/omega-6 PUFAs.
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PMID:Novel eicosapentaenoic acid-derived F3-isoprostanes as biomarkers of lipid peroxidation. 1952 Aug 54

Prostaglandin (PG)E(2) is a critical lipid mediator connecting chronic inflammation to cancer. The anti-carcinogenic epigallocatechin-3-gallate (EGCG) from green tea (Camellia sinensis) suppresses cellular PGE(2) biosynthesis, but the underlying molecular mechanisms are unclear. Here, we investigated the interference of EGCG with enzymes involved in PGE(2) biosynthesis, namely cytosolic phospholipase (cPL)A(2), cyclooxygenase (COX)-1 and -2, and microsomal prostaglandin E(2) synthase-1 (mPGES-1). EGCG failed to significantly inhibit isolated COX-2 and cPLA(2) up to 30 microM and moderately blocked isolated COX-1 (IC(50)>30 microM). However, EGCG efficiently inhibited the transformation of PGH(2) to PGE(2) catalyzed by mPGES-1 (IC(50)=1.8 microM). In lipopolysaccharide-stimulated human whole blood, EGCG significantly inhibited PGE(2) generation, whereas the concomitant synthesis of other prostanoids (i.e., 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid and 6-keto PGF(1alpha)) was not suppressed. Conclusively, mPGES-1 is a molecular target of EGCG, and inhibition of mPGES-1 is seemingly the predominant mechanism underlying suppression of cellular PGE(2) biosynthesis by EGCG.
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PMID:Green tea epigallocatechin-3-gallate inhibits microsomal prostaglandin E(2) synthase-1. 1966

Prostaglandin E(2) (PGE(2)) plays a crucial role in the apparent link between tumor growth and chronic inflammation. Cyclooxygenase (COX)-2 and microsomal PGE(2) synthase-1, which are overexpressed in many cancers, are functionally coupled and thus produce massive PGE(2) in various tumors. Curcumin, a polyphenolic beta-diketone from tumeric with anti-carcinogenic and anti-inflammatory activities, was shown to suppress PGE(2) formation and to block the expression of COX-2 and of microsomal PGE(2) synthase-1. Here, we identified microsomal PGE(2) synthase-1 as a molecular target of curcumin and we show that inhibition of microsomal PGE(2) synthase-1 activity is the predominant mechanism of curcumin to suppress PGE(2) biosynthesis. Curcumin reversibly inhibited the conversion of PGH(2) to PGE(2) by microsomal PGE(2) synthase-1 in microsomes of interleukin-1beta-stimulated A549 lung carcinoma cells with an IC(50) of 0.2 to 0.3 micromol/L. Closely related polyphenols (e.g., resveratrol, coniferyl alcohol, eugenol, rosmarinic acid) failed in this respect, and isolated ovine COX-1 and human recombinant COX-2 were not inhibited by curcumin up to 30 micromol/L. In lipopolysaccharide-stimulated human whole blood, curcumin inhibited COX-2-derived PGE(2) formation from endogenous or from exogenous arachidonic acid, whereas the concomitant formation of COX-2-mediated 6-keto PGF(1)alpha and COX-1-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid was suppressed only at significant higher concentrations. Based on the key function of PGE(2) in inflammation and carcinogenesis, inhibition of microsomal PGE(2) synthase-1 by curcumin provides a molecular basis for its anticarcinogenic and anti-inflammatory activities.
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PMID:Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1. 1967 57


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