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

Possible effects of nonsteroidal antiinflammatory drugs (NSAID) on inflammatory mediators other than arachidonic acid metabolites which might contribute to the antiinflammatory effects of these drugs have not been fully explored. We investigated the effects of an NSAID, flurbiprofen, on production of the cytokines tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) by human peripheral blood monocytes and by the human cell lines U-937 and THP-1. Cytokine production was induced by 1 microgram/ml bacterial lipopolysaccharide (LPS) in both monocytes and cell lines, and cytokine levels in supernatants were measured by enzyme immunoassay. In monocytes, IL-6 was the major product while in both cell lines, TNF alpha was the major product. Flurbiprofen caused moderate inhibition of IL-1 beta and TNF alpha production by stimulated monocytes, but did not affect IL-6 production. In contrast, flurbiprofen completely abolished IL-6 production by both cell lines and substantially inhibited IL-1 beta and TNF alpha production. These observations raise the possibility that inhibition of cytokine production by flurbiprofen may contribute to the antiinflammatory properties of this drug.
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PMID:Effect of flurbiprofen on cytokine production by human monocytes and U-937 and THP-1 cell lines. 140 30

Chronic inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD). The present study compared the effects of chronic neuroinflammation, produced by infusion of lipopolysaccharide (LPS) into the fourth ventricle, upon memory in young, adult, and old rats. Nonsteroidal anti-inflammatory drug (NSAID) therapy may delay the onset of AD. We show that NO-Flurbiprofen (NFP), a novel NSAID that lacks gastrointestinal side effects, attenuated the neuroinflammatory reaction and reduced the inflammation-induced memory deficit. Chronic LPS infusions impaired performance of young rats but not adult or old rats. Treatment with NFP improved the performance of LPS-infused young rats, but not LPS-infused adult or old rats. LPS infusions increased the number of activated microglia in young and adult rats but not old rats. NFP treatment attenuated the effects of LPS upon microglia activation in young and adult rats, but not old rats. The results suggest that NSAID therapies designed to influence the onset of AD should be initiated in adults before age-associated inflammatory processes within the brain have a chance to develop.
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PMID:The effects of a novel NSAID on chronic neuroinflammation are age dependent. 1058 78

A series of experiments were conducted in adult ewes to delineate the release profile of activin A and its relationship to other cytokines following an i.v. injection of the bacterial cell wall component, lipopolysaccharide (LPS). Following this challenge, plasma activin A increased rapidly and appeared to be released in a biphasic manner, slightly preceding the release of tumour necrosis factor-alpha (TNFalpha) and before elevation of interleukin (IL)-6 and follistatin levels. The concentration of activin A was correlated with body temperature during the response to LPS. A second experiment compared cytokine concentrations in matched blood and cerebrospinal fluid (CSF) samples. This revealed that activin A was not released centrally in the CSF following a peripheral LPS injection, nor was TNFalpha or the activin binding protein, follistatin, but IL-6 showed a robust elevation. In a third experiment, the stimulus for activin A release was examined by blocking prostaglandin synthesis. Flurbiprofen, a prostaglandin synthesis inhibitor, effectively attenuated the fever response to LPS and partly inhibited cortisol release, but the cytokine profiles were unaffected. Finally, the bioactivity of TNFalpha and/or IL-1 was blocked using soluble receptor antagonists. These treatments did not affect the initial release of activin A, but blockade of TNFalpha depressed the second activin peak. These studies define more rigorously the release of activin A into the circulation following acute inflammatory challenge. The response is rapid and probably biphasic, independent of prostaglandin- mediated pathways and does not depend upon stimulation by TNFalpha or IL-1. The data suggest that activin A release is an early event in the inflammatory cascade following the interaction of LPS with its cellular receptor.
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PMID:Characterisation of the rapid release of activin A following acute lipopolysaccharide challenge in the ewe. 1522 32

The biosynthesis of both nitric oxide (NO) and hydrogen sulfide (H2S) is increased in lipopolysaccharide (LPS)-injected mice and rats but their interaction in these models is not known. In this study we examined the effect of the NO donor, nitroflurbiprofen (and the parent molecule flurbiprofen) on NO and H2S metabolism in tissues from LPS-pretreated rats. Administration of LPS (10 mg kg(-1), i.p.; 6 h) resulted in an increase (P<0.05) in plasma TNF-alpha, IL-1beta and nitrate/nitrite (NO(x)) concentrations, liver H2S synthesis (from added cysteine), CSE mRNA, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO) activity (marker for neutrophil infiltration) and nuclear factor-kappa B (NF-kappaB) activation. Nitroflurbiprofen (3-30 mg kg(-1), i.p.) administration resulted in a dose-dependent inhibition of the LPS-mediated increase in plasma TNF-alpha, IL-1beta and NO(x) concentration, liver H2S synthesis (55.00+/-0.95 nmole mg protein(-1), c.f. 62.38+/-0.47 nmole mg protein(-1), n = 5, P<0.05), CSE mRNA, iNOS, MPO activity and NF-kappaB activation. Flurbiprofen (21 mg kg(-1), i.p.) was without effect. These results show for the first time that nitroflurbiprofen downregulates the biosynthesis of proinflammatory H2S and suggest that such an effect may contribute to the augmented anti-inflammatory activity of this compound. These data also highlight the existence of 'crosstalk' between NO and H2S in this model of endotoxic shock.
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PMID:Nitric oxide-releasing flurbiprofen reduces formation of proinflammatory hydrogen sulfide in lipopolysaccharide-treated rat. 1649 Oct 94

While the expression of the C-C chemokine ligand 2 (CCL2) in the central nervous system (CNS) is associated with numerous neuroinflammatory conditions, the critical cellular sources of this chemokine, which is responsible for disease processes-as well as associated pathogenic mechanisms, remain unresolved. As the potential for anti-CCL2 therapeutics in treating neuroinflammatory disease is likely to be contingent upon effective drug delivery to the source(s) and/or target(s) of CCL2 action in the CNS, tools to highlight the course of CCL2 action during neuroinflammation are imperative. In response to this need, we used the Cre/loxP and FLP-FRT recombination system to develop the first two, cell-conditional CCL2 knockout mice-separately targeting CCL2 gene elimination to astrocytes and endothelial cells, both of which have been considered to play crucial though undefined roles in neuroinflammatory disease. Specifically, mice containing a floxed CCL2 allele were intercrossed with GFAP-Cre or Tie2-Cre transgenic mice to generate mice with CCL2-deficient astrocytes (astrocyte KO) or endothelial cells (endothelial KO), respectively. Polymerase chain reaction, reverse transcription polymerase chain reaction/quantitative reverse transcriptase polymerase chain reaction, and enzyme-linked immunosorbent assay of CCL2 gene, RNA, and protein, respectively, from cultured astrocytes and brain microvascular endothelial cells (BMEC) established the efficiency and specificity of the CCL2 gene deletions and a CCL2 null phenotype in these CNS cells. Effective cell-conditional knockout of CCL2 was also confirmed in an in vivo setting, wherein astrocytes and BMEC were retrieved by immune-guided laser capture microdissection from their in situ positions in the brains of mice experiencing acute, lipopolysaccharide-mediated endotoxemia to induce CCL2 gene expression. In vivo analysis further revealed apparent cross-talk between BMEC and astrocytes regarding the regulation of astrocyte CCL2 expression. Use of astrocyte KO and endothelial KO mice should prove critical in elaborating the pathogenic mechanisms of and optimizing the treatments for neuroinflammatory disease.
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PMID:Astrocyte- and endothelial-targeted CCL2 conditional knockout mice: critical tools for studying the pathogenesis of neuroinflammation. 1934 Jun 10

Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate (11)C radionuclide into various 2-arylpropionic acids that have a common methylated structure, particularly among nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, we developed a novel (11)C-radiolabeling methodology based on rapid C-[(11)C]methylation by the reaction of [(11)C]CH(3)I with enolate intermediates generated from the corresponding esters under basic conditions. One-pot hydrolysis of the above [(11)C]methylation products also allows the synthesis of desired (11)C-incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [(11)C]Ibuprofen, [(11)C]Naproxen, [(11)C]Flurbiprofen, [(11)C]Fenoprofen, [(11)C]Ketoprofen, and [(11)C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)-induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [(11)C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general (11)C-labeling of 2-arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression.
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PMID:General method for the (11)C-labeling of 2-arylpropionic acids and their esters: construction of a PET tracer library for a study of biological events involved in COXs expression. 2022 90