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)

In order to delineate the mechanism involved in the anti-inflammatory activity of rutaecarpine, its effects on the production of prostaglandin (PG) and therein involved enzymes were examined. Rutaecarpine reduced the production of PGE(2) in RAW264.7 cells treated with lipopolysaccharide (LPS) in a dose dependent manner when added to the culture media at the time of stimulation. However, the inhibition of total cellular cyclooxygenase (COX) activity under the same experimental condition was observed only at high concentrations of rutaecarpine. Rutaecarpine did not affected the levels of COX-2 mRNA and protein in macrophages stimulated with LPS. Calcium ionophore A23187 induced-PG production and [(3)H]-arachidonic acid release were significantly decreased by the pretreatment of rutaecarpine for 30 minutes. With the same treatment schedule, however, rutaecarpine failed to alter the activities of cellular COX-1 and COX-2. Collectively, our data suggest that anti-inflammatory effect of rutaecarpine is, at least in part, ascribed to the diminution of PG production through inhibition of arachidonic acid release albeit the nature of its effects on PLA(2) activity remains to be elaborated.
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PMID:Rutaecarpine, a quinazolinocarboline alkaloid, inhibits prostaglandin production in RAW264.7 macrophages. 1150 68

Tissue-type plasminogen activator (t-PA) participates in the control of synaptic plasticity and memory formation in the central nervous system (CNS). Transgenic mice harbouring either 9.5, 3.0 or 1.4 kb of the human t-PA promoter fused to the LacZ reporter gene were used to assess t-PA promoter-directed expression in vivo. The 9.5 kb t-PA promoter directed expression to the brain, most notably to the dentate gyrus, superior colliculus, hippocampus, thalamus and piriform cortex. Staining was also observed in the retrosplenial and somatosensory cortex. The 3.0 kb t-PA promoter directed generalized and poorly defined expression to the cortex and hippocampus, while the 1.4 kb t-PA promoter directed expression selectively to the medial habenula. Intravenous administration of lipopolysaccharide into mice harbouring the 9.5 kb t-PA promoter resulted in an increase in reporter gene activity in the lateral orbital cortex and thalamus. Results of in vitro transfection experiments of NT2 cells with a series of t-PA promoter deletion constructs confirmed the presence of regulatory elements throughout the 9.5 kb promoter region. Finally, we describe a cis-acting element related to the NFAT recognition site that provides a protein-binding site and which may play a role in the selective expression of the 1.4 t-PA promoter in the medial habenula. These results indicate that elements between -3.0 and -9.5 kb of the t-PA promoter confer constitutive and inducible expression to specific regions of the CNS.
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PMID:Control elements between -9.5 and -3.0 kb in the human tissue-type plasminogen activator gene promoter direct spatial and inducible expression to the murine brain. 1157 84

Vitamin A and its active metabolite retinoic acid (RA) modulate host-pathogen interactions by interfering with the host immune and inflammatory response including prostaglandin (PG) biosynthesis. The effects of RA on phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) isoforms in vitro are controversial, and few in vivo studies exist. We investigated the in vivo effects of RA on PG biosynthesis in the presence or absence of lipopolysaccharide (LPS) in rats. RA alone [10 mg/(kg. d) for 5 d] increased plasma and liver PG concentrations by increasing COX-1 protein expression (twofold that of control rats). RA acted synergistically with LPS to increase plasma (400-fold) and liver (15-fold) concentrations of prostaglandin E(2) (PGE(2)) and significantly, but to a lesser extent, other PG compared with RA rats, in the absence of major differences in PLA(2) expression or activity or COX-1 and COX-2 mRNA or protein expression. The RA + LPS-mediated increase in PGE(2) was significantly attenuated (97%) by aminoguanidine (AG), a relatively specific inhibitor of the inducible nitric oxide synthase (NOS2), consistent with the previously reported synergistic effect of RA and LPS on NOS2 expression and activity. In addition, RA and LPS induced the expression of the microsomal isoform of PGE synthase (mPGES). In conclusion, in vivo, RA and LPS increased PG and especially PGE(2) concentrations. The PGE(2) increase was associated with NOS2-mediated activation of COX and induction of mPGES. These results contribute to the characterization of the effects of vitamin A on the host inflammatory response.
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PMID:Retinoic acid and lipopolysaccharide act synergistically to increase prostanoid concentrations in rats in vivo. 1158 82

OBJECTIVE: To elucidate the effects of lipopolysaccharide (LPS), phospholipase A(2) (PLA(2)) and oxygen free radical (OFR) on proton transmembrane translocation and H(+)-ATPase. METHODS: The normal rats were sacrificed for preparetion liver mitochondria and submitochondrial particles for experiments in vitro. Submitochondrial particles were incubated with LPS (100 &mgr;g/mL), PLA(2) (10 u/mL) and FeSO(4)/Vit C (30/90 &mgr;mol/L) at 30 degrees C for 30 min. The proton translocation of submitochondrial particles (SMPs) were assayed with the fluorescent probe ACMA (9-amino-6-chloro-2 methoxya cridine). The mitochondria were incubated with different concentration of LPS, PLA(2) and FeSO(4)/Vit C. The H(+)-ATPase, PLA(2) and malondialdehyde (MDA) were assayed. RESULTS: The fluorescent quenching of ACMA and H(+)-ATPase activity in high dose was significantly decreased after treatment with LPS, PLA(2), FeSO(4)/Vit C (P<0.05). The mitochondrial PLA(2) activity and MDA content were significantly increased after treatment with LPS (P<0.01). CONCLUSIONS: FeSO(4)/Vit C in low dose causes increases H(+)-ATPase activity. LPS, PLA(2), FeSO(4)/Vit C might be the important factors changing H(+)-ATPase and proton translocation across the membrane.
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PMID:Effects of LPS, PLA(2) and OFR on proton translocation across inner mitochondrial membrane and H(+)-ATPase in the liver. 1190 57

1. In acute respiratory distress syndrome (ARDS) induced by endotoxins, a high production of inflammatory mediators by microvascular lung endothelial cells (LMVEC) can be observed. Activation of cells by endotoxins may result in elevated secretion of phospholipase A(2) (sPLA(2)) which is thought to contribute to tissue damage. The present study was undertaken to investigate the role of sPLA(2) in chemokine production in human lung microvascular endothelial cells (LMVEC) stimulated with the endotoxins lipopolysaccharide (LPS) and lipoteichoic acid (LTA). In particular, we investigated the effects of sPLA(2) inhibitors, specifically, the extracellular PLA(2) inhibitors (ExPLIs), composed of N-derivatized phosphatidyl-ethanolamine linked to polymeric carriers, and LY311727, a specific inhibitor of non-pancreatic sPLA(2). 2. ExPLIs markedly inhibited LPS and LTA induced production and mRNA expression of the neutrophile attracting chemokines IL-8, Gro-alpha and ENA-78, as well as of the adhesion molecules ICAM-1 and E-selectin. Concomitantly, ExPLIs inhibited the LPS-induced activation of NF-kappaB by LPS but not its activation by TNF-alpha or IL-1. 3. Endotoxin mediated chemokine production in LMVEC seems not to involve PLA(2) activity, since LPS stimulation was not associated with activation of intracellular or secreted PLA(2). It therefore seems that the inhibitory effect of the ExPLIs was not due to their PLA(2) inhibiting capacity. This was supported by the finding that the LPS-induced chemokine production was not affected by the selective sPLA(2) inhibitor LY311727. 4. It is proposed that the ExPLIs may be considered a prototype of potent suppressors of specific endotoxin-induced inflammatory responses, with potential implications for the therapy of subsequent severe inflammation.
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PMID:Inhibition of LPS-induced chemokine production in human lung endothelial cells by lipid conjugates anchored to the membrane. 1193 6

Expression of tissue factor (TF) by activated monocytes may initiate thrombotic episodes associated with diseases, such as thrombosis and atherosclerosis. In this study, steps in the regulatory pathways of lipopolysaccharide (LPS)-induced monocyte TF activity and released TNF-alpha in human whole blood were probed for using an array of inhibitors, comprising specific inhibitors of cytosolic phospholipase A(2) (PLA(2)) (AACOCF(3)), secretory PLA(2) (SB-203347), protein kinase (PK) (staurosporine), PKC (GF-109203; BIM), and serine protease (Pefabloc SC), antagonists of thromboxane prostanoid (TP) receptor (R) (SQ-29548), platelet activating factor (PAF) R (BN-52021), leukotriene B(4) R (SC-41930), serotonin R (cyproheptadine), fibronectin/fibrinogen R (RGDS), and finally, creatine phosphate/creatine phosphokinase (CP/CPK) which removes ADP. Whereas when added alone neither of these agents significantly inhibited LPS-induced TF or TNF-alpha, when presented as a reference cocktail comprising all the agents, TF activity and TNF-alpha were reduced by 77% and 49%, respectively. By subsequently testing a series of incomplete inhibitory cocktails equal to the reference except for deleted single agents or combinations of two or three active agents, the inhibitory effect of the reference cocktail could be shown to depend on the presence of the protease inhibitor and the thromboxane A(2) and PAF antagonists.
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PMID:The central role of thromboxane and platelet activating factor receptors in ex vivo regulation of endotoxin-induced monocyte tissue factor activity in human whole blood. 1223 Sep 18

Oxidative modification of low-density lipoproteins (LDLs) plays a key role in the development of atherosclerosis and the onset of coronary artery disease. LDL oxidation alters the antithrombotic balance of human endothelial cells inducing surface tissue factor (TF) pathway activity, which results in enhanced fibrin deposition. Fibrinolysis, which is strictly regulated by plasminogen activator inhibitor-1 (PAL-1) and tissue-type plasminogen activator (tPA). Is also dysregulated by LDL oxidation with a net increase in the inhibitory rate. Oxidized LDLs (oxLDLs) also affect many aspects of macrophage function linked to the inflammatory response of these cells, In particular, oxLDLs downregulate inducible cyclooxigenase (Cox-2) in human monocyte-derived macrophages exposed to bacterial lipopolysaccharide. This observation may support the hypothesis that, within atheromata, the transformation macrophages into foam cells results in the attenuation of the inflammatory response, thus contributing to the progression of athrogenesis. Among lipid constituents of oxLDLs, Ox-PAPC, a mixture of oxidized arachidonic acid-containing phospholipids, prevents Cox-2 expression, suggesting that it could be considered responsible for the biological activity of oxLDLs.
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PMID:Oxidized LDLs influence thrombotic response and cyclooxygenase 2. 1232 37

The febrile response to lipopolysaccharide (LPS) consists of three phases (phases I-III), all requiring de novo synthesis of prostaglandin (PG) E(2). The major mechanism for activation of PGE(2)-synthesizing enzymes is transcriptional upregulation. The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS (50 microg/kg) was studied. Using real-time RT-PCR, the expression of seven PGE(2)-synthesizing enzymes in the LPS-processing organs (liver and lungs) and the brain "febrigenic center" (hypothalamus) was quantified. Phase I involved transcriptional upregulation of the functionally coupled cyclooxygenase (COX)-2 and microsomal (m) PGE synthase (PGES) in the liver and lungs. Phase II entailed robust upregulation of all enzymes of the major inflammatory pathway, i.e., secretory (s) phospholipase (PL) A(2)-IIA --> COX-2 --> mPGES, in both the periphery and brain. Phase III was accompanied by the induction of cytosolic (c) PLA(2)-alpha in the hypothalamus, further upregulation of sPLA(2)-IIA and mPGES in the hypothalamus and liver, and a decrease in the expression of COX-1 and COX-2 in all tissues studied. Neither sPLA(2)-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPLA(2)-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy.
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PMID:Prostaglandin E(2)-synthesizing enzymes in fever: differential transcriptional regulation. 1237 4

Phospholipase A(2) (PLA(2)) appears to play a fundamental role in cell injury in the central nervous system. We have investigated PLA(2) expression in the astrocytoma cell line 1231N1, and found that GIVA, GIVB, GIVC and GVI PLA(2) messages are expressed. PLA(2) activity is increased by inflammatory/injury stimuli such as interleukin-1beta and lipopolysaccharide in these cells but with very different time courses. The arachidonic acid liberated is converted to prostaglandin E(2), possibly by cyclooxygenase-2, which is induced by inflammatory stimuli. This cell system emerges as a model to study injury/inflammation-related activation of the new PLA(2) forms GIVB and GIVC.
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PMID:Expression and function of phospholipase A(2) in brain. 1240 Nov 95

Arachidonic acid (AA) mainly released from the cell membrane by phospholipase A(2) (PLA(2)) is converted to eicosanoids by the action of cyclooxygenase (COX) and lipoxygenase (LO). In order to find the specific inhibitors of AA metabolism especially PLA(2) and COX-2, 300 plant extracts were evaluated for their inhibitory activity on PGD(2) production from cytokine-induced mouse bone marrow-derived mast cells in vitro. From this screening procedure, the methanol extract of Salvia miltiorrhiza was found to inhibit PGD(2) production and the ethyl acetate subfraction gave the strongest inhibition of five subfractions tested. From this ethyl acetate subfraction, an activity-guided isolation finally gave tanshinone I as an active principle. This investigation deals with the effects of tanshinone I on AA metabolism from lipopolysaccharide (LPS)-induced RAW 264.7 cells and in vivo antiinflammatory activity. Tanshinone I inhibited PGE(2) formation from LPS-induced RAW macrophages (IC(50) = 38 microM). However, this compound did not affect COX-2 activity or COX-2 expression. Tanshinone I was found to be an inhibitor of type IIA human recombinant sPLA(2)(IC(50) = 11 microM) and rabbit recombinant cPLA(2) (IC(50) = 82 microM). In addition, tanshinone I showed in vivo antiinflammatory activity in rat carrageenan-induced paw oedema and adjuvant-induced arthritis.
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PMID:Effects of tanshinone I isolated from Salvia miltiorrhiza bunge on arachidonic acid metabolism and in vivo inflammatory responses. 1241 May 40


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