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 effects of selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors (valeryl salicylate and SC-58236, respectively) on Escherichia coli O111:B4 lipopolysaccharide (LPS)-induced dual thermoregulatory changes and serum tumor necrosis factor-alpha elevation were investigated in rats. LPS (50 microg/kg, intraperitoneal) produced an initial hypothermia that was then followed by fever. Serum tumor necrosis factor-alpha levels elevated at the initial phase of hypothermia. Valeryl salicylate injections (20, 40, and 80 mg/kg, subcutaneous [s.c.]) completely inhibited hypothermia without any effect on the elevated serum tumor necrosis factor-alpha levels and on the subsequent fever. On the other hand, SC-58236 injections (10, 20, and 40 mg/kg, s.c.) only partially abolished the hypothermia. SC-58236 had no effect on the initiation of fever, however completely inhibited the maintenance of fever. The serum tumor necrosis factor-alpha elevation was not reduced by SC-58236 treatment. The combination of valeryl salicylate and SC-58236 also failed to inhibit the initiation of fever. These findings suggest that cycloxygenase-1 may have a predominant role for the development of LPS-induced hypothermia, but cyclooxygenase-1 does not seem to be involved in the mediation of LPS-induced fever. Meanwhile, cyclooxgenase-2 may be critical for the late phase rather than the initiation of the fever response in rats.
 ...
PMID:Effects of selective cyclooxygenase enzyme inhibitors on lipopolysaccharide-induced dual thermoregulatory changes in rats. 1184 24

It is well known that Down syndrome (DS) is a premature ageing syndrome. Periodontal disease in individuals with DS develops rapidly and extensively in a relatively younger age bracket compared with that in healthy controls. The mechanisms involved in the periodontal inflammatory processes in DS patients are not fully understood. In the present study, the non-inflamed gingival fibroblasts isolated from seven patients with DS (DGF) and seven healthy controls (NDGF) were stimulated with lipopolysaccharide (LPS) derived from Actinobacillus actinomycetemcomitans (A. a.). We measured the level of prostaglandin E2 (PGE2) production by DGF and NDGF by radioimmunoassay, and also measured the mRNA expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) by using the real-time PCR method. We found the higher levels of LPS-stimulated COX-2 mRNA expression and PGE2 production in DGF when compared with those in NDGF. This study may indicate that overexpression of LPS-stimulated COX-2 induced a greater ability of DGF to produce PGE2, and that these phenomena may be responsible for the severer periodontal disease in DS patients.
 ...
PMID:Enhancement of lipopolysaccharide-stimulated cyclooxygenase-2 mRNA expression and prostaglandin E2 production in gingival fibroblasts from individuals with Down syndrome. 1185 29

We examined the in vivo effect of lipopolysaccharide (LPS) on Sp1 (promoter-selective transcription factor 1) DNA binding activity and studied the mechanisms involved in mouse lungs. The Sp1 DNA complex displayed a major band composed of Sp1, Sp2, and Sp3 trimer and a minor band composed of Sp3 homodimer. Compared with control, nuclear proteins from lungs challenged with LPS for 60, 90, 120, 150, 180, and 240 min, respectively, showed a markedly reduced Sp1 binding activity. Down-regulation of Sp1 binding activity was accompanied by a reduced expression of two Sp1-dependent genes (endothelial nitric oxide synthase and cyclooxygenase-1). Immunoprecipitation-Western blot experiments demonstrated that LPS dephosphorylated Sp1 protein at serine and threonine residues but not at the tyrosine residue. Dephosphorylation of Sp1 protein in vitro significantly reduced Sp1 DNA binding activity. Deglycosylation of Sp1 protein also reduced Sp1 binding activity. However, LPS did not cause Sp1 deglycosylation. LPS markedly reduced nuclear Sp1 protein level but had no significant effect on Sp1 mRNA abundance and on Sp1 protein nuclear translocation. Both Sp1 protein dephosphorylation and Sp1 protein degradation are temporally correlated to the reduced Sp1 binding activity. Our results demonstrate that challenge of mice with LPS in vivo down-regulates Sp1 DNA binding activity through promoting Sp1 protein dephosphorylation and degradation.
 ...
PMID:Lipopolysaccharide down-regulates Sp1 binding activity by promoting Sp1 protein dephosphorylation and degradation. 1208 57

Previously, several prenylated flavonoids having a C-8 lavandulyl moiety were found to inhibit cyclooxygenase-1 (COX-1) as well as 5-lipoxygenase (5-LOX), and sophoraflavanone G was the most potent inhibitor against these eicosanoid generating enzymes among 19 prenylated flavonoids tested. In this investigation, effects of sophoraflavanone G on COX-2 induction from RAW 264.7 cells and in vivo inflammatory response were studied. Sophoraflavanone G inhibited prostaglandin E2 (PGE2) production from lipopolysaccharide (LPS)-treated RAW cells by COX-2 down-regulation at 1-50 uM. Other prenylated flavonoids including kuraridin and sanggenon D also down-regulated COX-2 induction at 10-25 uM, while kurarinone and echinoisoflavanone did not. In addition, sophoraflavanone G showed in vivo anti-inflammatory activity against mouse croton oil-induced ear edema and rat carrageenan paw edema via oral (2-250 mg/kg) or topical administration (10-250 microg/ear). Although the potencies of inhibition were far less than that of a reference drug, prednisolone, this compound showed higher anti-inflammatory activity when applied topically, suggesting a potential use for several eicosanoid-related skin inflammation such as atopic dermatitis.
 ...
PMID:Effects of sophoraflavanone G, a prenylated flavonoid from Sophora flavescens, on cyclooxygenase-2 and in vivo inflammatory response. 1213 6

Because the metabolites of arachidonic acid participate in many physiopathological responses, including inflammation and platelet aggregation, cyclooxygenase inhibitors are important in the treatment of associated diseases. A biologically active compound, 5-ethyl-4-methoxy-2-phenylquinoline (KTC-5), selectively and concentration dependently inhibited aggregation of platelets from man and ATP release caused by arachidonic acid (200 microM) and collagen (10 microg mL(-1)) without affecting the aggregation caused by thrombin (0.1 U mL(-1)) and U46619 (2 microM). The IC50 value (drug concentration inhibiting maximum response by 50%) of KTC-5 for aggregation induced by arachidonic acid and collagen was 0.11+/-0.04 microM and 0.20+/-0.03 microM, respectively. This inhibitory effect of KTC-5 was reversible and time dependent. KTC-5 specifically inhibited intracellular calcium mobilization initiated by arachidonic acid or collagen without affecting that caused by thrombin or U46619 in human platelets. Furthermore, KTC-5 inhibited thromboxane B2 and prostaglandin D2 formation provoked by arachidonic acid. The IC50 value of KTC-5 for arachidonic-acid-induced thromboxane B2 formation was 0.07+/-0.02 microM. Based on these observations, the data indicated that KTC-5 potently inhibited human platelet aggregation and ATP release mainly via the inhibition of the cyclooxygenase-1 activity. Moreover, KTC-5 inhibited lipopolysaccharide-induced prostaglandin E2 formation in RAW264.7 cells in the presence of external arachidonic acid with an IC50 value of 0.17+/-0.06 microM. Immunoblot analysis showed that KTC-5 did not affect the cyclooxygenase-2 expression in the presence of lipopolysaccharide on RAW264.7 cells. This result indicated that KTC-5 affects the activity of cyclooxygenase-2. According to these data, we concluded that KTC-5 is a cyclooxygenase inhibitor for both subtypes.
 ...
PMID:Effect of a potent cyclooxygenase inhibitor, 5-ethyl-4-methoxy-2-phenylquinoline (KTC-5), on human platelets. 1216 16

Involvements of kinin and prostaglandin and their interaction in noxious thermal stimuli were investigated in noninflamed and inflamed rats. The nociceptive response was evaluated from the escape latency of foot withdrawal to the thermal stimuli with a beam of light. The escape latency in kininogens-deficient Brown Norway (B/N-) Katholiek rats was significantly longer than that in the normal strain, B/N-Kitasato rats. The latency in B/N-Kitasato rat was prolonged by administration of a bradykinin (BK) B2 receptor antagonist, FR173657 (30 mg/kg, p.o.), whereas it was shortened by pretreatment with a kininase II inhibitor, captopril (10 mg/kg, i.p.). Both agents did not affect the latency in B/N-Katholiek rats. In normal Sprague-Dawley (SD) rat, administration of indomethacin did not change the escape latency against the thermal stimuli. In contrast, administration of indomethacin or a relatively cyclooxygenase-1-selective inhibitor, mofezolac (10 mg/kg, p.o.) significantly reduced numbers of writhing reaction in mice induced by acetic acid solution. Injection of lipopolysaccharide (1 mg/kg, i.v.) resulted in shortening escape latency at 8 h after the injection in B/N-Kitasato rats. This hyperalgesia could be reversed by pretreatment of the rats with indomethacin, a cyclooxygenase-2-selective inhibitor JTE-522 (10 mg/kg, p.o.), or FR173657, but not with mofezolac. The hyperalgesia was not seen in B/N-Katholiek rats. These results indicate that kinin has major participation in peripheral skin thermal nociception under noninflamed condition, although cyclooxygenases may have little participation. Prostaglandins produced by cyclooxygenase-2 could coordinate with BK to elicit hyperalgesia during inflammation induced by lipopolysaccharide.
 ...
PMID:Role of kinin and prostaglandin in cutaneous thermal nociception. 1248 14

Identification and use of effective cancer chemopreventive agents have become an important issue in public health-related research. For identification of potential cancer chemopreventive constituents we have set up a battery of cell- and enzyme-based in vitro marker systems relevant for prevention of carcinogenesis in vivo. These systems include modulation of drug metabolism (inhibition of Cyp1A activity, induction of NAD(P)H:quinone reductase (QR) activity in Hepa1c1c7 murine hepatoma cell culture), determination of radical scavenging (DPPH scavenging) and antioxidant effects (scavenging of superoxide anion-, hydroxyl- and peroxyl-radicals), anti-inflammatory mechanisms (inhibition of lipopolysaccharide (LPS)-mediated nitric oxide (NO) generation by inducible NO synthase (iNOS) in Raw 264.7 murine macrophages, cyclooxygenase-1 (Cox-1) inhibition), and anti-tumor promoting activities (inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity in 308 murine keratinocytes). We have tested a series of known chemopreventive substances belonging to several structural classes as reference compounds for the identification of novel chemopreventive agents or mechanisms. These include organosulfur compounds (phenethylisothiocyanate (PEITC), diallylsulfide, diallyldisulfide), terpenes (limonene, perillyl alcohol, oleanolic acid, 18-beta-glycyrrhetinic acid), short-chain fatty acids (sodium butyrate), indoles (indole-3-carbinol), isoflavonoids (quercetin, silymarin, genistein), catechins ((-)-epigallocatechin gallate (EGCG)), simple phenols (ellagic acid, resveratrol, piceatannol, curcumin), pharmaceutical agents (piroxicam, acetylsalicylic acid, tamoxifen), and vitamins/derivatives (ascorbic acid, Trolox). We confirmed known chemopreventive mechanisms of these compounds. Additionally, we could demonstrate the usefulness of our approach by identification of hitherto unknown mechanisms of selected agents. As an example, we detected anti-inflammatory properties of PEITC, based on NF-kappaB-mediated inhibition of NO production. Further, PEITC inhibited phorbol ester-induced superoxide anion radical production in granulocytes, and ODC induction in the 308 cell line. These mechanisms might contribute to the chemopreventive potential of PEITC.
 ...
PMID:Mechanism-based in vitro screening of potential cancer chemopreventive agents. 1262 14

Prostaglandin E2 (PGE2), which is generated by the enzymatic activity of cyclooxygenase-1 and -2 (COX-1/2), plays a central role in the maturation process of dendritic cells (DC). Since regulation of COX-1/2 expression in human DC is only partially understood, we addressed the expression and activity of COX-1/2 in these cells. Here we show that lipopolysaccharide (lps) induces COX-2 mRNA and protein synthesis as well as the release of PGE2 in human interleukin-4 and granulocyte/macrophage colony-stimulating factor-differentiated monocyte-derived DC cultivated in the presence of 1% human plasma. Moreover, we found that lps induces p38 stress-activated protein kinase (p38) in these cells and inhibitors of p38 blocked lps-induced COX-2 expression and activity. Our data indicate that during lps-induced maturation p38 regulates COX-2 expression and PGE2 synthesis in DC.
 ...
PMID:Prostaglandin E2 synthesis in human monocyte-derived dendritic cells. 1279 14

Blood-derived monocytes are found at sites of inflammation as well as in solid tumors and atherosclerotic arteries. They are an abundant source of inflammatory eicosanoids such as prostaglandin E2 (PGE2) and thromboxane A2, which are formed via arachidonic acid (AA) metabolism by cyclooxygenase-1/2 (COX-1/2). In vitro studies of inflammatory mediator production are conducted invariably in room air, which does not reflect the oxygen tensions found in monocyte-containing lesions, which are frequently hypoxic. In this work we examined the effects of hypoxia at levels reported in these lesions, on monocyte COX-2 expression, the related events that lead to eicosanoid synthesis, and relationships with tumor necrosis factor (TNF)-alpha synthesis. In fresh human monocytes exposed to hypoxia (1% O2), there was an increase in COX-2 protein compared with cells in normoxia, and this was attributable to increased transcription and mRNA stability. However, the synthesis of PGE2 and thromboxane A2 was reduced in hypoxia and did not reflect the increased level of COX-2. Monocytes prelabeled with [3H]AA followed by lipopolysaccharide stimulation in the presence of hypoxia showed a reduced release of AA compared with cells in normoxia. In addition, hypoxia resulted in decreased phosphorylation of the p44/42 mitogen-activated protein kinase and of cytosolic phospholipase A2. Hypoxia also increased TNF-alpha synthesis, which appeared to play a role in COX-2 expression, and the observed increase TNF-alpha synthesis appeared to result from reduced PGE2 synthesis. Overall, the results suggest the existence of an autocrine loop of regulation between monocyte eicosanoid and TNF-alpha production, which is dysregulated in hypoxia and establishes hypoxia as being an important environmental determinant of inflammatory mediator production.
 ...
PMID:Effects of hypoxia on monocyte inflammatory mediator production: Dissociation between changes in cyclooxygenase-2 expression and eicosanoid synthesis. 3059 34

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible protein recently shown to be an important source of inflammatory PGE2. Here we have used mPGES-1 wild type, heterozygote, and null mice to assess the impact of reduction or absence mPGES-1 protein on the production of PGE2 and other prostaglandins in lipopolysaccharide (LPS)-treated macrophages and mice. Thioglycollate-elicited peritoneal macrophages with mPGES-1 deficiency were found to lose their ability to produce PGE2 upon LPS stimulation. Resident mPGES-1(-/-) peritoneal macrophages exhibited severely impaired PGE2-releasing activity but retained some LPS-inducible PGE2 production capacity. Both macrophage types showed a 50% decrease in PGE2 production with removal of one copy of the mPGES-1 gene. In vivo, mPGES-1 deletion abolished the LPS-stimulated production of PGE2 in spleen, kidney, and brain. Surprisingly, lack of mPGES-1 activity resulted in an 80-90% decrease in basal, cyclooxygenase-1 (COX-1)-dependent PGE2 production in stomach and spleen, and a 50% reduction in brain and kidney. Other prostaglandins (thromboxane B2, PGD2, PGF(2alpha), and 6-keto-PGF(1alpha)) were significantly elevated in stomachs of mPGES-1-null mice but not in other tissues. Examination of mRNA for several terminal prostaglandin synthases did not reveal changes in expression levels associated with mPGES-1 deficiency, indicating that gastric prostaglandin changes may be due to shunting of cyclooxygenase products to other terminal synthases. These data demonstrate for the first time a dual role for mPGES-1 in both inflammatory and COX-1-mediated PGE2 production and suggest an interdependence of prostanoid production with tissue-specific alterations of prostaglandin levels in the absence of mPGES-1.
 ...
PMID:Deletion of microsomal prostaglandin E2 (PGE2) synthase-1 reduces inducible and basal PGE2 production and alters the gastric prostanoid profile. 1501 22


<< Previous 1 2 3 4 5 6 7 Next >>