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 inducible nitric oxide synthase (iNOS) expression in vascular smooth muscle cells is an important factor for pathogenesis of septic shock or multiple organ dysfunction syndrome. The mechanisms of iNOS expression in such conditions are partly known. This study tried to clarify the signal transduction of lipopolysaccharide (LPS) single stimulation that induces iNOS mRNA and protein in vascular smooth muscle cells (VSMC). VSMC were primarily cultured from rat aorta. The concentrations of nitrite in culture media were measured by the Griess reaction. Western blottings and immunoreaction for iNOS, nuclear factor kappaB (NFkappaB) p65, and CD14 protein were performed. mRNAs of iNOS and tumor necrosis factor (TNF) alpha were analyzed by RT-PCR. Genistein inhibited LPS induced early phase nitrite production, while pyrrolidine dithiocarbamate (PDTC) inhibited nitrite production at a late phase. PDTC significantly reduced NFkappaB p65 and iNOS protein expression by LPS. TNFalpha mRNA expression by LPS was not detected in VSMC. Membranous CD14 glycoprotein was detected in VSMC and soluble CD14 glycoprotein was not detected in fetal bovine serum added in culture media. These results suggest that CD14 glycoprotein is present on the cell membranes of VSMC, a non-myelomonocyte lineage, acting as an LPS receptor. Activations of tyrosine kinase and NFkappaB p65 are essential for iNOS expression by LPS single stimulation, while TNFalpha is not a concern to iNOS expression in VSMC.
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PMID:CD14 glycoprotein expressed in vascular smooth muscle cells. 1515 52

In the present study a possible role of glycosphingolipids (GSLs) in inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) production after spinal cord injury (SCI) in rats has been established. In primary rat astrocytes lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) treatment increased the intracellular levels of lactosylceramide (LacCer) and induced iNOS gene expression. d-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol.HCI (PDMP), a glucosylceramide synthase and LacCer synthase (galactosyltransferase, GalT-2) inhibitor, inhibited LPS/IFN-gamma induced iNOS expression, which was reversed by exogenously supplied LacCer, but not by other glycosphingolipids. LPS/IFN-gamma caused a rapid increase in the activity of GalT-2 and synthesis of LacCer. Silencing of GalT-2 gene with the use of antisense oligonucleotides resulted in decreased LPS/IFN-gamma-induced iNOS, TNF-alpha, and IL-1beta gene expression. The PDMP-mediated reduction in LacCer production and inhibition of iNOS expression correlated with decreased Ras and ERK1/2 activation along with decreased IkappaB phosphorylation, NF-kappaB DNA binding activity, and NF-kappaB-luciferase reporter activity. LacCer-mediated Ras activation was redox-mediated and was attenuated by antioxidants N-acetyl cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). In vivo administration of PDMP after SCI resulted in improved functional outcome (Basso, Beattie, Bresnahan score); inhibition of iNOS, TNF-alpha, and IL-1beta expression; decreased neuronal apoptosis; and decreased tissue necrosis and demyelination. The in vivo studies supported the conclusions drawn from cell culture studies and provided evidence for the possible role of GalT-2 and LacCer in SCI-induced inflammation and pathology. To our knowledge this is the first report of a role of LacCer in iNOS expression and the advantage of GSL depletion in attenuating post-SCI inflammation to improve the outcome of SCI.
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PMID:A novel role of lactosylceramide in the regulation of lipopolysaccharide/interferon-gamma-mediated inducible nitric oxide synthase gene expression: implications for neuroinflammatory diseases. 1522 42

Two studies were performed to investigate the effects of an acute bout of physical exercise on the nuclear protein kappaB (NF-kappaB) signaling pathway in rat skeletal muscle. In Study 1, a group of rats (n=6) was run on the treadmill at 25 m/min, 5% grade, for 1 h or until exhaustion (Ex), and compared with a second group (n=6) injected with two doses of pyrrolidine dithiocarbamate (PDTC, 100 mg/kg, i.p.) 24 and 1 h prior to the acute exercise bout. Three additional groups of rats (n=6) were injected with either 8 mg/kg (i.p.) of lipopolysaccharide (LPS), 1 mmol/kg (i.p.) t-butylhydroperoxide (tBHP), or saline (C) and killed at resting condition. Ex rats showed higher levels of NF-kappaB binding and P50 protein content in muscle nuclear extracts compared with C rats. Cytosolic IkappaBalpha and IkappaB kinase (IKK) contents were decreased, whereas phospho-IkappaBalpha and phospho-IKK contents were increased, comparing Ex vs. C. The exercise-induced activation of NF-kappaB signaling cascade was partially abolished by PDTC treatment. LPS, but not tBHP, treatment mimicked and exaggerated the effects observed in Ex rats. In Study 2, the time course of exercise-induced NF-kappaB activation was examined. Highest levels of NF-kappaB binding were observed at 2 h postexercise. Decreased cytosolic IkappaBalpha and increased phosphor-IkappaBalpha content were found 0-1 h postexercise whereas P65 reached peak levels at 2-4 h. These data suggest that the NF-kappaB signaling pathway can be activated in a redox-sensitive manner during muscular contraction, presumably due to increased oxidant production. The cascade of intracellular events may be the overture to elevated gene expression of manganese superoxide dismutase reported earlier (Pfluegers Arch. 442, 426-434, 2001).
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PMID:Acute exercise activates nuclear factor (NF)-kappaB signaling pathway in rat skeletal muscle. 1546 58

Reperfusion after cardiopulmonary bypass causes induction of reactive oxygen species (ROS), elevated plasma levels of bacterial lipopolysaccharide (LPS), and production of tumor necrosis factor-alpha (TNF) by the heart. Nuclear factor-kappaB (NF-kappaB) regulates the expression of TNF. Because NF-kappaB is activated by both LPS and ROS, we hypothesized that an inhibitor of NF-kappaB, pyrrolidine dithiocarbamate (PDTC), would block release of TNF from the heart stimulated by these two agents. With Institutional animal care and use committee (IACUC) approval, rat hearts were perfused Langendorf style. LPS was infused and ROS were generated with a hypoxanthine/xanthine oxidase system. PDTC was added to the perfusion buffer. Other hearts were treated with forskolin in order to elevate cyclic AMP. Timed collections of coronary effluent were made for the determination of coronary flow and measurement of TNF. LPS stimulated TNF release to a maximum of 2247 +/- 133 pg/min at 150 minutes. PDTC inhibited LPS-stimulated TNF release. For instance, at 150 minutes, LPS-stimulated TNF release was 449 +/- 49 pg/min with 100 microM PDTC and was 70 +/- 65 pg/mL with 250 microM PDTC (P < 0.05 vs LPS alone). ROS stimulated TNF release was 1494 +/- 130 pg/min at 150 minutes and was not affected by PDTC. Forskolin almost completely blocked TNF release stimulated by LPS or ROS. These data are consistent with the notion that inhibitors of NF-kappaB block cytokine production stimulated by some agents but not others.
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PMID:Regulation of tumor necrosis factor-alpha production in the isolated rat heart stimulated by bacterial lipopolysaccharide or reactive oxygen. 1548 Dec 97

N1-Benzyl-4-methylbenzene-1,2-diamine (JSH-21) and its analogs were chemically synthesized and their anti-inflammatory potentials investigated. JSH-21 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7 in a dose-dependent manner, with an IC50 value of 9.2 microM, where pyrrolidine dithiocarbamate and parthenolide as positive controls exhibited IC50 values of 29.3 and 3.6 microM, respectively. The inhibitory effect of JSH-21 on the NO production was attributable to its down-regulatory action on LPS-inducible NO synthase (iNOS), which was documented by iNOS promoter activity. In the mechanism of the anti-inflammatory action, JSH-21 exhibited inhibitory effects on LPS-induced DNA binding activity and transcriptional activity of nuclear factor-kappa B (NF-kappaB). Structural analogs of JSH-21 also inhibited both the LPS-induced NO production and NF-kappaB transcriptional activity, where diamine substitution at positions 1 and 2 of JSH-21 seems to play an important role in the anti-inflammatory activity.
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PMID:Anti-inflammatory effects of N1-benzyl-4-methylbenzene-1,2-diamine (JSH-21) analogs on nitric oxide production and nuclear factor-kappa B transcriptional activity in lipopolysaccharide-stimulated macrophages RAW 264.7. 1555 64

Total saponin of heat-processed ginseng (TSHG) stimulated the production of nitric oxide (NO) in interferon-gamma (IFN-gamma)-primed macrophages through the increased expression of inducible nitric oxide synthase (iNOS). However, TSHG by itself had a very weak effect on the NO synthesis without IFN-gamma priming. The saponins of white ginseng inhibited the NO production in lipopolysaccharide (LPS)/IFN-gamma activated macrophages rather than the stimulation of NO production found in IFN-gamma primed macrophages. The NO production by TSHG-stimulated macrophages was inhibited by the NOS inhibitor (N(G)-monomethyl-L-arginine (L-NMMA)) and nuclear factor-kappaB inhibitor (pyrrolidine dithiocarbamate (PDTC)). TSHG showed different serum-dependence from LPS on the activation of IFN-gamma primed macrophages. This property of TSHG may explain the intensified anti-tumor properties of heat-processed ginseng through its immunostimulating activity.
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PMID:Induction of nitric oxide synthase by saponins of heat-processed ginseng. 1591 6

Genes regulated by NF-kappaB play an important role on secondary damage and repair after spinal cord injury (SCI). To assess the early effects of the pharmacological inhibition and overactivation of NF-kappaB, pyrrolidine dithiocarbamate (PDTC) or lipopolysaccharide were given to rats before or after SC contusion. The amount of spared SC tissue was higher (P < 0.05) at 24 h postinjury in rats post-treated with PDTC; both PDTC-treated rats showed no significant trend to decrease polymorphonuclear infiltrate. p65 subunit was present in inflammatory cells, neurons, and astrocytes at the injury site. These data support further investigation on functional effects of NF-kappaB inhibition in acute SCI.
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PMID:Early effects of modulating nuclear factor-kappaB activation on traumatic spinal cord injury in rats. 1617 17

Porphyromonas gingivalis is one of the suspected periodontopathic bacteria. The lipopolysaccharide (LPS) of P. gingivalis is a key factor in the development of periodontitis. Inflammatory cytokines play important roles in the gingival tissue destruction that is a characteristic of periodontitis. Macrophages are prominent at chronic inflammatory sites and are considered to contribute to the pathogenesis of periodontitis. Xylitol stands out and is widely believed to possess anticaries properties. However, to date, little is known about the effect of xylitol on periodontitis. The aim of the present study was to determine tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) expression when RAW 264.7 cells were stimulated with P. gingivalis LPS (hereafter, LPS refers to P. gingivalis LPS unless stated otherwise) and the effect of xylitol on the LPS-induced TNF-alpha and IL-1beta expression. The kinetics of TNF-alpha and IL-1beta levels in culture supernatant after LPS treatment showed peak values at 1 h (TNF-alpha) and 2 to 4 h (IL-1beta), respectively. NF-kappaB, a transcription factor, was also activated by LPS treatment. These cytokine expressions and NF-kappaB activation were suppressed by pretreatment with pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB). Pretreatment with xylitol inhibited LPS-induced TNF-alpha and IL-1beta gene expression and protein synthesis. LPS-induced mobilization of NF-kappaB was also inhibited by pretreatment with xylitol in a dose-dependent manner. Xylitol also showed inhibitory effect on the growth of P. gingivalis. Taken together, these findings suggest that xylitol may have good clinical effect not only for caries but also for periodontitis by its inhibitory effect on the LPS-induced inflammatory cytokine expression.
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PMID:Xylitol inhibits inflammatory cytokine expression induced by lipopolysaccharide from Porphyromonas gingivalis. 1627 42

2-Methyl-2-(2-methylpropenyl)-2,3-dihydronaphthoquinone[2,3-b]furan-4,9-dione (NFD-37) is a synthetic furonaphthoquinone compound. In this study, we determined that NFD-37 could inhibit the lipopolysaccharide (LPS)-induced production of inflammatory mediators in macrophages RAW 264.7. This compound inhibited LPS-induced nitric oxide (NO) or prostaglandin (PG) E2 production in dose-dependent manners, with IC50 values of 7.2 microM and 5.3 microM, respectively. As the positive controls, pyrrolidine dithiocarbamate (30 microM) exhibited a 57% inhibition of NO production, and NS-398 (1 microM) manifested a 48% inhibition of PGE2 production. The inhibitory effects of NFD-37 on NO and PGE2 production were determined to occur in conjunction with the suppression of inducible NO synthase or cyclooxygenase-2 expression. NFD-37 also inhibited the production of LPS-inducible tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6, at IC50 values of 4.8-8.9 microM. We also determined the anti-inflammatory efficacy of NFD-37 using carrageenin-induced paw edema in experimental mice.
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PMID:Suppressive effects of furonaphthoquinone NFD-37 on the production of lipopolysaccharide-inducible inflammatory mediators in macrophages RAW 264.7. 1627 75

The diuretic ethacrynic acid (EA) has been shown to inhibit signaling by the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB). Accordingly, we sought to determine whether this compound is capable of inhibiting the release of cytokines [interleukin (IL)-6 and IL-10] and NO from RAW 264.7 murine macrophage-like cells stimulated with lipopolysaccharide (LPS). Additionally, we sought to determine whether EA can inhibit secretion of high-mobility group box 1 (HMGB1), a nuclear protein that is secreted by immunostimulated macrophages and functions in the extracellular milieu as a proinflammatory mediator. In a concentration-dependent manner, EA inhibited secretion of IL-6, IL-10, nitric oxide, and HMGB1. As expected, EA inhibited NF-kappaB DNA binding in LPS-stimulated RAW 264.7 cells. Treating these cells with pyrrolidine dithiocarbamate, SN50 (amino acid sequence AAVALLPAVLLALLAPVQRKRQKLMP) or 5-(thien-3-yl)-3-aminothiophene-2-carboxamide (SC-514) also inhibited LPS-induced NF-kappaB DNA binding, but these compounds failed to inhibit LPS-induced HMGB1 secretion. These findings suggested that inhibition of HMGB1 secretion by EA might occur via a mechanism unrelated to the NF-kappaB signaling pathway. Because EA is an electrophilic compound that is known to be capable of inducing expression of so-called phase 2 proteins, we sought to determine whether two other phase 2 enzyme inducers, oltipraz and DL-sulforaphane, also are capable of inhibiting HMGB1 release from immunostimulated macrophages. Incubating RAW 264.7 cells with either oltipraz or DL-sulforaphane inhibited LPS-induced HMGB1 secretion. Moreover, both EA and DL-sulforaphane inhibited relocalization of nuclear HMGB1 into the cytoplasm of LPS-stimulated RAW 264.7 cells. These data suggest that phase 2 inducers may exert anti-inflammatory effects by inhibiting secretion of the cytokine-like nuclear protein HMGB1.
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PMID:The phase 2 enzyme inducers ethacrynic acid, DL-sulforaphane, and oltipraz inhibit lipopolysaccharide-induced high-mobility group box 1 secretion by RAW 264.7 cells. 1638 25


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