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)

The aim of the study was to elucidate the effect of lipopolysaccharide (LPS) administration in vivo (Escherichia coli endotoxin, 1 mg/kg body weight) on the expression and cellular activity of glucose-6-phosphate dehydrogenase (G6PDH, EC 1.1.1.49), the rate-limiting enzyme of the hexose monophosphate shunt in hepatic cells. Under basal conditions, Kupffer cells displayed higher activity of G6PDH than endothelial or parenchymal cells. In vivo LPS treatments for 7 and 22 h resulted in 40 and 60% increases, respectively, in the cellular activity of G6PDH in Kupffer cells. G6PDH activity was increased by 140 and 90% after 7- and 22-h LPS treatments in endothelial cells. G6PDH activity in parenchymal cells prepared from animals after 22 h of LPS treatment was decreased by approximately 60% compared with that in cells from saline-injected animals. Total cellular RNA or protein extracts from these cells were analyzed by Northern or Western blots. Under basal conditions, G6PDH mRNA levels relative to total cellular RNA were higher in Kupffer than in endothelial cells and were not detectable in parenchyma cells. LPS injection caused a time-dependent increase in G6PDH mRNA expression in Kupffer and endothelial cells. Western blot analysis of Kupffer cell extracts also showed that LPS treatments caused markedly elevated expression of protein in these cells. These results show that endotoxemia results in marked induction of G6PDH in Kupffer and hepatic endothelial cells but has no such effect in the parenchymal cells. These findings also suggest that the elevated cellular expression of G6PDH is an important regulatory event in the adaptive responses of hepatic nonparenchymal cells to infections. The elevated expression of G6PDH may be important for support of the upregulated NADPH-dependent pathways, such as superoxide anion and nitric oxide production, macromolecular synthesis, or the maintenance of cellular glutathione status.
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PMID:Endotoxin stimulates the expression of glucose-6-phosphate dehydrogenase in Kupffer and hepatic endothelial cells. 793 Sep 40

The effects of methylprednisolone succinate (MP) on plasma lipid peroxidation, plasma SOD activity and superoxide production in polymorphonuclear leukocytes (PMNs) induced by lipopolysaccharide (LPS) were examined in rats in vivo and in vitro. In rats subjected to LPS treatment, plasma phosphatidylcholine hydroperoxide (PCOOH) levels significantly increased, and the plasma Cu,Zn-SOD activity decreased by about 75%. When rats were given 30 mg/kg of MP intravenously, MP suppressed the elevation of plasma PCOOH levels and partially inhibited the decrease in plasma Cu,Zn-SOD activity. MP also suppressed PMA-induced superoxide production in PMNs primed by LPS. In in vitro experiments, low concentrations of MP had no effect on NADPH-dependent lipid peroxidation, but 4 mM MP produced 50% inhibition. MP had little effect on PMA-induced superoxide production in PMNs primed by LPS. Moreover, MP had no radical-trapping effect on superoxide, hydroxyl radical and stable DPPH radical. These results suggest that the suppressive effect of plasma lipid peroxidation by MP is not due to radical-trapping effects or preventive anti-oxidation, but may involve the suppression of the lipid chain reaction in liver membrane resulting from PMA-induced superoxide anions generated by PMNs.
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PMID:Effect of methylprednisolone on plasma lipid peroxidation induced by lipopolysaccharide. 802 18

To better understand the extrarenal production of active vitamin D metabolites by cells of the monocyte/macrophage lineage, we investigated the 25-hydroxyvitamin D (25OHD)-1-hydroxylation reaction in the v-myc-transformed chick myelomonocytic cell line HD-11; the 1-hydroxylation reaction in this cell line has a high affinity for 25-hydroxylated vitamin D substrates, is localized to mitochondria, and is associated with cytochrome P450 activity. In this study we demonstrated that the HD-11 cell 1-hydroxylation reaction in vitro is not affected by the majority of extracellular regulatory factors that modulate expression of the renal 25OHD-1-hydroxylase in vivo. A 50% increase in extracellular calcium and phosphate concentrations, physiological inhibitory events for renal 1,25-dihydroxyvitamin D [1,25-(OH)2D] synthesis, did not decrease basal expression of the HD-11 cell 1-hydroxylation reaction, nor did a 50% decrease in extracellular calcium and phosphate concentrations, stimulatory signals for the 1-hydroxylase in vivo, increase 1,25-(OH)2D3 synthesis in vitro. Receptor-saturating concentrations of PTH and PTH-related peptide were similarly without effect. In contrast, the HD-11 1-hydroxylation reaction was significantly stimulated in a dose-dependent fashion by the macrophage stimulatory agents lipopolysaccharide [P < 0.001 at a maximum effective concentration (EC100) of 25 micrograms/ml] and interferon-gamma (P < 0.001 at EC100 of 1000 IU/ml) and by insulin-like growth factor-I (P < 0.01 at EC100 of 15 nM) with the rank order of stimulation being interferon-gamma > lipopolysaccharide > insulin-like growth factor-I. Dexamethasone (> or = 10 nM) and the cytochrome P450 inhibitors (EC100, 20 microM), ketoconazole, clotrimazole, and menadione, all significantly inhibited the HD-11 cell 1-hydroxylation reaction. The naphthoquinone menadione, which blocks electron transfer to the P450-associated enzyme, was the most effective inhibitor of the reaction in both intact cells (3 +/- 1% of basal expression; P < or = 0.002) and after reconstitution of HD-11 cell mitochondrial extracts with a ferredoxin, reductase, O2, and NADPH (5 +/- 1% of basal; P < or = 0.02). We have also shown that 1,25-(OH)2D3 produced from substrate 25OHD3 appears to exert an endogenous (intracrine) inhibitory effect on HD-11 cell growth; incubation of HD-11 cells with a concentration of ketoconazole (10 microM) known to reduce 1,25-(OH)2D3 production by roughly 50% restored 50% of the growth deficit induced by 1,25-(OH)2D3 (EC100, 100 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulated production and intracrine action of 1,25-dihydroxyvitamin D3 in the chick myelomonocytic cell line HD-11. 819 84

Interleukin 8 (IL-8) is a recently described cytokine that functions as a potent neutrophil chemoattractant and activator. We sought to examine the link between the generation of reactive oxygen intermediates (ROI) and the regulation of IL-8 gene expression to specifically test the hypothesis that ROI would induce production of IL-8 mRNA and protein. In lipopolysaccharide-stimulated human whole blood, the OH radical scavenger dimethyl sulfoxide (Me2SO) dramatically inhibited (approximately 90%) IL-8 production, but had minimal effects on the production of tumor necrosis factor, interleukin 1 beta (IL-1), and IL-6. To determine whether NADPH-oxidase-generated free radicals were critical in the regulation of IL-8, studies were performed using blood from patients with chronic granulomatous disease. In both normal individuals and patients with chronic granulomatous disease, production of IL-8 could be initiated with lipopolysaccharide, phytohemagglutinin, or aggregated immune complexes, and this production could be inhibited by Me2SO (1% v/v). To examine if oxidant stress represents a ubiquitous mechanism for the induction of IL-8, experiments were performed in cultured cell lines. In the human hepatoma cell line Hep-G2, Me2SO dose-dependently inhibited tumor necrosis factor-stimulated IL-8 production, with a 74 +/- 1% reduction observed at a Me2SO concentration of 1%. Direct exposure to ROI demonstrated that H2O2 stimulated IL-8 production in a dose-dependent manner in Hep-G2 cells, A549 pulmonary type II epithelial cells, and human skin fibroblasts; this induction could be prevented by addition of catalase. The production of IL-8 appeared to be specific to an oxidant stress since exposure of the cells to heat shock or chemical stress did not induce expression of IL-8. These studies demonstrate that oxidant stress is an important regulator of IL-8 gene expression and support the hypothesis that low levels of ROI may serve to initiate IL-8 production which then serves to recruit neutrophils to sites of inflammation.
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PMID:Regulation of interleukin 8 gene expression by oxidant stress. 824 94

Mononuclear phagocytes generate microbicidal oxygen metabolites spontaneously and after phagocytic stimulation by a NADPH-dependent enzymatic reaction called the oxidative burst. The spontaneous release of reactive oxygen radicals and intermediates (ROI) increases five- to eightfold after treatment of monocytes with the lymphokine interferon-gamma (IFN-gamma). The effect of the IFN-gamma-activated release of ROI by human monocytes on the infectivity of free human immunodeficiency virus (HIV) in the supernatant was investigated with the following results. First, IFN-gamma-activated, but neither control monocytes nor lipopolysaccharide-stimulated monocytes effectively decreased the infectivity of cell-free HIV-1 in culture medium supernatant. Second, the mechanism of inactivation was dependent on the enhanced spontaneous release of ROI by IFN-gamma-activated mononuclear phagocytes, since either the enzyme catalase or the free radical scavenger butylated hydroxyanisole (BHA) could block this activity. Third, soluble and solid-phase HIV-1 outer envelope glycoprotein (gp120) failed to trigger the oxidative burst activity after specific gp120-monocytic CD4 receptor interaction. These results indicate an anti-viral effect of IFN-gamma-activated monocytes/macrophages on HIV-1 which may have important implications for our understanding of spread of the virus in the body and the development of full-blown AIDS after a long period of latency.
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PMID:Interferon-gamma-activated monocytes impair infectivity of HIV particles by an oxygen metabolite-dependent reaction. 847 9

To investigate a possible role by cytochrome P450 (P450) in ethyl carbamate-induced immunosuppression, an attempt to assess the ability of ethyl carbamate, its metabolites produced by P450 (i.e., ethyl N-hydroxycarbamate and vinyl carbamate), and methyl carbamate to suppress the polyclonal antibody response induced by bacterial lipopolysaccharide was made in splenocyte cultures isolated from female Balb/C mice. The results showed that vinyl carbamate and ethyl N-hydroxycarbamate were more immunosuppressive compared to ethyl carbamate. A structurally related analogue, methyl carbamate, did not suppress the antibody response. These results indicate that metabolism of ethyl carbamate by P450 may produce more immunosuppressive metabolites as in ethyl carbamate-induced carcinogenicity. A pre-incubation study with phenobarbital-induced liver microsomes in the presence of NADPH-generating system showed that the antibody response was suppressed by ethyl carbamate when splenocytes were pre-incubated with ethyl carbamate and microsomes simultaneously. Moreover, the suppression was completely recovered by the addition of a P450 inhibitor, aminoacetonitrile, in the pre-incubation. Taken together, the present results indicate that metabolism of ethyl carbamate by P450 enzyme(s) may be an important pathway to cause immunosuppression.
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PMID:Effects of ethyl carbamate and its metabolites on the antibody response in splenocyte cultures from female Balb/C mice. 868 41

Nitric oxide (NO) may be an important mediator of tumour angiogenesis and metastasis formation. Tumour cell derived NO may be important in the regulation of angiogenesis and vasodilatation of the blood vessels surrounding a tumour. The aims of the present study were, firstly, to determine whether malignant melanoma cells and normal melanocytes had nitric oxide synthase (NOS) activity (measured by the conversion of L-arginine to L-citrulline) and, secondly, to determine whether there was a difference in NOS activity between malignant and normal cell types. This paper assays NOS activity directly in lysates from normal human melanocyte and malignant melanoma cell lines. The enzyme activity was not inducible with bacterial lipopolysaccharide and could be heat denatured. The activity of NOS was demonstrated to be both NADPH- and calcium-dependent and it was inhibitable in a dose-dependent manner by the NOS inhibitor Nw-nitro-L-arginine methyl ester. We conclude that melanoma and melanocyte cells express a constitutive form of NOS. Finally, nitric oxide synthase activity in melanoma cell lines was found to be significantly greater than in normal melanocytes. These findings suggest that NO synthesis is elevated in malignant melanoma. An elevated NO concentration in melanoma is expected to promote metastases by maintaining a vasodilator tone in the blood vessels in and around the melanoma.
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PMID:Nitric oxide synthase activity is up-regulated in melanoma cell lines: a potential mechanism for metastases formation. 879 Dec 69

Tissue macrophages from patients with granuloma-forming disease, most notably sarcoidosis, express a 25-hydroxyvitamin D-1-hydroxylase which can produce in vivo sufficient quantities of the active vitamin D metabolite 1,25-dihydroxyvitamin D to cause hypercalcemia. In contrast to the NADPH-dependent cytochrome P450-linked mixed function oxidase which is normally only expressed in significant quantity in proximal renal tubular cells and regulated in an endocrine fashion, the mitochondrial-based 1-hydroxylase in the macrophage [1] is stimulated in a paracrine mode by cytokines (i.e., IFN-gamma) and lipopolysaccharide (LPS) [2] requires an extracellular source of L-arginine for full basal expression and [3] can be regulated in an intracrine fashion by nitric oxide (NO). In these experiments we employed inducible nitric oxide synthase (iNOS)-free, intact mitochondria preparations from the avain macrophage-like cell line HD-11, which constitutively express the 1-hydroxylase, and nonenzymatically-generated NO to investigate NO-mediated autoregulation of the macrophage 1-hydroxylase. Sodium nitroprusside (SNP)- or S-nitroso-N-acetyl-penicillamine (SNAP)-induced up-regulation of the 1-hydroxylase required the presence of either NADPH or NADP in the reaction mixture, while NO-induced inhibition of mitochondrial 1,25-(OH)2D3 synthesis was NO-dependent and NADP/NADPH-independent. These data suggest NO has bifunctional effects on the macrophage 1-hydroxylase. At relatively high concentrations NO competes with O2 for enzyme binding, inhibiting hormone synthesis. At lower production levels, NO serves as a source of reducing equivalents for the enzyme by providing for the reduction of NADP to NADPH.
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PMID:Autoregulation of 1,25-dihydroxyvitamin D synthesis in macrophage mitochondria by nitric oxide. 882 16

Nitric oxide (NO) has been shown to play a significant role in inflammation. To clarify the role of NO in acute pancreatitis, we investigated the serum concentrations of NO chi (NO2- plus NO3-) and tumor necrosis factor-alpha (TNF-alpha) and the grade of pancreatitis in cerulein-induced pancreatitis in mice pretreated with lipopolysaccharide (LPS) or not. LPS pretreatment aggravated the cerulein pancreatitis in association with a transient increase in serum TNF-alpha, which was followed by a gradual elevation of serum NO chi. This elevation of serum NO chi concentration was inhibited by the NO synthase inhibitor NG-nitro-L-arginine (L-NNA). In addition, the activity of NADPH-diaphorase (NADPH-d), a marker for NO synthase, appeared in the peritoneal macrophages of LPS-pretreated mice after the induction of pancreatitis. No elevation of serum NO chi or appearance of NADPH-d activity in peritoneal cells was found in mice without LPS pretreatment. Administration of L-NNA enhanced the elevation of pancreatitis-induced serum amylase in mice untreated with LPS, while L-NNA inhibited the elevation in LPS-pretreated mice. The effects of L-NNA were reversed by the administration of L-arginine but were not affected by D-arginine. These results suggested that (a) inflammatory cells may not be fully activated to produce excessive NO in uncomplicated edematous pancreatitis, and (b) edematous pancreatitis may be aggravated by excessively produced NO if bacterial infection is complicated and inflammatory cells are activated to express inducible NO synthase.
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PMID:The role of nitric oxide in mouse cerulein-induced pancreatitis with and without lipopolysaccharide pretreatment. 892 22

The O-side-chain polysaccharide in the lipopolysaccharide of Klebsiella pneumoniae O1 is based on a backbone structure of repeat units of [-->3)-beta-D-Galf-(1-->3)-alpha-D-Galp-(1-->]; this structure is termed D-galactan I. The rfb (O-antigen biosynthesis) gene cluster directs the synthesis of D-galactan I and consists of six genes termed rfbA-FKPO1. In this paper we show that rfbDKPO1 encodes a UDP-galactopyranose mutase (NAD(P)H-requiring) (EC 5.4.99. 9), which forms uridine 5'-(trihydrogen diphosphate) P'-alpha-D-galactofuranosyl ester (UDP-Galf), the biosynthetic precursor of galactofuranosyl residues. The deduced amino acid sequence of rfbDKPO1 shows 85% and 37.5% identity to the rfbDKPO8 gene of K. pneumoniae serotype O8 and the glf gene of Escherichia coli, respectively. The molecular mass of the purified RfbDKPO1 enzyme is 45 kDa as determined by SDS-polyacrylamide gel electrophoresis, while gel filtration revealed a molecular mass of 92 kDa, suggesting a dimeric structure for the native protein. The rfbDKPO1 gene product interconverts uridine 5'-(trihydrogen diphosphate) P'-alpha-D-galactopyranosyl ester (UDP-Galp) and UDP-Galf. Unlike Glf, RfbDKPO1 showed a requirement for NADH or NADPH, which could not be replaced by NAD or NADP. RfbDKPO1 was used to synthesize milligram quantities of UDP-Galf, allowing this compound to be purified and fully characterized in an intact form for the first time. The structure of UDP-Galf was proven by NMR spectroscopy.
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PMID:UDP-galactofuranose precursor required for formation of the lipopolysaccharide O antigen of Klebsiella pneumoniae serotype O1 is synthesized by the product of the rfbDKPO1 gene. 902 Jan 23


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