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)

We investigated the mechanism of nitric oxide (NO) action on hepatic methionine adenosyltransferase (MAT) activity using S-nitrosoglutathione (GSNO) as NO donor. Hepatic MAT plays an essential role in the metabolism of methionine, converting this amino acid into S-adenosylmethionine. Hepatic MAT exists in two oligomeric states: as a tetramer (MAT I) and as a dimer (MAT III) of the same subunit. This subunit contains 10 cysteine residues. In MAT I, S-nitrosylation of 1 thiol residue per subunit was associated with a marked inactivation of the enzyme (about 70%) that was reversed by glutathione (GSH). In MAT III, S-nitrosylation of 3 thiol residues per subunit led to a similar inactivation of the enzyme, which was also reversed by GSH. Incubation of isolated rat hepatocytes with S-nitrosoglutathione monoethyl ester (EGSNO), a NO donor permeable through the cellular membrane, induced a dose-dependent inactivation of MAT that was reversed by removing the NO donor from the cell suspension. MAT, purified from isolated rat hepatocytes, contained S-nitrosothiol groups and the addition of increasing concentrations of EGSNO to the hepatocyte suspension led to a progressive S-nitrosylation of the enzyme. Removal of the NO donor from the incubation media resulted in loss of most NO groups associated to the enzyme. Finally, induction in rats of the production of NO, by the administration of bacterial lipopolysaccharide (LPS), induced a fivefold increase in the S-nitrosylation of hepatic MAT, which led to a marked inactivation of the enzyme. Thus, the activity of liver MAT appears to be regulated in vivo by S-nitrosylation.
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PMID:Nitric oxide inactivates rat hepatic methionine adenosyltransferase In vivo by S-nitrosylation. 975 42

We previously showed that heat-killed Borrelia burgdorferi spirochetes and lipidated outer surface protein A (L-OspA) stimulated the in vitro production of interleukin-10 (IL-10) in peripheral blood mononuclear cells (PBMC) from uninfected humans and rhesus monkeys (G. Giambartolomei et al., Infect. Immun. 66:2691-2697, 1998). Here we demonstrate that uninfected human peripheral blood monocytes, but not B or T cells, are the cells that transcribe the IL-10 cytokine gene in response to heat-killed B. burgdorferi. B. burgdorferi similarly induced an upregulation of the IL-1beta and IL-6 cytokine genes in monocytes and the production of IL-10 and IL-6 in culture supernatants of the human monocytic cell line THP-1. Purified L-OspA (but not unlipidated OspA [U-OspA] or U-OspC) also stimulated the production of both cytokines in THP-1 cells in a dose-dependent fashion, suggesting that acylation of the OspA protein molecule is required for the production of both anti- and pro-inflammatory cytokines in naive monocytes. A lipohexapeptide that contained the tripalmitoyl-modified cysteine motif (Pam3Cys-Hex) of B. burgdorferi lipoproteins but with an arbitrary peptide sequence had the same effect. Monoclonal antibodies (MAbs) MY4 and 60bca, both of which bind to CD14 and are known to block lipopolysaccharide (LPS)-mediated cytokine production, were able to block L-OspA-mediated IL-10 and IL-6 cytokine production. In contrast, MAb 26ic, which also binds to CD14 but does not block LPS function, failed to inhibit L-OspA-mediated cytokine production. These data suggest that activation of monocytes and production of both anti- and pro-inflammatory cytokines induced by lipoproteins proceeds via the CD14 receptor. LPS binding protein was not required for OspA-induced cytokine production. Our results demonstrate that pro- and anti-inflammatory cytokines induced by B. burgdorferi lipoproteins in PBMC are produced by monocytes and that lipoprotein and LPS signaling pathways share at least the initial signaling event that involves the CD14 receptor.
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PMID:Induction of pro- and anti-inflammatory cytokines by Borrelia burgdorferi lipoproteins in monocytes is mediated by CD14. 986 8

Bactenecin, a 12-amino acid cationic antimicrobial peptide from bovine neutrophils, has two cysteine residues, which form one disulfide bond, making it a cyclic molecule. To study the importance of the disulfide bond, a linear derivative Bac2S was made and the reduced form (linear bactenecin) was also included in this study. Circular dichroism spectroscopy showed that bactenecin existed as a type I beta-turn structure regardless of its environment, while the reduced form and linear bactenecin adopted different conformations according to the lipophilicity of the environment. Bactenecin was more active against the Gram-negative wild type bacteria Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhimurium than its linear derivative and reduced form, while all three peptides were equally active against the outer membrane barrier-defective mutants of the first two bacteria. Only the two linear peptides showed activity against the Gram-positive bacteria Staphylococcus epidermidis and Enterococcus facaelis. Bactenecin interacted well with the outer membrane and its higher affinity for E. coli UB1005 lipopolysaccharide and improved ability to permeabilize the outer membrane seemed to account for its better antimicrobial activity against Gram-negative bacteria. The interaction of bactenecin with the cytoplasmic membrane was determined by its ability to dissipate the membrane potential by using the fluorescence probe 3, 3-dipropylthiacarbocyanine and an outer membrane barrier-defective mutant E. coli DC2. It was shown that the linear derivative and reduced form were able to dissipate the membrane potential at much lower concentrations than bactenecin despite the similar minimal inhibitory concentrations of all three against this barrier-defective mutant.
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PMID:Interaction of the cyclic antimicrobial cationic peptide bactenecin with the outer and cytoplasmic membrane. 986 6

Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger and indirect antioxidant. In terms of its scavenging activity, melatonin has been shown to quench the hydroxyl radical, superoxide anion radical, singlet oxygen, peroxyl radical, and the peroxynitrite anion. Additionally, melatonin's antioxidant actions probably derive from its stimulatory effect on superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase and its inhibitory action on nitric oxide synthase. Finally, melatonin acts to stabilize cell membranes, thereby making them more resistant to oxidative attack. Melatonin is devoid of prooxidant actions. In models of oxidative stress, melatonin has been shown to resist lipid peroxidation induced by paraquat, lipopolysaccharide, ischemia-reperfusion, L-cysteine, potassium cyanide, cadmium chloride, glutathione depletion, alloxan, and alcohol ingestion. Likewise, free radical damage to DNA induced by ionizing radiation, the chemical carcinogen safrole, lipopolysaccharide, and kainic acid are inhibited by melatonin. These findings illustrate that melatonin, due to its high lipid solubility and modest aqueous solubility, is able to protect macromolecules in all parts of the cell from oxidative damage. Melatonin also prevents the inhibitory action of ruthenium red at the level of the mitochondria, thereby promoting ATP production. In humans, the total antioxidative capacity of serum is related to melatonin levels. Thus, the reduction in melatonin with age may be a factor in increased oxidative damage in the elderly.
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PMID:Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin. 992 48

The contribution of nuclear factor-kappaB (NF-kappaB) and interferon-gamma (IFN-gamma) signaling to nitric oxide generation is not completely understood. The effect of NF-kappaB release and its inhibition on nitrite production and the involvement of Janus kinase 2 (JAK2) in inducible nitric oxide synthase (iNOS) induction were investigated. The following assays were performed. (1) Nitrite produced by rat mesangial cells in primary culture was measured in incubations with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS), with or without IFN-gamma. Cells were stimulated with TNF-alpha or LPS plus IFN-gamma in the presence of NF-kappaB inhibitors, herbimycin A (HerA), or the more specific JAK2 inhibitor AG490. (2) Immunoblotting was performed against the p65 and p50 subunits of NF-kappaB and iNOS. (3) Electrophoretic mobility shift assays were performed against NF-kappaB in the presence of NF-kappaB inhibitors or AG490. (4) iNOS promoter activity was measured in the presence of AG490 or JAK2 antisense oligonucleotides. TNF-alpha or LPS alone did not induce nitrite production, but with IFN-gamma these compounds did induce nitrite production. Pyrrolidine dithiocarbamate (PDTC), N-acetyl-L-cysteine, dexamethasone (Dex), HerA, and AG490 partially inhibited LPS/ IFN-gamma- or TNF-alpha/IFN-gamma-induced nitrite production. p65 was inhibited by the three NF-kappaB inhibitors described above, whereas p50 was not. PDTC and Dex completely inhibited the p65/p50 heterodimer, but HerA and AG490 had little effect on p65/p50. AG490 and JAK2 antisense oligonucleotides suppressed iNOS promoter activity. It can be concluded that (1) iNOS can be induced without active NF-kappaB; (2) Dex, acetylsalicylic acid, and PDTC inhibit only p65; and (3) JAK2 is involved in iNOS induction, and the contribution of JAK2 to nitrite production is greater than that of NF-kappaB.
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PMID:Inducible nitric oxide synthase can be induced in the absence of active nuclear factor-kappaB in rat mesangial cells: involvement of the Janus kinase 2 signaling pathway. 1020 55

Mammalian beta-defensins are endogenous cysteine-rich peptide antibiotics that are produced either by epithelial cells lining the respiratory, digestive, and urogenital tracts or by granulocytes and macrophages. A growing body of evidence has implicated these peptides in host defense, particularly mucosal innate immunity. We previously reported the cloning of the full-length cDNA for a porcine beta-defensin (pBD-1), which was found to be expressed throughout the airway and oral mucosa. Here, we provide the structural organization of the pBD-1 gene, showing that the entire gene spans approximately 1.9 kilobases with two short exons separated by a 1.5-kilobase intron. Fluorescence in situ hybridization mapped the pBD-1 gene to porcine chromosome 15q14-q15. 1 within a region of conserved synteny to the chromosomal locations of human and mouse alpha- and beta-defensins. We also provide several independent lines of evidence showing that the pBD-1 gene is expressed constitutively during inflammation and infection, despite its resemblance to many inducible epithelial beta-defensins in amino acid sequence, genomic structure, and sites of expression. First, stimulation of primary porcine tongue epithelial cells with lipopolysaccharide, tumor necrosis factor-alpha, and interleukin (IL)-1beta failed to up-regulate the expression of pBD-1 mRNA. Second, pBD-1 gene expression was not enhanced in either digestive or respiratory mucosa of pigs following a 2-day infection with Salmonella typhimurium or Actinobacillus pleuropneumoniae. Last, direct transfection of the pBD-1 gene promoter into NIH/3T3 cells showed no difference in reporter gene activity in response to stimulation by lipopolysaccharide and IL-1beta. The constitutive expression of pBD-1 in airway and oral mucosa, which is consistent with a lack of consensus binding sites for nuclear factor-kappaB or NF-IL-6 in its promoter region, suggests that it may play a surveillance role in maintaining the steady state of microflora on mucosal surfaces.
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PMID:Cloning and characterization of the gene for a new epithelial beta-defensin. Genomic structure, chromosomal localization, and evidence for its constitutive expression. 1044 72

Protegrins are small, arginine- and cysteine-rich, beta-sheet peptides with potent activity against bacteria, fungi, and certain enveloped viruses. We report that protegrins form weakly anion-selective channels in planar phospholipid bilayers, induce potassium leakage from liposomes and form moderately cation-selective channels in planar lipid membranes that contain bacterial lipopolysaccharide. The disruption of microbial membranes may be a central attribute related to the host defense properties of protegrins.
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PMID:Membrane channel formation by antimicrobial protegrins. 1044 87

A variety of environmental stresses stimulate the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEKK) > stress-activated protein kinase (SAPK)-ERK kinase (SEK) > SAPK/c-Jun NH(2)-terminal kinase (JNK) stress-activated protein kinase cascade and coordinately activate the transcription factor NFkappaB. Mechanisms of stress activation upstream of MEKK1 have not been precisely determined. Redox mechanisms involving sulfhydryls are likely because N-acetyl-cysteine at millimolar concentrations blocks stress signals. Because intracellular sulfhydryl concentrations can be regulated through redox cycling involving reactive quinones (1), we tested the ability of quinone reductase inhibitors to alter stress signaling. Several quinone reductases are inhibited by dicoumarol, a coumarin derivative. Dicoumarol prevented SAPK activation in vivo by chemical cell stressors and also prevented SAPK activation induced by expression of the tumor necrosis factor alpha (TNFalpha) receptor-associated protein TRAF2 but not by expression of truncated active MEKK1. Other coumarin derivatives failed to block SAPK activation, but other inhibitors of quinone reductases, particularly menadione, similarly blocked SAPK activation. Cells deficient in a major quinone reductase, NQO1, displayed hypersensitivity to dicoumarol stress inhibition, whereas SAPK in cells reconstituted with the NQO1 gene displayed relative dicoumarol resistance. Consistent with the proposed role of overlapping upstream signaling cascades in activation of NFkappaB, dicoumarol also blocked NFkappaB activation in primary macrophages stimulated with either lipopolysaccharide or TNFalpha. In addition, dicoumarol strongly potentiated TNFalpha-induced apoptosis in HeLa cells, probably by blocking the anti-apoptotic effect of NFkappaB. The ability of dicoumarol to simultaneously inhibit SAPK and NFkappaB activation and to potentiate apoptotic cell death suggests that SAPK is not an obligate participant in apoptosis. Dicoumarol, currently in clinical use as an oral anticoagulant, represents a potential therapeutic inhibitor of the SAPK and NFkappaB response.
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PMID:Quinone reductase inhibitors block SAPK/JNK and NFkappaB pathways and potentiate apoptosis. 1053 5

Electron spin resonance (ESR) was used to investigate the reaction of aspirin toward reactive oxygen species, such as hydroxyl radicals (*OH), superoxide radicals (O2-) and H2O2. The Fenton reaction (Fe(II) + H2O2 ---> FE(III) + *OH + OR) was used as a source of *OH radicals. The results show that aspirin is an efficient *OH radical scavenger with a reaction rate constant of k = 3.6 x 10(10) M(-1) sec(-1), which is faster than several well established antioxidants, such as ascorbate, glutathione and cysteine. However, aspirin is not a good scavenger for O2- or H2O2. Through its antioxidant property, aspirin exhibited a protective effect against silica-induced lipid peroxidation and DNA strand breakage. Aspirin also inhibited the activation of nuclear transcription factor-kappaB induced by silica, lipopolysaccharide or the transition metal, Fe(II), as demonstrated by electrophoretic mobility shift assay. The results show that aspirin functions as an antioxidant via its ability to scavenge *OH radicals. This antioxidant property may explain some of its various physiological and pharmacological actions.
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PMID:Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production. 1054 57

Ambroxol (100 microM and 1 mM) and the thiols (all 1 mM), glutathione, tiopronin and cysteine, significantly attenuated the myeloperoxidase, H(2)O(2) and Cl(-) system-caused destruction of alpha(1)-antiproteinase and the HOCl-induced destruction of collagen, whereas they did not affect the elastase-induced destruction of collagen. Glutathione, tiopronin and cysteine almost completely decomposed both HOCl and H(2)O(2), while ambroxol up to 1 mM did not show a scavenging action on H(2)O(2). Ambroxol (1 to 100 microM) and 1 mM thiol compounds markedly inhibited the HOCl-induced alteration of elastase activity. Thiol compounds significantly attenuated the HOCl production caused by degraded immunoglobulin G-activated neutrophils. Ambroxol depressed superoxide and H(2)O(2) production induced by degraded immunoglobulin G-activated neutrophils and by lipopolysaccharide-activated alveolar macrophages in a dose-dependent manner. The results show that ambroxol may interfere with oxidative tissue damage and decrease proteolytic tissue destruction by attenuation of oxidative stress-induced inactivation of alpha(1)-antiproteinase through both decomposition of HOCl and inhibition of the respiratory burst in phagocytic cells.
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PMID:The inhibitory effect of ambroxol on hypochlorous acid-induced tissue damage and respiratory burst of phagocytic cells. 1055 85


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