UNIPROT:P43026 - FACTA Search

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)

Sulfite, which is known as a major constituent of volcanic gas, is endogenously produced in mammals, and its concentration in serum is increased in patients with pneumonia. It has been reported that sulfite is produced by oxidation from hydrogen sulfide (H2S) as an intermediate in the mammalian body. The objective of this study was to investigate the ability of reactive oxygen species from neutrophils to produce sulfite from H2S. Sulfite production from activated neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine gradually increased with an increased concentration of sodium hydrosulfide (NaHS) in the medium. The production of sulfite was markedly suppressed with an NADPH oxidase inhibitor, diphenyleneiodonium. When NaHS was added to the supernatant of activated neutrophils, a significant amount of sulfite was synthesized in the test tubes. Furthermore, when a medium containing NaHS was incubated with a water-soluble radical initiator, 2,2'-azobis-(amidinopropane) dihydrochloride, sulfite was formed in the solution and this increase was markedly suppressed by ascorbic acid. Finally, we determined serum concentrations of sulfite and H2S in an in vivo model of neutrophil activation induced by systemic injection of lipopolysaccharide (LPS) into rats. We found a significant increase in serum sulfite and H2S after LPS injection. Importantly, coadministration of ascorbic acid with LPS further increased serum H2S but suppressed sulfite levels. This finding implies that oxidative stress-dependent conversion of H2S to sulfite might occur in vivo. Thus, the oxidation of H2S is a novel sulfite production pathway in the inflammatory condition, and this chemical synthesis might be responsible for the upregulation of sulfite production in inflammatory conditions such as pneumonia.
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PMID:Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils. 1631 83

Carbon monoxide (CO) arising from heme degradation, catalyzed particularly by the stress-inducible heme oxygenase-1 (HO-1), has recently been demonstrated to provide cytoprotection against cell death in macrophages stimulated with bacterial lipopolysaccharide (LPS). In the present study, we determined the effects of CO on the production of reactive oxygen species (ROS) and nitric oxide (NO) by the LPS-stimulated RAW 264.7 macrophages. In addition, effect of CO-exposure on the production of superoxide (O(2)(-)) in the phorbol myristate acetate (PMA)-stimulated PLB-985 neutrophils was determined. Production of ROS by the LPS-stimulated macrophages pretreated with 50microM [Ru(CO)(3)Cl(2)](2), a CO-releasing molecule (CORM-2), was abolished and the production of O(2)(-) by the PMA-stimulated neutrophils pretreated with the CORM-2 was decreased markedly. The CORM-2 (50microM) was not cytotoxic to both the unstimulated and LPS-stimulated macrophages when determined by employing mitochondrial reductase function test (MTT assay). In macrophages pretreated with increasing doses of CORM-2, both the LPS-derived upregulations of iNOS (NO production) and HO-1 expression (CO production) were suppressed in a dose-dependent manner. Alternatively, when the macrophages were treated with LPS and CO-donor together, the LPS-derived increase in NO production was decreased. Conversely, when the control and LPS-stimulated macrophages were treated with zinc protoporphyrin IX (ZnPP) to inhibit the HO activity blocking endogenous production of CO (basal and enhanced), macrophages died extensively. Interestingly, production of NO in the LPS-stimulated macrophages increased significantly following the ZnPP treatment. Addition of CORM-2 to the LPS-treated cells that were being treated additionally with ZnPP did not prevent the cell death. However, endogenous overproduction of CO by super-induction of HO-1 (obtained by pretreatment of macrophages with either buthionine sulfoximine or hemin) decreased the LPS-derived iNOS expression without affecting cell survival. Combined, these results indicated that enhanced HO activity is essential for the survival of LPS-stimulated macrophages. Thus, upregulation of HO-1 and overproduction of CO may allow the survival of LPS-stimulated macrophages; first, by eliminating the free heme to prevent Fenton reaction, second, by limiting the availability of free heme required for induction of NO-producing heme enzyme (i.e., iNOS), third, by limiting additional production of O(2)(-) and NO via CO-derived inhibition on the activities of heme enzymes like NADPH oxidase and iNOS, respectively. CO may allow the LPS-activated macrophages to return back to the normal quiet state insensitive to additional stimuli causing oxidative stress.
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PMID:CO from enhanced HO activity or from CORM-2 inhibits both O2- and NO production and downregulates HO-1 expression in LPS-stimulated macrophages. 1632 99

We previously conducted screening tests of the chloroform extracts from a total of 89 species of Japanese plant food items for their suppressive effects on superoxide (O(2) ()) generation through both NADPH oxidase and xanthine oxidase, and reported that mioga ginger (Zingiber mioga Roscoe) indicated the strongest suppressive activities. In this study, the suppressive effects of mioga ginger constituents, aframodial, and galanal B, together with [6]-gingerol and galanolactone occurring in ginger, on free radical generation and inducible proinflammatory gene expressions were investigated. Of these constituents, aframodial (20 microM) exhibited marked suppressive effects on 12-O-tetradecanoylphorbol-13-acetate-induced O(2) () generation in HL-60 cells and lipopolysaccharide (LPS)/interferon-gamma-induced nitric oxide (NO) generation in RAW264.7 cells (inhibition rates [IRs]=84.6% and 95.9%, respectively). Aframodial also strongly suppressed the stimulated HL-60 cell-induced mutagenicity in AS52 cells (IR=95.9%). The LPS-induced expression of inducible proinflammatory genes such as inducible NO synthase, interleukin (IL)-1beta, IL-6, and granulocyte-macrophage colony-stimulating factor was significantly abolished (IRs=99.1%, 74.6%, 74.0%, and 64.4%, respectively) by aframodial. In addition, degradation of the inhibitor of nuclear factor kappaB was suppressed by this compound (IR=100%), suggesting that the suppression of nuclear factor kappaB activation, at least in part, is involved. Taken together, these results suggest that aframodial has potent antioxidative and anti-inflammatory potentials, and may be a promising candidate in prevention and/or therapy for chronic inflammationassociated carcinogenesis.
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PMID:Suppressive effects of mioga ginger and ginger constituents on reactive oxygen and nitrogen species generation, and the expression of inducible pro-inflammatory genes in macrophages. 1635 25

Hepatic encephalopathy is seen as a clinical manifestation of a chronic low grade cerebral edema, which is thought to trigger disturbances of astrocyte function, glioneuronal communication, and finally HE symptoms. In cultured astrocytes, hypoosmotic swelling triggers a rapid oxidative stress response, which involves the action of NADPH oxidase isoenzymes, followed by tyrosine nitration of distinct astrocytic proteins. Oxidative stress and protein tyrosine nitration (PTN) are also observed in response to ammonia, inflammatory cytokines, such as TNF-alpha or interferons, and benzodiazepines with affinity to the peripheral benzodiazepine receptor (PBR). NMDA receptor activation was identified as upstream event in protein tyrosine nitration (PTN). Cerebral PTN is also found in vivo after administration of ammonia, benzodiazepines or lipopolysaccharide and in portocaval shunted rats. PTN predominantly affects astrocytes surrounding cerebral vessels with potential impact on blood-brain-barrier permeability. Among the tyrosine-nitrated proteins, glutamine synthetase, GAPDH, extracellular signal-regulated kinase and the PBR were identified. PTN of glutamine synthetase is associated with inactivation of the enzyme. Thus, factors known to trigger hepatic encephalopathy induce oxidative/nitrosative stress on astrocytes with protein modifications through PTN. The pathobiochemical relevance of astrocytic PTN for the development of HE symptoms remains to be established.
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PMID:Protein tyrosine nitration in hyperammonemia and hepatic encephalopathy. 1638 39

Anaplasma (formerly Ehrlichia) phagocytophilum and Ehrlichia chaffeensis, upon infection of humans, replicate in host leukocyte granulocytes and monocytes/macrophages, respectively. These unusual Gram-negative bacteria lack genes for biosynthesis of the lipopolysaccharide and peptidoglycan that activate host leukocytes. Caveolae-mediated endocytosis directs A. phagocytophilum and E. chaffeensis to an intracellular compartment secluded from oxygen-dependent and -independent killing. Furthermore, these bacteria orchestrate a remarkable series of events that culminate in suppression of NADPH oxidase, phagocyte activation and differentiation pathways, apoptosis, and interferon-gamma signaling in host leukocytes. They offer a fascinating example of how pathogens employ intricate strategies to usurp and subvert host cell function.
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PMID:Ehrlichia subversion of host innate responses. 1640 79

The superoxide-generating phagocytic NADPH oxidase is an important component of the innate immune response against microbial agents, and is involved in shaping the cellular response to a variety of physiological and pathological signals. One of the downstream targets of NADPH oxidase-derived radicals is the ubiquitous transcription factor NF-kappaB, which controls the expression of a large array of genes involved in immune function and cell survival. Here we show that NF-kappaB itself is a key factor in controlling NADPH oxidase expression and function. In monocytic and microglial cell lines, the expression of the NADPH oxidase subunit gp91(phox) was induced by lipopolysaccharide/interferon gamma treatment and was inhibited in cells constitutively expressing IkappaBalpha. Furthermore, inducible reactive oxygen species production was inhibited in IkappaBalpha overexpressing cells. gp91(phox) expression was very low in RelA(-/-) fibroblasts and could be induced by reconstituting these cells with p65/RelA. Thus, gp91(phox) expression is dependent on the presence of p65/RelA. We also found that gp91(phox) transcription is dependent on NF-kappaB and we identified two potential cis-acting elements in the murine gp91(phox) promoter that control NF-kappaB-dependent regulation. The findings raise the possibility of a positive feedback loop in which NF-kappaB activation by oxidative stress leads to further radical production via NADPH oxidase.
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PMID:NF-kappaB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. 1640 83

Inflammation plays an essential role in atherosclerosis and post-angioplasty restenosis and the synthesis and release of inflammatory cytokines from vascular smooth muscle cells is an important contributor to these pathologies. It is assumed that drugs that prevent the overproduction of inflammatory cytokines may inhibit cardiovascular disorders. In the present study, the effects of a water-soluble antioxidant, salvianolic acid B (Sal B), derived from a Chinese herb, on the expression of cyclooxygenase (COX) in lipopolysaccharide (LPS)-treated human aortic smooth muscle cells (HASMCs) and in the aortas of cholesterol-fed apoE deficient mice were investigated. In unstimulated HASMCs, COX-2 mRNA and protein were almost undetectable, but were strongly upregulated in response to LPS. In contrast, HASMCs with or without LPS treatment showed constitutive expression of COX-1 mRNA and protein. The activation of COX-2 protein synthesis in LPS-stimulated HASMCs was shown to involve the activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathway. Incubation of HASMCs with Sal B before LPS stimulation resulted in pronounced downregulation of COX-2 expression. Sal B treatment suppressed ERK1/2 and JNK phosphorylation and attenuated the increase in prostaglandin E(2) production and NADPH oxidase activity in LPS-treated HASMCs. When apoE-deficient mice were fed a 0.15% cholesterol diet with or without supplementation with 0.3% Sal B for 12 weeks, the intima/media area ratio in the thoracic aortas was significantly reduced in the Sal B group (0.010 +/- 0.009%) compared to the apoE-deficient group (0.114 +/- 0.043%) and there was a significant reduction in COX-2 protein expression in the thickened intima. These results demonstrate that Sal B has anti-inflammatory properties and may explain its anti-atherosclerotic properties. This new mechanism of action of Sal B, in addition to its previously reported inhibition of LDL oxidation, may help explain its efficacy in the treatment of atherosclerosis.
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PMID:Salvianolic acid B attenuates cyclooxygenase-2 expression in vitro in LPS-treated human aortic smooth muscle cells and in vivo in the apolipoprotein-E-deficient mouse aorta. 1644 Mar 26

Gut-derived, endotoxin-mediated hepatocellular damage has been postulated to play a crucial role in the pathogenesis of alcohol-induced liver injury in rodents. Endotoxins induce production of tumor necrosis factor alpha (TNF-alpha) by Kupffer cells via Toll-like receptor (TLR) 4 and contribute to liver injury. This study addressed the contribution of other TLRs and ligands to alcoholic fatty liver. C57Bl6/J mice were fed a modified Lieber-DeCarli diet. Serum aminotransferase measurements, histological analysis, and quantification of liver TNF-alpha and TLR1-9 messenger RNA (mRNA) were performed. The effect of TLR ligands on liver injury was assessed in vivo. Neomycin and metronidazole or diphenyleneiodonium sulfate (DPI) were administered to evaluate the role of gut bacteria and NADPH oxidase activity, respectively, in hepatic TLR expression. Enteral ethanol (EtOH) exposure induced steatosis and increased liver weight, aminotransferase levels, and expression of TLR1, 2, 4, 6, 7, 8, and 9 liver mRNA. Injection of lipoteichoic acid, peptidoglycan (PGN), lipopolysaccharide (LPS), loxoribine, and oligonudeotide containing CpG (ISS-ODN) increased TNF-alpha mRNA expression more in the livers of EtOH-fed mice than in control mice. PGN, LPS, flagellin, and ISS-ODN induced liver inflammatory infiltrate in EtOH-fed mice but not control mice. Addition of antibiotics reduced the severity of alcoholic fatty liver without affecting TLR expression, whereas daily DPI injections reduced the EtOH-mediated upregulation of TLR2, 4, 6, and 9 mRNA. In conclusion, EtOH-fed mice exhibited an oxidative stress dependent on upregulation of multiple TLRs in the liver and are sensitive to liver inflammation induced by multiple bacterial products recognized by TLRs.
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PMID:Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. 1662 28

The role of anti-inflammatory cytokines in Parkinson's disease is not completely understood. In this study, using mesencephalic neuron-glia cultures, we report that both pretreatment and post-treatment of rat mesencephalic neuron-glia cultures with interleukin (IL)-10, a natural immune modulator, reduced lipopolysaccharide (LPS)-induced DA neurotoxicity. The main purpose of this study was to elucidate the molecular mechanism underlying IL-10-elicited neuroprotection. IL-10 significantly inhibited LPS-induced production of tumor necrosis factor-alpha, nitric oxide, and extracellular superoxide in microglia cells. In addition, using reconstituted neuron and glia cell cultures, IL-10 was shown to be neuroprotective only in the presence of microglia. More importantly, IL-10 failed to protect DA neurons in cultures from mice lacking NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells, suggesting the critical role of PHOX in IL-10 neuroprotection. This conclusion was further supported by the finding that IL-10 inhibited LPS-induced translocation of the cytosolic subunit of NADPH oxidase p47(phox) to the membrane. When the Janus tyrosine kinase (JAK) 1 signaling pathway was blocked, IL-10 failed to attenuate LPS-induced superoxide production, indicating that the JAK1 signaling cascade mediates the inhibitory effect of IL-10. Together, our results suggest that IL-10 inhibits LPS-induced DA neurotoxicity through the inhibition of PHOX activity in a JAK1-dependent mechanism.
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PMID:Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase. 1680 59

CXCL16 is a transmembrane non-ELR CXC chemokine that signals via CXCR6 to induce aortic smooth muscle cell (ASMC) proliferation. While bacterial lipopolysaccharide (LPS) has been shown to stimulate CXCL16 expression in SMC, its effects on CXCR6 are not known. Here, we demonstrate that LPS upregulates CXCR6 mRNA, protein, and surface expression in human ASMC. Inhibition of TLR4 with neutralizing antibodies or specific siRNA interference blocked LPS-mediated CXCR6 expression. LPS stimulated both AP-1 (c-Fos, c-Jun) and NF-kappaB (p50 and p65) activation, but only inhibition of AP-1 attenuated LPS-induced CXCR6 expression. Using dominant negative expression vectors and siRNA interference, we demonstrate that LPS induces AP-1 activation via MyD88, TRAF6, ERK1/2, and JNK signaling pathways. Furthermore, the flavoprotein inhibitor diphenyleniodonium chloride significantly attenuated LPS-mediated AP-1-dependent CXCR6 expression, as did inhibition of NOX4 NADPH oxidase by siRNA. Finally, CXCR6 knockdown inhibited CXCL16-induced ASMC proliferation. These results demonstrate that LPS-TLR4-NOX4-AP-1 signaling can induce CXCR6 expression in ASMC, and suggest that the CXCL16-CXCR6 axis may be an important proinflammatory pathway in the pathogenesis of atherosclerosis.
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PMID:TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells. 1687 Jan 45

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