Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bioassay-guided fractionation of protective agents against sepsis-induced lethality from the root cortex of Paeonia suffruticosa ANDREWS (Ranunculaceae) led to the isolation of eight known compounds: paeonol (1), 2,5-dihydroxy-4-methoxyacetophenone (2), acetovanillone (3), paeonoside (4), paeoniflorin (5), oxypaeoniflorin (6), apiopaeonoside (7), and methyl 3-hydroxy-4-methoxybenzoate (8). Among them, 3 showed the highest survival rate (100% with a dose of 30 mg/kg versus 17% for the control experiment) and reduced alanine aminotransferase level to be a half of the control value on the sepsis model induced by lipopolysaccharide/D-galactosamine.
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PMID:Protective constituents against sepsis in mice from the root cortex of Paeonia suffruticosa. 1559 14

Dextromethorphan (DM) is a dextrorotatory morphinan and an over-the-counter non-opioid cough suppressant. We have previously shown that DM protects against LPS-induced dopaminergic neurodegeneration through inhibition of microglia activation. Here, we investigated protective effects of DM against endotoxin shock induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice and the mechanism underlying its protective effect. Mice were given multiple injections of DM (12.5 mg/kg, s.c.) 30 min before and 2, 4 h after an injection of LPS/GalN (20 microg/700 mg/kg). DM administration decreased LPS/GalN-induced mortality and hepatotoxicity, as evidenced by increased survival rate, decreased serum alanine aminotransferase activity and improved pathology. Furthermore, DM was also effective when it was given 30 min after LPS/GalN injection. The protection was likely associated with reduced serum and liver tumor necrosis factor alpha (TNF-alpha) levels. DM also attenuated production of superoxide and intracellular reactive oxygen species in Kupffer cells and neutrophils. Real-time RT-PCR analysis revealed that DM administration suppressed the expression of a variety of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intercellular adhesion molecular-1 and interleukin-6. DM also decreased the expression of genes related to cell-death pathways, such as the DNA damage protein genes GADD45 and GADD153. In summary, DM is effective in protecting mice against LPS/GalN-induced hepatotoxicity, and the mechanism is likely through a faster TNF-alpha clearance, and decrease of superoxide production and inflammation and cell-death related components. This study not only extends neuroprotective effect of DM, but also suggests that DM may be a novel compound for the therapeutic intervention for sepsis.
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PMID:Protective effect of dextromethorphan against endotoxic shock in mice. 1562 75

Lipopolysaccharide (LPS) is a highly proinflammatory molecule isolated from bacteria. This study demonstrated the existence of LPS in a medicinal fungus, Antrodia camphorata. Because no LPS had been identified in any fungus organism, the purification of LPS from A. camphorata was attempted. LPSs from six strains of A. camphorata (35396, 35398, 35716, B71, B85, and B86) were isolated. Chemical and functional properties were investigated on the fungus LPS. Compositional analysis revealed that sorbitol, fucose, galactose, and glucose were the neutral sugars in LPS of A. camphorata. Galactosamine, glucosamine, galactose, and glucose were the predominant monosaccharide species in E. coli O129 LPS molecules, whereas galactosamine and glucosamine were absent in A. camphorata LPS. Because these properties are different from those of bacterial LPS, the functions between fungus and bacterial LPS are also discussed. The vascular endothelial lining of blood vessels, which controls leucocyte traffic and activation, may be one of the primary targets of LPS action during sepsis. Assays for biological activity were performed on endothelial cells with anti-inflammatory effects associated with sepsis. A. camphorata LPS apparently showed a lesser extent of cytotoxicity than bacterial LPS. In contrary to the proinflammatory property of bacterial LPS, LPS from A. camphorata differentially reversed bacterial LPS-induced intercellular adhersion molecule-1 and monocyte adhesion; both were indicators during inflammatory process. In conclusion, basic chemical properties categorized A. camphorata extracts into lipopolysaccharide. However, the detailed functional structures and bioactivities of A. camphorata LPS were totally different from those of bacterial LPS. The investigation of the existence and anti-inflammatory effect of fungus LPS is at present a truly novel and important finding. These results show that LPS isolated from A. camphorata offers a novel therapeutic target for anti-inflammation against E. coli infection.
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PMID:Characterization and functional study of Antrodia camphorata lipopolysaccharide. 1565 90

In the course of isolating agents preventing sepsis from the EtOAc extract of the roots of Angelica dahurica, four known furanocoumarins, isoimperatorin (1), oxypeucedanin (2), (+/-)-byakangelicin (3), and (+)-oxypeucedanin hydrate (4), were isolated as active compounds based on the in vivo assay model of sepsis induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Among them, 3 showed the highest survival rate (100% with a dose of 30 mg/kg versus 20% for the control experiment) and decreased the plasma levels of tumor necrosis factor-alpha and alanine aminotransferase in mice adminstered LPS/D-GalN.
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PMID:Agents protecting against sepsis from the roots of Angelica dahurica. 1568 6

Lipopolysaccharides (LPS), otherwise termed "endotoxins", are outer membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. In this paper, the interactions of a series of acylated homologated spermine compounds with LPS have been characterized. The optimal acyl chain length for effective sequestration of LPS was identified to be C(16) for the monoacyl compounds. The most promising of these compounds, 4e, binds LPS with an ED(50) of 1.37 muM. Nitric oxide production in murine J774A.1 cells, as well as TNF-alpha in human blood, is inhibited in a dose-dependent manner by 4e at concentrations orders of magnitude lower than toxic doses. Administration of 4e to d-galactosamine-sensitized mice challenged with supralethal doses of LPS provided significant protection against lethality. Potent antiendotoxic activity, low toxicity, and ease of synthesis render this class of compounds candidate endotoxin-sequestering agents of potential significant therapeutic value.
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PMID:Lipopolysaccharide sequestrants: structural correlates of activity and toxicity in novel acylhomospermines. 1580 49

Susceptibility to bacterial infections after a primary immune stimulation differs drastically depending on the presensitization of the innate immune system. To determine the conditions that either induce protection or enhanced susceptibility to infection with Salmonella enterica serovar Typhimurium, we pretreated mice either with tumor necrosis factor (TNF), whole killed bacteria, or sublethal cecal ligation and puncture (CLP) as a mouse model for septic peritonitis. Impaired production of the cytokines TNF, interleukin-6 (IL-6), and IL-10 was induced by these pretreatment schedules, with TNF-signaling not being essential for this effect. Injection of TNF or killed bacteria enhanced survival of mice infected subsequently with serovar Typhimurium. In contrast, sepsis such as that induced by CLP only protected from shock induced by d-galactosamine and lipopolysaccharide or by a high dose of bacteria but sensitized to a secondary bacterial infection. Such sepsis-induced enhanced susceptibility to infection was critically dependent on TNF function.
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PMID:Divergence of protection induced by bacterial products and sepsis-induced immune suppression. 1604 Oct 4

Sepsis resulting from gram-negative bacterial infections is characterized by an excessive inflammatory immune response initiated by exposure of the host innate immune system to either bacteria or bacterial products, primarily lipopolysaccharide (LPS). Engagement of the Toll-like receptor (TLR) 4 on immune cells by LPS induces production of inflammatory mediators, leading to tissue damage. We recently identified a peptide, termed P13, which was previously shown to be a potent inhibitor of in vitro TLR signaling. In this study, we demonstrate that the use of this novel peptide significantly reduces the in vitro production of inflammatory mediators seen after exposure of hepatocytes/nonparenchymal cell cocultures and endothelial cells to LPS. In addition, in vivo treatment of mice with this peptide was effective at inhibiting LPS-induced production of inflammatory mediators and significantly limited liver damage. Peptide treatment significantly increased survival of LPS-/D-galactosamine-treated mice and mice treated with high-dose LPS. These results demonstrated the therapeutic potential of peptide P13 to limit an LPS-induced inflammatory response and enhance survival in murine models of inflammation.
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PMID:A novel inhibitory peptide of Toll-like receptor signaling limits lipopolysaccharide-induced production of inflammatory mediators and enhances survival in mice. 1741 17

Sepsis occurs when microbes activate toll-like receptors (TLRs) stimulating widespread inflammation and activating coagulation cascades. TLR4 signal transduction has been recognized as a key pathway for lipopolysaccharide (LPS)-induced activation of various cells and an attractive target for treatment of sepsis. We found a new benzisothiazole derivative, M62812 that inhibits TLR4 signal transduction. This compound suppressed LPS-induced upregulation of inflammatory cytokines, adhesion molecules and procoagulant activity in human vascular endothelial cells and peripheral mononuclear cells. The half maximal inhibitory concentrations in these assays ranged from 1 to 3 microg/ml. Single intravenous administration of M62812 (10-20 mg/kg) protected mice from lethality and reduced inflammatory and coagulatory parameters in a murine d-galactosamine-sensitized endotoxin shock model. M62812 (20 mg/kg) also prevented mice from lethality in a murine cecal ligation and puncture model. These results suggest that inhibition of TLR4 signal transduction can suppress coagulation as well as inflammation during sepsis and may be clinically beneficial in sepsis treatment.
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PMID:Toll-like receptor 4 signal transduction inhibitor, M62812, suppresses endothelial cell and leukocyte activation and prevents lethal septic shock in mice. 1758 63

Lipopolysaccharide (LPS) is a component of the outer membrane of Gram-negative bacteria. It is a ligand for Toll-like receptor 4 (TLR4), which plays an essential role in innate immunity. Macrophages and dendritic cells exposed to LPS overproduce proinflammatory mediators, leading to septic shock. In this study, we screened for peptides that associate with TLR4 with a yeast two-hybrid screen using the human TLR4 extracellular domain as bait. A peptide (STM28) isolated from the screen inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activation in human and mouse macrophage cells and interacted with TLR4 in yeast and mammalian cells. STM28 showed no inhibitory effects against NF-kappaB activation induced by TLR1/2, TLR3 and TLR9 ligands in a mouse macrophage cell line, RAW 264. In addition, STM28 suppressed LPS-induced tumor necrosis factor-alpha production by differentiated THP-1 cells. Moreover, LPS-induced lethality in d-galactosamine-sensitized mice was significantly repressed by STM28 in a dose-dependent manner. These results demonstrate that STM28 selectivity inhibits TLR4-induced macrophage activation, and suggest that STM28 may have utility as a novel therapeutic agent for Gram-negative bacterial sepsis.
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PMID:A novel TLR4-binding peptide that inhibits LPS-induced activation of NF-kappaB and in vivo toxicity. 1870 Jan 40

The effects of decursinol on various models of sepsis were investigated. Intra-peritoneal pretreatment of mice with various doses of decursinol (1~100 mg/kg) effectively suppressed lethality induced in three mouse models of experimental sepsis, i.e., lipopolysaccharide (LPS)/D-galactosamine (GalN), high-dose LPS (20 mg/kg), and cecal ligation and puncture (CLP). Intra-peritoneal pretreatment of mice with decursinol (50 mg/kg) markedly enhanced the LPS/GalN-induced increase of plasma interleukin-10 (IL-10) levels, without affecting plasma TNF-alpha, IL-6 and IL-12 levels. These results suggest that decursinol could be effective for prevention or treatment of sepsis.
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PMID:Protective effect of decursinol on mouse models of sepsis: enhancement of interleukin-10. 2015 98


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