UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study describes the antiapoptotic action of (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378), a novel benzopyran analog, in human umbilical vein endothelial cells (HUVECs) in comparison with its acetylated metabolite, (2S,3S,4R)-N"-cyano-N-(6-acetylamino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31612), and with alpha-tocopherol. Exposure of HUVECs to lipopolysaccharide (LPS) (1 microg/ml) induced time- and concentration-dependent cytotoxicity and oligonucleosomal DNA fragmentation. KR-31378, KR-31612, and alpha-tocopherol potently suppressed LPS-induced cell death in association with significant reduction in the intracellular reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha) that are stimulated by LPS. KR-31378 more effectively protected HUVECs from LPS-induced DNA fragmentation and was more effective in peroxyl radical scavenging than alpha-tocopherol. Incubation with LPS markedly decreased the Bcl-2 level, which was totally reversed by KR-31378 and to a lesser degree by KR-31612 and by alpha-tocopherol. In contrast, the greatly increased Bax protein and cytochrome c release stimulated by LPS were markedly suppressed by KR-31378 and by KR-31612, and to a lesser degree by alpha-tocopherol. Taken together, KR-31378 strongly inhibited cell death in HUVECs in association with antiapoptotic effects, which were accompanied by up-regulation of Bcl-2 protein expression and down-regulation of Bax protein and suppression of cytochrome c release. KR-31378 also showed the properties to scavenge the intracellular ROS and peroxyl radicals, and to reduce the TNF-alpha production induced by LPS.
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PMID:Prevention of lipopolysaccharide-induced apoptosis by (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine, a benzopyran analog, in endothelial cells. 1180 14

This work describes the pharmacological inhibition by cilostazol and its metabolites, OPC-13015 and OPC-13213, of the apoptosis in the human umbilical vein endothelial cells (HUVECs) damaged by lipopolysaccharide (LPS) in comparison with its analog, cilostamide. Cilostazol and OPC-31213 caused a significant suppression of cell death induced by LPS (1 microg/ml) in a concentration-dependent manner but a modest suppression by cilostamide and OPC-13015. These compounds potently inhibited the 5,5-dimethyl-1-pyrroline-1-oxide (DMPO)/(*)OH adduct formation and significantly reduced the increased intracellular reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha) production induced by LPS (1 microg/ml). An apoptotic death of HUVECs by 1 microg/ml LPS (DNA ladders on electrophoresis) was strongly suppressed by all these compounds. Incubation with LPS caused a marked decrease in Bcl-2 protein, which was significantly reversed by cilostazol and its analogs. The greatly increased Bax protein expression and cytochrome c release by LPS were, in contrast, suppressed by cilostazol and, to a lesser degree, by others. In conclusion, cilostazol and its analogs exert a strong protection against apoptotic cell death by scavenging hydroxyl radicals and intracellular ROS with reduction in TNF-alpha formation and by increasing Bcl-2 protein expression and decreasing Bax protein and cytochrome c release.
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PMID:Inhibition of lipopolysaccharide-induced apoptosis by cilostazol in human umbilical vein endothelial cells. 1180 37

Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNFalpha to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNFalpha, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4-5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-kappaB and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.
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PMID:Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. 1181 69

The effect of liquid depth on the synthesis of NO and O(2)(-) was studied in murine macrophage-like RAW 264.7 cells activated by bacterial lipopolysaccharide and interferon-gamma. Rates of NO(2)(-) and NO(3)(-) accumulation were determined 8-11 h after stimulation. The rate of NO synthesis was computed by using a reaction-diffusion model to correct NO(2)(-) and NO(3)(-) accumulation for physical loss of NO, whereas O(2)(-) synthesis was equated with NO(3)(-) formation. Rates of O(2)(-) synthesis determined by a spectrophotometric (cytochrome c) assay were in good agreement with those from NO(3)(-) accumulation and showed production of O(2)(-) to be detectable immediately, in contrast to the approximately 6 h time lag for NO. The assumption that NO(2)(-) and NO(3)(-) are stable end products of the extracellular oxidation of NO by O(2) and O(2)(-), respectively, was supported by the fact that NO(2)(-) and NO(3)(-) concentrations remained constant in the presence of unstimulated cells or stimulated cells where NO synthesis was inhibited. Data were obtained for media depths ranging from 1 to 4 mm. The physical loss of NO was found to be quite significant, exceeding NO(2)(-) and NO(3)(-) accumulation by an order of magnitude at the smallest depth. The principal finding was that the rates of NO(2)(-) and NO(3)(-) accumulation each remained nearly constant over the 4-fold range of liquid depths. Because greater depths should greatly facilitate the trapping of NO as NO(2)(-), this implies that NO synthesis decreased markedly with increasing depth. In contrast, O(2)(-) synthesis remained approximately constant. Oxygen availability is likely to have affected NO synthesis, in that diffusional limitations will yield the lowest cellular O(2) concentrations when the liquid depth is greatest and NO synthesis is known to decrease when O(2) levels are reduced. Concentrations of NO near the cells were calculated to remain at approximately 1 microM for all conditions examined, suggesting that regulation of NO synthase activity by NO might also have mediated the effect of liquid depth.
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PMID:Effect of liquid depth on the synthesis and oxidation of nitric oxide in macrophage cultures. 1195 34

The production of nitric oxide (NO) is an essential determinant in auto- and paracrine signaling. NO is generated under inflammatory conditions and may serve as a cytotoxic molecule to produce cell demise along an apoptotic or necrotic pathway. NO also gained attention as a regulator of immune function and a death inhibitor. Cytotoxicity because of substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and antiapoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, and DNA fragmentation. However, NO-toxicity is not a constant value and NO may protect several cell types from entering programmed cell death. Preactivation of macrophages with a nontoxic dose of S-nitrosoglutathione (200 microM) or lipopolysaccharide/interferon-gamma/N(G)-monomethyl-L-arginine for 15 hours attenuated death in response to various agonists, suppressed p53 accumulation, and abrogated caspase activation. Prestimulation of macrophages with cytokines or low-level NO activated the transcription factor NF-kappaB as well as AP-1 and promoted immediate early gene expression of cyclooxygenase-2 (COX-2). NF-kappaB activation comprised p50/p65-heterodimer formation, IkappaB degradation, and activation of a luciferase reporter construct, that contained four copies of the NF-kappaB-site derived from the murine COX-2 promoter. A NF-kappaB decoy approach (oligonucleotides directed against NF-kappaB) or transfection of a dominant-negative c-Jun mutant (TAM67) abrogated not only the COX-2 expression but also the inducible protection. Blocking NO- or cytokine-mediated inducible protection at the level of NF-kappaB and/or AP-1 restored the occurrence of apoptotic features. Our experiments underscore the role of COX-2 in attenuating natural occurring cell death (i.e., apoptosis).
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PMID:The role of nitric oxide and cyclooxygenase-2 in attenuating apoptosis. 1208 96

Thioredoxin (Trx) is a small redox-active protein with antioxidant and antiapoptotic effects. Trx transgenic (Tg) mice are more resistant to cerebral infarction and survive longer than wild-type (WT) C57BL/6 mice. The aim of the present study was to investigate the protective role of Trx in acute hepatitis models. The expression of endogenous Trx was decreased in thioacetamide (TAA)-induced acute hepatitis. TAA (100 microg/g) was injected intraperitoneally in WT and Tg mice. Survival rate after TAA injection was higher in Tg mice than in WT mice. The level of oxidative stress was significantly less in Tg mice than in WT mice, as shown by the protein carbonylation assay and lipid peroxidation assay. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells were less in Tg mice than in WT mice, which was consistent with DNA laddering assay. Caspase-3 and caspase-9 activities and cytochrome c release were significantly inhibited in Tg mice compared with those in WT mice. In addition, lipopolysaccharide (LPS) plus d-galactosamine (GalN), or anti-Fas antibody (Jo2) were injected. Survival rate after LPS plus GalN injection was much higher in Tg mice than in WT mice. In contrast, there was no difference in survival rate after Jo2 injection between WT and Tg mice. In conclusion, transgene of Trx attenuated TAA- or LPS-induced acute lethal hepatitis. In addition to an antioxidant effect, Trx has the potential to protect acute liver injury via an antiapoptotic effect, which mainly inhibits mitochondria-mediated apoptosis signaling.
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PMID:Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolysaccharide in mice. 1271 82

Phagocytosis of serum- and IgG-opsonized zymosan (SOZ and IOZ, respectively) particles into J774A.1 macrophages induced apoptosis of the cells, accompanied by the expression of p21(WAF1), one of cyclin-dependent protein kinase (CDK) inhibitors. Furthermore, phagocytosis of SOZ and IOZ particles into macophages induced superoxide formation. Tat-superoxide dismutase (SOD), which is readily transduced into the cells using Tat-domain, protected the cells from the apoptosis induced by phagocytosis of SOZ and IOZ particles. lipopolysaccharide (LPS) /interferon-gamma (IFN-gamma) also caused the apoptosis of the cells. However, Tat-SOD could not protect the cells from LPS/IFN-gamma induced apoptosis, suggesting that apoptosis mechanisms involved are different from each other. In the present study, we determined the amounts of nitric oxide (NO) produced by SOZ, IOZ, and LPS/IFN-gamma, and found that SOZ and IOZ did not induce the generation of NO in macrophages, whereas LPS/ IFN-gamma did. The apoptosis due to phagocytosis was accompanied with the release of cytochrome c from mitochondrial membrane to cytosolic fraction. Furthermore, SOZ and IOZ induced the cleavage of procasapase-3 (35 kDa) to give rise to an active caspase-3 (20 kDa), which was blocked by Tat- SOD but not by 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO), a scavenger of NO. On the other hand, LPS/IFN-gamma caused the activation of procaspase-3, which was blocked by PTIO but not by Tat-SOD. Taken together, phagocytosis of SOZ and IOZ particles induced apoptosis through superoxide but not NO in macrophages, accompanied with the release of cytochrome c and the activation of caspase-3.
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PMID:Phagocytosis of serum- and IgG-opsonized zymosan particles induces apoptosis through superoxide but not nitric oxide in macrophage J774A.1. 1285 21

IL-3-dependent mucosal-like mast cells undergo apoptosis upon withdrawal of IL-3. Generally, the apoptosis is mediated by the activation of caspases and inhibited by addition of the pan-caspase inhibitors z-VAD-FMK or BOC-D-FMK. However, DNA fragmentation, a typical characteristic of apoptosis, is not inhibited by z-VAD-FMK or BOC-D-FMK in mast cell apoptosis. In this study, we demonstrate that the apoptosis of mast cells is mediated by both caspase-dependent and -independent mechanisms. The caspase-independent apoptosis is mediated by the translocation of endonuclease G from mitochondria into nuclei. Withdrawal of IL-3 caused down-regulation of Bcl-xL, resulting in a drop in mitochondrial membrane transition potential followed by the release of cytochrome c and endonuclease G from mitochondria. However, stimulation of mast cells through Toll-like receptor 4 (TLR4) by lipopolysaccharide prevented mast cell apoptosis by inducing expression of Bcl-xL. Moreover, the activation of mast cells by LPS is enhanced in the presence of IFN-gamma, which up-regulates the expression of cell surface TLR4. Taken together, these observations provide evidence that mast cells play important roles not only in allergic reactions but also in innate immunity recognizing enterobacteria through TLR4, and are regulated differently from allergic inflammation by Th1 cytokines.
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PMID:Caspase-dependent and -independent apoptosis of mast cells induced by withdrawal of IL-3 is prevented by Toll-like receptor 4-mediated lipopolysaccharide stimulation. 1288 89

A hallmark of tumorigenesis is resistance to apoptosis. To explore whether resistance to cell death precedes tumor formation, we have studied the short-term effects of the hepatocarcinogen 2-acetylaminofluorene (AAF) on liver mitochondria, on hepatocytes, and on the response to bacterial endotoxin lipopolysaccharide (LPS) in albino Wistar rats. We show that after as early as two weeks of AAF feeding liver mitochondria developed an increased resistance to opening of the permeability transition pore (PTP), an inner membrane channel that is involved in various forms of cell death. Consistent with a mitochondrial adaptive response in vivo, (i) AAF feeding increased the expression of BCL-2 in mitochondria, and (ii) hepatocytes isolated from AAF-fed rats became resistant to PTP-dependent depolarization, cytochrome c release, and cell death, which were instead observed in hepatocytes from rats fed a control diet. AAF-fed rats were fully protected from the hepatotoxic effects of the injection of 20-30 microg of LPS plus 700 mg of d-galactosamine (d-GalN) x kg-1 of body weight, a treatment that in control rats readily caused a large increase of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells in liver cryosections and release of alanine and aspartate aminotransferase into the bloodstream. Treatment with LPS and d-GalN triggered cleavage of BID, a BCL-2 family member, in the livers of both control- and AAF-fed animals, whereas caspase 3 was cleaved only in control-fed animals, indicating that the mitochondrial proapoptotic pathway had been selectively suppressed during AAF feeding. Phenotypic reversion was observed after stopping the carcinogenic diet. These results underscore a key role of mitochondria in apoptosis and demonstrate that regulation of the mitochondrial PTP is altered early during AAF carcinogenesis, which matches, and possibly causes, the increased resistance of hepatocytes to death stimuli in vivo. Both events precede tumor formation, suggesting that suppression of apoptosis may contribute to the selection of a resistant phenotype, eventually increasing the probability of cell progression to the transformed state.
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PMID:Early resistance to cell death and to onset of the mitochondrial permeability transition during hepatocarcinogenesis with 2-acetylaminofluorene. 1290 2

2-Oxo-3,23-isopropylidene-asiatate (AS2006A), a wound-healing asiatate derivative, exerts anti-inflammatory effect. Macrophages produce cytokines that recruit other inflammatory cells and are responsible for the diverse effects of inflammation. In the present study, we comparatively evaluated the cytotoxicity of AS2006A to Raw264.7, H4IIE and L-929 cells as part of the studies on its anti-inflammatory effect. Among the cells examined, AS2006A was selectively cytotoxic to Raw264.7 cells, a macrophage cell line. AS2006A increased the number of cells positively stained with TdT-mediated dUTP nick end labeling (TUNEL), and upregulated the expression of the genes implicated with apoptosis, which included caspase-8, c-myc, iNOS, mdm2, NF-kappaB1, I-kappaBalpha and NF-kappaB p105 genes, as assessed by the membrane DNA array technique. The expression of the genes related with cell cycle control was not changed. Thus, the primary targets of AS2006A in macrophages might include the genes implicated with apoptosis. Immunoblot analysis revealed that AS2006A caused the release of cytochrome c from the mitochondria to the cytoplasm in macrophages. Caspase-3 activity and poly(ADP-ribose) polymerase cleavage were both increased by AS2006A in macrophages, indicating that AS2006A induced apoptosis. Viability of macrophages activated by lipopolysaccharide and their NO production were also decreased by AS2006A in a concentration-dependent manner. These results demonstrated that AS2006A selectively induces apoptosis of macrophages with cytochrome c release, caspase 3 activation and poly(ADP-ribose) polymerase cleavage, and that cytotoxicity of AS2006A to macrophages may contribute to anti-inflammatory and wound-healing effects.
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PMID:2-Oxo-3,23-isopropylidene-asiatate (AS2006A), a wound-healing asiatate derivative, exerts anti-inflammatory effect by apoptosis of macrophages. 1294 39

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