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)

Sepsis and endotoxemia are involved in the development of fulminant hepatic failure, the prognosis of which is extremely poor and the mortality is high, with no available effective therapy. Here, we report that hepatocyte growth factor (HGF) exerts potent antiapoptotic effects in vivo and effectively prevents endotoxin-induced fulminant hepatic failure in mice. The animals were intraperitoneally injected three times with 120 micrograms human recombinant HGF or saline 6 hours and 30 minutes before and 3 hours after an intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (GalN). Administration of LPS + GalN, without HGF, rapidly led to massive hepatocyte apoptosis and severe liver injury, and all mice died of hepatic failure within 8 hours. In contrast, administration of human recombinant HGF strongly suppressed extensive progress of hepatocyte apoptosis and the liver injury induced by LPS + GalN, and 75% of the HGF-treated mice survived. Moreover, HGF strongly induced Bcl-xL expression and blocked apoptotic signal transduction upstream of CPP32 (caspase-3) in the liver, thereby leading to inhibition of massive hepatocyte apoptosis. We suggest that HGF may well have the potential to prevent fulminant hepatic failure, at least through its potent antiapoptotic action.
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PMID:Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. 1038 75

Cycloheximide (CHX) is known to stimulate or to prevent apoptosis, according to the cell type used. We found that CHX, in a dose-dependent way, exerted the two opposite effects in B lymphocytes. CHXhigh (2.5 microg/mL) inhibited protein synthesis (>90%) and greatly increased B cell apoptosis but failed to prevent apoptosis induction by dexamethasone (DEX) or dibutyryl-cAMP (dbcAMP), which is in opposition with CHX activity in thymocytes. On the contrary, CHXlow (0.05 microg/mL), modestly inhibited protein synthesis (<15%) and reduced spontaneous as well as drug-induced apoptosis and further augmented the protection conferred by interleukin-4 or lipopolysaccharide. To examine the role of caspases in CHX effects, we used the broad spectrum peptide caspase inhibitor Z-VAD-fmk: it totally abrogated spontaneous as well as drug- and CHXhigh-induced cell death. Apoptosis was associated with CPP32/caspase-3 activation, since cleavage of CPP32/caspase-3 and caspase-3 activity were increased by DEX, dbcAMP as well as by CHXhigh treatment. Meanwhile, caspase-3 activity was reduced by CHXlow treatment. Therefore, CHX exerts opposite effects on B lymphocyte apoptosis which are associated with a dual action on caspase-3 activation.
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PMID:Specific dual effect of cycloheximide on B lymphocyte apoptosis: involvement of CPP32/caspase-3. 1040 22

We applied the animal model of H. pylori lipopolysaccharide-induced gastritis to assess the effect of antiulcer agent, sulglycotide, on the mucosal inflammatory responses by analyzing the interplay between the activity of a key apoptotic caspase, caspase-3, epithelial cell apoptosis, and the expression of constitutive (cNOS) and inducible (NOS-2) nitric oxide synthase. H. pylori lipopolysaccharide applied intragastrically elicited within 4 days a pattern of mucosal responses resembling that of acute gastritis. This was accompanied by an 11.2-fold increase in epithelial cell apoptosis, a 6.5-fold induction in mucosal expression of NOS-2 and a 2.2-fold decline in cNOS, and a 5.4-fold increase in caspase-3 activity. Treatment with sulglycotide led to a 56.7% reduction in the extent of mucosal inflammatory changes elicited by H. pylori lipopolysaccharide and an 88.3% decrease in the epithelial cells apoptosis. Furthermore, this effect of sulglycotide was associated with a 51% decrease in mucosal expression of caspase-3 activity, a 73.7% decline in NOS-2, and a 64.1% increase in cNOS. The findings suggest that sulglycotide suppresses the H. pylori-induced mucosal inflammatory responses by up-regulating cNOS and interfering with the events propagated by NOS-2 and caspase-3.
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PMID:Gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide: down-regulation of nitric oxide synthase-2 and caspase-3 by sulglycotide. 1040 16

Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a disease with marked expansion of granulocytes and macrophages that frequently progresses to a fatal blast crisis, thus resembling human chronic myelogenous leukemia (CML). One important feature of CML is decreased responsiveness of myeloid cells to apoptotic stimuli. Here we show that myeloid cells from mice deficient in ICSBP exhibit reduced spontaneous apoptosis and a significant decrease in sensitivity to apoptosis induced by DNA damage. In contrast, apoptosis in thymocytes from ICSBP-deficient mice is unaffected. We also show that overexpression of ICSBP in the human U937 monocytic cell line enhances the rate of spontaneous apoptosis and the sensitivity to apoptosis induced by etoposide, lipopolysaccharide plus ATP, or rapamycin. Programmed cell death induced by etoposide was specifically blocked by peptides inhibitory for the caspase-1 or caspase-3 subfamilies of caspases. Studies of proapoptotic genes showed that cells overexpressing ICSBP have enhanced expression of caspase-3 precursor protein. In addition, analyses of antiapoptotic genes showed that overexpression of ICSBP results in decreased expression of Bcl-X(L). These data suggest that ICSBP modulates survival of myeloid cells by regulating expression of apoptosis-related genes.
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PMID:Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. 1043 Jun 29

Tumor necrosis factor (TNF) is a highly pleiotropic cytokine whose activity is at least partially regulated by the redox status of the cell. The cellular redox status is controlled primarily by glutathione, a major cellular antioxidant, whose synthesis is regulated by the rate-limiting enzyme gamma-glutamylcysteine synthetase (gamma-GCS). In the present report we investigated the effect of gamma-GCS overexpression on the TNF-induced activation of nuclear transcription factors NF-kappa B and AP-1, stress-activated protein kinase/c-Jun amino-terminal kinase (JNK) and apoptosis. Transfection of cells with gamma-GCS cDNA blocked TNF-induced NF-kappa B activation, cytoplasmic I kappa B alpha degradation, nuclear translocation of p65, and NF-kappa B-dependent gene transcription. gamma-GCS overexpression also completely suppressed NF-kappa B activation induced by phorbol ester and okadaic acid, whereas that induced by H2O2, ceramide, and lipopolysaccharide was minimally affected. gamma-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF-induced activation of JNK and mitogen-activated protein kinase kinase. TNF-mediated cytotoxicity and activation of caspase-3 were both abrogated in gamma-GCS-overexpressing cells. Overall, our results indicate that most of the pleiotropic actions of TNF are regulated by the glutathione-controlled redox status of the cell.
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PMID:Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1. 1043 45

1. Endothelial cell damage in glomeruli and kidney arterioles appears to play a pivotal role in glomerular inflammatory diseases. Glomerular endothelial cells, a specialized microvascular cell type involved in the regulation of glomerular ultrafiltration, die by apoptosis in response to tumour necrosis factor-alpha (TNF-alpha), TNF-alpha/basic fibroblast growth factor (bFGF), TNF-alpha/cycloheximide, and bacterial lipopolysaccharide (LPS). Apoptotic cell death is characterized by extensive DNA cleavage, DNA ladder formation, and characteristic morphological alterations. 2. In search for apoptosis-preventing signals, we identified glucocorticoids as potent death preventing factors. Co-treatment of cells with 10 nM dexamethasone and TNF-alpha, TNF-alpha/bFGF, TNF-alpha/cycloheximide, or LPS blocked roughly 90% of apoptotic cell death in glomerular endothelial cells. 3. Similarly to dexamethasone (TNF-alpha- and LPS-induced apoptosis are prevented with IC50 values of 0.8 and 0.9 nM, respectively), other synthetic and natural forms of glucocorticoids, such as fluocinolone, prednisolone, hydrocortisone, and corticosterone potently inhibited cell death with IC50 values of 0.2, 6, 50 and 1000 nM, for TNF-alpha and 0.7, 8, 100 and 500 nM for LPS, respectively. 4. Apart from glucocorticoids, mineralocorticoids such as aldosterone also blocked TNF-alpha/LPS-induced apoptosis (IC50 approximately 500 nM for TNF-alpha and approximately 500 nM for LPS), whereas sex hormones, i. e. beta-estradiol and testosterone remained without effect. 5. The protective effect of glucocorticoids (and mineralocorticoids) required glucocorticoid receptor binding as it could be antagonized by the glucocorticoid receptor antagonist RU-486. Concerning TNF-alpha and LPS signal transduction, we found that dexamethasone efficiently prevented TNF-alpha- and LPS-induced activation of caspase-3-like proteases. Therefore, we postulate inhibitory mechanisms upstream of terminal death pathways.
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PMID:Glucocorticoids potently block tumour necrosis factor-alpha- and lipopolysaccharide-induced apoptotic cell death in bovine glomerular endothelial cells upstream of caspase 3 activation. 1045 20

The earliest observed apoptotic change in a macrophage-like cell line, J774.1, treated with lipopolysaccharide (LPS) in the presence of cycloheximide (CHX) was a selective increase in caspase-3-like activity. The addition of polymyxin B, TPCK, herbimycin A, or genistein, all of which inhibited LPS-induced tumor necrosis factor alpha (TNF-alpha) production by macrophages, suppressed the activation of the caspase-3-like protease in these macrophages treated simultaneously with CHX. However, SB202190 and SB203580, inhibitors of MAP kinase, and PD98059, an inhibitor of MAP-kinase kinase (MEK), showed no effect on the activation of the caspase-3-like protease or on the cell damage of the macrophages treated with LPS and CHX, whereas they inhibited LPS-induced TNF-alpha production. These results suggest that some of the early signals in LPS-treated macrophages are common to the subsequent pathways for TNF-alpha production and caspase-3-like protease activation, but the later signals, like MAP-kinase kinase or MAP-kinase, are not involved in the pathways for caspase-3-like protease activation.
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PMID:LPS-induced signals in activation of caspase-3-like protease, a key enzyme regulating apoptotic cell damage into a macrophage-like cell line, J774.1, in the presence of cycloheximide. 1053 27

Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-delta12,14 prostaglandin J2 (PGJ2) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ2 can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPARgamma in vivo and in vitro, our data suggest that activation of CGC PPARgamma mediates iNOS suppression and reduced cell death. Because PPARgamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in AD.
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PMID:Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. 1069 26

The addition of lipopolysaccharide (LPS) together with cycloheximide (CHX) induced apoptosis in a subline of a J774.1 macrophage-like cell line, JA-4, as judged by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL)-staining and poly(adenosine 5'-diphosphate (ADP)-ribose) polymerase (PARP)-cleavage. Caspase activities were examined in these macrophages in vitro using fluorogenic substrates such as acetyl-DEVD-aminomethyl coumarine (Ac-DEVD-AMC, caspase-3-like), acetyl-YVAD-aminomethyl coumarine (Ac-YVAD-AMC, caspase-1-like), acetyl-VEID-aminomethyl coumarine (Ac-VEID-AMC, caspase-6-like), and carbobenzoxy-IETD-aminofluoro coumarine (Z-IETD-AFC; caspase-8-like). Kinetic studies revealed these caspase activities with different Km and Vmax values in extracts of apoptotic macrophages. In the course of apoptosis, caspase-3-like activity increased first at 75 min, simultaneously with the appearance of TUNEL staining and prior to PARP cleavage, and then caspase-6 and 8-like activities increased at 90 and 105 min, respectively. However, caspase-1-like activity did not change throughout the experiment. Furthermore, removal of LPS and CHX by extensive washing of the cells for 60 min completely abolished the apoptosis and the subsequent release of lactate dehydrogenase (LDH) during additional incubation until 4 h after LPS addition. However, washing of the cells after 75 min or later resulted in the progress of apoptosis and LDH release, which was coordinated with the elevation of caspase-3-like activity at 60 min and that of caspase-6 or 8-like activity at 90 min, but not with that of caspase-1-like activity. These results suggest that caspase-3-like activity represents the most apical caspase among these caspases in terms of the intiation of apoptosis in macrophages treated with LPS and CHX. In the present study, we also provide evidence on the relatively low specificities of a series of caspase inhibitors other than acetyl-DEVD-aldehyde (Ac-DEVD-CHO) which specifically inhibited the caspase-3-like activity.
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PMID:Changes of caspase activities involved in apoptosis of a macrophage-like cell line J774.1/JA-4 treated with lipopolysaccharide (LPS) and cycloheximide. 1070 74

Tumour necrosis factor-alpha (TNF-alpha)- and lipopolysaccharide (LPS)-induced apoptosis of bovine glomerular endothelial cells is now recognized as an important part in the pathogenesis of glomerulonephritis characterized by early mitochondrial cytochrome c release, mitochondrial permeability transition, Bak protein upregulation, Bcl-X(L) protein downregulation and caspase-3 activation. Co-treatment of cells with 10 nM dexamethasone and TNF-alpha or LPS blocked roughly 90% of apoptotic cell death in glomerular endothelial cells. The action of glucocorticoids could be documented in that they prevented all apoptotic markers such as DNA laddering, DNA fragmentation measured by the diphenylamine assay as well as morphological alterations. To mechanistically elucidate the action of glucocorticoids we evaluated whether glucocorticoids elicit a time-dependent effect. For dexamethasone, to maximally inhibit DNA fragmentation a preincubation period was not required. Even if dexamethasone was supplemented 6 h following TNF-alpha or LPS we observed a maximal inhibitory effect. Concerning its influence on TNF-alpha and LPS signal transduction, we found that dexamethasone only partially prevented cytochrome-c-release as a first sign of apoptotic cell death but efficiently blocked mitochondrial permeability transition. Moreover, TNF-alpha- and LPS-induced Bak upregulation, Bcl-X(L)-downregulation, and the activation of caspase-3-like proteases, measured fluorometrically using DEVD-AMC and PARP cleavage, were efficiently blocked by dexamethasone. We postulate that glucocorticoids exert their inhibitory action upstream of the terminal death pathways but downstream of primary receptor mediated signals by blocking pro-apoptotic signals pre- and/or post cytochrome c release and mitochondrial signalling.
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PMID:Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways. 1078 Sep 73


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