Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Although tumor necrosis factor (TNF)-alpha is implicated in numerous cardiac pathologies, the intracellular events leading to its production by heart cells are largely unknown. The goal of the present study was to identify the role of the transcription factor nuclear factor (NF)-kappaB in this process. Among the many inducers of TNF-alpha expression in myeloid cells, only lipopolysaccharide (LPS) led to its induction in cultured neonatal myocytes. LPS also activated the NF-kappaB pathway, as evidenced by the degradation of the inhibitory protein IkappaB and the appearance of NF-kappaB-binding complexes in nuclear extracts. Furthermore, inhibitors of NF-kappaB activation, such as lactacystin, MG132, and pyrrolidine dithiocarbamate, were found to completely block the production of TNF-alpha in response to LPS stimulation, indicating a requirement of NF-kappaB for TNF-alpha expression. However, interleukin-1beta and phorbol 12-myristate 13-acetate also activated NF-kappaB but did not evoke TNF-alpha expression, revealing that this factor is not sufficient for cytokine production. Detailed examination of the NF-kappaB cascade revealed that cardiac cells displayed a unique pattern of IkappaB degradation in response to LPS, with IkappaBbeta but not IkappaBalpha being degraded upon stimulation. Additionally, two specific p65-containing DNA-binding complexes were observed in the nuclear extracts of neonatal cardiomyocytes: an inducible complex that is necessary for TNF-alpha expression and a constitutive species. Taken together, these results reveal that NF-kappaB is not only involved in cytokine production but also may be linked to other pathways that subserve a constitutive, protective mechanism for the heart cell.
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PMID:Endotoxin stress-response in cardiomyocytes: NF-kappaB activation and tumor necrosis factor-alpha expression. 1183 81

The regulation of cytokine gene transcription and biosynthesis involves the reduction-oxidation (redox)-sensitive nuclear factor-kappaB (NF-kappaB), whose activation is mediated by an upstream kinase that regulates the phosphorylation of inhibitory-kappaB (IkappaB). It was hypothesized that lipopolysaccharide (LPS)-induced biosynthesis of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in vitro is regulated by redox equilibrium. In alveolar epithelial cells, we investigated the role of L-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), which inhibits glutathione oxidized disulfide reductase, pyrrolidine dithiocarbamate (PDTC), an antioxidant/prooxidant thiuram, and N-acetyl-L-cysteine (NAC), an antioxidant and GSH precursor, in regulating LPS-induced cytokine biosynthesis and IkappaB-alpha/NF-kappaB signaling. BSO blockaded the phosphorylation of IkappaB-alpha, reduced its degradation, and inhibited NF-kappaB activation, besides augmenting LPS-mediated biosynthesis of cytokines. BCNU up-regulated LPS-induced release of cytokines, an effect associated with partial phosphorylation/degradation of IkappaB-alpha and inhibition of the DNA binding activity. PDTC, which partially affected LPS-induced IkappaB-alpha phosphorylation/degradation, otherwise blockading NF-kappaB activation, reduced LPS-dependent up-regulation of cytokine release. Pretreatment with BSO did not abolish the NAC-dependent reduction of LPS-induced cytokine release, despite the fact that NAC marginally amplified IkappaB-alpha phosphorylation/degradation and suppressed NF-kappaB activation. These results indicate that cytokines are redox-sensitive mediators and that the IkappaB-alpha/NF-kappaB pathway is redox-sensitive and differentially implicated in mediating redox-dependent regulation of LPS-induced release of proinflammatory cytokines.
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PMID:Redox signaling-mediated regulation of lipopolysaccharide-induced proinflammatory cytokine biosynthesis in alveolar epithelial cells. 1197 Aug 52

Nitric oxide (NO; 1 microM) or an NO donor (500 microM diethylenetriamine-nitric oxide, DETA-NONOate) caused rapid glutamate and ATP release from cultured rat cortical astrocytes. NO-induced glutamate release was prevented by calcium chelators (EGTA or BAPTA-AM) and an inhibitor of vesicular exocytosis (botulinum neurotoxin C, BoTx-C), but not by a glutamate transport inhibitor, L-trans-pyrrolidine-2,4-dicarboxylate (t-PDC), a cyclooxygenase inhibitor (indomethacin), or an inhibitor of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), and was not induced by mitochondrial respiratory inhibitors (myxothiazol or azide). Similarly to glutamate, NO-induced ATP release was also completely blocked by BAPTA-AM and BoTx-C, suggesting again a vesicular, calcium-dependent mechanism of release. Addition of DETA-NONOate (500 microM) to fura-2-loaded astrocytes induced a rapid, transient increase in intracellular calcium levels followed by a lower, sustained level of calcium entry. The latter was blocked by gadolinium (1 microM), an inhibitor of capacitative Ca(2+) entry. Thus, NO appears to cause rapid exocytosis of vesicular glutamate and ATP from astrocytes by raising intracellular calcium levels. Astrocytes activated by lipopolysaccharide/endotoxin and interferon-gamma to express inducible NO synthase (iNOS) maintained substantially higher extracellular glutamate levels than nonactivated cells or activated cells treated with an iNOS inhibitor (1400W), but the rate of glutamate uptake by these cells was similar. This suggests that NO from inflammatory-activated astrocytes causes release of astrocytic glutamate. NO-induced release of astrocytic glutamate and ATP may be important in physiological or pathological communication between astrocytes and neurons.
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PMID:Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes. 1242 Mar 11

Preadministration of antioxidants such as pyrrolidine dithiocarbamate (PDTC) and phenyl N-tert-butyl nitrone (PBN) protects animals from lethality in sepsis models. However, the requirement of preadministration greatly diminishes the clinical significance of these studies. Although the synthetic antioxidant PBN has been shown to effectively protect rodents from lethality in endotoxemia (lipopolysaccharide [LPS] model), preliminary screening indicates that pre- or postadministration of PBN does not protect in the rat cecal ligation and puncture (CLP) model. We show in this report that in a rat CLP model, the administration of PBN (150 mg/kg, 30 min after CLP) followed by the antibiotic imipenem (IMP; 10 mg/kg, 1 h after CLP) significantly increased survival compared with other single treatment groups. Previously, we have shown that PBN's protection in a rat LPS model is mediated by the overproduction of the anti-inflammatory cytokine interleukin (IL)-10. We show in this study that the increase in survival found in the PBN + IMP-treated group was abrogated by immunoneutralization with anti-IL-10 antibody, indicating that endogenous IL-10 is an effective protective factor. Plasma LPS levels were shown to be elevated after imipenem treatment, and the increased LPS level could have assisted to overproduce endogenous IL-10, as in the case of the PBN-treated LPS model. Statistical analysis indicated that the increase of IL-10 in PBN + IMP-treated group at early time period has significant association to the improvement of survival.
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PMID:Antioxidant amplifies antibiotic protection in the cecal ligation and puncture model of microbial sepsis through interleukin-10 production. 1263 May 25

We have previously shown that interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha mRNA levels in rat alveolar macrophages are increased in by endotoxin (lipopolysaccharide; LPS)- stimulation and further enhanced by culturing with low-Mg2+ medium. We have now investigated the mechanisms of underlying this enhancement by using some specific signal transduction inhibitors. The enhanced elevation of both mRNAs levels was suppressed by pretreatment with TMB-8 (which inhibits calcium release from the endoplasmic reticulum) or dexamethasone (which inhibits nuclear factor [NF]-kappaB and activator protein [AP]-1), but not with verapamil or nifedipine (which inhibits calcium channels). The enhancment of IL-1beta, but not TNF-alpha mRNA levels, was suppressed by pretreatment with W-7 (which inhibits calmodulin), whereas the enhancement of TNF-alpha mRNA levels was suppressed by pretreatment with U73122 (which inhibits phospholipase C). Curcumin (an inhibitor of AP-1), suppressed the increases in both mRNAs induced by low-Mg2+ medium alone, but had no suppressive effect on the levels of either mRNA after LPS-stimulation in low-Mg2+ medium. Pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB) prevented the elevation of TNF-alpha mRNA levels induced by low-Mg2+ medium without LPS-stimulation, but had no suppressive effect on IL-1beta mRNA levels. From these results, we conclude that the enhanced elevation of IL-1beta and TNF-alpha mRNA levels seen in LPS-stimulated alveolar macrophages in low-Mg2+ medium occurs partly via the same, and partly via different, signaling pathways.
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PMID:Mechanisms underlying the enhanced elevation of IL-1beta and TNF-alpha mRNA levels following endotoxin challenge in rat alveolar macrophages cultured with low-Mg2+ medium. 1263 66

beta-Glucans are major structural components of fungi. We have recently reported that the pathogenic fungus Pneumocystis carinii assembles a beta-glucan-rich cell wall that potently activates alveolar macrophages to release pro-inflammatory cytokines and chemokines. Purified P. carinii beta-glucans predictably induce both cytokine generation and associated neutrophilic lung inflammation. Herein, we demonstrate that P. carinii beta-glucan-induced macrophage stimulation results from activation of NF-kappaB. Although analogous to macrophage activation induced by bacterial lipopolysaccharide (LPS), P. carinii beta-glucan-induced macrophage NF-kappaB activation exhibits distinctly different kinetics, with slower induction and longer duration compared with LPS stimulation. Macrophage activation in response to P. carinii beta-glucan was also substantially inhibited with the NF-kappaB antagonist pyrrolidine dithiocarbamate. In addition to different kinetics of NF-kappaB activation, P. carinii beta-glucan and LPS also utilize different receptor systems to induce macrophage activation. Macrophages from Toll-like receptor 4-deficient and wild type mice produced equivalent amounts of tumor necrosis factor alpha when stimulated with P. carinii beta-glucan. However, Toll-like receptor 4-deficient macrophages were refractory to stimulation with LPS. In contrast, MyD88-deficient macrophages exhibited a significant (though partial) blunted response to P. carinii beta-glucan. These data demonstrate that P. carinii beta-glucan acts as potent inducer of macrophage activation through NF-kappaB utilizing cellular receptors and signaling pathways distinct from LPS.
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PMID:Pneumocystis carinii cell wall beta-glucans initiate macrophage inflammatory responses through NF-kappaB activation. 1271 85

1. In rat aortic smooth muscle cells (RASMCs), the putative nuclear factor kappa B (NFkappaB) inhibitor Pyrrolidine dithiocarbamate (PDTC) was found to inhibit lipopolysaccharide (LPS)-stimulated NFkappaB DNA-binding. However, further investigation identified the site of inhibition as being at, or upstream of, the inhibitory kappa B kinases (IKKs) as their kinase activity was substantially reduced. 2. In addition, PDTC potentiated LPS-stimulated c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAP kinase) and MAP kinase-activated protein kinase-2 activity (the downstream target of p38 MAP kinase). 3. Another inhibitor of NFkappaB signalling, the serine protease inhibitor Nalphap-tosyl-L-lysine chloro-methylketone (TLCK), also inhibited LPS-stimulated IKK activity and potentiated JNK activity in response to LPS, suggesting that cross-talk may occur between the NFkappaB and stress-activated protein kinase pathways at the level of IKK or at a common point upstream. 4. Infection of RASMCs with an adenovirus encoding either inhibitory kappa Balpha or a dominant-negative IKKbeta potentiated LPS-stimulated JNK activity. 5. These studies therefore suggest that the loss of NFkappaB DNA-binding and resultant transcriptional activity, rather than the loss of IKK activity, is sufficient to cause an increase in JNK activity. This shows that either pharmacological or molecular inhibition of NFkappaB DNA-binding enhances JNK activation in vascular smooth muscle cells, an effect that may contribute to the pathophysiological effects of LPS.
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PMID:Enhancement of lipopolysaccharide-stimulated JNK activity in rat aortic smooth muscle cells by pharmacological and adenovirus-mediated inhibition of inhibitory kappa B kinase signalling. 1283 79

Caffeic acid phenethyl ester (CAPE) is an antioxidant component of propolis, a natural product secreted by honeybee. Recent literature shows that CAPE inhibits nuclear factor kappa B (NFkappaB) activation in cell lines. Since NFkappaB was shown to be a crucial factor in neuroinflammation and to be associated with some neuropathologies, CAPE might reduce these disorders in brain too and have therapeutic applications. To test this hypothesis we used a model of endotoxic insult (interferon-gamma, followed by lipopolysaccharide) on rat organotypic hippocampal cultures. Cerebral inflammatory responses were strongly inhibited by CAPE (100 microM): reductions of NFkappaB nuclear activity, tumor necrosis factor alpha and nitric oxide productions were observed. At the dose of maximal effects (100 microM), an increase of cAMP-responsive element binding protein (CREB) activity, which anti-inflammatory role is well known, was seen. We compared CAPE effects with those of other drugs: anti-inflammatory as acetyl-salicylate and dexamethasone (glucocorticoid), antioxidant as pyrrolidine dithiocarbamate, or selective permeant inhibitor of NFkappaB as SN 50 peptide. These studies lead us to conclude that CAPE presents an interesting and original neuropharmacological profile compared to these drugs and might be helpful in the prevention of neurotoxic events due to excessive inflammatory reaction in brain. CAPE interferes with several effectors of neuroinflammation that might have complementary and synergic effects and allows a rather durable control since an acute treatment at the time of endotoxin exposure allows to control inflammatory factors for over 48 h.
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PMID:Caffeic acid phenethyl ester (CAPE) prevents inflammatory stress in organotypic hippocampal slice cultures. 1287 82

Regulation of intracellular protein stability by the ubiquitin-dependent proteasome system plays a crucial role in cell function. HO-1 (haem oxygenase) is a stress response protein, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homoeostasis. In the present study, we found a novel action of proteasome inhibitors MG132 and MG262 on HO-1 induction, and characterized the underlying mechanisms. MG132 (> or =0.1 microM) treatment resulted in a marked time- and concentration-dependent induction of the steady-state level of HO-1 mRNA in RAW264.7 macrophages, followed by a corresponding increase in HO-1 protein. Actinomycin D and cycloheximide inhibited MG132-responsive HO-1 protein expression, indicating a requirement for transcription and de novo protein synthesis. The involvement of signal pathways in MG132-induced HO-1 gene expression was examined using chemical inhibitors. Antioxidant N -acetylcysteine and SB203580, an antioxidant and inhibitor of p38 MAPK (mitogen-activated protein kinase), abolished MG132-inducible HO-1 expression. Furthermore, MG132 activated the p38 MAPK pathway. The half-life of HO-1 protein was prolonged by MG132, indicating that the upregulation of HO-1 by proteasome inhibitor is partially attributable to the inhibition of protein degradation. MG132 can ablate IkappaBalpha degradation and NF-kappaB (nuclear factor kappaB) activation induced by lipopolysaccharide, similar to the effect of another NF-kappaB inhibitor pyrrolidine dithiocarbamate. We found HO-1 upregulation by MG132 and pyrrolidine dithiocarbamate is unrelated to their inhibition of NF-kappaB, since leptomycin B, another NF-kappaB inhibitor, did not elicit similar induction of HO-1. Taken together, we found a novel effect of proteasome inhibitor on induction of HO-1 expression. This action is ascribed to the activation of the p38 MAPK pathway, but is not dependent on NF-kappaB inhibition.
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PMID:Proteasome inhibitors up-regulate haem oxygenase-1 gene expression: requirement of p38 MAPK (mitogen-activated protein kinase) activation but not of NF-kappaB (nuclear factor kappaB) inhibition. 1473 Nov 12

We have previously demonstrated irradiation-induced up-regulation of CD80 expression in A20-HL B lymphoma cells by inducing expression of tumour necrosis factor-alpha (TNF-alpha) and CD154. In the present study, we investigated whether irradiation also up-regulates CD80 expression in mouse spleen B cells. Because freshly prepared spleen B cells are highly sensitive to irradiation, we employed spleen B cells stimulated with lipopolysaccharide (LPS-B cells). X-irradiation (8 Gy) followed by incubation (9-12 hr) highly and selectively up-regulated CD80 expression in LPS-B cells, whereas the same treatment slightly increased expression of CD54 and did not affect expression of CD86, major histocompatibility complex class II, CD11a or surface immunoglobulin M. The irradiation-induced up-regulation of CD80 expression resulted in enhanced APC function of LPS-B cells. Up-regulation of CD80 expression on LPS-B cells was accompanied by an increase in CD80 mRNA accumulation and nuclear factor (NF)-kappaB activation. Activation of NF-kappaB was shown to be critical for up-regulation of CD80 expression as pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB, severely decreased the observed up-regulation. X-irradiation of LPS-B cells induced expression of TNF-alpha but not CD154. However, anti-TNF-alpha monoclonal antibody (mAb) with anti-CD154 mAb did not inhibit X-irradiation-induced up-regulation of CD80 expression in LPS-B cells, whereas these mAbs almost completely inhibited this up-regulation in A20-HL cells and bone marrow-derived dendritic cells (DCs). In contrast, a thiol antioxidant, N-acetyl-l-cysteine, completely blocked X-irradiation-induced up-regulation of CD80 expression in LPS-B cells, but not in A20-HL cells or in DCs. Based on these findings, we concluded that X-irradiation up-regulates CD80 expression not only in A20-HL cells and DCs but also in LPS-B cells, and that this up-regulation in LPS-B cells via NF-kappaB activation is dependent on the generation of reactive oxygen species, while that in A20-HL cells and DCs is not.
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PMID:Irradiation up-regulates CD80 expression through two different mechanisms in spleen B cells, B lymphoma cells, and dendritic cells. 1514 65


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