Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beneficial effects of moderate red wine consumption have been attributed, in part, to the presence of antioxidant components. Oxidant stress is an activating stimulus for the NF (nuclear factor)-KB/Rel family of transcription factors, which have binding sites in the promoter regions of many genes involved in inflammatory and immune responses. The effect of lipopolysaccharide (LPS)-stimulated activation of NF-KB and the subsequent production of tumor necrosis factor alpha (TNF-alpha) and NO was determined in the macrophage cell line RAW 264.7. Unexpectedly, the wine polyphenolics quercetin and resveratrol and the antioxidant N-acetylcysteine (NAC) did not inhibit LPS-induced activation of the NF-KB complex p50/65, as determined by mobility shift. Quercetin inhibited LPS-induced p50/50. Northern blot analysis indicated that quercetin (0.1 and 0.2 mM) inhibited LPS-dependent production of inducible nitric oxide synthase (iNOS) mRNA and decreased NO release, as measured by the Griess reaction. This flavonoid had no effect on LPS-induced TNF-alpha mRNA, but decreased LPS-stimulated TNF-alpha release, as measured by ELISA. Resveratrol (0.05 and 0.1 mM) posttranscriptionally decreased LPS-induced nitrite release. It increased basal levels of TNF-alpha mRNA and protein and enhanced LPS-induced TNF-alpha mRNA and cytokine release. Our results do not support the view that wine antioxidants inhibit LPS-induced NF-KB activation but instead that they have a more selective action on genes activated by LPS.
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PMID:Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages. 1008 29

Resveratrol, naringenin and naringin are naturally occurring flavonoids in grapes and grapefruits. The anti-inflammatory effects of these flavonoids have been well documented, but the mechanism is poorly characterized. High concentration of NO are produced by inducible NO synthase (iNOS) in inflammation, and the prevention of the expression of iNOS may be an important anti-inflammatory mechanism. In this study, the effects of these flavonoids on the induction of NO synthase (NOS) in RAW 264.7 cells activated with bacterial lipopolysaccharide (LPS, 50 ng ml(-1)) were investigated. Resveratrol was found strongly to inhibit NO generation in activated macrophages, as measured by the amount of nitrite released into the culture medium, and resveratrol strongly reduced the amount of cytosolic iNOS protein and steady state mRNA levels. However, the inhibitory abilities of naringenin were lower, and the inhibitory abilities of naringin were almost negligible. In electrophoretic mobility shift assays, the activation of NFkappaB induced by LPS for 1 h was inhibited by resveratrol (30 microM). Furthermore, in immunoblotting analysis, cells treated with LPS plus resveratrol showed an inhibition of phosphorylation as well as degradation of IkappaBalpha, and a reduced nuclear content of NFkappaB subunits. The flavonoids may be of value for inhibiting the enhanced expression of iNOS in inflammation through down-regulation of NFkappaB binding activity.
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PMID:Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol. 1018 78

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring compound shown to inhibit carcinogen-induced preneoplastic lesion formation in mouse mammary organ culture and tumorigenesis in the two-stage mouse skin model. Cancer chemopreventive potential was also suggested in various assays reflective of the three major stages of carcinogenesis. Anti-initiation activity was indicated by its antioxidant and antimutagenic effects, inhibition of the hydroperoxidase function of cyclooxygenase (COX), and induction of phase II drug-metabolizing enzymes. Antipromotion activity was indicated by antiinflammatory effects, inhibition of production of arachidonic acid metabolites catalyzed by either COX-1 or COX-2, and chemical carcinogen-induced neoplastic transformation of mouse embryo fibroblasts. Antiprogression activity was demonstrated by its ability to induce human promyelocytic leukemia (HL-60) cell differentiation. Moreover, pretreatment of mouse skin with resveratrol significantly counteracted 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress, as evidenced by numerous biochemical responses. Resveratrol reduced the generation of hydrogen peroxide, and normalized levels of myeloperoxidase and oxidized-glutathione reductase activities. It also restored glutathione levels and superoxide dismutase activity. As judged by the reverse transcriptase-polymerase chain reaction, resveratrol selectively inhibited TPA-induced expression of c-fos and transforming growth factor-beta 1 (TGF-beta 1), but did not affect other TPA-induced gene products including COX-1, COX-2, c-myc, c-jun, and tumor necrosis factor-alpha. These data indicate that resveratrol may interfere with reactive oxidant pathways and/or modulate the expression of c-fos and TGF-beta 1 to inhibit tumorigenesis in mouse skin. As reported herein, in addition to the activities described above, resveratrol inhibited the de novo formation of inducible nitric oxide synthase (iNOS) in mouse macrophages stimulated with lipopolysaccharide. This finding suggests an additional mechanism by which resveratrol may function as a cancer chemopreventive agent.
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PMID:Cancer chemopreventive activity of resveratrol. 1037 Aug 67

Resveratrol (trans-3,4',5-trihydroxystibene) is a phytopolyphenol isolated from the seeds and skins of grapes. Recent studies indicate that resveratrol can block the process of multistep carcinogenesis, namely, tumor initiation, promotion and progression. Resveratrol can also reduce the risk of cardiovascular disease in man. The molecular mechanisms of resveratrol in chemoprevention of cancer and cardiovascular disease are interesting and under intensive investigation. Resveratrol was found to strongly inhibit nitric oxide (NO) generation in activated macrophages, as measured by the amount of nitrite released into the culture medium, and resveratrol strongly reduced the amount of cytosolic inducible nitric oxide synthase (iNOS) protein. The activation of nuclear factor kappa B (NF kappa B) induced by lipopolysaccharide (LPS) was inhibited by resveratrol. The phosphorylation and degradation of nuclear factor inhibitor kappa B alpha (I kappa B alpha) were inhibited by resveratrol simultaneously. Reactive oxygen species (ROS) are regarded as having carcinogenic potential and have been associated with tumor promotion. Resveratrol may act as a reactive oxygen species scavenger to suppress tumor development. In addition, resveratrol may block multistep carcinogenesis through mitotic signal transduction blockade. Reactive oxygen species are pivotal factors in the genesis of heart disease. Meanwhile, efficient endogenous antioxidants, including superoxide dismutase (SOD), glutathione peroxidase (GSHPx), and catalase, are present in tissues. A fine balance between reactive oxygen species and endogenous antioxidants is believed to exist. Any disturbance of this balance in favor of reactive oxygen species causes an increase in oxidative stress and initiates subcellular changes, leading to cardiomyopathy and heart failure. The experimental results indicate that exogenous antioxidant resveratrol is of value in chemopreventing the development of heart disease. It is urgent that more efforts be made to investigate newer therapies employing antioxidants for the chemoprevention of cardiovascular disease and cancer.
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PMID:Chemoprevention of cancer and cardiovascular disease by resveratrol. 1049 90

The effect of resveratrol (trans-3,4',5-trihydroxystilbene) on the release of adenine nucleotides and proteins from blood platelets activated by lipopolysaccharide (LPS), from Proteus mirabilis and by thrombin, were studied. Thrombin stimulated the release of adenine nucleotides from dense granules and proteins from alpha-granules. The LPS (0.3 microg/10(8) platelets, 5 min, 37 degrees C), like thrombin (2.5 U/10(8) platelets, 5 min, 37 degrees C) was found to cause a release of adenine nucleotides and proteins (p <0.05). Resveratrol (6.25-100 microg/ml, 30 min, 37 degrees C) had a different effect on the platelet release reaction caused by either LPS or thrombin. The results indicated that resveratrol inhibited, in dose-dependent manner, the secretory process (release of adenine nucleotides and proteins) induced by thrombin (p <0.05), but it significantly stimulated the liberation of proteins from blood platelets activated by LPS (p <0.05).
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PMID:The effect of resveratrol on the platelet secretory process induced by endotoxin and thrombin. 1136 92

Resveratrol (3,4',5-trihydroxystilbene) is a natural molecule with antioxidant action. It is also considered to be a molecule with antiplatelet, anticancer and anti-inflammatory action. The effects of trans-resveratrol on the reactive oxygen species (ROS) generation and thiobarbituric acid-reactive substances (TBARS) in blood platelets induced by endotoxin (lipopolysaccharide, LPS) or thrombin were studied in vitro. The production of superoxide radicals (O2.-) and other reactive oxygen species (H2O2, singlet oxygen, and organic radicals) in the presence of resveratrol was measured by a chemiluminescence method in resting blood platelets and platelets stimulated by LPS (0.3 microg/ 10(8) platelets) or thrombin (2.5 U/10(8) platelets). We have shown that resveratrol (6.25-100 microg/ml) inhibits chemiluminescence and generation of O2.- in blood platelets. It has an inhibitory effect on the production of ROS and TBARS in platelets caused by LPS or thrombin.
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PMID:Antioxidant activity of resveratrol in endotoxin-stimulated blood platelets. 1149 95

Tissue factor (TF) is a cell surface receptor for factor VII(a), and the binding of factor VII(a) to TF initiates the coagulation cascade. Inappropriate in vivo expression of TF in vascular cells has been shown to be responsible for thrombotic disorders associated with a variety of pathological conditions, including gram-negative sepsis, cancer and atherosclerosis. A number of epidemiological studies suggest that moderate consumption of red wine provides protective effects against coronary heart disease mortality. Recently, we have shown that resveratrol, a polyphenolic compound found in wine, inhibited the induction of TF expression in endothelial cells and mononuclear cells (Pendurthi UR, Williams JT, Rao LVM. Arterioscler Thromb Vasc Biol 1999: 19: 419-426). In the present study, we examined the mechanism by which resveratrol inhibits the expression of TF in monocytes by using a monocytic cell line, THP-1, as a model cell. Northern blot analysis, gel mobility shift assays and transfection studies with various TF promoter constructs, as well as other transcription regulatory constructs, were used to elucidate the inhibitory mechanism of resveratrol. The data show that resveratrol inhibited lipopolysaccharide (LPS)-induced expression of TF in human monocytes and monocytic cell line, THP-1 in a dose dependent manner. Resveratrol did not significantly alter the binding of various transcription factors involved in TF gene expression to DNA. However, resveratrol suppressed the transcription of cloned human TF promoter. Further experiments revealed that resveratrol reduced kappaB- but not AP-1-driven transcriptional activity. Additional experiments showed that resveratrol suppressed the phosphorylation of p65 and its transactivation. In summary, our results indicate that resveratrol does not inhibit the activation or translocation of NF-kappaB/Rel proteins but inhibits NF-kappaB/Rel-dependent transcription by impairing the transactivation potential of p65.
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PMID:Mechanism of resveratrol-mediated suppression of tissue factor gene expression. 1185 83

Resveratrol (3, 4', 5-trihydroxystilbene), a natural polyphenol, is found in some plants that are used in human nutrition. Grapes are a major source for resveratrol, and a significant amount can also be found in red wine. Several experimental studies have demonstrated biological properties of resveratrol, especially its anti-inflammatory, antioxidant, anti-platelet and antitumor effects. In the present study, we investigated the first step of platelet activation-platelet adhesion stimulated by lipopolysaccharide (LPS) from Proteus mirabilis (weak stimulator) and thrombin (strong activator) in the presence of resveratrol. Our studies show that endotoxin (0.3 microg/10(8) platelets), like thrombin (0.2 U/10(8) platelets), induced the adhesion of platelets (expressed as absorbance of cell attached proteins) to collagen and fibrinogen. Preincubation of washed platelets with resveratrol at physiological plasma concentrations (25-100 microg/ml, 30 min, 37 degrees C) had an inhibitory effect on adhesion of platelets to collagen after activation by LPS alone or LPS with thrombin. The strongest effect on this process was caused by resveratrol at the concentration of 100 microg/ml. Pretreatment of platelets with resveratrol (25-100 microg/ml, 30 min, 37 degrees C) had also inhibitory effects on adhesion of platelets to fibrinogen after stimulation of these cells by LPS alone or by LPS with thrombin at the same concentration. In conclusion, we suggest that resveratrol present in human diet may be an important compound responsible for the reduction of platelet adhesion and changed reactivity of blood platelets in inflammatory process.
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PMID:Effect of resveratrol, a natural polyphenolic compound, on platelet activation induced by endotoxin or thrombin. 1243 80

Resveratrol derivatives are of interest as inhibitors of cyclo-oxygenase-2 and as antiinflammatory agents. The prenylated resveratrol derivative 4-(3-methyl-but-1-enyl)-3,5,3',4'-tetrahydroxystilbene was purified from fungally infected peanuts by thin layer chromatography and its structure was confirmed by mass spectrometry. 4-(3-Methyl-but-1-enyl)-3,5,3',4'-tetrahydroxystilbene inhibited lipopolysaccharide-induced expression of cyclo-oxygenase-2 protein and cyclo-oxygenase-2 mRNA in mouse macrophages at concentrations that were non-cytotoxic. 4-(3-Methyl-but-1-enyl)-3,5,3',4'-tetrahydroxystilbene warrants further evaluation as an antiinflammatory agent.
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PMID:Inhibition of cyclo-oxygenase-2 expression in mouse macrophages by 4-(3-methyl-but-1-enyl)-3,5,3',4'-tetrahydroxystilbene, a resveratrol derivative from peanuts. 1611 95

Resveratrol, a natural polyphenolic antioxidant found in red wine and grapes, has been reported to exert a variety of important pharmacological effects, including anti-inflammatory, cardioprotective, and cancer chemopreventive properties. In the present study, we investigated the effect of resveratrol on the production of nitric oxide (NO) and prostaglandin (PG) E2 by lipopolysaccharide (LPS)-activated C6 microglia. Exposure of cultured rat C6 astroglioma cells to LPS increased their release of NO and PGE2 and their inducible expression of NO synthase and cyclooxygenase-2, all of which were significantly inhibited by resveratrol pretreatment. Further studies revealed that resveratrol suppressed LPS-induced nuclear translocation and activation of nuclear factor kappaB (NF-kappaB). These results demonstrate a potent suppressive effect of resveratrol on pro-inflammatory responses of microglia by modulation of NF-kappaB activity, suggesting a therapeutic potential for this compound in neurodegenerative diseases accompanied by microglial activation.
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PMID:Resveratrol inhibits nitric oxide and prostaglandin E2 production by lipopolysaccharide-activated C6 microglia. 1765 Oct 55


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