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1.
In the present study, we report the inhibitory effect of equol on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) gene expression in murine macrophages. In vivo administration of equol (i.p.) attenuated NO production by peritoneal adherent cells isolated from lipopolysaccharide (LPS)-treated mice. Equol dose-dependently inhibited the LPS-induced production of NO in isolated peritoneal adherent cells and RAW 264.7 cells. The mRNA expression of iNOS was also blocked by equol in LPS-stimulated RAW 264.7 cells. Further study demonstrated that the LPS-induced activation of Akt was suppressed by equol in RAW 264.7 cells while the activation of ERK, SAPK/JNK and p38 MAP kinase was not affected. Equol also blocked LPS-induced NF-kappaB activation. Moreover, the LPS-induced NO production and NF-kappaB activation was inhibited by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase/Akt pathway, in RAW 264.7 cells. These results suggest that equol might inhibit NO production and iNOS gene expression, at least in part, by blocking Akt activation and subsequent down-regulation of NF-kappaB activity.  相似文献   

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The extracts or constituents from the bark of Magnolia (M.) obovata are known to have many pharmacological activities. 4-Methoxyhonokiol, a neolignan compound isolated from the stem bark of M. obovata, was found to exhibit a potent anti-inflammatory effect in different experimental models. Pretreatment with 4-methoxyhonokiol (i.p.) dose-dependently inhibited the dye leakage and paw swelling in an acetic-acid-induced vascular permeability assay and a carrageenan-induced paw edema assay in mice, respectively. In the lipopolysaccharide (LPS)-induced systemic inflammation model, 4-methoxyhonokiol significantly inhibited plasma nitric oxide (NO) release in mice. To identify the mechanisms underlying this anti-inflammatory action, we investigated the effect of 4-methoxyhonokiol on LPS-induced responses in a murine macrophage cell line, RAW 264.7. The results demonstrated that 4-methoxyhonokiol significantly inhibited LPS-induced NO production as well as the protein and mRNA expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, 4-methoxyhonokiol inhibited LPS-mediated nuclear factor-kappaB (NF-kappaB) activation via the prevention of inhibitor kappaB (IkappaB) phosphorylation and degradation. 4-Methoxyhonokiol had no effect on the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), whereas it attenuated the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) in a concentration-dependent manner. Taken together, our data suggest that 4-methoxyhonokiol is an active anti-inflammatory constituent of the bark of M. obovata, and that its anti-inflammatory property might be a function of the inhibition of iNOS and COX-2 expression via down-regulation of the JNK and p38 MAP kinase signal pathways and inhibition of NF-kappaB activation in RAW 264.7 macrophages.  相似文献   

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In cultures of the murine macrophage cell line RAW 264.7, effects of four 2'-hydroxychalcone derivatives, 2'-hydroxy-4'-methoxychalcone (compound 1), 2',4-dihydroxy-4'-methoxychalcone (compound 2), 2',4-dihydroxy-6'-methoxychalcone (compound 3) and 2'-hydroxy-4,4'-dimethoxychalcone (compound 4), on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha were examined. Compounds 1, 2 and 3 at 3-30microM inhibited the production with almost the same potency. Compound 4 showed no inhibitory activity. Compounds 1, 2 and 3 at 3-30microM inhibited the LPS-induced expression of inducible nitric oxide synthase (iNOS) and TNF-alpha mRNA. To clarify the mechanism involved, effects of compounds 1, 2 and 3 on the activation of nuclear factor (NF)-kappaB and activator protein-1 (AP-1) were examined. Both the LPS-induced activation of NF-kappaB and AP-1 were blocked by compounds 1, 2 and 3 at 3-30microM. Moreover, the three compounds at such concentrations inhibited the LPS-induced IkappaB degradation and the phosphorylation of c-jun N-terminal kinase (JNK) and c-jun. These findings suggest that the inhibition of the LPS-induced production of NO and TNF-alpha by the 2'-hydroxychalcone derivatives is due to the inhibition of NF-kappaB and AP-1 activations.  相似文献   

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Excessive nitric oxide (NO) produced by inducible NO synthase (iNOS) acts as a causative regulator in various inflammatory disease states. Carpesium divaricatum has been used in Korean traditional herbal medicine for its antipyretic, analgesic, vermifugic, and anti-inflammatory properties. We investigated the molecular mechanism for the suppression of lipopolysaccharide/interferon-gamma (LPS/IFN-gamma)-induced NO production in RAW 264.7 macrophages by the sesquiterpene lactone 2beta,5-epoxy-5,10-dihydroxy-6alpha-angeloyloxy-9beta-isobutyloxy-germacran-8alpha,12-olide (C-1), which has been identified recently as a new compound from C. divaricatum. C-1 decreased NO production in LPS/IFN-gamma-stimulated RAW 264.7 cells in a concentration-dependent manner, with an IC50 of approximately 2.16 microM; however, it had no direct effect on the iNOS activity of fully LPS/IFN-gamma-stimulated RAW 264.7 cells. Furthermore, treatment with C-1 led to a decrease in iNOS protein and mRNA. These effects appear to be due to inhibition of nuclear factor-kappaB (NF-kappaB) activation through a mechanism involving stabilization of the NF-kappaB/inhibitor of the kappaB (I-kappaB) complex, since inhibition of NF-kappaB DNA binding activity by C-1 was accompanied by a parallel reduction of nuclear translocation of subunit p65 of NF-kappaB and I-kappaBalpha degradation. Taken together, the results suggest that the ability of C-1 to inhibit iNOS gene expression may be responsible, in part, for its anti-inflammatory effects.  相似文献   

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In the present study, we investigated the effect of asiatic acid (the aglycon of asiaticoside) and asiaticoside isolated from the leaves of Centella asiatica (Umbelliferae) on LPS-induced NO and PGE(2) production in RAW 264.7 macrophage cells. Asiatic acid more potently inhibited LPS-induced NO and PGE(2) production than asiaticoside. Consistent with these observations, the protein and mRNA expression levels of inducible iNOS and COX-2 enzymes were inhibited by asiatic acid in a concentration-dependent manner. In addition, asiatic acid dose-dependently reduced the production of IL-6, IL-1 beta and TNF-alpha in LPS-stimulated RAW 264.7 macrophage cells. Furthermore, asiatic acid inhibited the NF-kappaB activation induced by LPS, and this was associated with the abrogation of I kappa B-alpha degradation and with subsequent decreases in nuclear p65 and p50 protein levels. Moreover, the phosphorylations of IKK, p38, ERK1/2, and JNK in LPS-stimulated RAW 264.7 cells were suppressed by asiatic acid in a dose-dependent manner. These results suggest that the anti-inflammatory properties of asiatic acid might be the results from the inhibition of iNOS, COX-2, IL-6, IL-1 beta, and TNF-alpha expressions through the down-regulation of NF-kappaB activation via suppression of IKK and MAP kinase (p38, ERK1/2, and JNK) phosphorylation in RAW 264.7 cells.  相似文献   

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Hematein, a natural compound, is a known anti-inflammatory and antiatherogenic agent in the rabbit model. The authors investigated the effects of this compound on atherogenesis and possible mechanisms of the actions in the hyperlipidemic mice. Low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed a high-cholesterol diet alone for 8 weeks developed the fatty streak lesion in the aortic sinus, whereas this lesion was significantly reduced by hematein treatment without a change in plasma lipid levels compared with control mice. Hematein treatment reduced plasma levels of lipid peroxide and superoxide generation in LPS-stimulated peritoneal macrophage. Hematein treatment inhibited NF-kappaB-DNA binding activity in peritoneal macrophages from Ldlr-/- mice and the activation of NF-kappaB in RAW264.7 macrophages. This compound suppressed plasma nitrite/nitrate levels in Ldlr-/- mice and NO production and iNOS expression in LPS+IFNgamma-stimulated peritoneal macrophages. Hematein treatment also suppressed the activity of iNOS promoters in RAW264.7 macrophages, and reduced the plasma levels of TNF-alpha and IL-1beta and the production of these cytokines in LPS+IFNgamma-stimulated peritoneal macrophages. These results suggest that hematein inhibits atherosclerotic lesion formation, possibly by reducing proinflammatory mediators through a decrease in reactive oxygen species generation and NF-kappaB activation.  相似文献   

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Induction of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production is thought to have beneficial immunomodulatory effects in acute and chronic inflammatory disorders. In Raw 264.7 cells stimulated with lipopolysaccharide (LPS) to mimic inflammation, withaferin A inhibited LPS-induced expression of both iNOS protein and mRNA in a dose-dependent manner. To investigate the mechanism by which withaferin A inhibits iNOS gene expression, we examined activation of mitogen-activated protein kinases (MAPKs) and Akt in Raw 264.7 cells. We did not observe any significant changes in the phosphorylation of p38 MAPK in cells treated with LPS alone or LPS plus withaferin A. However, LPS-induced Akt phosphorylation was markedly inhibited by withaferin A, while the phosphorylation of p42/p44 extracellular signal-regulated kinases (ERKs) was slightly inhibited by withaferin A treatment. Withaferin A prevented IkappaB phosphorylation, blocking the subsequent nuclear translocation of nuclear factor-kappaB (NF-kappaB) and inhibiting its DNA binding activity. LPS-induced p65 phosphorylation, which is mediated by extracellular signal-regulated kinase (ERK) and Akt pathways, was attenuated by withaferin A treatment. Moreover, LPS-induced NO production and NF-kappaB activation were inhibited by SH-6, a specific inhibitor of Akt. Taken together, these results suggest that withaferin A inhibits inflammation through inhibition of NO production and iNOS expression, at least in part, by blocking Akt and subsequently down-regulating NF-kappaB activity.  相似文献   

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Nitric oxide (NO) is recognized as a mediator and regulator of inflammatory responses. Rengyolone, a cyclohexylethanoid isolated from the fruits of Forsythia koreana, exhibits anti-inflammatory activity with unknown mechanism. In this study, we found that rengyolone has a strong inhibitory effect on the production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Rengyolone also inhibited inducible nitric oxide synthase (iNOS) gene expression and cyclooxygenase 2 (COX-2) by lipopolysaccharide (LPS). In order to explore the mechanism responsible for the inhibition of iNOS gene expression by rengyolone, we investigated its effect on LPS-induced nuclear factor-kappaB (NF-kappaB) activation. The LPS-induced DNA binding activity of NF-kappaB was significantly inhibited by rengyolone, and this effect was mediated through inhibition of the degradation of inhibitory factor-kappaBalpha and phosphorylation of p38 MAP kinase. Furthermore, rengyolone suppressed the expression of ICE protein in IL-1beta-treated D10S cells. Taken together, these results suggest that rengyolone attenuates the inflammation through inhibition of NO production and iNOS expression by blockade of NF-kappaB and p38 MAPK activation in LPS-stimulated RAW 264.7 cells.  相似文献   

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Eutigoside C, a compound isolated from the leaves of Eurya emarginata, is thought to be an active anti-inflammatory compound which operates through an unknown mechanism. In the present study we investigated the molecular mechanisms of eutigoside C activity in lipopolysacchardide (LPS)-stimulated murine macrophage RAW 264.7 cells. Treatment with eutigoside C inhibited LPS-stimulated production of nitric oxide (NO), prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6). To further elucidate the mechanism of this inhibitory effect of eutigoside C, we studied LPS-induced nuclear factor (NF)-kappaB activation and mitogen-activated protein (MAP) kinase phosphorylation. Eutigoside C suppressed NF-kappaB DNA binding activity, interfering with nuclear translocation of NF-kappaB. Eutigoside C suppressed the phosphorylation of three MAP kinases (ERK1/2, JNK and p38). These results suggest that eutigoside C inhibits the production of inflammatory mediators (NO, PGE(2) and interleukin-6) by suppressing the activation and translocation of NF-kappaB and the phosphorylation of MAP kinases (ERK1/2, JNK and p38) in LPS-stimulated murine macrophage RAW 264.7 cells.  相似文献   

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Cordyceps militaris, a caterpillar-grown traditional medicinal mushroom, produces an important bioactive compound, cordycepin (3'-deoxyadenosine). Cordycepin is reported to possess many pharmacological activities including immunological stimulating, anti-cancer, anti-virus and anti-infection activities. The molecular mechanisms of cordycepin on pharmacological and biochemical actions of macrophages in inflammation have not been clearly elucidated yet. In the present study, we tested the role of cordycepin on the anti-inflammation cascades in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. In LPS-activated macrophage, nitric oxide (NO) production was inhibited by butanol fraction of C. militaris and the major component of C. militaris butanol faction was identified as cordycepin by high performance liquid chromatography. To investigate the mechanism by which cordycepin inhibits NO production and inducible nitric oxide synthase (iNOS) expression, we examined the activation of Akt and MAP kinases in LPS-activated macrophage. Cordycepin markedly inhibited the phosphorylation of Akt and p38 in dose-dependent manners in LPS-activated macrophage. Moreover, cordycepin suppressed tumor necrosis factor (TNF-alpha) expression, IkappaB alpha phosphorylation, and translocation of nuclear factor-kappaB (NF-kappaB). The expressions of cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were significantly decreased in RAW 264.7 cell by cordycepin. Taken together, these results suggest that cordycepin inhibits the production of NO production by down-regulation of iNOS and COX-2 gene expression via the suppression of NF-kappaB activation, Akt and p38 phosphorylation. Thus, cordycepin may provide a potential therapeutic approach for inflammation-associated disorders.  相似文献   

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Taurine is an abundant free amino acid in inflammatory cells that protects cells from inflammatory damages. Although the protection mechanism remains unclear, taurine chloramine (Tau-Cl) produced by the reaction between taurine and hypochlorous acid in neutrophils plays an important role. In this study, we investigated the mechanism(s) by which Tau-Cl inhibits LPS-induced NO production in macrophages. Tau-Cl inhibited LPS-induced iNOS expression and NO production in RAW 264.7 cells. LPS treatment elevated the level of active Ras-GTP, and Tau-Cl inhibited LPS-induced Ras activation. Tau-Cl also inhibited ERK1/2 activation in a dose-dependent manner in both RAW 264.7 cells and murine peritoneal macrophages, whereas it did not exert any effect on p38 MAPK activation. Furthermore, Tau-Cl inhibited NF-kappaB activation without affecting AP-1 activity. These results suggest that Tau-Cl suppresses LPS-induced NO production by inhibiting specific signaling pathways. Thus, Tau-Cl protects cells from inflammatory injury resulting from overproduction of NO in a signaling pathway-specific manner.  相似文献   

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