Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The colchicine-derived CT20126 compound has recently been shown to exert an immune regulatory effect and prolong the survival of allograft skins. In this study, we explored the anti-inflammatory and anti-arthritic effects of CT20126 in vivo and in vitro as well as investigated its underlying action mechanism. CT20126 suppressed the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2, tumor necrosis factor-alpha, and interleukin-1beta as well as the production of nitric oxide and prostaglandin E(2) in lipopolysaccharide (LPS)-treated macrophages as well as LPS-administered mice. This drug also inhibited the production of nitric oxide, prostaglandin E(2), and the chemokines, RANTES, GROalpha, and ENA-78, in cytokine-stimulated human synoviocytes. CT20126 suppressed NF-kappaB activation and iNOS promoter activity, which correlated with its inhibitory effect on phosphorylation-dependent IkappaB kinase activation, IkappaB phosphorylation and degradation, and NF-kappaB nuclear translocation, in LPS-stimulated macrophages. This compound also inhibited LPS-induced NF-kappaB-inducing kinase (NIK) and Akt phosphorylation, which are upstream of NF-kappaB activation. Furthermore, CT20126 significantly decreased the incidence and severity of arthritis as well as inhibited the expression of inflammatory cytokines, chemokines, iNOS, and cyclooxygenase-2 in the paws of collagen-induced arthritic mice. These findings indicate that CT20126 exerts an anti-inflammatory effect through NF-kappaB-responsive inflammatory gene expression by inhibiting the NIK- and Akt-dependent canonical NF-kappaB pathway and can be used as a therapeutic agent for rheumatoid arthritis related to chronic inflammation.
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PMID:CT20126, a novel immunosuppressant, prevents collagen-induced arthritis through the down-regulation of inflammatory gene expression by inhibiting NF-kappaB activation. 1851 3

Resveratrol, a phytoalexin present in grapes, has been reported to inhibit multistage mouse skin carcinogenesis. Recent studies showed that topically applied resveratrol significantly inhibited cyclooxygenase-2 (COX-2) expression and activation of nuclear factor-kappaB (NF-kappaB) induced by tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis. The aim of the present study was to further explore the effect of resveratrol on TPA-induced signaling pathways in mouse epidermis and to compare with its dimethylether, pterostilbene. Resveratrol and pterostilbene significantly reduced activator protein 1 (AP-1) and NF-kappaB activation. In the case of AP-1, the binding of c-Jun subunit was particularly affected, while only slight effect on c-Fos binding to TPA-responsive element (AP-1 binding consensus sequence) (TRE) site was observed. Both stilbenes inhibited the activation of NF-kappaB by blocking the translocation of p65 to the nucleus and increasing the retention of IkappaBa in the cytosol. The latter might be related to decreased activity of IkappaB kinase and/or proteasome 20S. Reduced activation of transcription factors decreased the expression and activity of COX-2 and inducible nitric oxide synthase (iNOS). In most assays, pterostilbene was either equally or significantly more potent than resveratrol. Pterostilbene might show higher biological activity due to its possible better bioavailability, since substitution of hydroxy with methoxy group increases lipophilicity.
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PMID:Pterostilbene is equally potent as resveratrol in inhibiting 12-O-tetradecanoylphorbol-13-acetate activated NFkappaB, AP-1, COX-2, and iNOS in mouse epidermis. 1855 58

Berberine, an isoquinoline alkaloid derived from a plant used traditionally in Chinese and Ayurvedic medicine, has been reported to exhibit chemopreventive and anti-inflammatory activities through unknown mechanism. Because of the critical role of the transcription factor nuclear factor-kappaB (NF-kappaB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-kappaB activation found in certain tumor cells. Suppression of NF-kappaB activation occurred through the inhibition of phosphorylation and degradation of IkappaBalpha by the inhibition of IkappaB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-kappaB reporter activity. Inhibition of IKK by berbeine was direct and could be reversed by reducing agents. Site-specific mutagenesis suggested the involvement of cysteine residue 179 in IKK. Berberine also suppressed the expression of NF-kappaB-regulated gene products involved in antiapoptosis (Bcl-xL, Survivin, IAP1, IAP2, and cFLIP), proliferation (cyclin D1), inflammation (cyclooxygenase-2), and invasion (matrix metalloproteinase-9). Suppression of antiapoptotic gene products correlated with enhancement of apoptosis induced by tumor necrosis factor (TNF)-alpha and chemotherapeutic agents and with inhibition of TNF-induced cellular invasion. Overall, our results indicate that chemopreventive, apoptotic, and anti-inflammatory activities displayed by berberine may be mediated in part through the suppression of the NF-kappaB activation pathway. This may provide the molecular basis for the ability of berberine to act as an anticancer and anti-inflammatory agent.
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PMID:Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. 1859 39

Reactive oxygen species (ROS) have been implicated in the regulation of NF-kappaB activation, which plays an important role in inflammation and cell survival. However, the molecular mechanisms of ROS in NF-kappaB activation remain poorly defined. We found that the non-provitamin A carotenoid, lutein, decreased intracellular H(2)O(2) accumulation by scavenging superoxide and H(2)O(2) and the NF-kappaB-regulated inflammatory genes, iNOS, TNF-alpha, IL-1beta, and cyclooxygenase-2, in lipopolysaccharide (LPS)-stimulated macrophages. Lutein inhibited LPS-induced NF-kappaB activation, which highly correlated with its inhibitory effect on LPS-induced IkappaB kinase (IKK) activation, IkappaB degradation, nuclear translocation of NF-kappaB, and binding of NF-kappaB to the kappaB motif of the iNOS promoter. This compound inhibited LPS- and H(2)O(2)-induced increases in phosphatidylinositol 3-kinase (PI3K) activity, PTEN inactivation, NF-kappaB-inducing kinase (NIK), and Akt phosphorylation, which are all upstream of IKK activation, but did not affect the interaction between Toll-like receptor 4 and MyD88 and the activation of mitogen-activated protein kinases. The NADPH oxidase inhibitor apocynin and gp91(phox) deletion reduced the LPS-induced NF-kappaB signaling pathway as lutein did. Moreover, lutein treatment and gp91(phox) deletion decreased the expressional levels of the inflammatory genes in vivo and protected mice from LPS-induced lethality. Our data suggest that H(2)O(2) modulates IKK-dependent NF-kappaB activation by promoting the redox-sensitive activation of the PI3K/PTEN/Akt and NIK/IKK pathways. These findings further provide new insights into the pathophysiological role of intracellular H(2)O(2) in the NF-kappaB signal pathway and inflammatory process.
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PMID:The non-provitamin A carotenoid, lutein, inhibits NF-kappaB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-kappaB-inducing kinase pathways: role of H(2)O(2) in NF-kappaB activation. 1862 44

Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also to induce apoptosis in various types of cancer cells. Here, we investigated the inhibitory effects of pterostilbene on the induction of NO synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with lipopolysaccharide (LPS). Western blotting and real-time polymerase chain reaction (PCR) analyses demonstrated that pterostilbene significantly blocked the protein and mRNA expression of iNOS and COX-2 in LPS-induced macrophages. Treatment with pterostilbene resulted in the reduction of LPS-induced nuclear translocation of the nuclear factor-kappaB (NFkappaB) subunit and the dependent transcriptional activity of NFkappaB by blocking phosphorylation of inhibitor kappaB (IkappaB)alpha and p65 and subsequent degradation of IkappaB alpha. Transient transfection experiments using NFkappaB reporter constructs indicated that pterostilbene inhibits the transcriptional activity of NFkappaB in LPS-stimulated mouse macrophages. We found that pterostilbene also inhibited LPS-induced activation of PI3K/Akt, extracellular signal-regulated kinase 1/2 and p38 MAPK. Taken together, these results show that pterostilbene down regulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NFkappaB by interfering with the activation of PI3K/Akt/IKK and MAPK. These results have an important implication for using pterostilbene toward the development of an effective anti-inflammatory agent.
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PMID:Pterostilbene suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. 1865 26

Ginger, the rhizome of Zingiber officinale, is a traditional medicine with carminative effect, antinausea, anti-inflammatory, and anticarcinogenic properties. In this study, we investigated the inhibitory effects of 6-shogaol and a related compound, 6-gingerol, on the induction of nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with LPS. Western blotting and reverse transcription-PCR analyses demonstrated that 6-shogaol significantly blocked protein and mRNA expression of inducible NOS (iNOS) and COX-2 in LPS-induced macrophages. The in vivo anti-inflammatory activity was evaluated by a topical 12-O-tetradecanoylphorbol 13-acetate (TPA) application to mouse skin. When applied topically onto the shaven backs of mice prior to TPA, 6-shogaol markedly inhibited the expression of iNOS and COX-2 proteins. Treatment with 6-shogaol resulted in the reduction of LPS-induced nuclear translocation of nuclear factor-kappaB (NF kappaB) subunit and the dependent transcriptional activity of NF kappaB by blocking phosphorylation of inhibitor kappaB (I kappaB)alpha and p65 and subsequent degradation of I kappaB alpha. Transient transfection experiments using NF kappaB reporter constructs indicated that 6-shogaol inhibits the transcriptional activity of NF kappaB in LPS-stimulated mouse macrophages. We found that 6-shogaol also inhibited LPS-induced activation of PI3K/Akt and extracellular signal-regulated kinase 1/2, but not p38 mitogen-activated protein kinase (MAPK). Taken together, these results show that 6-shogaol downregulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NF kappaB by interfering with the activation PI3K/Akt/I kappaB kinases IKK and MAPK.
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PMID:6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. 1868 23

Intestinal subepithelial myofibroblasts (SEMFs) is a specific population of cells involved in intestinal inflammation and carcinogenesis via an elaborate network of cytokines, chemokines and other inflammatory factors, including PGE(2). Sphingosine-1-phosphate (S1P) has been implicated as an important mediator of inflammation and cancer and in certain cell types increases cyclooxygenase-2 (COX-2) expression. In the present study, we aimed to assess involvement of S1P in COX-2 expression by SEMFs. Primary SEMFs were obtained from C57BL/6J mouse and their identity was verified by fluorescent staining of specific marker proteins. Expression of S1P receptors 1, 2, 3 and sphingosine kinases 1 and 2 in SEMFs were determined by RT-PCR analysis. COX-2 expression and PGE(2) production were assayed by Western blotting and ELISA, respectively. COX-2 mRNA stability was assayed by Northern blotting. S1P produced dose-dependent increase in COX-2 expression, resulting in increased PGE(2) release from SEMFs. Using specific inhibitors, we show that actions of p38, ERK, IKK, and PKC were involved in S1P-induced COX-2 expression. On the other hand, p38 and PKC had lesser roles in IL-1beta-induced COX-2 expression. Inhibition of sphingosine kinase to block S1P production did not affect IL-1beta-induced COX-2 expression, but S1P amplified IL-1beta-induced p38 activation and COX-2 expression. PKC inhibition blocked S1P amplified COX-2 expression. S1P addition increased COX-2 mRNA stability. In SEMFs, S1P amplifies IL-1beta-induced COX-2 expression through increased mRNA stability. These observations point to involvement of S1P in activation of SEMFs that may contribute to intestinal inflammation and carcinogenesis.
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PMID:Sphingosine-1-phosphate enhances IL-1{beta}-induced COX-2 expression in mouse intestinal subepithelial myofibroblasts. 1870 38

To determine the chemical constituents responsible for pharmacological effects of Inula britannica-F., three specific sesquiterpene lactones in Inula britannica were isolated from chloroform extract and identified, including britannilactone (BL), 1-O-acetylbritannilactone (ABLO), and 1,6-O,O-diacetylbritannilactone (ABLOO). Electrophoretic mobility shift assay (EMSA) was performed to detect the nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65. The expressions of IkappaBalpha, pIkappaBalpha, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IkappaB kinase alpha/beta (IKKalpha/beta) and NF-kappaB kinase (NIK) were detected by Western blot and RT-PCR. We found that acetyl side groups enhanced the inhibitory action of the agents on LPS/IFN-gamma-induced iNOS and COX-2 expression. Their inhibiting activity was positive correlation with the acetyl side group number. The effects of LPS/IFN-gamma were reversed by ABLOO, and BL without acetyl side groups showed only a weak inhibitory action. Further study indicated that ABLOO markedly inhibited the phosphorylation of IKKbeta down to based level, but not IKKalpha, corresponding with decreased in IkappaBalpha degradation and phosphorylation induced by LPS/IFN-gamma, resulting in the suppression of NF-kappaB nuclear translocation and activity. These results suggest that the acetyl moieties add to the lipophilicity, and consequently enhance cellular penetration, so that ABLOO possess the most anti-inflammatory effect and may be a potent lead structure for the development of therapeutic and cytokine-suppressing remedies valuable for the treatment of various inflammatory diseases.
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PMID:1,6-O,O-diacetylbritannilactones inhibits IkappaB kinase beta-dependent NF-kappaB activation. 1892 78

We investigated the effect of desmethylanhydroicaritin (DMAI), a major compound of the Chinese herbal medicine Epimedium, on inflammatory gene expression and the NF-kappaB signaling pathway. We found that DMAI suppressed the expression of NF-kappaB-responsive genes, such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1beta, and tumor necrosis factor-alpha, in lipopolysaccharide (LPS)-stimulated macrophages and endotoxemic mice as well as protected mice against LPS-induced lethality. DMAI inhibited NF-kappaB activation through the inhibition of IkappaB kinase (IKK) activation, IkappaB phosphorylation and degradation, and NF-kappaB nuclear translocation in LPS-stimulated macrophages. This compound inhibited in vitro and in vivo LPS-induced phosphatidylinositol 3-kinase (PI3K) activation, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) oxidation, and Akt phosphorylation, which are upstream modulators of IKK activation. Moreover, treatment with DMAI was not observed to affect the interaction between the Toll-like receptor 4, MyD88, and TRAF6 as well as mitogen-activated protein kinase activation. DMAI also suppressed intracellular H(2)O(2) accumulation, hydroxyl radical production, and glutathione oxidation without affecting superoxide generation and accumulation by NADPH oxidase. Moreover, DMAI inhibited redox-sensitive activation of the PI3K/PTEN/Akt pathway and NF-kappaB activation in macrophages treated with H(2)O(2). These results indicate that DMAI negatively regulates canonical NF-kappaB-regulated inflammatory gene expression by functioning as an inhibitor of the NF-kappaB pathway through the suppression of redox-based PI3K activation and PTEN inactivation and therefore can be considered as a potential drug for inflammatory diseases.
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PMID:Desmethylanhydroicaritin inhibits NF-kappaB-regulated inflammatory gene expression by modulating the redox-sensitive PI3K/PTEN/Akt pathway. 1902 2

Long regarded as proinflammatory molecules, prostaglandins (PGs) also have anti-inflammatory effects. Both prostaglandin D2 (PGD2) and its dehydration end product 15-deoxy-Delta-prostaglandin J2 (15d-PGJ2) seem to play important roles in regulating inflammation, via both receptor-dependent (DP1 and DP2 receptors) and receptor-independent mechanisms. Intracellular effects of PGD2 and 15d-PGJ2 that may suppress inflammation include inhibition of nuclear factor-kappaB (NF-kappaB) by multiple mechanisms (IkappaB kinase inhibition and blockade of NF-kappaB nuclear binding) and activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Prostaglandin F2alpha (PGF2alpha) may also have important anti-inflammatory effects, although current data are limited. In animal models, expression of both PGD and PGF synthases declines during acute inflammation, only to rise again during the resolution phase, suggesting their possible role in resolving inflammation. Prostaglandin E2 (PGE2), the classic model of a proinflammatory lipid mediator, also has anti-inflammatory effects that are both potent and context dependent. Thus, accumulating data suggest that PGs not only participate in initiation, but may also actively contribute to the resolution of inflammation. Indeed, classic inhibitors of PG synthesis such as nonselective and cyclooxygenase-2 (COX-2) selective inhibitors (nonsteroidal anti-inflammatory drugs) may actually prolong inflammation when administered during the resolution phase. These effects may regulate not only tissue inflammation but also vascular disease, possibly shedding light on the controversy surrounding nonsteroidal anti-inflammatory drug use and its relation to myocardial infarction. In this review, we summarize the current understanding of PGs as dichotomous molecules in the inflammatory process.
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PMID:The anti-inflammatory effects of prostaglandins. 1924 Jun 48


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