• Bulletin of the Korean Chemical Society
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• v.32 no.12
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• pp.4397-4402
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• 2011

The NF-${\kappa}B$ system of transcription factors plays a crucial role in inflammatory diseases, making it an important drug target. We combined quantitative structure activity relationships for predicting the activity of new compounds and quantitative dynamic models for the NF-${\kappa}B$ network with intracellular concentration models. GFA-MLR QSAR analysis was employed to determine the optimal QSAR equation. To validate the predictability of the $IKK{\beta}$ QSAR model for an external set of inhibitors, a set of ordinary differential equations and mass action kinetics were used for modeling the NF-${\kappa}B$ dynamic system. The reaction parameters were obtained from previously reported research. In the IKKb QSAR model, good cross-validated $q^2$ (0.782) and conventional $r^2$ (0.808) values demonstrated the correlation between the descriptors and each of their activities and reliably predicted the $IKK{\beta}$ activities. Using a developed simulation model of the NF-${\kappa}B$ signaling pathway, we demonstrated differences in $I{\kappa}B$ mRNA expression between normal and different inhibitory states. When the inhibition efficiency increased, inhibitor 1 (PS-1145) led to long-term oscillations. The combined computational modeling and NF-${\kappa}B$ dynamic simulations can be used to understand the inhibition mechanisms and thereby result in the design of mechanism-based inhibitors.

• Proceedings of the Korean Society of Toxicology Conference
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• 2005.05a
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• pp.85-90
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• 2005

Diesel exhaust Particles (DEPs) are known to induce allergic responses in airway epithelial cells, such as the production of various cytokines via nuclear factor-kappa B ($NF-{\kappa}B$). However. the intracellular signal transduction pathways underlying this phenomenon have not been fully examined. This study showed that DEP induced $NF-{\kappa}B$ activity via transforming growth factor-${\beta}$ activated kinase 1 (TAK1) and $NF-{\kappa}B$-inducing kinase (NIK) in L2 rat lung epithelial cells. DEP induced the $NF-{\kappa}B$ dependent reporter activity approximately two-to three-fold in L2 cells. However, this effect was abolished by the expression of the dominant negative forms of TAK1 or NIK. Furthermore, it was shown that DEP induced TAK1 phosphorylation in the L2 cells. These results suggest that TAK1 and NIK are important mediators of DEP-induced $NF-{\kappa}B$ activation.

• Biomolecules & Therapeutics
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• v.16 no.4
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• pp.385-393
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• 2008

As an attempt to search for bioactive natural products exerting anti-inflammatory activity, we evaluated the effects of the methanol extract of Polytrichum commune Hedw (PCM) (Polytrichaceae) on lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin $E_2$ ($PGE_2$) and pro-inflammatory cytokines release in murine macrophage cell line RAW 264.7. PCM potently inhibits the production of NO, $PGE_2$, tumor necrosis factor (TNF)-$\alpha$ and interleukin (IL)-6. Consistent with these results, PCM also concentration-dependently inhibited LPS-induced inducible NO synthase (iNOS) and cyclooxygase (COX)-2 at the protein levels, and iNOS, COX-2, TNF-$\alpha$ and IL-6 at the mRNA levels without an appreciable cytotoxic effect on RAW 264.7 macrophag cells. Furthermore, PCM inhibited LPS-induced nuclear factor-kappa B (NF-$\kappa$B) activation as determined by NF-$\kappa$B reporter gene assay, and this inhibition was associated with a decrease in the nuclear translocation of p65 and p50 NF-$\kappa$B. Taken together, these results suggest that PCM may play an anti-inflammatory role in LPS-stimulated RAW 264.7 macrophages through the inhibitory regulation of iNOS, COX-2, TNF-$\alpha$ and IL-6 via NF-$\kappa$B inactivation.

• Journal of Life Science
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• v.21 no.10
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• pp.1377-1384
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• 2011

Astaxanthin (ATX) is a red-orange carotenoid pigment that occurs naturally in a wide variety of living organisms. In this study we investigated the inhibitory effects of ATX on the induction of inducible nitric oxide synthase (iNOS), nitric oxide (NO), proinflammatory cytokines, nuclear factor-kappa B(NF-${\kappa}B$) and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In addition, we tested the superoxide radical scavenging activity of ATX by scavenging assay. iNOS and NF-${\kappa}B$ expressions were determined by immunoblot analysis. Interleukin (IL)-6 and tumour necrosis factor-${\alpha}$ (TNF-${\alpha}$) were assayed by ELISA. NO production was monitored by measuring the amount of nitrite. ROS was examined by using the 2', 7'-Dichlorodihydrofluorescin diacetate (DCFH-DA) method. At a concentration of 100 ${\mu}M$, ATX inhibited the expression level of LPS-induced NF-${\kappa}B$, as well as the production of LPS-induced NO and proinflammatory cytokines (IL-6 and TNF-${\alpha}$), by suppressing iNOS expression. In particular, the maximal inhibition rate of IL-6 and TNF-${\alpha}$ production by ATX (100 ${\mu}M$) was 65.2----- and 21.2-----, respectively. In addition, ATX inhibited the LPS-induced transcriptional activity of NF-${\kappa}B$, and this was associated with suppressing the translocations of NF-${\kappa}B$ from the cytosol to the nucleus. Moreover, at various concentrations (25-100 ${\mu}M$), ATX inhibited the intracellular level of ROS. At a concentration of 5 mg/ml, the superoxide radical scavenging activity of ATX was 1.33 times higher than ${\alpha}$-tocopherol of the same concentration. These results showed that ATX inhibited the expression of iNOS and the production of NO and proinflammatory cytokines resulting from ROS production and NF-${\kappa}B$ activation in macrophages. Furthermore, ATX was found to be more effective in superoxide radical scavenging activities compared to ${\alpha}$-tocopherol. These findings are expected to strengthen the position of ATX as anti-inflammatory medicine and antioxidant.

• Journal of Life Science
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• v.23 no.4
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• pp.471-478
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• 2013

Human adipose tissue-derived mesenchymal stem cells (hADSCs) have therapeutic potential, including the ability to self-renew and differentiate into multiple lineages. Understanding of molecular mechanisms of stem cell differentiation is important for improving the therapeutic efficacies of stem cell transplantation. In this study, we determined the role of nuclear factor of activated T cells (NFAT5) in the osteogenic differentiation of hADSCs. The down-regulation of NFAT5 expression by the transfection of a specific siRNA significantly inhibited osteogenic differentiation of hADSCs and decreased the activity of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-${\kappa}B$) promoter without affecting their proliferation and adipogenic differentiation. The inhibition of NFAT5 expression inhibited the basal and Tumor Necrosis Factor ${\alpha}$ (TNF-${\alpha}$) induced activation of NF-${\kappa}B$, but it did not affect TNF-${\alpha}$-induced degradation of the $I{\kappa}B$ protein. These findings indicate that NFAT5 plays an important role in the osteogenic differentiation of hADSCs through the modulation of the NF-${\kappa}B$ pathway.

• Natural Product Sciences
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• v.21 no.4
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• pp.240-247
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• 2015

Viridicatol (1) has previously been isolated from the extract of the marine-derived fungus Penicillium sp. SF-5295. In the course of further biological evaluation of this quinolone alkaloid, anti-inflammatory effect of 1 in RAW264.7 and BV2 cells stimulated with lipopolysaccharide (LPS) was observed. In this study, our data indicated that 1 suppressed the expression of well-known pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and consequently inhibited the production of iNOS-derived nitric oxide (NO) and COX-2-derived prostaglandin E2 ($PGE_2$) in LPS stimulated RAW264.7 and BV2 cells. Compound 1 also reduced mRNA expression of pro-inflammatory cytokines such as $interleukin-1{\beta}$ ($IL-1{\beta}$), interleukin-6 (IL-6), and tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$). In the further evaluation of the mechanisms of these anti-inflammatory effects, 1 was shown to inhibit nuclear factor-kappa B ($NF-{\kappa}B$) pathway in LPS-stimulated RAW264.7 and BV2 cells. Compound 1 blocked the phosphorylation and degradation of inhibitor kappa B $(I{\kappa}B)-{\alpha}$ in the cytoplasm, and suppressed the translocation of $NF-{\kappa}B$ p65 and p50 heterodimer in nucleus. In addition, viridicatol (1) attenuated the DNA-binding activity of $NF-{\kappa}B$ in LPS-stimulated RAW264.7 and BV2 cells.

• Biomedical Science Letters
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• v.23 no.3
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• pp.175-184
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• 2017

Cholera toxin (CT) is an ADP-ribosylating bacterial exotoxin that has been used as an adjuvant in animal studies of oral immunization. The mechanisms of mucosal immunogenicity and adjuvanticity of CT remain to be established. In this study, we investigated the role of indoleamine 2,3-dioxygenase (IDO), which participates in the induction of immune tolerance, in CT-mediated breakdown of oral tolerance. When IDO-deficient ($IDO^{-/-}$) mice and their littermates were given oral ovalbumin, significant changes in antibody responses, footpad swelling and $CD4^+$ T cell proliferation were not observed in $IDO^{-/-}$ mice. Feeding of CT decreased IDO expression in mesenteric lymph nodes (MLN) and Peyer's patch (PP). CT-induced downregulation of IDO expression was reversed by inhibitors of nuclear factor-kappa B (NF-${\kappa}B$), pyrrolidine dithiocarbamate and p50 small interfering RNA. IDO expression was downregulated by the NF-${\kappa}B$ inducers lipopolysaccharide and tumor necrosis factor-${\alpha}$. CT dampened IDO activity and mRNA expression in dendritic cells from MLN and PP. These data indicate that CT disrupts oral tolerance by activating NF-${\kappa}B$, which in turn downregulates IDO expression. This study betters the understanding of the molecular mechanism underlying CT-mediated abrogation of oral tolerance.

• Journal of Physiology & Pathology in Korean Medicine
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• v.24 no.2
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• pp.278-283
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• 2010

Inducible nitric oxide synthase (iNOS) are important inflammation enzyme and severe up-nitric oxide (NO) production by this enzyme has been intricate with pathogenesis of atopy dermatitis. The present study was designed in order to determine whether Lonicera japonica could inhibit atopy dermatitis through modulation of iNOS by NF-${\kappa}B$ suppression. We found that IKK mRNA and iNOS mRNA expression in RAW 264.7 macrophages stimulated with lipopolysaccharide dose-dependantly decreased by Lonicera japonica (0.4 - 1.0 mg/$m{\ell}$) and NO production decreased. The distribution of NF-${\kappa}B$ p65 and iNOS positive reacted cell in NC/Nga mice with atopy dermatitis were decreased by Lonicera japonica (45 mg/kg/day) and apoptosis were increased. These data likely indicate that Lonicera japonica may act as inflammatory regulator for atopy dermatitis through iNOS modulation by NF-${\kappa}B$B suppression and may be possible to develop useful agent for chemoprevention of NO intricate inflammatory diseases.

• Biomolecules & Therapeutics
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• v.23 no.2
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• pp.110-118
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• 2015

According to the expansion of lifespan, neuronal disorder based on inflammation has been social problem. Therefore, we isolated shikonin from Lithospermum erythrorhizon and evaluated anti-inflammatory effects of shikonin in lipopolysaccharide (LSP)-stimulated BV2 microglial cells. Shikonin dose-dependently inhibits the expression of the proinflammatory mediators, nitric oxide (NO), prostaglandin $E_2$ ($PGE_2$), and tumor necrosis factor-${\kappa}B$ (TNF-${\alpha}$) as well as their main regulatory genes and products such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-${\alpha}$ in LPS-stimulated BV2 microglial cells. Additionally, shikonin suppressed the LPS-induced DNA-binding activity of nuclear factor-${\kappa}B$ (NF-${\kappa}B$) to regulate the key regulatory genes of the proinflammatory mediators, such as iNOS, COX-2, and TNF-${\alpha}$, accompanied with downregulation of reactive oxygen species (ROS) generation. The results indicate that shikonin may downregulate the expression of proinflammatory genes involved in the synthesis of NO, $PGE_2$, and TNF-${\alpha}$ in LPS-treated BV2 microglial cells by suppressing ROS and NF-${\kappa}B$. Taken together, our results revealed that shikonin exerts downregulation of proinflammatory mediators by interference the ROS and NF-${\kappa}B$ signaling pathway.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9835-9839
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• 2014

Fisetin is an effective compound extracted from lacquer which has been used in the treatment of various diseases. Preliminary data indicate that it also exerts specific anti-cancer effects. However, the manner in which fisetin regulates cancer growth remains unknown. In this study, we elucidated interference of fisetin with targets of the nuclear factor ${\kappa}B$ signal transduction pathway activated by Epstein-Barr virus encoding latent membrane protein 1 (LMP1)in nasopharyngeal carcinoma (NPC) cells, Results showed that fisetin inhibited the survival rate of CNE-LMP1 cells and NF-${\kappa}B$ activation caused by LMP1. Fisetin also suppressed nuclear translocation of NF-${\kappa}B$ (p65) and $I{\kappa}B{\alpha}$ phosphorylation, while inhibiting CyclinD1, all key targets of the NF-${\kappa}B$ signal transduction pathway. It was suggested that interference effects of fisetin with signal transduction activated by LMP1 encoded by the Epstein-Barr virus may play an important role in its anticancer potential.