• YAKHAK HOEJI
• /
• v.56 no.3
• /
• pp.186-190
• /
• 2012

Nuclear factor-${\kappa}B$ (NF-${\kappa}B$) has been considered as one of the major targets for therapeutic agents of diverse human diseases. In the previous studies, 6-hydroxy-7-methoxychroman-2-carboxylic acid N-phenylamide (KL-1156) and chroman-2-carboxylic acid N-(4-chlorophenyl)amide were identified as good inhibitors of NF-${\kappa}B$ activation. In this continuous study, we describe the synthesis and NF-${\kappa}B$ inhibitory activities of chroman derivatives containing N-heteroaryl groups for exploration of SAR (structure-activity relationship). In addition, inhibitory effects of cell proliferation are evaluated against human cancer cell lines (NCI-H23 and PC-3).

• The Korean Journal of Physiology and Pharmacology
• /
• v.19 no.3
• /
• pp.211-218
• /
• 2015

The present study showed that silymarin, a polyphenolic flavonoid isolated from milk thistle (Silybum marianum), inhibited lipopolysaccharide (LPS)-induced morphological changes in the mouse RAW264.7 macrophage cell line. We also showed that silymarin inhibited the nuclear translocation and transactivation activities of nuclear factor-kappa B (NF-${\kappa}B$), which is important for macrophage activation-associated changes in cell morphology and gene expression of inflammatory cytokines. BAY-11-7085, an NF-${\kappa}B$ inhibitor, abrogated LPS-induced morphological changes and NO production, similar to silymarin. Treatment of RAW264.7 cells with silymarin also inhibited LPS-stimulated activation of mitogen-activated protein kinases (MAPKs). Collectively, these experiments demonstrated that silymarin inhibited LPS-induced morphological changes in the RAW264.7 mouse macrophage cell line. Our findings indicated that the most likely mechanism underlying this biological effect involved inhibition of the MAPK pathway and NF-${\kappa}B$ activity. Inhibition of these activities by silymarin is a potentially useful strategy for the treatment of inflammation because of the critical roles played by MAPK and NF-${\kappa}B$ in mediating inflammatory responses in macrophages.

• Journal of Veterinary Clinics
• /
• v.28 no.2
• /
• pp.190-195
• /
• 2011

Nuclear factor ${\kappa}B$ (NF-${\kappa}B$) is a nuclear transcription factor that modulates the expression of inflammatory cytokines such as tumor necrosis factor (TNF)-${\alpha}$. trans-10, cis-12 (t10c12)-conjugated linoleic acid (CLA) participates in the inhibition of TNF-${\alpha}$ production upon lipopolysaccharide (LPS)-stimulation. However, in our previous study, t10c12-CLA enhanced the production of TNF-${\alpha}$ by LPS-unstimulated porcine peripheral blood mononuclear cells (PBMCs) and RAW 264.7 macrophages in vitro. To resolve this apparent contradiction, we hypothesized that the effect of t10c12-CLA on TNF-${\alpha}$ production depends on NF-${\kappa}B$ activation induced by LPS stimulation. To test this hypothesis, we assessed the in vitro effect of t10c12-CLA on TNF-${\alpha}$ production and NF-${\kappa}B$ p65 activity in LPS-stimulated and LPS-unstimulated porcine PBMCs. t10c12-CLA treatment resulted in increased TNF-${\alpha}$ production by LPS-unstimulated PBMCs but decreased TNF-${\alpha}$ production by LPS-stimulated PBMCs. t10c12-CLA increased the degradation of inhibitory ${\kappa}B$ ($I{\kappa}B$)-${\alpha}$ protein and activated NF-${\kappa}B$ p65 in LPS-unstimulated PBMCs, but had the opposite effect in LPS-stimulated PBMCs. Notably, t10c12-CLA enhanced NF-${\kappa}B$ p65 binding activity in LPS-unstimulated PBMCs exposed to caffeic acid phenethyl ester (CAPE), a NF-${\kappa}B$ inhibitor. Conversely, it inhibited NF-${\kappa}B$ p65 binding activity in LPS-stimulated PBMCs exposed to CAPE. These results suggest that t10c12-CLA may have different actions under different physiological conditions, and that its effect may be associated with a change in NF-${\kappa}B$ p65 activity.

• Food Science and Biotechnology
• /
• v.17 no.6
• /
• pp.1294-1298
• /
• 2008

Toll-like receptors (TLRs) induce innate immune responses recognizing conserved microbial structural molecules. All TLR signaling pathways culminate in the activation of nuclear factor-${\kappa}B$ (NF-${\kappa}B$). The activation of NF-${\kappa}B$ leads to the induction of inflammatory gene products such as cyclooxygenase-2 (COX-2). Guggul has been used for centuries to treat a variety of diseases. Guggulstreone, one of the active ingredients in guggul, has been used to treat many chronic diseases. However, the mechanism as to how guggulsterone mediate the health effects is largely unknown. Here, we report biochemical evidence that guggulsterone inhibits the NF-${\kappa}B$ activation and COX-2 expression induced by TLR2, TLR3, and TLR4 agonists. Guggulsterone also inhibits the NF-${\kappa}B$ activation induced by downstream signaling components of TLRs, myeloid differential factor 88 (MyD88), $I{\kappa}B$ kinase ${\beta}$ ($IKK{\beta}$), and p65. These results imply that guggulsterone can modulate the immune responses regulated by TLR signaling pathways.

• Tuberculosis and Respiratory Diseases
• /
• v.54 no.5
• /
• pp.542-550
• /
• 2003

Background : Synthetic glucocorticoids are widely used in many chronic inflammatory diseases because of their excellent anti-inflammatory activity. Enhancing the transcription of $I{\kappa}B$ and preventing activated NF-${\kappa}B$ from binding to ${\kappa}B$ sites are thought to be the underlying mechanisms. But these data are largely derived from in vitro studies using cell lines. In this study, after administrating a steroid to volunteers, we evaluated the effect on the NF-${\kappa}B$ system. Methods : Prednisolone(0.5mg/kg/d) was orally administered to 5 healthy volunteers for 7 days. Before and after the administration, we sampled their peripheral blood monocytes, and performed western blot analysis both with stimulation, using IL-$1{\beta}$, LPS, TNF, and without stimulation(baseline). We also performed EMSA after stimulation with LPS. Results : After ingestion of the steroid, baseline expressions of $I{\kappa}B{\alpha}$ were increased in two of the subjects, while suppressed degradations of $I{\kappa}B{\alpha}$ to stimulations were observed in all five. In addition, the binding capacity of NF-${\kappa}B$ after the administration was decreased. Conclusion : Steroid plays such roles as enhancing the transcription of $I{\kappa}B{\alpha}$, suppressing the DNA binding capacity of NF-${\kappa}B$, and suppressing the degradation of $I{\kappa}B{\alpha}$.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.7
• /
• pp.4441-4446
• /
• 2013

Cholangiocarcinoma (CCA) is a tumor of biliary ducts, which has a high mortality rate and dismal prognosis. Constitutively activation of the transcription factor nuclear factor kappa-B (NF-${\kappa}B$) has been previously demonstrated in CCA. It is therefore a potential target for CCA treatment. Effects of diethyldithiocarbamate (DDTC) on NF-${\kappa}B$-dependent apoptosis induction in cancer have been reported; however, anti-metastasis has never been addressed. Therefore, here the focus was on DDTC effects on CCA migration and adhesiond. Anti-proliferation, anti-migration and anti-adhesion activities were determined in CCA cell lines, along with p65 protein levels and function. NF-${\kappa}B$ target gene expression was determined by quantitative RT-PCR. DDTC inhibited CCA cell proliferation. Suppression of migration and adhesion were observed prior to anti-CCA proliferation. These effects were related to decreased p65, reduction in NF-${\kappa}B$ DNA binding, and impaired activity. Moreover, suppression of ICAM-1 expression supported NF-${\kappa}B$-dependent anti-metastatic effects of DDTC. Taken together, DDTC suppression of CCA migration and adhesion through inhibition of NF-${\kappa}B$ signaling pathway is suggested from the current study. This might be a promising treatment choice against CCA metastasis.

• Korean Journal of Food Science and Technology
• /
• v.38 no.6
• /
• pp.829-834
• /
• 2006

LP-BM5 murine leukemia retrovirus induces the immune dysfunction by imbalanced secretion of Th1 and Th2 cytokines in the murine AIDS model. In the present study, it was investigated whether pycnogenol (Pyc) administration could deactivate $NF-{\kappa}B$ to regulate the gene expression of Th1 and Th2 cytokines in C57BL/6 mice with murine AIDS. Treatment with Pyc for 12 weeks significantly inhibited the loss of body weight and enlargement of spleen and lymph node usually seen with AIDS. Moreover, Pyc increased the plasma level of Th1 cytokines, IL-2 and $IFN-{\gamma}$, while reducing the plasma level of Th2 cytokines, IL-6, IL-10, and $TNF-{\alpha}$. In primary culture of splenocytes, mRNA expression of Th2 cytokines was suppressed, but that of Th1 cytokines was not affected. The LP-BM5 retrovirus infection stimulated the cytoplasmic activation of $NF-{\kappa}B$ and nuclear translocation of $I-{\kappa}B$, whereas Pyc administration significantly reduced $NF-{\kappa}B$ activation and $I-{\kappa}B$ degradation. These results suggested that the inhibitory effect of Pyc on Th2 cytokines in mice with murine AIDS was dependent on suppression of the $NF-{\kappa}B$ signaling pathway and was not dependent on $INF-{\gamma}$ level, which regulates Th2 cytokines.

• Korean Journal of Veterinary Research
• /
• v.51 no.3
• /
• pp.217-225
• /
• 2011

Glatiramer acetate (GA; Copaxone) has been shown to be effective in preventing and suppressing experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). It has been recently shown that GA-reactive T cells migrate through the blood-brain barrier, accumulate in the central nervous system (CNS), secrete antiinflammatory cytokines and suppress production of proinflammatory cytokines of EAE and MS. Development of EAE requires coordinated expression of a number of genes involved in the activation and effector functions of inflammatory cells. Activation of inflammatory cells is regulated at the transcriptional level by several families of transcription factors. One of these is the nuclear factor kappa B ($NF{\kappa}B$) family which is present in a variety of cell types and involved in the activation of immune-relative genes during inflammatory process. Since it is highly activated at site of inflammation, $NF{\kappa}B$ activation is also implicated in the pathogenesis of EAE. In this study, we examined whether the inhibition of $NF{\kappa}B$ activation induced by GA can have suppressive therapeutic effects in EAE mice. We observed the expression of $NF{\kappa}B$ and phospho-$I{\kappa}B$ proteins increased in GA-treated EAE mice compared to EAE control groups. The immunoreactivity in inflammatory cells and glial cells of $NF{\kappa}B$ and phospho-$I{\kappa}B$ significantly decreased at the GA-treated EAE mice. These results suggest that treatment of GA in EAE inhibits the activation of $NF{\kappa}B$ and phophorylation of $I{\kappa}B$ in the CNS. Subsequently, the inhibition of $NF{\kappa}B$ activation and $I{\kappa}B$ phosphorylation leads to the anti-inflammatory effects thereby to reduce the progression and severity of EAE.

• Journal of the Society of Cosmetic Scientists of Korea
• /
• v.42 no.4
• /
• pp.311-320
• /
• 2016

Kava (Piper methysticum, P. methysticum) is used as traditional herbal medicine for urogenital diseases, rheumatisms, gastrointestinal problems, respiratory irritations, and pulmonary pains. We identified a flavokavain C (FKC) from P. methysticum, which showed anti-inflammatory activity on nuclear factor ${\kappa}B$ (NF-${\kappa}B$)-dependent nitric oxide (NO) production and expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. FKC inhibited accumulation of reactive oxygen species (ROS), such as hydrogen peroxide, and was able to dose-dependently reduce the LPS-induced NO production and the expression of various inflammation-associated genes (iNOS, IL-$1{\beta}$, IL-6) through inhibition of NF-${\kappa}B$ and MAPKs (ERK and JNK). In conclusion, these results indicate that FKC may have the potential to prevent inflammation process including NF-${\kappa}B$ and MAPKs pathways, and it could be applicable to functional cosmetics for anti-inflammation and antioxidant properties.

• Journal of Ginseng Research
• /
• v.43 no.3
• /
• pp.452-459
• /
• 2019

Background: Ginsenoside compound K(C-K), a major metabolite of ginsenoside, exhibits anticancer activity in various cancer cells and animal models. A cell signaling study has shown that C-K inhibited nuclear factor-kappa B ($NF-{\kappa}B$) pathway in human astroglial cells and liver cancer cells. However, the molecular targets of C-K and the initiating events were not elucidated. Methods: Interaction between C-K and Annexin A2 was determined by molecular docking and thermal shift assay. HepG2 cells were treated with C-K, followed by a luciferase reporter assay for $NF-{\kappa}B$, immunofluorescence imaging for the subcellular localization of Annexin A2 and $NF-{\kappa}B$ p50 subunit, coimmunoprecipitation of Annexin A2 and $NF-{\kappa}B$ p50 subunit, and both cell viability assay and plate clone formation assay to determine the cell viability. Results: Both molecular docking and thermal shift assay positively confirmed the interaction between Annexin A2 and C-K. This interaction prevented the interaction between Annexin A2 and $NF-{\kappa}B$ p50 subunit and their nuclear colocalization, which attenuated the activation of $NF-{\kappa}B$ and the expression of its downstream genes, followed by the activation of caspase 9 and 3. In addition, the overexpression of Annexin A2-K320A, a C-K binding-deficient mutant of Annexin A2, rendered cells to resist C-K treatment, indicating that C-K exerts its cytotoxic activity mainly by targeting Annexin A2. Conclusion: This study for the first time revealed a cellular target of C-K and the molecular mechanism for its anticancer activity.