• Tuberculosis and Respiratory Diseases
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• v.54 no.5
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• pp.495-509
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• 2003

Background : Neutrophil-mediated inflammation is usually self-limiting, because neutrophils have a remarkably short life span. Prolonged neutrophil survival, which is caused by decreased spontaneous apoptosis, leads to persistent inflammation in sepsis. Because many inflammatory cytokines, which generate signals that delay apoptosis, are regulated by nuclear factor-${\kappa}B$ transcription factor, we hypothesized that nuclear factor-${\kappa}B$ might be related to the reduced neutrophil apoptosis observed in sepsis. Methods : Neutrophils of healthy volunteers and sepsis patients were freshly isolated from venous blood. Neutrophil apoptosis was assayed with two approaches : by counting apoptotic cells under a microscope and by flow cytometry using Annexin V. The activity of nuclear factor-${\kappa}B$ was assessed by immunofluorescent staining or electrophoretic mobility shift assay. Expression of X-linked inhibitor of apoptosis was measured by western blot assay. Results : We confirmed reduced spontaneous neutrophil apoptosis in patients with sepsis. The number of apoptotic neutrophils in patients with sepsis increased to the level of that in healthy controls after cycloheximide treatment, suggesting that decreased spontaneous neutrophil apoptosis is dependent on de novo protein synthesis. In patients with sepsis, basal neutrophil nuclear factor-${\kappa}B$ was activated compared to the level in healthy controls. Moreover, a blockade of nuclear factor-${\kappa}B$ activity reversed the decreased spontaneous neutrophil apoptosis in sepsis patients. Meanwhile, X-linked inhibition of apoptosis expression, which is regulated by nuclear factor-${\kappa}B$, decreased 24 hours after incubation in healthy persons, but persisted for 24 hours in patients with sepsis. Conclusion : These observations suggest that the reduced spontaneous neutrophil apoptosis observed in patients with sepsis may be related to the induction of survival protein by nuclear factor-${\kappa}B$.

• Biomolecules & Therapeutics
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• v.24 no.3
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• pp.268-282
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• 2016

In the present study, we investigated the anti-inflammatory properties of Eucommia ulmoides Oliv. Bark. (EUE) in lipopolysaccharide (LPS)-stimulated microglial BV-2 cells and found that EUE inhibited LPS-mediated up-regulation of pro-inflammatory response factors. In addition, EUE inhibited the elevated production of pro-inflammatory cytokines, mediators, and reactive oxygen species (ROS) in LPS-stimulated BV-2 microglial cells. Subsequent mechanistic studies revealed that EUE suppressed LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs), phosphoinositide-3-kinase (PI3K)/Akt, glycogen synthase $kinase-3{\beta}$ ($GSK-3{\beta}$), and their downstream transcription factor, nuclear factor-kappa B ($NF-{\kappa}B$). EUE also blocked the nuclear translocation of $NF-{\kappa}B$ and inhibited its binding to DNA. We next demonstrated that EUE induced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated heme oxygenase-1 (HO-1) expression. We determined that the significant up-regulation of HO-1 expression by EUE was a consequence of Nrf2 nuclear translocation; furthermore, EUE increased the DNA binding of Nrf2. In contrast, zinc protoporphyrin (ZnPP), a specific HO-1 inhibitor, blocked the ability of EUE to inhibit NO and $PGE_2$ production, indicating the vital role of HO-1. Overall, our results indicate that EUE inhibits pro-inflammatory responses by modulating MAPKs, PI3K/Akt, and $GSK-3{\beta}$, consequently suppressing $NF-{\kappa}B$ activation and inducing Nrf2-dependent HO-1 activation.

• Molecules and Cells
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• v.20 no.3
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• pp.364-370
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• 2005

We show that sulforaphane inhibits osteoclastogenesis in the presence of macrophage colony-stimulating factor (M-CSF) and receptor for activation of nuclear factor-${\kappa}B$ ligand (RANKL) in osteoclast (OC) precursors. Sulforaphane, an aliphatic isothiocyanate, is a known cancer chemo-preventative agent with anti-oxidative properties. Nuclear factor-${\kappa}B$ (NF-${\kappa}B$) is a critical transcription factor in RANKL-induced osteoclastogenesis, and electrophoretic mobility shift assays (EMSAs) and assay of NF-${\kappa}B$-mediated secreted alkaline phosphatase (SEAP) revealed that sulforaphane selectively inhibited NF-${\kappa}B$ activation induced by RANKL. Inhibition may involve interaction of sulforaphane with thiol groups, since it was prevented by reducing agents.

• Molecules and Cells
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• v.40 no.10
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• pp.706-713
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• 2017

Osteoclasts are bone-resorbing cells that are derived from hematopoietic precursor cells and require macrophage-colony stimulating factor and receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL) for their survival, proliferation, differentiation, and activation. The binding of RANKL to its receptor RANK triggers osteoclast precursors to differentiate into osteoclasts. This process depends on RANKL-RANK signaling, which is temporally regulated by various adaptor proteins and kinases. Here we summarize the current understanding of the mechanisms that regulate RANK signaling during osteoclastogenesis. In the early stage, RANK signaling is mediated by recruiting adaptor molecules such as tumor necrosis factor receptorassociated factor 6 (TRAF6), which leads to the activation of mitogen-activated protein kinases (MAPKs), and the transcription factors nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and activator protein-1 (AP-1). Activated NF-${\kappa}B$ induces the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the key osteoclastogenesis regulator. In the intermediate stage of signaling, the co-stimulatory signal induces $Ca^{2+}$ oscillation via activated phospholipase $C{\gamma}2$ ($PLC{\gamma}2$) together with c-Fos/AP-1, wherein $Ca^{2+}$ signaling facilitates the robust production of NFATc1. In the late stage of osteoclastogenesis, NFATc1 translocates into the nucleus where it induces numerous osteoclast-specific target genes that are responsible for cell fusion and function.

• BMB Reports
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• v.48 no.10
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• pp.559-564
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• 2015

We investigated the effects of mangiferin on the expression and activity of metalloproteinase (MMP)-9 and the invasion of tumor necrosis factor (TNF)-$\alpha$-stimulated human LNCaP prostate carcinoma cells. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that mangiferin significantly reversed TNF-$\alpha$-induced mRNA and protein expression of MMP-9 expression. Zymography data confirmed that stimulation of cells with TNF-$\alpha$ significantly increased MMP-9 activity. However, mangiferin substantially reduced the TNF-$\alpha$-induced activity of MMP-9. Additionally, a matrigel invasion assay showed that mangiferin significantly reduced TNF-$\alpha$-induced invasion of LNCaP cells. Compared to untreated controls, TNF-$\alpha$-stimulated LNCaP cells showed a significant increase in nuclear factor-${\kappa}B$ (NF-${\kappa}B$) luciferase activity. However, mangiferin treatment markedly decreased TNF-$\alpha$-induced NF-${\kappa}B$ luciferase activity. Furthermore, mangiferin suppressed nuclear translocation of the NF-${\kappa}B$ subunits p65 and p50. Collectively, our results indicate that mangiferin is a potential anti-invasive agent that acts by suppressing NF-${\kappa}B$-mediated MMP-9 expression.

• Proceedings of the Korean Nuclear Society Conference
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• 2005.10a
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• pp.622-623
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• 2005

• Journal of agriculture & life science
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• v.50 no.2
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• pp.151-160
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• 2016

Inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with osteoporosis. Sulforaphane, isolated from the Broccoli(Brassica oleracea var. italia) florets, inhibits the production of inflamatory cytokine. In the present study, we determined inhibitory effect of sulforaphane on Receptor activator of nuclear factor κB ligand(RANKL)-induced osteoclast formation. Sulforaphane inhibited the expression of osteoclast marker genes, such as tartrate-resistant acid phosphatase(TRAP), cathepsin K, matrix metalloproteinase 9(MMP-9), and calcitonin receptor in RANKL-induced RAW 264.7 macrophage. Also, sluforaphane inhibited the expression of osteoclast protein, such as TRAP, MMP-9, tumor necrosis factor receptor-associated factor 6(TRAF6) and transcription factor nuclease factor of activated T cells(NFAT)c1. Sulforaphane inhibited RANKL-induced activiation of nuclear factor kappaB(NF-kappaB) by suppression RANKL-mediated NF-kappaB transcriptional acitivation. We are confirmed that sulforaphane inhibits not only transcriptional activity of NF-kappaB but also expressions of the osteoclastogenesis factors(TRAP, cathepsin K, MMP-9, calcitonin, TRAF6) and trranscription factor NFATc1.

• Nuclear Engineering and Technology
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• v.46 no.1
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• pp.81-92
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• 2014

This study suggests 5 evaluation criteria (safety and technology, environmental impact, economic feasibility, social factors, and institutional factors) and 24 evaluation indicators for a NFC (nuclear fuel cycle) derived using factor analysis. To do so, a survey using 1 on 1 interview was given to nuclear energy experts and local residents who live near nuclear power plants. In addition, by conducting a factor analysis, homogeneous evaluation indicators were grouped with the same evaluation criteria, and unnecessary evaluation criteria and evaluation indicators were dropped out. As a result of analyzing the weight of evaluation criteria with the sample of nuclear power experts and the general public, both sides recognized safety as the most important evaluation criterion, and the social factors such as public acceptance appeared to be ranked as more important evaluation criteria by the nuclear energy experts than the general public.

• Biomolecules & Therapeutics
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• v.25 no.4
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• pp.427-433
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• 2017

Previously, we demonstrated that galangin (3,5,7-trihydroxyflavone) protects human keratinocytes against ultraviolet B (UVB)-induced oxidative damage. In this study, we investigated the effect of galangin on induction of antioxidant enzymes involved in synthesis of reduced glutathione (GSH), and investigated the associated upstream signaling cascades. By activating nuclear factor-erythroid 2-related factor (Nrf2), galangin treatment significantly increased expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS). This activation of Nrf2 depended on extracellular signal-regulated kinases (ERKs) and protein kinase B (AKT) signaling. Inhibition of GSH in galangin-treated cells attenuated the protective effect of galangin against the deleterious effects of UVB. Our results reveal that galangin protects human keratinocytes by activating ERK/AKT-Nrf2, leading to elevated expression of GSH-synthesizing enzymes.

• Journal of Ginseng Research
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• v.42 no.4
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• pp.436-446
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• 2018

Background: The potential therapeutic values of Korean Red Ginseng extract (KRGE) in autoimmune disorders of nervous system have not been fully investigated. Methods: We used an acute experimental autoimmune encephalomyelitis animal model of multiple sclerosis and determined the effects and mechanism of KRGE on spinal myelination. Results: Pretreatment with KRGE (100 mg/kg, orally) for 10 days before immunization with myelin basic protein $(MBP)_{68-82}$ peptide exerted a protective effect against demyelination in the spinal cord, with inhibited recruitment and activation of immune cells including microglia, decreased mRNA expression of detrimental inflammatory mediators (interleukin-6, interferon-${\gamma}$, and cyclooxygenase-2), but increased mRNA expression of protective inflammatory mediators (insulin-like growth factor ${\beta}1$, transforming growth factor ${\beta}$, and vascular endothelial growth factor-1). These results were associated with significant downregulation of p38 mitogen-activated protein kinase and nuclear factor-${\kappa}B$ signaling pathways in microglia/macrophages, T cells, and astrocytes. Conclusion: Our findings suggest that KRGE alleviates spinal demyelination in acute experimental autoimmune encephalomyelitis through inhibiting the activation of the p38 mitogen-activated protein kinase/nuclear factor-${\kappa}B$ signaling pathway. Therefore, KRGE might be used as a new therapeutic for autoimmune disorders such as multiple sclerosis, although further investigation is needed.