• Molecular & Cellular Toxicology
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• v.5 no.2
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• pp.141-146
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• 2009

Toll-like receptors (TLRs) induce innate immune responses by recognizing conserved microbial structural molecules. All TLR signaling pathways culminate in the activation of nuclear factor kappa-B (NF-$\kappa$B) leading to the induction of inflammatory gene products such as cyclooxygenase-2 (COX-2). Deregulated activation of TLRs can lead to the development of severe systemic inflammation. Divalent heavy metals, cadmium and mercury, have been used for thousands of years. While cadmium and mercury are clearly toxic to most mammalian organ systems, especially the immune system, their underlying toxic mechanism(s) remain unclear. Here, we report biochemical evidence that cadmium, but not mercury, inhibits NF-$\kappa$B activation and COX-2 expression induced by TLR2 or TLR4 agonists, while cadmium does not inhibit NF-$\kappa$B activation induced by the downstream signaling component of TLRs, MyD88. Thus, the target of cadmium to inhibit NF-$\kappa$B activation may be upstream of MyD88 including TLRs themselves, or events leading to TLR activation by agonists.

• BMB Reports
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• v.50 no.9
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• pp.454-459
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• 2017

Tumor suppressor candidate 2 (Tusc2, also known as Fus1) regulates calcium signaling, and $Ca^{2+}$-dependent nuclear factor of activated T-cells (NFAT) and nuclear factor kappa B ($NF-{\kappa}B$) pathways, which play roles in osteoclast differentiation. However, the role of Tusc2 in osteoclasts remains unknown. Here, we report that Tusc2 positively regulates the differentiation of osteoclasts. Overexpression of Tusc2 in osteoclast precursor cells enhanced receptor activator of nuclear factor ${\kappa}B$ ligand (RANKL)-induced osteoclast differentiation. In contrast, small interfering RNA-mediated knockdown of Tusc2 strongly inhibited osteoclast differentiation. In addition, Tusc2 induced the activation of RANKL-mediated $NF-{\kappa}B$ and calcium/calmodulin-dependent kinase IV (CaMKIV)/cAMP-response element (CRE)-binding protein CREB signaling cascades. Taken together, these results suggest that Tusc2 acts as a positive regulator of RANKL-mediated osteoclast differentiation.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.4
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• pp.1657-1663
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• 2015

Background: Early diagnosis of hepatocellular carcinoma (HCC) is the most important step in successful treatment. However, it is usually rare due to the lack of a highly sensitive specific biomarker so that the HCC is usually fatal within few months after diagnosis. The aim of this work was to study the role of plasma nuclear factor kappa B (NF-${\kappa}B$) and serum peroxiredoxin 3 (PRDX3) as diagnostic biomarkers for early detection of HCC in a high-risk population. Materials and Methods: Plasma nuclear factor kappa B level (NF-${\kappa}B$) and serum peroxiredoxin 3 (PRDX3) levels were measured using enzyme linked immunosorbent assay (ELISA), in addition to alpha-fetoprotein (AFP) in 72 cirrhotic patients, 64 patients with HCC and 29 healthy controls. Results: NF-${\kappa}B$ and PRDX3 were significantly elevated in the HCC group in relation to the others. Higher area under curve (AUC) of 0.854 (for PRDX3) and 0.825 (for NF-${\kappa}B$) with sensitivity of 86.3% and 84.4% and specificity of 75.8% and 75.4% respectively, were found compared to AUC of alpha-fetoprotein (AFP) (0.65) with sensitivity of 72.4% and specificity of 64.3%. Conclusions: NF-${\kappa}B$ and PRDX3 may serve as early and sensitive biomarkers for early detection of HCC facilitating improved management. The role of nuclear factor kappa B (NF-${\kappa}B$) as a target for treatment of liver fibrosis and HCC must be widely evaluated.

• Journal of Korean Neurosurgical Society
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• v.56 no.5
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• pp.375-382
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• 2014

Objective : To assess the effect of bone marrow mononuclear cells (BMMNCs) transplantation in the expression of nuclear factor-${\kappa}B$ (NF-${\kappa}B$) in spinal cord injury (SCI) in rats. Methods : BMMNCs were isolated from tibia and femur by a density gradient centrifugation. After establishment of acute transection SCI, rats were divided into experiment (BMMNCs), experiment control (0.1 M PBS infused) and sham surgery groups (laminectomy without any SCI). Locomotor function was assessed weekly for 5 weeks post-injury using BBB locomotor score and urinary bladder function daily for 4 weeks post-injury. Activity of NF-${\kappa}B$ in spinal cord was assessed by immunohistochemistry and reverse transcriptase polymerase chain reaction. Results : At each time point post-injury, sham surgery group had significantly higher Basso, Beattie, Bresnahan locomotor and urinary bladder function scores than experiment and experiment control group (p<0.05). At subsequent time interval there were gradual improvement in both experiment and experiment control group, but experiment group had higher score in comparison to experiment control group (p<0.05). Comparisons were also made for expression of activated NF-${\kappa}B$ positive cells and level of NF-${\kappa}B$ messenger RNA in spinal cord at various time points between the groups. Activated NF-${\kappa}B$ immunoreactivity and level of NF-${\kappa}B$ mRNA expression were significantly higher in control group in comparison to experiment and sham surgery group (p<0.05). Conclusion : BMMNCs transplantation attenuates the expression of NF-${\kappa}B$ in injured spinal cord tissue and thus helps in recovery of neurological function in rat models with SCI.

• 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.

• 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.

• Proceedings of the PSK Conference
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• 2001.10a
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• pp.109-113
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• 2001

Oxidized low-density lipoprotein (oxLDL) has been shown to modulate transactivations by the peroxisome proliferator activated receptor (PPAR)$\gamma$ and nuclear factor-kappa B (NF$\kappa$B). In this study, the oxLDL signaling pathways involved with the NF$\kappa$B transactivation were investigated by utilizing a reporter construct driven by three upstream NF$\kappa$B binding sites, and various pharmacological inhibitors. OxLDL and its constituent lysophophatidylcholine (lysoPC) induced a rapid and transient increase of intracellular calcium and stimulated the NF-KB transactivation in resting RAW264.7 macrophage cells in an oxidation-dependent manner. The NF$\kappa$B activation by oxLDL or lysoPC was inhibited by protein kinase C inhibitors or an intracellular calcium chelator. Tyrosine kinase or PI3 kinase inhibitors did not block the NF$\kappa$B transactivation. Furthermore, the oxLDL-induced NF$\kappa$B activity was abolished by the PPAR$\gamma$ ligands. When the endocytosis of oxLDL was blocked by cytochalasin B, the NF$\kappa$B transactivation by oxLDL was synergistically increased, while PPAR transactivation was blocked. These results suggest that oxLDL activates NF-$\kappa$B in resting macrophages via protein kinase C- and/or calcium-dependent pathways, which does not involve the endocytic processing of oxLDL. The endocytosis-dependent PPAR$\gamma$ activation by oxLDL may function as an inactivation route of the oxLDL induced NF$\kappa$B signal. Short heterodimer partner (SHP), specifically expressed in liver and a limited number of other tissues, is an unusual orphan nuclear receptor that lacks the conventional DNA-binding domain. In this work, we found that SHP expression is abundant in murine macrophage cell line RAW 264.7 but suppressed by oxLDL and its constituent I3-HODE, a ligand for peroxisome proliferator-activated receptor y. Furthermore, SHP acted as a transcription coactivator of nuclear factor-$\kappa$B (NF$\kappa$B) and was essential for the previously described NF$\kappa$B transactivation by lysoPC, one of the oxLDL constituents. Accordingly, NF$\kappa$B, transcriptionally active in the beginning, became progressively inert in oxLDL-treated RAW 264.7 cells, as oxLDL decreased the SHP expression. Thus, SHP appears to be an important modulatory component to regulate the transcriptional activities of NF$\kappa$B in oxLDL-treated, resting macrophage cells.

• Journal of Microbiology and Biotechnology
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• v.18 no.10
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• pp.1683-1688
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• 2008

Lactobacillus casei 3260 (L. casei 3260) was evaluated in relation to the inflammatory response mediated by lipopolysaccharide (LPS)-induced nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and cyclooxygenase-2 (COX-2) expression in Raw264.7 macrophage cells. The treatment of Raw264.7 cells with L. casei 3260 significantly inhibited the secretion of tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and prostaglandins $E_{2}\;(PGE_{2})$, followed by suppression of COX-2. To clarify the molecular mechanism, the inhibitory effect of L. casei 3260 on the NF-${\kappa}B$ signaling pathway was examined based on the luciferase reporter activity. Although the treatment of Raw264.7 cells with L. casei 3260 did not affect the transcriptional activity of NF-${\kappa}B$, it did inhibit NF-${\kappa}B$ activation, as determined by the cytosolic p65 release and degradation of I-${\kappa}B{\alpha}$. Therefore, these findings suggest that the suppression of COX-2 through inhibiting the NF-${\kappa}B$ activation by LPS may be associated with the antiinflammatory effects of L. casei 3260 on Raw264.7 cells.

• 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.

• Biomedical Science Letters
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• v.21 no.4
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• pp.218-226
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• 2015

The present study investigated the mechanisms of licochalcone B (LicB)-mediated inhibition of the inflammatory response in murine macrophages. RAW264.7 murine macrophages were cultured in the absence or presence of lipopolysacharide (LPS) with LicB. LicB suppressed the generation of nitric oxide and the pro-inflammatory cytokines interleukin (IL)-$1{\beta}$, IL-6 and tumor necrosis factor-${\alpha}$. LicB also inhibited the expression of mRNA for inducible nitric oxide synthase and pro-inflammatory cytokines induced by LPS. Moreover, LicB inhibited nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and activator protein-1 translocation into the nucleus in a dose-dependent manner. Thus, LicB mainly exerts its anti-inflammatory effects by inhibiting the LPS-induced NF-${\kappa}B$ and activator protein-1 signaling pathways in macrophages, which subsequently diminishes the expression and release of various inflammatory mediators. LicB shows promise as a therapeutic agent in inflammatory diseases.