• Journal of Ginseng Research
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• 제35권2호
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• pp.200-208
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• 2011

Ginsenoside (G) $Rp_1$ is a ginseng saponin derivative with anti-cancer and anti-inflammatory activities. In this study, we examined the mechanism by which G-$Rp_1$ inhibits inflammatory responses of cells. We did this using a strategy in which DNA constructs containing cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) promoters were transfected into HEK293 cells. G-$Rp_1$ strongly inhibited the promoter activities of COX-2 and iNOS; it also inhibited lipopolysaccharide induced upregulation of COX-2 and iNOS mRNA levels in RAW264.7 cells. In HEK293 cells G-$Rp_1$ did not suppress TANK binding kinase 1-, Toll-interleukin-1 receptor-domain-containing adapter-inducing interferon-${\beta}$ (TRIF)-, TRIF-related adaptor molecule (TRAM)-, or activation of interferon regulatory factor (IRF)-3 and nuclear factor (NF)-${\kappa}$B by the myeloid differentiation primary response gene (MyD88)-induced. However, G-$Rp_1$ strongly suppressed NF-${\kappa}$B activation induced by I${\kappa}$B kinase (IKK)${\beta}$ in HEK293 cells. Consistent with these results, G-$Rp_1$ substantially inhibited IKK${\beta}$-induced phosphorylation of $I{\kappa}B{\alpha}$ and p65. These results suggest that G-$Rp_1$ is a novel anti-inflammatory ginsenoside analog that can be used to treat IKK${\beta}$/NF-${\kappa}$B-mediated inflammatory diseases.

• BMB Reports
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• 제35권1호
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• pp.28-40
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• 2002

Apoptosis is a mode of cell death that plays an important role in both pathological and physiological processes. Research during the last decade has delineated the entire machinery needed for cell death, and its constituents were found to pre-exist in cells. The apoptotic cascade is triggered when cells are exposed to an apoptotic stimulus. It has been known for several years that inhibitors of protein synthesis can potentiate apoptosis that is induced by cytokines and other inducers. Until 1996, it was not understood why protein synthesis inhibitors potentiate apoptosis. Then three reports appeared that suggested the role of the transcription factor NF-${\kappa}B$ activation in protecting the cells from TNF-induced apoptosis. Since then several proteins have been identified that are regulated by NF-${\kappa}B$ and are involved in cell survival, proliferation, and protection from apoptosis. It now seems that when a cell is attacked by an apoptotic stimulus, the cell responds first by activating anti-apoptotic mechanisms, which mayor may not be followed by apoptosis. Whether or not a cell undergoes proliferation, the survival, or apoptosis, appears to involve a balance between the two mechanisms. Inhibitors of protein synthesis seem to suppress the appearance of protein that are involved in anti-apoptosis. The present review discusses how NF-${\kappa}B$ controls apoptosis.

• 한국자원식물학회지
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• 제33권6호
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• pp.659-665
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• 2020

Adenophorae Radix (AR) has been used as a traditional medicine for various diseases. However, the regulatory mechanisms of AR in allergic inflammation are not yet understood. The present study was conducted to investigate the effect and mechanisms of AR on the mast cell-mediated allergic response. To determine the pharmacological mechanisms of AR in allergic inflammation, we evaluated the effects of AR on the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β and IL-8 as well as the activation of nuclear factor-κB (NF-κB) and caspase-1 in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated human mast cells (HMC-1). Our results demonstrated that AR effectively attenuated the PMACI-induced production of TNF-α, IL-6, IL-1β and IL-8 in stimulated HMC-1. Additionally, we showed that the inhibitory effect of AR on inflammatory cytokines in PMACI-stimulated HMC-1 cells involved the suppression of the activation NF-kB/caspase-1 in PMACI-stimulated HMC-1. Collectively, these findings provide experimental evidence that AR may be a useful candidate for the treatment of allergic inflammation.

• 대한한의학방제학회지
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• 제18권1호
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• pp.105-120
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• 2010

Paeonia Suffruticosa and Prunus Persica have been used as oriental medicine for removal of fever, alleviation of pain, an anti-phlogistic effect and removal of extravasated blood. However, it has been never shown the effects of these herbal medicines on anti-inflammatory processes. This experiment was performed to show how these herbs could act as anti-inflammatory medicines at cellular level. Anti-inflammation effects of water extracts from Paeonia Suffruticosa and Prunus Persica as well as their mixture have been investigated, and the results were follows; 1) each extract slightly suppressed the expression and production of inflammatory mediators and enzymes such as NO, iNOS, IL-$1{\beta}$, and TNF-$\alpha$ in lipopolysaccharid(LPS)-stimulated RAW264.7 cells and mouse primary peritoneal macrophages in a dose-dependent manner. These suppressive effects, however, were synergistically increased by their mixture. 2) Each extract of Paeonia Suffruticosa and Prunus Persica insignificantly suppressed the activation and activity of NF-${\kappa}B$ in LPS-stimulated RAW264.7 cells, which controls the expression of inflammatory mediators such as NO, iNOS, IL-$1{\beta}$, and TNF-$\alpha$. However, extract mixture of Paeonia Suffruticosa and Prunus Persica suppressed effectively the activation and activity of NF-${\kappa}B$. 3) Each of Paeonia Suffruticosa and Prunus Persica induced translocation of NF-${\kappa}B$ to the nucleus from the cytosol and DNA-binding activity of nuclear NF-${\kappa}B$ in LPS-activated RAW264.7 cells. The extract mixture of Paeonia Suffruticosa and Prunus Persica showed more significant suppression of the NF-${\kappa}B$ translocation and its DNA-binding activity, as compared to those of the each extract. These results suggest that the extract mixture of Paeonia Suffruticosa and Prunus Persica may affect different control mechanisms for NF-${\kappa}B$ activation and the expression and production of NF-${\kappa}B$-dependent inflammatory mediators, indicating that this extract mixture may be useful for treatment of inflammatory diseases.

• BMB Reports
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• 제41권4호
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• pp.328-333
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• 2008

A variety of anti-inflammatory agents have been shown to exert chemopreventive activity via targeting of transcription factors such as NF-${\kappa}B$ and AP-1. Lithospermum erythrorhizon (LE) has long been used in traditional oriental medicine. In this study, we demonstrated the inhibitory effects of LE extracts on lipopolysaccharide (LPS)-stimulated production of inflammatory cytokines. As an underlying mechanism of inhibition, LE extracts reduced LPS-induced transactivation of AP-1 as well as NF-${\kappa}B$ in mouse macrophage cells. Electrophoretic mobility shift assays indicated that LE extracts inhibited the DNA binding activities of AP-1 and NF-${\kappa}B$. In addition, phosphorylation of $I{\kappa}B-{\alpha}$ protein was suppressed by LE extracts. Moreover, LE extracts inhibited c-Jun N-terminal kinase and extracellular signal-regulated signaling pathways. Our results suggest that the anti-inflammatory activity of LE extracts may be mediated by the inhibition of signal transduction pathways that normally lead to the activation of AP-1and NF-${\kappa}B$. These inhibitory effects may be useful for chemoprevention of cancer or other chronic inflammatory diseases.

• 대한약학회:학술대회논문집
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• 대한약학회 2001년도 Proceedings of International Convention of the Pharmaceutical Society of Korea
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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.

• IMMUNE NETWORK
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• 제10권5호
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• pp.145-152
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• 2010

Background: The flowers of Inula japonica (Inulae Flos) have long been used in traditional medicine for the treatment of inflammatory diseases. In the present study, we investigated the anti-inflammatory properties of Inulae Flos Extract (IFE). Methods: The anti-inflammatory effects of IFE against nitric oxide (NO), $PGE_2$, TNF-${\alpha}$, and IL-6 release, as well as NF-${\kappa}B$ and MAP kinase activation were evaluated in RAW 264.7 cells. Results: IFE inhibited the production of NO and the expression of inducible nitric oxide synthase (iNOS) in LPS-stimulated RAW264.7 cells. In addition, IFE reduced the release of pro-inflammatory cytokines, such as TNF-${\alpha}$ and IL-6. Furthermore, IFE inhibited the NF-${\kappa}B$ activation induced by LPS, which was associated with the abrogation of $I{\kappa}B-{\alpha}$ degradation and subsequent decreases in nuclear p65 and p50 levels. Moreover, the phosphorylation of ERK, JNK, and p38 MAP kinases in LPS-stimulated RAW 264.7 cells was suppressed by IFE in a dose-dependent manner. Conclusion: These results suggest that the anti-inflammation activities of IFE might be attributed to the inhibition of NO, iNOS and cytokine expression through the down-regulation of NF-${\kappa}B$ activation via suppression of $I{\kappa}B{\alpha}$ and MAP kinase phosphorylation in macrophages.

• 한국식품위생안전성학회지
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• 제21권3호
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• pp.181-188
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• 2006

Tumor necrosis ftctor-alpha$(TNF-{\alpha})$는 세포의 고사, 염증 및 면역 등의 다양한 생물학적 기능에 대한 역할을 한다. PTEN 역시 세포의 성장과 증식 그리고 세포의 유주와 분화 등의 세포학적인 다양한 기능을 갖는다 그러므로 이들 두 분자들 사이의 상호관계가 있을 것으로 제안되고 있으며, $TNF-{\alpha}$는 사람의 대장세포 주인 HT-29에서 nuclear factor-kappa $B(NF-{\kappa}B)$ 경로를 통해 PTEN downregulate 기능이 있는 것으로 알려져 왔다. 그러나 저자 등은 본 연구에서 HL-60 cells에서 $TNF-{\alpha}$가 $NF-{\kappa}B$를 통해 PTEN를 upregulates하는 기존의 반대 현상을 확인하였다. $TNF-{\alpha}$는 HL-60 cells에서 time과 dose의존성 방법으로 PTEN 발현을 증가시켰지만 반응은 p65 anisense oligonucleotide 또는 pyrrolidine dithiocarbamate(PDTC)으로 $NF-{\kappa}B$를 분해함으로 파괴되었다. 따라서 저자 등은 $TNF-{\alpha}$가 $NF-{\kappa}B$경로를 활성화시킴을 확인하였고, $TNF-{\alpha}$를 처리 할 경우 핵에 대하여 p65 전위에 의해 $TNF-{\alpha}$가 활성화됨을 증명하였다. 결국 HL-60세포에서 $NF-{\kappa}B$의 활성화에 따라 PTEN 발현의 upregulation이 유도되는 것으로 결론지었다.

• BMB Reports
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• 제50권1호
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• pp.25-30
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• 2017

In the central nervous system, viral infection can induce inflammation by up-regulating pro-inflammatory mediators that contribute to enhanced infiltration of immune cells into the central nervous areas. Celastrol is known to exert various regulatory functions, including anti-microbial activities. In this study, we investigated the regulatory effects and the mechanisms of action of celastrol against astrocytes activated with polyinosinic-polycytidylic acid (poly(I:C)), a synthetic dsRNA, as a model of pro-inflammatory mediated responses. Celastrol significantly inhibited poly(I:C)-induced expression of adhesion molecules, such as ICAM-1/VCAM-1, and chemokines, such as CCL2, CXCL8, and CXCL10, in CRT-MG human astroglioma cells. In addition, celastrol significantly suppressed poly(I:C)-induced activation of JNK MAPK and STAT1 signaling pathways. Furthermore, celastrol significantly suppressed poly(I:C)-induced activation of the $NF-{\kappa}B$ signaling pathway. These results suggest that celastrol may exert its regulatory activity by inhibiting poly(I:C)-induced expression of pro-inflammatory mediators by suppressing activation of JNK MAPK-STAT1/$NF-{\kappa}B$ in astrocytes.

• Molecules and Cells
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• 제43권1호
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• pp.23-33
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• 2020

NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB-inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the TP53 gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.