• 대한한의학회지
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• 제23권1호
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• pp.50-60
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• 2002

Objectives: Sunghyangjunggisan (SHJS) is a commonly prescribed drug with a wide neuropharmacological spectrum. The water extracts of SHJS were found to be protective against neurotoxicity elicited by deprivation of serum and glucose. Methods: The morphological examination and Hoechst staining of nucleus also clearly showed that the extracts attenuated the cell shrinkage, membrane blebbing, representing typical neuronal apoptotic phenomena and nucleosome-sized fragmentation under the microscope in PC 12 rat pheochromocytoma cells. Results: Activation of protein kinase A (PKA) with dibutyl-cAMP and forskolin also protected during glucose deprivation, although it was not additive with the effect provided by phorbol ester. Interestingly, treatment with the protein kinase A inhibitor, KT5720, was not neuroprotective in the presence of SHJS. Electrophoretic mobility shift assays were used to characterize the neuroprotective binding of nuclear proteins to consensus sequences for AP-l, nuclear factor kappa B ($NF-{\kappa}B$) after glucose deprivation. When PC 12 cells are induced to undergo apoptosis by serum deprivation, AP-l and $NF-{\kappa}B$ DNA binding activity transiently increases to a slight degree. This stimulation is blocked by the water extracts of SHJS. The site of action of the drugs appeared to involve specific inhibition of AP-1 and nuclear factor kB binding activity. Conclusions: Taken together, these results suggested the possibility that the extracts of SHJS might provide a neurotrophic-like activity in PC 12 cells.

• The Korean Journal of Physiology and Pharmacology
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• 제23권6호
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• pp.493-499
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• 2019

Macrophage-associated inflammation is crucial for the pathogenesis of diverse diseases including metabolic disorders. Rhodanthpyrone (Rho) is an active component of Gentiana rhodantha, which has been used in traditional Chinese medicine to treat inflammation. Although synthesis procedures of RhoA and RhoB were reported, the biological effects of the specific compounds have never been explored. In this study, the anti-inflammatory activity and mechanisms of action of RhoA and RhoB were studied in lipopolysaccharide (LPS)-stimulated macrophages. Pretreatment with RhoA and RhoB decreased inducible nitric oxide synthase and cyclooxygenase-2 expressions in RAW 264.7 cells and in thioglycollate-elicited mouse peritoneal macrophages. In addition, it downregulated transcript levels of several inflammatory genes in LPS-stimulated RAW 264.7 cells, including inflammatory cytokines/chemokines (Tnfa, Il6, and Ccl2) and inflammatory mediators (Nos2 and Ptgs2). Macrophage chemotaxis was also inhibited by treatment with the compounds. Mechanistic studies revealed that RhoA and RhoB suppressed the nuclear factor $(NF)-{\kappa}B$ pathway, but not the canonical mitogen activated protein kinase pathway, in LPS-stimulated condition. Moreover, the inhibitory effect of RhoA and RhoB on inflammatory gene expressions was attenuated by treatment with an $NF-{\kappa}B$ inhibitor. Our findings suggest that RhoA and RhoB play an anti-inflammatory role at least in part by suppressing the $NF-{\kappa}B$ pathway during macrophage-mediated inflammation.

• Biomolecules & Therapeutics
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• 제24권3호
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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.

• Asian Pacific Journal of Cancer Prevention
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• 제17권1호
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• pp.117-123
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• 2016

Taxol (paclitaxel) is a powerful anti-cancer drug widely used against several types of malignant tumors. Because Taxol may exert several side effects, a variety of formulations have been developed. One of these features liposomes, regarded as one of the most promising drug carriers, biocompatible and best able to reduce drug toxicity without changing efficacy against tumor cells. Eruca sativa seed extract (SE) is considered a promising natural product from cruciferous vegetables against breast cancer, increasing chemotherapeutic and eliminating harmful side effects. The effects of Taxol-encapsulated liposomes (T) alone and in combination between Eruca sativa seed extract on nuclear factor kappa B (NF-${\kappa}B$), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels were investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(${\alpha}$) anthracene (DMBA) using qRT-PCR. The results showed that DMBA increased NF-${\kappa}B$, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while decreasing glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. T and T-SE treatment reduced NF-${\kappa}B$, COX-2 and Bcl-2 gene expression levels and LP. Hence, T and T-SE treatment appeared to reduce inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC.

• 대한의생명과학회지
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• 제18권3호
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• pp.181-192
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• 2012

Toll-like receptors (TLRs) induce innate immune responses that are essential for host defense against invading microbial pathogens. In general, TLRs have two major downstream signaling pathways; myeloid differential factor 88 (MyD88) and Toll/IL-1R domain-containing adaptor inducing IFN-${\beta}$ (TRIF) leading to the activation of NF-${\kappa}B$ and IRF3. Numerous studies demonstrated that certain phytochemicals possessing anti-inflammatory effects inhibit NF-${\kappa}B$ activation induced by pro-inflammatory stimuli including lipopolysaccharide and tumor necrosis factor-${\alpha}$ ($TNF{\alpha}$). However, the direct molecular targets for such anti-inflammatory phytochemicals are not fully identified. In this paper, we will discuss about the molecular targets of phytochemicals in TLRs signaling pathways. These results present a novel anti-inflammatory mechanism of phytochemicals in TLRs signaling.

• BMB Reports
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• 제36권3호
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• pp.251-257
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• 2003

Agmatine, an amine and organic cation, reduced $H_2O_2$ that was generated by hyperglycemia, and transcription factors such as NF-${\kappa}B$ and AP-1 activity in the mesangial cells that were exposed to high glucose. However, spermine which shares a strong nucleophilic structure with agmatine decreased the $H_2O_2$ levels and AP-1, but not the NF-${\kappa}B$ activity. Possible roles for agmatine and spermine in decreasing fibronectin are discussed, and the signaling pathway for agmatine-reduced fibronectin accumulation is presented.

• Nutrition Research and Practice
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• 제8권3호
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• pp.233-240
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• 2014

Epidemiology studies indicate that diet or specific dietary components can reduce the risk for cancer, cardiovascular disease and diabetes. An underlying cause of these diseases is chronic inflammation. Dietary components that are beneficial against disease seem to have multiple mechanisms of action and many also have a common mechanism of reducing inflammation, often via the $NF{\kappa}B$ pathway. Thus, a plant based diet can contain many components that reduce inflammation and can reduce the risk for developing all three of these chronic diseases. We summarize dietary components that have been shown to reduce cancer risk and two studies that show that dietary walnut can reduce cancer growth and development. Part of the mechanism for the anticancer benefit of walnut was by suppressing the activation of $NF{\kappa}B$. In this brief review, we focus on reduction of cancer risk by dietary components and the relationship to suppression of inflammation. However, it should be remembered that most dietary components have multiple beneficial mechanisms of action that can be additive and that suppression of chronic inflammation should reduce the risk for all three chronic diseases.

• 동의생리병리학회지
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• 제26권5호
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• pp.738-744
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• 2012

Gastrodia elata Blume is used for a variety of purposes including treatment of inflammation in the Korean medicine. The present study investigated whether the G. elata extracts have the anti-inflammatory effect on lipopolysaccharide(LPS)-stimulated BV-2 microglia cells. G. elata extracts showed an anti-inflammatory effects in the morphological and nitric oxide(NO) analysis, especially in hexane extract. So we investigated the hexane extract from G. elata in the following experiments. Hexane extract significantly inhibited the secretion of NO with protein level of inducible nitric oxide synthase in LPS-stimulated BV2 microglia cells. Hexane extract also inhibited LPS-stimulated inflammatory responses involving the degradation of cytosolic inhibitory(I)-${\kappa}B{\alpha}$ and the translocation of nuclear factor(NF)-${\kappa}Bp65$ to nucleus in LPS-stimulated BV-2 microglia cells by morphological analysis. Western blot analyse confirmed that I-${\kappa}B{\alpha}$ and NF-${\kappa}Bp65$ showed a similar pattern as morphological analysis. Our results suggest that G. elata extracts, especially hexane extract, may act as a therapeutic agent for inflammatory disease in the central nervous system through a selective regulation of NO production and NF-${\kappa}B$ activation.

• 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.

• 미생물학회지
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• 제49권4호
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• pp.301-308
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• 2013

Programmed Death-1 (PD-1)은 중요한 면역조절분자들 중 하나로 다양한 면역활성인자에 자극된 T 세포, B 세포, NKT 세포 및 대식세포에서 발현된다. Lipopolysaccaride (LPS)는 그람음성세균의 세포벽구성물질로 PD-1 발현을 유도하는 중요 면역원들 중 하나로 알려져 있다. 그러나 선천면역세포에서 PD-1 발현기전에 관한 연구는 미비한 실정이다. 본 연구에서는 LPS에 의해 자극된 Raw264.7 세포주를 대상으로 PD-1 발현 및 발현조전기전을 RT-PCR, Western Blot, 유세포분석기, ChIP assay 및 co-immunoprecipitation 방법으로 조사하였다. Raw264.7 세포주가 LPS로 자극되었을 때 PI3K 및 p38 신호전달경로를 경유하여 PD-1 발현이 크게 증가되었다. 또한 LPS 주사된 생쥐의 비장유래 대식세포에서도 PD-1 발현이 증가됨을 확인 하였다. PD-1 유전자의 프로모터 분석을 통해서 NF-${\kappa}B$ 및 IRF-1 결합부위가 PD-1 발현에 중요함을 알 수 있었다. 또한 PD-1 발현을 극대화하기 위하여 전사조절인자 NF-${\kappa}B$ 및 IRF-1의 공동활성이 필수적임을 확인하였다. 본 연구결과는 LPS 유도 생쥐패혈증모델에서 선천면역세포에 발현된 PD-1분자의 제어를 통한 질병 연구에 유용한 자료로 이용될 수 있을 것으로 사료된다.