• 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.

• Toxicological Research
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• 제25권4호
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• pp.159-173
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• 2009

Nuclear factor erythroid derived 2-related factor-2 (Nrf2) is a master transcription regulator of antioxidant and cytoprotective proteins that mediate cellular defense against oxidative and inflammatory stresses. Disruption of cellular stress response by Nrf2 deficiency causes enhanced susceptibility to infection and related inflammatory diseases as a consequence of exacerbated immune-mediated hypersensitivity and autoimmunity. The cellular defense capacity potentiated by Nrf2 activation appears to balance the population of $CD4^+$ and $CD8^+$ of lymph node cells for proper innate immune responses. Nrf2 can negatively regulate the activation of pro-inflammatory signaling molecules such as p38 MAPK, NF-${\kappa}B$, and AP-1. Nrf2 subsequently functions to inhibit the production of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, COX-2 and iNOS. Although not clearly elucidated, the antioxidative function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the expression of pro-inflammatory mediators.

• 약학회지
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• 제59권5호
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• pp.215-221
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• 2015

Glucocorticoids are known to have anti-inflammatory effect. To investigate whether corticosterone pretreatment enhances or not lipopolysaccharide (LPS)-induced production of inflammatory mediators, RAW 264.7 cells were pretreated with various concentrations of corticosterone for 24 h and then cultured without corticosterone in the presence or absence of LPS. Our results demonstrated that LPS remarkably increased production of TNF-${\alpha}$, IL-6, IL-$1{\beta}$, vascular endothelial growth factor (VEGF), and NO (nitric oxide). Corticosterone pretreatment significantly attenuated LPS-induced production of TNF-${\alpha}$, IL-$1{\beta}$, and VEGF, while significantly enhanced IL-6 and NO. These findings suggest that corticosterone pretreatment may contribute to LPS-induced inflammatory responses in macrophages via pro- and anti-inflammatory imbalance of inflammatory mediators.

• IMMUNE NETWORK
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• 제14권3호
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• pp.123-127
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• 2014

Interleukin-32 (IL-32) is a cytokine inducing crucial inflammatory cytokines such as tumor necrosis factor-${\alpha}(TNF{\alpha})$ and IL-6 and its expression is elevated in various inflammatory autoimmune diseases, certain cancers, as well as viral infections. IL-32 gene was first cloned from activated T cells, however IL-32 expression was also found in other immune cells and non-immune cells. IL-32 gene was identified in most mammals except rodents. It is transcribed as multiple-spliced variants in the absence of a specific activity of each isoform. IL-32 has been studied mostly in clinical fields such as infection, autoimmune, cancer, vascular disease, and pulmonary diseases. It is difficult to investigate the precise role of IL-32 in vivo due to the absence of IL-32 gene in mouse. The lack of mouse IL-32 gene restricts in vivo studies and restrains further development of IL-32 research in clinical applications although IL-32 new cytokine getting a spotlight as an immune regulatory molecule processing important roles in autoimmune, infection, and cancer. In this review, we discuss the regulation and function of IL-32 in inflammatory bowel diseases and rheumatoid arthritis.

• BMB Reports
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• 제55권11호
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• pp.519-527
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• 2022

Macrophage activation has long been implicated in a myriad of human pathophysiology, particularly in the context of the dysregulated capacities of an unleashing intracellular or/and extracellular inflammatory response. A growing number of studies have functionally coupled the macrophages' inflammatory capacities with dynamic metabolic reprogramming which occurs during activation, albeit the results have been mostly interpreted through classic metabolism point of view; macrophages take advantage of the rewired metabolism as a source of energy and for biosynthetic precursors. However, a specific subset of metabolic products, namely immune-modulatory metabolites, has recently emerged as significant regulatory signals which control inflammatory responses in macrophages and the relevant extracellular milieu. In this review, we introduce recently highlighted immuno-modulatory metabolites, with the aim of understanding their physiological and pathological relevance in the macrophage inflammatory response.

• Biomolecules & Therapeutics
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• 제22권4호
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• pp.295-300
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• 2014

The actin cytoskeleton plays an important role in macrophage-mediated inflammatory responses by modulating the activation of Src and subsequently inducing nuclear factor (NF)-${\kappa}B$ translocation. In spite of its critical functions, few papers have examined how the actin cytoskeleton can be regulated by the activation of toll-like receptor (TLR). Therefore, in this study, we further characterized the biological value of the actin cytoskeleton in the functional activation of macrophages using an actin cytoskeleton disruptor, cytochalasin B (Cyto B), and explored the actin cytoskeleton's involvement in morphological changes, cellular attachment, and signaling events. Cyto B strongly suppressed the TLR4-mediated mRNA expression of inflammatory genes such as cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-${\alpha}$, and inducible nitric oxide (iNOS), without altering cell viability. This compound also strongly suppressed the morphological changes induced by lipopolysaccharide (LPS), a TLR4 ligand. Cyto B also remarkably suppressed NO production under non-adherent conditions but not in an adherent environment. Cyto B did not block the co-localization between surface glycoprotein myeloid differentiation protein-2 (MD2), a LPS signaling glycoprotein, and the actin cytoskeleton under LPS conditions. Interestingly, Cyto B and PP2, a Src inhibitor, enhanced the phagocytic uptake of fluorescein isothiocyanate (FITC)-dextran. Finally, it was found that Cyto B blocked the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at 1 min and the phosphorylation of heat shock protein 27 (HSP27) at 5 min. Therefore, our data suggest that the actin cytoskeleton may be one of the key components involved in the control of TLR4-mediated inflammatory responses in macrophages.

• BMB Reports
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• 제51권12호
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• pp.654-659
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• 2018

Antioxidant 1 (ATOX1) protein has been reported to exhibit various protective functions, including antioxidant and chaperone. However, the effects of ATOX1 on the inflammatory response has not been fully elucidated. Thus, we prepared cell permeable Tat-ATOX1 and studied the effects on lipopolysaccharide (LPS)- and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced inflammation. Experimental results showed that transduced Tat-ATOX1 protein significantly suppressed LPS-induced intracellular reactive oxygen species (ROS). Also, Tat-ATOX1 protein markedly inhibited LPS- and TPA-induced inflammatory responses by decreasing cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and further inhibited phosphorylation of mitogen activated protein kinases (MAPKs; JNK, ERK and p38) and the nuclear factor-kappaB ($NF-{\kappa}B$) signaling pathway. These results indicate that the Tat-ATOX1 protein has a pivotal role in inflammation via inhibition of inflammatory responses, suggesting Tat-ATOX1 protein may offer a therapeutic strategy for inflammation.

• 대한본초학회지
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• 제28권2호
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• pp.9-15
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• 2013

Objectives : The root of Codonopsis pilosula (Fr.) Nannf. (Codonopsis Pilosulae Radix) has been traditionally used as a oriental medicine with an anti-thrombotic, antidiabetic, anticancer, and anti-gastric ulcer effects and immunological adjuvant. In this study, we investigated the effect of 70% ethanol extract of Codonopsis Pilosulae Radix (CPR-E) on ovalbumin (OVA)-induced allergic responses in mice. Methods : Mice were sensitized (1, 8, and 15 days) with OVA and airway challenged(22, 24, 26, 28, and 30 days) to induced allergic responses. CPR-E extract at doses of 50 and 100 mg/kg/body weight was orally administered from days 21 to 30 consecutively. The levels of allergic mediators such as histamine, OVA-specific immunoglobulin (Ig) E, and Th1/Th2 cytokines such as IFN-${\gamma}$ and IL-4 were measured in the sera of mice by ELISA. The histological change of lung tissue was observed by hematoxylin and eosin (H&E) staining. Results : CPR-E extract significantly decreased the serum levels of histamine, OVA-specific IgE, and IL-4 compared with those of OVA control group, but significantly increased the serum level of IFN-${\gamma}$. Based on H&E staining, CPR-E extract inhibited the infiltration of inflammatory cells into lung tissues with histological changes. Conclusions : These results indicate that CPR-E extract has anti-inflammatory and anti-allergic responses through regulating the cytokine balance, suggesting that the extract may be useful for the treatment of allergic inflammatory diseases such as bronchial asthma and allergic rhinitis.

• 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.

• The Korean Journal of Physiology and Pharmacology
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• 제22권6호
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• pp.627-636
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• 2018

Endometriosis (EM) is one of the most common gynaecological disorder affecting women in their reproductive age. Mechanisms involved in the pathogenesis of EM remains poorly understood, however inflammatory responses have been reported to be significantly involved. The efficacy of 6-shogaol on proliferation of endometriotic lesions and inflammatory pathways in experimentally-induced EM model was explored in this study. EM was stimulated in Sprague-Dawley rats by implantation of autologous endometrium onto the peritoneum abdominal wall. Separate groups were treated with 6-shogaol (50, 100 or 150 mg/kg b.wt/day) via oral gavage for one month period. Gestrinone (GTN) group received GTN (0.5 mg/kg/day) as positive control. Five weeks after implantation, the spherical volume of ecto-uterine tissues was determined. Treatment with 6-shogaol significantly reduced the implant size. Histological analysis reported atrophy and regression of the lesions. 6-shogaol administration effectively down-regulated $NF-{\kappa}B$ signaling, VEGF and VEGFR-2 (Flk-1) expression in the endometriotic lesions. Excess production of $IL-1{\beta}$ and IL-6 (pro-inflammatory cytokines), PGE2 and nitric oxide (NO) were reduced. Overall, the results of the study reveal the efficacy of 6-shogaol against endometriosis via effectively suppressing proliferation of the lesions and modulating angiogenesis and $COX-2/NF-{\kappa}B$-mediated inflammatory cascades.