• Molecules and Cells
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• v.27 no.2
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• pp.211-215
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• 2009

Toll-like receptors (TLRs) play a critical role in sensing microbial components and inducing innate immune and inflammatory responses by recognizing invading microbial pathogens. Lipopolysaccharide-induced dimerization of TLR4 is required for the activation of downstream signaling pathways including nuclear factor-kappa B ($NF-{\kappa}B$). Therefore, TLR4 dimerization may be an early regulatory event in activating ligand-induced signaling pathways and induction of subsequent immune responses. Here, we report biochemical evidence that 6-shogaol, the most bioactive component of ginger, inhibits lipopolysaccharide-induced dimerization of TLR4 resulting in the inhibition of $NF-{\kappa}B$ activation and the expression of cyclooxygenase-2. Furthermore, we demonstrate that 6-shogaol can directly inhibit TLR-mediated signaling pathways at the receptor level. These results suggest that 6-shogaol can modulate TLR-mediated inflammatory responses, which may influence the risk of chronic inflammatory diseases.

• Development and Reproduction
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• v.22 no.1
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• pp.95-104
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• 2018

CREBZF (cAMP-response element binding protein zhangfei) is a member of ATF/CREB family, and which regulates various cellular functions by suppressing major factors with direct interaction. In this study, we have examined the expression of CREBZF on mouse endometrium during uterus estrous cycles and estrogen (E2) treatment. In uterus, CREBZF mRNA expression was higher than other organs and mRNA and protein of CREBZF was increased in proestrus phase and decreased in estrus phase. The expression of CREBZF in 3-weeks old mouse uterus was reduced by E2 injection in endometrium. In addition, the expression of progesterone receptor, a marker of E2 in ovariectomized mice was found to be strongly expressed in stroma, while CREBZF was only expressed in epithelium. Also, we conformed that E2-suppressed CREBZF was restored by co-injection of ICI 182,780, an estrogen receptor antagonist. Overall, these results suggest that CREBZF is regulated by estrogen and involved in ER signaling pathway in mouse uterus.

• Biomolecules & Therapeutics
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• v.27 no.5
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• pp.435-441
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• 2019

The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.

• Biomolecules & Therapeutics
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• v.32 no.2
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• pp.192-204
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• 2024

Generally, odorant molecules are detected by olfactory receptors, which are specialized chemoreceptors expressed in olfactory neurons. Besides odorant molecules, certain volatile molecules can be inhaled through the respiratory tract, often leading to pathophysiological changes in the body. These inhaled molecules mediate cellular signaling through the activation of the Ca²⁺-permeable transient receptor potential (TRP) channels in peripheral tissues. This review provides a comprehensive overview of TRP channels that are involved in the detection and response to volatile molecules, including hazardous substances, anesthetics, plant-derived compounds, and pheromones. The review aims to shed light on the biological mechanisms underlying the sensing of inhaled volatile molecules. Therefore, this review will contribute to a better understanding of the roles of TRP channels in the response to inhaled molecules, providing insights into their implications for human health and disease.

• International Journal of Oral Biology
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• v.31 no.3
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• pp.87-92
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• 2006

Schwann cells play an important role in peripheral nerve regeneration. Upon nerve injury, Schwann cells are activated and produce various proinflammatory mediators including IL-6, LIF and MCP-1, which result in the recruitment of macrophages and phagocytosis of myelin debris. However, it is unclear how the nerve injury induces Schwann cell activation. Recently, it was reported that necrotic cells induce immune cell activation via toll-like receptors (TLRs). This suggests that the TLRs expressed on Schwann cells may recognize nerve damage by binding to the endogenous ligands secreted by the damaged nerve, thereby inducing Schwann cell activation. To explore the possibility, we stimulated iSC, a rat Schwann cell line, with damaged neuronal cell extracts (DNCE). The stimulation of iSC with DNCE induced the expression of various inflammatory mediators including IL-6, LIF, MCP-1 and iNOS. Studies on the signaling pathway indicate that $NF-{\kappa}B$, p38 and JNK activation are required for the DNCE-induced inflammatory gene expression. Furthermore, treatment of either anti-TLR3 neutralizing antibody or ribonuclease inhibited the DNCE-induced proinflammatory gene expression in iSC. In summary, these results suggest that damaged neuronal cells induce inflammatory Schwann cell activation via TLR3, which might be involved in the Wallerian degeneration after a peripheral nerve injury.

• Molecules and Cells
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• v.37 no.8
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• pp.628-635
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• 2014

2-(Trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient megakaryopoiesis. Here, we show that (R)-TEMOSPho blocks osteoclast maturation from progenitor cells of hematopoietic origin, as well as blocking the resorptive function of mature osteoclasts. The inhibitory effect of (R)-TEMOSPho on osteoclasts was due to a disruption of the actin cytoskeleton, resulting from impaired downstream signaling of c-Fms, a receptor for macrophage-colony stimulating factor linked to c-Cbl, phosphoinositol-3-kinase (PI3K), Vav3, and Rac1. In addition, (R)-TEMOSPho blocked inflammation-induced bone destruction by reducing the numbers of osteoclasts produced in mice. Thus, (R)-TEMOSPho may represent a promising new class of antiresorptive drugs for the treatment of bone loss associated with increased osteoclast maturation and activity.

• Journal of Photoscience
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• v.9 no.2
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• pp.201-204
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• 2002

Epidermal cells produce a panel of antioxidants as well as cytokines after UVB irradiation, which counteract reactive oxygen species, however, how these antioxidants might regulate melanogenesis is unclear. An important constituent of the cellular antioxidant buffering system which controls the redox state of proteins is thioredoxin (TRX), a 13-kD protein that catalyzes thiol-disulfide exchange reactions, regulates activation of transcription factors, and possesses several other biological functions similar to cytokines. TRX suppressed the UVB-induced production and secretion of $\alpha$-melanocyte stimulating hormone ($\alpha$-MSH) and of adrenocorticotropic hormone (ACTH), and also suppressed proopiomelanocortin (POMC) mRNA expression by normal human keratinocyte (KC)s. Further, L-cysteine, N-acetyl-cysteine, $\alpha$-tocopheryl ferulate showed suppressive effect on UVB-induced POMC mRNA expression. However, TRX released from UVB-irradiated KCs stimulated melanogenesis by up-regulating MSH receptor expression and its binding activity in melanocyte (MC)s. UVB-induced KC derived cytokines such as IL1, IL6, and ET1 upregulated MSH-receptor binding ability as well as MCl-R mRNA expression in cultured normal human MCs. MCl-R has a tendency to be upregulated by UVB-induced KC-derived cytokines as well as by direct UVB irradiation. These results suggest that antioxidants such as TRX suppresses UVB induction of POMC, but in the case of MCl-R, this gene can be mainly in the trend of upregulation by UVB-induced KC-derived factors including TRX.

• Molecules and Cells
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• v.24 no.3
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• pp.372-377
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• 2007

The orphan nuclear receptor, SF-1, plays a pivotal role in the development and differentiation of the endocrine and reproductive systems, and also regulates the transcription of a host of genes, including those encoding several steroidogenic enzymes and gonadotropins. We found that a previously unidentified repressor, EID-1, is an SF-1-interacting protein that inhibits the transactivation of SF-1. A transient transfection assay revealed that EID-1 inhibits SF-1, but not LRH-1, $ERR{\gamma}$, or mCAR. Using the yeast two hybrid and GST pull-down assays, we determined that EID-1 interacted strongly with SF-1. In addition, it colocalized with SF-1 in mammalian cells and interacted specifically with the AF-2 domain of SF-1, competing with SRC-1 to inhibit SF-1 transactivation. EID-1 is expressed in the mouse testis, and its expression decreases during testis development. The results of the present study suggest that EID-1 can act as a repressor, regulating the function of SF-1.

• Proceedings of the Korean Environmental Sciences Society Conference
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• 2008.11a
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• pp.538-544
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• 2008

Activated protein C (APC) is thought to exert antiinflammatory activities through the endothelial protein C receptor (EPCR)-dependent cleavage of protease activated receptor 1 (PAR-1) in endothelial cells. Since thrombin cleaves PAR-1 with $\sim$3-4-orders of magnitude higher efficiency, and PAR-1 is a target for proinflammatory activities of thrombin, it is not understood how APC can elicit protective responses through the cleavage of PAR-1. In this study, we demonstrate that EPCR is associated with caveolin-1 in endothelial lipid rafts, but its occupancy by protein C leads to its dissociation from caveolin-1 and subsequent recruitment of PAR-1 to protective signaling pathways through the coupling of PAR-1 to Gi-protein. When EPCR is bound by protein C, the PAR-1-dependent protective response in endothelial cells can be mediated by either thrombin or APC. These results provide a new paradigm for understanding the mechanism through which PAR-1 and EPCR participate in cellular signaling events in endothelial cells.

• IMMUNE NETWORK
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• v.12 no.6
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• pp.240-246
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• 2012

Natural killer (NK) cells play a pivotal role in early surveillance against virus infection and cellular transformation, and are also implicated in the control of inflammatory response through their effector functions of direct lysis of target cells and cytokine secretion. NK cell activation toward target cell is determined by the net balance of signals transmitted from diverse activating and inhibitory receptors. A distinct feature of NK cell activation is that stimulation of resting NK cells with single activating receptor on its own cannot mount natural cytotoxicity. Instead, specific pairs of co-activation receptors are required to unleash NK cell activation via synergy- dependent mechanism. Because each co-activation receptor uses distinct signaling modules, NK cell synergy relies on the integration of such disparate signals. This explains why the study of the mechanism underlying NK cell synergy is important and necessary. Recent studies revealed that NK cell synergy depends on the integration of complementary signals converged at a critical checkpoint element but not on simple amplification of the individual signaling to overcome intrinsic activation threshold. This review focuses on the signaling events during NK cells activation and recent advances in the study of NK cell synergy.