• 생약학회지
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• 제44권2호
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• pp.118-124
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• 2013

Mast cells is the key effector cells for IgE-mediated allergic responses. In this study, we investigated whether Rhus trichocarpa extract (RT) inhibited IgE-mediated allergic responses in mast cells and an allergic animal model. We further tried to find its mechanism of action in mast cells. We found that RT suppressed antigen-stimulated degranulation and production of TNF-${\alpha}$ and IL-4 in rat basophilic leukemia (RBL)-2H3 mast cells and bone marrow-derived mast cells (BMMC), as well as IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. As the mechanism of action of RT, it inhibited the activation of spleen tyrosine kinase (Syk), a pivotal signaling molecule for activation of mast cells and that of LAT, a downstream adaptor molecule of Syk in $Fc{\varepsilon}RI$-mediated signal pathways. RT also suppressed the activation of mitogen-activated protein (MAP) kinases and Akt. The current results demonstrated for the first time that RT has the anti-allergic effect through inhibiting degranulation and secretion of cytokines by suppression of Syk in antigen-stimulated mast cells. Therefore, RT might be useful for allergic diseases.

• Molecules and Cells
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• 제38권6호
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• pp.482-495
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• 2015

Sphingolipids such as ceramide, sphingosine-1-phosphate and sphingomyelin have been emerging as bioactive lipids since ceramide was reported to play a role in human leukemia HL-60 cell differentiation and death. Recently, it is well-known that ceramide acts as an inducer of cell death, that sphingomyelin works as a regulator for microdomain function of the cell membrane, and that sphingosine-1-phosphate plays a role in cell survival/proliferation. The lipids are metabolized by the specific enzymes, and each metabolite could be again returned to the original form by the reverse action of the different enzyme or after a long journey of many metabolizing/synthesizing pathways. In addition, the metabolites may serve as reciprocal biomodulators like the rheostat between ceramide and sphingosine-1-phosphate. Therefore, the change of lipid amount in the cells, the subcellular localization and the downstream signal in a specific subcellular organelle should be clarified to understand the pathobiological significance of sphingolipids when extracellular stimulation induces a diverse of cell functions such as cell death, proliferation and migration. In this review, we focus on how sphingolipids and their metabolizing enzymes cooperatively exert their function in proliferation, migration, autophagy and death of hematopoetic cells, and discuss the way developing a novel therapeutic device through the regulation of sphingolipids for effectively inhibiting cell proliferation and inducing cell death in hematological malignancies such as leukemia, malignant lymphoma and multiple myeloma.

• 한국환경성돌연변이발암원학회지
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• 제26권1호
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• pp.1-6
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• 2006

To enhance our understanding of toxicity mediated through the pathway by which TCDD stimulates gene expression, we have investigated genes whose expressions are changed after treatment with TCDD and/or MNNG in human Chang liver cell. First, we treated with MNNG and TCDD for two weeks to transform human Chang liver cell. We obtained cell looks like to be transformed and compared the differential gene expression by using cDNA chip (Macrogen) which carrys genes related with signal transduction pathways, oncogenes and tumor suppressor genes, etc. We found that TCDD up- or down-regulated 203 and 111 genes including oncogenes and tumor suppressor genes in human Chang liver cell two fold or more, respectively. Second, we compared the differential gene expression after treatment with TCDD only by using cDNA chip (Superarray) which carrys genes related with cell cycle regulations, and found that TCDD up regulated genes related with cell proliferation as well as cell growth inhibition in human Chang liver cell two fold or more, respectively. These results suggest that toxicity induced by TCDD may reflect sustained alterations in the expression of many genes and that the changes reflect both direct and indirect effects of TCDD.

• Molecular & Cellular Toxicology
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• 제3권4호
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• pp.231-237
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• 2007

Exposure to DNA-damaging agents can elicit a variety of stress-related responses that may alter the expression of genes associated with numerous biological pathways. We used 19 k whole human genome chip to detect gene expression profiles and potential signature genes in human normal hepatocytes (THLE-3) by treatment of five direct acting mutagens, furylfuramide (AF-2), N-nitroso-N-methylurea (MNU), methylmethanesulfonate (MMS), 4-nitroquinoline-N-oxide (4-NQO) and 2-nitrofluorene (2NF) of the $IC_{20}$ concentration for 3 h. Fifty one up-regulated common genes and 45 down-regulated common genes above 1.5-fold by five direct-acting mutagens were identified by clustering analysis. Many of these changed genes have some association with apoptosis, control of cell cycle, regulation of transcription and signal transduction. Genes related to these functions, as TP73L, E2F5, MST016, SOX5, MAFB, LIF, SII3, TFIIS, EMR1, CYTL1, CX3CR1 and RHOH are up-regulated. Down-regulated genes are ALOX15B, xs155, IFITM1, BATF, VAV2, CD79A, DCDC2, TNFSF8 and KOX8. We suggest that gene expression profiling on mutagens by toxicogenomic analysis affords promising opportunities to reveal potential new mechanistic markers of genotoxicity.

• 한국식물병리학회:학술대회논문집
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• 한국식물병리학회 2003년도 정기총회 및 추계학술발표회
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• pp.84.1-84
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• 2003

Magnaporthe grisea, the casual agent of rice blast, forms an appressorium to penetrate its host. Much has been learned about environmental cues and signal transduction pathways, especially those involving CAMP and MAP kinases, on appressorium formation during the last decade. More recently, pharmacological data suggest that calcium/calmodulin-dependent signaling system is involved in its appressorium formation. To determine the role of phosphoinositide-specific phospholipase C (PI-PLC) on appressorium formation, a gene (WPLCl) encoding PI-PLC was cloned and characterized from M. grisea strain 70-15. Sequence analysis showed that MPLCl has alt five conserved domains present in other phospholipase C genes from several filamentous fungi and mammals. Null mutants (mplcl) generated by targeted gene disruption exhibited pleiotropic effects on conidial morphology, appressorium formation, fertility and pathogenicity. mplcl mutants developed nonfunctional appressoria and are also defective in infectious growth in host tissues. Defects in appressorium formation and pathogenicity in mplcl mutants were complemented by a mouse PLCdelta-1 cDNA under the control of the MPLCl promoter. These results suggest that cellular signaling mediated by MPLCl plays crucial and diverse roles in development and pathogenicity of M. grisea, and functional conservation between fungal and mammalian Pl-PLCs.

• BMB Reports
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• 제48권12호
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• pp.696-701
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• 2015

Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA. It stimulates pro-inflammatory cytokine and interferon production. Here we reported the expression of a novel isoform of TLR3 in human astrocyte cell lines whose message is generated by alternative splicing. The isoform represents the N-terminus of the protein. It lacks many of the leucine-rich repeat domains, the transmembrane domain, and the intracellular Toll/interleukin-1 receptor domain of TLR3. Type I interferons (interferon-α and interferon-β) induced the expression of this isoform. Exogenous overexpression of this isoform inhibited interferon regulatory factor 3, signal transducers and activators of transcription 1, and Inhibitor of kappa B α signaling following stimulation. This isoform of TLR3 also inhibited the production of chemokine interferon-γ-inducible protein 10. Our study clearly demonstrated that the expression of this isoform of TLR3 was a negative regulator of signaling pathways and that it was inducible by type I interferons. We also found that this isoform could modulate inflammation in the brain.

• BMB Reports
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• 제48권12호
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• pp.647-654
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• 2015

Energy homeostasis in our body system is maintained by balancing the intake and expenditure of energy. Excessive accumulation of fat by disrupting the balance system causes overweight and obesity, which are increasingly becoming global health concerns. Understanding the pathogenesis of obesity focused on studying the genes related to familial types of obesity. Recently, a rare human genetic disorder, ciliopathy, links the role for genes regulating structure and function of a cellular organelle, the primary cilium, to metabolic disorder, obesity and type II diabetes. Primary cilia are microtubule based hair-like membranous structures, lacking motility and functions such as sensing the environmental cues, and transducing extracellular signals within the cells. Interestingly, the subclass of ciliopathies, such as Bardet-Biedle and Alström syndrome, manifest obesity and type II diabetes in human and mouse model systems. Moreover, studies on genetic mouse model system indicate that more ciliary genes affect energy homeostasis through multiple regulatory steps such as central and peripheral actions of leptin and insulin. In this review, we discuss the latest findings in primary cilia and metabolic disorders, and propose the possible interaction between primary cilia and the leptin and insulin signal pathways which might enhance our understanding of the unambiguous link of a cell's antenna to obesity and type II diabetes.

• 동의생리병리학회지
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• 제21권5호
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• pp.1297-1302
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• 2007

Uncaria sinensis(OIi.) Havil (USH) is used in traditional Korean medicine to treat inflammation such as amebic dysentery. In this study, we investigated the anti-inflammatory effect of USH. The water extract of USH significantly inhibits lipopolysaccharide (LPS)-induced nitrite oxide (NO), tumor necrosis factor $(TNF)-{\alpha}$, interleukin (IL)-6and IL-12 productions in murine peritoneal macrophages. Furthermore, USH selectively inhibited activation of the extracellular signal-regulated kinase (ERK) but not of p38 MAPK, c-Jun N-terminal kinase (JNK) and nuclear $factor-{\kappa}B$ $(NF-{\kappa}B)$. In murine model, we found that administration of USH reduced serum levels of $TNF-{\alpha}$, IL-6 and IL-12 productions in LPS-treated mice. Our results suggest that USH exerts ant-inflammatory effects in macrophages via inhibition of ERK activation and may be a useful therapeutic approach to inflammatory diseases.

• Journal of Korean Neurosurgical Society
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• 제39권1호
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• pp.52-57
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• 2006

Objective : It has been suggested that the occurrence of persistent pain signal during the early postnatal period may alter an individual's response to pain later in life. The aim of this study is to assess whether neonatal nerve injury resulted in long-lasting consequences on nociceptive system in the rat. Methods : We examined whether neuropathic pain behaviors and the changes of spinal neuropeptides [SP, CGRP, VIP and VIP] induced by peripheral nerve injury within 1 day after birth [Neonate group] were different from those at 8 weeks after birth [Mature group]. Results : The Neonate group showed more robust and long-lasting pain behaviors than the Mature group. Immunohistochemical findings demonstrated that spinal SP- & CGRP-immunoreactivities[ir] of the ipsilateral to the contralateral side increased in the Neonate group, whereas those decreased in the Mature group. In addition, increase in spinal VIP- & NPY-ir of the ipsilateral to the contralateral side was more robust in the Mature group than in the Neonate group. Conclusion : These results suggest that peripheral nerve injury in the early postnatal period may result in long-lasting and potentially detrimental alterations in nociceptive pathways.

• BMB Reports
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• 제53권9호
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• pp.453-457
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• 2020

The right-handed double-helical structure of DNA (B-DNA), which follows the Watson-Crick model, is the canonical form of DNA existing in normal physiological settings. Even though an alternative left-handed structure of DNA (Z-DNA) was discovered in the late 1970s, Z-form nucleic acid has not received much attention from biologists, because it is extremely unstable under physiological conditions, has an ill-defined mechanism of its formation, and has obscure biological functions. The debate about the physiological relevance of Z-DNA was settled only after a class of proteins was found to potentially recognize the Z-form architecture of DNA. Interestingly, these Z-DNA binding proteins can bind not only the left-handed form of DNA but also the equivalent structure of RNA (Z-RNA). The Z-DNA/RNA binding proteins present from viruses to humans function as important regulators of biological processes. In particular, the proteins ADAR1 and ZBP1 are currently being extensively re-evaluated in the field to understand potential roles of the noncanonical Z-conformation of nucleic acids in host immune responses and human disease. Despite a growing body of evidence supporting the biological importance of Z-DNA/RNA, there remain many unanswered principal questions, such as when Z-form nucleic acids arise and how they signal to downstream pathways. Understanding Z-DNA/RNA and the sensors in different pathophysiological conditions will widen our view on the regulation of immune responses and open a new door of opportunity to develop novel types of immunomodulatory therapeutic possibilities.