• BMB Reports
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• v.50 no.2
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• pp.55-57
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• 2017

Toll-like receptor 4 (TLR4) together with MD2, one of the key pattern recognition receptors for a pathogen-associated molecular pattern, activates innate immunity by recognizing lipopolysaccharide (LPS) of Gram-negative bacteria. Although LBP and CD14 catalyze LPS transfer to the TLR4/MD2 complex, the detail mechanisms underlying this dynamic LPS transfer remain elusive. Using negative-stain electron microscopy, we visualized the dynamic intermediate complexes during LPS transfer-LBP/LPS micelles and ternary CD14/LBP/LPS micelle complexes. We also reconstituted the entire cascade of LPS transfer to TLR4/MD2 in a total internal reflection fluorescence (TIRF) microscope for a single molecule fluorescence analysis. These analyses reveal longitudinal LBP binding to the surface of LPS micelles and multi-round binding/unbinding of CD14 to single LBP/LPS micelles via key charged residues on LBP and CD14. Finally, we reveal that a single LPS molecule bound to CD14 is transferred to TLR4/MD2 in a TLR4-dependent manner. These discoveries, which clarify the molecular mechanism of dynamic LPS transfer to TLR4/MD2 via LBP and CD14, provide novel insights into the initiation of innate immune responses.

• Journal of the korean veterinary medical association
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• v.48 no.3
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• pp.177-191
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• 2012

2011년도 Nobel 생리(生理) 의학상(醫學賞) : 자연(自然)(선천)(先天) 면역(免疫)(innate immunity)의 활성화에 관한 연구업적으로 B. A. Beutler와 J. A. Hoffmann, 그리고 수지상세포(樹枝狀細胞)(dendritic cell; DC)발견과 적응(適應)(획득)(獲得)면역(免疫)(adaptive immunity)에 있어서의 그들 세포의 역할을 밝혀낸 R. M. Steinman의 공동수상으로 금년도 Nobel 생리 의학상 수상자가 결정되었다는 보도가 지난 10월 3일 있었다(1-3). 그들의 업적을 요약하면 대략 다음과 같다. (Steinman교수는 Nobel수상자 발표 3일전인 9월 30일 암으로 사망함). 그들은 면역기구(immune system)의 활성화의 관건(key)이 되는 원리를 밝혀냄으로써, 면역기구에 관한 우리들의 이해를 혁신하였던 것이다. 과학자들은 오랫동안 세균(bacteria)이나 기타 미생물병원체들에 의한 공격에 대비하여 그들 자신을 방어하는 사람이나 기타 동물체에서의 면역응답(免疫應答)(immune response)의 문지기들을 탐색해 왔다. Beutler와 Hoffmann은 그와 같은 병원미생물을 인식하여 생체의 면역응답의 첫 단계인 자연면역을 활성화 할 수 있는 수용체 단백질(toll-like receptor protein)을 규명한 것이다(4,5). 한편 Steinmann은 면역계의 수지상세포(DC)와 병원미생물이 생체로부터 배제되는 면역응답의 후기단계인 적응면역을 활성화하고 조절하는 그들의 독특한 재능을 규명해 낸 것이다(6-8). 그들 3명의 발명은, 면역응답의 자연 및 적응 양상(樣相)이 어떻게 활성화되는 가를 밝혀냄으로써 질병의 기전에 관한 참신한 식견(識見)을 제공한 것이다. 그들의 연구는 감염병(感染病)(infectious disease), 암(癌)(cancer) 그리고 염증성질환(炎症性疾患)(inflammatory disease)에 대응하는 예방과 치료의 개발을 위한 새로운 방법을 개척한 것이다.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.2329-2334
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• 2014

Curcumin can inhibit proliferation of liver cancer cells by inducing apoptosis, but the specific signaling pathways involved are not completely clear. Here, we report that curcumin inhibited proliferation of MHCC97H liver cancer cells by induction of apoptosis in a concentration dependent manner via stimulating intracellular reactive oxygen species (ROS) generation. Also, we showed that increased intracellular ROS formation activated the TLR-4/MyD-88 signaling pathway, resulting in activation of caspase-8 and caspase-3, which eventually led to apoptosis in MHCC97H cells. These results showed that as an prooxidant, curcumin exerts anti-cancer effects by inducing apoptosis via the TLR-4/MyD-88 signaling pathway.

• Parasites, Hosts and Diseases
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• v.50 no.4
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• pp.281-286
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• 2012

Helminthic infections afflict over 1.5 billion people worldwide, while Mycobacterium tuberculosis infects one third of the world's population, resulting in 2 million deaths per year. Although tuberculosis and helminthic infections coexist in many parts of the world, and it has been demonstrated that the T-helper 2 and T-regulatory cell responses elicited by helminths can affect the ability of the host to control mycobacterial infection, it is still unclear whether helminth infections in fact affect tuberculosis disease. In this review article, current progress in the knowledge about the immunomodulation induced by helminths to diminish the protective immune responses to bacille Calmette-Guerin vaccination is reviewed, and the knowledge about the types of immune responses modulated by helminths and the consequences for tuberculosis are summarized. In addition, recent data supporting the significant reduction of both M. tuberculosis antigen-specific Toll-like receptor (TLR) 2 and TLR9 expression, and pro-inflammatory cytokine responses to TLR2 and TLR9 ligands in individuals with M. tuberculosis and helminth co-infection were discussed. This examination will allow to improve understanding of the immune responses to mycobacterial infection and also be of great relevance in combating human tuberculosis.

• Development and Reproduction
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• v.21 no.4
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• pp.361-370
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• 2017

Koi herpesvirus (KHV), also known as Cyprinid herpes virus 3 (Cyprinid 3) is lethal disease in common carp and koi (Cyprinus carpio). Two different groups (KK and RK) were infected KHV by intraperitoneal injection. Fish for gene expression analysis were sampled at 0 h, 12 h, 24 h, 48 h and 72 h post infection (p.i). The results showed that two immune related gene, Interferons (INFs) ${\alpha}{\beta}$ and Interleukin (IL)-12 p35 induced a high response in RK. The IL-12 p35 cytokine and Toll-like receptor (TLR) 9 were significantly high expressed on 48 h post infection (p.i) in RK as compared to the KK. The histopatological examination reveals focal necrosis in liver and infiltrate of lymphocytes in spleen of KK as compared to the RK. In immunohistochemistry analysis, the KHV protein high expressed in the infected kidney cell and slenocyte of KK. Therefore, the expression of IL-12 p35, IFN ${\alpha}{\beta}$ and TLR 9 may provide a potentially genes related with KHV resistance in Koi and red common carp ${\times}$ koi.

• Molecules and Cells
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• v.44 no.12
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• pp.861-878
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• 2021

The human genome contains many retroviral elements called human endogenous retroviruses (HERVs), resulting from the integration of retroviruses throughout evolution. HERVs once were considered inactive junk because they are not replication-competent, primarily localized in the heterochromatin, and silenced by methylation. But HERVs are now clearly shown to actively regulate gene expression in various physiological and pathological conditions such as developmental processes, immune regulation, cancers, autoimmune diseases, and neurological disorders. Recent studies report that HERVs are activated in patients suffering from coronavirus disease 2019 (COVID-19), the current pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. In this review, we describe internal and external factors that influence HERV activities. We also present evidence showing the gene regulatory activity of HERV LTRs (long terminal repeats) in model organisms such as mice, rats, zebrafish, and invertebrate models of worms and flies. Finally, we discuss several molecular and cellular pathways involving various transcription factors and receptors, through which HERVs affect downstream cellular and physiological events such as epigenetic modifications, calcium influx, protein phosphorylation, and cytokine release. Understanding how HERVs participate in various physiological and pathological processes will help develop a strategy to generate effective therapeutic approaches targeting HERVs.

• Journal of Physiology & Pathology in Korean Medicine
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• v.36 no.1
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• pp.28-34
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• 2022

Echinacea purpurea (Asteraceae family) is widely used in the European countries and the United States due to its proven immune enhancement and anti-inflammatory effects. Echinacea purpurea has been reported prevent and treat upper respiratory tract infections and common cold, but the underlying molecular mechanisms are not well understood. In the present study, we examined the anti-inflammatory effects and molecular mechanisms of Echinacea purpurea (EP) extract using lipopolysaccharide (LPS)-stimulated signal pathways in RAW264.7 cells. Our results suggest that EP extract exerts anti-inflammatory effects by down-regulating the expression of LPS-induced toll-like receptor 4 (TLR4), subsequently inhibiting the activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways and suppression of the release of pro-inflammatory cytokines. These results suggest that EP extract is a potential therapeutic agent for inflammatory diseases.

• Korean Journal of Plant Resources
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• v.35 no.6
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• pp.697-703
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• 2022

Under the COVID-19 pandemic, interest in immune enhancement is increasing. Although the immune-enhancing activity of plants of the genus Hibiscus has been reported, there is no study on the immune-enhancing activity of H. syriacus. Thus, in this study, we investigated the immune-enhancing activity of Hibiscus syriacus leaves (HSL) in mouse macrophages, RAW264.7 cells, and immunosuppressed mice. HSL increased the production of immunostimulatory factors such as nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) and activated the phagocytosis in RAW264.7 cells. The HSL-mediated production of immunostimulatory factors was dependent on toll-like receptor 4 (TLR4), p38, and c-Jun N-terminal kinase (JNK) in RAW264.7 cells. In the immunosuppressed mouse model, HSL increased the spleen index, the levels of the cytokines, and the numbers of lymphocytes, neutrophils, and monocytes. Taken together, HSL may be considered to have immune-enhancing activity and be expected to be used as a potential immune-enhancing agent.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.2
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• pp.177-185
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• 2023

The excessive inflammatory response induced by myocardial infarction exacerbates heart injury and leads to the development of heart failure. Recent studies have confirmed the involvement of multiple transcription factors in the modulation of cardiovascular disease processes. However, the role of KLF9 in the inflammatory response induced by cardiovascular diseases including myocardial infarction remains unclear. Here, we found that the expression of KLF9 significantly increased during myocardial infarction. Besides, we also detected high expression of KLF9 in infiltrated macrophages after myocardial infarction. Our functional studies revealed that KLF9 deficiency prevented cardiac function and adverse cardiac remodeling. Furthermore, the downregulation of KLF9 inhibited the activation of NF-κB and MAPK signaling, leading to the suppression of inflammatory responses of macrophages triggered by myocardial infarction. Mechanistically, KLF9 was directly bound to the TLR2 promoter to enhance its expression, subsequently promoting the activation of inflammation-related signaling pathways. Our results suggested that KLF9 is a pro-inflammatory transcription factor in macrophages and targeting KLF9 may be a novel therapeutic strategy for ischemic heart disease.

• Journal of Ginseng Research
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• v.46 no.2
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• pp.315-319
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• 2022