• Archives of Pharmacal Research
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• v.29 no.2
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• pp.113-122
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• 2006

Among the effector molecules connected with the group of cell surface receptors, Ras proteins have essential roles in transducing extracellular signals to diverse intracellular events, by controlling the activities of multiple signaling pathways. For over 20 years since the discovery of Ras proteins, an enormous amount of knowledge has been accumulated as to how the proteins function in overlapping or distinct fashions. The signaling networks they regulate are very complex due to their multiple functions and cross-talks. Much attention has been paid to the pathological role of Ras in tumorigenesis. In particular, human tumors very frequently express Ras proteins constitutively activated by point mutations. Up to date, three members of the Ras family have been identified, namely H-Ras, K-Ras (A and B), and N-Ras. Although these Ras isoforms function in similar ways, many evidences also support the distinct molecular function of each Ras protein. This review summarizes differential functions of Ras and highlights the current view of the distinct signaling network regulated by each Ras for its contribution to the malignant phenotypic conversion of breast epithelial cells. Four issues are addressed in this review: (1) Ras proteins, (2) membrane localization of Ras, (3) effector molecules downstream of Ras, (4) Ras signaling in invasion. In spite of the accumulation of information on the differential functions of Ras, much more remains to be elucidated to understand the Ras-mediated molecular events of malignant phenotypic conversion of cells in a greater detail.

• IMMUNE NETWORK
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• v.15 no.1
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• pp.9-15
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• 2015

Streptococcus pneumoniae (the pneumococcus) causes a major upper respiratory tract infection often leading to severe illness and death in the elderly. Thus, it is important to induce safe and effective mucosal immunity against this pathogen in order to prevent pnuemocaccal infection. However, this is a very difficult task to elicit protective mucosal IgA antibody responses in older individuals. A combind nasal adjuvant consisting of a plasmid encoding the Flt3 ligand cDNA (pFL) and CpG oligonucleotide (CpG ODN) successfully enhanced S. pneumoniae-specific mucosal immunity in aged mice. In particular, a pneumococcal surface protein A-based nasal vaccine given with pFL and CpG ODN induced complete protection from S. pneumoniae infection. These results show that nasal delivery of a combined DNA adjuvant offers an attractive potential for protection against the pneumococcus in the elderly.

• BMB Reports
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• v.51 no.3
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• pp.143-150
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• 2018

The Hippo signaling pathway plays an essential role in adult tissue homeostasis and organ size control. Abnormal regulation of Hippo signaling can be a cause for multiple types of human cancers. Since the awareness of the importance of the Hippo signaling in a wide range of biological fields has been continually grown, it is also understood that a thorough and well-rounded comprehension of the precise dynamics could provide fundamental insights for therapeutic applications. Several components in the Hippo signaling pathway are known to be targeted for proteasomal degradation via ubiquitination by E3 ligases. ${\beta}-TrCP$ is a well-known E3 ligase of YAP/TAZ, which leads to the reduction of YAP/TAZ levels. The Hippo signaling pathway can also be inhibited by the E3 ligases (such as ITCH) which target LATS1/2 for degradation. Regulation via ubiquitination involves not only complex network of E3 ligases but also deubiquitinating enzymes (DUBs), which remove ubiquitin from its targets. Interestingly, non-degradative ubiquitin modifications are also known to play important roles in the regulation of Hippo signaling. Although there has been much advanced progress in the investigation of ubiquitin modifications acting as regulators of the Hippo signaling pathway, research done to date still remains inadequate due to the sheer complexity and diversity of the subject. Herein, we review and discuss recent developments that implicate ubiquitin-mediated regulatory mechanisms at multiple steps of the Hippo signaling pathway.

• BMB Reports
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• v.51 no.1
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• pp.21-26
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• 2018

Delta-like ligand 4 (DLL4) expression in endothelial cells is intimately associated with angiogenic sprouting and vascular remodeling, but the precise mechanism of transcriptional regulation of DLL4 remains incompletely understood. Here, we showed that LIM-domain binding protein 2 (LDB2) plays an important role in regulating basal DLL4 and VEGF-induced DLL4 expression. Knockdown of LDB2 using siRNA enhanced endothelial sprouting and tubular network formation in vitro. Injection of ldb2-morpholino resulted in defective development of intersegmental vessels in zebrafish. Reduction or over-expression of LDB2 in endothelial cells decreased or increased DLL4 expression. LDB2 regulated DLL4 promoter activity by binding to its promoter region and the same promoter region was occupied and regulated by the LMO2/TAL1/GATA2 complex. Interestingly, LDB2 also mediated VEGF-induced DLL4 expression in endothelial cells. The regulation of DLL4 by the LDB2 complex provides a novel mechanism of DLL4 transcriptional control that may be exploited to develop therapeutics for aberrant vascular remodeling.

• IMMUNE NETWORK
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• v.13 no.2
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• pp.75-79
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• 2013

Evidence for immunoregulatory roles of prostaglandins (PGs) is accumulating. Since our observation of PG production by human follicular dendritic cells (FDCs), we investigated the regulatory mechanism of PG production in FDC and attempted to understand the functions of released PGs in the responses of adjacent lymphocytes. Here, using FDC-like cells, HK cells, we analyzed protein expression alterations in cyclooxygenase-2 (COX-2) in the presence of IL-4 or histone deacetylase (HDAC) inhibitors. Both IL-4 and HDAC inhibitors suppressed COX-2 expression in dose-dependent manners. Their effect was specific to COX-2 and did not reach to COX-1 expression. Interestingly, HDAC inhibitors gave rise to an opposing effect on COX-2 expression in peripheral blood monocytes. Our results suggest that IL-4 may regulate COX-2 expression in FDCs by affecting chromatin remodeling and provide insight into the role of cellular interactions between T cells and FDC during the GC reaction. Given the growing interests in wide-spectrum HDAC inhibitors, the differential results on COX-2 expression in HK cells and monocytes raise cautions on their clinical use.

• The Journal of Korean Medicine Ophthalmology and Otolaryngology and Dermatology
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• v.22 no.1
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• pp.11-32
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• 2009

Objective : This study was designed to investigate anti-cancer and whitening activities (LC). So it was investigated the effects of LC on proliferation rates of melanoma genetic profile by LC. Methods : The genetic profile for the effect of LC on human derived melanoma cell, SK-MEL-2, was measured using microarray technique, and the functional analysis on these genes were conducted. Total 441 genes were up-regulated and 830 genes down-regulated in cells treated with LC. Genes induced or suppressed by LC were all mainly concerned with basic signalling pathways, which are involved in cell growth, differentiation and migration. Especially, many genes, which are related in apoptosis and cell cycle arrest were up-regulated by treatment with LC, and genes related in cell cycle were down-regulated. Result : The network of total protein interactions were identified by using cytoscape program, and some key molecules, such as BCL2L1, SIN3A, SMAD2 and c-myc that can be used for elucidation of therapeutical mechanism of medicine in the future. Conclusion : These results suggest possibility of LC as addition drug and whitening cosmetics. In addition, it was also suggested that related mechanisms are involved in BCL2L1, SIN3A, SMAD2 and c-myc related signalling pathways.

• Environmental Mutagens and Carcinogens
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• v.26 no.4
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• pp.97-112
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• 2006

Heme oxygenase(HO)-1 is an important antioxidant enzyme that plays a pivotal role in cellular adaptation and protection in response to a wide array of noxious stimuli. Thus, HO-1 induction has been associated with prevention or mitigation of pathogenesis of various diseases, including acute inflammation, atherosclerosis, degenerative diseases, and carcinogenesis. Recent progress in our understanding of the function of molecules in the cellular signaling network as key modulators of gene transcription sheds light on the molecular mechanisms underlyuing HO-1 gene expression. A panel of redox-sensitive transcription factors such as activator protein-1, nuclear factor-kB, and nuclear factor E2-related factor-2, and some of the upstream kinases have been identified as prime regulators of HO-1 gene induction. This review summarizes molecular mechanisms underlying HO-1 expression and the significance of targeted induction of HO-1 as a potential chemopreventive or chemoprotective strategy.

• IMMUNE NETWORK
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• v.11 no.6
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• pp.399-405
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• 2011

Background: Endogenous uveitis is a chronic inflammatory eye disease of human, which frequently leads to blindness. Experimental autoimmune uveoretinitis (EAU) is an animal disease model of human endogenous uveitis and can be induced in susceptible animals by immunization with retinal antigens. EAU resembles the key immunological characteristics of human disease in that both are $CD4^+$ T-cell mediated diseases. Dendritic cells (DCs) are specialized antigen-presenting cells that are uniquely capable of activating naive T cells. Regulation of immune responses through modulation of DCs has thus been tried extensively. Recently our group reported that donor strain-derived immature DC pretreatment successfully controlled the adverse immune response during allogeneic transplantation. Methods: EAU was induced by immunization with human interphotoreceptor retinoid-binding protein (IRBP) $peptide_{1-20}$. Dendritic cells were differentiated from bone marrow in the presence of recombinant GM-CSF. Results: In this study, we used paraformaldehyde-fixed bone marrow-derived DCs to maintain them in an immature state. Pretreatment with fixed immature DCs, but not fixed mature DCs, ameliorated the disease progression of EAU by inhibiting uveitogenic $CD4^+$ T cell activation and differentiation. Conclusion: Application of iBMDC prepared according to the protocol of this study would provide an important treatment modality for the autoimmune diseases and transplantation rejection.

• Archives of Plastic Surgery
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• v.46 no.5
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• pp.470-474
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• 2019

Congenital absent sternum is a rare birth defect that requires early intervention for optimal long-term outcomes. Descriptions of the repair of absent sternum are limited to case reports, and no preferred method for management has been described. Herein, we describe the use of porcine acellular dermal matrix to reconstruct the sternum of an infant with sternal infection following attempted repair using synthetic mesh. The patient was a full-term male with trisomy 21, agenesis of corpus callosum, ventricular septal defect, patent ductus arteriosus, right-sided aortic arch, and congenital absence of sternum with no sternal bars. Following removal of the infected synthetic mesh, negative pressure wound therapy with instillation was used to manage the open wound and provide direct antibiotic therapy. When blood C-reactive protein levels declined to ${\leq}2mg/L$, the sternum was reconstructed using porcine acellular dermal matrix. At 21 months postoperative, the patient demonstrated no respiratory issues. Physical examination and computed tomography imaging identified good approximation of the clavicular heads and sternal cleft and forward curvature of the ribs. This case illustrates the benefits of negative pressure wound therapy and acellular dermal matrix for the reconstruction of absent sternum in the context of infected sternal surgical site previously repaired with synthetic mesh.

• Journal of Microbiology and Biotechnology
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• v.31 no.6
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• pp.765-774
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• 2021

Although research on the osteal signaling pathway has progressed, understanding of gut microbial-dependent signaling pathways for metabolic and immune bone homeostasis remains elusive. In recent years, the study of gut microbiota has shed light on our understanding of bone homeostasis. Here, we review microbiota-mediated gut-bone crosstalk via bone morphogenetic protein/SMADs, Wnt and OPG/receptor activator of nuclear factor-kappa B ligand signaling pathways in direct (translocation) and indirect (metabolite) manners. The mechanisms underlying gut microbiota involvement in these signaling pathways are relevant in immune responses, secretion of hormones, fate of osteoblasts and osteoclasts and absorption of calcium. Collectively, we propose a signaling network for maintaining a dynamic homeostasis between the skeletal system and the gut ecosystem. Additionally, the role of gut microbial improvement by dietary intervention in osteal signaling pathways has also been elucidated. This review provides unique resources from the gut microbial perspective for the discovery of new strategies for further improving treatment of bone diseases by increasing the abundance of targeted gut microbiota.