• Asian-Australasian Journal of Animal Sciences
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• v.31 no.5
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• pp.650-657
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• 2018

Objective: The study investigated the biological functions and mechanisms for controlling cashmere growth of Liaoning cashmere goat by ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) and decorin (DCN) genes. Methods: cDNA library of Liaoning cashmere goat was constructed in early stages. OCIAD2 and DCN genes related to cashmere growth were identified by homology analysis comparison. The expression location of OCIAD2 and DCN genes in primary and secondary hair follicles (SF) was performed using in situ hybridization. The expression of OCIAD2 and DCN genes in primary and SF was performed using real-time polymerase chain reaction (PCR). Results: In situ hybridization revealed that OCIAD2 and DCN were expressed in the inner root sheath of Liaoning cashmere goat hair follicles. Real-time quantitative PCR showed that these genes were highly expressed in SF during anagen, while these genes were highly expressed in primary hair follicle in catagen phase. Melatonin (MT) inhibited the expression of OCIAD2 and promoted the expression of DCN. Insulin-like growth factors-1 (IGF-1) inhibited the expression of OCIAD2 and DCN, while fibroblast growth factors 5 (FGF5) promoted the expression of these genes. MT and IGF-1 promoted OCIAD2 synergistically, while MT and FGF5 inhibited the genes simultaneously. MT+IGF-1/MT+FGF5 inhibited DCN gene. RNAi technology showed that OCIAD2 expression was promoted, while that of DCN was inhibited. Conclusion: Activation of bone morphogenetic protein (BMP) signaling pathway up-regulated OCIAD2 expression and stimulated SF to control cell proliferation. DCN gene affected hair follicle morphogenesis and periodic changes by promoting transforming growth $factor-{\beta}$ ($TGF-{\beta}$) and BMP signaling pathways. OCIAD2 and DCN genes have opposite effects on $TGF-{\beta}$ signaling pathway and inhibit each other to affect the hair growth.

• Journal of Life Science
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• v.29 no.4
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• pp.499-508
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• 2019

Cancer stem cells (CSCs), which are primarily responsible for metastasis and recurrence, have self-renewal, differentiation, therapeutic resistance, and tumor formation abilities. Numerous studies have demonstrated the signaling pathways essential for the acquisition and maintenance of CSC characteristics, such as WNT/${\beta}$-catenin, Hedgehog, Notch, B lymphoma Mo-MLV insertion region 1 homolog (BMI1), Bone morphogenetic protein (BMP), and TGF-${\beta}$ signals. However, few therapeutic strategies have been developed that can selectively eliminate CSCs. Recently, neutralizing antibodies against Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1), immune checkpoint inhibitors (ICIs), have shown promising outcomes in clinical trials of melanoma, lung cancer, and pancreatic cancer, as well as in hematologic malignancies. ICIs are considered to outperform conventional anticancer drugs by maintaining long-lasting anti-cancer effects, with less severe side effects. Several studies reported that ICIs successfully blocked CSC properties in head and neck squamous carcinomas, melanomas, and breast cancer. Together, these findings suggest that novel and effective anticancer therapeutic modalities using ICIs for selective elimination of CSCs may be developed in the near future. In this review, we highlight the origin and characteristics of CSCs, together with critical signaling pathways. We also describe progress in ICI-mediated anticancer treatment to date and present perspectives on the development of CSC-targeting ICIs.

• The Journal of Korean Academy of Prosthodontics
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• v.48 no.3
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• pp.202-208
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• 2010

Purpose: This study was aimed to evaluate the effect of rhPMP-2 coated implants on alveolar ridge augmentation in dogs. Materials and methods: Six Beagle dogs were used in this study. Six 8.0 mm long anodized surface titanium implants were placed 5 mm into the mandibular alveolar ridge following 6 month of healing period after extraction. Each animal received three implants coated with rhBMP-2 and three uncoated control implants using the randomized split-mouth design. Radiographic examinations were undertaken immediately at implant placement (baseline), at weeks 4 and 8 after implant placement. The amount of bone augmentation was evaluated by measuring the distance from the uppermost point of the coverscrew to the marginal bone. Implant Stability Quotient (ISQ) values were measured immediately at implant placement and 8 weeks after implant placement. For the statistical analysis, Man-Whitney ranksum test and Wilcoxon signed rank test of SPSS 12.0 software were used (P=.05). Results: The BMP group exhibited radiographic vertical bone augmentation about $0.6{\pm}0.7$ mm at 8 weeks later while controls showed bone loss about $0.4{\pm}0.6$ mm. There was significant difference among the rhBMP-2 group and controls in bone level change (P<.05). The ISQ values were significantly higher in the BMP-2 group than the control group at 8 weeks later (P<.05), while there was no significant difference at surgery. Conclusion: Within the limitation of this study, the rhBMP-2 coated on anodized implant could stimulate vertical alveolar bone augmentation, which may increase implant stability significantly on completely healed alveolar ridge.

• Journal of Periodontal and Implant Science
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• v.34 no.1
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• pp.49-59
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• 2004

The goal of periodontal treatment is not only to arrest the progression of the disease but also to promote the functional, esthetic regeneration of the periodontium. Flap operation, bone graft, guided tissue regeneration, growth factors and bone morphogenetic protein have been used for this purpose. Among these techniques of regeneration, alloplastic graft, especially calcium phosphate is getting more attention recently. The purpose of this study was to evaluate the effects of calcium phosphate glass on mouse calvarial cell in vitro. The toxicity of calcium phosphate glass was measured using MTT assay, the synthesis of collagen was measured using collagen assay, and ALP activity was measured. The experimental groups were cultured with calcium phosphate glass(both AQ-, and HT-CPG) in concentration of 0.01, 0.02, 0.1, 0.2g/ml. The results are as follows 1. In concentrations not exceeding 0.02g/ml, both the groups(AQ-CPG, HT-CPG) didn't show any toxicity on mouse calvarial cell(p<0.05). 2. In both the experimental groups are the concentration of 0.02g/ml, collagen expressions were significantly up-regulated (p<0.05). 3. In both the experimental groups are the concentration of 0.02g/ml, ALP activity was not significantly up-regulated, but ALP activity in both experimental groups were greater than control group(p<0.05). The results suggested that the use of calcium phosphate glass may promotes periodontal regeneration. Ongoing studies are necessary in order to determine their regeneration effects.

• International Journal of Oral Biology
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• v.36 no.4
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• pp.173-178
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• 2011

Tumor necrosis factor alpha ($TNF{\alpha}$) is a multifunctional cytokine that is elevated in inflammatory diseases such as atherosclerosis, diabetes and rheumatoid arthritis. Recent evidence has suggested that ${\beta}2$ adrenergic receptor (${\beta}2AR$) activation in osteoblasts suppresses osteogenic activity. In the present study, we explored whether $TNF{\alpha}$ modulates ${\beta}AR$ expression in osteoblastic cells and whether this regulation is associated with the inhibition of osteoblast differentiation by $TNF{\alpha}$. In the experiments, we used C2C12 cells, MC3T3-E1 cells and primary cultured mouse bone marrow stromal cells. Among the three subtypes of ${\beta}AR$, ${\beta}2$ and ${\beta}3AR$ were found in our analysis to be upregulated by $TNF{\alpha}$. Moreover, isoproterenol-induced cAMP production was observed to be significantly enhanced in $TNF{\alpha}$-primed C2C12 cells, indicating that $TNF{\alpha}$ enhances ${\beta}2AR$ signaling in osteoblasts. $TNF{\alpha}$ was further found in C2C12 cells to suppress bone morphogenetic protein 2-induced alkaline phosphatase (ALP) activity and the expression of osteogenic marker genes including Runx2, ALP and osteocalcin. Propranolol, a ${\beta}2AR$ antagonist, attenuated this $TNF{\alpha}$ suppression of osteogenic differentiation. $TNF{\alpha}$ increased the expression of receptor activator of NF-${\kappa}B$ ligand (RANKL), an essential osteoclastogenic factor, in C2C12 cells which was again blocked by propranolol. In summary, our data show that $TNF{\alpha}$ increases ${\beta}2AR$ expression in osteoblasts and that a blockade of ${\beta}2AR$ attenuates the suppression of osteogenic differentiation and stimulation of RANKL expression by $TNF{\alpha}$. These findings imply that a crosstalk between $TNF{\alpha}$ and ${\beta}2AR$ signaling pathways might occur in osteoblasts to modulate their function.

• The Journal of the Korean bone and joint tumor society
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• v.1 no.1
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• pp.7-16
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• 1995

In countries where confucianism is popular, it is extremely hard to get fresh cadaver bone for allograft. Therefore in Korea, the reimplantation of resected autoclaved autogenous bone segments has been increasingly performed for limb reconstruction of extremities with malignancies. To preserve the bone morphogenetic protein and mechanical strength of heated bone, many studies have reported that pasteurization of bone is far better than autoclaving over $100^{\circ}C$. Based on this assumption, replacement with a pasteurized autogenous bone graft after resection of a malignant bone tumor was deemed feasible for reconstruction. However, little is known about how high a temperature and how much time for pasteurization is needed to make tumors completely necrotic and to maintain the mechanical strength of bone. Consequantly, experimental studies were carried out to test heat conductivity of human bone and torsional strength of porcine tibia after pasteurization. First, two pairs of human proximal tibia and distal femur were used. We used T-type thermocoples to check core temperature of the bone and a computerized data acquisition system to record results. Without reaming of the medullary cavity, in a $60^{\circ}C$-thermostatic saline tub, it took 32 minutes and 50 seconds to raise the core temperature of human proximal tibia from $20^{\circ}C$ to $58^{\circ}C$, and 30 minutes for distal femur. In a $80^{\circ}C$ saline tub, it took 12 minutes and 50 seconds for proximal tibia, and 11 minutes and 10 seconds for distal femur. In contrast, using porcine tibia whose cortical thickness is similar to that of human tibia, after reaming of the medullary canal, it took less than 3 minutes and 30 seconds in a $60^{\circ}C$ saline tub, less than 1 minute and 45 seconds in a $70^{\circ}C$ tub, and less than 1 minute in a $80^{\circ}C$ tub to elevate core temperature from $20^{\circ}C$ to $58^{\circ}C$. Second, based on data of the heat conductivity test, we compared the torsional strength before and after pasteurization. Twenty matched pairs of porcine tibia were used, The left one was used as a non-heated control group and the right one as a pasteurized experimental group. Wighout reaming of the medullary cavity, there was no statistical difference in torsional strength between the pasteurization of the $60^{\circ}C$-35minute and of $80^{\circ}C$-15minute. With reaming, we also found no statistical difference among pasteurization of $60^{\circ}C$-15 minute, of $70^{\circ}C$-15 minute, and of $80^{\circ}C$-15 minute groups. In conclusion, reaming of the medullary canal is very helpful in saving pasteurization time. And, in a $60^{\circ}C$ saline tub, no significant weakness in torsional strength occurs with pasteurization of the bone for up to 35 minutes. Also no significant weakness in torsional strength occurs with an exposure of 15 minutes to the $80^{\circ}C$ saline tub.

• The korean journal of orthodontics
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• v.26 no.2 s.55
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• pp.187-196
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• 1996

Underlying malocclusions and dentofacial deformities are often related to variations in the craniofacial development. Type I and type II collagens are considered the major collagens of bone and cartilage respectively. Monitoring the patterns of those protein expressions during development will Provide a basis for the understanding of normal and abnormal growths. This study was undertaken to investigate the morphogenetic changes and the expression patterns of type I and II collagen proteins involved in the developing mandible of human embryos and fetuses. 50 embryos and fetuses were studied with Hematoxylin and Eosin, Alcian, blue-PAS, Masson Trichrome, md Immunohistochemical stains. The results were as follows : 1. A 13.5 mm embryo showed the stomatodeum with dental lamina, maxillary and mandibular processes. Meckel's cartilage appeared in the mandibular arch of a 20.5 mm embryo. New bone formation was bilaterally initiated at the outer side of middle portion of Meckel's cartilage of 22-38 mm embryos. 2. Meckel'cartilage was resorbed at the 15th week fetus. The endochondral ossification was observed where there was direct replacement of cartilage by bone. Meckel'cartilage disappeared and membraneous ossification were observed at the 25th week. 3. Before the appearance of Meckel's cartilage, the expression of type I collagen was moderate at the odontogenic epithelium of maxillary & mandibular process, but mild for the expression of type II collagen. 4. During the appearance of Meckel's cartilage and new bone formation, the immunoactivity of type II collagen was more expressed than type I collagen at the Meckel's cartilage and new bone. 5. During intrarmembranous bone formation, the expression of type II collagen was rare in the bony trabeculae. There was a switch for the expression of collagens from type II to type I during the appearance of Meckel's cartilage.

• Journal of the korean academy of Pediatric Dentistry
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• v.28 no.2
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• pp.238-246
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• 2001

Bone morphogenetic proteins(BMPs), members of the transforming growth factor $\beta$(TGF-$\beta$) superfamily were first identified as the factors that induce ectopic bone formation in vivo, when implanted into muscular tissue. Especially BMP-2 inhibits terminal differentiation of C2C12 myoblasts and converts them into osteoblast lineage cells. In the molecular mechanism of the signal transduction of TGF-$\beta$ and related factors, intracellular signaling proteins were identified as Smad. In previous study, it has been reported that Smad 1 and Smad 5, which belong to the R-Smad family mediate BMP signaling, were involved in the induction of osteoblast differentiation in C2C12 cells. To understnad the role of Smads involved in osteogenic transdifferentiation in C2C12 cell, in present study, after we stably transfected C2C12 cells with each. Smad(Smad 1,Smad 5) expression vector, cultured for 3 days and stained for alkaline phophatase activity. ALP activity positive cells appeared in the Smad 1, Smad 5 stably transfected cell even in the abscence of BMP. After transiently co-transfected C2C12 cells with each Smad expression vector and ALP promoter, it was examined that Smad 1 and Smad 5 expression vector had increased about 2 fold ALP promoter activity in the abscence of BMP. These result suggested that both Smad 1 and Smad 5 were involved in the intracellular BMP signals which induce osteoblast differentiation in C2C12 cells. The effect of BMP on C2C12 cells with Smad 1, Smad 5 transfected were studied by using northern blot analysis. the treatment of BMP upregulated ALP mRNA level in three groups, especially upregulation of ALP was larger in Smad 1, Smad 5 transfected cell than control group. Pretreatment with cycloheximide($10{\mu}g/ml$), a protein synthesis inhibitor resulted in blocking the ALP gene expression even in BMP(100ng/ml) treated cell. These results suggested that Smad increased the level of ALP mRNA via the synthesis of a certain transcriptional regulatory protein.

• The Journal of Korean Academy of Prosthodontics
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• v.51 no.2
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• pp.82-89
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• 2013

Purpose: The present study is aimed to evaluate the combined effect of recombinant human bone morphogenetic protein 2 (rhBMP-2) and recombinant human vascular endothelial growth factor (rhVEGF) coated onto anodized implants on osseointeration. Materials and methods: Six New Zealand white rabbit were used in this study. Each animal received 4 implants that were either coated with rhBMP-2 and rhVEGF (Study group) or anodized implant (Control group) in both tibia. This was performed using a randomized split-mouth design. A total 24 implants were used. The implant stability quotient (ISQ) value using resonance frequency analyser and removal torque (RTQ) measurement were investigated at 2 and 8 weeks. The t-test was used for statistical analysis (${\alpha}$=.05). Results: Control and study group showed good osseointegration at 8 weeks. The ISQ and RTQ values of study group were significant compared with the control group at 8 weeks (P<.05). However, No statistical significance was observed at 2 weeks (P>.05). Conclusion: It was concluded that rhBMP-2 with rhVEGF coated onto anodized implants can induce better osseointegration at late healing period.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6813-6823
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• 2015

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor ${\beta}$ ($TGF{\beta}$) superfamily is a large group of structurally related proteins including $TGF{\beta}$ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The $TGF{\beta}$ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlike growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (${\alpha}v{\beta}3$, ${\alpha}5{\beta}1$) and GBM initiating cells (GICs) as well as inducing a GBM mesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the $TGF{\beta}$ subfamily yields advantageous results, enhancing BMPs production is also beneficial.