• The Korean Journal of Physiology and Pharmacology
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• v.19 no.4
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• pp.365-372
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• 2015

Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor $(NF)-{\kappa}B$, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages.

• International Journal of Oral Biology
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• v.30 no.1
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• pp.23-30
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• 2005

Bone remodeling is a process controlled by the action of two major bone cells; the bone forming osteoblast and the bone resorbing osteoclast. In the process of osteoclastogenesis, stromal cells and osteoblast produce RANKL, OPG, and M-CSF, which in turn regulate the osteoclastogenesis. During the bone resorption by activated osteoclasts, extracellular $Ca^{2+}/{PO_4}^{2-}$ concentration and degraded organic materials goes up, providing the hypertonic microenvironment. In this study, we tested the effects of hypertonicity due to the degraded organic materials on osteoclastogenesis in co-culture system. It was examined the cellular response of osteoblastic cell in terms of osteoclastogenesis by applying the sucrose, and mannitol, as a substitute of degraded organic materials to co-culture system. Apart from the sucrose, mannitol, and NaCl was tested to be compared to the effect of organic osmotic particles. The addition of sucrose and mannitol (25, 50, 100, 150, or 200 mM) to co-culture medium inhibited the number of tartrate-resistant acid phosphatase (TRAP) positive multinucleated cells induced by 10 nM $1{\alpha},25(OH)_2vitaminD_3$ ($1{\alpha},25(OH)_2D_3$). However, NaCl did exert harmful effect upon the cells in this co-culture system, which is attributed to DNA damage in high concentration of NaCl. To further investigate the mechanism by which hypertonicity inhibits $1{\alpha},25(OH)_2D_3$-induced osteoclastogenesis, the mRNA expressions of receptor activator of nuclear factor (NF)-kB ligand (RANKL) and osteoprotegerin (OPG) were monitored by RT-PCR. In the presence of sucrose (50 mM), RANKL mRNA expression was decreased in a dose-dependent manner, while the change in OPG and M-CSF mRNA were not occurred in significantly. The RANKL mRNA expression was inhibited for 48 hours in the presence of sucrose (50 mM), but such a decrement recovered after 72 hours. However, there were no considerable changes in the expression of OPG and M-CSF mRNA. Conclusively, these findings strongly suggest that hypertonic stress down-regulates $1{\alpha},25(OH)_2D_3$-induced osteoclastogenesis via RANKL signal pathway in osteoblastic cell, and may playa pivotal role as a regulator that modulates osteoclastogenesis.

• Journal of Physiology & Pathology in Korean Medicine
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• v.26 no.6
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• pp.869-873
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• 2012

Balance between bone-forming osteoblasts and bone-resorbing osteoclasts is important in bone homeostasis. Unusual balance between bone-forming osteoblasts and bone-resorbing osteoclasts leads to bone diseases, such as osteoporosis. Saururus chinensis has been widely used in oriental medicine. Saururus chinensis has been known that has antioxidant and anticancer effect. But, the effect of Saururus chinensis in osteoclast differentation remains unknown. We examined the effect of Saururus chinensis in receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL)-induced osteoclast differentiation. From the results of our study, we found that saururus chinensis clearly inhibited RANKL-induced osteoclast differentiation in bone marrow macrophages (BMM) in a dose dependent manner without toxicity. Saururus chinensis inhibited the phosphorylation of JNK, P38, AKT, and ERK induced by RANKL. The mRNA expression of NFATc1, TRAP, and OSCAR induced by RANKL was inhibited by Saururus chinensis treatment. Moreover Saururus chinensis suppressed the protein expression of c-Fos and NFATc1 in BMMs treated with RANKL. These results suggest that Saururus chinensis may be a useful drug in the treatment of bone-related disease.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.146-156
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• 2018

Spermidine is a naturally occurring polyamine compound that has recently emerged with anti-aging properties and suppresses inflammation and oxidation. However, its mechanisms of action on anti-inflammatory and antioxidant effects have not been fully elucidated. In this study, the potential of spermidine for reducing pro-inflammatory and oxidative effects in lipopolysaccharide (LPS)-stimulated macrophages and zebrafish was explored. Our data indicate that spermidine significantly inhibited the production of pro-inflammatory mediators such as nitric oxide (NO) and prostaglandin $E_2$ ($PGE_2$), and cytokines including tumor necrosis $factor-{\alpha}$ and $interleukin-1{\beta}$ in RAW 264.7 macrophages without any significant cytotoxicity. The protective effects of spermidine accompanied by a marked suppression in their regulatory gene expression at the transcription levels. Spermidine also attenuated the nuclear translocation of $NF-{\kappa}B$ p65 subunit and reduced LPS-induced intracellular accumulation of reactive oxygen species (ROS) in RAW 264.7 macrophages. Moreover, spermidine prevented the LPS-induced NO production and ROS accumulation in zebrafish larvae and was found to be associated with a diminished recruitment of neutrophils and macrophages. Although more work is needed to fully understand the critical role of spermidine on the inhibition of inflammation-associated migration of immune cells, our findings clearly demonstrate that spermidine may be a potential therapeutic intervention for the treatment of inflammatory and oxidative disorders.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.36 no.5
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• pp.392-401
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• 2010

Introduction: Diabetes mellitus, as a major health problem for the elderly has been shown to alter the properties of the bone and impair bone healing around a titanium implant in both humans and animals. The aim of this study was to examine the effect of adipose-derived stem cells on the healing process around a titanium implant in streptozotocin-induced diabetic rats. Materials and Methods: Thirteen rats were divided into two groups: adipose-derived stem cells injected group and a control group. A titanium screw implant (diameter: 2.0 mm, length: 3.5 mm) was placed into both tibia of 13 rats: 13 right tibia as the control group and 13 left tibia as the experimental group. The rats were sacrificed at different intervals (1, 2, and 4 weeks) after implantation for histopathology observations and immunohistochemistric analysis. Results: The histopathological findings revealed earlier new formed bone in the experimental group than the control group. In particular, at 1 week after implantation, the experimental group showed more newly formed bone and collagen around the implant than the control group. In immunohistochemistric analysis, osteoprotegerin (OPG) expression in the experimental group increased early compared to that of the control group until 2 weeks after implantation. However, after 2 weeks, OPG expression in the experimental group was similar to OPG expression in the control group. The receptor activator of nuclear factor ${\kappa}B$ ligand (RANKL) expression in the experimental group increased early compared to that of the control group, and then decreased at 2 weeks. After 2 weeks, the level of RANKL expression was similar in both groups. Conclusion: These results suggest that adipose-derived stem cells in implantation can promote bone healing around titanium, particularly in diabetes mellitus induced animals.

• Tuberculosis and Respiratory Diseases
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• v.78 no.3
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• pp.218-226
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• 2015

Background: Eph receptors and ephrin ligands have several functions including angiogenesis, cell migration, axon guidance, fluid homeostasis, oncogenesis, inflammation and injury repair. The EphA2 receptor potentially mediates the regulation of vascular permeability and inflammation in response to lung injury. Methods: Mice were divided into 3 experimental groups to study the role of EphA2 signaling in the lipopolysaccharide (LPS)-induced lung injury model i.e., IgG+phosphate-buffered saline (PBS) group (IgG instillation before PBS exposure), IgG+LPS group (IgG instillation before LPS exposure) and EphA2 monoclonal antibody (mAb)+LPS group (EphA2 mAb pretreatment before LPS exposure). Results: EphA2 and ephrinA1 were upregulated in LPS-induced lung injury. The lung injury score of the EphA2 mAb+LPS group was lower than that of the IgG+LPS group ($4.30{\pm}2.93$ vs. $11.45{\pm}1.20$, respectively; p=0.004). Cell counts (EphA2 mAb+LPS: $11.33{\times}10^4{\pm}8.84{\times}10^4$ vs. IgG+LPS: $208.0{\times}10^4{\pm}122.6{\times}10^4$; p=0.018) and total protein concentrations (EphA2 mAb+LPS: $0.52{\pm}0.41mg/mL$ vs. IgG+LPS: $1.38{\pm}1.08mg/mL$; p=0.192) were decreased in EphA2 mAb+LPS group, as compared to the IgG+LPS group. In addition, EphA2 antagonism reduced the expression of phospho-p85, phosphoinositide 3-kinase $110{\gamma}$, phospho-Akt, nuclear factor ${\kappa}B$, and proinflammatory cytokines. Conclusion: This results of the study indicated a role for EphA2-ephrinA1 signaling in the pathogenesis of LPS-induced lung injury. Furthermore, EphA2 antagonism inhibits the phosphoinositide 3-kinase-Akt pathway and attenuates inflammation.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.38 no.1
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• pp.14-19
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• 2012

Introduction: This study was conducted to evaluate ssrA expression resulting from adaptation of Escherichia coli (E. coli) to oral pathogens through signal exchange. Materials and Methods: Human cell lines Hep2 and HT29, wild-type E. coli (WT K-12), ssrA knock-out E. coli (${\Delta}K$-12), and Scleropages aureus (S. aureus) were used. A single culture consisting of Hep2, HT29, WT K-12, and ${\Delta}K$-12, and mixed cultures consisting of Hep2 and WT K-12, Hep2 and ${\Delta}K$-12, WT K-12 and S. aureus, ${\Delta}K$-12 and S. aureus, and Hep2, WT K-12, and S. aureus were prepared. For HT29, a mixed culture was prepared with WT K-12 and with WT K-12 and S. aureus. Total RNA was extracted from each culture with the resulting expression of ssrA, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-${\kappa}B$), and p53 was evaluated by Reverse transcription polymerase chain reaction (RT-PCR). Results: The expression of ssrA in a single culture of WT K-12 was lower than that observed in the mixed culture of WT K-12 with S. aureus. Greater ssrA expression was observed in the mixed culture of WT K-12 with Hep2 than in the single culture of WT K-12. The expression of NF-${\kappa}B$ was higher in the mixed culture of Hep2 with ${\Delta}K$-12 than that in the mixed culture of Hep2 with WT K-12, and was lowest in the single culture of Hep2. The expression of ssrA was higher in the mixed culture of WT K-12 with Hep2 and S. aureus than in the mixed culture of WT K-12 with Hep2. Conclusion: These results suggest that ssrA plays an important role in the mechanism of E. coli adaptation to a new environment.

• Journal of Physiology & Pathology in Korean Medicine
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• v.27 no.6
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• pp.771-781
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• 2013

This study was performed to investigate the anti-photoaging effects of Persimmon leaf tea(PLT) in hairless mice(SKH-1) exposed to UVB irradiation. The animals were divided into non-treated group (normal, N) and UV-radiated groups. UV-radiated groups were divided into only UV-radiated group(control, C) and UV-radiated and PLT treated experimental groups[first extraction treated group(PLT-I), second extraction treated group(PLT-II), and third extraction treated group(PLT-III)]. Three PLT treated experimental groups of mice were treated with both oral administration(300 mg/Kg B.W./day) and topical application (100 ul of 2% conc./mouse/day) for 4 weeks. Anti-photoaging effects of Persimmon leaf were evaluated by anti oxidative reaction, stereomicroscopic and microscopic observations. The expression of photoaging skin related factors including mast cell tryptase, proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) was examined by immunohistochemical staining. Treatment of PLT-I, -II, -III prevented the wrinkle formation as well as epidermal hyperplasia, inflammatory cells, disruption of collagen in photoaged skin induced by UVB radiation. It also reduced the PCNA and VEGF expression in the UVB irradiated dorsal skin. Furthermore, it significantly decreased the number of mast cells in the UVB irradiated dermis(p<0.05 and p<0.01). On the effects of oxidative stress and antioxidant function on the treatment with water extract from Persimmon leaf tea(PLT), the activity of superoxide dismutase(SOD) was significantly increased in PLT-III group(p<0.05), and catalase(CAT) was significantly increased in PLT-I and PLT-III groups(p<0.05), and PLT-II group(p<0.001). These extracts showed relatively antioxidant activity and protective effect on UVB-induced oxidative stress in hairless mice(SKH-1). Our results suggest that Persimmon leaf tea may serve as an useful radical scavenging antioxidant and anti-photoaging skin agents in the UVB irradiated skin.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.33 no.3
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• pp.199-209
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• 2011

Purpose: Osteoporosis, is a major health problem for the elderly and post-menopausal women and shown to alter the properties of bone as well as impair bone healing around titanium implants in both human and animals. The objective of this study was to examine the effect of LIPUS with adipose-derived stem cells on the healing process around a titanium implant in rats with osteoporosis. Methods: Sixteen osteoporosis-induced rats were divided into two groups: an adipose-derived stem cell injected with Low Intensity Pulsed Ultrasound (LIPUS) application group and a control group. Titanium screw implants (diameter, 2.0 mm: length, 3.5 mm, Cowell Medi, Korea) were placed into both tibia of 16 rats, on 8 rats as the control group and the other 8 rats as the experimental group. Rats were sacrificed at different intervals from 1, 2, 4 and 8 weeks after implantation for histopathologic and immunohistochemical analyses. Results: Histopathological analysis revealed newly formed bone in experimental group earlier than that in control group. Especially at 1 week after implantation, more amounts of new bone matrix and collagen around the implant in the experimental group were seen compared with the control group. Immunohistochemical analysis showed that the levels of osteoprotegerin (OPG) expression in the experimental group were increased at early stages compared with that of control group until 2 weeks after implantation. But after 2 weeks, the expression level of OPG similar in both groups. The expression levels of receptor activator of nuclear factor kB ligand (RANKL) were stronger in the experimental group than the control group until 2 weeks after implantation. After 4 weeks, expression of RANKL in experimental group was similar to the control group. Conclusion: The results of this study suggest that LIPUS with Adipose-Derived Stem Cells in implantation could promote bone healing around titanium implants in rats with osteoporosis.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.36 no.5
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• pp.386-391
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• 2010

Introduction: Bone resorption is a unique function of osteoclasts. Osteoclasts are a specialized macrophage polykaryon whose differentiation is regulated principally by macrophage colony-stimulating factors, receptor activator of nuclear factor ${\kappa}B$ ligand (RANK) ligand, osteoprotegerin (OPG), and interleukins (IL). Reflecting the integrin-mediated signals, osteoclasts develop a specialized cytoskeleton that allows it to establish an isolated micro-environment between itself and the bone, wherein matrix degradation occurs by a process involving proton transport. The levels of IL-1, IL-6, OPG, and prostaglandin $E_2$ ($PGE_2$) expression were evaluated to study the correlations between dental implant teeth and the adjacent teeth. Materials and Methods: The exudate of the gingival crevice acquired from dental implants, adjacent teeth, opposite teeth and contralateral teeth of 24 patients. Results: 1. The levels of IL-1, IL-6, OPG and $PGE_2$ expression in dental implant teeth were higher than those of the contralateral teeth. 2. IL-1 revealed a higher expression level in the adjacent teeth than in dental implant teeth. 3. The dental implant teeth and adjacent teeth did not show a remarkable difference in the level of IL-1 expression. 4. All the other cytokines were strongly expressed in the dental implant compared to the adjacent teeth. Conclusion: These results suggest that there might be close correlation between dental implant teeth and adjacent teeth in terms of the expressions of cytokines that affect the development and regulation of osteoclasts.