• The Korean Journal of Physiology and Pharmacology
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• v.28 no.4
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• pp.303-312
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• 2024

Atopic dermatitis (AD) is the most common inflammatory pruritic skin disease worldwide, characterized by the infiltration of multiple pathogenic T lymphocytes and histological symptoms such as epidermal and dermal thickening. This study aims to investigate the effect of vinpocetine (Vinp; a phosphodiesterase 1 inhibitor) on a 1-chloro-2,4-dinitrobenzene (DNCB)-induced AD-like model. DNCB (1%) was administered on day 1 in the AD model. Subsequently, from day 14 onward, mice in each group (Vinp-treated groups: 1 mg/kg and 2 mg/kg and dexamethasone-treated group: 2 mg/kg) were administered 100 µl of a specific drug daily, whereas 0.2% DNCB was administered every other day for 30 min over 14 days. The Vinp-treated groups showed improved Eczema Area and Severity Index scores and trans-epidermal water loss, indicating the efficacy of Vinp in improving AD and enhancing skin barrier function. Histological analysis further confirmed the reduction in hyperplasia of the epidermis and the infiltration of inflammatory cells, including macrophages, eosinophils, and mast cells, with Vinp treatment. Moreover, Vinp reduced serum concentrations of IgE, interleukin (IL)-6, IL-13, and monocyte chemotactic protein-1. The mRNA levels of IL-1β, IL-6, Thymic stromal lymphopoietin, and transforming growth factor-beta (TGF-β) were reduced by Vinp treatment. Reduction of TGF-β protein by Vinp in skin tissue was also observed. Collectively, our results underscore the effectiveness of Vinp in mitigating DNCB-induced AD by modulating the expression of various biomarkers. Consequently, Vinp is a promising therapeutic candidate for treating AD.

• Microbiology and Biotechnology Letters
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• v.49 no.4
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• pp.543-551
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• 2021

Nocardiopsis species produce bioactive compounds, such as antimicrobial and anti-cancer agents and toxins. However, no reports have described their anti-inflammatory and anti-fibrotic effects during nasal polyp (NP) formation. In this study, we investigated whether marine-derived bacterial Nocardiopsis sp. 13G027 exerts anti-inflammatory and anti-fibrotic effects on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and transforming growth factor (TGF)-β1-induced NP-derived fibroblasts (NPDFs). Nitric oxide (NO) and prostaglandin E₂ (PGE₂) levels were analyzed. Extract from Nocardiopsis sp. 13G027 significantly inhibited the upregulation of NO and PGE₂ in LPS-activated RAW 264.7 macrophages. The expression of mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt/PKB) in LPS-induced RAW 264.7 macrophages was evaluated; smooth muscle alpha-actin (α-SMA), collagen type I (Col-1), and fibronectin also phosphorylated small mothers against decapentaplegic (SMAD) 2 and 3 in TGF-β1-stimulated NPDFs. The Nocardiopsis sp. 13G027 extract suppressed the phosphorylation of MAPKs and Akt and the DNA-binding activity of activator protein 1 (AP-1). The expression of pro-fibrotic components such as α-SMA, Col-1, fibronectin, and SMAD2/3 was inhibited in TGF-β1-exposed NPDFs. These findings suggest that Nocardiopsis sp. 13G027 has the potential to treat inflammatory disorders, such as NP formation.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.1
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• pp.1-8
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• 2023

Hypothyroidism alone can lead to myocardial fibrosis and result in heart failure, but traditional hormone replacement therapy does not improve the fibrotic situation. Hydrogen sulfide (H₂S), a new gas signaling molecule, possesses anti-inflammatory, antioxidant, and anti-fibrotic capabilities. Whether H₂S could improve hypothyroidism-induced myocardial fibrosis are not yet studied. In our study, H₂S could decrease collagen deposition in the myocardial tissue of rats caused by hypothyroidism. Furthermore, in hypothyroidism-induced rats, we found that H₂S could enhance cystathionine-gamma-lyase (CSE), not cystathionine β-synthase (CBS), protein expressions. Finally, we noticed that H₂S could elevate autophagy levels and inhibit the transforming growth factor-β1 (TGF-β1) signal transduction pathway. In conclusion, our experiments not only suggest that H₂S could alleviate hypothyroidism-induced myocardial fibrosis by activating autophagy and suppressing TGF-β1/SMAD family member 2 (Smad 2) signal transduction pathway, but also show that it can be used as a complementary treatment to conventional hormone therapy.

• Clinical and Experimental Reproductive Medicine
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• v.50 no.4
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• pp.292-298
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• 2023

Objective: Ovarian torsion is a gynecological disorder that causes ischemia-reperfusion injuries in the ovary. Our study investigated berberine's short- and long-term effects on ovarian ischemia-reperfusion injuries. Methods: This study included 28 Wistar albino female rats weighing 180 to 220 g, which were divided into four groups: sham (S), torsion/detorsion (T/D), torsion/ detorsion+single dose berberine (T/D+Bb), and torsion/detorsion+15 days berberine (T/D+15Bb). The torsion and detorsion model was applied in all non-sham groups. In the T/D+Bb group, a single dose of berberine was administered, while in the T/D+15Bb group, berberine was administered over a period of 15 days. After the rats were euthanized, their ovaries were excised. The left ovaries were used for histopathologic evaluation, which included ovarian injury scoring and follicle count, while the right ovaries were used for biochemical analyses (tissue transforming growth factor-β [TGF-β] and alpha-smooth muscle actin [α-SMA] levels). Results: The histopathologic evaluation scores for the ovaries were significantly lower in the T/D+B group (p<0.05) and the T/D+15B group (p<0.005) than in the T/D group. The follicle counts in the T/D group were lower than those in both the sham and treated groups (p<0.005). The TGF-β levels were significantly lower in the T/D+15B group (p<0.005), whereas the α-SMA levels did not show a significant difference. Conclusion: Both short- and long-term berberine use could potentially have therapeutic effects on ovarian torsion. Long-term berberine use exhibited anti-inflammatory effects by reducing TGF-β levels, thereby preventing ischemia-reperfusion injuries. Therefore, we suggest that long-term berberine use could be beneficial for ovarian torsion.

• The Journal of Internal Korean Medicine
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• v.27 no.1
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• pp.228-236
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• 2006

Objectives : Macrophage has an important innate defense role in the immune system. When we are infected with pathogens, macrophage ingests them through phagocytosis or endocytosis, and then secretes many cytokines, such as IL-1, IL-6 and $TGF{\alpha}$, which are regulators of immune responses. The aim of this study is to determine how Samjunghwan effects the expression of cytokine and other immune-related genes in macrophages. Methods : Cells were treated directly with Samjunghwan and/or LPS at regular intervals. Total RNA of cells was isolated using TRIzol reagent, and the changes in cytokine gene expressions were investigated using RT-PCR, western blot and ELISA. Results : $IL-1{\alpha},\;IL-1{\beta}$ and COX-2 genes were inducibly expressed specifically by Samjunghwan in macrophage. Especially, $IL-1{\beta}$ gene was induced most strongly by treatment with Samjunghwan. Over time, treatment with Samjunghwan showed that the expression levels of $IL-1{\alpha}\;and\;$IL-1{\beta}$ genes increased from 1 to 4h, and then decreased from 4 to ISh. However, the expression level of COX-2 gene increased continuously up to 11h. $IL-1{\alpha},\;IL-1{\beta}$ and COX-2 genes were expressed synergistically by a simultaneous treatment of both Samjunghwan and LPS in macrophages. Secretion levels of translated $IL-1{\beta}$ increased continuously up to 11h. Conclusions : Though this study is only a start in the investigation of the efficasy of Samjunghwan, these results suggest that Samjunghwan has positive effects on immune responses.

• The korean journal of orthodontics
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• v.34 no.3 s.104
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• pp.261-267
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• 2004

Nonsyndromic cleft lip and/or palate (NSCLP) is one of the most common congenital deformities and its prevalence in Far East Asia, such as within Korean and Japanese populations, is relatively high. However, in the eastern part of Europe, clefts are relatively rare situations. These ethnic differences infer a genetic background of the disease. The objective of this study was to compare the frequency of single nucleotide polymorphism (SNP) in $TGF-{\beta}3$ between Korean and Romanian cleft families. Korean cleft families samples were collected from twenty-six families (n=78) and Romanian cleft families samples were collected from eighteen families (n=41). For sequencing, the blood or saliva of the subjects was sampled. A single nucleotide polymorphism was observed in the intron 5 of $TGF-{\beta}3$ (Al8141G). The frequency of each allele was significantly different between the Korean and Romanian samples. The Ah allele was present in 18 out of 78 Korean samples (23.1%) and in 27 out of 41 Romanian samples (65.9%). The AG was present in 27 (34.6%) out of 78 Koreans and in 13 (31.7%) out of 41 Romanians. The GG was found in 33 (42.3%) Koreans and in 1 (2.4%) Romanian. The difference between the groups was significant (p<0.001). In conclusion, the frequency of observed SNP was significantly different between the two countries. SNP in $TGF-{\beta}3$ in the Korean population seemed to have a higher possibility of occurrence for nonsyndromic cleft palate than the Romanian population.

• Journal of the korean academy of Pediatric Dentistry
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• v.30 no.3
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• pp.391-405
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• 2003

Craniosynostosis, known as a premature fusion of cranial sutures, is a developmental disorder characterized by precocious differentiation and mineralization of osteoblasts in the calvarial sutures. Recent genetic studies have demonstrated that mutation in the homeobox gene Msx2 causes Boston-type human craniosynostosis. Additionally, the phenotype of Dlx5 homozygote mutant mouse presents craniofacial abnormalities including a delayed ossification of calvarial bone. Furthermore transcription of osteocalcin, a mature osteoblast marker, is reciprocally regulated by the homeodomain proteins Msx2 and Dlx5. These facts suggest important roles of osteocalcin, Msx2 and Dlx5 genes in the calvarial bone growth and suture morphogenesis. To elucidate the function of these molecules in the early morphogenesis of mouse cranial sutures, we have first analyzed by in situ hybridization the expression of osteocalcin, Msx2 and Dlx5 genes in the developing parietal bone and sagittal suture of mouse calvaria during the embryonic (E15-E18) stage. Osteocalcin mRNA was found in the periosteum of parietal bones from E15, and gradually more highly expressed with aging. Msx2 mRNA was intensely expressed in the sutural mesenchyme, osteogenic fronts and mildly expressed in the dura mater during the embryonic stage. Dlx5 mRNA was intensely expressed osteogenic fronts and the periostem of parietal bones. To further examine the upstream signaling molecules of transcription factor Msx2 and Dlx5, we have done in vitro experiments in E15.5 mouse calvarial explants. Interestingly, implantation of BMP2-, BMP4-soaked beads onto the osteogenic fronts after 48 hours organ culture induced etopic expressions of Msx2 and Dlx5 genes. On the other hand, overexpression of $TGF{\beta}1$, GDF-6, -7, FGF-2, -4 and Shh did not induce the expression of Msx2 and Dlx5. Taken together. these data indicate that transcription factor Msx2 and Dlx5 play critical roles in the calvarial bone and suture development, and that BMP siganling is involved in the osteogenesis of calvarial bones and the maintenance of cranial sutures through regulating these two transcriotpn factors. Furthermore, different expression patterns between Msx2 and Dlx5 suggest their specific functions in the osteoblast differentiation.

• The korean journal of orthodontics
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• v.34 no.2 s.103
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• pp.131-142
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• 2004

The movement of tooth-bone segments by osteotomy can simultaneously shift tooth and surrounding alveolar bone in a relatively short period. The purpose of this study was to evaluate the tissue changes in pulp, periodontal ligament, and alveolar bone in rapid tooth-bone movement with osteotomy. The mandibular 3rd premolar of a dog was extracted and cortical bones of the buccal and lingual area were eliminated, and then cortical bones around the mesial and distal area of root, and below the root apex of the mandibular 4th premolar were osteotomized. After a one-week latency period, a tooth-borne distraction device was activated for 6 days. And pulp, periodontal ligament and alveolar bone were evaluated clinically, radiologically, histologically and immunohistochemically at 0, 1, 2, 4, 6, 8 weeks of the consolidation Period and conclusions were roached as follows. 1. Latency period didn't affect total amount or tooth movement and healing process of tissue during consolidation period. 2. Bone formation continued through 8 weeks of consolidation in distracted side, with a high peak at 1-2 weeks, and the lowest at 6-8 weeks or consolidation. 3. At 1 week of consolidation, alveolar bone resorption, osteoclast appearance and inflammatory cell infiltration were the most active, and dentinoclasts characteristically appeared on the pulp and pressure side of the periodontal ligament. 4. The expression of $TGF-\beta$ was area-specific, as it was strong-positive at bone matrix, osteoblast osteoclast of alveolar bone, and dentinoclast inside pulp, but weak in pulp, cementoblast and acellular cementum. 5. The expression of $TGF-\beta$ was generally observed at the initial 1-2 weeks of consolidation at vessels, periodontal ligament cells, and osteoblast near alveolar bone on the distraction side of the periodontal ligament, and was significantly decreased after 6 weeks of consolidation.

• Tuberculosis and Respiratory Diseases
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• v.50 no.4
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• pp.450-461
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• 2001

Background : The underlying pathogenesis of radiation-induced lung fibrosis (RTLF) has not been very well defined. However, the role of TGF-$\beta$ in the generation of RTLF has been a major focus because there is an increase in the expression of both the TGF-${\beta}m$-RNA and its protein preceding RTLF lesions. The down stream signal after a TGF-$\beta$ stimulated lung fibrosis includes the activation of many mediators such as Smad and c-Jun N-terminal kinase (JNK) through TAK1. It is we hypothesized that JNK activation may play a pivotal role in RTLF pathogenesis through increased transcription of the fibrogenic cytokines. The present study evaluates JNK activity in alveolar macrophages after irradiation and the relationship between JNK activity and the amount of collagen in the lung tissues. Methods : C57BL/6 mice(20-25 gr, males) received chlorotetracycline(2g/L) in their drinking water 1 week prior to irradiation and continuously there after. The mice were irradiated once with 1400 cGy of $60CO{\gamma}$-ray over the whole chest. The cellular composition of the whole lung bronchoalveoalr lavage fluids(BALF), elastin expression in the lung tissues, the level of hydroxyproline in lung tissues, and an in vitro JNK assay was measured before irradiation and one, four, and eight weeks after irradiation (RT). Results : The volumes of BALF retrieved from instilled 4 mL of saline with 2% heparin were 3.7-3.8 mL for each group. The cell numbers were similar before($4.1{\times}10^4{\pm}0.5{\times}10^4/mL$) and 1 week($3.1{\times}10^4{\pm}0.5{\times}10^4/mL$) after RT. At four and eight weeks after RT, the cell number reached to $14.0{\times}10^4{\pm}1.5{\times}10^4mL$ and $10.0{\times}10^4{\pm}1.3{\times}10^4/mL$, respectively. There we no changes in the lymphocytes and neutrophils population observed in the BALF after RT. The H-E stain of the lung tissues did not show any structural and fibrotic change in the lung tissues at 4 and 8 weeks after RT. In addition, the amount of elastin and collagen were not different on Verhoeff staining of the lung tissues before RT to eight weeks after RT. The hydroxyproine content was measured with the left lung dissected from the left main bronchus. The lung were homogenized and hydrolyzed with 6 N Hel for 12 hours at $110^{\circ}C$ then measured as previously described. The content of hydroxyproline, standardized with a lung protein concentration, reached a peak 4 weeks after RT, and thereafter showed a plateau. AnIn vitro JNK assay using c-$Jun_{1-79}$-GST sepharose beads were performed with the alveolar macrophages obtained from the BAL. JNK activity was not detected prior to RT, However, the JNK activity increased from one week after RT and reached a peak four weeks after RT. Conclusion : JNK may be involved in the pathogenesis because the JNK activity showed similar pattern observed with the hydroxyproine content. However, it is necessary to clarify that the JNK increases the transcription of fibrogenic cyiokines through the transcription factor.

• Archives of Pharmacal Research
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• v.25 no.6
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• pp.917-922
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• 2002

We investigated the long term effects of Sopungsungi-won (SP), a Korean traditional formula used for senile constipation and diabetes mellitus, on the development of diabetic nephropathy (DN) in Zucker diabetic fatty (ZDF) rats. ZDF rats were fed regular laboratory chow mixed with SP or rosiglitazone (RSG) for an 8-week period. Kidney hypertrophy was developed with increasing plasma glucose level, and glomerular hypertrophy was improved by 22% and 45% in SP- and RSG-treated rats, respectively. Urinary glucose and albumin excretions were also significantly lower in SP-treated rats than in ZDF control rats. Activation of the mitogen-activated protein kinase (MAPK)-transforming growth factor ${\beta}1$ (TGF ${\beta}1$)-fibronectin pathway in kidney, responsible for glomerular dysfunction, was markedly blunted by SP treatment in a dose dependent manner. Our findings, for the first time, provide strong evidence that long-term administration of SP formula prevents the development and progression of DN in ZDF rats. Human trials are needed to confirm these experimental results.