• IMMUNE NETWORK
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• v.23 no.6
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• pp.45.1-45.22
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• 2023

Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DWMSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.

• Journal of Pharmacopuncture
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• v.27 no.1
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• pp.1-13
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• 2024

Background: Diabetic nephropathy (DN) is one of the major complications of chronic hyperglycaemia affecting normal kidney functioning. The ayurvedic medicine curcumin (CUR) is pharmaceutically accepted for its vast biological effects. Objectives: The Curcuma-derived diferuloylmethane compound CUR, loaded on Poly (lactide-co-glycolic) acid (PLGA) nanoparticles was utilized to combat DN-induced renal apoptosis by selectively targeting and modulating Bcl2. Methods: Upon in silico molecular docking and screening study CUR was selected as the core phytocompound for nanoparticle formulation. PLGA-nano-encapsulated-curcumin (NCUR) were synthesized following standard solvent displacement method. The NCUR were characterized for shape, size and other physico-chemical properties by Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Fourier-Transform Infrared (FTIR) Spectroscopy studies. For in vivo validation of nephro-protective effects, Mus musculus were pre-treated with CUR at a dose of 50 mg/kg b.w. and NCUR at a dose of 25 mg/kg b.w. (dose 1), 12.5 mg/kg b.w (dose 2) followed by alloxan administration (100 mg/kg b.w) and serum glucose levels, histopathology and immunofluorescence study were conducted. Results: The in silico study revealed a strong affinity of CUR towards Bcl2 (dock score -10.94 Kcal/mol). The synthesized NCUR were of even shape, devoid of cracks and holes with mean size of ~80 nm having -7.53 mV zeta potential. Dose 1 efficiently improved serum glucose levels, tissue-specific expression of Bcl2 and reduced glomerular space and glomerular sclerosis in comparison to hyperglycaemic group. Conclusion: This study essentially validates the potential of NCUR to inhibit DN by reducing blood glucose level and mitigating glomerular apoptosis by selectively promoting Bcl2 protein expression in kidney tissue.

• Journal of Applied Biological Chemistry
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• v.66
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• pp.213-220
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• 2023

The most common skin disease, acne, often occurs in adolescence, but it is also detected/observed in adults due to air pollution and drug abuse. One of the causative agents of acne, Cutibacterium acnes (C. acnes) plays a role in the development of skin acne by inducing inflammatory mediators. Torreya nucifera (TN) is an evergreen tree of the family Taxaceae, having well reported antioxidant, anti-proliferative, liver protection, and nerve protection properties. Improvement of these bioactive properties of natural products is one of the purposes of natural product chemistry and pharmaceuticals. We believe biorenovation could be one improvement strategy that utilizes microbial metabolism to produce unique derivatives having enhanced bioactivity. Therefore, in this study, the C. acnes-induced RAW264.7 inflammation model was used to evaluate the anti-inflammatory activity of the biorenovated Torreya nucifera product (TNB). The results showed improved viability of TNB-treated cells compared to TN-treated cells in the concentration range of 50, 100, and 200 ㎍/mL. At non-toxic concentrations, TNB inhibited the production of nitric oxide and prostaglandin E2 by suppression of inducible nitric oxide synthase and cyclooxygenase-2 protein expression. TNB also attenuated the expression of interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor-α induced by C. acnes. Furthermore, TNB inhibited the nuclear factor-κB signaling pathway, a transcription factor known to regulate inflammatory mediators. Based on these results, this study suggests the potential of using TNB as natural material for the treatment of acnes and thus, supporting our postulation of biorenovation as an bioactivity improvement strategy.

• The Korean Journal of Pharmacology
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• v.25 no.1
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• pp.115-134
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• 1989

Combined effects of ganciclovir (GCV) and vidarabine (ara-A) on the replication, DNA synthesis, and gene expression of wild type-1 herpes simplex virus (HSV-1) and three acyclovir (ACV)-resistant HSV-1 mutants were studied. These mutants include a virus expressing no thymidine kinase $(ACV^r)$, a virus expressing thymidine kinase with altered substrate specificity $(IUdR^r)$, and a mutant expressing altered DNA polymerase $(PAA^r5)$. GCV, an agent activated by herpesvirus specific thymidine kinase, showed potent antiviral activity against the wild type HSV-1(KOS) and DNA polymerase mutant $(PAA^r5)$. The ACV-resistant mutants with thymidine kinase gene $(ACV^r\;and\;IUdR^r)$ were resistant to GCV. All tested wild type HSV-1 or ACV-resistant HSV-1 mutants did not display resistance to vidarabine (are-A). Combined GCV and ara-A showed potentiating synergistic antiviral activity against wild type KOS and $PAA^r5$, and showed subadditive combnined ativiral activity against thymidine kinase mutants. Combined GCV and ara-A more significantly inhibited the viral DNA synthesis in wild type KOS and $PAA^r5-infected$ cells to a greater extent than either agent alone, but the synergism was not determined in $ACV^r$ or $IUdR^r-infected$ cells. These data clearly indicate that combined GCV and ara-A therapy might be useful for the treatment of infections caused by wild type HSV-1 or ACV-resistant HSV-1 with DNA polymerase mutation. ACV-resistant viruses with the mutation in thymidine kinase gene are also, resistant to GCV, but susecptible to ara-A, indicating that ara-A would the drug of choice for the treatment of ACV-resistant HSV-1 which does not express thymidine kinase or expresses thymidine kinase with altered substrate specificity. While the synthesis of viral ${\alpha}-proteins$ of wild type HSV-1 was not affected by ACV, GCV, ara-A, or combined GCV and ara-A, the synthesis of ${\beta}-proteins$ was slightly but significantly increased at the later stage of viral infection by the antiviral agents. The synthesis of ${\gamma}-proteins$ of wild type HSV- 1 was significantly inhibited by ACV, GCV, ara-A, and combined GCV and ara-A. Combined GCV $(5-{\mu}M)$ and ara-A $(100-{\mu}M)$ also significantly altered the expression of viral ${\beta}-and$ ${\gamma}-proteins$, of which efffct was similar to that of GCV $(10-{\mu}M)$ alone. Although ACV at the concentration of $10-{\mu}M$ did not alter the expression of ${\alpha}-$, ${\beta}-$, and ${\gamma}-proteins$ of ACV-resistant $PAA^r5$, GCV and ara-A significantly alter the epression of ${\beta}-and$ ${\gamma}-proteins$, not ${\alpha}-protein$, as same manner as they altered the expression of those proteins in cells inffcted with wild type HSV-1. Combined GCV $(5-{\mu}M)$ and ara-A $(100-{\mu}M)$ altered the expression ${\beta}-and$ ${\gamma}-proteins$ in $PAA^r5$ infected cells, and the effect of combined regimen was comparable of that of GCV $(10-{\mu}M)$. These data indicate that the alteration in the expression of ${\beta}-and$ ${\gamma}-proteins$ in wild type HSV-1 or $PAA^r5$ infected cells could be more significantly affected by combined GCV and are-A than individual GCV or ara-A. In view of the fact that (a) viral ${\alpha}-$, ${\beta}-$, and ${\gamma}-proteins$ are synthesized in a cascade manner; (b) ${\beta}-proteins$ are essential for the synthesis of viral DNA; (c) the synthesis of ${\beta}-proteins$ are inhibited by ${\gamma}-proteins$; and (d) most ${\gamma}-proteins$ are made from the newly synthesized progeny virus, it is suggested that GCV and ara-A, alone or in combination, primarily inhibit the synthesis of viral DNA, and by doing so might exhibit their antiherpetic activity. The alteration in viral protein synthesis in the presence of tested antiviral agents could result from the alteration in viral DNA synthesis. From the present study, it can be concluded that (a) combined GCV and ara-A therapy would be beneficial for the control of inffctions caused by wild type HSV-1 or ACV-resistant DNA polymerase mutants; (b) the combined synergistic activity of GCV and ara-A is due to further decrease in the viral DNA by the combined regimen; (c) ara-A is the drug of choice for the infection caused by ACV-resistant HSV-1 with thymidine kinase mutation; and (d) the alteration in viral protein synthesis by GCV and ars-A, alone or in combination, is mostly due to the decreased synthesis of viral DAN.

• Journal of Life Science
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• v.26 no.5
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• pp.509-518
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• 2016

Asparagus cochinchinensis is a medical plant that has long been used to treat fever, cough, kidney disease, breast cancer, inflammatory disease and brain disease in northeast Asian countries. Although several studies have been conducted on the anti-neuroinflammatory effects of A. cochinchinensis, the correlation between these effects and nerve growth factor (NGF) has not yet been examined. In this study, we investigated the effects of an aqueous extract of A. cochinchinensis (AEAC) on the secretion and action mechanism of NGF in neuronal cells. The concentration of the NGF protein in the supernatant collected from cultured cells increased significantly in B35 cells treated with AEAC in comparison with the vehicle-treated group without any specific cytotoxicity. Furthermore, the mRNA expression of NGF showed a very similar pattern to its protein concentration. To examine the bioactivity of NGF secreted from B35 cells, undifferentiated PC12 cells were cultured in an AEAC-conditioned medium and neuritic outgrowth was observed. The dendrite length of PC12 cells in the AEAC-treated group was significantly higher than that in the vehicle-treated group. Moreover, the level of the downstream effectors p-TrkA and p-ERK of the high-affinity NGF receptor was significantly higher in the AEAC-treated group, while the expression of the downstream effectors of the low-affinity NGF receptor was significantly lower in the same group. These results suggest that AEAC may contribute to the regulation of NGF expression and secretion in neuronal cells; it is therefore an excellent candidate for further investigation as a therapeutic drug for neurodegenerative diseases.

• The Journal of the Korean bone and joint tumor society
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• v.15 no.2
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• pp.111-121
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• 2009

Background: Osteosarcoma is one of the most common primary malignant tumors of bone occurring mainly in children and adolescents. Although surgery combined with chemotherapy has markedly improved patient survival during the last years, the use of anticancer drugs is still associated with serious problem, such as the frequent acquisition of drug-resistant phenotypes and occurrence of "secondary malignancies". Several solid tumors display enhanced expression of matrix metalloproteinases (MMPs), and recently clinical trials have been initiated on MMP-inhibitors. On the other hand, bisphosphonates (BPs) are inhibitors of bone resorption, and widely used to treat osteoclast-mediated bone diseases. Also they appear to possess direct antitumor activity. Methods: One osteosarcoma cell line (U2OS) was treated with ibandronate (0, 0.1, 1, $10{\mu}M$) for 48 hours. Cell viabilities were determined using MTT assay, the mRNA levels of MMP-2 and MT1-MMP were detected by reverse-transcription polymerase chain reaction, the amount of MMP-2 and MT1-MMP protein were measured by Westernblot, the activities of MMP-2 were observed by Gelatin zymography, and Matrigel invasion assays were used to investigate the invasive potential of osteosarcoma cell lines before and after ibandronate treatment. Results: The invasiveness of U2OS cell line was reduced dose-dependently following 48 hour treatment of up to $10{\mu}M$ of the ibandronate at which concentration no cytotoxicity occurred. Furthermore, the gelatinolytic activities and protein and mRNA levels of MMP-2 and MT1-MMP were also suppressed by increasing ibandronate concentrations. Conclusion: Given that MMP-2 is instrumental in tumor cell invasion, it is very likely that the reduction in osteosarcoma cell invasion by ibandronate is a consequence, at least in part, of suppressed expression of both MMP-2 and MT1-MMP. Isolation of a molecule (s) responsible for the bisphosphonate inhibition of tumor cell invasion would pave the way for the development of a new generation of metastasis inhibitors.

• Journal of the Korean Society of Food Science and Nutrition
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• v.36 no.3
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• pp.276-283
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• 2007

This study was carried out to investigate the effect of isoflavone on the atherogenic effect in C57BL/6 mice. C57BL/6 female mice, 5 weeks of age, were fed on chow diets for 2 weeks during adjustment period. Mice weighing approximately $17.9{\pm}0.9\;g$ were divided into 4 groups and were fed on the experimental diets containing isoflavone for 8 weeks. Experimental groups were control (atherogenic diet), IF-10 (atherogenic diet with isoflavone 10 mg/100 g diet), IF-40 (atherogenic diet with isoflavone 40 mg/100 g diet) and IF-100 (atherogenic diet with isoflavone 100 mg/100 g diet). Food efficiency ratio was not different among the experimental groups. Plasma triglyceride (TG) concentrations were lower after 4 weeks in isoflavone supplementation groups than in control group, whereas monocyte chemoattractant protein-1 and thiobarbituric acid reactive substances (TBARS) levels of plasma were significantly (p<0.05) decreased in the isoflavone supplementation groups in a dose dependent manner. Both hepatic TG and cholesterol levels were significantly lowered in IF-100 than control. Hepatic glutathione concentrations were higher in the IF-100 group than in the other groups. Hepatic antioxidant enzyme activities including glutathione-reductase, glutathione-peroxidase, catalase, and Mn-superoxide dismutase were significantly higher in the isoflavone supplemen-tation groups in a dose dependent manner. From the above results, it is concluded that isoflavone may reduce the risk of atherosclerosis via hypolipidemic, anti-oxidative and anti-inflammatory effects.

• Pediatric Infection and Vaccine
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• v.10 no.2
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• pp.159-166
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• 2003

Purpose : Streptococcus pneumoniae is part of the normal flora but is also responsible for causing many invasive diseases such as pneumonia, meningitis, and sepsis in addition to noninvasive diseases such as otitis in children. Multi-drug resistant strains has raised a lot of concern worldwide and thus the importance of prevention has been emphasized. We have analyzed the current serotypes and antibiotic sensitivity of each serotype as a baseline study to estimate the efficacy of the pneumococcal vaccine in Korean children. Methods : One hundred sixteen cases of pneumococcus cultured at Yonsei Medical Center from September 2001 to January 2003 were analyzed. The serotyping was done with the Quellung reaction and penicillin resistance was tested using the oxacillin disc diffusion method. Results : Pneumococcus were cultured from the sputum in 76 cases(65.5%), from the blood in 13 cases(11.2%), from the ear discharge in 12 cases(10.3%), from the throat in 7 cases(6.0%), from the nasal cavity in 2 cases(1.7%), and one case(0.9%) each from the cerebrospinal fluid, eye discharge, peritoneal fluid, post-operational wound, brain abscess, and catheter tip. Serotyping was possible with 98 cases and the following serotypes were found; 15 cases of type 19F(15.3%), 11 cases of 19A(11.2%), 8 cases of 11A(8.2%), 7 cases each of 6A, 14 and 3(7.1%), 6 cases each of 35, 6B and 23F(6.1%). Eighty two cases(70.7%) out of 116 cases were penicillin resistant and serotypes 19F, 19A, 11A, 23F, 6A, 9V constituted the majority, 48 cases(59.8%). These serotypes showed resistance to cotrimoxazole (74.4%), tetracycline(69.5%), and erythromycin(90.3%) as well. In the 22 cases cultured from children, 19A and 19F were found in 25.0%, 6A, 6B, and 23F in 10.0%, 11A, 14, 19, and 29 in 5.0%. Fifty percent(10/20) of the clinical isolates were represented in the current 7-valent pneumococcal protein conjugate vaccine, and 85%(17/20) when the cross-reacting serotypes were included. Penicillin resistance was found in 86.4%(19/22). Conclusion : The percentage of serotypes included in the 7 valent pneumococcal protein conjugate vaccine found in our study was 40.8% which was less than other prior studies. In anticipation of a change of pneumococcal serotypes, a nationwide multicenter study is needed before the initiation of pneumococcal vaccines in Korea.

• Journal of Nutrition and Health
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• v.41 no.8
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• pp.733-741
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• 2008

In the present study, we comprehensively examined the associations of plasma levels of total adiponectin and high molecular weight (HMW) adiponectin with the features of cardiometabolic risks including body fat distribution, dyslipidemia, insulin resistance and inflammatory markers in a cross-sectional study of 110 treated hypertensive patients. Blood lipid profiles, high sensitivity C-reactive protein (hsCRP) and homeostasis model assessment of insulin resistance (HOMA- IR) derived from fasting glucose and insulin concentrations were determined. Plasma levels of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were analyzed using ELISA. The results showed that plasma levels of HMW-adiponectin were negatively associated with body mass index (BMI, r = - 0.203, p < 0.05) and waist circumference (r = -0.307, p < 0.01), which was not shown in total adiponectin. Plasma levels of HMW-adiponectin were negatively associated with triglyceride (r = -0.223, p < 0.05) and positively associated with HDL-cholesterol (r = 0.228, p < 0.05). Plasma levels of adiponectin were positively associated with HDL-cholesterol (r = 0.224, p < 0.05). Plasma levels of HMW-adiponectin were negatively associated with hsCRP (r = -0.276, p < 0.01) and IL-6 (r = -0.272, p < 0.01). In addition, there were weak associations between plasma levels of HMWadiponectin and TNF-${\alpha}$ (r = -0.163, p = 0.07) and ICAM-1 (r = -0.158, p = 0.09). However, there were no significant associations of total adiponectin with inflammatory markers except hsCRP (r = -0.203, p < 0.05). Stepwise multiple linear regression analysis showed that only plasma levels of HMW-adiponectin was an independent factor influencing serum levels of hsCRP, a marker of systemic low grade inflammation, after adjusting for age, gender, BMI, waist circumference, alcohol intake, smoking status, blood lipids, total adiponectin and drug use (p < 0.01). These results suggest that HMW-adiponectin, rather than total adiponectin, is likely to be closely associated with the features of cardiometabolic risks in treated hypertensive patients and might be effective biomarker for the prediction of cardiovascular disease.

• Journal of Life Science
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• v.19 no.8
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• pp.1073-1080
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• 2009

A number of studies have demonstrated that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risks of colorectal, oesophageal and lung cancers. NSAIDs have been shown to exert their anti-cancer effects through inducing apoptosis in cancer cells. The susceptibility of tumor cells to anti-tumor drug-induced apoptosis appears to depend on the balance between pro-apoptotic and anti-apoptotic programs such as nuclear factor kB (NF-kB), phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) and MEK1/2-ERK1/2 pathways. We examined the effects of pro-survival PI3K and ERK1/2 signal pathways on cell cycle arrest and apoptosis in response to NSAIDs including sulindac sulfide and NS398. We show that simultaneous inhibition of the Akt/PKB and ERK1/2 signal cascades could synergistically enhance the potential pro-apoptotic activities of sulindac sulfide and NS398. Similar enhancement was observed in cells treated with sulindac sulfide or NS398 and 100 ${\mu}$M genistein, an inhibitor of receptor tyrosine kinases (RTKs) that are upstream of PI3K and MEK1/2 signaling. We further demonstrate that NAG-1 is induced and plays a critical role(s) in apoptosis by NSAIDs-based combined treatment. In sum, our results show that combinatorialtreatment of sulindac sulfide or NS398 and genistein results in a highlysynergistic induction of apoptotic cell death to increase the chemopreventive effects of the NSAIDs, sulindac sulfide and NS398.