• Journal of Pharmaceutical Investigation
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• 제31권1호
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• pp.43-47
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• 2001

Sterically stabilized liposomes (SSL) have been introduced for longer circulation in blood than conventional liposomes (CL). However, there are a couple of problems in SSL preparation due to the instability of phospholipid and the degradation of drug in aqueous conditions. To solve these problems, it is necessary to go through lyophilization process. Therefore, in this study, effects of lyophilization on SSL were evaluated for physical characteristics changes upon rehydration of lyophilized SSL such as the particle size, efficiency of drug entrapment, turbidity and drug release. SSL containing streptozocin, a water-soluble anticancer drug as a model compound, were prepared with DSPC and DSPE-PEG 2000. The size was controlled to 100 nm by extrusion with polycarbonate membrane, and sucrose was used as a cryoprotectant for lyophilization at the 1:3 (lipid:sucrose) ratio. Upon rehydration of lyophilized SSL, the average size was in the range of $50{\sim}200\;nm$ which is adequate for longer circulation in blood, and the encapsulation efficiency was kept as its initial state. Rehydrated SSL were not adsorbed to rat plasma protein and revealed a similar drug release profile to that of fresh SSL before lyophilization. Therefore, lyophilization could be introduced efficiently to overcome aqueous instability problems of SSL.

• Molecules and Cells
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• 제39권2호
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• pp.156-162
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• 2016

Estrogen receptor ${\alpha}$ (ER-${\alpha}$), which is involved in bone metabolism and breast cancer, has been shown to have transcriptional targets. Dlx3 is essential for the skeletal development and plays an important role in osteoblast differentiation. Various osteogenic stimulators and transcription factors can induce the protein expression of Dlx3. However, the regulatory function of ER-${\alpha}$ in the Dlx3 mediated osteogenic process remains unknown. Therefore, we investigated the regulation of Dlx3 and found that ER-${\alpha}$ is a positive regulator of Dlx3 transcription in BMP2-induced osteoblast differentiation. We also found that ER-${\alpha}$ interacts with Dlx3 and increases its transcriptional activity and DNA binding affinity. Furthermore, we demonstrated that the regulation of Dlx3 activity by ER-${\alpha}$ is independent of the ligand (estradiol) binding domain. These results indicate that Dlx3 is a novel target of ER-${\alpha}$, and that ER-${\alpha}$ regulates the osteoblast differentiation through modulation of Dlx3 expression and/or interaction with Dlx3.

• 통합자연과학논문집
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• 제15권4호
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• pp.145-152
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• 2022

Colon rectal cancer is one of the frequently diagnosed cancers worldwide. In recent times the drug discovery for colon cancer is challenging because of their speedy metastasis and morality of these patients. C-jun N-terminal kinase signaling pathway controls the cell cycle survival and apoptosis. Evidence has shown that JNK1 promotes the tumor progression in various types of cancers like colon cancer, breast cancer and lung cancer. Recent study has shown that inhibiting, JNK1 pathway is identified as one of the important cascades in drug discovery. One of the recent approaches in the field of drug discovery is drug repurposing. In drug repurposing approach we have virtually screened ChEMBL dataset against JNK1 protein and their interactions have been studied through Molecular docking. Cross docking was performed with the top compounds to be more specific with JNK1 comparing the affinity with JNK2 and JNK3.The drugs which exhibited higher binding were subjected to Conceptual - Density functional theory. The results showed mainly Entrectinib and Exatecan showed better binding to the target.

• Molecules and Cells
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• 제23권1호
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• pp.11-16
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• 2007

N,N-dimethyl-D-erythro-sphingosine (DMS) is an N-methyl derivative of sphingosine and an inhibitor of protein kinase C (PKC) and sphingosine kinase (SK). In the present study, we examined the effects of DMS on intracellular $Ca^{2+}$ concentration, pH, and glutamate uptake in human 1321N1 astrocytes. DMS increased intracellular $Ca^{2+}$ concentration and cytosolic pH in a concentration-dependent manner. Pretreatment of the cells with the $G_{i/o}$ protein inhibitor PTX and the PLC inhibitor U73122 had no obvious effect. However, removal of extracellular $Ca^{2+}$ with the $Ca^{2+}$ chelator EGTA or depletion of intracellular $Ca^{2+}$ stores with thapsigargin impeded the DMS-induced increase of intracellular $Ca^{2+}$ concentration. Pretreatment of cells with $NH_4Cl$ or monensin reduced the DMS-induced $Ca^{2+}$ increase. However, inhibition of the DMS-induced $Ca^{2+}$ increase with BAPTA did not influence the DMS-induced pH increase. DMS also inhibited glutamate uptake by the 1321N1 astrocytes in a concentration-dependent manner. It also increased intracellular $Ca^{2+}$ and pH in PC12 neuronal cells. Our observations on the effects of DMS on 1321N1 astrocytes and PC12 neuronal cells point to a physiological role of DMS in the brain.

• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.6321-6326
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• 2013

Introduction: Lung cancer is extremely harmful to human health and has one of the highest worldwide incidences of all malignant tumors. Approximately 80% of lung cancers are classified as non-small cell lung cancers (NSCLCs). Cisplatin-based multidrug chemotherapy regimen is standard for such lesions, but drug resistance is an increasing problem. F-box/WD repeat-containing protein 7 (FBW7) is a member of the F-box protein family that regulates cell cycle progression, and cell growth and differentiation. FBW7 also functions as a tumor suppressor. Methods: We used cell viability assays, Western blotting, and immunofluorescence combined with siRNA interference or plasmid transfection to investigate the underlying mechanism of cisplatin resistance in NSCLC cells. Results: We found that FBW7 upregulation significantly increased cisplatin chemosensitivity and that cells expressing low levels of FBW7, such as NCI-H1299 cells, have a mesenchymal phenotype. Furthermore, siRNA-mediated silencing or plasmid-mediated upregulation of FBW7 resulted in altered epithelial-mesenchymal transition (EMT) patterns in NSCLC cells. These data support a role for FBW7 in regulating the EMT in NSCLC cells. Conclusion: FBW7 is a potential drug target for combating drug resistance and regulating the EMT in NSCLC cells.

• Nutrition Research and Practice
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• 제13권1호
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• pp.11-16
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• 2019

BACKGROUND/OBJECTIVES: Fasting and postprandial hyperglycemia should be controlled to avoid complications of diabetes mellitus. This study investigated the effects of autumn olive (Elaeagnus umbellata Thunb.) berry (AOB) on fasting and postprandial hyperglycemia in mice. MATERIALS/METHODS: In vitro ${\alpha}$-glucosidase inhibitory effect of AOB was determined. Maltose solution (2 g/kg) with and without AOB extract at 500 mg/kg or acarbose at 50 mg/kg was orally administered to normal mice after overnight fasting and glucose levels were measured. To study the effects of chronic consumption of AOB, db/db mice received the basal diet or a diet containing AOB extract at 0.4% or 0.8%, or acarbose at 0.04% for 7 weeks. Blood glycated hemoglobin and serum glucose and insulin levels were measured. Expression of adiponectin protein in epididymal white adipose tissue was determined by Western blotting. RESULTS: In vitro inhibitory effect of AOB extract on ${\alpha}$-glucosidase was 92% as strong as that of acarbose. The AOB extract (500 mg/kg) or acarbose (50 mg/kg) significantly suppressed the postprandial rise of blood glucose after maltose challenge and the area under the glycemic response curve in normal mice. The AOB extract at 0.4% or 0.8% of diet or acarbose at 0.04% of diet significantly lowered levels of serum glucose and blood glycated hemoglobin and homeostasis model assessment for insulin resistance values in db/db mice. The expression of adiponectin protein in adipose tissue was significantly elevated by the consumption of AOB at 0.8% of diet. CONCLUSIONS: Autumn olive (E. umbellata Thunb.) berry may reduce postprandial hyperglycemia by inhibiting ${\alpha}$-glucosidase in normal mice. Chronic consumption of AOB may alleviate fasting hyperglycemia in db/db mice partly by inhibiting ${\alpha}$-glucosidase and upregulating adiponectin expression.

• 약학회지
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• 제41권5호
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• pp.629-637
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• 1997

Tumor necrosis factor-${alpha}$ (TNF) induced a cytotoxic response in ME-180 cervical carcinoma cells in vitro. This cytotoxic response was accompanied by a temporal series of mitogenic stimuli : increased c-fos, c-jun and jun-B expression. Depletion of protein kinase C (PKC) by exposure of ME-180 cells to 100ng/ml phorbol myristate acetate (PMA) for 24hours almost completely abolished TNF-mediated increase in these signals, indicating that a PKC-dependent pathway is involved in TNF-mediated increases in the expression of c-fos, c-jun and jun-B. Characteristics of TNF receptors after exposure to 100ng/ml PMA or 24hours were not altered, suggesting that diminished induction of these oncogenes by TNF after PMA treatment is not due to any changes at the receptor level. To examine whether a PKC-dependent pathway is involved in TNF-mediated cytotoxicity in ME-180 cells, cytotoxicity was measured after depletion of PKC. No apparent changes in cytototoxicity after PKC depletion suggest that a PKC-dependent pathway is not involved in TNF-mediated cytotoxicity. Furthermore, results from cytotoxicity tests after exposure to staurosporine (PKC inhibitor) did not show any changes in the TNF-mediated cytotoxicity, confirming that a PKC-dependent pathway is not involved in this process. These data indicate that 1) TNF induces expression of c-fos, c-jun and jun-B oncogenes via a PKC-dependent pathway and 2) PKC-dependent expression of these three oncogenes by TNF may not be involved in TNF-mediated cytotoxicity in ME-180 cells.

• Bulletin of the Korean Chemical Society
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• 제32권3호
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• pp.1000-1006
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• 2011

The discovery of carbohydrate-based bioactive compounds has recently received considerable interest in the drug development. This paper stresses on the application of 1-methoxy-O-glucoside as the central scaffold, whereas salicylic pharmacophores were introduced with diverse spatial orientations probing into the structural preference of an enzymatic target, i.e. protein tyrosine phosphatase 1B (PTP1B). By employing regioselective protection and deprotection strategy, 2,6-, 3,4-, 4,6- and 2,3-di-O-propynyl 1-methoxy-O-glucosides were previously synthesized and then coupled with azido salicylate via click chemistry in forming the desired bidentate salicylic glucosides with high yields. The inhibitory assay of the obtained triazolyl derivatives leads to the identification of the 2,3-disubstituted salicylic 1-methoxy-O-glucoside as the structurally privileged PTP1B inhibitor among this bidentate compound series with micromole-ranged $IC_{50}$ value and reasonable selectivity over other homologous PTPs tested. In addition, docking simulation was conducted to propose a plausible binding mode of this authorized inhibitor with PTP1B. This research might furnish new insight toward the construction of structurally different bioactive compounds based on the monosaccharide scaffold.

• The Korean Journal of Physiology and Pharmacology
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• 제19권6호
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• pp.485-489
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• 2015

Diabetic nephropathy (DN) is the leading cause of end-stage failure of the kidney, but the efficacy of currently available strategies for the prevention of DN remains unsatisfactory. In this study, we investigated the effects of free anthraquinones (FARs) extract, which was extracted from the rhubarb and purified by macroporous resin DM130 with gradient mixtures of ethanol/water as the lelution solvents, in high glucose-cultured glomerular mesangial cells (MCs). The cell proliferation was determined by CCK-8 assay, the levels of TGF-${\beta}1$, CTGF, ColIV and FN proteins in the supernatant of MCs were measured by ELISA assays, and the mRNA levels of these four genes were detected by RT-PCR. The results showed that the increased proliferation of MCs, the mRNA levels and protein expression of TGF-${\beta}1$, CTGF, ColIV and FN induced by high glucose were inhibited after the treatment with the FARs extract. This indicated that FARs extract could inhibit cell proliferation and the expression of main extracellular matrix induced by high glucose in MCs. The FARs extract exhibited potential values for prophylaxis and therapy of DN.

• 한국식품위생안전성학회지
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• 제15권1호
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• pp.41-45
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• 2000

Induction of DNA fragmentation of rat embryonic midbrain cells was studied to see whether apoptosis plays a role in OTA-induced microcephaly observed in cultured rat whole embryos during embryogenesis. We first cultured whole embryos (prepared from day 9.5 gestation rats) for 48 hrs with OTA and found that OTA induced microcephaly in cultured rat whole embryos. We also examined whether the microcephaly seen in cultured whole embryos is partially related to the increase of apoptosis of undifferentiated embryonic midbrain cells. Embryonic midbrain cells were prepared from day 12 gestation rat embryos, and cultured in the mixture media of Dulbecco's modified eagle's medium nutrient and Ham's F12 (1：1) containing 10% Nuserum, 100 $\mu\textrm{g}$/ml of streptomycin and 100 units/ml of penicillin for 96 hrs. Induction of DNA fragmentation was increased by 0.25-1 $\mu\textrm{g}$/ml OTA in a dose dependent manner in the embryonic midbrain cells. We also tested whether increase of apoptosis by OTA would be associated with change of apoptosis-related proteins (TNF-$\alpha$ and P$^{53}$ ) level in embryonic midbrain cells. OTA also increased TNF-$\alpha$ and P$^{53}$ levels. These results show that OTA induced microcephaly in cultured whole embryos and this effect may be at least a part due to the induction of apoptosis and apoptosis-related protein levels of undifferentiated embryonic midbrain cells.