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( Yong Pil Hwang ),( Jae Ho Choi ),( Eun Hee Han ),( Hyung Gyun Kim ),( Ji Hyang Wee ),( Kyung Ok Jung ),( Kyung Hee Jung ),( Kwang Il Kwon ),( Tae Cheon Jeong ),( Young Chul Chung ),( Hye Gwang Jeong 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
Purple sweet potato is a functional food rich in anthocyanins that possess disease-preventive properties. Anthocyanins are known to possess potent antidiabetic properties. However, the effect of the anthocyanin fraction (AF) from purple sweet potato on hepatic lipid metabolism remains unclear. Our hypothesis is that AF inhibits hepatic lipid accumulation through the activation of adenosinemonophosphate-activated protein kinase (AMPK) signaling pathways in vitro and in vivo. In this study, we evaluated body weight, liver histology, and hepatic lipid content in high-fat diet (HFD)-fed ICR mice treated with AF. In addition, we characterized the underlying mechanism of AF`s effects in HepG2 hepatocytes through Western blot analysis. Anthocyanin fraction (200 mg/kg per day) reduced weight gain and hepatic triglyceride accumulation and improved serum lipid parameters in mice fed an HFD for 4 weeks. Anthocyanin fraction significantly increased the phosphorylation of AMPK and acetyl-coenzyme A carboxylase (ACC) in the liver and HepG2 hepatocytes. In addition, AF down-regulated the levels of sterol regulatory element-binding protein 1 and its target genes including ACC and fatty acid synthase (FAS). The specific AMPK inhibitor compound C attenuated the effects of AF on the expression of lipid metabolism-related proteins such as SREBP-1 and FAS in HepG2 hepatocytes. The beneficial effects of AF on HFD-induced hepatic lipid accumulation are thus mediated through AMPK signaling pathways, suggesting a potential target for the prevention of obesity.ⓒ2011 Elsevier Inc. All rights reserved.
( Eun Young Kim ),( Won Ku Kang ),( Kwang Il Kwon ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
악물요법에 있어 약물이상반응은 환자의 사망률과 이환율에 영향을 미치는 중요한 요인이다. 약물이상반응 발생시 이를 신속히 보고하는 것과 함께 약물치료과정에서 일어날 수 있는 약물 관련부작용을 조기에 인지하고 능동적으로. 조치함으로써 환자에게 가해지는 위해를 최소화하는 것 또한 실게 환자치료의 질적인 관리에서 중요한 부분이다. 본 연구에서는 의료기록의 전산화에 따른 전산데이터들을 활용한 약물이상반응감시방법 중 하나로 평가 받고 있는 Computerized surveillance system (CSS)에 대한 사례 연구들의 방법들을 비교해 보고, 제시된 관련 시그널들 중 약물이상반응을 능동적인 방법 즉 실시간 혹은 예방적으로 적용 가능한 시그널들을 찾아 정리해 보고자 하였다. 이를 위해 가장 대표적인 연구가 진행되었던 연구사례들을 분석하였고 약 20여 개의 시그널들을 선정하여 분야별로 제시하였다.
( Yue Lu ),( Ju Hye Yang ),( Xian Li ),( Kyoung Hwang Bo ),( Seung Lark Hwang ),( Yoshitaka Taketomi ),( Makoto Murakami ),( Young Chae Chang ),( Cheorl Ho Kim ),( Jong Keun Son ),( Hycun Wook Chang ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
The high-affinity receptor for IgE (Fc□RI)-mediated activation of mast cells plays an important role in allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Emodin, a naturally occurring anthraquinone derivative in oriental herbal medicines, has several beneficial pharmacologic effects, such as anti-cancer and anti-diabetic activities. However, the anti-allergic effect of emodin has not yet been investigated. To assess the anti-allergic activity of emodin, in vivo passive anaphylaxis animal model and in vitro mouse bone marrow-derived mast cells were used to investigate the mechanism of its action on mast cells. Our results showed that emodin inhibited degranulation, generation of eicosanoids (prostaglandin D(2) and leukotriene C(4)), and secretion of cytokines (TNF-α and IL-6) in a dose-dependent manner in IgE/Ag-stimulated mast cells. Biochemical analysis of the Fc□RI-mediated signaling pathways demonstrated that emodin inhibited the phosphorylation of Syk and multiple downstream signaling processes including mobilization of intracellular Ca(2+) and activation of the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and NF-κB pathways. When administered orally, emodin attenuated the mast cell-dependent passive anaphylactic reaction in IgE-sensitized mice. Thus, emodin inhibits mast cell activation and thereby the anaphylactic reaction through suppression of the receptor-proximal Syk-dependent signaling pathways. Therefore, emodin might provide a basis for development of a novel anti-allergic drug.
( Jong Suk Lee ),( Youra Kang ),( Jong Tae Kim ),( Dinesh Tha Pa ),( Eung Seok Lee ),( Jung Ae Kim ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
Abnormal angiogenesis plays a critical role in the pathogenesis of various diseases such as cancer and chronic inflammation. A variety of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), exert their action through endothelial receptor tyrosine kinases (RTKs). The syntheticphenylpropenone derivatives, used in this study were the following: 1,3-diphenyl-propenone (DPhP), 3-phenyl-1-thiophen-2-yl-propenone (PhT2P), 3-phenyl-1-thiophen-3-yl-propenone (PhT3P) and 1-furan-2-yl-3-phenyl-propenone (FPhP). These derivatives were screened for their inhibitory effect on VEGF-induced angiogenesis in vitro using HUVECs and in vivo using chick chorioallantoic membrane (CAM). The order of anti-angiogenic activity was DPhP>FPhP>PhT3P>PhT2P. The most effective compound DPhP, also known as chalcone, showed weak VEGF receptor tyrosine kinase activity compared with the specific inhibitor, SU4312 (3-[[4-(dimethylamino)phenyl]methylene]-1,3-dihydro-2H-indol-2-one). However, DPhP also inhibited several other receptor tyrosine kinases including Tie-2, epithermal growth factor (EGF) receptor, EphB2, fibroblast growth factor (FGF) receptor 3 and insulin-like growth factor-1 (IGF-1) receptor, as revealed by a receptor tyrosine kinase array assay. In addition, the down-stream signaling, including ERK phosphorylation and NF-κB activation, after receptor activation was significantly inhibited by DPhP. Furthermore, in the HT29 human colon cancer cell-inoculated CAM assay, the tumor growth and tumor-induced angiogenesis was significantly inhibited by DPhP (10μg/ml). These results suggest that the simple flavonoid, DPhP (chalcone), has valuable potential as an antiangiogenic and anti-cancer agent, and its action is mediated through the inhibition of multi-target RTKs including VEGF receptor 2.ⓒ 2011 Elsevler B.B. All rights reserved.
효율적인 의약품 평가를 위한 약물계량학 분석법 도입의 전략 방안
( Sang Min Lee ),( Boyoon Choi ),( Hwi Yeol Yun ),( Da Hae Jun ),( Myung Gou Kim ),( Ji Hye Ha ),( Young Hoon Kim ),( Eun Hee Ji ),( Won Ku Kang ),( Na Young Han ),( Wan Gyoon Shin ),( Jung Mi Oh ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
Over the past few decades, drug regulatory agencies in advanced countries have been emphasizing pharmacomctrics as a tool for an effective and efficient drug evaluation. Despite this international movement, the value of pharmacometrics is still poorly recognized by the Korean drug evaluation system. This study aimed to analyze the current state of utiliza-tion of pharmacometrics by foreign drug regulatory agencies and develop a road map to guide the implementation phar- macometrics into the Krean drug evaluation system. MEDLINE and foreign drug regulatory agency database were extensively searched to obtain scientific research articles, guidance, regulations and pharmacometric review reports on foreign pharmacometric drug evaluation system. A systematic roadmap comprised of 3 stages to implement pharmaco-metrics in Lorean drug evaluation system was formulated after analyzing the collected data in tune with the current evaluation system. Pharmacometrics is an urgently required tool to achieve an efficient drug evaluation and review in Korea. The road map developed by this study is expected to aid in setting up a policy to implement and utilize phar-macometrics in Korea.
( Seung Lark Hwang ),( Hyeun Wook Chang ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
The aim of this study was to elucidate the effects of natural vanadium-containing Jeju ground water on glucose uptake in L6 myotubes and adipogensesis in 3T3 L1 cells. The Jeju ground water samplescontaining vanadium components were designated as S1 (8.0 ± 0.9 μg/l), S2 (24.0 ± 2.0 μg/l), and S3 (26.0 ± 2.0 μg/l), respectively. To investigate the effects of the Jeju ground water on glucose uptake in L6 myotubes, L6 cells were differentiated in media containing deionized distilled water (DDW group) and the water samples (S1, S2, and S3 groups). After daily changes in cultured media containing theJeju ground water samples for 1 week, all samples had increased glucose uptake compared to the DDW group and the order of glucose uptake increased in parallel with vanadium content (S3 > S2 > S1). In addition, S3 significantly stimulated the phosphorylation of the Thr-172 residue of the AMP-activated protein kinase-α subunit and the Ser-79 subunit of acetyl-CoA carboxylase compared to the DDW group. The effect of glucose uptake by S3 was reversed by pretreatment with Compound C, an AMPK inhibitor. Interestingly, vanadium pentoxide also increased glucose uptake and activated AMPK activity in a dose-dependent manner. Furthermore, as compared to the DDW treated group, S3 treatment inhibited adipogenesis of 3T3-L1 cells by down regulation of expressions of adipogenic transcription factors. Taken together, these findings suggest that S3 displays beneficial effects in the treatment of diabetes, at least in part through the activation of AMPK activity.
( Kyeum Han Noh ),( Eun Young Kim ),( Tae Cheon Jeong ),( Min Kyun Na ),( Mon Chang Ba다 ),( Kwang Hyeon Liu ),( Pil Hoon Park ),( Beom Soo Shin ),( Won Ku Kang ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
Glimepiride, a second-generation sulfonylurea, is a glucose-lowering agent widely used to treat diabetes mellitus. It is converted into metabolite M1 by CYP2C9, and M1 is then transformed into the carboxyl derivative M2 by cytosolic enzymes. In this study, we introduce a sensitive liquidchromatography/tandem mass spectrometry (LC/MS/MS) method for determining glimepiride, M1, and M2 in human plasma. After simple protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase CN column with a mobile phase of 10 mM ammonium acetate aqueous solution and acetonitrile (1:1, v/v). The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of glimepiride, M1, and M2 in plasma after a single oral 2-mg dose ofglimepiride in volunteers.