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Park J.B.,Catholic University of Korea | Bae S.H.,Catholic University of Korea | Jang S.-M.,Catholic University of Korea | Noh W.J.,Daewon Foreign Language High School | And 4 more authors.
Journal of Separation Science | Year: 2013

A simple, robust, and rapid LC-MS/MS method has been developed and validated for the simultaneous quantitation of clopidogrel and its active metabolite (AM) in human plasma. Tris(2-carboxyethyl)phosphine (TCEP) was used as a reducing agent to detect the AM as a disulfide-bonded complex with plasma proteins. Mixtures of TCEP and human plasma were deproteinized with acetonitrile containing 10 ng/mL of clopidogrel-d4 as an internal standard (IS). The mixtures were separated on a C18 RP column with an isocratic mobile phase consisting of 0.1% formic acid in acetonitrile and water (90:10, v/v) at a flow rate of 0.3 mL/min. Detection and quantification were performed using ESI-MS. The detector was operated in selected reaction-monitoring mode at m/z 322.0→211.9 for clopidogrel, m/z 356.1→155.2 for the AM, and m/z 326.0→216.0 for the IS. The linear dynamic range for clopidogrel and its AM were 0.05-20 and 0.5-200 ng/mL, respectively, with correlation coefficients (r) greater than 0.9976. Precision, both intra- and interday, was less than 8.26% with an accuracy of 87.6-106%. The validated method was successfully applied to simultaneously analyze clinical samples for clopidogrel and its AM. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Choi B.-H.,Catholic University of Korea | Kang K.-S.,Daewon Foreign Language High School | Kwak M.-K.,Catholic University of Korea
Molecules | Year: 2014

Chronic kidney disease (CKD) is featured by a progressive decline of kidney function and is mainly caused by chronic diseases such as diabetes mellitus and hypertension. CKD is a complex disease due to cardiovascular complications and high morbidity; however, there is no single treatment to improve kidney function in CKD patients. Since biological markers representing oxidative stress are significantly elevated in CKD patients, oxidative stress is receiving attention as a contributing factor to CKD pathology. Nuclear factor erythroid-2 related factor 2 (NRF2) is a predominant transcription factor that regulates the expression of a wide array of genes encoding antioxidant proteins, thiol molecules and their generating enzymes, detoxifying enzymes, and stress response proteins, all of which can counteract inflammatory and oxidative damages. There is considerable experimental evidence suggesting that NRF2 signaling plays a protective role in renal injuries that are caused by various pathologic conditions. In addition, impaired NRF2 activity and consequent target gene repression have been observed in CKD animals. Therefore, a pharmacological intervention activating NRF2 signaling can be beneficial in protecting against kidney dysfunction in CKD. This review article provides an overview of the role of NRF2 in experimental CKD models and describes current findings on the renoprotective effects of naturally occurring NRF2 activators, including sulforaphane, resveratrol, curcumin, and cinnamic aldehyde. These experimental results, coupled with recent clinical experiences with a synthetic triterpenoid, bardoxolone methyl, have brought a light of hope for ameliorating CKD progression by preventing oxidative stress and maintaining cellular redox homeostasis. © 2014 by the authors.

Ryoo I.-G.,Catholic University of Korea | Shin D.-H.,Yeungnam University | Kang K.-S.,Daewon Foreign Language High School | Kwak M.-K.,Catholic University of Korea
Archives of Pharmacal Research | Year: 2015

Transforming growth factor-β1 (TGFβ1) induces epithelial-to-mesenchymal transition (EMT) in cultured renal tubular epithelial cells. This phenotypic transition has been known to be involved in the development of chronic kidney diseases by activating profibrotic gene expression. Since oxidative stress has been recognized as one of the contributors to this TGFβ1-mediated pathology, we investigated the potential involvement of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which is a key transcription factor for the regulation of multiple antioxidant genes, in TGFβ1-stimulated EMT gene changes using the rat proximal tubular epithelial cell line NRK52E. The treatment of NRK52E with TGFβ1 led to changes in EMT gene expression, including increased α-Sma and decreased E-cadherin expression. In these cells, the TGFβ1 treatment decreased the transcript level of the catalytic subunit of γ-glutamate cysteine ligase (Gclc), a glutathione (GSH) biosynthetic enzyme, and reduced the total GSH content with a concomitant decrease in Nrf2 transcription activity. Accordantly, pre-incubation with the GSH precursor N-acetylcysteine attenuated TGFβ1-stimulated EMT gene changes. The involvement of Nrf2 in EMT gene changes has been demonstrated using NRK52E cells with nrf2 knockdown or pharmacological activation. When the expression of Nrf2 was stably silenced in NRK52E cells using interfering RNA administration, Gclc expression was significantly reduced and the increase in the levels of α-Sma and fibronectin-1 by TGFβ1 was greater than those in the nonspecific RNA control group. Conversely, Nrf2 activation and subsequent Gclc increase by Nrf2-activating sulforaphane alleviated the TGFβ1-stimulated α-Sma increase and E-cadherin decrease. Collectively, these results indicate that Nrf2-GSH signaling can modulate TGFβ1-stimulated EMT gene changes and further suggest a beneficial role of Nrf2 inducers in renal pathogenesis. © 2014 The Pharmaceutical Society of Korea.

Kim Y.,Daewon Foreign Language High School | Park K.,Yonsei University | Kang W.,Yeungnam University
Biopharmaceutics and Drug Disposition | Year: 2010

A diabetic patient may suffer simultaneously from cardiovascular disease; thus, lipid-lowering or anti-hypertensive agents could be given together with nateglinide. The pharmacokinetics of nateglinide were investigated in the presence and absence of HMG-CoA reductase inhibitors (fluvastatin, lovastatin) and calcium channel blockers (verapamil, nifedipine) in rabbits. A pharmacokinetic modeling approach was used to quantify the effects of the drugs that significantly influenced the pharmacokinetics of nateglinide. Fluvastatin and nifedipine shifted the time course of serum nateglinide concentrations upwards; there was no significant change with verapamil or lovastatin. The Cmax and AUCinf increased 1.5- (p<0.05) and 1.3-fold in the presence of fluvastatin and 1.8- (p<0.01) and 2.4-fold (p<0.01) in the presence of nifedipine, respectively. In a simultaneous nonlinear regression, fluvastatin and nifedipine decreased the elimination rate constant, by 76% and 32%, respectively. Fluvastatin and nifedipine increased the systemic exposure of nateglinide in rabbits, probably due to their inhibitory action on the metabolism of nateglinide by CYP2C5 (human CYP2C9). The concomitant use of fluvastatin and/or nifedipine with nateglinide is quite likely; therefore, the clinical consequences of long-term treatments must be considered. Copyright © 2010 John Wiley & Sons, Ltd.

Choi H.J.,Daewon Foreign Language High School | Hong J.B.,Daewon Foreign Language High School | Park J.J.,Daewon Foreign Language High School | Chi W.-J.,Myongji University | And 3 more authors.
Biotechnology and Bioprocess Engineering | Year: 2011

The agar degrading bacterial strain GNUM-08124 was isolated from Enteromorpha compressa collected in the East Sea of Korea by using a selective artificial sea water (ASW) agar plate containing agar as the sole carbon source. GNUM-08124 grows to produce a circular, smooth, yellow-colored, and raised colony. Its ability to hydrolyze agar was confirmed by staining the ASW agar plate with Lugol's solution. In liquid culture, the cell density (A 600) increased exponentially and reached a maximum level on the third day of cultivation. The specific agarase activity also increased in proportion to the cell density and reached maximum agarolytic activity on the third day. The 16S rRNA sequence of GNUM-08124 showed a close relationship to Micrococcus luteus (99.65%) and Micrococcus endophyticus (99.15%), which led us to assign it to the genus Micrococcus. Physiological studies indicated that optimal growth conditions were between 30 and 40°C, pH 4 and 7, using media containing between 5 and 10% NaCl (w/v), respectively. The GNUM-08124 strain was a grampositive, urease-positive, and catalase-positive bacterium. It could not hydrolyze gelatin, cellulose, xylan, or starch, but fermented a broader range of substrates, including D-glucose, D-galactose, D-fructose, D-lactose, D-trehalose, D-mannitol, D-melibiose, D-raffinose, D-xylose, methyl-α-D-glucopyranoside, N-acetyl-glucosamine, and xylitol, than those fermented by M. luteus or M. endophyticus, suggesting GNUM-08124 is a novel agar hydrolyzing microorganism belonging to Genus Micrococcus. Micrococcus sp. GNUM-08124 showed the highest agarase activity when it was cultured in ASW-YP medium supplemented with 0.4% glucose, but demonstrated lower activity in rich media (LB or TSB), in spite of superior cell growth, implying that agarase production is tightly regulated in an agar-dependent manner and repressed in rich conditions. © The Korean Society for Biotechnology and Bioengineering and Springer 2011.

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