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Phospholipase D activates HIF-1-VEGF pathway via phosphatidic acid
Han, Songyi,Huh, Jeongsoon,Kim, Wooseong,Jeong, Seongkeun,Min, Do Sik,Jung, Yunjin Nature Publishing Group 2014 Experimental and molecular medicine Vol.46 No.12
<P>Growth factor-stimulated phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC), generating phosphatidic acid (PA) which may act as a second messenger during cell proliferation and survival. Therefore, PLD is believed to play an important role in tumorigenesis. In this study, a potential mechanism for PLD-mediated tumorigenesis was explored. Ectopic expression of PLD1 or PLD2 in human glioma U87 cells increased the expression of hypoxia-inducible factor-1α (HIF-1α) protein. PLD-induced HIF-1 activation led to the secretion of vascular endothelial growth factor (VEGF), a HIF-1 target gene involved in tumorigenesis. PLD induction of HIF-1α was significantly attenuated by 1-butanol which blocks PA production by PLD, and PA <I>per se</I> was able to elevate HIF-1α protein level. Inhibition of mTOR, a PA-responsive kinase, reduced the levels of HIF-1α and VEGF in PLD-overexpressed cells. Epidermal growth factor activated PLD and increased the levels of HIF-1α and VEGF in U87 cells. A specific PLD inhibitor abolished expression of HIF-1α and secretion of VEGF. PLD may utilize HIF-1-VEGF pathway for PLD-mediated tumor cell proliferation and survival.</P>
Shinae Yu,Hee Jae Huh,Kyo Won Lee,Jae Berm Park,Sung Joo Kim,Wooseong Huh,Hye Ryoun Jang,Ghee Young Kwon,Hyung Hwan Moon,Eun-Suk Kang 대한진단검사의학회 2020 Annals of Laboratory Medicine Vol.40 No.5
Background: Non-HLA antibodies, anti-angiotensin II type 1 receptor antibodies (anti-AT1R) and anti-endothelial cell antibodies (AECA), are known to play a role in allograft rejection. We evaluated the role of both antibodies in predicting post-transplant outcomes in low-risk living donor kidney transplantation (LDKT) recipients. Methods: In 94 consecutive LDKT recipients who were ABO compatible and negative for pre-transplant HLA donor-specific antibodies, we determined the levels of anti-AT1Rs using an enzyme-linked immunosorbent assay and the presence of AECAs using a flow cytometric endothelial cell crossmatch (ECXM) assay with pre-transplant sera. Hazard ratio (HR) was calculated to predict post-transplant outcomes. Results: Pre-transplant anti-AT1Rs (≥11.5 U/mL) and AECAs were observed in 36 (38.3%) and 22 recipients (23.4%), respectively; 11 recipients had both. Pre-transplant anti-AT1Rs were a significant risk factor for the development of acute rejection (AR) (HR 2.09; P=0.018), while a positive AECA status was associated with AR or microvascular inflammation only (HR 2.47; P=0.004) throughout the follow-up period. In particular, AECA (+) recipients with ≥11.5 U/mL anti-AT1Rs exhibited a significant effect on creatinine and estimated glomerular filtration rate (P<0.001; P=0.028), although the risk of AR was not significant. Conclusions: Pre-transplant anti-AT1Rs and AECAs have independent negative effects on post-transplant outcomes in low-risk LDKT recipients. Assessment of both antibodies would be helpful in stratifying the pre-transplant immunological risk, even in low-risk LDKT recipients.
( Sang-min Kim ),( Jae-wan Huh ),( Eun-young Kim ),( Min-kyung Shin ),( Ji-eun Park ),( Seong Who Kim ),( Wooseong Lee ),( Bongkun Choi ),( Eun-ju Chang ) 생화학분자생물학회(구 한국생화학분자생물학회) 2019 BMB Reports Vol.52 No.2
Endothelial dysfunction-induced lipid retention is an early feature of atherosclerotic lesion formation. Apoptosis of vascular smooth muscle cells (VSMCs) is one of the major modulating factors of atherogenesis, which accelerates atherosclerosis progression by causing plaque destabilization and rupture. However, the mechanism underlying VSMC apoptosis mediated by endothelial dysfunction in relation to atherosclerosis remains elusive. In this study, we reveal differential expression of several genes related to lipid retention and apoptosis, in conjunction with atherosclerosis, by utilizing a genetic mouse model of endothelial nitric oxide synthase (eNOS) deficiency manifesting endothelial dysfunction. Moreover, eNOS deficiency led to the enhanced susceptibility against pro-apoptotic insult in VSMCs. In particular, the expression of aggrecan, a major proteoglycan, was elevated in aortic tissue of eNOS deficient mice compared to wild type mice, and administration of aggrecan induced apoptosis in VSMCs. This suggests that eNOS deficiency may elevate aggrecan expression, which promotes apoptosis in VSMC, thereby contributing to atherosclerosis progression. These results may facilitate the development of novel approaches for improving the diagnosis or treatment of atherosclerosis. [BMB Reports 2019; 52(2): 145-150]
Yang, Jeong Soo,Cho, Eun Gi,Huh, Wooseong,Ko, Jae-Wook,Jung, Jin Ah,Lee, Soo-Youn Korean Chemical Society 2013 Bulletin of the Korean Chemical Society Vol.34 No.8
A simple, fast and robust analytical method was developed to determine imatinib in human plasma using liquid chromatography-tandem mass spectrometry with electrospray ionization in the positive ion mode. Imatinib and labeled internal standard were extracted from plasma with a simple protein precipitation. The chromatographic separation was performed using an isocratic elution of mobile phase involving 5.0 mM ammonium formate in water-5.0 mM ammonium formate in methanol (30:70, v/v) over 3.0 min on reversed-stationary phase. The detection was performed using a triple-quadrupole tandem mass spectrometer in multiple-reaction monitoring mode. The developed method was validated with lower limit of quantification of 10 ng/mL. The calibration curve was linear over 10-2000 ng/mL ($R^2$ > 0.99). The method validation parameters met the acceptance criteria. The spiked samples and standard solutions were stable under conditions for storage and handling. The reliable method was successfully applied to real sample analyses and thus a pharmacokinetic study in 27 healthy Korean male volunteers.
Park, Sehoon,Kim, Yon Su,Lee, Jungpyo,Huh, Wooseong,Yang, Chul Woo,Kim, Young-Lim,Kim, Yeong Hoon,Kim, Joong Kyung,Oh, Chang-Kwon,Park, Su-Kil International Scientific Literature, Inc. 2018 Annals of transplantation Vol.23 No.-
<P><B>Background</B></P><P>Minimizing the tacrolimus dosage in patients with stable allograft function needs further investigation.</P><P><B>Material/Methods</B></P><P>We performed an open-label, randomized, controlled study from 2010 to 2016 in 7 tertiary teaching hospitals in Korea and enrolled 345 kidney transplant recipients with a stable graft status. The study group received reduced-dose tacrolimus, 1080–1440 mg/day of enteric-coated mycophenolate sodium (EC-MPS), and corticosteroids. The control group received the standard tacrolimus dosage and 540–720 mg/day of EC-MPS with steroids. The primary endpoint was the mean estimated glomerular filtration rate (eGFR) and change in the eGFR at 12 months after randomization.</P><P><B>Results</B></P><P>The mean tacrolimus trough level of the study group was 4.51±1.62 ng/mL, which was lower than that of the control group, at 6.75±2.82 ng/mL (P<0.001). The primary endpoint was better in the study group in terms of change in eGFR (P<0.001). The month 12 eGFRs were 73.6±28.4 and 68.3±18.1 mL/min/1.73 m<SUP>2</SUP> in the study and the control groups, respectively, but the difference did not reach statistical significance (P=0.07). The incidence of adverse events was similar between the study and the control groups.</P><P><B>Conclusions</B></P><P>Minimizing tacrolimus to a trough level below 5 ng/mL combined with conventional EC-MPS can be considered in patients with a steady follow-up, as it was associated with small benefits in the changes of the eGFR (Clinicaltrials.gov number: NCT01159080).</P>
Woo, Hye In,Kim, Suk Ran,Huh, Wooseong,Ko, Jae-Wook,Lee, Soo-Youn Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-
<P><B>Background</B></P><P>Statins are effective agents in the primary and secondary prevention of cardiovascular disease, but treatment response to statins varies among individuals. We analyzed multiple genetic polymorphisms and assessed pharmacokinetic and lipid-lowering responses after atorvastatin 80 mg treatment in healthy Korean individuals.</P><P><B>Methods</B></P><P>Atorvastatin 80 mg was given to 50 healthy Korean male volunteers. Blood samples were collected to measure plasma atorvastatin and lipid concentrations up to 48 hours after atorvastatin administration. Subjects were genotyped for 1,936 drug metabolism and transporter genetic polymorphisms using the Affymetrix DMET plus array.</P><P><B>Results</B></P><P>The pharmacokinetics and lipid-lowering effect of atorvastatin showed remarkable interindividual variation. Three polymorphisms in the <I>SLCO1B1</I>, <I>SLCO1B3</I>, and <I>ABCC2</I> genes were associated with either the maximum concentration (C<SUB>max</SUB>) of atorvastatin or changes in total cholesterol or low-density lipoprotein cholesterol (LDL-C). Minor homozygotes (76.5 ng/mL) of <I>SLCO1B1</I> c.-910G>A showed higher C<SUB>max</SUB> than heterozygotes (34.0 ng/mL) and major homozygotes (33.5 ng/mL, false discovery rate <I>P</I>=0.040). C<SUB>max</SUB> and the area under the plasma concentration curve from hour 0 to infinity (AUC<SUB>∞</SUB>) were higher in carriers of the <I>SLCO1B1</I>*17 haplotype that included c.-910G>A than in noncarriers (46.1 vs 32.8 ng/mL for C<SUB>max</SUB>; 221.5 vs 154.2 ng/mL for AUC<SUB>∞</SUB>). <I>SLCO1B3</I> c.334G>T homozygotes (63.0 ng/mL) also showed higher C<SUB>max</SUB> than heterozygotes (34.7 ng/mL) and major homozygotes (31.4 ng/mL, FDR <I>P</I>=0.037). A nonsynonymous <I>ABCC2</I> c.1249G>A was associated with small total cholesterol and LDL-C responses (0.23% and −0.70% for G/A vs −11.9% and −17.4% for G/G). The C<SUB>max</SUB> tended to increase according to the increase in the number of minor allele of <I>SLCO1B1</I> c. −910G>A and <I>SLCO1B3</I> c.334G>T.</P><P><B>Conclusion</B></P><P>Genetic polymorphisms in transporter genes, including <I>SLCO1B1</I>, <I>SLCO1B3</I>, and <I>ABCC2</I>, may influence the pharmacokinetics and lipid-lowering response to atorvastatin administration.</P>
Hwang, Jin Ho,Han, Seung Seok,Huh, Wooseong,Park, Su-Kil,Joo, Dong Jin,Kim, Myoung Soo,Kim, Yu Seun,Min, Sang-Il,Ha, Jongwon,Kim, Sang Joon,Kim, Suhnggwon,Kim, Yon Su Springer International ; Oxford University Press 2012 Nephrology, dialysis, transplantation Vol.27 No.6
<P>Idiopathic focal segmental glomerulosclerosis (FSGS) occurring at young age is known to predispose to poor graft outcome, but the outcome of adulthood-onset FSGS (A-FSGS) has not been thoroughly investigated. Here, we compared the graft outcomes between kidney recipients with A-FSGS and childhood-onset FSGS (C-FSGS).</P>