Serine palmitoyltransferase inhibitor myriocin induces growth inhibition of B16F10 melanoma cells through G₂/M phase arrest

Lee, Y.‐,S.,Choi, K.‐,M.,Choi, M.‐,H.,Ji, S.‐,Y.,Lee, S.,Sin, D.‐,M.,Oh, K.‐,W.,Lee, Y.‐,M.,Hong, J.‐,T.,Yun, Y.‐,P.,Yoo, H.‐,S. Blackwell Publishing Ltd 2011 Cell proliferation Vol.44 No.4

<P><B>Abstract</B></P><P><B>Objectives: </B> Melanoma is the most aggressive form of skin cancer, and it resists chemotherapy. Candidate drugs for effective anti‐cancer treatment have been sought from natural resources. Here, we have investigated anti‐proliferative activity of myriocin, serine palmitoyltransferase inhibitor, in the <I>de novo</I> sphingolipid pathway, and its mechanism in B16F10 melanoma cells.</P><P><B>Material and methods: </B> We assessed cell population growth by measuring cell numbers, DNA synthesis, cell cycle progression, and expression of cell cycle regulatory proteins. Ceramide, sphingomyelin, sphingosine and sphingosine‐1‐phosphate levels were analysed by HPLC.</P><P><B>Results: </B> Myriocin inhibited proliferation of melanoma cells and induced cell cycle arrest in the G<SUB>2</SUB>/M phase. Expressions of cdc25C, cyclin B1 and cdc2 were decreased in the cells after exposure to myriocin, while expression of p53 and p21<SUP>waf1/cip1</SUP> was increased. Levels of ceramide, sphingomyelin, sphingosine and sphingosine‐1‐phosphate in myriocin‐treated cells after 24 h were reduced by approximately 86%, 57%, 75% and 38%, respectively, compared to levels in control cells.</P><P><B>Conclusions: </B> Our results suggest that inhibition of sphingolipid synthesis by myriocin in melanoma cells may inhibit expression of cdc25C or activate expression of p53 and p21<SUP>waf1/cip1</SUP>, followed by inhibition of cyclin B1 and cdc2, resulting in G<SUB>2</SUB>/M arrest of the cell cycle and cell population growth inhibition. Thus, modulation of sphingolipid metabolism by myriocin may be a potential target of mechanism‐based therapy for this type of skin cancer.</P>

Comparison of 90‐day case‐fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis

Yu, K‐,H.,Hong, K‐,S.,Lee, B‐,C.,Oh, M‐,S.,Cho, Y‐,J.,Koo, J‐,S.,Park, J‐,M.,Bae, H‐,J.,Han, M‐,K.,Ju, Y‐,S.,Kang, D‐,W.,Appelros, P. Blackwell Publishing Ltd 2011 Acta neurologica Scandinavica Vol.123 No.5

<P>Yu K‐H, Hong K‐S, Lee B‐C, Oh M‐S, Cho Y‐J, Koo J‐S, Park J‐M, Bae H‐J, Han M‐K, Ju Y‐S, Kang D‐W, Appelros P, Norrving B, Terent A. Comparison of 90‐day case‐fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis. 
Acta Neurol Scand: 2011: 123: 325–331. 
© 2010 John Wiley & Sons A/S.</P><P><B>Background – </B> It has not been clarified whether the disparity in ischemic stroke outcome between populations is caused by ethnic and geographic differences or by variations in case mix. Propensity score matching (PSM) analysis can overcome some analytical problems but is rarely used in stroke outcome research. This study was to compare the ischemic stroke case‐fatality between two PSM cohorts of Sweden and Korea.</P><P><B>Methods – </B> Prognostic variables related to baseline characteristics and stroke care were included in our PSM model. Then, we selected 7675 Swedish and 1220 Korean patients with ischemic stroke from each stroke registers and performed one‐to‐one matching based on propensity scores of each patient.</P><P><B>Results – </B> After PSM, all measured variables were well balanced in 1163 matched subjects, and the 90‐day case‐fatality was identical 6.2% (HR 0.997, 95%CI 0.905–1.099) in Sweden and Korea.</P><P><B>Conclusions – </B> No difference is found in the 90‐day case‐fatality in propensity score‐matched Swedish and Korean patients with ischemic stroke.</P>

N-Methyl, N-propynyl-2-phenylethylamine (MPPE), a Selegiline Analog, Attenuates MPTP-induced Dopaminergic Toxicity with Guaranteed Behavioral Safety: Involvement of Inhibitions of Mitochondrial Oxidative Burdens and p53 Gene-elicited Pro-apoptotic Change

Shin, E. J.,Nam, Y.,Lee, J. W.,Nguyen, P. K.,Yoo, J. E.,Tran, T. V.,Jeong, J. H.,Jang, C. G.,Oh, Y. J.,Youdim, M. B. HUMANA PRESS INC 2016 Molecular Neurobiology Vol.53 No.9

<P>Selegiline is a monoamine oxidase-B (MAO-B) inhibitor with anti-Parkinsonian effects, but it is metabolized to amphetamines. Since another MAO-B inhibitor N-Methyl, N-propynyl-2-phenylethylamine (MPPE) is not metabolized to amphetamines, we examined whether MPPE induces behavioral side effects and whether MPPE affects dopaminergic toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Multiple doses of MPPE (2.5 and 5 mg/kg/day) did not show any significant locomotor activity and conditioned place preference, whereas selegiline (2.5 and 5 mg/kg/day) significantly increased these behavioral side effects. Treatment with MPPE resulted in significant attenuations against decreases in mitochondrial complex I activity, mitochondrial Mn-SOD activity, and expression induced by MPTP in the striatum of mice. Consistently, MPPE significantly attenuated MPTP-induced oxidative stress and MPPE-mediated antioxidant activity appeared to be more pronounced in mitochondrial-fraction than in cytosolic-fraction. Because MPTP promoted mitochondrial p53 translocation and p53/Bcl-xL interaction, it was also examined whether mitochondrial p53 inhibitor pifithrin-mu attenuates MPTP neurotoxicity. MPPE, selegiline, or pifithrin-mu significantly attenuated mitochondrial p53/Bcl-xL interaction, impaired mitochondrial transmembrane potential, cytosolic cytochrome c release, and cleaved caspase-3 in wild-type mice. Subsequently, these compounds significantly ameliorated MPTP-induced motor impairments. Neuroprotective effects of MPPE appeared to be more prominent than those of selegiline. MPPE or selegiline did not show any additional protective effects against the attenuation by p53 gene knockout, suggesting that p53 gene is a critical target for these compounds. Our results suggest that MPPE possesses anti-Parkinsonian potentials with guaranteed behavioral safety and that the underlying mechanism of MPPE requires inhibition of mitochondrial oxidative stress, mitochondrial translocation of p53, and pro-apoptotic process.</P>

Phosphorylation and isoform use in p120-catenin during development and tumorigenesis

Hong, J.Y.,Oh, I.H.,McCrea, P.D. Elsevier Biomedical Press 2016 Biochimica et biophysica acta, Molecular cell rese Vol.1863 No.1

P120-catenin is essential to vertebrate development, modulating cadherin and small-GTPase functions, and growing evidence points also to roles in the nucleus. A complexity in addressing p120-catenin's functions is its many isoforms, including optional splicing events, alternative points of translational initiation, and secondary modifications. In this review, we focus upon how choices in the initiation of protein translation, or the earlier splicing of the RNA transcript, relates to primary sequences that harbor established or putative regulatory phosphorylation sites. While certain p120 phosphorylation events arise via known kinases/phosphatases and have defined outcomes, in most cases the functional consequences are still to be established. In this review, we provide examples of p120-isoforms as they relate to phosphorylation events, and thereby to isoform dependent protein-protein associations and downstream functions. We also provide a view of upstream pathways that determine p120's phosphorylation state, and that have an impact upon development and disease. Because other members of the p120 subfamily undergo similar processing and phosphorylation, as well as related catenins of the plakophilin subfamily, what is learned regarding p120 will by extension have wide relevance in vertebrates.

Effect of Dietary Lysine Restriction and Energy Density on Performance, Nutrient Digestibility and Meat Quality in Finishing Pigs

Jin, Y.H.,Oh, H.K.,Piao, L.G.,Jang, S.K.,Choi, Y.H.,Heo, P.S.,Jang, Y.D.,Kim, Y.Y. Asian Australasian Association of Animal Productio 2010 Animal Bioscience Vol.23 No.9

This experiment evaluated the effects of dietary lysine restriction and energy density on growth performance, nutrient digestibility and meat quality of finishing pigs. A $2{\times}2$ factorial arrangement of treatments was utilized in a randomized complete block (RCB) design, and factor 1 was lysine restriction and factor 2 was energy density. The control diet was formulated to contain 3.265 Mcal of ME/kg, 0.75% lysine in the early-finishing phase and 3.265 Mcal of ME/kg, 0.60% lysine in the late-finishing phase and other nutrients met or exceeded NRC (1998) standards. Compared to the control diet (CON), lysine levels of experimental diets were restricted to 15% (treatment EL, EEL) or 30% (treatment ELL, EELL), whereas energy level of experimental diets was increased by 0.100 or 0.200 Mcal of ME/kg. A total of 100 crossbred pigs ([Yorkshire${\times}$Landrace]${\times}$Duroc), with average initial body weight of $58.47{\pm}1.42\;kg$, were allotted to 5 dietary treatments based on sex and body weight. Each treatment had 5 replicates with 4 pigs (two barrows and two gilts) per pen. ADG, ADFI and feed efficiency were calculated in an 8-week growth trial. In the late finishing period (5-8 weeks), pigs fed ELL or EELL diets had decreased ADG and feed efficiency (p<0.01), however, when the EEL diet was provided, a similar growth performance was observed compared to those fed the CON diet during the whole experimental period (p>0.05). In a metabolic trial, 15 pigs were used to evaluate the effect of dietary lysine restriction and energy density on nutrient digestibility. The digestibility of dry matter, crude fat and crude ash was not improved by restricting dietary lysine or energy density. However, crude protein digestibility was decreased (p<0.05) as dietary lysine was restricted. When dietary lysine was restricted, fecal nitrogen was increased whereas nitrogen retention was decreased. BUN concentration was affected by dietary lysine restriction; treatments ELL and EELL had higher BUN values than other treatments (p<0.01). Carcass characteristics and meat quality were measured when average body weight of pigs reached $107.83{\pm}1.50\;kg$. Treatment ELL had higher last rib backfat depth (p<0.05) than treatment CON, but ELL and EEL did not differ significantly. The ELL and EEL treatments had higher (p<0.05) subjective marbling score than treatment CON. Treatment EEL showed higher longissimus fat content than treatment EL and CON (p<0.01). The results indicated that finishing pigs fed a diet with 15% lysine restriction and 3.465 Mcal of ME/kg energy density had no detrimental effects on growth performance and N utilization, and could achieve substantial increases in marbling and longissimus fat content of pork.

Alteration by p11 of mGluR5 localization regulates depression-like behaviors

Lee, K-W,Westin, L,Kim, J,Chang, J C,Oh, Y-S,Amreen, B,Gresack, J,Flajolet, M,Kim, D,Aperia, A,Kim, Y,Greengard, P Macmillan Publishers Limited 2015 Molecular psychiatry Vol.20 No.12

Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and it has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors. Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membrane, and p11 increases cell surface availability of the receptor. Whereas p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity.

One-year clinical outcomes of everolimus- versus sirolimus-eluting stents in patients with acute myocardial infarction

other Korea Acute Myocardial Infarction Registry Investigators,Chen, K.Y.,Rha, S.W.,Wang, L.,Li, Y.J.,Li, G.P.,Choi, C.U.,Park, C.G.,Seo, H.S.,Oh, D.J.,Jeong, M.H.,Ahn, Y.K.,Hong, T.J.,Kim, Y.J.,Chae, Elsevier/North-Holland Biomedical Press 2014 INTERNATIONAL JOURNAL OF CARDIOLOGY Vol.176 No.3

Background: In contrast to many studies comparing everolimus-eluting stent (EES) with paclitaxel-eluting stent (PES), data directly comparing EES with sirolimus-eluting stent (SES) are limited, especially in patients with acute myocardial infarction (AMI). Methods: This study includes 2911 AMI patients treated with SES (n=1264) or EES (n=1701) in Korea Acute Myocardial Infarction Registry (KAMIR). Propensity score matching was applied to adjust for baseline imbalance in clinical and angiographic characteristics, yielding a total of 2400 well-matched patients (1200 receiving SES and 1200 receiving EES). One-year clinical outcomes were compared between the two propensity score matched groups. Results: Baseline clinical and angiographic characteristics were similar between the two propensity score matched groups. One-year clinical outcomes of the propensity score matched cohort were comparable between the EES versus the SES groups including the rates of cardiac death (4.8% vs. 4.8%, P=1.000), recurrent myocardial infarction (1.4% vs. 1.7%, P=0.619), target lesion revascularization (1.4% vs. 1.6%, P=0.737), target lesion failure (7.0% vs. 7.3%, P=0.752), and probable or definite stent thrombosis (0.5% vs. 0.9%, P=0.224) except for a trend toward lower incidence of target vessel revascularization (1.9% vs. 3.0%, P=0.087) and a lower rate of total major adverse cardiac events (9.3% vs. 11.9%, P=0.034) in the EES group. Conclusions: The present propensity score matched analysis performed in a large-scale, prospective, multicenter registry suggests that the second-generation drug-eluting stent EES has at least comparable or even better safety and efficacy profiles as compared with SES in the setting of AMI.

TP53, MSH4, and LATS1 Germline Mutations in a Family with Clustering of Nervous System Tumors

Kim, Y.H.,Ohta, T.,Oh, J.E.,Le Calvez-Kelm, F.,McKay, J.,Voegele, C.,Durand, G.,Mittelbronn, M.,Kleihues, P.,Paulus, W.,Ohgaki, H. American Association of Pathologists and Bacteriol 2014 The American journal of pathology Vol.184 No.9

Exome DNA sequencing of blood samples from a Li-Fraumeni family with a TP53 germline mutation (codon 236 deletion) and multiple nervous system tumors revealed additional germline mutations. Missense mutations in the MSH4 DNA repair gene (c.2480T>A; p.I827N) were detected in three patients with gliomas (two anaplastic astrocytomas, two glioblastomas). Two family members without a TP53 germline mutation who developed peripheral schwannomas also carried the MSH4 germline mutation, and in addition, a germline mutation of the LATS1 gene (c.286C>T; p.R96W). LATS1 is a downstream mediator of the NF2, but has not previously been found to be related to schwannomas. We therefore screened the entire coding sequence of the LATS1 gene in 65 sporadic schwannomas, 12 neurofibroma/schwannoma hybrid tumors, and 4 cases of schwannomatosis. We only found a single base deletion at codon 827 (exon 5) in a spinal schwannoma, leading to a stop at codon 835 (c.2480delG; p.*R827Kfs*8). Mutational loss of LATS1 function may thus play a role in some inherited schwannomas, but only exceptionally in sporadic schwannomas. This is the first study reporting a germline MSH4 mutation. Since it was present in all patients, it may have contributed to the subsequent acquisition of TP53 and LATS1 germline mutations.

Fabrication and mechanical properties of powder metallurgy tantalum prepared by hot isostatic pressing

Kim, Y.,Kim, E.P.,Noh, J.W.,Lee, S.H.,Kwon, Y.S.,Oh, I.S. MPR Pub. Services 2015 INTERNATIONAL JOURNAL OF REFRACTORY METALS AND HAR Vol.48 No.-

The fabrication process of a powder metallurgy (P/M) tantalum product with full density and fine microstructure was developed by using cold and hot isostatic pressing techniques. In order to increase the compact density and make the uniform density distribution, cold isostatic pressing (CIPing) of tantalum powders was conducted. Prior to hot isostatic pressing (HIPing), the CIPed billet was encapsulated and degassed to remove the contaminants in the container. After degassing, HIPing was performed twice and full densification of the tantalum powders was accomplished, regardless of powder size. The effect of processing conditions on the microstructure and mechanical properties of P/M tantalum billets was investigated. As the number of processing steps and temperature increased, the grain size of HIPed tantalum billets increased. Moreover, contrary to the Hall-Petch relation, the mechanical strength was increased in spite of increasing the grain size. This is because the oxygen content of the billets increased with rising in temperature and the number of processing steps. Therefore, in case of tantalum, it is found that the mechanical properties of tantalum may be highly influenced by the amount of interstitial elements, especially oxygen, rather than microstructural properties.

Enhanced photoluminescence due to Bi³⁺ → Eu³⁺ energy transfer and re-precipitation of RE doped homogeneous sized Y₂O₃ nanophosphors

Jadhav, A.P.,Thi Dinh, T.D.,Khan, S.,Lee, S.Y.,Park, J.K.,Park, S.W.,Oh, J.H.,Moon, B.K.,Jang, K.,Yi, S.S.,Kim, J.H.,Cho, S.H.,Jeong, J.H. Pergamon Press 2016 Materials research bulletin Vol.83 No.-

Precipitation and re-precipitation of metal ions has been carried out from original and supernatant solution producing Bi<SUP>3+</SUP> - Eu<SUP>3+</SUP> doped Y<SUB>2</SUB>O<SUB>3</SUB>:Eu<SUP>3+</SUP> and Eu<SUP>3+</SUP>/Tb<SUP>3+</SUP> doped Y<SUB>2</SUB>O<SUB>3</SUB>, respectively. Shorter reaction time is unable to consume all metal ions present in the solution which can be utilized through re-precipitation process. The doping of Bi<SUP>3+</SUP> - Eu<SUP>3+</SUP> in Y<SUB>2</SUB>O<SUB>3</SUB> helps to absorb maximum UV light. The activation of Y<SUB>2</SUB>O<SUB>3</SUB> matrix by Bi<SUP>3+</SUP> and Eu<SUP>3+</SUP> ions, together and separately, were studied considering the excitation energy transfer to the luminescence centers. The successful replacement of Y<SUP>3+</SUP> by RE<SUP>3+</SUP> ions can help for fine tuning of emission wavelength. Re-precipitation of supernatant solution by adding terbium precursor can successively produce uniform sized Tb<SUP>3+</SUP> doped Y<SUB>2</SUB>O<SUB>3</SUB>:Eu<SUP>3+</SUP>. The re-precipitation of the supernatant solution ensures maximum consumption of metal ions for higher product yield and possible fine tuning of emission wavelengths.