P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma

Suh, Dong&#x2010,Hyeon,Trinh, Hoang Kim Tu,Liu, Jing&#x2010,Nan,Pham, Le Duy,Park, Sang Myun,Park, Hae&#x2010,Sim,Shin, Yoo Seob CAROL DAVILA UNIVERSITY PRESS 2016 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.20 No.2

<P><B>Abstract</B></P><P>Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty‐eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA‐sensitized and ‐challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus‐containing goblet cells were reduced in clopidogrel‐administered mice compared to vehicle‐treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL‐1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma.</P>

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Lee, Junghee,Kim, Yunha,Liu, Tian,Hwang, Yu Jin,Hyeon, Seung Jae,Im, Hyeonjoo,Lee, Kyungeun,Alvarez, Victor E.,McKee, Ann C.,Um, Soo&#x2010,Jong,Hur, Manwook,Mook&#x2010,Jung, Inhee,Kowall, Neil W.,Ry John Wiley and Sons Inc. 2018 Aging cell Vol.17 No.1

<P><B>Summary</B></P><P>Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.</P>

Combustion synthesis and photocatalytic properties of magnetically separable Zn_1-xCd_xS/γ-Fe₂O₃ composites

Liu, J.,Zhang, D.,Pu, X.,Dong, D.,Cai, P.,Seo, H.J. North-Holland 2014 Materials letters Vol.130 No.-

Magnetically separable Zn<SUB>1-x</SUB>Cd<SUB>x</SUB>S/γ-Fe<SUB>2</SUB>O<SUB>3</SUB> (x=0-1) photocatalysts were synthesized by a one-step combustion method. The structures, morphologies, absorbance, optical and photocatalytic properties of the samples were studied by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, ultraviolet-visible spectrophotometry and photoluminescence. The experimental results show that the formation of hexagonal Zn<SUB>1-x</SUB>Cd<SUB>x</SUB>S and γ-Fe<SUB>2</SUB>O<SUB>3</SUB> and the combination of them were one-pot achieved. The Cd<SUP>2+</SUP> content has a significant influence on the absorbance of visible light and fluorescence properties. The magnetic properties of samples ensure the magnetic separation by using a magnet. CdS/γ-Fe<SUB>2</SUB>O<SUB>3</SUB> shows the best photocatalytic performance compared with other samples, ascribed to its small energy band gap and matching energy band structure between CdS and γ-Fe<SUB>2</SUB>O<SUB>3</SUB>. Moreover, no obvious deterioration was observed in the stability tests.

The Nedd8‐activating enzyme inhibitor MLN 4924 ( TAK ‐924/Pevonedistat) induces apoptosis via c‐Myc‐Noxa axis in head and neck squamous cell carcinoma

Zhang, Wenjuan,Liang, Yupei,Li, Lihui,Wang, Xiaofang,Yan, Zi,Dong, Changsheng,Zeng, Mu&#x2010,Sheng,Zhong, Qian,Liu, Xue&#x2010,Kui,Yu, Jinha,Sun, Shuyang,Liu, Xiaojun,Kang, Jihui,Zhao, Hu,Jeong, Lak BLACKWELL SCIENTIFIC PUBLICATIONS 2019 CELL PROLIFERATION Vol.52 No.2

Immobilization of Large, Aliovalent Cations in the Small‐Pore Zeolite K‐Natrolite by Means of Pressure

Lee, Yongjae,Lee, Yongmoon,Seoung, Donghoon,Im, Jun&#x2010,Hyuk,Hwang, Hee&#x2010,Jung,Kim, Tae&#x2010,Hyun,Liu, Dan,Liu, Zhenxian,Lee, Seung Yeop,Kao, Chi&#x2010,Chang,Vogt, Thomas WILEY‐VCH Verlag 2012 Angewandte Chemie Vol.124 No.20

<P><B>Hochdruck‐Ionenaustausch</B> an dem kleinporigen Zeolith K‐Natrolit ermöglicht die Immobilisierung von nominell nicht austauschbaren aliovalenten Kationen wie dreiwertigem Europium. Eine Probe, an der bei 3.0(1) GPa und 250 °C ein Ionenaustausch vorgenommen wurde, enthält ungefähr 4.7 Eu<SUP>III</SUP>‐Ionen pro Elementarzelle, was einem Austausch von über 90 % der K<SUP>+</SUP>‐Ionen entspricht (siehe Bild).</P>

Excited Spin-State Trapping in Spin Crossover Complexes on Ferroelectric Substrates

Wa&#x308,ckerlin, Christian,Donati, Fabio,Singha, Aparajita,Baltic, Romana,Decurtins, Silvio,Liu, Shi-Xia,Rusponi, Stefano,Dreiser, Jan American Chemical Society 2018 JOURNAL OF PHYSICAL CHEMISTRY C - Vol.122 No.15

<P>We have studied thin films of Fe(II) spin crossover complexes deposited on differently poled ferroelectric PMN-PT ([Pb(Mg<SUB>1/3</SUB>Nb<SUB>2/3</SUB>)O<SUB>3</SUB>]<SUB>1-<I>x</I></SUB>[PbTiO<SUB>3</SUB>]<SUB><I>x</I></SUB>, <I>x</I> = 0.32) substrates by X-ray absorption spectroscopy. The X-ray spectra reveal the temperature-driven conversion between high-spin and low-spin states without any observable effect of the ferroelectric polarization on the spin state of the molecules down to 100 K. In the soft X-ray-induced excited spin-state trapping (SOXIESST) regime at 3 K, large differences occur between the two ferroelectric polarizations. The efficiency of X-rays in exciting the molecules to the high-spin state is more than an order of magnitude larger when the ferroelectric dipoles of the substrate are pointing toward the surface compared to the opposite polarization. We explain our findings by a modulation of the polarization-dependent efficiency of the scattering of X-ray-generated secondary electrons at the molecules. Our results provide a deep insight into the SOXIESST mechanism and suggest that such molecules could be used as detectors for electrons traveling in the substrate at energies lower than the substrate electron affinity.</P> [FIG OMISSION]</BR>

<i>In Situ</i> Atomic-Scale Observation of Surface-Tension-Induced Structural Transformation of Ag-NiP_<i>x</i> Core-Shell Nanocrystals

Huang, Xing,Liu, Zhongqiang,Millet, Marie-Mathilde,Dong, Jichen,Plodine, Milivoj,Ding, Feng,Schlo&#x308,gl, Robert,Willinger, Marc-Georg American Chemical Society 2018 ACS NANO Vol.12 No.7

<P>The properties of nanocrystals are highly dependent on their morphology, composition, and structure. Tailored synthesis over these parameters is successfully applied for the production of nanocrystals with desired properties for specific applications. However, in order to obtain full control over the properties, the behavior of nanocrystals under external stimuli and application conditions needs to be understood. Herein, using Ag-NiP<SUB><I>x</I></SUB> nanocrystals as a model system, we investigate the structural evolution upon thermal treatment by <I>in situ</I> aberration-corrected scanning transmission electron microscopy. A combination of real-time imaging with elemental analysis enables the observation of the transformation from a Ag-NiP<SUB><I>x</I></SUB> core-shell configuration to a Janus structure at the atomic scale. The transformation occurs through dewetting and crystallization of the NiP<SUB><I>x</I></SUB> shell and is accompanied by surface segregation of Ag. Further temperature increase leads to a complete sublimation of Ag and formation of individual Ni<SUB>12</SUB>P<SUB>5</SUB> nanocrystals. The transformation is rationalized by theoretical modeling based on density functional theory calculations. Our model suggests that the transformation is driven by changes of the surface energy of NiP<SUB><I>x</I></SUB> and the interfacial energy between NiP<SUB><I>x</I></SUB> and Ag. The direct observation of atomistic dynamics during thermal-treatment-induced structural modification will help to understand more complex transformations that are induced by aging over time or the interaction with a reactive gas phase in applications such as catalysis.</P> [FIG OMISSION]</BR>

Activation of mammalian target of rapamycin complex 1 (mTORC1) and Raf/Pyk2 by growth factor‐mediated Eph receptor 2 (EphA2) is required for cholangiocarcinoma growth and metastasis

Cui, Xiang&#x2010,Dan,Lee, Mi&#x2010,Jin,Kim, Jong&#x2010,Hyun,Hao, Pei&#x2010,Pei,Liu, Lan,Yu, Goung&#x2010,Ran,Kim, Dae&#x2010,Ghon Wiley Subscription Services, Inc., A Wiley Company 2013 Hepatology Vol.57 No.6

<P><B>Abstract</B></P><P>Eph receptor 2 (EphA2) overexpression is frequently accompanied by the loss of its cognate ligand during tumor progression. However, the molecular mechanism of this ligand‐independent promotion of tumor by EphA2 remains unclear in highly malignant and fatal cholangiocarcinoma (CC). We examined the biological role of EphA2 in tumor growth and metastasis in CC tissues and cells according to the degree of differentiation and we explored the downstream signaling pathways of EphA2. Growth factor‐mediated EphA2 overexpression itself leads to the activation of the mammalian target of rapamycin complex 1 (mTORC1) and extracellular signal‐regulated kinase (ERK) pathways through ligand‐independent activation of EphA2 (phosphorylation of S897). An <I>in vitro</I> soft agar assay and <I>in vivo</I> orthotopic or subcutaneous tumor model showed that EphA2 enhanced colony formation and accelerated tumor growth, and which seemed to be mainly associated with Akt (T308)/mTORC1 activation. Aberrant expression and activation of EphA2 was also associated with poorer differentiation and higher metastatic ability. Enhanced metastatic ability was also observed in an orthotopic tumor model or lung metastasis model, correlating with Pyk2(Y402)/c‐Src/ERK activation in addition to activation of the canonical Raf/MEK/ERK pathway. The mTORC1 and Raf/Pyk2 pathways also appeared to affect each other. These results suggest that growth factor‐mediated EphA2 might be involved in tumor growth and metastasis through activation of the mTORC1 and Raf/Pyk2 pathways. Therapeutic strategies that target EphA2 and its downstream effectors may be useful to control CC. (H<SMALL>EPATOLOGY</SMALL> 2013;57:2248–2260)</P>

Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index

Jiang, Fen,Desta, Zeruesenay,Shon, Ji&#x2010,Hong,Yeo, Chang&#x2010,Woo,Kim, Ho&#x2010,Sook,Liu, Kwang&#x2010,Hyeon,Bae, Soo&#x2010,Kyung,Lee, Sang&#x2010,Seop,Flockhart, David A.,Shin, Jae&#x2010,Goo Blackwell Publishing Ltd 2013 British journal of clinical pharmacology Vol.75 No.1

<P><B>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT</B></P><P>• Cytochrome P450 (CYP) 2B6 is the enzyme primarily responsible for the metabolism of many clinically important drugs, including efavirenz, which it converts to 8‐hydroxyefavirenz and then to 8,14‐hydroxyefavirenz.</P><P>• The CYP2B6*6 polymorphism influences efavirenz pharmacokinetics, but a validated phenotyping method for predicting CYP2B6 activity in human subjects is not yet available.</P><P>• The disposition of 8,14‐dihydroxyefavirenz in humans <I>in vivo</I> is unknown.</P><P><B>WHAT THIS STUDY ADDS</B></P><P>• This study is the first quantitative examination of 8,14‐dihydroxyefavirenz pharmacokinetics in human subjects.</P><P>• The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio correlates with efavirenz oral clearance and is sensitive and specific to CYP2B6 activity alterations.</P><P>• The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio may be a useful phenotyping index for CYP2B6 activity <I>in vivo</I>.</P><P><B>AIMS</B> To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to the <I>CYP2B6</I>*<I>6</I> genotype and explore potential phenotyping indices for CYP2B6 activity <I>in vivo</I> using a low dose of oral efavirenz.</P><P><B>METHODS</B> We conducted a randomized three phase crossover study in 17 healthy Korean subjects pre‐genotyped for the <I>CYP2B6</I>*<I>6</I> allele (<I>CYP2B6</I>*<I>1</I>/*<I>1</I>, <I>n</I>= 6; *<I>1</I>/*<I>6</I>, <I>n</I>= 6; *<I>6</I>/*<I>6</I>, <I>n</I>= 5). Subjects were pretreated with clopidogrel (75 mg day<SUP>−1</SUP> for 4 days), itraconazole (200 mg day<SUP>−1</SUP> for 6 days), or placebo and then given a single dose of efavirenz (200 mg). The plasma (0–120 h) and urine (0–24 h) concentrations of efavirenz and its metabolites (7‐ and 8‐hydroxyefavirenz and 8,14‐dihydroxyefavirenz) were determined by LC/MS/MS.</P><P><B>RESULTS</B> This study is the first to delineate quantitatively the full (phase I and II) metabolic profile of efavirenz and its three hydroxyl metabolites in humans. Clopidogrel pretreatment markedly decreased AUC(0,48 h), <I>C</I><SUB>max</SUB> and Ae(0,24 h) for 8,14‐dihydroxyefavirenz, compared with placebo; 95% CI of the ratios were 0.55, 0.73, 0.30, 0.45 and 0.25, 0.47, respectively. The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio was significantly correlated with the weight‐adjusted CL/<I>F</I> of efavirenz (<I>r</I><SUP>2</SUP>≈ 0.4, <I>P</I> < 0.05), differed with <I>CYP2B6</I>*<I>6</I> genotype and was affected by clopidogrel pretreatment (<I>P</I> < 0.05) but not by itraconazole pretreatment.</P><P><B>CONCLUSIONS</B> The disposition of 8,14‐dihydroxy‐EFV appears to be sensitive to CYP2B6 activity alterations in human subjects. The 8,14‐dihydroxyefaviremz : efavirenz AUC(0,120 h) ratio is attractive as a candidate phenotyping index for CYP2B6 activity <I>in vivo</I>.</P>

Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese Type 2 diabetes

Yang, Hyekyung,Suh, Dong Ho,Kim, Dae Hee,Jung, Eun Sung,Liu, Kwang&#x2010,Hyeon,Lee, Choong Hwan,Park, Cheol&#x2010,Young John Wiley and Sons Inc. 2018 British journal of pharmacology Vol.175 No.17

<P><B>Background and Purpose</B></P><P>Thiazolidinediones, acting as PPAR‐γ ligands, reduce hepatic steatosis in humans and animals. However, the underlying mechanism of this action remains unclear. The purpose of this study was to investigate changes in hepatic metabolites and lipids in response to treatment with the thiazolidinedione pioglitazone in an animal model of obese Type 2 diabetes.</P><P><B>Experimental Approach</B></P><P>Male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were orally administered either vehicle (control) or pioglitazone (30 mg·kg<SUP>−1</SUP>) and fed a high‐fat diet (60% kcal fat) for 12 weeks. Hepatic metabolites were analysed <I>via</I> metabolomic and lipidomic analyses. Gene expression and PLA<SUB>2</SUB> activity were analysed in livers from pioglitazone‐treated and control rats.</P><P><B>Key Results</B></P><P>OLETF rats that received pioglitazone showed decreased fat accumulation and improvement of lipid profiles in the liver compared to control rats. Pioglitazone treatment significantly altered levels of hepatic metabolites, including free fatty acids, lysophosphatidylcholines and phosphatidylcholines, in the liver. In addition, pioglitazone significantly reduced the expression of genes involved in hepatic <I>de novo</I> lipogenesis and fatty acid uptake and transport, whereas genes related to fatty acid oxidation were up‐regulated. Gene expression and enzyme activity of PLA<SUB>2</SUB>, which hydrolyzes phosphatidylcholines to release lysophosphatidylcholines and free fatty acids, were significantly decreased in the livers of pioglitazone‐treated rats compared to control rats.</P><P><B>Conclusions and Implications</B></P><P>Our results present evidence for the ameliorative effect of pioglitazone on hepatic steatosis, largely due to the regulation of lipid metabolism, including fatty acids, lysophosphatidylcholines, phosphatidylcholines and related gene‐expression patterns.</P>