Anti‐inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide‐stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase‐1 expression

Jung, Ji&#x2010,Sun,Shin, Jin A.,Park, Eun&#x2010,Mi,Lee, Jung&#x2010,Eun,Kang, Young&#x2010,Sook,Min, Sung&#x2010,Won,Kim, Dong&#x2010,Hyun,Hyun, Jin&#x2010,Won,Shin, Chan‐,Young,Kim, Hee&#x201 Blackwell Publishing Ltd 2010 Journal of Neurochemistry Vol.115 No.6

<P> <I>J. Neurochem.</I> (2010) <B>115,</B> 1668–1680.</P><P><B>Abstract</B></P><P>Microglia activation plays a pivotal role in neurodegenerative diseases, and thus controlling microglial activation has been suggested as a promising therapeutic strategy for neurodegenerative diseases. In the present study, we showed that ginsenoside Rh1 inhibited inducible nitric oxide synthase, cyclooxygenase‐2, and pro‐inflammatory cytokine expression in lipopolysaccharide (LPS)‐stimulated microglia, while Rh1 increased anti‐inflammatory IL‐10 and hemeoxygenase‐1 (HO‐1) expression. Suppression of microglial activation by Rh1 was also observed in the mouse brain following treatment with LPS. Subsequent mechanistic studies revealed that Rh1 inhibited LPS‐induced MAPK phosphorylation and nuclear factor‐κB (NF‐κB)‐mediated transcription without affecting NF‐κB DNA binding. As the increase of pCREB (cAMP responsive element‐binding protein) is known to result in suppression of NF‐κB‐mediated transcription, we examined whether Rh1 increased pCREB levels. As expected, Rh1 increased pCREB, which was shown to be related to the anti‐inflammatory effect of Rh1 because pre‐treatment with protein kinase A inhibitors attenuated the Rh1‐mediated inhibition of nitric oxide production and the up‐regulation of IL‐10 and HO‐1. Furthermore, treatment of HO‐1 shRNA attenuated Rh1‐mediated inhibition of nitric oxide and reactive oxygen species production. Through this study, we have demonstrated that protein kinase A and its downstream effector, HO‐1, play a critical role in the anti‐inflammatory mechanism of Rh1 by modulating pro‐ and anti‐inflammatory molecules in activated microglia.</P>

PD‐L1 expression in <i>ROS1</i> ‐rearranged non‐small cell lung cancer: A study using simultaneous genotypic screening of <i>EGFR</i> , <i>ALK</i> , and <i>ROS1</i>

Lee, Jongmin,Park, Chan Kwon,Yoon, Hyoung&#x2010,Kyu,Sa, Young Jo,Woo, In Sook,Kim, Hyo Rim,Kim, Sue Youn,Kim, Tae&#x2010,Jung Wiley-Blackwells 2019 Thoracic cancer Vol.10 No.1

<P><B>Background</B></P><P>The aim of the current study was to investigate the prevalence and clinicopathologic characteristics of <I>ROS1</I>‐rearranged non‐small cell lung cancer (NSCLC) in routine genotypic screening in conjunction with the study of PD‐L1 expression, a biomarker for first‐line treatment decisions.</P><P><B>Methods</B></P><P>Reflex simultaneous genotypic screening for <I>EGFR</I> by peptide nucleic acid clamping, and <I>ALK</I> and <I>ROS1</I> by fluorescence in situ hybridization (FISH) was performed on consecutive NSCLC cases at the time of initial pathologic diagnosis. We evaluated genetic aberrations, clinicopathologic characteristics, and PD‐L1 tumor proportion score (TPS) using a PD‐L1 22C3 assay kit.</P><P><B>Results</B></P><P>In 407 consecutive NSCLC patients, simultaneous genotyping identified 14 (3.4%) <I>ROS1</I> and 19 (4.7%) <I>ALK</I> rearrangements, as well as 106 (26%) <I>EGFR</I> mutations. These mutations were mutually exclusive and were found in patients with similar clinical features, including younger age, a prevalence in women, adenocarcinoma, and advanced stage. The PD‐L1 assay was performed on 130 consecutive NSCLC samples. High PD‐L1 expression (TPS ≥ 50%) was observed in 29 (22.3%) tumors. PD‐L1 expression (TPS ≥ 1%) was significantly associated with wild type <I>EGFR</I>, while <I>ROS1</I> rearrangement was associated with high PD‐L1 expression. Of the 14 cases with <I>ROS1</I> rearrangement, 12 (85.7%) showed PD‐L1 expression and 5 (35.7%) showed high PD‐L1 expression.</P><P><B>Conclusion</B></P><P>In the largest consecutive routine Asian NSCLC cohort analyzed to date, we found that high PD‐L1 expression frequently overlapped with <I>ROS1</I> rearrangement, while it negatively correlated with <I>EGFR</I> mutations.</P>

MicroRNA‐320a and microRNA‐4496 attenuate <i>Helicobacter pylori</i> cytotoxin‐associated gene A (CagA)‐induced cancer‐initiating potential and chemoresistance by targeting β‐catenin and ATP‐binding casse

Kang, Dong Woo,Yang, Eun Sun,Noh, Yu Na,Hwang, Won Chan,Jo, Se&#x2010,Young,Suh, Young&#x2010,Ah,Park, Won Sang,Choi, Kang&#x2010,Yell,Min, Do Sik John Wiley Sons, Ltd 2017 The Journal of pathology Vol.241 No.5

<P><B>Abstract</B></P><P>Infection with <I>Helicobacter pylori</I> is closely linked to an increased risk of gastric cancer. Although cytotoxin‐associated gene A (CagA), a major virulence factor of <I>H. pylori</I>, is known to be a causal factor for gastric carcinogenesis, the molecular link between CagA and gastric cancer‐initiating cell (CIC)‐like properties remains elusive. Here, we demonstrate that CagA is required for increased expression of β‐catenin and its target CIC markers via downregulation of microRNA (miR)‐320a and miR‐4496. CagA promoted gastric CIC properties and was responsible for chemoresistance. miR‐320a and miR‐4496 attenuated the <I>in vitro</I> self‐renewal and tumour‐initiating capacity of CagA‐expressing CICs by targeting β‐catenin. Moreover, miR‐320a and miR‐4496 decreased CagA‐induced chemoresistance by targeting ATP‐binding cassette, subfamily G, member 2 (ABCG2) at the transcriptional and post‐transcriptional levels, respectively. Combination therapy with 5‐fluorouracil and miR‐320a/miR‐4496 suppressed gastric tumourigenesis and metastatic potential in an orthotopic mouse model, probably via suppression of CagA‐induced CIC properties and chemoresistance. Our results provide novel evidence that CIC properties, chemoresistance and tumourigenesis associated with <I>H. pylori</I> are linked to CagA‐induced upregulation of β‐catenin and ABCG2. These data provide novel insights into the molecular mechanisms of CagA‐induced carcinogenisis and the therapeutic potential of of miR‐320a and miR‐4496. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</P>

RNA activation‐independent DNA targeting of the Type III CRISPR‐Cas system by a Csm complex

Park, Kwang&#x2010,Hyun,An, Yan,Jung, Tae&#x2010,Yang,Baek, In&#x2010,Young,Noh, Haemin,Ahn, Woo&#x2010,Chan,Hebert, Hans,Song, Ji&#x2010,Joon,Kim, Jeong&#x2010,Hoon,Oh, Byung&#x2010,Ha,Woo, Eui&#x201 unknown 2017 EMBO reports Vol.18 No.5

<P>The CRISPR-Cas system is an adaptive and heritable immune response that destroys invading foreign nucleic acids. The effector complex of the Type III CRISPR-Cas system targets RNA and DNA in a transcription-coupled manner, but the exact mechanism of DNA targeting by this complex remains elusive. In this study, an effector Csm holocomplex derived from Thermococcus onnurineus is reconstituted with a minimalistic combination of Csm1(1)2(1)3(3)4(1)5(1), and shows RNA targeting and RNA-activated single-stranded DNA (ssDNA) targeting activities. Unexpectedly, in the absence of an RNA transcript, it cleaves ssDNA containing a sequence complementary to the bound crRNA guide region in a manner dependent on the HD domain of the Csm1 subunit. This nuclease activity is blocked by a repeat tag found in the host CRISPR loci. The specific cleavage of ssDNA without a target RNA suggests a novel ssDNA targeting mechanism of the Type III system, which could facilitate the efficient and complete degradation of foreign nucleic acids.</P>

Improved pre‐osteoblast response and mechanical compatibility of ultrafine‐grained Ti–13Nb–13Zr alloy

Park, Chan Hee,Lee, Chong Soo,Kim, Youn&#x2010,Jeong,Jang, Je&#x2010,Hee,Suh, Jo&#x2010,Young,Park, Jin&#x2010,Woo Blackwell Publishing Ltd 2011 Clinical oral implants research Vol.22 No.7

<P><B>Abstract</B></P><P><B>Objective: </B> Metallic implantation materials having high yield strength, low elastic modulus, and non‐cytotoxic alloying elements would be advantageous for the long‐term stability of implants. This study assessed the surface and mechanical properties, and also <I>in vitro</I> osteoconductivity of ultrafine‐grained (UFG) Ti–13Nb–13Zr alloy produced by dynamic globularization without any severe deformation for future biomedical applications as an endosseous implant material.</P><P><B>Material and methods: </B> The surface characteristics and mechanical properties were investigated by orientation image microscopy, contact angle measurements, optical profilometry, and uniaxial tension tests. Mouse calvaria‐derived pre‐osteoblastic cell (MC3T3‐E1) attachment, spreading, viability, alkaline phosphatase (ALP) activity, and quantitative analysis of osteoblastic gene expression on UFG Ti–13Nb–13Zr alloy were compared with coarse‐grained (CG) Ti–13Nb–13Zr and CG Ti–6Al–4V alloys.</P><P><B>Results: </B> Dynamic globularized Ti–13Nb–13Zr alloy has an ultrafine grain size (0.3 μm) and an excellent combination of yield strength and elastic modulus compared with CG alloys, which displayed significantly lower water contact angles compared with CG alloys (<I>P</I><0.05). The UFG and CG Ti–13Nb–13Zr alloys displayed significantly increased cellular attachment compared with CG Ti–6Al–4V alloy (<I>P</I><0.05). The UFG Ti–13Nb–13Zr supported better cell spreading and more numerous focal adhesions. ALP activity (<I>P</I><0.05) and mRNA expressions of the osteoblast transcription factor genes (osterix, Runx2) and marker gene for osteoblast differentiation (osteocalcin) were markedly increased in cells grown on the UFG substrate compared with CG substrates at early incubation timepoints.</P><P><B>Conclusion: </B> Enhanced pre‐osteoblast response to UFG Ti–13Nb–13Zr substrate is attributable to the non‐cytotoxic alloying elements and the submicron scale grain size contributes to the superior surface hydrophilicity and abundant grain boundaries favorable for cell behavior. These findings indicate that dynamic globularized UFG Ti–13Nb–13Zr alloy is promising for load‐bearing endosseous implant material because of excellent mechanical and biological compatibilites.</P><P> <B>To cite this article:</B> 
Park CH, Lee CS, Kim Y‐J, Jang J‐H, Suh J‐Y, Park J‐W. Improved pre‐osteoblast response and mechanical compatibility of ultrafine‐grained Ti–13Nb–13Zr alloy.
<I>Clin. Oral Impl. Res</I>. <B>22</B>, 2011; 735–742
doi: 10.1111/j.1600‐0501.2010.02053.x</P>

Identification of a novel starfish neuropeptide that acts as a muscle relaxant

Kim, Chan‐,Hee,Kim, Eun Jung,Go, Hye&#x2010,Jin,Oh, Hye Young,Lin, Ming,Elphick, Maurice R.,Park, Nam Gyu John Wiley and Sons Inc. 2016 Journal of Neurochemistry Vol.137 No.1

<P><B>Abstract</B></P><P>Neuropeptides that act as muscle relaxants have been identified in chordates and protostomian invertebrates but little is known about the molecular identity of neuropeptides that act as muscle relaxants in deuterostomian invertebrates (e.g. echinoderms) that are ‘evolutionary intermediates’ of chordates and protostomes. Here, we have used the apical muscle of the starfish <I>Patiria pectinifera</I> to assay for myorelaxants in extracts of this species. A hexadecapeptide with the amino acid sequence Phe‐Gly‐Lys‐Gly‐Gly‐Ala‐Tyr‐Asp‐Pro‐Leu‐Ser‐Ala‐Gly‐Phe‐Thr‐Asp was identified and designated starfish myorelaxant peptide (SMP). Cloning and sequencing of a cDNA encoding the SMP precursor protein revealed that it comprises 12 copies of SMP as well as 3 peptides (7 copies in total) that are structurally related to SMP. Analysis of the expression of SMP precursor transcripts in <I>P. pectinifera</I> using qPCR revealed the highest expression in the radial nerve cords and lower expression levels in a range of neuromuscular tissues, including the apical muscle, tube feet and cardiac stomach. Consistent with these findings, SMP also caused relaxation of tube foot and cardiac stomach preparations. Furthermore, SMP caused relaxation of apical muscle preparations from another starfish species – <I>Asterias amurensis</I>. Collectively, these data indicate that SMP has a general physiological role as a muscle relaxant in starfish. Interestingly, comparison of the sequence of the SMP precursor with known neuropeptide precursors revealed that SMP belongs to a bilaterian family of neuropeptides that include molluscan pedal peptides (PP) and arthropodan orcokinins (OK). This is the first study to determine the function of a PP/OK‐type peptide in a deuterostome.</P><P> Pedal peptide/orcokinin (PP/OK)‐type peptides are a family of structurally related neuropeptides that were first identified and functionally characterised in protostomian invertebrates. Here, we report the discovery of starfish myorelaxant peptide (SMP), a novel member of the PP/OK‐type neuropeptide identified in the starfish <I>Patiria pectinifera</I> (phylum Echinodermata). SMP is the first PP/OK‐type neuropeptide to be functionally characterised in a deuterostome.</P>

Interleukin‐15 enhances proliferation and chemokine secretion of human follicular dendritic cells

Gil, Minchan,Park, Seo&#x2010,Jeong,Chung, Yoo&#x2010,Sam,Park, Chan‐,Sik Blackwell Publishing Ltd 2010 Immunology Vol.130 No.4

<P><B>Summary</B></P><P>The germinal centre (GC) is a specialized microenvironment where high‐affinity antibodies are produced through hypermutation and isotype switching. Follicular dendritic cells (FDCs) are the stromal cells of the GC. The timely expansion and establishment of an FDC network is essential for a protective GC reaction; however, only a few factors modulating FDC development have been recognized. In this study, we report that interleukin‐15 (IL‐15) enhances human primary FDC proliferation and regulates cytokine secretion. The FDCs express IL‐15 receptor complexes for IL‐15 signal transduction as well as for specific binding. Moreover, the secretion of chemokines CCL‐2, CCL‐5, CXCL‐5 and CXCL‐8 was reduced by blocking IL‐15 signalling while the secretion of other cytokines, and the expression of CD14, CD44, CD54 (ICAM‐1) and CD106 (VCAM‐1) proteins remained unchanged. These results suggest that IL‐15 plays a crucial role in the development of FDC networks during GC reaction, offering a new target for immune modulation.</P>

High‐risk human papillomavirus and cervical lymph node metastasis in patients with oropharyngeal cancer

Joo, Young&#x2010,Hoon,Jung, Chan‐,Kwon,Sun, Dong&#x2010,Il,Park, Jun&#x2010,Ook,Cho, Kwang&#x2010,Jae,Kim, Min&#x2010,Sik Wiley Subscription Services, Inc., A Wiley Company 2012 Head & neck Vol.34 No.1

<P><B>Abstract</B></P><P><B>Background</B></P><P>The purpose of this study was to determine the role of high‐risk human papillomavirus (HPV) in lymph node metastasis and the depth of invasion in oropharyngeal cancer.</P><P><B>Methods</B></P><P>The study included patients with 90 oral carcinomas and 66 oropharyngeal carcinomas. High‐risk HPV in situ hybridization was performed to detect HPV infection.</P><P><B>Results</B></P><P>The positive rate of high‐risk HPV in situ hybridization was 15.4% (24 of 156). There was a significant difference in the fraction of positive high‐risk HPV between oral (6.7%) and oropharyngeal (27.3%) cancers (<I>p</I> < .000). Significant correlations were found between positive high‐risk HPV and cervical lymph node metastasis, tumor depth of invasion in patients with oropharyngeal cancer (<I>p</I> = .002, <I>p</I> = .016, respectively). There was a statistically significant association between high‐risk HPV positivity and the disease‐specific survival in patients with oropharyngeal cancer (<I>p</I> = .035).</P><P><B>Conclusion</B></P><P>High‐risk HPV infection was significantly related to cervical lymph node metastasis and depth of invasion in patients with oropharyngeal cancer. © 2011 Wiley Periodicals, Inc. Head Neck, 2012</P>

Tight orbit syndrome resulting from large globe with high myopia: intractable glaucoma treated by orbital decompression

Park, Hae&#x2010,Young Lopilly,Paik, Ji Sun,Cho, Won&#x2010,Kyung,Park, Chan Kee,Yang, Suk&#x2010,Woo Blackwell Publishing Asia 2012 Clinical & experimental ophthalmology Vol.40 No.2

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

Park, Dongsun,Yang, Goeun,Bae, Dae Kwon,Lee, Sun Hee,Yang, Yun&#x2010,Hui,Kyung, Jangbeen,Kim, Dajeong,Choi, Ehn&#x2010,Kyoung,Choi, Kyung&#x2010,Chul,Kim, Seung U.,Kang, Sung Keun,Ra, Jeong Chan,Kim, Wiley Subscription Services, Inc., A Wiley Company 2013 JOURNAL OF NEUROSCIENCE RESEARCH - Vol.91 No.5

<P><B>Abstract</B></P><P>Brain ageing leads to atrophy and degeneration of the cholinergic nervous system, resulting in profound neurobehavioral and cognitive dysfunction from decreased acetylcholine biosynthesis and reduced secretion of growth and neurotrophic factors. Human adipose tissue‐derived mesenchymal stem cells (ADMSCs) were intravenously (1 × 10<SUP>6</SUP> cells) or intracerebroventricularly (4 × 10<SUP>5</SUP> cells) transplanted into the brains of 18‐month‐old mice once or four times at 2‐week intervals. Transplantation of ADMSCs improved both locomotor activity and cognitive function in the aged animals, in parallel with recovery of acetylcholine levels in brain tissues. Transplanted cells differentiated into neurons and, in part, into astrocytes and produced choline acetyltransferase proteins. Transplantation of ADMSCs restored microtubule‐associated protein 2 in brain tissue and enhanced Trk B expression and the concentrations of brain‐derived neurotrophic factor and nerve growth factor. These results indicate that human ADMSCs differentiate into neural cells in the brain microenvironment and can restore physical and cognitive functions of aged mice not only by increasing acetylcholine synthesis but also by restoring neuronal integrity that may be mediated by growth/neurotrophic factors. © 2013 Wiley Periodicals, Inc.</P>