Down‐regulation of <i>GIGANTEA</i> ‐ <i>like</i> genes increases plant growth and salt stress tolerance in poplar

Ke, Qingbo,Kim, Ho Soo,Wang, Zhi,Ji, Chang Yoon,Jeong, Jae Cheol,Lee, Haeng&#x2010,Soon,Choi, Young&#x2010,Im,Xu, Bingcheng,Deng, Xiping,Yun, Dae&#x2010,Jin,Kwak, Sang&#x2010,Soo John Wiley and Sons Inc. 2017 Plant biotechnology journal Vol.15 No.3

<P><B>Summary</B></P><P>The flowering time regulator GIGANTEA (GI) connects networks involved in developmental stage transitions and environmental stress responses in <I>Arabidopsis</I>. However, little is known about the role of GI in growth, development and responses to environmental challenges in the perennial plant poplar. Here, we identified and functionally characterized three <I>GI‐like</I> genes (<I>PagGIa</I>,<I> PagGIb</I> and <I>PagGIc)</I> from poplar (<I>Populus alba × Populus glandulosa</I>). <I>PagGIs</I> are predominantly nuclear localized and their transcripts are rhythmically expressed, with a peak around zeitgeber time 12 under long‐day conditions. Overexpressing <I>PagGIs</I> in wild‐type (WT) <I>Arabidopsis</I> induced early flowering and salt sensitivity, while overexpressing <I>PagGIs</I> in the <I>gi‐2</I> mutant completely or partially rescued its delayed flowering and enhanced salt tolerance phenotypes. Furthermore, the PagGIs‐PagSOS2 complexes inhibited PagSOS2‐regulated phosphorylation of PagSOS1 in the absence of stress, whereas these inhibitions were eliminated due to the degradation of PagGIs under salt stress. Down‐regulation of <I>PagGIs</I> by RNA interference led to vigorous growth, higher biomass and enhanced salt stress tolerance in transgenic poplar plants. Taken together, these results indicate that several functions of <I>Arabidopsis GI</I> are conserved in its poplar orthologues, and they lay the foundation for developing new approaches to producing salt‐tolerant trees for sustainable development on marginal lands worldwide.</P>

7‐Methoxy‐luteolin‐8‐C‐<i>β</i>‐6‐deoxy‐xylo‐pyranos‐3‐uloside exactly (mLU8C‐PU) isolated from <i>Arthraxon hispidus</i> inhibits migratory and invasive responses media

Kim, Soo‐,Jin,Pham, Thu&#x2010,Huyen,Bak, Yesol,Ryu, Hyung&#x2010,Won,Oh, Sei&#x2010,Ryang,Yoon, Do&#x2010,Young John Wiley Sons, Inc. 2018 Environmental toxicology Vol.33 No.11

<P><B>Abstract</B></P><P>7‐Methoxy‐luteolin‐8‐C‐<I>β</I>‐6‐deoxy‐xylo‐pyranos‐3‐uloside (mLU8C‐PU) is a glycosylflavone of luteolin isolated from <I>Arthraxon hispidus</I> (Thunb.). Luteolin is known to exert anti‐migratory and anti‐invasive effects on tumor cells. However, there are no reports on the effects of mLU8C‐PU on tumor invasiveness and associated signaling pathways. In this study, we demonstrated the anti‐migratory and anti‐invasive effects of mLU8C‐PU in 12‐<I>O</I>‐tetradecanoylphorbol‐13‐acetate (TPA)‐treated MCF‐7 breast cancer cells. We also investigated the effect of mLU8C‐PU on invasion‐ related signal transducers, including protein kinase Cα (PKCα), c‐Jun N terminal kinase (JNK), activator protein‐1 (AP‐1), and nuclear factor‐kappa B (NF‐ĸB). TPA‐induced membrane translocation of PKCα, phosphorylation of JNK, and the nuclear translocations of AP‐1 and NF‐κB were downregulated by mLU8C‐PU in MCF‐7 cells. In addition, mLU8C‐PU also inhibited matrix metalloproteinase‐9 (MMP‐9) and interleukin‐8 (IL‐8) expression. These results indicate that mLU8C‐PU inhibits migratory and invasive responses in MCF‐7 breast cancer cells by suppressing MMP‐9 and IL‐8 expression through mitigating TPA‐induced PKCα, JNK activation, and the nuclear translocation of AP‐1 and NF‐κB. These results suggest that mLU8C‐PU may be used as an anti‐metastatic agent.</P>

Compressive mechanical force augments osteoclastogenesis by bone marrow macrophages through activation of c‐Fms‐mediated signaling

Cho, Eui&#x2010,Sic,Lee, Keun&#x2010,Soo,Son, Young&#x2010,Ok,Jang, Yong&#x2010,Suk,Lee, Seung&#x2010,Youp,Kwak, So‐,Yeong,Yang, Yeon&#x2010,Mi,Park, Seung&#x2010,Moon,Lee, Jeong&#x2010,Chae Wiley Subscription Services, Inc., A Wiley Company 2010 Journal of cellular biochemistry Vol.111 No.5

<P><B>Abstract</B></P><P>Little is known about the effects of mechanical forces on osteoclastogenesis by bone marrow macrophages (BMMs) in the absence of mechanosensitive cells, including osteoblasts and fibroblasts. In this study, we examined the effects of mechanical force on osteoclastogenesis by applying centrifugal force to BMMs using a horizontal microplate rotor. Our findings, as measured by an in vitro model system, show that tumor necrosis factor (TNF)‐α is capable of inducing osteoclast differentiation from BMMs and bone resorption in the presence of macrophage‐colony stimulating factor (M‐CSF) and is further facilitated by receptor activator of nuclear factor‐kappaB (NF‐κB) ligand (RANKL). Application of force to BMMs accelerated TNF‐α‐induced osteoclastogenesis; this was inhibited either by anti‐TNF‐α or anti‐TNF‐α receptor but not by OPG. TNF‐α also increased c‐Fms expression at both mRNA and protein levels in BMMs. An anti‐c‐Fms antibody completely inhibited osteoclast differentiation and bone resorption induced by TNF‐α but partially blocked osteoclastogenesis stimulated in combination with RANKL. These results suggest that TNF‐α (in the presence of M‐CSF) is capable of inducing osteoclastogenesis from BMMs, and that osteoclastogenesis is significantly stimulated by force application through the activation of c‐Fms‐mediated signaling. Overall, the present study reveals the facilitating effect of mechanical force on osteoclastic differentiation from BMMs without the addition of mechanosensitive cells. J. Cell. Biochem. 111: 1260–1269, 2010. © 2010 Wiley‐Liss, Inc.</P>

RAR‐Related Orphan Receptor Gamma (ROR‐γ) Mediates Epithelial‐Mesenchymal Transition Of Hepatocytes During Hepatic Fibrosis

Kim, Sung Min,Choi, Jung Eun,Hur, Wonhee,Kim, Jung&#x2010,Hee,Hong, Sung Woo,Lee, Eun Byul,Lee, Joon Ho,Li, Tian Zhu,Sung, Pil Soo,Yoon, Seung Kew John Wiley and Sons Inc. 2017 Journal of cellular biochemistry Vol.118 No.8

<P><B>ABSTRACT</B></P><P>The epithelial‐mesenchymal transition (EMT) is involved in many different types of cellular behavior, including liver fibrosis. In this report, we studied a novel function of RAR‐related orphan receptor gamma (ROR‐γ) in hepatocyte EMT during liver fibrosis. To induce EMT in vitro, primary hepatocytes and FL83B cells were treated with TGF‐β1. Expression of ROR‐γ was analyzed by Western blot in the fibrotic mouse livers and human livers with cirrhosis. To verify the role of ROR‐γ in hepatocyte EMT, we silenced ROR‐γ in FL83B cells using a lentiviral short hairpin RNA (shRNA) vector. The therapeutic effect of ROR‐γ silencing was investigated in a mouse model of TAA‐induced fibrosis by hydrodynamic injection of plasmids. ROR‐γ expression was elevated in hepatocyte cells treated with TGF‐β1, and ROR‐γ protein levels were elevated in the fibrotic mouse livers and human livers with cirrhosis. Knockdown of ROR‐γ resulted in the attenuation of TGF‐β1‐induced EMT in hepatocytes. Strikingly, ROR‐γ bound to ROR‐specific DNA response elements (ROREs) in the promoter region of TGF‐β type I receptor (Tgfbr1) and Smad2, resulting in the downregulation of Tgfbr1 and Smad2 after silencing of ROR‐γ. Therapeutic delivery of shRNA against ROR‐γ attenuated hepatocyte EMT and ameliorated liver fibrosis in a mouse model of TAA‐induced liver fibrosis. Overall, our results suggest that ROR‐γ regulates TGF‐β‐induced EMT in hepatocytes during liver fibrosis. We suggest that ROR‐γ may become a potential therapeutic target in treating liver fibrosis. J. Cell. Biochem. 118: 2026–2036, 2017. © 2016 The Authors. <I>Journal of Cellular Biochemistry</I> Published by Wiley Periodicals Inc.</P>

Highly Efficient p‐i‐n and Tandem Organic Light‐Emitting Devices Using an Air‐Stable and Low‐Temperature‐Evaporable Metal Azide as an n‐Dopant

Yook, Kyoung Soo,Jeon, Soon Ok,Min, Sung&#x2010,Yong,Lee, Jun Yeob,Yang, Ha&#x2010,Jin,Noh, Taeyong,Kang, Sung&#x2010,Kee,Lee, Tae&#x2010,Woo WILEY‐VCH Verlag 2010 Advanced Functional Materials Vol.20 No.11

<P><B>Abstract</B></P><P>Cesium azide (CsN<SUB>3</SUB>) is employed as a novel n‐dopant because of its air stability and low deposition temperature. CsN<SUB>3</SUB> is easily co‐deposited with the electron transporting materials in an organic molecular beam deposition chamber so that it works well as an n‐dopant in the electron transport layer because its evaporation temperature is similar to that of common organic materials. The driving voltage of the p‐i‐n device with the CsN<SUB>3</SUB>‐doped n‐type layer and a MoO<SUB>3</SUB>‐doped p‐type layer is greatly reduced, and this device exhibits a very high power efficiency (57 lm W<SUP>−1</SUP>). Additionally, an n‐doping mechanism study reveals that CsN<SUB>3</SUB> was decomposed into Cs and N<SUB>2</SUB> during the evaporation. The charge injection mechanism was investigated using transient electroluminescence and capacitance–voltage measurements. A very highly efficient tandem organic light‐emitting diodes (OLED; 84 cd A<SUP>−1</SUP>) is also created using an n–p junction that is composed of the CsN<SUB>3</SUB>‐doped n‐type organic layer/MoO<SUB>3</SUB> p‐type inorganic layer as the interconnecting unit. This work demonstrates that an air‐stable and low‐temperature‐evaporable inorganic n‐dopant can very effectively enhance the device performance in p‐i‐n and tandem OLEDs, as well as simplify the material handling for the vacuum deposition process.</P>

3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

Kang, Li&#x2010,Jung,Kwon, Eun&#x2010,Soo,Lee, Kwang Min,Cho, Chanmi,Lee, Jae&#x2010,In,Ryu, Young Bae,Youm, Tae Hyun,Jeon, Jimin,Cho, Mi Ra,Jeong, Seon&#x2010,Yong,Lee, Sang&#x2010,Rae,Kim, Wook,Yang John Wiley and Sons Inc. 2018 British journal of pharmacology Vol.175 No.23

<P><B>Background and Purpose</B></P><P>3′‐Sialyllactose (3′‐SL) is a safe compound that is present in high levels in human milk. Although it has anti‐inflammatory properties and supports immune homeostasis, its effect on collagen‐induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3′‐SL on the progression of rheumatoid arthritis (RA) in <I>in vitro</I> and <I>in vivo</I> models.</P><P><B>Experimental Approach</B></P><P>The anti‐arthritic effect of 3′‐SL was analysed with fibroblast‐like synoviocytes <I>in vitro</I> and an <I>in vivo</I> mouse model of CIA. RT‐PCR, Western blotting and ELISA were performed to evaluate its effects <I>in vitro</I>. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin‐O and haematoxylin staining.</P><P><B>Key Results</B></P><P>3′‐SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3′‐SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro‐inflammatory cytokines, https://en.wikipedia.org/wiki/Matrix_metalloproteinases and osteoclastogenesis <I>via</I> NF‐κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF‐κB signalling pathway, was totally blocked by 3′‐SL in the RA models.</P><P><B>Conclusions and Implications</B></P><P>3′‐SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated <I>via</I> blockade of the NF‐κB signalling pathway. Therefore, 3′‐SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.</P>

Protein‐Induced Pluripotent Stem Cells Ameliorate Cognitive Dysfunction and Reduce Aβ Deposition in a Mouse Model of Alzheimer's Disease

Cha, Moon&#x2010,Yong,Kwon, Yoo&#x2010,Wook,Ahn, Hyo&#x2010,Suk,Jeong, Hyobin,Lee, Yong Yook,Moon, Minho,Baik, Sung Hoon,Kim, Dong Kyu,Song, Hyundong,Yi, Eugene C.,Hwang, Daehee,Kim, Hyo&#x2010,Soo,Mo John Wiley and Sons Inc. 2017 Stem cells translational medicine Vol.6 No.1

<P><B>Abstract</B></P><P>Transplantation of stem cells into the brain attenuates functional deficits in the central nervous system via cell replacement, the release of specific neurotransmitters, and the production of neurotrophic factors. To identify patient‐specific and safe stem cells for treating Alzheimer's disease (AD), we generated induced pluripotent stem cells (iPSCs) derived from mouse skin fibroblasts by treating protein extracts of embryonic stem cells. These reprogrammed cells were pluripotent but nontumorigenic. Here, we report that protein‐iPSCs differentiated into glial cells and decreased plaque depositions in the 5XFAD transgenic AD mouse model. We also found that transplanted protein‐iPSCs mitigated the cognitive dysfunction observed in these mice. Proteomic analysis revealed that oligodendrocyte‐related genes were upregulated in brains injected with protein‐iPSCs, providing new insights into the potential function of protein‐iPSCs. Taken together, our data indicate that protein‐iPSCs might be a promising therapeutic approach for AD. S<SMALL>TEM</SMALL> C<SMALL>ELLS</SMALL> T<SMALL>RANSLATIONAL</SMALL> M<SMALL>EDICINE</SMALL><I>2017;6:293–305</I></P>

Upregulated microRNA‐193a‐3p is responsible for cisplatin resistance in CD 44(+) gastric cancer cells

Lee, So D.,Yu, Dayeon,Lee, Do Y.,Shin, Hyun&#x2010,Soo,Jo, Jeong&#x2010,Hyeon,Lee, Yong C. John Wiley and Sons Inc. 2019 Cancer Science Vol.110 No.2

<P>Cisplatin is a well‐known anticancer drug used to treat various cancers. However, development of cisplatin resistance has hindered the efficiency of this drug in cancer treatment. Development of chemoresistance is known to involve many signaling pathways. Recent attention has focused on microRNAs (miRNAs) as potentially important upstream regulators in the development of chemoresistance. CD44 is one of the gastric cancer stem cell markers and plays a role in regulating self‐renewal, tumor initiation, metastasis and chemoresistance. The purpose of the present study was to examine the mechanism of miRNA‐mediated chemoresistance to cisplatin in CD44‐positive gastric cancer stem cells. We sorted gastric cancer cells according to level of CD44 expression by FACS and analyzed their miRNA expression profiles by microarray analysis. We found that miR‐193a‐3p was significantly upregulated in CD44(+) cells compared with CD44(−) cells. Moreover, SRSF2 of miR‐193a‐3p target gene was downregulated in CD44(+) cells. We studied the modulation of Bcl‐X and caspase 9 mRNA splicing by SRSF2 and found that more pro‐apoptotic variants of these genes were generated. We also found that downstream anti‐apoptotic genes such as Bcl‐2 were upregulated, whereas pro‐apoptotic genes such as Bax and cytochrome C were downregulated in CD44(+) cells compared to CD44(−) cells. In addition, we found that an elevated level of miR‐193a‐3p triggered the development of cisplatin resistance in CD44(+) cells. Inhibition of miR‐193a‐3p in CD44(+) cells increased SRSF2 expression and also altered the levels of multiple apoptotic genes. Furthermore, inhibition of miR‐193a‐3p reduced cell viability and increased the number of apoptotic cells. Therefore, miR‐193a‐3p may be implicated in the development of cisplatin resistance through regulation of the mitochondrial apoptosis pathway. miR‐193a‐3p could be a promising target for cancer therapy in cisplatin‐resistant gastric cancer.</P>

A liver‐specific gene expression panel predicts the differentiation status of <i>in vitro</i> hepatocyte models

Kim, Dae&#x2010,Soo,Ryu, Jea&#x2010,Woon,Son, Mi&#x2010,Young,Oh, Jung&#x2010,Hwa,Chung, Kyung&#x2010,Sook,Lee, Sugi,Lee, Jeong&#x2010,Ju,Ahn, Jun&#x2010,Ho,Min, Ju&#x2010,Sik,Ahn, Jiwon,Kang, Hyun Mi John Wiley and Sons Inc. 2017 Hepatology Vol.66 No.5

<P>Alternative cell sources, such as three‐dimensional organoids and induced pluripotent stem cell–derived cells, might provide a potentially effective approach for both drug development applications and clinical transplantation. For example, the development of cell sources for liver cell–based therapy has been increasingly needed, and liver transplantation is performed for the treatment for patients with severe end‐stage liver disease. Differentiated liver cells and three‐dimensional organoids are expected to provide new cell sources for tissue models and revolutionary clinical therapies. However, conventional experimental methods confirming the expression levels of liver‐specific lineage markers cannot provide complete information regarding the differentiation status or degree of similarity between liver and differentiated cell sources. Therefore, in this study, to overcome several issues associated with the assessment of differentiated liver cells and organoids, we developed a liver‐specific gene expression panel (LiGEP) algorithm that presents the degree of liver similarity as a “percentage.” We demonstrated that the percentage calculated using the LiGEP algorithm was correlated with the developmental stages of <I>in vivo</I> liver tissues in mice, suggesting that LiGEP can correctly predict developmental stages. Moreover, three‐dimensional cultured HepaRG cells and human pluripotent stem cell–derived hepatocyte‐like cells showed liver similarity scores of 59.14% and 32%, respectively, although general liver‐specific markers were detected. <I>Conclusion</I>: Our study describes a quantitative and predictive model for differentiated samples, particularly liver‐specific cells or organoids; and this model can be further expanded to various tissue‐specific organoids; our LiGEP can provide useful information and insights regarding the differentiation status of <I>in vitro</I> liver models. (H<SMALL>EPATOLOGY</SMALL> 2017;66:1662–1674).</P>

Association of 5‐hydroxytryptamine (serotonin) receptor 4 (5‐HTR4) gene polymorphisms with asthma

KIM, TAE&#x2010,HOON,AN, SUNG&#x2010,HYE,CHA, JI&#x2010,YEON,SHIN, EUN&#x2010,KYONG,LEE, JI&#x2010,YEON,YOON, SANG&#x2010,HYUK,LEE, YOUNG&#x2010,MOK,UH, SOO‐,TAEK,PARK, SUNG&#x2010,WOO,PARK, JON Blackwell Publishing Asia 2011 RESPIROLOGY Vol.16 No.4

<P><B>ABSTRACT</B></P><P><B>Background and objective: </B> The neurotransmitter, 5‐hydroxytryptamine, acts as an immunomodulator by stimulating the release of inflammatory cytokines and regulating the function of dendritic cells and monocytes. The 5‐hydroxytryptamine receptor 4 (<I>HTR4</I>) gene is located in a region previously linked to an increased risk of asthma and atopy. The aim of this study was to investigate the association between <I>HTR4</I> and asthma.</P><P><B>Methods: </B> Thirty‐two single nucleotide polymorphisms (SNP) in <I>HTR4</I> were investigated by direct sequencing of 24 DNA samples from unrelated Korean subjects.</P><P><B>Results: </B> The 32 genetic variants comprised 22 intronic SNP, two SNP in the 3′‐untranslated region (exon 7) and eight SNP in the 3′‐downstream region. Logistic regression analysis showed that two intronic polymorphisms were significantly associated with the risk of asthma. Two minor <I>HTR4</I> alleles, +<I>142828G</I> > <I>A</I> and +<I>122769G</I> > <I>A</I>, occurred at significantly higher frequencies in the asthmatic group than in the healthy control group (49.59% vs 42.29%, <I>P</I> = 0.003, and 47.99% vs 40.35%, <I>P</I> = 0.008, respectively), and these differences remained significant after correction for multiple testing (<I>P</I> = 0.05, dominant mode of inheritance; and <I>P</I> = 0.03, dominant mode, respectively). Haplotype analysis revealed three haplotype blocks. The frequency of haplotype 1 in block 2 was significantly higher in asthmatics (<I>P</I> = 0.003, dominant mode), whereas the frequency of haplotype 4 in block 3 was significantly lower in asthmatics (<I>P</I> = 0.0009, dominant mode).</P><P><B>Conclusions: </B> SNP and haplotypes of the <I>HTR4</I> gene were associated with the asthma phenotype and genetic variation of <I>HTR4</I> may affect susceptibility to the development of asthma.</P>