3′‐Sialyllactose protects against osteoarthritic development by facilitating cartilage homeostasis

Jeon, Jimin,Kang, Li&#x2010,Jung,Lee, Kwang Min,Cho, Chanmi,Song, Eun Kyung,Kim, Wook,Park, Tae Joo,Yang, Siyoung John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.1

<P><B>Abstract</B></P><P>3′‐Sialyllactose has specific physiological functions in a variety of tissues; however, its effects on osteoarthritic development remain unknown. Here, we demonstrated the function of 3′‐sialyllactose on osteoarthritic cartilage destruction. <I>In vitro</I> and <I>ex vivo</I>, biochemical and histological analysis demonstrated that 3′‐sialyllactose was sufficient to restore the synthesis of Col2a1 and accumulation of sulphated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development, and blocked the expression of Mmp3, Mmp13 and Cox2 induced by IL‐1β, IL‐6, IL‐17 and TNF‐α, which mediates cartilage degradation. Further, reporter gene assays revealed that the activity of Sox9 as a transcription factor for Col2a1 expression was accelerated by 3′‐sialyllactose, whereas the direct binding of NF‐κB to the <I>Mmp3</I>,<I> Mmp13</I> and <I>Cox2</I> promoters was reduced by 3′‐sialyllactose in IL‐1β‐treated chondrocytes. Additionally, IL‐1β induction of Erk phosphorylation and IκB degradation, representing a critical signal pathway for osteoarthritic development, was totally blocked by 3′‐sialyllactose in a dose‐dependent manner. <I>In vivo</I>, 3′‐sialyllactose protected against osteoarthritic cartilage destruction in an osteoarthritis mouse model induced by destabilization of the medial meniscus, as demonstrated by histopathological analysis. Our results strongly suggest that 3′‐sialyllactose may ameliorate osteoarthritic cartilage destruction by cartilage regeneration <I>via</I> promoting Col2a1 production and may inhibit cartilage degradation and inflammation by suppressing Mmp3, Mmp13 and Cox2 expression. The effects of 3′‐sialyllactose could be attributed in part to its regulation of Sox9 or NF‐κB and inhibition of Erk phosphorylation and IκB degradation. Taken together, these effects indicate that 3′‐sialyllactose merits consideration as a natural therapeutic agent for protecting against osteoarthritis.</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>

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>

Probing the nature of high‐<i>z</i> short GRB 090426 with its early optical and X‐ray afterglows

Xin, Li&#x2010,Ping,Liang, En&#x2010,Wei,Wei, Jian&#x2010,Yan,Zhang, Bing,Lv, Hou&#x2010,Jun,Zheng, Wei&#x2010,Kang,Urata, Yuji,Im, Myungshin,Wang, Jing,Qiu, Yu&#x2010,Lei,Deng, Jin&#x2010,Song,Huang, Blackwell Publishing Ltd 2011 MONTHLY NOTICES- ROYAL ASTRONOMICAL SOCIETY Vol.410 No.1

<P><B>ABSTRACT</B></P><P>GRB 090426 is a short‐duration burst detected by <I>Swift</I> (<IMG src='/wiley-blackwell_img/equation/MNR_17419_mu1.gif' alt ='inline image'/> s in the observer frame and <IMG src='/wiley-blackwell_img/equation/MNR_17419_mu2.gif' alt ='inline image'/> s in the burst frame at <I>z</I>= 2.609). Its host galaxy properties and some gamma‐ray‐related correlations are analogous to those seen in long‐duration gamma‐ray bursts (GRBs), which are believed to be of a massive star origin (so‐called Type II GRBs). We present the results of its early optical observations with the 0.8‐m Tsinghua University–National Astronomical Observatory of China Telescope (TNT) at Xinglong Observatory and the 1‐m LOAO telescope at Mt Lemmon Optical Astronomy Observatory in Arizona. Our well‐sampled optical afterglow light curve covers from <IMG src='/wiley-blackwell_img/equation/MNR_17419_mu3.gif' alt ='inline image'/> to 10<SUP>4</SUP> s after the GRB trigger. It shows two shallow decay episodes that are likely due to energy injection, which end at <IMG src='/wiley-blackwell_img/equation/MNR_17419_mu4.gif' alt ='inline image'/> and 7100 s, respectively. The decay slopes after the injection phases are consistent with each other (<IMG src='/wiley-blackwell_img/equation/MNR_17419_mu5.gif' alt ='inline image'/>). The X‐ray afterglow light curve appears to trace the optical, although the second energy‐injection phase was missed due to visibility constraints introduced by the <I>Swift</I> orbit. The X‐ray spectral index is <IMG src='/wiley-blackwell_img/equation/MNR_17419_mu6.gif' alt ='inline image'/> without temporal evolution. Its decay slope is consistent with the prediction of the forward shock model. Both X‐ray and optical emission are consistent with being in the same spectral regime above the cooling frequency (<IMG src='/wiley-blackwell_img/equation/MNR_17419_mu7.gif' alt ='inline image'/>). The fact that <IMG src='/wiley-blackwell_img/equation/MNR_17419_mu8.gif' alt ='inline image'/> is below the optical band from the very early epoch of the observation provides a constraint on the burst environment, which is similar to that seen in classical long‐duration GRBs. We therefore suggest that death of a massive star is the possible progenitor of this short burst.</P>

Novel oral transforming growth factor‐β signaling inhibitor EW ‐7197 eradicates CML ‐initiating cells

Naka, Kazuhito,Ishihara, Kaori,Jomen, Yoshie,Jin, Cheng Hua,Kim, Dong&#x2010,Hyun,Gu, Yoon&#x2010,Kang,Jeong, Eun&#x2010,Sook,Li, Shaoguang,Krause, Daniela S.,Kim, Dong&#x2010,Wook,Bae, Eunjin,Takihar John Wiley and Sons Inc. 2016 CANCER SCIENCE Vol.107 No.2

<P>Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia‐initiating cells (CML‐LICs). However, little is known about the therapeutic benefits such CML‐LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW‐7197, an orally bioavailable transforming growth factor‐β signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML‐LICs <I>in vivo</I>. Compared to TKI treatment alone, administration of TKI plus EW‐7197 to CML‐affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW‐7197 plus TKI was effective in eliminating CML‐LICs even if they expressed the TKI‐resistant T315I mutant <I>BCR‐ABL1</I> oncogene. Collectively, these results indicate that EW‐7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML‐LICs.</P>

K _Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

Choi, Shinkyu,Kim, Ji Aee,Li, Hai&#x2010,yan,Shin, Kyong&#x2010,Oh,Oh, Goo Taeg,Lee, Yong&#x2010,Moon,Oh, Seikwan,Pewzner&#x2010,Jung, Yael,Futerman, Anthony H.,Suh, Suk Hyo BLACKWELL PUBLISHING 2016 AGING CELL Vol.15 No.5

<P><B>Summary</B></P><P>Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial K<SUB>Ca</SUB>3.1, which contributes to EDR, is upregulated by H<SUB>2</SUB>O<SUB>2</SUB>. We investigated whether K<SUB>Ca</SUB>3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H<SUB>2</SUB>O<SUB>2</SUB> levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and K<SUB>Ca</SUB>3.1 upregulation. Catalase/GPX1 double knockout (catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP>) upregulated K<SUB>Ca</SUB>3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP>MAECs. However, K<SUB>Ca</SUB>3.1 activation‐induced, NG‐nitro‐<SMALL>L</SMALL>‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP> mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated K<SUB>Ca</SUB>3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H<SUB>2</SUB>O<SUB>2</SUB> and thereby upregulate K<SUB>Ca</SUB>3.1 expression and function via a H<SUB>2</SUB>O<SUB>2</SUB>/Fyn‐mediated pathway. Altogether, enhanced K<SUB>Ca</SUB>3.1 activity may compensate for decreased NO signaling during vascular aging.</P>

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via KC _a 1.1 upregulation

Choi, Shinkyu,Kim, Ji Aee,Kim, Tae Hun,Li, Hai&#x2010,yan,Shin, Kyong&#x2010,Oh,Lee, Yong&#x2010,Moon,Oh, Seikwan,Pewzner&#x2010,Jung, Yael,Futerman, Anthony H.,Suh, Suk Hyo BLACKWELL PUBLISHING 2015 AGING CELL Vol.14 No.6

<P><B>Summary</B></P><P>KC<SUB>a</SUB>1.1 regulates smooth muscle contractility by modulating membrane potential, and age‐associated changes in KC<SUB>a</SUB>1.1 expression may contribute to the development of motility disorders of the gastrointestinal tract. Sphingolipids (SLs) are important structural components of cellular membranes whose altered composition may affect KC<SUB>a</SUB>1.1 expression. Thus, in this study, we examined whether altered SL composition due to aging may affect the contractility of gastric smooth muscle (GSM). We studied changes in ceramide synthases (CerS) and SL levels in the GSM of mice of varying ages and compared them with those in young CerS2‐null mice. The levels of C16‐ and C18‐ceramides, sphinganine, sphingosine, and sphingosine 1‐phosphate were increased, and levels of C22, C24:1 and C24 ceramides were decreased in the GSM of both aged wild‐type and young CerS2‐null mice. The altered SL composition upregulated KC<SUB>a</SUB>1.1 and increased KC<SUB>a</SUB>1.1 currents, while no change was observed in KC<SUB>a</SUB>1.1 channel activity. The upregulation of KC<SUB>a</SUB>1.1 impaired intracellular Ca2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3‐kinase, protein kinase C<SUB>ζ</SUB>, c‐Jun N‐terminal kinases, and nuclear factor kappa‐B were found to be involved in KC<SUB>a</SUB>1.1 upregulation. Our findings suggest that age‐associated changes in SL composition or CerS2 ablation upregulate KC<SUB>a</SUB>1.1 via the phosphoinositide 3‐kinase/protein kinase C<SUB>ζ</SUB>/c‐Jun N‐terminal kinases/nuclear factor kappa‐B‐mediated pathway and impair Ca2+ mobilization, which thereby induces the contractile dysfunction of GSM. CerS2‐null mice exhibited similar effects to aged wild‐type mice; therefore, CerS2‐null mouse models may be utilized for investigating the pathogenesis of aging‐associated motility disorders.</P>

Hybrid Light‐Emitting Diodes: Electrically Driven Quantum Dot/Wire/Well Hybrid Light‐Emitting Diodes (Adv. Mater. 45/2011)

Ko, Young&#x2010,Ho,Kim, Je&#x2010,Hyung,Jin, Li&#x2010,Hua,Ko, Suk&#x2010,Min,Kwon, Bong&#x2010,Joon,Kim, Joosung,Kim, Taek,Cho, Yong&#x2010,Hoon WILEY‐VCH Verlag 2011 ADVANCED MATERIALS Vol.23 No.45

<P>Electrically driven hybrid light‐emitting diodes (LEDs) consisting of quantum dots, wires, and wells based on the nanometer‐sized pyramid GaN structure are reported by Taek Kim, Yong‐Hoon Cho, and co‐workers on page 5364. The LEDs exhibit mixed emissions from InGaN quantum dots, wires, and wells formed at the tops, edges, and sidewalls of the pyramids, respectively. The hybrid LEDs containing low‐dimensional quantum structures provide a broad‐band, highly efficient visible lighting source. </P>

In Situ Observation of Voltage‐Induced Multilevel Resistive Switching in Solid Electrolyte Memory

Choi, Sang&#x2010,Jun,Park, Gyeong&#x2010,Su,Kim, Ki&#x2010,Hong,Cho, Soohaeng,Yang, Woo&#x2010,Young,Li, Xiang&#x2010,Shu,Moon, Jung&#x2010,Hwan,Lee, Kyung&#x2010,Jin,Kim, Kinam WILEY‐VCH Verlag 2011 ADVANCED MATERIALS Vol.23 No.29

<P><B>Solid electrolyte memories</B> utilizing voltage‐induced resistance change display the capability of multilevel switching, but understanding of the microscopic switching mechanism has been left incomplete. Here, in situ TEM observation of voltage‐induced changes in the microstructure of a solid electrolyte memory is reported, revealing that the multilevel switching originates from the growth of multiple conducting filaments with nanometer‐sized diameter and spacing. </P>

Titania nanopores with dual micro-/nano-topography for selective cellular bioactivity

Gulati, Karan,Moon, Ho-Jin,Li, Tao,Sudheesh Kumar, P.T.,Ivanovski, Sa&#x161,o Elsevier 2018 Materials Science and Engineering C Vol.91 No.-

<P><B>Abstract</B></P> <P>This letter describes a simple surface modification strategy based on a single-step electrochemical anodization towards generating dual micro- and nano-rough horizontally-aligned TiO<SUB>2</SUB> nanopores on the surface of clinically utilized micro-grooved titanium implants. Primary macrophages, osteoblasts and fibroblasts were cultured on the nano-engineered implants, and it was demonstrated that the modified surfaces selectively reduced the proliferation of macrophages (immunomodulation), while augmenting the activity of osteoblasts (osseo-integration) and fibroblasts (soft-tissue integration). Additionally, the mechanically robust nanopores also stimulated osteoblast and fibroblast adhesion, attachment and alignment along the direction of the pores/grooves, while macrophages remained oval-shaped and sparsely distributed. This study for the first time reports the use of cost-effectively prepared nano-engineered titanium surface via anodization, with aligned multi-scale micro/nano features for selective cellular bioactivity, without the use of any therapeutics.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Single-step fabrication of dual micro-rough and nanoporous titanium surfaces </LI> <LI> Mechanically robust aligned nanopores with preserved underlying micro-features </LI> <LI> Upregulated attachment and adhesion of osteoblasts and fibroblasts </LI> <LI> Reduced macrophage proliferation and adherence </LI> <LI> Osteoblasts and fibroblasts align parallel to the nanopore arrangement. </LI> </UL> </P>