22‐ S ‐Hydroxycholesterol protects against ethanol‐induced liver injury by blocking the auto/paracrine activation of MCP ‐1 mediated by LXRα

Na, Tae&#x2010,Young,Han, Young&#x2010,Hyun,Ka, Na&#x2010,Lee,Park, Han&#x2010,Su,Kang, Yun Pyo,Kwon, Sung Won,Lee, Byung‐,Hoon,Lee, Mi&#x2010,Ock John WileySons, Ltd 2015 The Journal of pathology Vol.235 No.5

<P><B>Abstract</B></P><P>Chronic ethanol consumption causes hepatic steatosis and inflammation, which are associated with liver hypoxia. Monocyte chemoattractant protein‐1 (MCP‐1) is a hypoxia response factor that determines recruitment and activation of monocytes to the site of tissue injury. The level of MCP‐1 is elevated in the serum and liver of patients with alcoholic liver disease (ALD); however, the molecular details regarding the regulation of MCP‐1 expression are not yet understood completely. Here, we show the role of liver X receptor α (LXRα) in the regulation of MCP‐1 expression during the development of ethanol‐induced fatty liver injury, using an antagonist, 22‐S‐hydroxycholesterol (22‐S‐HC). First, administration of 22‐S‐HC attenuated the signs of liver injury with decreased levels of MCP‐1 and its receptor CCR2 in ethanol‐fed mice. Second, hypoxic conditions or treatment with the LXRα agonist GW3965 significantly induced the expression of MCP‐1, which was completely blocked by treatment with 22‐S‐HC or infection by shLXRα lentivirus in the primary hepatocytes. Third, over‐expression of LXRα or GW3965 treatment increased MCP‐1 promoter activity by increasing the binding of hypoxia‐inducible factor‐1α to the hypoxia response elements, together with LXRα. Finally, treatment with recombinant MCP‐1 increased the level of expression of LXRα and LXRα‐dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXRα and its ligand‐induced up‐regulation of MCP‐1 and MCP‐1‐induced LXRα‐dependent lipogenesis play a key role in the autocrine and paracrine activation of MCP‐1 in the pathogenesis of alcoholic fatty liver disease, and that this activation may provide a promising new target for ALD therapy.Copyright © 2014 The Authors. <I>The Journal of Pathology</I> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</P>

Glycogen synthase kinase 3β and β‐catenin pathway is involved in toll‐like receptor 4‐mediated NADPH oxidase 1 expression in macrophages

Kim, Jin&#x2010,Sik,Yeo, Seungeun,Shin, Dong&#x2010,Gu,Bae, Yoe&#x2010,Sik,Lee, Jae&#x2010,Jin,Chin, Byung‐,Rho,Lee, Chu&#x2010,Hee,Baek, Suk&#x2010,Hwan Blackwell Publishing Ltd 2010 FEBS JOURNAL Vol.277 No.13

<P>Macrophage activation contributes to the pathogenesis of atherosclerosis. In the vascular system, the major source of reactive oxygen species is the NADPH oxidase (Nox) family. Nox1 is induced by lipopolysaccharide (LPS) in macrophages, but the expression mechanism is not fully understood. We found that LPS causes β‐catenin accumulation by glycogen synthase kinase 3β (GSK3β) inactivation, and that β‐catenin accumulation increases Nox1 expression. LPS induced Nox1 mRNA expression and reactive oxygen species generation in Raw264.7 cells. Using bone marrow‐derived macrophages from toll‐like receptor 4 mutant mice, we also tested whether LPS‐induced Nox1 expression is toll‐like receptor 4 dependent. LPS caused GSK3β phosphorylation, induced β‐catenin accumulation and increased nuclear translocation. The GSK3β inhibitor LiCl potentiated LPS‐induced Nox1 expression in accordance with β‐catenin accumulation and nuclear translocation. Conversely, ectopic expression of a constitutively active GSK3β mutant severely attenuated Nox1 expression. These findings identify a novel regulatory pathway controlling Nox1 expression by LPS‐stimulated macrophages.</P>

Pro‐apoptotic Noxa is involved in ablative focal irradiation‐induced lung injury

Kim, Jee&#x2010,Youn,An, Yong&#x2010,Min,Choi, Won Hoon,Kim, Jin&#x2010,Mo,Cho, Samju,Yoo, Byung Rok,Kang, Jeong Wook,Lee, Yun&#x2010,Sil,Lee, Yoon&#x2010,Jin,Cho, Jaeho CAROL DAVILA UNIVERSITY PRESS 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.4

<P><B>Abstract</B></P><P>Although lung injury including fibrosis is a well‐documented side effect of lung irradiation, the mechanisms underlying its pathology are poorly understood. X‐rays are known to cause apoptosis in the alveolar epithelial cells of irradiated lungs, which results in fibrosis due to the proliferation and differentiation of fibroblasts and the deposition of collagen. Apoptosis and BH3‐only pro‐apoptotic proteins have been implicated in the pathogenesis of pulmonary fibrosis. Recently, we have established a clinically analogous experimental model that reflects focal high‐dose irradiation of the ipsilateral lung. The goal of this study was to elucidate the mechanism underlying radiation‐induced lung injury based on this model. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice for 14 days. About 9 days after irradiation, the mice began to show increased levels of the pro‐apoptotic protein Noxa in the irradiated lung alongside increased apoptosis and fibrosis. Suppression of Noxa expression by small interfering RNA protected cells from radiation‐induced cell death and decreased expression of fibrogenic markers. Furthermore, we showed that reactive oxygen species participate in Noxa‐mediated, radiation‐induced cell death. Taken together, our results show that Noxa is involved in X‐ray‐induced lung injury.</P>

Survival benefits from reduced‐intensity conditioning in allogeneic stem cell transplantation for young lower‐risk MDS patients without significant comorbidities

Lee, Sung&#x2010,Eun,Kim, Yoo&#x2010,Jin,Yahng, Seung&#x2010,Ah,Cho, Byung‐,Sik,Eom, Ki&#x2010,Sung,Lee, Seok,Min, Chang&#x2010,Ki,Kim, Hee&#x2010,Je,Cho, Seok&#x2010,Goo,Kim, Dong&#x2010,Wook,L Blackwell Publishing Ltd 2011 European journal of haematology Vol.87 No.6

<P><B>Abstract</B></P><P><I>Objective:</I> The aim of this study was to determine the optimum conditioning intensity for allogeneic stem cell transplantation (SCT) in young (age ≤50), lower‐risk (INT‐1 by IPSS) Myelodysplastic syndrome (MDS) patients without significant comorbidities (hematopoietic cell transplantation‐comorbidity index score ≤3). <I>Methods:</I> Transplant outcomes from 46 consecutive patients were retrospectively analyzed according to the conditioning intensity: reduced‐intensity conditioning (RIC; <I>n</I> = 14), intensified RIC by adding low‐dose total body irradiation (iRIC; <I>n</I> = 15), and myeloablative conditioning (MAC; <I>n</I> = 17). <I>Results:</I> After a median follow‐up of 73.7 months, RIC had a better 4‐yr overall survival (OS) (92.9%) compared with the iRIC (64.2%) or MAC (70.6%). Multivariate analysis showed that RIC was associated with improved OS compared with the MAC [relative risk (RR) of 0.08, <I>P </I>=<I> </I>0.022] because of a lower transplant‐related mortality (TRM) (RR, 0.08, <I>P </I>=<I> </I>0.035). iRIC failed to show survival benefits over the MAC (RR of 0.77, <I>P </I>=<I> </I>0.689) because of similarly high TRM (RR of 0.41, <I>P </I>=<I> </I>0.480). Cumulative incidence of acute and chronic graft‐versus‐host disease (GVHD) after RIC was higher, but GVHD‐specific survival was significantly better (RIC 100% vs. iRIC 45.7% vs. MAC, <I>P </I>=<I> </I>0.018). Relapse rate was not different among the three groups, but in the RIC group, azacitidine was available and useful for inducing remission in two patients. <I>Conclusion:</I> This study shows that RIC improved OS by directly lowering TRM and indirectly giving an additional chance for relapsed MDS in the era of hypomethylating treatment. RIC–SCT should be considered for relative healthy lower‐risk MDS patients.</P>

Targeted Genome Engineering to Control VEGF Expression in Human Umbilical Cord Blood‐Derived Mesenchymal Stem Cells: Potential Implications for the Treatment of Myocardial Infarction

Cho, Hyun&#x2010,Min,Kim, Pyung&#x2010,Hwan,Chang, Hyun&#x2010,Kyung,Shen, Yi&#x2010,ming,Bonsra, Kwaku,Kang, Byung‐,Jae,Yum, Soo&#x2010,Young,Kim, Joo&#x2010,Hyun,Lee, So&#x2010,Yeong,Choi, Min John Wiley and Sons Inc. 2017 Stem cells translational medicine Vol.6 No.3

<P><B>Abstract</B></P><P>Human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs) exhibit potency for the regeneration of infarcted hearts. Vascular endothelial growth factor (VEGF) is capable of inducing angiogenesis and can boost stem cell‐based therapeutic effects. However, high levels of VEGF can cause abnormal blood vessel growth and hemangiomas. Thus, a controllable system to induce therapeutic levels of VEGF is required for cell therapy. We generated an inducible VEGF‐secreting stem cell (VEGF/hUCB‐MSC) that controls the expression of VEGF and tested the therapeutic efficacy in rat myocardial infarction (MI) model to apply functional stem cells to MI. To introduce the inducible VEGF gene cassette into a safe harbor site of the hUCB‐MSC chromosome, the transcription activator‐like effector nucleases system was used. After confirming the integration of the cassette into the locus, VEGF secretion in physiological concentration from VEGF/hUCB‐MSCs after doxycycline (Dox) induction was proved in conditioned media. VEGF secretion was detected in mice implanted with VEGF/hUCB‐MSCs grown via a cell sheet system. Vessel formation was induced in mice transplanted with Matrigel containing VEGF/hUCB‐MSCs treated with Dox. Moreover, seeding of the VEGF/hUCB‐MSCs onto the cardiac patch significantly improved the left ventricle ejection fraction and fractional shortening in a rat MI model upon VEGF induction. Induced VEGF/hUCB‐MSC patches significantly decreased the MI size and fibrosis and increased muscle thickness, suggesting improved survival of cardiomyocytes and protection from MI damage. These results suggest that our inducible VEGF‐secreting stem cell system is an effective therapeutic approach for the treatment of MI. S<SMALL>TEM</SMALL> C<SMALL>ELLS</SMALL> T<SMALL>RANSLATIONAL</SMALL> M<SMALL>EDICINE</SMALL><I>2017;6:1040–1051</I></P>

Signal transducer and activator of transcription 3‐mediated CD133 up‐regulation contributes to promotion of hepatocellular carcinoma

Won, Cheolhee,Kim, Byung‐,Hak,Yi, Eun Hee,Choi, Kyung&#x2010,Ju,Kim, Eun&#x2010,Kyung,Jeong, Jong&#x2010,Min,Lee, Jae&#x2010,Ho,Jang, Ja&#x2010,June,Yoon, Jung&#x2010,Hwan,Jeong, Won&#x2010,Il,P John Wiley and Sons Inc. 2015 Hepatology Vol.62 No.4

<P>Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin‐6/signal transducer and activator of transcription 3 (IL‐6/STAT3) signaling up‐regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL‐6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL‐6, with a concomitant decrease of hypoxia‐inducible factor 1 alpha (HIF‐1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF‐κB) p65 subunit to positively regulate the transcription of HIF‐1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF‐1α and CD133 expression were not observed in Toll‐like receptor 4/IL‐6 double‐knockout mice. Long‐term silencing of CD133 by a lentiviral‐based approach inhibited cancer cell‐cycle progression and suppressed <I>in vivo</I> tumorigenicity by down‐regulating expression of cytokinesis‐related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF‐1α proteins. <I>Conclusion</I>: IL‐6/STAT3 signaling induces expression of CD133 through functional cooperation with NF‐κB and HIF‐1α during liver carcinogenesis. Targeting STAT3‐mediated CD133 up‐regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment. (H<SMALL>EPATOLOGY</SMALL> 2015;62:1160‐1173)</P>

Tolerability, effectiveness and predictive parameters for the therapeutic usefulness of exenatide in obese, K orean patients with type 2 diabetes

Song, Sun Ok,Kim, Kwang Joon,Lee, Byung‐,Wan,Kang, Eun Seok,Cha, Bong Soo,Lee, Hyun Chul Wiley-Blackwell 2014 Journal of diabetes investigation Vol.5 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction</B></P><P>We assessed the tolerability, effectiveness and predictive parameters for the therapeutic usefulness of exenatide in obese Korean participants with type 2 diabetes. We also evaluated the characteristics of participants who respond adequately to glucagon‐like peptide‐1 (GLP‐1) analog therapy in terms of glycated hemoglobin (HbA1c) level reductions and weight loss.</P><P><B>Materials and Methods</B></P><P>This prospective, observational, single‐arm (exenatide b.i.d. in combination with both metformin and sulphonylurea), open‐label study of GLP‐1 analog treatment with close monitoring of metabolic parameters and weight changes was carried out for up to 22 weeks.</P><P><B>Results</B></P><P>Of the 110 enrolled obese participants, 37 participants dropped out during the 22‐week treatment period. A total of 73 participants completed the study (median age 55.0 years, interquartile range 44.0–65.0). The median duration of diabetes was 8.0 years (interquartile range 3.5–12.5) with a mean HbA1c value of 7.6% (interquartile range 7.00–8.55). The median body mass index was 30.78 kg/m<SUP>2</SUP> (interquartile range 27.89–33.92). After 22 weeks, median changes from baseline for HbA1c levels and weight were −0.7% and −3.0 kg, respectively, which were significant. No severe hypoglycemic events were observed. Multivariate regression analysis showed that C‐peptide values were a significant independent predictor for a reduction in HbA1c levels (β = 0.865, <I>P</I> = 0.018) with exenatide BID in combination with both sulphonylurea and metformin in obese Korean participants with type 2 diabetes and insulin naïveté.</P><P><B>Conclusions</B></P><P>Clinical and laboratory parameters, such as insulin naïveté and preserved β‐cell function, should be taken into consideration as important factors in the choice of GLP‐1 analog when predicting GLP‐1 analog responsiveness. This trial was registered with the local committee at Yonsei University in Korea (4‐2011‐0032).</P>

Cable‐Type Flexible Lithium Ion Battery Based on Hollow Multi‐Helix Electrodes

Kwon, Yo Han,Woo, Sang&#x2010,Wook,Jung, Hye&#x2010,Ran,Yu, Hyung Kyun,Kim, Kitae,Oh, Byung Hun,Ahn, Soonho,Lee, Sang&#x2010,Young,Song, Seung&#x2010,Wan,Cho, Jaephil,Shin, Heon&#x2010,Cheol,Kim, Je Y WILEY‐VCH Verlag 2012 Advanced Materials Vol.24 No.38

<P><B>The mechanical flexibility of a cable‐type battery</B> reaches levels far beyond what is possible with conventional designs. The hollow‐spiral (helical) multi‐helix anode architecture is critical to the robustness under mechanical stress and facilitates electrolyte wetting of the battery components. This design enables the battery to reliably power an LED screen or an MP3 player even under severe mechanical twisting and bending.</P>

Role of NADPH oxidase‐2 in lipopolysaccharide‐induced matrix metalloproteinase expression and cell migration

Kim, So&#x2010,Yeon,Lee, Jin&#x2010,Gu,Cho, Woo&#x2010,Sung,Cho, Kyong&#x2010,Hyun,Sakong, Jun,Kim, Jae&#x2010,Ryong,Chin, Byung‐,Rho,Baek, Suk&#x2010,Hwan Nature Publishing Group 2010 Immunology and Cell Biology Vol.88 No.2

<P>This study examined the hypothesis that the control of NADPH oxidase‐2 (Nox2)‐mediated reactive oxygen species (ROS) regulates the expression of matrix metalloproteinases (MMPs) and the migration of macrophages. Lipopolysaccharide (LPS) stimulation of Raw264.7 cells and mice peritoneal macrophages increased the expression of MMP‐9, 10, 12 and 13 mRNA, and also increased Raw264.7 cell migration. Treatment with an antioxidant (<I>N</I>‐acetyl cysteine) or Nox inhibitors strongly inhibited the expression of MMPs by LPS and inhibited cell migration. LPS caused ROS production in macrophages and increased the mRNA expression of Nox isoforms Nox1 and Nox2 by 20‐fold and two‐fold, respectively. While Nox1 small interfering RNA (siRNA) did not inhibit LPS‐mediated expression of MMPs, Nox2 siRNA inhibited the expressions of MMP‐9, 10 and 12. Neither Nox1 nor Nox2 siRNA influenced the LPS‐mediated expression of MMP‐13. In addition, NAC or apocynin attenuated LPS‐induced ROS production and MMP‐9 expression. MMP‐9 expression and cell migration were controlled by ERK1/2–ROS signaling. Collectively, these results suggest that LPS stimulates ROS production via ERK and induce various types of MMPs expression and cell migration.</P>

Line‐time optimization technology for ultra‐large and high‐resolution liquid crystal displays

Lee, Seung&#x2010,Hyuck,Jeon, Dong&#x2010,Hwan,Kim, Jong&#x2010,Man,Kim, Minkoo,Yu, Byung‐,Chang,Lee, Seung&#x2010,Woo John Wiley Sons Ltd 2017 JOURNAL- SOCIETY FOR INFORMATION DISPLAY Vol.25 No.6