Publications by authors named "Won Jung Kim"

25 Publications

  • Page 1 of 1

Multiplexed targeting of miRNA-210 in stem cell-derived extracellular vesicles promotes selective regeneration in ischemic hearts.

Exp Mol Med 2021 Apr 20;53(4):695-708. Epub 2021 Apr 20.

Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea.

Extracellular vesicles (EVs) are cell derivatives containing diverse cellular molecules, have various physiological properties and are also present in stem cells used for regenerative therapy. We selected a "multiplexed target" that demonstrates multiple effects on various cardiovascular cells, while functioning as a cargo of EVs. We screened various microRNAs (miRs) and identified miR-210 as a candidate target for survival and angiogenic function. We confirmed the cellular and biological functions of EV-210 (EVs derived from ASC) secreted from adipose-derived stem cells (ASCs) transfected with miR-210 (ASC). Under hypoxic conditions, we observed that ASC inhibits apoptosis by modulating protein tyrosine phosphatase 1B (PTP1B) and death-associated protein kinase 1 (DAPK1). In hypoxic endothelial cells, EV-210 exerted its angiogenic capacity by inhibiting Ephrin A (EFNA3). Furthermore, EV-210 enhanced cell survival under the control of PTP1B and induced antiapoptotic effects in hypoxic H9c2 cells. In cardiac fibroblasts, the fibrotic ratio was reduced after exposure to EV-210, but EVs derived from ASC did not communicate with fibroblasts. Finally, we observed the functional restoration of the ischemia/reperfusion-injured heart by maintaining the intercommunication of EVs and cardiovascular cells derived from ASC. These results suggest that the multiplexed target with ASC is a useful tool for cardiovascular regeneration.
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http://dx.doi.org/10.1038/s12276-021-00584-0DOI Listing
April 2021

Regulation of alternative macrophage activation by MSCs derived hypoxic conditioned medium, via the TGF-β1/Smad3 pathway.

BMB Rep 2020 Nov;53(11):600-604

Department of Biology Education, College of Education, Pusan National University, Busan 46241, Korea.

Macrophages are re-educated and polarized in response to myocardial infarction (MI). The M2 anti-inflammatory phenotype is a known dominator of late stage MI. Mesenchymal stem cells (MSCs) represent a promising tool for cell therapy, particularly heart related diseases. In general, MSCs induce alteration of the macrophage subtype from M1 to M2, both in vitro and in vivo. We conjectured that hypoxic conditions can promote secretome productivity of MSCs. Hypoxia induces TGF-β1 expression, and TGF-β1 mediates M2 macrophage polarization for anti-inflammation and angiogenesis in infarcted areas. We hypothesized that macrophages undergo advanced M2 polarization after exposure to MSCs in hypoxia. Treatment of MSCs derived hypoxic conditioned medium (hypo-CM) promoted M2 phenotype and neovascularization through the TGF-β1/Smad3 pathway. In addition, hypo-CM derived from MSCs improved restoration of ischemic heart, such as attenuating cell apoptosis and fibrosis, and ameliorating microvessel density. Based on our results, we propose a new therapeutic method for effective MI treatment using regulation of macrophage polarization. [BMB Reports 2020; 53(11): 600-604].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704222PMC
November 2020

Improved angular color uniformity and hydrothermal reliability of phosphor-converted white light-emitting diodes by using phosphor sedimentation.

Opt Express 2018 Oct;26(22):28634-28640

We investigated the effect of phosphor deposition methods on the correlated color temperature (CCT), luminous flux and thermal characteristics of packaged white light-emitting diodes (WLEDs) for use in mobile display products. For both the samples, the CCT decreased with increasing viewing angle. Phosphor sedimentation samples displayed much better angular color uniformity than phosphor dispersion samples. The phosphor sedimentation sample had higher luminous flux and luminous efficacy at 20 mA than the phosphor dispersion sample. The phosphor sedimentation sample displayed much better high-temperature/humidity (85 °C/85%) reliability and lower package temperatures compared with the phosphor dispersion sample.
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http://dx.doi.org/10.1364/OE.26.028634DOI Listing
October 2018

Exosomes derived from microRNA-584 transfected mesenchymal stem cells: novel alternative therapeutic vehicles for cancer therapy.

BMB Rep 2018 Aug;51(8):406-411

Department of Biology Education, College of Education, Pusan National University, Busan 46241, Korea.

Exosomes are small membranous vesicles which contain abundant RNA molecules, and are transferred from releasing cells to uptaking cells. MicroRNA (miRNA) is one of the transferred molecules affecting the adopted cells, including glioma cells. We hypothesized that mesenchymal stem cells (MSCs) can secrete exosomes loading miRNA and have important effects on the progress of gliomas. To determine these effects by treating exosomal miRNA in culture media of miRNA mimic transfected MSCs, we assessed the in vitro cell proliferation and invasion capabilities, and the expression level of relative proteins associated with cell apoptosis, growth and migration. For animal studies, the mice injected with U87 cells were exposed to exosomes derived from miRNA-584-5p transfected MSCs, to confirm the influence of exosomal miRNA on the progress of glioma. Based on our results, we propose a new targeted cancer therapy wherein exosomes derived from miRNA transfected MSCs could be used to modulate tumor progress as the anticancer vehicles. [BMB Reports 2018; 51(8): 406-411].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130835PMC
http://dx.doi.org/10.5483/bmbrep.2018.51.8.105DOI Listing
August 2018

Tristetraprolin activation by resveratrol inhibits the proliferation and metastasis of colorectal cancer cells.

Int J Oncol 2018 Sep 25;53(3):1269-1278. Epub 2018 Jun 25.

Department of Physiology, Institute of Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk 54907, Republic of Korea.

Resveratrol (RSV) is a polyphenolic compound that naturally occurs in grapes, peanuts and berries. Considerable research has been conducted to determine the benefits of RSV against various human cancer types. Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability and has decreased expression in human cancer. The present study investigated the biological effect of RSV on TTP gene regulation in colon cancer cells. RSV inhibited the proliferation and invasion/metastasis of HCT116 and SNU81 colon cancer cells. Furthermore, RSV induced a dose-dependent increase in TTP expression in HCT116 and SNU81 cells. The microarray experiment revealed that RSV significantly increased TTP expression by downregulating E2F transcription factor 1 (E2F1), a downstream target gene of TTP and regulated genes associated with inflammation, cell proliferation, cell death, angiogenesis and metastasis. Although TTP silencing inhibited TTP mRNA expression, the expression was subsequently restored by RSV. Small interfering RNA-induced TTP inhibition attenuated the effects of RSV on cell growth. In addition, RSV induced the mRNA-decaying activity of TTP and inhibited the relative luciferase activity of baculoviral IAP repeat containing 3 (cIAP2), large tumor suppressor kinase 2 (LATS2), E2F1, and lin‑28 homolog A (Lin28) in HCT116 and SNU81 cells. Therefore, RSV enhanced the inhibitory activity of TTP in HCT116 and SNU81 cells by negatively regulating cIAP2, E2F1, LATS2, and Lin28 expression. In conclusion, RSV suppressed the proliferation and invasion/metastasis of colon cancer cells by activating TTP.
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http://dx.doi.org/10.3892/ijo.2018.4453DOI Listing
September 2018

Impermeable flexible liquid barrier film for encapsulation of DSSC metal electrodes.

Sci Rep 2016 06 6;6:27422. Epub 2016 Jun 6.

Centre for Integrated Nanostructure Physics (CINAP), Institute of Basic Science (IBS), Department of Chemistry, and Department of Energy Science, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do, Korea.

Encapsulation of electronic devices such as dye-sensitized solar cells (DSSCs) is prone to degradation under normal atmospheric conditions, even with hermetic barriers on the metal electrodes. Overcoming this problem is crucial to increasing DSSC lifetimes and making them commercially viable. Herein, we report a new impermeable flexible liquid barrier film using polyvinyl alcohol (PVA) and partially reduced graphene oxide (PrGO), which dramatically enhances the lifetime of Ag metal electrodes (typically used in DSSCs) immersed in a highly acidic iodolyte solution. The Ag metal electrode encapsulated by the PVA/PrGO film survived for over 500 hrs, superior to existing barriers of glass frits, epoxy resins and polymers. The PVA/PrGO film strongly adheres to the Ag metal surface, and the resulting PVA/PrGO/Ag electrode is stable even on a curved substrate, with a sheet resistance nearly independent of curvature. These results give new insight for the design of high-performance and solution-processable flexible liquid barrier films for a wide range of applications, in particular for the encapsulation of electronic devices with liquid electrolytes.
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http://dx.doi.org/10.1038/srep27422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893703PMC
June 2016

Highly sensitive and novel point-of-care system, aQcare Chlamydia TRF kit for detecting Chlamydia trachomatis by using europium (Eu) (III) chelated nanoparticles.

Ann Lab Med 2015 Jan 8;35(1):50-6. Epub 2014 Dec 8.

Department of Laboratory Medicine, Kyungpook National University Hospital, Daegu, Korea. ; Department of Clinical Pathology, Kyungpook National University School of Medicine, Daegu, Korea.

Background: The bacterium Chlamydia trachomatis is one of the leading causes of sexually transmitted diseases worldwide. Since no simple and effective tool exists to diagnose C. trachomatis infections, we evaluated a novel point-of-care (POC) test, aQcare Chlamydia TRF kit, which uses europium-chelated nanoparticles and a time-resolved fluorescence reader.

Methods: The test performance was evaluated by comparing the results obtained using the novel POC testing kit with those obtained using a nucleic acid amplification test (NAAT), using 114 NAAT-positive and 327 NAAT-negative samples.

Results: The cut-off value of the novel test was 20.8 with a detection limit of 0.27 ng/mL. No interference or cross-reactivity was observed. Diagnostic accuracy showed an overall sensitivity of 93.0% (106/114), specificity of 96.3% (315/327), positive predictive value (PPV) of 89.8% (106/118), and negative predictive value (NPV) of 97.5% (315/323). The sensitivity of the novel test was much higher than that of currently available POC tests. Furthermore, the relative ease and short turnaround time (30 min) of this assay enables C. trachomatis-infected individuals to be treated without a diagnostic delay.

Conclusions: This simple and novel test is a potential tool to screen a larger population, especially those in areas with limited resources.
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http://dx.doi.org/10.3343/alm.2015.35.1.50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272965PMC
January 2015

Combination of multiplex reverse-transcription loop-mediated isothermal amplification with an immunochromatographic strip for subtyping influenza A virus.

Anal Chim Acta 2015 Jan 16;853:541-547. Epub 2014 Oct 16.

Department of Chemical and Biomolecular Engineering (BK21+ Program) and Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea. Electronic address:

Considering the fatal human victims and economic loss by the annual epidemic influenza virus, the development of a rapid and convenient genetic analysis methodology is demanding for timely on-site pathogen detection. In this study, we utilized reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for multiplex target gene amplification, and the resultant amplicons were analyzed on the immunochromatographic strip (ICS) for subtyping influenza A virus. Through the optimized primer design, reaction temperature and time, and concentration of enzymes (Bst DNA polymerase and AMV reverse transcriptase) and dNTP, the HA (H1, H3, and H5 gene) and conserved M gene were amplified. The ICS contains two test lines in addition to a control line in order to detect the presence of the HA and M gene, thereby informing us of influenza virus A type as well as its subtype (H1N1, H3N2, and H5N1). The combination of the multiplex RT-LAMP with the ICS could be complete in 40 min and the pathotyping and subtyping of influenza A virus were performed even with 10 copies of viral RNA templates. Moreover, the subtyping of clinical samples, which were obtained from patients infected by influenza A virus was successfully confirmed using the multiplex RT-LAMP and ICS techniques, showing great feasibility of our methodology for real sample analysis with high speed, simplicity and sensitivity.
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http://dx.doi.org/10.1016/j.aca.2014.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094724PMC
January 2015

A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF-κB activities in HT1080 cells.

Cell Biol Int 2012 Jul;36(7):683-8

School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702701, Korea.

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. We have analysed a derivative of decursin (CSL-32) for activity against inflammatory activation of cancer cells, such as migration, invasion and expression of pro-inflammatory mediators. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumour necrosis factor α) in the presence or absence of CSL-32. The cellular responses and modification of signalling adapters were analysed with respect to the production of pro-inflammatory mediators, as also migration, adhesion and invasion. Treatment of HT1080 cells with CSL-32 inhibited their proliferation, without affecting cell viability, and TNFα-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8). CSL-32 also suppressed phosphorylation and degradation of IκB (inhibitory κB), phosphorylation of p65 subunit of NF-κB (nuclear factor-κB) and nuclear translocation of NF-κB, which are required for the expression of pro-inflammatory mediators. In addition, CSL-32 inhibited invasion and migration of HT1080 cells, as also cellular adhesion to fibronectin, an ECM (extracellular matrix) protein. CSL-32 treatment resulted in a dose-dependent inhibition of PI3K (phosphoinositide 3-kinase) activity, required for the cellular migration. The analyses show that CSL-32 inhibits processes associated with inflammation, such as the production of pro-inflammatory mediators, as well as adhesion, migration and invasion in HT1080 cells.
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http://dx.doi.org/10.1042/CBI20110257DOI Listing
July 2012

Integrated microdevice of reverse transcription-polymerase chain reaction with colorimetric immunochromatographic detection for rapid gene expression analysis of influenza A H1N1 virus.

Biosens Bioelectron 2012 Mar 8;33(1):88-94. Epub 2012 Jan 8.

Department of Chemical and Biomolecular Engineering (BK21 Program), Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Korea.

An integrated microdevice of a reverse transcription-polymerase chain reaction (RT-PCR) reactor and an immunochromatographic strip was constructed for colorimetric detection of gene expression of influenza A virus subtype H1N1. An RT-PCR cocktail, which included Texas Red-labeled primers, dNTP including biotin-labeled dUTP, and RNA templates of influenza A H1N1 virus, was filled in the PCR chamber through the micropump, and the RT-PCR was performed to amplify the target H1 gene (102 bp). The resultant amplicons bearing biotin moieties and Texas Red haptens were subsequently eluted to the immunochromatographic strip, in which they were first conjugated with the gold nanoparticle labeled anti-hapten antibody in the conjugation pad, and then captured on the streptavidin coated test line through the biotin-streptavidin interaction. By observing a violet color in the test line which was derived from the gold nanoparticle, we confirmed the H1N1 target virus. The entire process on the integrated microdevice consisting of a micropump, a 2 μL PCR chamber, and an immunochromatographic strip was carried out on the portable genetic analyzer within 2.5h, enabling on-site colorimetric pathogen identification with detection sensitivity of 14.1 pg RNA templates.
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http://dx.doi.org/10.1016/j.bios.2011.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126693PMC
March 2012

Gastropericardial fistula-induced pyopneumopericardium after esophagectomy with esophagogastrectomy.

Ann Thorac Surg 2011 Jan;91(1):e10-1

Department of Radiology, Korea University Medical Center, Seoul, South Korea.

Gastropericardial fistula is an acquired disorder presenting as an abnormal communication between the stomach and the pericardium, with a rare incidence and extremely high mortality rate. We recently experienced a case of life-threatening gastropericardial fistula occurring as an unusual complication after an esophagectomy with an esophagogastrostomy for esophageal cancer treatment. A 68-year-old man with a history of esophagectomy and esophagogastrostomy using the gastric pedicle for the esophageal cancer 13 years ago, visited the hospital with a complaint of dyspnea for 3 days. Chest roentgenogram, computed tomographic scan, and endoscopy showed a pneumopericardium and huge ulcer with central perforation in the posterior wall of the gastric pedicle.
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http://dx.doi.org/10.1016/j.athoracsur.2010.09.082DOI Listing
January 2011

Cell to Cell Interaction Can Activate Membrane-bound APRIL Which Are Expressed on Inflammatory Macrophages.

Immune Netw 2010 Oct 31;10(5):173-80. Epub 2010 Oct 31.

School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, Korea.

Background: APRIL, originally known as a cytokine involved in B cell survival, is now known to regulate the inflammatory activation of macrophages. Although the signal initiated from APRIL has been demonstrated, its role in cellular activation is still not clear due to the presence of BAFF, a closely related member of TNF superfamily, which share same receptors (TACI and BCMA) with APRIL.

Methods: Through transfection of siRNA, BAFF-deficient THP-1 cells (human macrophage-like cells) were generated and APRIL-mediated inflammatory activities were tested. The expression patterns of APRIL were also tested in vivo.

Results: BAFF-deficient THP-1 cells responded to APRIL-stimulating agents such as monoclonal antibody against APRIL and soluble form of TACI or BCMA. Furthermore, co-incubation of the siBAFF-deficient THP-1 cells with a human B cell line (Ramos) resulted in an activation of THP-1 cells which was dependent on interactions between APRIL and TACI/BCMA. Immunohistochemical analysis of human pathologic samples detected the expression of both APRIL and TACI in macrophage-rich areas. Additionally, human macrophage primary culture expressed APRIL on the cell surface.

Conclusion: These observations indicate that APRIL, which is expressed on macrophages in pathologic tissues with chronic inflammation, may mediate activation signals through its interaction with its counterparts via cell-to-cell interaction.
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http://dx.doi.org/10.4110/in.2010.10.5.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993949PMC
October 2010

Decursinol angelate blocks transmigration and inflammatory activation of cancer cells through inhibition of PI3K, ERK and NF-kappaB activation.

Cancer Lett 2010 Oct 8;296(1):35-42. Epub 2010 Apr 8.

School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, Republic of Korea.

Inflammation is known to be closely associated with the development of cancer. Decursinol angelate (DA), a coumarin compound isolated from Angelica gigas and related compounds have been shown to possess potent anti-inflammatory activities. However, little is known about their effects on the inflammatory processes associated with cancer. In this study, the anti-inflammatory effect of DA was evaluated in cancer cell lines with respect to cellular invasion through the extracellular matrix (ECM) and the expression of pro-inflammatory mediators such as cytokine, cell adhesion molecules and matrix metalloproteinase (MMP)-9. DA inhibited the invasion of fibrosarcoma cell line, HT1080 and breast cancer cell line, MDA-MB-231 in the Matrigel invasion assay. DA-mediated suppression of cancer cell invasion was accomplished by suppression of PI3K activity known to be associated with cytoskeletal rearrangement related to cellular migration. DA also suppressed the adhesion of cancer cells to ECM mediated by down-regulation of beta(1)-integrin expression levels. Furthermore, DA inhibited the expression of pro-inflammatory cytokines and MMP-9 through suppression of PI3K, ERK and NF-kappaB activation. These results demonstrate that DA suppresses invasion and inflammatory activation of cancer cells through modulation of PI3K/AKT, ERK and NF-kappaB. These anti-inflammatory activities of DA may contribute to its anti-cancer activity.
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http://dx.doi.org/10.1016/j.canlet.2010.03.012DOI Listing
October 2010

The Stimulation of CD147 Induces MMP-9 Expression through ERK and NF-kappaB in Macrophages: Implication for Atherosclerosis.

Immune Netw 2009 Jun 30;9(3):90-7. Epub 2009 Jun 30.

The School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, Korea.

Background: CD147, as a cellular receptor for cyclophilin A (CypA), is a multifunctional protein involved in tumor invasion, inflammation, tissue remodeling, neural function, and reproduction. Recent observations showing the expression of CD147 in leukocytes indicate that this molecule may have roles in inflammation.

Methods: In order to investigate the role of CD147 and its ligand in the pathogenesis of atherosclerosis, human atherosclerotic plaques were analyzed for the expression pattern of CD147 and CypA. The cellular responses and signaling molecules activated by the stimulation of CD147 were then investigated in the human macrophage cell line, THP-1, which expresses high basal level of CD147 on the cell surface.

Results: Staining of both CD147 and CypA was detected in endothelial cell layers facing the lumen and macrophage-rich areas. Stimulation of CD147 with its specific monoclonal antibody induced the expression of matrix metalloproteinase (MMP)-9 in THP-1 cells and it was suppressed by inhibitors of both ERK and NF-kappaB. Accordingly, the stimulation of CD147 was observed to induce phosphorylation of ERK, phosphorylation-associated degradation of IkappaB, and nuclear translocation of NF-kappaB p65 and p50 subunits.

Conclusion: These results suggest that CD147 mediates the inflammatory activation of macrophages that leads to the induction of MMP-9 expression, which could play a role in the pathogenesis of inflammatory diseases such as atherosclerosis.
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http://dx.doi.org/10.4110/in.2009.9.3.90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803300PMC
June 2009

Reverse signaling through BAFF differentially regulates the expression of inflammatory mediators and cytoskeletal movements in THP-1 cells.

Immunol Cell Biol 2010 Feb 20;88(2):148-56. Epub 2009 Oct 20.

School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Korea.

Most members of the tumor-necrosis factor superfamily have been reported to mediate reverse signaling in T cells, macrophages, and/or dendritic cells. BAFF has been reported to have important functions in B-cell survival through forward signaling, but the presence of reverse signaling has not been explored. To investigate the possibility of BAFF-mediated reverse signaling, the expression patterns and functions of BAFF were analyzed in monocytic cell lines including the human macrophage-like cell line, THP-1. The expression of BAFF and its receptors was detected in monocytic cell lines, either before or after activation. The stimulation of BAFF induced the expression of matrix metalloproteinase (MMP)-9, interleukin -8, and transforming growth factor-beta-induced gene product (beta ig-h3) and the upregulation of intercellular adhesion molecule-1 in THP-1 cells. The activation of mitogen-activated protein kinase extracellular signal-regulated kinase1/2 and nuclear factor-kappaB was required for these responses. In addition to these stimulatory effects, BAFF-mediated signaling inhibited processes involving cytoskeletal movement such as phagocytosis and transmigration through blocking the activation of phosphatidylinositol 3-kinase/AKT and Rac-1. Furthermore, murine primary macrophage culture such as peritoneal macrophages expressed BAFF and stimulation of it induced the expression of MMP-9. These observations show that the reverse signaling initiated from BAFF induces the expression of inflammatory mediators while suppressing the cytoskeletal movements associated with phagocytosis and transmigration.
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http://dx.doi.org/10.1038/icb.2009.75DOI Listing
February 2010

Ionic-liquid-assisted formation of silver nanowires.

Angew Chem Int Ed Engl 2009 ;48(21):3806-9

Department of Materials Science and Engineering, Korea University, 5-1 Anam-dong, Seongbuk-gu, Seoul 137-713, Korea.

Down to the wire: A simple and effective method to synthesize silver nanowires through an ionic-liquid-assisted polyol process is developed (see scheme; scale bar=5 nm). The ionic liquids are tuned to provide the anisotropic growth of silver nanoparticles into nanowires.
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http://dx.doi.org/10.1002/anie.200806379DOI Listing
June 2009

Comparative analysis of the expression patterns of various TNFSF/TNFRSF in atherosclerotic plaques.

Immunol Invest 2008 ;37(4):359-73

Department of Genetic Engineering, School of Life Sciences and Biotechnology School of Medicine, Kyungpook National University, Daegu, Korea.

Members of the TNFSF/TNFRSF are involved in the immunoregulation of various immune reactions and diseases. Recently, LIGHT/TR2, GITRL/GITR, and TL1A/DR3 have been reported as playing roles in the inflammatory reactions in atherosclerosis, but a comparative analysis of these molecules has not been conducted. In order to compare their expression patterns, immunohistochemical analyses were performed using six human carotid endoarterectomy samples. The expression of these molecules was detected in the various cell types that constitute atherosclerotic plaques. The expression of all analyzed molecules was detected, albeit at various levels, mainly in foamy macrophages in all tested samples. The strong expression of these molecules in endothelial and smooth muscle cells was also detected in 2 and 1 plaque samples, respectively, while others express only some of the tested molecules. Flow cytometry analyses of human monocyte/macrophage cell lines, U937 and THP-1, detected the expression of the tested molecules while a relatively undifferentiated monocytic cell line, TF-1A, failed to express them. These data indicate that activated and differentiated macrophages are the main cell type expressing tested molecules in atherosclerotic plaques while endothelial and smooth muscle cells can express them in limited cases. Pro-inflammatory activities of the tested molecules may contribute to the atherogenesis by stimulating the cells expressing them in atherosclerotic plaques and the successful treatment of atherosclerosis may require cooperative regulation of these activities.
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http://dx.doi.org/10.1080/08820130802123139DOI Listing
August 2008

Macrophages express granzyme B in the lesion areas of atherosclerosis and rheumatoid arthritis.

Immunol Lett 2007 Jul 8;111(1):57-65. Epub 2007 Jun 8.

Department of Genetic Engineering, School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-201, Republic of Korea.

Granzyme B is a major mediator of the cytotoxic immune response by inducing target cell death when internalized in the presence of perforin. Recently, several studies have focused on another role of granzyme B, which is extracellular matrix (ECM) remodeling through the degradation of ECM proteins. In order to investigate the expression pattern of granzyme B in the lesion areas of atherosclerosis and rheumatoid arthritis, we performed immunohistochemistry and in situ hybridization analyses using human atherosclerotic plaques and the synovial tissues of rheumatoid arthritic- and osteoarthritic-joints. In atherosclerotic plaques, granzyme B was expressed by macrophages in areas such as the boundary regions between media and intima, areas around necrotic cores, and in shoulder regions. In the synovial tissues of rheumatoid arthritic-joints, the expression of granzyme B was strongly observed in the lining layers where the majority of cells are macrophages and also in perivascular areas where macrophages and a small number of lymphocytes were mixed to form diffuse cellular aggregates. Granzyme B-positive cells were not detected in osteoarthritic synovium. Furthermore, the expression of granzyme B has been induced in the human macrophage cell line, THP-1, by ECM proteins or agents which induce macrophage differentiation. These observations indicate that macrophages should be added to the list of cell types that express granzyme B in human inflammatory diseases and that granzyme B may play a role in macrophage functions that are associated with disease progression.
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http://dx.doi.org/10.1016/j.imlet.2007.05.004DOI Listing
July 2007

Reverse signaling initiated from GITRL induces NF-kappaB activation through ERK in the inflammatory activation of macrophages.

Mol Immunol 2008 Jan 28;45(2):523-33. Epub 2007 Jun 28.

Department of Genetic Engineering, School of Life Sciences and Biotechology, Kyungpook National University, Taegu 702-701, Republic of Korea.

Glucocorticoid-induced TNF receptor family related protein ligand (GITRL) is known to interact with its cognate receptor GITR. In order to investigate the potential role of GITRL in the pro-inflammatory activation of macrophages and the signaling pathway induced by GITRL, we stimulated the macrophage cell line, THP-1, and primary macrophages with an anti-GITRL monoclonal antibody or a GITR:Fc fusion protein and analyzed the cellular responses. The stimulation of GITRL induced the expression of pro-inflammatory cytokines and matrix metalloproteinase (MMP)-9 and up-regulated ICAM-1 expression levels, which was responsible for enhanced cellular aggregation and adhesion to extracellular matrix proteins. The activation of these pro-inflammatory mediators required the activation of ERK1/2 mitogen-activated protein kinase (MAPK) and negatively regulated by p38 MAPK and JNK. Immunofluorescence analysis detected nuclear translocation of the NF-kappaB p50 subunit and this was blocked by ERK inhibitor, indicating that GITRL stimulation induced ERK1/2 phosphorylation and subsequent activation of NF-kappaB. Furthermore, the expression of GITRL and GITR was detected in macrophages in inflammatory disease specimens such as atherosclerotic plaques and synovial tissues of rheumatoid arthritis. These observations raise the possibility that the GITRL-mediated inflammatory activation of macrophages is involved in the pathogenesis of inflammatory diseases.
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http://dx.doi.org/10.1016/j.molimm.2007.05.013DOI Listing
January 2008

Glucocorticoid-induced tumour necrosis factor receptor family related protein (GITR) mediates inflammatory activation of macrophages that can destabilize atherosclerotic plaques.

Immunology 2006 Nov;119(3):421-9

Department of Genetic Engineering, School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Korea.

Glucocorticoid-induced tumour necrosis factor receptor family related protein (GITR) is the 18th member of the tumour necrosis factor receptor superfamily (TNFRSF18) and is known to interact with its cognate ligand GITRL (TNFSF18). We investigated the potential role of GITR in the pro-inflammatory activation of macrophages. Immunohistochemistry and in situ hybridization analyses of human atherosclerotic plaques demonstrated that GITR and its ligand are expressed mainly in lipid-rich macrophages. We then investigated the role of GITR in human and mouse monocyte/macrophage functions. Stimulation of GITR caused nuclear factor (NF)-kappaB-dependent activation of matrix metalloproteinase-9 (MMP-9) and pro-inflammatory cytokine expression in both the human and mouse monocytic/macrophage cell lines, THP-1 and RAW264.7, respectively. These cellular responses were also observed when the THP-1 cells were treated with phorbol-12 myristate-13 acetate (PMA), which is known to induce macrophage differentiation. To demonstrate that these responses are not restricted to cultured cell lines, we tested primary macrophages. Both peritoneal and bone marrow-derived macrophages responded to GITR stimulation with induction of MMP-9 and tumour necrosis factor-alpha (TNF-alpha). Furthermore, the GITR staining pattern overlapped with those of MMP-9 and TNF-alpha in atherosclerotic plaques. These data indicate that GITR-mediated macrophage activation may promote atherogenesis via the induction of pro-atherogenic cytokines/chemokines, and destabilize the atherosclerotic plaques via the induction of the matrix-degrading enzyme, MMP-9.
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http://dx.doi.org/10.1111/j.1365-2567.2006.02453.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1819571PMC
November 2006

Z39Ig is expressed on macrophages and may mediate inflammatory reactions in arthritis and atherosclerosis.

J Leukoc Biol 2006 Oct 1;80(4):922-8. Epub 2006 Aug 1.

Department of Genetic Engineering, Kyungpook National University, Taegu 702-701, Korea.

Z39Ig is a transmembrane protein containing two Ig homology domains with unknown functions. Immunohistochemical analyses of human carotid atherosclerotic plaques detected Z39Ig staining in areas rich in foamy macrophages. Z39Ig staining was also observed in macrophages in the lining layers and sublining areas of rheumatoid arthritis synovium. Z39Ig staining in the osteoarthritis synovium was restricted to macrophages in the lining layers. To identify the role(s) of Z39Ig in the function of macrophages, we used human monocytic cell lines TF-1A (Z39Ig-negative) and THP-1 (Z39Ig-positive). The expression of Z39Ig was induced in TF-1A cells ,when they were differentiated into macrophages by treatment with PMA. The stimulation of PMA-treated TF-1A or THP-1 cells with immobilized anti-Z39Ig mAb induced the secretion of IL-8 and matrix metalloproteinase (MMP)-9, which was dependent on NF-kappaB activation. These data indicate that the macrophage Z39Ig is involved in the pathogenesis of inflammatory diseases through chemokine induction, which will promote the migration of inflammatory cells into the lesion area, and MMP-9 induction, which will contribute to cartilage destruction or extracellular matrix degradation.
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http://dx.doi.org/10.1189/jlb.0306160DOI Listing
October 2006

Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages.

Clin Immunol 2005 Sep;116(3):217-24

Department of Genetic Engineering, Kyungpook National University, Daegu 702-701, Republic of Korea.

Cyclophilin A (CypA) levels increase in the sera and synovial fluids of rheumatoid arthritis (RA) patients, but the cell types expressing CypA and the function of CypA in the pathogenesis of RA are not known yet. Immunohistochemistry analyses revealed high level CypA staining in the macrophages in the lining layers of human RA and osteoarthritis synovium. Low level CypA staining was also detected in endothelial cells, lymphocytes, and smooth muscle cells in RA synovium. Further investigation of the CypA function using monocyte/macrophage cell lines revealed that CypA induced expression of cytokine/chemokines such as TNF-alpha, IL-8, MCP-1, and IL-1beta and matrix metalloproteinase (MMP)-9 through a pathway that is dependent on NFkappaB activation. Furthermore, MMP-9 staining pattern overlapped with that of CypA in both RA and OA synovium. Our data suggest that CypA may stimulate macrophages to degrade joint cartilage via MMP-9 expression and promote inflammation via pro-inflammatory cytokine secretion.
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http://dx.doi.org/10.1016/j.clim.2005.05.004DOI Listing
September 2005

Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis.

Cytokine 2005 Mar;29(5):229-35

Department of Genetic Engineering, Kyungpook National University, Taegu 702-701, Republic of Korea.

TL1A (VEGI/TNFSF15) is the ligand for DR3 (TNFRSF12) and is a newly identified member of the tumor necrosis factor superfamily (TNFSF). Previously, DR3 has been shown to have a role in atherogenesis through stimulation of matrix degrading enzymes including matrix metalloproteinase (MMP)-9. Immunohistochemical staining of human carotid atherosclerotic plaques revealed a high-level expression of TL1A in regions rich in macrophage/foam cells. To investigate the role of TL1A and DR3 in the functioning of macrophage/foam cells in relation to atherogenesis, we have analyzed cellular events mediated by TL1A and DR3 in a human macrophage-like cell line, THP-1. Treatment of THP-1 cells with immobilized anti-DR3 monoclonal antibody in combination with IFN-gamma caused induction of pro-atherogenic cytokines/chemokines such as TNF-alpha, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-8. Treatment of THP-1 cells with recombinant TL1A in combination with IFN-gamma also caused induction of MMP-9 and IL-8. Furthermore, the expression of DR3 in peripheral blood monocytes was induced after atherogenic stimulation. These data suggest that TL1A and DR3 is involved in atherosclerosis via the induction of pro-inflammatory cytokines/chemokines and decreasing plaque stability by inducing extracellular matrix degrading enzymes.
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http://dx.doi.org/10.1016/j.cyto.2004.12.001DOI Listing
March 2005

LIGHT is involved in the pathogenesis of rheumatoid arthritis by inducing the expression of pro-inflammatory cytokines and MMP-9 in macrophages.

Immunology 2005 Feb;114(2):272-9

Department of Genetic Engineering, Kyungpook National University, Taegu 702-701, Korea.

Macrophages play a crucial role in the perpetuation of inflammation and irreversible cartilage damage during the development of rheumatoid arthritis (RA). LIGHT (TNFSF14) and its receptor TR2 (TNFRSF14) are known to have pro-inflammatory activities in foam cells of atherosclerotic plaques. We tested a hypothesis that LIGHT and TR2 are involved in activation of monocyte/macrophages in RA synovium. Immunohistochemical analysis of RA synovial tissue samples revealed that both LIGHT and TR2 are expressed in CD68 positive macrophages. In contrast, synovial tissue samples from osteoarthritis (OA) patients failed to reveal the expression of LIGHT. Expression of TR2 in RA synovial macrophages was also detected using flow cytometry analysis. To identify the role of LIGHT in the functioning of macrophages in RA, we isolated macrophage enriched cells from RA synovial fluid and stimulated them with LIGHT. LIGHT induced expression of matrix metalloproteinase-9 and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8. These data indicate that LIGHT and TR2 expressed in macrophages are involved in the pathogenesis of RA by inducing the expression pro-inflammatory cytokines and matrix degrading enzymes.
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http://dx.doi.org/10.1111/j.1365-2567.2004.02004.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782076PMC
February 2005

TWEAK can induce pro-inflammatory cytokines and matrix metalloproteinase-9 in macrophages.

Circ J 2004 Apr;68(4):396-9

Cardiology Division, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

The expression of TWEAK (TNFSF12) and TweakR/Fn14 was detected in regions rich in macrophage/foam cells in atherosclerotic plaques. The role of TWEAK in monocytes in relation to atherogenesis was investigated by analyzing the cellular events induced by TWEAK in a human macrophage-like cell line, THP-1. TWEAK induced various molecular mediators of atherogenesis, such as IL-6, MCP-1, IL-8 and MMP-9, and the induction was augmented by interferon-gamma. TWEAK-induced activation of MMP-9 was mediated by activation of NF-kappaB. These results suggest that TWEAK is involved in atherosclerosis by inducing pro-inflammatory cytokines and extracellular matrix degrading enzymes, which reduce plaque stability.
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http://dx.doi.org/10.1253/circj.68.396DOI Listing
April 2004