Publications by authors named "Eun-Kyung Bae"

35 Publications

Overexpression of a Poplar RING-H2 Zinc Finger, , Confers Enhanced Drought Tolerance via Reduced Water Loss and Ion Leakage in .

Int J Mol Sci 2020 Dec 11;21(24). Epub 2020 Dec 11.

Department of Plant & Environmental New Resources, Kyung Hee University, Yongin 17104, Korea.

Drought stress is one of the major environmental problems in the growth of crops and woody perennials, but it is getting worse due to the global climate crisis. XERICO, a RING (Really Interesting New Gene) zinc-finger E3 ubiquitin ligase, has been shown to be a positive regulator of drought tolerance in plants through the control of abscisic acid (ABA) homeostasis. We characterized a poplar () RING protein family and identified the closest homolog of called . Expression of is induced by both salt and drought stress, and by ABA treatment in poplars. Overexpression of in Arabidopsis confers salt and ABA hypersensitivity in young seedlings, and enhances drought tolerance by decreasing transpirational water loss. Consistently, transgenic hybrid poplars overexpressing demonstrate enhanced drought tolerance with reduced transpirational water loss and ion leakage. Subsequent upregulation of genes involved in the ABA homeostasis and drought response was confirmed in both transgenic Arabidopsis and poplars. Taken together, our results suggest that will serve as a focal point to improve drought tolerance of woody perennials.
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http://dx.doi.org/10.3390/ijms21249454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764267PMC
December 2020

Human Milk Oligosaccharide 2'-Fucosyllactose Reduces Neurodegeneration in Stroke Brain.

Transl Stroke Res 2020 10 2;11(5):1001-1011. Epub 2020 Jan 2.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.

2'-Fucosyllactose (2'-FL) is a major oligosaccharide in human milk and is present at trace levels in cow milk. 2'-FL reduces inflammation in the gastrointestinal tract. Its action in the central nervous system has not been well characterized. The purpose of this study is to determine 2'-FL-mediated neural protection and repair in culture and stroke brain. In rat primary cortical neuronal cultures, 2'-FL significantly antagonized N-methyl-D-aspartate (NMDA) or glutamate-mediated changes in ATP production, MAP2 immunoreactivity, and TUNEL. The influx of Ca (Cai) was examined in primary cortical neurons expressing GCaMP5, an endogenous calcium probe. NMDA increased Cai; 2'-FL significantly attenuated this reaction. In a rat middle cerebral artery occlusion model of stroke, we found that intracerebroventricular pretreatment or oral posttreatment with 2'-FL significantly reduced brain infarction, mitigated microglial activation, improved locomotor activity, and upregulated brain-derived neurotrophic factor (BDNF) expression. Post-stroke delivery of 2'-FL increased bromodeoxyuridine (BrdU) labeling in the perilesioned area. These BrdU cells co-expressed NeuN, or nestin, or GFAP. Using subventricular Matrigel cultures, we demonstrated that 2'-FL increased cell migration from subventricular zone explant. This response was reduced by anti-BDNF blocking antibody. In conclusion, our data suggest that 2'-FL has neuroprotective action through inhibition of Cai, inflammation, and apoptosis. Posttreatment with 2'-FL facilitates neural repair in stroke brain.
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http://dx.doi.org/10.1007/s12975-019-00774-zDOI Listing
October 2020

Ginseng-derived patatin-related phospholipase PgpPLAIIIβ alters plant growth and lignification of xylem in hybrid poplars.

Plant Sci 2019 Nov 20;288:110224. Epub 2019 Aug 20.

Department of Applied Plant Science, College of Agriculture and Life Science, Chonnam National University, Gwangju, 61186, Republic of Korea. Electronic address:

Patatin-liked phospholipase A (pPLAs) are major lipid acyl hydrolases that participate in various biological functions in plant growth and development. Previously, a ginseng-derived pPLAIII homolog was reported to reduce lignin content in Arabidopsis. This led us to evaluate its possible usefulness as a biomass source in wood plant. Herein, we report that there are six members in the pPLAIII gene family in poplar. Overexpression of pPLAIIIβ derived from ginseng resulted in a reduced plant height with radially expanded stem growth in hybrid poplars. Compared with the wild type (WT), the chlorophyll content was increased in the overexpression poplar lines, whereas the leaf size was smaller. The secondary cell wall structure in overexpression lines was also altered, exhibiting reduced lignification in the xylem. Two transcription factors, MYB92 and MYB152, which control lignin biosynthesis, were downregulated in the overexpression lines. The middle xylem of the overexpression line showed heavy thickening, making it thicker than the other xylem parts and the WT xylem, which rather could have been contributed by the presence of more cellulose in the selected surface area. Taken together, the results suggest that PgpPLAIIIβ plays a role not only in cell elongation patterns, but also in determining the secondary cell wall composition.
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http://dx.doi.org/10.1016/j.plantsci.2019.110224DOI Listing
November 2019

Spondyloarthritis features in zymosan-induced SKG mice.

Joint Bone Spine 2018 10 29;85(5):583-591. Epub 2017 Nov 29.

Division of Rheumatology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea. Electronic address:

Objectives: Spondyloarthritis (SpA) encompasses a group of disorders including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and enteropathic arthritis. SpA pathogenesis is still not well understood. Animal models are important for studying disease mechanisms and identifying new therapeutic agents. Recently, a β-glucan-induced SKG mouse was used as an animal model for SpA. The aim of this study was to evaluate the clinical and molecular characteristics of a zymosan-induced SKG mouse.

Methods: Zymosan was injected intraperitoneally into SKG mice. Clinical arthritis scores were measured, and fluorine-18 fluorodeoxyglucose (F-FDG) small-animal positron emission tomography/computed tomography (PET/CT) was performed to quantify joint inflammation. Histologic features of the joints, intestines, skin, and eyes were evaluated. Inflammatory cytokine and Wnt inhibitor expression was measured in mouse serum.

Results: Zymosan exposure triggered SpA-like diseases in SKG mice, including peripheral arthritis, spondylitis, dactylitis, enteritis, and psoriatic skin lesions. F-FDG uptake was significantly higher in the zymosan-treated mice compared with controls. The expression of tumor necrosis factor α, interleukin (IL)-6, and Dickkopf-1 increased significantly, while IL-4 and sclerostin expression decreased significantly in zymosan-induced mice compared with control mice.

Conclusions: Zymosan-induced SKG mice developed articular and extra-articular features as well as molecular changes that resembled those of human SpA. These findings suggest that the zymosan-induced SKG mouse is a good animal model to reflect the complex features of human SpA.
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http://dx.doi.org/10.1016/j.jbspin.2017.11.008DOI Listing
October 2018

Estrogen attenuates the spondyloarthritis manifestations of the SKG arthritis model.

Arthritis Res Ther 2017 09 7;19(1):198. Epub 2017 Sep 7.

Division of Rheumatology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul, 06351, South Korea.

Background: Ankylosing spondylitis (AS) is a male-predominant disease, and radiographic evidence of damage is also more severe in males. Estrogen modulates immune-related processes such as T cell differentiation and cytokine production. This study aimed to evaluate the effect of estrogen on the disease activity of spondyloarthritis (SpA).

Methods: The effects of estrogen on the development of arthritis were evaluated by performing ovariectomy and 17β-estradiol (E2) pellet implantation in zymosan-treated SKG mice. Clinical arthritis scores were measured, and F-fluorodeoxyglucose (F-FDG) small-animal positron emission tomography/computed tomography performed to quantify joint inflammation. The expression of inflammatory cytokines in joint tissue was measured.

Results: E2-treated mice showed remarkable suppression of arthritis clinically and little infiltration of inflammatory cells in the Achilles tendon and intervertebral disc. F-FDG uptake was significantly lower in E2-treated mice than in sham-operated (sham) and ovariectomized mice. Expression of TNF, interferon-γ, and IL-17A was significantly reduced in E2-treated mice, whereas expression of sclerostin and Dickkopf-1 was increased in E2-treated mice compared with sham and ovariectomized mice.

Conclusions: Estrogen suppressed arthritis development in SKG mice, a model of SpA. Results of this study suggest that estrogen has an anti-inflammatory effect on the spondyloarthritis manifestations of the SKG arthritis model.
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http://dx.doi.org/10.1186/s13075-017-1407-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590166PMC
September 2017

A novel histone deacetylase 6-selective inhibitor suppresses synovial inflammation and joint destruction in a collagen antibody-induced arthritis mouse model.

Int J Rheum Dis 2015 Jun 20;18(5):514-23. Epub 2014 Dec 20.

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

Aim: To investigate the effects of Tubastatin A, a selective histone deacetylase-6 inhibitor, on synovial inflammation and joint destruction in a collagen antibody-induced arthritis (CAIA) mouse model.

Methods: Collagen antibody-induced arthritis mice were given daily intraperitoneal injections of various concentrations of Tubastatin A (0, 10, 50, 100 mg/kg). The clinical score and paw thickness were measured. Mice were sacrificed on day 15, and the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6 in the serum were analyzed using enyme-linked immunosorbent assay (ELISA). Two pathologists independently measured the synovitis score. Micro-computed tomography (CT) scans of the joints were performed to quantify joint destruction. The expression of IL-6 from human fibroblast-like synoviocytes (FLSs) after incubation with various doses of Tubastatin A (0, 0.75, 1.5, 3 μmol/L) was measured using ELISA.

Results: The clinical arthritis score was significantly attenuated and paw thickness was lower in the group treated with 100 mg/kg Tubastatin A compared with those treated with vehicle alone. The synovitis score was significantly reduced in the 100 mg/kg Tubastatin A-treated group compared with the control group. Micro-CT showed that quantitative measures of joint destruction were significantly attenuated in the 100 mg/kg Tubastatin A-treated group compared with the control. The expression of IL-6 in the sera was lower in the mice treated with Tubastatin A compared with the control. The expression of IL-6 in human FLSs decreased dose-dependently after incubation with Tubastatin A without affecting cell viability.

Conclusions: Tubastatin A successfully ameliorated synovial inflammation and protected against joint destruction in CAIA mice, at least in part, by modulating IL-6 expression.
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http://dx.doi.org/10.1111/1756-185X.12501DOI Listing
June 2015

Response to drought and salt stress in leaves of poplar (Populus alba × Populus glandulosa): expression profiling by oligonucleotide microarray analysis.

Plant Physiol Biochem 2014 Nov 26;84:158-168. Epub 2014 Sep 26.

Department of Forest Genetic Resources, Korea Forest Research Institute, 39 Onjeong-ro, Suwon 441-847, Republic of Korea. Electronic address:

Drought and salt stresses are major environmental constraints on forest productivity. To identify genes responsible for stress tolerance, we conducted a genome-wide analysis in poplar (Populus alba × Populus glandulosa) leaves exposed to drought and salt (NaCl) stresses. We investigated gene expression at the mRNA level using oligonucleotide microarrays containing 44,718 genes from Populus trichocarpa. A total of 1604 and 1042 genes were up-regulated (≥2-fold; P value < 0.05) by drought and salt stresses, respectively, and 765 genes were up-regulated by both stresses. In addition, 2742 and 1685 genes were down-regulated by drought and salt stresses, respectively, and 1564 genes were down-regulated by both stresses. The large number of genes regulated by both stresses suggests that crosstalk occurs between the drought and salt stress responses. Most up-regulated genes were involved in functions such as subcellular localization, signal transduction, metabolism, and transcription. Among the up-regulated genes, we identified 47 signaling proteins, 65 transcription factors, and 43 abiotic stress-related genes. Several genes were modulated by only one of the two stresses. About 25% of the genes significantly regulated by these stresses are of unknown function, suggesting that poplar may provide an opportunity to discover novel stress-related genes.
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http://dx.doi.org/10.1016/j.plaphy.2014.09.008DOI Listing
November 2014

Establishment and characterization of bortezomib-resistant U266 cell line: constitutive activation of NF-κB-mediated cell signals and/or alterations of ubiquitylation-related genes reduce bortezomib-induced apoptosis.

BMB Rep 2014 May;47(5):274-9

Cancer Research Institute, Seoul National University College of Medicine; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.

Bortezomib has been known as the most promising anti-cancer drug for multiple myeloma (MM). However, recent studies reported that not all MM patients respond to bortezomib. To overcome such a stumbling-block, studies are needed to clarify the mechanisms of bortezomib resistance. In this study, we established a bortezomib-resistant cell line (U266/velR), and explored its biological characteristics. The U266/velR showed reduced sensitivity to bortezomib, and also showed crossresistance to the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation, known as stem-like feature, compared to parental U266 cells. U266/velR showed relatively less inhibitory effect of prosurvival NF-κB signaling by bortezomib. Further analysis of RNA microarray identified genes related to ubiquitination that were differentially regulated in U266/velR. Moreover, the expression level of CD52 in U266 cells was associated with bortezomib response. Our findings provide the basis for developing therapeutic strategies in bortezomib-resistant relapsed and refractory MM patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163865PMC
http://dx.doi.org/10.5483/bmbrep.2014.47.5.134DOI Listing
May 2014

TNF α mediated IL-6 secretion is regulated by JAK/STAT pathway but not by MEK phosphorylation and AKT phosphorylation in U266 multiple myeloma cells.

Biomed Res Int 2013 16;2013:580135. Epub 2013 Sep 16.

Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Jongro-gu, Seoul 110-799, Republic of Korea.

IL-6 and TNF α were significantly increased in the bone marrow aspirate samples of patients with active multiple myeloma (MM) compared to those of normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6 and TNF α than those with MM in plateau phase. TNF α increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in signaling pathways by which TNF α promotes IL-6 secretion from MM cells are largely unknown. In our study, we found that TNF α treatments induce MEK and AKT phosphorylation. TNF α -stimulated IL-6 production was abolished by inhibition of JAK2 and IKK β or by small interfering RNA (siRNA) targeting TNF receptors (TNFR) but not by MEK, p38, and PI3K inhibitors. Also, TNF α increased phosphorylation of STAT3 (ser727) including c-Myc and cyclin D1. Three different types of JAK inhibitors decreased the activation of the previously mentioned pathways. In conclusion, blockage of JAK/STAT-mediated NF- κ B activation was highly effective in controlling the growth of MM cells and, consequently, an inhibitor of TNF α -mediated IL-6 secretion would be a potential new therapeutic agent for patients with multiple myeloma.
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http://dx.doi.org/10.1155/2013/580135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787550PMC
June 2014

Neuronal Responses in the Globus Pallidus during Subthalamic Nucleus Electrical Stimulation in Normal and Parkinson's Disease Model Rats.

Korean J Physiol Pharmacol 2013 Aug 30;17(4):299-306. Epub 2013 Jul 30.

Department of Biomedical Engineering, College of Health Science, Yonsei University, Wonju 220-710, Korea.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been widely used as a treatment for the movement disturbances caused by Parkinson's disease (PD). Despite successful application of DBS, its mechanism of therapeutic effect is not clearly understood. Because PD results from the degeneration of dopamine neurons that affect the basal ganglia (BG) network, investigation of neuronal responses of BG neurons during STN DBS can provide informative insights for the understanding of the mechanism of therapeutic effect. However, it is difficult to observe neuronal activity during DBS because of large stimulation artifacts. Here, we report the observation of neuronal activities of the globus pallidus (GP) in normal and PD model rats during electrical stimulation of the STN. A custom artifact removal technique was devised to enable monitoring of neural activity during stimulation. We investigated how GP neurons responded to STN stimulation at various stimulation frequencies (10, 50, 90 and 130 Hz). It was observed that activities of GP neurons were modulated by stimulation frequency of the STN and significantly inhibited by high frequency stimulation above 50 Hz. These findings suggest that GP neuronal activity is effectively modulated by STN stimulation and strongly dependent on the frequency of stimulation.
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http://dx.doi.org/10.4196/kjpp.2013.17.4.299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741486PMC
August 2013

The effect of Radachlorin® PDT in advanced NSCLC: a pilot study.

Photodiagnosis Photodyn Ther 2013 May 16;10(2):120-6. Epub 2013 Mar 16.

Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Background: Palliative effect of PDT in advanced NSCLC has been proven. Radachlorin® is a second generation photosensitizer that has quicker pharmacokinetics than first generation photosensitizers. Although there are reports describing Radachlorin®, limited data are available regarding its advantages in PDT.

Methods: Advanced NSCLC patients with central airway obstruction were enrolled. Patients who had comorbidity effects on drug metabolism were excluded. All patients received 1mg/kg of Radachlorin®, 4 h before light irradiation. 200 J/cm² of laser was irradiated during 11 min 6 s. Bronchial toileting was performed the following day. A PFT was performed before and after PDT. The primary treatment outcome was improvement of airway obstruction, which was evaluated according to bronchoscopic findings and improvement of FEV1. Secondary treatment outcomes included the rate of PDT-related complications, one year survival rate and progression free survival.

Results: Ten patients were enrolled between June 2010 and May 2011. Their median age was 58.5 years and their baseline cancer stage was more than IIIA. 20% of patients showed successful results, 70% showed partially successful results and 10% showed an unsuccessful result. All patients showed improvement in their obstructive symptoms. The mean FEV1 before PDT was 1.70±0.69 L, while the mean FEV1 after PDT was 1.99±0.60 L (P=0.029). No patients had major complications. Eight patients were undergoing additional treatment after resolving airway obstruction. The one year survival rate after PDT was 70%.

Conclusions: Radachlorin®-based PDT is safe and effective treatment for relieving central airway obstruction in advanced NSCLC.
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http://dx.doi.org/10.1016/j.pdpdt.2013.01.004DOI Listing
May 2013

The role of α-defensin-1 and related signal transduction mechanisms in the production of IL-6, IL-8 and MMPs in rheumatoid fibroblast-like synoviocytes.

Rheumatology (Oxford) 2013 Aug 25;52(8):1368-76. Epub 2013 Apr 25.

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.

Objectives: To investigate the effect of α-defensin-1 on the expression of IL-6, IL-8 and MMPs as well as the signal transduction mechanisms responsible for their expression in RA fibroblast-like synoviocytes (FLS).

Methods: The concentrations of α-defensin-1 in SF were measured by ELISA. In RA FLS, mRNA expression of IL-6, IL-8 and MMPs and activation of signalling molecules were examined by real-time PCR, western blotting and electrophoretic mobility shift assay.

Results: Concentrations of SF α-defensin-1 were significantly increased in RA patients compared with OA patients. The levels of mRNA expression of IL-6, IL-8, MMP-1 and MMP-3 were significantly increased in RA FLS treated with α-defensin-1 compared with controls. Furthermore, α-defensin-1 activated JNK and ERK in RA FLS, respectively. Treatment of RA FLS with ERK or JNK inhibitors prior to α-defensin-1 treatment resulted in reduced expression of IL-6, IL-8, MMP-1, and MMP-3 compared with controls. Remarkably, treatment of RA FLS with an ERK inhibitor prior to α-defensin-1 stimulation significantly reduced production of IL-6 and MMP-1 by approximately 71% and 98% compared with controls, respectively. The JNK inhibitor significantly suppressed α-defensin-1-induced MMP-1 production by approximately 73% compared with controls. Finally, there was a significant induction of NF-κB DNA binding activity in response to α-defensin-1.

Conclusion: Our results suggest that α-defensin-1 may play a role in RA pathogenesis by regulating the production of MMPs as well as IL-6 and IL-8. These processes were dependent on the regulation of the JNK and/or ERK and NF-κB pathways.
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http://dx.doi.org/10.1093/rheumatology/ket147DOI Listing
August 2013

A role for benzo[a]pyrene and Slug in invasive properties of fibroblast-like synoviocytes in rheumatoid arthritis: a potential molecular link between smoking and radiographic progression.

Joint Bone Spine 2013 Dec 6;80(6):621-5. Epub 2013 Apr 6.

Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 135-710, Republic of Korea. Electronic address:

Objectives: To investigate the effects of benzo[a]pyrene (B[a]P), a major toxic component of cigarette smoke, on the expression of Slug and to determine the effect of B[a]P/Slug on the invasive properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS).

Method: The expression of Slug was measured by real-time PCR following the stimulation of FLS with different concentrations of B[a]P or EGF. The phosphorylation of the key enzymes in the signaling pathway was analyzed by western blots. Inhibitors of PI3K/Akt/mTOR pathway were used to confirm the critical pathway for Slug expression. An in vitro cell invasion assay was performed using RA FLS treated with Slug cDNA, Slug small interference RNA, or control.

Results: Slug expression increased significantly following treatment with B[a]P or EGF in a dose-dependent manner. The stimulation of FLS with B[a]P or EGF induced the phosphorylation of Akt kinase, but not in ERK, JNK and p38. The Slug mRNA expression induced by B[a]P and EGF decreased significantly following the treatment with PI3K/Akt/mTOR inhibitors. Slug overexpression using Slug cDNA upregulated the invasive function of FLS, and Slug depletion using siRNA showed the opposite effect compared with the control. In addition, the stimulation with B[a]P increased the invasive function of the control siRNA-treated FLS but not in the Slug siRNA-treated FLS.

Conclusion: Our data showed that B[a]P regulates the invasive properties of RA FLS through Slug expression. This mechanism may provide a novel molecular link underlying the association between smoking and increased radiographic progression in RA.
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http://dx.doi.org/10.1016/j.jbspin.2013.02.009DOI Listing
December 2013

CIP2A facilitates apoptotic resistance of fibroblast-like synoviocytes in rheumatoid arthritis independent of c-Myc expression.

Rheumatol Int 2013 Sep 2;33(9):2241-8. Epub 2013 Mar 2.

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.

The aim of this study is to investigate the effects of CIP2A (Cancerous inhibitor of protein phosphatase 2A) on the apoptosis of RA FLS. Proliferation and apoptotic activity of RA FLS following treatment with CIP2A siRNA or control siRNA were analyzed using MTT assays and Cell Death Detection kit. RA FLS was treated with CIP2A siRNA or control siRNA in 3-, 6-, and 9-day intervals for a Western blot analysis to determine C-Myc expression. To evaluate the signal transduction pathways engaged in apoptosis, caspase-3 activity, caspase-9 activity, PARP, and phosphorylation of the Akt kinase were analyzed by Western blot. Cell viability of RA FLS was significantly lower in the CIP2A siRNA-treated group compared with the control after 7 days (p = 0.022). Apoptosis of RA FLS was significantly higher in the CIP2A siRNA-treated group compared with the control when incubated for 3, 6, and 9 days (p = 0.029, p = 0.021, p = 0.043, respectively). C-Myc expression did not change with the different incubation periods. CIP2A siRNA-treated FLS expressed higher level of activated caspase-3, caspase-9, and PARP (p = 0.014, p = 0.020, p = 0.021, respectively) and lower level of phosphorylated Akt (p = 0.001) compared with those treated with the control siRNA. Our data show that CIP2A expression in RA FLS is an important mediator of dysfunctional apoptosis independent of c-Myc stabilization. Expression of CIP2A may contribute to apoptotic resistance of RA FLS through the activation of Akt and deactivation of caspase-3, caspase-9, and PARP. Inhibition of CIP2A may therefore constitute a novel, promising therapeutic target in RA.
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http://dx.doi.org/10.1007/s00296-013-2711-6DOI Listing
September 2013

Microarray and suppression subtractive hybridization analyses of gene expression in hybrid poplar (Populus alba × Populus tremula var. glandulosa) cell suspension cultures after exposure to NaCl.

Plant Physiol Biochem 2012 Sep 2;58:151-8. Epub 2012 May 2.

Division of Forest Biotechnology, Korea Forest Research Institute, 39 Onjeong-ro, Suwon 441-847, Republic of Korea.

The gene expression profiles of hybrid poplar (Populus alba × Populus tremula var. glandulosa) cells in suspension culture after exposure to salinity (NaCl) induced stress were examined by constructing two suppression subtractive hybridization (SSH) libraries. cDNA from non-treated cells was used as a driver and cDNA samples from cell suspension cultures exposed to 150 mM NaCl for 2 or 10 h were used as testers. Randomly selected clones from each SSH library were sequenced and 727 high-quality expressed sequence tags (ESTs) were obtained and analyzed. Four novel ESTs were identified. Between the two libraries, 542 unique SSH clones were selected for placement on a cDNA microarray. In total, 18 differentially expressed genes were identified with 4 and 12 genes being significantly differentially expressed 2 and 10 h after the treatment, respectively. Genes related to metabolism and protein synthesis and several genes whose protein products are implicated in salt or other abiotic stress-related responses were expressed in the salt-stressed cells.
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http://dx.doi.org/10.1016/j.plaphy.2012.04.015DOI Listing
September 2012

A quantitative comparison of basal ganglia neuronal activities of normal and Parkinson's disease model rats.

Neurosci Lett 2011 Nov 10;505(2):113-8. Epub 2011 Oct 10.

Department of Biomedical Engineering, College of Health Science, Yonsei University, 234 Maeji-ri, Heungup-myun, Wonju 220-710, Gangwon-do, Republic of Korea.

The purpose of this study was to identify consistent characteristic changes of neuronal activity in basal ganglia (BG) nuclei associated with Parkinson's disease (PD) so that a reliable index of PD can be derived. A simple algorithm for automatic identification of firing patterns was devised as an essential tool to achieve this goal. A detailed quantitative analysis of firing patterns as well as firing rate was performed in three BG nuclei: the subthalamic nucleus (STN), the substantia nigra pars reticulate (SNpr), and the globus pallidus (GP). The results showed that the firing rate of STN neurons was not significantly altered in PD model rats. We also did not find a significant alteration in firing rates in the SNpr and GP between normal and PD model rats. In contrast, consistent changes of firing patterns were observed in all three BG nuclei in that the percentage of neurons with a regular firing pattern decreased whereas those with irregular, mixed, or burst patterns increased. This enables a simple algorithm based on burst detection and the shape of the interspike interval histogram to identify whether the neuronal activity is from normal or PD model rats.
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http://dx.doi.org/10.1016/j.neulet.2011.10.001DOI Listing
November 2011

Underexpression of TIM-3 and blunted galectin-9-induced apoptosis of CD4+ T cells in rheumatoid arthritis.

Inflammation 2012 Apr;35(2):633-7

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

The aim of this study is to compare the expression of TIM-3 from CD4+ T cells from rheumatoid arthritis (RA) patients and healthy controls and to evaluate the effect of galectin-9 (Gal-9) on apoptosis of CD4+ T cells in these patients. CD4+ T cells from RA patients and healthy controls were isolated from peripheral blood mononuclear cells and were activated. The expression of TIM-3 mRNA in CD4+ T cells was measured using real-time polymerase chain reaction. CD4+ T cells were activated in the presence of graded doses of Gal-9 or control, and Gal-9-induced cytotoxicity and apoptotic activity of CD4+ T cells were analyzed using MTT assays and annexin-V staining, respectively. TIM-3 mRNA expression was significantly lower in CD4+ T cells from RA patients compared with those in healthy controls (p = 0.028). CD4+ T cell survival as measured by MTT assay when incubated with Gal-9 (15 nM) was significantly higher in RA patients than in healthy controls (p = 0.002). Apoptotic activity of CD4+ T cells from healthy controls as measured by annexin staining increased with graded doses of Gal-9 (0 nM vs. 30 nM, 0 nM vs. 90 nM, p = 0.016 each). However, apoptotic activity of CD4+ T cells from RA patients did not change despite the stimulation with Gal-9. Gal-9-mediated apoptosis of CD4+ T cells is dysfunctional in RA patients. Blunted Gal-9-mediated apoptosis may be exerted through underexpression of TIM-3 that negatively regulates Th1 response. Our data suggest that TIM-3 and its interaction with Gal-9 may play an important role in the pathogenesis of RA and may represent a potential therapeutic target.
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http://dx.doi.org/10.1007/s10753-011-9355-zDOI Listing
April 2012

Drought, salt and wounding stress induce the expression of the plasma membrane intrinsic protein 1 gene in poplar (Populus alba×P. tremula var. glandulosa).

Gene 2011 Sep 27;483(1-2):43-8. Epub 2011 May 27.

Biotechnology Division, Korea Forest Research Institute, Suwon, Republic of Korea.

Water uptake across cell membranes is a principal requirement for plant growth at both the cellular and whole-plant levels; water movement through plant membranes is regulated by aquaporins (AQPs) or major intrinsic proteins (MIPs). We examined the expression characteristics of the poplar plasma membrane intrinsic protein 1 gene (PatPIP1), a type of MIP, which was isolated from a suspension cell cDNA library of Populus alba×P. tremula var. glandulosa. Examination of protoplasts expressing the p35S-PatPIP1::sGFP fusion protein revealed that the protein was localized in the plasma membrane. Northern blot analysis revealed that the gene was strongly expressed in poplar roots and leaves. Gene expression was inducible by abiotic factors including drought, salinity, cold temperatures and wounding, and also by plant hormones including gibberellic acid, jasmonic acid and salicylic acid. Since we found that the PatPIP1 gene was strongly expressed in response to mannitol, NaCl, jasmonic acid and wounding, we propose that PatPIP1 plays an essential role in the defense of plants against water stress.
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http://dx.doi.org/10.1016/j.gene.2011.05.015DOI Listing
September 2011

The role of Raf kinase inhibitor protein in rheumatoid fibroblast-like synoviocytes invasiveness and cytokine and matrix metalloproteinase expression.

Inflammation 2012 Apr;35(2):474-83

Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Fibroblast-like synoviocytes (FLS) play an important role in the pathogenesis of rheumatoid arthritis. Raf kinase inhibitor protein (RKIP) negatively regulates the Raf/MEK/ERK and NF-κB pathway. The role of RKIP in rheumatoid FLS is unknown. The purpose of the present study was to investigate the function of RKIP in rheumatoid FLS. Rheumatoid FLS were transfected with either RKIP-expressing plasmids or RKIP small interfering RNA (siRNA). RKIP protein was detected in rheumatoid synovial tissue (ST) and FLS. RKIP overexpression significantly decreased IL-6 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP overexpression also showed a decreased trend in IL-8, MMP-1, and MMP-3 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP silencing resulted in significantly increased MMP-1 and MMP-3 mRNA expression in TNF-α-stimulated rheumatoid FLS. RKIP silencing also increased IL-6 and IL-8 mRNA expression in TNF-α-stimulated rheumatoid FLS, but this increase did not reach statistical significance. TNF-α-induced ERK and NF-κB activation was suppressed in FLS with RKIP overexpression. RKIP silencing resulted in a significantly higher invasion index in TNF-α-stimulated rheumatoid FLS compared to controls. These results suggest that RKIP might be a potential therapeutic target for rheumatoid arthritis.
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http://dx.doi.org/10.1007/s10753-011-9336-2DOI Listing
April 2012

Extracellular high-mobility group box 1 is increased in patients with Behçet's disease with intestinal involvement.

J Korean Med Sci 2011 May 21;26(5):697-700. Epub 2011 Apr 21.

Department of Internal Medicine, Kangbuk Samsung Hospital, Seoul, Korea.

High-mobility group box 1 (HMGB1) protein has been demonstrated to play an important role in chronic inflammatory diseases including rheumatoid arthritis, and systemic lupus erythematosus. This study investigated the association between extracellular HMGB1 expression and disease activity, and clinical features of Behçet's disease (BD). Extracellular HMGB1 expression in the sera of 42 BD patients was measured and was compared to that of 22 age- and sex-matched healthy controls. HMGB1 expression was significantly increased in BD patients compared to healthy controls (78.70 ± 20.22 vs 10.79 ± 1.90 ng/mL, P = 0.002). In addition, HMGB1 expression was significantly elevated in BD patients with intestinal involvement compared to those without (179.61 ± 67.95 vs 61.89 ± 19.81 ng/mL, P = 0.04). No significant association was observed between HMGB1 concentration and other clinical manifestations, or disease activity. It is suggested that extracellular HMGB1 may play an important role in the pathogenesis of BD.
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http://dx.doi.org/10.3346/jkms.2011.26.5.697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082127PMC
May 2011

CIP2A expression is associated with synovial hyperplasia and invasive function of fibroblast-like synoviocytes in rheumatoid arthritis.

Rheumatol Int 2012 Jul 9;32(7):2023-30. Epub 2011 Apr 9.

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that leads to cellular proliferation in cancer cells. We aim to investigate CIP2A expression in fibroblast-like synoviocytes (FLS) and its association with the histopathological grade of synovitis and the invasive function of FLS in rheumatoid arthritis (RA). CIP2A protein expression was measured in 8 RA FLS and 8 OA FLS using Western blot analysis. CIP2A mRNA expression from 19 RA FLS and 7 OA FLS was measured using real-time PCR. Synovitis score of RA FLS-matched synovial tissues was semiquantitatively measured by two independent pathologists. An in vitro cell invasion assay was performed using RA FLS treated with CIP2A small interfering RNA (siRNA) or with control vector. Western blot analysis showed that CIP2A is more frequently overexpressed in RA FLS compared with OA FLS. CIP2A mRNA expression was higher in RA FLS compared with those in OA FLS, but did not reach statistical significance (P = 0.076). In RA, total synovitis score was strongly correlated with FLS CIP2A mRNA expression (rs = 0.849, P = 0.043). TNF-α treatment induced a robust increase in the invasive function of control FLS (P = 0.0021), but no significant effect was observed in CIP2A siRNA-treated FLS. Our data demonstrate that CIP2A expression is closely associated with the histopathological score of synovitis and invasive function of FLS in RA. These results suggest that CIP2A may play a critical role in the destructive process in RA and warrant further investigation of CIP2A as a therapeutic target.
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http://dx.doi.org/10.1007/s00296-011-1927-6DOI Listing
July 2012

Increased α-defensin-1 expression in Korean patients with Behcet's disease.

Joint Bone Spine 2011 Dec 26;78(6):593-7. Epub 2011 Mar 26.

Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Objectives: The aim of this study is to measure α-defensin-1 expression in the peripheral blood of patients with Behçet's disease (BD) and healthy control (HC) and to assess the association between α-defensin-1 expression and clinical features of BD.

Methods: Our patients fulfilled the diagnostic criteria of the international BD study group. ELISA and real-time PCR were performed to measure α-defensin-1 protein level in the sera and α-defensin-1 mRNA level in peripheral blood mononuclear cells (PBMC), respectively.

Results: The α-defensin-1 mRNA expression was significantly higher in BD patients (n=59) than HC (n=34) (0.49±0.10 vs. 0.19±0.45, P=0.03). The level of α-defensin-1 mRNA and protein was significantly higher in active patients than inactive patients (n=15, 0.91±0.28 vs. n=44, 0.35±0.09, P<0.001 and n=21, 7.50±2.14ng/ml vs. n=50, 3.32±0.96ng/ml, P=0.001, respectively). The level of α-defensin-1 mRNA was significant higher in patients with arthritis (n=20) than those without arthritis (n=39).

Conclusion: α-defensin-1 mRNA and protein levels are significantly increased in BD patients, especially in active BD patients. Furthermore, α-defensin-1 mRNA is over-expressed in the PBMC of BD patients with arthritis. The present study suggests that α-defensin-1 may be involved in the pathogenesis of BD and can be used as valuable biologic marker for estimation of disease activity in BD.
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http://dx.doi.org/10.1016/j.jbspin.2011.01.012DOI Listing
December 2011

Slug suppression induces apoptosis via Puma transactivation in rheumatoid arthritis fibroblast-like synoviocytes treated with hydrogen peroxide.

Exp Mol Med 2010 Jun;42(6):428-36

Department of Medicine, Samsung Medical Center, Seoul 135-710, Korea.

Inadequate apoptosis contributes to synovial hyperplasia in rheumatoid arthritis (RA). Recent study shows that low expression of Puma might be partially responsible for the decreased apoptosis of fibroblast-like synoviocytes (FLS). Slug, a highly conserved zinc finger transcriptional repressor, is known to antagonize apoptosis of hematopoietic progenitor cells by repressing Puma transactivation. In this study, we examined the expression and function of Slug in RA FLS. Slug mRNA expression was measured in the synovial tissue (ST) and FLS obtained from RA and osteoarthritis patients. Slug and Puma mRNA expression in FLS by apoptotic stimuli were measured by real-time PCR analysis. FLS were transfected with control siRNA or Slug siRNA. Apoptosis was quantified by trypan blue exclusion, DNA fragmentation and caspase-3 assay. RA ST expressed higher level of Slug mRNA compared with osteoarthritis ST. Slug was significantly induced by hydrogen peroxide (H2O2) but not by exogenous p53 in RA FLS. Puma induction by H2O2 stimulation was significantly higher in Slug siRNA-transfected FLS compared with control siRNA-transfected FLS. After H2O2 stimulation, viable cell number was significantly lower in Slug siRNA-transfected FLS compared with control siRNA-transfected FLS. Apoptosis enhancing effect of Slug siRNA was further confirmed by ELISA that detects cytoplasmic histone-associated DNA fragments and caspase-3 assay. These data demonstrate that Slug is overexpressed in RA ST and that suppression of Slug gene facilitates apoptosis of FLS by increasing Puma transactivation. Slug may therefore represent a potential therapeutic target in RA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892596PMC
http://dx.doi.org/10.3858/emm.2010.42.6.044DOI Listing
June 2010

Increased extracellular survivin in the synovial fluid of rheumatoid arthritis patients: fibroblast-like synoviocytes as a potential source of extracellular survivin.

Inflammation 2010 Dec;33(6):381-8

Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Survivin belongs to the family of inhibitor of apoptosis proteins and plays an important role in the hyperplastic growth of tissues and tumors. In this study, we assessed the expression of survivin in rheumatoid synovial fluids (SF) and synovial tissues (ST) of rheumatoid arthritis (RA) patients in order to investigate the role of extracellular survivin in the pathogenesis of RA. The survivin level from SF was significantly higher in RA patients (n = 38) than in osteoarthritis patients (n = 18; 10.68 ± 2.76 vs. 1.0 ± 0.56 pg/ml, p = 0.02). In addition, SF survivin level was higher in erosive RA patients (n = 23) than in non-erosive RA patients (n = 15; 15.26 ± 4.26 vs. 4.47 ± 1.12 pg/ml, p = 0.05). SF survivin level in RA was positively correlated with disease activity score 28, but did not reach statistical significance (r = 0.309, p = 0.07). RA SF survivin level was also positively correlated with peripheral blood leukocyte counts (r = 0.443, p = 0.005). The immunohistochemical staining and Western blot analysis revealed survivin expression in the ST and fibroblast-like synoviocytes of RA patients, respectively. These findings suggest that extracellular survivin may be produced from rheumatoid FLS and may play an important role in the destructive RA process.
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http://dx.doi.org/10.1007/s10753-010-9196-1DOI Listing
December 2010

Isolation and characterization of osmotic stress-induced genes in poplar cells by suppression subtractive hybridization and cDNA microarray analysis.

Plant Physiol Biochem 2010 Feb-Mar;48(2-3):136-41. Epub 2009 Nov 18.

Forest Biotechnology Division, Korea Forest Research Institute, 44-3 Omokchundong, Suwon 441-350, Republic of Korea.

Osmotic stress induces changes in the expression of various genes including those associated with drought tolerance, cell wall metabolism and defense. We isolated 852 cDNA clones, the expression of which is induced by osmotic stress, from cells of a hybrid poplar (Populus alba x Populus tremula var. glandulosa) by suppression subtractive hybridization after mannitol treatment. We examined how stress affected their expression using cDNA microarray analysis, which identified 104 genes significantly up-regulated by osmotic stress. These include genes with functions related to transcription, signal transduction, cell wall metabolism and defense. Other gene transcripts encoding cysteine protease and aquaporin are also up-regulated during osmotic stress. The function of about one-third of the genes in poplar cells that were significantly up-regulated by stress is not known, suggesting that the cell suspension may offer an opportunity of finding novel genes otherwise never expressed and that we still need more information at the molecular level.
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http://dx.doi.org/10.1016/j.plaphy.2009.11.002DOI Listing
September 2010

Differential expression of a poplar SK2-type dehydrin gene in response to various stresses.

BMB Rep 2009 Jul;42(7):439-43

Biotechnology Division, Korea Forest Research Institute, Suwon, Korea.

Dehydrins are group II, late embryogenesis abundant proteins that act putatively as chaperones in stressed plants. To elucidate the function of dehydrins in poplar, we isolated the SK(2)-type dehydrin gene Podhn from Populus alba x P. tremula var. glandulosa suspension cells and analyzed its expression following treatments of abiotic stress, wounding and plant growth regulator. Sequence homology and phylogenetic analyses indicate Podhn encodes an acidic dehydrin (pI 5.14, 277 amino acids, predicted size 25.6 kDa) containing two lysine-rich "K-segments" and a 7-serine residue "S-segment", both characteristic of SK(2)-type dehydrins. Southern blots show Podhn genes form a small gene family in poplar. Podhn was expressed in all tissues examined under unstressed conditions, but most strongly in cell suspensions (especially in the stationary phase). Drought, salt, cold and exogenous abscisic acid (ABA) treatments enhanced Podhn expression, while wounding and jasmonic acid caused its reduction. Therefore, Podhn might be involved in ABA or stress response.
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http://dx.doi.org/10.5483/bmbrep.2009.42.7.439DOI Listing
July 2009

Non-A type nucleophosmin 1 gene mutation predicts poor clinical outcome in de novo adult acute myeloid leukemia: differential clinical importance of NPM1 mutation according to subtype.

Int J Hematol 2009 Jul 30;90(1):1-5. Epub 2009 May 30.

Department of Internal Medicine, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, Republic of Korea.

Mutations of nucleophosmin gene (NPM1) are known to be related to good prognosis in AML patients lacking FLT3 internal tandem duplication (FLT3-ITD). Recently, NPM1 mutations other than type A were reported, but their clinical significance is not well known. Retrospective medical record review of 106 de novo AML patients lacking FLT3-ITD, who received induction chemotherapy from three centers in Korea between 1997 and 2007, was performed. Direct sequencing of NPM1 and RT-PCR for FLT3-ITD was performed on genomic DNA derived from blood samples of patients before induction chemotherapy for detection of mutations. NPM1 mutation was detected in 18 patients, where 13 were type A mutants and 5 were non-type A mutants. CR, CR1-D and OS was not different according to NPM1 mutational status overall. But, non-type A NPM1 mutation was related to shorter CR1-D when compared with NPM1 wild types and NPM1 type A mutation (p = 0.004). OS was shorter in non-type A mutants when compared with NPM1 wild-type patients and NPM1 type A mutants (p = 0.001). The type of mutation of NPM1 is important for prognosis in de novo AML lacking FLT3-ITD. Non-A type NPM1 mutation is a poor prognostic factor.
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http://dx.doi.org/10.1007/s12185-009-0350-1DOI Listing
July 2009

Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells.

Mol Oncol 2008 Dec 7;2(4):317-26. Epub 2008 Oct 7.

Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Growth of multiple myeloma cells is controlled by various factors derived from host bone marrow microenvironments. Interaction between multiple myeloma cells and bone marrow stromal cells (BMSCs) plays an important role in the expression of adhesive molecules and secretion of growth factors involved in multiple myeloma (MM) cell growth, survival, and resistance to anticancer drugs. Recently, the possibility of developing novel anti-cancer therapeutic strategies targeting both MM cells and MM cell-BMSC interactions has been discussed. Here we present data showing that curcumin, a major constituent of turmeric compounds extracted from the rhizomes of the plant Curcuma longa, effectively reduced the growth of MM cells and BMSCs. Upon treatment with curcumin, IL-6/sIL-6R-induced STAT3 and Erk phosphorylation was dramatically reduced in the co-cultured cells. In addition, curcumin inhibited the production of pro-inflammatory cytokines and VEGF, factors that are associated with the progression of multiple myeloma, from both MM cells and BMSCs. In a combination treatment with curcumin and bortezomib, IL-6/sIL-6R-induced STAT3 and Erk phosphorylation was effectively inhibited. Moreover, this combination treatment synergistically inhibited the growth of MM cells co-cultured with BMSCs as compared to controls. Taken together, these results indicate that curcumin potentiates the therapeutic efficacy of bortezomib in MM suggesting this combination therapy to be of value in the clinical management of MM.
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http://dx.doi.org/10.1016/j.molonc.2008.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527772PMC
December 2008

Phenotypic characterization and invasive properties of synovial fluid-derived adherent cells in rheumatoid arthritis.

Inflammation 2008 Dec;31(6):365-71

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 IIwon-Dong, Gangnam-Gu, Seoul, 135-710, South Korea.

The present study aimed at characterizing the phenotype and functions of adherent synovial fluid (SF) cells derived from rheumatoid arthritis (RA), comparing with fibroblast-like synoviocytes (FLS) derived from RA synovial tissue (ST). Adherent SF-derived cells were spindle-shaped from passages 1-6 under light microscopy. The cell surface marker profile in SF-derived cells from passage 1-6 was similar to that of ST-derived FLS. Levels of MMP-1 and MMP-3 were not significantly different between SF-derived cells and ST-derived FLS (p = 0.20 and p = 0.40, respectively). There was no significant difference in the optical density value between two cell types in the cell invasion assay (p = 0.10). SF-derived adherent cells have a fibroblast-like phenotype from very early culture passages and have the potential to produce MMPs with the invasive capacity to degrade cartilage, identical to ST-derived FLS. Therefore, these cells could substitute for ST-derived FLS in studying the pathogenesis of RA.
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http://dx.doi.org/10.1007/s10753-008-9087-xDOI Listing
December 2008

Blockage of interleukin-6 signaling with 6-amino-4-quinazoline synergistically induces the inhibitory effect of bortezomib in human U266 cells.

Anticancer Drugs 2008 Sep;19(8):777-82

Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

The transcription factor nuclear factor-kappa B (NF-kappaB) regulates the transcription of a number of genes involved in a variety of cellular responses, including cell survival, inflammation, and differentiation. NF-kappaB is activated by a variety of stimuli, proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. Aberrant NF-kappaB expression is considered to be one of the oncogenic factors of cancer and the constitutive activation of NF-kappaB is observed in several hematologic disorders [classic Hodgkin's lymphoma, diffuse large B cell lymphoma, and multiple myeloma (MM)], and the modulation of NF-kappaB activation is emerging as a promising novel anticancer therapeutic strategy.Therefore, we focused on the regulation of NF-kappaB activation in MM. When U266 cells were treated with 6-amino-4-quinazoline, an NF-kappaB activation inhibitor, we determined that it most effectively blocked the interleukin (IL)-6-induced activation of MAPK and JAK/STAT pathways among different signaling inhibitors. The results of the luciferase assay indicated that 6-amino-4-quinazoline inhibited NF-kappaB activation with diminished NF-kappaB protein bound to NF-kappaB DNA binding sites. In addition, 6-amino-4-quinazoline suppressed the production of IL-6, which affected MM cell proliferation. Furthermore, combined treatment with bortezomib and 6-amino-4-quinazoline effectively inhibited the IL-6 and soluble IL-6R-induced activation of STAT3 and extracellular signal-regulated kinase phosphorylation. Our data showed that the inhibition of NF-kappaB activation abrogated MM cell proliferation induced by the IL-6 pathway, and might represent a promising therapeutic strategy for the treatment of MM.
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http://dx.doi.org/10.1097/CAD.0b013e32830c236aDOI Listing
September 2008