Publications by authors named "Sejin Hwang"

23 Publications

  • Page 1 of 1

Cancer-associated fibroblasts induce an aggressive phenotypic shift in non-malignant breast epithelial cells via interleukin-8 and S100A8.

J Cell Physiol 2021 Mar 21. Epub 2021 Mar 21.

Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University, Seoul, Korea.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment have been associated with tumor progression in breast cancer. Although crosstalk between breast cancer cells and CAFs has been studied, the effect of CAFs on non-neoplastic breast epithelial cells is not fully understood to date. Here, we investigated the effect of CAFs on aggressive phenotypes in non-neoplastic MCF10A breast epithelial cells. CAFs induced epithelial-to-mesenchymal transition (EMT) and invasive phenotype in MCF10A cells. S100A8, a potential prognostic marker in several cancers, was markedly increased in MCF10A cells by CAFs. S100A8 was crucial for CAFs-induced invasive phenotype of MCF10A cells. Among cytokines increased by CAFs, interleukin (IL)-8 induced S100A8 through transcription factors p65 NF-κB and C/EBPβ. In a xenograft mouse model with MCF10A cells and CAFs, tumor was not developed, suggesting that coinjection with CAFs may not be sufficient for in vivo tumorigenicity of MCF10A cells. Xenograft mouse tumor models with MDA-MB-231 breast carcinoma cells provided an in vivo evidence for the effect of CAFs on breast cancer progression as well as a crucial role of IL-8 in tumor growth and S100A8 expression in vivo. Using a tissue microarray of human breast cancer, we showed that S100A8 expression was correlated with poor outcomes. S100A8 expression was more frequently detected in cancer-adjacent normal human breast tissues than in normal breast tissues. Together, this study elucidated a novel mechanism for the acquisition of invasive phenotype of non-neoplastic breast cells induced by CAFs, suggesting that targeting IL-8 and S100A8 may be an effective strategy against breast cancer.
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http://dx.doi.org/10.1002/jcp.30364DOI Listing
March 2021

The Effect of a Modified Constant Flow Insufflation of Oxygen during Cardiopulmonary Resuscitation in a Rat Model of Respiratory Cardiac Arrest on Arterial Oxygenation, Alveolar Barotrauma, and Brain Tissue Injury.

Emerg Med Int 2020 31;2020:8913571. Epub 2020 Mar 31.

Department of Emergency Medicine, Hanyang University Guri Hospital, Hanyang University, Seongdong-gu, Republic of Korea.

Aim: Intermittent positive pressure ventilation (IPPV) can adversely affect cardiopulmonary resuscitation outcomes by increasing the intrathoracic pressure. Continuous flow insufflation of oxygen (CFIO) has been investigated as a potential alternative, but evidence supporting its superiority over intermittent positive pressure ventilation in cases of cardiac arrest is scant. The aim of the current study was to compare the effects of continuous flow insufflation of oxygen using a one-way valve during cardiopulmonary-resuscitation with intermittent positive pressure ventilation in a rat model of respiratory arrest.

Methods: Male Sprague-Dawley rats weighing 400∼450 g (from minimum to maximum) were randomly assigned to either a sham, IPPV, or CFIO group ( = 10 per group). Respiratory arrest was induced by blocking the endotracheal tube. Arterial blood gas analysis was performed during cardiopulmonary resuscitation to compare the oxygenation levels. Tissues were then harvested to compare the degrees of pulmonary barotrauma and ischemic brain injury.

Results: Return of spontaneous circulation was observed in 6/10 rats in the IPPV group and 5/10 in the CFIO group. During cardiopulmonary resuscitation, the mean PaO was significantly higher in the CFIO group (83.10 mmHg) than in the IPPV group (56.10 mmHg). Lung biopsy revealed more inflammatory cells and marked thickening of the alveolar wall in the IPPV group; the group also exhibited a higher frequency of neuroglial cells and apoptotic bodies of pyramidal cells, resulting from ischemic injury.

Conclusion: In a rat model of respiratory arrest, CFIO using a one-way valve resulted in a greater level of oxygenation and less lung and brain injuries than with IPPV.
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http://dx.doi.org/10.1155/2020/8913571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150730PMC
March 2020

Experimentally derived viscoelastic properties of human skin and muscle in vitro.

Med Eng Phys 2018 11 18;61:25-31. Epub 2018 Aug 18.

School of Mechanical Engineering, Hanyang University, Wangshimni-ro 222, Seongdong-gu, Seoul 04763, South Korea. Electronic address:

Measurement of the mechanical properties of human skin in vivo is challenging. Moreover, those with regard to excitation frequency have been rarely reported thus far. In this study, a vibration-based experimental method was employed to measure the viscoelastic properties with regard to the excitation frequency. Pieces of human skin and skeletal muscle excised from cadavers immediately post mortem were stored in a sealed container. As the experiment began, they were removed from the container and used to measure the viscoelastic properties as time elapsed. Young's moduli of the samples of human skin tissue that were immediately removed from the container were found to be similar to those obtained with in-vivo indentation methods. They were also found to be approximately one-third of those of human skeletal muscles. The viscoelastic properties of human skin were found to remain almost constant within the frequency range up to 120 Hz and are similar to those of porcine tissue. Young's moduli of the human skin and skeletal muscle were also found to reach the maximum values approximately five days post mortem. However, the loss factor of the human skin did not vary significantly as time elapses.
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http://dx.doi.org/10.1016/j.medengphy.2018.08.001DOI Listing
November 2018

Continuous-wave THz vector imaging system utilizing two-tone signal generation and self-mixing detection.

Opt Express 2017 Aug;25(17):20718-20726

We propose and demonstrate a continuous-wave vector THz imaging system utilizing a photonic generation of two-tone THz signals and self-mixing detection. The proposed system measures amplitude and phase information simultaneously without the local oscillator reference or phase rotation scheme that is required for heterodyne or homodyne detection. In addition, 2π phase ambiguity that occurs when the sample is thicker than the wavelength of THz radiation can be avoided. In this work, THz signal having two frequency components was generated with a uni-traveling-carrier photodiode and electro-optic modulator on the emitter side and detected with a Schottky barrier diode detector used as a self-mixer on the receiver side. The proposed THz vector imaging system exhibited a 50-dB signal to noise ratio and 0.012-rad phase fluctuation with 100-μs integration time at 325-GHz. With the system, we demonstrate two-dimensional THz phase contrast imaging. Considering the recent use of two-dimensional arrays of Schottky barrier diodes as a THz image sensor, the proposed system is greatly advantageous for realizing a real-time THz vector imaging system due to its simple receiver configuration.
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http://dx.doi.org/10.1364/OE.25.020718DOI Listing
August 2017

Optical frequency switching scheme for a high-speed broadband THz measurement system based on the photomixing technique.

Opt Express 2017 May;25(10):11767-11777

This study presents an optical frequency switching scheme for a high-speed broadband terahertz (THz) measurement system based on the photomixing technique. The proposed system can achieve high-speed broadband THz measurements using narrow optical frequency scanning of a tunable laser source combined with a wavelength-switchable laser source. In addition, this scheme can provide a larger output power of an individual THz signal compared with that of a multi-mode THz signal generated by multiple CW laser sources. A swept-source THz tomography system implemented with a two-channel wavelength-switchable laser source achieves a reduced time for acquisition of a point spread function and a higher depth resolution in the same amount of measurement time compared with a system with a single optical source.
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http://dx.doi.org/10.1364/OE.25.011767DOI Listing
May 2017

Coexistence of ulcerative colitis and Sjögren's syndrome in a patient with Takayasu's arteritis and Hashimoto's thyroiditis.

Intest Res 2017 Apr 27;15(2):255-259. Epub 2017 Apr 27.

Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea.

A 31-year-old woman with a 15-year history of Takayasu's arteritis (TA) and a 13-year history of Hashimoto's thyroiditis presented with hematochezia. She received a diagnosis of Sjögren's syndrome at 1 month before her visit to Kyungpook National University Medical Center. Her colonoscopic findings were compatible with a diagnosis of ulcerative colitis (UC). She was treated with oral mesalazine, and her hematochezia symptoms subsequently disappeared. The coexistence of UC and TA has been reported; however, reports on the coexistence of UC and Sjögren's syndrome, or of UC and Hashimoto's thyroiditis are rare. Although the precise etiologies of these diseases are unknown, their presence together suggests that they may have a common pathophysiologic background. Furthermore, in patients with autoimmune or vascular diseases, including TA, systemic manifestations should be assessed with consideration of inflammatory bowel diseases including UC in the presence of gastrointestinal symptoms such as diarrhea and hematochezia.
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http://dx.doi.org/10.5217/ir.2017.15.2.255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430020PMC
April 2017

Early Activation of Phosphatidylinositol 3-Kinase after Ischemic Stroke Reduces Infarct Volume and Improves Long-Term Behavior.

Mol Neurobiol 2017 09 2;54(7):5375-5384. Epub 2016 Sep 2.

Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.

Phosphatidylinositol 3-kinases (PI3Ks) have recently been implicated in apoptosis and ischemic cell death. We tested the efficacy of early intervention with a peptide PI3K activator in focal cerebral ischemia. After determining the most effective dose (24 μg/kg) and time window (2 h after MCAO) of treatment, a total of 48 rats were subjected to middle cerebral artery occlusion (MCAO). Diffusion weighted MRI (DWI) was performed 1 h after MCAO and rats with lesion sizes within a predetermined range were randomized to either PI3K activator or vehicle treatment arms. Fluid attenuated inversion recovery (FLAIR) MRI, neurological function, western blots, and immunohistochemistry were blindly assessed. Initial DWI lesion volumes were nearly identical between two groups prior to treatment. However, FLAIR showed significantly smaller infarct volumes in the PI3K activator group compared with vehicle (146 ± 81 mm and 211 ± 96 mm, p = 0.045) at 48 h. The PI3K activator group also had better neurological function for up to 2 weeks. In addition, PI3K activator decreased the number of TUNEL-positive cells in the peri-infarct region compared with the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473) and GSK-3β (Ser9) and decreased expression of cleaved caspase-9 and caspase-3. Our results suggest a neuroprotective role of early activation of PI3K in ischemic stroke. The use of DWI in the randomization of experimental groups may reduce bias.
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http://dx.doi.org/10.1007/s12035-016-0063-4DOI Listing
September 2017

The Novel Scoring System for 30-Day Mortality in Patients with Non-variceal Upper Gastrointestinal Bleeding.

Dig Dis Sci 2016 07 26;61(7):2002-10. Epub 2016 Feb 26.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Hospital, Gumi, South Korea.

Background: Although the mortality rates for non-variceal upper gastrointestinal bleeding (NVUGIB) have recently decreased, it remains a significant medical problem.

Aim: The main aim of this prospective multicenter database study was to construct a clinically useful predictive scoring system by using our predictors and compare its prognostic accuracy with that of the Rockall scoring system.

Methods: Data were collected from consecutive patients with NVUGIB. Logistic regression analysis was performed to identify the independent predictors of 30-day mortality. Each independent predictor was assigned an integral point proportional to the odds ratio (OR) and we used the area under the curve to compare the discrimination ability between the new predictive model and the Rockall score.

Results: The independent predictors of mortality included age >65 years [OR 2.627; 95 % confidence interval (CI) 1.298-5.318], hemodynamic instability (OR 2.217; 95 % CI 1.069-4.597), serum blood urea nitrogen level >40 mg/dL (OR 1.895; 95 % CI 1.029-3.490), active bleeding at endoscopy (OR 2.434; 95 % CI 1.283-4.616), transfusions (OR 3.811; 95 % CI 1.640-8.857), comorbidities (OR 3.481; 95 % CI 1.405-8.624), and rebleeding (OR 10.581; 95 % CI 5.590-20.030). The new predictive model showed a high discrimination capability and was significantly superior to the Rockall score in predicting the risk of death (OR 0.837;95 % CI 0.818-0.855 vs. 0.761; 0.739-0.782; P = 0.0123).

Conclusions: The new predictive score was significantly more accurate than the Rockall score in predicting death in NVUGIB patients. We need to prospectively validate the accuracy of this score for predicting mortality in NVUGIB patients.
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http://dx.doi.org/10.1007/s10620-016-4087-4DOI Listing
July 2016

Directly converted patient-specific induced neurons mirror the neuropathology of FUS with disrupted nuclear localization in amyotrophic lateral sclerosis.

Mol Neurodegener 2016 Jan 22;11. Epub 2016 Jan 22.

Department of Translational Medicine, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 133-792, Republic of Korea.

Background: Mutations in the fused in sarcoma (FUS) gene have been linked to amyotrophic lateral sclerosis (ALS). ALS patients with FUS mutations exhibit neuronal cytoplasmic mislocalization of the mutant FUS protein. ALS patients' fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons have been developed as models for understanding ALS-associated FUS (ALS-FUS) pathology; however, pathological neuronal signatures are not sufficiently present in the fibroblasts of patients, whereas the generation of iPSC-derived neurons from ALS patients requires relatively intricate procedures.

Results: Here, we report the generation of disease-specific induced neurons (iNeurons) from the fibroblasts of patients who carry three different FUS mutations that were recently identified by direct sequencing and multi-gene panel analysis. The mutations are located at the C-terminal nuclear localization signal (NLS) region of the protein (p.G504Wfs*12, p.R495*, p.Q519E): two de novo mutations in sporadic ALS and one in familial ALS case. Aberrant cytoplasmic mislocalization with nuclear clearance was detected in all patient-derived iNeurons, and oxidative stress further induced the accumulation of cytoplasmic FUS in cytoplasmic granules, thereby recapitulating neuronal pathological features identified in mutant FUS (p.G504Wfs*12)-autopsied ALS patient. Importantly, such FUS pathological hallmarks of the patient with the p.Q519E mutation were only detected in patient-derived iNeurons, which contrasts to predominant FUS (p.Q519E) in the nucleus of both the transfected cells and patient-derived fibroblasts.

Conclusions: Thus, iNeurons may provide a more reliable model for investigating FUS mutations with disrupted NLS for understanding FUS-associated proteinopathies in ALS.
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http://dx.doi.org/10.1186/s13024-016-0075-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722778PMC
January 2016

Granulocyte-colony stimulating factor as a treatment for diabetic neuropathy in rat.

Mol Cell Endocrinol 2015 Oct 17;414:64-72. Epub 2015 Jul 17.

Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, CA, USA; Department of Neurosciences, School of Medicine, University of California at San Diego, CA, USA. Electronic address:

Effective treatment of diabetic neuropathy (DN) remains unsolved. We serendipitously observed dramatic relief of pain in several patients with painful DN receiving granulocyte-colony stimulating factor (G-CSF). The aim of this study was to determine if G-CSF could treat DN in an animal model and to ascertain its mechanism of action. In a rodent model of DN, G-CSF dramatically recovered nerve function, retarded histological nerve changes and increased the expression of neurotrophic factors within nerve. A sex-mismatched bone marrow transplantation (BMT) study revealed that G-CSF treatment increased the abundance of bone marrow (BM)-derived cells in nerves damaged by DN. However, we did not observe evidence of transdifferentiation or cell fusion of BM-derived cells. The beneficial effects of G-CSF were dependent on the integrity of BM. In conclusion, G-CSF produced a therapeutic effect in a rodent model of DN, which was attributed, at least in part, to the actions of BM-derived cells.
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http://dx.doi.org/10.1016/j.mce.2015.07.014DOI Listing
October 2015

Effect of fluoxetine on the expression of tryptophan hydroxylase and 14-3-3 protein in the dorsal raphe nucleus and hippocampus of rat.

J Chem Neuroanat 2012 Mar 20;43(2):96-102. Epub 2012 Jan 20.

Division of Molecular and Life Science, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea.

The serotonergic system is one of the major systems targeted in the pharmacological treatment of mood disorders including depression. Fluoxetine, one of the selective serotonin reuptake inhibitors (SSRIs), has been reported to induce the expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin. The 14-3-3 protein family not only activates neuronal enzymes, including TPH, but also plays a role in a wide variety of cell signaling. The aim of the present study was to determine whether fluoxetine regulates both the interaction of TPH and 14-3-3 proteins as well as the increase of those proteins in the dorsal raphe nucleus and the hippocampus. Sprague-Dawley rats were administered fluoxetine or vehicle for 5 and 14 days and sacrificed at 5 and 14 days after initial treatment. The intensity of immunoreactivity for TPH and 14-3-3 proteins in the dorsal raphe nucleus of the midbrain and in the hippocampus was measured, and the colocalization of both proteins was observed with double-labeling immunofluorescence. At 5 days after initial treatment with fluoxetine, immunoreactivity of 14-3-3 protein increased in both the dorsal raphe nucleus and the hippocampus, while that of TPH did not change in either region. In addition, at 14 days after initial treatment with fluoxetine, immunoreactivity of 14-3-3 protein significantly increased in both the dorsal raphe nucleus and hippocampus, while that of TPH showed few changes in either region. Colocalization of TPH and 14-3-3 proteins was observed in the cell bodies of dorsal raphe nucleus, whereas it was not observed in the hippocampus. These results suggest that the time-dependent regulation of 14-3-3 protein may be one of the various factors associated with delayed pharmacological effects of SSRIs.
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http://dx.doi.org/10.1016/j.jchemneu.2012.01.001DOI Listing
March 2012

Amelioration of diabetic neuropathy by TAT-mediated enhanced delivery of metallothionein and SOD.

Endocrinology 2012 Jan 29;153(1):81-91. Epub 2011 Nov 29.

Department of Internal Medicine and Bioengineering, Hanyang University College of Medicine and Engineering, Seongdong-gu, Seoul 471-020, Korea.

Because diabetic neuropathy (DN) appears to result from oxidative stress in neuronal tissues, antioxidant treatment should counteract the condition. Metallothionein (MT) and superoxide dismutase (SOD) are free-radical scavengers, but their ability to cross biological membranes is limited. Applying cell penetrating peptide technologies, we made Tat-MT and Tat-SOD constructs and tested their ability to protect PC12 cells, as surrogates of peripheral nerve cells, from various forms of oxidative damage. Tat-MT and Tat-SOD were successfully delivered to PC12 cells, and the intracellular activities of MT and SOD increased in line with the amount of protein delivered. These agents inhibited cellular damage and apoptotic signaling caused by three different types of injuries (high glucose, hypoxia, and advanced glycation end product injury). We also examined transduction of Tat-MT and Tat-SOD into Otsuka Long-Evans Tokushima fatty rats. A single ip injection of Tat-MT and Tat-SOD resulted in increased radical scavenging activity and decreased apoptosis, by inhibiting nuclear factor κB and MAPK signaling. Continuous treatment resulted in improved myelination of sciatic nerves and delayed the clinical development of DN. We conclude that effective delivery of a combination antioxidant treatment may facilitate the repair of damage in patients with DN.
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http://dx.doi.org/10.1210/en.2011-1639DOI Listing
January 2012

β-PIX is critical for transplanted mesenchymal stromal cell migration.

Stem Cells Dev 2012 Jul 26;21(11):1989-99. Epub 2012 Jan 26.

Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

Bone marrow-derived mesenchymal stromal cells (MSCs) have been used successfully as a source of stem cells for treating neurodegenerative diseases. However, for reasons that are not clear, autologous MSC transplants have not yielded successful results in human trials. To test one possible reason, we compared the migratory ability of MSCs from amyotrophic lateral sclerosis (ALS) patients with those of healthy controls. We found that MSCs derived from ALS patients (ALS-MSCs) had a reduced ability to migrate, which may explain why autologous transplantation is not successful. We also found that expression of one of the intracellular factors implicated in migration, β-PIX, was significantly reduced in ALS-MSCs compared with healthy stem cells. Restoration of β-PIX expression by genetic manipulation restored the migratory ability of ALS-MSCs, and inhibition of β-PIX expression with shRNA reduced the migration of healthy MSCs. We suggest that transplantation of allogeneic or genetically modified autologous stem cells might be a more promising strategy for ALS patients than transplantation of autologous stem cells.
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http://dx.doi.org/10.1089/scd.2011.0430DOI Listing
July 2012

Neuropathological abnormalities of astrocytes, GABAergic neurons, and pyramidal neurons in the dorsolateral prefrontal cortices of patients with major depressive disorder.

Eur Neuropsychopharmacol 2012 May 2;22(5):330-8. Epub 2011 Oct 2.

Department of Neuropsychiatry, College of Medicine and Institute of Mental Health, Hanyang University, Seoul, Republic of Korea.

Human post-mortem brain studies have revealed reduced density and size of neurons and glial cells in the dorsolateral prefrontal cortex (dlPFC) in major depressive disorder (MDD). However, the basis of these cytoarchitectural abnormalities and the relationship between them are not understood. We hypothesized that the reduced density of GABAergic neurons and glial cells was associated with altered glutamate neurotransmission in the dlPFC. In order to test this hypothesis, we examined a specific marker type (i.e., calretinin, CR: as a marker of GABAergic neurons) and also attempted to identify the neuropathological markers that correlate with the density of CR-immunoreactive (IR) GABAergic neurons in the dlPFC, using the Stanley Neuropathology Consortium Integrative Database (SNCID, http://sncid.stanleyresearch.org/), which is a web-based tool used to integrate Stanley Medical Research Institute (SMRI) data sets. We found that the density of CR-IR GABAergic neurons was significantly lower in layer I of the dlPFC of MDD patients (n=15) than in that of unaffected controls (n=15) (p=0.021). CR-IR GABAergic neuronal changes were positively correlated with changes in several markers for glial cells and pyramidal neurons in the dlPFC of all SNC subjects (n=60). We also found that the glutamate changes negatively correlated with glial fibrillary acidic protein (GFAP) expression levels and CR-IR GABAergic neuronal density in the prefrontal cortex of all SNC subjects (P<0.05). These findings yield some insight into the mechanism by which increased glutamatergic neurotransmission leads to excitotoxic damage both in neurons and glial cells in the dlPFC of MDD patients.
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http://dx.doi.org/10.1016/j.euroneuro.2011.09.001DOI Listing
May 2012

Sphingosine 1-phosphate regulates matrix metalloproteinase-9 expression and breast cell invasion through S1P3-Gαq coupling.

J Cell Sci 2011 Jul 7;124(Pt 13):2220-30. Epub 2011 Jun 7.

College of Pharmacy, Duksung Women's University, Seoul 132-714, Korea.

Recent evidence suggests that inflammation is involved in malignant progression of breast cancer. Sphingosine 1-phosphate (S1P), acting on the G-protein-coupled receptors, is known as a potent inflammatory mediator. In this study, the effect of the inflammatory lipid S1P on the regulation of invasive/migratory phenotypes of MCF10A human breast epithelial cells was investigated to elucidate a causal relationship between inflammation and the control of invasiveness of breast cells. We show that S1P causes induction of matrix metalloproteinase-9 (MMP-9) in vitro and in vivo, and thus enhances invasion and migration. We also show that fos plays a crucial role in the transcriptional activation of MMP-9 by S1P. In addition, activation of extracellular-signal-regulated kinases 1 and 2 (ERK1/2), p38 and alpha serine/threonine-protein kinase (Akt) are involved in the process of S1P-mediated induction of MMP-9 expression and invasion. Activation of the S1P receptor S1P₃ and G(αq) are required for S1P-induced invasive/migratory responses, suggesting that the enhancement of S1P-mediated invasiveness is triggered by the specific coupling of S1P₃ to the heterotrimeric G(αq) subunit. Activation of phospholipase C-β₄ and intracellular Ca²⁺ release are required for S1P-induced MMP-9 upregulation. Taken together, this study demonstrated that S1P regulates MMP-9 induction and invasiveness through coupling of S1P₃ and G(αq) in MCF10A cells, thus providing a molecular basis for the crucial role of S1P in promoting breast cell invasion.
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http://dx.doi.org/10.1242/jcs.076794DOI Listing
July 2011

A toenail flap based on the fibro-osseous hiatus branch for fingernail reconstruction.

Microsurgery 2011 Jul 31;31(5):371-5. Epub 2011 May 31.

Department of Plastic Surgery, Gwang myung Sung Ae General Hospital, Gwangmyung-si, Gyunggi-do, 423-711, Korea.

This study included two parts: 1) cadaver dissection to elucidate the perfusion of toenail flaps by the fibro-osseous hiatus branch (FHB), and 2) clinical application of the toenail flap for reconstruction of a fingernail defect. Four second toes of two fresh Korean cadavers were dissected. The plantar digital artery (PDA) and terminal segment branch (TSB) were ligated, and red latex was injected distally into the ligated PDA. Perfusion of the dye into the toenail bed through the FHB was observed. From Oct 2004 to Sep 2009, eight toenail flaps based on the FHB pedicle with or without the distal phalanx and pulp were applied to seven patients for finger nail reconstruction. The toenail flap was marked at 5 mm distal to the nail fold and 5 mm lateral to the paronychium. The toenail complex based on the FHB was elevated and transferred to the finger. The nail and matrix were elevated with or without including the distal phalanx. The results of perfusion study showed that one side of the unilateral FHB was identified and traced proximal to the PDA, which was ligated. The distal toenail bed was perfused by the dye through the FHB. In clinical application, all the toenail flaps flourished and survived. We suggest that the toenail flap based on the FHB may be useful for fingernail reconstruction with minimal donor morbidity.
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http://dx.doi.org/10.1002/micr.20881DOI Listing
July 2011

The expression of corticotropin-releasing factor and its receptors in the spinal cord and dorsal root ganglion in a rat model of neuropathic pain.

Anat Cell Biol 2011 Mar 31;44(1):60-8. Epub 2011 Mar 31.

Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul, Korea.

Corticotropin-releasing factor (CRF) is a peptide involved in the activation of the hypothalamic-pituitary-adrenal (HPA) axis. CRF is distributed not only along the HPA axis but also throughout pain-relevant anatomical sites. CRF elicits potent antinociception at the three main levels of pain transmissions: namely, the brain, spinal cord, and peripheral sensory neurons. The widespread distribution of CRF receptors 1 and 2 in the brain offers several targets wherein CRF could alter pain, some of which may be independent of the HPA axis. In this study, we assessed the expression of CRF and its receptors, CRF receptor type (CRFR)1 and CRFR2, in the spinal dorsal horn and dorsal root ganglion (DRG) in a rat model of neuropathic pain induced by spinal nerve injury (SNI). CRF was expressed in a few DRG neurons and primary afferent fibers in the dorsal horns of naїve rats, and the CRF-positive neurons in DRG and fibers in the spinal dorsal horn were found to have increased after SNI. CRFR1 was not expressed in DRG or the dorsal horn and CRFR2 was expressed weakly in the small neurons in DRG in the naїve rats. After SNI, CRFR1 was expressed in the activated microglia in the ipsilateral dorsal horn, and immunoreaction for CRFR2 was increased in the contralateral DRG following SNI. Consequently, it has been suggested that the increased expression of CRF and CRFR2 in DRG neurons and primary afferent fibers in dorsal horn, and CRFR1 in the activated microglia, may be involved in the mediation of stress responses as well as in microglial activation in the neuropathic pain state following SNI.
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http://dx.doi.org/10.5115/acb.2011.44.1.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080009PMC
March 2011

The expression of corticotropin-releasing factor in the central nucleus of the amygdala, induced by colorectal distension, is attenuated by general anesthesia.

J Korean Med Sci 2010 Nov 26;25(11):1646-51. Epub 2010 Oct 26.

Department of Neuropsychiatry, College of Medicine and Institute of Mental Health, Hanyang University, Seoul, Korea.

Corticotrophin-releasing factor (CRF), a key regulator of the hypothalamic-pituitary axis, is expressed in the central nucleus of the amygdala (CeA) and its expression is upregulated in stress-related disorders. We investigated here the effect of noxious colorectal distension (CRD) on the expression of CRF in the CeA of conscious and unconscious rats. Adult male rats with or without general anesthesia were exposed to visceral pain induced by CRD for 5 min; this procedure was repeated 3 times with 1 min resting after each distension. The rats were sacrificed and sections of the CeA were immunostained for CRF as an indicator for anxiety response, and for phosphorylated extracellular signal-regulated kinase (p-ERK) as a marker for pain-specific activation of neurons; sections of lumbosacral spinal cord were immunostained for c-Fos as a marker for activation of spinal neurons. CRD elicited a significant increase in the expression of CRF and p-ERK in the CeA and of c-Fos in the spinal cord. General anesthesia attenuated the increase in CRF and p-ERK in the CeA, but did not affect the expression of spinal c-Fos. These results suggest that conscious recognition of pain at higher brain centers is an important determinant of CRF expression in the CeA.
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http://dx.doi.org/10.3346/jkms.2010.25.11.1646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967003PMC
November 2010

Arterial anatomy of the second toe nail bed related to toenail transfer.

Microsurgery 2010 Nov 14;30(8):646-8. Epub 2010 Sep 14.

Department of Plastic Surgery, Center for Advanced Medical Education by BK21 Project, Inha University School of Medicine, Incheon, Korea.

The aim of this study was to elucidate the exact course of the terminal branches of the plantar digital artery (PDA) to the nail bed of the second toe. Thirteen second toes from seven fresh Korean cadavers were dissected (age range 74-92 years, four men and three women). The terminal segmental branches (TSB) branched off from the PDA at 7.6 ± 0.7 mm proximal to the nail fold. The fibro-osseous hiatus branch (FHB) branched off from the PDA at 3.3 ± 0.7 mm from the nail fold. They were 3.8 ± 1.0 mm lateral to the paronychium. Diameters of TSB and FHB were 0.8 ± 0.2 mm and 0.7 ± 0.1 mm, respectively. Diameter of PDA was 1.4 ± 0.2 mm. Surgeons should stay at least 4 mm proximal to the nail fold to avoid injury to the terminal branch. We believe that second toenail with minimum amount of soft tissue may be transferred using FHB-based vascularized toenail flap. Perfusion study and clinical application should be followed.
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http://dx.doi.org/10.1002/micr.20819DOI Listing
November 2010

Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice.

Neurosci Lett 2010 Jan 29;468(3):190-4. Epub 2009 Oct 29.

Department of Neurology, College of Medicine, Hanyang University, #17 Haengdang-dong, Seongdong-gu, Seoul, 133-791, Republic of Korea.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Although the underlying cause of the disease remains unclear, a variety of pathogenic mechanisms have been proposed. Despite promising preclinical studies showing the modification of the disease progression, most trials have failed to demonstrate any significant improvement in outcome. Stem cell therapy therefore has been proposed as an alternative therapy for ALS. In this study, we evaluated the dose-dependent effects of human bone marrow mesenchymal stem cells (hMSCs) obtained from an ALS patient (ALS-hMSCs) on SOD1 mice via intrathecal injection and showed its practicality for hMSCs. We transplanted different doses (1x10(4), 2x10(5), and 1x10(6)) of ALS-hMSCs into the cisterna magna and performed clinical observations including symptom onset, survival time, and locomotor performance using the rotarod test. Nissl staining was performed to evaluate motor neurons in lumbar spinal cord sections at 109 days, and transplanted cells were evaluated by immuno-fluorescence staining at the end stage. A cell dose of 1x10(6) cells significantly prolonged life span and delayed the decline of motor performance. At this dose, the average number of motor neurons was significantly higher than those of the untreated and 1x10(4) cell treated groups. Most injected hMSCs distributed in the ventricular system and subarachnoid space, while some migrated into the brain and spinal cord. These data suggest that intrathecal injection with an optimized cell number could be a potential route for stem cell therapy in ALS patients.
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http://dx.doi.org/10.1016/j.neulet.2009.10.074DOI Listing
January 2010

Oral administration of 1,4-aryl-2-mercaptoimidazole inhibits T-cell proliferation and reduces clinical severity in the murine experimental autoimmune encephalomyelitis model.

J Pharmacol Exp Ther 2009 Dec 9;331(3):1005-13. Epub 2009 Sep 9.

Molecular Immunology Division, Mogam Biotechnology Research Institute, Yongin, Korea.

T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC(50) of 5 microM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kappaB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRM-III reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRM-III as a potential lead compound for the treatment of T-cell-driven autoimmune diseases.
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http://dx.doi.org/10.1124/jpet.109.154948DOI Listing
December 2009

Inhibition of glycogen synthase kinase-3 suppresses the onset of symptoms and disease progression of G93A-SOD1 mouse model of ALS.

Exp Neurol 2007 Jun 12;205(2):336-46. Epub 2007 Mar 12.

Department of Neurology, College of Medicine, Hanyang University, #17 Haengdang-dong, Seongdong-gu, Seoul, 133-791, South Korea.

Glycogen synthase kinase (GSK)-3 has recently been implicated in the pathogenesis of neurodegenerative diseases. Although the neuroprotective effects of GSK-3 inhibitors in Alzheimer's disease have been established, their effects on amyotrophic lateral sclerosis (ALS) have not been well defined. This study was undertaken to evaluate the effects of GSK-3 inhibition in the G93A-SOD1 mouse model of ALS. Groups of G93A-SOD1 mice were treated with varying concentrations of GSK-3 inhibitor VIII, a specific GSK-3 inhibitor that crosses the BBB, intraperitoneally 5 days a week after 60 days of age. The GSK-3 inhibitor VIII treatment significantly delayed the onset of symptoms and prolonged the life span of the animals, and inhibited the activity of GSK-3 in a concentration-dependent manner. Furthermore, this treatment preserved survival signals and attenuated death and inflammatory signals. These data suggest that GSK-3 plays an important role in the pathogenic mechanisms of ALS and that inhibition of GSK-3 could be a potential therapeutic candidate for ALS.
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http://dx.doi.org/10.1016/j.expneurol.2007.03.004DOI Listing
June 2007

Differential actions of the proneural genes encoding Mash1 and neurogenins in Nurr1-induced dopamine neuron differentiation.

J Cell Sci 2006 Jun;119(Pt 11):2310-20

Department of Microbiology, Hanyang University, Seoul, Korea.

The steroid receptor-type transcription factor Nurr1 has a crucial role in the development of the mesencephalic dopamine (DA) neurons. Although ectopic expression of Nurr1 in cultured neural precursor cells is sufficient in establishing the DA phenotype, Nurr1-induced DA cells are morphologically and functionally immature, suggesting the necessity of additional factor(s) for full neuronal differentiation. In this study, we demonstrate that neurogenic basic helix-loop-helix (bHLH) factors Mash1, neurogenins (Ngns) and NeuroD play contrasting roles in Nurr1-induced DA neuronal differentiation. Mash1, but not Ngn2, spatially and temporally colocalized with aldehyde dehydrogenase 2 (AHD2), a specific midbrain DA neuronal progenitor marker, in the early embryonic ventral mesencephalon. Forced expression of Mash1 caused immature Nurr1-induced DA cells to differentiate into mature and functional DA neurons as judged by electrophysiological characteristics, release of DA, and expression of presynaptic DA neuronal markers. By contrast, atonal-related bHLHs, represented by Ngn1, Ngn2 and NeuroD, repressed Nurr1-induced expression of DA neuronal markers. Domain-swapping experiments with Mash1 and NeuroD indicated that the helix-loop-helix domain, responsible for mediating dimerization of bHLH transcription factors, imparts the distinct effect. Finally, transient co-transfection of the atonal-related bHLHs with Nurr1 resulted in an E-box-independent repression of Nurr1-induced transcriptional activation of a reporter containing Nurr1-binding element (NL3) as well as a reporter driven by the native tyrosine hydroxylase gene promoter. Taken together, these findings suggest that Mash1 contributes to the generation of DA neurons in cooperation with Nurr1 in the developing midbrain whereas atonal-related bHLH genes inhibit the process.
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http://dx.doi.org/10.1242/jcs.02955DOI Listing
June 2006