Daegu Gyeongbuk Medical Innovation Foundation

Daegu, South Korea

Daegu Gyeongbuk Medical Innovation Foundation

Daegu, South Korea
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Lee S.-H.,Daegu Gyeongbuk Medical Innovation Foundation | Suk K.,Kyungpook National University
Biochemical Pharmacology | Year: 2017

Neuroinflammation is mediated by resident central nervous system glia, neurons, peripherally derived immune cells, blood-brain barrier, and inflammatory mediators secreted from these cells. Neuroinflammation has been implicated in stroke and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Protein kinases have been one of the most exploited therapeutic targets in the current pharmacological research, especially in studies on cancer and inflammation. To date, 32 small-molecule protein kinase inhibitors have been approved by the United States Food and Drug Administration for the treatment of cancer and inflammation. However, there is no drug effectively targeting neuroinflammation and/or neurodegenerative diseases. Recent studies have advanced several protein kinases as important drug targets in neuroinflammation and/or neurodegenerative diseases. Here, we review emerging protein kinases potentially involved in neuroinflammation and subsequent neurodegenerative diseases. © 2017 Elsevier Inc.

Velliste M.,University of Pittsburgh | Kennedy S.D.,University of Pittsburgh | Schwartz A.B.,University of Pittsburgh | Whitford A.S.,University of Pittsburgh | And 4 more authors.
Journal of Neuroscience | Year: 2014

Prosthetic devices are being developed to restore movement for motor-impaired individuals. A robotic arm can be controlled based on models that relate motor-cortical ensemble activity to kinematic parameters. The models are typically built and validated on data from structured trial periods during which a subject actively performs specific movements, but real-world prosthetic devices will need to operate correctly during rest periods as well. To develop a model of motor cortical modulation during rest, we trained monkeys (Macaca mulatta) to perform a reaching task with their own arm while recording motor-cortical single-unit activity. When a monkey spontaneously put its arm down to rest between trials, our traditional movement decoder produced a nonzero velocity prediction, which would cause undesired motion when applied to a prosthetic arm. During these rest periods, a marked shift was found in individual units' tuning functions. The activity pattern of the whole population during rest (Idle state) was highly distinct from that during reaching movements (Active state), allowing us to predict arm resting from instantaneous firing rates with 98% accuracy using a simple classifier. By cascading this state classifier and the movement decoder, we were able to predict zero velocity correctly, which would avoid undesired motion in a prosthetic application. Interestingly, firing rates during hold periods followed the Active pattern even though hold kinematics were similar to those during rest with near-zero velocity. These findings expand our concept of motor-cortical function by showing that population activity reflects behavioral context in addition to the direct parameters of the movement itself. © 2014 the authors.

Jung B.,University of California at Riverside | Jung B.,Daegu Gyeongbuk Medical Innovation Foundation | Vullev V.I.,University of California at Riverside | Anvari B.,University of California at Riverside
IEEE Journal on Selected Topics in Quantum Electronics | Year: 2014

Indocyanine green (ICG) remains as the only near infrared dye approved by the FDA. Despite its long history of usage in clinical medicine, a systematic study of the effects of serum proteins at physiologically relevant levels and temperature on absorption and fluorescence characteristics of ICG has been missing. We incubated ICG at concentrations in the range of 0.6-25.8 μM in McCoy's 5a cell culture medium, without and with supplemental fetal bovine serum (FBS) at 5% and 10% levels. Our analyses of absorption and fluorescence spectra indicate that the peak absorbance of ICG associated with its monomeric form increases in the presence of FBS. For example, at ICG concentration of 25.8 μM, the monomer absorbance is increased by nearly 100% in the presence of 10% FBS. Similarly, there is an increase in the relative fluorescence quantum yield of ICG, by as much as nearly 3.5 times in the presence of FBS. When incubated at 37 °C, the presence of FBS in the cell culture medium helps maintain the monomeric absorption of ICG and sustain the increased fluorescence emission. We offer explanations to describe the possible photophysical mechanisms underlying the observed effects and discuss the importance of these results to in-vivo applications of ICG. © 1995-2012 IEEE.

Yu J.H.,Daegu Gyeongbuk Medical Innovation Foundation
World Journal of Gastroenterology | Year: 2014

Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-in-duced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined. © 2014 Baishideng Publishing Group Inc. All rights reserved.

Kim K.,Incheon National University | Yang D.K.,Mount Sinai School of Medicine | Kim S.,Daegu Gyeongbuk Medical Innovation Foundation | Kang H.,Incheon National University
Journal of Cellular Biochemistry | Year: 2015

The transforming growth factor β (TGFβ) signaling pathway is critical for the promotion and maintenance of the contractile phenotype of vascular smooth muscle cells (VSMCs). Though multiple microRNAs (miRNAs) implicated in the regulation of the VSMC phenotype have been identified, the modulation of miRNAs in the VSMCs by TGFβ signaling has not been fully described. In this study, we identified microRNA-142-3p (miR-142-3p) as a modulator of the VSMC phenotype in response to TGFβ signaling. We show that miR-142-3p is induced upon TGFβ signaling, leading to the repression of a novel target, dedicator of cytokinesis 6 (DOCK6). The downregulation of DOCK6 by miR-142-3p is critical for cell migration. Thus, this study demonstrates that miR-142-3p is a key regulator of the TGFβ-mediated contractile phenotype of VSMCs that acts through inhibiting cell migration through targeting DOCK6. J. Cell. Biochem. 116: 2325-2333, 2015. © 2015 Wiley Periodicals, Inc.

Pai J.,Yonsei University | Yoon T.,Yonsei University | Kim N.D.,Daegu Gyeongbuk Medical Innovation Foundation | Lee I.-S.,Konkuk University | And 2 more authors.
Journal of the American Chemical Society | Year: 2012

A rapid and quantitative method to evaluate binding properties of hairpin RNAs to peptides using peptide microarrays has been developed. The microarray technology was shown to be a powerful tool for high-throughput analysis of RNA-peptide interactions by its application to profiling interactions between 111 peptides and six hairpin RNAs. The peptide microarrays were also employed to measure hundreds of dissociation constants (Kd) of RNA-peptide complexes. Our results reveal that both hydrophobic and hydrophilic faces of amphiphilic peptides are likely involved in interactions with RNAs. Furthermore, these results also show that most of the tested peptides bind hairpin RNAs with submicromolar Kd values. One of the peptides identified by using this method was found to have good inhibitory activity against TAR-Tat interactions in cells. Because of their great applicability to evaluation of nearly all types of RNA-peptide interactions, peptide microarrays are expected to serve as robust tools for rapid assessment of peptide-RNA interactions and development of peptide ligands against RNA targets. © 2012 American Chemical Society.

Aryal M.,Boston College | Aryal M.,Harvard University | Park J.,Daegu Gyeongbuk Medical Innovation Foundation | Vykhodtseva N.,Harvard University | And 2 more authors.
Physics in Medicine and Biology | Year: 2015

Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the 'blood tumor barrier' (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823 ± 600, 1817 ± 732 and 2432 ± 448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P<0.05, P<0.01, and P<0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222 ± 784, 3687 ± 796 and 5658 ± 821 ng g-1) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P<0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (∼100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used. © 2015 Institute of Physics and Engineering in Medicine.

Koo J.E.,Catholic University of Korea | Park Z.-Y.,Gwangju Institute of Science and Technology | Kim N.D.,Daegu Gyeongbuk Medical Innovation Foundation | Lee J.Y.,Catholic University of Korea
Biochemical and Biophysical Research Communications | Year: 2013

Toll-like receptors (TLRs) are key pattern-recognition receptors that recognize invading pathogens and non-microbial endogenous molecules to induce innate and adaptive immune responses. Since activation of TLRs is deeply implicated in the pathological progress of autoimmune diseases, sepsis, metabolic diseases, and cancer, modulation of TLR activity is considered one of the most important therapeutic approaches. Lipopolysaccharide (LPS), an endotoxin of gram-negative bacteria, is a well-known agonist for TLR4 triggering inflammation and septic shock. LPS interacts with TLR4 through binding to a hydrophobic pocket in myeloid differentiation 2 (MD2), a co-receptor of TLR4. In this study, we showed that sulforaphane (SFN) interfered with the binding of LPS to MD2 as determined by in vitro binding assay and co-immunoprecipitation of MD2 and LPS in a cell system. The inhibitory effect of SFN on the interaction of LPS and MD2 was reversed by thiol supplementation with N-acetyl-L-cysteine or dithiothreitol showing that the inhibitory effect of SFN is dependent on its thiol-modifying activity. Indeed, micro LCMS/MS analysis showed that SFN preferentially formed adducts with Cys133 in the hydrophobic pocket of MD2, but not with Cys95 and Cys105. Molecular modeling showed that SFN bound to Cys133 blocks the engagement of LPS and lipid IVa to hydrophobic pocket of MD2. Our results demonstrate that SFN interrupts LPS engagement to TLR4/MD2 complex by direct binding to Cys133 in MD2. Our data suggest a novel mechanism for the anti-inflammatory activity of SFN, and provide a novel target for the regulation of TLR4-mediated inflammatory and immune responses by phytochemicals. © 2013 Elsevier Inc. All rights reserved.

Yoon J.H.,Yeungnam University | Cho Y.-J.,Daegu Gyeongbuk Medical Innovation Foundation | Park H.H.,Yeungnam University
Acta Crystallographica Section D: Biological Crystallography | Year: 2014

The TNF receptor-associated factor (TRAF) proteins are structurally similar scaffold proteins that mediate between members of the TNF receptor (TNFR) family and downstream effector molecules such as kinases in the immune signalling pathway. Seven TRAFs have been identified, including TRAF4, which is a unique member that participates in many ontogenic processes, including nerve-system development. TRAFs commonly contain the TRAF domain, which mediates interaction with target receptors and effectors. As a first step towards elucidating the molecular mechanisms of the TRAF4-mediated signalling pathway, the first crystal structure of the human TRAF4 TRAF domain with a coiled-coil domain is reported at 2.3 Å resolution. © 2014 International Union of Crystallography.

Shin J.-H.,Daegu Gyeongbuk Medical Innovation Foundation
Journal of Mechanical Science and Technology | Year: 2015

Time-varying pressure produced in a cylinder chamber of an axial hydraulic pump is closely associated with various crucial issues such as system noise emission, swash-plate control, lubrication in sliding parts and etc. In this paper a computational study was performed to investigate the dynamic behavior of the cylinder pressure considering a general system of a piston pump, a hydraulic line, and an end resistance. Combined lumped and distributed parameter model was used, and led to successful fitting with existing experimental data obtained from a pump/line/resistance system which included a pressure relief valve in series. Using the developed tool, the effects of several dimension and operation parameters were investigated assuming that the end resistance was a simple orifice valve. The calculation results, depicted in both time domain and frequency domain, showed that the harmonics of the dynamic pressure and their amplitudes varied with line size capriciously. It was also shown that the harmonic of maximum pulsation amplitude changed in a periodic way as rotating frequency increased. Lastly, the pulsation amplitudes increased with the increase of discharge pressure proportionally with no change of the harmonics. © 2015, The Korean Society of Mechanical Engineers and Springer-Verlag Berlin Heidelberg.

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