Publications by authors named "Ok Kyu Park"

79 Publications

Enhanced Chemodynamic Therapy by Cu-Fe Peroxide Nanoparticles: Tumor Microenvironment-Mediated Synergistic Fenton Reaction.

ACS Nano 2022 02 26;16(2):2535-2545. Epub 2022 Jan 26.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea.

An urgent need in chemodynamic therapy (CDT) is to achieve high Fenton catalytic efficiency at small doses of CDT agents. However, simple general promotion of the Fenton reaction increases the risk of damaging normal cells along with the cancer cells. Therefore, a tailored strategy to selectively enhance the Fenton reactivity in tumors, for example, by taking advantage of the characteristics of the tumor microenvironment (TME), is in high demand. Herein, a heterogeneous CDT system based on copper-iron peroxide nanoparticles (CFp NPs) is designed for TME-mediated synergistic therapy. CFp NPs degrade under the mildly acidic conditions of TME, self-supply HO, and the released Cu and Fe ions, with their larger portions at lower oxidation states, cooperatively facilitate hydroxyl radical production through a highly efficient catalytic loop to achieve an excellent tumor therapeutic efficacy. This is distinct from previous heterogeneous CDT systems in that the synergism is closely coupled with the Cu-assisted conversion of Fe to Fe rather than their independent actions. As a result, almost complete ablation of tumors at a minimal treatment dose is demonstrated without the aid of any other therapeutic modality. Furthermore, CFp NPs generate O during the catalysis and exhibit a TME-responsive T magnetic resonance imaging contrast enhancement, which are useful for alleviating hypoxia and monitoring of tumors, respectively.
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http://dx.doi.org/10.1021/acsnano.1c09171DOI Listing
February 2022

Multifunctional Injectable Hydrogel for Diagnostic and Therapeutic Applications.

ACS Nano 2022 Jan 11. Epub 2022 Jan 11.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea.

Injectable hydrogels show high potential for biomedical applications owing to their distinctive mode of administration into the human body. In this study, we propose a material design strategy for developing a multifunctional injectable hydrogel with good adhesiveness, stretchability, and bioresorbability. Its multifunctionality, whereupon multiple reactions occur simultaneously during its injection into the body without requiring energy stimuli and/or additives, was realized through meticulous engineering of bioresorbable precursors based on hydrogel chemistry. The multifunctional injectable hydrogel can be administered through a minimally invasive procedure, form a conformal adhesive interface with the target tissue, dynamically stretch along with the organ motions with minimal mechanical constraints, and be resorbed after a specific period. Further, the incorporation of functional nanomaterials into the hydrogel allows for various diagnostic and therapeutic applications, without compromising the original multifunctionality of the hydrogel. These features are verified through theranostic case studies on representative organs, including the skin, liver, heart, and bladder.
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http://dx.doi.org/10.1021/acsnano.1c07649DOI Listing
January 2022

Tissue-like skin-device interface for wearable bioelectronics by using ultrasoft, mass-permeable, and low-impedance hydrogels.

Sci Adv 2021 05 7;7(19). Epub 2021 May 7.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea.

Hydrogels consist of a cross-linked porous polymer network and water molecules occupying the interspace between the polymer chains. Therefore, hydrogels are soft and moisturized, with mechanical structures and physical properties similar to those of human tissue. Such hydrogels have a potential to turn the microscale gap between wearable devices and human skin into a tissue-like space. Here, we present material and device strategies to form a tissue-like, quasi-solid interface between wearable bioelectronics and human skin. The key material is an ultrathin type of functionalized hydrogel that shows unusual features of high mass-permeability and low impedance. The functionalized hydrogel acted as a liquid electrolyte on the skin and formed an extremely conformal and low-impedance interface for wearable electrochemical biosensors and electrical stimulators. Furthermore, its porous structure and ultrathin thickness facilitated the efficient transport of target molecules through the interface. Therefore, this functionalized hydrogel can maximize the performance of various wearable bioelectronics.
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http://dx.doi.org/10.1126/sciadv.abd3716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104866PMC
May 2021

Localized Delivery of Theranostic Nanoparticles and High-Energy Photons using Microneedles-on-Bioelectronics.

Adv Mater 2021 Jun 6;33(24):e2100425. Epub 2021 May 6.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea.

The low delivery efficiency of light-responsive theranostic nanoparticles (NPs) to target tumor sites, particularly to brain tumors due to the blood-brain barrier, has been a critical issue in NP-based cancer treatments. Furthermore, high-energy photons that can effectively activate theranostic NPs are hardly delivered to the target region due to the strong scattering of such photons while penetrating surrounding tissues. Here, a localized delivery method of theranostic NPs and high-energy photons to the target tumor using microneedles-on-bioelectronics is presented. Two types of microneedles and flexible bioelectronics are integrated and mounted on the edge of surgical forceps. Bioresorbable microneedles containing theranostic NPs deliver the NPs into target tumors (e.g., glioblastoma, pituitary adenoma). Magnetic resonance imaging can locate the NPs. Then, light-guiding/spreading microneedles deliver high-energy photons from bioelectronics to the NPs. The high-energy photons activate the NPs to treat tumor tissues by photodynamic therapy and chemotherapy. The controlled thermal actuation by the bioelectronics accelerates the diffusion of chemo-drugs. The proposed method is demonstrated with mouse tumor models in vivo.
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http://dx.doi.org/10.1002/adma.202100425DOI Listing
June 2021

Durable and Fatigue-Resistant Soft Peripheral Neuroprosthetics for In Vivo Bidirectional Signaling.

Adv Mater 2021 May 19;33(20):e2007346. Epub 2021 Mar 19.

Department of Electrical and Computer Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Soft neuroprosthetics that monitor signals from sensory neurons and deliver motor information can potentially replace damaged nerves. However, achieving long-term stability of devices interfacing peripheral nerves is challenging, since dynamic mechanical deformations in peripheral nerves cause material degradation in devices. Here, a durable and fatigue-resistant soft neuroprosthetic device is reported for bidirectional signaling on peripheral nerves. The neuroprosthetic device is made of a nanocomposite of gold nanoshell (AuNS)-coated silver (Ag) flakes dispersed in a tough, stretchable, and self-healing polymer (SHP). The dynamic self-healing property of the nanocomposite allows the percolation network of AuNS-coated flakes to rebuild after degradation. Therefore, its degraded electrical and mechanical performance by repetitive, irregular, and intense deformations at the device-nerve interface can be spontaneously self-recovered. When the device is implanted on a rat sciatic nerve, stable bidirectional signaling is obtained for over 5 weeks. Neural signals collected from a live walking rat using these neuroprosthetics are analyzed by a deep neural network to predict the joint position precisely. This result demonstrates that durable soft neuroprosthetics can facilitate collection and analysis of large-sized in vivo data for solving challenges in neurological disorders.
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http://dx.doi.org/10.1002/adma.202007346DOI Listing
May 2021

Epitaxially Strained CeO /Mn O Nanocrystals as an Enhanced Antioxidant for Radioprotection.

Adv Mater 2020 Aug 10;32(31):e2001566. Epub 2020 Jun 10.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea.

Nanomaterials with antioxidant properties are promising for treating reactive oxygen species (ROS)-related diseases. However, maintaining efficacy at low doses to minimize toxicity is a critical for clinical applications. Tuning the surface strain of metallic nanoparticles can enhance catalytic reactivity, which has rarely been demonstrated in metal oxide nanomaterials. Here, it is shown that inducing surface strains of CeO /Mn O nanocrystals produces highly catalytic antioxidants that can protect tissue-resident stem cells from irradiation-induced ROS damage. Manganese ions deposited on the surface of cerium oxide (CeO ) nanocrystals form strained layers of manganese oxide (Mn O ) islands, increasing the number of oxygen vacancies. CeO /Mn O nanocrystals show better catalytic activity than CeO or Mn O alone and can protect the regenerative capabilities of intestinal stem cells in an organoid model after a lethal dose of irradiation. A small amount of the nanocrystals prevents acute radiation syndrome and increases the survival rate of mice treated with a lethal dose of total body irradiation.
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http://dx.doi.org/10.1002/adma.202001566DOI Listing
August 2020

Deep Tumor Penetration of Drug-Loaded Nanoparticles by Click Reaction-Assisted Immune Cell Targeting Strategy.

J Am Chem Soc 2019 09 22;141(35):13829-13840. Epub 2019 Aug 22.

Center for Nanoparticle Research , Institute for Basic Science (IBS) , Seoul 08826 , Republic of Korea.

Nanoparticles have been extensively used to deliver therapeutic drugs to tumor tissues through the extravasation of a leaky vessel via enhanced permeation and retention effect (EPR, passive targeting) or targeted interaction of tumor-specific ligands (active targeting). However, the therapeutic efficacy of drug-loaded nanoparticles is hampered by its heterogeneous distribution owing to limited penetration in tumor tissue. Inspired by the fact that cancer cells can recruit inflammatory immune cells to support their survival, we developed a click reaction-assisted immune cell targeting (CRAIT) strategy to deliver drug-loaded nanoparticles deep into the avascular regions of the tumor. Immune cell-targeting CD11b antibodies are modified with -cyclooctene to enable bioorthogonal click chemistry with mesoporous silica nanoparticles functionalized with tetrazines (MSNs-Tz). Sequential injection of modified antibodies and MSNs-Tz at intervals of 24 h results in targeted conjugation of the nanoparticles onto CD11b myeloid cells, which serve as active vectors into tumor interiors. We show that the CRAIT strategy allows the deep tumor penetration of drug-loaded nanoparticles, resulting in enhanced therapeutic efficacy in an orthotopic 4T1 breast tumor model. The CRAIT strategy does not require ex vivo manipulation of cells and can be applied to various types of cells and nanovehicles.
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http://dx.doi.org/10.1021/jacs.9b04621DOI Listing
September 2019

A therapeutic human antibody against the domain 4 of the Bacillus anthracis protective antigen shows protective efficacy in a mouse model.

Biochem Biophys Res Commun 2019 02 31;509(2):611-616. Epub 2018 Dec 31.

Division of High-risk Pathogens, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Cheongju, 28159, South Korea. Electronic address:

Since Bacillus anthracis is a high-risk pathogen and a potential tool for bioterrorism, numerous therapeutic methods including passive immunization have been actively developed. Using a human monoclonal antibody phage display library, we screened new therapeutic antibodies for anthrax infection against protective antigen (PA) of B. anthracis. Among 5 selected clones of antibodies based on enzyme-linked immunosorbent assay (ELISA) results, 7B1 showed neutralizing activity to anthrax lethal toxin (LT) by inhibiting binding of the domain 4 of PA (PD4) to its cellular receptors. Through light chain shuffling process, we improved the productivity of 7B1 up to 25 folds. The light chain shuffled 7B1 antibody showed protective activity against LT both in vitro and in vivo. Furthermore, the antibody also conferred protection of mice from 3 × LD challenges of fully virulent anthrax spores. Our result expands the possibility of developing a new therapeutic antibody for anthrax cure.
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http://dx.doi.org/10.1016/j.bbrc.2018.12.146DOI Listing
February 2019

Highly conductive, stretchable and biocompatible Ag-Au core-sheath nanowire composite for wearable and implantable bioelectronics.

Nat Nanotechnol 2018 11 13;13(11):1048-1056. Epub 2018 Aug 13.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Republic of Korea.

Wearable and implantable devices require conductive, stretchable and biocompatible materials. However, obtaining composites that simultaneously fulfil these requirements is challenging due to a trade-off between conductivity and stretchability. Here, we report on Ag-Au nanocomposites composed of ultralong gold-coated silver nanowires in an elastomeric block-copolymer matrix. Owing to the high aspect ratio and percolation network of the Ag-Au nanowires, the nanocomposites exhibit an optimized conductivity of 41,850 S cm (maximum of 72,600 S cm). Phase separation in the Ag-Au nanocomposite during the solvent-drying process generates a microstructure that yields an optimized stretchability of 266% (maximum of 840%). The thick gold sheath deposited on the silver nanowire surface prevents oxidation and silver ion leaching, making the composite biocompatible and highly conductive. Using the nanocomposite, we successfully fabricate wearable and implantable soft bioelectronic devices that can be conformally integrated with human skin and swine heart for continuous electrophysiological recording, and electrical and thermal stimulation.
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http://dx.doi.org/10.1038/s41565-018-0226-8DOI Listing
November 2018

Muramyl dipeptide potentiates a Bacillus anthracis poly-γ-d-glutamic acid capsule surrogate that induces maturation and activation of mouse dendritic cells.

Cytokine 2018 10 12;110:350-356. Epub 2018 Apr 12.

Division of High-risk Pathogens, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Republic of Korea. Electronic address:

Poly-γ-d-glutamic acid (PGA) of anthrax is an important pathogenic factor due to its anti-phagocytic activity. Additionally, PGA has the ability to activate mouse macrophages for the secretion of cytokines through Toll-like receptor (TLR) 2. Peptidoglycan (PGN), a major bacterial cell-wall component, induces inflammatory responses in the host. We assessed whether PGA can induce maturation and cytokine expression in immature mouse dendritic cells (DCs) in the existence of muramyl dipeptide (MDP), the minimum motif of PGN with immunostimulatory activity. Stimulation of immature DCs with PGA or MDP alone augmented expression of costimulatory molecules and MHC class II proteins, which are all cell surface markers indicative of maturation. The observed effects were further enhanced by costimulation of PGA and MDP. PGA alone was sufficient to induce expression of TNF-α, IL-6, MCP-1, and MIP1-α, whereas MDP alone did not under the same conditions. Treatment with MDP enhanced PGA-induced expression of the tested inflammatory mediators; however, the synergistic effect found for PGA and MDP was not observed in TLR2- or nucleotide-binding oligomerization domain (NOD) 2-knockout DCs. Additionally, MDP augmented PGA-induced MAP kinases and NF-κB activation, which is crucial for expression of cytokines. Furthermore, MAP kinase and NF-κB inhibitors attenuated MDP enhancement of PGA-induced cytokine production. In addition, co-culture of splenocytes and PGA/MDP-matured DCs induced higher expression of IL-2 and IFN-γ compared to that of splenocytes and PGA-matured DCs. Collectively, our results suggest that PGA and MDP cooperatively induce inflammatory responses in mouse DCs through TLR2 and NOD2 via MAP kinase and NF-κB pathways, subsequently leading to lymphocyte activation.
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http://dx.doi.org/10.1016/j.cyto.2018.04.004DOI Listing
October 2018

General and Facile Coating of Single Cells via Mild Reduction.

J Am Chem Soc 2018 01 5;140(4):1199-1202. Epub 2018 Jan 5.

School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University , Seoul 08826, Republic of Korea.

Cell surface modification has been extensively studied to enhance the efficacy of cell therapy. Still, general accessibility and versatility are remaining challenges to meet the increasing demand for cell-based therapy. Herein, we present a facile and universal cell surface modification method that involves mild reduction of disulfide bonds in cell membrane protein to thiol groups. The reduced cells are successfully coated with biomolecules, polymers, and nanoparticles for an assortment of applications, including rapid cell assembly, in vivo cell monitoring, and localized cell-based drug delivery. No adverse effect on cellular morphology, viability, proliferation, and metabolism is observed. Furthermore, simultaneous coating with polyethylene glycol and dexamethasone-loaded nanoparticles facilitates enhanced cellular activities in mice, overcoming immune rejection.
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http://dx.doi.org/10.1021/jacs.7b08440DOI Listing
January 2018

Human eye-inspired soft optoelectronic device using high-density MoS-graphene curved image sensor array.

Nat Commun 2017 11 21;8(1):1664. Epub 2017 Nov 21.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea.

Soft bioelectronic devices provide new opportunities for next-generation implantable devices owing to their soft mechanical nature that leads to minimal tissue damages and immune responses. However, a soft form of the implantable optoelectronic device for optical sensing and retinal stimulation has not been developed yet because of the bulkiness and rigidity of conventional imaging modules and their composing materials. Here, we describe a high-density and hemispherically curved image sensor array that leverages the atomically thin MoS-graphene heterostructure and strain-releasing device designs. The hemispherically curved image sensor array exhibits infrared blindness and successfully acquires pixelated optical signals. We corroborate the validity of the proposed soft materials and ultrathin device designs through theoretical modeling and finite element analysis. Then, we propose the ultrathin hemispherically curved image sensor array as a promising imaging element in the soft retinal implant. The CurvIS array is applied as a human eye-inspired soft implantable optoelectronic device that can detect optical signals and apply programmed electrical stimulation to optic nerves with minimum mechanical side effects to the retina.
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http://dx.doi.org/10.1038/s41467-017-01824-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698290PMC
November 2017

Multifunctional nanoparticles as a tissue adhesive and an injectable marker for image-guided procedures.

Nat Commun 2017 07 19;8:15807. Epub 2017 Jul 19.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea.

Tissue adhesives have emerged as an alternative to sutures and staples for wound closure and reconnection of injured tissues after surgery or trauma. Owing to their convenience and effectiveness, these adhesives have received growing attention particularly in minimally invasive procedures. For safe and accurate applications, tissue adhesives should be detectable via clinical imaging modalities and be highly biocompatible for intracorporeal procedures. However, few adhesives meet all these requirements. Herein, we show that biocompatible tantalum oxide/silica core/shell nanoparticles (TSNs) exhibit not only high contrast effects for real-time imaging but also strong adhesive properties. Furthermore, the biocompatible TSNs cause much less cellular toxicity and less inflammation than a clinically used, imageable tissue adhesive (that is, a mixture of cyanoacrylate and Lipiodol). Because of their multifunctional imaging and adhesive property, the TSNs are successfully applied as a hemostatic adhesive for minimally invasive procedures and as an immobilized marker for image-guided procedures.
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http://dx.doi.org/10.1038/ncomms15807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524935PMC
July 2017

In vitro photodynamic effects of scavenger receptor targeted-photoactivatable nanoagents on activated macrophages.

Int J Biol Macromol 2017 Apr 9;97:181-189. Epub 2017 Jan 9.

Korea Basic Science Institute Chuncheon Center, Chuncheon, Gangwon 200-701, Republic of Korea. Electronic address:

Scavenger receptors (SRs) expressed on the activated macrophages in inflammation sites have been considered as the most interesting and important target biomarker for targeted drug delivery, imaging and therapy. In the present study, we fabricated the scavenger receptor-A (SR-A) targeted-photoactivatable nanoagents (termed as Ce6/DS-DOCA) by entrapping chlorin e6 (Ce6) into the amphiphilic dextran sulfate-deoxycholic acid (DS-DOCA) conjugates via physically hydrophobic interactions. Insoluble Ce6 was easily encapsulated into DS-DOCA nanoparticles by a dialysis method and the loading efficiency was approximately 51.7%. The Ce6/DS-DOCA formed nano-sized self-assembled aggregates (28.8±5.6nm in diameter), confirmed by transmission electron microscope, UV/Vis and fluorescence spectrophotometer. The Ce6/DS-DOCA nanoagents could generate highly reactive singlet oxygen under laser irradiation. Also, in vitro studies showed that they were more specifically taken up by lipopolysaccharide (LPS)-induced activated macrophages (RAW 264.7) via a SR-A-mediated endocytosis, relative to by non-activated macrophages, and notably induced cell death of activated macrophages under laser irradiation. Therefore, SR-A targetable and photoactivatable Ce6/DS-DOCA nanoagents with more selective targeting to the activated macrophages will have great potential for treatment of inflammatory diseases.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.01.037DOI Listing
April 2017

3D Visualization of Developmental Toxicity of 2,4,6-Trinitrotoluene in Zebrafish Embryogenesis Using Light-Sheet Microscopy.

Int J Mol Sci 2016 Nov 17;17(11). Epub 2016 Nov 17.

Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea.

Environmental contamination by trinitrotoluene is of global concern due to its widespread use in military ordnance and commercial explosives. Despite known long-term persistence in groundwater and soil, the toxicological profile of trinitrotoluene and other explosive wastes have not been systematically measured using in vivo biological assays. Zebrafish embryos are ideal model vertebrates for high-throughput toxicity screening and live in vivo imaging due to their small size and transparency during embryogenesis. Here, we used Single Plane Illumination Microscopy (SPIM)/light sheet microscopy to assess the developmental toxicity of explosive-contaminated water in zebrafish embryos and report 2,4,6-trinitrotoluene-associated developmental abnormalities, including defects in heart formation and circulation, in 3D. Levels of apoptotic cell death were higher in the actively developing tissues of trinitrotoluene-treated embryos than controls. Live 3D imaging of heart tube development at cellular resolution by light-sheet microscopy revealed trinitrotoluene-associated cardiac toxicity, including hypoplastic heart chamber formation and cardiac looping defects, while the real time PCR (polymerase chain reaction) quantitatively measured the molecular changes in the heart and blood development supporting the developmental defects at the molecular level. Identification of cellular toxicity in zebrafish using the state-of-the-art 3D imaging system could form the basis of a sensitive biosensor for environmental contaminants and be further valued by combining it with molecular analysis.
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http://dx.doi.org/10.3390/ijms17111925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133921PMC
November 2016

Hydroquinone Strongly Alleviates Focal Ischemic Brain Injury via Blockage of Blood-Brain Barrier Disruption in Rats.

Toxicol Sci 2016 12 31;154(2):430-441. Epub 2016 Aug 31.

Department of Food Science and Nutrition, Hallym University, Chuncheon, 24252, South Korea.

Hydroquinone (HQ), a major benzene metabolite, occurs naturally in various plants and is manufactured for commercial use. Although HQ displays various biological effects, its neuroprotective effects following ischemic insults have not been investigated. In this study, we first examined neuroprotective effects of HQ in a rat model of transient focal cerebral ischemia. Animals were subjected to transient middle cerebral artery occlusion for 120 min. HQ (50 or 100 mg/kg) or vehicle was intraperitoneally administered once at 30 min after ischemia-reperfusion. Neuroprotection by treatment with 100 mg/kg of HQ was shown using evaluation of neurological deficits, positron-emission tomography (PET) and 2,3,5-triphenyltetrazoliumchloride (TTC) staining. In addition, HQ treatment significantly attenuated ischemia-induced Evans blue dye extravasation from blood vessels and significantly increased immunoreactivities of SMI-71 (an endothelial BBB marker) and glucose transporter-1 (GLUT-1, an endothelial cell marker) in ischemic cortex compared to the vehicle-treated ischemia-operated group. Confocal microscopy and western blot analysis also showed that HQ treatment maintained expressions of tight junction proteins (zonula occludens-1 and occludin) in the ischemic cortex. Post-treatment with HQ protected neurons from transient focal cerebral ischemic injury and the neuroprotective effect of HQ might be closely associated with prevention of BBB disruption via maintaining SMI-71 and GLUT-1 expressions as well as prevention of the degradation of zonula occludens-1 and occludin proteins.
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http://dx.doi.org/10.1093/toxsci/kfw167DOI Listing
December 2016

Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors.

Sci Rep 2016 Mar 7;6:22608. Epub 2016 Mar 7.

Multimodal Imaging and Theranostic Lab, Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea.

Macrophages mediate atheroma expansion and disruption, and denote high-risk arterial plaques. Therefore, they are substantially gaining importance as a diagnostic imaging target for the detection of rupture-prone plaques. Here, we developed an injectable near-infrared fluorescence (NIRF) probe by chemically conjugating thiolated glycol chitosan with cholesteryl chloroformate, NIRF dye (cyanine 5.5 or 7), and maleimide-polyethylene glycol-mannose as mannose receptor binding ligands to specifically target a subset of macrophages abundant in high-risk plaques. This probe showed high affinity to mannose receptors, low toxicity, and allowed the direct visualization of plaque macrophages in murine carotid atheroma. After the scale-up of the MMR-NIRF probe, the administration of the probe facilitated in vivo intravascular imaging of plaque inflammation in coronary-sized vessels of atheromatous rabbits using a custom-built dual-modal optical coherence tomography (OCT)-NIRF catheter-based imaging system. This novel imaging approach represents a potential imaging strategy enabling the identification of high-risk plaques in vivo and holds promise for future clinical implications.
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http://dx.doi.org/10.1038/srep22608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780083PMC
March 2016

3D Light-Sheet Fluorescence Microscopy of Cranial Neurons and Vasculature during Zebrafish Embryogenesis.

Mol Cells 2015 Nov 2;38(11):975-81. Epub 2015 Oct 2.

Department of Systems Immunology, College of Biomedical Science, Kangwon National University, Chuncheon 200-701, Korea.

Precise 3D spatial mapping of cells and their connections within living tissues is required to fully understand developmental processes and neural activities. Zebrafish embryos are relatively small and optically transparent, making them the vertebrate model of choice for live in vivo imaging. However, embryonic brains cannot be imaged in their entirety by confocal or two-photon microscopy due to limitations in optical range and scanning speed. Here, we use light-sheet fluorescence microscopy to overcome these limitations and image the entire head of live transgenic zebrafish embryos. We simultaneously imaged cranial neurons and blood vessels during embryogenesis, generating comprehensive 3D maps that provide insight into the coordinated morphogenesis of the nervous system and vasculature during early development. In addition, blood cells circulating through the entire head, vagal and cardiac vasculature were also visualized at high resolution in a 3D movie. These data provide the foundation for the construction of a complete 4D atlas of zebrafish embryogenesis and neural activity.
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http://dx.doi.org/10.14348/molcells.2015.0160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673412PMC
November 2015

Nanobody-targeted E3-ubiquitin ligase complex degrades nuclear proteins.

Sci Rep 2015 Sep 16;5:14269. Epub 2015 Sep 16.

Department of Molecular Bioscience, College of Biomedical Science, Kangwon National University, Chunchon, 200-701, Republic of Korea.

Targeted protein degradation is a powerful tool in determining the function of specific proteins or protein complexes. We fused nanobodies to SPOP, an adaptor protein of the Cullin-RING E3 ubiquitin ligase complex, resulting in rapid ubiquitination and subsequent proteasome-dependent degradation of specific nuclear proteins in mammalian cells and zebrafish embryos. This approach is easily modifiable, as substrate specificity is conferred by an antibody domain that can be adapted to target virtually any protein.
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http://dx.doi.org/10.1038/srep14269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571616PMC
September 2015

The poly-γ-d-glutamic acid capsule surrogate of the Bacillus anthracis capsule induces nitric oxide production via the platelet activating factor receptor signaling pathway.

Mol Immunol 2015 Dec 5;68(2 Pt A):244-52. Epub 2015 Sep 5.

Division of High-Risk Pathogen Research, Center for Infectious Diseases, Korea National Institute of Health, Cheongju-si, Chungcheongbuk-do 363-951, South Korea. Electronic address:

The poly-γ-d-glutamic acid (PGA) capsule, a major virulence factor of Bacillus anthracis, confers protection of the bacillus from phagocytosis and allows its unimpeded growth in the host. PGA capsules released from B. anthracis are associated with lethal toxin in the blood of experimentally infected animals and enhance the cytotoxic effect of lethal toxin on macrophages. In addition, PGA capsule itself activates macrophages and dendritic cells to produce proinflammatory cytokine such as IL-1β, indicating multiple roles of PGA capsule in anthrax pathogenesis. Here we report that PGA capsule of Bacillus licheniformis, a surrogate of B. anthracis capsule, induces production of nitric oxide (NO) in RAW264.7 cells and bone marrow-derived macrophages. NO production was induced by PGA in a dose-dependent manner and was markedly reduced by inhibitors of inducible NO synthase (iNOS), suggesting iNOS-dependent production of NO. Induction of NO production by PGA was not observed in macrophages from TLR2-deficient mice and was also substantially inhibited in RAW264.7 cells by pretreatment of TLR2 blocking antibody. Subsequently, the downstream signaling events such as ERK, JNK and p38 of MAPK pathways as well as NF-κB activation were required for PGA-induced NO production. In addition, the induced NO production was significantly suppressed by treatment with antagonists of platelet activating factor receptor (PAFR) or PAFR siRNA, and mediated through PAFR/Jak2/STAT-1 signaling pathway. These findings suggest that PGA capsule induces NO production in macrophages by triggering both TLR2 and PAFR signaling pathways which lead to activation of NF-kB and STAT-1, respectively.
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http://dx.doi.org/10.1016/j.molimm.2015.08.015DOI Listing
December 2015

The Poly-γ-d-Glutamic Acid Capsule Surrogate of the Bacillus anthracis Capsule Is a Novel Toll-Like Receptor 2 Agonist.

Infect Immun 2015 Oct 20;83(10):3847-56. Epub 2015 Jul 20.

Division of High-Risk Pathogen Research, Center for Infectious Diseases, National Institute of Health, Cheongju, Republic of Korea

Bacillus anthracis is a pathogenic Gram-positive bacterium that causes a highly lethal infectious disease, anthrax. The poly-γ-d-glutamic acid (PGA) capsule is one of the major virulence factors of B. anthracis, along with exotoxins. PGA enables B. anthracis to escape phagocytosis and immune surveillance. Our previous study showed that PGA activates the human macrophage cell line THP-1 and human dendritic cells, resulting in the production of the proinflammatory cytokine interleukin-1β (IL-1β) (M. H. Cho et al., Infect Immun 78:387-392, 2010, http://dx.doi.org/10.1128/IAI.00956-09). Here, we investigated PGA-induced cytokine responses and related signaling pathways in mouse bone marrow-derived macrophages (BMDMs) using Bacillus licheniformis PGA as a surrogate for B. anthracis PGA. Upon exposure to PGA, BMDMs produced proinflammatory mediators, including tumor necrosis factor alpha (TNF-α), IL-6, IL-12p40, and monocyte chemoattractant protein 1 (MCP-1), in a concentration-dependent manner. PGA stimulated Toll-like receptor 2 (TLR2) but not TLR4 in Chinese hamster ovary cells expressing either TLR2 or TLR4. The ability of PGA to induce TNF-α and IL-6 was retained in TLR4(-/-) but not TLR2(-/-) BMDMs. Blocking experiments with specific neutralizing antibodies for TLR1, TLR6, and CD14 showed that TLR6 and CD14 also were necessary for PGA-induced inflammatory responses. Furthermore, PGA enhanced activation of mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NF-κB), which are responsible for expression of proinflammatory cytokines. Additionally, PGA-induced TNF-α production was abrogated not only in MyD88(-/-) BMDMs but also in BMDMs pretreated with inhibitors of MAP kinases and NF-κB. These results suggest that immune responses induced by PGA occur via TLR2, TLR6, CD14, and MyD88 through activation of MAP kinase and NF-κB pathways.
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http://dx.doi.org/10.1128/IAI.00888-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567625PMC
October 2015

Cephalopod-Inspired Miniaturized Suction Cups for Smart Medical Skin.

Adv Healthc Mater 2016 Jan 20;5(1):80-7. Epub 2015 May 20.

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 151-742, Republic of Korea.

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http://dx.doi.org/10.1002/adhm.201500285DOI Listing
January 2016

Glycol chitosan-based fluorescent theranostic nanoagents for cancer therapy.

Mar Drugs 2014 Dec 17;12(12):6038-57. Epub 2014 Dec 17.

Division of Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Gangwon-do 200-701, Korea.

Theranostics is an integrated nanosystem that combines therapeutics with diagnostics in attempt to develop new personalized treatments with enhanced therapeutic efficacy and safety. As a promising therapeutic paradigm with cutting-edge technologies, theranostic agents are able to simultaneously deliver therapeutic drugs and diagnostic imaging agents and also monitor the response to therapy. Polymeric nanosystems have been intensively explored for biomedical applications to diagnose and treat various cancers. In recent years, glycol chitosan-based nanoagents have been developed as dual-purpose materials for simultaneous diagnosis and therapy. They have shown great potential in cancer therapies, such as chemotherapeutics and nucleic acid and photodynamic therapies. In this review, we summarize the recent progress and potential applications of glycol chitosan-based fluorescent theranostic nanoagents for cancer treatments and discuss their possible underlying mechanisms.
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http://dx.doi.org/10.3390/md12126038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278218PMC
December 2014

Neuroprotection via maintenance or increase of antioxidants and neurotrophic factors in ischemic gerbil hippocampus treated with tanshinone I.

Chin Med J (Engl) 2014 ;127(19):3396-405

Division of Food Science and Biotechnology, College of Agriculture and Life Sciences, Kangwon National University, Chuncheon 200-701, South Korea. Email:

Background: Danshen (Radix Salvia miltiorrhizae) has been used as a traditional medicine in Asia for treatment of various microcirculatory disturbance related diseases. Tanshinones are mainly hydrophobic active components, which have been isolated from Danshen and show various biological functions. In this study, we observed the neuroprotective effect of tanshinone I (TsI) against ischemic damage in the gerbil hippocampal CA1 region (CA1) after transient cerebral ischemia and examined its neuroprotective mechanism.

Methods: The gerbils were divided into vehicle-treated-sham-group, vehicle-treated-ischemia-group, TsI-treated-sham-group, and TsI-treated-ischemia-group. TsI was administrated intraperitoneally three times (once a day for three days) before ischemia-reperfusion. The neuroprotective effect of TsI was examined using H&E staining, neuronal nuclei (NeuN) immunohistochemistry and Fluoro-Jade B staining. To investigate the neuroprotective mechanism of TsI after ischemia-reperfusion, immunohistochemical (IHC) and Western blotting analyses for Cu, Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2), brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-I (IGF-I) were performed.

Results: Treatment with TsI protected pyramidal neurons from ischemia-induced neuronal death in the CA1 after ischemia-reperfusion. In addition, treatment with TsI maintained the levels of SOD1 and SOD2 as determined by IHC and Western blotting in the CA1 after ischemia-reperfusion compared with the vehicle-ischemia-group. In addition, treatment with TsI increased the levels of BDNF and IGF-I determined by IHC and Western blotting in the TsI-treated-sham-group compared with the vehicle-treated-sham-group, and their levels were maintained in the stratum pyramidale of the ischemic CA1 in the TsI-treated-ischemia-group.

Conclusion: Treatment with TsI protects pyramidal neurons of the CA1 from ischemic damage induced by transient cerebral ischemia via the maintenance of antioxidants and the increase of neurotrophic factors.
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April 2015

Extracellular-matrix-based and Arg-Gly-Asp-modified photopolymerizing hydrogels for cartilage tissue engineering.

Tissue Eng Part A 2015 Feb 14;21(3-4):757-66. Epub 2014 Nov 14.

1 School of Chemical and Biological Engineering, BioMAX Institute, Seoul National University , Seoul, Republic of Korea.

Articular cartilage damage is a persistent and increasing problem with the aging population. Strategies to achieve complete repair or functional restoration remain a challenge. Photopolymerizing-based hydrogels have long received an attention in the cartilage tissue engineering, due to their unique bioactivities, flexible method of synthesis, range of constituents, and desirable physical characteristics. In the present study, we have introduced unique bioactivity within the photopolymerizing-based hydrogels by copolymerizing polyethylene glycol (PEG) macromers with methacrylated extracellular matrix (ECM) molecules (hyaluronic acid and chondroitin sulfate [CS]) and integrin binding peptides (RGD peptide). Results indicate that cellular morphology, as observed by the actin cytoskeleton structures, was strongly dependent on the type of ECM component as well as the presence of integrin binding moieties. Further, CS-based hydrogel with integrin binding RGD moieties increased the lubricin (or known as superficial zone protein [SZP]) gene expression of the encapsulated chondrocytes. Additionally, CS-based hydrogel displayed cell-responsive degradation and resulted in increased DNA, GAG, and collagen accumulation compared with other hydrogels. This study demonstrates that integrin-mediated interactions within CS microenvironment provide an optimal hydrogel scaffold for cartilage tissue engineering application.
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http://dx.doi.org/10.1089/ten.TEA.2014.0233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333611PMC
February 2015

Bioinformatic analysis of nematode migration-associated genes identifies novel vertebrate neural crest markers.

PLoS One 2014 22;9(7):e103024. Epub 2014 Jul 22.

Department of Systems Immunology, Kangwon National University, Chuncheon, Korea; Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Korea.

Neural crest cells are highly motile, yet a limited number of genes governing neural crest migration have been identified by conventional studies. To test the hypothesis that cell migration genes are likely to be conserved over large evolutionary distances and from diverse tissues, we searched for vertebrate homologs of genes important for migration of various cell types in the invertebrate nematode and examined their expression during vertebrate neural crest cell migration. Our systematic analysis utilized a combination of comparative genomic scanning, functional pathway analysis and gene expression profiling to uncover previously unidentified genes expressed by premigratory, emigrating and/or migrating neural crest cells. The results demonstrate that similar gene sets are expressed in migratory cell types across distant animals and different germ layers. Bioinformatics analysis of these factors revealed relationships between these genes within signaling pathways that may be important during neural crest cell migration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103024PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106859PMC
December 2015

Anti-inflammatory effect of tanshinone I in neuroprotection against cerebral ischemia-reperfusion injury in the gerbil hippocampus.

Neurochem Res 2014 Jul 24;39(7):1300-12. Epub 2014 Apr 24.

Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 200-701, South Korea.

Tanshinone I (TsI) is an important lipophilic diterpene extracted from Danshen (Radix Salvia miltiorrhizae) and has been used in Asia for the treatment of cerebrovascular diseases such as ischemic stroke. In this study, we examined the neuroprotective effect of TsI against ischemic damage and its neuroprotective mechanism in the gerbil hippocampal CA1 region (CA1) induced by 5 min of transient global cerebral ischemia. Pre-treatment with TsI protected pyramidal neurons from ischemic damage in the stratum pyramidale (SP) of the CA1 after ischemia-reperfusion. The pre-treatment with TsI increased the immunoreactivities and protein levels of anti-inflammatory cytokines [interleukin (IL)-4 and IL-13] in the TsI-treated-sham-operated-groups compared with those in the vehicle-treated-sham-operated-groups; however, the treatment did not increase the immunoreactivities and protein levels of pro-inflammatory cytokines (IL-2 and tumor necrosis factor-α). On the other hand, in the TsI-treated-ischemia-operated-groups, the immunoreactivities and protein levels of all the cytokines were maintained in the SP of the CA1 after transient cerebral ischemia. In addition, we examined that IL-4 injection into the lateral ventricle did not protect pyramidal neurons from ischemic damage. In conclusion, these findings indicate that the pre-treatment with TsI can protect against ischemia-induced neuronal death in the CA1 via the increase or maintenance of endogenous inflammatory cytokines, and exogenous IL-4 does not protect against ischemic damage.
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http://dx.doi.org/10.1007/s11064-014-1312-4DOI Listing
July 2014

Activation of microglia and induction of pro-inflammatory cytokines in the hippocampus of type 2 diabetic rats.

Neurol Res 2014 Sep 27;36(9):824-32. Epub 2014 Feb 27.

Objectives: The majority of immune cells in the brain are comprised of microglia, which undergo morphological changes when activated to remove damaged neurons and infectious agents from the brain tissue. In this study, we investigated the effects of type 2 diabetes on microglial activation and the subsequent secretion of pro-inflammatory cytokines, such as interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta), in the hippocampus using Zucker diabetic fatty (ZDF) rats and Zucker lean control (ZLC) rats at various diabetic stages.

Methods: Zucker lean control and Zucker diabetic fatty rats were sacrificed at 12 (early diabetic stage), 20, or 30 weeks of age (chronic diabetic stage), and the hippocampus was obtained via transcardiac perfusion or dissection for immunohistochemistry and western blot analysis, respectively.

Results: Zucker diabetic fatty rats demonstrated significantly higher glucose levels at 12 and 30 weeks of age compared to ZLC rats. Microglia immunoreactive to ionized calcium-binding adapter molecule 1 (Iba-1) had hypertrophied cytoplasm with retracted processes at 30 weeks of age. In contrast, Iba-1-immunoreactive microglia displayed similar morphology in ZDF and ZLC rats at 12 and 20 weeks of age. Similarly, IFN-gamma and IL-1beta protein levels were significantly increased in ZDF rats compared to ZLC rats at 30 weeks of age, but not at 12 and 20 weeks of age. Interleukin-1beta immunoreactivity in the ZDF rats predominantly increased in the dentate gyrus and CA1 region of the hippocampus compared to that of ZLC rats at 30 weeks of age. In addition, IL-1beta immunoreactive structures in ZDF rats at 30 weeks of age were detected near the astrocytes and microglia.

Conclusion: These results suggest that chronic diabetes activates microglia and significantly increases pro-inflammatory cytokine levels in the hippocampus.
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http://dx.doi.org/10.1179/1743132814Y.0000000330DOI Listing
September 2014

Novel drug combination for Mycobacterium abscessus disease therapy identified in a Drosophila infection model.

J Antimicrob Chemother 2014 Jun 10;69(6):1599-607. Epub 2014 Feb 10.

Institute Pasteur Korea, Seongnam-si, Gyeonggi-do, Korea

Objectives: Mycobacterium abscessus is known to be the most drug-resistant Mycobacterium and accounts for ∼80% of pulmonary infections caused by rapidly growing mycobacteria. This study reports a new Drosophila melanogaster-M. abscessus infection model that can be used as an in vivo efficacy model for anti-M. abscessus drug potency assessment.

Methods: D. melanogaster were challenged with M. abscessus, and infected flies were fed with a fly medium containing tigecycline, clarithromycin, linezolid, clofazimine, moxifloxacin, amikacin, cefoxitin, dinitrobenzamide or metronidazole at different concentrations (0, 100 and 500 mg/L). The survival rates of infected flies were plotted and bacterial colonization/dissemination in fly bodies was monitored by cfu determination and green fluorescent protein epifluorescence.

Results: The D. melanogaster-M. abscessus model enabled an assessment of the effectiveness of antibiotic treatment. Tigecycline was the best drug for extending the lifespan of M. abscessus-infected Drosophila, followed by clarithromycin and linezolid. Several different combinations of tigecycline, linezolid and clarithromycin were tested to determine the best combination. Tigecycline (25 mg/L) plus linezolid (500 mg/L) was the best drug combination and its efficacy was superior to conventional regimens, not only in prolonging infected fly survival but also against M. abscessus colonization and dissemination.

Conclusions: This D. melanogaster-M. abscessus infection/curing methodology may be useful for the rapid evaluation of potential drug candidates. In addition, new combinations using tigecycline and linezolid should be considered as possible next-generation combination therapies to be assessed in higher organisms.
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http://dx.doi.org/10.1093/jac/dku024DOI Listing
June 2014

Neuroprotection of posttreatment with risperidone, an atypical antipsychotic drug, in rat and gerbil models of ischemic stroke and the maintenance of antioxidants in a gerbil model of ischemic stroke.

J Neurosci Res 2014 Jun 31;92(6):795-807. Epub 2014 Jan 31.

Department of Integrative Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.

Risperidone, an atypical antipsychotic drug, has been discovered to have some beneficial effects beyond its original effectiveness. The present study examines the neuroprotective effects of risperidone against ischemic damage in the rat and gerbil induced by transient focal and global cerebral ischemia, respectively. The results showed that pre- and posttreatment with 4 mg/kg risperidone significantly protected against neuronal death from ischemic injury. Many NeuN-immunoreactive neurons and a few F-J B-positive cells were found in the rat cerebral cortex and gerbil hippocampal CA1 region (CA1) in the risperidone-treated ischemia groups compared with those in the vehicle-treated ischemia group. In addition, treatment with risperidone markedly attenuated the activation of microglia in the gerbil CA1. On the other hand, we found that treatment with risperidone significantly maintained the antioxidants levels in the ischemic gerbil CA1. Immunoreactivities of superoxide dismutases 1 and 2, catalase, and glutathione peroxidase were maintained in the stratum pyramidale of the CA1; the antioxidants were very different from those in the vehicle-treated ischemia groups. In brief, our present findings indicate that posttreatment as well as pretreatment with risperidone can protect neurons in the rat cerebral cortex and gerbils CA1 from transient cerebral ischemic injury and that the neuroprotective effect of risperidone may be related to attenuation of microglial activation as well as maintenance of antioxidants.
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http://dx.doi.org/10.1002/jnr.23360DOI Listing
June 2014
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