Publications by authors named "Ji-Woong Choi"

116 Publications

Potential Therapeutic Approaches through Modulating the Autophagy Process for Skin Barrier Dysfunction.

Int J Mol Sci 2021 Jul 23;22(15). Epub 2021 Jul 23.

Lab of Pharmaceutics, College of Pharmacy, Dongduk Women's University, Seoul 02748, Korea.

Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human genome research has focused on evaluating the relationship between autophagy and a wide variety of diseases, such as autoimmune diseases, cancers, and inflammatory diseases. The skin is the largest organ in the body and provides the first line of defense against environmental hazards, including UV damage, chemical toxins, injuries, oxidative stress, and microorganisms. Autophagy takes part in endogenous defense mechanisms by controlling skin homeostasis. In this manner, regulating autophagy might contribute to the treatment of skin barrier dysfunctions. Various studies are ongoing to elucidate the association between autophagy and skin-related diseases in order to find potential therapeutic approaches. However, little evidence has been gathered about the relationship between autophagy and the skin. In this review, we highlight the previous findings of autophagy and skin barrier disorders and suggest potential therapeutic strategies. The recent research regarding autophagy in acne and skin aging is also discussed.
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http://dx.doi.org/10.3390/ijms22157869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345957PMC
July 2021

Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses.

Int J Mol Sci 2021 Jul 23;22(15). Epub 2021 Jul 23.

College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Yeonsu-gu, Incheon 21936, Korea.

Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has drawn scientific interest because of its critical roles in pathogenies of diverse neurological diseases such as neuropathic pain, systemic sclerosis, spinal cord injury, multiple sclerosis, cerebral ischemia, traumatic brain injury, hypoxia, hydrocephalus, and neuropsychiatric disorders. Activation of microglia and/or astrocytes is a common pathogenic event shared by most of these CNS disorders, indicating that lysophospholipid receptors could influence glial activation. In fact, many studies have reported that several S1P and LPA receptors can influence glial activation during the pathogenesis of cerebral ischemia and multiple sclerosis. This review aims to provide a comprehensive framework about the roles of S1P and LPA receptors in the activation of microglia and/or astrocytes and their neuroinflammatory responses in CNS diseases.
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http://dx.doi.org/10.3390/ijms22157864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346064PMC
July 2021

The Role of Protein S-Nitrosylation in Protein Misfolding-Associated Diseases.

Life (Basel) 2021 Jul 17;11(7). Epub 2021 Jul 17.

Lab of Pharmacology, College of Pharmacy, Dongduk Women's University, Seoul 02748, Korea.

Abnormal and excessive nitrosative stress contributes to neurodegenerative disease associated with the production of pathological levels of misfolded proteins. The accumulated findings strongly suggest that excessive NO production can induce and deepen these pathological processes, particularly by the S-nitrosylation of target proteins. Therefore, the relationship between S-nitrosylated proteins and the accumulation of misfolded proteins was reviewed. We particularly focused on the S-nitrosylation of E3-ubiquitin-protein ligase, parkin, and endoplasmic reticulum chaperone, PDI, which contribute to the accumulation of misfolded proteins. In addition to the target proteins being S-nitrosylated, NOS, which produces NO, and GSNOR, which inhibits S-nitrosylation, were also suggested as potential therapeutic targets for protein misfolding-associated diseases.
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http://dx.doi.org/10.3390/life11070705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304259PMC
July 2021

Instant, multiscale dry transfer printing by atomic diffusion control at heterogeneous interfaces.

Sci Adv 2021 Jul 9;7(28). Epub 2021 Jul 9.

Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, South Korea.

Transfer printing is a technique that integrates heterogeneous materials by readily retrieving functional elements from a grown substrate and subsequently printing them onto a specific target site. These strategies are broadly exploited to construct heterogeneously integrated electronic devices. A typical wet transfer printing method exhibits limitations related to unwanted displacement and shape distortion of the device due to uncontrollable fluid movement and slow chemical diffusion. In this study, a dry transfer printing technique that allows reliable and instant release of devices by exploiting the thermal expansion mismatch between adjacent materials is demonstrated, and computational studies are conducted to investigate the fundamental mechanisms of the dry transfer printing process. Extensive exemplary demonstrations of multiscale, sequential wet-dry, circuit-level, and biological topography-based transfer printing demonstrate the potential of this technique for many other emerging applications in modern electronics that have not been achieved through conventional wet transfer printing over the past few decades.
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http://dx.doi.org/10.1126/sciadv.abh0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270493PMC
July 2021

Subthreshold electrical stimulation as a low power electrical treatment for stroke rehabilitation.

Sci Rep 2021 Jul 7;11(1):14048. Epub 2021 Jul 7.

Brain Engineering Convergence Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea.

As a promising future treatment for stroke rehabilitation, researchers have developed direct brain stimulation to manipulate the neural excitability. However, there has been less interest in energy consumption and unexpected side effect caused by electrical stimulation to bring functional recovery for stroke rehabilitation. In this study, we propose an engineering approach with subthreshold electrical stimulation (STES) to bring functional recovery. Here, we show a low level of electrical stimulation boosted causal excitation in connected neurons and strengthened the synaptic weight in a simulation study. We found that STES with motor training enhanced functional recovery after stroke in vivo. STES was shown to induce neural reconstruction, indicated by higher neurite expression in the stimulated regions and correlated changes in behavioral performance and neural spike firing pattern during the rehabilitation process. This will reduce the energy consumption of implantable devices and the side effects caused by stimulating unwanted brain regions.
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http://dx.doi.org/10.1038/s41598-021-93354-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263745PMC
July 2021

Isolated Traumatic Dislocation of the Malleus into the External Auditory Canal.

Ear Nose Throat J 2021 Jun 30:1455613211026529. Epub 2021 Jun 30.

Department of Otorhinolaryngology-Head and Neck Surgery, Chosun University College of Medicine, Gwangju, Republic of Korea.

We report a rare case of isolated malleus dislocation into the external auditory canal with lateralized intact tympanic membrane following a head trauma. The patient was a 63-year-old woman who presented at the outpatient department of our institute with hearing loss of 10 years' duration after a bicycle accident. During physical examination of the patient, total dislocation of the malleus-like bony structure into the external auditory canal on the right side was observed. In the computed tomography scan, an isolated malleus dislocation with intact incus-stapes articulation was identified. The patient was successfully treated with endoscopic exploratory tympanotomy and partial ossicular replacement prosthesis. The isolated malleus dislocation can rarely occur after trauma. A careful diagnostic step through history, physical examination, and temporal bone computed tomography scan are needed to confirm this rare condition.
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http://dx.doi.org/10.1177/01455613211026529DOI Listing
June 2021

Molecular Interactions between Two LMP2A PY Motifs of EBV and WW Domains of E3 Ubiquitin Ligase AIP4.

Life (Basel) 2021 Apr 22;11(5). Epub 2021 Apr 22.

The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 08826, Korea.

Interactions involving Epstein-Barr virus (EBV) LMP2A and Nedd4 family E3 ubiquitin-protein ligases promote the ubiquitination of LMP2A-associated proteins, which results in the perturbation of normal B-cell signaling. Here, we solved the solution structure of the WW2 domain of hAIP4 and investigated the binding mode involving the N-terminal domain of LMP2A and the WW2 domain. The WW2 domain presented a conserved WW domain scaffold with a three-stranded anti-parallel β-sheet and bound two PY motifs via different binding mechanisms. Our NMR titration and ITC data demonstrated that the PY motifs of LMP2A can recognize and interact weakly with the XP groove of the WW2 domain (residues located around the third β-strand), and then residues between two PY motifs optimize the binding by interacting with the loop 1 region of the WW2 domain. In particular, the residue Val15 in the hairpin loop region between β1 and β2 of the WW2 domain exhibited unique changes depending on the terminal residues of the PY motif. This result suggested that the hairpin loop is responsible for additional interactions outside the XP groove, and this hypothesis was confirmed in a deuterium exchange experiment. These weak but wide interactions can stabilize the complex formed between the PY and WW domains.
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http://dx.doi.org/10.3390/life11050379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190631PMC
April 2021

Tactile Avatar: Tactile Sensing System Mimicking Human Tactile Cognition.

Adv Sci (Weinh) 2021 04 8;8(7):2002362. Epub 2021 Feb 8.

Department of Information and Communication Engineering Daegu Gyeongbuk Institute of Science & Technology (DGIST) Daegu 711-873 Korea.

As a surrogate for human tactile cognition, an artificial tactile perception and cognition system are proposed to produce smooth/soft and rough tactile sensations by its user's tactile feeling; and named this system as "tactile avatar". A piezoelectric tactile sensor is developed to record dynamically various physical information such as pressure, temperature, hardness, sliding velocity, and surface topography. For artificial tactile cognition, the tactile feeling of humans to various tactile materials ranging from smooth/soft to rough are assessed and found variation among participants. Because tactile responses vary among humans, a deep learning structure is designed to allow personalization through training based on individualized histograms of human tactile cognition and recording physical tactile information. The decision error in each avatar system is less than 2% when 42 materials are used to measure the tactile data with 100 trials for each material under 1.2N of contact force with 4cm s of sliding velocity. As a tactile avatar, the machine categorizes newly experienced materials based on the tactile knowledge obtained from training data. The tactile sensation showed a high correlation with the specific user's tendency. This approach can be applied to electronic devices with tactile emotional exchange capabilities, as well as advanced digital experiences.
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http://dx.doi.org/10.1002/advs.202002362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024994PMC
April 2021

Receptor for Advanced Glycation End Products Is Involved in LPA-Mediated Brain Damage after a Transient Ischemic Stroke.

Life (Basel) 2021 Jan 22;11(2). Epub 2021 Jan 22.

College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea.

Lysophosphatidic acid receptor 5 (LPA) has been recently identified as a novel pathogenic factor for brain ischemic stroke. However, its underlying mechanisms remain unclear. Here, we determined whether the receptor for advanced glycation end products (RAGE) could be involved in LPA-mediated brain injuries after ischemic challenge using a mouse model of transient middle cerebral artery occlusion (tMCAO). RAGE was upregulated in the penumbra and ischemic core regions after tMCAO challenge. RAGE upregulation was greater at 3 days than that at 1 day after tMCAO challenge. It was mostly observed in Iba1-immunopositive cells of a post-ischemic brain. Suppressing LPA activity with its antagonist, TCLPA5, attenuated RAGE upregulation in the penumbra and ischemic core regions, particularly on Iba1-immunopositive cells, of injured brains after tMCAO challenge. It also attenuated blood-brain barrier disruption, one of the core pathogenesis upon RAGE activation, after tMCAO challenge. As an underlying signaling pathways, LPA could contribute to the activation of ERK1/2 and NF-κB in injured brains after tMCAO challenge. Collectively, the current study suggests that RAGE is a possible mediator for LPA-dependent ischemic brain injury.
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http://dx.doi.org/10.3390/life11020080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910825PMC
January 2021

REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment.

Int J Mol Sci 2020 Dec 13;21(24). Epub 2020 Dec 13.

Department of Health Sciences, The Graduate School of Dong-A University, Dong-A University, Busan 49315, Korea.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy.
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http://dx.doi.org/10.3390/ijms21249482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763153PMC
December 2020

Akt and calcium-permeable AMPA receptor are involved in the effect of pinoresinol on amyloid β-induced synaptic plasticity and memory deficits.

Biochem Pharmacol 2021 02 11;184:114366. Epub 2020 Dec 11.

Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Republic of Korea; Laboratory of Anti-viral Drug Discovery, Dong-A University, Busan, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, Republic of Korea. Electronic address:

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by memory deficits. Although no drug has given promising results, synaptic dysfunction-modulating agents might be considered potential candidates for alleviating this disorder. Pinoresinol, a lignan found in Forsythia suspensa, is a memory-enhancing agent with excitatory synaptic activation. In the present study, we tested whether pinoresinol reduces learning and memory and excitatory synaptic deficits in an amyloid β (Aβ)-induced AD-like mouse model. Pinoresinol enhanced hippocampal long-term potentiation (LTP) through calcium-permeable AMPA receptor, which was mediated by Akt activation. Moreover, pinoresinol ameliorated LTP deficits in amyloid β (Aβ)-treated hippocampal slices via Akt signaling. Oral administration of pinoresinol ameliorated Aβ-induced memory deficits without sensory dysfunction. Moreover, AD-like pathology, including neuroinflammation and synaptic deficit, were ameliorated by pinoresinol administration. Collectively, pinoresinol may be a good candidate for AD therapy by modulating synaptic functions.
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http://dx.doi.org/10.1016/j.bcp.2020.114366DOI Listing
February 2021

Doxorubicin-Loaded PLGA Nanoparticles for Cancer Therapy: Molecular Weight Effect of PLGA in Doxorubicin Release for Controlling Immunogenic Cell Death.

Pharmaceutics 2020 Nov 29;12(12). Epub 2020 Nov 29.

KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea.

Direct local delivery of immunogenic cell death (ICD) inducers to a tumor site is an attractive approach for leading ICD effectively, due to enabling the concentrated delivery of ICD inducers to the tumor site. Herein, we prepared doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using different molecular weight PLGA (7000 g/mol and 12,000 g/mol), showing different drug release kinetics. The different release kinetics of DOX might differently stimulate a tumor cell-specific immune response by releasing damage-associated molecular patterns (DAMPs), resulting in showing a different antitumor response in the living body. DOX-PLGA NPs showed faster DOX release kinetics than DOX-PLGA NPs in the physiological condition. DOX-PLGA NPs and DOX-PLGA NPs were successfully taken up by the CT-26 tumor cells, subsequently showing different DOX localization times at the nucleus. Released DOX successfully lead to cytotoxicity and HMGB1 release in vitro. Although the DOX-PLGA NPs and DOX-PLGA NPs showed different sustained DOX release kinetics in vitro, tumor growth of the CT-26 tumor was similarly inhibited for 28 days post-direct tumor injection. Furthermore, the immunological memory effect was successfully established by the ICD-based tumor-specific immune responses, including DC maturation and tumor infiltration of cytotoxic T lymphocytes (CTLs). We expect that the controlled release of ICD-inducible chemotherapeutic agents, using different types of nanomedicines, can provide potential in precision cancer immunotherapy by controlling the tumor-specific immune responses, thus improving the therapeutic efficacy.
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http://dx.doi.org/10.3390/pharmaceutics12121165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759870PMC
November 2020

NLRP3 Inflammasome Activation Is Involved in LPA-Mediated Brain Injury after Transient Focal Cerebral Ischemia.

Int J Mol Sci 2020 Nov 14;21(22). Epub 2020 Nov 14.

Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea.

Lysophosphatidic acid receptor 1 (LPA) contributes to brain injury following transient focal cerebral ischemia. However, the mechanism remains unclear. Here, we investigated whether nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation might be an underlying mechanism involved in the pathogenesis of brain injury associated with LPA following ischemic challenge with transient middle cerebral artery occlusion (tMCAO). Suppressing LPA activity by its antagonist attenuated NLRP3 upregulation in the penumbra and ischemic core regions, particularly in ionized calcium-binding adapter molecule 1 (Iba1)-expressing cells like macrophages of mouse after tMCAO challenge. It also suppressed NLRP3 inflammasome activation, such as caspase-1 activation, interleukin 1β (IL-1β) maturation, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, in a post-ischemic brain. The role of LPA in NLRP3 inflammasome activation was confirmed in vitro using lipopolysaccharide-primed bone marrow-derived macrophages, followed by LPA exposure. Suppressing LPA activity by either pharmacological antagonism or genetic knockdown attenuated NLRP3 upregulation, caspase-1 activation, IL-1β maturation, and IL-1β secretion in these cells. Furthermore, nuclear factor-κB (NF-κB), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 were found to be LPA-dependent effector pathways in these cells. Collectively, results of the current study first demonstrate that LPA could contribute to ischemic brain injury by activating NLRP3 inflammasome with underlying effector mechanisms.
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http://dx.doi.org/10.3390/ijms21228595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697439PMC
November 2020

Identifying potential biomarkers related to pre-term delivery by proteomic analysis of amniotic fluid.

Sci Rep 2020 11 12;10(1):19648. Epub 2020 Nov 12.

Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam, 463-707, Korea.

We sought to identify biomarkers in the amniotic fluid (AF) and specific signaling pathways related to spontaneous preterm delivery (SPTD, < 34 weeks) in women with preterm labor (PTL) without intra-uterine infection/inflammation (IUI). This was a retrospective cohort study of a total of 139 PTL women with singleton gestation (24 + 0 to 32 + 6 weeks) who underwent amniocentesis and who displayed no evidence of IUI. A nested case-control was conducted using pooled AF samples (n = 20) analyzed via label-free liquid chromatography-tandem mass spectrometry. In the total cohort, an ELISA validation study was performed for seven candidate proteins of interest. Proteomic analysis identified 77 differentially expressed proteins (DEPs, P < 0.05) in the AF from SPTD cases compared to term delivery controls. ELISA validation confirmed that women who had an SPTD before 34 weeks had significantly independently lower levels of VEGFR-1 and higher levels of lipocalin-2 and the Fc fragment of IgG binding protein in the AF. Five principle pathways associated with the 77 DEPs were identified, including glycolysis, gluconeogenesis, and iron homeostasis. The proteomic analysis data of AFs from women with PTL identified several novel biomarkers and specific protein pathways related to SPTD in the absence of IUI.
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http://dx.doi.org/10.1038/s41598-020-76748-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665029PMC
November 2020

BMS-986020, a Specific LPA Antagonist, Provides Neuroprotection against Ischemic Stroke in Mice.

Antioxidants (Basel) 2020 Nov 8;9(11). Epub 2020 Nov 8.

Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea.

Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA) antagonist under clinical trials for lung fibrosis and psoriasis, against both acute and sub-acute injuries after ischemic stroke by employing a mouse model with transient middle cerebral artery occlusion (tMCAO). BMS administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, neurological deficits, and cell apoptosis at day 1 after tMCAO. Neuroprotective effects of BMS were preserved even when administered at 3 h after reperfusion. Neuroprotection by BMS against acute injuries was associated with attenuation of microglial activation and lipid peroxidation in post-ischemic brains. Notably, repeated BMS administration daily for 14 days after tMCAO exerted long-term neuroprotection in tMCAO-challenged mice, as evidenced by significantly attenuated neurological deficits and improved survival rate. It also attenuated brain tissue loss and cell apoptosis in post-ischemic brains. Mechanistically, it significantly enhanced neurogenesis and angiogenesis in injured brains. A single administration of BMS provided similar long-term neuroprotection except survival rate. Collectively, BMS provided neuroprotection against both acute and sub-acute injuries of ischemic stroke, indicating that BMS might be an appealing therapeutic agent to treat ischemic stroke.
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http://dx.doi.org/10.3390/antiox9111097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695306PMC
November 2020

Impaired Hand Dexterity Function in a Non-human Primate Model with Chronic Parkinson's Disease.

Exp Neurobiol 2020 Oct;29(5):376-388

National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Korea.

Symptoms of Parkinson's disease (PD) caused by loss of dopaminergic neurons are accompanied by movement disorders, including tremors, rigidity, bradykinesia, and akinesia. Non-human primate (NHP) models with PD play an essential role in the analysis of PD pathophysiology and behavior symptoms. As impairments of hand dexterity function can affect activities of daily living in patients with PD, research on hand dexterity function in NHP models with chronic PD is essential. Traditional rating scales previously used in the evaluation of animal spontaneous behavior were insufficient due to factors related to subjectivity and passivity. Thus, experimentally designed applications for an appropriate apparatus are necessary. In this study, we aimed to longitudinally assess hand dexterity function using hand dexterity task (HDT) in NHP-PD models. To validate this assessment, we analyzed the alteration in Parkinsonian tremor signs and the functionality of presynaptic dopaminergic neuron using positron emission tomography imaging of dopamine transporters in these models. In addition, a significant inverse correlation between HDT and DAT level was identified, but no local bias was found. The correlation with intention tremor signs was lower than the resting tremor. In conclusion, the evaluation of HDT may reflect behavioral symptoms of NHP-PD models. Furthermore, HDT was effectively used to experimentally distinguish intention tremors from other tremors.
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http://dx.doi.org/10.5607/en20040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649085PMC
October 2020

Brain energy metabolism and multiple sclerosis: progress and prospects.

Arch Pharm Res 2020 Oct 29;43(10):1017-1030. Epub 2020 Oct 29.

College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, Korea.

Multiple sclerosis (MS) is an autoimmune disease accompanied with nerve pain and paralysis. Although various pathogenic causes of MS have been suggested, including genetic and environmental factors, how MS occurs remains unclear. Moreover, MS should be diagnosed based on clinical experiences because of no disease-specific biomarker and currently available treatments for MS just can reduce relapsing frequency or severity with little effects on disease disability. Therefore, more efforts are required to identify pathophysiology of MS and diagnosis markers. Recent evidence indicates another aspect of MS pathogenesis, energy failure in the central nervous system (CNS). For instance, inflammation that is a characteristic MS symptom and occurs frequently in the CNS of MS patients can result into energy failure in mitochondria and cytosol. Indeed, metabolomics studies for MS have reported energy failure in oxidative phosphorylation and alteration of aerobic glycolysis. Therefore, studies on the metabolism in the CNS may provide another insight for understanding complexity of MS and pathogenesis, which would facilitate the discovery of promising strategies for developing therapeutics to treat MS. This review will provide an overview on recent progress of metabolomic studies for MS, with a focus on the fluctuation of energy metabolism in MS.
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http://dx.doi.org/10.1007/s12272-020-01278-3DOI Listing
October 2020

Inhibition of LPA Activity Provides Long-Term Neuroprotection in Mice with Brain Ischemic Stroke.

Biomol Ther (Seoul) 2020 Nov;28(6):512-518

College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.

Stroke is a leading cause of long-term disability in ischemic survivors who are suffering from motor, cognitive, and memory impairment. Previously, we have reported suppressing LPA activity with its specific antagonist can attenuate acute brain injuries after ischemic stroke. However, it is unclear whether suppressing LPA activity can also attenuate chronic brain injuries after ischemic stroke. Here, we explored whether effects of LPA antagonist, TCLPA, could persist a longer time after brain ischemic stroke using a mouse model challenged with tMCAO. TCLPA was administered to mice every day for 3 days, starting from the time immediately after reperfusion. TCLPA administration improved neurological function up to 21 days after tMCAO challenge. It also reduced brain tissue loss and cell apoptosis in mice at 21 days after tMCAO challenge. Such long-term neuroprotection of TCLPA was associated with enhanced neurogenesis and angiogenesis in post-ischemic brain, along with upregulated expression levels of vascular endothelial growth factor. Collectively, results of the current study indicates that suppressing LPA activity can provide long-term neuroprotection to mice with brain ischemic stroke.
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http://dx.doi.org/10.4062/biomolther.2020.159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585638PMC
November 2020

Sphingosine 1-Phosphate Receptors in Cerebral Ischemia.

Neuromolecular Med 2021 03 10;23(1):211-223. Epub 2020 Sep 10.

College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Inchon, 21936, Republic of Korea.

Sphingosine 1-phosphate (S1P) is an important lipid biomolecule that exerts pleiotropic cellular actions as it binds to and activates its five G-protein-coupled receptors, S1P. Through these receptors, S1P can mediate diverse biological activities in both healthy and diseased conditions. S1P is produced by S1P-producing enzymes, sphingosine kinases (SphK1 and SphK2), and is abundantly present in different organs, including the brain. The medically important roles of receptor-mediated S1P signaling are well characterized in multiple sclerosis because FTY720 (Gilenya™, Novartis), a non-selective S1P receptor modulator, is currently used as a treatment for this disease. In cerebral ischemia, its role is also notable because of FTY720's efficacy in both rodent models and human patients with cerebral ischemia. In particular, some of the S1P receptors, including S1P, S1P, and S1P, have been identified as pathogenic players in cerebral ischemia. Other than these receptors, S1P itself and S1P-producing enzymes have been shown to play certain roles in cerebral ischemia. This review aims to compile the current updates and overviews about the roles of S1P signaling, along with a focus on S1P receptors in cerebral ischemia, based on recent studies that used in vivo rodent models of cerebral ischemia.
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http://dx.doi.org/10.1007/s12017-020-08614-2DOI Listing
March 2021

Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages.

Cells 2020 07 22;9(8). Epub 2020 Jul 22.

College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea.

The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA upregulation in injured skin. Suppressing the activity of LPA with TCLPA5, a selective LPA antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1β maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA knockdown. Overall, our findings establish a pathogenic role of LPA in psoriasis along with an underlying mechanism, further suggesting LPA antagonism as a potential strategy to treat psoriasis.
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http://dx.doi.org/10.3390/cells9081753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465035PMC
July 2020

Lysophosphatidic Acid Receptor 5 Plays a Pathogenic Role in Brain Damage after Focal Cerebral Ischemia by Modulating Neuroinflammatory Responses.

Cells 2020 06 10;9(6). Epub 2020 Jun 10.

College of Pharmacy, Gachon University, Incheon 21936, Korea.

Receptor-mediated lysophosphatidic acid (LPA) signaling has come to be considered an important event for various diseases. In cerebral ischemia, LPA has recently been identified as a receptor subtype that mediates brain injury, but the roles of other LPA receptor subtypes remain unknown. Here, we investigated the potential role of LPA as a novel pathogenic factor for cerebral ischemia using a mouse model of transient middle cerebral artery occlusion (tMCAO). LPA was upregulated in the ischemic core region after tMCAO challenge, particularly in activated microglia. When TCLPA5, a selective LPA antagonist, was given to tMCAO-challenged mice immediately after reperfusion, brain damage, including brain infarction, functional neurological deficit, and neuronal and non-neuronal apoptosis, was reduced in mice. Similarly, delayed TCLPA5 administration (at three hours after reperfusion) reduced brain infarction and neurological deficit. The histological results demonstrated that TCLPA5 administration attenuated microglial activation, as evidenced by the decreased Iba1 immunoreactivities, the number of amoeboid cells, and proliferation in an injured brain. TCLPA5 administration also attenuated the upregulation of the expression of pro-inflammatory cytokines at mRNA levels in post-ischemic brain, which was also observed in lipopolysaccharide-stimulated BV2 microglia upon LPA knockdown. Overall, this study identifies LPA as a novel pathogenic factor for cerebral ischemia, further implicating it as a promising target for drug development to treat this disease.
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http://dx.doi.org/10.3390/cells9061446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348986PMC
June 2020

Peripheral natural killer cells and myeloid-derived suppressor cells correlate with anti-PD-1 responses in non-small cell lung cancer.

Sci Rep 2020 06 3;10(1):9050. Epub 2020 Jun 3.

Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Korea.

Inhibition of immune checkpoint proteins like programmed death 1 (PD-1) is a promising therapeutic approach for several cancers, including non-small cell lung cancer (NSCLC). Although PD-1 ligand (PD-L1) expression is used to predict anti-PD-1 therapy responses in NSCLC, its accuracy is relatively less. Therefore, we sought to identify a more accurate predictive blood biomarker for evaluating anti-PD-1 response. We evaluated the frequencies of T cells, B cells, natural killer (NK) cells, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), mononuclear myeloid-derived suppressor cells (M-MDSCs), and Lox-1 PMN-MDSCs in peripheral blood samples of 62 NSCLC patients before and after nivolumab treatment. Correlation of immune-cell population frequencies with treatment response, progression-free survival, and overall survival was also determined. After the first treatment, the median NK cell percentage was significantly higher in responders than in non-responders, while the median Lox-1+ PMN-MDSC percentage showed the opposite trend. NK cell frequencies significantly increased in responders but not in non-responders. NK cell frequency inversely correlated with that of Lox-1 PMN-MDSCs after the first treatment cycle. The NK cell-to-Lox-1 PMN-MDSC ratio (NMR) was significantly higher in responders than in non-responders. Patients with NMRs ≥ 5.75 after the first cycle had significantly higher objective response rates and longer progression-free and overall survival than those with NMRs <5.75. NMR shows promise as an early predictor of response to further anti-PD-1 therapy.
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http://dx.doi.org/10.1038/s41598-020-65666-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270107PMC
June 2020

Roles of GABA receptor α5 subunit on locomotion and working memory in transient forebrain ischemia in mice.

Prog Neuropsychopharmacol Biol Psychiatry 2020 08 16;102:109962. Epub 2020 May 16.

Department of Life and Nanopharmaceutical Sciences, Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

The γ-aminobutyric acid A (GABA) receptor, which contains a chloride channel, is a typical inhibitory neurotransmitter receptor in the central nervous system. Although the GABAergic neurotransmitter system has been discovered to be involved in various psychological behaviors, such as anxiety, convulsions, and cognitive function, its functional changes under conditions of ischemic pathological situation are still uncovered. In the present study, we attempted to elucidate the functional changes in the GABAergic system after transient forebrain ischemia in mice. A bilateral common carotid artery occlusion for 20 min was used to establish a model of transient forebrain ischemia/reperfusion (tI/R). Delayed treatment with diazepam, a positive allosteric modulator of the GABA receptor, increased locomotor activity in the open field test and spontaneous alternations in the Y-maze test in tI/R mice, but not in shams. Delayed treatment with diazepam did not alter neuronal death or the number of GABAergic neurons in tI/R mice. However, tI/R induced changes in the protein levels of GABA receptor subunits in the hippocampus. In particular, the most marked increase in the tI/R group was found in the level of α5 subunit of the GABA receptor. Similar to delayed treatment with diazepam, delayed treatment with imidazenil, an α5-sensitive benzodiazepine, increased spontaneous alternations in the Y-maze in tI/R mice, whereas zolpidem, an α5-insensitive benzodiazepine, failed to show such effects. These results suggest that tI/R-induced changes in the level of the α5 subunit of the GABA receptor can alter the function of GABAergic drugs in a mouse model of forebrain ischemia.
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http://dx.doi.org/10.1016/j.pnpbp.2020.109962DOI Listing
August 2020

Prefrontal functional connectivity analysis of cognitive decline for early diagnosis of mild cognitive impairment: a functional near-infrared spectroscopy study.

Biomed Opt Express 2020 Apr 2;11(4):1725-1741. Epub 2020 Mar 2.

Department of Information and Communication Engineering, DGIST, Daegu 42988, South Korea.

Cognitive decline (CD) is a major symptom of mild cognitive impairment (MCI). Patients with MCI have an increased likelihood of developing Alzheimer's disease (AD). Although a cure for AD is currently lacking, medication therapies and/or daily training in the early stage can alleviate disease progression and improve patients' quality of life. Accordingly, investigating CD-related biomarkers via brain imaging devices is crucial for early diagnosis. In particular, "portable" brain imaging devices enable frequent diagnostic checks as a routine clinical tool, and therefore increase the possibility of early AD diagnosis. This study aimed to comprehensively investigate functional connectivity (FC) in the prefrontal cortex measured by a portable functional near-infrared spectroscopy (fNIRS) device during a working memory (WM) task known as the delayed matching to sample (DMTS) task. Differences in prefrontal FC between healthy control (HC) ( = 23) and CD groups ( = 23) were examined. Intra-group analysis (one-sample -test) revealed significantly greater prefrontal FC, especially left- and inter-hemispheric FC, in the CD group than in the HC. These observations could be due to a compensatory mechanism of the prefrontal cortex caused by hippocampal degeneration. Inter-group analysis (unpaired two-sample -test) revealed significant intergroup differences in left- and inter-hemispheric FC. These attributes may serve as a novel biomarker for early detection of MCI. In addition, our findings imply that portable fNIRS devices covering the prefrontal cortex may be useful for early diagnosis of MCI.
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http://dx.doi.org/10.1364/BOE.382197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173911PMC
April 2020

Proteomic Analysis of Amniotic Fluid Proteins for Predicting the Outcome of Emergency Cerclage in Women with Cervical Insufficiency.

Reprod Sci 2020 06 6;27(6):1318-1329. Epub 2020 Jan 6.

Departments of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.

We aimed to identify novel biomarkers in amniotic fluid (AF) that predict the outcome of emergency cerclage in women with cervical insufficiency. This retrospective cohort study included 40 singleton pregnant women who received emergency cerclage for cervical insufficiency (17-25 weeks) and underwent amniocentesis. Label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify AF proteins in pooled samples (n = 16) using a nested case-control approach. The six candidate biomarkers of interest were validated by enzyme-linked immunosorbent assays (ELISA) in the final cohort (n = 40). The differentially expressed proteins (DEPs) were analyzed by pathway analysis software. The primary outcome measure was failure of emergency cerclage [defined as spontaneous preterm delivery (SPTD) at < 34 weeks of gestation after cerclage placement]. Sixty-eight proteins were differentially expressed (P < 0.001) in AF from SPTD cases and near-term controls, of which 44 (64.7%) were upregulated and 24 (35.3%) were downregulated. Validation by ELISA confirmed that AF from women with cerclage failure contained significantly higher levels of myeloperoxidase, lactoferrin, glucose-6-phosphate isomerase, lipocalin-2, and lymphocyte cytosolic protein 1, the first four of which were independent of cervical dilatation at presentation. The five pathways with the most differentially regulated proteins were actin cytoskeleton signaling, acute phase response signaling, ILK signaling, glycolysis, and gluconeogenesis. Proteomic analyses of AF in this study identified DEPs and specific protein pathways related to poor prognosis after emergency cerclage for cervical insufficiency. Four novel independent biomarkers in AF for cerclage failure have been identified using proteomics.
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http://dx.doi.org/10.1007/s43032-019-00110-8DOI Listing
June 2020

Dracocephalum moldavica attenuates scopolamine-induced cognitive impairment through activation of hippocampal ERK-CREB signaling in mice.

J Ethnopharmacol 2020 May 6;253:112651. Epub 2020 Feb 6.

School of Natural Resources and Environmental Sciences, Kangwon National University, Chuncheon, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Dracocephalum moldavica (Moldavian balm) has been traditionally used for the treatment of intellectual disabilities, migraines and cardiovascular problems in East Asia. Recent scientific studies have demonstrated the usefulness of this plant to treat neurodegenerative disorders, including Alzheimer's disease.

Aim Of The Study: This study aimed to investigate the effects of the ethanolic extract of D. moldavica leaves (EEDM) on scopolamine-induced cognitive impairment in mice and the underlying mechanisms of action.

Materials And Methods: The behavioral effects of EEDM were examined using the step-through passive avoidance and Morris water maze tasks. To elucidate the underlying mechanism, we tested whether EEDM affects acetylcholinesterase activity and the expression of memory-related signaling molecules including extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus.

Results: EEDM (25, 50 or 100 mg/kg) significantly ameliorated the scopolamine-induced step-through latency reduction in the passive avoidance task in mice. In the Morris water maze task, EEDM (50 mg/kg) significantly attenuated scopolamine-induced memory impairment. Furthermore, the administration of EEDM increased the phosphorylation levels of ERK and CREB in the hippocampus but did not alter acetylcholinesterase activity.

Conclusions: These findings suggest that EEDM significantly attenuates scopolamine-induced memory impairment in mice and may be a promising therapeutic agent for improving memory impairment.
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http://dx.doi.org/10.1016/j.jep.2020.112651DOI Listing
May 2020

S1P contributes to microglial activation and M1 polarization following cerebral ischemia through ERK1/2 and JNK.

Sci Rep 2019 08 20;9(1):12106. Epub 2019 Aug 20.

College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, Republic of Korea.

Sphingosine 1-phosphate (S1P) signaling has emerged as a drug target in cerebral ischemia. Among S1P receptors, S1P was recently identified to mediate ischemic brain injury. But, pathogenic mechanisms are not fully identified, particularly in view of microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed whether microglial activation is the pathogenesis of S1P-mediated brain injury in mice challenged with transient middle cerebral artery occlusion (tMCAO). To suppress S1P activity, its specific antagonist, JTE013 was given orally to mice immediately after reperfusion. JTE013 administration reduced the number of activated microglia and reversed their morphology from amoeboid to ramified microglia in post-ischemic brain after tMCAO challenge, along with attenuated microglial proliferation. Moreover, JTE013 administration attenuated M1 polarization in post-ischemic brain. This S1P-directed M1 polarization appeared to occur in activated microglia, which was evidenced upon JTE013 exposure in vivo as suppressed M1-relevant NF-κB activation in activated microglia of post-ischemic brain. Moreover, JTE013 exposure or S1P knockdown reduced expression levels of M1 markers in vitro in lipopolysaccharide-driven M1 microglia. Additionally, suppressing S1P activity attenuated activation of M1-relevant ERK1/2 and JNK in post-ischemic brain or lipopolysaccharide-driven M1 microglia. Overall, our study demonstrated that S1P regulated microglial activation and M1 polarization in post-ischemic brain.
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http://dx.doi.org/10.1038/s41598-019-48609-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702157PMC
August 2019

Lysophosphatidic acid receptor 1 (LPA) plays critical roles in microglial activation and brain damage after transient focal cerebral ischemia.

J Neuroinflammation 2019 Aug 20;16(1):170. Epub 2019 Aug 20.

Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Yeonsu-gu, Incheon, 406-799, Republic of Korea.

Background: Lysophosphatidic acid receptor 1 (LPA) is in the spotlight because its synthetic antagonist has been under clinical trials for lung fibrosis and psoriasis. Targeting LPA might also be a therapeutic strategy for cerebral ischemia because LPA triggers microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed this possibility using a mouse model of transient middle cerebral artery occlusion (tMCAO).

Methods: To address the role of LPA in the ischemic brain damage, we used AM095, a selective LPA antagonist, as a pharmacological tool and lentivirus bearing a specific LPA shRNA as a genetic tool. Brain injury after tMCAO challenge was accessed by determining brain infarction and neurological deficit score. Role of LPA in tMCAO-induced microglial activation was ascertained by immunohistochemical analysis. Proinflammatory responses in the ischemic brain were determined by qRT-PCR and immunohistochemical analyses, which were validated in vitro using mouse primary microglia. Activation of MAPKs and PI3K/Akt was determined by Western blot analysis.

Results: AM095 administration immediately after reperfusion attenuated brain damage such as brain infarction and neurological deficit at 1 day after tMCAO, which was reaffirmed by LPA shRNA lentivirus. AM095 administration also attenuated brain infarction and neurological deficit at 3 days after tMCAO. LPA antagonism attenuated microglial activation; it reduced numbers and soma size of activated microglia, reversed their morphology into less toxic one, and reduced microglial proliferation. Additionally, LPA antagonism reduced mRNA expression levels of proinflammatory cytokines and suppressed NF-κB activation, demonstrating its regulatory role of proinflammatory responses in the ischemic brain. Particularly, these LPA-driven proinflammatory responses appeared to occur in activated microglia because NF-κB activation occurred mainly in activated microglia in the ischemic brain. Regulatory role of LPA in proinflammatory responses of microglia was further supported by in vitro findings using lipopolysaccharide-stimulated cultured microglia, showing that suppressing LPA activity reduced mRNA expression levels of proinflammatory cytokines. In the ischemic brain, LPA influenced PI3K/Akt and MAPKs; suppressing LPA activity decreased MAPK activation and increased Akt phosphorylation.

Conclusion: This study demonstrates that LPA is a new etiological factor for cerebral ischemia, strongly indicating that its modulation can be a potential strategy to reduce ischemic brain damage.
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http://dx.doi.org/10.1186/s12974-019-1555-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701099PMC
August 2019

Danshensu attenuates scopolamine and amyloid-β-induced cognitive impairments through the activation of PKA-CREB signaling in mice.

Neurochem Int 2019 12 16;131:104537. Epub 2019 Aug 16.

School of Natural Resources and Environmental Sciences, Kangwon National University, Chuncheon, Republic of Korea. Electronic address:

Alzheimer's disease (AD) is an important chronic neurodegenerative disorder and is mainly associated with cognitive dysfunction. At present, bioactive compounds from traditional medicinal plants have received much attention for the enhancement of cognitive function. Danshensu, a phenolic acid isolated from herbal medicines, has various pharmacological activities in the central nervous system, including anxiolytic-like and neuroprotective properties. The present study aimed to investigate the ameliorating effects of danshensu on scopolamine- and amyloid-β (Aβ) protein-induced cognitive impairments in mice. Danshensu (3 and 10 mg/kg, p.o.) effectively ameliorated scopolamine-induced cognitive dysfunction in mice, as measured in passive avoidance and Y-maze tasks. In a mechanistic study, danshensu inhibited monoamine oxidase A (MAO-A) activity but not MAO-B. Additionally, danshensu treatment increased the dopamine level and the phosphorylation levels of protein kinase A (PKA) and cAMP response element binding protein (CREB), in the cortex of the brain. Furthermore, the ameliorating effect of danshensu against scopolamine-induced cognitive impairment was fully blocked by H89, a PKA inhibitor. Finally, danshensu also ameliorated Aβ-induced cognitive impairments in an animal model of AD. The results revealed that danshensu treatment significantly improved scopolamine and Aβ-induced cognitive impairments in mice by facilitation of dopamine signaling cascade such as PKA and CREB due to MAO-A inhibition. Thus, danshensu could be used as a promising therapeutic agent for preventing and treating AD.
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http://dx.doi.org/10.1016/j.neuint.2019.104537DOI Listing
December 2019

Electronic Skin to Feel "Pain": Detecting "Prick" and "Hot" Pain Sensations.

Soft Robot 2019 12 23;6(6):745-759. Epub 2019 Jul 23.

Department of Information and Communication Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Korea.

An artificial tactile system has attracted tremendous interest and intensive study, since it can be applied as a new functional interface between humans and electronic devices. Unfortunately, most previous works focused on improving the sensitivity of sensors. However, humans also respond to psychological feelings for sensations such as pain, softness, or roughness, which are important factors for interacting with others and objects. Here, we present an electronic skin concept that generates a "pain" warning signal, specifically, to sharp "prick" and "hot" sensations. To simplify the sensor structure for these two feelings, a single-body tactile sensor design is proposed. By exploiting "hot" feeling based on the Seebeck effect instead of the pyroelectric property, it is possible to distinguish points registering a "hot" feeling from those generating a "prick" feeling, which is based on the piezoelectric effect. The control of free carrier concentration in nanowire induced the appropriate level of Seebeck current, which enabled the sensor system to be more reliable. The first derivatives of the piezo and Seebeck output signals are the key factors for the signal processing of the "pain" feeling. The main idea can be applied to mimic other psychological tactile feelings.
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http://dx.doi.org/10.1089/soro.2018.0049DOI Listing
December 2019
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