Publications by authors named "Seo Yeon Lee"

57 Publications

sp. nov., isolated from a sand dune.

Int J Syst Evol Microbiol 2021 Feb 22. Epub 2021 Feb 22.

Department of Food Science and Biotechnology, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Republic of Korea.

A Gram-stain-negative, aerobic, non-spore-forming, non-motile and rod-shaped bacterial strain, designated BSSL-BM3, was isolated from sand collected from a dune near the Yellow Sea, Republic of Korea, and subjected to a polyphasic taxonomic study. The neighbour-joining phylogenetic tree of 16S rRNA gene sequences showed that strain BSSL-BM3 fell within the clade comprising the type strains of species. Strain BSSL-BM3 exhibited 16S rRNA gene sequence similarity values of 98.0-99.0 % to the type strains of , , , and and of 94.2-96.7 % to the type strains of the other species. The averagenucleotide identity and digitalDNA-DNA hybridization values between strain BSSL-BM3 and the type strains of , , , and were 82.2-88.8 % and 25.0-36.5 %, respectively. The DNA G+C content of strain BSSL-BM3 from genomic sequence data was 38.75 mol%. Strain BSSL-BM3 contained MK-6 as the predominant menaquinone and iso-C 3-OH, summed feature 3 (C7 and/or C6) and iso-C G as the major fatty acids. The major polar lipids of strain BSSL-BM3 were phosphatidylethanolamine and two unidentified lipids. Distinguishing phenotypic properties, along with the phylogenetic and genetic distinctiveness, revealed that strain BSSL-BM3 is separated from recognized species. On the basis of the data presented here, strain BSSL-BM3 is considered to represent a novel species of the genus , for which the name sp. nov. is proposed. The type strain is BSSL-BM3 (=KACC 21632=NBRC 114502).
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http://dx.doi.org/10.1099/ijsem.0.004709DOI Listing
February 2021

Lower Urinary Tract Symptoms in Prostate Cancer Patients Treated With Radiation Therapy: Past and Present.

Int Neurourol J 2021 Jan 19. Epub 2021 Jan 19.

Department of Urology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea.

The incidence of prostate cancer (PCa) is increasing with the increase in aging population. Accordingly, interest and frequency of radiation therapy (RT) are also increasing. The types of RT may be broadly divided into external beam radiation therapy (EBRT), brachytherapy (BT), and combination therapy (EBRT + BT). The prevalence of lower urinary tract symptoms (LUTS) after RT for the treatment of PCa is common; however, there are few reviews on the relationship between RT and LUTS. Here, we review the causes and incidence of LUTS, as well as the evaluation and treatment options. Because of the reported risks of RT, patients undergoing RT should be counseled regarding the treatment challenges and informed that they may have higher failure rates than nonirradiated patients. Moreover, thorough evaluation and treatment strategies are needed to support treatment recommendations. With review of existing literature, this narrative article provides an overview to aid the urologist in treating patients presenting with complications associated with radiation cystitis. Further research is required to provide evidence of the effectiveness and feasibility of the management approach to the care of patients with LUTS after RT for the treatment of PCa.
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http://dx.doi.org/10.5213/inj.2040202.101DOI Listing
January 2021

ADM14 Induces Anti-Obesity Effects and Changes in Gut Microbiome in High-Fat Diet-Induced Obese Mice.

Nutrients 2020 Nov 30;12(12). Epub 2020 Nov 30.

Department of Food Science and Biotechnology, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea.

The aim of our study was to evaluate the anti-obesity effects of () ADM14 administration in a high-fat diet-induced obese mouse model and the resulting changes in the intestinal microbiota. Prior to in vivo testing, ADM14 was shown to inhibit adipogenesis through in vitro test and genetic analysis. Subsequently, mice were orally administered 0.85% saline supplemented or not with ADM14 to high-fat diet group and normal diet group daily. The results showed that administration of ADM14 reduced weight gain, epididymal fat expansion, and total blood cholesterol and glucose levels, and significantly decreased expression of lipid-related genes in the epididymal fat pad. Administration of ADM14 showed improvement in terms of energy harvesting while restoring the Firmicutes to Bacteroidetes ratio and also increased the relative abundance of specific microbial taxa such as and , which are abundant in non-obese people. ADM14 affected the modulation of gut microbiota, altered the strain profile of short-chain fatty acid production in the cecum and enhanced the stimulation of butyrate production. Overall, ADM14 showed potential as a therapeutic probiotic supplement for metabolic disorders, confirming the positive changes of in vivo indicators and controlling gut microbiota in a high-fat diet-induced obese mouse model.
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http://dx.doi.org/10.3390/nu12123703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761388PMC
November 2020

sp. nov., isolated from a tidal flat.

Int J Syst Evol Microbiol 2020 Dec;70(12):6301-6306

Department of Food Science and Biotechnology, Sungkyunkwan University, Jangan-gu, Suwon, Republic of Korea.

A Gram-stain-negative, aerobic, non-spore-forming, motile by single polar flagellum and ovoid or rod-shaped bacterial strain, designated JBTF-M23, was isolated from tidal flat sediment collected from the Yellow Sea, Republic of Korea. Neighbour-joining phylogenetic tree of 16S rRNA gene sequences showed that strain JBTF-M23 fell within the clade comprising the type strains of species, clustering with the type strains of and . Strain JBTF-M23 exhibited the highest 16S rRNA gene sequence similarity value (98.6 %) to the type strain of and sequence similarities of 98.3 and 97.7 % to the type strains of and respectively. The DNA G+C content of strain JBTF-M23 from genomic sequence data was 41.98 %. The ANI and dDDH values between strain JBTF-M23 and the type strains of , and were 71.3-76.6 and 19.4-19.9 %, respectively. Strain JBTF-M23 contained Q-8 as the predominant ubiquinone and C7 and/or C6, C and C7 as the major fatty acids. The major polar lipids of strain JBTF-M23 were phosphatidylethanolamine and one unidentified aminolipid. Distinguished phenotypic properties, along with the phylogenetic and genetic distinctiveness, revealed that strain JBTF-M23 is separated from recognized species. On the basis of the data presented, strain JBTF-M23is considered to represent a novel species of the genus , for which the name sp. nov. is proposed. The type strain is JBTF-M23(=KACC 19900=NBRC 113647).
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http://dx.doi.org/10.1099/ijsem.0.004532DOI Listing
December 2020

Electroacupuncture on the Scalp over the Motor Cortex Ameliorates Behavioral Deficits Following Neonatal Hypoxia-Ischemia in Rats via the Activation of Neural Stem Cells.

Life (Basel) 2020 Oct 14;10(10). Epub 2020 Oct 14.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Korea.

Electroacupuncture (EA) therapy via alternating current stimulation on the scalp over the motor cortex is used for the treatment of brain disorders. Perinatal hypoxia-ischemia (HI), a brain injury in newborns, leads to long-term neurologic complications. Here, we investigated whether EA could promote functional improvements and neurogenesis in a neonatal HI rat model. A neonatal HI rat model was induced by permanent ligation of the left carotid artery in postnatal day 7 pups. EA for neonatal HI rats was performed at 2 Hz (1, 3, or 5 mA; 20 min) from 4-6 weeks after birth. HI rats undergoing EA had improved motor and memory function, with the greatest improvement after 3 mA EA. The corpus callosum was significantly thicker and showed a significant increase in proliferating astrocytes in the 3 mA EA group. We observed proliferating cells and a greater number of newly developed neurons and astrocytes in the subventricular zone and dentate gyrus of the 3 mA EA group than in those of the HI group. These results suggest that EA promotes functional improvements following neonatal HI assault via the proliferation and differentiation of neural stem cells. This effect was the strongest after 3 mA EA, suggesting that this is the optimal treatment dose.
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http://dx.doi.org/10.3390/life10100240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602251PMC
October 2020

Isolinderalactone Induces Cell Death via Mitochondrial Superoxide- and STAT3-Mediated Pathways in Human Ovarian Cancer Cells.

Int J Mol Sci 2020 Oct 13;21(20). Epub 2020 Oct 13.

College of Pharmacy, Daegu Catholic University, Gyeongbuk 38430, Korea.

The mortality rate of ovarian cancer (OC) worldwide increases with age. OC is an often fatal cancer with a curative rate of only 20-30%, as symptoms often appear after disease progression. Studies have reported that isolinderalactone (ILL), a furanosesquiterpene derivative extracted from the dried root of , can inhibit several cancer cell lines' growth. However, the molecular mechanisms underlying ILL activities in human OC cells remain unexplored. This study investigated the antitumor activities of ILL in human OC cells by inducing mitochondrial superoxide (mtSO) and JAK-signal transducer and activator of transcription 3 (STAT3)-dependent cell death. ILL caused cell death in SKOV-3 and OVCAR-3 cells and increased the cell proportion in the subG1 phase. Additionally, ILL significantly induced mtSO production and reduced ROS production. Moreover, ILL downregulated mitochondrial membrane potential and the expression levels of anti-apoptotic Bcl-2 family proteins and superoxide dismutase (SOD)2. Results showed that ILL decreased phosphorylation of serine 727 and tyrosine 705 of STAT3 and expression of survivin, a STAT3-regulated gene. Furthermore, ILL-induced cell death was reversed by pretreatment of Mito-TEMPO, a mitochondria-specific antioxidant. These results suggest that ILL induces cell death by upregulation of mtSO, downregulation of mitochondrial SOD2, and inactivation of the STAT3-mediated pathway.
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http://dx.doi.org/10.3390/ijms21207530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589373PMC
October 2020

3D Bioprinted Vascularized Tumour for Drug Testing.

Int J Mol Sci 2020 Apr 23;21(8). Epub 2020 Apr 23.

School of Mechanical Engineering, Sungkyunkwan University, Suwon 16419, Korea.

An in vitro screening system for anti-cancer drugs cannot exactly reflect the efficacy of drugs in vivo, without mimicking the tumour microenvironment (TME), which comprises cancer cells interacting with blood vessels and fibroblasts. Additionally, the tumour size should be controlled to obtain reliable and quantitative drug responses. Herein, we report a bioprinting method for recapitulating the TME with a controllable spheroid size. The TME was constructed by printing a blood vessel layer consisting of fibroblasts and endothelial cells in gelatine, alginate, and fibrinogen, followed by seeding multicellular tumour spheroids (MCTSs) of glioblastoma cells (U87 MG) onto the blood vessel layer. Under MCTSs, sprouts of blood vessels were generated and surrounding MCTSs thereby increasing the spheroid size. The combined treatment involving the anti-cancer drug temozolomide (TMZ) and the angiogenic inhibitor sunitinib was more effective than TMZ alone for MCTSs surrounded by blood vessels, which indicates the feasibility of the TME for in vitro testing of drug efficacy. These results suggest that the bioprinted vascularized tumour is highly useful for understanding tumour biology, as well as for in vitro drug testing.
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http://dx.doi.org/10.3390/ijms21082993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215771PMC
April 2020

Fabrication of Bioabsorbable Polylactic-Co-Glycolic Acid/Polycaprolactone Nanofiber Coated Stent and Investigation of Biodegradability in Porcine Animal Model.

J Nanosci Nanotechnol 2020 Sep;20(9):5360-5364

Department of Bionanosystem Engineering, Jeonbuk National University, Jeonju, 54896, Jeonbuk, Republic of Korea.

Stent-mediated therapy is minimally invasive and fairly effective for the specific tissue and organs with tubal structures such as the esophagus, intestine, and blood vessels. Cerebral arteries are one of the most critical tubal structures to maintain the physiological function and the life of the human. Since the retrieval of the implanted vascular stent is difficult and risky, the one-step stent therapy is imperative. However, the placement of a current pipe-typed stent can also limit the nutritional supply to the vascular wall. Also, the non-degradable polymeric layer is possibly sensitized to the recipient as a foreign body after prolonged period after implantation. Herein, we developed PLGA/PCL nanofiber-coated stent for blocking the flow towards the aneurysm cavity as well as allowing nutritional support to the vessel with the biodegradability. The PLGA/PCL nanofiber-coated stent (NCS) was fabricated via electrospinning composite nanofibers onto a self-expandable mater metal stent. The as-fabricated NCS was physicochemically characterized using FT-IR, FE-SEM, and UTM, and experimented in vivo as implanted in porcine models and radiologically and histologically analyzed. The NCS demonstrated improved physicochemical properties for intracranial aneurysmal treatment including enhanced mechanical properties. The bioabsorbability of NCS was confirmed in the animal model.
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http://dx.doi.org/10.1166/jnn.2020.17674DOI Listing
September 2020

Hepatic stellate cell-specific knockout of transcriptional intermediary factor 1γ aggravates liver fibrosis.

J Exp Med 2020 06;217(6)

Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

Transforming growth factor β (TGFβ) is a crucial factor in fibrosis, and transcriptional intermediary factor 1γ (TIF1γ) is a negative regulator of the TGFβ pathway; however, its role in liver fibrosis is unknown. In this study, mesenchymal stem cells derived from human embryonic stem cells (hE-MSCs) that secrete hepatocyte growth factor (HGF) were used to observe the repair of thioacetamide (TAA)-induced liver fibrosis. Our results showed that TIF1γ was significantly decreased in LX2 cells when exposed to TGFβ1. Such decrease of TIF1γ was significantly prevented by co-culture with hE-MSCs. Interaction of TIF1γ with SMAD2/3 and binding to the promoter of the α-smooth muscle gene (αSMA) suppressed αSMA expression. Phosphorylation of cAMP response element-binding protein (CREB) and binding on the TIF1γ promoter region induced TIF1γ expression. Furthermore, hepatic stellate cell-specific TIF1γ-knockout mice showed aggravation of liver fibrosis. In conclusion, loss of TIF1γ aggravates fibrosis, suggesting that a strategy to maintain TIF1γ during liver injury would be a promising therapeutic approach to prevent or reverse liver fibrosis.
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http://dx.doi.org/10.1084/jem.20190402DOI Listing
June 2020

Korean Translation and Linguistic Validation of Urgency and Overactive Bladder Questionnaires.

Int Neurourol J 2020 Mar 31;24(1):66-76. Epub 2020 Mar 31.

Department of Urology, Seoul National University Hospital, Seoul, Korea.

Purpose: Given the importance of evaluating the severity of overactive bladder (OAB) symptoms and outcomes after treatment, several questionnaires have been developed to evaluate OAB patients. However, only limited questionnaires are available in Korea for use with Korean patients. Therefore, this study aimed to develop Korean versions of OAB questionnaires through a rigorous linguistic validation process.

Methods: The Indevus Urgency Severity Scale, Urgency Perception Scale, Urgency Severity Scale, and Patient Perception of Intensity of Urgency Scale underwent translation and linguistic validation. The linguistic validation procedure consisted of permission for translation, forward translations, reconciliation, back-translation, cognitive debriefing, and proofreading. Two independent bilingual translators translated the original version of each questionnaire, and a panel then discussed and reconciled the 2 initial translations. Next, a third independent bilingual translator performed a backward translation of the reconciled version into English. Five Korean patients diagnosed with OAB were interviewed for cognitive debriefing.

Results: Each item of the questionnaires was translated into 2 Korean versions in the forward translation process. Terms such as 'urgency' and 'wetting' were translated into ordinary language by the translators and adjusted by the panel members to more conceptually equivalent terms in a medical context. In the back-translation process, the panel made a few changes regarding details based on a comparison of the back-translated and original versions. During the cognitive debriefing process, 5 patients provided a few pieces of feedback on the naturalness of the wording of the questionnaires, but generally agreed on the translated terms.

Conclusion: In this study, the panel produced a successful linguistic validation of Korean versions of multiple OAB questionnaires, which can be utilized to evaluate the severity and treatment outcomes of OAB.
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http://dx.doi.org/10.5213/inj.1938164.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136437PMC
March 2020

AIM2 inflammasome contributes to brain injury and chronic post-stroke cognitive impairment in mice.

Brain Behav Immun 2020 07 19;87:765-776. Epub 2020 Mar 19.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Graduate Training Program of Korean Medicine for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea; Department of Korean Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea. Electronic address:

Although over one-third of stroke patients may develop post-stroke cognitive impairment (PSCI), the mechanisms underlying PSCI remain unclear. We explored here, the involvement of post-stroke inflammasomes in long-term PSCI development, using a 45 min-middle cerebral artery occlusion (MCAO)/reperfusion-induced PSCI model. Immunohistological assessment on day 1, 3, and 7 was followed by cognitive function test 28 days post-stroke. Evaluation of inflammasome sensor gene expression in aged mouse brains showed dominant expression of absent in melanoma 2 (Aim2) in 6-, 12-, and 18-month-old mouse brains. AIM2 mRNA and protein increased until 7 days post-stroke. PSCI decreased anxiety in elevated plus maze test and impaired spatial learning and memory functions in Morris water maze test 28 days post-stroke. AIM2 and other inflammasome subunit immunoreactivities, including those for caspase-1, interleukin (IL)-1β, and IL-18, were higher in the hippocampus and cortex of the PSCI than in those of the sham group 7 days post-stroke. AIM2 immunoreactivity of the PSCI group was primarily co-localized with Iba-1 (microglial marker) and CD31 (endothelial cell marker) immunoreactivities but not NeuN (neuronal marker) and GFAP (astrocyte marker) immunoreactivities, suggesting that microglia or endothelial cell-induced AIM2 production mediated PSCI pathogenesis. Additionally, inflammasome-induced pyroptosis might contribute to acute and chronic neuronal death after stroke. AIM2 knockout (KO) and Ac-YVAD-CMK-induced caspase-1 inhibition in mice significantly improved cognitive function and reversed brain volume in the hippocampus relative to those in stroke mice. Conclusively, AIM2 inflammasome-mediated inflammation and pyroptosis likely aggravated PSCI; therefore, targeting and controlling AIM2 inflammasome could potentially treat PSCI.
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http://dx.doi.org/10.1016/j.bbi.2020.03.011DOI Listing
July 2020

Subacute electroacupuncture at Baihui (GV 20) and Dazhui (GV 14) promotes post-stroke functional recovery via neurogenesis and astrogliosis in a photothrombotic stroke mouse model.

J Tradit Chin Med 2019 12;39(6):833-841

Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.

Objective: To investigate the optimal timing and underlying mechanism of electroacupuncture (EA) at Baihui (GV 20) and Dazhui (GV 14) for improved long-term functional recovery after focal cerebral ischemia in a photothrombotic stroke mouse model.

Methods: Totally 50 adult male C57BL/6J mice were assigned into 5 groups: (a) the control group, sham-operated mice (n = 10); (b) the vehicle group, focal cerebral ischemia induction without EA (n = 10); (c) the acute EA group, mice received EA immediately post-ischemia, followed by once-daily treatments for 7 consecutive days (n = 10); (d) the subacute EA group, mice received EA 4 days post-ischemia, followed by once-daily treatments for 7 consecutive days (n = 10); (e) the delayed EA group. EA stimulation (2 Hz, 2 V for 20 min) was applied to acupuncture points (acupoints), Baihui (GV 20) and Dazhui (GV 14), once a day for 7 consecutive days beginning immediately (acute treatment), 4 d (subacute treatment) and 10 d (delayed treatment) after focal cerebral ischemia in C57BL/6J mice. Behavioral assessments were conducted 21 and 28 d post-ischemia and histopathological analyses were performed 28 days post-ischemia.

Results: The subacute EA treatment at Baihui (GV 20) and Dazhui (GV 14) significantly improved functional recovery compared to the vehicle group 28 d after ischemic brain injury, although brain atrophy was not reduced. The number of NeuN+ and NeuN+/BrdU+ cells as well as GFAP intensity in the ipsilateral cortex were significantly increased in the subacute group compared to the vehicle group 28 d post-ischemia. We concluded that EA stimulation 4 d post-ischemia (subacute treatment) enhanced neurogenesis and astrogliosis, likely contributing to long-term functional recovery following focal cerebral ischemia.

Conclusion: Our findings suggest that the timing of the EA therapy at Baihui (GV 20) and Dazhui (GV 14) determines the therapeutic effects in mice with focal cerebral ischemia induced by photothrombotic occlusion.
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December 2019

Isolinderalactone suppresses human glioblastoma growth and angiogenic activity in 3D microfluidic chip and in vivo mouse models.

Cancer Lett 2020 05 12;478:71-81. Epub 2020 Mar 12.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Graduate Training Program of Korean Medicine for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. Electronic address:

Glioblastoma multiforme (GBM) is a lethal and highly vascular type of brain tumor. We previously reported that isolinderalactone enhances GBM apoptosis in vitro and in vivo, but its role in tumor angiogenesis is unknown. Here, we investigated the anti-angiogenic activity of isolinderalactone and its mechanisms. In a human GBM xenograft mouse model, isolinderalactone significantly reduced tumor growth and vessels. Isolinderalactone decreased the expression of vascular endothelial growth factor (VEGF) mRNA, protein, and VEGF secretion in hypoxic U-87 GBM cells and also in xenograft GMB tissue. In addition, we demonstrated that isolinderalactone significantly inhibited the proliferation, migration, and capillary-like tube formation of human brain microvascular endothelial cells (HBMECs) in the presence of VEGF. We also found that isolinderalactone decreased sprout diameter and length in a 3D microfluidic chip, and strongly reduced VEGF-triggered angiogenesis in vivo Matrigel plug assay. Isolinderalactone downregulated hypoxia-inducible factor-1α (HIF-1α) and HIF-2α proteins, decreased luciferase activity driven by the VEGF promoter in U-87 cells under hypoxic conditions, and suppressed VEGF-driven phosphorylation of VEGFR2 in HBMECs. Taken together, our results suggest that isolinderalactone is a promising candidate for GBM treatment through tumor angiogenesis inhibition.
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http://dx.doi.org/10.1016/j.canlet.2020.03.009DOI Listing
May 2020

Cucurbitacin D Overcomes Gefitinib Resistance by Blocking EGF Binding to EGFR and Inducing Cell Death in NSCLCs.

Front Oncol 2020 18;10:62. Epub 2020 Feb 18.

Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, Seoul, South Korea.

In this study, the mechanism of the anticancer effect through which cucurbitacin D (CuD) can overcome gefitinib resistance in NSCLC was investigated. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide assay, and cell migration and growth were observed by wound healing and colony formation assays, respectively. Levels of EGFR family members, protein kinase B, extracellular signal-regulated kinase, poly(ADP-ribose) polymerase, and G2/M phase-related proteins were detected by Western blot analysis. Immunofluorescence analysis was used to detect the intracellular expression of p-EGFR. Induction of apoptosis and cell cycle arrest was measured by flow cytometry. Solid-phase binding assays were used to determine binding to the EGFR family. CuD inhibits the phosphorylation of EGFR in gefitinib-resistant NSCLC cells and induces cell death via cell cycle arrest and apoptosis. CuD treatment or EGFR knockdown also suppressed the growth of gefitinib-resistant NSCLC cells. In addition, CuD overcame resistance by blocking EGF binding to EGFR in gefitinib-resistant NSCLC cells. In conclusion, we demonstrate that CuD overcomes gefitinib resistance by reducing the activation of EGFR-mediated survival in NSCLC and by inhibiting the combination of EGF and EGFR.
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http://dx.doi.org/10.3389/fonc.2020.00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041627PMC
February 2020

Covalent Surface Functionalization of Bovine Serum Albumin to Magnesium Surface to Provide Robust Corrosion Inhibition and Enhance In Vitro Osteo-Inductivity.

Polymers (Basel) 2020 Feb 13;12(2). Epub 2020 Feb 13.

Department of Bionanosystem Engineering, Graduate School, Jeonbuk National University, Jeonju 561-756, Korea.

Herein, we describe precisely a covalent modification of pure magnesium (Mg) surface and its application to induce in vitro osteogenic differentiation. The new concept of a chemical bonding method is proposed for developing stable chemical bonds on the Mg surface through the serial assembly of bioactive additives that include ascorbic acid (AA) and bovine serum albumin (BSA). We studied both the physicochemical and electrochemical properties using scanning electron microscopy and other techniques to confirm how the covalent bonding of BSA on Mg can, after coating, significantly enhance the chemical stability of the substrate. The modified Mg-OH-AA-BSA exhibits better anti-corrosion behavior with high corrosion potential (E = -0.96 V) and low corrosion current density (I = 0.2 µA cm) as compared to the pure Mg (E = -1.46 V, I = 10.42 µA cm). The outer layer of BSA on Mg protects the fast degradation rate of Mg, which is the consequence of the strong chemicals bonds between amine groups on BSA with carboxylic groups on AA as the possible mechanism of peptide bonds. Collectively, the results suggest that the surface-modified Mg provides a strong bio-interface, and enhances the proliferation and differentiation of pre-osteoblast (MC3T3-E1) cells through a protein-lipid interaction. We therefore conclude that the technique we describe provides a cost-effective and scalable way to generate chemically stable Mg surface that inherits a biological advantage in orthopedic and dental implants in clinical applications.
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http://dx.doi.org/10.3390/polym12020439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077681PMC
February 2020

Weisheng-Tang Ameliorates Acute Ischemic Brain Damage in Mice by Maintaining Blood-Brain Barrier Integrity.

Oxid Med Cell Longev 2019 3;2019:4379732. Epub 2019 Dec 3.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.

Stroke is one of the major causes of death and long-term disability worldwide; the associated breakdown of the blood-brain barrier (BBB) aggravates ischemic brain damage. Accordingly, many medicinal herbs and formulas have been used to treat stroke-related symptoms. In this study, we selected two Korean herbal medicine formulas, Weisheng-tang and Tongxuewan, through text-mining analysis, and evaluated their protective effect on BBB disruption and brain damage in stroke. Ischemic brain damage was induced in mice by photothrombotic cortical ischemia. The infarct volume, brain edema, neurological deficits, and motor function 24 h after ischemic injury were analyzed. We investigated BBB breakdown by measuring Evans blue extravasation in addition to endothelial cells, tight junction proteins, protease-activated receptor-1 (PAR-1), and matrix metalloproteinase-9 (MMP-9) using immunofluorescence staining and confocal microscopy. Pretreatment with Weisheng-tang significantly reduced infarct volume and edema and improved neurological and motor functions; however, Tongxuewan did not. In addition, Weisheng-tang decreased brain infarction and edema and recovered neurological and motor deficit in a dose-dependent manner (30, 100, and 300 mg/kg). Weisheng-tang pretreatment resulted in significantly less BBB damage and higher brain microvasculature after focal cerebral ischemia. Tight junction proteins, such as zonula occludens-1 (ZO-1) and claudin-5, were preserved in Weisheng-tang-pretreated mice. Moreover, the ischemic brain in these mice showed suppressed PAR-1 and MMP-9 expression. In conclusion, our findings show that Weisheng-tang, which was selected through literature analysis but has not previously been used as a stroke remedy, exerts protective effects against ischemic brain damage and suggest its possible application for potential stroke patients, especially in the elderly.
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http://dx.doi.org/10.1155/2019/4379732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914926PMC
June 2020

The MicroRNA-92a/Sp1/MyoD Axis Regulates Hypoxic Stimulation of Myogenic Lineage Differentiation in Mouse Embryonic Stem Cells.

Mol Ther 2020 01 3;28(1):142-156. Epub 2019 Sep 3.

Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address:

Hypoxic microenvironments exist in developing embryonic tissues and determine stem cell fate. We previously demonstrated that hypoxic priming plays roles in lineage commitment of embryonic stem cells. In the present study, we found that hypoxia-primed embryoid bodies (Hyp-EBs) efficiently differentiate into the myogenic lineage, resulting in the induction of the myogenic marker MyoD, which was not mediated by hypoxia-inducible factor 1α (HIF1α) or HIF2α, but rather by Sp1 induction and binding to the MyoD promoter. Knockdown of Sp1 in Hyp-EBs abrogated hypoxia-induced MyoD expression and myogenic differentiation. Importantly, in the cardiotoxin-muscle injury mice model, Hyp-EB transplantation facilitated muscle regeneration in vivo, whereas transplantation of Sp1-knockdown Hyp-EBs failed to do. Moreover, we compared microRNA (miRNA) expression profiles between EBs under normoxia versus hypoxia and found that hypoxia-mediated Sp1 induction was mediated by the suppression of miRNA-92a, which directly targeted the 3' untranslated region (3' UTR) of Sp1. Further, the inhibitory effect of miRNA-92a on Sp1 in luciferase assay was abolished by a point mutation in specific sequence in the Sp1 3' UTR that is required for the binding of miRNA-92a. Collectively, these results suggest that hypoxic priming enhances EB commitment to the myogenic lineage through miR-92a/Sp1/MyoD regulatory axis, suggesting a new pathway that promotes myogenic-lineage differentiation.
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http://dx.doi.org/10.1016/j.ymthe.2019.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951826PMC
January 2020

Endothelin-1 Augments Therapeutic Potency of Human Mesenchymal Stem Cells via CDH2 and VEGF Signaling.

Mol Ther Methods Clin Dev 2019 Jun 17;13:503-511. Epub 2019 May 17.

Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul 03080, Republic of Korea.

In our previous study, we identified differences in the levels of CDH2 and vascular endothelial growth factor (VEGF) between effective and ineffective clones of human umbilical cord blood (hUCB) mesenchymal stem cells (MSCs), with regard to the infarcted rat myocardium. In this study, we compared gene expression profiles between the effective and ineffective clones and identified that endothelin-1 () is enriched in the effective clone. In the mechanistic analyses, EDN1 significantly increased expression of CDH2 and VEGF through endothelin receptor A (EDNRA), which was prevented by EDNRA blocker, BQ123. To decipher how EDN1 induced gene expression of CDH2, we performed a promoter activity assay and identified GATA2 and MZF1 as inducers of CDH2. EDN1 significantly enhanced the promoter activity of the CDH2 gene, which was obliterated by the deletion or point mutation at GATA2 or MZF1 binding sequence. Next, therapeutic efficacy of EDN1-priming of hUCB-MSCs was tested in a rat myocardial infarction (MI) model. EDN1-primed MSCs were superior to naive MSCs at 8 weeks after MI in improving myocardial contractility (p < 0.05), reducing fibrosis area (p < 0.05), increasing engraftment efficiency (p < 0.05), and improving capillary density (p < 0.05). In conclusion, EDN1 induces CDH2 and VEGF expression in hUCB-MSCs, leading to the improved therapeutic efficacy in rat MI, suggesting that EDN1 is a potential priming agent for MSCs in regenerative medicine.
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http://dx.doi.org/10.1016/j.omtm.2019.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545354PMC
June 2019

Indoleamine 2,3-Dioxygenase-Dependent Neurotoxic Kynurenine Metabolism Contributes to Poststroke Depression Induced in Mice by Ischemic Stroke along with Spatial Restraint Stress.

Oxid Med Cell Longev 2018 30;2018:2413841. Epub 2018 Dec 30.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.

Aim: Poststroke depression (PSD), which occurs in approximately one-third of stroke survivors, is clinically important because of its association with slow functional recovery and increased mortality. In addition, the underlying pathophysiological mechanisms are still poorly understood.

Methods: We used a mouse model of PSD to examine the neurobiological mechanisms of PSD and the beneficial effects of aripiprazole, an atypical antipsychotic drug. PSD was induced in mice by combining middle cerebral artery occlusion (MCAO) with spatial restraint stress. The body weight, sucrose preference, and forced swim tests were performed at 5, 7, and 9 weeks and the Morris water maze test at 10 weeks after completing MCAO and spatial restraint stress.

Results: Mice subjected to MCAO and spatial restraint stress showed significant depressive-like behavior in the sucrose preference test and forced swim test as well as cognitive impairment in the Morris water maze test. The PSD-like phenotype was accompanied by an indoleamine 2,3-dioxygenase 1 (IDO1) expression increase in the nucleus accumbens, hippocampus, and hypothalamus, but not in the striatum. Furthermore, the increased IDO1 levels were localized in Iba-1(+) cells but not in NeuN(+) or GFAP(+) cells, indicating that microglia-induced IDO1 expression was prominent in the PSD mouse brain. Moreover, 3-hydroxyanthranilate 3,4-dioxygenase (HAAO), quinolinic acid (QUIN), and reactive oxygen species (ROS) were significantly increased in the nucleus accumbens, hippocampus, and hypothalamus of PSD mice. Importantly, a 2-week aripiprazole (1 mg/kg, ) regimen, which was initiated 1 day after MCAO, ameliorated depressive-like behavior and impairment of cognitive functions in PSD mice that was accompanied by downregulation of IDO1, HAAO, QUIN, and ROS.

Conclusions: Our results suggest that the IDO1-dependent neurotoxic kynurenine metabolism induced by microglia functions in PSD pathogenesis. The beneficial effect of aripiprazole on depressive-like behavior and cognitive impairment may be mediated by inhibition of IDO1, HAAO, QUIN, and ROS.
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http://dx.doi.org/10.1155/2018/2413841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332926PMC
February 2019

Isolinderalactone regulates the BCL-2/caspase-3/PARP pathway and suppresses tumor growth in a human glioblastoma multiforme xenograft mouse model.

Cancer Lett 2019 02 29;443:25-33. Epub 2018 Nov 29.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Graduate Training Program of Korean Medicine for Healthy-Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea. Electronic address:

Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which remains incurable. Plant extracts are a potential source of potent anticancer medicines. In this study, we investigated the effect of isolinderalactone from Lindera aggregata on tumor growth using U-87 human glioblastoma cells. Treatment with isolinderalactone inhibited cell viability and promoted apoptotic cell death. In addition, intraperitoneal injection of isolinderalactone significantly inhibited tumor growth in a human GBM xenograft mouse model. To identify the proteins involved in the induction of apoptosis in isolinderalactone-treated cells, we performed a human apoptosis proteome array analysis and western blotting. Isolinderalactone suppressed the expression of B-cell lymphoma 2 (BCL-2), as well as of survivin and X-linked inhibitor of apoptosis protein (XIAP), known as apoptosis inhibitors, and increased the level of cleaved caspase-3. In addition, isolinderalactone treatment increased cleaved poly(ADP-ribose) polymerase (PARP) and DNA damage. In xenograft tumor tissues, we observed high immunofluorescence of cleaved caspase-3 and TUNEL in isolinderalactone-treated group. Taken together, isolinderalactone enhances U-87 GBM cell apoptosis in vitro and in vivo and retards tumor growth, suggesting that isolinderalactone may be a potential candidate for anti-glioblastoma drug development.
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http://dx.doi.org/10.1016/j.canlet.2018.11.027DOI Listing
February 2019

Positive effects of α-asarone on transplanted neural progenitor cells in a murine model of ischemic stroke.

Phytomedicine 2018 Dec 2;51:151-161. Epub 2018 Oct 2.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; Graduate Training Program of Korean Medicine for Healthy-Aging, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan 50612, Republic of Korea. Electronic address:

Background: Some traditional Oriental herbal medicines, such as Acorus tatarinowii and Acorus gramineus, produce beneficial effects for cognition enhancement. An active compound in rhizomes and the bark of these plants is α-asarone.

Purpose: This study investigated the effects of α-asarone on the proliferation and differentiation of neural progenitor cells (NPCs) in a primary culture and a murine model of ischemic stroke.

Methods: NPCs were isolated from mouse fetal cerebral cortices on embryonic day 15, and all experiments were performed using passage 3 NPCs. We utilized a cell counting kit-8 assay, flow cytometry, western blot, and immunohistochemical analysis to assess proliferation and differentiation of NPCs and employed α-asarone in NPC transplanted ischemic stroke mice to evaluate stroke-related functional recovery using behavioral and immunohistochemical analysis.

Result: Treatment with 1 µM, 3 µM, or 10 μM α-asarone induced significant NPC proliferation compared to vehicle treatment. Induced NPCs expressed the neuronal marker neuronal nuclei (NeuN) or the astrocyte marker S100 calcium-binding protein B (S100β). Both immunohistochemistry and flow cytometry revealed that treatment with α-asarone increased the number of NeuN-immunoreactive cells and decreased the number of S100β-immunoreactive cells. Treatment with α-asarone also increased the expression of β-catenin, cyclin D1, and phosphorylated extracellular signal-regulated kinase (ERK) compared to vehicle treatment. In a murine model of ischemic stroke, treatment with α-asarone and transplanted NPCs alleviated stroke-related functional impairments. The corner and rotarod test results revealed that treatment with α-asarone in the NPC transplanted group had greater-than-additive effects on sensorimotor function and motor balance. Moreover, α-asarone treatment promoted the differentiation of transplanted NPCs into NeuN-, glial fibrillary acidic protein (GFAP)-, platelet-derived growth factor-α (PDGFR-α)-, and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)-immunoreactive cells.

Conclusion: α-asarone may promote NPC proliferation and differentiation into neuron-lineage cells by activating β-catenin, cyclin D1, and ERK. Moreover, α-asarone treatment facilitated neurofunctional recovery after NPC transplantation in a murine model of ischemic stroke. Therefore, α-asarone is a potential adjunct treatment to NPC therapy for functional restoration after brain injuries such as ischemic stroke.
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http://dx.doi.org/10.1016/j.phymed.2018.09.230DOI Listing
December 2018

Photobiomodulation Using a Low-Level Light-Emitting Diode Improves Cognitive Dysfunction in the 5XFAD Mouse Model of Alzheimer's Disease.

J Gerontol A Biol Sci Med Sci 2020 03;75(4):631-639

Korean Medical Science Research Center for Healthy Aging, Pusan National University, Yangsan.

Photobiomodulation using low-level light-emitting diode can be rapidly applied in neurological and physiological disorders safely and noninvasively. Photobiomodulation is effective for chronic diseases because of fewer side effects than drugs. Here we investigated the effects of photobiomodulation using light-emitting diode on amyloid plaques, gliosis, and neuronal loss to prevent and/or recover cognitive impairment, and optimal timing of photobiomodulation initiation for recovering cognitive function in a mouse model of Alzheimer's disease. 5XFAD mice were used as an Alzheimer's disease model. Animals receiving photobiomodulation treatment were divided into two groups: an early group starting photobiomodulation at 2 months of age (5XFAD+Early), and a late group starting photobiomodulation at 6 months of age (5XFAD+Delay). Both groups received photobiomodulation 20 minutes per session three times per week for 14 weeks. The Morris water maze, passive avoidance, and elevated plus maze tests were performed at 10 months of age. Immunohistochemistry and Western blot were performed after behavioral evaluation. The results showed that photobiomodulation treatment at early stages reduced amyloid accumulation, neuronal loss, and microgliosis and alleviated the cognitive dysfunction in 5XFAD mice, possibly by increasing insulin degrading enzyme related to amyloid-beta degradation. Photobiomodulation may be an excellent candidate for advanced preclinical Alzheimer's disease research.
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http://dx.doi.org/10.1093/gerona/gly240DOI Listing
March 2020

Therapeutic Potential of a Combination of Electroacupuncture and TrkB-Expressing Mesenchymal Stem Cells for Ischemic Stroke.

Mol Neurobiol 2019 Jan 22;56(1):157-173. Epub 2018 Apr 22.

Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, 50612, Republic of Korea.

We prepared and grafted tropomyosin receptor kinase B (TrkB) gene-transfected mesenchymal stem cells (TrkB-MSCs) into the ischemic penumbra and investigated whether electroacupuncture (EA) treatment could promote functional recovery from ischemic stroke. For the behavioral test, TrkB-MSCs+EA resulted in significantly improved motor function compared to that obtained with MSCs+EA or TrkB-MSCs alone. At 30 days after middle cerebral artery occlusion (MCAO), the largest number of grafted MSCs was detected in the TrkB-MSC+EA group. Some differentiation into immature neuroblasts and astrocytes was detected; however, only a few mature neuron-like cells were found. Compared to other treatments, TrkB-MSCs+EA upregulated the expression of mature brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT4) and induced the activation of TrkB receptor and its transcription factor cAMP response element-binding protein (CREB). At 60 days after MCAO, EA highly promoted the differentiation of TrkB-MSCs into mature neuron-like cells compared to the effect in MSCs. A selective TrkB antagonist, ANA-12, reverted the effect of TrkB-MSCs+EA in motor function recovery and survival of grafted MSCs. Our results suggest that EA combined with grafted TrkB-MSCs promotes the expression of BDNF and NT4, induces the differentiation of TrkB-MSCs, and improves motor function. TrkB-MSCs could serve as effective therapeutic agents for ischemic stroke if used in combination with BDNF/NT4-inducing therapeutic approaches.
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http://dx.doi.org/10.1007/s12035-018-1067-zDOI Listing
January 2019

Pretreatment with Shuanghe-Tang Extract Attenuates Postischemic Brain Injury and Edema in a Mouse Model of Stroke: An Analysis of Medicinal Herbs Listed in .

Oxid Med Cell Longev 2018 11;2018:2479602. Epub 2018 Feb 11.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.

Aim: Although stroke is among the leading causes of death and long-term disability, there are few effective treatments for limiting the severity of neurological sequelae. We evaluated the effects of 29 medicinal herbs listed in the chapter of the 17th century Korean medical text on stroke symptoms in a mouse model of cerebral ischemia.

Methods: Focal cerebral ischemia was induced via photothrombosis. Infarct volume, brain edema, and neurological deficits were evaluated. Immunofluorescence staining for tight junction proteins and aquaporin 4 (AQP4) was performed following ischemic injury.

Results: Based on our initial findings, we examined the effects of two prescriptions in which the candidate herbs comprised more than 60% of the total formula: Shuanghe-tang and Zengsunsiwu-tang. Pretreatment with Shuanghe-tang significantly reduced infarct volume, decreased blood-brain barrier (BBB) breakdown, attenuated edema, and improved neurological and motor functions in a dose-dependent manner (30, 100, and 300 mg/kg), while no such effects were observed in mice pretreated with Zengsunsiwu-tang. Immunohistochemical analysis revealed significant increases in ipsilateral occludin and zonula occludens 1 (ZO-1) expression in Shuanghe-tang-pretreated mice, as well as increased AQP4 immunofluorescence.

Conclusions: These results indicate that Shuanghe-tang may protect against brain injury and promote recovery of neurological function following ischemia.
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http://dx.doi.org/10.1155/2018/2479602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828342PMC
September 2018

Combination of Constraint-Induced Movement Therapy with Electroacupuncture Improves Functional Recovery following Neonatal Hypoxic-Ischemic Brain Injury in Rats.

Biomed Res Int 2018 7;2018:8638294. Epub 2018 Feb 7.

Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 50612, Republic of Korea.

Aim: Neonatal hypoxic-ischemia (HI) due to insufficient oxygen supply and blood flow during the prenatal and postnatal periods can cause cerebral palsy, a serious developmental condition. The purpose of this study was to investigate the efficacy of combining constraint-induced movement therapy (CIMT) and electroacupuncture to treat rat neonatal HI brain injury.

Methods: The left common carotid arteries of postnatal day 7 rats were ligated to induce HI brain injury, and the neonates were kept in a hypoxia chamber containing 8% oxygen for 2 hrs. Electroacupuncture at Baihui (GV 20) and Zusanli (ST 36) was performed concurrently with CIMT 3 weeks after HI induction for 4 weeks.

Results: Motor asymmetry after HI was significantly improved in the CIMT and electroacupuncture combination group, but HI lesion size was not improved. The combination of CIMT and electroacupuncture after HI injury increases NeuN and decreases GFAP levels in the cerebral cortex, suggesting that this combination treatment inversely regulates neurons and astrocytes. In addition, the combination treatment group reduced the level of cleaved caspase-3, a crucial mediator of apoptosis, in the cortex.

Conclusions: Our findings indicate that a combination of CIMT and electroacupuncture is an effective method to treat hemiplegia due to neonatal HI brain injury.
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http://dx.doi.org/10.1155/2018/8638294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820667PMC
September 2018

Nonenzymatic acetylation of ubiquitin Lys side chains is modulated by their neighboring residues.

FEBS J 2018 04 4;285(7):1277-1289. Epub 2018 Mar 4.

Protein Structure Group, Korea Basic Science Institute, Cheongju-Si, South Korea.

Nonenzymatic acetylation of Lys side chains (Lys-SCs) by various in vivo reactive molecules has been suggested to play novel regulatory roles. Ubiquitin (UB) has seven Lys residues that are utilized for synthesis of specific poly-UB chains. To understand the nature of these Lys-SC modifications, the chemical acetylation rate and pK and Hill coefficient of each UB-Lys-SC were measured. Mutagenesis studies combined with the determination of activation energy indicated that specific neighboring residues of the Lys-SCs have a potential catalytic activity during nonenzymatic acetylation. Based on the shared chemistry between nonenzymatic Lys acetylation and ubiquitylation, the characterized chemical properties of the UB-Lys-SCs could be a reference for deciphering both mechanisms. Our NMR approaches could be useful for studying general nonenzymatic Lys acylations of various proteins.
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http://dx.doi.org/10.1111/febs.14404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947880PMC
April 2018

Hepatocyte Growth Factor Improves the Therapeutic Efficacy of Human Bone Marrow Mesenchymal Stem Cells via RAD51.

Mol Ther 2018 03 19;26(3):845-859. Epub 2017 Dec 19.

Department of Internal Medicine, Seoul National University College of Medicine, Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address:

Human embryonic stem cell-derived mesenchymal stem cells (hE-MSCs) have greater proliferative capacity than other human mesenchymal stem cells (hMSCs), suggesting that they may have wider applications in regenerative cellular therapy. In this study, to uncover the anti-senescence mechanism in hE-MSCs, we compared hE-MSCs with adult bone marrow (hBM-MSCs) and found that hepatocyte growth factor (HGF) was more abundantly expressed in hE-MSCs than in hBM-MSCs and that it induced the transcription of RAD51 and facilitated its SUMOylation at K70. RAD51 induction/modification by HGF not only increased telomere length but also increased mtDNA replication, leading to increased ATP generation. Moreover, HGF-treated hBM-MSCs showed significantly better therapeutic efficacy than naive hBM-MSCs. Together, the data suggest that the RAD51-mediated effects of HGF prevent hMSC senescence by promoting telomere lengthening and inducing mtDNA replication and function, which opens the prospect of developing novel therapies for liver disease.
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http://dx.doi.org/10.1016/j.ymthe.2017.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910662PMC
March 2018

Translation and Linguistic Validation of the Korean Version of the Treatment Satisfaction Visual Analogue Scale and the Overactive Bladder Satisfaction With Treatment Questionnaire.

Int Neurourol J 2017 Dec 31;21(4):309-319. Epub 2017 Dec 31.

Department of Urology, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul, Korea.

Purpose: This study reports the development of the Korean Version of the Treatment Satisfaction Visual Analogue Scale (TS-VAS) and the Overactive Bladder Satisfaction with Treatment Questionnaire (OAB-SAT-q) based on the original versions, with subsequent linguistic validation by Korean patients with overactive bladder receiving active treatment from a physician.

Methods: Translation and linguistic validation were performed in 2016. The validation process included permission for translation, forward translation, reconciliation, backward translation, cognitive debriefing, and proofreading. The original versions of the TS-VAS and OAB-SAT-q were independently translated into Korean by 2 bilingual translators and were then reconciled into a single version. The third bilingual translator performed a backward translation of the reconciled version into English. A trained interviewer and 5 Korean-speaking patients with OAB carried out the cognitive debriefing.

Results: During the forward translation process, the terms used in the 2 questionnaires were adjusted to use more appropriate expressions in the Korean language than were used in the original versions. During the backward translation process, no changes were made in terms of semantic equivalence. In the cognitive debriefing session, 5 patients were asked to fill in the answers within 8 minutes; most of them reported that the translated questions were clear and easy to understand.

Conclusions: The present study presents successful linguistic validation of the Korean version of the TS-VAS and OAB-SAT-q, which could be useful tools for evaluating treatment satisfaction in patients.
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http://dx.doi.org/10.5213/inj.1734992.496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756819PMC
December 2017

Effects of Lobeglitazone, a New Thiazolidinedione, on Osteoblastogenesis and Bone Mineral Density in Mice.

Endocrinol Metab (Seoul) 2017 Sep;32(3):389-395

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Background: Bone strength is impaired in patients with type 2 diabetes mellitus despite an increase in bone mineral density (BMD). Thiazolidinedione (TZD), a peroxisome proliferator activated receptor γ agonist, promotes adipogenesis, and suppresses osteoblastogenesis. Therefore, its use is associated with an increased risk of fracture. The aim of this study was to examine the in vitro and in vivo effects of lobeglitazone, a new TZD, on bone.

Methods: MC3T3E1 and C3H10T1/2 cells were cultured in osteogenic medium and exposed to lobeglitazone (0.1 or 1 μM), rosiglitazone (0.4 μM), or pioglitazone (1 μM) for 10 to 14 days. Alkaline phosphatase (ALP) activity, Alizarin red staining, and osteoblast marker gene expression were analyzed. For in vivo experiments, 6-month-old C57BL/6 mice were treated with vehicle, one of two doses of lobeglitazone, rosiglitazone, or pioglitazone. BMD was assessed using a PIXImus2 instrument at the baseline and after 12 weeks of treatment.

Results: As expected, in vitro experiments showed that ALP activity was suppressed and the mRNA expression of osteoblast marker genes RUNX2 (runt-related transcription factor 2) and osteocalcin was significantly attenuated after rosiglitazone treatment. By contrast, lobeglitazone at either dose did not inhibit these variables. Rosiglitazone-treated mice showed significantly accelerated bone loss for the whole bone and femur, but BMD did not differ significantly between the lobeglitazone-treated and vehicle-treated mice.

Conclusion: These findings suggest that lobeglitazone has no detrimental effects on osteoblast biology and might not induce side effects in the skeletal system.
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http://dx.doi.org/10.3803/EnM.2017.32.3.389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620037PMC
September 2017

Integrated analysis of leaf morphological and color traits in different populations of Chinese cabbage (Brassica rapa ssp. pekinensis).

Theor Appl Genet 2017 Aug 2;130(8):1617-1634. Epub 2017 Jun 2.

Department of Horticulture, Chungnam National University, Daejeon, Korea.

Key Message: QTLs and candidate gene markers associated with leaf morphological and color traits were identified in two immortalized populations of Brassica rapa, which will provide genetic information for marker-assisted breeding. Brassica rapa is an important leafy vegetable consumed worldwide and morphology is a key character for its breeding. To enhance genetic control, quantitative trait loci (QTLs) for leaf color and plant architecture were identified using two immortalized populations with replications of 2 and 4 years. Overall, 158 and 80 QTLs associated with 23 and 14 traits were detected in the DH and RIL populations, respectively. Among them, 23 common robust-QTLs belonging to 12 traits were detected in common loci over the replications. Through comparative analysis, five crucifer genetic blocks corresponding to morphology trait (R, J&U, F and E) and color trait (F, E) were identified in three major linkage groups (A2, A3 and A7). These might be key conserved genomic regions involved with the respective traits. Through synteny analysis with Arabidopsis, 64 candidate genes involved in chlorophyll biosynthesis, cell proliferation and elongation were co-localized within QTL intervals. Among them, SCO3, ABI3, FLU, HCF153, HEMB1, CAB3 were mapped within QTLs for leaf color; and CYCD3;1, CYCB2;4, AN3, ULT1 and ANT were co-localized in QTL regions for leaf size. These robust QTLs and their candidate genes provide useful information for further research into leaf architecture with crop breeding.
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http://dx.doi.org/10.1007/s00122-017-2914-4DOI Listing
August 2017