Publications by authors named "Daeun Lee"

26 Publications

  • Page 1 of 1

Combined Exposure to Metals in Drinking Water Alters the Dopamine System in Mouse Striatum.

Int J Environ Res Public Health 2021 06 18;18(12). Epub 2021 Jun 18.

Collage of Pharmacy, Keimyung University, Daegu 42601, Korea.

Environmental exposure to arsenic (As), lead (Pb), and cadmium (Cd) frequently occurs; however, data on the specific effects of combined exposure on neurotransmission, specifically dopaminergic neurotransmission, are lacking. In this study, motor coordination and dopamine content, along with the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors (DRs), were examined in the striatum of adult male mice following exposure to drinking water containing As, Pb, and/or Cd. We found that exposure to a metal mixture impaired motor coordination. After 4 weeks of treatment, a significant decrease in dopamine content and expression of TH, DAT, and VMAT2 was observed in the striatum of metal-mixture-treated mice, compared to the controls or single-metal-exposed groups. However, DRD1 and DRD2 expression did not significantly change with metal treatment. These results suggest that altered dopaminergic neurotransmission by the collective action of metals may contribute to metal-mixture-induced neurobehavioral disorders.
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http://dx.doi.org/10.3390/ijerph18126558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296366PMC
June 2021

Exposure to lead on expression levels of brain immunoglobulins, inflammatory cytokines, and brain-derived neurotropic factor in fetal and postnatal mice with autism-like characteristics.

J Toxicol Environ Health A 2021 11 30;84(21):891-900. Epub 2021 Jun 30.

Department of Preventive Medicine, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea.

Autism spectrum disorders (ASD) are neurodevelopmental disorders, and their incidence is increasing worldwide. Increased exposure to environmental metal lead (Pb) has been proposed as a risk factor associated with ASD. In the present study, BTBR T+ /J (BTBR) mice with ASD-like behavioral characteristics and control FVB mice were exposed gestationally and/or neonatally to Pb, and compared with highly social FVB mice to investigate neuroimmunological abnormalities. IgG1 and IgG2a levels in fetal brains from BTBR dams exposed to Pb (BTBR-Pb) were significantly higher than those of BTBR-controls (BTBR-C). However, this change did not occur in FVB mice exposed to Pb. The IgG1:IgG2a ratio was higher in both fetal and postnatal brains of BTBR mice compared to FVB animals regardless of Pb exposure. The IL-4:IFN-γ ratio was elevated in BTBR-Pb relative to BTBR-C mice, but this ratio was not markedly affected following Pb exposure in FVB animals. These findings suggest the potential for a Pb-driven predominant T2-like reactivity profile in brain microenvironment present in BTBR mice. Brain-derived neurotrophic factor was decreased in fetal and postnatal BTBR-Pb brains relative to BTBR-C brains but not in FVB-Pb relative to FVB-C mice. Taken together, data demonstrate that Pb exposure might contribute to developmental brain abnormalities associated with ASD, particularly in individuals with genetic susceptibility to ASD.
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http://dx.doi.org/10.1080/15287394.2021.1945985DOI Listing
November 2021

Authors' Reply to: Bibliometric Studies and the Discipline of Social Media Mental Health Research. Comment on "Machine Learning for Mental Health in Social Media: Bibliometric Study".

J Med Internet Res 2021 Jun 17;23(6):e29549. Epub 2021 Jun 17.

Department of Applied Artificial Intelligence, Sungkyunkwan University, Seoul, Republic of Korea.

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http://dx.doi.org/10.2196/29549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277311PMC
June 2021

Effectiveness of depuration of Pacific Oyster (): removal of bioaccumulated by UV-treatment.

Food Sci Biotechnol 2021 May 15:1-7. Epub 2021 May 15.

Department of Food Science and Technology, Pukyong National University, Busan, 48513 Republic of Korea.

The present study aimed to evaluate the efficacy of a depuration system equipped with UV-irradiation to control infection such as septicemia (or sepsis) using alive oysters. After 6 h of bioaccumulation of , Pacific oyster were found to be contaminated by > 8.0 log MPN/g of cells. After 60 h of depuration, the cell number significantly decreased to < 4.0 log MPN/g. The present depuration process meets the standard effectiveness in reducing cells by > 3.52 log and < 30 MPN/g as recommended by the National Shellfish Sanitization Procedure Molluscan Shellfish Control guidelines. Furthermore, no significant changes in pH value and glycogen content indicate that the depuration process did not affect the freshness and quality of the oyster samples. The present study could help control any potential infection associated with the consumption of raw oysters without losing their quality.
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http://dx.doi.org/10.1007/s10068-021-00912-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123095PMC
May 2021

College student gratitude: A silver lining while evaluating a yearlong bathroom stall messaging campaign.

J Am Coll Health 2021 May 13:1-9. Epub 2021 May 13.

Brian Lamb School of Communication, Purdue University, West Lafayette, Indiana, USA.

Objective: Mental health concerns of college students are on the rise, prompting a need for communication campaigns to address ways to assist students. The current campaign utilized weekly bathroom stall messaging to address five key themes developed by a university's mental wellness task force. Undergraduate students at a large Midwestern university. : A survey at pre and post-campaign implementation. : No significant shifts in attitudes, and only one significant behavioral increase (i.e., reaching out to academic advisers), were revealed. One silver lining was that college students were found to express gratitude to someone new a median of 5 times per month. Gratitude tended to be displayed most recently to those in their social circles, and primarily for receiving instrumental support. : Narrowing the focus of future mental wellness campaigns is recommended. Additional recommendations for developing future mental wellness campaigns are also addressed.
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http://dx.doi.org/10.1080/07448481.2021.1910516DOI Listing
May 2021

Daily Life Changes and Life Satisfaction among Korean School-Aged Children in the COVID-19 Pandemic.

Int J Environ Res Public Health 2021 03 23;18(6). Epub 2021 Mar 23.

Department of Child Development and Family Studies, College of Human Ecology, Seoul National University, Seoul 08826, Korea.

The recent COVID-19 pandemic has been disrupting the daily lives of people across the world, causing a major concern for psychological well-being in children. This study aimed to examine (1) how life satisfaction and its potential predictors have been affected by the pandemic among school-aged children in Korea, and (2) which factors would predict their life satisfaction during the pandemic. We surveyed 166 fourth-graders in the Seoul metropolitan area to assess their psychological well-being and potentially related variables during the pandemic. The data were compared with those available from two pre-COVID-19 surveys, the 2018 Korean Children and Youth Panel Survey ( = 1236) and the 2019 Korean Children and Youth Well-being Index Survey ( = 334). Higher levels of stress were observed in children during the COVID-19 pandemic; however, the level of their life satisfaction remained unchanged when compared with data from the pre-COVID-19 surveys. The pandemic also affected peer relationship quality and susceptibility to smartphone addiction, but not perceived parenting style nor academic engagement. Interestingly, peer relationship quality no longer predicted life satisfaction during the pandemic; perceived parenting styles and parent-child conversation time predicted life satisfaction. The results suggest a central role of parent-child relationship in supporting the psychological well-being of school-aged children during the pandemic.
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http://dx.doi.org/10.3390/ijerph18063324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004811PMC
March 2021

Machine Learning for Mental Health in Social Media: Bibliometric Study.

J Med Internet Res 2021 03 8;23(3):e24870. Epub 2021 Mar 8.

Department of Applied Artificial Intelligence, Sungkyunkwan University, Seoul, Republic of Korea.

Background: Social media platforms provide an easily accessible and time-saving communication approach for individuals with mental disorders compared to face-to-face meetings with medical providers. Recently, machine learning (ML)-based mental health exploration using large-scale social media data has attracted significant attention.

Objective: We aimed to provide a bibliometric analysis and discussion on research trends of ML for mental health in social media.

Methods: Publications addressing social media and ML in the field of mental health were retrieved from the Scopus and Web of Science databases. We analyzed the publication distribution to measure productivity on sources, countries, institutions, authors, and research subjects, and visualized the trends in this field using a keyword co-occurrence network. The research methodologies of previous studies with high citations are also thoroughly described.

Results: We obtained a total of 565 relevant papers published from 2015 to 2020. In the last 5 years, the number of publications has demonstrated continuous growth with Lecture Notes in Computer Science and Journal of Medical Internet Research as the two most productive sources based on Scopus and Web of Science records. In addition, notable methodological approaches with data resources presented in high-ranking publications were investigated.

Conclusions: The results of this study highlight continuous growth in this research area. Moreover, we retrieved three main discussion points from a comprehensive overview of highly cited publications that provide new in-depth directions for both researchers and practitioners.
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http://dx.doi.org/10.2196/24870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985801PMC
March 2021

When Doctors Swear, Do Patients Care? Two Experiments Examining Physicians Cursing in the Presence of Patients.

Health Commun 2021 Jan 3:1-9. Epub 2021 Jan 3.

Brian Lamb School of Communication, Purdue University.

Swearing in everyday conversation has become more normalized in recent years; but less certain, however, is how accepting Americans are when a doctor swears in their presence. Two online experiments (Study 1: n = 497; Study 2: n = 1,224) were conducted with US participants to investigate the impact of a doctor swearing in the course of examining a patient's infected wound (i.e., "You've got a lot of nasty [shit/stuff] in there that we're going to want to flush out"), or swearing when dropping papers in a patient's presence while varying the intensity of a swear (i.e., "[Shit!/Damn!/Whoops!]"), with or without an apology (i.e., "I'm sorry"). Overall findings reveal a main effect for swearing, with a swearing doctor generally seen as less likable, and in Study 1, less trustworthy, approachable, and less of an expert. However, the majority of participants exposed to a swearing doctor still said they would visit that physician again. Open-ended responses from these participants revealed that they perceived a swearing doctor as more human. Results from Study 2 also found that if a doctor swore, the negative impact was lessened if the doctor apologized immediately after cursing. While results from these studies indicate it is wise for doctors to refrain from swearing, most participants were still willing to make a future appointment with a cursing doctor.
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http://dx.doi.org/10.1080/10410236.2020.1865610DOI Listing
January 2021

Mycobacterium tuberculosis Rv2626c-derived peptide as a therapeutic agent for sepsis.

EMBO Mol Med 2020 12 1;12(12):e12497. Epub 2020 Dec 1.

Department of Molecular and Life Science, Hanyang University, Ansan, South Korea.

The Rv2626c protein of Mycobacterium tuberculosis is a promising vaccine candidate owing to its strong serum antibody response in patients with tuberculosis. However, there is limited information regarding the intracellular response induced by Rv2626c in macrophages. In this study, we demonstrated that Rv2626c interacts with the RING domain of TRAF6 and inhibits lysine (K) 63-linked polyubiquitination of TRAF6 (E3 ubiquitin ligase activity); this results in the suppression of TLR4 inflammatory signaling in macrophages. Furthermore, we showed that the C-terminal 123-131-amino acid Rv2626c motif promotes macrophage recruitment, phagocytosis, M2 macrophage polarization, and subsequent bacterial clearance. We developed rRv2626c-CA, a conjugated peptide containing the C-terminal 123-131-amino acid Rv2626c that targets macrophages, penetrates the cell membrane, and has demonstrated significant therapeutic effects in a mouse model of cecal ligation and puncture-induced sepsis. This multifunctional rRv2626c-CA has considerably improved potency, with an IC that is 250-fold (in vitro) or 1,000-fold (in vivo) lower than that of rRv2626c-WT. We provide evidence for new peptide-based drugs with anti-inflammatory and antibacterial properties for the treatment of sepsis.
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http://dx.doi.org/10.15252/emmm.202012497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721357PMC
December 2020

A Patient with Neutropenia and Splenomegaly: A Case Report from Department of Family Medicine in Tertiary Hospital Center.

Korean J Fam Med 2021 May 22;42(3):250-254. Epub 2020 May 22.

Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Pancytopenia represents a unique challenge for primary care doctors and its etiological causes encompass various specialties, including hematology and rheumatology. Despite the existence of effective tests such as bone marrow biopsy and immunoassays to rule out the potential causes of pancytopenia, it is often difficult to pinpoint the exact diagnosis. In this case report, we have described such a 'gray zone' patient, who presented with pancytopenia, neutropenia, and splenomegaly, and was being treated for fungal pneumonia before being transferred to Severance Hospital (department of family medicine). As the patient had a 10-year history of multiple, long-term hospital admissions that were having a severely debilitating impact on the quality of life, we performed a partial splenic embolization as a potential cure for the symptoms. Although this induced acute blood count recovery, it failed to prevent eventual mortality from septic shock.
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http://dx.doi.org/10.4082/kjfm.19.0130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164928PMC
May 2021

Dietary schizophyllan reduces mitochondrial damage by activating SIRT3 in mice.

Arch Pharm Res 2020 Apr 31;43(4):449-461. Epub 2020 Mar 31.

Department of Molecular and Life Science, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan-si, Gyeonggi-do, 15588, South Korea.

Schizophyllan (SPG), produced by Schizophyllum commune, is an exopolysaccharide with multiple academic and commercial uses, including in the food industry and for various medical functions. We previously demonstrated that SPG conjugated with c-Src peptide exerted a significant therapeutic effect on mouse models of the acute inflammatory diseases polymicrobial sepsis and ulcerative colitis. Here we extended these results by investigating whether SPG exerted a protective effect against mitochondrial damage in the liver via sirtuin 3 (SIRT3) induction, focusing on the deacetylation of succinate dehydrogenase A (SDHA) and superoxide dismutase 2 (SOD2). Liver damage models induced by alcohol or conjugated linoleic acid (CLA, which simulates lipodystrophy) in SIRT3, SOD2, and SDHA mice were used. Results showed that dietary supplementation with SPG induced SIRT3 activation; this was involved in mitochondrial metabolic resuscitation that countered the adverse effects of alcoholic liver disease and CLA-induced damage. The mitochondrial SIRT3 mediated the deacetylation and activation of SOD2 in the liver and SDHA in adipose tissues, suggesting that SPG supplementation reduced ethanol-induced liver damage and CLA-induced adverse dietary effects via SIRT3-SOD2 and SIRT3-SDHA signaling, respectively. Together, these results suggest that dietary SPG has a previously unrecognized role in SIRT3-mediated mitochondrial metabolic resuscitation during mitochondria-related diseases.
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http://dx.doi.org/10.1007/s12272-020-01231-4DOI Listing
April 2020

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis.

Sci Rep 2020 03 12;10(1):4570. Epub 2020 Mar 12.

Department of Molecular & Life Science, Hanyang University, Ansan, 15588, South Korea.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA's pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox-Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA.
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http://dx.doi.org/10.1038/s41598-020-61630-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067850PMC
March 2020

GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer.

Oncotarget 2020 Jan 7;11(1):62-73. Epub 2020 Jan 7.

Department of Molecular and Life Science, Hanyang University, Ansan 15588, S. Korea.

Targeted tumor and efficient, specific biological drug delivery has been one of the main challenges in protein-based cancer-targeted therapies. Mitochondria are potential therapeutic targets for various anti-cancer drugs. We have previously reported that protein kinase Cα-mediated phosphorylation of GRA8 is required for mitochondrial trafficking and regulating the interaction of the C-terminal of GRA8 with ATP5A1/SIRT3 in mitochondria. Furthermore, SIRT3 facilitates ATP5A1 deacetylation, mitochondrial activation, and subsequent antiseptic activity . Herein we developed a recombinant acidity-triggered rational membrane (ATRAM)-conjugated multifunctional GRA8 peptide (rATRAM-G8-M/AS) comprising ATRAM as the cancer-targeting cell-penetrating peptide, and essential/minimal residues for mitochondrial targeting or ATP5A1/SIRT3 binding. This peptide construct showed considerably improved potency about cancer cell death via mitochondria activity and biogenesis compared with rGRA8 alone in HCT116 human carcinoma cells, reaching an IC value of up to 200-fold lower and 500-fold lower . Notably, rATRAM-G8-M/AS treatment showed significant therapeutic effects in a mouse xenograft model through mitochondrial metabolic resuscitation, and it produced negligible immunogenicity and immune responses . Thus, these results demonstrate that rATRAM-G8-M/AS represents a useful therapeutic strategy against tumors, particularly colon cancer. This strategy represents an urgently needed paradigm shift for therapeutic intervention.
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http://dx.doi.org/10.18632/oncotarget.27417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967779PMC
January 2020

A potent antibacterial activity of new short d-enantiomeric lipopeptide against multi drug resistant bacteria.

Biochim Biophys Acta Biomembr 2019 01 26;1861(1):34-42. Epub 2018 Oct 26.

School of Life Sciences, Gwangju Institute of Science and Technology, 123, Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea. Electronic address:

The emergence of drug-resistant pathogenic bacteria threatens human health. Resistance to existing antibiotics is increasing, while the emergence of new antibiotics is slowing. Cationic antimicrobial peptides (CAMPs) are fascinating alternative antibiotics because they possess a broad spectrum of activity, being active against both Gram-positive and Gram-negative bacteria including those resistant to traditional antibiotics. However, low bioavailability resulting from enzymatic degradation and attenuation by divalent cations like Mg and Ca limits their use as antibiotic agents. Here, we report the design of new CAMPs showing both high antibacterial activity and serum stability under physiological ion concentrations. The peptides were designed by applying two approaches, the use of d-enantiomer and lipidation. Based on the sequence of the CopW (LLWIALRKK-NH), a nonapeptide derived from coprisin, a series of novel d-form CopW lipopeptides with different acyl chain lengths (C6, C8, C10, C12, C14, and C16) were synthesized and evaluated with respect to their activity and salt sensitivity. Among the analogs, the d-form lipopeptide dCopW3 exhibited MIC values ranging from 1.25 to 5 μM against multidrug-resistant bacteria. Significantly, this compound did not induce bacterial resistance and was highly stable in human serum proteases. The results emphasize the potential of cationic d-form lipopeptide as therapeutically valuable antibiotics for treating drug-resistant bacterial infections.
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http://dx.doi.org/10.1016/j.bbamem.2018.10.014DOI Listing
January 2019

Therapeutic Effect of L. Extract on Insulin Resistance and the Gut Microbiome in Lep/Lep Mice.

Evid Based Complement Alternat Med 2018 5;2018:8159261. Epub 2018 Feb 5.

Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.

Obesity results in the progression of metabolic disorders, especially type 2 diabetes (T2DM). Obesity-induced insulin resistance (IR) is a causative factor of T2DM morbidity in obese people. It is generally held by clinicians that IR is caused by adiposity-related inflammation that is mediated by changes in composite ions in the gut microbiome. This experimental study was designed to investigate the effects of L. (Cucumis) on obesity-induced IR in genetically leptin-deficient Lep/Lep mice. Specifically, we examined the anti-inflammatory effects of Cucumis and the effects of Cucumis on the gut microbiota. We evaluated glucose control by measuring FBS, performing the OGTT, quantifying serum IR, calculating the HOMA-IR, and determining the lipid profiles. To see whether inflammation was reduced, we analyzed adipose tissue macrophages as well as monocytes in the blood. We also profiled the gut microbiota to determine whether the ratios of microbial phyla changed. We found that Cucumis improved IR in obese mice and relieved inflammation in adipose tissue and blood. Simultaneously, the microbiota composition ratios changed. In conclusion, administration of Cucumis improved IR by reducing inflammation, thereby changing the gut microbiota composition. Cucumis is thus a promising treatment for obesity-induced insulin resistance and the inflammatory state.
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http://dx.doi.org/10.1155/2018/8159261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830983PMC
February 2018

Crystal structure of D-glycero-Β-D-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei.

Proteins 2018 Jan 31;86(1):124-131. Epub 2017 Oct 31.

College of Pharmacy, Ewha W. University, Seoul, Republic of Korea.

The crystal structure of HldC from B. pseudomallei (BpHldC), the fourth enzyme of the heptose biosynthesis pathway, has been determined. BpHldC converts ATP and d-glycero-β-d-manno-heptose-1-phosphate into ADP-d-glycero-β-d-manno-heptose and pyrophosphate. The crystal structure of BpHldC belongs to the nucleotidyltransferase α/β phosphodiesterase superfamily sharing a common Rossmann-like α/β fold with a conserved T/HXGH sequence motif. The invariant catalytic key residues of BpHldC indicate that the core catalytic mechanism of BpHldC may be similar to that of other closest homologues. Intriguingly, a reorientation of the C-terminal helix seems to guide open and close states of the active site for the catalytic reaction.
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http://dx.doi.org/10.1002/prot.25398DOI Listing
January 2018

Crystal structure of D-glycero-Β-D-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei.

Proteins 2018 Jan 31;86(1):124-131. Epub 2017 Oct 31.

College of Pharmacy, Ewha W. University, Seoul, Republic of Korea.

The crystal structure of HldC from B. pseudomallei (BpHldC), the fourth enzyme of the heptose biosynthesis pathway, has been determined. BpHldC converts ATP and d-glycero-β-d-manno-heptose-1-phosphate into ADP-d-glycero-β-d-manno-heptose and pyrophosphate. The crystal structure of BpHldC belongs to the nucleotidyltransferase α/β phosphodiesterase superfamily sharing a common Rossmann-like α/β fold with a conserved T/HXGH sequence motif. The invariant catalytic key residues of BpHldC indicate that the core catalytic mechanism of BpHldC may be similar to that of other closest homologues. Intriguingly, a reorientation of the C-terminal helix seems to guide open and close states of the active site for the catalytic reaction.
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http://dx.doi.org/10.1002/prot.25398DOI Listing
January 2018

General assay for enzymes in the heptose biosynthesis pathways using electrospray ionization mass spectrometry.

Appl Microbiol Biotechnol 2017 Jun 9;101(11):4521-4532. Epub 2017 Mar 9.

Department of Pharmacy, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Global Top 5 Research Program, Ewha W. University, Seoul, 03760, Republic of Korea.

The ADP-L-glycero-β-D-manno-heptose and the GDP-6-deoxy-α-D-manno-heptose biosynthesis pathways play important roles in constructing lipopolysaccharide of Gram-negative bacteria. Blocking the pathways is lethal or increases antibiotic susceptibility to pathogens. Therefore, the enzymes involved in the pathways are novel antibiotic drug targets. Here, we designed an efficient method to assay the whole enzymes in the pathways using mass spectrometry and screened 148 compounds. One promising lead is (-)-nyasol targeting D-glycero-α-D-manno-heptose-1-phosphate guanylyltransferase (HddC) included in the GDP-6-deoxy-α-D-manno-heptose biosynthesis pathway from Burkholderia pseudomallei. The inhibitory activity of the lead compound against HddC has been confirmed by blocking the system transferring the guanosine monophosphate (GMP) moiety to α-D-glucose-1-phosphate. (-)-Nyasol exhibits the half maximal inhibitory concentration (IC50) value of 17.6 μM. A further study is going on using (-)-nyasol derivatives to find better leads with high affinity.
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http://dx.doi.org/10.1007/s00253-017-8148-1DOI Listing
June 2017

Expression and crystallographic studies of D-glycero-β-D-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei.

Acta Crystallogr F Struct Biol Commun 2017 02 19;73(Pt 2):90-94. Epub 2017 Jan 19.

College of Pharmacy, Ewha W. University, 52 Ewhayeodae-gil, Seoul 03760, Republic of Korea.

The Gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosis. D-glycero-β-D-manno-Heptose-1-phosphate adenylyltransferase (HldC) is the fourth enzyme of the ADP-L-glycero-β-D-manno-heptose biosynthesis pathway, which produces an essential carbohydrate comprising the inner core of lipopolysaccharide. Therefore, HldC is a potential target of antibiotics against melioidosis. In this study, HldC from B. pseudomallei has been cloned, expressed, purified and crystallized. Synchrotron X-ray data from a selenomethionine-substituted HldC crystal were also collected to 2.8 Å resolution. The crystal belonged to the primitive triclinic space group P1, with unit-cell parameters a = 74.0, b = 74.0, c = 74.9 Å, α = 108.4, β = 108.4, γ = 108.0°. Eight protomers are present in the unit cell and three out of five selenomethionines were found in each protomer using the PHENIX software suite. A full structural determination is in progress to elucidate the structure-function relationship of the protein.
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http://dx.doi.org/10.1107/S2053230X16020537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297929PMC
February 2017

A preliminary X-ray study of 3-deoxy-D-manno-oct-2-ulosonic acid 8-phosphate phosphatase (YrbI) from Burkholderia pseudomallei.

Acta Crystallogr F Struct Biol Commun 2015 Jun 22;71(Pt 6):790-3. Epub 2015 May 22.

Global Top 5 Research Program, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.

3-Deoxy-D-manno-oct-2-ulosonic acid 8-phosphate phosphatase (YrbI), the third enzyme in the pathway for the biosynthesis of 3-deoxy-D-manno-oct-2-ulosonic acid (KDO), hydrolyzes KDO 8-phosphate to KDO and inorganic phosphate. YrbI belongs to the haloacid dehalogenase (HAD) superfamily, which is a large family of magnesium-dependent phosphatase/phosphotransferase enzymes. In this study, YrbI from Burkholderia pseudomallei, the causative agent of melioidosis, has been cloned, expressed, purified and crystallized. Synchrotron X-ray data were also collected to 2.25 Å resolution. The crystal belonged to the primitive orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 63.7, b = 97.5, c = 98.0 Å. A full structural determination is in progress to elucidate the structure-function relationship of this protein.
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http://dx.doi.org/10.1107/S2053230X15006135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461349PMC
June 2015

Successful live births after surgical treatments for symptomatic cesarean scar pregnancies: report of 3 cases.

Gynecol Obstet Invest 2014 10;78(3):208-12. Epub 2014 Sep 10.

Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Seoul, Korea.

There is no current consensus on the best treatment modality for cesarean scar pregnancy (CSP) with favorable reproductive and pregnancy outcome. We treated 3 cases of symptomatic CSP with fetal cardiac activity. The first case underwent laparoscopic repair at 6 weeks' gestational age of unruptured CSP. The second patient underwent laparoscopic repair due to massive vaginal bleeding after suction curettage. Both patients conceived naturally 6 months later and underwent repeated cesarean section at term. These were successful live births although the second patient was treated with uterine artery embolization for postpartum hemorrhage. The last patient underwent emergency exploratory laparotomy due to ruptured CSP and delivered a preterm baby. Earlier surgical treatment of CSP is indicated for a subsequent successful pregnancy and live birth. The laparoscopic approach might be advisable prior to uterine rupture.
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http://dx.doi.org/10.1159/000364867DOI Listing
June 2015

A preliminary X-ray study of murine Tnfaip8/Oxi-α.

Int J Mol Sci 2014 Mar 14;15(3):4523-30. Epub 2014 Mar 14.

College of Pharmacy and Graduate School of Pharmaceutical Sciences, Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Korea.

Tnfaip8/oxidative stress regulated gene-α (Oxi-α) is a novel protein expressed specifically in brain dopaminergic neurons and its over-expression has been reported to protect dopaminergic cells against OS-induced cell death. In this study, murine C165S mutant Tnfaip8/Oxi-α has been crystallized and X-ray data have been collected to 1.8 Å using synchrotron radiation. The crystal belonged to the primitive orthorhombic space group P21212, with unit-cell parameters a = 66.9, b = 72.3, c = 93.5 Å. A full structural determination is under way in order to provide insights into the structure-function relationships of this protein.
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http://dx.doi.org/10.3390/ijms15034523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975411PMC
March 2014

Structure-activity relationships of the intramolecular disulfide bonds in coprisin, a defensin from the dung beetle.

BMB Rep 2014 Nov;47(11):625-30

School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.

Defensins, which are small cationic molecules produced by organisms as part of their innate immune response, share a common structural scaffold that is stabilized by three disulfide bridges. Coprisin is a 43-amino acid defensin-like peptide from Copris tripartitus. Here, we report the intramolecular disulfide connectivity of cysteine-rich coprisin, and show that it is the same as in other insect defensins. The disulfide bond pairings of coprisin were determined by combining the enzymatic cleavage and mass analysis. We found that the loss of any single disulfide bond in coprisin eliminated all antibacterial, but not antifungal, activity. Circular dichroism (CD) analysis showed that two disulfide bonds, Cys20-Cys39 and Cys24-Cys41, stabilize coprisin's α-helical region. Moreover, a BLAST search against UniProtKB database revealed that coprisin's α-helical region is highly homologous to those of other insect defensins.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281341PMC
http://dx.doi.org/10.5483/bmbrep.2014.47.11.262DOI Listing
November 2014

Synthesis and antimicrobial activity of cysteine-free coprisin nonapeptides.

Biochem Biophys Res Commun 2014 Jan 7;443(2):483-8. Epub 2013 Dec 7.

School of Life Sciences, Gwangju Institute of Science and Technology, Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea. Electronic address:

Coprisin is a 43-mer defensin-like peptide from the dung beetle, Copris tripartitus. CopA3 (LLCIALRKK-NH₂), a 9-mer peptide containing a single free cysteine residue at position 3 of its sequence, was derived from the α-helical region of coprisin and exhibits potent antibacterial and anti-inflammatory activities. The single cysteine implies a tendency for dimerization; however, it remains unknown whether this cysteine residue is indispensible for CopA3's antimicrobial activity. To address this issue, in the present study we synthesized eight cysteine-substituted monomeric CopA3 analogs and two dimeric analogs, CopA3 (Dimer) and CopIK (Dimer), and evaluated their antimicrobial effects against bacteria and fungi, as well as their hemolytic activity toward human erythrocytes. Under physiological conditions, CopA3 (Mono) exhibits a 6/4 (monomer/dimer) molar ratio in HPLC area percent, indicating that its effects on bacterial strains likely reflect a CopA3 (Mono)/CopA3 (Dimer) mixture. We also report the identification of CopW, a new cysteine-free nonapeptide derived from CopA3 that has potent antimicrobial activity with virtually no hemolytic activity. Apparently, the cysteine residue in CopA3 is not essential for its antimicrobial function. Notably, CopW also exhibited significant synergistic activity with ampicillin and showed more potent antifungal activity than either wild-type coprisin or melittin.
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http://dx.doi.org/10.1016/j.bbrc.2013.11.125DOI Listing
January 2014

Structure and in silico substrate-binding mode of ADP-L-glycero-D-manno-heptose 6-epimerase from Burkholderia thailandensis.

Acta Crystallogr D Biol Crystallogr 2013 Apr 14;69(Pt 4):658-68. Epub 2013 Mar 14.

The Center for Cell Signaling and Drug Discovery Research, College of Pharmacy, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.

ADP-L-glycero-D-manno-heptose 6-epimerase (AGME), the product of the rfaD gene, is the last enzyme in the heptose-biosynthesis pathway; it converts ADP-D-glycero-D-manno-heptose (ADP-D,D-Hep) to ADP-L-glycero-D-manno-heptose (ADP-L,D-Hep). AGME contains a catalytic triad involved in catalyzing hydride transfer with the aid of NADP(+). Defective lipopolysaccharide is found in bacterial mutants lacking this gene. Therefore, it is an interesting target enzyme for a novel epimerase inhibitor for use as a co-therapy with antibiotics. The crystal structure of AGME from Burkholderia thailandensis (BtAGME), a surrogate organism for studying the pathogenicity of melioidosis caused by B. pseudomallei, has been determined. The crystal structure determined with co-purified NADP(+) revealed common as well as unique structural properties of the AGME family when compared with UDP-galactose 4-epimerase homologues. They form a similar architecture with conserved catalytic residues. Nevertheless, there are differences in the substrate- and cofactor-binding cavities and the oligomerization domains. Structural comparison of BtAGME with AGME from Escherichia coli indicates that they may recognize their substrate in a `lock-and-key' fashion. Unique structural features of BtAGME are found in two regions. The first region is the loop between β8 and β9, affecting the binding affinity of BtAGME for the ADP moiety of ADP-D,D-Hep. The second region is helix α8, which induces decamerization at low pH that is not found in other AGMEs. With the E210G mutant, it was observed that the resistance of the wild type to acid-induced denaturation is related to the decameric state. An in silico study was performed using the Surflex-Dock GeomX module of the SYBYL-X 1.3 software to predict the catalytic mechanism of BtAGME with its substrate, ADP-D,D-Hep. In the in silico study, the C7'' hydroxymethyl group of ADP-D,D-Hep is predicted to form hydrogen bonds to Ser116 and Gln293. With the aid of these interactions, the hydroxyl of Tyr139 forms a hydrogen bond to O6″ of ADP-D,D-Hep and the proton at C6″ orients closely to C4 of NADP(+). Therefore, the in silico study supports a one-base mechanism as a major catalytic pathway, in which Tyr139 solely functions as a catalytic acid/base residue. These results provide a new insight into the development of an epimerase inhibitor as an antibiotic adjuvant against melioidosis.
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http://dx.doi.org/10.1107/S0907444913001030DOI Listing
April 2013

A preliminary X-ray study of transketolase from Burkholderia pseudomallei.

Acta Crystallogr Sect F Struct Biol Cryst Commun 2012 Dec 28;68(Pt 12):1554-6. Epub 2012 Nov 28.

The Center for Cell Signaling and Drug Discovery Research, College of Pharmacy, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.

TktA is the most critical enzyme in the nonoxidative pentose phosphate pathway. It catalyzes the conversion of xylulose 5-phosphate and ribose 5-phosphate into sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate, and its products are used in the biosynthesis of acetyl-CoA, aromatic amino acids, nucleic acids and ADP-L-glycero-β-D-manno-heptose. TktA also has an unexpected role in chromosome structure that is independent of its metabolic responsibilities. Therefore, it is a new potent antibiotic target. In this study, TktA from Burkholderia pseudomallei has been cloned, expressed, purified and crystallized. Synchrotron X-ray data were also collected to 2.0 Å resolution. The crystal belonged to the monoclinic space group C2, with unit-cell parameters a=146.2, b=74.6, c=61.6 Å, β=113.0°. A full structural determination is under way in order to provide insight into the structure-function relationship of this protein.
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http://dx.doi.org/10.1107/S1744309112044375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509987PMC
December 2012
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