Publications by authors named "Sang-Hee Lee"

354 Publications

Targeting YAP-p62 signaling axis suppresses the EGFR-TKI-resistant lung adenocarcinoma.

Cancer Med 2021 Feb 23;10(4):1405-1417. Epub 2021 Jan 23.

Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

Background: Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR-TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance.

Methods: We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR-TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor.

Results: In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR-TKI-resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR-TKI-resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR-mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP-p62 axis, we treated EGFR-TKI-resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR-TKI-resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD-L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1.

Conclusion: Finally, we suggest that targeting YAP-p62 signaling axis can be useful to suppress the EGFR-TKI-resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD-L1 at the same time.
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http://dx.doi.org/10.1002/cam4.3734DOI Listing
February 2021

Chloroplast genome sequence of the hybrid variety 'Gagsi', one of the colored calla lilies ( spp.).

Mitochondrial DNA B Resour 2020 Oct 5;5(3):3478-3480. Epub 2020 Oct 5.

Department of Horticulture, Daegu University, Gyeongsan, South Korea.

The complete chloroplast genome of spp. in the family Araceae was constituted by assembly using a small amount of whole genome sequencing data. The chloroplast genome of spp. was the circular DNA molecule with a length of 175,448 bp and consisted of 90,244 bp of large single copy, 8334 bp of small single copy, and 38,435 bp of a pair of inverted repeat regions. A total of 163 genes were annotated including 109 protein-coding genes, 46 tRNA genes and eight rRNA genes. Maximum likelihood phylogenetic analysis with 16 Araceae species revealed that spp. is expectedly grouped with other species.
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http://dx.doi.org/10.1080/23802359.2020.1827060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782914PMC
October 2020

The complete chloroplast genome sequence of the hybrid variety 'Hanhera'.

Mitochondrial DNA B Resour 2020 Dec 24;5(4):3808-3809. Epub 2020 Dec 24.

Department of Horticulture, Daegu University, Gyeongsan, South Korea.

, a member of the Alstroemeriaceae family, is a species from South America. The chloroplast genome of spp. was completed by assembly using a small amount of whole genome sequencing data. The chloroplast genome of spp. was 155,672 bp in length consisting of 84,379 bp of large single copy, 17,815 bp of small single copy, and 26,739 bp of a pair of inverted repeat regions. A total of 157 genes were annotated including 103 protein-coding genes (PCGs), 46 genes, and eight genes. Maximum likelihood phylogenetic analysis with seven species belonging to the Alstroemeriaceae or Liliaceae family revealed that spp. is grouped with the species in the Alstroemeriaceae family.
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http://dx.doi.org/10.1080/23802359.2020.1840936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759260PMC
December 2020

What Is Needed for a Successful Second Chance for Accused Researchers?

Iran J Public Health 2020 Oct;49(10):2003-2005

National Leading Research Laboratory, Department of Biological Sciences, Myongji University, Yongin, Gyeonggido 17058, Republic of Korea.

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http://dx.doi.org/10.18502/ijph.v49i10.4707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719657PMC
October 2020

Preventive Effects of Extract on Bone Metabolism and .

Evid Based Complement Alternat Med 2020 18;2020:6975646. Epub 2020 Nov 18.

Research Group of Natural Materials and Metabolism, Food Functionality Research, Korea Food Research Institute, Jeonju, Jeollabuk-Do, Republic of Korea.

Osteoporosis is characterized by decreased bone mass and bone microarchitectural failure, leading to an enhanced risk of bone fractures. . (CC) is a natural plant with powerful antioxidant activity. This study investigated the antiosteoporotic effects of CC extracts in cell cultures and bone loss animal models. CC stimulated osteoblast differentiation and mineralized bone formation by osteoblasts by increasing the expression of bone formation markers (alkaline phosphatase, osteoprotegerin, and osteoprotegerin/receptor activator nuclear factor-B ligand ratio) in the murine preosteoblastic cell line MC3T3-E1. Additionally, CC was found to inhibit osteoclast differentiation by downregulating bone resorption markers (tartrate-resistant acid phosphatase, cathepsin K, dendritic cell-specific transmembrane protein, and calcitonin receptor) in the murine macrophage-like cell line RAW264.7. CC prevented ovariectomy-induced bone loss, preserved trabecular microarchitecture, and improved serum bone turnover markers in an osteoporotic mouse model. These findings suggest that CC extract may be considered as a natural therapeutic or preventive agent for osteoporotic bone loss.
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http://dx.doi.org/10.1155/2020/6975646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688366PMC
November 2020

A New Measure to Characterize the Degree of Self-Similarity of a Shape and Its Applicability.

Entropy (Basel) 2020 Sep 22;22(9). Epub 2020 Sep 22.

Division of Industrial Mathematics, National Institute for Mathematical Sciences, Daejeon 34047, Korea.

We propose a new measure () to quantify the degree of self-similarity of a shape using branch length similarity (BLS) entropy which is defined on a simple network consisting of a single node and its branches. To investigate the properties of this measure, we computed the values for 70 object groups (20 shapes in each group) in the MPEG-7 shape database and performed grouping on the values. With relatively high values, identical groups had visually similar shapes. On the other hand, the identical groups with low values had visually different shapes. However, the aspect of topological similarity of the shapes also warrants consideration. The shapes of statistically different groups exhibited significant visual difference from each other. Also, in order to show that the can have a wide variety of applicability when properly used with other variables, we showed that the finger gestures in the (, ) space are successfully classified. Here, the means a correlation coefficient value between entropy profiles for gesture shapes. As shown in the applications, has a strong advantage over conventional geometric measures in that it captures the geometrical and topological properties of a shape together. If we could define the BLS entropy for color, could be used to characterize images expressed in RGB. We briefly discussed the problems to be solved before the applicability of can be expanded to various fields.
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http://dx.doi.org/10.3390/e22091061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597137PMC
September 2020

Association between fetoplacental Doppler results, placental pathology, and angiogenic factors among pregnant women with anxiety.

Taiwan J Obstet Gynecol 2020 Nov;59(6):842-847

Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Electronic address:

Objective: This study aimed to evaluate whether state and trait anxiety among pregnant women were associated with fetoplacental Doppler findings, abnormal placental pathology, and placental angiogenic factors.

Materials And Methods: A total of 102 pregnant women at 32-35 gestational weeks were recruited and examined prospectively. State and trait anxiety were measured using the State-Trait Anxiety Inventory. Using Doppler ultrasound, pulsatility index (PI) of the umbilical artery (UA), middle cerebral artery (MCA), and uterine artery (UtA) and cerebroplacental ratio (CPR) were determined. Doppler parameters were converted into multiples of the median (MoM). Abnormal placental pathology was classified into 2 groups: vascular underperfusion (VU) and histological chorioamnionitis (HCA). Immunohistochemical analysis was performed to examine placental cells staining positive for placental growth factor (PLGF) and hypoxia-inducible factor-1-α (HIF-1α), which are markers for angiogenesis and hypoxic status, respectively.

Results: Women with high state anxiety scores had low MCA-PI MoM and CPR MoM, while those with high trait anxiety scores had low MCA-PI MoM. VU was associated with a higher incidence of high trait anxiety scores, and HCA was associated with a higher incidence of high state and trait anxiety scores. Regression analysis showed a relationship between maternal state anxiety on MCA-PI MoM and HCA after controlling for covariates. Maternal trait anxiety exhibited relationships with VU and HCA after adjustment.

Conclusion: Our results demonstrated that maternal anxiety is associated with altered fetal cerebral blood flow and abnormal placental pathology but is not associated with uteroplacental insufficiency and placental angiogenic factors.
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http://dx.doi.org/10.1016/j.tjog.2020.09.011DOI Listing
November 2020

Emerging Strategies to Combat β-Lactamase Producing ESKAPE Pathogens.

Int J Mol Sci 2020 Nov 12;21(22). Epub 2020 Nov 12.

Microbiology Immunology Department and The Research Institute of the University of Bucharest, Faculty of Biology, University of Bucharest, 020956 Bucharest, Romania.

Since the discovery of penicillin by Alexander Fleming in 1929 as a therapeutic agent against staphylococci, β-lactam antibiotics (BLAs) remained the most successful antibiotic classes against the majority of bacterial strains, reaching a percentage of 65% of all medical prescriptions. Unfortunately, the emergence and diversification of β-lactamases pose indefinite health issues, limiting the clinical effectiveness of all current BLAs. One solution is to develop β-lactamase inhibitors (BLIs) capable of restoring the activity of β-lactam drugs. In this review, we will briefly present the older and new BLAs classes, their mechanisms of action, and an update of the BLIs capable of restoring the activity of β-lactam drugs against ESKAPE ( spp., , and spp.) pathogens. Subsequently, we will discuss several promising alternative approaches such as bacteriophages, antimicrobial peptides, nanoparticles, CRISPR (clustered regularly interspaced short palindromic repeats) cas technology, or vaccination developed to limit antimicrobial resistance in this endless fight against Gram-negative pathogens.
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http://dx.doi.org/10.3390/ijms21228527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697847PMC
November 2020

Potential Benefits of Allogeneic Haploidentical Adipose Tissue-Derived Stromal Vascular Fraction in a Hutchinson-Gilford Progeria Syndrome Patient.

Front Bioeng Biotechnol 2020 21;8:574010. Epub 2020 Oct 21.

National Leading Research Laboratory, Department of Biological Sciences, Myongji University, Yongin, South Korea.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal, and genetic disorder in the gene encoding for prelamin A. Normally, prelamin A is processed to become lamin A protein. In HGPS patients, there is a heterozygous mutation in gene, in which there is a deletion of genetic codes responsible for 50 amino acids at the C-terminus of prelamin A. The processing of the abnormal prelamin A results in abnormal lamin A protein, called progerin, causing symptoms of accelerated early aging, probably due to the inflammaging process. It is well known that adipose tissue-derived mesenchymal stem cells (MSCs) have anti-inflammatory effects by modulating inflammatory cytokines and by extracellular vesicles. Here, we present a case of an HGPS patient who responded positively to injections of allogeneic haploidentical adipose tissue-derived stromal vascular fractions containing MSCs by showing rapid height and weight growth along with increased blood level of insulin-like growth factor 1.
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http://dx.doi.org/10.3389/fbioe.2020.574010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643450PMC
October 2020

ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota.

Autophagy 2020 Dec 15:1-20. Epub 2020 Dec 15.

Department of Microbiology, Chungnam National University School of Medicine , Daejeon Korea.

The orphan nuclear receptor ESRRA (estrogen related receptor alpha) is critical in mitochondrial biogenesis and macroautophagy/autophagy function; however, the roles of ESRRA in intestinal function remain uncharacterized. Herein we identified that ESRRA acts as a key regulator of intestinal homeostasis by amelioration of colonic inflammation through activation of autophagic flux and control of host gut microbiota. -deficient mice presented with increased susceptibility to dextran sodium sulfate (DSS)-induced colitis with upregulation of intestinal inflammation. In addition, -null mice had depressed AMP-activated protein kinase phosphorylation (AMPK), lower levels of TFEB (transcription factor EB), and accumulation of SQSTM1/p62 (sequestosome 1) with defective mitochondria in intestinal tissues. -deficient mice showed distinct gut microbiota composition and significantly higher microbial diversity than wild-type (WT) mice. Cohousing or fecal microbiota transplantation from WT mice to -deficient mice ameliorated DSS-induced colitis severity. Importantly, patients with ulcerative colitis (UC) had significantly decreased expression in intestinal mucosal tissues that correlated with disease activity, suggesting clinical relevance of ESRRA in UC. Taken together, our results show that ESRRA contributes to intestinal homeostasis through autophagy activation and gut microbiota control to protect the host from detrimental inflammation and dysfunctional mitochondria.
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http://dx.doi.org/10.1080/15548627.2020.1847460DOI Listing
December 2020

Quercitrin Ameliorates Hyperlipidemia and Hepatic Steatosis in Ovariectomized Mice.

Life (Basel) 2020 Oct 15;10(10). Epub 2020 Oct 15.

Research Group of Natural Materials and Metabolism, Food Functionality Research, Korea Food Research Institute, Jeollabuk-Do 55365, Korea.

Nonalcoholic fatty liver disease (NAFLD) is associated with progressive metabolic diseases. Estrogen deficiency increases the NAFLD risk among postmenopausal women. Thus, effective agents to prevent and treat NAFLD in postmenopausal women are required. Quercitrin (Quer) is a natural glycosylated flavonoid with antimicrobial, anti-inflammatory, and hypolipidemic effects. This study investigated whether Quer improves dysregulated lipid metabolism and suppresses hepatic steatosis in ovariectomized (OVX) mice as an experimental model mimicking postmenopausal women. Mice were assigned to the following four groups: SHAM, OVX, OVX + β-estradiol (0.4 mg/kg diet), and OVX + Quer (500 mg/kg diet). Mice were administered a diet with or without Quer for three months. OVX mice displayed significantly higher body mass, epidermal fat, and liver weights than those of SHAM mice. However, these levels were reduced in Quer-treated mice. Quer treatment reduced the levels of serum lipid metabolites, including triglycerides, total cholesterol, and low-density lipoprotein cholesterol. Furthermore, Quer reduced liver lipid steatosis and inhibited the expression of proinflammatory cytokines, such as tumor necrosis factor-α, IL-6, and IL-1β. The results of the present study indicate that Quer improves dysregulated lipid metabolism and reduces hepatic steatosis and inflammation by compensating for estrogen deficiency, suggesting that Quer may potentially exert protective effects during hepatic steatosis in postmenopausal women.
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http://dx.doi.org/10.3390/life10100243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602720PMC
October 2020

Porcine follicular fluid derived from > 8 mm sized follicles improves oocyte maturation and embryo development during maturation of pigs.

Zygote 2021 Feb 22;29(1):27-32. Epub 2020 Sep 22.

College of Animal Life Sciences, Kangwon National University, Chuncheon24341, Republic of Korea.

The aim of the present study was to investigate the effects of porcine follicular fluid (pFF) from large-sized (LFF; >8 mm in diameter) and medium-sized (MFF; 3-6 mm in diameter) follicles on the maturation and developmental competence of porcine oocytes. Cumulus-oocyte complexes (COCs) were collected from follicles 3-6 mm in diameter. The collected COCs were incubated for 22 h with LFF or MFF (in vitro maturation (IVM)-I stage) and were incubated subsequently for 22 h with LFF or MFF (IVM-II stage). Cumulus expansion was confirmed after the IVM-I stage and nuclear maturation was evaluated after the IVM-II stage. Intracellular glutathione (GSH) and reactive oxygen species (ROS) levels were measured and embryonic development was evaluated. Relative cumulus expansion and GSH levels were higher in the LFF group compared with in the MFF group after the IVM-I stage (P < 0.05). After the IVM-II stage, the numbers of oocytes in metaphase-II were increased in the LFF group and GSH content was higher in all of the LFF treatment groups compared with in the MFF treatment groups during both IVM stages (P < 0.05). ROS levels were reduced by LFF treatment regardless of IVM stage (P < 0.05). Blastocyst formation and the total numbers of cells in blastocysts were increased in all LFF treatment groups compared with the control group (P < 0.05). These results suggested that pFF from large follicles at the IVM stage could improve nucleic and cytoplasmic maturation status and further embryonic development through reducing ROS levels and enhancing responsiveness to gonadotropins.
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http://dx.doi.org/10.1017/S0967199420000398DOI Listing
February 2021

Sirtuin 3 is essential for host defense against infection through regulation of mitochondrial homeostasis.

Virulence 2020 12;11(1):1225-1239

Department of Microbiology, Chungnam National University College of Medicine , Daejeon, Korea.

The global incidence of (Mabc), a rapidly growing nontuberculous mycobacterial strain that causes treatment-refractory pulmonary diseases, is increasing. Despite this, the host factors that allow for protection against infection are largely unknown. In this study, we found that sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, plays a critical role in host defense against Mabc infection. Mabc decreased SIRT3 and upregulated mitochondrial oxidative stress in macrophages. SIRT3 deficiency led to increased bacterial loads, histopathological, and mitochondrial damage, and pathological inflammation during Mabc infection. Administration of scavengers of mitochondrial reactive oxygen species significantly decreased the in vivo Mabc burden and excessive inflammation, and induced SIRT3 expression in infected lungs. Notably, SIRT3 agonist (resveratrol) significantly decreased Mabc growth and attenuated inflammation in mice and zebrafishes, indicating the key role for SIRT3 in metazoan host defense. Collectively, these data strongly suggest that SIRT3 is a host-directed therapeutic target against Mabc infection by controlling mitochondrial homeostasis.
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http://dx.doi.org/10.1080/21505594.2020.1809961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549921PMC
December 2020

[F]CB251 PET/MR imaging probe targeting translocator protein (TSPO) independent of its Polymorphism in a Neuroinflammation Model.

Theranostics 2020 23;10(20):9315-9331. Epub 2020 Jul 23.

Department of Nuclear Medicine, Seoul National University Hospital, Republic of Korea.

The 18 kDa translocator protein (TSPO) has been proposed as a biomarker for the detection of neuroinflammation. Although various PET probes targeting TSPO have been developed, a highly selective probe for detecting TSPO is still needed because single nucleotide polymorphisms in the human TSPO gene greatly affect the binding affinity of TSPO ligands. Here, we describe the visualization of neuroinflammation with a multimodality imaging system using our recently developed TSPO-targeting radionuclide PET probe [F]CB251, which is less affected by TSPO polymorphisms. To test the selectivity of [F]CB251 for TSPO polymorphisms, 293FT cells expressing polymorphic TSPO were generated by introducing the coding sequences of wild-type (WT) and mutant (Alanine → Threonine at 147 Amino Acid; A147T) forms. Competitive inhibition assay was conducted with [H]PK11195 and various TSPO ligands using membrane proteins isolated from 293FT cells expressing TSPO WT or mutant-A147T, representing high-affinity binder (HAB) or low-affinity binder (LAB), respectively. IC values of each ligand to [H]PK11195 in HAB or LAB were measured and the ratio of IC values of each ligand to [H]PK11195 in HAB to LAB was calculated, indicating the sensitivity of TSPO polymorphism. Cellular uptake of [F]CB251 was measured with different TSPO polymorphisms, and phantom studies of [F]CB251-PET using 293FT cells were performed. To test TSPO-specific cellular uptake of [F]CB251, TSPO expression was regulated with pCMV-TSPO (or shTSPO)/eGFP vector. Intracranial lipopolysaccharide (LPS) treatment was used to induce regional inflammation in the mouse brain. Gadolinium (Gd)-DOTA MRI was used to monitor the disruption of the blood-brain barrier (BBB) and infiltration by immune cells. Infiltration of peripheral immune cells across the BBB, which exacerbates neuroinflammation to produce higher levels of neurotoxicity, was also monitored with bioluminescence imaging (BLI). Peripheral immune cells isolated from luciferase-expressing transgenic mice were transferred to syngeneic inflamed mice. Neuroinflammation was monitored with [F]CB251-PET/MR and BLI. To evaluate the effects of anti-inflammatory agents on intracranial inflammation, an inflammatory cytokine inhibitor, 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid methyl ester (CDDO-Me) was administered in intracranial LPS challenged mice. : The ratio of IC values of [F]CB251 in HAB to LAB indicated similar binding affinity to WT and mutant TSPO and was less affected by TSPO polymorphisms. [F]CB251 was specific for TSPO, and its cellular uptake reflected the amount of TSPO. Higher [F]CB251 uptake was also observed in activated immune cells. Simultaneous [F]CB251-PET/MRI showed that [F]CB251 radioactivity was co-registered with the MR signals in the same region of the brain of LPS-injected mice. Luciferase-expressing peripheral immune cells were located at the site of LPS-injected right striatum. Quantitative evaluation of the anti-inflammatory effect of CDDO-Me on neuroinflammation was successfully monitored with TSPO-targeting [F]CB251-PET/MR and BLI. Our results indicate that [F]CB251-PET has great potential for detecting neuroinflammation with higher TSPO selectivity regardless of polymorphisms. Our multimodal imaging system, [F]CB251-PET/MRI, tested for evaluating the efficacy of anti-inflammatory agents in preclinical studies, might be an effective method to assess the severity and therapeutic response of neuroinflammation.
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http://dx.doi.org/10.7150/thno.46875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415805PMC
July 2020

Factors associated with sleep disturbance in patients with chronic obstructive pulmonary disease.

Clin Respir J 2020 Nov 13;14(11):1018-1024. Epub 2020 Aug 13.

Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea.

Introduction: Poor sleep quality in patients with chronic obstructive pulmonary disease (COPD) has been associated with poor health outcomes. However, there is a lack of research on factors associated with sleep disturbance in patients with COPD.

Objectives: We investigated patterns of sleep disturbance and factors associated with sleep impairment in patients with COPD.

Methods: This was a prospective, multicenter cross-sectional study enrolling a sample of 245 COPD subjects. All patients completed the patient-reported measure, the COPD and Asthma Sleep Impact Scale (CASIS) to assess sleep impairment. The St. George's Respiratory Questionnaire (SGRQ), the 36-item Short-Form health survey (SF-36), Hospital Anxiety and Depression Scale (HADS), and the COPD Self-Efficacy Scale (CSES) were utilized to assess health-related quality of life (HRQL), anxiety/depression and self-efficacy, respectively.

Results: About 35.1% of the patients reported that they had a bad night's sleep. Univariate analysis showed that the CASIS total score was significantly correlated with the modified Medical Research Council dyspnea scale, SGRQ total score, SF-36 PCS, SF-36 MCS, HADS-A, HADS-D and CSES (all P < 0.05). In a multivariate analysis, SGRQ total (r = 0.19, P = 0.006), SF-36 PCS (r = 0.14, P = 0.037), HADS-D (r = 0.24, P ≤ 0.001), and CSES(r = -0.12, P = 0.010) were independently associated with the CASIS score.

Conclusions: In this study, 35% of clinically stable patients with COPD reported poor sleep quality. Depression, poorer HRQL and self-efficacy were significantly associated with sleep disturbance in patients with COPD.
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http://dx.doi.org/10.1111/crj.13235DOI Listing
November 2020

Structural Study of Metal Binding and Coordination in Ancient Metallo-β-Lactamase PNGM-1 Variants.

Int J Mol Sci 2020 Jul 12;21(14). Epub 2020 Jul 12.

Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea.

The increasing incidence of community- and hospital-acquired infections with multidrug-resistant (MDR) bacteria poses a critical threat to public health and the healthcare system. Although β-lactam antibiotics are effective against most bacterial infections, some bacteria are resistant to β-lactam antibiotics by producing β-lactamases. Among β-lactamases, metallo-β-lactamases (MBLs) are especially worrisome as only a few inhibitors have been developed against them. In MBLs, the metal ions play an important role as they coordinate a catalytic water molecule that hydrolyzes β-lactam rings. We determined the crystal structures of different variants of PNGM-1, an ancient MBL with additional tRNase Z activity. The variants were generated by site-directed mutagenesis targeting metal-coordinating residues. In PNGM-1, both zinc ions are coordinated by six coordination partners in an octahedral geometry, and the zinc-centered octahedrons share a common face. Structures of the PNGM-1 variants confirm that the substitution of a metal-coordinating residue causes the loss of metal binding and β-lactamase activity. Compared with PNGM-1, subclass B3 MBLs lack one metal-coordinating residue, leading to a shift in the metal-coordination geometry from an octahedral to tetrahedral geometry. Our results imply that a subtle change in the metal-binding site of MBLs can markedly change their metal-coordination geometry and catalytic activity.
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http://dx.doi.org/10.3390/ijms21144926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404133PMC
July 2020

Predictors of Low-Level Disease-Specific Knowledge in Patients with Chronic Obstructive Pulmonary Disease.

Int J Chron Obstruct Pulmon Dis 2020 19;15:1103-1110. Epub 2020 May 19.

Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea.

Background: Disease-specific knowledge is associated with outcomes of patients, but the knowledge level of chronic obstructive pulmonary disease (COPD) patients is known to be low.

Objective: We measured the level of disease-specific knowledge and defined factors associated with poor disease knowledge in COPD patients.

Materials And Methods: A cross-sectional survey was performed in five hospitals in South Korea. At enrolment, all patients completed the Bristol COPD Knowledge Questionnaire (BCKQ), Satisfaction with Life Scale (SWLS), Personal Resource Questionnaire (PRQ), St. George's Respiratory Questionnaire (SGRQ), 36-item Short-Form Health Survey (SF-36), and the Hospital Anxiety and Depression Scale (HADS). The data were analyzed via linear regression to identify factors associated with low-level knowledge of COPD.

Results: A total of 245 COPD patients were enrolled in this study. The mean total BCKQ score was 28.1 (SD, 7.4). The lowest scores were seen for items exploring knowledge of "Oral steroids" and "Inhaled steroids". In univariate analysis, higher level of education (r = 0.17), low income (r = 0.13), the post-bronchodilator FEV % predicted (r = -0.24), the post-bronchodilator FEV/FVC ratio (r = -0.13), SWLS (r = 0.15), PRQ (r = 0.16), SF-36 MCS (r = 0.13), HADS-A (r = -0.17), and HADS-D (r = -0.28) scores correlated with the BCKQ score (all < 0.05). FEV (r = -0.25, p < 0.001) and HADS-D score (r = -0.29, p < 0.001) were significantly associated with the total BCKQ score in multivariate analysis.

Conclusion: Our Korean patients with COPD lacked knowledge on oral and inhaled steroid treatments. In particular, patients with higher-level lung function and/or depressive symptoms exhibited poorer disease-specific knowledge; such patients may require additional education.
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http://dx.doi.org/10.2147/COPD.S244925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245443PMC
May 2020

Important factors causing high fatal cases of Naegleria fowleri primary amoebic meningoencephalitis in Pakistan.

Int J Infect Dis 2020 08 1;97:230-232. Epub 2020 Jun 1.

National Leading Research Laboratory, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 17058, South Korea. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2020.05.094DOI Listing
August 2020

Freshwater viral metagenome reveals novel and functional phage-borne antibiotic resistance genes.

Microbiome 2020 06 1;8(1):75. Epub 2020 Jun 1.

Department of Biological Sciences, Inha University, Incheon, 22212, Republic of Korea.

Background: Antibiotic resistance developed by bacteria is a significant threat to global health. Antibiotic resistance genes (ARGs) spread across different bacterial populations through multiple dissemination routes, including horizontal gene transfer mediated by bacteriophages. ARGs carried by bacteriophages are considered especially threatening due to their prolonged persistence in the environment, fast replication rates, and ability to infect diverse bacterial hosts. Several studies employing qPCR and viral metagenomics have shown that viral fraction and viral sequence reads in clinical and environmental samples carry many ARGs. However, only a few ARGs have been found in viral contigs assembled from metagenome reads, with most of these genes lacking effective antibiotic resistance phenotypes. Owing to the wide application of viral metagenomics, nevertheless, different classes of ARGs are being continuously found in viral metagenomes acquired from diverse environments. As such, the presence and functionality of ARGs encoded by bacteriophages remain up for debate.

Results: We evaluated ARGs excavated from viral contigs recovered from urban surface water viral metagenome data. In virome reads and contigs, diverse ARGs, including polymyxin resistance genes, multidrug efflux proteins, and β-lactamases, were identified. In particular, when a lenient threshold of e value of ≤ 1 × e and query coverage of ≥ 60% were employed in the Resfams database, the novel β-lactamases bla and bla were found. These genes had unique sequences, forming distinct clades of class A and subclass B3 β-lactamases, respectively. Minimum inhibitory concentration analyses for E. coli strains harboring bla and bla and catalytic kinetics of purified HRV-1 and HRVM-1 showed reduced susceptibility to penicillin, narrow- and extended-spectrum cephalosporins, and carbapenems. These genes were also found in bacterial metagenomes, indicating that they were harbored by actively infecting phages.

Conclusion: Our results showed that viruses in the environment carry as-yet-unreported functional ARGs, albeit in small quantities. We thereby suggest that environmental bacteriophages could be reservoirs of widely variable, unknown ARGs that could be disseminated via virus-host interactions. Video abstract.
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http://dx.doi.org/10.1186/s40168-020-00863-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265639PMC
June 2020

Toxicological evaluation of exosomes derived from human adipose tissue-derived mesenchymal stem/stromal cells.

Regul Toxicol Pharmacol 2020 Aug 22;115:104686. Epub 2020 May 22.

ExoCoBio Exosome Institute (EEI), ExoCoBio Inc., Seoul, 08594, Republic of Korea. Electronic address:

Several studies report that the therapeutic mechanism of action of mesenchymal stem/stromal cells (MSCs) is mainly mediated by paracrine factors that are released from MSCs such as exosomes. Exosomes are nano-sized extracellular vesicles that are transferred to target cells for cell-to-cell communication. Although MSC-derived exosomes (MSC-exosomes) are suggested as novel cell-free therapeutics for various human diseases, evaluation studies for the safety and toxicity of MSC-exosomes are limited. The purpose of our study was to evaluate the toxicological profile, including skin sensitization, photosensitization, eye and skin irritation, and acute oral toxicity using exosomes derived from human adipose tissue-derived MSCs (ASC-exosomes) in accordance with the OECD guidelines and the principles of Good Laboratory Practice. The ASC-exosomes were classified as a potential non-sensitizer in the skin sensitization test, UN GHS no category in the eye irritation test, and as a skin non-irritant in the skin irritation test, and did not induce any toxicity in the phototoxicity test or in acute oral toxicity testing. Our findings are the first to suggest that ASC-exosomes are safe for use as a topical treatment, with no adverse effects in toxicological testing, and have potential application as a therapeutic agent, cosmetic ingredient, or for other biological uses.
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http://dx.doi.org/10.1016/j.yrtph.2020.104686DOI Listing
August 2020

Loop-Mediated Isothermal Amplification (LAMP)-Based Turn on Fluorescent Paper (ToFP) Device for Detecting .

J Biomed Nanotechnol 2020 Feb;16(2):166-178

White root rot (WRR) disease caused by , a fungal pathogen, results in severe damage to various fruit trees, decreasing their marketability. Regular monitoring is a major process because the pathogen can remain in the soil around the host for a long time. Loop-mediated isothermal amplification (LAMP) is a highly sensitive and efficient amplification technology of nucleic acids (DNA or RNA) that can be performed at constant temperatures. Thus, it has been spotlighted as a useful tool for detecting several infectious agents. In the present study, LAMP-based Turn-on Fluorescent Paper (ToFP) devices were designed and applied to detect . LAMP conditions were optimized and found to be optimal at a reaction temperature (62 °C) and a reaction time (30 minutes). These reaction conditions were confirmed by applying them to infectious soil samples collected from the field. The limitation of detection was identified as 10 fg of genomic DNA under optimized LAMP conditions. These LAMP-based ToFP devices were generated with easily available stationery materials and the utility of these devices to analyze the LAMP results were confirmed through several experiments on a total of 14 field samples. The results showed that the developed LAMP-based detection system was very sensitive and had the advantages of rapid detection and high availability in the field.
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http://dx.doi.org/10.1166/jbn.2020.2889DOI Listing
February 2020

Effect of Early Tracheostomy on Clinical Outcomes in Patients with Prolonged Acute Mechanical Ventilation: A Single-Center Study.

Tuberc Respir Dis (Seoul) 2020 Apr;83(2):167-174

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea.

Background: The purpose of this study was to investigate the effect of early tracheostomy on clinical outcomes in patients requiring prolonged acute mechanical ventilation (≥96 hours).

Methods: Data from 575 patients (69.4% male; median age, 68 years), hospitalized in the medical intensive care unit (ICU) of a university-affiliated tertiary care hospital March 2008-February 2017, were retrospectively evaluated. Early and late tracheostomy were designated as 2-10 days and >10 days after translaryngeal intubation, respectively.

Results: The 90-day cumulative mortality rate was 47.5% (n=273) and 258 patients (44.9%) underwent tracheostomy. In comparison with the late group (n=115), the early group (n=125) had lower 90-day mortality (31.2% vs. 47.8%, p=0.012), shorter stays in hospital and ICU, shorter ventilator length of stay (median, 43 vs. 54; 24 vs. 33; 23 vs. 28 days; all p<0.001), and a higher rate of transfer to secondary care hospitals with post-intensive care settings (67.2% vs. 43.5% p<0.001). Also, the total medical costs of the early group were lower during hospital stays than those of the late group (26,609 vs. 36,973 USD, p<0.001).

Conclusion: Early tracheostomy was associated with lower 90-day mortality, shorter ventilator length of stay and shorter lengths of stays in hospital and ICU, as well as lower hospital costs than late tracheostomy.
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http://dx.doi.org/10.4046/trd.2019.0082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105433PMC
April 2020

Minimizing moving distance in deposition behavior of the subterranean termite.

Ecol Evol 2020 Feb 29;10(4):2145-2152. Epub 2020 Jan 29.

Division of Industrial Mathematics National Institute for Mathematical Sciences Daejeon Korea.

Subterranean termite nests are located underground and termites forage out by constructing tunnels to reach food resources, and tunneling behavior is critical in order to maximize the foraging efficiency. Excavation, transportation, and deposition behavior are involved in the tunneling, and termites have to move back and forth to do this. Although there are three sequential behaviors, excavation has been the focus of most previous studies. In this study, we investigated the deposition behavior of the Formosan subterranean termite, Shiraki, in experimental arenas having different widths (2, 3, and 4 mm), and characterized the function of deposited particles. We also simulated moving distance of the termites in different functions. Our results showed that total amounts of deposited particles were significantly higher in broad (4 mm width) than narrow (2 mm) tunnels and most deposited particles were observed near the tip of the tunnel regardless of tunnel widths. In addition, we found that deposited particles followed a quadratic decrease function, and simulation results showed that moving distance of termites in this function was the shortest. The quadratic decrease function of deposited particles in both experiment and simulation suggested that short moving distance in the decrease quadratic function is a strategy to minimize moving distance during the deposition behavior.
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http://dx.doi.org/10.1002/ece3.6051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042759PMC
February 2020

The relationship between acrosome reaction and polyunsaturated fatty acid composition in boar sperm.

Reprod Domest Anim 2020 May 15;55(5):624-631. Epub 2020 Mar 15.

College of Animal Life Sciences, Kangwon National University, Chuncheon, Korea.

This study investigated the relationship between acrosome reactions and fatty acid composition with respect to fertility in boar sperm. The acrosome reaction was induced more than 85% by 60 mM methyl-beta-cyclodextrin (MBCD), and plasma membrane integrity was significantly reduced dependent on the MBCD level in boar sperm (p < .05). The acrosome-reacted sperm exhibited significantly higher saturated fatty acids (SFAs) and lower polyunsaturated fatty acids (PUFAs) composition compared to the non-acrosome reaction group (p < .0001). In addition, the PUFAs, C22:5n-6 (docosapentaenoic acid [DPA]; p < .01) and C22:6n-3 (docosahexaenoic acid [DHA]; p < .0001) were significantly decreased, and cleavage and blastocyst formation of oocytes were significantly (p < .0001) decreased in acrosome-reacted sperm relative to non-acrosome-reacted sperm. Moreover, acrosome reaction was positively correlated with SFAs, whereas negatively correlated with PUFAs, of the PUFAs, the DPA (p = .0005) and DHA (p = <.0001) were negatively correlated with the acrosome reaction. Therefore, these results suggest that the PUFAs composition of sperm is closely involved in acrosome reaction in pigs.
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http://dx.doi.org/10.1111/rda.13661DOI Listing
May 2020

Inhibits the Differentiation of Osteoclasts and Prevents Ovariectomy-Induced Bone Loss.

Evid Based Complement Alternat Med 2020 7;2020:1927017. Epub 2020 Feb 7.

Research Group of Natural Materials and Metabolism, Food Functionality Research, Korea Food Research Institute, Jeollabuk-do, Republic of Korea.

Bone homeostasis is dynamically balanced between bone forming osteoblasts and bone resorbing osteoclasts. Osteoclasts play an important role in bone destruction and osteoporosis, and they are derived from monocyte/macrophages in response to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor B (NF-B) ligand (RANKL). L. (AM) is a plant with powerful antioxidant and other biological activities including anti-inflammatory, antidiabetic, and antihyperlipidemic effects. However, its effects on bone health are unknown. In this study, we explored whether AM could affect RANK-mediated osteoclastogenesis. AM significantly suppressed RANKL-induced osteoclast differentiation and expression of osteoclast-specific genes, TRAP, cathepsin K, NF-activated T-cells (NFATc1), and Dc-stamp in RAW 264.7 cells. Moreover, AM significantly inhibited extracellular signal-regulated kinase (ERK), Akt, and NF-B signaling pathways in RAW 264.7 cells. In addition, AM preserved ovariectomy-induced bone loss in mice. Taken together, our results suggest that AM might be a potential candidate for the treatment of postmenopausal osteoporosis.
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http://dx.doi.org/10.1155/2020/1927017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029261PMC
February 2020

Clinical Outcomes after Apical Surgery on the Palatal Root of the Maxillary First Molar Using a Palatal Approach.

J Endod 2020 Apr 20;46(4):464-470. Epub 2020 Feb 20.

Microscope Center, Department of Conservative Dentistry and Oral Science Research Center, College of Dentistry, Yonsei University, Seoul, Korea. Electronic address:

Introduction: Clinicians are often reluctant to use the palatal approach in apical surgery for the maxillary first molar. This study aimed to investigate the outcomes and complications associated with apical surgery on the palatal root of the maxillary first molar by using a palatal approach.

Methods: We searched for patients who underwent apical surgery with a palatal approach on the palatal root of the maxillary first molar between March 2010 and September 2017 by a single operator. A total of 46 teeth from 46 subjects were included, and they were examined at 6 and 12 months after surgery and annually thereafter. To evaluate whether there was nerve damage on the surgical side, a pinprick test and cotton swab test were used with a 0-10 numerical rating scale, and the results were statistically compared by using the Wilcoxon signed-rank test.

Results: Of the total 35 recall cases (recall rate, 76%; average follow-up time, 3.5 years), success was considered achieved in 32; 30 cases showed complete healing, and 2 had incomplete healing. Three cases resulted in failure, all occurring within 1 year after surgery. The pinprick test results showed that all the numerical rating scale scores were higher than 7, and the responses on the surgical site were not statistically different from those on the contralateral site (P = .109). All subjects showed normosensitivity to the cotton swab test.

Conclusions: Apical surgery on the palatal root of the maxillary first molar using a palatal approach was predictable and successful, and the number of complications resulting from artery and nerve damage was small.
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http://dx.doi.org/10.1016/j.joen.2020.01.005DOI Listing
April 2020

Multimodal Imaging Probe Development for Pancreatic β Cells: From Fluorescence to PET.

J Am Chem Soc 2020 02 10;142(7):3430-3439. Epub 2020 Feb 10.

Laboratory of Bioimaging Probe Development , Singapore Bioimaging Consortium, Agency for Science, Technology and Research , Singapore 138667 , Singapore.

Pancreatic β cells are responsible for insulin secretion and are important for glucose regulation in a healthy body and diabetic disease patient without prelabeling of islets. While the conventional biomarkers for diabetes have been glucose and insulin concentrations in the blood, the direct determination of the pancreatic β cell mass would provide critical information for the disease status and progression. By combining fluorination and diversity-oriented fluorescence library strategy, we have developed a multimodal pancreatic β cell probe for both fluorescence and for PET (positron emission tomography). By simple tail vein injection, stains pancreatic β cells specifically and allows intraoperative fluorescent imaging of pancreatic islets. -injected pancreatic tissue even facilitated an antibody-free islet analysis within 2 h, dramatically accelerating the day-long histological procedure without any fixing and dehydration step. Not only islets in the pancreas but also the low background of in the liver allowed us to monitor the intraportal transplanted islets, which is the first in vivo visualization of transplanted human islets without a prelabeling of the islets. Finally, we could replace the built-in fluorine atom in with radioactive 18F and successfully demonstrate in situ PET imaging for pancreatic islets.
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http://dx.doi.org/10.1021/jacs.9b11173DOI Listing
February 2020

The potential function of endometrial-secreted factors for endometrium remodeling during the estrous cycle.

Anim Sci J 2020 Jan-Dec;91(1):e13333. Epub 2020 Jan 7.

College of Animal Life Sciences, Kangwon National University, Chuncheon, Republic of Korea.

Uterine has a pivotal role in implantation and conceptus development. To prepare a conducive uterine condition for possibly new gestation during the estrous cycle, uterine endometrium undergoes dramatic remodeling. In addition, angiogenesis is an indispensable biological process of endometrium remodeling. Furthermore, essential protein expressions related to important biological processes of endometrium remodeling, which are vascular endothelial growth factor (VEGF), myoglobin (MYG), collagen type IV (COL4), fucosyltransferase IV (FUT4), and cysteine-rich protein 2 (CRP2), were detected in the endometrial tissue reported in many previous studies and recently discovered in histotroph substrates during the estrous cycle. Those proteins, which are liable for provoking new vessel development, cell proliferation, cell adhesion, and cell migration, were expressed higher in the histotroph during the luteal phase than follicular phase. Histotroph proteins considerably contribute to endometrium remodeling during the estrous cycle. To that end, the following review will discuss and highlight the relevant information and evidence of the uterine fluid proteins as endometrial-secreted factors that adequately indicate the potential role of the uterine secretions to be involved in the endometrial remodeling process.
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http://dx.doi.org/10.1111/asj.13333DOI Listing
August 2020

The Occurrence and Characterization of Extended-Spectrum-Beta-Lactamase-Producing Isolated from Clinical Diagnostic Specimens of Equine Origin.

Animals (Basel) 2019 Dec 21;10(1). Epub 2019 Dec 21.

Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77845, USA.

isolates were recovered from clinical specimens of equine patients admitted to the Texas A&M Veterinary Medical Teaching Hospital over a five-year period. Ceftiofur resistance was used as a marker for potential extended-spectrum beta-lactamase (ESBL)-activity, and of the 48 ceftiofur-resistant isolates, 27.08% ( = 13) were phenotypically ESBL-positive. Conventional PCR analysis followed by the Finder multiplex PCR detected the ESBL genes, CTX-M-1 and SHV, in seven out of the 13 isolates. Moreover, beta-lactamase genes of TEM-1-type, BER-type (AmpC), and OXA-type were also identified. Sequencing of these genes resulted in identification of a novel TEM-1-type gene, called , and a study is currently underway to determine if this gene confers the ESBL phenotype. Furthermore, this report is the first to have found ST1308 in horses. This subtype, which has been reported in other herbivores, harbored the SHV-type ESBL gene. Finally, one out of 13 E. coli isolates was PCR-positive for the carbapenemase gene, despite the lack of phenotypically proven resistance to imipenem. With the identification of novel ESBL gene variant and the demonstrated expansion of sequence types in equine patients, this study underscores the need for more investigation of equines as reservoirs for ESBL-producing pathogens.
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http://dx.doi.org/10.3390/ani10010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022413PMC
December 2019

Dual activity of PNGM-1 pinpoints the evolutionary origin of subclass B3 metallo--lactamases: a molecular and evolutionary study.

Emerg Microbes Infect 2019 ;8(1):1688-1700

National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, Yongin, Republic of Korea.

Resistance to -lactams is one of the most serious problems associated with Gram-negative infections. -Lactamases are able to hydrolyze -lactams such as cephalosporins and/or carbapenems. Evolutionary origin of metallo--lactamases (MBLs), conferring critical antibiotic resistance threats, remains unknown. We discovered PNGM-1, the novel subclass B3 MBL, in deep-sea sediments that predate the antibiotic era. Here, our phylogenetic analysis suggests that PNGM-1 yields insights into the evolutionary origin of subclass B3 MBLs. We reveal the structural similarities between tRNase Zs and PNGM-1, and demonstrate that PNGM-1 has both MBL and tRNase Z activities, suggesting that PNGM-1 is thought to have evolved from a tRNase Z. We also show kinetic and structural comparisons between PNGM-1 and other proteins including subclass B3 MBLs and tRNase Zs. These comparisons revealed that the B3 MBL activity of PNGM-1 is a promiscuous activity and subclass B3 MBLs are thought to have evolved through PNGM-1 activity.
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http://dx.doi.org/10.1080/22221751.2019.1692638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882493PMC
December 2019