Publications by authors named "Eunhye Lee"

63 Publications

Comparison of Recurrent Laryngeal Nerve Identification Time in the Lower Central Triangle during Thyroid Surgery Using Neurophysiological Mapping and Monitoring.

Medicina (Kaunas) 2021 Jul 24;57(8). Epub 2021 Jul 24.

Department of Surgery, Seoul National University Hospital and College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea.

Preserving the recurrent laryngeal nerve (RLN) is important in thyroid surgery. However, no standardized surgical method for locating the RLN has been established. We defined a new anatomical definition termed "lower central triangle" (LCT) for consistent identification of RLN and used intraoperative nerve monitoring (IONM) to aid in identification and dissection of RLN. Patients undergone thyroidectomy were reviewed retrospectively in Seoul National University Bundang Hospital from January to September 2017. Patients with papillary thyroid carcinoma, follicular neoplasm, and Graves' Disease were included while right side non-RLN in arteriosus lusoria, cancer invasion, pre-existing vocal cord palsy, or under the age of 18 were excluded. RLNs were tested with IONM within LCT consisting of the lower pole as the apex and the common carotid artery as the opposite side. The samples were divided into two groups, IONM and non-IONM. Forty lobes in total were included, 22 in IONM group and 18 in non-IONM group. Groups were not significantly different in age, cancer proportion, and accompanying thyroiditis while sex and nodule size differed. RLN detection time was 10.43 s shorter ( < 0.001), and confirmation time was 10.67 s shorter ( = 0.09) in IONM group than in non-IONM group. Both right and left RLNs were located predominately in the middle of LCT. No transient or permanent vocal cord palsy occurred. While IONM is an appropriate aid for thyroidectomy, our approach using LCT to locate the RLN is a novel definition of anatomy that provides prompt identification of the RLN in thyroid surgery.
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http://dx.doi.org/10.3390/medicina57080748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401649PMC
July 2021

Direct aspiration thrombectomy as a first-pass approach for very elderly patients with ischemic stroke.

Clin Neurol Neurosurg 2021 08 6;207:106797. Epub 2021 Jul 6.

Department of Neurosurgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Objective: This study aimed to determine whether an age of ≥ 80 years would affect the radiological and clinical outcomes of the direct aspiration first pass strategy for large vessel occlusion.

Methods: This study analyzed single-center data of patients with stroke who were treated with mechanical thrombectomy between May 2018 and October 2020. Baseline characteristics, as well as radiological and clinical outcomes of patients were recorded, analyzed, and compared between the very elderly (≥80 years) and elderly patients (<80 years).

Results: Sixty patients underwent mechanical thrombectomy using the Sofia aspiration catheter for mainstem occlusion of the middle cerebral artery. The direct aspiration first pass strategy was effective in 56.3% (n = 9) and 54.4% (n = 24) in the very elderly and elderly groups, respectively (p = 0.907). The final successful recanalization rates (thrombolysis in cerebral infarction ≥2b) were 75.0% (n = 12) and 70.5% (n = 31) in the very elderly group and elderly groups, respectively (p = 0.999). There was no significant between-group difference in the good 90-day clinical outcome (modified Rankin Scale ≤2) (50.0% and 56.8% in the very elderly and elderly groups, respectively, p = 0.639). Further, there were no significant between-group differences in complication rates.

Conclusion: There was no difference in the recanalization rates and clinical outcomes of the direct aspiration first-pass strategy for patients aged ≥ 80 and < 80 years with occlusive lesions in large vessels.
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http://dx.doi.org/10.1016/j.clineuro.2021.106797DOI Listing
August 2021

Histopathological assessment of laterality defects in zebrafish development.

Anim Cells Syst (Seoul) 2021 26;25(3):136-145. Epub 2021 May 26.

Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea.

Laterality defects during embryonic development underlie the aetiology of various clinical symptoms of neuropathological and cardiovascular disorders; however, experimental approaches to understand the underlying mechanisms are limited due to the complex organ systems of vertebrate models. Zebrafish have the ability to survive even when the heart stops beating for a while during early embryonic development and those adults with cardiac abnormalities. Therefore, we induced laterality defects and investigated the occurrence of situs solitus, situs inversus, and situs ambiguus in zebrafish development. Histopathological analysis revealed heterotaxy in both embryos and juvenile fish. Additionally, randomization of left-right asymmetry of the brain and heart in individual zebrafish embryos under artificial experimental pressure further demonstrated the advantage of transparent zebrafish embryos as an experimental tool to select or reduce the embryos with laterality defects during early embryonic development for long-term studies, including behavioural and cognitive neuroscience investigations.
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http://dx.doi.org/10.1080/19768354.2021.1931443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253201PMC
May 2021

A Novel N-terminal Region to Chromodomain in CHD7 is Required for the Efficient Remodeling Activity.

J Mol Biol 2021 Sep 21;433(18):167114. Epub 2021 Jun 21.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), KAIST Institute of BioCentury, Daejeon 34141, Korea. Electronic address:

Chromodomain-Helicase DNA binding protein 7 (CHD7) is an ATP dependent chromatin remodeler involved in maintaining open chromatin structure. Mutations of CHD7 gene causes multiple developmental disorders, notably CHARGE syndrome. However, there is not much known about the molecular mechanism by which CHD7 remodels nucleosomes. Here, we performed biochemical and biophysical analysis on CHD7 chromatin remodeler and uncover that N-terminal to the Chromodomain (N-CRD) interacts with nucleosome and contains a high conserved arginine stretch, which is reminiscent of arginine anchor. Importantly, this region is required for efficient ATPase stimulation and nucleosome remodeling activity of CHD7. Furthermore, smFRET analysis shows the mutations in the N-CRD causes the defects in remodeling activity. Collectively, our results uncover the functional importance of a previously unidentified N-terminal region in CHD7 and implicate that the multiple domains in chromatin remodelers are involved in regulating their activities.
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http://dx.doi.org/10.1016/j.jmb.2021.167114DOI Listing
September 2021

A molecular approach to rationally constructing specific fluorogenic substrates for the detection of acetylcholinesterase activity in live cells, mice brains and tissues.

Chem Sci 2020 Sep 22;11(41):11285-11292. Epub 2020 Sep 22.

Department of Chemistry and Nanoscience, Ewha Womans University Seoul 03760 Republic of Korea

Acetylcholinesterase (AChE) is an extremely critical hydrolase tightly associated with neurological diseases. Currently, developing specific substrates for imaging AChE activity still remains a great challenge due to the interference from butyrylcholinesterase (BChE) and carboxylesterase (CE). Herein, we propose an approach to designing specific substrates for AChE detection by combining dimethylcarbamate choline with a self-immolative scaffold. The representative can effectively eliminate the interference from CE and BChE. The high specificity of has been proved imaging AChE activity in cells. Moreover, can also be used to successfully map AChE activity in different regions of a normal mouse brain, which may provide important data for AChE evaluation in clinical studies. Such a rational and effective approach can also provide a solid basis for designing probes with different properties to study AChE in biosystems and another way to design specific substrates for other enzymes.
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http://dx.doi.org/10.1039/d0sc04213gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162927PMC
September 2020

Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase.

Nat Commun 2021 05 5;12(1):2530. Epub 2021 May 5.

Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, USA.

Flaviviruses use a ~70 nucleotide stem-loop structure called stem-loop A (SLA) at the 5' end of the RNA genome as a promoter for RNA synthesis. Flaviviral polymerase NS5 specifically recognizes SLA to initiate RNA synthesis and methylate the 5' guanosine cap. We report the crystal structures of dengue (DENV) and Zika virus (ZIKV) SLAs. DENV and ZIKV SLAs differ in the relative orientations of their top stem-loop helices to bottom stems, but both form an intermolecular three-way junction with a neighboring SLA molecule. To understand how NS5 engages SLA, we determined the SLA-binding site on NS5 and modeled the NS5-SLA complex of DENV and ZIKV. Our results show that the gross conformational differences seen in DENV and ZIKV SLAs can be compensated by the differences in the domain arrangements in DENV and ZIKV NS5s. We describe two binding modes of SLA and NS5 and propose an SLA-mediated RNA synthesis mechanism.
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http://dx.doi.org/10.1038/s41467-021-22846-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100141PMC
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

Renal Protective Effect of Beluga Lentil Pretreatment for Ischemia-Reperfusion Injury.

Biomed Res Int 2021 31;2021:6890679. Epub 2021 Jan 31.

Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea.

Materials And Methods: Mice were divided into four groups: normal, untreated, low- (2 mg), and high-dose (8 mg) beluga lentil treatment groups. Beluga lentil was orally administered for 2 weeks, followed by bilateral renal ischemia for 20 min and reperfusion for 30 min. Blood samples and kidney tissues were collected and analyzed to investigate renal function, histopathology, epithelial and endothelial cell damage, apoptosis, oxidative stress, and inflammatory responses.

Results: The pretreated groups maintained renal function, with significantly lower blood urea nitrogen (BUN) and creatinine levels, compared with the other groups. The histopathological analysis showed reduced proximal tubule injury and decreased injury-related molecule (kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)) secretion in the pretreated groups compared with the other groups. Terminal deoxynucleotidyl transferase dUTP nick-end labeling- (TUNEL-) positive cells and the secretion of apoptosis-related molecules (Fas and caspase 3) were significantly reduced in the pretreated groups compared with the other groups. The pretreated groups showed positive microvessel-associated gene (cluster of differentiation (CD31)) expression and negative adhesion molecule (intracellular adhesion molecule 1 (ICAM-1)) expression. An antioxidant effect was observed in the pretreatment groups, with reduced malonaldehyde (MDA) expression and increased antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx)) secretion. In the pretreated groups, F4/80+ macrophages and CD4+ T cell infiltration were inhibited and proinflammatory cytokine (interleukin- (IL-) 1, IL-6, and tumor necrosis factor- (TNF-) ) levels decreased; however, the levels of anti-inflammatory cytokines (transforming growth factor- (TGF-) , IL-10, and IL-22) increased.

Conclusions: Beluga lentil pretreatment demonstrated protective effects against I/R-induced renal damage, via antiapoptotic, anti-inflammatory, and antioxidant activities.
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http://dx.doi.org/10.1155/2021/6890679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868138PMC
May 2021

IL-10 Deficiency Aggravates Renal Inflammation, Fibrosis and Functional Failure in High-Fat Dieted Obese Mice.

Tissue Eng Regen Med 2021 06 5;18(3):399-410. Epub 2021 Feb 5.

Department of Internal Medicine, School of Medicine, Yeungnam University, Daegu, Republic of Korea.

Background: High-fat diet-induced obesity is one of the major cause of chronic renal failure. This obesity-related renal failure is mainly caused by inflammatory processes. However, the role of the major anti-inflammatory cytokine interleukin (IL)-10 has not been researched intensively.

Methods: To evaluate the effect of IL-10 deficiency on obesity-related renal failure, the in vivo study was carried with four animal groups; (1) Low-fat dieted C57BL/6 mice, (2) Low-fat dieted IL-10 knockout (KO) mice, (3) High-fat dieted C57BL/6 mice and (4) High-fat dieted IL-10 KO mice group. The analysis was carried with blood/urine chemistry, H&E, Oil-Red-O, periodic acid-Schiff and Masson's trichrome staining immunohistochemistry and real-time PCR methods.

Results: At week 12, high-fat dieted IL-10 KO mice showed 1) severe lipid accumulation in kidneys, cholesterol elevation (in total, serum kidney) and low-density lipoprotein increasion through the SCAP-SREBP2-LDLr pathway; (2) serious histopathologic alterations showing glomerulosclerosis, tubulointerstitial fibrosis and immune cell infiltration; (3) increased pro-inflammatory cytokines and chemokines expression; (4) enhanced renal fibrosis; and (5) serious functional failure with high serum creatinine and BUN and proteinuria excretion compared to other groups.

Conclusion: IL-10 deficiency aggravates renal inflammation, fibrosis and functional failure in high-fat dieted obese mice, thus IL-10 therapy could be applied to obesity-related chronic renal failure.
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http://dx.doi.org/10.1007/s13770-020-00328-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169746PMC
June 2021

Yeast Chd1p Unwraps the Exit Side DNA upon ATP Binding to Facilitate the Nucleosome Translocation Occurring upon ATP Hydrolysis.

Biochemistry 2020 12 11;59(47):4481-4487. Epub 2020 Nov 11.

Department of Physics and Astronomy, Institute of Applied Physics, Seoul National University, Seoul 08826, Republic of Korea.

Chromodomain-helicase-DNA-binding protein 1 (CHD1) remodels chromatin by translocating nucleosomes along DNA, but its mechanism remains poorly understood. We use single-molecule fluorescence experiments to clarify the mechanism by which yeast CHD1 (Chd1p) remodels nucleosomes. We find that binding of ATP to Chd1p induces transient unwrapping of the DNA on the exit side of the nucleosome, facilitating nucleosome translocation. ATP hydrolysis is required to induce nucleosome translocation. The unwrapped DNA after translocation is then rewrapped after the release of the hydrolyzed nucleotide and phosphate, revealing that each step of the ATP hydrolysis cycle is responsible for a distinct step of nucleosome remodeling. These results show that Chd1p remodels nucleosomes via a mechanism that is unique among the other ATP-dependent chromatin remodelers.
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http://dx.doi.org/10.1021/acs.biochem.0c00747DOI Listing
December 2020

Differential expression of microRNAs in the saliva of patients with aggressive periodontitis: a pilot study of potential biomarkers for aggressive periodontitis.

J Periodontal Implant Sci 2020 Oct;50(5):281-290

Department of Periodontics, Asan Medical Center, Seoul, Korea.

Purpose: The aim of this study was to compare microRNA (miRNA) gene expression in saliva using miRNA polymerase chain reaction (PCR) arrays in healthy and aggressive periodontitis (AP) patients.

Methods: PCR arrays of 84 miRNAs related to the human inflammatory response and autoimmunity from the saliva samples of 4 patients with AP and 4 healthy controls were performed. The functions and diseases related to the miRNAs were obtained using TAM 2.0. Experimentally validated targets of differentially expressed miRNAs were obtained from mirTarBase. Gene ontology terms and pathways were analyzed using ConsensusPathDB.

Results: Four downregulated miRNAs (hsa-let-7a-5p, hsa-let-7f-5p, hsa-miR-181b-5p, and hsa-miR-23b-3p) were identified in patients with AP. These miRNAs are associated with cell death and innate immunity, and they target genes associated with osteoclast development and function.

Conclusions: This study is the first analysis of miRNAs in the saliva of patients with AP. Identifying discriminatory human salivary miRNA biomarkers reflective of periodontal disease in a non-invasive screening assay is crucial for the development of salivary diagnostics. These data provide a first step towards the discovery of key salivary miRNA biomarkers for AP.
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http://dx.doi.org/10.5051/jpis.2000120006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606899PMC
October 2020

Plasma Long Noncoding RNA is a Potential Diagnostic Marker for Non-Alcoholic Steatohepatitis.

Life (Basel) 2020 Oct 3;10(10). Epub 2020 Oct 3.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 41944, Korea.

Non-invasive diagnostic markers are needed to ease the diagnosis of non-alcoholic steatohepatitis (NASH) among patients with non-alcoholic fatty liver disease (NAFLD). The long noncoding RNA (lncRNA) is related to cholesterol metabolism and hepatic steatosis in mice, and its batch genome conversion in humans is TCONS_00016452. Here, we aimed to evaluate the potential of lncRNA as a non-invasive diagnostic marker for NASH. We analyzed a total of 44 NAFLD patients whose diagnosis was confirmed by a pathologist through analysis of a percutaneous liver biopsy. The expression of in the plasma of NAFLD patients with and without NASH was compared using quantitative real-time polymerase chain reaction. The expression of plasma was significantly higher in patients with NASH than in those with NAFL (8.2 (5.0-14.9); 4.6 (4.0-6.6), = 0.025). The area under the receiver operating characteristic curve was 0.743 (95% CI 0.590-0.895, < 0.001), and a sensitivity of 54.3% and specificity of 100% could be achieved for NASH diagnosis. Low was independently associated with NASH diagnosis in patients with NAFLD ( = 0.0349, odds ratio = 22.19 (5% CI, 1.25-395.22)). Therefore, circulating lncRNA could be a potential non-invasive diagnostic biomarker for NASH.
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http://dx.doi.org/10.3390/life10100230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601228PMC
October 2020

EMPAS: Electron Microscopy Screening for Endogenous Protein Architectures.

Mol Cells 2020 Sep;43(9):804-812

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

In cells, proteins form macromolecular complexes to execute their own unique roles in biological processes. Conventional structural biology methods adopt a bottom-up approach starting from defined sets of proteins to investigate the structures and interactions of protein complexes. However, this approach does not reflect the diverse and complex landscape of endogenous molecular architectures. Here, we introduce a top-down approach called Electron Microscopy screening for endogenous Protein ArchitectureS (EMPAS) to investigate the diverse and complex landscape of endogenous macromolecular architectures in an unbiased manner. By applying EMPAS, we discovered a spiral architecture and identified it as AdhE. Furthermore, we performed screening to examine endogenous molecular architectures of human embryonic stem cells (hESCs), mouse brains, cyanobacteria and plant leaves, revealing their diverse repertoires of molecular architectures. This study suggests that EMPAS may serve as a tool to investigate the molecular architectures of endogenous macromolecular proteins.
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http://dx.doi.org/10.14348/molcells.2020.0163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528680PMC
September 2020

A boronic acid-functionalized phthalocyanine with an aggregation-enhanced photodynamic effect for combating antibiotic-resistant bacteria.

Chem Sci 2020 Jun 18;11(22):5735-5739. Epub 2020 May 18.

Department of Chemistry and Nanoscience , Ewha Womans University , Seoul 120-750 , Republic of Korea . Email:

Most existing photosensitizers (, porphyrins) are often aggregated in aqueous solution because of their large conjugated molecular structures. This aggregation usually results in a lack or low levels of reactive oxygen species (ROS) generation due to aggregation-caused quenching, which severely hampers the application of photosensitizers in photodynamic therapy (PDT). Herein, we make an interesting finding that a boronic acid-functionalized phthalocyanine (PcN4-BA) displays an uncommon phenomenon, an aggregation-enhanced photodynamic effect. The combination of the ability to form uniform nanostructured self-assemblies in water, highly efficient ROS generation and boronic acid-induced targeting give PcN4-BA excellent performances in antimicrobial PDT.
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http://dx.doi.org/10.1039/d0sc01351jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425080PMC
June 2020

Expression of the Long Noncoding RNA GAS5 Correlates with Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease.

Genes (Basel) 2020 05 13;11(5). Epub 2020 May 13.

Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea.

Background: Advanced liver fibrosis is the most important prognostic factor in nonalcoholic fatty liver disease (NAFLD). The long noncoding RNA (lncRNA), growth arrest-specific transcript 5 (GAS5), is associated with the inhibition of liver fibrogenesis, and its levels are decreased in cirrhotic liver.

Methods: We analyzed 51 patients with NAFLD, the diagnosis of which was confirmed by liver biopsy. Expression of GAS5 in both the liver and plasma of the patients was analyzed using a quantitative real-time polymerase chain reaction according to the fibrosis stage.

Results: Plasma GAS5 expression was significantly higher in patients with advanced fibrosis than in those without. As the fibrosis progressed, GAS5 expression in plasma increased, with the exception of that in cirrhotic livers. Plasma levels of GAS5 were lower in patients with cirrhosis than in those with advanced fibrosis.

Conclusion: Elevated circulating levels of the lncRNA GAS5 are associated with the progression of liver fibrosis prior to the development of cirrhosis.
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http://dx.doi.org/10.3390/genes11050545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291058PMC
May 2020

WRKY10 transcriptional regulatory cascades in rice are involved in basal defense and Xa1-mediated resistance.

J Exp Bot 2020 06;71(12):3735-3748

National Institute of Agricultural Science, Rural Development Administration, Jeonju, Korea.

WRKY proteins play essential roles as negative or positive regulators of pathogen defense. This study explored the roles of different OsWRKY proteins in basal defense and Xa1-mediated resistance to Xanthomonas oryzae pv. oryzae (Xoo) infection in rice. Assays of disease in OsWRKY10KD and OsWRKY88KD lines following infection with an incompatible Xoo race, which induced Xa1-mediated resistance in wild-type plants, showed that OsWRKY10 and OsWRKY88 were positive regulators of Xa1-mediated resistance. OsWRKY10 also acted as a positive regulator in basal defense by directly or indirectly activating transcription of defense-related genes. OsWRKY10 activated the OsPR1a promoter by binding to specific WRKY binding sites. Two transcriptional regulatory cascades of OsWRKY10 were identified in basal defense and Xa1-mediated resistance. In the first transcriptional regulatory cascade, OsWRKY47 acted downstream of OsWRKY10 whereas OsWRKY51 acted upstream. OsWRKY10 activated OsPR1a in two distinct ways: by binding to its promoter and, at the same time, by indirect activation through OsWRKY47. In the second transcriptional regulatory cascade, OsWRKY47 acted downstream of OsWRKY10, and OsWRKY88 acted upstream. These OsWRKY10 transcriptional regulatory cascades played important roles in basal defense and Xa1-mediated resistance to enable the mounting of a rapid immune response against pathogens.
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http://dx.doi.org/10.1093/jxb/eraa135DOI Listing
June 2020

Identification of the Antidepressant Vilazodone as an Inhibitor of Inositol Polyphosphate Multikinase by Structure-Based Drug Repositioning.

Mol Cells 2020 Mar;43(3):222-227

Department of Biological Sciences, KAIST, Daejeon 34141, Korea.

Inositol polyphosphate multikinase (IPMK) is required for the biosynthesis of inositol phosphates (IPs) through the phosphorylation of multiple IP metabolites such as IP3 and IP4. The biological significance of IPMK's catalytic actions to regulate cellular signaling events such as growth and metabolism has been studied extensively. However, pharmacological reagents that inhibit IPMK have not yet been identified. We employed a structure-based virtual screening of publicly available U.S. Food and Drug Administration-approved drugs and chemicals that identified the antidepressant, vilazodone, as an IPMK inhibitor. Docking simulations and pharmacophore analyses showed that vilazodone has a higher affinity for the ATP-binding catalytic region of IPMK than ATP and we validated that vilazodone inhibits IPMK's IP kinase activities in vitro . The incubation of vilazodone with NIH3T3-L1 fibroblasts reduced cellular levels of IP5 and other highly phosphorylated IPs without influencing IP4 levels. We further found decreased Akt phosphorylation in vilazodone-treated HCT116 cancer cells. These data clearly indicate selective cellular actions of vilazodone against IPMK-dependent catalytic steps in IP metabolism and Akt activation. Collectively, our data demonstrate vilazodone as a method to inhibit cellular IPMK, providing a valuable pharmacological agent to study and target the biological and pathological processes governed by IPMK.
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http://dx.doi.org/10.14348/molcells.2020.0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103885PMC
March 2020

Reactive oxygen species (ROS)-responsive ferrocene-polymer-based nanoparticles for controlled release of drugs.

J Mater Chem B 2020 03;8(9):1906-1913

Center for Convergence Bioceramic Materials, Convergence R&D Division, Korea Institute of Ceramic Engineering and Technology, 202, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea.

Ferrocene-containing nanoparticles show reversible redox activity that could trigger drug release mediated by reactive oxygen species (ROS). In this study, four ferrocene-containing polymers, comprising ferrocenylmethyl methacrylate (FMMA)-methacrylic acid (MA) random copolymers, i.e., poly(FMMA-r-MA), were synthesized via radical polymerization, resulting in self-assembled ferrocene nanoparticles (FNPs) with outstanding performance in environments in which ROS are present. These spherical FNPs have tunable diameters ranging from 270 nm to 180 nm and surface charges from -20 mV to -50 mV. Importantly, the diameters and surface charges of the FNPs changed dramatically after 2 h of post-treatment using 0.4 M hydrogen peroxide (H2O2) as the oxidant, indicating that the FNPs were highly ROS-sensitive. Furthermore, the controlled release of a model drug from the FNPs, reflected in the release profiles, indicates that these novel FNPs could be potentially used as drug carriers for the effective therapy of ROS-related diseases such as cancer and inflammation.
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http://dx.doi.org/10.1039/c9tb02533bDOI Listing
March 2020

Sex-biased differences in the correlation between epithelial-to-mesenchymal transition-associated genes in cancer cell lines.

Oncol Lett 2019 Dec 29;18(6):6852-6868. Epub 2019 Oct 29.

Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea.

There is a wide disparity in the incidence, malignancy and mortality of different types of cancer between each sex. The sex-specificity of cancer seems to be dependent on the type of cancer. Cancer incidence and mortality have been demonstrated as sex-specific in a number of different types of cancer, such as liver cancer, whereas sex-specificity is not noticeable in certain other types of cancer, including colon and lung cancer. The present study aimed to elucidate the molecular basis for sex-biased gene expression in cancer. The mRNA expression of the epithelial-to-mesenchymal transition-associated genes was investigated, including E-cadherin (also termed CDH1), vimentin (VIM), discoidin domain receptor 1 (DDR1) and zinc finger E-box binding homeobox 1 (ZEB1) in female- and male-derived cancer cell lines by reverse transcription (RT)-PCR and the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) database analysis. A negative correlation was observed between DDR1 and ZEB1 only in the female-derived cancer cell lines via RT-PCR analysis. A negative correlation between DDR1 index (defined by the logarithmic value of DDR1 divided by ZEB1, based on the mRNA data from the RT-PCR analysis) and an invasive phenotype was observed in cancer cell lines in a sex-specific manner. Analysis of the CCLE database demonstrated that DDR1 and ZEB1, which are already known to be sex-biased, were negatively correlated in female-derived liver cancer cell lines, but not in male-derived liver cancer cell lines. In contrast, cell lines of colon and lung cancer did not reveal any sex-dependent difference in the correlation between DDR1 and ZEB1. Kaplan-Meier survival curves using the transcriptomic datasets such as Gene Expression Omnibus, European Genome-phenome Archiva and The Cancer Genome Atlas databases suggested a sex-biased difference in the correlation between DDR1 expression pattern and overall survival in patients with liver cancer. The results of the present study indicate that sex factors may affect the regulation of gene expression, contributing to the sex-biased progression of the different types of cancer, particularly liver cancer. Overall, these findings suggest that analyses of the correlation between DDR1 and ZEB1 may prove useful when investigating sex-biased cancers.
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http://dx.doi.org/10.3892/ol.2019.11016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876332PMC
December 2019

HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways.

Nat Commun 2019 10 11;10(1):4670. Epub 2019 Oct 11.

Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea.

The mechanisms by which many human cytomegalovirus (HCMV)-encoded proteins help the virus to evade immune surveillance remain poorly understood. In particular, it is unknown whether HCMV proteins arrest Toll-like receptor (TLR) signaling pathways required for antiviral defense. Here, we report that US7 and US8 as key suppressors that bind both TLR3 and TLR4, facilitating their destabilization by distinct mechanisms. US7 exploits the ER-associated degradation components Derlin-1 and Sec61, promoting ubiquitination of TLR3 and TLR4. US8 not only disrupts the TLR3-UNC93B1 association but also targets TLR4 to the lysosome, resulting in rapid degradation of the TLR. Accordingly, a mutant HCMV lacking the US7-US16 region has an impaired ability to hinder TLR3 and TLR4 activation, and the impairment is reversed by the introduction of US7 or US8. Our findings reveal an inhibitory effect of HCMV on TLR signaling, which contributes to persistent avoidance of the host antiviral response to achieve viral latency.
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http://dx.doi.org/10.1038/s41467-019-12641-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789044PMC
October 2019

Clinical significance and prognostic role of hypoxia-induced microRNA 382 in gastric adenocarcinoma.

PLoS One 2019 9;14(10):e0223608. Epub 2019 Oct 9.

BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu, South Korea.

Hypoxia and angiogenesis are critical components in the progression of solid cancer, including gastric cancers (GCs). miR-382 has been identified as a hypoxia-induced miR (hypoxamiR), but the clinical significance in GCs has not been identified yet. To explore the clinical and prognostic importance of miR-382 in GCs, the surgical specimens of 398 patients with GCs in KNU hospital in Korea, the total of 183 patients was randomly selected using simple sampling methods and big data with 446 GCs and 45 normal tissues from the data portal (https://portal.gdc.cancer.gov/) were analysed. Expression of miR-382 as well as miR-210, as a positive control hypoxamiR by qRT-PCR in histologically malignant region of GCs showed significantly positive correlation (R = 0.516, p<0.001). High miR-210 and miR-382 expression was significantly correlated with unfavorable prognosis including advanced GCs (AGC), higher T category, N category, pathologic TNM stage, lymphovascular invasion, venous invasion, and perinueral invasion, respectively (all p<0.05). In univariate analysis, high miR-210 expression was significantly associated with worse overall survival (OS) (p = 0.036) but not high miR-382. In paired 60 gastric normal and cancer tissues, miR-382 expression in cancer tissues was significantly higher than normal counterpart (p = 0.003), but not miR-210 expression. However, by increasing the patient number from the big data analysis, miR-210 as well as miR-382 expression in tumor tissues was significantly higher than the normal tissues. Our results suggest that miR-382, as novel hypoxamiR, can be a prognostic marker for advanced GCs and might be correlated with metastatic potential. miR-382 might play important roles in the aggressiveness, progression and prognosis of GCs. In addition, miR-382 give a predictive marker for progression of GCs compared to the normal or preneoplastic lesion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785122PMC
March 2020

Efficacy of a novel endoscopically deliverable muco-adhesive hemostatic powder in an acute gastric bleeding porcine model.

PLoS One 2019 11;14(6):e0216829. Epub 2019 Jun 11.

Division of Gastroenterology, Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea.

This study investigated the effectiveness of new hemostatic adhesive powder (UI-EWD) in a swine mode of acute gastric bleeding. Gastric ulcer bleeding was induced endoscopically at two locations in each of eight heparinized mini-pigs. UI-EWD and saline were sprayed endoscopically in the experimental (n = 5) and control groups (n = 3), respectively. The hemostatic effect and hydrogel persistence on ulcers were periodically evaluated endoscopically. Initial hemostasis was achieved successfully in all lesions in the experimental group. Follow-up endoscopy showed minor delayed bleeding in 10% at 6 hours in the experimental group, whereas re-bleeding was observed in 50% at 6 hours in the control group. UI-EWD gel persisted at 90%, 80%, and 50% of ulcer bases at 6, 18, and 42 hours post-application, respectively. This study suggests that muco-adhesive UI-EWD may be effective in the endoscopic treatment of active ulcer bleeding.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559629PMC
February 2020

CNBP controls tumor cell biology by regulating tumor-promoting gene expression.

Mol Carcinog 2019 08 13;58(8):1492-1501. Epub 2019 May 13.

Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.

Cellular nucleic acid-binding protein (CNBP) is associated with cell proliferation, and its expression is elevated in human tumors, but the molecular mechanisms of CNBP in tumor cell biology have not been fully elucidated. In this study, we report that CNBP is a transcription factor essential for regulating matrix metalloproteinases mmp-2, mmp-14, and transcription factor e2f2 gene expression by binding to their promoter regions via a sequence-specific manner. Importantly, epidermal growth factor stimulation is required to induce CNBP phosphorylation and nuclear transport, thereby promoting the expression of mmp-2, mmp-14, and e2f2 genes. As a consequence, loss of cnbp attenuates the ability of tumor cell growth, invasion, and migration. Conversely, overexpression of cnbp is associated with tumor cell biology. Collectively, our findings reveal CNBP as a key transcriptional regulator of tumor-promoting target genes to control tumor cell biology.
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http://dx.doi.org/10.1002/mc.23030DOI Listing
August 2019

Sex-Dependent Adverse Drug Reactions to 5-Fluorouracil in Colorectal Cancer.

Biol Pharm Bull 2019 ;42(4):594-600

Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University.

Sex-related incidence and outcomes were reported in various cancers, including colorectal cancer. 5-Fluorouracil (5-FU) is widely used as an essential chemotherapeutic agent for colorectal cancer. However, sex-based differences in 5-FU toxicity have yet to be reported in human cancer cell lines and xenograft mouse models to date. Here, we investigated, for the first time, sex-based differences in 5-FU toxicity using human colon cancer cell lines, xenograft mouse models, and Korean patients' data. Female-derived colon cancer cell lines exhibited greater 5-FU-induced cytotoxicity than male-derived colon cancer cell lines. We established two xenograft mouse models: one with a male-derived human colon cancer cell line injected into male mice (a male-xenograft model) and another involving a female-derived human colon cancer cell line injected into female mice (a female xenograft model). Treatment with 5-FU inhibited tumor growth and led to hematological toxicity in a female xenograft model more potently than in a male xenograft model. We analyzed the data obtained from Korean patients with colorectal cancer to examine sex differences in adverse drug reactions caused by 5-FU. Korean female patients with colorectal cancer who received 5-FU chemotherapy experienced more frequent adverse drug reactions including alopecia and leukopenia than male patients. Taken together, we demonstrated that female may be associated with increased risk of toxicity to 5-FU treatment in colorectal cancer based on in vitro and in vivo investigations and clinical data analysis. Our study suggests sex as an important clinical factor, which predicts induction of toxicity related to 5-FU treatment.
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http://dx.doi.org/10.1248/bpb.b18-00707DOI Listing
August 2019

Molecular architecture of a cylindrical self-assembly at human centrosomes.

Nat Commun 2019 03 11;10(1):1151. Epub 2019 Mar 11.

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

The cell is constructed by higher-order structures and organelles through complex interactions among distinct structural constituents. The centrosome is a membraneless organelle composed of two microtubule-derived structures called centrioles and an amorphous mass of pericentriolar material. Super-resolution microscopic analyses in various organisms revealed that diverse pericentriolar material proteins are concentrically localized around a centriole in a highly organized manner. However, the molecular nature underlying these organizations remains unknown. Here we show that two human pericentriolar material scaffolds, Cep63 and Cep152, cooperatively generate a heterotetrameric α-helical bundle that functions in conjunction with its neighboring hydrophobic motifs to self-assemble into a higher-order cylindrical architecture capable of recruiting downstream components, including Plk4, a key regulator for centriole duplication. Mutations disrupting the self-assembly abrogate Plk4-mediated centriole duplication. Because pericentriolar material organization is evolutionarily conserved, this work may offer a paradigm for investigating the assembly and function of centrosomal scaffolds in various organisms.
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http://dx.doi.org/10.1038/s41467-019-08838-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411776PMC
March 2019

Efficacy of a novel hemostatic adhesive powder in patients with refractory upper gastrointestinal bleeding: a pilot study.

Endoscopy 2019 05 10;51(5):458-462. Epub 2019 Jan 10.

Digestive Disease Center, Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea.

Background: A new hemostatic adhesive powder (UI-EWD) has been developed to reduce the high re-bleeding rates associated with the currently available hemostatic powders. The current study aimed to assess the efficacy of UI-EWD as a salvage therapy for the treatment of refractory upper gastrointestinal bleeding (UGIB).

Methods: A total of 17 consecutive patients who had failed to achieve hemostasis with conventional endoscopic procedures and had undergone treatment with UI-EWD for endoscopic hemostasis in refractory UGIB were prospectively enrolled in the study. We evaluated the success rate of initial hemostasis and rate of re-bleeding within 30 days.

Results: All patients underwent successful UI-EWD application at the bleeding site. Initial hemostasis occurred in 16/17 patients (94 %). Re-bleeding within 30 days occurred in 3/16 patients (19 %) who had achieved initial hemostasis. In the second-look endoscopy after 24 hours, hydrogel from UI-EWD was found attached at the bleeding site in 11/16 patients (69 %).

Conclusion: UI-EWD has a high success rate for initial hemostasis in refractory UGIB and shows promising results in the prevention of re-bleeding.
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http://dx.doi.org/10.1055/a-0809-5276DOI Listing
May 2019

Biosynthesis of organic photosensitizer Zn-porphyrin by diphtheria toxin repressor (DtxR)-mediated global upregulation of engineered heme biosynthesis pathway in Corynebacterium glutamicum.

Sci Rep 2018 09 27;8(1):14460. Epub 2018 Sep 27.

Department of Biotechnology, Korea University, Seoul, 02841, Republic of Korea.

Zn-porphyrin is a promising organic photosensitizer in various fields including solar cells, interface and biomedical research, but the biosynthesis study has been limited, probably due to the difficulty of understanding complex biosynthesis pathways. In this study, we developed a Corynebacterium glutamicum platform strain for the biosynthesis of Zn-coproporphyrin III (Zn-CP III), in which the heme biosynthesis pathway was efficiently upregulated. The pathway was activated and reinforced by strong promoter-induced expression of hemA (encoding mutated glutamyl-tRNA reductase) and hemL (encoding glutamate-1-semialdehyde aminotransferase) genes. This engineered strain produced 33.54 ± 3.44 mg/l of Zn-CP III, while the control strain produced none. For efficient global regulation of the complex pathway, the dtxR gene encoding the transcriptional regulator diphtheria toxin repressor (DtxR) was first overexpressed in C. glutamicum with hemA and hemL genes, and its combinatorial expression was improved by using effective genetic tools. This engineered strain biosynthesized 68.31 ± 2.15 mg/l of Zn-CP III. Finally, fed-batch fermentation allowed for the production of 132.09 mg/l of Zn-CP III. This titer represents the highest in bacterial production of Zn-CP III reported to date, to our knowledge. This study demonstrates that engineered C. glutamicum can be a robust biotechnological model for the production of photosensitizer Zn-porphyrin.
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http://dx.doi.org/10.1038/s41598-018-32854-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160403PMC
September 2018

SIRT2 is required for efficient reprogramming of mouse embryonic fibroblasts toward pluripotency.

Cell Death Dis 2018 08 30;9(9):893. Epub 2018 Aug 30.

Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, 41566, Republic of Korea.

The role of sirtuins (SIRTs) in cancer biology has been the focus of recent research. The similarities between underlying pathways involved in the induction of pluripotent stem cells and transformation of cancer cells revealed the role of SIRTs in cellular reprogramming. Seven SIRTs have been identified in mammals and downregulation of SIRT2 was found to facilitate the generation of primed pluripotent stem cells, such as human induced pluripotent stem cells. Herein, we evaluated the role of SIRT2 in naive pluripotent stem cell generation using murine cells. We found that absolute depletion of SIRT2 in mouse embryonic fibroblasts resulted in a notable reduction in reprogramming efficiency. SIRT2 depletion not only upregulated elements of the INK4/ARF locus, which in turn had an antiproliferative effect, but also significantly altered the expression of proteins related to the PI3K/Akt and Hippo pathways, which are important signaling pathways for stemness. Thus, this study demonstrated that SIRT2 is required for cellular reprogramming to naive states of pluripotency in contrast to primed pluripotency states.
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http://dx.doi.org/10.1038/s41419-018-0920-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117269PMC
August 2018

Tumor-associated macrophages secrete CCL2 and induce the invasive phenotype of human breast epithelial cells through upregulation of ERO1-α and MMP-9.

Cancer Lett 2018 11 27;437:25-34. Epub 2018 Aug 27.

Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University, Seoul, South Korea. Electronic address:

Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that promote invasion and metastasis of cancer cells. In this study, we investigated the effect of TAMs on phenotypic conversion of non-neoplastic MCF10A human breast epithelial cells using an indirect co-culture system. Co-culture with TAMs induced epithelial-to-mesenchymal transition, invasive phenotype, and MMP-9 upregulation in MCF10A cells. Comparative proteomic analysis revealed that endoplasmic reticulum oxidoreductase (ERO)1-α was increased in MCF10A cells co-cultured with TAMs compared to that in mono-cultured cells. ERO1-α was crucial for TAMs-induced invasive phenotype and MMP-9 upregulation involving transcription factors c-fos and c-Jun. Cytokine array analysis showed that levels of interleukin (IL)-6, C-X-C motif ligand (CXCL)1, C-C motif ligand (CCL)2, growth-regulated protein (GRO), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in conditioned media of co-cultured cells. Among these cytokines increased in conditioned media of co-cultured cells, CCL2 was secreted from TAMs, leading to induction of ERO1-α, MMP-9 upregulation, and invasiveness in MCF10A cells. Our findings elucidated a molecular mechanism underlying the aggressive phenotypic change of non-neoplastic breast cells by co-culture with TAMs, providing useful information for prevention or treatment of recurrent breast cancer.
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http://dx.doi.org/10.1016/j.canlet.2018.08.025DOI Listing
November 2018

A Regulation of Regiodivergent Routes for Enantioselective Aldol Addition of 2-Alkyl Allenoates with Aldehydes: α-Addition versus γ-Addition.

Org Lett 2018 03 2;20(6):1521-1525. Epub 2018 Mar 2.

Department of Chemistry , Sungkyunkwan University , Suwon 16419 , Republic of Korea.

A method for the regioselective asymmetric aldol addition of 2-alkyl allenoates with aldehydes to provide an α- or γ-adduct depending on the aldehyde pair is reported. In most cases, except enals, a mixture of a chiral bromoborane with 2-alkyl allenoates in the presence of iPrNEt can react with aldehydes to provide efficient γ-addition products as single isomers containing axial and central chirality. On the other hand, observations indicate that enals undergo α-addition to yield highly functionalized adducts, including an α-carbon quaternary center in high levels of diastereo- and enantioselectivity.
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http://dx.doi.org/10.1021/acs.orglett.8b00219DOI Listing
March 2018
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