Publications by authors named "Gyoonhee Han"

84 Publications

Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury.

Int J Mol Sci 2021 Jul 26;22(15). Epub 2021 Jul 26.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea.

The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1β production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.
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http://dx.doi.org/10.3390/ijms22157946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348609PMC
July 2021

Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction.

Bioorg Chem 2021 07 20;112:104907. Epub 2021 Apr 20.

Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 03722, Republic of Korea; Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; Department of pharmacy, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea. Electronic address:

The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. However, BC-LI-0186 exhibited poor solubility and was metabolized by human liver microsomes. In this study, in silico physicochemical properties and metabolite analysis of BC-LI-0186 are used to investigate the addition of functional groups to improve solubility and microsomal stability. In vitro experiments demonstrated that 7b and 8a had improved chemical properties while still maintaining inhibitory activity against mTORC1. The results suggest a new strategy for the discovery of novel drug candidates and the treatment of diverse mTORC1-related diseases.
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http://dx.doi.org/10.1016/j.bioorg.2021.104907DOI Listing
July 2021

Novel positive allosteric modulator of protease-activated receptor 1 promotes skin wound healing in hairless mice.

Br J Pharmacol 2021 09 14;178(17):3414-3427. Epub 2021 May 14.

College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.

Background And Purpose: Protease-activated receptor 1 (PAR1) is a GPCR expressed in several skin cell types, including keratinocyte and dermal fibroblast. PAR1 activation plays a crucial role in the process of skin wound healing such as thrombosis, inflammation, proliferation and tissue repair. In the present study, we identified a novel positive allosteric modulator of PAR1, GB83, and investigated its effect on skin wound healing.

Experimental Approach: The enhancement of PAR1 activity by GB83 was measured using Fluo-4 calcium assay. In silico docking analysis of GB83 in PAR1 was performed using dock ligands method (CDOCKER) with CHARMm force field. Effects of GB83 on cell viability and gene expression were observed using MTS assay and quantitative real-time PCRs, respectively. SKH-1 hairless mice were used to investigate the wound healing effect of GB83.

Key Results: We demonstrated that GB83 did not activate PAR1 by itself but strongly enhanced PAR1 activation by thrombin and PAR1-activating peptide (AP). In silico docking analysis revealed that GB83 can bind to the PAR1 binding site of vorapaxar. GB83 significantly promoted PAR1-mediated cell viability and migration. In addition, the enhancement of PAR1 activity by GB83 strongly increased gene expression of TGF-β, fibronectin and type I collagen in vitro and promoted skin wound healing in vivo.

Conclusion And Implications: Our results revealed that GB83 is the first positive allosteric modulator of PAR1 and it can be a useful pharmacological tool for studying PAR1 and a potential therapeutic agent for skin wound healing.
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http://dx.doi.org/10.1111/bph.15489DOI Listing
September 2021

Suppression of Wnt/β-catenin and RAS/ERK pathways provides a therapeutic strategy for gemcitabine-resistant pancreatic cancer.

Biochem Biophys Res Commun 2021 04 1;549:40-46. Epub 2021 Mar 1.

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea; CK Biotechnology Inc., Building 117, 50 Yonsei Ro, Seodaemun-Gu, Seoul, 03722, South Korea. Electronic address:

Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/β-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both β-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both β-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabine-resistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/β-catenin and RAS/ERK pathways by destabilizing β-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.076DOI Listing
April 2021

Randomized, Controlled Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients With Type 2 Diabetes Mellitus: The IDDIA Trial.

Circulation 2021 Feb 13;143(5):510-512. Epub 2020 Nov 13.

Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051992DOI Listing
February 2021

Inhibition of Pendrin by a small molecule reduces Lipopolysaccharide-induced acute Lung Injury.

Theranostics 2020 7;10(22):9913-9922. Epub 2020 Aug 7.

Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea.

Pendrin is encoded by and its mutation leads to congenital hearing loss. Additionally, pendrin is up-regulated in inflammatory airway diseases such as chronic obstructive pulmonary disease, allergic rhinitis, and asthma. In this study, the effects of a novel pendrin inhibitor, YS-01, were investigated in an LPS-induced acute lung injury (ALI) mice model, and the mechanism underlying the effect of YS-01 was examined. Lipopolysaccharide (LPS, 10 mg/kg) was intranasally instilled in wild type (WT) and pendrin-null mice. YS-01 (10 mg/kg) was administered intra-peritoneally before or after LPS inhalation. Lung injury parameters were assessed in the lung tissue and bronchoalveolar lavage fluid (BALF). Pendrin levels in the BALF of 41 patients with acute respiratory distress syndrome (ARDS) due to pneumonia and 25 control (solitary pulmonary nodule) patients were also measured. LPS instillation induced lung injury in WT mice but not in pendrin-null mice. Pendrin expression was increased by LPS stimulation both and . YS-01 treatment dramatically attenuated lung injury and reduced BALF cell counts and protein concentration after LPS instillation in WT mice. Proinflammatory cytokines and NFB activation were suppressed by YS-01 treatment in LPS-induced ALI mice. In BALF of patients whose ARDS was caused by pneumonia, pendrin expression was up-regulated compared to that in controls (mean, 24.86 vs. 6.83 ng/mL, 0.001). A novel pendrin inhibitor, YS-01, suppressed lung injury in LPS-induced ALI mice and our data provide a new strategy for the treatment of inflammatory airway diseases including sepsis-induced ALI.
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http://dx.doi.org/10.7150/thno.46417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481407PMC
May 2021

PRMT5 promotes DNA repair through methylation of 53BP1 and is regulated by Src-mediated phosphorylation.

Commun Biol 2020 08 5;3(1):428. Epub 2020 Aug 5.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.

PRMT5 participates in various cellular processes, including transcription regulation, signal transduction, mRNA splicing, and DNA repair; however, its mechanism of regulation is poorly understood. Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity. Either phosphorylation or substitution of the Y324 residue suppresses PRMT5 activity by preventing its binding with the methyl donor S-adenosyl-L-methionine. Additionally, we show that PRMT5 activity is associated with non-homologous end joining (NHEJ) repair by methylating and stabilizing p53-binding protein 1 (53BP1), which promotes cellular survival after DNA damage. Src-mediated phosphorylation of PRMT5 and the subsequent inhibition of its activity during the DNA damage process blocks NHEJ repair, leading to apoptotic cell death. Altogether, our findings suggest that PRMT5 regulates DNA repair through Src-mediated Y324 phosphorylation in response to DNA damage.
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http://dx.doi.org/10.1038/s42003-020-01157-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406651PMC
August 2020

Diversity-oriented generation and biological evaluation of new chemical scaffolds bearing a 2,2-dimethyl-2H-chromene unit: Discovery of novel potent ANO1 inhibitors.

Bioorg Chem 2020 08 8;101:104000. Epub 2020 Jun 8.

College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea. Electronic address:

Chemical territory bearing a 2,2-dimethyl-2H-chromene motif was expanded by utilizing an o-hydroxy aldehyde group of 5-hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde as a synthetic handle to install distinctive morphology and functionality of each scaffold. Cell based assays and in silico docking analysis led us to discover that these new compounds exhibit inhibitory effect on anoctamin1 (ANO1). ANO1 is amplified and highly expressed in various carcinomas including prostate cancer, esophageal cancer, breast cancer, and pancreatic cancer. Biological assays revealed that (E)-1-(7,7-dimethyl-7H-furo[2,3-f]chromen-2-yl)-3-(1H-pyrrol-2-yl)prop-2-en-1-one (3n, Ani-FCC) is a novel, potent and selective ANO1 inhibitor with an IC value of 1.23 μM. 3n showed 144 times stronger activity on ANO1 inhibition than ANO2 inhibition and did not alter the chloride channel activity of CFTR and the intracellular calcium signaling. Notably, 3n strongly decreased cell viability of PC-3 and FaDu cells expressing high levels of ANO1 with a decrease in ANO1 protein levels. In addition, 3n significantly enhanced apoptosis via activation of caspase 3 and cleavage of PARP in PC-3 and FaDu cells. This study shows that a novel ANO1 inhibitor, 3n, can be a potential candidate for the treatment of cancers overexpressing ANO1, such as prostate cancer and esophageal cancer.
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http://dx.doi.org/10.1016/j.bioorg.2020.104000DOI Listing
August 2020

Discovery of Chemicals to Either Clear or Indicate Amyloid Aggregates by Targeting Memory-Impairing Anti-Parallel Aβ Dimers.

Angew Chem Int Ed Engl 2020 07 7;59(28):11491-11500. Epub 2020 May 7.

Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, South Korea.

Amyloid-β (Aβ) oligomers are implicated in Alzheimer disease (AD). However, their unstable nature and heterogeneous state disrupts elucidation of their explicit role in AD progression, impeding the development of tools targeting soluble Aβ oligomers. Herein parallel and anti-parallel variants of Aβ(1-40) dimers were designed and synthesized, and their pathogenic properties in AD models characterized. Anti-parallel dimers induced cognitive impairments with increased amyloidogenesis and cytotoxicity, and this dimer was then used in a screening platform. Through screening, two FDA-approved drugs, Oxytetracycline and Sunitinib, were identified to dissociate Aβ oligomers and plaques to monomers in 5XFAD transgenic mice. In addition, fluorescent Astrophloxine was shown to detect aggregated Aβ in brain tissue and cerebrospinal fluid samples of AD mice. This screening platform provides a stable and homogeneous environment for observing Aβ interactions with dimer-specific molecules.
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http://dx.doi.org/10.1002/anie.202002574DOI Listing
July 2020

Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI.

Biomolecules 2020 03 27;10(4). Epub 2020 Mar 27.

Chemical Genomics Global Research Lab., Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.

Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.
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http://dx.doi.org/10.3390/biom10040508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226133PMC
March 2020

Novel pendrin inhibitor attenuates airway hyperresponsiveness and mucin expression in experimental murine asthma.

J Allergy Clin Immunol 2019 11 27;144(5):1425-1428.e12. Epub 2019 Jul 27.

Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.07.016DOI Listing
November 2019

FusionPro, a Versatile Proteogenomic Tool for Identification of Novel Fusion Transcripts and Their Potential Translation Products in Cancer Cells.

Mol Cell Proteomics 2019 08 17;18(8):1651-1668. Epub 2019 Jun 17.

§Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address:

Fusion proteoforms are translation products derived from gene fusion. Although very rare, the fusion proteoforms play important roles in biomedical science. For example, fusion proteoforms influence the development of tumors by serving as cancer markers or cell cycle regulators. Although numerous studies have reported bioinformatics tools that can predict fusion transcripts, few proteogenomic tools are available that can predict and identify proteoforms. In this study, we develop a versatile proteogenomic tool "FusionPro," which facilitates the identification of fusion transcripts and their potential translatable peptides. FusionPro provides an independent gene fusion prediction module and can build sequence databases for annotated fusion proteoforms. FusionPro shows greater sensitivity than the available fusion finders when analyzing simulated or real RNA sequencing data sets. We use FusionPro to identify 18 fusion junction peptides and three potential fusion-derived peptides by MS/MS-based analysis of leukemia cell lines (Jurkat and K562) and ovarian cancer tissues from the Clinical Proteomic Tumor Analysis Consortium. Among the identified fusion proteins, we molecularly validate two fusion junction isoforms and a translation product of Moreover, sequence analysis suggests that the fusion protein participates in the cell cycle progression. In addition, our prediction results indicate that fusion transcripts often have multiple fusion junctions and that these fusion junctions tend to be distributed in a nonrandom pattern at both the chromosome and gene levels. Thus, FusionPro allows users to detect various types of fusion translation products using a transcriptome-informed approach and to gain a comprehensive understanding of the formation and biological roles of fusion proteoforms.
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http://dx.doi.org/10.1074/mcp.RA119.001456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683003PMC
August 2019

Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer.

Ther Adv Med Oncol 2019 19;11:1758835919846798. Epub 2019 May 19.

Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University, 4th Floor, Research Center for Future Medicine, 20, Eonju-ro 63-gil, Gangnam-gu, Seoul, 06229, South Korea.

Objective: Leucyl-tRNA synthetase (LRS) is an aminoacyl-tRNA synthetase catalyzing ligation of leucine to its cognate tRNA and is involved in the activation of mTORC1 by sensing cytoplasmic leucine. In this study, the usefulness of LRS as a therapeutic target of non-small cell lung cancer (NSCLC) and the anticancer effect of the LRS inhibitor, BC-LI-0186, was evaluated.

Methods: LRS expression and the antitumor effect of BC-LI-0186 were evaluated by immunohistochemical staining, immunoblotting, and live cell imaging. The antitumor effect of BC-LI-0186 was evaluated using Lox-Stop-Lox (LSL) K-ras G12D mice.

Results: LRS was frequently overexpressed in NSCLC tissues, and its expression was positively correlated with mTORC1 activity. The guanosine-5'-triphosphate (GTP) binding status of RagB was related to the expression of LRS and the S6K phosphorylation. RNA against LRS inhibited leucine-mediated mTORC1 activation and cell growth. BC-LI-0186 selectively inhibited phosphorylation of S6K without affecting phosphorylation of AKT and leucine-mediated co-localization of Raptor and LAMP2 in the lysosome. BC-LI-0186 induced cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3 and increase of p62 expression, showing that it has the autophagy-inducing property. BC-LI-0186 has the cytotoxic effect at nanomolar concentration and its GI value was negatively correlated with the degree of LRS expression. BC-LI-0186 showed the antitumor effect, which was comparable with that of cisplatin, and mTORC1 inhibitory effect in a lung cancer model.

Conclusions: BC-LI-0186 inhibits the noncanonical mTORC1-activating function of LRS. These results provide a new therapeutic strategy for NSCLC and warrant future clinical development by targeting LRS.
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http://dx.doi.org/10.1177/1758835919846798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535710PMC
May 2019

Nontranslational function of leucyl-tRNA synthetase regulates myogenic differentiation and skeletal muscle regeneration.

J Clin Invest 2019 04 15;129(5):2088-2093. Epub 2019 Apr 15.

Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Illinois, USA.

Aside from its catalytic function in protein synthesis, leucyl-tRNA synthetase (LRS) has a nontranslational function in regulating cell growth via the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway by sensing amino acid availability. mTOR also regulates skeletal myogenesis, but the signaling mechanism is distinct from that in cell growth regulation. A role of LRS in myogenesis has not been reported. Here we report that LRS negatively regulated myoblast differentiation in vitro. This function of LRS was independent of its regulation of protein synthesis, and it required leucine-binding but not tRNA charging activity of LRS. Local knock down of LRS accelerated muscle regeneration in a mouse injury model, and so did the knock down of Rag or Raptor. Further in vitro studies established a Rag-mTORC1 pathway, which inhibits the IRS1-PI3K-Akt pathway, to be the mediator of the nontranslational function of LRS in myogenesis. BC-LI-0186, an inhibitor reported to disrupt LRS-Rag interaction, promoted robust muscle regeneration with enhanced functional recovery, and this effect was abolished by cotreatment with an Akt inhibitor. Taken together, our findings revealed what we believe is a novel function for LRS in controlling the homeostasis of myogenesis, and suggested a potential therapeutic strategy to target a noncanonical function of a housekeeping protein.
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http://dx.doi.org/10.1172/JCI122560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486340PMC
April 2019

CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth.

Life Sci Alliance 2019 04 10;2(2). Epub 2019 Apr 10.

Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea

Longitudinal bone growth ceases with growth plate senescence during puberty. However, the molecular mechanisms of this phenomenon are largely unexplored. Here, we examined Wnt-responsive genes before and after growth plate senescence and found that CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt/β-catenin pathway, was gradually elevated with reduction of Wnt/β-catenin signaling during senescent changes of rodent growth plate. mice demonstrated delayed growth plate senescence and tibial elongation. As CXXC5 functions by interacting with dishevelled (DVL), we sought to identify small molecules capable of disrupting this interaction. screening assay monitoring CXXC5-DVL interaction revealed that several indirubin analogs were effective antagonists of this interaction. A functionally improved indirubin derivative, KY19382, elongated tibial length through delayed senescence and further activation of the growth plate in adolescent mice. Collectively, our findings reveal an important role for CXXC5 as a suppressor of longitudinal bone growth involving growth plate activity.
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http://dx.doi.org/10.26508/lsa.201800254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458850PMC
April 2019

Simultaneous Suppression of Multiple Programmed Cell Death Pathways by miRNA-105 in Cardiac Ischemic Injury.

Mol Ther Nucleic Acids 2019 Mar 10;14:438-449. Epub 2019 Jan 10.

Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Republic of Korea; Catholic Kwandong University, International St. Mary's Hospital, Incheon Metropolitan City 404-834, Republic of Korea. Electronic address:

Recent studies have shown that several upstream signaling elements of apoptosis and necroptosis are closely associated with acute injury in the heart. In our study, we observed that miR-105 was notably dysregulated in rat hearts with myocardial infarction (MI). Thus, the purpose of this study was to test the hypothesis that miR-105 participates in the regulation of RIP3/p-MLKL- and BNIP3-dependent necroptosis/apoptosis in H9c2 cells and MI rat hearts. Our results show that the RIP3/p-MLKL necroptotic pathway and BNIP3-dependent apoptosis signaling are enhanced in H9c2 cells under hypoxic conditions, whereas, compared with these pathways in the controls, those in miR-105-treated H9c2 cells are suppressed. Mechanistically, we identified miR-105 as the miRNA directly suppressing the expression of RIP3 and BNIP3, two important mediators involved in cell necroptosis and apoptosis. Furthermore, MI rat hearts injected with miR-105 had decreased infarct sizes, indicating that miR-105 is among three miRNAs that function simultaneously to suppress necroptotic/apoptotic cell death pathways and to inhibit MI-induced cardiomyocyte cell death at multiple levels. Taken together, miR-105 may constitute a new therapeutic strategy for cardioprotection in ischemic heart disease.
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http://dx.doi.org/10.1016/j.omtn.2018.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369328PMC
March 2019

A Ras destabilizer KYA1797K overcomes the resistance of EGFR tyrosine kinase inhibitor in KRAS-mutated non-small cell lung cancer.

Sci Rep 2019 01 24;9(1):648. Epub 2019 Jan 24.

Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.

The epidermal growth factor receptor (EGFR) inhibitors such as erlotinib and gefitinib are widely used for treatment of non-small cell lung cancer (NSCLC), but they have shown limited efficacy in an unselected population of patients. The KRAS mutations, which are identified in approximately 20% of NSCLC patients, have shown to be associated with the resistance to the EGFR tyrosine kinase inhibitors (TKIs). Currently, there is no clinically available targeted therapy which can effectively inhibit NSCLC tumors harboring KRAS mutations. This study aims to show the effectiveness of KYA1797K, a small molecule which revealed anti-cancer effect in colorectal cancer by destabilizing Ras via inhibiting the Wnt/β-catenin pathway, for the treatment of KRAS-mutated NSCLC. While erlotinib fail to have anti-transforming effect in NSCLC cell lines harboring KRAS mutations, KYA1797K effectively inhibited the Ras-ERK pathway in KRAS-mutant NSCLC cell lines. As a result, KYA1797K treatment suppressed the growth and transformation of KRAS mutant NSCLC cells and also induced apoptosis. Furthermore, KYA1797K effectively inhibited Kras-driven tumorigenesis in the Kras mouse model by suppressing the Ras-ERK pathway. The destabilization of Ras via inhibition of the Wnt/β-catenin pathway is a potential therapeutic strategy for KRAS-mutated NSCLC that is resistant to EGFR TKI.
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http://dx.doi.org/10.1038/s41598-018-37059-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345925PMC
January 2019

Optimization of Vinyl Sulfone Derivatives as Potent Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Parkinson's Disease Therapy.

J Med Chem 2019 01 20;62(2):811-830. Epub 2018 Dec 20.

Convergence Research Center for Diagnosis, Treatment & Care System of Dementia , Korea Institute of Science & Technology (KIST) , Seoul 02792 , Republic of Korea.

We previously developed a novel series of vinyl sulfones as nuclear factor erythroid 2-related factor 2 (Nrf2) activators with therapeutic potential for Parkinson's disease (PD). However, the previously developed lead compound (1) exhibited undesirable druglike properties. Here, we optimized vinyl sulfones by introducing nitrogen heterocycles to improve druglike properties. Among the synthesized compounds, 17e was the most promising drug candidate with good druglike properties. Compound 17e showed superior effects on Nrf2 activation in cell-based assays compared to compound 1 (17e: half-maximal effective concentration (EC) = 346 nM; 1: EC = 530 nM). Compound 17e was further confirmed to induce expression of Nrf2-dependent antioxidant enzymes at both mRNA and protein levels. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, 17e significantly attenuated loss of tyrosine hydroxylase-immunopositive dopaminergic neurons, suppressed microglial activation, and alleviated PD-associated motor dysfunction. Thus, 17e is a novel Nrf2 activator with excellent druglike properties and represents a potential therapeutic candidate for PD.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01527DOI Listing
January 2019

RNA-dependent chaperone (chaperna) as an engineered pro-region for the folding of recombinant microbial transglutaminase.

Biotechnol Bioeng 2019 03 4;116(3):490-502. Epub 2019 Jan 4.

Department of Biotechnology, College of Life science and Biotechnology, Yonsei University, Seoul, Korea.

Transglutaminase (TGase) induces the cross-linking of proteins by catalyzing an acyl transfer reaction. TGase is a zymogen, activated by the removal of its pro-region. Because the pro-region is crucial for folding and inhibition of the TGase activity, the recombinant expression of the mature TGase (mTGase) without the pro-region, usually results in inactive inclusion bodies or low protein yield. Here, Streptomyces netropsis TGase was fused with Escherichia coli lysyl-tRNA synthetase (LysRS), as a module with chaperoning activity in an RNA dependent manner (chaperna). The TGase activity from purified fusion protein induced via the removal of LysRS by tev protease in vitro. Moreover, active mTGase was produced in E. coli via an intracellular cleavage system, wherein LysRS-mTGase was cleaved by the coexpressed tev protease in vivo. The results suggest that LysRS essentially mimics pro-region, which exerts a dual function-folding of TGase into active conformation and keeping it as dormant state-in an RNA-dependent manner. Thus, trans-acting RNAs, prompt the cis-acting chaperone function of LysRS, while being mechanistically similar to the intramolecular chaperone function of the pro-region. These results could be implemented and extended for the folding of "difficult-to-express" recombinant proteins, by harnessing the chaperna function.
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http://dx.doi.org/10.1002/bit.26879DOI Listing
March 2019

A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab.

Exp Mol Med 2018 11 20;50(11):1-12. Epub 2018 Nov 20.

Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.

Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both β-catenin and Ras via GSK3β activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both β-catenin and RAS as well as EGFR via targeting the Wnt/β-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/β-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.
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http://dx.doi.org/10.1038/s12276-018-0182-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244225PMC
November 2018

β-Catenin-RAS interaction serves as a molecular switch for RAS degradation via GSK3β.

EMBO Rep 2018 12 9;19(12). Epub 2018 Nov 9.

Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea

RAS proteins play critical roles in various cellular processes, including growth and transformation. RAS proteins are subjected to protein stability regulation via the Wnt/β-catenin pathway, and glycogen synthase kinase 3 beta (GSK3β) is a key player for the phosphorylation-dependent RAS degradation through proteasomes. GSK3β-mediated RAS degradation does not occur in cells that express a nondegradable mutant (MT) β-catenin. Here, we show that β-catenin directly interacts with RAS at the α-interface region that contains the GSK3β phosphorylation sites, threonine 144 and threonine 148 residues. Exposure of these sites by prior β-catenin degradation is required for RAS degradation. The introduction of a peptide that blocks the β-catenin-RAS interaction by binding to β-catenin rescues the GSK3β-mediated RAS degradation in colorectal cancer (CRC) cells that express MT β-catenin. The coregulation of β-catenin and RAS stabilities by the modulation of their interaction provides a mechanism for Wnt/β-catenin and RAS-ERK pathway cross-talk and the synergistic transformation of CRC by both and mutations.
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http://dx.doi.org/10.15252/embr.201846060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280641PMC
December 2018

Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway.

Proc Natl Acad Sci U S A 2018 06 21;115(23):E5279-E5288. Epub 2018 May 21.

Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, South Korea;

A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. However, its significance in mTORC1 signaling and cancer growth and its functional relationship with other suggested leucine signal mediators are not well-understood. Here we show the kinetics of the Rag GTPase cycle during leucine signaling and that LRS serves as an initiating "ON" switch via GTP hydrolysis of RagD that drives the entire Rag GTPase cycle, whereas Sestrin2 functions as an "OFF" switch by controlling GTP hydrolysis of RagB in the Rag GTPase-mTORC1 axis. The LRS-RagD axis showed a positive correlation with mTORC1 activity in cancer tissues and cells. The GTP-GDP cycle of the RagD-RagB pair, rather than the RagC-RagA pair, is critical for leucine-induced mTORC1 activation. The active RagD-RagB pair can overcome the absence of the RagC-RagA pair, but the opposite is not the case. This work suggests that the GTPase cycle of RagD-RagB coordinated by LRS and Sestrin2 is critical for controlling mTORC1 activation, and thus will extend the current understanding of the amino acid-sensing mechanism.
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http://dx.doi.org/10.1073/pnas.1801287115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003318PMC
June 2018

Glycosylation of Hemagglutinin and Neuraminidase of Influenza A Virus as Signature for Ecological Spillover and Adaptation among Influenza Reservoirs.

Viruses 2018 04 7;10(4). Epub 2018 Apr 7.

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.

Glycosylation of the hemagglutinin (HA) and neuraminidase (NA) of the influenza provides crucial means for immune evasion and viral fitness in a host population. However, the time-dependent dynamics of each glycosylation sites have not been addressed. We monitored the potential N-linked glycosylation (NLG) sites of over 10,000 HA and NA of H1N1 subtype isolated from human, avian, and swine species over the past century. The results show a shift in glycosylation sites as a hallmark of 1918 and 2009 pandemics, and also for the 1976 "abortive pandemic". Co-segregation of particular glycosylation sites was identified as a characteristic of zoonotic transmission from animal reservoirs, and interestingly, of "reverse zoonosis" of human viruses into swine populations as well. After the 2009 pandemic, recent isolates accrued glycosylation at canonical sites in HA, reflecting gradual seasonal adaptation, and a novel glycosylation in NA as an independent signature for adaptation among humans. Structural predictions indicated a remarkably pleiotropic influence of glycans on multiple HA epitopes for immune evasion, without sacrificing the receptor binding of HA or the activity of NA. The results provided the rationale for establishing the ecological niche of influenza viruses among the reservoir and could be implemented for influenza surveillance and improving pandemic preparedness.
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http://dx.doi.org/10.3390/v10040183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923477PMC
April 2018

Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson's disease therapy.

Bioorg Med Chem 2018 01 24;26(1):232-244. Epub 2017 Nov 24.

Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea. Electronic address:

Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson's disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.
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http://dx.doi.org/10.1016/j.bmc.2017.11.036DOI Listing
January 2018

Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction.

Nat Commun 2017 09 29;8(1):732. Epub 2017 Sep 29.

Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, 08826, South Korea.

Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiological significance of its activity is not well understood. Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. We identified compounds that inhibit the leucine-dependent mTORC1 pathway by specifically inhibiting the GTPase activating function of LRS, while not affecting the catalytic activity. For further analysis, we selected one compound, BC-LI-0186, which binds to the RagD interacting site of LRS, thereby inhibiting lysosomal localization of LRS and mTORC1 activity. It also effectively suppressed the activity of cancer-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. These findings suggest new strategies for controlling tumor growth that avoid the resistance to existing mTOR inhibitors resulting from cancer-associated MTOR mutations.Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. Here, the authors identify inhibitors of the GTPase activating function of LRS, not affecting its catalytic activity, and demonstrate that the leucine sensor function of LRS can be a new target for mTORC1 inhibition.
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http://dx.doi.org/10.1038/s41467-017-00785-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622079PMC
September 2017

HDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis.

Cancer Lett 2017 04 30;391:162-171. Epub 2017 Jan 30.

College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea. Electronic address:

HDAC6-selective inhibitors represent promising new cancer therapeutic agents, but their precise mechanisms of action are not well understood. In particular, p53's role in HDAC6 inhibitor-induced effects has not been fully elucidated. In this study, we show that an HDAC6-selective inhibitor, A452, increased wild-type p53 levels by destabilizing MDM2, but decreased mutant p53 by inducing MDM2 and inhibiting Hsp90-mutant p53 complex formation. Interestingly, HDAC6 levels inversely correlated with p53 acetylation at lysines 381/382 associated with p53 functional activation. A452 blocked HDAC6 nuclear localization, resulting in increased levels of acetylated p53 at Lys381/382. HDAC6 bound to the C-terminal region of p53 via its deacetylase domain. A452 disrupted the HDAC6-Hsp90 chaperone machinery via Hsp90 acetylation and degradation. Furthermore, it chemosensitized cancer cells to the Hsp90 inhibitor 17-AAG. Overall, silencing of HDAC6 showed similar effects. These findings suggest that the anticancer action of HDAC6 inhibitors requires p53 and Hsp90 and targeting of HDAC6 may represent a new therapeutic strategy for cancers regardless of p53's mutation status.
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http://dx.doi.org/10.1016/j.canlet.2017.01.033DOI Listing
April 2017

Synthetic strategy for increasing solubility of potential FLT3 inhibitor thieno[2,3-d]pyrimidine derivatives through structural modifications at the C and C positions.

Bioorg Med Chem Lett 2017 02 23;27(3):496-500. Epub 2016 Dec 23.

Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea; Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea. Electronic address:

Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic progenitor cell. In AML, a mutation in FLT3 is commonly occurs and is associated with poor prognosis. We have previously reported that thieno[2,3-d]pyrimidine derivative compound 1 exhibited better antiproliferative activity against MV4-11 cells which harbor mutant FLT3 than AC220, which is a well-known FLT3 inhibitor, and has good microsomal stability. However, compound 1 had poor solubility. We then carried out further structural modification at the C and the C positions of thieno[2,3-d]pyrimidine scaffold. Compound 13b, which possesses a thiazole moiety at the C position, exhibited better antiproliferative activity than compound 1 and showed increased solubility and moderate microsomal stability. These results indicate that compound 13b could be a promising potential FLT inhibitor for AML chemotherapy.
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http://dx.doi.org/10.1016/j.bmcl.2016.12.034DOI Listing
February 2017

Improving potency and metabolic stability by introducing an alkenyl linker to pyridine-based histone deacetylase inhibitors for orally available RUNX3 modulators.

Eur J Med Chem 2017 Jan 1;126:997-1010. Epub 2016 Dec 1.

Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 120-749, Republic of Korea. Electronic address:

RUNX3, a tumor suppressor, is suppressed in various cancers by abnormal epigenetic changes. Histone deacetylases (HDACs) can deacetylate the lysine residues of RUNX3, followed by degradation via a ubiquitin-mediated pathway. Inhibition of HDAC leads to functional restoration of the RUNX3 protein by epigenetic expression and RUNX3 protein stabilization. We previously reported a series of HDAC inhibitors that restored RUNX3 function. In the present study, we introduced an alkenyl linker group to pyridine-based HDAC inhibitors to improve their potencies and chemical properties. This alkenyl linker made the compounds more rigid, facilitating a better fit than alkyl moieties to the active site of HDAC proteins. Most compounds in this series exhibited potent RUNX activities, HDAC inhibitory activities, and inhibitory activities towards the growth of human cancer cell lines. Notably, one of these derivatives, (E)-3-(1-cinnamyl-2-oxo-1,2-dihydropyridin-3-yl)-N-hydroxyacrylamide (7k), showed excellent properties in a microsomal stability study, in a xenograft study, and in an in vivo pharmacokinetic evaluation. Modulation of RUNX3 therefore results in highly potent and orally available anticancer chemotherapeutic agents.
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http://dx.doi.org/10.1016/j.ejmech.2016.11.055DOI Listing
January 2017

KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer.

Oncotarget 2016 Dec;7(49):81727-81740

Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea.

APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APCMin/+/K-RasG12DLA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.
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http://dx.doi.org/10.18632/oncotarget.13172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348425PMC
December 2016

Potential therapeutic application of small molecule with sulfonamide for chondrogenic differentiation and articular cartilage repair.

Bioorg Med Chem Lett 2016 10 22;26(20):5098-5102. Epub 2016 Aug 22.

Catholic Kwandong University International St. Mary's Hospital, Seo-go, Incheon Metropolitan City 22711, Republic of Korea; Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 25601, Republic of Korea. Electronic address:

The restoration of damaged articular cartilage is a long-pursued goal in regenerative medicine. Chondrocyte-specific differentiation of mesenchymal stem cells (MSCs) may be an effective means of repairing damaged cartilage. We identified small molecule 6 with sulfonamide as an agent that promotes specific chondrogenic differentiation of human adipose-derived MSCs (hASCs). Unlike other chondrogenic differentiation media composed of various defined components, simply adding compound 6 into culture medium was sufficient to induce chondrogenesis in this study. In an animal osteoarthritis model, both the small molecule 6 and the 6-treated hASCs exhibited enhanced recovery of injured articular cartilage. This work provides new insight into MSC differentiation induced by small molecules and potential new therapeutic approaches for articular cartilage injury.
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http://dx.doi.org/10.1016/j.bmcl.2016.08.069DOI Listing
October 2016
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