Publications by authors named "Myeong-Sok Lee"

88 Publications

Preventive and Prebiotic Effect of α-Galacto-Oligosaccharide against Dextran Sodium Sulfate-Induced Colitis and Gut Microbiota Dysbiosis in Mice.

J Agric Food Chem 2021 Aug 11;69(33):9597-9607. Epub 2021 Aug 11.

School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao 266003, China.

β-Galacto-oligosaccharide (β-GOS) showed great potential in ulcerative colitis (UC) adjuvant therapy. Herein, the preventive and prebiotic effect of enzymatic-synthesized α-linked galacto-oligosaccharide (α-GOS) was investigated in dextran sodium sulfate-induced colitis and gut microbiota dysbiosis mice. Compared with β-GOS, the α-GOS supplement was more effective in improving preventive efficacy, promoting colonic epithelial barrier integrity, and alleviating inflammation cytokines. Moreover, the activation of the NOD-like receptor (NLR) family member NLRP3 inflammasome-mediated inflammation was significantly inhibited by both α-GOS and β-GOS. Gut microbiota analysis showed that α-GOS treatment reshaped the dysfunctional gut microbiota. The subsequent Spearman's correlation coefficient analysis indicated that these gut microbiota changes were significantly correlated with the inflammatory parameters. These results suggested that the enzymatic-synthesized α-GOS is a promising therapeutic agent in UC prevention and adjuvant treatment by maintaining intestinal homeostasis.
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http://dx.doi.org/10.1021/acs.jafc.1c03792DOI Listing
August 2021

[Corrigendum] Cryptotanshinone inhibits IgE‑mediated degranulation through inhibition of spleen tyrosine kinase and tyrosine‑protein kinase phosphorylation in mast cells.

Mol Med Rep 2021 Sep 19;24(3). Epub 2021 Jul 19.

Department of Biological Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.

Following the publication of the above article, an interested reader drew to the authors' attention that they had mentioned that activated PKCδ phosphorylates IKKβ in order that IKKβ is relocated to the plasma membrane, resulting in the induction of mast cell degranulation; however, four references the authors had included did not seem to support this statement. The authors have re-examined their paper, and realized that the four references the reader mentioned were indeed cited incorrectly, and wish to rectify this error through revising the third paragraph in the Discussion section, the References section, and an associated figure (Fig. 6C) in order to avoid any further misunderstandings on the part of the readership. First, the authors wish to revise the wording of the third and fourth paragraphs of the Discussion, as featured on pp. 1101-1102, to the following (changed text is indicated in bold): 'We showed that CRT exerts anti-AD effect through inhibition of the mast cell degranulation in mast cells. Upon IgE/antigen stimulation, the immunoreceptor tyrosine-based activation motif (ITAM) region of FcεRI receptor which is on the mast cell surface is phosphorylated and the initial signalling protein kinases Lyn and Syk are recruited to the ITAM (28,29). Then, the activated Lyn and Syk leads to phosphorylation of the transmembrane adaptor linker for activation of T cells (LAT). Phosphorylated LAT which is a scaffold for multimolecular signalling complexes and activates PLCγ through phosphorylation. The activated PLCγ hydrolyses phosphatidylinositol biphosphate (PIP2) to generate second signalling molecules IP3 and DAG, which activate PKCs including PKCδ to induce the mast cell degranulation (30,31). On the other hand, cross-linking of FcεRI also activates IKKβ, which moves to the lipid raft fractions and phosphorylates synaptosomal-associated protein 23 (SNAP-23) leading to degranulation (7). Since PKCδ phosphorylates IKKα, but not IKKβ (32), it is not likely that two signalling pathways are directly connected. In this study, novel function of CRT on phosphorylations of Lyn/Syk kinases in mast cells is elucidated for the first time. Furthermore, it is likely that this inhibitory effect of CRT on Lyn/Syk kinases negatively affected activities of their downstream signalling molecules including PLCγ, PKCδ, and IKKβ, which leads to decrease in mast cell degranulation by CRT treatment. Besides the inhibitory effect of CRT on mast cell degranulation, here we provide additional evidence that CRT exerts anti-AD effects through inactivation of MAPK and NF‑κB. It has been reported that CRT regulates the activities of MAPK and NF‑κB in various cell types. In rhabdomyosarcoma, hepatoma, and breast carcinoma, CRT activates MAPK p38/JNK and suppresses ERK1/2, followed by caspase-independent apoptosis (10,33,34). In chronic myeloid leukaemia cells, CRT enhances TNF‑α-induced apoptosis through the activation of MAPK p38 (35). In smooth muscle cells, CRT exerts anti-migration/invasion effect as it inhibits TNF‑α/NF‑κB signalling pathway (36).' Secondly, the authors wish to make the following changes to the Reference list: New references 30-32 have been inserted to the list, as follows: 30. Ozawa K, Szallasi Z, Kazanietz MG, Blumberg PM, Mischak H, Mushinski JF and Beaven MA: Ca-dependent and Ca-independent isozymes of protein kinase C mediate exocytosis in antigen-stimulated rat basophilic RBL-2H3 cell. J Biol Chem 268: 1749-1756, 1993. 31. Cho SH, Woo CH, Yoon SB and Kim JH: Protein kinase Cδ functions downstream of Ca mobilization in FcεRI signaling to degranulation in mast cells. J Allergy Clin Immunol 114: 1085-1092, 2004. 32. Yamaguchi T, Miki Y and Yoshida K: Protein kinase Cδ activates IκB-kinase α to induce the p53 tumor suppressor in response to oxidative stress. Cell Signal 19: 2088-2097, 2007. The addition of these new references means that the former references 30-33 have been accordingly renumbered to references 33-36. Finally, the authors have revised Fig. 6C, as it appeared on p. 1102, in order to assist the understanding of the readers, and the corrected version of Fig. 6 appears on the next page. All these corrections have been approved by all the authors, with the exception of the first author, Sumiyasuren Buyanravjikh, who is no longer uncontactable. The authors regret that these errors were included in the paper, even though they did not substantially alter any of the major conclusions reported in the study, are grateful to the Editor for allowing them this opportunity to publish a Corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published in 18: 1095‑1193, 2018; DOI: 10.3892/mmr.2018.9042].
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http://dx.doi.org/10.3892/mmr.2021.12283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299195PMC
September 2021

An efficient enzyme-triggered controlled release system for colon-targeted oral delivery to combat dextran sodium sulfate (DSS)-induced colitis in mice.

Drug Deliv 2021 Dec;28(1):1120-1131

Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women's University, Seoul, Korea.

Oral route colon-targeted drug delivery systems (CDDSs) are desirable for the treatment of ulcerative colitis (UC). However, CDDSs are challenging owing to the physiological and anatomical barriers associated with the gastrointestinal tract (GIT). In this study, we developed an effective enzyme-triggered controlled release system using curcumin-cyclodextrin (CD-Cur) inclusion complex as core and low molecular weight chitosan and unsaturated alginate resulting nanoparticles (CANPs) as shell. The formed CD-Cur-CANPs showed a narrow particle-size distribution and a compact structure. drug release determination indicated that CD-Cur-CANPs showed pH-sensitive and α-amylase-responsive release characteristics. Furthermore, experiments demonstrated that oral administration of CD-Cur-CANPs had an efficient therapeutic efficacy, strong colonic biodistribution and accumulation, rapid macrophage uptake, promoted colonic epithelial barrier integrity and modulated production of inflammatory cytokines, reshaped the gut microbiota in mice with dextran sodium sulfate (DSS)-induced colitis. Taken together, our synthetic CD-Cur-CANPs are a promising synergistic colon-targeted approach for UC treatment.
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http://dx.doi.org/10.1080/10717544.2021.1934189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205034PMC
December 2021

Anti-breast cancer action of carbonic anhydrase IX inhibitor 4-[4-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-benzylidene-hydrazinocarbonyl]-benzenesulfonamide (BSM-0004): and studies.

J Enzyme Inhib Med Chem 2021 Dec;36(1):954-963

Department of Biosystem, Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Sookmyung Women's University, Seoul, Republic of Korea.

Anti-breast cancer action of novel human carbonic anhydrase IX (hCA IX) inhibitor BSM-0004 has been investigated using and models of breast cancer. BSM-0004 was found to be a potent and selective hCA IX inhibitor with a Ki value of 96 nM. anticancer effect of BSM-0004 was analysed against MCF 7 and MDA-MA-231 cells, BSM-0004 exerted an effective cytotoxic effect under normoxic and hypoxic conditions, inducing apoptosis in MCF 7 cells. Additionally, this compound significantly regulates the expression of crucial biomarkers associated with apoptosis. The investigation was extended to confirm the efficacy of this hCA IX inhibitor against model of breast cancer. The results specified that the treatment of BSM-0004 displayed an effective anticancer effect, reducing tumour growth in a xenograft cancer model. Hence, our investigation delivers an effective anti-breast cancer agent that engenders the anticancer effect by inhibiting hCA IX.
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http://dx.doi.org/10.1080/14756366.2021.1909580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118463PMC
December 2021

MiR-146a Regulates Migration and Invasion by Targeting NRP2 in Circulating-Tumor Cell Mimicking Suspension Cells.

Genes (Basel) 2020 12 30;12(1). Epub 2020 Dec 30.

Research Institute for Women's Health, Sookmyung Women's University, Seoul 04310, Korea.

Cancer metastasis is the primary cause of cancer-related death and metastatic cancer has circulating-tumor cells (CTCs), which circulate in the bloodstream before invading other organs. Thus, understanding the precise role of CTCs may provide new insights into the metastasis process and reduce cancer mortality. However, the molecular characteristics of CTCs are not well understood due to a lack of number of CTCs. Therefore, suspension cells were generated from MDA-MB-468 cells to mimic CTCs, and we investigate the microRNA (miRNA)-dependent molecular networks and their role in suspension cells. Here, we present an integrated analysis of mRNA and miRNA sequencing data for suspension cell lines, through comparison with adherent cells. Among the differentially regulated miRNA-mRNAs axes, we focus on the miR-146a-Neuropilin2 (NRP2) axis, which is known to influence tumor aggressiveness. We show that miR-146a directly regulates NRP2 expression and inhibits Semaphorin3C (SEMA3C) signaling. Functional studies reveal that miR-146a represses SEMA3C-induced invasion and proliferation by targeting NRP2. Finally, high-NRP2 is shown to be associated with poor outcomes in breast cancer patients. This study identifies the key role of the miR-146a-NRP2 signaling axis that is critical for the regulation of migration and invasion in CTC-mimicking cells.
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http://dx.doi.org/10.3390/genes12010045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824086PMC
December 2020

MicroRNA 34a-AXL Axis Regulates Vasculogenic Mimicry Formation in Breast Cancer Cells.

Genes (Basel) 2020 12 23;12(1). Epub 2020 Dec 23.

Division of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea.

Targeting the tumor vasculature is an attractive strategy for cancer treatment. However, the tumor vasculature is heterogeneous, and the mechanisms involved in the neovascularization of tumors are highly complex. Vasculogenic mimicry (VM) refers to the formation of vessel-like structures by tumor cells, which can contribute to tumor neovascularization, and is closely related to metastasis and a poor prognosis. Here, we report a novel function of AXL receptor tyrosine kinase (AXL) in the regulation of VM formation in breast cancer cells. MDA-MB-231 cells exhibited VM formation on Matrigel cultures, whereas MCF-7 cells did not. Moreover, AXL expression was positively correlated with VM formation. Pharmacological inhibition or AXL knockdown strongly suppressed VM formation in MDA-MB-231 cells, whereas the overexpression of AXL in MCF-7 cells promoted VM formation. In addition, AXL knockdown regulated epithelial-mesenchymal transition (EMT) features, increasing cell invasion and migration in MDA-MB-231 cells. Finally, the overexpression of microRNA-34a (miR-34a), which is a well-described EMT-inhibiting miRNA and targets AXL, inhibited VM formation, migration, and invasion in MDA-MB 231 cells. These results identify a miR-34a-AXL axis that is critical for the regulation of VM formation and may serve as a therapeutic target to inhibit tumor neovascularization.
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http://dx.doi.org/10.3390/genes12010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823537PMC
December 2020

Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases.

Biomedicines 2020 Dec 21;8(12). Epub 2020 Dec 21.

Division of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea.

Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy have been mainly used as therapy owing to these characteristics, their effectiveness does not meet expectations. Therefore, a better understanding of the etiology and new therapeutic approaches are needed. Endothelial cells (ECs) line the inner walls of blood vessels and maintain vascular homeostasis by protecting vascular cells from pathological stimuli. Chronic stimulation of ECs by various factors, including pro-inflammatory cytokines and hypoxia, leads to ECs undergoing an imbalance of endothelial homeostasis, which results in endothelial dysfunction and is closely associated with vascular diseases. Emerging studies suggest that endothelial to mesenchymal transition (EndMT) contributes to endothelial dysfunction and plays a key role in the pathogenesis of vascular diseases. EndMT is a process by which ECs lose their markers and show mesenchymal-like morphological changes, and gain mesenchymal cell markers. Despite the efforts to elucidate these molecular mechanisms, the role of EndMT in the pathogenesis of lung disease still requires further investigation. Here, we review the importance of EndMT in the pathogenesis of pulmonary vascular diseases and discuss various signaling pathways and mediators involved in the EndMT process. Furthermore, we will provide insight into the therapeutic potential of targeting EndMT.
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http://dx.doi.org/10.3390/biomedicines8120639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767472PMC
December 2020

Exploring the Role of TRIP-Brs in Human Breast Cancer: An Investigation of Expression, Clinicopathological Significance, and Prognosis.

Mol Ther Oncolytics 2020 Dec 16;19:105-126. Epub 2020 Sep 16.

Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women's University, Hyochangwon gil-52, Yongsan-Gu, Seoul 140-742, Republic of Korea.

TRIP-Brs, a group of transcription factors (TFs) that modulate several mechanisms in higher organisms. However, the novel paradigm to target TRIP-Brs in specific cancer remains to be deciphered. In particular, comprehensive analysis of TRIP-Brs in clinicopathological and patients' prognosis, especially in breast cancer (BRCA), is being greatly ignored. Therefore, we explored the key roles of TRIP-Br expression, modulatory effects, mutations, immune infiltration, and prognosis in BRCA using multidimensional approaches. We found elevated levels of TRIP-Brs in numerous cancer tissues than normal. Higher expression of TRIP-Br-2/4/5 was shown to be positively associated with lower survival, tumor grade, and malignancy of patients with BRCA. Additionally, higher TRIP-Br-3/4 were also significantly linked with worse/short survival of BRCA patients. TRIP-Br-1/4/5 were significantly overexpressed and enhanced tumorigenesis in large-scale BRCA datasets. The mRNA levels of TRIP-Brs have been also correlated with tumor immune infiltrate in BRCA patients. In addition, TRIP-Brs synergistically play a pivotal role in central carbon metabolism, cancer-associated pathways, cell cycle, and thyroid hormone signaling, which evoke that TRIP-Brs may be a potential target for the therapy of BRCA. Thus, this investigation may lay a foundation for further research on TRIP-Br-mediated management of BRCA.
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http://dx.doi.org/10.1016/j.omto.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554327PMC
December 2020

Production of a thermo-tolerant κ-carrageenase via a food-grade host and anti-oxidant activity of its enzymatic hydrolysate.

Food Chem 2021 Mar 8;339:128027. Epub 2020 Sep 8.

Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women's University, Seoul, South Korea. Electronic address:

κ-Carrageenase cleaves the β-(1-4) linkages of κ-carrageenan into κ-carrageenan oligosaccharides (κ-COS), which exhibit various biological activities. In this study, a glycoside hydrolase (GH) family 16 κ-carrageenase gene, cgkA, was cloned from the marine bacterium Vibrio sp. SY01 and secretory expressed in a food-grade host, Yarrowia lipolytica. The specific activity of the purified CgkA was 12.5 U/mg. Determination of biochemical properties showed that CgkA was a thermo-tolerant enzyme, and 59.9% of the initial enzyme activity was recovered by immediately placing the sample at 20 °C for 30 min after enzymatic inactivation by boiling for 5 min. The recombinant CgkA was an endo-type enzyme, the main enzymatic product was κ-carradiaose (accounting for 87.6% of total products), and κ-carratetraose was the minimum substrate. Additionally, in vitro and in vivo analyses indicated that enzymatic κ-carradiaose possesses anti-oxidant activity. These features make CgkA as a promising candidate for biotechnological applications in the production of anti-oxidant κ-COS.
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http://dx.doi.org/10.1016/j.foodchem.2020.128027DOI Listing
March 2021

Angiogenesis and vasculogenic mimicry as therapeutic targets in ovarian cancer.

BMB Rep 2020 Jun;53(6):291-298

Division of Biological Sciences, Sookmyung Women's University, Seoul 04310; Research Institute for Women's Health, Sookmyung Women's University, Seoul 04310, Korea.

Tumor angiogenesis is an essential process for growth and metastasis of cancer cells as it supplies tumors with oxygen and nutrients. During tumor angiogenesis, many pro-angiogenic factors are secreted by tumor cells to induce their own vascularization via activation of pre-existing host endothelium. However, accumulating evidence suggests that vasculogenic mimicry (VM) is a key alternative mechanism for tumor vascularization when tumors are faced with insufficient supply of oxygen and nutrients. VM is a tumor vascularization mechanism in which tumors create a blood supply system, in contrast to tumor angiogenesis mechanisms that depend on pre-existing host endothelium. VM is closely associated with tumor progression and poor prognosis in many cancers. Therefore, inhibition of VM may be a promising therapeutic strategy and may overcome the limitations of anti-angiogenesis therapy for cancer patients. In this review, we provide an overview of the current anti-angiogenic therapies for ovarian cancer and the current state of knowledge regarding the links between microRNAs and the VM process, with a focus on the mechanism that regulates associated signaling pathways in ovarian cancer. Moreover, we discuss the potential for VM as a therapeutic strategy against ovarian cancer. [BMB Reports 2020; 53(6): 291-298].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330806PMC
June 2020

Biochemical Characterization of a New Oligoalginate Lyase and Its Biotechnological Application in Degradation.

Front Microbiol 2020 10;11:316. Epub 2020 Mar 10.

Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women's University, Seoul, South Korea.

Oligoalginate lyases catalyze the degradation of alginate polymers and oligomers into monomers, a prerequisite for biotechnological utilizing alginate. In this study, we report the cloning, expression and biochemical characterization of a new polysaccharide lyase (PL) family 17 oligoalginate lyase, OalV17, from the marine bacterium sp. SY01. The recombinant OalV17 showed metal ion independent and detergent resistant properties. Furthermore, OalV17 is an exo-type enzyme that yields alginate monomers as the main product and recognizes alginate disaccharides as the minimal substrate. Site-directed mutagenesis followed by kinetic analysis indicates that the residue Arg plays a key role in substrate specificity. Furthermore, a rapid and efficient alginate monomer-producing method was developed directly from . These results suggest that OalV17 is a potential candidate for saccharification of alginate.
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http://dx.doi.org/10.3389/fmicb.2020.00316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076127PMC
March 2020

Enhancing the Thermo-Stability and Anti-Biofilm Activity of Alginate Lyase by Immobilization on Low Molecular Weight Chitosan Nanoparticles.

Int J Mol Sci 2019 Sep 14;20(18). Epub 2019 Sep 14.

Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women's University, Hyochangwon gil-52, Yongsan-Gu, Seoul 140-742, Korea.

Bacterial biofilm causes severe antibiotic resistance. An extracellular polymeric substance (EPS) is the main component in the bacterial biofilm. Alginate is a key EPS component in the biofilm of and responsible for surface adhesion and stabilization of biofilm. Alginate lyase has emerged as an efficient therapeutic strategy targeting to degrade the alginate in the biofilm of . However, the application of this enzyme is limited by its poor stability. In this study, chitosan nanoparticles (CS-NPs) were synthesized using low molecular weight chitosan and alginate lyase Aly08 was immobilized on low molecular weight chitosan nanoparticles (AL-LMW-CS-NPs). As a result, the immobilization significantly enhanced the thermal stability and reusability of Aly08. In addition, compared with free Aly08, the immobilized AL-LMW-CS-NPs exhibited higher efficiency in inhibiting biofilm formation and interrupting the established mature biofilm of , which could reduce its biomass and thickness confirmed by confocal microscopy. Moreover, the biofilm disruption greatly increased the antibiotic sensitivity of . This research will contribute to the further development of alginate lyase as an anti-biofilm agent.
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http://dx.doi.org/10.3390/ijms20184565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770906PMC
September 2019

Novel Carbazole-Piperazine Hybrid Small Molecule Induces Apoptosis by Targeting BCL-2 and Inhibits Tumor Progression in Lung Adenocarcinoma in Vitro and Xenograft Mice Model.

Cancers (Basel) 2019 Aug 25;11(9). Epub 2019 Aug 25.

Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women's University, Hyochangwon gil-52, Yongsan-Gu, Seoul 140-742, Korea.

Lung cancer is a type of deadly cancer and a leading cause of cancer associated death worldwide. BCL-2 protein is considered as an imperative target for the treatment of cancer due to their significant involvement in cell survival and death. A carbazole-piperazine hybrid molecule ECPU-0001 was designed and synthesized as a potent BCL-2 targeting agent with effective anticancer cancer activity. Interaction of ECPU-001 has been assessed by docking, molecular dynamics (MD) simulation, and thermal shift assay. Further, in vitro and in vivo anticancer activity was executed by cytotoxicity assay, FACS, colony formation and migration assay, western blotting, immunocyto/histochemistry and xenograft nude mice model. Molecular docking and MD simulation study confirmed that ECPU-0001 nicely interacts with the active site of BCL-2 by displaying a Ki value of 5.72 µM and binding energy (ΔG) of -8.35 kcal/mol. Thermal shift assay also validated strong interaction of this compound with BCL-2. ECPU-0001 effectively exerted a cytotoxic effect against lung adenocarnoma cells A459 with an IC value of 1.779 µM. Molecular mechanism of action have also been investigated and found that ECPU-0001 induced apoptosis in A459 cell by targeting BCL-2 to induce intrinsic pathway of apoptosis. Administration of ECPU-0001 significantly inhibited progression of tumor in a xenograft model without exerting severe toxicity and remarkably reduced tumor volume as well as tumor burden in treated animals. Our investigation bestowed ECPU-0001 as an effective tumoricidal agent which exhibited impressive anticancer activity in vitro as well as in vivo by targeting BCL-2 associated intrinsic pathway of apoptosis. Thus, ECPU-0001 may provide a valuable input for therapy of lung adenosarcoma in future, however, further extensive investigation of this compound will be needed.
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http://dx.doi.org/10.3390/cancers11091245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770606PMC
August 2019

Prognostic and Clinicopathological Significance of SERTAD1 in Various Types of Cancer Risk: A Systematic Review and Retrospective Analysis.

Cancers (Basel) 2019 Mar 8;11(3). Epub 2019 Mar 8.

Molecular Cancer Biology Laboratory, Cellular Heterogeneity Research Center, Department of Biosystem, Sookmyung Women's University, Hyochangwon gil-52, Yongsan-Gu, Seoul 140-742, Korea.

SERTAD/TRIP-Br genes are considered as a key nuclear transcriptional player in diverse mechanisms of cell including carcinogenesis. The Oncomine-Online Platform was used for differential expression and biological insights. Kaplan-Meier survival estimated by KM-plotter/cBioPortal/PrognoScan with 95% CI. SERTAD1 was found significantly elevated levels in most of tumor samples. Kaplan-Meier Plotter results distinctly showed the SERTAD1 over-expression significantly reduced median overall-survival (OS) of patients in liver ( = 364/Logrank-test = 0.0015), ovarian ( = 655/Logrank-test = 0.00011) and gastric ( = 631/Logrank-test = 0.1866). Increased level of SERTAD1 has a significantly higher survival rate in the initial time period, but after 100 months slightly reduced OS ( = 26/Logrank-test = 0.34) and RFS in HER2 positive breast cancer patients. In meta-analysis, cancer patients with higher SERTAD1 mRNA fold resulted worse overall survival than those with lower SERTAD1 levels. Heterogeneity was observed in the fixed effect model analysis DFS [Tau² = 0.0.073, (df = 4) = 15.536 ( = 0.004), I² = 74.253], DSS [Tau² = 1.015, (df = 2) = 33.214, ( = 0.000), I² = 93.973], RFS [Tau² = 0.492, (df = 7) = 71.133 ( = 0.000), I² = 90.159] (Figure 5). OS [Tau² = 0.480, (df = 17) = 222.344 ( = 0.000), I² = 92.354]. Lastly, SERTAD1 involved in several signaling cascades through interaction and correlation with many candidate factors as well as miRNAs. This meta-analysis demonstrates a robust evidence of an association between higher or lower SERTAD1, alteration and without alteration of SERTAD1 in cancers in terms of survival and cancer invasiveness.
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http://dx.doi.org/10.3390/cancers11030337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469047PMC
March 2019

Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia.

Am J Hum Genet 2019 03 14;104(3):439-453. Epub 2019 Feb 14.

Department of Bio and Brain Engineering, Korean Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407524PMC
March 2019

Kazinol U inhibits melanogenesis through the inhibition of tyrosinase-related proteins via AMP kinase activation.

Br J Pharmacol 2019 03 28;176(5):737-750. Epub 2019 Jan 28.

Department of Biological Science and Cellular Heterogeneity Research Center, Sookmyung Women's University, Seoul, Republic of Korea.

Background And Purpose: Kazinol U is a prenylated flavan isolated from an extract of Broussonetia kazinoki Sieb (Moraceae). Kazinol U has shown cytoprotective effects against cytokine-induced apoptotic cell death and induces AMP kinase (AMPK) activation through LKB1 activation. However, kazinol U has not been tested as a regulator of melanogenesis, although bark extract of B. kazinoki has been used as a cosmetic ingredient for skin conditioning.

Experimental Approach: We cultured mouse, human melanoma cells and normal human melanocytes to demonstrate anti-melanogenic effects of kazinol U. A tyrosinase activity assay, Western blot, RT-qPCR and a luciferase reporter gene assay were performed to determine the anti-melanogenic mechanisms of kazinol U. We confirmed its effect on melanogenesis in vivo using zebrafish.

Key Results: Kazinol U inhibited the expression and activity of tyrosinase, the rate-limiting enzyme in melanogenesis, and reduced tyrosinase expression and activity in response to cAMP-inducing agents. Kazinol U reduced the expression of other melanogenic enzymes, such as tyrosinase-related protein (Tyrp) 1 and Tyrp2, and down-regulated microphthalmia-associated transcription factor (MITF), the master regulator of the tyrosinase gene family. Moreover, kazinol U induced phosphorylation of AMPK and MAPK proteins, which are MITF inhibitors. It also exhibited anti-melanogenic effects in zebrafish, a recently developed in vivo model.

Conclusions And Implications: Our findings suggest that kazinol U reduces melanogenesis via its inhibitory effect on MITF and its downstream target genes, tyrosinase, Tyrp1 and Tyrp2. This work may provide a basis for the application of kazinol U for the treatment of hyperpigmentation skin disorders.
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http://dx.doi.org/10.1111/bph.14560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365358PMC
March 2019

Anticancer activity of gomisin J from Schisandra chinensis fruit.

Oncol Rep 2019 Jan 2;41(1):711-717. Epub 2018 Nov 2.

Department of Biological Sciences, Sookmyung Women's University, Seoul 04310, Republic of Korea.

In attempting to identify effective anticancer drugs from natural products that are harmless to humans, we found that the gomisin J from Schisandra chinensis fruit has anticancer activity. Schisandra chinensis fruits are used in traditional herbal medicine and gomisin J is one of their chemical constituents. In the present study, we examined the anticancer activity of gomisin J in MCF7 and MDA-MB-231 breast cancer cell lines and in MCF10A normal cell line, in a time- and concentration-dependent manner. Our data revealed that gomisin J exerted a much stronger cytotoxic effect on MCF7 and MDA-MB-231 cancer cells than on MCF10A normal cells. Gomisin J suppressed the proliferation and decreased the viability of MCF7 and MDA-MB-231 cells at relatively low (<10 µg/ml) and high (>30 µg/ml) concentrations, respectively. Our data also revealed that gomisin J induced necroptosis, a programmed form of necrosis, as well as apoptosis. Notably, gomisin J predominantly induced necroptosis in MCF7 cells that are known to have high resistance to many pro-apoptotic anticancer drugs, while MDA-MB-231 exhibited a much lower level of necroptosis but instead a higher level of apoptosis. This data indicated the possibility that it may be used as a more effective anticancer drug, especially in apoptosis-resistant malignant cancer cells. In an extended study, gomisin J exhibited a strong cytotoxic effect on all tested various types of 13 cancer cell lines, indicating its potential to be used against a wide range of different types of cancer cells.
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http://dx.doi.org/10.3892/or.2018.6850DOI Listing
January 2019

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation.

Int J Oncol 2019 Feb 14;54(2):702-712. Epub 2018 Nov 14.

Department of Biological Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.

Simultaneous induction of other types of programmed cell death, alongside apoptosis, in cancer cells may be considered an attractive strategy for the development of more effective anticancer therapies. The present study aimed to investigate the role of AMP‑activated protein kinase (AMPK) in nutrient/serum starvation‑induced necroptosis, which is a programmed form of necrosis, in the presence or absence of p53. The present study detected higher cell proliferation and lower cell death rates in the HCT116 human colon cancer cell line containing a p53 null mutation (HCT116 p53‑/‑) compared with in HCT116 cells harboring wild‑type p53 (HCT116 p53+/+), as determined using a cell viability assay. Notably, western blot analysis revealed a relatively lower level of necroptosis in HCT116 p53‑/‑ cells compared with in HCT116 p53+/+ cells. Investigating the mechanism, it was revealed that necroptosis may be induced in HCT116 p53+/+ cells by significantly increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), whereas little alterations were detected in HCT116 p53‑/‑ cells. Unexpectedly, a much lower level of ATP was detected in HCT116 p53‑/‑ cells compared with in HCT116 p53+/+ cells. Accordingly, AMPK phosphorylation on the Thr172 residue was markedly increased in HCT116 p53‑/‑ cells. Furthermore, western blot analysis and ROS measurements indicated that AMPK inhibition, using dorsomorphin dihydrochloride, accelerated necroptosis by increasing ROS generation in HCT116 p53‑/‑ cells. However, AMPK activation by AICAR did not suppress necroptosis in HCT116 p53+/+ cells. In conclusion, these data strongly suggested that AMPK activation may be enhanced in HCT116 p53‑/‑ cells under serum‑depleted conditions via a drop in cellular ATP levels. In addition, activated AMPK may be at least partially responsible for the inhibition of necroptosis in HCT116 p53‑/‑ cells, but not in HCT116 p53+/+cells.
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http://dx.doi.org/10.3892/ijo.2018.4634DOI Listing
February 2019

C1q/TNF-α-Related Protein 1 (CTRP1) Maintains Blood Pressure Under Dehydration Conditions.

Circ Res 2018 08;123(5):e5-e19

Department of Biological Sciences (K.H.Y., S.B., J.-S.L., M.-S.L., Y.Y.).

Rationale: Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation.

Objective: To investigate the physiological/pathophysiological role of CTRP1 in BP regulation.

Methods And Results: CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice.

Conclusions: For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312871DOI Listing
August 2018

Cryptotanshinone inhibits IgE‑mediated degranulation through inhibition of spleen tyrosine kinase and tyrosine‑protein kinase phosphorylation in mast cells.

Mol Med Rep 2018 Jul 22;18(1):1095-1103. Epub 2018 May 22.

Department of Biological Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.

Atopic dermatitis (AD) is a type of chronic skin inflammation and one of the most common relapsing allergic diseases, which presents with a severe rash and itchy skin lesions. The pathogenesis of AD is primarily associated with hyper‑activated mast cells, which makes them an effective treatment target. After cross‑linking the antigen/immunoglobulin (Ig) E complex binds to its high affinity receptor FcεRl on the surface of mast cells. The cells subsequently secrete excessive pro‑inflammatory mediators, including histamine and cytokines, which lead to pruritus and immune cell infiltration in the skin lesions. The present study screened natural compounds that have an inhibitory effect on IgE/antigen‑mediated secretory activity. It was revealed that cryptotanshinone (CRT), a natural compound extracted from Salvia miltiorrhiza Bunge, had inhibitory effects on the IgE/antigen complex. The underlying mechanism by which CRT exerted an anti‑allergy/inflammatory function was investigated using rat basophilic leukaemia (RBL) cells for degranulation assays and a 1‑chloro‑2,4‑dinitrobenzene (DNCB)‑induced AD Balb/c mouse model for in vivo study. CRT effectively mitigated the secretion of pro‑inflammatory cytokines, including tumor necrosis factor‑α and interleukin 1β, as well as immune cell infiltration into skin lesions in a mouse model of AD‑like skin disease induced by dinitrochlorobenzene. The inhibitory effect of CRT on IgE‑mediated mast cell degranulation was mediated by the inhibition of tyrosine kinase‑dependent degranulation signalling pathways involving spleen tyrosine kinase and Lyn. The present study revealed CRT as an inhibitor of mast cell degranulation. Therefore, CRT may be considered for development as a therapeutic drug to treat IgE‑mediated skin diseases.
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http://dx.doi.org/10.3892/mmr.2018.9042DOI Listing
July 2018

Anti-cancerous effect of cis-khellactone from through the induction of three programmed cell deaths.

Oncotarget 2018 Mar 30;9(24):16744-16757. Epub 2018 Mar 30.

Department of Biological Science, Sookmyung Women's University, Seoul, 14310, South Korea.

has traditionally been used to treat various medical problems. In this report, we introduce cis-khellactone as a new anti-cancer agent, which was isolated from the chloroform soluble fraction of the rhizomes of . Its anti-cancerous effect was at first tested in MCF7 and MDA-MB-231 breast cell lines, in which MCF7 is well known to be resistant to many anti-cancer drugs; MCF10A normal breast cell line was used as a control. experiments showed that cis-khellactone suppressed cell growth and proliferation at a relatively low concentrations (<5 μg/ml) and decreased cell viability at high concentrations (>10 μg/ml) in both cancer cell lines in a time- and concentration-dependent manner. This anti-cancerous effect was also checked in additional 16 different types of normal and cancer cell lines. Cis-khellactone treatment significantly suppressed cell proliferation and enhanced cell death in all tested cancer cell lines. Furthermore, Western blot analysis showed that cis-khellactone induced three types of programmed cell death (PCD): apoptosis, autophagy-mediated cell death, and necrosis/necroptosis. Cis-khellactone concentration-dependently decreased cell viability by increasing the level of reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), which are related to all three types of PCD. Mitochondrial fractionation data revealed that cis-khellactone induced the translocation of BAX and BAK into mitochondria as well as the overexpression of VDAC1, which probably accelerates MMP disruption and finally cell death. Importantly, our extended studies with xenograft model further confirmed these findings of anti-cancerous effects and showed no harmful effects in normal tissues, suggesting that there would be no side effects in humans.
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http://dx.doi.org/10.18632/oncotarget.24686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908283PMC
March 2018

Endothelial to Mesenchymal Transition Represents a Key Link in the Interaction between Inflammation and Endothelial Dysfunction.

Front Immunol 2018 20;9:294. Epub 2018 Feb 20.

Division of Biological Sciences, Sookmyung Women's University, Seoul, South Korea.

Endothelial cells that line the inner walls of blood vessels are in direct contact with blood and display remarkable heterogeneity in their response to exogenous stimuli. These ECs have unique location-dependent properties determined by the corresponding vascular beds and play an important role in regulating the homeostasis of the vascular system. Evidence suggests that vascular endothelial cells exposed to various environments undergo dynamic phenotypic switching, a key biological program in the context of endothelial heterogeneity, but that might result in EC dysfunction and, in turn, cause a variety of human diseases. Emerging studies show the importance of endothelial to mesenchymal transition (EndMT) in endothelial dysfunction during inflammation. EndMT is a complex biological process in which ECs lose their endothelial characteristics, acquire mesenchymal phenotypes, and express mesenchymal cell markers, such as alpha smooth muscle actin and fibroblast-specific protein 1. EndMT is induced by inflammatory responses, leading to pathological states, including tissue fibrosis, pulmonary arterial hypertension, and atherosclerosis, dysfunction of the vascular system. Although the mechanisms associated with inflammation-induced EndMT have been identified, unraveling the specific role of this phenotypic switching in vascular dysfunction remains a challenge. Here, we review the current understanding on the interactions between inflammatory processes, EndMT, and endothelial dysfunction, with a focus on the mechanisms that regulate essential signaling pathways. Identification of such mechanisms will guide future research and could provide novel therapeutic targets for the treatment of vascular diseases.
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http://dx.doi.org/10.3389/fimmu.2018.00294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826197PMC
March 2019

Development of suspension cell culture model to mimic circulating tumor cells.

Oncotarget 2018 Jan 7;9(1):622-640. Epub 2017 Dec 7.

Department of Biological Sciences, Sookmyung Women's University, Seoul 04312, Republic of Korea.

Circulating tumor cells (CTCs) are essential for the establishment of distant metastasis. Numerous studies have characterized CTCs as metastatic precursors; however, the molecular nature of CTCs has not been completely revealed yet due to the low number of CTCs in the blood stream. As an alternative approach, we developed a long-term suspension cell culture model using human breast cancer cell lines to mimic CTCs. We found that more than 40 passaged suspension cells acquired the ability to enhance metastasis like cancer stem cells. To identify molecular changes acquired during the suspension cell culture, we analyzed metabolic and lipidomic profiles as well as transcriptome in MDA-MB-468 suspension cells. Glutamate and leucine levels increased in suspension cells, and cholesterol synthesis pathway was altered. The inhibition of glutamate metabolic pathway decreased the proliferation of suspension cells compared to that of adherent cells. In the lipidomic profile, PC species containing long chain and polyunsaturated fatty acids increased in suspension cells and these species could be authentic and specific biomarkers for highly metastatic cancers. As this CTC-mimicking suspension cell culture model may easily apply to various types of cancer, we suggest this model as a great tool to develop therapeutic targets and drugs to eradicate metastatic cancer cells.
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http://dx.doi.org/10.18632/oncotarget.23079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787494PMC
January 2018

Endothelial miR-26a regulates VEGF-Nogo-B receptor-mediated angiogenesis.

BMB Rep 2017 Jul;50(7):384-389

Division of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea.

The Nogo-B receptor (NgBR) is necessary for not only Nogo-B-mediated angiogenesis but also vascular endothelial growth factor (VEGF) -induced angiogenesis. However, the molecular mechanisms underlying the regulatory role of the VEGF-NgBR axis in angiogenesis are not fully understood. Here, we report that miR-26a serves as a critical regulator of VEGF-mediated angiogenesis through directly targeting NgBR in endothelial cells (ECs). Stimulation of ECs by VEGF increased the expression of NgBR and decreased the expression of miR-26a. In addition, miR-26a decreased the VEGF-induced migration and proliferation of ECs. Moreover, miR-26a overexpression in ECs decreased the VEGF-induced phosphorylation of the endothelial nitric oxide synthase (eNOS) and the production of nitric oxide, which is important for angiogenesis. Overall, our data suggest that miR-26a plays a key role in VEGF-mediated angiogenesis through the modulation of eNOS activity, which is mediated by its ability to regulate NgBR expression by directly targeting the NgBR 3'-UTR. [BMB Reports 2017; 50(7): 384-389].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584747PMC
http://dx.doi.org/10.5483/bmbrep.2017.50.7.085DOI Listing
July 2017

Clinical significance linked to functional defects in bone morphogenetic protein type 2 receptor, BMPR2.

BMB Rep 2017 Jun;50(6):308-317

Department of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea.

Bone morphogenetic protein type 2 receptor (BMPR2) is one of the transforming growth factor-β (TGF-β) superfamily receptors, performing diverse roles during embryonic development, vasculogenesis, and osteogenesis. Human BMPR2 consists of 1,038 amino acids, and contains functionally conserved extracellular, transmembrane, kinase, and C-terminal cytoplasmic domains. Bone morphogenetic proteins (BMPs) engage the tetrameric complex, composed of BMPR2 and its corresponding type 1 receptors, which initiates SMAD proteins-mediated signal transduction leading to the expression of target genes implicated in the development or differentiation of the embryo, organs and bones. In particular, genetic alterations of BMPR2 gene are associated with several clinical disorders, including representative pulmonary arterial hypertension, cancers, and metabolic diseases, thus demonstrating the physiological importance of BMPR2. In this mini review, we summarize recent findings regarding the molecular basis of BMPR2 functions in BMP signaling, and the versatile roles of BMPR2. In addition, various aspects of experimentally validated pathogenic mutations of BMPR2 and the linked human diseases will also be discussed, which are important in clinical settings for diagnostics and treatment. [BMB Reports 2017; 50(6): 308-317].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498141PMC
http://dx.doi.org/10.5483/bmbrep.2017.50.6.059DOI Listing
June 2017

Negative regulation of NOD1 mediated angiogenesis by PPARγ-regulated miR-125a.

Biochem Biophys Res Commun 2017 Jan 9;482(1):28-34. Epub 2016 Nov 9.

Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea. Electronic address:

Infection with pathogens activates the endothelial cell and its sustained activation may result in impaired endothelial function. Endothelial dysfunction contributes to the pathologic angiogenesis that is characteristic of infection-induced inflammatory pathway activation. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a protein receptor which recognizes bacterial molecules and stimulates an immune reaction in various cells; however, the underlying molecular mechanisms in the regulation of inflammation-triggered angiogenesis are not fully understood. Here we report that peroxisome proliferator-activated receptor gamma (PPARγ)-mediated miR-125a serves as an important regulator of NOD1 agonist-mediated angiogenesis in endothelial cells by directly targeting NOD1. Treatment of human umbilical vein endothelial cells with natural PPARγ ligand, 15-Deoxy-Delta12,14-prostaglandin J2, led to inhibition of NOD1 expression; contrarily, protein levels of NOD1 were significantly increased by PPARγ knockdown. We report that PPARγ regulation of NOD1 expression is a novel microRNA-mediated regulation in endothelial cells. MiR-125a expression was markedly decreased in human umbilical vein endothelial cells subjected to PPARγ knockdown while 15-Deoxy-Delta12,14-prostaglandin J2 treatment increased the level of miR-125a. In addition, NOD1 is closely regulated by miR-125a, which directly targets the 3' untranslated region of NOD1. Moreover, both overexpression of miR-125a and PPARγ activation led to inhibition of NOD1 agonist-induced tube formation in endothelial cells. Finally, NOD1 agonist increased the formation of cranial and subintestinal vessel plexus in zebrafish, and this effect was abrogated by concurrent PPARγ activation. Overall, these findings identify a PPARγ-miR-125a-NOD1 signaling axis in endothelial cells that is critical in the regulation of inflammation-mediated angiogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2016.11.032DOI Listing
January 2017

Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function.

J Leukoc Biol 2016 12 6;100(6):1273-1284. Epub 2016 Sep 6.

Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea;

Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6GLy6CGr1CD11b) and MO-MDSCs (Ly6GLy6CGr-1CD11b) have an immune suppressive function. Interferon regulatory factor 4 (IRF4) has a role in the negative regulation of TLR signaling and is associated with lymphoid cell development. However, the roles of IRF4 in myeloid cell differentiation are unclear. In this study, we found that IRF4 expression was remarkably suppressed during the development of MDSCs in the tumor microenvironment. Both the mRNA and protein levels of IRF4 in MDSCs were gradually reduced, depending on the development of tumors in the 4T1 model. siRNA-mediated knockdown of IRF4 in bone marrow cells promoted the differentiation of PMN-MDSCs. Similarly, IRF4 inhibition in bone marrow cells using simvastatin, which has been known to inhibit IRF4 expression, increased PMN-MDSC numbers. In contrast, IRF4 overexpression in bone marrow cells inhibited the total numbers of MDSCs, especially PMN-MDSCs. Notably, treatment with IL-4, an upstream regulator of IRF4, induced IRF4 expression in the bone marrow cells, and consequently, IL-4-induced IRF4 expression resulted in a decrease in PMN-MDSC numbers. Finally, we confirmed that IRF4 expression in MDSCs can modulate their activity to inhibit T cell proliferation through IL-10 production and ROS generation, and myeloid-specific deletion of IRF4 leads to the increase of MDSC differentiation. Our present findings indicate that IRF4 reduction induced by tumor formation can increase the number of MDSCs, and increases in the IRF4 expression in MDSCs may infringe on the immune-suppressive function of MDSCs.
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http://dx.doi.org/10.1189/jlb.1A0215-068RRDOI Listing
December 2016

Inhibitory role of TRIP-Br1 oncoprotein in hypoxia-induced apoptosis in breast cancer cell lines.

Int J Oncol 2016 Jun 24;48(6):2639-46. Epub 2016 Mar 24.

Department of Biological Science, Sookmyung Women's University, Seoul 140-742, Republic of Korea.

TRIP-Br1 oncoprotein is known to be involved in many vital cellular functions. In this study, we examined the role of TRIP-Br1 in hypoxia-induced cell death. Exposure to the overcrowded and CoCl2-induced hypoxic conditions increased TRIP-Br1 expression at the protein level in six breast cancer cell lines (MCF7, MDA-MB-231, T47D, Hs578D, BT549, and MDA-MB-435) but resulted in no significant change in three normal cell lines (MCF10A, MEF and NIH3T3). Our result revealed that CoCl2-induced hypoxia stimulated apoptosis and autophagy, in which TRIP-Br1 expression was found to be upregulated. Interestingly, TRIP-Br1 silencing in the MCF7 and MDA-MB-231 cancer cells accelerated apoptosis and destabilization of XIAP under the CoCl2-induced hypoxic condition, implying that TRIP-Br1 may render cancer cells resistant to apoptosis through the stabilization of XIAP. We also propose that TRIP-Br1 seems to be upregulated at least partly as a result of the inhibition of PI3K/AKT signaling pathway and the overexpression of HIF-1α. In conclusion, our findings suggest that TRIP-Br1 functions as an oncogenic protein by providing cancer cells resistance to the hypoxia-induced cell death.
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http://dx.doi.org/10.3892/ijo.2016.3454DOI Listing
June 2016

Antimelanogenic effect of 4-hydroxylonchocarpin through the inhibition of tyrosinase-related proteins and MAPK phosphatase.

Exp Dermatol 2016 07;25(7):574-6

Department of Biological Science and the Research Center for Women's Diseases, Sookmyung Women's University, Seoul, Korea.

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http://dx.doi.org/10.1111/exd.13004DOI Listing
July 2016

Inhibition of osteoclast differentiation by overexpression of NDRG2 in monocytes.

Biochem Biophys Res Commun 2015 Dec 4;468(4):611-6. Epub 2015 Nov 4.

Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul 140-742, Republic of Korea. Electronic address:

N-Myc downstream-regulated gene 2 (NDRG2), a member of the NDRG family of differentiation-related genes, has been characterized as a regulator of dendritic cell differentiation from monocytes, CD34(+) progenitor cells, and myelomonocytic leukemic cells. In this study, we show that NDRG2 overexpression inhibits the differentiation of U937 cells into osteoclasts in response to stimulation with a combination of macrophage colony-stimulating factor (M-CSF) and soluble receptor activator of NF-κB ligand (RANKL). U937 cells stably expressing NDRG2 are unable to differentiate into multinucleated osteoclast-like cells and display reduced tartrate-resistant acid phosphatase (TRAP) activity and resorption pit formation. Furthermore, NDRG2 expression significantly suppresses the expression of genes that are crucial for the proliferation, survival, differentiation, and function of osteoclasts, including c-Fos, Atp6v0d2, RANK, and OSCAR. The activation of ERK1/2 and p38 is also inhibited by NDRG2 expression during osteoclastogenesis, and the inhibition of osteoclastogenesis by NDRG2 correlates with the down-regulation of the expression of the transcription factor PU.1. Taken together, our results suggest that the expression of NDRG2 potentially inhibits osteoclast differentiation and plays a role in modulating the signal transduction pathway responsible for osteoclastogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2015.10.167DOI Listing
December 2015
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