Publications by authors named "Kyung-Sook Chung"

126 Publications

Florigen sequestration in cellular membranes modulates temperature-responsive flowering.

Science 2021 09 1;373(6559):1137-1142. Epub 2021 Sep 1.

Department of Life Sciences, Korea University, Seoul 02841, Korea.

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http://dx.doi.org/10.1126/science.abh4054DOI Listing
September 2021

Improved tumor-suppressive effect of OZ-001 combined with cisplatin mediated by mTOR/p70S6K and STAT3 inactivation in A549 human lung cancer cells.

Biomed Pharmacother 2021 Oct 28;142:111961. Epub 2021 Jul 28.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Republic of Korea. Electronic address:

We previously reported the anticancer activity of 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(N,N-dimethylureido)-N'-methylpropylamino]-3,4-dihydroquinazoline (OZ-001), a T-type calcium channel (TTCC) blocker, against non-small cell lung cancer (NSCLC) in vitro and in vivo. Here, we evaluated the synergistic effect of OZ-001 and cisplatin on A549 human lung cancer cells and A549 xenograft mice. Our study demonstrated that treatment with OZ-001 and cisplatin sensitized A549 cells to cisplatin and significantly inhibited cell growth, increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, and induced poly (ADP-ribose) polymerase (PARP) cleavage in A549 cells and an A549 xenograft tumor mouse model. Moreover, our findings showed that mechanistic target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), and signal transducer and activator of transcription (STAT3) inactivation was required for apoptosis induced by the combination of OZ-001 and cisplatin in in vitro and in vivo experiments. Our results suggest that combined treatment with OZ-001 and cisplatin could potentiate antiproliferative effects via suppression of the mTOR/p70S6K and STAT3 pathways and may be considered a potential therapeutic agent for NSCLC.
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http://dx.doi.org/10.1016/j.biopha.2021.111961DOI Listing
October 2021

The development of a functional human small intestinal epithelium model for drug absorption.

Sci Adv 2021 Jun 2;7(23). Epub 2021 Jun 2.

Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.

Advanced technologies are required for generating human intestinal epithelial cells (hIECs) harboring cellular diversity and functionalities to predict oral drug absorption in humans and study normal intestinal epithelial physiology. We developed a reproducible two-step protocol to induce human pluripotent stem cells to differentiate into highly expandable hIEC progenitors and a functional hIEC monolayer exhibiting intestinal molecular features, cell type diversity, and high activities of intestinal transporters and metabolic enzymes such as cytochrome P450 3A4 (CYP3A4). Functional hIECs are more suitable for predicting compounds metabolized by CYP3A4 and absorbed in the intestine than Caco-2 cells. This system is a step toward the transition from three-dimensional (3D) intestinal organoids to 2D hIEC monolayers without compromising cellular diversity and function. A physiologically relevant hIEC model offers a novel platform for creating patient-specific assays and support translational applications, thereby bridging the gap between 3D and 2D culture models of the intestine.
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http://dx.doi.org/10.1126/sciadv.abh1586DOI Listing
June 2021

Rosmarinic acid represses colitis-associated colon cancer: A pivotal involvement of the TLR4-mediated NF-κB-STAT3 axis.

Neoplasia 2021 06 31;23(6):561-573. Epub 2021 May 31.

Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju-si, Gangwon-do, Korea. Electronic address:

Previously, we found that rosmarinic acid (RA) exerted anti-inflammatory activities in a dextran sulfate sodium (DSS)-induced colitis model. Here, we investigated the anti-tumor effects of RA on colitis-associated colon cancer (CAC) and the underlying molecular mechanisms. We established an azoxymethane (AOM)/DSS-induced CAC murine model for in vivo studies and used a conditioned media (CM) culture system in vitro. H&E staining, immunohistochemistry, western blot assay, enzyme-linked immunosorbent assay, molecular docking, co-immunoprecipitation, and immunofluorescence assay were utilized to investigate how RA prevented colorectal cancer. In the AOM/DSS-induced CAC murine model, RA significantly reduced colitis severity, inflammation-related protein expression, tumor incidence, and colorectal adenoma development. It significantly modulated toll-like receptor-4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, thus attenuating the expression of anti-apoptotic factors, which mediate transcription factor-dependent tumor growth. In vitro, RA inhibited CM-induced TLR4 overexpression and competitively inhibited TLR4-myeloid differentiation factor 2 complex in an inflammatory microenvironment. Thus, RA suppressed NF-κB and STAT3 activation in colon cancer cells in an inflammatory microenvironment. Therefore, RA suppressed colitis-associated tumorigenesis in the AOM/DSS-induced CAC murine model and abrogated human colon cancer progression in an inflammatory microenvironment by propitiating TLR4-mediated NF-κB and STAT3 activation, pleiotropically.
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http://dx.doi.org/10.1016/j.neo.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180929PMC
June 2021

Standardized hot water extract from the leaves of Hydrangea serrata (Thunb.) Ser. alleviates obesity via the AMPK pathway and modulation of the gut microbiota composition in high fat diet-induced obese mice.

Food Funct 2021 Mar 3;12(6):2672-2685. Epub 2021 Mar 3.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea.

Obesity is an increasing health problem worldwide as it is the major risk factor for metabolic diseases. In the present study, we investigated the anti-obesity effects of WHS by examining its effects on high fat diet (HFD)-induced obese mice. Male C57BL/6 mice were fed either a normal diet (ND) or a high fat diet (HFD) with or without WHS. At the end of the experiment, we observed the changes in their body weight and white adipose tissue (WAT) weight and lipid profiles in plasma. We performed western blot and histological analyses of WAT and liver to elucidate the molecular mechanisms of action. We also conducted fecal 16S rRNA analysis for investigating the gut microbiota. Our results indicated that pre- and post-oral administration of WHS significantly prevented body weight gain and reduced body fat weight in HFD-induced obese mice. In addition, WHS was found to improve adipocyte hypertrophy and liver fat accumulation by regulating the AMPK and AKT/mTOR pathways. WHS ameliorated hyperlipidemia by reducing total cholesterol and low-density lipoprotein (LDL) and decreased the energy metabolism-related hormones, leptin and insulin, in mouse plasma. Furthermore, we found that WHS modulated gut dysbiosis by normalizing HFD-induced changes. Taken together, our in vivo data implicate that WHS can be considered as a potential dietary supplement for alleviating obesity.
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http://dx.doi.org/10.1039/d0fo02185gDOI Listing
March 2021

Protective effect of exopolysaccharide fraction from Bacillus subtilis against dextran sulfate sodium-induced colitis through maintenance of intestinal barrier and suppression of inflammatory responses.

Int J Biol Macromol 2021 May 27;178:363-372. Epub 2021 Feb 27.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea. Electronic address:

We previously reported that an exopolysaccharide-enriched fraction from Bacillus subtilis J92 (B-EPS) could improve immune functions by regulating the immunological parameters of IFN-γ-primed macrophages, CD3/CD28-stimulated splenocytes, and in cyclophosphamide-induced immunosuppressed mice. In the present study, we investigated whether B-EPS contributes to the maintenance of intestinal barrier integrity in a dextran sodium sulfate (DSS)-induced colitis mouse model that mimics human inflammatory bowel disease (IBD). B-EPS treatment improved histological characteristics and common features including a high disease activity index (DAI), an increased spleen weight, and colon shortening in DSS-induced colitis. B-EPS also effectively restored intestinal barrier function by modulating tight junction-related proteins (claudin-1, claudin-2, and occludin) and epithelial-mesenchymal transition (EMT) marker proteins (E-cadherin, N-cadherin, and vimentin). Moreover, B-EPS downregulated immune cell infiltration and inflammatory responses including the production of inflammatory cytokines, such as IL-6 and IL-1β, and activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Taken together, these results suggest that B-EPS could serve as a functional food ingredient for improving intestinal barrier function and alleviating colonic inflammation in IBD.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.02.186DOI Listing
May 2021

Effect of Microbial Short-Chain Fatty Acids on CYP3A4-Mediated Metabolic Activation of Human Pluripotent Stem Cell-Derived Liver Organoids.

Cells 2021 01 11;10(1). Epub 2021 Jan 11.

Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea.

The early and accurate prediction of the hepatotoxicity of new drug targets during nonclinical drug development is important to avoid postmarketing drug withdrawals and late-stage failures. We previously established long-term expandable and functional human-induced pluripotent stem cell (iPSC)-derived liver organoids as an alternative source for primary human hepatocytes. However, PSC-derived organoids are known to present immature fetal characteristics. Here, we treated these liver organoids with microbial short-chain fatty acids (SCFAs) to improve metabolic maturation based on microenvironmental changes in the liver during postnatal development. The effects of the three main SCFA components (acetate, propionate, and butyrate) and their mixture on liver organoids were determined. Propionate (1 µM) significantly promoted the / expression ratio, and acetate (1 µM), propionate (1 µM), and butyrate (1 µM) combination treatment, compared to no treatment (control), substantially increased CYP3A4 activity and albumin secretion, as well as gene expression. More importantly, mixed SCFA treatment accurately revealed troglitazone-induced hepatotoxicity, which was redeemed on a potent CYP3A4 inhibitor ketoconazole treatment. Overall, we determined, for the first time, that SCFA mixture treatment might contribute to the accurate evaluation of the CYP3A4-dependent drug toxicity by improving metabolic activation, including CYP3A4 expression, of liver organoids.
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http://dx.doi.org/10.3390/cells10010126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827634PMC
January 2021

Role of Splicing factor SF1 in Temperature-Responsive Alternative Splicing of pre-mRNA.

Front Plant Sci 2020 1;11:596354. Epub 2020 Dec 1.

Division of Life Sciences, Korea University, Seoul, South Korea.

Small changes in temperature affect plant ecological and physiological factors that impact agricultural production. Hence, understanding how temperature affects flowering is crucial for decreasing the effects of climate change on crop yields. Recent reports have shown that β, the major spliced isoform of ()-a flowering time gene, contributes to temperature-responsive flowering in . However, the molecular mechanism linking pre-mRNA processing and temperature-responsive flowering is not well understood. Genetic and molecular analyses identified the role of an splicing factor homolog, , in regulating temperature-responsive flowering. The loss-of-function mutant shows temperature insensitivity at different temperatures and very low levels of β transcript, but a significantly increased transcript level of the alternative splicing (AS) isoform, . An RNA immunoprecipitation (RIP) assay revealed that AtSF1 is responsible for ambient temperature-dependent AS of pre-mRNA, resulting in the temperature-dependent production of functional β transcripts. Moreover, alterations in other splicing factors such as / (/) and () did not impact the β/ ratio at different temperatures. Taken together, our data suggest that a temperature-dependent interaction between AtSF1 and pre-mRNA controls flowering time in response to temperature fluctuations.
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http://dx.doi.org/10.3389/fpls.2020.596354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735993PMC
December 2020

Immunostimulatory Effects of Live K040706 on the CYP-Induced Immunosuppression Mouse Model.

Nutrients 2020 Nov 22;12(11). Epub 2020 Nov 22.

Department of Pharmaceutical Biochemistry, College of Pharmacy Kyung Hee University, Seoul 02447, Korea.

Our previous studies have shown that heat-killed K040706 exerts immunostimulatory and anti-inflammatory activities in macrophages, cyclophosphamide (CYP)-treated mice, and dextran sulfate sodium-induced colitis mice. However, the immunostimulatory effects of live K040706 (live K040706) against CYP-induced immunosuppression and its underlying molecular mechanisms remain unknown. Therefore, we investigated the immunostimulatory effects of live K040706 (10 or 10 colony forming unit (CFU)/day, p.o.) in CYP-induced immunosuppressed mice. Oral administration of live K040706 prevented the CYP-induced decreases in body weight, thymus index, natural killer (NK) cell activity, T and B cell proliferation, and cytokine (interferon (IFN)-γ, interleukin (IL)-2, and IL-12) production. The administration of live K040706 also exerted positive effects on the gut microbiota of CYP-induced mice, resulting in a microbiota composition similar to that of normal mice. Moreover, live K040706 significantly enhanced IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in the splenocytes and Peyer's patch (PP) cells of mice and increased bone marrow (BM) cell proliferation. Taken together, our data indicate that live K040706 may effectively accelerate recovery from CYP-induced immunosuppression, leading to activation of the immune system. Therefore, live K040706 may serve as a potential immunomodulatory agent against immunosuppression.
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http://dx.doi.org/10.3390/nu12113573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700367PMC
November 2020

A new experimental model to study human drug responses.

Biofabrication 2020 09 25;12(4):045029. Epub 2020 Sep 25.

Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.

Accurate prediction of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics is critical for drug development. Oral drugs are particularly difficult because they are absorbed by the intestine and metabolized in the liver before systemic metabolism in vivo; this is called the first-pass effect and is a critical factor for predicting oral bioavailability (BA). Here, we fabricated a new networking and circulating cell culture system (NCCS), mimicking the circulatory system and interaction of organs for studying the pharmacokinetic and pharmacodynamics of oral drugs in vitro. NCCS consisted of a micro-pump for circulating fluids, two types of multi-insert culture dishes for culturing different cell types, and an orbital shaker for mixing; flow rate and shaking-speed were controlled by weight-sensors and drivers. A first-pass effect test was performed using functionally differentiated HepaRG and Caco-2 cell lines, using a new modified spheroid forming unit (SFU) protocol. To verify the similarity of PK (first-pass effect) data of NCCS with the data from the human body, 15 reference drugs were chosen and their associated data were obtained by liquid chromatography-mass spectrometry analysis. NCCS generated absorption and metabolism data showed >70% similarity to human data respectively. NCCS can also be used to demonstrate species differences. Animal models are the primary basis for drug discovery, development, and testing. However, the weak correlation between humans and animals, particularly regarding absorption and metabolism, is a substantial limitation for the use of animal models. Here we compare human and mouse acetaminophen (APAP) metabolism using NCCS, and its application can be extended to assess cellular responses, such as efficacy and toxicity, simultaneously.
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http://dx.doi.org/10.1088/1758-5090/abb652DOI Listing
September 2020

Diarylurea derivatives comprising 2,4-diarylpyrimidines: Discovery of novel potential anticancer agents via combined failed-ligands repurposing and molecular hybridization approaches.

Bioorg Chem 2020 10 22;103:104121. Epub 2020 Jul 22.

Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address:

A series of diarylurea derivatives comprising 2,4-diarylpyrimidines were synthesized based on a combination of postulated molecular hybridization design and failed-ligands repurposing approaches, which enabled the discovery of novel potential antiproliferative agents. Towards credible biological evaluation, an in vitro anticancer activity assay was conducted employing a library of 60 cancer cell lines constituting nine panels representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. The results revealed high effectiveness and broad-spectrum anticancer activity of compounds 4m and 4g. Five-dose assay of compounds 4m and 4g proved their high potency that surpassed that of four standard kinase inhibitors FDA-approved anticancer drugs against many cancer cells. Towards the identification of their molecular target, screening of kinase inhibitory profile employing a panel of 51 kinases involved in cancer revealed inhibition of several kinases from the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) kinase family, which might mediate, at least in part, the antiproliferative activity. Molecular docking of 4g into the crystal structure of the Feline McDonough Sarcoma (FMS) kinase predicted that it binds to a pocket formed by the juxtamembrane domain, the catalytic loop, and the αE helix, thus stabilizing the inhibited conformation of the kinase. Flow cytometric study of the cytotoxic effects of compound 4g in A549 cells showed it induces dose- and time-dependent apoptotic events leading to cell death. Collectively, this work presents compound 4g as a potential broad-spectrum anticancer agent against multiple cancer types.
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http://dx.doi.org/10.1016/j.bioorg.2020.104121DOI Listing
October 2020

Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers.

Bioorg Med Chem 2020 06 14;28(11):115491. Epub 2020 Apr 14.

Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivativesusing an electron acceptor group was reported to be potent T-type calcium channel blockers and exhibit strong cytotoxic effects against various cancerous cell lines. To investigate the role of the guanidine moiety in the 2-amino-3,4-dihydroquinazoline scaffold as a pharmacophore for dual biological activity, a new series of 2-thio-3,4-dihydroquniazoline derivatives using an electron donor group at the C2-position was synthesized and evaluated for T-type calcium channel blocking activity and cytotoxic effects against two human cancerous cell lines (lung cancer A549 and colon cancer HCT-116). Among them, compound 6g showed potent inhibition of Ca3.2 currents (83% inhibition) at 10 µM concentrations. The compound also exhibited IC values of 5.0 and 6.4 µM against A549 and HCT-116 cell lines, respectively, which are comparable to the parental lead compound KYS05090. These results indicate that the isothiourea moiety similar to the guanidine moiety of 2-amino-3,4-dihydroquinazoline derivatives may be an essential pharmacophore for the desired biological activities. Therefore, our preliminary work can provide the opportunity to expand a chemical repertoire to improve affinity and selectivity for T-type calcium channels.
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http://dx.doi.org/10.1016/j.bmc.2020.115491DOI Listing
June 2020

Long-Term Expansion of Functional Human Pluripotent Stem Cell-Derived Hepatic Organoids.

Int J Stem Cells 2020 Jul;13(2):279-286

Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.

A human cell-based liver model capable of long-term expansion and mature hepatic function is a fundamental requirement for pre-clinical drug development. We previously established self-renewing and functionally mature human pluripotent stem cell-derived liver organoids as an alternate to primary human hepatocytes. In this study, we tested long-term prolonged culture of organoids to increase their maturity. Organoid growing at the edge of Matrigel started to deteriorate two weeks after culturing, and the expression levels of the functional mature hepatocyte marker were decreased at four weeks of culture. Replating the organoids weekly at a 1:2 ratio in fresh Matrigel, resulted in healthier morphology with a thicker layer compared to organoids maintained on the same Matrigel and significantly increased expression until three weeks, although, it decreased sharply at four weeks. The levels of the fetal hepatocyte marker were considerably increased in long-term cultures of organoids. Therefore, we performed serial passaging of organoids, whereby they were mechanically split weekly at a 1:3∼1:5 ratio in fresh Matrigel. The organoids expanded so far over passage 55, or 1 year, without growth retardation and maintained a normal karyotype after long-term cryopreservation. Differentiation potentials were maintained or increased after long-term passaging, while expression considerably decreased after passaging. Therefore, these data demonstrate that organoids can be exponentially expanded by serial passaging, while maintaining long-term functional maturation potential. Thus, hepatic organoids can be a practical and renewable cell source for human cell-based and personalized 3D liver models.
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http://dx.doi.org/10.15283/ijsc20060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378903PMC
July 2020

Optimization of 3D hydrogel microenvironment for enhanced hepatic functionality of primary human hepatocytes.

Biotechnol Bioeng 2020 06 8;117(6):1864-1876. Epub 2020 Apr 8.

Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.

Although primary human hepatocytes (PHHs) are the gold standard in drug efficacy and metabolism studies, long-term survival of PHHs and maintenance of their hepatic function are still challenging. In this study, we focused on the effect of the initial microenvironment on upregulation and long-term preservation of hepatic function of PHHs encapsulated within biodegradable hydrogel systems. PHHs were encapsulated in RGD-functionalized hybrid hydrogels with various degrees of degradability, and their hepatic functionality was analyzed. Regardless of the hydrogel elastic modulus, the combination with nondegradable hydrogels had a predominantly negative effect on the prompt engraftment of PHHs, whereas a degradable hydrogel with intermediate initial degradability was most effective in maintaining hepatic function. Efficient network formation by PHHs and cocultured cells, along with the control of hydrogel degradation, governed the hepatic functionality at an early stage and upon long-term cultivation. Under optimized conditions, expression of genes involved in biological processes such as focal adhesions, cell survival, cytoskeleton formation, and extracellular matrix interactions was significantly higher than that in a control with relatively delayed initial degradation. Thus, we suggest that the orchestrated control of initial cellular remodeling may play an important role in the maintenance of hepatic function in a three-dimensional PHH culture.
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http://dx.doi.org/10.1002/bit.27328DOI Listing
June 2020

KCP10043F Represses the Proliferation of Human Non-Small Cell Lung Cancer Cells by Caspase-Mediated Apoptosis via STAT3 Inactivation.

J Clin Med 2020 Mar 5;9(3). Epub 2020 Mar 5.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

We previously reported that 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(-dimethylureido)--methylpropylamino]-3,4-dihydroquinazoline (KCP10043F) can induce G-phase arrest and synergistic cell death in combination with etoposide in lung cancer cells. Here, we investigated the underlying mechanism by which KCP10043F induces cell death in non-small cell lung cancer (NSCLC). Propidium iodide (PI) and annexin V staining revealed that KCP10043F-induced cytotoxicity was caused by apoptosis. KCP10043F induced a series of intracellular events: (1) downregulation of Bcl-2 and Bcl-xL and upregulation of Bax and cleaved Bid; (2) loss of mitochondrial membrane potential; (3) increase of cytochrome release; (4) cleavage of procaspase-8, procaspase-9, procaspase-3, and poly (ADP-ribose) polymerase (PARP). In addition, KCP10043F exhibited potent inhibitory effects on constitutive or interleukin-6 (IL-6)-induced signal transducer and activator of transcription (STAT3) phosphorylation and STAT3-regulated genes including survivin, Mcl-1, and cyclin D. Furthermore, STAT3 overexpression attenuated KCP10043F-induced apoptosis and the cleavage of caspase-9, caspase-3, and PARP. Docking analysis disclosed that KCP10043F could bind to a pocket in the SH2 domain of STAT3 and prevent STAT3 phosphorylation. The oral administration of KCP10043F decreased tumor growth in an A549 xenograft mouse model, as associated with the reduced phosphorylated STAT3, survivin, Mcl-1, and Bcl-2 expression and increased TUNEL staining and PARP cleavage in tumor tissues. Collectively, our data suggest that KCP10043F suppresses NSCLC cell growth through apoptosis induction via STAT3 inactivation.
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http://dx.doi.org/10.3390/jcm9030704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141374PMC
March 2020

Protective Effect of L. (Chickpea) Ethanol Extract in the Dextran Sulfate Sodium-Induced Mouse Model of Ulcerative Colitis.

Nutrients 2020 Feb 12;12(2). Epub 2020 Feb 12.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

Inflammatory bowel disease (IBD) is a major risk factor of colorectal cancer. Drugs currently used for IBD exhibit adverse effects including vomiting, nausea, and diarrhea. Naturally derived novel alternative therapies are required to overcome these limitations. In this study, we investigated the protective effects of ethanol extract of (CEE) in a dextran sodium sulfate (DSS)-induced mouse model of colitis. CEE markedly improved DSS-induced clinical symptoms and histological status, such as the disease activity index, spleen weight, and colon length. Moreover, CEE-treated mice showed significant recovery of DSS-induced crypt damage and cell death. CEE suppressed myeloperoxidase (MPO) activity and macrophage marker F4/80 mRNA expression in colonic tissue of mice with DSS-induced colitis, indicating neutrophil infiltration and macrophage accumulation, respectively. Although DSS upregulated pro-inflammatory mediators and activated transcription factors, CEE downregulated the mRNA expression of cytokines including interleukin-6, interleukin-1β, and tumor necrosis factor-α, protein expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as activation of nuclear factor-kappa B (NF-кB) and signal transducer and activator of transcription 3 (STAT3). Hence, our findings reveal that the anti-inflammatory properties of CEE, involving the downregulation of the expression of pro-inflammatory mediators by inactivating NF-кB and STAT3 in DSS-induced colitis mice.
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http://dx.doi.org/10.3390/nu12020456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071501PMC
February 2020

High-Fat Diet Propelled AOM/DSS-Induced Colitis-Associated Colon Cancer Alleviated by Administration of via STAT3 Signaling Pathway.

Biology (Basel) 2020 Feb 2;9(2). Epub 2020 Feb 2.

Department of Pharmacology, College of Korean Medicine, Sangji University, 83 Sangjidae-gil, Wonju-si, Gangwon-do 26339, Korea.

Many epidemiological observational studies suggest that a high-fat diet (HFD) accelerates the risk of colorectal cancer (CRC). Inflammation can play a key role in the relationship between colon cancer and HFD. Although reported by several studies, controlled experimental studies have not explored this relationship. We established an HFD-fed colitis-associated colon cancer (CAC) mice model and evaluated the anti-tumorigenic effects of AG on HFD-propelled CAC along with its mechanism of action. Previously, we found that (AG) exerts chemopreventive effects on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC in a mice model, and has anti-adipogenic effects in a HFD-induced obesity mice model. In the HFD-propelled CAC mice model, AG significantly reduced cancer-related death, prevented body weight loss, and alleviated splenic enlargement. Additionally, AG prevented colon shortening and reduced the number of colorectal polyps. Histological studies demonstrated the up-regulation of inflammation, hyperplasia, and neoplasia in HFD-propelled CAC mice, whereas AG suppressed colonic disease progression and tumorigenesis. Furthermore, AG significantly inhibited the signal transducer and activator of transcription 3 (STAT3) signaling pathway and attenuated the protein expression of the STAT3 target gene, which mediates transcription factor-dependent tumor cell proliferation. These results indicate that AG abrogates inflammation-induced tumor progression in HFD-propelled CAC mice by inhibiting STAT3 activation.
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http://dx.doi.org/10.3390/biology9020024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168234PMC
February 2020

The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation.

Cancers (Basel) 2019 Dec 3;11(12). Epub 2019 Dec 3.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea.

We previously reported the potential anti-proliferative activity of 3-(5,6,7-trimethoxy-4-oxo-4-chromen-2-yl)--(3,4,5-trimethoxyphenyl) benzamide (TMS-TMF-4f) against human cancer cells; however, the underlying molecular mechanisms have not been investigated. In the present study, TMS-TMF-4f showed the highest cytotoxicity in human cervical cancer cells (HeLa and CaSki) and low cytotoxicity in normal ovarian epithelial cells. Annexin V-FITC and propidium iodide (PI) double staining revealed that TMS-TMF-4f-induced cytotoxicity was caused by the induction of apoptosis in both HeLa and CaSki cervical cancer cells. The compound TMS-TMF-4f enhanced the activation of caspase-3, caspase-8, and caspase-9 and regulated Bcl-2 family proteins, which led to mitochondrial membrane potential (MMP) loss and resulted in the release of cytochrome and Smac/DIABLO into the cytosol. Also, TMS-TMF-4f suppressed both constitutive and IL-6-inducible levels of phosphorylated STAT3 (p-STAT3) and associated proteins such as Mcl-1, cyclin D1, survivin, and c-Myc in both cervical cancer cells. STAT-3 overexpression completely ameliorated TMS-TMF-4f-induced apoptotic cell death and PARP cleavage. Docking analysis revealed that TMS-TMF-4f could bind to unphosphorylated STAT3 and inhibit its interconversion to the activated form. Notably, intraperitoneal administration of TMS-TMF-4f (5, 10, or 20 mg/kg) decreased tumor growth in a xenograft cervical cancer mouse model, demonstrated by the increase in TUNEL staining and PARP cleavage and the reduction in p-STAT3, Mcl-1, cyclin D1, survivin, and c-Myc expression levels in tumor tissues. Taken together, our results suggest that TMS-TMF-4f may potentially inhibit human cervical tumor growth through the induction of apoptosis via STAT3 suppression.
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http://dx.doi.org/10.3390/cancers11121927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966466PMC
December 2019

β-Caryophyllene in the Essential Oil from Induces G Phase Cell Cycle Arrest in Human Lung Cancer Cells.

Molecules 2019 Oct 18;24(20). Epub 2019 Oct 18.

College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

is a plant widespread in East Asia, used in folk medicine to treat various disorders, such as pneumonia, colitis, stomatitis, and carbuncle. Whether the essential oil from (ECB) and its active constituents have anti-proliferative activities in lung cancer is unknown. Therefore, we investigated the cytotoxic effects of ECB in A549 and NCI-H358 human lung cancer cells. Culture of A549 and NCI-H358 cells with ECB induced apoptotic cell death, as revealed by an increase in annexin V staining. ECB treatment reduced mitochondrial membrane potential (MMP), disrupted the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and activated caspase-8, -9, and -3, as assessed by western blot analysis. Interestingly, pretreatment with a broad-spectrum caspase inhibitor (z-VAD-fmk) significantly attenuated ECB-induced apoptosis. Furthermore, gas chromatography-mass spectrometry (GC/MS) analysis of ECB identified six compounds. Among them, β-caryophyllene exhibited a potent anti-proliferative effect, and thus was identified as the major active compound. β- Caryophyllene induced G cell cycle arrest by downregulating cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, and RB phosphorylation, and by upregulating p21 and p27. These results indicate that β-caryophyllene exerts cytotoxic activity in lung cancer cells through induction of cell cycle arrest.
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http://dx.doi.org/10.3390/molecules24203754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832734PMC
October 2019

Anti-Inflammatory Mechanisms of Koreanaside A, a Lignan Isolated from the Flower of , against LPS-Induced Macrophage Activation and DSS-Induced Colitis Mice: The Crucial Role of AP-1, NF-κB, and JAK/STAT Signaling.

Cells 2019 09 27;8(10). Epub 2019 Sep 27.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

The current treatment options for inflammatory bowel disease (IBD) are unsatisfactory. Therefore, novel and safer therapies are needed. We previously reported that koreanaside A (KA) showed high radical scavenging activity and suppressed vascular cell adhesion molecule 1 (VCAM-1) expression in vascular smooth muscle cells. However, the molecular mechanisms involved in its anti-inflammatory effect have not been reported. KA inhibited pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), and prostaglandin E (PGE). KA inhibited the production and mRNA expression of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) induced by LPS. KA downregulated the myeloid differentiation primary response 88 (MyD88)-dependent inflammatory gene expressions in the MyD88-overexpressed cells. KA suppressed the LPS-induced transcriptional and DNA-binding activities of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB). KA was found to inhibit the phosphorylation of Janus kinase 1/2 (JAK1/2) and signal transducers and activators of transcription 1/3 (STAT1/3). In DSS-induced colitis mice, KA relieved the symptoms of colitis by suppressing inflammatory cell infiltration, restoring tight junction (TJ)- and epithelial-mesenchymal transition (EMT)-related protein expression, and inactivating AP-1, NF-κB, and STAT1/3. Therefore, KA reduced inflammatory responses by downregulating AP-1, NF-κB, and JAK/STAT signaling in LPS-induced macrophages and DSS-induced colitis mice.
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http://dx.doi.org/10.3390/cells8101163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829247PMC
September 2019

Protective Effects of Dietary MUFAs Mediating Metabolites against Hypertension Risk in the Korean Genome and Epidemiology Study.

Nutrients 2019 Aug 16;11(8). Epub 2019 Aug 16.

Center for Biomedical Sciences, Korea National Institute of Health, Cheongju 28159, Korea.

Background And Aims: Metabolites related to dietary factors can be used to identify biological markers to prevent metabolic disease. However, most studies have been conducted in the United States and Europe, and those in the Asian region are limited. We investigated the effects of dietary monounsaturated fatty acids (MUFAs) and metabolites on new-onset hypertension in the Korean Genome and Epidemiology Study.

Method And Results: A total of 1529 subjects without hypertension were divided into tertiles of dietary MUFAs intake. After a 4-year follow-up, 135 serum metabolites were measured using the AbsoluteIDQ p180 kit. During the 4-year follow-up period, 193 new-onset hypertension incidences were observed. The highest MUFAs intake group was inversely associated with the risk of hypertension compared with the lowest MUFAs intake group (odds ratio (OR) = 0.49, (95% confidence interval (CI) = 0.29-0.82)). Of the 135 metabolites, eight were significantly associated with MUFAs intake. Phosphatidylcholine-diacyl (PC aa) C 38:1 and hydroxysphingomyelin (SM OH) C 16:1 were associated with a decrease in hypertension risk (PC aa C 38:1, OR = 0.60 (95% CI = 0.37-0.96); SM OH C 16:1, OR = 0.42 (95% CI = 0.20-0.90)). The highest MUFAs intake group had a significantly decreased risk of hypertension, even considering PC aa C 38:1 and SM (OH) C 16:1 as a mediator.

Conclusion: We confirmed that dietary MUFAs intake, and PC aa C 38:1 and SM (OH) C 16:1 had protective effects against hypertension. Furthermore, high MUFAs intake combined with PC aa C 38:1 and SM (OH) C 16:1 has the most significant effect on reducing the risk hypertension.
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http://dx.doi.org/10.3390/nu11081928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722700PMC
August 2019

Targeting CYP4A attenuates hepatic steatosis in a novel multicellular organotypic liver model.

J Biol Eng 2019 8;13:69. Epub 2019 Aug 8.

1Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 Republic of Korea.

Background: Non-alcoholic fatty liver disease (NAFLD) begins as simple hepatic steatosis, but further progress to chronic liver diseases results in severe liver damage and hepatic failure. However, therapeutic options are scarce due to the lack of reliable human in vitro liver models for understanding disease progression mechanisms and developing therapies.

Results: We describe here a novel method for generating 3D hepatic spheroids using HepaRG cells, vascular endothelial cells, and mesenchymal stem cells cultured on a thick layer of soft matrix in a narrow conical tube; this method improved self-organization efficiency and functional competence. We further developed a 3D hepatic steatosis model with excess glucose and palmitate, accurately recapitulating steatosis phenotypes such as neutral lipid accumulation, enhanced expression of lipogenesis and gluconeogenesis markers, increased intracellular triglyceride content, and reduced glucose uptake. The expression and activity of cytochrome P450 4A (CYP4A), a hepatic glucose and lipid homeostasis enzyme, that is highly expressed in liver tissues from NAFLD patients, was induced in our in vitro steatosis model, and inhibiting CYP4A with the selective inhibitor HET0016 or a specific siRNA ameliorated steatosis-related pathology through reduced ER stress and improved insulin signaling.

Conclusions: We provide here a novel 3D human cell-based hepatic model that can be easily generated and reliably simulate hepatic steatosis pathology. We have experimentally validated its potential for target validation and drug evaluation by focusing on CYP4A, which may serve as a translational platform for drug development.
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http://dx.doi.org/10.1186/s13036-019-0198-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686528PMC
August 2019

Generation of expandable human pluripotent stem cell-derived hepatocyte-like liver organoids.

J Hepatol 2019 11 9;71(5):970-985. Epub 2019 Jul 9.

Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-gu, Daejeon 34113, Republic of Korea. Electronic address:

Background & Aims: The development of hepatic models capable of long-term expansion with competent liver functionality is technically challenging in a personalized setting. Stem cell-based organoid technologies can provide an alternative source of patient-derived primary hepatocytes. However, self-renewing and functionally competent human pluripotent stem cell (PSC)-derived hepatic organoids have not been developed.

Methods: We developed a novel method to efficiently and reproducibly generate functionally mature human hepatic organoids derived from PSCs, including human embryonic stem cells and induced PSCs. The maturity of the organoids was validated by a detailed transcriptome analysis and functional performance assays. The organoids were applied to screening platforms for the prediction of toxicity and the evaluation of drugs that target hepatic steatosis through real-time monitoring of cellular bioenergetics and high-content analyses.

Results: Our organoids were morphologically indistinguishable from adult liver tissue-derived epithelial organoids and exhibited self-renewal. With further maturation, their molecular features approximated those of liver tissue, although these features were lacking in 2D differentiated hepatocytes. Our organoids preserved mature liver properties, including serum protein production, drug metabolism and detoxifying functions, active mitochondrial bioenergetics, and regenerative and inflammatory responses. The organoids exhibited significant toxic responses to clinically relevant concentrations of drugs that had been withdrawn from the market due to hepatotoxicity and recapitulated human disease phenotypes such as hepatic steatosis.

Conclusions: Our organoids exhibit self-renewal (expandable and further able to differentiate) while maintaining their mature hepatic characteristics over long-term culture. These organoids may provide a versatile and valuable platform for physiologically and pathologically relevant hepatic models in the context of personalized medicine.

Lay Summary: A functionally mature, human cell-based liver model exhibiting human responses in toxicity prediction and drug evaluation is urgently needed for pre-clinical drug development. Here, we develop a novel human pluripotent stem cell-derived hepatocyte-like liver organoid that is critically advanced in terms of its generation method, functional performance, and application technologies. Our organoids can contribute to the better understanding of liver development and regeneration, and provide insights for metabolic studies and disease modeling, as well as toxicity assessments and drug screening for personalized medicine.
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http://dx.doi.org/10.1016/j.jhep.2019.06.030DOI Listing
November 2019

Rice Hull Extract (RHE) Suppresses Adiposity in High-Fat Diet-Induced Obese Mice and Inhibits Differentiation of 3T3-L1 Preadipocytes.

Nutrients 2019 May 24;11(5). Epub 2019 May 24.

Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju-si 220702, Korea.

Obesity is one of major health challenges in the industrial world. Although rice hull has been reported to show various bioactivities, no studies have evaluated its anti-obesity effect. We hope to demonstrate the anti-obesity effect of rice hull extract (RHE) and the underlying mechanism in high-fat diet (HFD)-induced obese mice and 3T3-L1 preadipocytes. Serum lipid profiles were determined by enzymatic methods. Histological analysis of liver and epididymis fat tissues was carried out with hematoxylin and eosin stain. The mRNA expression of adipogenic markers was analyzed with qRT-PCR and western blotting. Oral administration of RHE reduced body weight gain and fat accumulation in HFD-fed mice. RHE also reduced lipid accumulation by inhibiting the mRNA expression of adipogenic-related genes in HFD-fed obese mice and differentiated preadipocytes. The downregulation of adipogenesis by RHE was mediated through the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC). In addition, RHE induced the phosphorylation of c-Jun N-terminal kinases (JNK) and extracellular-signal-regulated kinases (ERK) in liver and epididymis adipose tissues of HFD-fed obese mice. Taken together, these findings indicate that RHE could inhibit the differentiation of adipose cell and prevent HFD-induced obesity, suggesting its potential in the prevention of obesity and metabolic syndrome and related-disorders.
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http://dx.doi.org/10.3390/nu11051162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566172PMC
May 2019

Hippo signaling is intrinsically regulated during cell cycle progression by APC/C.

Proc Natl Acad Sci U S A 2019 05 18;116(19):9423-9432. Epub 2019 Apr 18.

Department of Developmental Biology, Harvard Stem Cell Institute, Harvard School of Dental Medicine, Boston, MA 02215;

The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration and its dysregulation is widely implicated in various cancers. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, large tumor suppressor (LATS) kinases and YAP/TAZ transcription factors, oscillate during mitotic cell cycle. We further identified that the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase complex, which plays a key role governing eukaryotic cell cycle progression, intrinsically regulates Hippo signaling activities. CDH1 recognizes LATS kinases to promote their degradation and, hence, YAP/TAZ regulation by LATS phosphorylation is under cell cycle control. As a result, YAP/TAZ activities peak in G1 phase. Furthermore, we show in eye and wing development that Cdh1 is required in vivo to regulate the LATS homolog Warts with a conserved mechanism. Cdh1 reduction increased Warts levels, which resulted in reduction of the eye and wing sizes in a Yorkie dependent manner. Therefore, LATS degradation by APC/C represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.
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http://dx.doi.org/10.1073/pnas.1821370116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511010PMC
May 2019

Genetic interactions reveal the antagonistic roles of FT/TSF and TFL1 in the determination of inflorescence meristem identity in Arabidopsis.

Plant J 2019 08 17;99(3):452-464. Epub 2019 May 17.

Department of Life Sciences, Korea University, 145 Anamro, Seongbuk-Gu, Seoul, 02841, South Korea.

During the transition to the reproductive phase, the shoot apical meristem switches from the developmental program that generates vegetative organs to instead produce flowers. In this study, we examined the genetic interactions of FLOWERING LOCUS T (FT)/TWIN SISTER OF FT (TSF) and TERMINAL FLOWER 1 (TFL1) in the determination of inflorescence meristem identity in Arabidopsis thaliana. The ft-10 tsf-1 mutants produced a compact inflorescence surrounded by serrated leaves (hyper-vegetative shoot) at the early bolting stage, as did plants overexpressing TFL1. Plants overexpressing FT or TSF (or both FT and TFL1) generated a terminal flower, as did tfl1-20 mutants. The terminal flower formed in tfl1-20 mutants converted to a hyper-vegetative shoot in ft-10 tsf-1 mutants. Grafting ft-10 tsf-1 or ft-10 tsf-1 tfl1-20 mutant scions to 35S::FT rootstock plants produced a normal inflorescence and a terminal flower in the scion plants, respectively, although both scions showed similar early flowering. Misexpression of FT in the vasculature and in the shoot apex in wild-type plants generated a normal inflorescence and a terminal flower, respectively. By contrast, in ft-10 tsf-1 mutants the vasculature-specific misexpression of FT converted the hyper-vegetative shoot to a normal inflorescence, and in the ft-10 tsf-1 tfl1-20 mutants converted the shoot to a terminal flower. TFL1 levels did not affect the inflorescence morphology caused by FT/TSF overexpression at the early bolting stage. Taking these results together, we proposed that FT/TSF and TFL1 play antagonistic roles in the determination of inflorescence meristem identity, and that FT/TSF are more important than TFL1 in this process.
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http://dx.doi.org/10.1111/tpj.14335DOI Listing
August 2019

Developing scalable cultivation systems of hepatic spheroids for drug metabolism via genomic and functional analyses.

Biotechnol Bioeng 2019 06 4;116(6):1496-1508. Epub 2019 Mar 4.

Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.

Spheroids, a widely used three-dimensional (3D) culture model, are standard in hepatocyte culture as they preserve long-term hepatocyte functionality and enhance survivability. In this study, we investigated the effects of three operation modes in 3D culture - static, orbital shaking, and under vertical bidirectional flow using spheroid forming units (SFUs) on hepatic differentiation and drug metabolism to propose the best for mass production of functionally enhanced spheroids. Spheroids in SFUs exhibited increased hepatic gene expression, albumin secretion, and cytochrome P450 3A4 (CYP3A4) activity during the differentiation period (12 days). SFUs advantages include facilitated mass production and a relatively earlier peak of CYP3A4 activity. However, CYP3A4 activity was not well maintained under dimethyl sulfoxide (DMSO)-free conditions (13-18 days), dramatically reducing drug metabolism capability. Continued shear stimulation without differentiation stimuli in assay conditions markedly attenuated CYP3A4 activity, which was less severe in static conditions. In this condition, SFU spheroids exhibited dedifferentiation characteristics, such as increased proliferation and Notch signaling genes. We found that the dedifferentiation could be overcome by using the serum-free medium formulation. Therefore, we suggest that SFUs represent the best option for the mass production of functionally improved spheroids and so the serum-free conditions should be maintained during drug metabolism analysis.
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http://dx.doi.org/10.1002/bit.26954DOI Listing
June 2019

Cationic amino acid transporter PQLC2 is a potential therapeutic target in gastric cancer.

Cancer Sci 2019 Apr 19;110(4):1453-1463. Epub 2019 Mar 19.

Biomedical Translational Research Center, KRIBB, Daejeon, Korea.

Tumor cells overexpress amino acid transporters to meet the increased demand for amino acids. PQ loop repeat-containing (PQLC)2 is a cationic amino acid transporter that might be involved in cancer progression. Here, we show that upregulation of PQLC2 is critical to gastric cancer (GC) development in vitro and in vivo. Both PQLC2 mRNA and protein were overexpressed in GC tissues, especially of the diffuse type. Overexpression of PQLC2 promoted cell growth, anchorage independence, and tumor formation in nude mice. This was due to activation of MEK/ERK1/2 and PI3K/AKT signaling. Conversely, PQLC2 knockdown caused growth arrest and cell death of cancer cells and suppressed tumor growth in a mouse xenograft model. These results suggest that targeting PQLC2 is an effective strategy for GC treatment.
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http://dx.doi.org/10.1111/cas.13966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447956PMC
April 2019

Chinese Skullcap (Scutellaria baicalensis Georgi) inhibits inflammation and proliferation on benign prostatic hyperplasia in rats.

J Ethnopharmacol 2019 May 29;235:481-488. Epub 2019 Jan 29.

Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju-si, Gangwon-do 220-702, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Chinese Skullcap (Scutellaria baicalensis Georgi), which is part of the 50 fundamental herbs of Traditional Chinese Medicine, has been extensively used in the several East Asian countries to treat pyrexia, micturition disorder and inflammation. Although skullcap has effective properties on various diseases, the effects and molecular mechanism of Chinese Skullcap on BPH are still needed for better understanding.

Aim Of The Study: In present study, we aimed to demonstrate the efficacy of Chinese Skullcap root extract (SRE) in testosterone-induced BPH rats and investigate the exact regulatory mechanism involved.

Materials And Methods: We followed a protocol of testosterone-induced BPH. Rats were allocated into five groups: Group 1, control; Group 2, BPH-induced rats; Group 3, BPH-induced rats administrated with finasteride; Group 4, BPH-induced rats administrated with SRE 100 mg/kg/day; Group 5 - BPH-induced rats administrated with SRE 200 mg/kg/day. We measured the weight of prostate, and thickness of prostate using H&E staining. Western blotting, immunostaining and real-time PCR were used to measure proliferation- and inflammation-relative markers. To confirm the effects of SRE on apoptotic events in BPH-induced tissues, we performed the TUNEL assay.

Results: Compared with the untreated group, the SRE administration group suppressed pathological alterations, such as prostate growth and increase in serum DHT and 5α-reductase levels. Furthermore, SRE significantly obliterated the expression of AR and PCNA. SRE also restored Bax/Bcl-2 balance, inducing apoptosis in rats with BPH. These effect of SRE was more prevalent than commercial 5α-reductase inhibitor, finasteride.

Conclusions: Taken together, we propose that SRE suppresses abnormal androgen events in prostate tissue and inhibits the development of BPH by targeting inflammation- and apoptosis-related markers. These finding strengthens that SRE could be used as plant-based 5α-reductase inhibitory alternative.
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http://dx.doi.org/10.1016/j.jep.2019.01.039DOI Listing
May 2019

Anti-Colitic Effects of Ethanol Extract of Mill. through Suppression of Pro-Inflammatory Mediators via NF-κB/STAT3 Inactivation in Dextran Sulfate Sodium-Induced Colitis Mice.

Int J Mol Sci 2019 Jan 5;20(1). Epub 2019 Jan 5.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Mill, cv. Hass, also known as avocado, has been reported to possess hypolipidemic, anti-diabetic, anti-oxidant, cardioprotective, and photoprotective potencies. However, few studies have reported its anti-colitic effects. In this study, we investigated anti-colitic effects of ethanol extract of (EEP) in dextran sulfate sodium (DSS)-induced colitic mice and the involved molecular mechanisms. EEP effectively improved clinical signs and histological characteristics of DSS-induced colitis mice. In DSS-exposed colonic tissues, EEP reduced expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. Moreover, EEP suppressed DSS-induced activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Consistent with in vivo results, EEP also suppressed protein and mRNA expression levels of iNOS, COX-2, and pro-inflammatory cytokines via NF-κB and STAT3 inactivation in LPS-induced RAW 264.7 macrophages. Taken together, our data indicate that ethanol extract of avocado may be used as a promising therapeutic against inflammatory bowel diseases by suppressing the NF-κB and STAT3 signaling pathway.
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http://dx.doi.org/10.3390/ijms20010177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337306PMC
January 2019
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