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GM-CSF Induces Inflammatory Macrophages by Regulating Glycolysis and Lipid Metabolism
Na, Yi Rang,Gu, Gyo Jung,Jung, Daun,Kim, Young Won,Na, Juri,Woo, Jin Sun,Cho, Joo Youn,Youn, Hyewon,Seok, Seung Hyeok The American Association of Immunologists, Inc. 2016 JOURNAL OF IMMUNOLOGY Vol.197 No.10
<P>GM-CSF induces proinflammatory macrophages, but the underlying mechanisms have not been studied thus far. In this study, we investigated the mechanisms of how GM-CSF induces inflammatory macrophages. First, we observed that GM-CSF increased the extent of LPS-induced acute glycolysis in murine bone marrow-derived macrophages. This directly correlates with an inflammatory phenotype because glycolysis inhibition by 2-deoxyglucose abolished GM-CSF-mediated increase of TNF-alpha,IL-1 beta, IL-6, and IL-12p70 synthesis upon LPS stimulation. Increased glycolytic capacity is due to de novo synthesis of glucose transporter ( GLUT)-1,-3, and-4, as well as c-myc. Mean while, GM-CSF increased 3-hydroxy-3-methyl-glutaryl-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway. Inhibition of acute glycolysis or 3-hydroxy-3-methyl-glutaryl-CoA reductase abrogated the inflammatory effects of GM-CSF priming in macrophages. Finally, mice with inflamed colons exposed to dextran sodium sulfate containing GLUT-1(high) macrophages led to massive uptake of [F-18]-fluorodeoxyglucose, but GM-CSF neutralization reduced the positron-emission tomography signal in the intestine and also decreased GLUT-1 expression in colonic macrophages. Collectively, our results reveal glycolysis and lipid metabolism created by GM-CSF as the underlying metabolic constructs for the function of inflammatory macrophages.</P>
Park, Juri,Park, Sung Woo,Yoon, Kun Ho,Kim, Sung Rae,Ahn, Kyu Jeung,Lee, Jae Hyuk,Mok, Ji Oh,Chung, Choon Hee,Han, Kyung Ah,Koh, Gwan Pyo,Kang, Jun Goo,Lee, Chang Beom,Kim, Seong Hwan,Kwon, Na Young,K DIABETES OBESITY AND METABOLISM 2017 DIABETES OBESITY AND METABOLISM Vol.19 No.12
<P>Conclusions: In this 24-week study, once-daily evogliptin monotherapy significantly improved glycaemic control and was well tolerated in patients with T2D.</P>
Lee, Kyung-Jo,Lee, Na Yeon,Han, Yang-Soo,Kim, Juri,Lee, Kyu-Ho,Park, Soon-Jung American Society for Microbiology 2010 Infection and immunity Vol.78 No.6
<B>ABSTRACT</B><P><I>Vibrio vulnificus</I> is a Gram-negative bacterium that causes a fatal septicemia. One of its virulence factors is a membrane-bound lipoprotein, IlpA, which can induce cytokine production in human immune cells. In the present study, the role of IlpA as an adhesion molecule was investigated. An <I>ilpA</I>-deleted <I>V. vulnificus</I> mutant showed significantly decreased adherence to INT-407 human intestinal epithelial cells, which in turn resulted in reduced cytotoxicity. The <I>ΔilpA</I> mutant recovered the adherence ability of the wild type by complementation in <I>trans</I> with the intact <I>ilpA</I> gene. In addition, pretreatment of <I>V. vulnificus</I> with anti-IlpA polyclonal antibodies resulted in a significant reduction of bacterial adherence. To localize the domain of IlpA required for cytoadherence, three truncated recombinant IlpA polypeptides were constructed and tested for the ability to adhere to human cells by a ligand-binding immunoblot assay and fluorescence microscopy. The polypeptide containing the carboxy (C)-terminal hydrophilic domain exhibited direct binding to INT-407 cells. Therefore, the C-terminal domain of IlpA allows this protein to be an adhesion molecule of <I>V. vulnificus</I>.</P>
Kwon, Su-Jung,Lee, Seul-Ki,Na, Juri,Lee, Shin-Ai,Lee, Han-Sae,Park, Ji-Hye,Chung, June-Key,Youn, Hyewon,Kwon, Jongbum American Association for Cancer Research 2015 Molecular Cancer Therapeutics Vol.14 No.2
<P>Radiotherapy treats cancer by inducing DNA double-strand breaks (DSB) in tumor cells using ionizing radiation. However, DNA repair in tumor cells often leads to radioresistance and unsuccessful outcome. Inhibition of DNA repair by targeting repair proteins can increase radiosensitivity of tumor cells. The BRG1 chromatin remodeling enzyme assists DSB repair by stimulating γ-H2AX formation and BRG1 binding to acetylated histones at DSBs via bromodomain (BRD) is critical for this activity. Here, we show that ectopic expression of BRG1-BRD inhibited γ-H2AX and DSB repair after irradiation and increased the radiosensitivity in various human cancer cells, including HT29 colon cancer. Dimerization of BRG1-BRD, increasing its chromatin binding affinity, aggravated the defects in γ-H2AX and DSB repair and further enhanced the radiosensitivity. While little affecting the upstream ATM activation, BRG1-BRD in irradiated HT29 cells inhibited the recruitment of 53BP1 to damaged chromatin, the downstream event of γ-H2AX, and compromised the G<SUB>2</SUB>–M checkpoint and increased apoptosis. Importantly, in a xenograft mouse model, BRG1-BRD increased the radiosensitivity of HT29 tumors, which was further enhanced by dimerization. These data suggest that BRG1-BRD radiosensitizes tumor cells by a dominant negative activity against BRG1, which disrupts γ-H2AX and its downstream 53BP1 pathways, leading to inefficient DNA repair, G<SUB>2</SUB>–M checkpoint defect, and increased apoptosis. This work therefore identifies BRG1-BRD as a novel tumor radiosensitizer and its action mechanism, providing the first example of chromatin remodeler as a target for improving cancer radiotherapy. <I>Mol Cancer Ther; 14(2); 597–607. ©2014 AACR</I>.</P>
Yoo, Jeong-Ju,Yu, Su Jong,Na, Juri,Kim, Kyungmin,Cho, Young Youn,Lee, Yun Bin,Cho, Eun Ju,Lee, Jeong-Hoon,Kim, Yoon Jun,Youn, Hyewon,Yoon, Jung-Hwan MDPI 2019 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.20 No.6
<P>This study aimed to examine whether inhibition of hexokinase (HK)-II activity enhances the efficacy of sorafenib in in-vivo models of hepatocellular carcinoma (HCC), and to evaluate the prognostic implication of HK-II expression in patients with HCC. We used 3-bromopyruvate (3-BP), a HK-II inhibitor to target HK-II. The human HCC cell line was tested as both subcutaneous and orthotopic tumor xenograft models in BALB/c nu/nu mice. The prognostic role of HK-II was evaluated in data from HCC patients in The Cancer Genome Atlas (TCGA) database and validated in patients treated with sorafenib. Quantitative real-time PCR, western blot analysis, and immunohistochemical staining revealed that HK-II expression is upregulated in the presence of sorafenib. Further analysis of the endoplasmic reticulum-stress network model in two different murine HCC models showed that the introduction of additional stress by 3-BP treatment synergistically increased the in vivo/vitro efficacy of sorafenib. We found that HCC patients with increased HK-II expression in the TCGA database showed poor overall survival, and also confirmed similar results for TCGA database HCC patients who had undergone sorafenib treatment. These results suggest that HK-II is a promising therapeutic target to enhance the efficacy of sorafenib and that HK-II expression might be a prognostic factor in HCC.</P>
( Jeong-ju Yoo ),( Su Jong Yu ),( Juri Na ),( Kyungmin Kim ),( Young Youn Cho ),( Hyeki Cho ),( Dong Hyeon Lee ),( Eun Ju Cho ),( Jeong-hoon Lee ),( Yoon Jun Kim ),( Chung Yong Kim ),( Hyewon Youn ),( 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Aims: Enhancing sorafenib sensitivity is essential for achieving efficient control of intractable hepatocellular carcinoma (HCC). Considering that sorafenib exerts its effect by endoplasmic reticulum (ER) stress due to hypoxia and energy depletion through anti-angiogenic aspect, hexokinase (HK) II which is an important rate-limiting glycolytic enzyme can be a key player in countervailing the effect of sorafenib. Pyruvate analog 3-bromopyruvate (3-BP), a HK II inhibitor, can promote tumor cell death by augmenting endoplasmic reticulum (ER) stress in human HCC cell lines. We evaluated inhibition of HK II potentiated sorafenib-induced ER stress in HCC cells. We also postulated that simultaneous treatment with sorafenib and 3-BP might synergistically enhance their anti-tumor efficacies against HCCs in vivo models. Methods: HCC apoptotic cell death was assessed by DAPI staining and apoptotic signaling pathways were explored by immunoblot analysis. Energy depletion was assessed by lactate assay. In vivo ectopic model of HCC was established in BALB-c nu/nu mice intradermally implanted with SNU-761 cells. Moreover, orthotopic model of HCC was established by subcapsular injection of SNU-761 cells via mini-laparotomy in BALB-c nu/nu mice. Sorafenib with/without 3-BP was subsequently administered. The anti-tumor efficacies were
Thyroid-Related Protein Expression in the Human Thymus
Kim, Mi Jeong,Oh, So Won,Youn, Hyewon,Na, Juri,Kang, Keon Wook,Park, Do Joon,Park, Young Joo,Jang, Ja June,Lee, Kyu Eun,Jung, Kyeong Cheon,Chung, June-Key Hindawi 2017 International Journal of endocrinology Vol.2017 No.-
<P>Radioiodine whole body scan (WBS), related to sodium iodide symporter (NIS) function, is widely used to detect recurrence/metastasis in postoperative patients with thyroid cancer. However, the normal thymic uptake of radioiodine has occasionally been observed in young patients. We evaluated the expression of thyroid-related genes and proteins in the human thymus. Thymic tissues were obtained from 22 patients with thyroid cancer patients of all ages. The expression of NIS, thyroid-stimulating hormone receptor (TSHR), thyroperoxidase (TPO), and thyroglobulin (Tg) was investigated using immunohistochemistry and quantitative RT-PCR. NIS and TSHR were expressed in 18 (81.8%) and 19 samples (86.4%), respectively, whereas TPO was expressed in five samples (22.7%). Three thyroid-related proteins were localized to Hassall's corpuscles and thymocytes. In contrast, Tg was detected in a single patient (4.5%) localized to vascular endothelial cells. The expression of thyroid-related proteins was not increased in young thymic tissues compared to that in old thymic tissues. In conclusion, the expression of NIS and TSHR was detected in the majority of normal thymus samples, whereas that of TPO was detected less frequently, and that of Tg was detected rarely. The increased thymic uptake of radioiodine in young patients is not due to the increased expression of NIS.</P>