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Singh, Thoudam Debraj,Song, Jaeyoung,Kim, Jina,Chin, Jungwook,Ji, Hyun Dong,Lee, Jae-Eon,Lee, Sang Bong,Yoon, Heeseok,Yu, Ji Hoon,Kim, Sang Kyoon,Yoon, Ghil Suk,Hwang, Hayoung,Lee, Ho Won,Oh, Ji Min,L American Association for Cancer Research 2019 Clinical Cancer Research Vol.25 No.16
<P><B>Purpose:</B></P><P>New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy–refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC<SUB>50</SUB> = 0.006 μmol/L), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC.</P><P><B>Experimental Design:</B></P><P>We sought to identify better ERRγ-targeting ligands and explored the crystal structure of ERRγ in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumor–bearing mice were orally administered with DN200434, followed by <SUP>124</SUP>I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor–bearing mice treated with DN200434 were administered <SUP>131</SUP>I (beta ray–emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRγ expression status in normal tissue and ATC tissue, respectively.</P><P><B>Results:</B></P><P>DN200434–ERRγ complex crystallographic studies revealed that DN200434 binds to key ERRγ binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by <SUP>124</SUP>I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRγ expression in tumors than in normal tissue, supporting ERRγ as a therapeutic target for ATC.</P><P><B>Conclusions:</B></P><P>DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.</P>
MEGF10 functions as a receptor for the uptake of amyloid-β
Singh, Thoudam Debraj,Park, Seung-Yoon,Bae, Jae-sung,Yun, Youngeun,Bae, Yong-Chul,Park, Rang-Woon,Kim, In-San Elsevier 2010 FEBS letters Vol.584 No.18
<P><B>Abstract</B></P><P>MEGF10 is predominantly expressed in the brain and known to function as a phagocytic receptor. Here, we provide evidence that MEGF10 is involved in the uptake of amyloid-β peptide (Aβ42) in the brain. Overexpression of MEGF10 dramatically increased Aβ42 uptake in Hela cells. Knockdown of endogenous MEGF10 expression significantly decreased Aβ42 uptake in N2A neuroblastoma cells. MEGF10-mediated Aβ uptake is mostly dependent on lipid raft endocytosis pathway. Furthermore, site-directed mutagenesis revealed that the conserved cytoplasmic NPxY and YxxØ motifs are crucial for MEGF10-mediated uptake of Aβ42 peptide. Thus, the identification of the MEGF10 as a functional receptor that mediates the uptake of amyloid-β peptide will help elucidate the molecular mechanisms of amlyoid-β clearance in Alzheimer’s disease.</P><P><B>Structured summary</B></P><P>MINT-7993537: <I>ctxB</I> (uniprotkb:P01556) and <I>Abeta</I> (uniprotkb:P05067) <I>colocalize</I> (MI:0403) by <I>fluorescence microscopy</I> (MI:0416)</P>
Lee, Ho Won,Singh, Thoudam Debraj,Lee, Sang‐,Woo,Ha, Jeoung‐,Hee,Rehemtulla, Alnawaz,Ahn, Byeong‐,Cheol,Jeon, Young Hyun,Lee, Jaetae Federation of American Society for Experimental Bi 2014 The FASEB Journal Vol.28 No.7
Natural killer (NK) cell-based immunotherapy is a promising strategy for cancer treatment, and caspase-3 is an important effector molecule in NK cell-mediated apoptosis in cancers. Here, we evaluated the antitumor effects of NK cell-based immunotherapy by serial noninvasive imaging of apoptosis using a caspase-3 sensor in mice with human glioma xenografts. Human glioma cells expressing both a caspase-3 sensor as a surrogate marker for caspase-3 activation and Renilla luciferase (Rluc) as a surrogate marker for cell viability were established and referred to as D54-CR cells. Human NK92 cells were used as effector cells. Treatment with NK92 cells resulted in a time-and effector number-dependent increase in bioluminescence imaging (BLI) activity of the caspase-3 sensor in D54-CR cells in vitro. Caspase-3 activation by NK92 treatment was blocked by Z-VAD treatment in D54-CR cells. Transfusion of NK92 cells induced an increase of the BLI signal by caspase-3 activation in a dose-and time-dependent manner in D54-CR tumor-bearing mice but not in PBS-treated mice. Accordingly, sequential BLI with the Rluc reporter gene revealed marked retardation of tumor growth in the NK92-treatment group but not in the PBS-treatment group. These data suggest that noninvasive imaging of apoptosis with a caspase-3 sensor can be used as an effective tool for evaluation of therapeutic efficacy as well as for optimization of NK cell-based immunotherapy.
KIM, HUI-HUN,LEE, SOYOUNG,SINGH, THOUDAM S.K.,CHOI, JIN KYEONG,SHIN, TAE-YONG,KIM, SANG-HYUN UNKNOWN 2012 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.30 No.2
<P>Allergic inflammatory disease such as food allergy, asthma and atopic dermatitis are increasing worldwide. In this study, we investigated the effect of water extract of Sparassis crispa (WESC) Fr. (Aphyllophoromycetideae) on mast cell-mediated allergic inflammation and the possible mechanisms of action. WESC inhibited compound 48/80-induced systemic anaphylaxis and serum histamine release in mice. WESC decreased immunoglobulin?E (IgE)-mediated passive cutaneous anaphylaxis. Additionally, WESC reduced histamine release and intracellular calcium in human mast cells activated by phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187. WESC decreased PMA and A23187-stimulated expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, inlerleukin (IL)-6 and IL-1β. The inhibitory effect of WESC on pro-inflammatory cytokines was nuclear factor-κB, extracellular signal-regulated kinase and p38 mitogen-activated protein kinase-dependent. Our results suggest potential therapeutic application of WESC in allergic inflammatory diseases.</P>
Ahn, Su-Bi,Lee, Sang Bong,Singh, Thoudam Debraj,Cho, Sung Jin,Kim, Sang Kyoon,Lee, In-Kyu,Jeong, Shin Young,Ahn, Byeong-Cheol,Lee, Jaetae,Lee, Sang-Woo,Jeon, Yong Hyun Neoplasia Press 2017 Translational oncology Vol.10 No.2
<P>Here, we sought to monitor bone marrow–derived dendritic cell (BMDC) migration and antitumor effects using a multimodal reporter imaging strategy in living mice. BMDCs were transduced with retroviral vector harboring human sodium iodide symporter (<I>hNIS</I>, nuclear imaging reporter), firefly <I>luc2</I> (optical imaging reporter), and <I>thy1.1</I> (surrogate marker of <I>NIS</I> and <I>luc2</I>) genes (BMDC/NF cells). No significant differences in biological functions, including cell proliferation, antigen uptake, phenotype expression, and migration ability, were observed between BMDC and BMDC/NF cells. Combined bioluminescence imaging and I-124 positron emission tomography/computed tomography clearly revealed the migration of BMDC/NF cells to draining popliteal lymph nodes at day 7 postinjection. Interestingly, marked tumor protection was observed in mice immunized with TC-1 lysate-pulsed BMDC/NF cells. Our findings suggested that multimodal reporter gene imaging of NIS and luciferase could provide insights into the biological behaviors of dendritic cells in living organisms and could be a useful tool for the optimization of DC-based immunotherapy protocols.</P>
Flavonoids Inhibit Histamine Release and Expression of Proinflammatory Cytokines in Mast Cells
박효현,이소영,손희영,박승빈,김미선,Thoudam S.K.,하정희,이만기,김정은,현명철,권택규,김여향,최은주,김상현 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.10
Mast cells participate in allergy and inflammation by secreting inflammatory mediators such as histamine and proinflammatory cytokines. Flavonoids are naturally occurring molecules with antioxidant, cytoprotective, and antiinflammatory actions. However, effect of flavonoids on the release of histamine and proinflammatory mediator, and their comparative mechanism of action in mast cells were not well defined. Here, we compared the effect of six flavonoids (astragalin, fisetin, kaempferol, myricetin, quercetin, and rutin) on the mast cell-mediated allergic inflammation. Fisetin, kaempferol, myricetin, quercetin, and rutin inhibited IgE or phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-mediated histamine release in RBL-2H3 cells. These five flavonoids also inhibited elevation of intracellular calcium. Gene expressions and secretion of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-8 were assessed in PMACI-stimulated human mast cells (HMC-1). Fisetin, quercetin, and rutin decreased gene expression and production of all the proinflammatory cytokines after PMACI stimulation. Myricetin attenuated TNF-α and IL-6 but not IL-1β and IL-8. Fisetin, myricetin, and rutin suppressed activation of NF-κB indicated by inhibition of nuclear translocation of NF-κB, NF-κB/DNA binding, and NF-κB-dependent gene reporter assay. The pharmacological actions of these flavonoids suggest their potential activity for treatment of allergic inflammatory diseases through the down-regulation of mast cell activation.
Choi, Yun Ju,Oh, Seul-Gi,Singh, Thoudam Debraj,Ha, Jeoung-Hee,Kim, Dong Wook,Lee, Sang Woo,Jeong, Shin Young,Ahn, Byeong-Cheol,Lee, Jaetae,Jeon, Young Hyun Neoplasia Press 2016 Neoplasia Vol.18 No.3
<P>We sought to visualize the migration of tumor-associated macrophages (TAMs) to tumor lesions and to evaluate the effects of anti-inflammatory drugs on TAM-modulated tumor progression in mice with colon cancer using a multimodal optical reporter gene system. Murine macrophage Raw264.7 cells expressing an enhanced firefly luciferase (Raw/effluc) and murine colon cancer CT26 cells coexpressing Rluc and mCherry (CT26/Rluc-mCherry, CT26/RM) were established. CT26/RM tumor-bearing mice received Raw/effluc via their tail veins, and combination of bioluminescence imaging (BLI) and fluorescence imaging (FLI) was conducted for <I>in vivo</I> imaging of TAMs migration and tumor progression. Dexamethasone (DEX), a potent anti-inflammatory drug, was administered intraperitoneally to tumor-bearing mice following the intravenous transfer of Raw/effluc cells. The migration of TAMs and tumor growth was monitored by serial FLI and BLI. The migration of Raw/effluc cells to tumor lesions was observed at day 1, and BLI signals were still distinct at tumor lesions on day 4. Localization of BLI signals from migrated Raw/effluc cells corresponded to that of FLI signals from CT26/RM tumors. <I>In vivo</I> FLI of tumors demonstrated enhanced tumor growth associated with macrophage migration to tumor lesions. Treatment with DEX inhibited the influx of Raw/effluc cells to tumor lesions and abolished the enhanced tumor growth associated with macrophage migration. These findings suggest that molecular imaging approach for TAM tracking is a valuable tool for evaluating the role of TAMs in the tumor microenvironment as well as for the development of new drugs to control TAM involvement in the modulation of tumor progression.</P>
Mohammad SUBHAN,Majed ALHARTHI,Md Shabbir ALAM,Prabha THOUDAM,Khaliquzzaman KHAN 한국유통과학회 2021 The Journal of Asian Finance, Economics and Busine Vol.8 No.12
In recent years, a significant number of empirical studies have examined the relationship between export and economic growth in India. However, this study analyses the relationship between exports and economic growth through the time series model. The main aim of this study is to investigate the causal relationship between exports and economic growth in India. The VAR model was used for the period 1961 to 2015 after verifying the stationarity of the variables through using Augmented Dickey-Fuller and Phillip-Perron tests. The Indian export sector has been found to have a significant and positive impact on economic growth and other long-term economic activities. The study also employed the Granger causality test to check the direction of causality and found that RXGS, RGDP, RPFC, and RGFC had a unidirectional relationship and RXGS and RMGS had a bidirectional relationship in long run. Also, the findings of this study suggest that a steady-state between exports and economic growth can be achieved in India over a long period. The overall outcome of this study provides a testimony of the fact that the export sector plays a vital role in economic growth in India and also leads to the long-term growth of other economic activities.