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      • Valproic Acid Induces Endocytosis-Mediated Doxorubicin Internalization and Shows Synergistic Cytotoxic Effects in Hepatocellular Carcinoma Cells

        Saha, Subbroto Kumar,Yin, Yingfu,Kim, Kyeongseok,Yang, Gwang-Mo,Abdal Dayem, Ahmed,Choi, Hye Yeon,Cho, Ssang-Goo MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.5

        <P>Valproic acid (VPA), a well-known histone deacetylase (HDAC) inhibitor, is used as an anti-cancer drug for various cancers, but the synergistic anti-cancer effect of VPA and doxorubicin (DOX) combination treatment and its potential underlying mechanism in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we evaluate the mono- and combination-therapy effects of VPA and DOX in HCC and identify a specific and efficient, synergistic anti-proliferative effect of the VPA and DOX combination in HCC cells, especially HepG2 cells; this effect was not apparent in MIHA cells, a normal hepatocyte cell line. The calculation of the coefficient of drug interaction confirmed the significant synergistic effect of the combination treatment. Concurrently, the synergistic apoptotic cell death caused by the VPA and DOX combination treatment was confirmed by Hoechst nuclear staining and Western blot analysis of caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Co-treatment with VPA and DOX enhanced reactive oxygen species (ROS) generation and autophagy, which were clearly attenuated by ROS and autophagy inhibitors, respectively. Furthermore, as an indication of the mechanism underlying the synergistic effect, we observed that DOX internalization, which was induced in the VPA and DOX combination-treated group, occurred via by the caveolae-mediated endocytosis pathway. Taken together, our study uncovered the potential effect of the VPA and DOX combination treatment with regard to cell death, including induction of cellular ROS, autophagy, and the caveolae-mediated endocytosis pathway. Therefore, these results present novel implications in drug delivery research for the treatment of HCC.</P>

      • KCI등재

        Prognostic role of EGR1 in breast cancer: a systematic review

        ( Subbroto Kumar Saha ),( S. M. Riazul Islam ),( Tripti Saha ),( Afsana Nishat ),( Polash Kumar Biswas ),( Minchan Gil ),( Lewis Nkenyereye ),( Shaker El-sappagh ),( Saiful Islam ),( Ssang-goo Cho ) 생화학분자생물학회 2021 BMB Reports Vol.54 No.10

        EGR1 (early growth response 1) is dysregulated in many cancers and exhibits both tumor suppressor and promoter activities, making it an appealing target for cancer therapy. Here, we used a systematic multi-omics analysis to review the expression of EGR1 and its role in regulating clinical outcomes in breast cancer (BC). EGR1 expression, its promoter methylation, and protein expression pattern were assessed using various publicly available tools. COSMIC-based somatic mutations and cBioPortal-based copy number alterations were analyzed, and the prognostic roles of EGR1 in BC were determined using Prognoscan and Kaplan-Meier Plotter. We also used bc-GenEx-Miner to investigate the EGR1 co-expression profile. EGR1 was more often downregulated in BC tissues than in normal breast tissue, and its knockdown was positively correlated with poor survival. Low EGR1 expression levels were also associated with increased risk of ER+, PR+, and HER2- BCs. High positive correlations were observed among EGR1, DUSP1, FOS, FOSB, CYR61, and JUN mRNA expression in BC tissue. This systematic review suggested that EGR1 expression may serve as a prognostic marker for BC patients and that clinicopathological parameters influence its prognostic utility. In addition to EGR1, DUSP1, FOS, FOSB, CYR61, and JUN can jointly be considered prognostic indicators for BC. [BMB Reports 2021; 54(10): 497-504]

      • Cytokeratin 19 <i>(KRT19)</i> has a Role in the Reprogramming of Cancer Stem Cell-Like Cells to Less Aggressive and More Drug-Sensitive Cells

        Saha, Subbroto Kumar,Kim, Kyeongseok,Yang, Gwang-Mo,Choi, Hye Yeon,Cho, Ssang-Goo MDPI AG 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.5

        <P>Cytokeratin 19 (<I>KRT19</I>) is a cytoplasmic intermediate filament protein, which is responsible for structural rigidity and multipurpose scaffolds. In several cancers, <I>KRT19</I> is overexpressed and may play a crucial role in tumorigenic transformation. In our previous study, we revealed the role of <I>KRT19</I> as signaling component which mediated Wnt/NOTCH crosstalk through NUMB transcription in breast cancer. Here, we investigated the function of <I>KRT19</I> in cancer reprogramming and drug resistance in breast cancer cells. We found that expression of <I>KRT19</I> was attenuated in several patients-derived breast cancer tissues and patients with a low expression of <I>KRT19</I> were significantly correlated with poor prognosis in breast cancer patients. Consistently, highly aggressive and drug-resistant breast cancer patient-derived cancer stem cell-like cells (konkuk university-cancer stem cell-like cell (KU-CSLCs)) displayed higher expression of cancer stem cell (CSC) markers, including <I>ALDH1</I>, <I>CXCR4</I>, and <I>CD133</I>, but a much lower expression of <I>KRT19</I> than that is seen in highly aggressive triple negative breast cancer MDA-MB231 cells. Moreover, we revealed that the knockdown of <I>KRT19</I> in MDA-MB231 cells led to an enhancement of cancer properties, such as cell proliferation, sphere formation, migration, and drug resistance, while the overexpression of <I>KRT19</I> in KU-CSLCs resulted in the significant attenuation of cancer properties. <I>KRT19</I> regulated cancer stem cell reprogramming by modulating the expression of cancer stem cell markers (<I>ALDH1</I>, <I>CXCR4</I>, and <I>CD133</I>), as well as the phosphorylation of Src and GSK3β (Tyr216). Therefore, our data may imply that the modulation of <I>KRT19</I> expression could be involved in cancer stem cell reprogramming and drug sensitivity, which might have clinical implications for cancer or cancer stem cell treatment. </P>

      • KCI등재

        Invited Mini Review : G protein-coupled receptors in stem cell maintenance and somatic reprogramming to pluripotent or cancer stem cells

        ( Hye Yeon Choi ),( Subbroto Kumar Saha ),( Kyeong Seok Kim ),( Sang Su Kim ),( Gwang Mo Yang ),( Bong Woo Kim ),( Jin Hoi Kim ),( Ssang Goo Cho ) 생화학분자생물학회(구 한국생화학분자생물학회) 2015 BMB Reports Vol.48 No.2

        G protein-coupled receptors (GPCRs) are a large class of transmembrane receptors categorized into five distinct families: rhodopsin, secretin, adhesion, glutamate, and frizzled. They bind and regulate 80% of all hormones and account for 20-50% of the pharmaceuticals currently on the market. Hundreds of GPCRs integrate and coordinate the functions of individual cells, mediating signaling between various organs. GPCRs are crucial players in tumor progression, adipogenesis, and inflammation. Several studies have also confirmed their central roles in embryonic development and stem cell maintenance. Recently, GPCRs have emerged as key players in the regulation of cell survival, proliferation, migration, and self-renewal in pluripotent (PSCs) and cancer stem cells (CSCs). Our study and other reports have revealed that the expression of many GPCRs is modulated during the generation of induced PSCs (iPSCs) or CSCs as well as during CSC sphere formation. These GPCRs may have crucial roles in the regulation of selfrenewal and other biological properties of iPSCs and CSCs. This review addresses the current understanding of the role of GPCRs in stem cell maintenance and somatic reprogramming to PSCs or CSCs. [BMB Reports 2015; 48(2): 68-80]

      • KCI등재
      • KCI등재

        Antibacterial and phytochemical properties of Aphanamixis polystachya essential oil

        Rahman, Md. Shahedur,Ahad, Abir,Saha, Subbroto Kumar,Hong, Jongki,Kim, Ki-Hyun The Korean Society of Analytical Science 2017 분석과학 Vol.30 No.3

        Now a day's rise of new antibiotic resistant bacterial strains is a global threat. Ethnic people of India have been employing Aphanamixis polystachya (Wall.) R. Parker wood extract in healing cancerous wounds. The aim of this study was to evaluate the antimicrobial activity and to identify the medicinally potent chemicals in the essential oil extract of A. polystachya. The antibacterial properties of various organic extracts were evaluated against a range of bacteria (gram-positive and gram-negative bacteria) based on the disc diffusion method and GC-MS based analysis for finding active oil extract components. All extracts of A. polystachya leaves showed potential antibacterial activity, notably ethyl acetate, while petroleum ether extracts revealed highly sensitive activity against all tested bacteria (zones of inhibition ranging from 8.83 to 11.23 mm). In addition, the petroleum ether extract had the lowest MIC value (32 to $256{\mu}g/mL$) against E. coli, S. lutea, X. campestris, and B. subtilis bacteria. The major compounds detected in oil [${\beta}$-elemene (16.04 %), ${\beta}$-eudesmol (12.78 %), ${\beta}$-caryophyllene (19.37 %), ${\beta}$-selinene (11.32 %), elemol (5.76 %), and ${\alpha}$-humulene (5.68 %)] are expected to be responsible for the potent antimicrobial activity. The results of this study offer valuable insights into the potent role of A. polystachya essential oil extract in pharmaceutical and antibiotic research.

      • KCI등재
      • Hydrodynamic shear stress promotes epithelial-mesenchymal transition by downregulating ERK and GSK3β activities

        Choi, Hye Yeon,Yang, Gwang-Mo,Dayem, Ahmed Abdal,Saha, Subbroto Kumar,Kim, Kyeongseok,Yoo, Youngbum,Hong, Kwonho,Kim, Jin-Hoi,Yee, Cassian,Lee, Kyung-Mi,Cho, Ssang-Goo BioMed Central 2019 Breast cancer research Vol.21 No.-

        <P><B>Background</B></P><P>Epithelial-mesenchymal transition (EMT) occurs in the tumor microenvironment and presents an important mechanism of tumor cell intravasation, stemness acquisition, and metastasis. During metastasis, tumor cells enter the circulation to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood.</P><P><B>Methods and results</B></P><P>Here, we present both in vivo and in vitro evidence that EMT-like transition also occurs in circulating tumor cells (CTCs) as a result of hydrodynamic shear stress (+SS), which promotes conversion of CD24<SUP>middle</SUP>/CD44<SUP>high</SUP>/CD133<SUP>middle</SUP>/CXCR4<SUP>low</SUP>/ALDH1<SUP>low</SUP> primary patient epithelial tumor cells into specific high sphere-forming CD24<SUP>low</SUP>/CD44<SUP>low</SUP>/CD133<SUP>high</SUP>/CXCR4<SUP>high</SUP>/ALDH1<SUP>high</SUP> cancer stem-like cells (CSLCs) or tumor-initiating cells (TICs) with elevated tumor progression and metastasis capacity in vitro and in vivo. We demonstrate that conversion of CSLCs/TICs from epithelial tumor cells via +SS is dependent on reactive oxygen species (ROS)/nitric oxide (NO) generation, and suppression of extracellular signal-related kinase (ERK)/glycogen synthase kinase (GSK)3β, a mechanism similar to that operating in embryonic stem cells to prevent their differentiation while promoting self-renewal.</P><P><B>Conclusion</B></P><P>Fluid shear stress experienced during systemic circulation of human breast tumor cells can lead to specific acquisition of mesenchymal stem cell (MSC)-like potential that promotes EMT, mesenchymal-epithelial transition, and metastasis to distant organs. Our data revealed that biomechanical forces appeared to be important microenvironmental factors that not only drive hematopoietic development but also lead to acquisition of CSLCs/TIC potential in cancer metastasis. Our data highlight that +SS is a critical factor that promotes the conversion of CTCs into distinct TICs in blood circulation by endowing plasticity to these cells and by maintaining their self-renewal signaling pathways.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (10.1186/s13058-018-1071-2) contains supplementary material, which is available to authorized users.</P>

      • Recent Advances in Disease Modeling and Drug Discovery for Diabetes Mellitus Using Induced Pluripotent Stem Cells

        Kawser Hossain, Mohammed,Abdal Dayem, Ahmed,Han, Jihae,Kumar Saha, Subbroto,Yang, Gwang-Mo,Choi, Hye Yeon,Cho, Ssang-Goo MDPI 2016 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.17 No.2

        <P>Diabetes mellitus (DM) is a widespread metabolic disease with a progressive incidence of morbidity and mortality worldwide. Despite extensive research, treatment options for diabetic patients remains limited. Although significant challenges remain, induced pluripotent stem cells (iPSCs) have the capacity to differentiate into any cell type, including insulin-secreting pancreatic β cells, highlighting its potential as a treatment option for DM. Several iPSC lines have recently been derived from both diabetic and healthy donors. Using different reprogramming techniques, iPSCs were differentiated into insulin-secreting pancreatic βcells. Furthermore, diabetes patient-derived iPSCs (DiPSCs) are increasingly being used as a platform to perform cell-based drug screening in order to develop DiPSC-based cell therapies against DM. Toxicity and teratogenicity assays based on iPSC-derived cells can also provide additional information on safety before advancing drugs to clinical trials. In this review, we summarize recent advances in the development of techniques for differentiation of iPSCs or DiPSCs into insulin-secreting pancreatic β cells, their applications in drug screening, and their role in complementing and replacing animal testing in clinical use. Advances in iPSC technologies will provide new knowledge needed to develop patient-specific iPSC-based diabetic therapies.</P>

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