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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 許麗卿 | zh_TW |
| dc.contributor.advisor | Lih-Ching Hsu | en |
| dc.contributor.author | 武華緯 | zh_TW |
| dc.contributor.author | Hwa-Wei Wu | en |
| dc.date.accessioned | 2021-07-11T15:30:02Z | - |
| dc.date.available | 2024-02-28 | - |
| dc.date.copyright | 2018-10-09 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | 1. Association AD. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014; 37:S81–S90.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78930 | - |
| dc.description.abstract | zh_TW | |
| dc.description.abstract | Sodium-coupled glucose co-transporters SGLT1 and SGLT2 are active glucose transporters responsible for glucose absorption in the intestine and glucose reabsorption in the kidney, respectively. Several selective SGLT2 inhibitors have been approved for the treatment of type 2 diabetes. It is also reported that SGLT1 and SGLT2 are overexpressed in many cancers. Therefore, SGLT inhibitors might be potential anticancer agents. We have established a non-radioactive cell-based method for screening SGLT inhibitors using 1-NBDG, a fluorescent D-glucose analogue, and transiently transfected COS-7 cells overexpressing hSGLT1 or hSGLT2 to perform glucose uptake assays. In this study, we found that two kaempferol glycosides, isolated from Cinnamomum macrostemon leaves, possessed potent SGLTs inhibitory activities. Based on the kaempferol core moiety, we further evaluated the inhibitory activities of a series of related flavonoids against SGLT1 and SGLT2. The assay results led to some conclusions of structure activity relationship (SAR). First, glycosyl residues are crucial since the kaempferol aglycon shows no SGLTs inhibitory activities. In addition, the sugar inter-linkage and their substitution position to the aglycon not only affect the activities but also the inhibitory selectivity toward SGLTs.
In order to search for selective SGLT2 inhibitors, 1-NBDG uptake assay in hSGLT2 transfected COS-7 cells was conducted to screen crude extracts from Lauraceae plants. ISC-1236l, ISC-1966s, and ISC-1827s showed the best inhibitory activities toward SGLT2 among the crude extracts, although they were much less than the leaf extract of Cinnamomum macrostemon. Besides, 1-NBDG uptake assay and RT-qPCR were conducted in OSCC cell lines, including SCC103, SCC104 and SCC131. The results indicated that the expression of SGLT1 and SGLT2 in SCC131 was the most abundant among three cell lines. Therefore, SCC131 was chosen for drug treatment examination and cell viability was detected by the MTT assay. Obvious difference of cell viability between cells treated with 0 and 100 M of phlorizin was observed when the assay was conducted in culture medium containing more FBS and/or less glucose. The combination of phlorizin with cisplatin, doxorubicin, paclitaxel, 5-fluorouracil, vinblastine, (R)(S)(S)-BF65, NVP-BEZ235, dihydroartemisinin, and phloretin were further examined in SCC131 cells. However, no synergistic effect was observed. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:30:02Z (GMT). No. of bitstreams: 1 ntu-107-R05423015-1.pdf: 3188737 bytes, checksum: aeb971eb211d0d581a56999be28ba193 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii ABSTRACT iv CONTENTS vi LIST OF FIGURES ix LIST OF TABLES xi LIST OF ABBREVIATIONS xii AIMS OF THE STUDY 1 Chapter 1 Introduction 2 1.1 Diabetes mellitus 2 1.1.1 Types of diabetes 2 1.1.2 Epidemiology 2 1.1.3 Diagnosis 3 1.1.4 Risk factor 3 1.1.5 Management 3 1.2 Oral cavity and oropharyngeal cancers 4 1.2.1 Epidemiology 4 1.2.2 Risk factors 5 1.2.3 Symptoms and diagnosis 5 1.2.4 Stages and survival rates 6 1.2.5 Treatment 7 1.3 Sodium-coupled glucose cotransporters (SGLTs) 8 1.3.1 SGLT1 8 1.3.2 SGLT2 9 1.4 SGLT inhibitors 9 1.4.1 Development of SGLT inhibitors 9 1.4.2 Current selective SGLT2 inhibitors 10 1.5 SGLT inhibitors as potential anticancer agents 11 1.6 Antidiabetic agents from natural products 12 1.7 1-NBDG 12 Chapter 2 Materials and Methods 23 2.1 Cell culture 23 2.2 Transfection 24 2.3 1-NBDG uptake assay 25 2.4 Cell viability assay 28 2.5 Reverse transcription-polymerase chain reaction (RT-PCR) 29 2.5.1 RNA extraction 29 2.5.2 Reverse-transcription 30 2.5.3 Quantitative real-time polymerase chain reaction (qPCR) 31 2.6 Data analysis 32 Chapter 3 Results 34 3.1 Screening of Natural compounds by the 1-NBDG system 34 3.2 Screening of natural flavonoids by the 1-NBDG system 34 3.3 Screening for selective SGLT2 inhibitors from crude extracts by the 1-NBDG system 35 3.4 Determination of Cell background and Na/Ch ratio (the ratio of total uptake over sodium-independent uptake) 36 3.5 Determination of SGLT1 and SGLT2 expression in SCC103, SCC104, and SCC131 cell lines. 37 3.6 Effect of SGLT inhibitors on cell viability by single treatment or combination with chemotherapeutic drugs in OSCC cell lines. 37 Chapter 4 Discussion 61 4.1 Effect of SGLT inhibitors on cancer treatment. 61 4.2 3-O glycosylation on flavonols is important to hSGLT inhibitory activities. 61 4.3 7-O glycosylation on flavonols may reduce hSGLT inhibitory activities. 62 4.4 8-C xylosylation on flavones shows better hSGLT2 inhibitory activity. 63 4.5 Effect of saturation of 2,3 double bond on flavonols on hSGLT inhibitory activities. 63 4.6 Effect of substituents in B ring of flavonoids on hSGLT inhibitory activities. 63 4.7 Effect of FBS and glucose concentration on cell viability of SCC131. 64 Chapter 5 Conclusion 72 REFERENCES 74 | - |
| dc.language.iso | en | - |
| dc.subject | SGLTs | zh_TW |
| dc.subject | 癌症 | zh_TW |
| dc.subject | 糖尿病 | zh_TW |
| dc.subject | 口腔鱗狀細胞癌 | zh_TW |
| dc.subject | 構效分析 | zh_TW |
| dc.subject | 黃酮? | zh_TW |
| dc.subject | Diabetes | en |
| dc.subject | cancer | en |
| dc.subject | SGLTs | en |
| dc.subject | flavonoid glycosides | en |
| dc.subject | SAR | en |
| dc.subject | OSCC | en |
| dc.title | SGLT1 和 SGLT2 之天然抑制劑篩選和構效分析 | zh_TW |
| dc.title | Screening and SAR analysis of natural products with inhibitory activities toward SGLT1 and SGLT2 | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 李水盛;顧記華 | zh_TW |
| dc.contributor.oralexamcommittee | ;; | en |
| dc.subject.keyword | 糖尿病,癌症,SGLTs,黃酮?,構效分析,口腔鱗狀細胞癌, | zh_TW |
| dc.subject.keyword | Diabetes,cancer,SGLTs,flavonoid glycosides,SAR,OSCC, | en |
| dc.relation.page | 84 | - |
| dc.identifier.doi | 10.6342/NTU201803889 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-08-17 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| dc.date.embargo-lift | 2023-10-09 | - |
| Appears in Collections: | 藥學系 | |
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| ntu-106-2.pdf Restricted Access | 3.11 MB | Adobe PDF |
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