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系統識別號 U0026-3008201817203600
論文名稱(中文) 製備苯甲酸修飾之聚賴胺基酸星狀高分子應用於脂多醣誘導的敗血症中作為有潛力之抗發炎劑
論文名稱(英文) Synthesis of benzoic acid-modified poly(L-lysine) star polymer as a potential anti-inflammatory agent in Lipopolysaccharide-induced sepsis
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 106
學期 2
出版年 107
研究生(中文) 林莉芳
研究生(英文) Li-Fang Lin
學號 P86054080
學位類別 碩士
語文別 英文
論文頁數 70頁
口試委員 指導教授-葉明龍
口試委員-詹正雄
口試委員-阮俊能
中文關鍵字 星狀聚胺基酸高分子  抗發炎劑  脂多醣  敗血症 
英文關鍵字 star-shaped polypeptides  anti-inflammatory agent  LPS  sepsis 
學科別分類
中文摘要 敗血症是由細菌感染引起的全身性炎症反應。已知星狀結構聚胺基酸高分子能有效地與細菌的外膜相互作用並增強抗微生物的能力。然而,很少有關於此類型結構對脂多醣 (LPS)誘導之敗血症抵抗能力的研究。為此,本研究通過N-羧酸酐 (NCA)的開環聚合 (ROP)反應合成出線性和星狀聚胺基酸高分子並以苯甲酸修飾作為側鏈官能團希望增加其抗發炎的能力。在這項研究中,這些合成的聚胺基酸高分子通過靜電力顯示出對LPS的高親和力,並且可以通過形成複合聚集物來降低LPS的毒性。此外,我們發現具有修飾的星狀聚胺基酸高分子能有效的抑制LPS刺激的RAW264.7巨噬細胞的促炎介質和細胞激素如一氧化氮,腫瘤壞死因子α (TNF-α) 和白細胞介素6 (IL-6) 的表達,相較於線性且具有苯甲酸修飾的聚胺基酸高分子和未修飾的星狀聚胺基酸高分子顯示出較顯著的抗發炎特性。機制研究表明,修飾過的星狀聚胺基酸高分子能降低發炎反應主要是通過抑制PI3K/Akt和部分MAPK訊息傳遞路徑的磷酸化以及降低作為調節炎症的主要轉錄因子p65的激活更進一步避免下調節的核轉位。此外,修飾的星狀聚胺基酸高分子降低LPS誘導的敗血症小鼠模型中TNF-α 及 IL-6的產生且不造成組織損傷。這些結果支持了這種具有附加功能且簡單合成的星狀聚胺基酸高分子在細菌誘導的疾病治療應用上為具有潛力的生物抑制劑。
英文摘要 Sepsis is a systemic inflammatory response caused by bacteria infection. It is known that star-shaped structure polypeptides efficiently interact with the outer membranes of bacteria and enhance antimicrobial activity. However, there were few studies reported their ability on LPS-induced sepsis. For this, linear and star polypeptides were synthesized by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs) with benzoic acid modified as functional group. In this study, these synthetic polypeptides show highly affinity to the endotoxin LPS by electrostatic force and may reduce the toxicity of LPS through forming a compounded aggregation. Furthermore, we found that star polypeptide with modification inhibited the expression of pro-inflammatory mediators and cytokines such as inflammatory nitric oxide, TNF-α and IL-6 from the LPS-stimulated RAW264.7 macrophages and exhibited significant anti-inflammatory properties as well compared to linear modified polypeptide and non-modified star polypeptide. Mechanism studies revealed that the inhibitory effects of modified star polypeptide was mainly mediated by the inhibition of phosphorylated PI3K/Akt pathway, partial MAPK pathway and the down-regulated nuclear translocation of p65 expression which is the main transcription factor to regulate the inflammation. Furthermore, modified star polypeptide decreased the production of TNF-α, IL-6 in the LPS-induced sepsis mice model without causing tissue damage. These results support that this simply synthesized star polypeptide with additional functionality is a promising therapeutic agent for bacteria induced diseases.
論文目次 Table of contents

中文摘要 I
Abstract III
誌謝 IV
Abbreviations V
Table of contents VI
List of tables X
List of Figures XI
Chapter 1 Introduction 1
1.1 Sepsis 1
1.1.1 Lipopolysaccharide (LPS) 1
1.1.2 LPS-induced inflammatory pathway 2
1.1.3 Pro-inflammatory mediators 4
1.2 Polypeptides 4
1.2.1 Antimicrobial peptides 5
1.2.2 Different shaped of polypeptides 6
1.2.3 Modification of polypeptides 8
1.3 Sepsis treatment 9
1.3.1 Current research on anti-sepsis agents 9
1.3.2 Clinical trials and the drug development 10
1.4 Motivations and Aims 15
Chapter 2 Materials and Methods 16
2.1 Materials 16
2.2 Instruments 17
2.3 Experiment flow chart 18
2.4 Drying solvent 18
2.5 Synthesis of poly(L-lysine-g-bezonic acid) 19
2.5.1 Synthesis of Z-L-lysine N-carboxyanhydrides (Lys –NCAs) 19
2.5.2 Synthesis of poly(Z-L-lysine) homopolymers 19
2.5.3 Synthesis of 3armed poly(Z-L-lysine) star polymers 19
2.5.4 Removing the protecting groups of homoplymers and star polymers 20
2.5.5 Modification of benzoic acid as functional group 20
2.6 Dynamic light scattering (DLS) 21
2.7 Cell lines and culture conditions 21
2.8 In vitro cytotoxicity assays 22
2.9 Scanning electron microscopy (SEM) 22
2.10 In vitro anti-inflammatory tests 23
2.10.1 Enzyme-Linked Immunosorbent Assay (ELISA) 23
2.10.2 Measurement of nitric oxide (NO) production 23
2.10.3 Western blot 23
2.10.4 Immunofluorescence 24
2.11 Hemolysis test 25
2.12 Mouse models of LPS-induced inflammatory responses 25
2.12.1 Histopathological evaluations 26
2.13 Statistical analysis 26
Chapter 3 Results 27
3.1 Synthesis of Polypeptides 27
3.2 Characterization of polypeptides 28
3.2.1 Chemical Structure Analysis and grafting ratio 28
3.2.2 Secondary structure analysis of polypeptides 34
3.3 Interaction between polypeptides and LPS 35
3.3.1 The size distribution of LPS and polypeptides neutralization 36
3.4 In vitro cytotoxicity test 37
3.5 SEM observation on polypeptides and LPS-treated RAW264.7 cell morphology 39
3.6 In vitro anti-inflammatory studies 40
3.6.1 3armed-PLL20-g-ben0.2 reduced the production of pro-inflammatory cytokines in LPS-activated RAW264.7 cells 40
3.6.2 3armed-PLL20-g-ben0.2 decreased the production of NO in LPS induced RAW264.7 cells 42
3.6.3 The effect of polypeptides for LPS-induced NF-κB, MAPK and PI3K pathway. 43
3.6.3.1 3armed-PLL20-g-ben0.2 inhibited LPS-induced NF-κB activation in RAW264.7 cells 43
3.6.3.2 3armed-PLL20-g-ben0.2 inhibited Akt-dependent NF-κB activity 44
3.6.3.3 3armed-PLL20-g-ben0.2 attenuated LPS-induced MAPK pathway 46
3.6.4 Inhibitory effects of polypeptides on LPS-induced nuclear translocation of NF-κB p65 in RAW264.7 cells 48
3.7 Hemolysis tests of polypeptides 49
3.8 3armed-PLL20-g-ben0.2 attenuated the secretion of serum cytokines in LPS-induced mice model 50
3.9 3armed-PLL20-g-ben0.2 exhibits protection against tissue damage in LPS-induced mice model 51
Chapter 4 Discussion 53
Chapter 5 Conclusion 60
References 61
Appendix 70


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