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系統識別號 U0026-3007201316240900
論文名稱(中文) 探討Dextromethorphan對於A群鏈球菌感染所提供之保護機制
論文名稱(英文) Study on the protective mechanisms of dextromethorphan in group A streptococcal infection
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 2
出版年 102
研究生(中文) 鄭妙慧
研究生(英文) Miao-Huei Cheng
學號 s46004098
學位類別 碩士
語文別 英文
論文頁數 59頁
口試委員 指導教授-林以行
口試委員-郭志峰
口試委員-羅伯安德森
口試委員-劉清泉
口試委員-林秋烽
中文關鍵字 A群鏈球菌  右旋美沙酚  NADPH氧化酶 
英文關鍵字 Group A streptococcus  dextromethorphan  NADPH oxidase 
學科別分類
中文摘要 A群鏈球菌感染是引起人類疾病的重要病原菌,較輕微感染會造成膿皰病及咽喉炎等;較嚴重的侵入性甚至危及性命的感染會導致壞死性筋膜炎及鏈球菌毒素休克症候群。右旋美沙酚是一個廣泛使用的鎮咳非處方用藥,此外右旋美沙酚也被研究證實具有抗發炎作用,並用來當作抗發炎試劑使用。近年來的研究報導指出右旋美沙酚可以藉由抑制NADPH oxidase的活性來降低reactive oxygen species (ROS)的表現量,進而達到神經保護性的效果。我們先前的研究證實,在A群鏈球菌感染的小鼠模式中,給予右旋美沙酚組別的老鼠,可以降低老鼠的發炎反應並提高A群鏈球菌感染小鼠的存活率。因此我們進一步利用細胞試驗的方式,試圖找出右旋美沙酚降低A群鏈球菌感染誘發發炎反應的分子機制。研究結果證實,小鼠的巨噬細胞在給予右旋美沙酚的情況下可以抑制NADPH oxidase p47次單位從細胞質移動到細胞膜的情形,來調控Akt/GSK-3β/NF-κB 的訊息傳遞,導致下游iNOS和NO的表現量下降。進一步的研究證實,小鼠的巨噬細胞給予右旋美沙酚處理可以顯著地降低A群鏈球菌感染所誘發ROS的表現量。綜合這些研究結果,右旋美沙酚可以透過抑制NADPH oxidase的活化降低ROS的表現量,並使得下游Akt/GSK-3β/NF-κB/iNOS/NO 的訊息傳遞受到抑制,來減緩A群鏈球菌感染所誘發的強大發炎反應,提供A群鏈球菌感染的保護性效果。
英文摘要 Group A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from relatively mild infections such as pharyngitis and impetigo, to life-threatening invasive diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM) is an over-the-counter antitussive. In addition, it has been identified as an anti-inflammatory agent. Recent studies indicate that DM has neuroprotective activity by inhibiting NADPH oxidase activity which leads to the reduction of reactive oxygen species (ROS). Our previous studies showed that DM treatment reduced inflammatory responses which contributed to an increased survival rate of GAS-infected mice. We used in vitro systems to further investigate the mechanisms underlying DM-mediated attenuation of inflammation in GAS-infected macrophages. Our results showed that DM treatment reduced Akt/GSK-3β/NF-κB signaling pathway activation, and also led to down-regulation of iNOS expression and NO production by inhibiting the membrane translocation of NADPH oxidase subunit p47phox in GAS-infected macrophages. In addition, DM can significantly decrease ROS production in GAS-infected macrophages. Taken together, DM can reduce GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production, which leads to down-regulation of the Akt/GSK-3β/NF-κB/iNOS/NO signaling pathway.
論文目次 中文摘要 i
Abstract ii
致謝 iii
Contents iv
List of Figures vii
Abbreviations viii
Introduction 1
GAS infection and host inflammation 1
GAS infection induces NO production 2
GAS infection induces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation 2
Dextromethorphan (DM) 3
DM has anti-inflammatory activity 4
Glycogen synthase kinase-3 beta (GSK-3β) 4
GSK-3β and NF-κB in bacterial infection 5
Reactive oxygen species (ROS) 6
ROS in phagocytic cells 8
GAS infection and ROS production 9
Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) 9
GAS infection and NADPH oxidase activation 11
DM and NADPH oxidase activation 11
Objective and Specific Aims 13
Materials and Methods 14
A. Materials 14
A-1 Cell 14
A-2 Bacteria 14
A-3 Drug and Reagents 14
A-4 Kits 17
A-5 Antibodies 17
A-6 Consumable 18
A-7 Instruments 19
B. Methods 21
B-1 Cell culture 21
B-2 Bacteria 21
B-3 Bacterial infection in RAW264.7 cells 22
B-4 Intracellular bacterial count 22
B-5 Western blotting analysis 23
B-6 Immunofluorescence confocal microscopy 23
B-7 Extracting macrophage membrane proteins 24
B-8 Measurement of intracellular ROS 24
B-9 Extraction of NF-κB nuclear protein 25
B-10 Nitrite assay 25
B-11 Statistics 26
Results 27
1. The role of DM in GAS infection-induced GSK-3β activation. 27
1.1 Investigation of GAS infection-induced Akt/GSK-3β signaling activation. 27
1.2 Investigation of the antioxidant effect of DM in GAS-activated GSK-3β. 27
2. The role of DM in GAS infection-induced NADPH oxidase activation and ROS production. 28
2.1 Detection of NADPH oxidase activation in GAS infection. 28
2.2 The effect of DM on GAS infection-induced NADPH oxidase activation. 28
2.3 Investigation of the role of DM on GAS infection-induced reactive oxygen species production. 29
3. The role of DM in GAS infection-induced NF-κB activation and 30
iNOS/NO expression. 30
3.1 The effect of DM on GAS infection-induced NF-κB activation. 30
3.2 The effect of DM on GAS infection-induced iNOS/NO expression. 31
Discussion 32
References 37
Curriculum Vitae 59
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