臺灣博碩士論文加值系統

Antacamphin M是一個從牛樟芝萃取出來的新化合物，而在我們過去的研究中也發現到，antacamphin M具有抗發炎的效果。然而它在內皮細胞的抗發炎效果仍未清楚。而本篇研究主旨是antacamphin M在HUVEC中由LPS刺激的發炎反應，所具有的抗發炎效果與機制。首先細胞在前30分鐘使用適當濃度的antacamphin M處理細胞，之後再用0.1 μg/ml的LPS刺激細胞。之後我們檢測了發炎的相關路徑。我們發現HUVEC並沒有明顯的死亡，並且antacamphin M能夠減少ICAM-1、VCAM-1與iNOS的蛋白量與cytokine及chemokine的表現量，但COX-2卻沒有明顯變化，並且LPS刺激的細胞內ROS的生成量也有所減少。除此之外，antacamphin M不只抑制了MAPK，NLRP3、NF-κB等等發炎路徑與黏附試驗，還顯著的提升了HO-1與LXR-α的蛋白表現。而當我們使用了siRNA去knock down掉Nrf2與LXR路徑後，我們發現這些保護性的效果都被抵銷了，之後我們也使用了co-IP確認它們之間的蛋白交互作用，發現在加入藥物後，LXR-α會大幅度的binding到NF-κB去抑制它。這些發現顯示了antacamphin M在LPS所誘導的血管傷害過程中，發揮了一個保護性的效果，也許未來能夠作為一個有潛能的藥物。

Antcamphin M, a new ergonoid from Antrodia cinnamomea mycelium, has anti-inflammatory activity in our previous studies. However, its effect on endothelial cells remains unclear. The study was designed to investigate the effects and mechanisms of antcamphin M on LPS-stimulated human umbilical vein endothelial cells (HUVECs). Cells were pretreated with the indicated concentrations of the antcamphin M 30 min prior to stimulation with 0.1 μg/ml lipopolysaccharide (LPS). The cell viability, and the inflammatory signaling pathways were then measured. We found that antcamphin M significantly diminished intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) along with the protein levels of inducible NO synthase (iNOS), but not cyclooxygenase 2 (COX2). In addition, antcamphin M not only inhibited activations of the mitogen-activated protein kinase (MAPK), AKT, NOD-like receptor protein 3 (NLRP3) inflammasome, and NF-κB signaling pathways, but also significantly increased the protein levels of heme oxygenase-1 (HO-1) and liver X receptor (LXR). In adhesion assay, we found that antcamphin M significantly decreased THP-1 cell adhered to the HUVECs. However, these protective effects were abolished while silencing either Nrf2 or LXR gene expression. We also found that antcamphin M dramatically increased the protein-protein interaction between LXR and NF-κB. These findings indicate that antacamphin M exerted a protective effect on LPS-induced vascular injury process and might be a potential agent against inflammatory response in blood vessels.

目錄
目錄 I
圖目錄 V
縮寫表 VII
中文摘要 IX
Abstract X
第一章 緒言 1
第一節、發炎反應與血管發炎(Inflammatory response and vascular inflammation) 1
第二節、內皮細胞 (endothelial cells) 2
第三節、細胞黏附因子(cell adhesion molecules, CAM) 3
第四節、脂多醣 (lipopolysaccharide, LPS) 4
第五節、類鐸受體 (Toll-like receptors, TLRs) 5
一、類鐸受體 (Toll-like receptors, TLRs) 5
二、第四類鐸受體 (Toll-like receptor 4, TLR4) 5
第六節、有絲分裂原活化蛋白質激酶(mitogen-activated protein kinase, MAPK) 6
第七節、核因子κB(nuclear transcription factor kappa B, NF-κB) 7
第八節、核因子紅細胞2相關因子(Nuclear factor erythroid-2-related factor, Nrf2) 8
第九節、血基質氧化酶(Heme oxygenase, HO) 8
第十節、肝X受體（liver X receptor） 9
第十一節、發炎體(Inflammasome) 10
第十二節、細胞自噬(autophagy) 11
第十三節、牛樟芝(Antrodia cinnamomea mycelium) 11
第十四節、研究動機 12
第二章 材料與方法 18
第一節、主要儀器及藥品試劑 18
一、儀器與器材 18
二、藥品試劑 18
三、抗體 20
四、antcamphin M來源 21
第二節、方法 21
一、HUVEC細胞培養 (Cell culture) American Type Culture Collection (ATCC; Manassas, VA, USA) 21
二、蛋白質濃度測定 (Protein assay) (Thermo, N. Meridian Rd, Rockford, U.S.A)23
三、西方墨點法 (Western blotting) 24
四、CCK8細胞生長率偵測試驗 Cell Counting Kit-8 reagent (Dojindo, Japan) 31
五、細胞激素分析 (ELISA Kit；(R&D Systems, Minneapolis, MN, USA)) 31
六、核質分離製備（Nuclear/Cytosol Fractionation Kit；BioVision）(BioVision, Milpitas, MN, USA) 32
七、ROS活性氧檢測 Reactive Oxygen Species (ROS) Detection (Cell Biolabs, Inc. Arjons Drive San Diego, USA) 34
八、細胞黏附檢測 Cell adhesion assay (Molecular Probes, Eugene, Oregon, USA)34
九、即時聚合酶鏈式反應(Quantitative PCR) 35
十、Gene knock down (siRNA) (Santa Cruz Biotechnology, Dallas, Texas. USA)36
十一、免疫共沉澱法 (Co-Immunoprecipitation) (Millipore Corporation, Burlington, Massachusetts. U.S.A) 37
第三章 結果 39
第一節、antcamphin M對於HUVECs的細胞毒性測試 39
第二節、antcamphin M對於HUVECs的iNOS與COX-2和adhesion molecules的表現 39
第三節、antcamphin M對於cytokine和chemokine的表現 40
第四節、antcamphin M對於MAPK路徑之表現 41
第五節、antcamphin M對於NF-κB路徑之表現 42
第六節、antcamphin M對於TLR4接受器與myD88蛋白之表現 43
第七節、antcamphin M對於Nrf2、HO-1蛋白之表現與ROS生成的影響 44
第八節、antcamphin M對於肝X受體蛋白與ABCA1、ABCG1 mRNA表現 45
第九節、antcamphin M對於單核球黏附之作用 46
第十節、利用siRNA研究抗發炎的機制 47
第十一節、antcamphin M對於發炎體(inflammasome)之表現 48
第十二節、antcamphin M對自噬作用(autophagy)之表現 49
第十三節、antcamphin M在Nrf2、LXR與NF-κB間protein-protein interaction 50
第十四節、antcamphin M在PKC ζ和PKC β之表現 51
第四章 討論 52
第一節、牛樟芝 52
一、牛樟芝之生物活性化合物 52
二、牛樟芝活性化合物antcamphin M之抗發炎路徑活化 52
三、與antcamphin M類似結構之抗發炎藥物 52
第二節、MAPK和NF-κB與發炎反應之相關性 53
第三節、ICAM-1、VCAM-1與內皮細胞發炎之關係 54
第四節、Nrf2和LXR在內皮之作用 54
第五節、發炎體的抑制、自噬作用與內皮細胞相關性 57
第六節、腸道菌群與動脈硬化之關係 58
第五章 結論 59
第六章 參考文獻 76


 
圖目錄
圖一、內皮與巨噬細胞的交互作用 13
圖二、HUVEC 人類臍靜脈內皮細胞 13
圖三、脂多醣 (lipopolysaccharide, LPS)示意圖 14
圖四、細胞黏附因子(cell adhesion molecules, CAM)示意圖 14
圖五、細胞黏附過程示意圖 15
圖六、類鐸受體 (TLRs)引起發炎反應的主要路徑 15
圖七、Nrf2-HO-1路徑 16
圖八、發炎體(Inflammasome)路徑 16
圖九、自噬作用(Autophagy) 17
Figure 1. Effect of antcamphin M on HUVECs cell viability 60
Figure 2. Effect of antcamphin M on ICAM-1, VCAM-1, iNOS, and COX-2 in LPS-stimulated cells 61
Figure 3. Effect of antcamphin M on LPS-triggered cytokines and chemokine production in HUVEC 62
Figure 4. Effect of antcamphin M on the MAPK signaling pathways in LPS-stimulated cells 63
Figure 5. Effect of antcamphin M on the NF-κB signaling pathways in LPS-stimulated cells 64
Figure 6. Effect of antcamphin M on TLR4, MyD88 in LPS-stimulated cells 65
Figure 7. Effect of antcamphin M on Nrf2, HO-1 in LPS-stimulated cells 66
Figure 8. Effect of antcamphin M on LXR-α and ABCA1, ABCG1 in LPS-stimulated cells 67
Figure 9. Effect of antcamphin M on monocyte adhesion to endothelial cells 68
Figure 10. Effect of siRNA on adhesion molecule 69
Figure 11. Effect of antcamphin M on the NLRP3 inflammasome in LPS-stimulated cells 71
Figure 12. Effect of antcamphin M on autophagy in LPS-stimulated cells. 72
Figure 13. Effect of antcamphin M on LXR-α, Nrf2 and NF-κB protein-protein interaction 73
Figure 14. Effect of antcamphin M on PKC ζ and PKC β 74
Figure 15. Proposed mechanisms of antcamphin M on LPS-induced inflammatory response in endothelial cells 75
 

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