研究牛樟芝萃取物 CCM111 的作用機制

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姓名

林胤宇(In-Yu Lin) 查詢紙本館藏

畢業系所

系統生物與生物資訊研究所

論文名稱

研究牛樟芝萃取物 CCM111 的作用機制
(Study of the mechanism of actions of CCM111, extract of Antrodia cinnamomea)

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摘要(中)

牛樟芝(Antrodia cinnamomea, AC)是台灣真菌類多孔菌目的特有種，傳統上被台灣原住民當作解酒與治療肝病的草藥，CCM111則是牛樟芝的水粗萃取物。先前研究指出牛樟芝含有許多生物活性，包括抗發炎，抗癌，抗乙型肝炎病毒，護肝和抗肝纖維化。因此，牛樟芝被認為是一種高價值的中藥。然而到目前為止，牛樟芝與其生物功能之間的機制仍不明確。
在研究中為了探索CCM111在免疫反應中的機制，我們建立了9株與免疫反應路徑相關的冷光訊息傳遞細胞並且偵測CCM111是否會影響訊息傳導路徑。實驗結果顯示CCM111可以顯著抑制Toll-like receptor 4 (TLR4), Nuclear factor kappa B (NF-κB)以及Signal transducer and activator of transcription 3 (STAT3)等訊息傳導路徑活性。在進一步的研究中，我們發現CCM111抑制發炎反應的機制是透過抑制STAT3與NF-κB訊息路徑活性，來抑制產生發炎因子的inducible nitric oxide synthase (iNOS)以及Cyclooxygenase-2 (COX-2)的蛋白質表現。因此我們的研究結果顯示CCM111具有作為抗發炎的潛力。
由於慢性的肝臟發炎會導致肝纖維化（Liver fibrosis）與肝硬化(Cirrhosis)，並且我們發現CCM111具有抗發炎的作用，因此我們研究CCM111是否具有抗肝纖維化的功能以及作用機制。我們發現CCM111能夠藉由抑制基質金屬蛋白酶-2 (metalloproteinase-2, MMP2)、α-平滑肌肌動蛋白(α-smooth muscle actin, α-SMA)的蛋白質表現與抑制Transforming Growth Factor β (TGF-β)來減輕誘導化學性肝纖維化四氯化碳(Tetrachloromethane, CCl4)造成的肝損傷。並且我們藉由次世代定序(Next-generation sequence)發現CCM111會去抑制TGF-β，STAT3和Wnt訊息傳導路徑下游的基因表現。為了驗證實驗結果，我們在肝臟星狀細胞上發現CCM111能夠透過抑制TGF-β，STAT3和Wnt訊息傳導路徑活性來降低代表肝纖維化的標記(marker)。我們的研究指出CCM111具有預防以及治療肝纖維化藥物的潛力。
在本研究結果中，闡述了CCM111在抗發炎、抗肝纖維化作用機制。

摘要(英)

CCM111 is an extract of Antrodia cinnamomea (AC), an endemic Polyporaceae fungus found in Taiwan. CCM111 has been used for the treatment of hangover and liver diseases. Previous studies showed that AC exerts various bioactivities, including anti-inflammation, anti-cancer, anti-hepatitis B virus, hepatoprotective, and anti-liver fibrosis effects. As a result, AC has been considered as a high-value traditional Chinese medicine. However, the biological functions of AC remain unclear.
In the present study, we examined the role of CCM111 in immune response by investigating signal transduction pathways. To monitor the activities of immune-related signaling pathways, we generated nine stable cell lines expressing transcriptional regulatory elements upstream of a luciferase reporter. We evaluated the effects of CCM111 on these signaling pathways and further investigated whether CCM111 can influence inflammatory function. Our results revealed that CCM111 treatment significantly inhibited the TLR4, NF-κB, and TLR4 signaling pathways. Further analyses showed that CCM111 significantly inhibited the inflammation response by downregulating the expression of the inflammatory proteins iNOS and COX-2 by inhibiting the STAT3 and NF-κB pathways. Therefore, our findings demonstrated the potential use of CCM111 as an anti-inflammatory agent.
Chronic liver inflammation plays an important role in the progression of liver fibrosis and cirrhosis. Our findings indicated that CCM111 exerts anti-inflammatory effects, thereby highlighting its potential applications for the treatment of liver fibrosis. During carbon tetrachloride (CCl4)-induced hepatic injury in vivo, CCM111 alleviated liver fibrosis by downregulating the expression of matrix metalloproteinase (MMP2) and α-smooth muscle actin (α-SMA) and inhibited the TGF-β pathway. Next-generation sequencing (NGS) analysis showed that CCM111 markedly downregulated the expression of genes involved in the TGF-β, Wnt, and STAT3 signaling pathways. CCM111 inhibited the expression of fibrosis markers by inhibiting the expression of TGF-β-, Wnt-, and STAT3-dependent proinflammatory and profibrotic mediators in HSC-T6, corroborating the results of the NGS analysis. These results highlight the potential use of CCM111 in the prevention and treatment of chronic fibrotic liver diseases.
Our current findings provided the basis for further elucidating the mechanisms underlying the anti-inflammatory and anti-liver fibrosis effects of CCM111.

關鍵字(中)

★ 牛樟芝
★ 免疫
★ 抗發炎
★ 抗肝纖維化
★ CCM111

關鍵字(英)

★ Antrodia Cinnamomea
★ Immune
★ Anti-inflammation
★ Anti-liver fibrosis
★ CCM111

論文目次

Table of contents
中文摘要I
Abstract .III
Acknowledgement .. V
List of figures .. XI
List of tables . XIV
List of abbreviations . XV
Chapter 1: Literature review 1
1.1. Introduction to Inflammation 1
1.1.1. Definition of inflammation .. 1
1.1.2. Inflammation, diseases and signal transduction pathways .. 1
1.2. Introduction to liver fibrosis .. 4
1.2.1. Liver and Liver fibrosis . 4
1.2.2. Hepatic stellate cells (HSCs) .. 4
1.2.3. The critical pathways involved in liver fibrosis 5
1.2.4. Liver fibrosis therapy . 7
1.3. Introduction to Antrodia cinnamomea . 8
1.3.1. Biological function of Antrodia cinnamomea 8
1.3.2. The preparation of CCM111 .. 9
1.3.3. Anti-inflammatory effects of Antrodia cinnamomea . 9
1.3.4. Anti-liver fibrosis effects of Antrodia cinnamomea . 10
1.4. Significances and purpose . 10
Chapter 2: Material and Method. 23
2.1. Cell lines and reagents . 23
2.2. Chemicals and reagents .. 23
2.3. Establishment of stable clones expressing the transcriptional response element
(TRE) luciferase reporter. 24
2.4. Preparation of the crude water extract. .. 25
2.5. Cell lines and establishment of stable cell lines. .. 25
2.6. Western blotting assay 26
2.7. Nitrite assay 27
2.8. Subcellular fractionation .. 27
2.9. HPLC-UV analysis 28
2.10. Antibody array . 28
2.11. Biochemical analysis of liver function 29
2.12. Cells and Toxicity assay . 29
2.13. Hematoxylin-eosin staining and Sirius Red/Fast Green staining . 30
2.14. Next-generation sequence . 30
2.15. Animals and treatments . 31
2.16. Statistical Analysis . 31
Chapter 3: CCM111 regulates immune-related activity through STAT3 and NF-κB
pathways ..33
3.1. Introduction .. 33
3.2. Results 34
3.2.1. The quality control of CCM111 by HPLC-UV and LC/MS 34
3.2.2. Effects of CCM111 on signal transduction pathways in Hela and HEK293 cells 35
3.2.3. CCM111 reduces the activity of STAT3 and NF-κB pathways in HEK293 cells 36
3.2.4. CCM111 reduces the activity of TLR4 pathway in HEK293 and RAW264.7 cells
36
3.2.5. CCM111 reduces the LPS-mediated activation of STAT3 and NF-κB signaling in
RAW264.7 . 37
3.2.6. CCM111 inhibits the expression of inflammatory cytokines in macrophages 39
3.2.7. Effects of CCM111 fractions on the NO production and the phosphorylation of
Tyk2 protein expression in RAW264.7 cells 40
3.3. Discussion 40
Chapter 4: CCM111 prevents hepatic fibrosis via cooperative inhibition of TGF-β, Wnt and
STAT3 signaling pathways .. 61
4.1. Introduction .. 61
4.3. Results 63
4.3.1. Effects of CCM111 on CCl 4 -treated mice . 63
4.3.2. The effects of CCl 4 -treated liver injury were evaluated by
histopathological examination of the liver sections. . 64
4.3.3. CCM111 represses the progression of liver ﬁbrosis through reducing activation of
the TGF-β pathway 64
4.3.4. CCM111 inhibits the expression of inflammation- and fibrogenesis-related genes 65
4.3.5. Effects of CCM111 on TGF-β1-induced MMP2, α-SMA and TGF-β pathway
activation in HSC-T6 66
4.3.6. Effects of CCM111 on TGF-β1-induced STAT3 and Wnt pathways activation in
HSC-T6 66
4.4. Discussion 67
Chapter 5: Concluding remarks and future direction 85
5.1. Conclusion remarks .. 85
5.2. Future direction .. 87
References ..89
Appendix A CCM111 inhibits the proliferation of melanoma cell line. 101
Appendix B Transcriptional regulatory elements (TRE) are the transcription factor binding
sequence. 102
Appendix C. Qualitative analysis of Fraction 4. .. 103
Appendix D. List of plasmids described in this thesis. . 104
Appendix E. Publication list. 114

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指導教授

馬念涵(Nianhan Ma)

審核日期

2018-11-26

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