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系統識別號 U0026-0501201701274200
論文名稱(中文) 探討兒茶素類似物在保護發炎相關疾病之功效與分子機制
論文名稱(英文) Mechanistic insight into the efficacy of catechin analogs in protecting against inflammation-related diseases
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 105
學期 1
出版年 105
研究生(中文) 邱依琇
研究生(英文) Yi-Shiou Chiou
學號 S78981048
學位類別 博士
語文別 英文
論文頁數 156頁
口試委員 指導教授-王應然
共同指導教授-潘敏雄
召集委員-何元順
口試委員-郭靜娟
口試委員-林秋烽
口試委員-黃步敏
口試委員-羅至佑
中文關鍵字 活性氧自由基  表觀遺傳學  發炎反應  Nrf2  NF-kB  化學預防  癌症幹細胞  腫瘤微環境  表没食子兒茶素没食子酸酯  乙醯化表没食子兒茶素没食子酸酯  表兒茶素沒食子酸酯  發炎性腸道疾病  腫瘤發展過程  PKD1  內毒素  TLR-4  Keap1  巨噬細胞  內毒素血症  氧化壓力 
英文關鍵字 ROS  epigenetic  inflammation  Nrf2  NF-kB  chemoprevention  CSCs  tumor microenvironment  EGCG  AcEGCG  ECG  IBD  tumorigenesis  PKD1  LPS  TLR-4  Keap1  macrophages  endotoxemia  oxidative stress 
學科別分類
中文摘要 細胞內的氧化還原狀態不平衡,與起始和促進發炎相關疾病發展有關,如癌症、代謝症候群、老化和敗血症。慢性或急性發炎反應誘導產生之活性氧自由基 (ROS) 與親電子試劑,不僅造成DNA損傷與突變,更引起癌初始細胞內多重基因之表觀遺傳學的改變,而導致腫瘤細胞增生和轉移。此外,轉錄因子NF-B和Nrf2 在毒物代謝、發炎疾病以及癌症化學預防領域上也扮演重要角色,加上癌症幹細胞在癌症的復發和轉移過程的貢獻,因此提出加強細胞的防禦力、逆轉表觀遺傳修飾、以及改善腫瘤微環境中的癌症幹細胞,具有預防、延遲和控制各種與發炎相關疾病發生的潛力。然而,現今對於發炎性疾病的治療策略有限,且具有毒性和副作用。有鑒於此,來自天然的功能性食品成分成為受注目的替代治療方式。現今,文獻更證實來自茶葉、蔬菜、水果和堅果中的兒茶酚類具有藥理學特性,可作為健康促進效益之天然保健食品。雖然兒茶酚類可發揮多種有益健康的功效,但對於細胞保護作用與發炎相關致癌過程中之具體的分子調控機制尚不明確。因此,本論文整體的研究目標為鑑定兒茶酚類化合物在生物學效應上的標的分子,並闡明其作用機制。本研究共分為三部分,相關成果分述如下:
第一部分的研究目的為建立DSS誘發的小鼠腸潰瘍與AOM/DSS誘導之潰瘍性腸致癌模式,以此模式主要比較並探討飲食添加兒茶酚類化合物,表没食子兒茶素没食子酸酯(EGCG) 或EGCG的前驅藥AcEGCG對腸道發炎反應、異常腺窩形成和腫瘤發展之影響。結果證實,AcEGCG可經由更改組蛋白與非組蛋白之乙醯化與去乙醯化的平衡,阻斷NF-kB調節之促發炎因子的分泌 (如腫瘤壞死因子,TNF-a) ,並增加Nrf2驅動之抗氧化酵素的表現 (如HO-1),進而比EGCG更有效改善小鼠潰瘍的病理症狀與腫瘤的形成。第一部分的研究成果建議,AcEGCG可發展成新穎的表觀遺傳治療試劑,特別是應用在發炎性腸道疾病 (IBD)相關的腸癌預防上。
在第二部分的研究中,我們以DMBA/TPA誘發的小鼠皮膚二階段致癌模式比較EGCG和AcEGCG對皮膚腫瘤形成之影響,並探討CD34+的皮膚癌幹細胞中PKD1的角色。與EGCG相比結果顯示,皮膚局部預處理AcEGCG後再給予誘導劑TPA能更有效降低DMBA/TPA誘導之皮膚腫瘤發生率與多樣性。其作用機制主要是通過抑制細胞周期調節蛋白,如p53、p21、c-Myc、cyclin B、p-CDK1 和 Cdc25A的表現,以及恢復細胞內ERK1/2激酶的活性,進而減少腫瘤細胞增生和有絲分裂的進行。第二部分的研究成果首次揭露在皮膚致癌過程中AcEGCG可作為非選擇性PKD1和CD34的抑制劑,並建議在臨床上PKD1可作為預防與治療皮膚癌的標靶對象。
第三部分的研究目的擬以細胞及動物實驗闡明兒茶酚類化合物 EGCG、AcEGCG和表兒茶素沒食子酸酯 (ECG) 對內毒素lipopolysaccharide (LPS) 引起之巨噬細胞發炎反應,與抗內毒素血症的功效,並釐清在發炎過程中Keap1-Nrf2和NF-kB訊號對HO-1的調節作用,與彼此在發炎訊號的拮抗分子機制。結果證實,ECG比EGCG和AcEGCG更有效抑制LPS誘導的巨噬細胞發炎反應。數據也發現,ERK1/2訊號的活化與轉錄因子Nrf2與NF-kB的串擾作用有關,且LPS或ECG調節的HO-1表達必需依賴此訊號。數據更指出,Nrf2/ARE驅動的抗氧化訊號可直接干擾NF-kB的轉錄活性,而防止LPS刺激的氧化壓力與發炎反應。因此,第三部分的研究成果不僅首次提出ECG可作為新穎的Keap1-Nrf2訊號干擾劑和TLR4活化的抑制劑外,更可預防和治療氧化壓力或發炎反應引起之相關疾病,及提供了創新的理念和策略。
整體而言,本研究證實兒茶酚類化合物可作為在抗發炎與癌症化學預防作用上的特異標靶分子,成果可為現代藥理學創造新的機會和革命性的新觀念。我們的研究成果建議,AcEGCG和ECG在干擾表觀遺傳修飾作用和發炎事件相關的疾病上,可望進入臨床前評估以及作為最終臨床試驗上的候選藥物。

英文摘要 An unbalanced redox state is believed to be responsible for the initiation and promotion of inflammation-related diseases including cancer, metabolic diseases, aging, and sepsis. Chronic (or acute) inflammation-induced generation of reactive oxygen species (ROS) and electrophiles stimulates DNA damage and mutations, and causes epigenetic alteration in multiple genes of initiated cells. It can also cause proliferation and metastasis. The impact of nuclear factor-kappa B (NF-B) and nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) on hormesis, management of inflammatory diseases, and chemoprevention has played a crucial role. Biological markers representing cancer stem cells (CSCs) are thought to contribute to tumor recurrence and metastasis in many cancers. Thus, enhancing cytoprotective capability, reversing epigenetic phenomena, and targeting CSCs in the tumor microenvironment has the potential to prevent, delay, and control various inflammation-related disorders and diseases. Most of the current therapeutic strategies for inflammatory disorders and diseases provide limited beneficial action and possess toxic side effects. For these reasons, alternative approaches have gained increasing attention, especially those derived from natural and functional foods. Recent research has demonstrated that catechins obtained from different dietary sources such as teas, vegetables, fruits, and nuts exhibit a wide range of biological and pharmaceutical properties with potential health-promoting benefits. Although catechins exert multiple benefits, the details of the specific regulatory molecular mechanisms that contribute to its integral roles in cytoprotection and inflammation-associated carcinogenesis are not well defined. A key objective of our research program is to identify the molecular target(s) by which catechin analogs elicit their biological effect and to elucidate their mechanism of action.
The aim of the first part of our study is to compare and explore the efficacy of (-)-epigallocatechin-3-gallate (EGCG) and EGCG prodrug (peracetylated (-)-epigallocatechin-3-gallate, AcEGCG) supplementation on the development of colonic inflammation, aberrant crypt foci (ACF), and colonic tumors in dextran sulfate sodium (DSS) and azoxymethane (AOM)/DSS-induced experimental colitis and colitis-driven colon cancer. The result clearly demonstrated that AcEGCG is more potent than EGCG for the improvement of colitis and tumor formation through blocking the NF-B–regulated pro-inflammatory mediators secretion (e.g. tumor necrosis factor-alpha, TNF-) and increasing the Nrf2-driven antioxidant enzyme expression (e.g. heme oxygenase-1, HO-1) by altering the balance of histone and nonhistone protein acetylation/deacetylation. This is the first investigation with evidence that dietary AcEGCG may be developed into an epigenetic therapeutic agent, especially for the prevention of inflammatory bowel disease (IBD) associated with tumorigenesis.
In the second part, we compare the effects of EGCG and AcEGCG on 7, 12-dimethylbenz[a]-anthracene (DMBA)/ 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis and seek to substantiate the role of protein kinase D1 (PKD1) in proliferative CD34-expressing CSCs. We demonstrated that topical application of AcEGCG before TPA treatment can be more effective than EGCG in reducing DMBA/TPA-induced tumor incidence and multiplicity. This activity appears to be mediated through a blockade of p53, p21, c-Myc, cyclin B, p-CDK1, and Cdc25A expression and a restoration of extracellular signal-regulated kinase 1/2 (ERK1/2) activity, which decreased tumor proliferation and the mitotic index. In this section, we reveal for the first time that AcEGCG can be used as a non-selective PKD1 and CD34 inhibitor during multistage mouse skin carcinogenesis and that PKD1 may be a preventive and therapeutic target for skin cancer in clinical settings.
In the third part, we first compare the anti-inflammatory efficacy of catechin analogs 【EGCG, AcEGCG and (-)-epicatechin-3-gallate (ECG)】, then characterize ECG in lipopolysaccharide (LPS)-induced macrophages and endotoxemia and elucidate its function in the mechanistic interaction between the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 and NF-B signaling cascades involved in HO-1induction. Our observation found that ECG was the most effective of these catechin analogs in inhibiting the generation of LPS-stimulated proinflammatory mediators. Findings from the third study also certified that ERK1/2 signaling regulated the crosstalk between Nrf2 and NF-B that was essential for the LPS or ECG-induced expression of HO-1. Our data also confirmed that the Nrf2/antioxidant response element (ARE) directly antagonized NF-B-dependent transcriptional activity, resulting in prevented LPS-stimulated cellular oxidative stress and inflammatory processes. In the outcome, we utilized both in vitro and in vivo experiments to coherently prove that ECG was a Keap1–Nrf2 interaction disruptor and LPS-induced Toll-like receptor-4 (TLR-4) activation inhibitor, thereby providing an innovative concept and strategy to prevent and treat immune, oxidative stress, and inflammation-related diseases.
Overall, we verify the anti-inflammatory and cancer chemopreventive activities of catechins and their specific molecular targets that may create new opportunities for innovation in modern pharmacology. In conclusion, we suggest that AcEGCG and ECG are promising candidates and can be advanced into pre-clinical evaluation, and ultimately in clinical trials, focused on interfering with epigenetic and inflammatory/autoimmune events associated with different disorders and diseases.
論文目次 Contents
Abstract in Chinese I
Abstract IV
Acknowledgement VII
Abbreviations XVI
Introduction 1
1. Oxidative stress, inflammation and diseases 1
2. The development of cancer in relation to genetic and epigenetic mechanisms 2
3. Colitis-associated colon cancer 7
4. The inflammatory response in sepsis 8
5. Roles of Keap1-Nrf2-ARE and NF-B pathway in inflammation, immune and carcinogenesis 10
a. Keap1/Nrf2/ARE pathway 10
b. NF-B 13
c. Cross-talk between Keap1/Nrf2 and NF-B signaling 14
6. Protective function of HO-1 16
7. CSCs in tumorigenesis 17
8. PKD1 and CD34 in skin carcinogenesis 19
9. Functional activities of of catechins 20
Objectives 23
Materials and Methods 24
Reagents and antibodies 24
Cell culture 25
Animals care 25
Experimental design of in vivo study 25
Part 1A: DSS-induced colitis 26
Part 1B: AOM/DSS-induced colitis-related colon cancer 26
Part 2: Two-stage tumorigenesis in mouse skin 26
Part 3: Endotoxin-induced acute inflammation 27
Blood samples 27
Analysis of complete blood count 27
Evaluation of DSS-induced DAI 28
Identification of ACF, ALN and tumor 28
Measurement of mitotic index 28
HAT activity assay 29
PKD1 Kinase Activity Assay 29
Analysis of ROS and GSH levels and GSH/GSSG ratio 29
Nitrite Assay 30
Measurement of prostaglandin E2 (PGE2) 30
Plasmids, transfection and shRNA knockdown 30
Luciferase assay 31
Cellular uptake and intracellular concentrations 31
HPLC analysis of ECG 32
In vitro ECG pull-down assay 32
Fluorescence emission spectroscopy 33
Western blot analysis 33
Reverse transcription–polymerase chain reaction (RT-PCR) 34
Electrophoretic mobility shift assay (EMSA) 35
Immunohistochemical analysis (IHC) 35
Statistical analysis 36
Experimental design 37
Results 38
Part 1. Peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) potently suppresses dextran sulfate sodium-induced colitis and colon tumorigenesis in mice 38
Part 1. Study design 38
Part 1. Study results 39
1.1. AcEGCG improved DSS-induced body weight loss, clinical symptoms and spleen enlargement better than EGCG 39
1.2. AcEGCG treatment prevented DSS-induced colitis better than EGCG 39
1.3. AcEGCG suppresses DSS-induced inflammatory mediator production by inhibiting NF-B-activating signaling pathway 40
1.4. AcEGCG blocks DSS-induced inflammation by activating Nrf2 signaling pathway and enhancing antioxidant enzyme expression 41
1.5. AcEGCG prevents colitis-related colon tumorigenesis induced by AOM plus DDS better than EGCG 43
Part 2. Peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) potently prevents skin carcinogenesis by suppressing the PKD1-dependent signaling pathway in CD34+ skin stem cells and skin tumors 44
Part 2. Study design 44
Part 2. Study results 45
2.1. AcEGCG prevented DMBA-initiated and TPA-promoted mouse skin tumorigenesis more effectively than EGCG 45
2.2. AcEGCG inhibited DMBA/TPA-promoted tumor proliferation by reducing the mitotic index 45
2.3. AcEGCG suppressed DMBA/TPA-induced PKD1 activation and CD34 expression 46
2.4. AcEGCG blocked DMBA/TPA-induced activation of the p38, JNK1/2 and PI3K/Akt signaling pathways and downregulation of target protein expression 48
Part 3. Directly interact with Keap1 and LPS is involved in the anti-inflammatory mechanisms of (-)-epicatechin-3-gallate (ECG) in LPS-induced macrophages and endotoxemia 50
Part 3. Study design 50
Part 3. Study results 51
3.1. ECG exhibited the most potent anti-inflammatory effects among the tested catechin analogs 51
3.2. ECG abatement of LPS-induced oxidative stress is the most effective among the tested catechin analogs 51
3.3. Nrf2 knockdown aggravates LPS-induced inflammatory responses 52
3.4. ECG interferes with the cross-talk between NF-B and Nrf2/ARE signaling 54
3.5. Nrf2 signaling is required for the advancement of ECG-induced anti-inflammatory effects 55
3.6. Anti-inflammatory effects of ECG partly require activation of ERK1/2 signaling to mediate HO-1 expression 55
3.7. ECG activates Nrf2/ARE-driven HO-1 expression via directly interrupting the Keap1-Nrf2 interaction 57
3.8. ECG interacts with LPS to block LPS-stimulated inflammatory signaling 58
3.9. ECG efficiently improves LPS-induced endotoxemia in mice 59
Discussion 60
Part 1. Study discussion 60
Part 2. Study discussion 64
Part 3. Study discussion 67
Conclusion 75
Reference 77
Figures 102
Appendix 139
Publications list 156

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