Mechanistic insight into the efficacy of catechin analogs in protecting against inflammation-related diseases

論文翻譯標題: 探討兒茶素類似物在保護發炎相關疾病之?效與分子機制
  • 邱 依琇

學生論文: Doctoral Thesis


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
獎項日期2017 一月 6
監督員Ying-Jan Wang (Supervisor)