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題名 | 以基因體研究平臺為基礎進行防治肝病相關中藥之研究(2-1)=Research and Development of Chinese Medicinal Herbs for Anti-Liver Diseases by the Genomic- Based Platform (2-1) |
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作者姓名(中文) | 侯庭鏞; | 書刊名 | 中醫藥年報 |
卷期 | 29:8 2011.09[民100.09] |
頁次 | 頁193-231 |
專輯 | 中醫藥基因體相關研究 |
分類號 | 414.33 |
關鍵詞 | 肝病; 中草藥; DNA微陣列; Liver diseases; Chinese medicinal herbs; DNA microarray; |
語文 | 中文(Chinese) |
中文摘要 | 研究目的:中醫利用方劑及單味藥治療肝病已有長久的經驗,例如小柴胡湯、龍膽瀉肝湯、三黃瀉心湯等,都是常見的治肝病方劑。雖然這些中草藥療法已有長久的臨床使用經驗,不過許多中草藥的作用機制並不清楚,而且中草藥於新藥開發的應用仍有很大的發展空間。 研究方法:本計畫主要利用DNA 微陣列為工具,分析中草藥對細胞基因的生物活性反應,以建立一套完整的中藥生物活性基因圖譜資料庫,並將資料庫應用於中草藥之作用機轉、傳統中醫藥之現代藥性、新藥的開發及臨床前藥物安全性之分析。 結果與結論:在中草藥之新藥開發的應用上,我們已將中藥組成份以TC0 及TC50 的劑量處理肝細胞,再進行DNA 微陣列分析。藉助Gene Ontology 的程式運算,我們發現許多中藥組成份所影響的基因,大多坐落於細胞週期及細胞凋亡等兩種群組,進一步利用k-means clustering 進行基因波動圖譜的分群,發現隨著中藥組成份劑量的上升,受activator protein 1 調節的基因,會呈現表現下降的趨勢。這些結果顯示,某些中藥組成份確實具有相類似的基因圖譜,而藉助與臨床上治療肝病常用之西藥的基因表現圖譜進行比對,將有助於中藥新藥的開發。在藥物安全性的分析方面,由我們分析的天然化合物中,發現某些蒽醌類化合物會降低phase II藥物代謝相關基因(例如:UDP glycosyltransferase…等)的表現,代表這類化合物可能會減緩藥物的排泄,增加藥物於體內存留的時間。在中藥方劑及單味藥的現代藥性方面,我們分析三黃瀉心湯及其單味藥的基因表現圖譜,發現這些藥物主要藉助p53, p53 activated 及DNA damage 等訊息傳導路徑,展現很獨特的抗細胞增殖模式,而利用network analysis,發現這些藥物影響的基因都與核心分子p53有關,進一步利用hierarchical clustering 分析,發現三黃瀉心湯之組成份—黃連所影響的基因波動圖譜非常類似於三黃瀉心湯所影響的基因波動圖譜,代表傳統醫學認為黃連為三黃瀉心湯之君藥的合理性,而這個結果也是首次利用現代生物技術,揭露中藥方劑及單味藥的相關性。 |
英文摘要 | Aim: Although several herbal formulae and herbal components have been used in patients with liver diseases, their applications in new drug development remain to be discovered. Method: We apply microarray technology to analyze and explain the modern biological activities of medicinal herbs. The gene expression databases established in this project can further provide the basis for the herb-activity relationship, modern definition of Traditional Chinese Medicine (TCM), new drug development, and preclinical drug safety analysis. Results and Discussion: Microarray data have been used for the development of new drugs. For examples, we treated human hepatocytes with herbal compounds at the dosages of TC0 and TC50, and analyzed microarray data by Cluster and Gene Ontology Tree Machine. Our results indicated that most herbal compounds affected clusters of genes involved in cell cycle and apoptosis. Genes down-regulated by herbal compounds were grouped into three gene ontology categories, including regulation of cellular process, cell cycle, and death. Furthermore, k-means clustering analysis showed that a cluster of activator protein 1-regulated genes was down-regulated by herbal compounds. Microarray data have also been used for the evaluation of drug safety. For examples, we found that the expressions of genes (UDP glycosyltransferases) involved in phase II drug metabolism were reduced during anthraquinone compounds treatments. These findings suggested that anthraquinone compounds may slow down the excretion of drugs, leading to increase the half-life of drugs. Furthermore, microarray data have been used for the modern definition of Traditional Chinese Medicine. For examples, San-Huang-Xie-Xin-Tang (SHXXT) has been used for the treatment of liver diseases for years. Gene set enrichment analysis indicated that SHXXT and its herbal components displayed a unique anti-proliferation pattern via p53, p53 activated, and DNA damage signaling pathways in HepG2 cells. Network analysis showed that most SHXXT-affected genes were regulated by a central molecular, p53. Additionally, hierarchical clustering analysis showed that Rhizoma Coptis shared a similar gene expression profile with SHXXT. These findings may explain why Rhizoma Coptis is the principal herb that exerts the major and leading effects in the herbal combination SHXXT in TCM. Moreover, this is the first time to reveal the relationship between formulae and their herbal components in TCM by microarray analysis and bioinformatics tools. |
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