教育演講3:轉譯醫學的現況與展望

程 序 表

E3-1
石蓮花藥物開發
徐士蘭
台中榮民總醫院醫研部

  肝臟纖維化病症是台灣慢性肝病中常見且具潛在致命的問題,其影響超過4%以上的人口。慢性肝炎轉變為肝硬化的發生十分普遍,但目前仍缺乏有效治療肝纖維化的方法。因此,發展有效藥物用於紓解及治療肝纖維化,以及找尋肝纖維化之診斷分子為一重要的研究工作。草本植物藥的使用在中國已有千百年的歷史,且目前在西方國家的運用也呈現增加的趨勢,利用草本植物藥替代西藥治療多種疾病,如炎症性疾病和慢性肝病(包括肝炎和纖維化)。本研究室在探討保肝作用的治療藥物過程中,發現一種台灣常用的草藥-石蓮花,呈現最佳的預防及治療肝纖維化的效果。在肝損傷之大鼠實驗中,口服石蓮花萃取物,可明顯緩解毒化物誘導之肝損傷、發炎及纖維化。且服用石蓮花之疾病鼠,其血液中之丙胺酸轉移?、天門冬胺酸轉移?、膽紅素、凝血?原活性、膠原蛋白和死亡率皆顯著下降。細胞學試驗得知,石蓮花可抑制大鼠肝星狀細胞增生、降低第一型膠原蛋白及α-平滑肌動蛋白的表現,並且可促使活化態的大鼠肝星狀細胞凋亡。此外,石蓮花透過降低一氧化氮、腫瘤壞死因子-α及細胞介白素-6的濃度和增加細胞激素-10的表現,而抑制了內毒素所引起之大鼠庫弗氏細胞的活化。總結,疾病動物試驗之研究結果,顯示使用石蓮花可以降低毒化物誘導之肝損傷和纖維化,而細胞試驗結果,得知其可抑制肝星狀細胞及庫弗氏細胞活化。因此,石蓮花可望用於肝發炎及肝纖維化的補充或替代之治療藥物。而我們也利用微陣列分析,確認有44種與細胞壞死或炎症相關和62種纖維化相關的基因可受到石蓮花處理的調節,這些實驗數據,除可深入了解肝損傷之分子機轉,並且提供診斷標的和治療靶點之方向。我們也純化鑑定出石蓮花中具有抗慢性肝病變之活性化合物,為縮合單寧家族的分子。
  Progression of hepatic fibrosis is a common and potentially lethal problem in chronic liver disease in Taiwan, affecting more than 4% of the population. Incidence of cirrhosis is growing as a result of the widespread occurrence of chronic hepatitis, as well as the evident lack of an established therapy for hepatic fibrosis. The quest for the identification of an effective drug treatment to improve the outcome of patients with liver fibrosis and to develop molecular markers for liver fibrosis diagnosis is an important task. Herbal medicines have been used in Chinese population for thousands of years and there has been a growing trend in Western countries to use as alternative medicine to treat a wide range of diseases, such as inflammatory diseases and chronic liver diseases (including hepatitis and fibrosis).? In the course of search for key therapeutic agents for hepatoprotective effect, a traditional Chinese medicine, Graptopetalum paraguayense, begins to emerge as the most potent one. Oral administration of Graptopetalum paraguayense extract significantly alleviated toxin-induced liver damage, inflammation and fibrosis. High levels of alanine transaminase, aspartate transaminase, bilirubin, prothrombin activity, collagen, and mortality rates also decreased in therapeutic rats compared with those of the liver-damaged rats. In the in vitro study, Graptopetalum paraguayense was found to inhibit proliferation, collagen I and alpha smooth muscle actin expression in primary cultured rat hepatic stellate cells. Furthermore, Graptopetalum paraguayense induced apoptotic cell death in activated rat hepatic stellate cells. Graptopetalum paraguayense also suppressed lipopolysaccharide-stimulated rat Kupffer cell activation by decreasing nitric oxide, tumor necrosis factor- and interleukin-6 production, and increasing interleukin-10 expression. Our observations show that the administration of Graptopetalum paraguayense attenuated toxin-induced hepatic damage and fibrosis in vivo and inhibited hepatic stellate cell and Kupffer cell activation in vitro, suggesting that Graptopetalum paraguayense might be a promising complementary or alternative therapeutic agent for liver inflammation and fibrosis. Using microarray analysis, we identified 44 necroinflammation-related and 62 fibrosis-related genes which provides useful insight into the molecular mechanisms underlying liver damage and provides potential candidates for the rational development of diagnostic markers and therapeutic targets. The active compounds with anti-chronic liver diseases have been identified from Graptopetalum paraguayense which belong to the condensed tannin family molecules.