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標題: 利用高解析超音波影像及差異性甲基化基因晶片評估中藥對於DMN誘導大鼠肝損傷模式之療效
Assessment on the Traditional Chinese Medicine Therapeutic Effect on DMN induced Rat Liver Injury by High Frequency Ultrasound Imaging and Differential Methylation Hybridization Microarray
作者: 陳俊宇
Chen, Jiun-Yu
關鍵字: 高解析超音波影像;High Frequency Ultrasound Imaging;甲基化基因晶片;中藥;大鼠肝損傷;Differential Methylation Hybridization Microarray;Traditional Chinese Medicine;Rat Liver Injury
出版社: 生命科學系所
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慢性傷害引起肝臟纖維化(liver fibrosis)反應的原因有很多種,其中以病毒感染 (HBV或 HCV)、飲酒過量、自體免疫反應、膽管阻塞、藥物濫用以及代謝異常所引起的狀況最常見到。此等慢性傷害可能會持續發生好幾個月甚至好幾年,在肝臟纖維化發生初期是可以被治療的,然而在纖維化的末期形成的肝硬化(liver cirrhosis)就沒有辦法被治療而復原。因此,了解纖維化在初期形成的因素及肝臟嚴重病變的過程,可以做為治療或延緩纖維化發生的參考。在一般正常的肝臟主要由hepatocytes、Kupffer cells、endothellal cells、stellata cells等四種不同型態細胞所組成;對肝臟持續性傷害所產生的肝硬化,在肝臟病變的初期stellata cells會過度活化,改變細胞外基質(extracellar matrix;ECM),造成纖維組織異常增生,會使得hepatocytes上的絨毛消失與走向凋亡,以及endothellal cells細胞間隙的分解,使得肝臟失去功能。
在一般臨床研究上,大多數的病患發現肝臟功能異常都在發生肝病的末期;然而在肝臟病變與復原的過程,並不清楚整個基因體組的改變。本研究藉由dimethylnitrosamine (DMN)引發肝損傷的動物模式建立,冀能從而瞭解不同時期肝臟之基因體組上異常修飾的情況,並能藉由完整基因表現圖譜、甲基化修飾圖譜DMH (differentiation methylation hybridization),與先前所發表的研究結果做對照,來解開肝臟纖維化與肝硬化的基因調控機制,做為後續使用中藥治療或藥效評估的重要參考指標。在本試驗中,利用DMN誘發八週大SD大白鼠肝臟產生纖維化,分別以用膈下逐瘀湯中藥複方與一貫煎中藥複方來治療DMN產生的肝纖維化,試驗結果證明未接受治療的肝纖維化實驗組,其血液生化值GOT (glutamate oxaloacetate transaminase)、GPT (glutamic pyruvic transaminase),分別均較正常對照組有顯著的升高(P<0.01);在膈下逐瘀湯與一貫煎處理組皆呈現顯著的下降趨勢(P<0.01)。經餵食一貫煎處理組在纖維化相關的基因表現方面,collagen type I、TIMP-1 (P<0.05)與alpha-SMA (P<0.001)有顯著的回復,且其組織切片顯示有較佳的修復效果;在餵食膈下逐瘀湯處理組在纖維化基因collagen type I (P<0.05)與alpha-SMA (P<0.01)明顯被恢復的情形,在hydroxyproline的表現量也有明顯減少,在人類肝臟星狀細胞株(LX-2)的實驗部分,膈下逐瘀湯處理會有dose-depend與time-depend的抑制生長的效果,經由ER-resident促進calpain 1的表現,活化下游caspase-12的表現,促進LX-2 cell在處理72小時走向apoptosis,能有抑制肝臟星狀細胞的活性減少纖維化的發生而達到保護肝臟的效果。
在肝癌形成的過程中,鑑於肝臟受到不同刺激造成慢性發炎反應,經由長時間的刺激造成肝臟基因的改變,目前已知有RASSF1A、p16與GSTP1…等腫瘤抑制基因甲基化異常與肝癌的形成有相關連。在本試驗中擬藉由Roche NimbleGen Rat DNA Methylation Promoter arrays的晶片分析,從而瞭解肝纖維化與肝硬化之基因變化與上遺傳基因修飾之機制參與肝臟病變的過程。本試驗分別使用肝纖維化、肝硬化與膈下逐瘀湯等...三種不同處理組,進行分析肝纖維組織增生與甲基化變異。經由三個不同處理組別交叉分析,結果發現多達147個基因,係在肝纖維化與肝硬化者,分別有較高的甲基化程度的表現。此外將這147個基因與先前研究之cDNA arraysy進行比較,結果發現其中39個基因有相關連者。進一步藉由mRNA的表現與promoter之CpG island等分析策略,分別選擇DnaJB5與Igr-1r,完成分析promoter區甲基化的比例;企圖瞭解甲基化參與早期調控纖維化形成之基因與肝硬化趨向肝癌在上遺傳修飾參與的機轉,作為診斷纖維化的生物標記。

Chronic liver disease generally progresses slowly from hepatitis to cirrhosis and is induced by many factors, including chronic hepatitis B or C viruses infections, alcoholic abuse, autoimmune, metabolic syndromes and drug abuse. Because of chronic damage to the liver, scar tissue slowly replaces normal functioning liver tissue, and progressively diminishing blood flow through the liver. In addition, protein production and other substances are produced by stellate cells multiply and surrounded by accumulation fibrillar matrix and contribute to loss hepatocyte microvilli and closure of endothelial fenestrae. Hepatic stellate cells (HSCs) play a major role in various types of liver fibrosis through initial myofibroblast transformation and are responsible for the excess production of extracellular matrix (ECM) components.
In general, liver biopsy is currently considered the definitive diagnostic modality for monitoring the severity of hepatic fibrosis, but the inadequate liver tissue may lead to false negative results. However, a non-invasive modality in small-animal imaging has low risk for excessive bleeding of biopsy. The high-frequency ultrasound (HFU) will be a useful tool for obtaining the images of biological tissues. Each scores of the liver surface, parenchymalechotexture, vasculature and spleen size were evaluated and then compared with the histological examination. An ultrasound evaluation of the liver fibrosis stage based on the scoring system using both high frequency probes was found to be a reliable and effective alternative to the histological staging in liver injury and herb therapy effect.
The present investigation was designed to identify assess the involvement of liver injury pathway in dimethylnitrosamine (DMN)-induced liver fibrosis in rats and increased production of ECM components and enhanced proliferation. Following DMN-treatment, body and liver weights were significantly decreased concurrent with increasing severity of liver damage assessed by bridging fibrosis, a histopathologic assessment and characteristic of human liver disease. In our study, the therapeutic effect of Chinese herb, Yi Guan Jian (YGJ), on hepatic fibrosis induced by DMN-treatment, remarkably prevented weight loss in the body and liver from DMN treatment and inhibited the elevation of serum GOT, GPT (P<0.01). Observations on the oral administration of YGJ would have significantly reduced the expression of collagen type I and alpha-SMA on hepatic fibrosis induced by DMN. In another study, the therapeutic effects of Chinese herb, Gexiazhuyu decoction (GXZYD), on hepatic fibrosis induced by DMN were measured in rat model, remarkably prevented weight loss in the body and liver from DMN treatment and inhibited the elevation of serum GOT, GPT (P<0.01). We observed oral administration of GXZYD significantly reduced the expression of collagen type I, transforming growth factor beta 1 (TGF-beta 1), and alpha-smooth muscle actin (alpha-SMA) on hepatic fibrosis induced by DMN, and GXZYD inhibited the activation of Human HSC cell line (LX-2). In contrast, the calpain 1 was activated at 48 hr after the decoction treatment and subsequently cleaved and activated ER-resident procaspase-12 and led to activation of the caspase-3 and downregulation of Bcl-2. Our data suggest that GXZYD may be useful in preventing the development of hepatic fibrosis in vivo and in vitro.
Aberrant DNA methylation can change the gene expression and chromatin organization over many cell generations, and plays an important epigenetic alteration in cancerogenesis. Various environmental agents and different way of life have to be risk factors for hepatocellular carcinoma (HCC) and are suspected to promote epigenetic change. The recent studies have exploited conceptual in epigenetic events with HCC tumors and non-tumor precancerous (cirrhosis) lesions. However, the molecular processes underlying the methylation phenotype, the contribution of hepatic fibrosis and cirrhosis are poorly understood. Liver in fibrosis, cirrhosis and GXZYD treated stages reveled different methylation patents appeared on 147 genes of the injured livers (fibrosis and cirrhosis). Our results showed that the promoter methylation changes were in 148 and among them 39 genes were in associations with the RNA expression changes when compared to cDNA array data as previous study. The genomic DNA was extracted from each injured liver and analyzed for the mentylation changes in the promoter region of DnaJB5 and Igf-1r genes by bisulfite sequencing. However, this study is first report on the global methylation profiling of different stage in liver injury. Here, the genome-wide methylation profile of the hepatic cirrhosis animal model and epigenetic changes studies after herb medicine therapy was aided in understanding the process of fibrogenesis, and a series of novel methylated genes found in the study have the potential to be biomarkers for the diagnosis.
其他識別: U0005-1908201110594000
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