臺灣博碩士論文加值系統

薑黃素 (curcumin; CUR) 的主要代謝物，四氫薑黃素 (tetrahydrocurcumin; THC)，具有良好的生物利用性與高抗氧化活性，能有效的抑制 dimethylnitrosamine (DMN) 所誘導的肝纖維化。因此，本研究以四氯化碳 (carbon tetrachloride; CCl4) 誘導大鼠肝纖維化模式，評估 THC 抑制 CCl4 所誘導的肝纖維化之活性與相關分子機制。實驗數據發現，大鼠合併處理 THC 10 與 50 mg/kg的劑量能顯著改善由 CCl4 誘導而提升的血清 ALT (alanine aminotransferase) 及 AST (aspartate aminotransferase) 含量。肝臟組織切片分析也發現大鼠合併處理 THC 10 與 50 mg/kg 均有顯著改善 CCl4 所引起的肝臟結構變性 (hepatic degeneration)，包括發炎細胞浸潤 (inflammatory cell infiltration)、脂肪空泡 (ballooning degeneration)、橋狀纖維形成 (bridging fibrosis) 、細胞凋亡 (apoptosis) 等現象。本篇研究也證實大鼠以 CCl4 誘導並合併處理 THC 10 與 50 mg/kg 能夠透過抑制 TGF-β/Smad pathway 及 TAK1/JNK/p38 pathway 進而減少肝臟中 α-smooth muscle actin (α-SMA) 及 collagen I 基因與蛋白質的表現。此外，以 CCl4 誘導並合併處理 THC 10 與 50 mg/kg 能有效抑制 CCl4 引起肝臟細胞產生 apoptosis，包括降低 casepase-3 活性和減少 PARP 降解以及減少 LC3B 的蛋白質表現。本研究進一步將肝臟組織進行雙染試驗結果證實，以 CCl4 誘導並合併處理 THC 10 與 50 mg/kg 能降低肝臟中靜止態的HSCs 透過 autophagy 消耗自體儲存的維生素A而活化並加速肝纖維化病程。 在細胞實驗發現 THC透過抑制 TGF-β/Smad pathway降低 HSC-T6 中由 TGF-β1 誘導而增加 α-SMA 的蛋白質表現。由研究實驗結果證實 THC 確實能有效的預防 CCl4 引起的肝毒性與肝纖維化形成，其預防效果優於 curcumin。此外，THC 也能使活化的 HSCs 回復為不活化態，在未來能進一步探討 THC 治療肝纖維化的功效。綜合以上結果證實 THC 相較於 curcumin 具有開發為保健食品之未來性且更具有成為抗肝纖維化的潛力藥物。

Tetrahydrocurcuin (THC), a major metabolite of curcumin, with high bioavailability and strong antioxidant property. According to a previous study, THC exhibited in vivo hepatoprotective and antifibrotic effects against liver injury induced by dimethylnitrosamine (DMN). In the present study, the protective effect and molecular mechanism of THC was investigated on carbontetrachloride (CCl4)-induced liver fibrosis in Sprague-Dawley (SD) rats. Our data showed that the administration of THC at doses of 10 and 50 mg/kg significantly reduced the elevated serum levels of alanine aminotransferase (ALT), aspartate amino-transferase (AST) in CCl4-treated rats. The histopathological examination showed that the administration of THC at doses of 10 and 50 mg/kg decreasing in regions of hepatic degeneration, inflammatory cell infiltration, hepatocyte ballooning, bridging firbrosis and apoptosis in CCl4-treated rats. THC also decreasd the protein and mRNA expression of -smooth muscle actin (α-SMA) and collagen I in CCl4-treated rats via blocked TGF-β/Smad pathway and TAK1/JNK/p38 pathway. In addition, the administration of THC at doses of 10 and 50 mg/kg significantly reduced apoptosis of hepatic cells, decreasd the protein expression of activated casepase-3 and cleaved of PARP in CCl4-treated rats. Furthermore, THC reduced the marker (LC3) of autophagy and α-SMA protein expression in CCl4-treated rats by double staining immune-histochemistry. TGF-β1-activated HSC-T6 cells were used to investigate the in vitro effects of THC. THC blocked phosphorylation of Smad2 and α-SMA protein expression in TGF-β1 activated HSC-T6. These results suggested that THC attenuated CCl4-induced liver fibrosis which may reversal of activated HSC-T6 cells to a inactivated-like phenotype. The results of the study reveal that THC shows more pronounced protective effect than curcumin against CCl4-induced liver fibrosis, and it also has developed into a health food in future.

目錄
圖表目錄
縮寫全名對照表
第壹章 研究背景與目的
第貳章 文獻回顧
2.1 薑黃中的活性成分－curcumin
2.2 Curcumin 的藥理活性與吸收
2.3 Curcumin 主要代謝物－THC
2.4 肝纖維化之病理機制
2.5 纖維化關鍵因素－HSCs 的活化
2.6 抗肝纖維化的標靶分子－TGF-β 信號路徑
2.7 抑制肝纖維化的策略
2.8 誘導肝纖維化的四氯化碳 (carbon tetrachloride; CCl4) 模式
第參章 實驗架構
第肆章 材料與方法
4.1 實驗材料
4.2 實驗方法
第伍章 結果與討論
5.1.1 CCl4 誘發慢性肝損傷大鼠之體重變化
5.1.2 CCl4 誘發慢性肝損傷大鼠之臟器差異與變化
5.1.3 血清生化檢測
5.1.4 THC 對 CCl4 誘導肝組織病變之改善情形
5.1.5 以 sirius red 染色法觀察 THC 減少在肝臟內膠原纖維沉積的情況
5.1.6 THC 抑制 CCl4 誘導大鼠肝臟中 HSCs 的活化
5.1.7 THC 藉由調節 TGF-β/Smad signaling pathway 降低 CCl4 誘導肝纖維化分子表現
5.1.8 THC 抑制 CCl4 誘導肝纖維化基因表現
5.1.9 THC 調節 CCl4 誘導 TAK1 pathway
5.1.10 THC 對 CCl4 所誘導的肝臟 apoptosis 與 autophagy 之影響
5.2.1 THC 對 HSC-T6 細胞株之細胞毒性影響
5.2.2 THC 回復以 TGF-β1 所誘導活化 HSC-T6 之影響
第陸章 結論
第柒章 參考文獻
第捌章 實驗圖表
8.1 動物實驗數據
8.2 細胞實驗數據

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