白皮杉醇對於四氯化碳誘導小鼠肝纖維化的護肝功效

Abstract

肝臟疾病為造成全球健康負荷的主要原因之一。肝纖維化則是肝受損時，肝臟中一種可逆的組織修復過程，也是預防及治療的介入重點。而多酚化合物為一群具有許多健康效益的植物化學物質，存在於葡萄等食物中的白皮杉醇 (Piceatannol) 為其中一種，在結構上比白藜蘆醇 (Resveratrol) 多一個羥基，且過去文獻指出皆具有抗發炎、抗氧化、抗癌等功效。因此，本研究欲探討並比較結構類似物白皮杉醇與白藜蘆醇在四氯化碳 (Carbon tetrachloride, CCl4) 誘導 ICR 小鼠肝纖維化模式中，其預防及治療功效與分子機制。實驗隨機將雄性 ICR 小鼠分為控制組 (Corn oil)、正控制組 (CCl4) 及天然物水飛薊素 (Silymarin)、白藜蘆醇、白皮杉醇與四氯化碳共同處理組。實驗結果顯示治療模式中的小鼠因後四周停止四氯化碳注射而引發肝臟自發性的修復作用，造成肝炎而非肝纖維化，投予白皮杉醇及白藜蘆醇後皆能顯著降低血清 AST (Aspartate aminotransferase) 含量而減緩四氯化碳誘導的肝發炎反應。而在預防模式中，白皮杉醇比白藜蘆醇更能顯著降低肝發炎指標 AST 的含量，及減輕肝細胞壞死、空泡化與免疫細胞浸潤等現象，並提升抗氧化酵素過氧化氫酶活性及穀胱甘肽含量，減輕氧化壓力，而預防肝損傷。此外，白皮杉醇亦比白藜蘆醇更能有效抑制 TGF-β (Transforming growth factor beta)/Smad2/3 訊息傳導路徑的活化、降低 TIMP-1 (Tissue inhibitor of metalloproteinase) 蛋白表現、減少 α-SMA (alpha-smooth muscle actin) 及 Collagen I 的表達，而阻斷細胞外基質的沉積，發揮抗纖維化的能力。綜合上述結果，本研究建議白皮杉醇比白藜蘆醇更具逆轉或延緩四氯化碳誘導小鼠肝纖維化發展的潛力，預期白皮杉醇未來可開發為護肝之功能性食品。

Liver disease is one of the major causes of global health burden. Liver fibrosis is a reversible wound-healing response that occurs following liver injury. Polyphenols are the biggest group of phytochemicals, and have been linked to many health benefits. Piceatannol, one of polyphenols found in grapes and other food products, is a hydroxylated analogue of resveratrol and has been reported that has antioxidant, anti-inflammatory and anti-cancer properties. In this study, we investigated and compared with the protective effects of structural analogs (piceatannol and resveratrol) on carbon tetrachloride (CCl4)-induced liver fibrosis in preventive and therapeutic model. Male ICR mice were randomly divided into Control (vehicle + corn oil), Positive (vehicle + CCl4), SIL (silymarin + CCl4), R (resveratrol + CCl4), P 30 (30 mg/kg piceatannol + CCl4) and P 60 (60 mg/kg piceatannol + CCl4) groups in preventive and therapeutic model, respectively. In therapeutic model, the results showed that positive group may fail to induce liver fibrosis but cause hepatitis because undergo spontaneous resolution following by withdrawal of CCl4 after four weeks of intoxication and piceatannol and resveratrol supplement significantly reduced serum AST (aspartate aminotransferase). In preventive model, the results showed that piceatannol compared with resveratrol can significantly ameliorate the CCl4-induced histopathological hepatic lesions include leukocytes infiltration, hepatocyte ballooning degeneration and decrease collagen deposition, lower the serum levels of AST, increase catalase activity and glutathione content, as well as a decrease of collagen I and α-SMA (alpha-smooth muscle actin) protein level via inhibiting TGF-β (Transforming growth factor beta)/Smad2/3 signaling pathway and down-regulating TIMP-1 (Tissue inhibitor of metalloproteinase) protein expression. Therefore, these findings suggest that piceatannol compared with resveratrol exhibits hepatoprotective effects on CCl4-induced liver fibrosis in mice, and have potent to develop to functional foods in the future.