Fu Yumei, Zheng Shizhong, Lin Jianguo, Ryerse Jan, Chen Anping
Department of Pathology, School of Medicine, Saint Louis University, 1402 S. Grand Blvd., St. Louis, MO 63104, USA.
Mol Pharmacol. 2008 Feb;73(2):399-409. doi: 10.1124/mol.107.039818. Epub 2007 Nov 15.
We previously demonstrated that curcumin, a polyphenolic antioxidant purified from turmeric, up-regulated peroxisome proliferator-activated receptor (PPAR)-gamma gene expression and stimulated its signaling, leading to the inhibition of activation of hepatic stellate cells (HSC) in vitro. The current study evaluates the in vivo role of curcumin in protecting the liver against injury and fibrogenesis caused by carbon tetrachloride (CCl(4)) in rats and further explores the underlying mechanisms. We hypothesize that curcumin might protect the liver from CCl(4)-caused injury and fibrogenesis by attenuating oxidative stress, suppressing inflammation, and inhibiting activation of HSC. This report demonstrates that curcumin significantly protects the liver from injury by reducing the activities of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, and by improving the histological architecture of the liver. In addition, curcumin attenuates oxidative stress by increasing the content of hepatic glutathione, leading to the reduction in the level of lipid hydroperoxide. Curcumin dramatically suppresses inflammation by reducing levels of inflammatory cytokines, including interferon-gamma, tumor necrosis factor-alpha, and interleukin-6. Furthermore, curcumin inhibits HSC activation by elevating the level of PPARgamma and reducing the abundance of platelet-derived growth factor, transforming growth factor-beta, their receptors, and type I collagen. This study demonstrates that curcumin protects the rat liver from CCl(4)-caused injury and fibrogenesis by suppressing hepatic inflammation, attenuating hepatic oxidative stress and inhibiting HSC activation. These results confirm and extend our prior in vitro observations and provide novel insights into the mechanisms of curcumin in the protection of the liver. Our results suggest that curcumin might be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis.
我们之前证实，姜黄素这种从姜黄中提纯的多酚类抗氧化剂，可上调过氧化物酶体增殖物激活受体（PPAR）-γ基因表达并刺激其信号传导，从而在体外抑制肝星状细胞（HSC）的激活。本研究评估了姜黄素在保护大鼠肝脏免受四氯化碳（CCl₄）所致损伤和纤维化方面的体内作用，并进一步探究其潜在机制。我们推测，姜黄素可能通过减轻氧化应激、抑制炎症以及抑制HSC激活来保护肝脏免受CCl₄所致损伤和纤维化。本报告表明，姜黄素可通过降低血清天冬氨酸转氨酶、丙氨酸转氨酶和碱性磷酸酶的活性，以及改善肝脏的组织学结构，显著保护肝脏免受损伤。此外，姜黄素通过增加肝脏谷胱甘肽含量来减轻氧化应激，从而降低脂质过氧化氢水平。姜黄素通过降低包括干扰素-γ、肿瘤坏死因子-α和白细胞介素-6在内的炎症细胞因子水平，显著抑制炎症。此外，姜黄素通过提高PPARγ水平并减少血小板衍生生长因子、转化生长因子-β及其受体以及I型胶原的丰度来抑制HSC激活。本研究表明，姜黄素通过抑制肝脏炎症、减轻肝脏氧化应激和抑制HSC激活，保护大鼠肝脏免受CCl₄所致损伤和纤维化。这些结果证实并扩展了我们之前的体外观察结果，并为姜黄素保护肝脏的机制提供了新的见解。我们的结果表明，姜黄素可能是一种治疗肝纤维化的抗纤维化治疗药物。
