Hsu Yi-Chao, Chiu Yung-Tsung, Lee Chang-Yin, Wu Ching-Fen, Huang Yi-Tsau
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, and Department of Medical Research and Education, Taichung Veterans General Hospital, Taiwan.
Can J Physiol Pharmacol. 2006 Oct;84(10):967-76. doi: 10.1139/y06-050.
Tetrandrine (Tet) (C38H42O8N2; molecular weight, 622), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to elicit anti-inflammatory and anti-fibrotic effects in pulmonary diseases, but the mechanism of action has yet to be investigated. In this study, we tested whether Tet exerts anti-fibrotic effects on rat hepatic fibrosis through anti-NFkappaB pathways. After bile-duct ligation, rats were given Tet (1 or 5 mg/kg) or silymarin (50 mg/kg, as a positive control) by gavage twice daily for 3 weeks. Liver sections were taken for Sirius red quantitative scoring, immunofluorescence double staining of alpha-smooth muscle actin (alpha-SMA) and NFkappaB, and for quantitative determinations of the mRNA expression levels of TGF-beta1, alpha-SMA, collagen 1alpha2, inducible nitric oxide synthase (iNOS), intercellular adhesion molecule 1 (ICAM-1), metallothionein, vascular endothelial growth factor (VEGF), and VEGF type II receptor (VEGFR2) genes. The results showed that both Tet and silymarin treatment significantly reduced the fibrosis scores and hepatic collagen content of BDL rats, compared with no treatment. Both Tet and silymarin treatments decreased the number of alpha-SMA- and NFkappaB-positive cells in fibrotic livers. Moreover, Tet and silymarin treatments attenuated the mRNA expression levels of TGF-beta1,alpha-SMA, collagen 1alpha2, iNOS, ICAM-1, VEGF, and VEGFR2 genes, and induced the mRNA expression of the metallothionein gene. This study suggests that the anti-fibrotic effects of Tet were related to the reduction of fibrosis-related gene transcription, the attenuation of NFkappaB-activated pathways, and the induction of metallothionein gene transcription in the livers of BDL rats.
汉防己甲素（Tet）（C38H42O8N2；分子量622）是从中药粉防己中分离出的一种生物碱，已被证明在肺部疾病中具有抗炎和抗纤维化作用，但其作用机制尚待研究。在本研究中，我们测试了汉防己甲素是否通过抗核因子κB（NFκB）途径对大鼠肝纤维化发挥抗纤维化作用。胆管结扎术后，大鼠每天经口灌胃给予汉防己甲素（1或5mg/kg）或水飞蓟宾（50mg/kg，作为阳性对照），持续3周，每日2次。取肝脏切片进行天狼星红定量评分、α平滑肌肌动蛋白（α-SMA）和NFκB免疫荧光双重染色，并对转化生长因子β1（TGF-β1）、α-SMA、Ⅰ型胶原α2（collagen 1α2）、诱导型一氧化氮合酶（iNOS）、细胞间黏附分子1（ICAM-1）、金属硫蛋白、血管内皮生长因子（VEGF）和VEGFⅡ型受体（VEGFR2）基因的mRNA表达水平进行定量测定。结果显示，与未治疗组相比，汉防己甲素和水飞蓟宾治疗均显著降低了胆管结扎（BDL）大鼠的纤维化评分和肝脏胶原含量。汉防己甲素和水飞蓟宾治疗均减少了纤维化肝脏中α-SMA和NFκB阳性细胞的数量。此外，汉防己甲素和水飞蓟宾治疗减弱了TGF-β1、α-SMA、collagen 1α2、iNOS、ICAM-1、VEGF和VEGFR2基因的mRNA表达水平，并诱导了金属硫蛋白基因的mRNA表达。本研究表明，汉防己甲素的抗纤维化作用与BDL大鼠肝脏中纤维化相关基因转录的减少、NFκB激活途径的减弱以及金属硫蛋白基因转录的诱导有关。
