Abstract

The usage of the chemotherapeutic agent methotrexate (MTX) was associated with hepatotoxicity that minimized its clinical use. The Ginkgo biloba extract (GBE) was used before to alleviate the MTX-induced liver injury through its antioxidant activity. This work was carried out to elucidate other molecular hepatoprotective mechanisms of GBE via examining the IL-6/STAT3 pathway in addition to the miRNA-21 expression in hepatic tissue. Sprague Dawley rats were allocated into four groups: normal control (NC); Ginkgo biloba extract control (GBEC); methotrexate (MTX); and Ginkgo biloba extract and methotrexate (GBE + MTX) group. GBE was administered orally 60 mg/kg/day for 10 days while MTX was intraperitoneally injected with 20 mg/kg on day 5. After the experiment, the serum was separated for liver enzyme determination while liver tissues were collected for biochemical and histopathological examinations. MTX induced marked elevation in the liver enzymes, hepatic IL-6, and HGF mRNA expressions, phospho-STAT3/STAT3 ratio, and miRNA-21 hepatic expression when compared with the NC group. Liver injury was observed histopathologically after MTX. The GBE administration reversed these biochemical alterations and improved liver histopathology. The hepatoprotective mechanism of GBE against MTX-induced hepatotoxicity via the modulation of the IL-6/STAT3 signaling pathway and the downregulation of the miRNA-21 hepatic expression was reported for the first time.

摘要

化疗剂甲氨蝶呤 (MTX) 的使用与肝毒性相关，从而最大限度地减少了其临床使用。银杏叶提取物 (GBE) 之前被用于通过其抗氧化活性减轻 MTX 诱导的肝损伤。除了肝组织中 miRNA-21 的表达外，这项工作旨在通过检查 IL-6/STAT3 通路来阐明 GBE 的其他分子肝保护机制。Sprague Dawley 大鼠被分为四组：正常对照组（NC）；银杏叶提取物对照（GBEC）；甲氨蝶呤（MTX）；和银杏提取物和甲氨蝶呤（GBE + MTX）组。GBE 60 mg/kg/d 口服给药10 d，MTX 20 mg/kg 于第5 天腹腔注射。实验结束后，分离血清进行肝酶测定，收集肝组织进行生化和组织病理学检查。与 NC 组相比，MTX 诱导肝酶、肝 IL-6 和 HGF mRNA 表达、磷酸化 STAT3/STAT3 比值和 miRNA-21 肝表达显着升高。MTX后组织病理学观察肝损伤。GBE 管理逆转了这些生化变化并改善了肝脏组织病理学。