Abdulaziz Bardi Daleya, Halabi Mohammed Farouq, Hassandarvish Pouya, Rouhollahi Elham, Paydar Mohammadjavad, Moghadamtousi Soheil Zorofchian, Al-Wajeeh Nahla Saeed, Ablat Abdulwali, Abdullah Nor Azizan, Abdulla Mahmood Ameen
Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
PLoS One. 2014 Oct 3;9(10):e109424. doi: 10.1371/journal.pone.0109424. eCollection 2014.
This study investigated the hepatoprotective effects of ethanolic Andrographis paniculata leaf extract (ELAP) on thioacetamide-induced hepatotoxicity in rats. An acute toxicity study proved that ELAP is not toxic in rats. To examine the effects of ELAP in vivo, male Sprague Dawley rats were given intraperitoneal injections of vehicle 10% Tween-20, 5 mL/kg (normal control) or 200 mg/kg TAA thioacetamide (to induce liver cirrhosis) three times per week. Three additional groups were treated with thioacetamide plus daily oral silymarin (50 mg/kg) or ELAP (250 or 500 mg/kg). Liver injury was assessed using biochemical tests, macroscopic and microscopic tissue analysis, histopathology, and immunohistochemistry. In addition, HepG2 and WRL-68 cells were treated in vitro with ELAP fractions to test cytotoxicity. Rats treated with ELAP exhibited significantly lower liver/body weight ratios and smoother, more normal liver surfaces compared with the cirrhosis group. Histopathology using Hematoxylin and Eosin along with Masson's Trichrome stain showed minimal disruption of hepatic cellular structure, minor fibrotic septa, a low degree of lymphocyte infiltration, and minimal collagen deposition after ELAP treatment. Immunohistochemistry indicated that ELAP induced down regulation of proliferating cell nuclear antigen. Also, hepatic antioxidant enzymes and oxidative stress parameters in ELAP-treated rats were comparable to silymarin-treated rats. ELAP administration reduced levels of altered serum liver biomarkers. ELAP fractions were non-cytotoxic to WRL-68 cells, but possessed anti-proliferative activity on HepG2 cells, which was confirmed by a significant elevation of lactate dehydrogenase, reactive oxygen species, cell membrane permeability, cytochrome c, and caspase-8,-9, and, -3/7 activity in HepG2 cells. A reduction of mitochondrial membrane potential was also detected in ELAP-treated HepG2 cells. The hepatoprotective effect of 500 mg/kg of ELAP is proposed to result from the reduction of thioacetamide-induced toxicity, normalizing reactive oxygen species levels, inhibiting cellular proliferation, and inducing apoptosis in HepG2 cells.
本研究调查了穿心莲叶乙醇提取物（ELAP）对硫代乙酰胺诱导的大鼠肝毒性的保肝作用。急性毒性研究证明ELAP对大鼠无毒。为了研究ELAP在体内的作用，雄性Sprague Dawley大鼠每周腹腔注射3次溶剂10%吐温-20（5 mL/kg，正常对照组）或200 mg/kg硫代乙酰胺（TAA，诱导肝硬化）。另外三组用硫代乙酰胺加每日口服水飞蓟宾（50 mg/kg）或ELAP（250或500 mg/kg）进行治疗。使用生化检测、大体和微观组织分析、组织病理学和免疫组织化学评估肝损伤。此外，用ELAP组分在体外处理HepG2和WRL-68细胞以测试细胞毒性。与肝硬化组相比，用ELAP治疗的大鼠肝/体重比显著降低，肝表面更光滑、更正常。苏木精和伊红染色以及Masson三色染色的组织病理学显示，ELAP治疗后肝细胞结构破坏最小、纤维间隔轻微、淋巴细胞浸润程度低且胶原沉积最少。免疫组织化学表明ELAP诱导增殖细胞核抗原下调。此外，ELAP治疗的大鼠肝脏抗氧化酶和氧化应激参数与水飞蓟宾治疗的大鼠相当。ELAP给药降低了血清肝生物标志物改变的水平。ELAP组分对WRL-68细胞无细胞毒性，但对HepG2细胞具有抗增殖活性，这通过HepG2细胞中乳酸脱氢酶、活性氧、细胞膜通透性、细胞色素c以及半胱天冬酶-8、-9和-3/7活性的显著升高得到证实。在ELAP处理的HepG2细胞中也检测到线粒体膜电位降低。500 mg/kg的ELAP的保肝作用被认为是由于降低了硫代乙酰胺诱导的毒性、使活性氧水平正常化、抑制细胞增殖以及诱导HepG2细胞凋亡。
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