Protective effects of n-Butanol extract and iridoid glycosides of Veronica ciliata Fisch. Against ANIT-induced cholestatic liver injury in mice
Protective effects of n-Butanol extract and iridoid glycosides of Veronica ciliata Fisch. Against ANIT-induced cholestatic liver injury in mice
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DOI：
10.1016/j.jep.2020.113432
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发表时间：
2021-02-10
影响因子：
5.4
通讯作者：
Tang, Lin
中科院分区：
文献类型：
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作者：
Hua, Wan;Zhang, Shiyan;Tang, Lin
民族药理学相关性：维罗妮卡。环烯醚萜苷是纤毛霉的主要活性成分，具有多种生物活性。研究目的：探讨纤毛藤正丁醇提取物（BE）和环烯醚萜苷（IG）对α -萘基异硫氰酸酯（ANIT）诱导的小鼠肝毒性和胆汁淤积的保护作用及其可能机制。材料与方法：小鼠按不同剂量灌胃BE、IG或阳性对照熊去氧胆酸（UCDA），每天1次，连续14 d，第12天给予ANIT致肝损伤。测定血清肝损伤标志物、胆汁淤积指标、肝脏指数及肝脏组织病理学水平，评价BE和IG对ANIT所致肝损伤的影响。通过对肿瘤坏死因子- α (tnf - α)、核因子κ B（nf - κ B）、白细胞介素-6 （IL-6）、Na+/牛磺胆酸共转运多肽（NTCP）、胆汁盐输出泵（BSEP）、多药耐药相关蛋白2 （MRP2）及肝组织氧化应激指标水平的研究，揭示BE和IG对抗抗氧化诱导的肝毒性和胆汁淤积的潜在保护机制。结果：毛霉正丁醇提取物（BE）和环烯醚萜苷（IG）可显著降低抗氧化小鼠血清中胆固醇肝损伤标志物天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、碱性磷酸酶（ALP）、γ -谷氨酰基转移酶（GGT）、总胆汁酸（TBA）、总胆红素（TBIL）和直接胆红素（DBIL）水平。肝组织病理学检查显示，经BE和IG处理后，病理损伤明显减轻。结果表明，BE和IG通过提高肝脏超氧化物歧化酶（SOD）、还原性谷胱甘肽（GSH）、过氧化氢酶（CAT）水平和降低肝脏丙二醛（MDA）含量，显著恢复肝脏相对重量，抑制ANIT诱导的氧化应激。Western blot结果显示，BE和IG可抑制促炎因子tgf - α、IL-6和NF-kappa b的表达，且BE和IG可使胆汁酸转运体NTCP、BSEP、MRP2的蛋白表达呈剂量依赖性上调。结论：BE和IG对anit诱导的小鼠急性肝内胆汁淤积肝损伤具有剂量依赖性的保护作用，其作用机制可能与BE和IG对氧化应激、炎症反应和胆汁酸转运的调节有关。此外，这些研究结果表明环烯醚萜苷作为纤毛莲的主要活性成分，在纤毛莲的保肝作用中起着至关重要的作用。
Ethnopharmacological relevance: Veronica ciliata Fisch. is a traditional medical herb that present in more than 100 types of Tibetan medicine prescriptions, most of which are used for liver disease therapy. Iridoid glycosides have been identified as the major active components of V.ciliata with a variety of biological activities.Aims of the study: The aim of this study is to explore the protective effect and potential mechanism of n-Butanol extract (BE) and iridoid glycosides (IG) from V.ciliata against alpha-naphthyl isothiocyanate (ANIT)-induced hepatotoxicity and cholestasis in mice.Materials and methods: Mice were intragastrically (i.g.) given BE and IG at different dose or positive control ursodeoxycholic acid (UCDA) once a day for 14 consecutive days, and were treated with ANIT to cause liver injury on day 12th. Serum levels of hepatic injury markers and cholestasis indicators, liver index and liver histopathology were measured to evaluate the effect of BE and IG on liver injury caused by ANIT. The protein levels of tumor necrosis factor-alpha (TNF-alpha), nuclear factor kappa B(NF-kappa B), interleukin-6 (IL-6), Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and the levels of oxidative stress indicators in liver tissue were investigated to reveal the underlying protective mechanisms of BE and IG against ANIT-induced hepatotoxicity and cholestasis.Results: The n-Butanol extract (BE) and iridoid glycosides (IG) isolated from V.ciliata significantly decreased serum level of cholestatic liver injury markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL) in ANIT-treated mice. Histopathology of the liver tissue showed that pathological damages were relieved upon BE and IG treatment. Meanwhile, the results indicated BE and IG notably restored relative liver weights, inhibited oxidative stress induced by ANIT through increasing hepatic level of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and decreasing hepatic content of malondialdehyde (MDA). Western blot revealed that BE and IG inhibited the expression of pro-inflammatory factors TGF-alpha, IL-6 and NF-kappa B. Furthermore, the decreased protein expression of bile acid transporters NTCP, BSEP, MRP2 were upregulated by BE and IG in a dose-dependent manner.Conclusion: The results have demonstrated that BE and IG exhibited a dose-dependently protective effect against ANIT-induced liver injury with acute intrahepatic cholestasis in mice, which might be related to the regulation of oxidative stress, inflammatory response and bile acid transport. In addition, these findings pointed out that iridoid glycosides as main active components of V.ciliata play a critical role in hepatoprotective effect of V.ciliata.