槐耳颗粒缓解奥沙利铂诱导肝脏损伤的作用及机制研究

目的：探究槐耳颗粒对奥沙利铂（OXA）诱导的肝脏损伤的保护作用及内在机制。方法：采用70只雄性C57BL/6小鼠，随机分为7组，分别为正常对照组，模型对照组，药物对照组，槐耳低、中、高剂量组及阳性对照组。除正常对照组和药物对照组给予等体积的5%葡萄糖溶液外，其余各组腹腔注射（i.p）10 mg·kg^-1 OXA溶液造模，每周一次，共6周。每周给予OXA造模的同时，槐耳不同剂量组分别灌胃（ig.）给予2、4、8 mg·g^-1的槐耳颗粒溶液，阳性对照组给予1.3 mg·g^-1的N-乙酰半胱氨酸（i.p），每日一次。药物对照组给予8 mg·g^-1的槐耳颗粒溶液（ig.），正常和模型对照组则给予0.9%的氯化钠溶液（ig.），连续42日。造模及给药结束后，取小鼠血清及肝脏组织，分别检测血清天门冬酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、碱性磷酸酶（AKP）和肝脏丙二醛（MDA）、超氧化物歧化酶（SOD）、还原型谷胱甘肽（GSH）及过氧化氢酶（CAT）水平；称体重、肝重，计算肝重比；HE染色观察肝脏组织病理学变化。Western blot法检测肝脏氧化应激通路PI3K、P-AKT、Nrf2、HO-1、NQO1、GCLM、GCLC的蛋白表达变化，并分析PI3K两种亚型PI3K p85、PI3K p110的变化。结果：槐耳颗粒能显著降低模型组小鼠肝重/体重的值，降低血清AST、ALT和肝脏MDA水平，升高肝脏SOD、GSH水平（P<0.05）；显著上调PI3K、P-AKT、Nrf2、HO-1、NQO1、GCLM和GCLC蛋白表达（P<0.05），且槐耳颗粒对PI3K p85和PI3K p110两种亚型均有上调作用。结论：槐耳颗粒可以缓解OXA诱导的肝脏损伤情况，其作用机制可能与通过PI3K/Akt/Nrf2信号通路调控氧化还原平衡有关。

Study on the effect and mechanism of Huaier granules in relieving oxaliplatin-induced liver injury

OBJECTIVE To explore the protective effect and mechanism of Huaier granule on oxaliplatin (OXA)-induced liver injury.METHODS A total of 70 male C57BL/6 mice were randomly divided into 7 groups of normal, model, drug control, low/medium/high-dose Huaier and positive control (n=10 each). Except normal and drug control groups receiving an equal volume of 5% glucose solution, the other groups were intraperitoneally injected with 10 mg·kg^-1 OXA solution for modeling once a week for 6 weeks. At the same time that OXA was given weekly for modeling, different dose groups of huaier received an intragastric gavage of 2,4,8 mg·g^-1 Huaier granule solution and positive control group received an intraperitoneal injection of 1.3 mg·g^-1 N-acetylcysteine once daily. Drug control group received 8 mg·g^-1 Huaier granule solution while normal and model groups 0.9% sodium chloride solution for 42 days. Then sera and liver tissues were harvested for detecting the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AKP) in sera and malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) in liver; body and liver weights were measured and liver weight ratio was calculated. The histopathological changes of liver were observed by staining. The protein expressions of PI3K,P-AKT, Nrf2, HO-1, NQO1, GCLM and GCLC were detected by Western blot and the changes of PI3K p85 and PI3K P110 were analyzed.RESULTS Huaier granule could significantly lower the ratio of liver weight/body weight, decrease the serum levels of AST, ALT and MDA and the hepatic levels of SOD and GSH (P<0.05) and significantly up-regulated the protein expressions of PI3K, P-AKT, Nrf2, HO-1, NQO1, GCLM and GCLC (P<0.05). Moreover, Huaier granule could up-regulate the subtypes of PI3K p85 and PI3K p110.CONCLUSION Huaier granule can alleviate OXA-induced liver injury. And its mechanism may be correlated with regulating redox balance through the PI3K/Akt/Nrf2 signaling pathway.