小柴胡汤对四氯化碳/乙醇诱发小鼠肝癌肠-肝-脑损伤的影响

目的:研究小柴胡汤对四氯化碳/乙醇诱发小鼠肝癌肠-肝-脑损伤的影响。方法:肝癌模型组:腹部皮下注射25%四氯化碳-橄榄油溶液(5 mL·kg-1,2次/周)和自由饮用8%乙醇溶液4周,自由饮用四氯化碳(0.5%)-乙醇(8%)溶液20周;肝癌肝郁脾虚模型组:在肝癌模型基础上,夹尾(30 min.d-1)、孤养及隔日禁食4周,自由饮用四氯化碳(0.5%)-乙醇(8%)溶液、孤养和隔日禁食20周;小柴胡汤8 g·kg-1·d-1组:肝癌肝郁脾虚模型制作4周后灌小柴胡汤8周。监测死亡率、体重和症状,通过积分系统估计肠、肝、脑病理损伤程度。结果:肝癌肝郁脾虚组死亡率显著高于肝癌组(分别为70%和35%),小柴胡汤治疗后显著降低;肝癌组死亡小鼠存在明显的小肠、盲肠、肝脏损害、盲肠积粪及脑质量增加,肝癌肝郁脾虚组死亡小鼠以上表现更明显,小柴胡汤治疗后显著改善;肝癌肝郁脾虚组肝癌发生率显著高于肝癌组(分别为67%和46%),小柴胡汤治疗后显著降低;肝癌组存活小鼠存在明显的小肠、盲肠、肝脏损伤(增生为主),脑质量略降低,肝癌肝郁脾虚组存活小鼠以上表现更明显,小柴胡汤治疗后显著改善。相关分析发现,死亡小鼠和存活小鼠小肠损害、盲肠损害、盲肠积粪、肝损害、脑质量之间均呈显著正/负相关。结论:小柴胡汤通过降低肠-肝-脑损伤及改善肠-肝-脑互作用,抵御肝郁脾虚和四氯化碳/乙醇诱导的肠-肝-脑损伤和炎症,降低四氯化碳/乙醇诱发小鼠肝癌时的死亡率和肝癌发生率,其分子机制有待进一步阐明。

Effects of Xiaochaihu Decoction on Damage of Gut-liver-brain in CCl4/Ethanol Induced Mouse Hepatocellular Carcinoma

Objective: To investigate the effects of Xiaochaihu Decoction on damage of gut-liver-brain in CCl₄/ethanol-induced mouse hepatocellular carcinoma. Method: Hepatocellular carcinoma group(HCC) were induced by subcutaneous injection with 25% CCl₄ olive oil solution(5 mL·kg^-1 twice per week) and allowed free access to a 8% ethanol solution as drinking fluid for 4 weeks,and allowed free access to 0.5% CCl₄-8% ethanol solution as drinking fluid for 20 weeks; in HCC combined with liver depression and spleen deficiency(LDSD) group(HCC-LDSD group), on the basis of HCC modelling, the mice were stimulated with the factor of LDSD,squeezing tails(30 min·d^-1),solitary breeding and intermittent fasting for 4 weeks, solitary breeding and intermittent fasting for 20 weeks; Xiaochaihu decoction(XCHD) treated group was administered by gavage for 8 weeks after 4 weeks of the HCC-LDSD modelling. The mortality rates and HCC incidence rates were calculated, weight and clinical signs were monitored daily. The degree of tissue injuries in the gut and liver were studied using a scoring system, and brain weights were measured. Result: The mortality rate in HCC-LDSD group was higher than that in the HCC group, after treatment with XCHD, the mortality rate decreased significantly.In death mouse of HCC group,significantly more injuries in small intestine,cecum,liver and fecal loading in the cecum, with the increased in brain weights,the most in HCC-LDSD group, after treatment with XCHD, all of which were improved. HCC incidence rate in the HCC-LDSD group was higher than that in the HCC group, after treatment with XCHD,the HCC incidence rate decreased significantly.In survival mouse of HCC group,significantly more injuries in small intestine,cecum, liver(mainly hyperplasia), with slight decreased in brain weights,the most in HCC-LDSD group, after treatment with XCHD, all of which were improved. Correlative analysis showed that there was a positive or negative correlation between small intestine injuries,cecum injuries,fecal loading in the cecum,liver injuries and brain weights in death mouse and survival mouse. Conclusion: XCHD offered protection against CCl₄/ethanol-induced inflammation by decreased the injury of gut-liver-brain, and improved gut-liver-brain interactions, and ultimately decreased mortality rates and HCC incidence rates in CCl₄/ethanol-induced mouse HCC,it need further research to understand the molecular mechanism of effects of XCHD.