摘要目的：观察组蛋白去乙酰化酶抑制剂MS-275对急性肝衰竭（ ALF）小鼠肝脏的保护作用及对NF-κB信号通路的影响。方法选取SPF级C57 BL／6雄性小鼠30只，并随机分为健康对照组、ALF模型组和MS-275治疗组，每组10只。 ALF模型组和MS-275治疗组小鼠采用D-氨基半乳糖以及脂多糖（ LPS）联合诱导小鼠ALF模型，其中MS-275治疗组小鼠在制备ALF模型前2 h腹腔注射MS-275。24 h后观察检测各组小组血清丙氨酸转氨酶（ ALT）、天冬氨酸转氨酶（ AST）、总胆红素（TBil）、肿瘤坏死因子（TNF）-α、干扰素（IFN）γ、白介素（IL）-1β、高迁移率族蛋白1（HMGB1）水平，取肝组织做HE染色观察肝组织结构并检测肝组织HDAC1、HDAC3、P65蛋白表达及乙酰化组蛋白、乙酰化、磷酸化P65蛋白的表达。采用t检验比较组间上述指标的差异。结果 HE染色结果显示，与ALF模型组相比，MS-275治疗组小鼠肝细胞损害程度明显降低，炎症细胞浸润减少。与ALF模型组相比，MS-275治疗组小鼠血清中 ALT、AST 和 TBil 水平明显降低（ t ＝－22．215、－11．914和－12．160，P值均＜0．05），但仍高于健康对照组（t ＝14．852、11．692和8．333，P值均＜0．05）；MS-275治疗组小鼠血清TNF-α、IFNγ、IL-1β、HMGB1表达水平也明显降低（ t＝－7．926、－3．427、－2．475和－5．920，P值均＜0．05），但仍高于健康对照组，其中TNF-α和IFNγ水平与健康对照组比较，差异有统计学意义（t＝5．541和5．514，P值均＜0．05）；MS-275治疗组小鼠肝组织中HDAC1和HDAC3蛋白表达明显下降（t＝－3．676和－10．576，P值均＜0．05），肝组织中乙酰化H3、H4和P65蛋白表达明显增加（t＝3．976、5．559和4．588，P值均＜0．05）。免疫组化结果提示，MS-275治疗组小鼠肝组织中P65表达总数及入核率均低于ALF模型组。结论 MS-275对ALF小鼠肝脏有保护作用，可能与非组蛋白的乙酰化调控有关。

abstractsObjective To investigate the effect of MS-275, an histone deacetylase ( HDAC ) inhibitor, on acute liver failure ( ALF ) induced by D-galactosamine and lipopolysaccharide in mice. Methods Thirty specific pathogen free (SPF) C57BL/6 male mice were randomly and equally divided into control, ALF model and MS-275 groups. ALF model was induced by D-galactosamine ( D-Gal ) and lipopolysaccharide (LPS), and the mice in MS-275 group received MS-275 (1 mg/kg) at 2 h before the induction of ALF.Serum and liver samples of mice were obtained at 24 h after ALF induction.The serum levels of ALT, AST, TBil and tumor necrosis factor-alpha ( TNF-α) , interferon γ( IFNγ) , interleukin ( IL )-1β, high mobility group box 1 ( HMGB1 ) were tested by biochemical methods or ELISA kit, respectively.The expression of HDAC1, HDAC3, acetylation of histone H3, H4, P65, acetylation and&nbsp;phosphorylation of P65 in liver were detected by Western blotting.The changes of histology in liver was detected by HE staining, and the translocation of P65 in liver was detected by immunohistochemistry. Comparison of variables among the groups was performed using t test.Results MS-275 inhibited the infiltration of inflammatory cells and improved the pathological changes of liver tissue.Compared with ALF group, serum ALT, AST, TBil levels were decreased in MS-275 group ( t =-22.215, -11.914 and-12.160, all P<0.05), but still higher than those in the control group (t=14.852, 11.692 and 8.333, all P<0.05); serum TNF-α, IFNγ, IL-1β, HMGB1 levels were also significantly decreased in MS-275 group (t=-7.926, -3.427, -2.475 and -5.920, all P<0.05), but TNF-αand IFNγwere still higher than those in the control group (t=5.541 and 5.514, all P<0.05).Compared with control group, the expression of class I HDAC in liver tissue was significantly decreased in MS-275 group ( t=-3.676 and-10.576, P<0.05), while the expressions of acetylation of histone H3, H4 and P65 were significantly increased (t=3.976, 5.559 and 4.588, all P<0.05).MS-275 inhibited the translocation of P65 from cytoplasm to the nucleus.Conclusion MS-275 can protect liver from acute failure in mice through enhancing the acetylation levels of non-histones.