Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.
Histol Histopathol. 2019 Oct;34(10):1173-1184. doi: 10.14670/HH-18-120. Epub 2019 Apr 29.
Histone deacetylases (HDAC) inhibitor has the effect of anti-tumor and inhibiting apoptosis, and could inhibit the release of inflammatory factors, reducing the damage to liver and enterocytes in acute liver failure (ALF). HDAC2 specific inhibitor CAY10683 was used to verify the protective effect on acute liver failure through reducing intestinal epithelial cell apoptosis by inhibiting mitochondrial apoptosis pathway.
Lipopolysaccharide/D-galactosamine (LPS/D-GalN) was used to induce ALF in Sprague-Dawley rats. A total of 18 healthy rats were randomly divided into three groups. Rats in ALF group and CAY10683 group were given the same amount of normal sodium or CAY10683 2 hours before ALF model protocol was conducted. NCM460 cells were given LPS/D-GalN to establish an apoptotic model. Flow cytometry analysis was used to determine the apoptosis of enterocytes, and TUNEL assay was used to observe the apoptosis of NCM460 cells. The expression of bax was observed by immunofluorescence. The expression of histone proteins, HDAC2 and molecules in the apoptotic signaling pathway were determined by Western blotting and real-time PCR.
CAY10683 improves histological and functional changes in ALF model. Compared with control group, LPS/D-GalN induced massive apoptosis of rat intestinal tissues and NCM460 cells (P<0.05), and the apoptosis rate was significantly reduced after CAY10683 treatment (P<0.05). The expression of bax was increased significantly in the model groups (P<0.05), and reduced with the treatment of CAY10683 (P<0.05). Compared with the model group, CAY10683 inhibits mitochondrial apoptosis in intestinal tissues and NCM460 cells (P<0.05).
CAY10683 reduces the damage to liver and intestinal tissue, and plays an important role in inhibiting mitochondrial apoptosis in ALF rats and in NCM460 cells.
组蛋白去乙酰化酶（HDAC）抑制剂具有抗肿瘤和抑制细胞凋亡的作用，能够抑制炎症因子的释放，减轻急性肝衰竭（ALF）中肝和肠上皮细胞的损伤。本研究使用 HDAC2 特异性抑制剂 CAY10683 通过抑制线粒体凋亡途径减少肠上皮细胞凋亡，验证其对急性肝衰竭的保护作用。
脂多糖/半乳糖胺（LPS/D-GalN）诱导 Sprague-Dawley 大鼠建立 ALF 模型。将 18 只健康大鼠随机分为三组，ALF 组和 CAY10683 组大鼠在 ALF 模型建立前 2 小时给予等体积生理盐水或 CAY10683，NCM460 细胞给予 LPS/D-GalN 建立凋亡模型。流式细胞术检测肠上皮细胞凋亡，TUNEL 法观察 NCM460 细胞凋亡，免疫荧光观察 bax 表达，Western blot 和实时 PCR 检测组蛋白、HDAC2 及凋亡信号通路分子表达。
CAY10683 改善 ALF 模型的组织学和功能变化。与对照组相比，LPS/D-GalN 诱导大鼠肠组织和 NCM460 细胞大量凋亡（P<0.05），CAY10683 处理后凋亡率明显降低（P<0.05）。模型组 bax 表达明显增加（P<0.05），CAY10683 处理后减少（P<0.05）。与模型组相比，CAY10683 抑制肠组织和 NCM460 细胞线粒体凋亡（P<0.05）。
CAY10683 减轻肝和肠组织损伤，在 ALF 大鼠和 NCM460 细胞中发挥重要作用，抑制线粒体凋亡。
