Liu Xiaojing, Yang Xueliang, Han Lingna, Ye Feng, Liu Min, Fan Wanhu, Zhang Kai, Kong Ying, Zhang Jian, Shi Lei, Chen Yunru, Zhang Xi, Lin Shumei
Department of Infectious Diseases, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Department of Physiology, Changzhi Medical College, Changzhi 046000, China.
Int Immunopharmacol. 2017 Aug;49:50-59. doi: 10.1016/j.intimp.2017.05.022. Epub 2017 May 25.
Liver injury occurs frequently during sepsis. Pterostilbene (Pte), a natural dimethylated analog of resveratrol from blueberries, exerts anti-inflammatory and anti-apoptotic effects in various diseases. However, the role of Pte in sepsis-induced liver injury and its underlying mechanisms remain unknown. The current study aimed to evaluate the protective effects of Pte on sepsis-induced liver injury and its potential mechanisms. Sepsis was induced using cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were administered Pte (5, 10, 15mg/kg, i.p.) at 0.5h, 2h, and 8h after CLP induction. The pathological changes of the liver were evaluated using hematoxylin and eosin (H&E) staining. The serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), myeloperoxidase (MPO), p38 mitogen-activated protein kinase (p38MAPK), Bax, and B-cell lymphoma 2 (Bcl-2) were also evaluated. Pte treatment attenuated the CLP-induced liver injury, as evidenced by the attenuated histopathologic injuries and the decreased serum aminotransferase levels. Pte reduced the serum inflammatory cytokine (TNF-α and IL-6) levels and hepatic mRNA levels of TNF-α and IL-6. Pte also reduced MPO activity and p38MAPK activation in the liver. Additionally, Pte significantly inhibited Bax expression and increased Bcl-2 expression. Moreover, Pte increased the expression of sirtuin-1 (SIRT1) and reduced the expression of acetylated forkhead box O1 (Ac-FoxO1), acetylated Ac-p53, and acetylated nuclear factor-kappa beta (Ac-NF-κB). However, SIRT1 small interfering RNA (siRNA) abolished Pte's effects on the expression levels of those protein. Notably, Pte improved the survival rate in septic mice. In conclusion, Pte alleviates sepsis-induced liver injury by reducing inflammatory response and inhibiting hepatic apoptosis, and the potential mechanism is associated with SIRT1 signaling activation.
肝脏损伤在脓毒症期间频繁发生。紫檀芪（Pte）是一种来自蓝莓的白藜芦醇天然二甲基化类似物，在各种疾病中发挥抗炎和抗凋亡作用。然而，Pte在脓毒症诱导的肝损伤中的作用及其潜在机制仍不清楚。本研究旨在评估Pte对脓毒症诱导的肝损伤的保护作用及其潜在机制。采用盲肠结扎穿孔术（CLP）诱导C57BL/6小鼠发生脓毒症。在CLP诱导后0.5小时、2小时和8小时给小鼠腹腔注射Pte（5、10、15mg/kg）。使用苏木精和伊红（H&E）染色评估肝脏的病理变化。测量血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平。还评估了肿瘤坏死因子-α（TNF-α）、白细胞介素（IL-6）、髓过氧化物酶（MPO）、p38丝裂原活化蛋白激酶（p38MAPK）、Bax和B细胞淋巴瘤2（Bcl-2）的水平。Pte治疗减轻了CLP诱导的肝损伤，组织病理学损伤减轻和血清转氨酶水平降低证明了这一点。Pte降低了血清炎性细胞因子（TNF-α和IL-6）水平以及肝脏中TNF-α和IL-6的mRNA水平。Pte还降低了肝脏中的MPO活性和p38MAPK活化。此外，Pte显著抑制Bax表达并增加Bcl-2表达。此外，Pte增加了沉默调节蛋白1（SIRT1）的表达并降低了乙酰化叉头框O1（Ac-FoxO1）、乙酰化Ac-p53和乙酰化核因子-κB（Ac-NF-κB）的表达。然而，SIRT1小干扰RNA（siRNA）消除了Pte对这些蛋白表达水平的影响。值得注意的是，Pte提高了脓毒症小鼠的存活率。总之，Pte通过减轻炎症反应和抑制肝脏细胞凋亡减轻脓毒症诱导的肝损伤，其潜在机制与SIRT1信号激活有关。
