柚皮苷通过 RhoA/ROCK 通路抑制 MLC 磷酸化和 NF-κB 激活，从而减轻脓毒症诱导的肠道损伤。
Naringin attenuates MLC phosphorylation and NF-κB activation to protect sepsis-induced intestinal injury via RhoA/ROCK pathway.
机构信息
Translational Medicine Center of Sepsis, The Third Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China; Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China; Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410078, People's Republic of China.
Translational Medicine Center of Sepsis, The Third Xiangya Hospital, Central South University, Changsha, 410013, People's Republic of China; Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410078, People's Republic of China.
出版信息
Biomed Pharmacother. 2018 Jul;103:50-58. doi: 10.1016/j.biopha.2018.03.163. Epub 2018 Apr 7.
BACKGROUND
Sepsis is commonly associated with excessive stimulation of host immune system and result in multi-organ failure dysfunction. Naringin has been reported to exhibit a variety of biological effects. The present study aimed to investigate the protective effect of naringin on sepsis-induced injury of intestinal barrier function in vivo and in vitro.
METHODS
Mice were randomly divided into 4 groups named sham (n = 20), CLP + vehicle (n = 20), CLP + NG (30 mg/kg) (n = 20) and CLP + NG (60 mg/kg) (n = 20) groups. Sepsis was induced by cecal ligation and puncture (CLP). H&E staining and transmission electron microscopy (TEM) were performed to observe intestinal mucosal morphology. ELISA was used to determine the intestinal permeability and inflammatory response in vivo and in vitro. Western blot and RhoA activity assay were performed to determine the levels of tight junction proteins and the activation of indicated signaling pathways. MTT assay was used to determine cell viability.
RESULTS
Naringin improved survival rate of CLP mice and alleviated sepsis-induced intestinal mucosal injury. Furthermore, naringin improved impaired intestinal permeability and inhibited the release of TNF-α and IL-6, while increased IL-10 level in CLP mice and lipopolysaccharide (LPS)-stimulated MODE-K cells in a dose-dependent manner. Naringin increased the expression of tight junction proteins ZO-1 and claudin-1 via RhoA/ROCK/NF-κB/MLCK/MLC signaling pathway in vivo and in vitro.
CONCLUSION
Naringin improved sepsis-induced intestinal injury via RhoA/ROCK/NF-κB/MLCK/MLC signaling pathway in vivo and in vitro.
背景
脓毒症通常与宿主免疫系统的过度刺激有关，并导致多器官功能衰竭。柚皮苷已被报道具有多种生物学效应。本研究旨在探讨柚皮苷对体内和体外脓毒症诱导的肠道屏障功能损伤的保护作用。
方法
小鼠随机分为 4 组，分别为假手术（n=20）、盲肠结扎穿孔（CLP）+载体（n=20）、CLP+NG（30mg/kg）（n=20）和 CLP+NG（60mg/kg）（n=20）组。采用盲肠结扎穿孔（CLP）法诱导脓毒症。进行 H&E 染色和透射电镜（TEM）观察肠道黏膜形态。采用 ELISA 法测定体内和体外肠道通透性和炎症反应。采用 Western blot 和 RhoA 活性测定法测定紧密连接蛋白水平和信号通路的激活。采用 MTT 法测定细胞活力。
结果
柚皮苷提高 CLP 小鼠的存活率，减轻脓毒症引起的肠道黏膜损伤。此外，柚皮苷改善了 CLP 小鼠受损的肠道通透性，并抑制了 TNF-α和 IL-6的释放，同时增加了 CLP 小鼠和脂多糖（LPS）刺激的 MODE-K 细胞中 IL-10 的水平，呈剂量依赖性。柚皮苷通过 RhoA/ROCK/NF-κB/MLCK/MLC 信号通路增加了紧密连接蛋白 ZO-1 和 claudin-1 的表达，无论是在体内还是体外。
结论
柚皮苷通过 RhoA/ROCK/NF-κB/MLCK/MLC 信号通路改善了体内和体外脓毒症引起的肠道损伤。
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