School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
J Ethnopharmacol. 2021 Jul 15;275:114103. doi: 10.1016/j.jep.2021.114103. Epub 2021 Apr 6.
Zuojin Pill (ZJP) has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. But its effect on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury (GI) is still uncharted.
This study aims to investigate the therapeutic effect and molecular mechanism of ZJP on indomethacin (IDO) induced gastric injury.
GI was induced in rat by oral administration of 5 mg/kg IDO. Then the rats were treated with ZJP (1.26, 2.52, 5.04 g/kg, ig). The changes of food intake, body weight, gastric pH and general state observation were carried out to determine the improvement of ZJP in IDO-induced GI: HE staining and AB-PAS staining was analyzed to characterize the thickness of gastric mucosa and micro mucosal injury; in order to elucidate the effect of ZJP on IDO-induced inflammatory injury, the inflammatory infiltration of gastric tissue was observed by MPO immunohistochemical method, and the contents of TNF-α, IL-6 and IL-10 were measured. Furthermore, the regulatory mechanism of ZJP in treating IDO-induced GI was predicted with the help of network pharmacology, and the expression levels of key proteins ERK, p-ERK, P38, p-P38, JNK, p-JNK were determined to elucidate the molecular mechanism of ZJP.
Current data strongly demonstrated that ZJP alleviated food intake reduction, weight loss and gastric injury caused by IDO and made gastric pH and mucosal thickness return to normal. In addition, ZJP could reduce the level of MPO to alleviate the inflammatory infiltration of gastric tissue. Simultaneously, ZJP could down regulate the expression of TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage caused by inflammatory, and create a healing environment. Furthermore, ZJP could significantly inhibit the phosphorylation of ERK, p38 and JNK, which leaded to the increase of inflammatory factors and the damage of gastric mucosa.
ZJP improved local inflammation by inhibiting MAPK signaling pathway, and had a good therapeutic effect on IDO-induced GI. This study has reference significance for the study of ZJP in the prevention and treatment of NSAID induced gastric injury. In addition, ZJP may be a new treatment option for the prevention and treatment of NSAID induced gastric disease.
自古以来，左金丸（ZJP）一直是中国治疗胃肠道疾病的经典方剂。但它对非甾体抗炎药（NSAIDs）诱导的胃损伤（GI）的作用仍未被探索。
本研究旨在探讨左金丸（ZJP）对吲哚美辛（IDO）诱导的胃损伤的治疗作用及分子机制。
通过口服 5mg/kg IDO 诱导大鼠 GI。然后用 ZJP（1.26、2.52、5.04g/kg，ig）处理大鼠。通过观察食物摄入量、体重、胃 pH 值和一般状态变化，确定 ZJP 对 IDO 诱导的 GI 的改善情况：通过 HE 染色和 AB-PAS 染色分析胃黏膜厚度和微黏膜损伤特征；为了阐明 ZJP 对 IDO 诱导的炎症损伤的作用，通过 MPO 免疫组化法观察胃组织的炎症浸润情况，并测定 TNF-α、IL-6 和 IL-10 的含量。此外，借助网络药理学预测 ZJP 治疗 IDO 诱导的 GI 的调控机制，并测定 ERK、p-ERK、P38、p-P38、JNK、p-JNK 等关键蛋白的表达水平，以阐明 ZJP 的分子机制。
目前的数据有力地证明，ZJP 缓解了 IDO 引起的食物摄入减少、体重减轻和胃损伤，并使胃 pH 值和黏膜厚度恢复正常。此外，ZJP 可以降低 MPO 水平，减轻胃组织的炎症浸润。同时，ZJP 可以下调 TNF-α和 IL-6 的表达，上调 IL-10 的表达，减轻炎症引起的损伤，营造愈合环境。此外，ZJP 可显著抑制 ERK、p38 和 JNK 的磷酸化，导致炎症因子增加和胃黏膜损伤。
ZJP 通过抑制 MAPK 信号通路改善局部炎症，对 IDO 诱导的 GI 具有良好的治疗作用。本研究对 ZJP 预防和治疗 NSAID 诱导的胃损伤具有参考意义。此外，ZJP 可能成为预防和治疗 NSAID 诱导的胃疾病的新治疗选择。
