Zhu Jinjiang, Sun Xiaoyun, Zhan Yakun
Department of Emergency, Yiwu Central Hospital, 322000 Yiwu, Zhejiang, China.
Department of Pharmacy, The Eighth Hospital of Wuhan, 430014 Wuhan, Hubei, China.
Discov Med. 2025 Mar;37(194):503-514. doi: 10.24976/Discov.Med.202537194.42.
One of the pharmacological effects of celastrol (Cel) is the amelioration of acute liver injury. In this study, we explored the mechanism of Cel underlying the alleviation of liver injury induced by traumatic hemorrhagic shock (THS).
The THS model was developed from Sprague-Dawley rats through transverse fractures, blood loss and fluid infusion. Then, the THS rats were intraperitoneally injected with 0.5, 1, and 1.5 mg/kg Cel. The rats were injected in the tail vein with lentivirus-mediated small interfering RNA (siRNA) negative control (siNC), siRNA targeting heat shock transcription factor 1 (), and siRNA targeting toll-like receptor 9 () 72 hours before the establishment of THS model. Hematoxylin-eosin (HE) staining was performed to highlight the pathological alterations in the rat liver tissue. Enzyme-linked immunosorbent Assay (ELISA) was utilized to determine the expression levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and total bilirubin (TB). The expression levels of B-cell lymphoma 2 () and B-cell lymphoma 2 associated X protein () were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The expression levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were determined to assess the extent of oxidative stress. Western blotting was used to evaluate the expression levels of heat shock transcription factor 1 (HSF1), toll-like receptor 9 (TLR9) and myeloid differentiation factor 88 (MyD88).
Cel was shown to therapeutically alleviate liver injury, decrease ALT and AST levels, and simultaneously downregulate inflammation factors levels (TNF-α, IL-1β), alleviated apoptosis, and decreased oxidative stress in the THS model in a concentration-dependent manner. Moreover, Cel increased the expression of and decreased the expression of and in the THS model. And silencing increased and expression. Further, the silencing of resulted in liver injury, inflammation and apoptosis, which could be reversed by silencing.
This study demonstrates that Cel attenuates THS-induced liver injury by positively regulating so as to inhibit the expression of .
雷公藤红素（Cel）的药理作用之一是改善急性肝损伤。在本研究中，我们探讨了Cel减轻创伤性失血性休克（THS）所致肝损伤的机制。
通过横向骨折、失血和液体输注建立Sprague-Dawley大鼠THS模型。然后，给THS大鼠腹腔注射0.5、1和1.5mg/kg的Cel。在建立THS模型前72小时，给大鼠尾静脉注射慢病毒介导的小干扰RNA（siRNA）阴性对照（siNC）、靶向热休克转录因子1（）的siRNA和靶向Toll样受体9（）的siRNA。进行苏木精-伊红（HE）染色以突出大鼠肝组织的病理改变。采用酶联免疫吸附测定（ELISA）法测定丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和总胆红素（TB）的表达水平。通过定量实时聚合酶链反应（qRT-PCR）评估B细胞淋巴瘤2（）和B细胞淋巴瘤2相关X蛋白（）的表达水平。测定活性氧（ROS）、丙二醛（MDA）、谷胱甘肽（GSH）和超氧化物歧化酶（SOD）的表达水平以评估氧化应激程度。采用蛋白质免疫印迹法评估热休克转录因子1（HSF1）、Toll样受体9（TLR9）和髓样分化因子88（MyD88）的表达水平。
结果显示，Cel在THS模型中具有治疗性减轻肝损伤、降低ALT和AST水平的作用，同时下调炎症因子水平（TNF-α、IL-1β），减轻细胞凋亡，并以浓度依赖的方式降低氧化应激。此外，在THS模型中，Cel增加了的表达，降低了和的表达。沉默会增加和的表达。此外，沉默会导致肝损伤、炎症和细胞凋亡，而沉默可使其逆转。
本研究表明，Cel通过正向调节从而抑制的表达来减轻THS诱导的肝损伤。
