补肾壮骨汤调控Nrf2/HO-1信号通路抑制铁死亡改善糖尿病性骨质疏松模型的机制研究
DOI:
作者:
作者单位:

1.山东中医药大学第一临床医学院;2.北京中医药大学;3.山东中医药大学附属医院

作者简介:

通讯作者:

中图分类号:

基金项目:

山东省中医药科技项目(Z-2022047;Q-2023124)


The mechanism of Bushen Zhuanggu Decoction regulating Nrf2 / HO-1 signaling pathway to inhibit ferroptosis and improve diabetic osteoporosis model
Author:
Affiliation:

1.First Clinical Medical College of Shandong University of Traditional Chinese Medicine;2.Beijing University of Traditional Chinese Medicine;3.Affiliated Hospital of Shandong University of Traditional Chinese Medicine

Fund Project:

Shandong Province Traditional Chinese Medicine Science and Technology Project (Z-2022047;Q-2023124)

  • 摘要
  • |
  • 图/表
  • |
  • 访问统计
  • |
  • 参考文献
  • |
  • 相似文献
  • |
  • 引证文献
  • |
  • 资源附件
  • |
  • 文章评论
    摘要:

    目的:通过LC/MS分析技术和网络药理学的综合策略,结合实验验证探讨补肾壮骨汤疗糖尿病性骨质疏松的有效成分和作用机制。 方法:采用UPLC-Q-Orbitrap-MS法对补肾壮骨汤中的有效化学成分进行分析鉴定,检索数据库中DOP与铁死亡的相关基因,取交集得到有效成分通过调控铁死亡途径治疗DOP的潜在靶点。腹腔注射链脲佐菌素联合高糖高脂喂养诱导的DOP大鼠模型,模型构建成功后进行补肾壮骨汤灌胃8周,检测体质量、血糖及糖化血红蛋白,取材后进行Micro-CT以获取骨形态学变化,试剂盒检测铁离子水平、SOD及MDA水平。Western Blot法检测骨组织Nrf2/HO-1信号及铁死亡相关蛋白表达。 结果:一、补肾壮骨汤中药入血化合物共预测到46种已识别化合物的848个靶点。通过比对GeneCards、CTD数据库和FerrDb数据库最终获得81个补肾壮骨汤可能通过调控铁死亡抗DOP的潜在靶点。PPI网络分析SIRT1、MTOR、STAT3、NFE2L2、SRC、EGFR、IL6、MAPK3、IL1B、PPARG、ALB等节点可能是补肾壮骨汤治疗DOP的重要靶点。KEGG通路富集分析得到关于交集靶基因的134条信号通路,主要通路为代谢途径、脂质与动脉粥样硬化、糖尿病并发症中的铁死亡信号通路等。二、体内实验结果显示,与正常组相比,模型组大鼠体重增长缓慢、血糖及糖化血红蛋白水平升高,骨小梁发生破坏,骨密度、骨体积分数、骨小梁厚度及密度下降,骨小梁分离度升高,骨组织铁离子及MDA水平上升,SOD活力下降,Nrf2、HO-1及铁死亡相关蛋白表达上升;与模型组相比,补肾壮骨汤干预后大鼠体重增长有所上升,血糖及糖化血红蛋白水平有所下降,骨小梁破坏减轻,骨密度、骨体积分数、骨小梁厚度及密度增加,骨小梁分离度下降,骨组织铁离子及MDA水平下降,SOD活力有所提升,Nrf2、HO-1及铁死亡相关蛋白表达下降。 结论:补肾壮骨汤治疗T2DOP具有多成分、多靶点、多途径的特点,体内实验结果显示补肾壮骨汤可通过调控Nrf2/HO-1信号通路,抑制氧化应激和铁死亡防治DOP。

    Abstract:

    Objective : Through the comprehensive strategy of LC / MS analysis technology and network pharmacology, combined with experimental verification, the effective components and mechanism of Bushen Zhuanggu Decoction in the treatment of diabetic osteoporosis were discussed. Methods : UPLC-Q-Orbitrap-MS method was used to analyze and identify the effective chemical components in Bushen Zhuanggu Decoction. The genes related to DOP and ferroptosis in the database were retrieved, and the intersection was obtained to obtain the potential targets of active ingredients for the treatment of DOP by regulating ferroptosis pathway. DOP rat model was induced by intraperitoneal injection of streptozotocin combined with high-sugar and high-fat feeding. After the model was successfully constructed, Bushen Zhuanggu Decoction was administered for 8 weeks. Body weight, blood glucose and glycosylated hemoglobin were measured. Micro-CT was performed to obtain bone morphological changes. Iron ion levels, SOD and MDA levels were detected by kits. Western blot was used to detect the expression of Nrf2 / HO-1 signal and ferroptosis-related protein in bone tissue. Results : 1.A total of 848 targets of 46 identified compounds were predicted in the blood compounds of Bushen Zhuanggu Decoction. By comparing GeneCards, CTD database and FerrDb database, 81 potential targets of Bushen Zhuanggu Decoction against DOP by regulating ferroptosis were finally obtained. PPI network analysis of SIRT1, MTOR, STAT3, NFE2L2, SRC, EGFR, IL6, MAPK3, IL1B, PPARG, ALB and other nodes may be important targets for Bushen Zhuanggu Decoction in the treatment of DOP. Through KEGG pathway enrichment analysis, 134 signaling pathways about intersection target genes were obtained. The main pathways were metabolic pathways, lipid and atherosclerosis, ferroptosis signaling pathways in diabetic complications, etc. The results of in vivo experiments showed that compared with the normal group, the body weight of rats in the model group increased slowly, the levels of blood glucose and glycosylated hemoglobin increased, the trabecular bone was destroyed, the bone mineral density, bone volume fraction, trabecular thickness and density decreased, the degree of trabecular separation increased, the levels of iron ions and MDA in bone tissue increased, the activity of SOD decreased, and the expression of Nrf2, HO-1 and ferroptosis-related proteins increased ; Compared with the model group, the weight gain of rats increased, the levels of blood glucose and glycosylated hemoglobin decreased, the destruction of bone trabecula decreased, the bone mineral density, bone volume fraction, bone trabecula thickness and density increased, the separation of bone trabecula decreased, the levels of iron ions and MDA in bone tissue decreased, the activity of SOD increased, and the expression of Nrf2, HO-1 and ferroptosis-related proteins decreased. Conclusion : Bushen Zhuanggu Decoction has the characteristics of multi-component, multi-target and multi-pathway in the treatment of T2DOP. The results of in vivo experiments show that Bushen Zhuanggu Decoction can prevent and treat DOP by regulating Nrf2 / HO-1 signaling pathway and inhibiting oxidative stress and ferroptosis.

    参考文献
    相似文献
    引证文献
引用本文
分享
文章指标
  • 点击次数:
  • 下载次数:
  • HTML阅读次数:
  • 引用次数:
历史
  • 收稿日期:2025-07-15
  • 最后修改日期:2025-10-13
  • 录用日期:2025-11-19
  • 在线发布日期:
  • 出版日期: