Effects of Xiaozhong Zhitong Mixture （消肿止痛合剂） on Angiogenesis and the Dll4/Notch1 Signaling Pathway in Wound Tissue of Diabetic Foot Ulcer Model Rats

HAN Xiao; LIU Tao; SONG Yuan; CHEN Jie; SHEN Jiaxuan; QIAO Jing; WANG Hengjie; WU Lewen; ZHAO Yazhou

doi:10.13288/j.11-2166/r.2025.16.012

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Effects of Xiaozhong Zhitong Mixture （消肿止痛合剂） on Angiogenesis and the Dll4/Notch1 Signaling Pathway in Wound Tissue of Diabetic Foot Ulcer Model Rats

更新时间：2025-08-13

- Effects of Xiaozhong Zhitong Mixture （消肿止痛合剂） on Angiogenesis and the Dll4/Notch1 Signaling Pathway in Wound Tissue of Diabetic Foot Ulcer Model Rats
- Journal of Traditional Chinese Medicine Vol. 66, Issue 16, Pages: 1695-1703(2025)
- 作者机构：
  
  1.甘肃中医药大学，甘肃省兰州市城关区定西东路35号，730030
  2.甘肃省中医院
  3.包头市蒙医中医医院
- 作者简介：
- 基金信息：
- DOI：10.13288/j.11-2166/r.2025.16.012
  CLC：
- Received：23 February 2025，
  
  Revised：2025-06-13，
  
  Published：17 August 2025
- 稿件说明：
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韩潇,刘涛,宋渊等.消肿止痛合剂对糖尿病足溃疡模型大鼠创面组织血管生成及Dll4/Notch1信号通路的影响[J].中医杂志,2025,66(16):1695-1703.

HAN Xiao,LIU Tao,SONG Yuan,et al.Effects of Xiaozhong Zhitong Mixture （消肿止痛合剂） on Angiogenesis and the Dll4/Notch1 Signaling Pathway in Wound Tissue of Diabetic Foot Ulcer Model Rats[J].Journal of Traditional Chinese Medicine,2025,66(16):1695-1703.
韩潇,刘涛,宋渊等.消肿止痛合剂对糖尿病足溃疡模型大鼠创面组织血管生成及Dll4/Notch1信号通路的影响[J].中医杂志,2025,66(16):1695-1703. DOI： 10.13288/j.11-2166/r.2025.16.012.

HAN Xiao,LIU Tao,SONG Yuan,et al.Effects of Xiaozhong Zhitong Mixture （消肿止痛合剂） on Angiogenesis and the Dll4/Notch1 Signaling Pathway in Wound Tissue of Diabetic Foot Ulcer Model Rats[J].Journal of Traditional Chinese Medicine,2025,66(16):1695-1703. DOI： 10.13288/j.11-2166/r.2025.16.012.

摘要

目的

探讨消肿止痛合剂治疗糖尿病足溃疡的可能作用机制。

方法

将50只SD大鼠随机分为空白组、模型组、消肿止痛合剂组、抑制剂组、消肿止痛合剂+抑制剂组，每组10只。除空白组外，其余各组大鼠采用高糖高脂高胆固醇饲料喂养、腹腔注射链脲佐菌素和皮肤缺损法构建糖尿病足溃疡大鼠模型。造模成功后，消肿止痛合剂组、消肿止痛合剂+抑制剂组给予消肿止痛合剂1 m/（100 g·d）灌胃，空白组、模型组、抑制剂组均给予等体积0.9%氯化钠注射液灌胃，灌胃30 min后抑制剂组、消肿止痛合剂+抑制剂组再腹腔注射Notch1抑制剂DAPT 5 mg/（kg·d），均每天灌胃1次。各组干预14天后，取空白组大鼠足背部皮肤组织及其余各组大鼠创面组织，采用HE染色法检测皮肤/创面组织病理学变化；免疫组化染色法检测皮肤/创面组织中微血管密度（MVD）；RT-PCR法和Western Blot法分别检测皮肤/创面组织中Notch 1同源蛋白（

Notch1

）、Delta样配体4（

Dll4

）、血管内皮生长因子A（

VEGFA

）、血管生成素2（

Ang

） mRNA表达及蛋白水平。

结果

病理学结果显示，空白组大鼠足背部正常皮肤组织中表皮结构完整；模型组创面组织中表皮组织呈现角化过度现象，胞质呈现空泡化状态，组织中存在大量炎症细胞浸润；消肿止痛合剂组创面组织中可见表皮层形成大量痂皮，未见明显炎症细胞浸润，成纤维细胞数量明显增多；消肿止痛合剂+抑制剂组和抑制剂组创面组织中可见表皮层部分痂皮形成，有少量炎症细胞浸润。与空白组比较，模型组创面组织中MVD升高，

Notch1、Dll4

mRNA表达及蛋白水平升高，

VEGFA、Ang

mRNA表达及其蛋白水平降低（

＜0.05或

＜0.01）。与模型组比较，各药物干预组创面组织中MVD升高，

Notch1、Dll4

mRNA表达及蛋白水平降低，

VEGFA、Ang

mRNA表达及蛋白水平升高（

＜0.05或

＜0.01）。与消肿止痛合剂组比较，抑制剂组、消肿止痛合剂+抑制剂组创面组织中MVD降低，

Notch1、Dll4

mRNA表达及蛋白水平升高，

VEGFA、Ang

mRNA表达及蛋白水平降低（

＜0.05或

＜0.01）。

结论

消肿止痛合剂能有效促进糖尿病足溃疡模型大鼠创面愈合，其作用机制可能与抑制创面组织中Dll4/Notch1信号通路，从而促进血管生成相关。

Abstract

Objective

To investigate the potential machanism of Xiaozhong Zhitong Mixture （消肿止痛合剂， XZM） in the treatment of diabetes foot ulcer （DFU）.

Methods

Fifty SD rats were randomly divided into blank group， model group， XZM group， inhibitor group， XZM plus inhibitor group （combination group）， with 10 rats in each group. Except for the blank group， rats were fed with high-sugar， high-fat， high-cholesterol diet， intraperitoneally injected with streptozotocin， and subjected to skin defect to establish DFU model. After successful modeling， the XZM group and the combination group were given 1 ml/（100 g·d）of XZM by gavage， while the blank group， model group， and inhibitor group were all given an equal volume of 0.9% sodium chloride injection by gavage. Thirty minutes later， the inhibitor group and the combination group were intraperitoneally injected with 5 mg/（kg·d） of Notch1 inhibitor DAPT. All groups were treated once a day. After 14 days of administration， the skin tissue from the dorsal foot of the blank group rats and wound tissue from the other groups were collected. The pathological changes of granulation tissue in the wound were detected using hematoxylin eosin （HE） staining. The microvascular density （MVD） in wounds was detected through immunohistochemical staining. Real time fluorescence quantitative polymerase chain reaction （RT-PCR） and western blotting were used to detect the mRNA and protein levels of Notch1 homolog （Notch1）， Delta-like ligand 4 （Dll4）， Delta-like ligand 4 （VEGF）， and angiopoietin 2 （Ang-2）， respectively.

Results

Histological results showed that the epidermal structure in the dorsal foot skin tissue of the rats in the blank group was intact. In the wound tissue of the model group， the epidermis exhibited excessive keratinization， vacuolar cytoplasm， and a large number of inflammatory cells infiltrating the tissue， while in the XZM group， a large amount of scab formation was observed in the epidermis， with no significant inflammatory cell infiltration and a noticeable increase in fibroblasts. In the combination group and the inhibitor group， partial epidermal scab formation was observed in the wound tissue with a small amount of inflammatory cell infiltration. Compared to those in the blank group， the MVD in the wound tissue increased in the model group， as well as the mRNA expression and p

rotein levels of Notch1 and Dll4， while VEGFA and Ang-2 mRNA expression and protein levels significantly decreased （

＜0.05 or

＜0.01）. Compared to those in the model group， the MVD in the wound tissue of all medication groups significantly increased， and the mRNA and protein levels of Notch1 and Dll4 decreased， while VEGFA and Ang-2 mRNA expression and protein levels increased （

＜0.05 or

＜0.01）. Compared to the XZM group， the inhibitor group and the combination group showed decreased MVD in wound tissue， increased Notch1 and Dll4 mRNA and protein levels， and decreased expression of VEGFA and Ang-2 mRNA and proteins （

＜0.05 or

＜0.01）.

Conclusion

XZM can effectively promote wound healing in DFU rats， and its mechanism of action may be related to the inhibition of Dll4/Notch1 signaling pathway in the wound tissue， therey promoting angiogenesis.

关键词

Keywords

references

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