Zuyangping (足疡平) formula promotes skin wound healing in diabetic rats

doi:10.19852/j.cnki.jtcm.2024.06.008

Abstract

Abstract:

OBJECTIVE: To evaluate the effects of Zuyangping (足疡平, ZYP) formula on wound healing in diabetic rats, as well as the molecular mechanisms involved.

METHODS: The main compounds in ZYP formula were identified by the Liquid chromatography-tandem mass spectrometry. Sprague-Dawley rats, injected with streptozotocin (STZ) to establish diabetes model, then, formed a defective skin trauma in the back, and each group was treated with corresponding drugs once a day. Granulation was taken from each time node for histological analysis. The Western blotting was used to measured protein expression of advanced glycation end products receptor (RAGE) and hypoxia-inducible factor-1α (HIF-1α) axis-related proteins. The relative expression levels of inflammatory cytokines and growth factors were measured by the enzyme-linked immunosorbent assay method.

RESULTS: The main ingredients were identified in the ZYP formula. Histological analysis showed that the ZYP formula could inhibit the expression of inflammation, promote angiogenesis and collagen deposition. In addition, the ZYP formula could regulate the expression of RAGE and HIF1-α axis-related proteins, thus promoting the wound healing in diabetic rats.

CONCLUSION: The ZYP formula could accelerate wound healing in diabetic rats.

Key words: wound healing, angiogenesis, diabetic skin ulcer, Zuyangping formula

MENG Junhua, ZHANG Hong, CAO Yuling, ZHANG Yu, WANG Xiong, SHENG Bi, AN Jing, CHEN Yonggang. Zuyangping (足疡平) formula promotes skin wound healing in diabetic rats[J]. Journal of Traditional Chinese Medicine, 2024, 44(6): 1194-1203.

Figures/Tables 5

Table 1 Changes in venous blood glucose levels in rats ($\bar{x}±s$, mmol/L)

Time point	Normal group (n = 5)	Model group (n = 5)	ZYP group (n = 5)	rhEGF group (n = 5)	SSD group (n = 5)
Before injection of STZ	6.59±0.35	6.78±0.44	6.72±0.43	6.70±0.48	6.64±0.60
Day 7 after STZ injection	6.17±0.40	29.72±3.30^a	30.44±2.66^a	28.20±1.78^a	29.78±3.34^a
Day 14 after STZ injection	6.28±0.23	31.94±1.38^a	32.90±0.46^a	30.04±2.86^a	29.30±3.87^a
Day 7 after treatment	6.21±0.41	30.28±3.44^a	27.32±2.70^a	28.40±3.19^a	28.94±3.47^a
Day 14 after treatment	6.26±0.31	30.02±2.62^a	24.68±2.06^ab	27.20±3.16^a	28.78±3.82^a

Figure 1 Morphological effects on rat wounds A: chromatograms of standard and ZYP extracts; A1: chromatograms of standard; A2: chromatograms of ZYP extracts. B1-B5: representative images of skin wounds at days 0 after surgery from all groups. B6-B10: representative images of skin wounds at days 7 after surgery from all groups. B11-B15: representative images of skin wounds at days 14 after surgery from all groups. B1, B6, B11: Normal group; B2, B7, B12: Model group; B3, B8, B13: ZYP group; B4, B9, B14: rhEGF group; B5, B10, B15: SSD group. C1-C2: wound closure rate at days 7 and 14 post surgery in each group. Normal group: normal rats with skin ulcer; Model group: non-intervention group after the establishment of diabetic ulcer model; ZYP group: after modelling diabetic ulcer, treatment with ZYP formula; rhEGF group: after modelling diabetic ulcer, treatment with epidermal growth factor; SSD group: after modelling diabetic ulcer, treatment with 1% sulfadiazine silver cream. ZYP: Zuyangping; rhEGF: epidermal growth factor; SSD: 1% sulfadiazine silver cream. Values are shown as mean ± standard deviation (n = 5). All the treated groups were compared with the model group using the Dunnett’s test. Student’s t-test was used to compare differences between the normal and model groups. aP < 0.05, compared with the normal group, bP < 0.05, compared with the model group.

Figure 2 Representative immunohistochemical staining of AGEs and CD31 in the granulation tissue of rats (×100) A1-A5: representative images of immunohistochemistry staining of AGEs at days 7 after surgery from all groups; A6-A10: Representative images of immunohistochemistry staining of AGEs at days 14 after surgery from all groups; A11-A15: representative images of immunohistochemistry staining of CD31 at days 7 after surgery from all groups; A16-A20: representative images of immunohistochemistry staining of CD31 at days 14 after surgery from all groups. A1, A6, A11, A16: Normal group; A2, A7, A12, A17: Model group; A3, A8, A13, A18: ZYP group; A4, A9, A14, A19: rhEGF group; A5, A10, A15, A20: SSD group. B1-B2: statistical analysis of AGEs staining positive cells at days 7 and 14 post surgery, cells were calculated by IPP software. C1-C2: statistical analysis of the number of capillary vessels at days 7 and 14 post surgery, capillary vessels per field were calculated by IPP software. Normal group: normal rats with skin ulcer; Model group: Non-intervention group after the establishment of diabetic ulcer model; ZYP group: after modelling diabetic ulcer, treatment with ZYP formula; rhEGF group: after modelling diabetic ulcer, treatment with epidermal growth factor; SSD group: after modelling diabetic ulcer, treatment with 1% sulfadiazine silver cream. AGEs: advanced glycation end products; CD31: platelet endothelial cell adhesion molecule-1; ZYP: Zuyangping; rhEGF: epidermal growth factor; SSD: 1% sulfadiazine silver cream. Values are shown as mean ± standard deviation (n = 3). All the treated groups were compared with the model group using the Dunnett’s test. Student’s t-test was used to compare differences between the normal and model groups. aP < 0.05, compared with the normal group; bP < 0.05, compared with the model group.

Figure 3 Expression of angiogenesis-associated molecules in granulation tissue of diabetic rats at days 7 and 14 post-surgery and the effect of ZYP formula A: Western blotting images at day 7 post surgery; B: after 7 d of surgery, statistical analysis of RAGE expression; C: after 7 d of surgery, statistical analysis of NF-κB p65 expression; D: after 7 d of surgery, statistical analysis of HIF-1α expression; D: after 7 d of surgery, statistical analysis of VEGF expression; F: Western blotting images at day 14 post surgery; G: after 14 d of surgery, statistical analysis of RAGE expression; H: after 14 d of surgery, statistical analysis of NF-κB p65 expression; I: after 14 d of surgery, statistical analysis of HIF-1α expression; J: after 7 d of surgery, statistical analysis of VEGF expression. Normal group: normal rats with skin ulcer; Model group: non-intervention group after the establishment of diabetic ulcer model; ZYP group: after modelling diabetic ulcer, treatment with ZYP formula; rhEGF group: after modelling diabetic ulcer, treatment with epidermal growth factor; SSD group: after modelling diabetic ulcer, treatment with 1% sulfadiazine silver cream. β-actin: beta-actin; RAGE: advanced glycation end products receptor; NF-κB p65: nuclear factor-κB p65; HIF-1α: hypoxia-inducible factor-1α; VEGF: vascular endothelial growth factor; ZYP: Zuyangping; rhEGF: epidermal growth factor; SSD: 1% sulfadiazine silver cream. Values are shown as mean ± standard deviation (n = 3). All the treated groups were compared with the model group using the Dunnett’s test. Student’s t-test was used to compare differences between the normal and model groups. aP < 0.05, compared with the normal group; bP < 0.05, compared with the model group.

Figure 4 ELISA method was used to detect the expression level of related cytokines in granulation tissue of diabetic rats at days 7 and 14 post-surgery and the effect of ZYP formula A: NF-κB p65 expression level at day 7 post-surgery; B: TNF-α expression level at days 7 post-surgery; C: IL-6 expression level at day 7 post-surgery, D: EGF expression level at day 7 post-surgery; E: bFGF expression level at day 7 post-surgery; F: NF-κB p65 expression level at day 14 post-surgery; G: TNF-α expression level at day 14 post-surgery; H: IL-6 expression level at days 14 post-surgery; I: EGF expression level at days 14 post-surgery; J: bFGF expression level at day 14 post-surgery. Normal group: normal rats with skin ulcer; Model group: non-intervention group after the establishment of diabetic ulcer model; ZYP group: after modelling diabetic ulcer, treatment with ZYP formula; rhEGF group: after modelling diabetic ulcer, treatment with epidermal growth factor; SSD group: after modelling diabetic ulcer, treatment with 1% sulfadiazine silver cream. ELISA: enzyme-linked immunosorbent assay; NF-κB p65: nuclear factor-κB p65; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α; EGF: epidermal growth factor; bFGF: basic fibroblast growth factor; ZYP: Zuyangping; rhEGF: epidermal growth factor; SSD: 1% sulfadiazine silver cream. Values are shown as mean ± standard deviation (n = 5). All the treated groups were compared with the model group using the Dunnett’s test. Student’s t-test was used to compare differences between the normal and model groups. aP < 0.05, compared with the normal group; bP < 0.05, compared with the model group.

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