丹参联合罗沙司他对糖尿病大鼠全层皮肤缺损创面愈合的影响及其机制

夏如意; 唐棣; 杨斌

doi:10.3760/cma.j.cn501225-20231020-00124

丹参联合罗沙司他对糖尿病大鼠全层皮肤缺损创面愈合的影响及其机制

doi: 10.3760/cma.j.cn501225-20231020-00124

夏如意¹,
唐棣²,
杨斌^{1, 2, ,}

1.
湖北中医药大学第一临床学院，武汉　　430060
2.
中部战区总医院烧伤整形科，武汉　　　　430070

基金项目:

国家自然科学基金面上项目 81872536

国家自然科学基金青年科学基金项目 82302818

湖北省自然科学基金 2021CFB164

详细信息

通讯作者:
杨斌，Email：pfkyb@foxmail.com

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出版历程
- 收稿日期: 2023-10-20

Effect of salvia miltiorrhiza combined with roxadustat on wound healing of full-thickness skin defects in diabetic rats and its mechanism

Xia Ruyi¹,
Tang Di²,
Yang Bin^{1, 2
, ,}

1.
The First Clinical College of Hubei University of Chinese Medicine, Wuhan 430060, China
2.
Department of Burns and Plastic Surgery, Central Theater Command General Hospital, Wuhan 430070, China

Funds:

General Program of National Natural Science Foundation of China 81872536

Youth Science Foundation Project of National Natural Science Foundation of China 82302818

Natural Science Foundation of Hubei Province of China 2021CFB164

More Information

Corresponding author: Yang Bin, Email: pfkyb@foxmail.com

摘要

摘要: 目的探究丹参联合罗沙司他对糖尿病大鼠全层皮肤缺损创面愈合的影响及其机制。方法该研究为实验研究。将20只8周龄雄性SD大鼠成功制成糖尿病模型后，在其背部制作全层皮肤缺损创面，之后将大鼠按照随机数字表法分为生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组，每组5只。伤后即刻，对生理盐水组大鼠予5 mL生理盐水灌胃，对单纯罗沙司他组大鼠予1.5 mg/mL的罗沙司他混悬液按照25 mg/kg灌胃，对单纯丹参组大鼠予18 mg/mL的丹参混悬液按照300 mg/kg灌胃，对罗沙司他+丹参组的大鼠予19.5 mg/mL的罗沙司他和丹参混悬液按照罗沙司他25 mg/kg、丹参300 mg/kg灌胃，均持续给药2周，1次/d。观察伤后0（即刻）、4、8、12 d创面情况，计算伤后4、8、12 d的创面愈合率（样本数为5）。伤后14 d，取腹主动脉血行血红蛋白、红细胞计数、白细胞计数检测（样本数为5）；取创面组织，行苏木精-伊红染色后观察炎性浸润、皮肤组织结构及新生血管生成情况，行Masson染色后观测胶原纤维占比（样本数为3），行蛋白质印迹法检测血管内皮生长因子（VEGF）、CD31、白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）、IL-1β的蛋白表达水平（样本数为3），行免疫组织化学染色检测表皮生长因子受体（EGFR）、缺氧诱导因子1α（HIF-1α）、增殖细胞核抗原（PCNA）的蛋白表达水平（样本数为3）。结果伤后0~12 d，4组大鼠创面面积均逐渐缩小。伤后4 d，单纯丹参组、罗沙司他+丹参组大鼠创面愈合率均明显高于生理盐水组和单纯罗沙司他组（ P<0.05）；伤后8 d，单纯罗沙司他组和单纯丹参组大鼠创面愈合率均明显高于生理盐水组（ P<0.05），罗沙司他+丹参组大鼠创面愈合率明显高于其余3组（ P值均<0.05）；伤后12 d，单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠创面愈合率均明显高于生理盐水组（ P<0.05）。伤后14 d，4组大鼠的血红蛋白和红细胞计数比较，差异均无统计学意义（ P>0.05）；单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠白细胞计数分别为（24.3±1.2）×10 ⁹/L、（26.3±2.4）×10 ⁹/L、（15.0±0.7）×10 ⁹/L，均明显低于生理盐水组的（33.8±2.7）×10 ⁹/L（ P<0.05）；罗沙司他+丹参组大鼠白细胞计数明显低于单纯罗沙司他组和单纯丹参组（ P值均<0.05）。伤后14 d，生理盐水组大鼠创面可见大量炎症细胞浸润，皮肤组织结构紊乱，新生血管少；其余3组大鼠创面可见少量炎症细胞浸润，皮肤组织结构紧密，新生血管丰富。4组大鼠创面的胶原纤维占比组间总体比较，差异无统计学意义（ P>0.05）。伤后14 d，单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠创面组织中VEGF、CD31的蛋白表达水平均明显高于生理盐水组（ P<0.05），罗沙司他+丹参组大鼠创面组织中CD31的蛋白表达水平明显高于单纯罗沙司他组和单纯丹参组（ P值均<0.05）。伤后14 d，单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠创面组织中IL-6、TNF-α、IL-1β的蛋白表达水平均明显低于生理盐水组（ P<0.05），罗沙司他+丹参组大鼠创面组织中IL-6、IL-1β的蛋白表达水平均明显低于单纯罗沙司他组和单纯丹参组（ P<0.05），罗沙司他+丹参组大鼠创面组织中TNF-α的蛋白表达水平明显低于单纯丹参组（ P<0.05）。伤后14 d，罗沙司他+丹参组大鼠创面组织中EGFR的蛋白表达水平明显高于其余3组（ P值均<0.05）；单纯罗沙司他组和罗沙司他+丹参组大鼠创面组织中HIF-1α的蛋白表达水平均明显高于生理盐水组（ P<0.05），罗沙司他+丹参组大鼠创面组织中HIF-1α的蛋白表达水平明显高于单纯丹参组（ P<0.05）；4组大鼠创面组织中PCNA的蛋白表达水平比较，差异无统计学意义（ P>0.05）。结论罗沙司他联合丹参可以通过促进血管再生、降低炎症反应，进而促进糖尿病大鼠全层皮肤缺损创面愈合。
- 糖尿病，实验性 /
- 伤口愈合 /
- 丹参 /
- 炎症 /
- 血管内皮生长因子类 /
- 受体，表皮生长因子 /
- 缺氧诱导因子1，α亚基 /
- 罗沙司他
Abstract: Objective To explore the effect of salvia miltiorrhiza combined with roxadustat on wound healing of full-thickness skin defects in diabetic rats and its mechanism. Methods This study was an experimental study. Twenty male 8-week-old Sprague-Dawley rats were used to successfully establish diabetic model, then full-thickness skin defect wounds on their backs were made. The rats were divided into normal saline group, roxadustat alone group, salvia miltiorrhiza alone group, and roxadustat+salvia miltiorrhiza group according to the random number table, with 5 rats in each group. Immediately after injury, the rats in normal saline group were given 5 mL normal saline by gavage, the rats in roxadustat alone group were given 1.5 mg/mL roxadustat suspension by gavage at 25 mg/kg, the rats in salvia miltiorrhiza alone group were given 18 mg/mL salvia miltiorrhiza suspension by gavage at 300 mg/kg, and the rats in roxadustat+salvia miltiorrhiza group were given 19.5 mg/mL roxadustat and salvia miltiorrhiza suspension at roxadustat 25 mg/kg and salvia miltiorrhiza 300 mg/kg. All were administered once a day for 2 weeks. The wounds at 0 (immediately), 4, 8, and 12 d after injury were observed, and the wound healing rates at 4, 8, and 12 d after injury were calculated ( n=5). At 14 d after injury, abdominal aortic blood was collected, and hemoglobin, red cell count, and white blood cell count were detected ( n=5). The wound tissue was collected for hematoxylin-eosin staining to observe inflammatory infiltration, skin tissue structure, and neovascularization, for Masson staining to observe the proportion of collagen fiber ( n=3), for Western blotting to detect the protein expression levels of vascular endothelial growth factor (VEGF), CD31, interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and IL-1β ( n=3), and for immunohistochemical staining to determine the protein expression levels of epidermal growth factor receptor (EGFR), hypoxia-inducible factor 1α (HIF-1α), and proliferating cell nuclear antigen (PCNA), with sample number of 3. Results From 0 to 12 d after injury, the wound areas of rats in 4 groups were gradually decreased. At 4 d after injury, the wound healing rates of rats in salvia miltiorrhiza alone group and roxadustat+salvia miltiorrhiza group were significantly higher than those in normal saline group and roxadustat alone group ( P<0.05). At 8 d after injury, the wound healing rates of rats in roxadustat alone group and salvia miltiorrhiza alone group were significantly higher than the rate in normal saline group ( P<0.05), and the wound healing rate of rats in roxadustat+salvia miltiorrhiza group was significantly higher than the rates in the other 3 groups (with P values all <0.05). At 12 d after injury, the wound healing rates of rats in roxadustat alone group, salvia miltiorrhiza alone group, and roxadustat+salvia miltiorrhiza group were significantly higher than the rate in normal saline group ( P<0.05). At 14 d after injury, there were no statistically significant differences in the hemoglobin or red blood cell count of rats in 4 groups ( P<0.05). The white blood cell count of rats in roxadustat alone group, salvia miltiorrhiza alone group, and roxadustat+salvia miltiorrhiza group were respectively (24.3±1.2)×10 ⁹/L, (26.3±2.4)×10 ⁹/L, and (15.0±0.7)×10 ⁹/L, which were significantly lower than (33.8±2.7)×10 ⁹/L in normal saline group ( P<0.05); the white blood cell count of rats in roxadustat+salvia miltiorrhiza group was significantly lower than that in roxadustat alone group and salvia miltiorrhiza alone group (with Pvalues both <0.05). At 14 d after injury, a large number of inflammatory cell infiltration, disordered skin tissue structure, and few new blood vessels were observed in the wounds of rats in normal saline group; while a small amount of inflammatory cell infiltration, tight skin tissue structure, and rich neovascularization were observed in the wounds of rats in the other 3 groups. There were no statistically significant differences in the proportion of collagen fiber of wounds in rats among the 4 groups ( P>0.05). At 14 d after injury, the protein expression levels of VEGF and CD31 in the wound tissue of rats in roxadustat alone group, salvia miltiorrhiza alone group, and roxadustat+salvia miltiorrhiza group were significantly higher than those in normal saline group ( P<0.05), the protein expression level of CD31 in the wound tissue of rats in roxadustat+salvia miltiorrhiza group was significantly higher than the levels in roxadustat alone group and salvia miltiorrhiza alone group (with P values both <0.05). At 14 d after injury, the protein expression levels of IL-6, TNF-α, and IL-1β in the wound tissue of rats in roxadustat alone group, salvia miltiorrhiza alone group, and roxadustat+salvia miltiorrhiza group were significantly lower than those in normal saline group ( P<0.05); the protein expression levels of IL-6 and IL-1β in the wound tissue of rats in roxadustat+salvia miltiorrhiza group were significantly lower than those in roxadustat alone group and salvia miltiorrhiza alone group ( P<0.05); the protein expression level of TNF-α in the wound tissue of rats in roxadustat+salvia miltiorrhiza group was significantly lower than that in salvia miltiorrhiza alone group ( P<0.05). At 14 d after injury, the protein expression level of EGFR in the wound tissue of rats in roxadustat+salvia miltiorrhiza group was significantly higher than the levels in the other 3 groups (with P values all <0.05); the protein expression levels of HIF-1α in the wound tissue of rats in roxadustat alone group and roxadustat+salvia miltiorrhiza group were significantly higher than the level in normal saline group ( P<0.05), and the protein expression level of HIF-1α in the wound tissue of rats in roxadustat+salvia miltiorrhiza group was significantly higher than that in salvia miltiorrhiza alone group ( P<0.05); there were no statistically significant differences in the protein expression level of PCNA in the wound tissue of rats in 4 groups ( P>0.05). Conclusions Roxadustat combined with salvia miltiorrhiza can promote the wound healing of full-thickness skin defects in diabetic rats by promoting blood vessel regeneration and reducing inflammatory response.
- Diabetes mellitus, experimental /
- Wound healing /
- Salvia miltiorrhiza /
- Inflammation /
- Vascular endothelial growth factors /
- Receptor, epidermal growth factor /
- Hypoxia-inducible factor 1, alpha subunit /
- Roxadustat
夏如意：实验操作、论文撰写、数据整理、统计学分析；唐棣：研究指导、论文修改；杨斌：研究指导、论文修改、经费支持

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1 4组糖尿病大鼠伤后各时间点全层皮肤缺损创面愈合情况。1A、1B、1C.分别为生理盐水组伤后0（即刻）、8、12 d创面情况；1D、1E、1F.分别为单纯罗沙司他组伤后0、8、12 d创面情况，图1E、1F创面面积分别小于图1B、1C； 1G、1H、1I，1J、1K、1L.分别为单纯丹参组、罗沙司他+丹参组伤后0、8、12 d创面情况，图1H、1K创面面积均小于图1B，图1I、1L创面面积均小于图1C

注：对生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠分别给予生理盐水、罗沙司他、丹参、罗沙司他+丹参灌胃

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2 4组糖尿病大鼠伤后14 d全层皮肤缺损创面组织病理变化和胶原纤维情况。2A、2B、2C、2D.分别为生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组的创面组织病理变化，图2D的创面皮肤组织结构和血管生成优于图2A、2B、2C，炎性浸润明显比图2A、2B、2C轻苏木精伊红×100；2E、2F、2G、2H.分别为生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组的创面胶原纤维（阳性染色为蓝色）情况，图2H的胶原纤维占比多于图2E、2F、2G Masson×100

注：对生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠分别给予生理盐水、罗沙司他、丹参、罗沙司他+丹参灌胃

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3 蛋白质印迹法检测的4组糖尿病大鼠伤后14 d全层皮肤缺损创面组织中VEGF和CD31的蛋白表达

注：VEGF为血管内皮生长因子，GAPDH为3-磷酸甘油醛脱氢酶；条带上方1、2、3、4分别指示给予生理盐水灌胃的生理盐水组、给予罗沙司他灌胃的单纯罗沙司他组、给予丹参灌胃的单纯丹参组、给予罗沙司他和丹参灌胃的罗沙司他+丹参组

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4 蛋白质印迹法检测的4组糖尿病大鼠伤后14 d全层皮肤缺损创面组织中炎症因子的蛋白表达

注：IL为白细胞介素，TNF-α为肿瘤坏死因子α，GAPDH为3-磷酸甘油醛脱氢酶；条带上方1、2、3、4分别指示给予生理盐水灌胃的生理盐水组、给予罗沙司他灌胃的单纯罗沙司他组、给予丹参灌胃的单纯丹参组、给予罗沙司他和丹参灌胃的罗沙司他+丹参组

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5 4组糖尿病大鼠伤后14 d全层皮肤缺损创面组织中EGFR、HIF-1α、PCNA的蛋白表达二氨基联苯胺苏木精×100。5A、5B、5C、5D.分别为生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠创面EGFR的表达情况，均有阳性表达，图5D阳性表达明显多于图5A、5B、5C；5E、5F、5G、5H.分别为生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠创面HIF-1α的表达情况，均有阳性表达，图5F、5H阳性表达明显多于图5E、5G；5I、5J、5K、5L.分别为生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠创面PCNA的表达情况，均有阳性表达，图5L阳性表达稍多于图5I、5J、5K

注：对生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠分别给予生理盐水、罗沙司他、丹参、罗沙司他+丹参灌胃；EGFR为表皮生长因子受体、HIF-1α为缺氧诱导因子1α、PCNA为增殖细胞核抗原；EGFR、HIF-1α、PCNA阳性表达均为棕色

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表1 4组糖尿病大鼠伤后各时间点全层皮肤缺损创面愈合率比较（%， x ¯ ± s ）

表1. Comparison of the wound healing rates of full-thickness skin defects in four groups of diabetic rats at various time points after injury

组别	样本数	4 d	8 d	12 d
生理盐水组	5	31.2±14.9	61.5±6.9	81.9±8.4
单纯罗沙司他组	5	30.4±8.0	72.4±3.9 ^a	93.8±1.8 ^a
单纯丹参组	5	52.5±8.8 ^ab	76.4±10.1 ^a	93.3±4.1 ^a
罗沙司他+丹参组	5	51.8±10.2 ^ab	85.9±3.9 ^abc	94.6±3.6 ^a
F值		6.51	11.33	6.69
P值		0.004	<0.001	0.004
注：对生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠分别给予生理盐水、罗沙司他、丹参、罗沙司他+丹参灌胃；处理因素主效应， F=12.50， P<0.001；时间因素主效应， F=260.32， P<0.001；两者交互作用， F=3.37， P=0.011；与生理盐水组比较， ^a P<0.05；与单纯罗沙司他组比较， ^b P<0.05；与单纯丹参组比较， ^c P<0.05

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表2 4组糖尿病全层皮肤缺损大鼠伤后14 d血常规指标比较（ x ¯ ± s ）

表2. Comparison of the blood routine indexes in four groups of diabetic rats with full-thickness skin defect wounds at 14 d after injury

组别	样本数	血红蛋白（g/L）	红细胞计数（×10 ¹²/L）	白细胞计数（×10 ⁹/L）
生理盐水组	5	102±16	3.0±0.3	33.8±2.7
单纯罗沙司他组	5	104±16	3.3±0.5	24.3±1.2 ^a
单纯丹参组	5	94±11	3.4±0.4	26.3±2.4 ^a
罗沙司他+丹参组	5	106±16	3.0±0.4	15.0±0.7 ^abc
F值		0.85	1.52	82.13
P值		0.485	0.248	<0.001
注：对生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠分别给予生理盐水、罗沙司他、丹参、罗沙司他+丹参灌胃；血红蛋白、红细胞计数、白细胞计数的罗沙司他主效应， F值分别为1.49、0.02、148.57， P值分别为0.241、0.904、<0.001；丹参主效应， F值分别为0.23、0.57、96.70， P值分别为0.638、0.566、<0.001；两者交互作用， F值分别为0.85、4.20、1.12， P值分别为0.371、0.057、0.305；与生理盐水组比较， ^a P<0.05；与单纯罗沙司他组比较， ^b P<0.05；与单纯丹参组比较， ^c P<0.05

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表3 4组糖尿病大鼠伤后14 d全层皮肤缺损创面组织中VEGF与CD31的蛋白表达比较（ x ¯ ± s ）

表3. Comparison of the protein expressions of VEGF and CD31 in the wound tissue of full-thickness skin defects in 4 groups of diabetic rats at 14 d after injury

组别	样本数	VEGF	CD31
生理盐水组	3	0.18±0.08	0.31±0.07
单纯罗沙司他组	3	0.75±0.26 ^a	0.61±0.05 ^a
单纯丹参组	3	0.53±0.12 ^a	0.54±0.09 ^a
罗沙司他+丹参组	3	0.86±0.20 ^a	0.83±0.11 ^abc
F值		8.57	20.58
P值		0.007	<0.001
注：VEGF为血管内皮生长因子；对生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠分别给予生理盐水、罗沙司他、丹参、罗沙司他+丹参灌胃；VEGF、CD31的蛋白表达的罗沙司他主效应， F值分别为19.39、39.09， P值分别为0.002、<0.001；丹参主效应， F值分别为4.97、22.64， P值分别为0.056、0.001；两者交互作用， F值分别为1.34、0.03， P值分别为0.281、0.870；与生理盐水组比较， ^a P<0.05；与单纯罗沙司他组比较， ^b P<0.05；与单纯丹参组比较， ^c P<0.05

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表4 4组糖尿病大鼠伤后14 d全层皮肤缺损创面组织中炎症因子的蛋白表达比较（ x ¯ ± s ）

表4. Comparison of the protein expressions of inflammatory factors in the wound tissue of full-thickness skin defects in 4 groups of diabetic rats at 14 d after injury

组别	样本数	IL-6	TNF-α	IL-1β
生理盐水组	3	0.98±0.19	0.97±0.17	0.895±0.024
单纯罗沙司他组	3	0.48±0.07 ^a	0.18±0.06 ^a	0.321±0.186 ^a
单纯丹参组	3	0.52±0.10 ^a	0.41±0.19 ^a	0.377±0.135 ^a
罗沙司他+丹参组	3	0.08±0.05 ^abc	0.08±0.06 ^ac	0.081±0.051 ^abc
F值		30.55	27.09	25.20
P值		<0.001	<0.001	<0.001
注：对生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠分别给予生理盐水、罗沙司他、丹参、罗沙司他+丹参灌胃；IL为白细胞介素，TNF-α为肿瘤坏死因子α；IL-6、TNF-α、IL-1β的蛋白表达的罗沙司他主效应， F值分别为49.57、53.18、40.63， P值分别为<0.001、<0.001、<0.001；丹参主效应， F值分别为41.92、19.30、30.82， P值分别为<0.001、0.002、0.001；两者交互作用， F值分别为0.16、8.80、4.14， P值分别为0.703、0.018、0.076；与生理盐水组比较， ^a P<0.05；与单纯罗沙司他组比较， ^b P<0.05；与单纯丹参组比较， ^c P<0.05

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表5 4组糖尿病大鼠伤后14 d全层皮肤缺损创面组织中促愈合蛋白的蛋白表达比较（%， x ¯ ± s ）

表5. Comparison of the protein expressions of pro-healing proteins in the wound tissue of full-thickness skin defects in 4 groups of diabetic rats at 14 d after injury

组别	样本数	EGFR	HIF-1α	PCNA
生理盐水组	3	7.6±2.1	12.6±1.5	15.5±2.4
单纯罗沙司他组	3	9.6±4.3	17.8±1.4 ^a	15.7±0.8
单纯丹参组	3	12.4±2.3	13.6±3.8	17.5±0.4
罗沙司他+丹参组	3	22.3±4.7 ^abc	22.4±4.6 ^ac	18.8±3.5
F值		10.19	8.32	1.60
P值		0.004	0.008	0.264
注：EGFR为表皮生长因子受体、HIF-1α为缺氧诱导因子1α、PCNA为增殖细胞核抗原；对生理盐水组、单纯罗沙司他组、单纯丹参组、罗沙司他+丹参组大鼠分别给予生理盐水、罗沙司他、丹参、罗沙司他+丹参灌胃；EGFR、HIF-1α、PCNA的蛋白表达的罗沙司他主效应， F值分别为8.57、20.42、0.35， P值分别为0.019、0.002、0.572；丹参主效应， F值分别为18.35、3.16、0.15， P值分别为0.003、0.113、0.705；两者交互作用， F值分别为3.76、1.38、3.70， P值分别为0.089、0.275、0.091；与生理盐水组比较， ^a P<0.05；与单纯罗沙司他组比较， ^b P<0.05；与单纯丹参组比较， ^c P<0.05

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