Effects of astragaloside Ⅰ on full-thickness skin defects in diabetic rats and its underlying mechanism
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摘要:
目的 探讨黄芪皂苷Ⅰ（AS-Ⅰ）对糖尿病大鼠全层皮肤缺损的影响及其机制。 方法 该研究为成组设计、重复测量设计的实验研究。将24只6~8周龄雄性SD大鼠按照随机数字表法（分组方法下同）分为对照组（6只）和造模组（18只）,后者在构建糖尿病大鼠模型成功后进一步分为模型组、低剂量AS-Ⅰ组和高剂量AS-Ⅰ组,每组6只。在所有大鼠背部均制备1个直径10 mm的全层皮肤缺损创面,对照组和模型组大鼠创面给予生理盐水处理,低剂量AS-Ⅰ组和高剂量AS-Ⅰ组大鼠创面分别给予1.15 mmol/L的AS-Ⅰ及11.50 mmol/L的AS-Ⅰ处理,连续给药3 d。计算大鼠伤后3、5、7、9、13、15 d的创面愈合率。伤后15 d,采用Masson染色检测创面组织中的胶原沉积情况,采用免疫组织化学染色检测创面组织中Ki-67的阳性表达情况并计算其表达量。采用网络药理学分析筛选AS-Ⅰ干预糖尿病创面的潜在关键靶点,利用分子对接模拟验证AS-Ⅰ与靶蛋白的结合能力,运用分子动力学模拟验证AS-Ⅰ与叉头框蛋白O1（FOXO1）蛋白相互作用的稳定性。采用蛋白质印迹法检测4组大鼠伤后15 d创面组织中表皮生长因子受体（EGFR）、细胞周期蛋白依赖性激酶2（CDK2）、生长因子受体结合蛋白2（GRB2）、磷脂酰肌醇3-激酶催化亚基α（PIK3CA）、信号转导和转录激活因子3（STAT3）、FOXO1蛋白的表达情况。 结果 与对照组相比,模型组大鼠伤后3、15 d的创面愈合率均显著降低（P<0.05）,低剂量AS-Ⅰ组大鼠伤后7、13 d与高剂量AS-Ⅰ组大鼠伤后5、7、9、13、15 d的创面愈合率均显著升高（P<0.05）；与模型组相比,低剂量AS-Ⅰ组、高剂量AS-Ⅰ组大鼠伤后3、9、13、15 d的创面愈合率均显著升高（P<0.05）。伤后15 d,对照组大鼠创面中胶原纤维排列规整致密；模型组大鼠创面中胶原纤维稀疏杂乱；低剂量AS-Ⅰ组大鼠创面中胶原沉积情况较模型组改善；高剂量AS-Ⅰ组大鼠创面中胶原纤维排列致密有序,成熟度高。伤后15 d,模型组大鼠创面组织中Ki-67表达量显著低于对照组（P<0.05）；低剂量AS-Ⅰ组大鼠创面组织中Ki-67表达量显著高于模型组（P<0.05）；高剂量AS-Ⅰ组大鼠创面组织中Ki-67表达量显著高于对照组、模型组和低剂量AS-Ⅰ组（P值均<0.05）。网络药理学分析结果显示AS-Ⅰ与糖尿病创面交集靶点63个,涉及FOXO信号通路与靶蛋白EGFR、CDK2、GRB2、PIK3CA、STAT3等核心靶点。分子对接模拟结果显示,AS-Ⅰ与前述靶蛋白及FOXO1蛋白可稳定结合。分子动力学模拟结果显示,AS-Ⅰ与FOXO1蛋白具有较强结合力。伤后15 d,与对照组比较,模型组大鼠创面组织中STAT3、GRB2、FOXO1蛋白表达明显上调（P值均<0.05）,而PIK3CA、EGFR、CDK2蛋白表达明显下调（P值均<0.05）；与模型组比较,低剂量AS-Ⅰ组、高剂量AS-Ⅰ组大鼠创面组织中STAT3、GRB2、FOXO1蛋白表达明显下调（P值均<0.05）,而PIK3CA、EGFR、CDK2蛋白表达明显上调（P值均<0.05）；与低剂量AS-Ⅰ组比较,高剂量AS-Ⅰ组大鼠创面组织中STAT3、GRB2、FOXO1蛋白表达明显下调（P值均<0.05）,而PIK3CA、EGFR、CDK2蛋白表达明显上调（P值均<0.05）。 结论 AS-Ⅰ可能通过调控FOXO信号通路,下调STAT3、GRB2、FOXO1蛋白表达,上调PIK3CA、EGFR、CDK2蛋白表达,从而促进糖尿病大鼠全层皮肤缺损创面愈合,改善胶原纤维排列。 Abstract:Objective To investigate the effects of astragaloside I (AS-Ⅰ) on full-thickness skin defects in diabetic rats and its underlying mechanism. Methods This study was an experimental study with grouped design and repeated measures design. Twenty-four male Sprague-Dawley rats aged 6-8 weeks were divided into control group (n=6) and modeling group (n=18) using a random number table method (the same grouping method was used throughout). After successful induction of diabetes mellitus, the modeling group was further divided into model group, low-dose AS-Ⅰ group, and high-dose AS-Ⅰ group, with 6 rats in each group. A full-thickness skin defect wound with a diameter of 10 mm was created on the back of each rat. Wounds in control group group and model group were treated with normal saline, while those in low-dose AS-Ⅰ group and high-dose AS-Ⅰ group were treated with 1.15 and 11.50 mmol/L AS-I, respectively, for 3 consecutive days. Wound healing rates of rats were calculated at post-injury days (PIDs) 3, 5, 7, 9, 13, and 15. At PIDs 15, Masson's trichrome staining was used to assess collagen deposition; immunohistochemical staining was performed to detect Ki-67 positive expression in wound tissues, and the expression level was quantified. Network pharmacology analysis was applied to screen for potential key targets of AS-Ⅰ intervention in diabetic wound healing. Molecular docking simulation was utilized to validate the binding of AS-Ⅰ to the target proteins, and molecular dynamics simulation was performed to verify the stability of the interaction between AS-Ⅰ and forkhead box protein O1 (FOXO1). At PIDs 15, Western blotting was used to determine the protein expression levels of epidermal growth factor receptor (EGFR), cyclin-dependent kinase 2 (CDK2), growth factor receptor-bound protein 2 (GRB2), phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA), signal transducer and activator of transcription 3 (STAT3), and FOXO1 in wound tissues of rats among four groups. Results Compared with those in control group, the wound healing rates of rats in model group at PIDs 3 and 15 were significantly decreased (P<0.05); whereas the healing rates of rats in low-dose AS-Ⅰ group at PIDs 7 and 13, and in high-dose AS-Ⅰ group at PIDs 5, 7, 9, 13, and 15 were significantly increased (P<0.05). Compared with those in model group, wound healing rates of wats in both low-dose AS-Ⅰ group and high-dose AS-I group at PIDs 3, 9, 13, and 15 were significantly increased (P<0.05). At PIDs 15, In control group, collagen fibers in the wounds of rats were regularly and densely arranged; in model group, they were sparse and disorganized; improved collagen deposition in the wounds of rats was observed in low-dose AS-Ⅰ group compared with the model group; collagen fibers in the wounds of rats in high-dose AS-Ⅰ group exhibited densely and orderly arranged with higher maturity. At PID 15, Compared with that in control group, the Ki-67 expression level in wound tissues of rats in model group was significantly lower (P<0.05); compared with that in model group, the Ki-67 expression level in wound tissues of rats in low-dose AS-Ⅰ group was significantly higher (P<0.05); compared with those in control group, model group, and low-dose AS-Ⅰ group, the Ki-67 expression level in wound tissues of rats in high-dose AS-Ⅰ group was significantly higher (with P values all <0.05). The results of network pharmacology analysis identified 63 overlapping targets between AS-Ⅰ-associated targets and diabetic-wound-related targets, involving the FOXO signaling pathway and protein targets including EGFR, CDK2, GRB2, PIK3CA, and STAT3. The results of molecular docking simulation indicated stable binding of AS-Ⅰ to these targets and to FOXO1 protein, while the results of molecular dynamics simulation demonstrated strong binding affinity between AS-Ⅰ and FOXO1 protein. Compared with those in control group, the protein expression levels of STAT3, GRB2, and FOXO1 in wound tissue of rats in model group were significantly upregulated (with P values all <0.05), while the protein expression levels of PIK3CA, EGFR, and CDK2 were significantly downregulated (with P values all <0.05). Compared with those in model group, the protein expression levels of STAT3, GRB2, and FOXO1 in wound tissue of rats in low-dose group and high-dose AS-Ⅰ group were significantly downregulated (with P values all <0.05), while the protein expression levels of PIK3CA, EGFR, and CDK2 were significantly upregulated (with P values all <0.05). Compared with those in low-dose AS-Ⅰ group, the protein expression levels of STAT3, GRB2, and FOXO1 in wound tissue of rats in high-dose AS-Ⅰ group were significantly downregulated (with P values all <0.05), while the protein expression levels of PIK3CA, EGFR, and CDK2 were significantly upregulated (with P values all <0.05). Conclusions AS-Ⅰ may promote wound healing in full-thickness skin defects of diabetic rats and improve collagen fiber arrangement by regulating the FOXO signaling pathway, which downregulates STAT3, GRB2, and FOXO1 protein expression and upregulates PIK3CA, EGFR, and CDK2 protein expression. -
参考文献
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图 1 4组大鼠伤后各时间点全层皮肤损伤创面愈合情况。1A、1B、1C、1D.分别为对照组、模型组、低剂量AS-Ⅰ组、高剂量AS-Ⅰ组大鼠伤后即刻创面情况；1E、1F、1G、1H.分别为对照组、模型组、低剂量AS-Ⅰ组、高剂量AS-Ⅰ组大鼠伤后7 d创面情况,图1G、1H创面面积均明显小于图1E；1I、1J、1K、1L.分别为对照组、模型组、低剂量AS-Ⅰ组、高剂量AS-Ⅰ组大鼠伤后15 d创面情况,图1I、1K、1L创面面积均明显小于图1J；图1L创面面积明显小于图1I
注：对照组大鼠正常饮食,其创面给予生理盐水处理；模型组、低剂量黄芪皂苷Ⅰ（AS-Ⅰ）组及高剂量AS-Ⅰ组大鼠在糖尿病模型构建成功后,其创面分别给予生理盐水、1.15 mmol/L的AS-Ⅰ及11.50 mmol/L的AS-Ⅰ处理；全层缺损创面直径为10 mm
图 2 4组糖尿病大鼠伤后15 d全层皮肤缺损创面组织学变化和胶原沉积情况。2A、2B、2C、2D.分别为对照组、模型组、低剂量AS-Ⅰ组、高剂量AS-Ⅰ组创面组织学变化,图2D中新生肉芽组织与上皮化程度明显优于图2B 苏木精-伊红 ×40；2E、2F、2G、2H.分别为对照组、模型组、低剂量AS-Ⅰ组、高剂量AS-Ⅰ组大鼠创面中胶原沉积情况,图2H较图2F、2G中胶原纤维排列更加有序致密 Masson ×80
注：对照组大鼠正常饮食,创面给予生理盐水处理；模型组、低剂量黄芪皂苷Ⅰ（AS-Ⅰ）组及高剂量AS-Ⅰ组大鼠在糖尿病模型构建成功后,其创面分别给予生理盐水、1.15 mmol/L的AS-Ⅰ及11.50 mmol/L的AS-Ⅰ处理
图 3 4组糖尿病大鼠伤后15 d全层皮肤缺损创面组织的增殖情况 辣根过氧化酶 ×400。3A、3B、3C、3D.分别为对照组、模型组、AS-Ⅰ低剂量、高剂量AS-Ⅰ组的大鼠创面组织中Ki-67阳性表达（反映增殖）情况,图3D中Ki-67表达量明显高于图3A、3B、3C
注：对照组大鼠正常饮食,其创面给予生理盐水处理；模型组、低剂量黄芪皂苷Ⅰ（AS-Ⅰ）组及高剂量AS-Ⅰ组大鼠在糖尿病模型构建成功后,其创面分别给予生理盐水、1.15 mmol/L的AS-Ⅰ及11.50 mmol/L的AS-Ⅰ处理
图 4 蛋白质印迹法检测的4组大鼠创面组织伤后15 d全层皮肤缺损创面组织中相关蛋白表达
注：STAT3为信号转导和转录激活因子3,PIK3CA为磷脂酰肌醇3-激酶催化亚基α,GRB2为生长因子受体结合蛋白2,FOXO1为叉头框蛋白O1,EGFR为表皮生长因子受体,CDK2为细胞周期蛋白依赖性激酶2；条带上方1、2、3、4分别代表对照组、模型组、低剂量黄芪皂苷Ⅰ（AS-Ⅰ）组、高剂量AS-Ⅰ组；对照组大鼠正常饮食,其创面给予生理盐水处理；模型组、低剂量AS-Ⅰ组及高剂量AS-Ⅰ组大鼠在糖尿病模型构建成功后,其创面分别给予生理盐水、1.15 mmol/L的AS-Ⅰ及11.50 mmol/L的AS-Ⅰ处理
Table 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（%,
组别 样本数 3 d 5 d 7 d 9 d 11 d 13 d 15 d 对照组 6 19.7±3.0 17.4±6.4 19.7±2.1 34.3±2.0 50.0±3.0 70.0±7.1 83.6±3.9 模型组 6 15.7±2.1a 22.1±2.6 23.7±5.1 31.7±2.5 52.2±3.8 64.8±3.5 76.4±2.5a 低剂量AS-Ⅰ组 6 19.6±1.9b 22.6±3.4 25.5±3.2a 39.4±5.7b 55.5±6.3 84.7±5.8ab 88.1±6.1b 高剂量AS-Ⅰ组 6 20.6±2.6b 25.3±2.6a 26.3±1.9a 42.4±1.9ab 59.6±9.5 88.9±6.1ab 94.2±1.9ab F值 5.83 3.92 4.76 12.00 2.67 23.10 21.71 P值 0.005 0.024 0.012 <0.001 0.074 <0.001 <0.001 注：对照组大鼠正常饮食,其创面给予生理盐水处理；模型组、低剂量黄芪皂苷Ⅰ（AS-Ⅰ）组及高剂量AS-Ⅰ组大鼠在糖尿病模型构建成功后,其创面分别给予生理盐水、1.15 mmol/L的AS-Ⅰ及11.50 mmol/L的AS-Ⅰ处理；处理因素主效应,F=215.60,P<0.001；时间因素主效应,F=398.00,P<0.001；两者交互作用,F=24.38,P<0.001；与对照组相比,aP<0.05；与模型组相比,bP<0.05 
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Table 2. 4组大鼠创面组织伤后15 d全层皮肤缺损创面组织中相关蛋白表达量比较（
组别 STAT3 PIK3CA GRB2 FOXO1 EGFR CDK2 对照组 0.365±0.017 1.404±0.029 0.276±0.018 0.470±0.012 1.209±0.008 1.415±0.016 模型组 1.305±0.036a 0.201±0.011a 1.364±0.027a 1.587±0.027a 0.101±0.009a 0.236±0.016a 低剂量AS-Ⅰ组 0.995±0.022bc 0.702±0.007bc 0.576±0.020bc 1.056±0.027bc 0.388±0.010bc 0.905±0.004bc 高剂量AS-Ⅰ组 0.590±0.029bc 1.163±0.044bc 0.207±0.014bc 0.656±0.020bc 0.784±0.022bc 1.317±0.017bc F值 713.80 1161.00 2061.00 1460.00 3942.00 4126.00 P值 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 注：对照组大鼠正常饮食,其创面给予生理盐水处理；模型组、低剂量黄芪皂苷Ⅰ（AS-Ⅰ）组及高剂量AS-Ⅰ组大鼠在糖尿病模型构建成功后,其创面分别给予生理盐水、1.15 mmol/L的AS-Ⅰ及11.50 mmol/L的AS-Ⅰ处理；STAT3为信号转导和转录激活因子3,PIK3CA为磷脂酰肌醇3-激酶催化亚基α,GRB2为生长因子受体结合蛋白2,FOXO1为叉头框蛋白O1,EGFR为表皮生长因子受体,CDK2为细胞周期蛋白依赖性激酶2；与对照组相比,aP<0.05；与模型组相比,bP<0.05；与低剂量AS-Ⅰ组相比,cP<0.05
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