Studies on Differences and Mechanisms of Various Fractions Extracted from Angelicae Sinensis Radix and Wine-Processed Angelicae Sinensis Radix on Activating Blood Circulation
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摘要:
目的 基于网络药理学和动物实验开展生当归和酒当归不同组分活血作用的差异性研究, 并探讨其潜在机制。 方法 借助网络药理学方法, 从药物成分及疾病相关数据库预测当归的成分作用靶点及血瘀证(Blood stasis, BS)相关靶点, 根据拓扑特征值筛选关键靶点、核心成分后, 进行基因本体(Gene ontology, GO)功能及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)通路富集分析; 采用皮下注射肾上腺素加冰水浴法诱导的急性血瘀大鼠模型开展生当归和酒当归不同组分活血作用的差异性研究, 并对预测的关键靶点及通路进行机制验证。 结果 网络药理学结果表明, 当归134个潜在活性成分含有1 062个相关靶点, 血瘀证相关靶点476个, 交集靶点145个。根据拓扑特征值筛选出当归治疗血瘀证的关键靶点15个, 与关键靶点关联的核心成分36个; 富集分析发现关键靶点主要与血管内皮生长因子产生(Vascular endotheial growth factor production)、一氧化氮生物合成过程的正调控(Positive regulation of nitric oxide biosynthetic process)、对缺氧的反应(Cellular response to hypoxia)等生物过程, 以及血管内皮生长因子(Vascular endothelial growth factor, VEGF)信号通路、磷脂酰肌醇-3-激酶/蛋白激酶B(Phosphatidylinositol 3-kinase/protein kinase B, PI3K/AKT)信号通路、肿瘤坏死因子(Tumor necrosis factor, TNF)信号通路等有关。动物实验结果显示: 与模型组相比, 酒当归正丁醇组分(WASB)具有较强的活血作用, 可显著改善血瘀模型大鼠的外观形态学和组织病理学表现, 降低脏器指数, 抑制炎性介质[一氧化氮(Nitric oxide, NO)、前列腺素E2(Prostaglandin E2, PGE2)、肿瘤坏死因子-α(Tumor necrosis factor-α, TNF-α)]的释放、抑制氧化应激, 显著下调VEGFA的蛋白表达, 抑制AKT、PI3K蛋白的磷酸化(P<0.05，P<0.01，P<0.001), 其他组分对急性血瘀模型大鼠活血作用不及该组分, 且生、酒当归同组分相比, 酒当归活性均强于生当归。 结论 当归酒炙后各组分的活血作用均较生当归同组分增强, 其效应增强的机制可能与下调VEGFA, p-AKT、p-PI3K的蛋白表达, 抑制VEGF和PI3K/AKT信号通路激活, 减少NO、TNF-α、PGE2等相关炎性介质的产生, 降低MDA水平、升高SOD活性发挥抑制氧化应激等有关。 Abstract:OBJECTIVE To explore the differences and the mechanisms of various fractions extracted from Angelicae Sinensis Radix (AS) and wine-processed Angelicae Sinensis Radix (WAS) on activating blood circulation based on network pharmacology and animal experiments validation. METHODS Drug targets of AS and blood stasis (BS)-associated targets were screened from disease and drug related database, and the key targets and the core components were screened according to topological eigenvalues. Gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were performed. The acute blood stasis model in rats induced by adrenaline hydrochloride and ice-water bath was used to explore the differences of various fractions extracted from AS and WAS. And then the screened targets based on network pharmacology were further verified. RESULTS A total of 134 potential active components, 1 062 targets of AS, 476 BS-associated targets, 145 common targets, 15 key targets and 36 core components were obtained. Enrichment analysis showed that the key targets were mainly involved in biological processes such as vascular endothelial growth factor production, positive regulation of nitric oxide biosynthetic process and cellular response to hypoxia, as well as Vascular endothelial growth factor (VEGF) signaling pathway, Phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, and Tumor necrosis factor (TNF) signaling pathway. The results of animal experiments showed that compared with the model group, the effect of activating circulation of n-butyl alcohol-soluble fraction from WAS (WASB) was superior to those of other fractions. WASB remarkably improved the histopathological manifestations and appearance morphological characteristics of the acute blood stasis model in rats, significantly reduced organ index, evidently inhibited the release of inflammatory mediators (Nitric oxide, NO; Prostaglandin E2, PGE2; Tumor necrosis factor-α, TNF-α), suppressed oxidative stress, and significantly restrained the expression of VEGFA and the phosphorylation of AKT and PI3K (P<0.05, 0.01, 0.001). The effects of various fractions extracted from WAS on activating blood circulation were superior to those of the same fractions of AS. CONCLUSION The mechanisms of the enhanced effects from WAS on activating blood circulation may be related to down-regulation the expression levels of VEGFA, p-AKT and p-PI3K, inhibition of VEGF and PI3K/AKT signal pathways, decrease of pro-inflammatory mediator production (such as NO, PGE2 and TNF-α), suppressing the production of MDA, and increasing the level of SOD to alleviate oxidative stress. -
Key words:
- Angelicae Sinensis Radix /
- wine-processed /
- blood stasis /
- network pharmacology /
- oxidative stress /
- VEGFA /
- PI3K/AKT
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图 6 “当归-关键靶点-核心成分-疾病-信号通路”网络图
注: 红色圆形代表中药当归; 绿色菱形代表关键靶点; 橙色三角形代表核心成分; 蓝色六边形代表疾病; 紫色V形代表信号通路
Figure 6. "Angelicae Sinensis Radix-key targets-core components-disease-signal pathways" network
图 7 生、酒当归不同组分对血瘀模型大鼠体质量的影响
注：BC-D. 二氯甲烷组分空白组; MC-D. 二氯甲烷组分模型组; AC-D. 二氯甲烷组分阿司匹林阳性组; ASDL. 生当归二氯甲烷组分低剂量组; ASDH. 生当归二氯甲烷组分高剂量组; WASDL. 酒当归二氯甲烷组分低剂量组; WASDH. 酒当归二氯甲烷组分高剂量组; BC-B. 正丁醇组分空白组; MC-B. 正丁醇组分模型组; AC-B. 正丁醇组分阿司匹林阳性组; ASBL. 生当归正丁醇组分低剂量组; ASBH. 生当归正丁醇组分高剂量组; WASBL. 酒当归正丁醇组分低剂量组; WASBH. 酒当归正丁醇组分高剂量组; BC-W. 水组分空白组; MC-W. 水组分模型组; AC-W. 水组分阿司匹林阳性组; ASWL. 生当归水组分低剂量组; ASWH. 生当归水组分高剂量组; WASWL. 酒当归水组分低剂量组; WASWH. 酒当归水组分高剂量组。与空白组相比, #P<0.05, ##P<0.01, ###P<0.001;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=10。
Figure 7. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on body weight in blood stasis rats
图 8 生、酒当归不同组分对血瘀模型大鼠舌面形态学的影响
注：A. BC-D组; B. MC-D组; C. AC-D组; D. ASDL组; E. ASDH组; F. WASDL组; G. WASDH组; H. BC-B组; I. MC-B组; J. AC-B组; K. ASBL组; L. ASBH组; M. WASBL组; N. WASBH组; O. BC-W组; P. MC-W组; Q. AC-W组; R. ASWL组; S. ASWH组; T. WASWL组; U. WASWH组。x±s, n=10。
Figure 8. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on the morphology of tongue surface in blood stasis rats
图 9 生、酒当归不同组分对血瘀模型大鼠舌面色度的影响
注：与空白组相比, ##P<0.01, ###P<0.001;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=10。
Figure 9. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on the tongue color in blood stasis rats
图 10 生、酒当归不同组分对血瘀模型大鼠足底形态学的影响
注：A. BC-D组; B. MC-D组; C. AC-D组; D. ASDL组; E. ASDH组; F. WASDL组; G. WASDH组; H. BC-B组; I. MC-B组; J. AC-B组; K. ASBL组; L. ASBH组; M. WASBL组; N. WASBH组; O. BC-W组; P. MC-W组; Q. AC-W组; R. ASWL组; S. ASWH组; T. WASWL组; U. WASWH组。x±s, n=10。
Figure 10. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on the morphology of plantar in blood stasis rats
图 11 生、酒当归不同组分对血瘀模型大鼠足底色度的影响
注：与空白组相比, ##P<0.01, ###P<0.001;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=10。
Figure 11. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on the plantar color in blood stasis rats
图 12 生、酒当归不同组分对血瘀模型大鼠肺指数的影响
注：与空白组相比, ###P<0.001;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=10。
Figure 12. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on the lung index in blood stasis rats
图 13 生、酒当归不同组分对血瘀模型大鼠胸腺指数的影响
注：与空白组相比, #P<0.05, ##P<0.01, ###P<0.001;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=10。
Figure 13. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on the thymus index in blood stasis rats
图 14 生、酒当归不同组分对血瘀模型大鼠肾脏指数的影响
注：与空白组相比, ###P<0.001;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=10。
Figure 14. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on renal index in blood stasis rats
图 15 生、酒当归不同组分对血瘀模型大鼠心肌组织病理学的影响
注：A. BC组; B. MC组; C. AC组; D. ASDL组; E. ASDH组; F. WASDL组; G. WASDH组; H. ASBL组; I. ASBH组; J. WASBL组; K. WASBH组; L. ASWL组; M. ASWH组; N. WASWL组; O. WASWH组。HE染色, ×400。
Figure 15. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on myocardial histopathology in blood stasis rats
图 16 ASD和WASD对急性血瘀模型大鼠VEGFA、p-PI3K、p-AKT蛋白水平的影响
注：与空白组相比, #P<0.05, ##P<0.01;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=3。
Figure 16. Effects of ASD and WASD on the protein levels of VEGFA, p-PI3K and p-AKT in blood stasis rats
图 17 ASB和WASB对急性血瘀模型大鼠VEGFA、p-PI3K、p-AKT蛋白水平的影响
注：与空白组相比, #P<0.05, ;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=3。
Figure 17. Effects of ASB and WASB on the protein levels of VEGFA, p-PI3K and p-AKT in blood stasis rats
图 18 ASW和WASW对急性血瘀模型大鼠VEGFA、p-PI3K、p-AKT蛋白水平的影响
注：与空白组相比, #P<0.05, ;与模型组相比, *P<0.05, **P<0.01, ***P<0.001。x±s, n=3。
Figure 18. Effects of ASW and WASW on the protein levels of VEGFA, p-PI3K and p-AKT in blood stasis rats
表 1 关键靶点网络拓扑学分析结果
Table 1. Key targets network topology analysis results
Name Degree Betweenness Closeness ERBB2 59 299.596 162 6 0.613 733 906 EGFR 75 677.252 263 0.658 986 175 ALB 94 1 877.167 002 0.733 333 333 TNF 91 1 248.800 356 0.718 592 965 AKT1 92 1 589.650 581 0.718 592 965 IL-1β 70 604.166 618 0.65 PPARG 60 733.230 682 0.619 047 619 HIF1A 68 590.471 496 5 0.632 743 363 CXCL8 60 271.002 840 6 0.616 379 31 PTGS2 59 444.407 225 8 0.600 840 336 VEGFA 85 822.184 893 3 0.687 5 IL-6 87 963.148 964 9 0.704 433 498 NOS3 60 668.243 865 5 0.624 454 148 HSP90AA1 64 1 174.613 989 0.621 739 13 SRC 75 842.874 208 4 0.658 986 175 
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表 2 当归治疗血瘀证关键靶点对应的核心成分网络拓扑分析结果(Degree前15)
Table 2. Topological analysis results of core components related to the key targets for Angelicae Sinensis Radix in treatment of blood stasis (Degree Top 15)
化合物名称 Degree Betweenness Closeness oplopandiol 6 1120.945 0.23222749 洋川芎内酯C(senkyunolide C) 5 554.3458 0.20675105 (1S)-2-O-E-feruloyl-1-(4-hydroxyphenyl)ethane-1,2-diol 5 629.10345 0.22374429 11-angeloylsenkyunolide F 4 304.63852 0.21491228 11(S), 16(R)-dihydroxy-octadeca-9Z,17-diene-12,14-diyn-1-yl acetate 4 451.5407 0.20940171 2-methyl-5-decanone 3 372.23337 0.2 酒渣碱(flazine) 3 327.21924 0.2139738 黄芩苷(baicalin) 3 205.89545 0.20762712 8-hydroxy-1-methoxy-9Z-heptadecene-4,6-diyn-3-one 3 306.69125 0.2139738 heptadeca-1-en-9,10-epoxy-4,6-diyne-3,8-diol 3 188.24715 0.20502092 p-hydroxyphenethyl trans-ferulate 3 162.02917 0.21212122 阿魏酸松柏酯(coniferyl ferulate) 3 216.37267 0.20675105 厚朴酚(magnolol) 3 221.31787 0.2033195 10-angeloylbutylphthalide 3 398.09262 0.2 欧当归内酯A(levistolide A) 2 140.97017 0.1835206
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表 3 生、酒当归不同组分对急性血瘀模型大鼠血液中各项生化指标的影响(x±s, n=10)
Table 3. Effects of different fractions from Angelicae Sinensis Radix and wine-processed Angelicae Sinensis Radix on biochemical indexes in blood stasis rats (x±s, n=10)
组别 剂量/(mg·kg-1) 炎性因子 氧化应激因子 PGE2/(pg·mL-1) TNF-α/(pg·mL-1) NO/(μmol·mL-1) MDA/(nmol·mL-1) SOD/(U·mL-1) BC-D - 1.99±0.75 31.67±9.28 22.19±3.03 3.80±0.61 72.06±2.46 MC-D - 44.91±15.97### 59.36±7.30### 56.81±9.61### 5.74±0.74### 67.40±0.93# AC-D 250 18.89±6.69*** 34.48±5.59*** 44.06±13.08 4.57±0.64* 69.39±1.36 ASDL 250 35.28±12.09 31.03±7.07*** 49.52±7.38* 5.11±1.20 68.42±2.88 ASDH 750 5.86±2.88*** 32.54±7.74*** 45.87±8.22*** 5.18±0.96 69.14±2.62 WASDL 250 8.86±4.85*** 30.27±8.34*** 50.93±5.38 5.37±0.67 68.15±3.86 WASDH 750 42.62±8.74 30.72±5.15*** 53.00±11.97 5.01±0.43 72.01±1.23 BC-B - 2.58±1.43 36.87±5.44 24.44±7.69 3.74±0.65 74.03±1.92 MC-B - 78.07±6.43### 63.36±5.71### 52.43±15.01### 6.92±0.90### 67.04±1.65### AC-B 250 20.66±11.40*** 45.45±6.94*** 45.89±8.39 4.06±0.40*** 68.95±2.04 ASBL 250 6.27±3.05*** 48.83±7.26** 38.78±7.29 5.47±0.39*** 69.43±3.89 ASBH 750 14.17±4.23*** 47.38±5.48*** 34.60±10.23* 6.20±0.32 70.73±2.70* WASBL 250 47.46±6.41*** 44.86±5.37*** 35.51±7.06* 5.78±0.34** 70.12±3.28 WASBH 750 10.77±5.08*** 40.50±6.33*** 40.13±7.26 5.74±0.42** 71.20±1.73* BC-W - 3.97±2.31 25.93±3.71 28.88±7.61 3.27±0.50 79.21±1.34 MC-W - 65.90±12.22### 35.33±5.19# 58.70±9.61### 5.12±0.53### 73.81±1.56### AC-W 250 10.31±2.76*** 24.70±6.16** 56.71±9.42 3.17±0.46*** 74.26±0.83 ASWL 250 9.77±3.76*** 25.70±6.76* 45.34±5.45 4.67±0.55 75.64±1.68 ASWH 750 52.33±7.30 25.31±4.21* 45.88±7.18 4.35±0.56 74.93±1.74 WASWL 250 9.34±6.38*** 24.70±4.29* 44.97±6.88 4.34±0.37* 77.03±1.52** WASWH 750 21.05±11.38*** 23.94±5.74** 44.89±5.54 4.24±0.45* 77.67±1.78*** 注: 与空白组比较, #P<0.05, ###P<0.001;与模型组比较, *P<0.05, **P<0.01, ***P<0.001。
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