基于分子对接及网络药理学的托里消毒散精简方促糖尿病创面愈合作用机制研究
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摘要
目的探索托里消毒散精简方中黄芪、当归、白芷、皂角刺4味中药促糖尿病创面愈合的药物成分及其潜在分子作用机制。方法采用UPLC-Q-TOF/MS在正、负离子模式下对方中的药物成分进行分析,分子对接技术对药物作用的靶蛋白进行预测,Uniprot、KEGG等相关数据库对靶蛋白功能及通路进行注释,利用Cytoscape软件构建药物成分-靶点-功能网络图。结果在正、负离子模式下从托里消毒散精简方醇提物中共鉴定出包含黄酮、皂苷、香豆素、甾体类及萜类成分的28个化合物。通过对分子对接的结果分析发现17个化合物可与17个靶蛋白相互作用,成分-靶点关系共计210对。其中与免疫调节相关的靶点5个,与抗菌、抗炎作用相关的靶点6个,与细胞分化相关的靶点6个,与细胞迁移相关的靶点10个,与血管新生相关的靶点6个,与上皮生长因子刺激相关的靶点2个,与血管的舒张功能相关的靶点6个,与雌激素相关的靶点2个。结论托里消毒散精简方中含有的黄酮、皂苷、香豆素、甾体类及萜类成分可通过调节NF-κB、MAPK、PI3K、ERK2等靶点进而调节NF-κB、PI3K/Akt/e NOS、MAPK等相关信号通路,从而共同产生抗菌、抗炎、免疫调节及促血管新生等生物学效应。
Objective To investigate the active ingredients and molecular mechanism of Astragalus membranaceus var. mongholicus,Angelica sinensis, Angelicae dahurica, and Gleditsia sinensis in Tuoli Xiaodu Powder in promoting of diabetic wound healing. Methods UPLC-Q-TOF/MS in positive and negative ion modes was applied to analyze the components in the ethanol extract from Tuoli Xiaodu Powder. Molecular docking technology was used to predict the targets proteins of these components. The function and pathway annotations of target proteins were performed through relevant databases such as Uniprot and KEGG. The drug components-target-function diagram was constructed using Cytoscape software. Results Twenty-eight compounds containing flavonoids, saponins, coumarins, alkaloids, and triterpenoids were identified in positive and negative ion modes. Among these compounds, 17 compounds could interact with 17 target proteins, and there were 210 pairs of component-target relationships by analyzing the results of molecular docking. Among them, five targets were related to immune regulation, six targets were related to antibacterial and anti-inflammatory effects, six targets were related to cell differentiation, 10 targets were related to cell migration, six targets were related to angiogenesis, two targets were related to stimulation of epithelial growth factor, six targets were related to vasodilation, and two targets were related to estrogen. Conclusion The flavonoids, saponins, coumarins, steroids, and triterpenoids contained in the simplified formula possess many biological effects such as antibacterial, anti-inflammatory, immune regulation, and angiogenesis. These functions may be related to its modulation of NF-κB, PI3 K/Akt/e NOS, and MAPK pathway through regulating NF-κB, MAPK, PI3 K, and ERK2 targets.
Objective To investigate the active ingredients and molecular mechanism of Astragalus membranaceus var. mongholicus,Angelica sinensis, Angelicae dahurica, and Gleditsia sinensis in Tuoli Xiaodu Powder in promoting of diabetic wound healing. Methods UPLC-Q-TOF/MS in positive and negative ion modes was applied to analyze the components in the ethanol extract from Tuoli Xiaodu Powder. Molecular docking technology was used to predict the targets proteins of these components. The function and pathway annotations of target proteins were performed through relevant databases such as Uniprot and KEGG. The drug components-target-function diagram was constructed using Cytoscape software. Results Twenty-eight compounds containing flavonoids, saponins, coumarins, alkaloids, and triterpenoids were identified in positive and negative ion modes. Among these compounds, 17 compounds could interact with 17 target proteins, and there were 210 pairs of component-target relationships by analyzing the results of molecular docking. Among them, five targets were related to immune regulation, six targets were related to antibacterial and anti-inflammatory effects, six targets were related to cell differentiation, 10 targets were related to cell migration, six targets were related to angiogenesis, two targets were related to stimulation of epithelial growth factor, six targets were related to vasodilation, and two targets were related to estrogen. Conclusion The flavonoids, saponins, coumarins, steroids, and triterpenoids contained in the simplified formula possess many biological effects such as antibacterial, anti-inflammatory, immune regulation, and angiogenesis. These functions may be related to its modulation of NF-κB, PI3 K/Akt/e NOS, and MAPK pathway through regulating NF-κB, MAPK, PI3 K, and ERK2 targets.
引文
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[23]白晓智,胡大海,刘佳琦,等.白芷活性提取物对人脐静脉内皮细胞生物特性的影响[J].中华损伤与修复杂志:电子版,2012,7(1):26-29.
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[31]Wang S,Chen J,Fu Y,et al.Promotion of astragaloside IV for EA-hy926 cell proliferation and angiogenic activity via ERK1/2 pathway[J].J Nanosci Nanotechnol,2015,15(6):4239-4244.
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[2]郝福明.托里消毒散研究述评[J].中华中医药学刊,2008,26(3):598-599.
[3]元建中.托里消毒散加减内服配合外用治疗压疮疗效分析[J].中医药临床杂志,2012,24(10):962-963.
[4]Zhang X N,Ma Z J,Wang Y,et al.The Four-Herb Chinese medicine formula Tuo-Li-Xiao-Du-San accelerates cutaneous wound healing in Streptozotocin-induced diabetic rats through reducing inflammation and increasing angiogenesis[J].J Diabetes Res,2016,doi:10.1155/2016/5639129.
[5]李玉珠,张晓娜,王颖,等.托里消毒散精简方对糖尿病皮肤溃疡大鼠创面愈合的影响及机制[J].中草药,2016,47(9):1560-1566.
[6]张彦琼,李梢.网络药理学与中医药现代研究的若干进展[J].中国药理学与毒理学杂志,2015,29(6):883-892.
[7]程肖蕊,周文霞,张永祥.网络药理学实验研究相关技术[J].中国药理学与毒理学杂志,2012,26(2):131-137.
[8]李泮霖,苏薇薇.网络药理学在中药研究中的最新应用进展[J].中草药,2016,47(16):2938-2942.
[9]董亚楠,韩彦琪,王磊,等.基于网络药理学的六经头痛片治疗偏头痛的作用机制探讨[J].中草药,2017,48(20):4174-4180.
[10]Liu C X,Liu R,Fan H R,et al.Network pharmacology bridges traditional application and modern development of traditional Chinese medicine[J].Chin Herb Med,2015,7(1):3-17.
[11]Cruciani G,Pastor M,Guba W.Vol Surf:A new tool for the pharmacokinetic optimization of lead compounds[J].Eur J Pharm Sci Off J Eur Feder Pharm Sci,2000,11(Suppl 2):S29-S39.
[12]孙晓磊,施森,何延政.糖尿病创面难愈机制的研究进展[J].西南军医,2008,10(5):92-94.
[13]Yuan X,Han L,Fu P,et al.Cinnamaldehyde accelerates wound healing by promoting angiogenesis via up-regulation of PI3K and MAPK signaling pathways[J].Lab Invest,2018,98(6):783-798.
[14]Zhang X,Ma Z,Wang Y,et al.Angelica dahurica ethanolic extract improves impaired wound healing by activating angiogenesis in diabetes[J].PLo S One,2017,12(5):e0177862.
[15]全国中草药汇编编写组.全国中草药汇编[M].北京:人民卫生出版社,2000.
[16]张蔷,高文远,满淑丽.黄芪中有效成分药理活性的研究进展[J].中国中药杂志,2012,37(21):3203-3207.
[17]杨晓峪,李振麟,濮社班,等.皂角刺化学成分及药理作用研究进展[J].中国野生植物资源,2015,34(3):38-41.
[18]Ding Y,Yuan S,Liu X,et al.Protective effects of astragaloside IV on db/db mice with diabetic retinopathy[J].PLo S One,2014,9(11):e112207.
[19]Gurtner G C,Werner S,Barrandon Y,et al.Wound repair and regeneration[J].Nature,2008,453(7193):314-321.
[20]Wetzler C,Kampfer H,Stallmeyer B,et al.Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mousu:prolonged persistence of neutrophils and macrophages during the late phase of repair[J].J Invest Dermatol,2000,115(2):245-253.
[21]张小鸿,徐先祥,汪宁卿.黄芪保护血管内皮细胞作用机制研究进展[J].中国药学杂志,2013,48(18):1526-1530.
[22]Lam H W,Lin H C,Lao S C,et al.The angiogenic effects of Angelica sinensis extract on HUVEC in vitro and zebrafish in vivo[J].J Cell Biochem,2008,103(1):195-211.
[23]白晓智,胡大海,刘佳琦,等.白芷活性提取物对人脐静脉内皮细胞生物特性的影响[J].中华损伤与修复杂志:电子版,2012,7(1):26-29.
[24]Ha H H,Park S Y,Ko W S,et al.Gleditsia sinensis thorns inhibit the production of NO through NF-kappa B suppression in LPS-stimulated macrophages[J].J Ethnopharmacol,2008,118(3):429-434.
[25]Schonfelder U,Abel M,Wiegand C,et al.Influence of selected wound dressings on PMN elastase in chronic wound fluid and their antioxidative potential in vitro[J].Biomaterials,2005,26(33):6664-6673.
[26]Adli M,Merkhofer E,Cogswell P,et al.IKKαand IKKβeach function to regulate NF-κB activation in the TNF-induced/canonical pathway[J].PLo S One,2010,5(2):e9428.
[27]Lee Y J,Kang D G,Kim J S,et al.Effect of Buddleja officinalis on high glucose-induced vascular inflammation in human umbilical vein endothelial cells[J].Exper Biol Med,2008,233(6):694-700.
[28]Keshet Y,Seger R.The MAP kinase signaling cascades:A system of hundreds of components regulates a diverse array of physiological functions[J].Methods Mol Biol,2010,661:3-38.
[29]Chen J L,Xu C,Alex Z,et al.Niaspan increases angiogenesis and improves functional recovery after stroke[J].Annal Neurol,2007,62(1):49-58.
[30]Zhang W J,Hufnagl P,Binder B R,et al.Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-kappa B activation and adhesion molecule expression[J].Thromb Haemost,2003,90(5):904-914.
[31]Wang S,Chen J,Fu Y,et al.Promotion of astragaloside IV for EA-hy926 cell proliferation and angiogenic activity via ERK1/2 pathway[J].J Nanosci Nanotechnol,2015,15(6):4239-4244.
[32]Wang S G,Xu Y,Chen J D,et al.Astragaloside IV stimulates angiogenesis and increase nitric oxide accumulation via JAK2/STAT3 and ERK1/2 pathway[J].Molecules,2013,18(10):12809-12819.
[33]Tang J Y,Li S,Li Z H,et al.Calycosin promotes angiogenesis involving estrogen receptor and mitogen-activated protein kinase(MAPK)signaling pathway in zebrafish and HUVEC[J].PLo S One,2010,5(7):e11822.