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Article(id=1199786455716429953, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199786450628735631, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0460, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1715616000000, receivedDateStr=2024-05-14, revisedDate=1720281600000, revisedDateStr=2024-07-07, acceptedDate=null, acceptedDateStr=null, onlineDate=1763980981996, onlineDateStr=2025-11-24, pubDate=1726070400000, pubDateStr=2024-09-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763980981996, onlineIssueDateStr=2025-11-24, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763980981996, creator=13701087609, updateTime=1763980981996, updator=13701087609, issue=Issue{id=1199786450628735631, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='9', pageStart='2417', pageEnd='2676', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763980980784, creator=13701087609, updateTime=1764225057364, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200810182063280632, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199786450628735631, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200810182063280633, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199786450628735631, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2545, endPage=2555, ext={EN=ArticleExt(id=1199786456047779989, articleId=1199786455716429953, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Analysis of the mechanisms of Guanxinning Tablet for antithrombotic and microthrombotic effects caused by COVID-19 based on network pharmacology, columnId=null, journalTitle=Acta Pharmaceutica Sinica, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Thrombosis is a key factor that increases the mortality rate of COVID-19 patients and causes long COVID sequelae. Guanxinning Tablet (GXNT), which is composed of Salvia miltiorrhiza and Ligusticum Chuanxiong, has significant antithrombotic activity, but the similarities and differences between its anti-conventional thrombus and microthrombus induced by COVID-19 remain unclear. In this paper, the main active components, potential targets and mechanisms of GXNT in the treatment of thrombus and microthrombus caused by COVID-19 were preliminarily revealed by using anti-platelet experiments in vitro, network pharmacology analysis, molecular docking technology and molecular biology experiments. The results of platelet aggregation and adhesion experiments in vitro showed that GXNT had significant anti-platelet aggregation and adhesion activities in a dose-dependent manner. Using network pharmacology analysis, it was revealed that salvianolic acid B, tanshinone ⅡA, caffeic acid and ligustrazine in GXNT could resist thrombus and microthrombus caused by COVID-19 through key targets as the high mobility group box 1 protein (HMGB1), tumor necrosis factor (TNF), interleukin 6 (IL6) and AKT serine/threonine kinase 1 (AKT1). HMGB1 signaling pathway is one of its key common mechanisms. Western blot also indicated that GXNT significantly inhibited the expression of HMGB1 protein in platelets. In summary, this paper explores the similarities and differences between the mechanism of GXNT against conventional thrombus and microthrombus caused by COVID-19 and provides drug reference and theoretical basis for clinical prevention and treatment of long COVID sequelae. The animal experiment has been approved by the Experimental Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine (No. TCM-LAEC2023187g1549).

, correspAuthors=Ming LÜ, Jin-qiang ZHU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Pei-yu GONG, Guang-xu XIAO, Wen-jun LI, Guan-wei FAN, Ming LÜ, Jin-qiang ZHU), CN=ArticleExt(id=1199786457813582088, articleId=1199786455716429953, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=基于网络药理学解析冠心宁片抗血栓及新冠病毒引起的微血栓的潜在机制, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

血栓形成是增加新冠肺炎患者死亡率和导致长新冠后遗症的关键因素。由活血化瘀中药丹参、川芎组成的冠心宁片(GXNT) 具有显著的抗血栓活性, 但其抗常规血栓与由新冠病毒引起微血栓机制之间的异同仍不清楚。本文运用体外抗血小板实验、网络药理学分析、分子对接技术和分子生物学实验, 初步揭示了GXNT治疗血栓及新冠病毒引起的微血栓的主要活性成分、潜在靶点和作用机制。体外血小板聚集和黏附实验结果表明, GXNT具有显著的抗血小板聚集和黏附的活性, 且呈一定的剂量依赖性。网络药理学分析发现, GXNT中的丹酚酸B、丹参酮ⅡA、咖啡酸和川芎嗪能够通过关键靶点高迁移率族蛋白B1 (high mobility group box 1 protein, HMGB1)、肿瘤坏死因子(tumor necrosis factor, TNF)、白细胞介素6 (interleukin-6, IL6) 和丝氨酸/苏氨酸激酶1 (AKT serine/threonine kinase 1, AKT1) 来抗血栓及由新冠病毒引起的微血栓。其中, HMGB1信号通路为其关键的共同机制之一。Western blot实验结果也表明, GXNT对血小板中HMGB1蛋白的表达水平有显著抑制作用。综上, 本文探究的GXNT抗常规血栓与由新冠病毒引起微血栓机制之间的异同为临床防治长新冠后遗症提供用药参考和理论依据。该动物实验已通过天津中医药大学实验动物伦理委员会审核批准(编号: TCM-LAEC2023187g1549)。

, correspAuthors=吕明, 朱金墙, authorNote=null, correspAuthorsNote=
*吕明, Tel: 18020039001, E-mail: ;
朱金墙, Tel: 18920772803, E-mail:
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Heart disease and stroke statistics-2023 update: a report from the American Heart Association [J]. Circulation, 2023, 147: e93-e621., articleTitle=null, refAbstract=null), Reference(id=1200378857128841981, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=null, journalName=null, refType=null, unstructuredReference=Ranucci M, Ballotta A, Di Dedda U, et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome [J]. 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A: The change curves of platelet aggregation at different time points in each group after thrombin activation of platelets; B: Quantification of thrombin activation of platelets for 45 min; C: Representative images of thrombin induced platelet adhesion to fibrinogen; D: Quantification of thrombin induced platelet adhesion to fibrinogen; E: Representative images of thrombin induced platelet adhesion to endothelial cells; F: Quantification of thrombin induced platelet adhesion to endothelial cells. <i>n</i> = 4, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s</i>. <sup>##</sup><i>P</i> < 0.01, <sup>###</sup><i>P</i> < 0.001 <i>vs</i> model group , figureFileSmall=bgfgG+p45qVKneLQz1Rflw==, figureFileBig=xB1gRW5gwN1d7HeRJn9UXA==, tableContent=null), ArticleFig(id=1200378853517546100, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=EN, label=null, caption=null, figureFileSmall=OJ4CZLHNPDgKrHCv151fJw==, figureFileBig=LVRufnbIonPPJmxNXLWi/w==, tableContent=null), ArticleFig(id=1200378853605626490, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=CN, label=Figure 2, caption= The "drugs-active ingredients-core targets-pathways" network diagram. A: GXNT against thrombosis; B: GXNT against microthrombosis induced by COVID-19 , figureFileSmall=OJ4CZLHNPDgKrHCv151fJw==, figureFileBig=LVRufnbIonPPJmxNXLWi/w==, tableContent=null), ArticleFig(id=1200378853739844227, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=EN, label=null, caption=null, figureFileSmall=3uNi41pn8Ldyx0v+nBpeeQ==, figureFileBig=tZ1ifWq7mZIRNZvh2aKZ8w==, tableContent=null), ArticleFig(id=1200378853869867657, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=CN, label=Figure 3, caption= The analysis of potential mechanisms. A: GO functional enrichment of GXNT against thrombosis; B: GO functional enrichment of GXNT against microthrombosis induced by COVID-19; C: KEGG pathway analysis of GXNT against thrombosis; D: KEGG pathway analysis of GXNT against microthrombosis induced by COVID-19; E: The HMGB1 signaling pathway , figureFileSmall=3uNi41pn8Ldyx0v+nBpeeQ==, figureFileBig=tZ1ifWq7mZIRNZvh2aKZ8w==, tableContent=null), ArticleFig(id=1200378853991502481, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=EN, label=null, caption=null, figureFileSmall=jSDFaR8SpPVogLG01D2hPw==, figureFileBig=EOlv5UCYFE6hMVsAII4hVw==, tableContent=null), ArticleFig(id=1200378854121525911, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=CN, label=Figure 4, caption= Molecular docking. A: The score of -cdocker energy of astilbin, salvianolic acid B, tanshinone ⅡA, caffeic acid, tetramethylpyrazine and TNF; B: The score of -cdocker energy of ginsenoside Rh1, salvianolic acid B, tanshinone ⅡA, caffeic acid, tetramethylpyrazine and IL6; C: The score of -cdocker energy of oridonin, salvianolic acid B, tanshinone ⅡA, caffeic acid, tetramethylpyrazine and AKT1; D: The score of -cdocker energy of glycyrrhizic acid, salvianolic acid B, tanshinone ⅡA, caffeic acid, tetramethylpyrazine and HMGB1; E: Heat map based on the -cdocker energy of salvianolic acid B, tanshinone ⅡA, caffeic acid, tetramethylpyrazine and TNF, IL6, HMGB1, AKT1; F-H: 3D model showed the active binding sites of caffeic acid interacting with HMGB1 (F), salvianolic acid B with AKT1 (G), and salvianolic acid B with IL6 (H); I-K: 2D model showed the active binding sites of caffeic acid interacting with HMGB1 (I), salvianolic acid B with AKT1 (J), and salvianolic acid B with IL6 (K) , figureFileSmall=jSDFaR8SpPVogLG01D2hPw==, figureFileBig=EOlv5UCYFE6hMVsAII4hVw==, tableContent=null), ArticleFig(id=1200378855321096861, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=EN, label=null, caption=null, figureFileSmall=d1/WkamrJtYkH/lSN3v3JA==, figureFileBig=3g3xaAfXXnZIeQMquKUDZw==, tableContent=null), ArticleFig(id=1200378855438537376, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=CN, label=Figure 5, caption= Effects of GXNT on the expression level of HMGB1 protein in HMGB1 signaling pathway. <i>n</i> = 5, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s</i>. <sup>##</sup><i>P</i> < 0.01 <i>vs</i> model group , figureFileSmall=d1/WkamrJtYkH/lSN3v3JA==, figureFileBig=3g3xaAfXXnZIeQMquKUDZw==, tableContent=null), ArticleFig(id=1200378855543394985, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. Symbol Entrez gene name Location Type P-value of overlap
1 TNF Tumor necrosis factor Extracellular space Cytokine 1.53E-56
2 APOE Apolipoprotein E Extracellular space Transporter 2.15E-50
3 NR3C1 Nuclear receptor subfamily 3 group C member 1 Nucleus Ligand-dependent nuclear receptor 2.15E-46
4 LEP Leptin Extracellular space Growth factor 3.84E-46
5 IL1B Interleukin 1 beta Extracellular space Cytokine 5.36E-46
6 IL6 Interleukin 6 Extracellular space Cytokine 7.29E-44
7 IL17A Interleukin 17A Extracellular space Cytokine 3.52E-39
8 IL10 Interleukin 10 Extracellular space Cytokine 1.28E-38
9 STAT3 Signal transducer and activator of transcription 3 Nucleus Transcription regulator 6.67E-38
10 TLR4 Toll like receptor 4 Plasma membrane Transmembrane receptor 4.81E-37
11 TNFRSF1A TNF receptor superfamily member 1A Plasma membrane Transmembrane receptor 2.73E-36
12 PPARG Peroxisome proliferator activated receptor gamma Nucleus Ligand-dependent nuclear receptor 3.48E-35
13 TLR2 Toll like receptor 2 Plasma membrane Transmembrane receptor 1.8E-34
14 HMOX1 Heme oxygenase 1 Cytoplasm Enzyme 3.71E-32
15 IL2 Interleukin 2 Extracellular space Cytokine 3.45E-30
16 MYD88 MYD88 innate immune signal transduction adaptor Plasma membrane Other 3.48E-30
17 F2 Coagulation factor Ⅱ, thrombin Extracellular space Peptidase 3.44E-23
18 JAK2 Janus kinase 2 Cytoplasm Kinase 4.76E-20
19 HMGB1 High mobility group box 1 Nucleus Transcription regulator 9.48E-17
20 AKT1 AKT serine/threonine kinase 1 Cytoplasm Kinase 8.22E-13
), ArticleFig(id=1200378855623086766, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=CN, label=Table 1, caption=

Network pharmacology analysis-core targets of GXNT against thrombosis

, figureFileSmall=null, figureFileBig=null, tableContent=
No. Symbol Entrez gene name Location Type P-value of overlap
1 TNF Tumor necrosis factor Extracellular space Cytokine 1.53E-56
2 APOE Apolipoprotein E Extracellular space Transporter 2.15E-50
3 NR3C1 Nuclear receptor subfamily 3 group C member 1 Nucleus Ligand-dependent nuclear receptor 2.15E-46
4 LEP Leptin Extracellular space Growth factor 3.84E-46
5 IL1B Interleukin 1 beta Extracellular space Cytokine 5.36E-46
6 IL6 Interleukin 6 Extracellular space Cytokine 7.29E-44
7 IL17A Interleukin 17A Extracellular space Cytokine 3.52E-39
8 IL10 Interleukin 10 Extracellular space Cytokine 1.28E-38
9 STAT3 Signal transducer and activator of transcription 3 Nucleus Transcription regulator 6.67E-38
10 TLR4 Toll like receptor 4 Plasma membrane Transmembrane receptor 4.81E-37
11 TNFRSF1A TNF receptor superfamily member 1A Plasma membrane Transmembrane receptor 2.73E-36
12 PPARG Peroxisome proliferator activated receptor gamma Nucleus Ligand-dependent nuclear receptor 3.48E-35
13 TLR2 Toll like receptor 2 Plasma membrane Transmembrane receptor 1.8E-34
14 HMOX1 Heme oxygenase 1 Cytoplasm Enzyme 3.71E-32
15 IL2 Interleukin 2 Extracellular space Cytokine 3.45E-30
16 MYD88 MYD88 innate immune signal transduction adaptor Plasma membrane Other 3.48E-30
17 F2 Coagulation factor Ⅱ, thrombin Extracellular space Peptidase 3.44E-23
18 JAK2 Janus kinase 2 Cytoplasm Kinase 4.76E-20
19 HMGB1 High mobility group box 1 Nucleus Transcription regulator 9.48E-17
20 AKT1 AKT serine/threonine kinase 1 Cytoplasm Kinase 8.22E-13
), ArticleFig(id=1200378855727944371, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. Symbol Entrez gene name Location Type P-value of overlap
1 IL1B Interleukin 1 beta Extracellular space Cytokine 4.66E-36
2 IL17A Interleukin 17A Extracellular space Cytokine 8.54E-33
3 TNF Tumor necrosis factor Extracellular space Cytokine 1.58E-32
4 IL10 Interleukin 10 Extracellular space Cytokine 2.82E-28
5 NR3C1 Nuclear receptor subfamily 3 group C member 1 Nucleus Ligand-dependent nuclear receptor 8.48E-28
6 HIF1A Hypoxia inducible factor 1 subunit alpha Nucleus Transcription regulator 2.08E-27
7 HMOX1 Heme oxygenase 1 Cytoplasm Enzyme 5.16E-27
8 IL6 Interleukin 6 Extracellular space Cytokine 1.16E-25
9 STAT3 Signal transducer and activator of transcription 3 Nucleus Transcription regulator 1.46E-25
10 EGFR Epidermal growth factor receptor Plasma membrane Kinase 7.86E-22
11 MAPK14 Mitogen-activated protein kinase 14 Cytoplasm Kinase 1.68E-19
12 PTGS2 Prostaglandin-endoperoxide synthase 2 Cytoplasm Enzyme 1.1E-17
13 TLR2 Toll like receptor 2 Plasma membrane Transmembrane receptor 2.54E-17
14 LDLR Low density lipoprotein receptor Plasma membrane Transporter 1.2E-16
15 MTOR Mechanistic target of rapamycin kinase Nucleus Kinase 3.83E-16
16 VEGFA Vascular endothelial growth factor A Extracellular space Growth factor 1.3E-15
17 HMGB1 High mobility group box 1 Nucleus Transcription regulator 1.67E-15
18 AKT1 AKT serine/threonine kinase 1 Cytoplasm Kinase 1.49E-09
19 HSPA5 Heat shock protein family A (Hsp70) member 5 Cytoplasm Enzyme 9.14E-05
20 MAPK1 Mitogen-activated protein kinase 1 Cytoplasm Kinase 3.72E-03
), ArticleFig(id=1200378855853773497, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=CN, label=Table 2, caption=

Network pharmacology analysis-core targets of GXNT against microthrombosis induced by COVID-19

, figureFileSmall=null, figureFileBig=null, tableContent=
No. Symbol Entrez gene name Location Type P-value of overlap
1 IL1B Interleukin 1 beta Extracellular space Cytokine 4.66E-36
2 IL17A Interleukin 17A Extracellular space Cytokine 8.54E-33
3 TNF Tumor necrosis factor Extracellular space Cytokine 1.58E-32
4 IL10 Interleukin 10 Extracellular space Cytokine 2.82E-28
5 NR3C1 Nuclear receptor subfamily 3 group C member 1 Nucleus Ligand-dependent nuclear receptor 8.48E-28
6 HIF1A Hypoxia inducible factor 1 subunit alpha Nucleus Transcription regulator 2.08E-27
7 HMOX1 Heme oxygenase 1 Cytoplasm Enzyme 5.16E-27
8 IL6 Interleukin 6 Extracellular space Cytokine 1.16E-25
9 STAT3 Signal transducer and activator of transcription 3 Nucleus Transcription regulator 1.46E-25
10 EGFR Epidermal growth factor receptor Plasma membrane Kinase 7.86E-22
11 MAPK14 Mitogen-activated protein kinase 14 Cytoplasm Kinase 1.68E-19
12 PTGS2 Prostaglandin-endoperoxide synthase 2 Cytoplasm Enzyme 1.1E-17
13 TLR2 Toll like receptor 2 Plasma membrane Transmembrane receptor 2.54E-17
14 LDLR Low density lipoprotein receptor Plasma membrane Transporter 1.2E-16
15 MTOR Mechanistic target of rapamycin kinase Nucleus Kinase 3.83E-16
16 VEGFA Vascular endothelial growth factor A Extracellular space Growth factor 1.3E-15
17 HMGB1 High mobility group box 1 Nucleus Transcription regulator 1.67E-15
18 AKT1 AKT serine/threonine kinase 1 Cytoplasm Kinase 1.49E-09
19 HSPA5 Heat shock protein family A (Hsp70) member 5 Cytoplasm Enzyme 9.14E-05
20 MAPK1 Mitogen-activated protein kinase 1 Cytoplasm Kinase 3.72E-03
), ArticleFig(id=1200378855992185535, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Category Target
Common targets of GXNT against thrombosis and microthrombosis induced by COVID-19 HMGB1, IL17A, AKT1, IL1B, STAT3, HMOX1, IL6, TNF, IL10, TLR2
Specific targets of GXNT against thrombosis TLR4, MYD88, JAK2, TNFRSF1A, PPARG, F2, APOE, IL2, LEP, NR3C1
Specific targets of GXNT against microthrombosis induced by COVID-19 VEGFA, MTOR, EGFR, HSPA5, MAPK1, LDLR, MAPK14, HIF1A, NR3C1, PTGS2
), ArticleFig(id=1200378856101237446, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199786455716429953, language=CN, label=Table 3, caption=

Comparison of core targets of GXNT against thrombosis and microthrombosis induced by COVID-19

, figureFileSmall=null, figureFileBig=null, tableContent=
Category Target
Common targets of GXNT against thrombosis and microthrombosis induced by COVID-19 HMGB1, IL17A, AKT1, IL1B, STAT3, HMOX1, IL6, TNF, IL10, TLR2
Specific targets of GXNT against thrombosis TLR4, MYD88, JAK2, TNFRSF1A, PPARG, F2, APOE, IL2, LEP, NR3C1
Specific targets of GXNT against microthrombosis induced by COVID-19 VEGFA, MTOR, EGFR, HSPA5, MAPK1, LDLR, MAPK14, HIF1A, NR3C1, PTGS2
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基于网络药理学解析冠心宁片抗血栓及新冠病毒引起的微血栓的潜在机制
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公佩钰 1, 2 , 肖光旭 1, 2 , 李文君 1, 2 , 樊官伟 1, 2 , 吕明 1, * , 朱金墙 1, *
药学学报 | 研究论文 2024,59(9): 2545-2555
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药学学报 | 研究论文 2024, 59(9): 2545-2555
基于网络药理学解析冠心宁片抗血栓及新冠病毒引起的微血栓的潜在机制
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公佩钰1, 2, 肖光旭1, 2, 李文君1, 2, 樊官伟1, 2, 吕明1, * , 朱金墙1, *
作者信息
  • 1.天津中医药大学, 组分中药国家重点实验室, 天津 301617
  • 2.天津中医药大学第一附属医院, 国家中医针灸临床医学研究中心, 天津 300193

通讯作者:

*吕明, Tel: 18020039001, E-mail: ;
朱金墙, Tel: 18920772803, E-mail:
Analysis of the mechanisms of Guanxinning Tablet for antithrombotic and microthrombotic effects caused by COVID-19 based on network pharmacology
Pei-yu GONG1, 2, Guang-xu XIAO1, 2, Wen-jun LI1, 2, Guan-wei FAN1, 2, Ming LÜ1, * , Jin-qiang ZHU1, *
Affiliations
  • 1. State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
  • 2. National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
出版时间: 2024-09-12 doi: 10.16438/j.0513-4870.2024-0460
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摘要
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血栓形成是增加新冠肺炎患者死亡率和导致长新冠后遗症的关键因素。由活血化瘀中药丹参、川芎组成的冠心宁片(GXNT) 具有显著的抗血栓活性, 但其抗常规血栓与由新冠病毒引起微血栓机制之间的异同仍不清楚。本文运用体外抗血小板实验、网络药理学分析、分子对接技术和分子生物学实验, 初步揭示了GXNT治疗血栓及新冠病毒引起的微血栓的主要活性成分、潜在靶点和作用机制。体外血小板聚集和黏附实验结果表明, GXNT具有显著的抗血小板聚集和黏附的活性, 且呈一定的剂量依赖性。网络药理学分析发现, GXNT中的丹酚酸B、丹参酮ⅡA、咖啡酸和川芎嗪能够通过关键靶点高迁移率族蛋白B1 (high mobility group box 1 protein, HMGB1)、肿瘤坏死因子(tumor necrosis factor, TNF)、白细胞介素6 (interleukin-6, IL6) 和丝氨酸/苏氨酸激酶1 (AKT serine/threonine kinase 1, AKT1) 来抗血栓及由新冠病毒引起的微血栓。其中, HMGB1信号通路为其关键的共同机制之一。Western blot实验结果也表明, GXNT对血小板中HMGB1蛋白的表达水平有显著抑制作用。综上, 本文探究的GXNT抗常规血栓与由新冠病毒引起微血栓机制之间的异同为临床防治长新冠后遗症提供用药参考和理论依据。该动物实验已通过天津中医药大学实验动物伦理委员会审核批准(编号: TCM-LAEC2023187g1549)。

冠心宁片  /  抗血栓  /  COVID-19  /  长新冠  /  HMGB1信号通路

Thrombosis is a key factor that increases the mortality rate of COVID-19 patients and causes long COVID sequelae. Guanxinning Tablet (GXNT), which is composed of Salvia miltiorrhiza and Ligusticum Chuanxiong, has significant antithrombotic activity, but the similarities and differences between its anti-conventional thrombus and microthrombus induced by COVID-19 remain unclear. In this paper, the main active components, potential targets and mechanisms of GXNT in the treatment of thrombus and microthrombus caused by COVID-19 were preliminarily revealed by using anti-platelet experiments in vitro, network pharmacology analysis, molecular docking technology and molecular biology experiments. The results of platelet aggregation and adhesion experiments in vitro showed that GXNT had significant anti-platelet aggregation and adhesion activities in a dose-dependent manner. Using network pharmacology analysis, it was revealed that salvianolic acid B, tanshinone ⅡA, caffeic acid and ligustrazine in GXNT could resist thrombus and microthrombus caused by COVID-19 through key targets as the high mobility group box 1 protein (HMGB1), tumor necrosis factor (TNF), interleukin 6 (IL6) and AKT serine/threonine kinase 1 (AKT1). HMGB1 signaling pathway is one of its key common mechanisms. Western blot also indicated that GXNT significantly inhibited the expression of HMGB1 protein in platelets. In summary, this paper explores the similarities and differences between the mechanism of GXNT against conventional thrombus and microthrombus caused by COVID-19 and provides drug reference and theoretical basis for clinical prevention and treatment of long COVID sequelae. The animal experiment has been approved by the Experimental Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine (No. TCM-LAEC2023187g1549).

Guanxinning Tablet  /  anti-thrombosis  /  COVID-19  /  long COVID  /  HMGB1 signaling pathway
公佩钰, 肖光旭, 李文君, 樊官伟, 吕明, 朱金墙. 基于网络药理学解析冠心宁片抗血栓及新冠病毒引起的微血栓的潜在机制. 药学学报, 2024 , 59 (9) : 2545 -2555 . DOI: 10.16438/j.0513-4870.2024-0460
Pei-yu GONG, Guang-xu XIAO, Wen-jun LI, Guan-wei FAN, Ming LÜ, Jin-qiang ZHU. Analysis of the mechanisms of Guanxinning Tablet for antithrombotic and microthrombotic effects caused by COVID-19 based on network pharmacology[J]. Acta Pharmaceutica Sinica, 2024 , 59 (9) : 2545 -2555 . DOI: 10.16438/j.0513-4870.2024-0460
正文
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血栓形成是一个多因素参与的、复杂的病理生理过程, 其导致的心肌梗死和缺血性脑卒中等缺血性事件是全球死亡和致残的主要原因[1]。在新型冠状病毒肺炎(COVID-19) 暴发后, 发现急性呼吸系统综合征冠状病毒2 (SARS-CoV-2) 能够引起COVID-19患者(尤其是长新冠患者) 凝块强度(CS) 增加、血小板对CS的贡献增加、纤维蛋白原对CS的贡献增加、D-二聚体水平升高等促凝特征, 其表现为微血栓[2]。微血栓的形成不仅与SARS-CoV-2引起的内皮炎症、补体激活、凝血酶生成有关, 而且SARS-CoV-2可能直接通过影响血小板功能来调节其血栓形成。目前, 预防微血栓是减轻长新冠后遗症的重要策略之一[3, 4]。
血小板作为血栓形成的主要参与者, 在缺血性脑卒中、动脉粥样硬化、深静脉血栓、心肌梗死以及COVID-19等疾病的发展过程中, 被活化而发生聚集和黏附, 进而参与血管内血栓的形成[3-6]。目前, 抗血小板药物主要有环加氧酶抑制剂(阿司匹林)、P2Y12拮抗剂(氯吡格雷、替卡格雷)、αIIbβ3拮抗剂(阿昔单抗) 等[7]。但这些药物存在一定的不良反应, 如引起胃肠道出血等[8, 9]。研究发现, 由活血化瘀中药丹参和川芎组成的冠心宁片(GXNT) 具有显著的抗血栓作用, 且不增加出血风险[10], 但GXNT抗血栓的潜在机制仍不清楚。因此, 本研究运用体外抗血小板实验、网络药理分析、分子对接技术和分子生物学实验的方法探讨GXNT中有效活性成分抗血栓及COVID-19引起微血栓的共同靶点与机制, 并通过体外血小板聚集实验、黏附实验和Western blot实验进行初步验证, 以期为GXNT的临床应用提供理论基础和科学依据。
材料与方法
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药品、试剂与细胞系  GXNT由正大青春宝药业有限公司提供(国药准字Z20150028)。TBS (G0001)、Tween-20 (GC204002) 和prestained protein marker Ⅱ (G2058-250UL) 购自武汉赛维尔生物科技有限公司。Y-Tec 5min (YWB0501) 即用型封闭液购自上海七纯生物科技有限公司。Future PAGETM (ET15412LGel) 蛋白预制胶购自常州伯仪生物科技有限公司。AffinityTM ECL kit (KF8003) 购自Affinity Biosciences公司。PierceTM BCA protein assay kits (23227) 购自Thermo Fisher Scientific公司。SDS-PAGE蛋白上样缓冲液(P0015L)、RIPA裂解液(P0013B) 和蛋白酶磷酸酶抑制剂混合物(P1045) 购自碧云天生物技术有限公司。高迁移率族蛋白B1 (high mobility group box 1 protein, HMGB1, ab18256) 和丝氨酸/苏氨酸激酶1 (AKT serine/threonine kinase 1, AKT1, ab245355) 购自Abcam公司。水蛭素(hirudin, H24700-1mg) 购自上海吉至生化科技有限公司。凝血酶(thrombin, T4648-1KU) 和纤维蛋白原(fibrinogen, F3879) 购自Sigma公司。Calcein-AM (C3100MP) 购自Invitrogen公司。4%细胞组织固定液(P1110) 购自北京索莱宝科技有限公司。DMEM高糖培养基(12800-017)、fetal bovine serum (10099-141) 和0.25% trypsin-EDTA (25200-072) 购自Gibco公司。Penicillin streptomycin (SV30010) 购自HyClone公司。EA.hy926人脐静脉细胞融合细胞系购自中国科学院上海生命科学研究院细胞资源中心。
多功能酶标仪(Varioskan Lux)、二氧化碳培养箱(51030670) 购自美国Thermo Fisher Scientific公司; 高内涵筛选系统(Operetta) 购自英国Perkin Elmer公司。
实验动物  健康雄性SD大鼠, 体重200~220 g, SPF级, 合格证号为110322231103253986, 购于北京华阜康生物科技股份有限公司, 许可证号为SCXK (津) 2020-0005。以上动物均在天津中医药大学实验室清洁级动物中心饲养, 室温20~25 ℃, 相对湿度40%~60%, 采用标准方式饲养, 明暗环境各交替12 h。该动物实验已通过天津中医药大学实验动物伦理委员会审核批准(编号: TCM-LAEC2023187g1549), 动物福利和实验过程均遵循天津中医药大学实验动物伦理委员会的规定。
血小板的提取  三溴乙醇将大鼠麻醉, 利用含有1 mL抗凝剂(ACD) 的10 mL注射器进行腹主动脉取血。血液200 ×g离心, 10 min后, 吸取上清液得到富血小板血浆(PRP)。在其中加入适量的前列腺素PGE1, 使其终浓度为1 μmol·L-1, 800 ×g离心10 min, 得到血小板和红细胞的分层液。用buffer缓冲液轻柔缓慢地重悬血小板, 并将血小板吸至干净的EP管中, 最后将每毫升血小板数量调整为2×108个。
血小板聚集实验  将血小板分为control组、模型(thrombin) 组、阳性药(水蛭素, hirudin, 20 μmol·L-1) 组、0.03 mg·mL-1 GXNT组、0.1 mg·mL-1 GXNT组和0.3 mg·mL-1 GXNT组。阳性药组和不同剂量GXNT组预给药2 h后, 取各组150 μL的预给药血小板加到96孔白板中, 并加入50 μL含激动剂thrombin和CaCl2的buffer缓冲液, 使thrombin的终浓度为0.3 U·mL-1, CaCl2的终浓度为2 mmol·L-1。Control组孔内血小板加入50 μL不含激动剂的buffer缓冲液。利用多功能酶标仪检测各组405 nm波长处的A值, 每次间隔30 s, 持续检测45 min, 观测各组A值变化。按照(At=0-At=n)/At=0×100%计算各组不同时间点的血小板聚集率, 减去control组得到去除自身干扰的血小板聚集率, 并绘制成曲线图。
血小板与纤维蛋白原的黏附实验  提取好的血小板加入Calcein-AM至终浓度为2 μmol·L-1, 室温染色30 min, 650 ×g离心3 min, 弃去上清液, buffer重悬并离心, 重复清洗3次, 最后用buffer将血小板稀释至原体积的5倍。分组处理同上述血小板聚集实验。阳性药组和不同剂量GXNT组预给药2 h后, 取各组99 μL的血小板加到铺有纤维蛋白原的96孔黑板中, 并加入1 μL 10 U·mL-1激动剂thrombin, 使其终浓度为0.1 U·mL-1。Control组孔内仅加100 μL血小板, 不加激动剂。37 ℃孵育30 min, 100 μL PBS清洗3次, 每孔加入100 μL的4%多聚甲醛溶液固定20 min。PBS清洗1次, 每孔再加入100 μL PBS, 用高内涵分析系统检测黏附的血小板数量。血小板黏附率= (Count模型组/实验组-Count空白组) / (Count模型组-Count空白组) × 100%。
血小板与内皮细胞的黏附实验  将EA.hy926细胞接种于96孔黑板中, 待细胞生长至90%以上时, 提取大鼠血小板。标记血小板的方法同上述血小板与纤维蛋白原黏附实验, 分组处理同上述血小板聚集实验。阳性药组和不同剂量GXNT组预给药2 h后, 取各组99 μL血小板加到铺有EA.hy926内皮细胞的96孔黑板中, 并加入1 μL 10 U·mL-1激动剂thrombin, 使其终浓度为0.1 U·mL-1。Control组孔内仅加100 μL血小板, 不加激动剂。37 ℃孵箱中继续培养24 h, 100 μL PBS清洗3次, 每孔加入100 μL的4%多聚甲醛溶液固定20 min, 高内涵分析系统检测黏附的血小板数量。
GXNT活性成分与靶点筛选  通过检索GXNT的成分鉴定文章并结合中国药典确定GXNT中的20种单体成分。PubMed文献查阅检索出丹参中的隐丹参酮、丹参素、二氢丹参酮Ⅰ、紫草酸、原儿茶醛、迷迭香酸、丹酚酸A、丹酚酸B、丹参酮Ⅰ、丹参酮ⅡA有296个已报道的相关靶点。川芎中的咖啡酸、绿原酸、阿魏酸、藁本内酯、原儿茶酸、洋川芎内酯A、洋川芎内酯H、洋川芎内酯Ⅰ、川芎嗪、香草醛有240个相关靶点。整合以上靶点删除重复数据后得到GXNT的靶点414个。
疾病靶点筛选  以“thrombosis”、“COVID-19”和“microthrombosis”为关键词, 以Gene Cards数据库的前30%为原则, 结合Ingenuity Pathway Analysis (IPA, http://www.ingenuity.com) 选取疾病相关靶点, 并查找重要组学文献对未筛选出的靶点进行补充。整合疾病靶点删除重复数据后得到thrombosis的靶点575个、COVID-19的靶点2 178个和microthrombosis的靶点535个。
药物与疾病交集靶点的筛选  运用Veney 2.1.0 (http://bioinfogp.cnb.csic.es/tools/venny/) 将GXNT中主要活性成分的靶点与thrombosis、COVID-19、microthrombosis相关的疾病靶点取交集, 制作韦恩图。
GO和KEGG富集分析  利用IPA的“overlay-canonical pathway”模块分析靶点相关的核心通路, 并进行类似基因组百科全书(Kyoto Encyclopedia of Genes and Genomes, KEGG) 和基因本体(Gene Ontology, GO) 的富集分析。通过IPA获得排名前20的通路和生物学疾病功能, 运用Origin 2022制作气泡图进行可视化展示。
构建蛋白质-蛋白质相互作用(PPI) 网络  利用IPA的“upstream regulator”模块和PPI数据关系, 并结合靶点数据库, 选取排名前20的核心靶点, 在“build-connection”模块中构建核心靶点与其他靶点的PPI关系图。
药物-活性成分-核心靶点-通路关系图  利用IPA的“overlay-canonical pathway”模块进行交集靶点的KEGG富集分析, 导出排名前20通路的数据信息, 结合核心成分和核心靶点, 运用Origin 2022制作桑基图进行可视化展示。
Western blot  对上述血小板聚集实验的各组血小板进行离心收集, 裂解得到含有蛋白的上清液, 用BCA蛋白浓度测定试剂盒检测蛋白浓度。利用SDS-PAGE对蛋白样品进行分离, 并转移至PVDF膜。Y-Tec 5 min即用型封闭液封闭10 min, 一抗(HMGB1, 1∶1 000; GAPDH, 1∶10 000) 孵育, 4 ℃过夜。次日, 洗膜, 二抗孵育, 室温1 h。利用化学发光成像仪检测蛋白条带, 用Image J软件分析条带灰度值。
分子对接  在PDB数据库(https://www.rcsb.org/) 中下载关键作用靶点蛋白的“PDB”格式晶体结构, 在PubChem数据库(https://pubchem.ncbi.nlm.nih.gov/) 中下载核心活性成分的“SDF”格式结构。通过Discovery Studio 2019 Client软件中的“大分子”模块对蛋白质进行去水、加氢等操作, 利用“小分子”模块对配体进行预处理。通过-cdocker energy评价受体-配体相互作用情况, 值越大则结合越好, 并展示3D和2D效果图。
统计学分析  使用GraphPad Prism 9.0软件进行统计学分析, 单因素多组之间比较采用单因素方差分析(one-way ANOVA), 数据均以x ± s的形式表示, P < 0.05表示差异有统计学意义。
结果
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1 GXNT对thrombin诱导血小板聚集和黏附的影响
为了检测GXNT的抗血小板活化作用, 本研究进行体外血小板聚集和黏附实验。在thrombin诱导血小板聚集实验中, thrombin能够导致血小板聚集, 且聚集率随时间增长而增加, 而阳性药hirudin和不同剂量GXNT能够显著降低thrombin诱导的血小板聚集(图 1A、B)。在血小板与细胞外基质的黏附实验中, 阳性药hirudin和不同剂量GXNT也显著降低thrombin诱导的血小板与纤维蛋白原的黏附(图 1C、D)。为了进一步模拟血管内的血小板黏附, 本研究使用thrombin诱导血小板与内皮细胞之间的黏附, 发现阳性药hirudin和剂量为0.1和0.3 mg·mL-1 GXNT显著抑制thrombin诱导的血小板与内皮细胞的黏附, 虽然0.03 mg·mL-1 GXNT未产生明显的抑制作用, 但仍存在一定的抑制趋势(图 1E、F)。总之, 这些结果指出GXNT能够对血小板的聚集和黏附产生显著的抑制作用。
2 GXNT抗血栓及COVID-19引起微血栓的作用靶点
为探究GXNT抗血栓及COVID-19引起微血栓的作用靶点, 将414个GXNT的作用靶点与575个血栓形成的作用靶点通过Venny图取交集, 得到117个共同靶点, 即GXNT抗血栓的潜在靶点。将414个GXNT作用靶点、2 178个COVID-19疾病靶点和535个微血栓形成的靶点通过Venny图取交集, 得到54个交集靶点, 即GXNT抗COVID-19引起微血栓的潜在靶点。将上述得到的117个交集靶点和54个交集靶点导入IPA进行PPI关系分析。再根据上游调控因子的P-value值, 分别列出GXNT抗血栓和抗COVID-19引起微血栓的前20个核心靶点(表 1、2)。其中, GXNT抗血栓及COVID-19引起微血栓的共同靶点有HMGB1、IL17A、AKT1、IL1B、STAT3、HMOX1、IL6、TNF、IL10、TLR2, GXNT抗血栓的特异靶点有TLR4、MYD88、JAK2、TNFRSF1A、PPARG、F2、APOE、IL2、LEP、NR3C1, GXNT抗COVID-19引起微血栓的特异靶点有VEGFA、MTOR、EGFR、HSPA5、MAPK1、LDLR、MAPK14、HIF1A、NR3C1、PTGS2 (表 3)。
3 药物-活性成分-核心靶点-通路网络图
GXNT抗血栓的药物-活性成分-核心靶点-通路网络图见图 2A, 抗COVID-19引起微血栓的网络图见图 2B。
4 GO功能富集与KEGG通路分析
GO富集分析表明, GXNT抗血栓排名前20的疾病与功能的相关条目包括心血管病、机体损伤和异常、炎症反应、细胞运动、免疫细胞运输、炎症性疾病、血液疾病、血液系统的发展与功能、细胞间的信号传导和相互作用、呼吸道疾病、清除自由基、有机体的生存、骨骼和肌肉疾病、心血管系统的发展与功能、有机体的发展、组织形态、结缔组织疾病、免疫疾病、内分泌系统疾病、胃肠道疾病(图 3A)。GXNT抗COVID-19引起微血栓排名前20的疾病与功能的相关条目包括细胞运动、免疫细胞运输、血液系统的发展与功能、心血管病、有机体损伤和异常、炎症反应、组织形态、组织发展、呼吸道疾病、细胞死亡与存活、清除自由基、心血管系统的发展与功能、有机体的发展、结缔组织疾病、炎症性疾病、骨骼和肌肉疾病、有机体的生存、细胞信号传导、小分子生物化学、免疫疾病(图 3B)。
KEGG富集分析表明, GXNT抗血栓排名前20的相关通路包括神经炎症信号通路、病原体诱导的细胞因子风暴信号通路、糖皮质激素受体信号通路、IL-33信号通路、HMGB1信号通路、IL-17信号通路、ID1信号通路、IL-12在巨噬细胞中的信号转导和产生、HIF-1α信号通路、IL-8信号通路、中性粒细胞胞外陷阱信号通路、急性相位反应信号、动脉粥样硬化信号通路、心肌肥厚信号(增强) 通路、冠状病毒发病途径、Th1通路通路、伤口愈合信号通路、多发性硬化信号通路、慢性阻塞性肺疾病的气道病理学、IL-6信号通路(图 3C)。GXNT抗COVID-19引起微血栓排名前20的相关通路包括糖皮质激素受体信号通路、IL-33信号通路、HMGB1信号通路、ID1信号通路、神经炎症信号通路、IL-8信号通路、IL-6信号通路、急性相位反应信号、IL-17信号通路、肺纤维化特发性信号通路、HIF-lα信号通路、病原体诱导的细胞因子风暴信号通路、中性粒细胞胞外陷阱信号通路、多发性硬化信号通路、肺愈合信号通路、冠状病毒发病途径、动脉粥样硬化信号通路、伤口愈合信号通路、IL-12在巨噬细胞中的信号转导和产生、心肌肥厚信号(增强) 通路(图 3D)。根据GXNT可调控的基因集合映射到通路中的基因数目与该通路总的基因数目比值, 即ratio, 最终发现HMGB1信号通路为GXNT抗血栓及COVID-19引起微血栓共同的关键信号通路, 该通路中涉及的蛋白分子见图 3E。
5 分子对接结果
通过“药物-活性成分-核心靶点-通路”网络图的可视化分析, 根据节点大小及连接线的数量, 发现GXNT中的4种关键活性成分为丹酚酸B、丹参酮ⅡA、咖啡酸、川芎嗪, 且抗血栓及COVID-19引起微血栓的关键靶点为TNF、IL6。KEGG富集分析结果可知, 靶点HMGB1与其相关性较高, GO富集分析结果可知, 心血管疾病与其相关性较高。因此, 将TNF、IL6、HMGB1和AKT1作为关键靶点进行分子对接, 并选用落新妇苷、人参皂苷Rh1、冬凌草甲素、甘草酸分别作为阳性对照, 配体和蛋白之间的结合情况用-cdocker energy表示, 值越大则结合越好(图 4)。通过上述分析和分子对接结果揭示了丹参酮ⅡA、咖啡酸和川芎嗪为GXNT通过HMGB1信号通路发挥抗血栓及COVID-19引起微血栓的重要活性成分。
6 GXNT对HMGB1信号通路中HMGB1蛋白表达的影响
为验证上述分析结果的准确性, 本研究通过Western blot评价GXNT对thrombin激活的血小板HMGB1信号通路中HMGB1蛋白表达的影响。结果显示, thrombin可以上调HMGB1蛋白的表达水平, 与模型组(thrombin) 比较, 0.1 mg·mL-1 GXNT能够导致HMGB1蛋白表达水平的显著降低(图 5), 此实验结果与上述KEGG预测结果保持一致。
讨论
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微血栓的高发不仅是COVID-19患者的临床特征之一, 也是导致一系列长新冠后遗症的重要因素[11]。本研究证实了GXNT对血小板聚集和黏附具有显著的抑制作用, 而这展示出GXNT对COVID-19引起微血栓的治疗潜力。通过网络药理学分析及分子对接发现, HMGB1信号通路为GXNT抗血栓及COVID-19引起微血栓的共同机制, 且丹参酮ⅡA、咖啡酸、川芎嗪是其主要活性成分。此外, Western blot实验结果也证明了GXNT能够降低激活后血小板中HMGB1蛋白的表达水平。而最近研究发现, 靶向HMGB1可能成为治疗COVID-19的潜在治疗策略[12]。SARS-CoV-2病毒能够激活血小板, 使其高表达HMGB1蛋白, 而对其进行抑制可阻止血栓形成[13]。Wei等[13]研究发现, 抑制HMGB1及下游通路是缓解小鼠模型中卡拉胶诱导血栓形成的重要策略。同时, 这些报道为本研究揭示HMGB1信号通路为GXNT抗血栓及COVID-19引起微血栓的共同机制提供了一定支持, 也增加了网络药理分析结果的可靠性。
除HMGB1外, IL17A、AKT1、IL1B、STAT3、HMOX1、IL6、TNF、IL10、TLR2也是GXNT抗血栓及COVID-19引起微血栓的共同靶点。由此发现, GXNT抗血栓及COVID-19引起微血栓的作用机制以抑制炎症反应为主。众所周知, COVID-19患者中出现的内皮炎症、补体激活、凝血酶生成、血小板和白细胞招募, 以及先天和适应性免疫反应的启动, 将最终导致免疫血栓形成[3]。因此, 减轻炎症反应和免疫应答是抑制COVID-19引起微血栓的关键[3, 14]。此外, 由表 3中差异靶点可知, 与抗常规血栓不同的是GXNT抗COVID-19引起的微血栓更偏向于调控MAPKs信号通路。MAPKs信号通路作为一种重要的血小板激活途径, 可以被胶原蛋白和凝血酶激活, 进而介导血小板变形、黏附和聚集, 参与血栓形成[15, 16]。GXNT对MAPKs信号通路中相关靶点的调控有助于减轻COVID-19引起的微血栓。以上这些说明GXNT可作为防治COVID-19患者中微血栓形成的候选药物。
然而, 本研究也存在一些局限性, GXNT的成分复杂, 其抗血栓形成的潜在机制可能是多方面的。对于GXNT抗血栓及COVID-19引起微血栓的其他共同机制, 如糖皮质激素受体信号通路、IL-33信号通路、IL-8信号通路等, 也应进一步验证。此外, 进行SARS-CoV-2病毒的研究, 对实验室条件要求较高, 导致相关实验不易开展, 虽然网络药理分析为揭示GXNT抗血栓及COVID-19引起微血栓的共同机制提供了可能, 却仍缺乏直接的实验证据。但是, 本研究探讨GXNT抗常规血栓与由COVID-19引起微血栓之间的共同机制, 不仅为临床治疗血栓导致的相关疾病提供了用药参考, 也为临床防治长新冠后遗症提供了理论依据和候选药物。
作者贡献: 朱金墙和吕明负责实验设计及论文指导; 公佩钰和肖光旭负责实验操作及文章撰写; 李文君协助实验开展; 樊官伟负责修订文章。
利益冲突: 本文所有作者均声明不存在利益冲突。
基金
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  • 国家自然科学基金项目(82274436)
  • 天津市教委科研计划项目(2023KJ149)
  • 正大青春宝药业有限公司技术服务委托项目(QCB-YXB-20220029)
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参考文献 引证文献
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2024年第59卷第9期
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doi: 10.16438/j.0513-4870.2024-0460
  • 接收时间：2024-05-14
  • 首发时间：2025-11-24
  • 出版时间：2024-09-12
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  • 收稿日期：2024-05-14
  • 修回日期：2024-07-07
基金
国家自然科学基金项目(82274436)
天津市教委科研计划项目(2023KJ149)
正大青春宝药业有限公司技术服务委托项目(QCB-YXB-20220029)
作者信息
    1.天津中医药大学, 组分中药国家重点实验室, 天津 301617
    2.天津中医药大学第一附属医院, 国家中医针灸临床医学研究中心, 天津 300193

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*吕明, Tel: 18020039001, E-mail: ;
朱金墙, Tel: 18920772803, E-mail:
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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