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Article(id=1239238830201565600, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239238829719220640, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.08.10, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1680192000000, receivedDateStr=2023-03-31, revisedDate=null, revisedDateStr=null, acceptedDate=1715097600000, acceptedDateStr=2024-05-08, onlineDate=1773387161064, onlineDateStr=2026-03-13, pubDate=1724515200000, pubDateStr=2024-08-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773387161064, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773387161064, creator=13701087609, updateTime=1773387161064, updator=13701087609, issue=Issue{id=1239238829719220640, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='8', pageStart='561', pageEnd='640', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773387160949, creator=13701087609, updateTime=1773387216554, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239239063014789867, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239238829719220640, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239239063014789868, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239238829719220640, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=618, endPage=626, ext={EN=ArticleExt(id=1239238830482583970, articleId=1239238830201565600, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Study on mechanism of endoplasmic reticulum stress and brain protective effect of cerebroprotein hydrolysate in ischemic stroke based on network pharmacology, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=
AIM

To study the protective effect of cerebroprotein hydrolysate and its related mechanism of regulating endoplasmic reticulum stress in ischemic stroke based on network pharmacology and animal experiments.

METHODS

GeneCards and OMIM databases were used to screen the targets related to ischemic stroke and endoplasmic reticulum stress, and Wayne diagram was drawn to get the intersection genes. The protein-protein interaction network diagram was downloaded from String database and visualized by Cytoscape software, and the top 10 genes were screened by cytoHubba plug-in. Finally, Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） were enriched and analyzed. Mouse models of ischemic stroke were made by the suture-occluded method, and randomly divided into sham group, model group, cerebroprotein hydrolysate 0.2 g·kg-1 group and 0.5 g·kg-1 group, and edaravone 8 mg·kg-1 group,with 11 mice in each group. The drug was administered continuously for 5 days after operation. The volume of cerebral infarction was measured by TTC staining, the contents of interleukin （IL）-6, IL-1β, γ-interferon （IFN-γ） and brain-derived neurotrophic factor （BDNF） in cerebral ischemic penumbra and serum were measured by ELISA, and the expression of Caspase-3 and AKT protein in brain tissue was observed by immunohistochemistry.

RESULTS

According to the results of network pharmacology, 41 intersection genes of ischemic stroke and endoplasmic reticulum stress were screened, and the top 10 genes screened were IL-6, ALB, INS, TNF, AKT1, CASP3, MAPK3, TP53, SIRT1 and VEGFA, respectively. GO enrichment resulted in 515 related entries. KEGG pathway enrichment involved lipid and atherosclerosis pathway, human cytomegalovirus infection, Alzheimer’s disease, phosphatidylinositol -3- kinase/ protein kinase B （PI3K/AKT） signaling pathway and so on. Compared with the model group, the cerebral infarction volume was significantly reduced （P<0.01）; the contents of IL-6, IL-1β and IFN-γ in serum and penumbra were decreased significantly （P<0.05）, and the contents of BDNF in serum and penumbra were increased significantly （P<0.05）; the expression of Caspase-3 in brain tissue was decreased significantly （P<0.05）, and the expression of AKT was increased significantly （P<0.05） in the two groups of cerebroprotein hydrolysate.

CONCLUSION

Based on the analysis of network pharmacology, the endoplasmic reticulum stress mechanism of ischemic stroke may be related to inflammation and apoptosis. The neuroprotective mechanism of cerebroprotein hydrolysate may be related to activating BDNF/PI3K/AKT pathway and inhibiting inflammation and apoptosis.

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目的

基于网络药理学方法和动物实验初步研究脑蛋白水解物的脑保护作用及其调控缺血性脑卒中内质网应激的相关作用机制。

方法

利用GeneCards和OMIM数据库筛选出缺血性脑卒中和内质网应激相关靶点，绘制韦恩图，得到两者交集基因，利用String数据库下载蛋白质-蛋白质相互作用网络图，通过Cytoscape软件进行可视化分析，并利用cytoHubba插件筛选出前10位基因，最后进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。采用线栓法制备小鼠缺血性脑卒中模型，随机分为假手术组，模型组，脑蛋白水解物0.2 g·kg-1组、0.5 g·kg-1组和依达拉奉8 mg·kg-1组，每组11只。术后连续给药5 d。TTC染色测定脑梗死体积，ELISA法测定脑缺血半暗带和血清中白细胞介素（IL）-6、IL-1β、γ-干扰素（IFN-γ）和脑源性神经营养因子（BDNF）的含量，免疫组化法观察脑组织中Caspase-3和 AKT蛋白的表达变化。

结果

网络药理学结果筛选得到41个缺血性脑卒中和内质网应激的交集基因，筛选出排前10的基因分别是IL-6、ALB、INS、TNF、AKT1、CASP3、MAPK3、TP53、SIRT1和VEGFA。GO富集得到515个相关条目，KEGG通路富集涉及脂质和动脉粥样硬化通路、人巨细胞病毒感染、阿尔茨海默病、磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/AKT）信号通路等。与模型组比较，脑蛋白水解物2个给药组小鼠的脑梗死体积明显减小（P<0.01），小鼠血清和半暗带中IL-6、IL-1β和IFN-γ含量显著降低、BDNF显著增加（P<0.05），脑组织中Caspase-3表达显著降低、AKT表达显著增强（P<0.05）。

结论

基于网络药理学分析，缺血性脑卒中的内质网应激机制可能与炎症和凋亡相关，脑蛋白水解物的神经保护机制可能与激活BDNF/PI3K/AKT 通路及抑制炎症和细胞凋亡有关。

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李炜，E-mail:
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史彩云，女，硕士在读，主要从事神经药理学的研究，E-mail:

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史彩云，女，硕士在读，主要从事神经药理学的研究，E-mail:

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史彩云，女，硕士在读，主要从事神经药理学的研究，E-mail:

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Front Pharmacol, 2019, 10 : 1245., articleTitle=Cerebrolysin ameliorates focal cerebral ischemia injury through neuroinflammatory inhibition via CREB/PGC-1α pathway, refAbstract=null)], funds=[Fund(id=1239238840938984188, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, awardId=H2020405298, language=CN, fundingSource=河北省自然科学基金(H2020405298), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1239238834626556413, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, xref=1., ext=[AuthorCompanyExt(id=1239238834630750718, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, companyId=1239238834626556413, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.School of Pharmacy, Hebei North University, Zhangjiakou HEBEI 075000, China), AuthorCompanyExt(id=1239238834639139327, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, companyId=1239238834626556413, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.河北北方学院药学院，河北 张家口 075000)]), AuthorCompany(id=1239238834706248194, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, xref=2., ext=[AuthorCompanyExt(id=1239238834718831107, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, companyId=1239238834706248194, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.Hebei Provincial Key Laboratory of Neuropharmacology, Zhangjiakou HEBEI 075000, China), AuthorCompanyExt(id=1239238834727219716, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, companyId=1239238834706248194, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.河北省神经药理学重点实验室，河北 张家口075000)])], figs=[ArticleFig(id=1239238838866997924, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=ByDsRkna3+T4EgGaNHfFoA==, figureFileBig=iveXY7b/PwwjligXPlHA1Q==, tableContent=null), ArticleFig(id=1239238838963466920, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=图1, caption=缺血性脑卒中与内质网应激交集基因韦恩图, figureFileSmall=ByDsRkna3+T4EgGaNHfFoA==, figureFileBig=iveXY7b/PwwjligXPlHA1Q==, tableContent=null), ArticleFig(id=1239238839168987825, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=hbf1YpJhRZs/X6VDCI5iuQ==, figureFileBig=dZdw5U7Xp8B6e7JiMhJSHg==, tableContent=null), ArticleFig(id=1239238839248679603, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=图2, caption=缺血性脑卒中与内质网应激交集的蛋白质-蛋白质相互作用网络图

天蓝色代表从数据库获得，紫色代表实验验证，绿色代表基因邻接，红色代表基因融合，蓝色代表基因共现，浅黄色代表文本挖掘证据得出的两者有相互关系，黑色代表共表达，浅蓝代表蛋白同源

, figureFileSmall=hbf1YpJhRZs/X6VDCI5iuQ==, figureFileBig=dZdw5U7Xp8B6e7JiMhJSHg==, tableContent=null), ArticleFig(id=1239238839345148600, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=FsNDV4qDWPAc8qtBQLzSVA==, figureFileBig=JuJD1FYoS0UyUTAMex36Gw==, tableContent=null), ArticleFig(id=1239238839429034685, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=图3, caption=缺血性脑卒中与内质网应激交集的关键靶点可视化分析图

圆点越大，颜色越趋于红色，表明其发挥的作用越大；圆点越小，颜色越趋于蓝色，表明其发挥作用越小

, figureFileSmall=FsNDV4qDWPAc8qtBQLzSVA==, figureFileBig=JuJD1FYoS0UyUTAMex36Gw==, tableContent=null), ArticleFig(id=1239238839525503682, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=T3gEoq1VUF30SNBnGP2wew==, figureFileBig=nxq91eO3wDM/AwOBX8/e2A==, tableContent=null), ArticleFig(id=1239238839601001158, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=图4, caption=基因本体富集分析图

BP：生物过程，CC：细胞组分，MF：分子功能

, figureFileSmall=T3gEoq1VUF30SNBnGP2wew==, figureFileBig=nxq91eO3wDM/AwOBX8/e2A==, tableContent=null), ArticleFig(id=1239238839710053065, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=u02O1YB/sqhaHbejHhwPfw==, figureFileBig=ZXw5Z6NOCYAhw2qMqzX8bA==, tableContent=null), ArticleFig(id=1239238839802327757, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=图5, caption=京都基因与基因组百科全书富集分析图, figureFileSmall=u02O1YB/sqhaHbejHhwPfw==, figureFileBig=ZXw5Z6NOCYAhw2qMqzX8bA==, tableContent=null), ArticleFig(id=1239238839873630929, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=GLKgY0CAC9rOt1NacxMPCg==, figureFileBig=1Zs30pOgSNbkGjgFeKLlaw==, tableContent=null), ArticleFig(id=1239238839940739795, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=图6, caption=TTC染色检测各组小鼠脑梗死体积

A：假手术组，B：模型组，C： 脑蛋白水解物0.2 g·kg-1组，D： 脑蛋白水解物0.5 g·kg-1组，E：依达拉奉8 mg·kg-1组

, figureFileSmall=GLKgY0CAC9rOt1NacxMPCg==, figureFileBig=1Zs30pOgSNbkGjgFeKLlaw==, tableContent=null), ArticleFig(id=1239238840041403098, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=KPoQzf9P5PutL867DqNZzg==, figureFileBig=N25m/FH5l/F1vZ/peLYe5A==, tableContent=null), ArticleFig(id=1239238840121094878, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=图7, caption=脑蛋白水解物对各组小鼠脑组织Caspase-3表达的影响（n=3， DAB染色，×400，标尺：1 cm代表100 µm）

A：假手术组，B： 模型组，C： 脑蛋白水解物0.2 g·kg-1组，D： 脑蛋白水解物0.5 g·kg-1组，E：依达拉奉8 mg·kg-1组。经LSD-t检验：与假手术组相比，cP<0.01；与模型组相比，eP<0.05

, figureFileSmall=KPoQzf9P5PutL867DqNZzg==, figureFileBig=N25m/FH5l/F1vZ/peLYe5A==, tableContent=null), ArticleFig(id=1239238840209175264, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=o2VuvKDE4yQ8iGtZy48NpQ==, figureFileBig=JsbS+IbxgCNIgEkhXEXe0A==, tableContent=null), ArticleFig(id=1239238840288867044, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=图8, caption=脑蛋白水解物对各组小鼠脑组织AKT表达的影响（n=3， DAB染色，×400，标尺：1 cm代表100 µm）

A： 假手术组，B： 模型组，C： 脑蛋白水解物0.2 g·kg-1组，D：脑蛋白水解物0.5 g·kg-1组，E： 依达拉奉8 mg·kg-1组。经LSD-t检验：与假手术组相比，cP<0.01；与模型组相比，eP<0.05, fP<0.01

, figureFileSmall=o2VuvKDE4yQ8iGtZy48NpQ==, figureFileBig=JsbS+IbxgCNIgEkhXEXe0A==, tableContent=null), ArticleFig(id=1239238840368558823, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
条目描述基因
hsa05417脂质和动脉粥样硬化通路AKT1, APOB, BCL2, CASP3, HSPA4, IL-6, CXCL8, NFE2L2, NOS3, MAPK3, CCL2,
SOD2, TLR4, TNF, TP53, CYCS,
hsa05163人巨细胞病毒感染AKT1, CALR, CASP3, IL-6, CXCL8, MAPK3, PTGS2, CCL2, TNF, TP53, VEGFA, CYCS
hsa05010阿尔茨海默病AKT1, APOE, APP, CASP3, IL-6, INS, MAPT, MAPK3, PSEN1, PTGS2, TNF, CYCS
hsa04151磷脂酰肌醇-3-激酶/蛋白激酶B信号通路AKT1, BCL2, BDNF, IL-6, INS, NOS3, MAPK3, TLR4, TP53, VEGFA, VWF
hsa04211长寿调节途径AKT1, INS, SOD2, TP53, ADIPOQ, SIRT1
hsa04218细胞衰老AKT1, IL-6, CXCL8, MAPK3, TP53, SIRT1
hsa04726血清素能突触APP, CASP3, MAPK3, PTGS2
hsa04612抗原加工和呈递CALR, HSPA4, TNF
hsa04141内质网中的蛋白质加工BCL2, CALR, NFE2L2
), ArticleFig(id=1239238840452444907, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=表1, caption=

京都基因与基因组百科全书富集分析得到的各通路靶点基因分布

, figureFileSmall=null, figureFileBig=null, tableContent=
条目描述基因
hsa05417脂质和动脉粥样硬化通路AKT1, APOB, BCL2, CASP3, HSPA4, IL-6, CXCL8, NFE2L2, NOS3, MAPK3, CCL2,
SOD2, TLR4, TNF, TP53, CYCS,
hsa05163人巨细胞病毒感染AKT1, CALR, CASP3, IL-6, CXCL8, MAPK3, PTGS2, CCL2, TNF, TP53, VEGFA, CYCS
hsa05010阿尔茨海默病AKT1, APOE, APP, CASP3, IL-6, INS, MAPT, MAPK3, PSEN1, PTGS2, TNF, CYCS
hsa04151磷脂酰肌醇-3-激酶/蛋白激酶B信号通路AKT1, BCL2, BDNF, IL-6, INS, NOS3, MAPK3, TLR4, TP53, VEGFA, VWF
hsa04211长寿调节途径AKT1, INS, SOD2, TP53, ADIPOQ, SIRT1
hsa04218细胞衰老AKT1, IL-6, CXCL8, MAPK3, TP53, SIRT1
hsa04726血清素能突触APP, CASP3, MAPK3, PTGS2
hsa04612抗原加工和呈递CALR, HSPA4, TNF
hsa04141内质网中的蛋白质加工BCL2, CALR, NFE2L2
), ArticleFig(id=1239238840536330991, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别IL-6IL-1βIFN-γBDNF
假手术0.31±0.040.56±0.063.50±0.419.55±1.47
模型0.65±0.08c1.11±0.31c7.90±0.98c5.41±0.86c
脑蛋白水解物0.2 g·kg-10.41±0.11f0.71±0.01f4.22±0.91f6.97±0.99f
脑蛋白水解物0.5 g·kg-10.39±0.04f0.74±0.04f5.30±0.36f9.15±1.46f
依达拉奉8 mg·kg-10.32±0.05f0.69±0.11f3.61±1.27f6.67±1.51e
), ArticleFig(id=1239238840607634162, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=表2, caption=

各组小鼠血清中白细胞介素（IL）-6、IL-1β、γ-干扰素（IFN-γ）和脑源性神经营养因子（BDNF）的含量

, figureFileSmall=null, figureFileBig=null, tableContent=
组别IL-6IL-1βIFN-γBDNF
假手术0.31±0.040.56±0.063.50±0.419.55±1.47
模型0.65±0.08c1.11±0.31c7.90±0.98c5.41±0.86c
脑蛋白水解物0.2 g·kg-10.41±0.11f0.71±0.01f4.22±0.91f6.97±0.99f
脑蛋白水解物0.5 g·kg-10.39±0.04f0.74±0.04f5.30±0.36f9.15±1.46f
依达拉奉8 mg·kg-10.32±0.05f0.69±0.11f3.61±1.27f6.67±1.51e
), ArticleFig(id=1239238840687325940, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别IL-6IL-1βIFN-γBDNF
假手术0.34±0.040.61±0.074.13±0.828.52±1.61
模型0.64±0.08c1.31±0.47c7.04±1.31c4.51±0.38c
脑蛋白水解物0.2 g·kg-10.49±0.09e0.87±0.18e5.12±0.75e7.02±1.53f
脑蛋白水解物0.5 g·kg-10.56±0.04e0.94±0.21e6.89±0.70e7.05±0.50f
依达拉奉8 mg·kg-10.39±0.05f0.72±0.17e4.60±0.63e5.67±1.76e
), ArticleFig(id=1239238840834126583, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239238830201565600, language=CN, label=表3, caption=

各组小鼠脑缺血半暗带中白细胞介素（IL）-6、IL-1β、γ-干扰素（IFN-γ）和脑源性神经营养因子（BDNF）的含量

, figureFileSmall=null, figureFileBig=null, tableContent=
组别IL-6IL-1βIFN-γBDNF
假手术0.34±0.040.61±0.074.13±0.828.52±1.61
模型0.64±0.08c1.31±0.47c7.04±1.31c4.51±0.38c
脑蛋白水解物0.2 g·kg-10.49±0.09e0.87±0.18e5.12±0.75e7.02±1.53f
脑蛋白水解物0.5 g·kg-10.56±0.04e0.94±0.21e6.89±0.70e7.05±0.50f
依达拉奉8 mg·kg-10.39±0.05f0.72±0.17e4.60±0.63e5.67±1.76e
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基于网络药理学探讨缺血性脑卒中内质网应激机制及脑蛋白水解物的脑保护作用
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史彩云 1 , 郝路格 1 , 张奇 1 , 张建东 1 , 李炜 1, 2
中国新药与临床杂志 | 论著 2024,43(8): 618-626
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中国新药与临床杂志 | 论著 2024, 43(8): 618-626
基于网络药理学探讨缺血性脑卒中内质网应激机制及脑蛋白水解物的脑保护作用
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史彩云1 , 郝路格1, 张奇1, 张建东1, 李炜1, 2
作者信息
  • 1.河北北方学院药学院，河北 张家口 075000
  • 2.河北省神经药理学重点实验室，河北 张家口075000

    • 史彩云，女，硕士在读，主要从事神经药理学的研究，E-mail:

通讯作者:

李炜，E-mail:
Study on mechanism of endoplasmic reticulum stress and brain protective effect of cerebroprotein hydrolysate in ischemic stroke based on network pharmacology
Cai-yun SHI1 , Lu-ge HAO1, Qi ZHANG1, Jian-dong ZHANG1, Wei LI1, 2
Affiliations
  • 1.School of Pharmacy, Hebei North University, Zhangjiakou HEBEI 075000, China
  • 2.Hebei Provincial Key Laboratory of Neuropharmacology, Zhangjiakou HEBEI 075000, China
出版时间: 2024-08-25 doi: 10.14109/j.cnki.xyylc.2024.08.10
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摘要
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目的

基于网络药理学方法和动物实验初步研究脑蛋白水解物的脑保护作用及其调控缺血性脑卒中内质网应激的相关作用机制。

方法

利用GeneCards和OMIM数据库筛选出缺血性脑卒中和内质网应激相关靶点，绘制韦恩图，得到两者交集基因，利用String数据库下载蛋白质-蛋白质相互作用网络图，通过Cytoscape软件进行可视化分析，并利用cytoHubba插件筛选出前10位基因，最后进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。采用线栓法制备小鼠缺血性脑卒中模型，随机分为假手术组，模型组，脑蛋白水解物0.2 g·kg-1组、0.5 g·kg-1组和依达拉奉8 mg·kg-1组，每组11只。术后连续给药5 d。TTC染色测定脑梗死体积，ELISA法测定脑缺血半暗带和血清中白细胞介素（IL）-6、IL-1β、γ-干扰素（IFN-γ）和脑源性神经营养因子（BDNF）的含量，免疫组化法观察脑组织中Caspase-3和 AKT蛋白的表达变化。

结果

网络药理学结果筛选得到41个缺血性脑卒中和内质网应激的交集基因，筛选出排前10的基因分别是IL-6、ALB、INS、TNF、AKT1、CASP3、MAPK3、TP53、SIRT1和VEGFA。GO富集得到515个相关条目，KEGG通路富集涉及脂质和动脉粥样硬化通路、人巨细胞病毒感染、阿尔茨海默病、磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/AKT）信号通路等。与模型组比较，脑蛋白水解物2个给药组小鼠的脑梗死体积明显减小（P<0.01），小鼠血清和半暗带中IL-6、IL-1β和IFN-γ含量显著降低、BDNF显著增加（P<0.05），脑组织中Caspase-3表达显著降低、AKT表达显著增强（P<0.05）。

结论

基于网络药理学分析，缺血性脑卒中的内质网应激机制可能与炎症和凋亡相关，脑蛋白水解物的神经保护机制可能与激活BDNF/PI3K/AKT 通路及抑制炎症和细胞凋亡有关。

网络药理学  /  缺血性卒中  /  内质网应激  /  脑蛋白水解物  /  炎症  /  细胞凋亡
AIM

To study the protective effect of cerebroprotein hydrolysate and its related mechanism of regulating endoplasmic reticulum stress in ischemic stroke based on network pharmacology and animal experiments.

METHODS

GeneCards and OMIM databases were used to screen the targets related to ischemic stroke and endoplasmic reticulum stress, and Wayne diagram was drawn to get the intersection genes. The protein-protein interaction network diagram was downloaded from String database and visualized by Cytoscape software, and the top 10 genes were screened by cytoHubba plug-in. Finally, Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） were enriched and analyzed. Mouse models of ischemic stroke were made by the suture-occluded method, and randomly divided into sham group, model group, cerebroprotein hydrolysate 0.2 g·kg-1 group and 0.5 g·kg-1 group, and edaravone 8 mg·kg-1 group,with 11 mice in each group. The drug was administered continuously for 5 days after operation. The volume of cerebral infarction was measured by TTC staining, the contents of interleukin （IL）-6, IL-1β, γ-interferon （IFN-γ） and brain-derived neurotrophic factor （BDNF） in cerebral ischemic penumbra and serum were measured by ELISA, and the expression of Caspase-3 and AKT protein in brain tissue was observed by immunohistochemistry.

RESULTS

According to the results of network pharmacology, 41 intersection genes of ischemic stroke and endoplasmic reticulum stress were screened, and the top 10 genes screened were IL-6, ALB, INS, TNF, AKT1, CASP3, MAPK3, TP53, SIRT1 and VEGFA, respectively. GO enrichment resulted in 515 related entries. KEGG pathway enrichment involved lipid and atherosclerosis pathway, human cytomegalovirus infection, Alzheimer’s disease, phosphatidylinositol -3- kinase/ protein kinase B （PI3K/AKT） signaling pathway and so on. Compared with the model group, the cerebral infarction volume was significantly reduced （P<0.01）; the contents of IL-6, IL-1β and IFN-γ in serum and penumbra were decreased significantly （P<0.05）, and the contents of BDNF in serum and penumbra were increased significantly （P<0.05）; the expression of Caspase-3 in brain tissue was decreased significantly （P<0.05）, and the expression of AKT was increased significantly （P<0.05） in the two groups of cerebroprotein hydrolysate.

CONCLUSION

Based on the analysis of network pharmacology, the endoplasmic reticulum stress mechanism of ischemic stroke may be related to inflammation and apoptosis. The neuroprotective mechanism of cerebroprotein hydrolysate may be related to activating BDNF/PI3K/AKT pathway and inhibiting inflammation and apoptosis.

network pharmacology  /  ischemic stroke  /  endoplasmic reticulum stress  /  cerebroprotein hydrolysate  /  inflammation  /  apoptosis
史彩云, 郝路格, 张奇, 张建东, 李炜. 基于网络药理学探讨缺血性脑卒中内质网应激机制及脑蛋白水解物的脑保护作用. 中国新药与临床杂志, 2024 , 43 (8) : 618 -626 . DOI: 10.14109/j.cnki.xyylc.2024.08.10
Cai-yun SHI, Lu-ge HAO, Qi ZHANG, Jian-dong ZHANG, Wei LI. Study on mechanism of endoplasmic reticulum stress and brain protective effect of cerebroprotein hydrolysate in ischemic stroke based on network pharmacology[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (8) : 618 -626 . DOI: 10.14109/j.cnki.xyylc.2024.08.10
正文
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脑卒中是一种高发病率、高死亡率和高致残率的疾病。《中国脑卒中防治报告2020》指出，我国缺血性脑卒中发病率处于逐年上升趋势，目前溶栓治疗是缺血性脑卒中的主要治疗方法，但治疗后由于血液再通，往往造成脑缺血再灌注损伤［1,2］。研究证实，脑缺血再灌注后，内质网应激通过诱导细胞自噬和神经细胞凋亡，加重脑损伤［3,4］；过度的内质网应激亦可增强炎症反应和氧化应激，从而进一步加重缺血再灌注后的脑组织损伤［5,6］。
网络药理学整合了生物、药理以及其他学科的技术与内容，通过靶点筛选、通路分析以及分子对接等方法了解并分析药物、靶点和疾病之间的作用关系，有助于更好地了解疾病作用机制［7］。本研究旨在通过网络药理学，从分子水平研究缺血性脑卒中与内质网应激之间的潜在作用靶点和通路，并围绕理论推测结果，通过动物实验探讨脑蛋白水解物与调控内质网应激相关的作用机制，为后续实验研究提供参考。
材料与方法
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药品与试剂
注射用脑蛋白水解物（Ⅲ） ［规格为30 mg（以总氮计），批准文号为国药准字H20052266］购自海南通用同盟药业有限公司，依达拉奉注射液（规格为20 mL 30 mg，批准文号为国药准字H20080056）购自国药集团国瑞药业有限公司。肝素购自北京博奥拓达科技有限公司；线栓购自北京西浓科技有限公司；2，3，5-氯化三苯基四氮唑购自北京博奥拓达科技有限公司；白细胞介素（IL）-6、IL-1β、γ-干扰素（IFN-γ）和脑源性神经营养因子（BDNF）ELISA试剂盒均购自武汉纯度生物；即用型SABC-POD（小鼠/兔IgG）试剂盒购自武汉博士德生物工程有限公司；抗胱天蛋白酶-3（Caspase-3）单克隆抗体、抗蛋白激酶B（AKT）抗体均购自Proteintech公司；柠檬酸钠抗原修复液购自碧云天生物技术有限公司；DAB显色试剂盒及中性树胶均购自北京索莱宝科技有限公司。
实验仪器
Infinite M200 PRO全波长酶标仪购于瑞士TECAN公司，LE225D电子天平购于德国Sartorius公司，Sigma 3K30高速冷冻离心机购于美国Sigma公司，DNP-9162电热恒温培养箱购于宁波江南仪器厂，EG1150H生物组织包埋机、RM2245轮转式石蜡切片机、DM3000成像显微镜均购于德国Leica公司，摊片机、烤片机购于浙江省金华市科迪仪器设备有限公司，超纯水设备购于美国Millipore公司。
实验动物
SPF级昆明种小鼠，♂，购自斯贝福生物技术有限公司，质量检测单位为苏州西山生物技术有限公司，许可证号：SCXK（京）2019-0010。全部小鼠随机分组后置于河北北方学院药学动物实验室内饲养2周，自由摄食饮水，饮用水为煮沸后的超纯水。环境温度为20~25 ℃。小鼠适应环境后用于实验，实验时小鼠的体重为32~37 g。动物实验经河北北方学院实验动物福利伦理审查委员会批准。
缺血性脑卒中和内质网应激相关靶点收集与筛选
通过 GeneCards数据库（https://www.genecards.org/）和OMIM数据库（https://www.omim.org/），以缺血性脑卒中（ischemic stroke）和内质网应激（endoplasmic reticulum stress）为关键词，检索得到“缺血性脑卒中”和“内质网应激”相关基因，筛选去除重复基因，取得共同靶点基因；在Venny2.1.0制图平台（https://bioinfogp.cnb.csic.es/）输入筛选所得到的基因，绘制韦恩图。
蛋白质-蛋白质相互作用（PPI）网络的构建与分析
将所得的共同靶点基因导入String数据库（https://cn.string-db.org/），最低相互作用值设置为0.4，并剔除游离靶点，获得PPI网络图，将保存的TSV文件导入Cytoscape 3.9.1进行可视化分析，根据度值调整节点大小和颜色，节点越大，节点颜色越趋于红色，表明其在PPI网络中发挥的作用越重要。利用Cytoscape插件cytoHubba提取出关键基因。MCC算法对PPI网络中的关键蛋白预测精度较高，故通过MCC算法对PPI网络中的关键蛋白进行预测，得到PPI网络中排名前10的基因。
基因本体（GO）富集分析和京都基因与基因组百科全书（KEGG）富集分析
将所得的共同靶点基因导入Metascape数据库（https://metascape.org/）进行GO ［包括生物过程（biological process， BP）、细胞组分（cellular component，CC）和分子功能（molecular function，MF）三部分］ 富集分析和KEGG富集分析，利用微生信平台（https://www.bioinformatics.com.cn/）绘制BP、CC和MF三合一分析图，横轴是对各分析条目的描述，纵轴是-log10（P-value）值，值越大，表明此条目越重要。KEGG得到各通路存在的交集靶点，绘制图表。
造模与分组
采用线栓法通过小鼠大脑中动脉缺血再灌注损伤制备缺血性脑卒中模型［8］。将栓线插至小鼠颈内动脉，进线长度约10 mm，缺血1 h后将栓线拔出，假手术组只分离右侧颈总动脉、颈内动脉和颈外动脉，不穿孔放置栓线；大脑中动脉缺血再灌注24 h后，参考Zea-Longa 5分制法［9］，进行神经功能缺损评分，评分为1~3分的小鼠纳入后续实验，随机分为模型组、脑蛋白水解物0.2 g·kg-1组、脑蛋白水解物0.5 g·kg-1组［10,11］、依达拉奉8 mg·kg-1（阳性药对照）组，每组11只。每日固定给药时间，假手术组和模型组小鼠给予生理盐水，各治疗组分别给予相应剂量脑蛋白水解物溶液和依达拉奉注射液，给药量均为每10克体重0.2 mL，术后连续给药5 d。
TTC染色测定脑梗死体积［12］
小鼠麻醉处死后迅速取出全脑，将大脑切成2 mm等距的冠状脑片。切片用TTC避光染色，37 ℃孵育10 min。脑梗死区为白色，未梗死区为红色。切片用多聚甲醛固定24 h，拍照。用Image-Pro Plus6.0软件进行分析：梗死体积百分比（%）=（对侧正常脑组织容积-同侧正常脑组织容积）/对侧正常脑组织容积×100%。
ELISA法测定小鼠血清、半暗带中IL-6、IL-1β、IFN-γ和BDNF水平
组织取材：小鼠麻醉后断头处死，参考已有的方法［13］，取出脑缺血半暗带15 mg，制成脑组织匀浆，以936×g、4 ℃离心20 min，取上清液。血液取材：小鼠断头取血，室温静置10~20 min，以936×g、4 ℃离心20 min，取上清液，-80 ℃冷冻保存备用。按ELISA试剂盒说明书进行操作，分别测定小鼠血清和半暗带中IL-6、IL-1β、IFN-γ和BDNF的水平，分析其含量的变化和差异。
免疫组化检测Caspase-3和AKT蛋白表达
小鼠麻醉后断头处死，取出大脑制作石蜡切片［14］，经脱蜡水化、抗原修复和封闭后，一抗（Caspase-3稀释比例为1300，AKT稀释比例为1250）4 ℃孵育过夜，滴加二抗和试剂SABC，DAB显色后进行苏木素复染，中性树胶封片。根据平均吸光度值=累积吸光度值/区域面积，分析各组Caspase-3和AKT蛋白表达情况。
统计学分析
采用SPSS 20.0软件处理分析数据，计量资料以均数±标准差（）表示，多组间均数比较采用单因素方差分析，组间两两比较采用LSD-t检验，P<0.05为具有显著差异。
结　果
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缺血性脑卒中和内质网应激相关靶点筛选结果
通过GeneCards数据库和OMIM 数据库，筛选后得到缺血性脑卒中相关靶点共有3 744个、内质网应激相关靶点8 675个，通过筛选得到缺血性脑卒中相关基因187个、内质网应激相关基因423个，取两者共同靶点共41个基因，绘制韦恩图如图1所示。
PPI网络构建与分析结果
将所得的共同靶点基因导入String数据库，得到缺血性脑卒中与内质网应激交集的PPI网络图，见图2。通过Cytoscape 3.9.1进行可视化分析，PPI网络中有37个节点，390条边，即有37个相互作用蛋白，390条相互作用关系，见图3。MCC算法排名前10的基因分别是IL-6、ALB、INS、TNF、AKT1、CASP3、MAPK3、TP53、SIRT1和VEGFA。
GO富集分析结果
BP分析共得到428个分析条目，最多对应交集基因17个，最少3个；CC分析有45个分析条目，最多对应交集基因10个，最少3个；MF有42个分析条目，最多对应交集基因10个，最少对应交集基因3个。微生信平台BP、CC和MF三合一分析结果如图4所示，通过对BP、CC和MF前10个条目进行分析可知：BP方面，交集基因与对氧化应激的反应、神经元死亡的调节、细胞分化的负调节、对肿瘤坏死因子的反应、对氧气水平降低的应答等有关；CC方面，与薄膜筏、光滑型内质网、内质网腔、核膜、小凹 等组分有关；MF方面，与信号受体激活剂活性、伴侣结合、蛋白酶结合、磷酸酶结合、支架蛋白结合等有关。Metascape数据库分析得到前9类通路，共122条通路，最多对应交集基因16个，最少3个，41个交集基因与脂质和动脉粥样硬化通路、人巨细胞病毒感染、阿尔茨海默病、磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/AKT）信号通路、长寿调节途径、细胞衰老、血清素能突触、抗原加工和呈递以及内质网中的蛋白质加工等有关，见图5，参加各通路的具体基因见表1。
脑梗死体积测定
TTC染色结果显示，假手术组未出现梗死，模型组和各给药组出现了不同程度的梗死，见图6。与模型组梗死体积（46.17±1.26）%相比，脑蛋白水解物0.2 g·kg-1组、0.5 g·kg-1组和依达拉奉8 mg·kg-1组的梗死体积均显著减少（P<0.01），分别为（34.99±3.18）%、（37.12±1.71）%和（10.27±2.31）%。
血清和脑缺血半暗带中IL-6、IL-1β、IFN-γ和BDNF水平
与假手术组相比，模型组血清中的IL-6、IL-1β和IFN-γ含量明显升高（P<0.01），BDNF含量明显降低（P<0.01）；与模型组相比，各给药组血清中的IL-6、IL-1β、IFN-γ含量均明显降低（P<0.01），BDNF含量显著升高（P<0.05）。见表2。
与假手术组相比，模型组半暗带中IL-6、IL-1β和IFN-γ含量明显升高（P<0.01），BDNF含量明显降低（P<0.01）；与模型组相比，各给药组半暗带中的IL-6、IL-1β和IFN-γ含量均显著降低（P<0.05），BDNF显著升高（P<0.05）。见表3。
脑组织中Caspase-3和 AKT表达
与假手术组相比，模型组Caspase-3表达明显升高（P<0.01）；与模型组比较，各给药组Caspase-3表达显著下降（P<0.05），见图7。与假手术组相比，模型组 AKT表达明显降低（P<0.01）；与模型组相比，各给药组 AKT表达显著升高（P<0.05），见图8。
讨　论
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本研究利用网络药理学通过对缺血性脑卒中与内质网应激相关作用靶点进行筛选，得到IL-6、AKT、CASP3和TNF等与炎症和凋亡相关的关键基因。GO富集分析得到对氧化应激的反应、神经元死亡的调节、细胞分化的负调节、对肿瘤坏死因子的反应等生物学过程；KEGG富集分析得到脂质和动脉粥样硬化通路、人巨细胞病毒感染、阿尔茨海默病、PI3K/ AKT等信号通路。基于缺血性脑卒中和内质网应激相关靶点筛选以及GO和KEGG富集分析的结果，笔者认为炎症及凋亡等生物学过程参与脑缺血再灌注。脑缺血再灌注后，BDNF表达降低，谷氨酸诱导的神经毒性，激活了内质网应激，降低了磷酸化AKT蛋白的表达水平，上调了磷酸化c-Jun氨基末端激酶的表达，进而增加Caspase-3的表达，触发细胞凋亡信号；另有报道指出，脑缺血再灌注后，AKT及其下游分子雷帕霉素靶蛋白表达量下降，Caspase-3级联反应启动，引起细胞内代谢紊乱，加重脑损伤［15-17］。在炎症过程中，刺激小胶质细胞和星形胶质细胞会增加IL-6的分泌，IL-1β和TNF等炎症因子也能促进IL-6分泌增加，加重炎症，而抑制Toll-样受体4则会抑制小胶质细胞的活化，并减轻小胶质细胞内的内质网应激［18,19］。研究发现小胶质细胞通过AKT/核因子-κB通路，促进其向M1促炎表型极化，分泌大量炎症因子如IL-6、IL-1β等，抑制M2表型发挥抗炎及修复受损脑组织作用［20-22］。IFN-γ主要由自然杀伤细胞和抗活化T细胞生成，主要作用是刺激白细胞合成的黏附分子和血管内皮细胞等。临床研究表明，创伤性脑出血患者术后早期IFN-γ明显升高，提示与早期创伤应激和炎症有关［23］。本研究实验结果显示，与假手术组相比，模型组Caspase-3含量明显升高， AKT含量明显降低，提示脑缺血再灌注后，PI3K/AKT通路被抑制，Caspase-3上调触发细胞凋亡过程。ELISA结果表明，模型组小鼠血清和半暗带组织中的IL-6、IL-1β和IFN-γ等炎症因子的含量较假手术组显著升高，BDNF的含量显著下降。脑缺血再灌注损伤机制可能与抑制BDNF、释放IL-6和IL-1β等炎症因子、提高Caspase-3表达有关。
脑蛋白水解物又名脑活素，是从猪脑中提取出的一种神经肽混合物，能加快轴突髓鞘形成，增强轴突重塑，对受损的神经元具有保护作用［24］。BDNF由神经元和胶质细胞合成并分泌，具有促进神经系统发育、恢复受损组织的作用，它与酪氨酸激酶受体B特异性结合，激活PI3K/AKT通路，进而抑制抗凋亡蛋白的表达，减少细胞凋亡［25,26］。研究发现，脑蛋白水解物可上调BDNF的表达以降低脑内小胶质细胞的密度，抑制小胶质细胞的活化，降低TNF-α的含量，具有抗炎作用［27］。脑蛋白水解物可以增加磷酸化环磷腺苷效应元件结合蛋白，进而调节过氧化物酶体增殖物激活受体-γ共激活因子-1α，促使小胶质细胞M2极化，抑制促炎基因表达，减少炎症因子释放以缓解炎症［28］。本研究动物实验也证明了相较于模型组，脑蛋白水解物2个剂量组能显著降低脑缺血再灌注损伤小鼠血清和半暗带中IL-6、IL-1β、IFN-γ水平，增加脑内BDNF和 AKT的含量，降低脑组织中Caspase-3的表达，提示脑蛋白水解物抗炎和抗凋亡机制可能是通过BDNF/PI3K/AKT通路，抑制炎症信号通路和细胞凋亡信号的激活，从而起到神经保护作用。
综上所述，基于网络药理学分析，缺血性脑卒中的内质网应激机制可能与炎症和凋亡相关；动物实验表明脑蛋白水解物可以促进BDNF表达，抑制IL-6、IL-1β和IFN-γ，降低Caspase-3的表达水平，其神经保护机制可能与激活BDNF/PI3K/AKT通路，抑制炎症和细胞凋亡有关。具体机制还需后续实验进一步验证。
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2024年第43卷第8期
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doi: 10.14109/j.cnki.xyylc.2024.08.10
  • 接收时间：2023-03-31
  • 首发时间：2026-03-13
  • 出版时间：2024-08-25
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  • 收稿日期：2023-03-31
  • 录用日期：2024-05-08
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河北省自然科学基金(H2020405298)
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    1.河北北方学院药学院，河北 张家口 075000
    2.河北省神经药理学重点实验室，河北 张家口075000

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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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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