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Article(id=1315688464637612098, tenantId=1146029695717560320, journalId=1315121837170065538, issueId=1315688435411694395, articleNumber=null, orderNo=null, doi=10.16368/j.issn.1674-8999.2025.12.412, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1751385600000, receivedDateStr=2025-07-02, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1791614174279, onlineDateStr=2026-10-10, pubDate=1765296000000, pubDateStr=2025-12-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1791614174279, onlineIssueDateStr=2026-10-10, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1791614174279, creator=13701087609, updateTime=1791614174279, updator=13701087609, issue=Issue{id=1315688435411694395, tenantId=1146029695717560320, journalId=1315121837170065538, year='2025', volume='40', issue='12', pageStart='2487', pageEnd='2712', issueExtLink='null', onlineDate='null', pubDate='1765296000000', pubDateStr='2025-12-10', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1791614167309, creator='13701087609', updateTime=1791616084449, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1315696476567744680, tenantId=1146029695717560320, journalId=1315121837170065538, issueId=1315688435411694395, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1315696476571938985, tenantId=1146029695717560320, journalId=1315121837170065538, issueId=1315688435411694395, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2636, endPage=2649, ext={EN=ArticleExt(id=1315688464834744387, articleId=1315688464637612098, tenantId=1146029695717560320, journalId=1315121837170065538, language=EN, title=Action Mechanism of Shenghui Decoction Alleviating Oxidative Stress via Nrf2/HO-1 Signaling Pathway and Improving Cognitive Dysfunction in Alzheimer′s Disease, columnId=1315688455783428135, journalTitle=Acta Chinese Medicine, columnName=Experimental Study, runingTitle=null, highlight=null, articleAbstract=

Objective:This study aims to investigate the mechanism by which Shenghui Decoction alleviates cognitive dysfunction in Alzheimer's disease（AD）by counteracting oxidative stress through the Nrf2/HO-1 signaling pathway.Methods:From a total of 45 mice，9 were randomly selected as the normal control group，while the remaining 36 were injected with Aβ25-35 oligomers via stereotaxic brain injection to establish an AD model.The model mice were divided into a model group，a low-dose Shenghui Decoction group，a high-dose Shenghui Decoction group，and a donepezil group，with 9 mice in each group.（1）Behavioral experiments were conducted to assess learning and memory abilities. Immunofluorescence technology was used to detect hippocampal amyloid β-protein（Aβ）deposition in mice，and the effects of Shenghui Decoction on AD-related oxidative stress were explored in combination with fluorescent probes and enzyme-linked immunosorbent assay（ELISA）.（2）Through network pharmacology methods，the active components and related targets of Shenghui Decoction were screened and intersected with disease targets for AD and oxidative stress，thereby constructing a ″Shenghui Decoction active components-targets-AD-oxidative stress″network and protein-protein interaction（PPI）network.Key active components of Shenghui Decoction were identified.In addition，Metascape database and MCODE algorithm were used to obtain target cluster modules，and molecular docking of key active components with cluster module targets was validated using AutoDockTools software.（3）Western blot（WB）experiments were performed to assess the protein expression levels of molecules with the best docking binding energies.Results:Behavioral experiments indicated that Shenghui Decoction（SHD）can improve learning and memory abilities in AD mice，reduce Aβdeposition（P＜0.05），increase superoxide dismutase levels（P＜0.05），and decrease reactive oxygen species and malondialdehyde content（P＜0.05）.Atotal of 48 active components and 114 overlapping targets related to ″AD-SHD-oxidative stress″were identified.The key active components include kaempferol，β-sitosterol，stigmasterol，scopolamine，and tetrahydropalmatine.Eight core targets were involved in important biological processes such as oxidative stress response，reactive nitrogen species response，and hypoxia response，including caspase -3（CASP3），signal transducer and activator of transcription 1（STAT1），peroxisome proliferator-activated receptor gamma（PPARG），nuclear factor erythroid 2（Nrf2），intercellular adhesion molecule-1（ICAM-1），heme oxygenase-1（HO-1），vascular cell adhesion molecule 1（VCAM1），and caspase-1（CASP1）.Molecular docking results showed that the core target HO-1 had the best binding effect with key active components of SHD.WB experiments verified that SHD exerts antioxidant effects by regulating the expression levels of Nrf2 and HO-1. Conclusion:SHD can improve learning and memory abilities in AD mice，reduce Aβproduction，and inhibit oxidative stress，with its mechanism related to the regulation of protein expression levels in the Nrf2/HO-1 pathway.

, authors=Yuhan KANG, Jihong LIU, Haoran WANG, Rihong LUO, Zijuan ZHANG, Li HAO, authorsList=Yuhan KANG, Jihong LIU, Haoran WANG, Rihong LUO, Zijuan ZHANG, Li HAO, authorCompany=null, correspAuthors=Li HAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, 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, fund=null), CN=ArticleExt(id=1315688468987105390, articleId=1315688464637612098, tenantId=1146029695717560320, journalId=1315121837170065538, language=CN, title=生慧汤通过Nrf2/HO-1信号通路抗氧化应激改善阿尔茨海默病认知障碍的作用机制, columnId=1315688455959588905, journalTitle=中医学报, columnName=实验研究, runingTitle=null, highlight=null, articleAbstract=

目的：本研究旨在探讨生慧汤通过Nrf2/HO-1信号通路抗氧化应激改善阿尔茨海默病（Alzheimer's disease，AD）认知障碍的作用机制。方法：从45只小鼠中随机抽取9只作为正常组，其余36只采用脑立体定位注射Aβ25-35寡聚体构建AD模型，模型小鼠分为模型组、生慧汤低剂量组、生慧汤高剂量组和多奈哌齐组，每组9只。（1）通过行为学实验评估学习记忆能力，利用免疫荧光技术检测小鼠海马β-淀粉样蛋白（amyloid β-protein，Aβ）沉积程度，并结合荧光探针法、酶联免疫吸附试验（enzyme linked immunosorbent assay，ELISA），探究生慧汤对AD氧化应激的影响。（2）通过网络药理学方法，筛选生慧汤的活性成分及相关靶点，并与AD、氧化应激的疾病靶点取交集，进而构建“生慧汤有效成分-靶点-AD-氧化应激”网络和蛋白相互作用（protein-protein interaction，PPI）网络，筛选生慧汤关键有效成分。此外，利用Metascape数据库和MCODE算法获取目标聚类模块靶点，并借助AutoDockTools软件对关键有效成分和聚类模块靶点进行分子模拟对接验证。（3）蛋白质免疫印迹（Western Blot，WB）实验评估对接结合能最佳分子的蛋白表达水平。结果：行为学实验结果表明，生慧汤可改善AD小鼠的学习记忆能力，减少Aβ沉积（P＜0.05），提升超氧化物歧化酶水平（P＜0.05），降低活性氧和丙二醛含量（P＜0.05）。获得“AD-生慧汤-氧化应激”有效成分48个和交集靶点114个。其中，关键有效成分为山柰酚、β-谷甾醇、豆甾醇、去甲莨菪碱和四氢鸭脚木碱。有8个核心靶点参与了氧化应激反应、活性氮反应及低氧反应等重要生物过程，包括胱天蛋白酶3（Caspase-3，CASP3）、信号转导与转录激活因子1（signal transducer and activator of transcription1，STAT1）、过氧化物酶体增生激活受体γ（peroxisome proliferative activated receptor gamma，PPARG）、核因子红细胞系2（nuclear factor erythroid 2，Nrf2）、细胞间黏附分子-1（intercellular cell adhesion molecule-1，ICAM-1）、血红素加氧酶1（heme oxygenase-1，HO-1）、血管细胞黏附分子1（vascular cell adhesion molecule 1，VCAM1）和胱天蛋白酶1（caspase-1，CASP1）。分子对接结果显示，核心靶点HO-1与生慧汤关键有效成分结合效果最佳，WB实验验证生慧汤通过调控Nrf2和HO-1的表达水平，发挥抗氧化应激作用。结论：生慧汤可改善AD小鼠的学习记忆能力，减少Aβ生成，抑制氧化应激反应，其作用机制与调控Nrf2/HO-1通路中相关蛋白表达水平有关。

, authors=亢钰涵, 刘继红, 王浩然, 罗日红, 张紫娟, 郝莉, authorsList=亢钰涵, 刘继红, 王浩然, 罗日红, 张紫娟, 郝莉, authorCompany=null, correspAuthors=郝莉, authorNote=

亢钰涵（1997 -），女，河南灵宝人，硕士研究生，主要从事中医药抗衰老研究。

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郝莉（1971 -），女，教授，硕士研究生导师，研究方向：中医药抗衰老研究。E-mail:
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亢钰涵（1997 -），女，河南灵宝人，硕士研究生，主要从事中医药抗衰老研究。

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亢钰涵（1997 -），女，河南灵宝人，硕士研究生，主要从事中医药抗衰老研究。

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注：紫色表示生慧汤、AD和氧化应激的共同靶点（共114个）；绿色表示有效成分（共48个）。A代表熟地黄、山茱萸和柏子仁共有成分，熟地黄为主要来源；B代表山茱萸和人参共有成分，山茱萸为主要来源；C代表石菖蒲和人参共有成分，石菖蒲为主要来源；D代表熟地黄、山茱萸和人参共有成分，熟地黄为主要来源；E代表山茱萸和人参共有成分，山茱萸为主要来源。

, figureFileSmall=5/353ijPwHXj6Lyw/gG4bA==, figureFileBig=pKwpY33rrMeQc2sFkyhy4w==, tableContent=null), ArticleFig(id=1315688472569041059, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=Voq0s/QFRzgRMaeb9ks4mQ==, figureFileBig=tH3CGTUJ7xrJg11bcwyF+w==, tableContent=null), ArticleFig(id=1315688472627761316, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=图4, caption=交集靶点PPI及MCODE网络图, figureFileSmall=Voq0s/QFRzgRMaeb9ks4mQ==, figureFileBig=tH3CGTUJ7xrJg11bcwyF+w==, tableContent=null), ArticleFig(id=1315688472690675877, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=+nHjTcA4Gf3PMJfDE6z3rA==, figureFileBig=hkAbGkPHH06UiFVCtmBtJw==, tableContent=null), ArticleFig(id=1315688472753590438, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=图5A, caption=核心靶点GO富集前20条分析结果, figureFileSmall=+nHjTcA4Gf3PMJfDE6z3rA==, figureFileBig=hkAbGkPHH06UiFVCtmBtJw==, tableContent=null), ArticleFig(id=1315688472837476519, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=/lqHn4a1opJWS0LH/DUklw==, figureFileBig=8ISd3s8fySs5KcFHYVdX4g==, tableContent=null), ArticleFig(id=1315688472912973992, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=图5B, caption=核心靶点KEGG通路富集分析结果

注：条形越长代表该信号通路富集的共同关联核心靶点就越多，颜色越接近红色代表P值越小。

, figureFileSmall=/lqHn4a1opJWS0LH/DUklw==, figureFileBig=8ISd3s8fySs5KcFHYVdX4g==, tableContent=null), ArticleFig(id=1315688472971694249, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=6EfcDHl1v3/+j/NANRlOrg==, figureFileBig=UGMYW1pvril/NlMMTLPnjA==, tableContent=null), ArticleFig(id=1315688473051386026, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=图6, caption=关键有效成分与核心靶点蛋白的结合能热图

注：数值越小、颜色越深说明结合效果好。

, figureFileSmall=6EfcDHl1v3/+j/NANRlOrg==, figureFileBig=UGMYW1pvril/NlMMTLPnjA==, tableContent=null), ArticleFig(id=1315688473118494891, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=JfObpia+TbUNCzO0suzVfA==, figureFileBig=nQFtfslufhCP4yJQf1Ko5A==, tableContent=null), ArticleFig(id=1315688473185603756, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=图7, caption=关键有效成分与核心靶点蛋白的分子对接模型图

注：图A、C、E、G、I为HO -1分别和成分山柰酚、β-谷甾醇、豆甾醇、去甲莨菪碱和四氢鸭脚木碱的对接结果；图B、D、F、H、J为Nrf2分别和成分山柰酚、β-谷甾醇、豆甾醇、去甲莨菪碱和四氢鸭脚木碱的对接结果。其中黄色和绿色为形成的氢键及氢键连接的残基。

, figureFileSmall=JfObpia+TbUNCzO0suzVfA==, figureFileBig=nQFtfslufhCP4yJQf1Ko5A==, tableContent=null), ArticleFig(id=1315688473265295533, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=0QFNun90+1aBgEs17uZouQ==, figureFileBig=ZQDpiySSKRizbMCRU3UsTA==, tableContent=null), ArticleFig(id=1315688473324015790, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=图8, caption=各组小鼠Aβ1-42染色结果（×100，×200）

注：Aβ1-42单因素方差分析，F（4，10） =815.200。

, figureFileSmall=0QFNun90+1aBgEs17uZouQ==, figureFileBig=ZQDpiySSKRizbMCRU3UsTA==, tableContent=null), ArticleFig(id=1315688473386930351, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=Ha6B2WcCxMpnwrOdPLMZiQ==, figureFileBig=Hv1Rx/ncj+xwmfugiKqvNg==, tableContent=null), ArticleFig(id=1315688473454039216, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=图9, caption=各组小鼠ROS荧光探针结果（×400）, figureFileSmall=Ha6B2WcCxMpnwrOdPLMZiQ==, figureFileBig=Hv1Rx/ncj+xwmfugiKqvNg==, tableContent=null), ArticleFig(id=1315688473521148081, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=zw16mDPYqNpbW5zLp5F40A==, figureFileBig=mi/ZOvR3dzuPUfOp+d+D8w==, tableContent=null), ArticleFig(id=1315688473592451250, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=图10, caption=各组海马Nrf2、Keap1和HO-1蛋白印迹图

注：Nrf2/β-actin单因素方差分析，F（4，10）=7.403。Keap1/β-actin单因素方差分析，F（4，10）=19.180。HO-1/β-actin单因素方差分析，F（4，10）=204.300。

, figureFileSmall=zw16mDPYqNpbW5zLp5F40A==, figureFileBig=mi/ZOvR3dzuPUfOp+d+D8w==, tableContent=null), ArticleFig(id=1315688473663754419, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
代号有效成分连接度口服利用度/%类药性主要来源
C山柰酚（Kaempferol）3641.880.24石菖蒲
Bβ-谷甾醇（β-sitosterol）2236.910.75山茱萸
D豆甾醇（Stigmasterol）2143.830.76熟地黄
YZ4去甲莨菪碱（Norhyoscyamine）1660.340.17远志
SZY14四氢鸭脚木碱（Tetrahydroalstonine）1532.420.81山茱萸
BJZ4芥子醛（Sinapaldehyde）1563.160.07白芥子
RS17富马碱（Fumarine）1459.260.83人参
YZ65，6，7 -三甲氧基香豆素（5，6，7 -Trimethoxycoumarin）1432.540.12远志
SZR1乌药碱（（S）-Coclaurine）1342.350.24酸枣仁
BJZ24 -羟基苯甲酰胆碱（4 -hydroxybenzoylcholine）132.150.07白芥子
BJZ3芥子酸胆碱（Sinapine）131.210.18白芥子
YZ12哈尔满碱（Harman）1233.10.1远志
SCP18 -异戊二酰-山柰酚（8 -Isopentenyl-Kaempferol）1138.040.39石菖蒲
RS11稀有人参皂苷Rh2（Ginsenoside rh2）1036.320.56人参
YZ9橙花醛（Neral）919.480.02远志
YZ10骆驼蓬碱（Yajeine）956.80.13远志
RS4高丽槐素（Inermin）865.830.54人参
RS10灌木远志酮A（Frutinone A）865.90.34人参
SZR4酸李碱（Zizyphusine）841.530.55酸枣仁
RS6阿朴天仙子碱（Aposiopolamine）766.650.22人参
), ArticleFig(id=1315688473743446196, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表1, caption=

生慧汤连接度前20位有效成分

, figureFileSmall=null, figureFileBig=null, tableContent=
代号有效成分连接度口服利用度/%类药性主要来源
C山柰酚（Kaempferol）3641.880.24石菖蒲
Bβ-谷甾醇（β-sitosterol）2236.910.75山茱萸
D豆甾醇（Stigmasterol）2143.830.76熟地黄
YZ4去甲莨菪碱（Norhyoscyamine）1660.340.17远志
SZY14四氢鸭脚木碱（Tetrahydroalstonine）1532.420.81山茱萸
BJZ4芥子醛（Sinapaldehyde）1563.160.07白芥子
RS17富马碱（Fumarine）1459.260.83人参
YZ65，6，7 -三甲氧基香豆素（5，6，7 -Trimethoxycoumarin）1432.540.12远志
SZR1乌药碱（（S）-Coclaurine）1342.350.24酸枣仁
BJZ24 -羟基苯甲酰胆碱（4 -hydroxybenzoylcholine）132.150.07白芥子
BJZ3芥子酸胆碱（Sinapine）131.210.18白芥子
YZ12哈尔满碱（Harman）1233.10.1远志
SCP18 -异戊二酰-山柰酚（8 -Isopentenyl-Kaempferol）1138.040.39石菖蒲
RS11稀有人参皂苷Rh2（Ginsenoside rh2）1036.320.56人参
YZ9橙花醛（Neral）919.480.02远志
YZ10骆驼蓬碱（Yajeine）956.80.13远志
RS4高丽槐素（Inermin）865.830.54人参
RS10灌木远志酮A（Frutinone A）865.90.34人参
SZR4酸李碱（Zizyphusine）841.530.55酸枣仁
RS6阿朴天仙子碱（Aposiopolamine）766.650.22人参
), ArticleFig(id=1315688473823137973, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别n第1天第2天第3天第4天第5天
正常组944.73 ±15.2740.96 ±19.0439.18 ±20.8235.60 ±15.0824.80 ±5.54
模型组949.19 ±10.8147.43 ±12.5738.15 ±21.8538.00 ±14.4038.34 ±8.99*
生慧汤低剂量组945.52 ±14.4943.46 ±10.6538.03 ±8.3036.62 ±13.1124.15 ±8.84#
生慧汤高剂量组943.02 ±12.6742.89 ±17.1239.95 ±6.7237.82 ±14.3328.62 ±10.03
多奈哌齐组942.24 ±17.7641.36 ±8.5831.78 ±5.4927.45 ±8.5824.03 ±5.76#
F值0.7590.0990.1500.3251.717
P值0.5740.9800.9580.2540.022
), ArticleFig(id=1315688473902829750, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表2, caption=

各组小鼠逃避潜伏期比较

, figureFileSmall=null, figureFileBig=null, tableContent=
组别n第1天第2天第3天第4天第5天
正常组944.73 ±15.2740.96 ±19.0439.18 ±20.8235.60 ±15.0824.80 ±5.54
模型组949.19 ±10.8147.43 ±12.5738.15 ±21.8538.00 ±14.4038.34 ±8.99*
生慧汤低剂量组945.52 ±14.4943.46 ±10.6538.03 ±8.3036.62 ±13.1124.15 ±8.84#
生慧汤高剂量组943.02 ±12.6742.89 ±17.1239.95 ±6.7237.82 ±14.3328.62 ±10.03
多奈哌齐组942.24 ±17.7641.36 ±8.5831.78 ±5.4927.45 ±8.5824.03 ±5.76#
F值0.7590.0990.1500.3251.717
P值0.5740.9800.9580.2540.022
), ArticleFig(id=1315688474016075959, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别n穿越平台次数/次目标象限停留时间（t/s）
正常组92.29 ±0.2838.28 ±2.29
模型组90.57 ±0.20*21.48 ±1.99*
生慧汤低剂量组91.86 ±0.34#37.20 ±4.73#
生慧汤高剂量组91.57 ±0.20#27.00 ±2.23
多奈哌齐组92.00 ±0.45#36.49 ±3.09#
F值13.76018.080
P值＜0.001＜0.001
), ArticleFig(id=1315688474091573432, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表3, caption=

各组小鼠空间探索能力结果比较

, figureFileSmall=null, figureFileBig=null, tableContent=
组别n穿越平台次数/次目标象限停留时间（t/s）
正常组92.29 ±0.2838.28 ±2.29
模型组90.57 ±0.20*21.48 ±1.99*
生慧汤低剂量组91.86 ±0.34#37.20 ±4.73#
生慧汤高剂量组91.57 ±0.20#27.00 ±2.23
多奈哌齐组92.00 ±0.45#36.49 ±3.09#
F值13.76018.080
P值＜0.001＜0.001
), ArticleFig(id=1315688474167070905, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别n进臂次数/次自发交替率/%
正常组926.88 ±6.8336.84 ±5.43
模型组922.75 ±4.5916.25 ±5.91*
生慧汤低剂量组921.17 ±4.9223.50 ±4.12#
生慧汤高剂量组920.38 ±3.9622.60 ±3.13#
多奈哌齐组925.88 ±6.4728.50 ±6.14#
F值0.8226.854
P值0.5390.006
), ArticleFig(id=1315688474250956986, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表4, caption=

各组小鼠在Y迷宫中的进臂次数与自发交替率

, figureFileSmall=null, figureFileBig=null, tableContent=
组别n进臂次数/次自发交替率/%
正常组926.88 ±6.8336.84 ±5.43
模型组922.75 ±4.5916.25 ±5.91*
生慧汤低剂量组921.17 ±4.9223.50 ±4.12#
生慧汤高剂量组920.38 ±3.9622.60 ±3.13#
多奈哌齐组925.88 ±6.4728.50 ±6.14#
F值0.8226.854
P值0.5390.006
), ArticleFig(id=1315688474318065851, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别n理毛次数/次运动总距离（s/cm）
正常组983.10 ±5.911584.23 ±115.00
模型组936.00 ±6.04**1430.34 ±148.65
生慧汤低剂量组982.92 ±3.35#1292.23 ±127.74
生慧汤高剂量组959.51 ±6.741363.42 ±64.73
多奈哌齐组976.51 ±7.16#1480.26 ±91.44
F值33.8402.905
P值＜0.0010.078
), ArticleFig(id=1315688474397757628, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表5, caption=

各组小鼠在旷场中的理毛次数与运动总距离

, figureFileSmall=null, figureFileBig=null, tableContent=
组别n理毛次数/次运动总距离（s/cm）
正常组983.10 ±5.911584.23 ±115.00
模型组936.00 ±6.04**1430.34 ±148.65
生慧汤低剂量组982.92 ±3.35#1292.23 ±127.74
生慧汤高剂量组959.51 ±6.741363.42 ±64.73
多奈哌齐组976.51 ±7.16#1480.26 ±91.44
F值33.8402.905
P值＜0.0010.078
), ArticleFig(id=1315688474460672189, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别nROS荧光强度
正常组38.21 ±0.81
模型组312.13 ±0.21*
生慧汤低剂量组39.64 ±0.79#
生慧汤高剂量组310.34 ±1.36
多奈哌齐组39.72 ±0.89#
F值7.625
P值0.004
), ArticleFig(id=1315688474557141182, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表6, caption=

各组小鼠ROS荧光强度

, figureFileSmall=null, figureFileBig=null, tableContent=
组别nROS荧光强度
正常组38.21 ±0.81
模型组312.13 ±0.21*
生慧汤低剂量组39.64 ±0.79#
生慧汤高剂量组310.34 ±1.36
多奈哌齐组39.72 ±0.89#
F值7.625
P值0.004
), ArticleFig(id=1315688474641027263, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别nMDA含量（U·mg-1）
正常组31.99 ±0.30
32.78 ±0.19*
模型组生慧汤低剂量组31.98 ±0.21#
生慧汤高剂量组32.16 ±0.18
多奈哌齐组31.82 ±0.33#
F值6.745
P值0.006
), ArticleFig(id=1315688474712330432, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表7, caption=

各组小鼠MDA含量比较

, figureFileSmall=null, figureFileBig=null, tableContent=
组别nMDA含量（U·mg-1）
正常组31.99 ±0.30
32.78 ±0.19*
模型组生慧汤低剂量组31.98 ±0.21#
生慧汤高剂量组32.16 ±0.18
多奈哌齐组31.82 ±0.33#
F值6.745
P值0.006
), ArticleFig(id=1315688474787827905, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别nSOD含量（U·mg-1）
正常组3151.92 ±11.16
模型组353.12 ±7.34**
生慧汤低剂量组3127.79 ±11.82#
生慧汤高剂量组391.29 ±9.58
多奈哌齐组3113.68 ±11.17#
F值39.580
P值＜0.001
), ArticleFig(id=1315688474854936770, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表8, caption=

各组小鼠SOD含量比较

, figureFileSmall=null, figureFileBig=null, tableContent=
组别nSOD含量（U·mg-1）
正常组3151.92 ±11.16
模型组353.12 ±7.34**
生慧汤低剂量组3127.79 ±11.82#
生慧汤高剂量组391.29 ±9.58
多奈哌齐组3113.68 ±11.17#
F值39.580
P值＜0.001
), ArticleFig(id=1315688474930434243, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别nN rf2HO-1Keap1
正常组31.14 ±0.071.01 ±0.021.02 ±0.17
模型组30.67 ±0.87**0.68 ±0.03**1.23 ±0.02**
生慧汤低剂量组31.05 ±0.13##1.04 ±0.09##1.03 ±0.07##
生慧汤高剂量组30.81 ±0.340.75 ±0.091.05 ±0.01##
多奈哌齐组30.97 ±0.24#1.11 ±0.02##1.02 ±0.03##
F值7.403204.30019.180
P值＜0.05＜0.01＜0.01
), ArticleFig(id=1315688475010126020, tenantId=1146029695717560320, journalId=1315121837170065538, articleId=1315688464637612098, language=CN, label=表9, caption=

各组海马Nrf2、Keap1和HO -1蛋白印迹表达水平比较

, figureFileSmall=null, figureFileBig=null, tableContent=
组别nN rf2HO-1Keap1
正常组31.14 ±0.071.01 ±0.021.02 ±0.17
模型组30.67 ±0.87**0.68 ±0.03**1.23 ±0.02**
生慧汤低剂量组31.05 ±0.13##1.04 ±0.09##1.03 ±0.07##
生慧汤高剂量组30.81 ±0.340.75 ±0.091.05 ±0.01##
多奈哌齐组30.97 ±0.24#1.11 ±0.02##1.02 ±0.03##
F值7.403204.30019.180
P值＜0.05＜0.01＜0.01
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生慧汤通过Nrf2/HO-1信号通路抗氧化应激改善阿尔茨海默病认知障碍的作用机制
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亢钰涵 , 刘继红 , 王浩然 , 罗日红 , 张紫娟 , 郝莉
中医学报 | 实验研究 2025,40(12): 2636-2649
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中医学报 |实验研究 2025 , 40 (12) : 2636 -2649
生慧汤通过Nrf2/HO-1信号通路抗氧化应激改善阿尔茨海默病认知障碍的作用机制
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亢钰涵, 刘继红, 王浩然, 罗日红, 张紫娟, 郝莉
作者信息
  • 河南中医药大学，河南 郑州 450046
通讯作者:
郝莉（1971 -），女，教授，硕士研究生导师，研究方向：中医药抗衰老研究。E-mail:
作者简介:

亢钰涵（1997 -），女，河南灵宝人，硕士研究生，主要从事中医药抗衰老研究。

Action Mechanism of Shenghui Decoction Alleviating Oxidative Stress via Nrf2/HO-1 Signaling Pathway and Improving Cognitive Dysfunction in Alzheimer′s Disease
Yuhan KANG, Jihong LIU, Haoran WANG, Rihong LUO, Zijuan ZHANG, Li HAO
Affiliations
  • Henan University of Chinese Medicine, Zhengzhou Henan China 450046
出版时间: 2025-12-10 doi: 10.16368/j.issn.1674-8999.2025.12.412
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摘要
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目的：本研究旨在探讨生慧汤通过Nrf2/HO-1信号通路抗氧化应激改善阿尔茨海默病（Alzheimer's disease，AD）认知障碍的作用机制。方法：从45只小鼠中随机抽取9只作为正常组，其余36只采用脑立体定位注射Aβ25-35寡聚体构建AD模型，模型小鼠分为模型组、生慧汤低剂量组、生慧汤高剂量组和多奈哌齐组，每组9只。（1）通过行为学实验评估学习记忆能力，利用免疫荧光技术检测小鼠海马β-淀粉样蛋白（amyloid β-protein，Aβ）沉积程度，并结合荧光探针法、酶联免疫吸附试验（enzyme linked immunosorbent assay，ELISA），探究生慧汤对AD氧化应激的影响。（2）通过网络药理学方法，筛选生慧汤的活性成分及相关靶点，并与AD、氧化应激的疾病靶点取交集，进而构建“生慧汤有效成分-靶点-AD-氧化应激”网络和蛋白相互作用（protein-protein interaction，PPI）网络，筛选生慧汤关键有效成分。此外，利用Metascape数据库和MCODE算法获取目标聚类模块靶点，并借助AutoDockTools软件对关键有效成分和聚类模块靶点进行分子模拟对接验证。（3）蛋白质免疫印迹（Western Blot，WB）实验评估对接结合能最佳分子的蛋白表达水平。结果：行为学实验结果表明，生慧汤可改善AD小鼠的学习记忆能力，减少Aβ沉积（P＜0.05），提升超氧化物歧化酶水平（P＜0.05），降低活性氧和丙二醛含量（P＜0.05）。获得“AD-生慧汤-氧化应激”有效成分48个和交集靶点114个。其中，关键有效成分为山柰酚、β-谷甾醇、豆甾醇、去甲莨菪碱和四氢鸭脚木碱。有8个核心靶点参与了氧化应激反应、活性氮反应及低氧反应等重要生物过程，包括胱天蛋白酶3（Caspase-3，CASP3）、信号转导与转录激活因子1（signal transducer and activator of transcription1，STAT1）、过氧化物酶体增生激活受体γ（peroxisome proliferative activated receptor gamma，PPARG）、核因子红细胞系2（nuclear factor erythroid 2，Nrf2）、细胞间黏附分子-1（intercellular cell adhesion molecule-1，ICAM-1）、血红素加氧酶1（heme oxygenase-1，HO-1）、血管细胞黏附分子1（vascular cell adhesion molecule 1，VCAM1）和胱天蛋白酶1（caspase-1，CASP1）。分子对接结果显示，核心靶点HO-1与生慧汤关键有效成分结合效果最佳，WB实验验证生慧汤通过调控Nrf2和HO-1的表达水平，发挥抗氧化应激作用。结论：生慧汤可改善AD小鼠的学习记忆能力，减少Aβ生成，抑制氧化应激反应，其作用机制与调控Nrf2/HO-1通路中相关蛋白表达水平有关。

生慧汤  /  Nrf2/HO-1信号通路  /  阿尔茨海默病  /  认知障碍  /  氧化应激  /  分子对接

Objective:This study aims to investigate the mechanism by which Shenghui Decoction alleviates cognitive dysfunction in Alzheimer's disease（AD）by counteracting oxidative stress through the Nrf2/HO-1 signaling pathway.Methods:From a total of 45 mice，9 were randomly selected as the normal control group，while the remaining 36 were injected with Aβ25-35 oligomers via stereotaxic brain injection to establish an AD model.The model mice were divided into a model group，a low-dose Shenghui Decoction group，a high-dose Shenghui Decoction group，and a donepezil group，with 9 mice in each group.（1）Behavioral experiments were conducted to assess learning and memory abilities. Immunofluorescence technology was used to detect hippocampal amyloid β-protein（Aβ）deposition in mice，and the effects of Shenghui Decoction on AD-related oxidative stress were explored in combination with fluorescent probes and enzyme-linked immunosorbent assay（ELISA）.（2）Through network pharmacology methods，the active components and related targets of Shenghui Decoction were screened and intersected with disease targets for AD and oxidative stress，thereby constructing a ″Shenghui Decoction active components-targets-AD-oxidative stress″network and protein-protein interaction（PPI）network.Key active components of Shenghui Decoction were identified.In addition，Metascape database and MCODE algorithm were used to obtain target cluster modules，and molecular docking of key active components with cluster module targets was validated using AutoDockTools software.（3）Western blot（WB）experiments were performed to assess the protein expression levels of molecules with the best docking binding energies.Results:Behavioral experiments indicated that Shenghui Decoction（SHD）can improve learning and memory abilities in AD mice，reduce Aβdeposition（P＜0.05），increase superoxide dismutase levels（P＜0.05），and decrease reactive oxygen species and malondialdehyde content（P＜0.05）.Atotal of 48 active components and 114 overlapping targets related to ″AD-SHD-oxidative stress″were identified.The key active components include kaempferol，β-sitosterol，stigmasterol，scopolamine，and tetrahydropalmatine.Eight core targets were involved in important biological processes such as oxidative stress response，reactive nitrogen species response，and hypoxia response，including caspase -3（CASP3），signal transducer and activator of transcription 1（STAT1），peroxisome proliferator-activated receptor gamma（PPARG），nuclear factor erythroid 2（Nrf2），intercellular adhesion molecule-1（ICAM-1），heme oxygenase-1（HO-1），vascular cell adhesion molecule 1（VCAM1），and caspase-1（CASP1）.Molecular docking results showed that the core target HO-1 had the best binding effect with key active components of SHD.WB experiments verified that SHD exerts antioxidant effects by regulating the expression levels of Nrf2 and HO-1. Conclusion:SHD can improve learning and memory abilities in AD mice，reduce Aβproduction，and inhibit oxidative stress，with its mechanism related to the regulation of protein expression levels in the Nrf2/HO-1 pathway.

Shenghui Decoction  /  Nrf2/HO-1  /  signaling pathway  /  Alzheimer's Disease  /  cognitive dysfunction  /  Oxidative stress  /  molecular docking
亢钰涵, 刘继红, 王浩然, 罗日红, 张紫娟, 郝莉. 生慧汤通过Nrf2/HO-1信号通路抗氧化应激改善阿尔茨海默病认知障碍的作用机制. 中医学报, 2025 , 40 (12) : 2636 -2649 . DOI: 10.16368/j.issn.1674-8999.2025.12.412
Yuhan KANG, Jihong LIU, Haoran WANG, Rihong LUO, Zijuan ZHANG, Li HAO. Action Mechanism of Shenghui Decoction Alleviating Oxidative Stress via Nrf2/HO-1 Signaling Pathway and Improving Cognitive Dysfunction in Alzheimer′s Disease[J]. Acta Chinese Medicine, 2025 , 40 (12) : 2636 -2649 . DOI: 10.16368/j.issn.1674-8999.2025.12.412
正文
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阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，主要症状是认知功能障碍[1]。随着全球老龄化加剧，AD发病率正逐年攀升。预计到2050年，全球AD患者将达到1.52亿。我国AD患者约占世界痴呆总人口25%，且发病率逐年升高，给国家和家庭造成沉重的经济负担[2]。AD主要病理特征是细胞外β-淀粉样蛋白（amyloid β-protein，Aβ）沉积和细胞内Tau蛋白过度磷酸化。由于大脑耗氧高、抗氧化水平低，极易发生氧化应激，造成活性氧（reactive oxygen species，ROS）不断积累，并加快了Aβ的沉积，形成老年斑[3-4]。临床研究同样显示氧化应激损伤程度与AD发病进程密切相关[5]。临床前研究表明，靶向氧化应激的相关分子可改善AD患者学习记忆能力障碍[6]。因此，寻找安全、可靠和有效的抗氧化药物用于AD治疗具有较大的临床应用价值。
中药遵循中医基础理论整体观念进行辨证论治，具有多成分、多靶点、多环节和多系统的治疗优势。AD在中医学中属于“痴呆”范畴，以“心肾不足”证型为主，主要表现为“老年健忘，近事多不记忆，虽人述其前事，犹若茫然[7]”。生慧汤始载于《辨证录》，由熟地黄、人参、山茱萸、远志、生枣仁、柏子仁（去油）、茯神、石菖蒲和白芥子组成[8]。君药为熟地黄，其滋阴补血、益肾填精，乃“精血形质中第一纯厚之药[9]”。臣药为人参和山茱萸，前者大补脾肾之气，后者补肾填精。书中亦描述此方“心肾兼补，上下互资，实治健忘之圣药[8]”。动物研究表明，熟地黄对AD大鼠具有神经保护作用[10-11]；人参通过调节微生物-肠-脑轴缓解AD症状[12]；山茱萸可改善AD大鼠的认知功能[13]。核因子红细胞系2（nuclear factor erythroid 2，Nrf2）/血红素加氧酶1（heme oxygenase -1，HO -1）是重要的抗氧化通路。然而，生慧汤改善AD相关学习记忆障碍的抗氧化作用机制尚未阐明。
本研究运用网络药理学与分子对接技术获取生慧汤治疗AD的关键有效成分和核心靶点，并对该生物信息学分析结果进行动物实验验证。实验以临床上常用的AD治疗药物多奈哌齐为阳性对照，确保结果的科学可靠性与临床相关性。研究旨在明确生慧汤改善AD学习记忆障碍的作用效果，并探讨其中可能的抗氧化作用机制，为生慧汤临床应用于改善AD奠定实验基础。
1　材料
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1.1　动物
SPF级C57BL/6小鼠，45只，8周龄，体质量（25～30）g，购自河南斯克贝斯生物科技股份有限公司（SCXK（豫）2020-0004）。小鼠造模前于标准笼适应性喂养，自由进食，饲养条件为温度（22 ±2）℃，光/暗周期为12 h/12 h，相对湿度50%～60%。实验过程均遵循河南中医药大学实验动物福利伦理委员会要求（DWLL201907311）进行规范化操作。
1.2　药物与试剂
生慧汤由熟地黄30 g，山茱萸12 g，人参10 g，远志6g，生枣仁15 g，柏子仁（去油）15 g，茯神10 g，石菖蒲1.5g和白芥子6g组成。饮片购自河南中医药大学第一附属医院。Aβ25-35（货号118M4893），美国Sigma -Aldrich公司；多奈哌齐（货号1701069），中国卫材药业有限公司。组织包埋剂（货号MM1501），美国Sakura公司；驴血清封闭液（货号SL050）、BCA蛋白检测试剂盒（货号SL038）、柠檬酸钠抗原修复液（货号PC0020）、5%BSA封闭液（货号C1032）、高效RIPA裂解液（货号SW3015），北京Solarbio公司；山羊抗兔IgG HRP（1∶5 000，货号ab0101）、山羊抗鼠IgG HRP（1∶5 000，货号ab0102），北京Abways Technology公司；驴抗兔IgG（1∶400，货号ab150072），Aβ1-42（1∶1 000，货号ab201060），英国abcam公司；β-actin（1∶5 000，货号BM0627）、Keap1（1∶1 000，货号PB0813），武汉博士德生物公司；HO-1（1∶1 000，货号GTX101147）、Nrf2（1∶1 000，货号GTX101147），美国Gene Tex公司；MDA试剂盒（货号E -EL -0060）、SOD试剂盒（货号E -BC -K020-M），武汉Elabscience公司；ROS荧光探针试剂盒（货号BB470536），上海贝博生物公司。
1.3　仪器
水迷宫（深圳瑞沃德生命科技有限公司，63031型）、Y迷宫（深圳瑞沃德生命科技有限公司，63006型）、旷场行为学仪器（深圳瑞沃德生命科技有限公司，63041型）、显微镜（德国ZEISS公司，Axioscope5型）、精密天平（瑞士METTLER TOLEDO公司，ME54型）、石蜡切片机（德国LECIA公司，RM2245型）、组织脱水机（德国LECIA公司，TP1020型）、石蜡包埋机（德国LECIA公司，EG1150型）、低温离心机（美国Thermo Fisher公司，Heraeus FresCO21型）、脱色摇床（海门市其林贝尔仪器公司，TS-1000型）、电泳转膜仪（北京六一生物公司，DYY-6C型）、核酸蛋白成像显影仪（美国BIO -RAD公司，731BR02542型）。
2　方法
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2.1　药物制备、立体定位注射及给药
熟地黄30 g，山茱萸12 g，人参10 g，远志6g，生酸枣仁15 g，柏子仁（去油）15 g，茯神10 g，石菖蒲1.5g和白芥子6g，加8倍量无菌蒸馏水浸泡20 min、武火煮沸后文火慢熬20 min，第2次加入6倍量无菌蒸馏水同法煎煮；合并2次煎液，浓缩制成2.7 g·mL-1低质量浓度和5.4 g·mL-1高质量浓度生慧汤汤剂，置于4 ℃保存、备用。小鼠给药质量浓度选择参照张美亚等[14-15]的动物研究。Aβ25-35溶于无菌蒸馏水，于5%CO2、37 ℃培养箱内孵育1周以诱导其成为Aβ25-35寡聚体，后封存于-20 ℃保存、备用。多奈哌齐溶于生理盐水，置于4 ℃保存、备用。
45只小鼠进行适应性饲养，1周后随机抽取9只为正常组小鼠，其余36只为造模小鼠。小鼠用异氟烷空气麻醉、备皮后，将其固定于脑立体定位仪上，使用微量注射器将生理盐水、Aβ25-35分别注射小鼠CA1区域（注射严格按照小鼠脑立体定位图谱进行[16]，确定小鼠前后囟为同一水平线，以前囟为零点，前囟后、左右旁开、硬膜下分别为2.2 mm、2.0 mm、1.7 mm），使用无菌生理盐水润洗微量注射器3次后，用配置好的Aβ25-35寡聚体进行注射。缓慢进针在到达目标位置后静置5 min后开始注射，每侧脑室均为3 mg·kg-1，结束注射后针头停滞脑内约3 min（以上缓慢操作有助于注射液体在目标区域扩散吸收），缓慢退出针头。结束操作后使用特制明胶海绵压迫止血、消毒后使用缝合线缝合皮肤，共注射7 d。
造模小鼠分为模型组、生慧汤低剂量组、生慧汤高剂量组和多奈哌齐组，每组9只。分别给予生理盐水、低剂量生慧汤（2.7 g·mL-1）、高剂量生慧汤（5.4 g·mL-1）和多奈哌齐（0.75 g·mL-1），灌胃60 d，每日1次，每次0.1 mL。动物给药剂量严格按照动物与人体质量的等效剂量系数折算法进行[17]。第54天—第60天对小鼠进行行为学实验，实验流程见图1。多奈哌齐是治疗AD的一线临床药物，具有缓解AD疾病进程的效果，本研究用其作为阳性对照药[18]。
2.2　网络药理学研究方法
2.2.1　生慧汤有效成分及作用靶点筛选
通过中药系统药理学数据库与分析平台（Traditional Chinese Medicine System Pharmacology Database and Analysis Platform，TCMSP，https://www.tcmspw.com/tcmsp.php），以口服生物利用度（oral bioavailability，OB）≥30%和类药性（drug likeness，DL）≥0.18为筛选条件，检索生慧汤中熟地黄、人参、山茱萸、柏子仁、石菖蒲和酸枣仁的潜在有效成分及其作用靶点。同时，借助本草图鉴（HERB，http://herb.ac.cn）数据库补充检索远志、茯神和白芥子的潜在有效成分，并通过PubChem（https://pubchem.ncbi.nlm.nih. gov）数据库校准这些成分的标准SMILES编号。随后，利用SWISS ADME数据库（http://www.swissadme.ch/index.php）进一步筛选出符合高消化吸收程度且满足类药五原则中任意三项“yes”的有效成分。通过SwissTargetPrediction（https://www. swisstargetprediction.ch）数据库，获取有效成分的作用靶点。结合美国化学文摘服务社（Chemical Abstracts Service，CAS）编号，对生慧汤9种药物的有效成分进行确认、整合并剔除重复项，获得最终的有效成分及其对应的作用靶点。
2.2.2　筛选与AD和氧化应激相关的靶点
在线人类孟德尔遗传（Online Mendelian Inheritance in Man，OMIM，https://omim.org）数据库和基因卡（Genecards，http://genecards.com）数据库中输入关键词“Alzheimer's disease”和“Oxidative stress”，获取与AD和氧化应激相关的靶点。以“蛋白质相关编码基因”为筛选条件对氧化应激靶点进行筛选，并保留Score大于中位数的靶点。使用Venny 2.1.0软件对生慧汤有效成分靶点、AD相关靶点和氧化应激相关靶点取交集，并进行可视化分析，得到生慧汤经氧化应激途径抗AD的交集靶点。
2.2.3　构建“生慧汤有效成分-靶点-AD-氧化应激”网络图
利用Cytoscape 3.8.2软件对生慧汤有效成分和交集靶点可视化，构建“生慧汤有效成分-靶点-AD-氧化应激”网络图，展现其药理关系。借助CytoNCA插件获取网络节点的连接度（Degree）信息，并以Degree值排名前5位的有效成分作为关键有效成分。
2.2.4　蛋白质相互作用（protein-protein interaction，PPI）网络构建及聚类模块分析
通过STRING（https://string-db.org）在线数据库进行PPI网络分析。将交集靶点导入STRING数据库，限定“Homo Sapiens”物种，置信度得分高于0.700，随后下载相关数据导入Cytoscape 3.8.2软件进行可视化分析。利用Cytoscape 3.8.2软件中的CytoNCA插件分析交集靶点的Degree值、介度（Betweenness）值及紧密度（Closeness）值，并以这3项参数均大于其中位数作为筛选条件得到核心网络及其靶点。网络中的节点颜色反映了连接度的大小。此外，通过模块功能（MCODE）插件对PPI网络进行聚类分析，以获取PPI网络中的全部聚类模块。
2.2.5　GO功能富集分析、KEGG通路富集分析及核心靶点筛选
将上述聚类模块分别输入Metascape（http://metascape.org/gp/index.html）数据库进行GO功能和KEGG通路富集分析，限定“Homo sapiens”物种、筛选P＜0.01的条目，以确定与氧化应激相关的聚类模块为目标模块，并将其包含的靶点定义为核心靶点。随后，借助微生信在线平台（https://www.bioinformatics.com.cn）对目标聚类模块的数据进行可视化处理。
2.2.6　药物关键有效成分-核心靶点分子对接
将核心靶点与关键有效成分进行分子对接，以验证药物作用的可能性。在TCMSP和PubChem数据库中获取关键有效成分的二级结构，并通过Uniprot（https://www.uniprot.org）和RCSB（https://www. rcsb.org）数据库获取核心靶点的3D结构。随后，利用软件Chem 3D 19.0将核心靶点的二级结构转化为三级结构，并借助PyMOLWin 2.6软件去除关键有效成分的残基和水分子；采用AutoDockTools 1.5.7软件对处理后的关键有效成分和核心靶点进行对接分析，获得对接数据并评估其结合稳定性。最后，利用软件PyMOLWin 2.6对分子对接结果可视化。
2.3　动物实验方法
2.3.1　行为学实验
水迷宫实验：水迷宫是由直径为1.5m的圆形恒温泳池和直径3cm的圆形站台组成，泳池被划分为4个象限。前5d进行定位航行实验：将小鼠背对游泳池从不同入水点放入水中（每只小鼠每天4次），记录其从入水到找到平台所需的时间（限时1 min）。第6天进行空间探索实验：撤去平台，将小鼠背对游泳池放入水中，记录其在1 min内的探索行为数据。
Y迷宫实验：Y迷宫由3个夹角为120°的长臂连接组成，调整光源确保Y迷宫内光照均匀一致。将小鼠置于中心区域，记录其在5 min内穿梭进入3个臂的轨迹、进入各臂的次数及准确交替次数。
旷场实验：实验箱体尺寸为长宽各50 cm、高40 cm，顶部开放，调整光源保证实验过程中光照一致。将小鼠放置于底板中心区域，记录其在5 min内运动总距离及理毛次数。
2.3.2　组织免疫荧光
每组随机取3只小鼠，经颈椎脱臼法处死后，暴露颅骨，剥离脑壳取出全脑，置于4%多聚甲醛溶液中固定。固定完成后，对组织进行石蜡包埋，制备连续切片并贴附于载玻片。随后依次进行脱水、脱蜡、H2O2灭活、抗原修复及血清封闭处理，孵育一抗Aβ1-42（1∶1 000稀释）过夜。次日，孵育二抗（驴抗兔IgG，1∶400稀释），之后进行DAPI核染色。通过显微镜观察并采集图像，使用ImageJ 1.8.0软件分析图像的平均光密度。
2.3.3　活性氧（reactive oxygen species，ROS）荧光探针法
每组随机选取3只小鼠，取出全脑，用4%多聚甲醛和20%、30%蔗糖溶液梯度固定，冰冻切片机切片。切片转移至24孔板，清洗3次后用DHE活性氧荧光探针染色（37 ℃避光孵育）。染色完成后，PBS缓冲液清洗3次，甘油封片。显微镜观察并采集图像，数据分析方法同2.3.2。
2.3.4　酶联免疫吸附试验法（enzyme linked immunosorbent assay，ELISA）
每组随机选取3只小鼠，取其一侧新鲜海马组织，经漂洗、匀浆和低温离心处理后收集上清液。按试剂盒说明书配置工作液，将上清液加入充分混匀，测定超氧化物歧化酶（superoxide dismutase，SOD）活性和丙二醛（malondialdehyde，MDA）含量。随后在指定波长下测量吸光度，并结合标准曲线计算具体含量。
2.3.5　蛋白质免疫印迹技术（Western blot，WB）
取2.3.4中同一批3只小鼠的另一侧新鲜海马组织。将组织蛋白裂解后，在低温条件下高速离心分离，收集上清液。加入5 ×Loading Buffer并高温变性处理。根据样品浓度计算上样量，配制SDS -PAGE胶并完成电泳和转膜操作。转膜后，使用封闭液封闭非特异性结合位点，依次孵育一抗（Keap1:1∶1 000；Nrf2:1∶1 000；HO-1:1∶1 000；β-actin:1∶5 000）。次日，用相应二抗（1∶5 000）孵育，显影液浸泡后通过核酸蛋白成相显影仪成像分析。最后，使用ImageJ 1.8.0软件对条带灰度值进行定量分析。
2.3.6　统计学方法
数据以均数±标准差（±s）表示，使用GraphPad Prism 10.1.2软件进行统计分析。多组样本经正态分布和方差齐性检验后，逃避潜伏期数据采用双因素方差分析（two -way ANOVA），其他数据采用单因素方差分析（one -way ANOVA）。组间两两比较采用Tukey法。P＜0.05为差异具有统计学意义。
3　结果
收起
3.1　网络药理学研究结果
3.1.1　生慧汤有效成分筛选及其作用靶点的获取
通过TCMSP、HERB数据库筛选获得符合标准的生慧汤有效成分48个，如表1所示。其中，利用TCMSP、SwissTarget（http://www.swisstargetpre diction.ch）以及PharmMapper（http://www.lilabecust. cn/pharmmapper/）等平台系统搜集了这些有效成分的作用靶点，整合数据后剔除重复项，共获得270个靶点。
3.1.2　生慧汤抗AD有效成分的靶点筛选
通过使用Genecards和OMIM数据库，系统收集了1 842个AD相关靶点和3 962个氧化应激相关靶点。将这些靶点与生慧汤的270个有效成分靶点进行交集分析，筛选出114个同时与生慧汤、AD及氧化应激相关的靶点。为直观展示结果，使用韦恩图工具（https://bioinfogp.cnb.csic.es/tools/venny/index. html）对数据进行了可视化处理，具体见图2。
3.1.3　“生慧汤有效成分-靶点-疾病-通路”网络图构建
将获得的有效成分及交集靶点导入Cytoscape 3.8.2软件，构建“生慧汤有效成分-靶点-AD-氧化应激”网络图（图3）。其中，5种成分为药物间的共有成分。节点之间的连线反映了“生慧汤有效成分-靶点-疾病-通路”之间的靶向关系，连线数量越多表明节点在网络中的相关性越强。通过筛选Degree值排名前五的药物化学成分，确定其为关键有效成分，具体信息详见表1。
3.1.4　交集靶点的PPI网络构建及聚类分析
使用STRING数据库对交集靶点进行分析，并利用Cy toNCA插件计算各靶点的Degree、Betweenness及Closenesss值并进行排序。其中，节点颜色深浅与Degree、Betweenness及Closeness值呈正相关。使用MCODE算法对包含412个节点的网络进行分析，获得4个聚类模块，具体结果见图4。
3.1.5　核心靶点的筛选及GO、KEGG通路富集分析结果
利用Metascape数据库对MCODE 1至MCODE 4聚类模块进行了GO功能和KEGG富集分析。结果显示，MCODE 1与细胞凋亡及激素调节通路相关；MCODE 2与G蛋白偶联受体信号通路相关；MCODE 3与氧化应激相关；MCODE 4与细胞色素代谢相关。进一步确定MCODE 3中的关键靶点为核心靶点，包括胱天蛋白酶3（Caspase -3，CASP3）、信号转导与转录激活因子1（signal transducer and activator of transcription1，STAT1）、过氧化物酶体增生激活受体γ（peroxisome proliferative activated receptor gamma，PPARG）、Nrf2、细胞间黏附分子-1（intercellular cell adhesion molecule-1，ICAM-1）、HO-1、血管细胞黏附分子1（vascular cell adhesion molecule 1，VCAM1）和胱天蛋白酶1（Caspase-1，CASP1）。随后，对MCODE 3的GO分析中P值排名前20位的生物过程（biological processes，BP）进行可视化，涵盖氧化应激反应、活性氮反应调控及低氧反应调控（图5A）。此外，对9条KEGG信号通路进行可视化展示（图5B），包括血脂与动脉粥样硬化[19]、AGE-RAGE信号通路[20]、TNF信号通路[21]及致癌相关信号通路[22]，这些通路通过影响氧化应激机制参与机体的生理病理过程。
3.1.6　生慧汤关键有效成分和核心靶点蛋白的对接结果
将生慧汤的关键有效成分与核心靶点蛋白进行分子对接，共获得40组结果。结合能小于0 kJ·mol-1的结果表明，核心靶点蛋白可自发结合关键有效成分，且结合能越低，结合活性越高，结合能力越强[23]（图6）。进一步观察发现，HO-1在核心靶点蛋白中表现出最高的平均结合活性。鉴于Nrf2和HO-1为经典的氧化应激相关蛋白[24-25]，利用PyMOLWin 2.6软件对HO-1、Nrf2与关键有效成分的结合结果进行了可视化处理（图7）。
3.2　动物实验结果
3.2.1　生慧汤对AD小鼠空间学习记忆能力的影响
Morris水迷宫用于评估小鼠的空间学习记忆能力。定位航行实验结果显示，第1—4天各组间逃避潜伏期无显著差异；第5天时，模型组小鼠的逃避潜伏期显著长于正常组（P＜0.05）。与模型组相比，生慧汤低剂量组和多奈哌齐组的逃避潜伏期显著缩短（P＜0.05），高剂量组有缩短趋势（P＞0.05），详见表2。空间探索实验中，模型组小鼠穿越平台次数减少且目标象限停留时间缩短（P＜0.05）；与模型组相比，生慧汤低剂量组及多奈哌齐组的穿越平台次数和目标象限停留时间均显著增加（P＜0.05），高剂量组的穿越平台次数显著增加（P＜0.05），目标象限停留时间有延长趋势（P＞0.05），详见表3。上述结果表明，生慧汤可改善AD小鼠的学习记忆能力。
3.2.2　生慧汤对AD小鼠空间工作记忆能力的影响
Y迷宫实验评估小鼠空间工作记忆能力。结果显示，与正常组相比，模型组小鼠的自发交替率显著降低（P＜0.05）。经生慧汤低剂量组、高剂量组及多奈哌齐组干预后，各组小鼠的自发交替率均显著高于模型组（P＜0.05）。然而，各组小鼠的进臂次数无明显差异（P＞0.05）。上述结果表明，生慧汤可改善AD模型小鼠的空间工作记忆能力，且不影响其运动能力（表4）。
3.2.3　生慧汤对AD小鼠空间探索能力的影响
旷场实验用于评估小鼠空间探索能力。结果表明，与正常组相比，模型组小鼠的理毛次数显著减少（P＜0.01）。与模型组相比，生慧汤低剂量组和多奈哌齐组均增加小鼠的理毛次数（P＜0.05），而高剂量组呈现增加趋势（P＞0.05）。此外，各组间运动总距离无显著差异。上述结果提示，生慧汤可在不改变小鼠运动能力的前提下改善其空间探索能力（表5）。
3.2.4　生慧汤对AD小鼠中Aβ沉积的影响
Aβ沉积是AD的标志性病理特征[26]。本实验通过检测Aβ1-42斑块的沉积情况来评估AD小鼠的病理变化程度。组织免疫荧光染色实验结果显示：与正常组相比，模型组小鼠位于海马CA1区的Aβ1-42平均荧光强度增强（P＜0.01）；与模型组相比，生慧汤低剂量组、高剂量组和多奈哌齐组的海马CA1区Aβ1-42平均荧光强度均有所降低（P＜0.05），见图8。这表明生慧汤具有减轻海马CA1区Aβ沉积的作用。
3.2.5　生慧汤对AD小鼠氧化应激损伤的影响
氧化应激是神经不可逆损伤的重要因素，本研究通过检测与氧化应激相关的指标，观察了生慧汤对AD小鼠氧化应激损伤的影响。ROS是氧化应激过程中的重要代谢产物[27]，结果显示：与正常组相比，模型组ROS水平升高（P＜0.05）；经生慧汤、多奈哌齐干预后，生慧汤低剂量组和多奈哌齐组的ROS水平降低（P＜0.05），生慧汤高剂量组有降低的趋势（P＞0.05），见表6、图9。
MDA是一种脂质与氧自由基反应形成的产物，其含量可反映脂质过氧化的程度[28]。ELISA结果表明：与正常组相比，模型组MDA含量增加（P＜0. 05）；经生慧汤和多奈哌齐干预后，各组MDA含量均低于模型组，其中生慧汤低剂量组和多奈哌齐组的MDA含量与模型组相比均具有统计学意义（P＜0.05），生慧汤高剂量组有降低的趋势（P＞0.05），见表7。
SOD是衡量机体抗氧化能力的重要指标[29]。ELISA结果显示：与正常组比较，模型组SOD含量明显减少（P＜0.01）；经生慧汤和多奈哌齐干预后，各组SOD含量均高于模型组，生慧汤低剂量组、多奈哌齐组SOD含量与模型组相比均具有统计学意义（P＜0.05），生慧汤高剂量组有升高的趋势（P＞0.05），见表8。
3.2.6　生慧汤对AD小鼠抗氧化应激蛋白的影响
Nrf2和HO -1是抗氧化应激关键蛋白[24-25]，Keap1为Nrf2的上游调控因子。为了验证网络药理学分析结果，本实验通过检测Keap1、Nrf2和HO-1的表达水平，探讨生慧汤对AD小鼠抗氧化应激通路的作用机制。WB结果显示，与正常组相比，模型组中Keap1的表达升高（P＜0.05）。经生慧汤低剂量组、高剂量组以及多奈哌齐组干预后，Keap1的表达水平显著下降（P＜0.05）。此外，Nrf2和HO-1的表达情况显示，模型组相较于正常组表达降低（P＜0.05）。经生慧汤及多奈哌齐干预后，低剂量组和多奈哌齐组中Nrf2和HO-1的表达显著上调（P＜0.05），见表9、图10。
4　讨论
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AD的病理机制涉及氧化应激、神经炎症和线粒体功能障碍等多种因素[4]。生慧汤作为中医古籍中治疗健忘的经典方剂，其改善AD相关学习记忆能力的作用机制尚不明确。本研究通过网络药理学、分子对接及体内动物实验，探讨了生慧汤改善Aβ诱导建立的AD小鼠模型认知功能障碍、减轻海马Aβ沉积，其作用机制可能与调节Nrf2/HO-1抗氧化通路相关。
Aβ25-35是Aβ1-40和Aβ1-42的关键折叠片段，由11个氨基酸组成，保留了全长Aβ的生物学特性，因此成为构建AD动物模型的常用诱导剂[30-31]。本研究采用脑立体定位技术将Aβ25-35注射至小鼠海马CA1区，建立AD小鼠模型。行为学结果显示，Morris水迷宫中模型组的逃避潜伏期显著延长、穿越平台次数减少以及目标象限停留时间缩短；Y迷宫中模型组自发交替率下降，这些结果与Hou等[32]的AD转基因小鼠实验结果一致。此外，免疫荧光定量分析显示，模型组海马区存在明显的Aβ斑块沉积，从而验证了AD小鼠模型构建成功。
有临床研究表明，生慧汤可改善AD患者的学习记忆能力[18]。此外，相关研究发现，生慧汤对糖尿病脑病引起的认知障碍具有缓解作用[33]。本研究行为学结果显示，生慧汤可改善AD小鼠模型的学习记忆能力，且低剂量组的效果优于高剂量组。Aβ沉积是AD的主要病理特征之一，已有实验证明生慧汤可减少秀丽隐杆线虫中的Aβ沉积[34]。本研究观察到生慧汤能够减轻AD小鼠海马区的Aβ沉积。此外，氧化应激作为AD的重要分子机制，与Aβ沉积密切相关。
为进一步探讨生慧汤通过抗氧化应激途径干预AD的作用机制，本研究采用网络药理学方法筛选了生慧汤、AD和氧化应激之间的共同靶点。通过构建“生慧汤有效成分-AD-氧化应激”网络，筛选出5种关键有效成分，其中山柰酚[35]、β-谷甾醇[36]和豆甾醇[36]具有提高ROS清除能力、调节神经元突触可塑性、激活相关转录因子以及减轻神经元氧化应激的作用，从而有助于缓解认知障碍。为进一步验证生慧汤对AD小鼠海马氧化应激的影响，本研究检测了ROS、MDA和SOD的水平。结果显示，生慧汤能够降低AD小鼠海马中ROS和MDA的表达，同时升高SOD表达水平，表明生慧汤可通过改善AD小鼠海马的氧化损伤发挥神经保护作用。
本研究通过PPI网络构建及模块聚类分析，揭示了生慧汤通过氧化应激途径抗AD的核心靶点，包括CASP3、STAT1、PPARG、Nrf2、ICAM -1、HO-1、VCAM1和CASP1。分子对接结果显示，生慧汤关键有效成分与HO-1及Nrf2的结合亲和力优于其他靶点，提示二者可能是其调控抗氧化应激的关键分子靶标。生慧汤通过调控Nrf2/HO-1信号通路改善AD的分子机制，核心在于其多组分协同激活内源性抗氧化系统。Nrf2/HO-1作为氧化还原稳态的核心调控通路，在生理状态下通过Keap1-Nrf2复合物解离实现动态平衡：当ROS积累时，Nrf2核转位并激活HO -1等抗氧化酶的表达[37]。而AD中，Keap1的异常高表达抑制Nrf2入核，导致HO-1生成不足，加剧神经元氧化损伤和Aβ毒性[38-42]。生慧汤的关键成分山柰酚和β-谷甾醇显示出特异性调控潜力。研究表明，山柰酚通过干扰Keap1-Nrf2复合物构象稳定性，促进Nrf2核转位[43]；β-谷甾醇则通过增强Nrf2转录活性上调HO-1表达，其作用机制在帕金森病模型中已得到验证[44]，但在AD中的效应仍需进一步阐明。此外，熟地黄-何首乌药对中的豆甾醇可能通过干预Keap1泛素化修饰调控Nrf2稳定性，但其直接作用靶点尚未明确[45]。本实验数据显示，生慧汤干预可降低AD模型小鼠海马区Keap1蛋白表达，同时上调Nrf2核蛋白及HO -1水平，表明其通过解除Keap1对Nrf2的抑制作用激活抗氧化防御系统。
行为学与分子生物学结果显示，生慧汤低剂量组在改善学习记忆、降低Aβ沉积以及调节Nrf2/HO-1通路方面效果优于高剂量组。高剂量组在部分行为学指标（如水迷宫实验中的逃避潜伏期和目标象限停留时间，旷场实验中的理毛次数）上与模型组无统计学差异。这提示生慧汤多组分间可能存在非线性协同效应，其具体机制可能与海马区氧化应激指标变化不显著有关，表现为ROS和MDA水平未显著下降、SOD活性未显著提升，Nrf2及HO-1表达水平无统计学差异。此外，分子对接分析进一步表明，生慧汤的活性成分对HO-1和Nrf2的结合亲和力高于其他靶点，这与网络药理学预测结果一致。
本研究存在以下局限性：（1）AD发病率在性别上存在差异，女性高于男性[46]。未来需分别探讨生慧汤在雌性与雄性动物模型中的药效差异及其作用机制。（2）生慧汤对Nrf2/HO-1通路的调控作用已获验证，但受其多组分特性限制，核心药效物质基础尚未明确，后续需对关键成分开展靶向验证。（3）在AD小鼠症候评估中，高剂量生慧汤虽表现出改善趋势（如缩短逃避潜伏期、增加目标象限停留时间等），但差异无统计学意义。原因可能包括中医证候类型对疗效的影响（如肾虚、脾虚等）以及药物剂量增加引发的毒性或代谢改变[47]。未来研究需扩大样本量，并根据不同证候类型优化生慧汤剂量，以进一步确认其药理特性和最佳用药方案。
综上所述，本研究通过网络药理学、分子对接及体内动物实验，观察到生慧汤可改善Aβ诱导的AD小鼠模型认知功能障碍，其作用机制可能与调控Nrf2/HO-1抗氧化通路相关，这为生慧汤临床用于AD治疗奠定了理论和实验基础。

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doi: 10.16368/j.issn.1674-8999.2025.12.412
  • 接收时间：2025-07-02
  • 首发时间：2026-10-10
  • 出版时间：2025-12-10
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  • 收稿日期：2025-07-02
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    河南中医药大学，河南 郑州 450046

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郝莉（1971 -），女，教授，硕士研究生导师，研究方向：中医药抗衰老研究。E-mail:
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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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