Article(id=1322608105830077279, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1322608013010120712, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202506411, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1750694400000, receivedDateStr=2025-06-24, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1793263945299, onlineDateStr=2026-10-29, pubDate=1762704000000, pubDateStr=2025-11-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793263945299, onlineIssueDateStr=2026-10-29, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793263945299, creator=13701087609, updateTime=1793263945299, updator=13701087609, issue=Issue{id=1322608013010120712, tenantId=1146029695717560320, journalId=1227665162245664772, year='2025', volume='52', issue='21', pageStart='3841', pageEnd='4032', issueExtLink='null', onlineDate='null', pubDate='1762704000000', pubDateStr='2025-11-10', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793263923169, creator='13701087609', updateTime=1793264266929, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1322609454932149086, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1322608013010120712, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1322609454932149087, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1322608013010120712, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=4001, endPage=4008, ext={EN=ArticleExt(id=1322608106023015264, articleId=1322608105830077279, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=Network pharmacology and experimental validation of β-carotene in alleviating hyperuricemic renal injury via suppressing NLRP3 inflammasome activation, columnId=1228016572065837304, journalTitle=Modern Preventive Medicine, columnName=Experimental Technology and Applications, runingTitle=null, highlight=null, articleAbstract=
Objective

To explore the potential targets and mechanisms of β-carotene in the treatment of hyperuricemia (HUA) by integrating network pharmacology analysis with in vivo mouse experiments.

Methods

Targets related to β-carotene were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), CTDbase, and Swiss Target Prediction databases. Therapeutic targets for HUA were obtained from the GeneCards, DigSee, and DisGeNET databases. Venn diagram analysis was used to identify overlapping targets between β-carotene-related targets and HUA disease targets, and a protein-protein interaction (PPI) network was constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the identified overlapping targets. C57BL/6 mice were divided into 5 groups: normal group, HUA (model group), positive control allopurinol (62.5 mg/kg) group, 20 mg/kg β-carotene group, and 40 mg/kg β-carotene group. Except for the control group, all other groups were induced to establish the HUA mouse model using potassium oxonate and hypoxanthine. Serum levels of uric acid (UA), urea nitrogen (BUN), and creatinine (CRE) were measured using biochemical assay kits. Renal tissue injury was observed using hematoxylin-eosin (H&E) staining.Levels of interleukin-1β (IL-1β) and IL-18 were detected using enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used to detect protein expression levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and cleaved Caspase-1. Immunohistochemical staining was used to observe NLRP3 expression levels in renal tissue.

Results

Matching 254 β-carotene-related targets with 170 HUA-related targets yielded 15 overlapping β-carotene-HUA target genes. KEGG enrichment indicated that β-carotene primarily treated HUA by involving inflammation and apoptosis pathways, with NLRP3 inflammasome enrichment being the most significant. Compared to the model group, both 20 mg/kg β-carotene and 40 mg/kg β-carotene significantly reduced serum UA (F=119.3, P<0.01), BUN (F=112.7, P<0.01), and CRE (F=80.76, P<0.01) levels in HUA mice, alleviated renal injury, decreased renal tissue levels of IL-1β (F=97.8, P<0.01) and IL-18(F=137.0, P<0.01), and downregulated the expression levels of NLRP3 (F=178.4, P<0.01), ASC (F=392.5, P<0.01), and cleaved-Caspase-1 (F=171.6, P<0.01).

Conclusion

β-Carotene can alleviate renal injury and reduce inflammatory responses in HUA mice. Its mechanism may be associated with inhibiting the activation of the NLRP3 inflammasome.

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目的

利用网络药理学结合小鼠高尿酸血症(hyperuricemia,HUA)模型验证,探索β-胡萝卜素治疗HUA的潜在作用靶点及机制。

方法

利用中药系统药理学数据库和分析平台(Traditional Chinese Medicine Systems Pharmacology Database,TCMSP)、CTDbase和Swiss Target Prediction数据库获取β-胡萝卜素的相关靶点,在GeneCards、Digsee和DisGeNET数据库中获取HUA治疗靶点。通过维恩图分析获得β-胡萝卜素相关靶点与HUA疾病靶点的重叠靶点,构建蛋白质-蛋白质相互作用(protein-protein interactions,PPI)网络。对所得交集靶点进行基因本体(gene ontology,GO)与京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)富集分析。C57BL/6小鼠分为五组:正常组、HUA(模型组)、阳性药别嘌醇(62.5 mg/kg)组、20 mg/kg β-胡萝卜素组和40 mg/kg β-胡萝卜素组。除正常组外,所有组均用氧嗪酸钾和次黄嘌呤诱导构建HUA模型。采用生化试剂盒测定血清尿酸、尿素氮和肌酐水平。用苏木精-伊红(hematoxylin-eosin,HE)染色法观察肾组织损伤情况。应用酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)试剂盒检测白介素-1β(interleukin-1 β,IL-1β)和IL-18的水平。采用western blot检测NOD样受体蛋白3(NOD-like receptor protein 3,NLRP3)、凋亡相关斑点样蛋白(apoptosis-related spotted protein,ASC)和活化的半胱氨酸天冬氨酸蛋白酶-1(cleaved-Caspase-1)蛋白表达水平。免疫组织化学染色法观察肾组织中NLRP3表达水平。

结果

通过254个β-胡萝卜素相关靶点和170个HUA相关靶点的匹配,得到15个重叠靶点基因。KEGG富集结果显示,β-胡萝卜素治疗HUA主要涉及炎症和细胞凋亡通路,其中NLRP3炎性小体富集最显著。与模型组相比,20 mg/kg β-胡萝卜素和40 mg/kg β-胡萝卜素均显著降低HUA小鼠血清尿酸(F=119.3,P<0.01)、尿素氮(F=112.7,P<0.01)和肌酐(F=80.76,P<0.01)水平,减轻HUA小鼠肾脏损伤,降低肾组织中IL-1β(F=97.8,P<0.01)和IL-18(F=137.0,P<0.01)水平,下调NLRP3(F=178.4,P<0.01)、ASC(F=392.5,P<0.01)和cleaved-Caspase1(F=171.6,P<0.01)表达水平。

结论

β-胡萝卜素减轻HUA小鼠肾脏损伤,降低炎性反应,其机制可能与抑制NLRP3炎症小体的活化有关。

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杜瑛培(1988—),女,硕士,主管药师,研究方向:药理学

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周佳莹,E-mail:
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Drug Design,Development and Therapy, 2022, 16: 3353-3364., articleTitle=Baicalin alleviates Contrast-Induced acute kidney injury through ROS/NLRP3/caspase-1/GSDMD Pathway-Mediated proptosis in vitro, refAbstract=null), Reference(id=1322608119121826755, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, doi=null, pmid=null, pmcid=null, year=2023, volume=28, issue=22, pageStart=7540, pageEnd=7557, url=null, language=null, rfNumber=[27], rfOrder=34, authorNames=Wu S, Chen R, Chen J, journalName=Molecules, refType=null, unstructuredReference=Wu S, Chen R, Chen J, et al. Study of the anti-inflammatory mechanism of β-carotene based on network pharmacology [J]. Molecules, 2023, 28 (22): 7540-7557., articleTitle=Study of the anti-inflammatory mechanism of β-carotene based on network pharmacology, refAbstract=null), Reference(id=1322608119197324228, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, doi=null, pmid=null, pmcid=null, year=2025, volume=18, issue=3, pageStart=403, pageEnd=null, url=null, language=null, rfNumber=[28], rfOrder=35, authorNames=Shanaida M, Mykhailenko O, Lysiuk R, journalName=Pharmaceuticals(Basel, Switzerland), refType=null, unstructuredReference=Shanaida M, Mykhailenko O, Lysiuk R, et al. Carotenoids for antiaging: nutraceutical, pharmaceutical, and cosmeceutical applications [J]. Pharmaceuticals(Basel, Switzerland), 2025, 18 (3): 403., articleTitle=Carotenoids for antiaging: nutraceutical, pharmaceutical, and cosmeceutical applications, refAbstract=null)], funds=[Fund(id=1322608114902356896, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, awardId=2019JZZY011121, language=CN, fundingSource=山东省重大科技创新工程项目(2019JZZY011121), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1322608109881774960, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, xref=1., ext=[AuthorCompanyExt(id=1322608109890163569, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, companyId=1322608109881774960, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Pharmacy, The Eighth People’s Hospital of Qingdao, Qingdao, Shandong 266000, China), AuthorCompanyExt(id=1322608109898552178, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, companyId=1322608109881774960, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.青岛市第八人民医院药学部,山东 青岛 266000)]), AuthorCompany(id=1322608109974049651, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, xref=2., ext=[AuthorCompanyExt(id=1322608110007604084, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, companyId=1322608109974049651, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.青岛市公共卫生临床中心药剂科,山东 青岛 266000)])], figs=[ArticleFig(id=1322608113560179604, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=EN, label=Figure 1, caption=Intersection of β-Carotene targets and HUA disease targets, figureFileSmall=ZWG4+yqfhxY/SrLrlW+1tQ==, figureFileBig=T4AFo8vegSEJnuRtZibiaQ==, tableContent=null), ArticleFig(id=1322608113623094165, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=CN, label=图1, caption=β-胡萝卜素作用靶点与HUA疾病靶点交集, figureFileSmall=ZWG4+yqfhxY/SrLrlW+1tQ==, figureFileBig=T4AFo8vegSEJnuRtZibiaQ==, tableContent=null), ArticleFig(id=1322608113837003670, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=EN, label=Figure 2, caption=PPI network of target proteins, figureFileSmall=WMmu3nFMcrnfk9+pvBJd2Q==, figureFileBig=T8Rb3QzUNvu1DMgmFgUFjg==, tableContent=null), ArticleFig(id=1322608114071884695, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=CN, label=图2, caption=靶点蛋白PPI网络

注:ALB为白蛋白;PTGS2为环氧酶2。

, figureFileSmall=WMmu3nFMcrnfk9+pvBJd2Q==, figureFileBig=T8Rb3QzUNvu1DMgmFgUFjg==, tableContent=null), ArticleFig(id=1322608114138993560, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=EN, label=Figure 3, caption=Enrichment analysis, figureFileSmall=ZBMOuunUBarRi8pxHT037Q==, figureFileBig=Jc3BrXfxdpSCiBuak/A9MA==, tableContent=null), ArticleFig(id=1322608114214491033, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=CN, label=图3, caption=富集分析

注:图A为GO基因生物过程富集;图B为GO细胞成分富集;图C为GO分子功能富集;图D为KEGG信号通路富集。

, figureFileSmall=ZBMOuunUBarRi8pxHT037Q==, figureFileBig=Jc3BrXfxdpSCiBuak/A9MA==, tableContent=null), ArticleFig(id=1322608114428400538, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=EN, label=Figure 4, caption=Effects of β-Carotene on serum UA, CRE, BUN and inflammatory cytokines in HUA mice, figureFileSmall=3d2hrmmukQ5tvWEBbHy62w==, figureFileBig=BP52OV5m5ztvugCdnmH9Uw==, tableContent=null), ArticleFig(id=1322608114491315099, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=CN, label=图4, caption=β-胡萝卜素对HUA小鼠血清尿酸、肌酐和尿素氮及炎性因子水平的影响

注:图A血清尿酸水平;图B血清肌酐水平;图C血尿尿素氮水平;图D ELISA检测肾组织中IL-1β水平;图E 肾组织中IL-18水平;与正常组相比,**P<0.01;与模型组相比,#P<0.05,##P<0.01。

, figureFileSmall=3d2hrmmukQ5tvWEBbHy62w==, figureFileBig=BP52OV5m5ztvugCdnmH9Uw==, tableContent=null), ArticleFig(id=1322608114562618268, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=EN, label=Figure 5, caption=Effect of β-Carotene on renal histopathology in HUA mice, figureFileSmall=QywvcCrW1SDpiW9fS8uWTg==, figureFileBig=or7Q2vJO+FmbwMO/8qdwSQ==, tableContent=null), ArticleFig(id=1322608114638115741, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=CN, label=图5, caption=β-胡萝卜素对HUA小鼠肾脏组织病理学变化的影响

注:图A小鼠肾组织;图B肾组织HE染色(×200);绿色圈代表肾小球,黑色箭头代表肾小管。

, figureFileSmall=QywvcCrW1SDpiW9fS8uWTg==, figureFileBig=or7Q2vJO+FmbwMO/8qdwSQ==, tableContent=null), ArticleFig(id=1322608114709418910, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=EN, label=Figure 6, caption=Effect of β-Carotene on NLRP3 inflammasome activation, figureFileSmall=jotaTN5dMtk7WnaPl/UnAQ==, figureFileBig=9Ghv3kj+WAh2eq8ZLnyqMA==, tableContent=null), ArticleFig(id=1322608114797499295, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1322608105830077279, language=CN, label=图6, caption=β-胡萝卜素对NLRP3炎症小体激活的影响

注:图A免疫组化染色法检测肾组织中NLRP3表达水平图(×200);图B NLRP3蛋白阳性染色百分比;图C Western blot检测肾组织中NLRP3、ASC和cleaved-Caspase1的表达水平;图D蛋白表达量灰度比值;与正常组相比,**P<0.01;与模型组相比,#P<0.05,##P<0.01。

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网络药理学联合实验验证β-胡萝卜素抑制NLRP3炎症小体活化改善高尿酸血症肾损伤
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杜瑛培 1 , 王薇薇 1 , 卢震坤 2 , 周佳莹 2
现代预防医学 | 实验技术及其应用 2025,52(21): 4001-4008
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现代预防医学 |实验技术及其应用 2025 , 52 (21) : 4001 -4008
网络药理学联合实验验证β-胡萝卜素抑制NLRP3炎症小体活化改善高尿酸血症肾损伤
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杜瑛培1, 王薇薇1, 卢震坤2, 周佳莹2
作者信息
  • 1.青岛市第八人民医院药学部,山东 青岛 266000
  • 2.青岛市公共卫生临床中心药剂科,山东 青岛 266000
通讯作者:
周佳莹,E-mail:
作者简介:

杜瑛培(1988—),女,硕士,主管药师,研究方向:药理学

Network pharmacology and experimental validation of β-carotene in alleviating hyperuricemic renal injury via suppressing NLRP3 inflammasome activation
Ying-pei DU1, Wei-wei WANG1, Zhen-kun LU2, Jia-ying ZHOU2
Affiliations
  • Department of Pharmacy, The Eighth People’s Hospital of Qingdao, Qingdao, Shandong 266000, China
出版时间: 2025-11-10 doi: 10.20043/j.cnki.MPM.202506411
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目的

利用网络药理学结合小鼠高尿酸血症(hyperuricemia,HUA)模型验证,探索β-胡萝卜素治疗HUA的潜在作用靶点及机制。

方法

利用中药系统药理学数据库和分析平台(Traditional Chinese Medicine Systems Pharmacology Database,TCMSP)、CTDbase和Swiss Target Prediction数据库获取β-胡萝卜素的相关靶点,在GeneCards、Digsee和DisGeNET数据库中获取HUA治疗靶点。通过维恩图分析获得β-胡萝卜素相关靶点与HUA疾病靶点的重叠靶点,构建蛋白质-蛋白质相互作用(protein-protein interactions,PPI)网络。对所得交集靶点进行基因本体(gene ontology,GO)与京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)富集分析。C57BL/6小鼠分为五组:正常组、HUA(模型组)、阳性药别嘌醇(62.5 mg/kg)组、20 mg/kg β-胡萝卜素组和40 mg/kg β-胡萝卜素组。除正常组外,所有组均用氧嗪酸钾和次黄嘌呤诱导构建HUA模型。采用生化试剂盒测定血清尿酸、尿素氮和肌酐水平。用苏木精-伊红(hematoxylin-eosin,HE)染色法观察肾组织损伤情况。应用酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)试剂盒检测白介素-1β(interleukin-1 β,IL-1β)和IL-18的水平。采用western blot检测NOD样受体蛋白3(NOD-like receptor protein 3,NLRP3)、凋亡相关斑点样蛋白(apoptosis-related spotted protein,ASC)和活化的半胱氨酸天冬氨酸蛋白酶-1(cleaved-Caspase-1)蛋白表达水平。免疫组织化学染色法观察肾组织中NLRP3表达水平。

结果

通过254个β-胡萝卜素相关靶点和170个HUA相关靶点的匹配,得到15个重叠靶点基因。KEGG富集结果显示,β-胡萝卜素治疗HUA主要涉及炎症和细胞凋亡通路,其中NLRP3炎性小体富集最显著。与模型组相比,20 mg/kg β-胡萝卜素和40 mg/kg β-胡萝卜素均显著降低HUA小鼠血清尿酸(F=119.3,P<0.01)、尿素氮(F=112.7,P<0.01)和肌酐(F=80.76,P<0.01)水平,减轻HUA小鼠肾脏损伤,降低肾组织中IL-1β(F=97.8,P<0.01)和IL-18(F=137.0,P<0.01)水平,下调NLRP3(F=178.4,P<0.01)、ASC(F=392.5,P<0.01)和cleaved-Caspase1(F=171.6,P<0.01)表达水平。

结论

β-胡萝卜素减轻HUA小鼠肾脏损伤,降低炎性反应,其机制可能与抑制NLRP3炎症小体的活化有关。

β-胡萝卜素  /  高尿酸血症  /  IL-1β  /  IL-18  /  NLRP3
Objective

To explore the potential targets and mechanisms of β-carotene in the treatment of hyperuricemia (HUA) by integrating network pharmacology analysis with in vivo mouse experiments.

Methods

Targets related to β-carotene were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), CTDbase, and Swiss Target Prediction databases. Therapeutic targets for HUA were obtained from the GeneCards, DigSee, and DisGeNET databases. Venn diagram analysis was used to identify overlapping targets between β-carotene-related targets and HUA disease targets, and a protein-protein interaction (PPI) network was constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the identified overlapping targets. C57BL/6 mice were divided into 5 groups: normal group, HUA (model group), positive control allopurinol (62.5 mg/kg) group, 20 mg/kg β-carotene group, and 40 mg/kg β-carotene group. Except for the control group, all other groups were induced to establish the HUA mouse model using potassium oxonate and hypoxanthine. Serum levels of uric acid (UA), urea nitrogen (BUN), and creatinine (CRE) were measured using biochemical assay kits. Renal tissue injury was observed using hematoxylin-eosin (H&E) staining.Levels of interleukin-1β (IL-1β) and IL-18 were detected using enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used to detect protein expression levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and cleaved Caspase-1. Immunohistochemical staining was used to observe NLRP3 expression levels in renal tissue.

Results

Matching 254 β-carotene-related targets with 170 HUA-related targets yielded 15 overlapping β-carotene-HUA target genes. KEGG enrichment indicated that β-carotene primarily treated HUA by involving inflammation and apoptosis pathways, with NLRP3 inflammasome enrichment being the most significant. Compared to the model group, both 20 mg/kg β-carotene and 40 mg/kg β-carotene significantly reduced serum UA (F=119.3, P<0.01), BUN (F=112.7, P<0.01), and CRE (F=80.76, P<0.01) levels in HUA mice, alleviated renal injury, decreased renal tissue levels of IL-1β (F=97.8, P<0.01) and IL-18(F=137.0, P<0.01), and downregulated the expression levels of NLRP3 (F=178.4, P<0.01), ASC (F=392.5, P<0.01), and cleaved-Caspase-1 (F=171.6, P<0.01).

Conclusion

β-Carotene can alleviate renal injury and reduce inflammatory responses in HUA mice. Its mechanism may be associated with inhibiting the activation of the NLRP3 inflammasome.

β-Carotene  /  Hyperuricemia  /  IL-1β  /  IL-18  /  NLRP3
杜瑛培, 王薇薇, 卢震坤, 周佳莹. 网络药理学联合实验验证β-胡萝卜素抑制NLRP3炎症小体活化改善高尿酸血症肾损伤. 现代预防医学, 2025 , 52 (21) : 4001 -4008 . DOI: 10.20043/j.cnki.MPM.202506411
Ying-pei DU, Wei-wei WANG, Zhen-kun LU, Jia-ying ZHOU. Network pharmacology and experimental validation of β-carotene in alleviating hyperuricemic renal injury via suppressing NLRP3 inflammasome activation[J]. Modern Preventive Medicine, 2025 , 52 (21) : 4001 -4008 . DOI: 10.20043/j.cnki.MPM.202506411
血清尿酸(uric acid)水平过高或排泄减少会导致高尿酸血症(hyperuricemia,HUA),因此减少血清尿酸的产生和促进患者排泄血清尿酸是治疗HUA的关键[1]。但别嘌呤醇、苯溴马隆和雷西纳德在内的临床治疗药物,常伴有副作用,不适合长期使用。因此,迫切需要找到有效、更安全的治疗HUA的候选药物。β-胡萝卜素是一种天然的脂溶性抗氧化剂,研究表明其对包括癌症、心血管疾病、囊性纤维化以及支气管扩张在内的多种疾病具有一定治疗功效[2]。有文献证实β-胡萝卜素的摄入可能对预防HUA有益[3-4],但β-胡萝卜素用于治疗HUA缺乏实验研究结果支撑。
NOD样受体蛋白3(NOD-like receptor protein 3,NLRP3)炎性小体是免疫系统的重要组成部分,在机体的炎症反应和免疫反应中发挥着重要作用。NLRP3炎性小体的活化导致半胱天冬酶-1(Caspase-1)的裂解,形成活化形式的Caspase-1(cleaved-Caspase-1),其随后促进白介素-1β(interleukin-1β,IL-1β)和IL-18的成熟和释放,参与炎症反应过程[5-6]。HUA患者体内高浓度的可溶性血清尿酸激活NLRP3炎性小体,从而诱发炎症反应[7]。抑制NLRP3炎症小体可减轻HUA小鼠的肾脏炎症反应,降低血清尿酸、尿素氮(urea nitrogen)和肌酐(creatinine)水平[8]。此外,抑制NLRP3/Caspase-1通路可降低促炎细胞因子水平、减轻HUA小鼠肾脏组织中肾小管上皮细胞的凋亡[9]。β-胡萝卜素在其他疾病中的研究与抑制NLRP3炎性小体相关,但β-胡萝卜素对HUA肾脏组织中NLRP3炎性小体的影响未见报道[10]。
本研究通过网络药理学预测了β-胡萝卜素治疗HUA的可能机制,并利用HUA小鼠模型证实了β-胡萝卜素可降低血清尿酸、尿素氮和肌酐水平和炎性因子IL-1β、IL-18水平,抑制肾组织中NLRP3炎性小体的激活。
氧嗪酸钾(货号:E0353)、次黄嘌呤(货号:S2424)、β-胡萝卜素(货号:S1767,C40H56,≥98%)和别嘌醇(货号:S1630)由Selleck公司提供;血清尿酸(货号:C012-2-1)、尿素氮(货号:C013-2-1)和肌酐(货号:C011-2-1)检测试剂盒购自南京建成生物工程研究所;鼠源IL-18和IL-1β的酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)试剂盒购自碧云天生物技术有限公司;兔抗小鼠NLRP3(货号:ab270449)、ASC(货号:ab309497)、GAPDH(货号:ab8245)一抗和山羊抗兔IgG二抗(货号:ab6721)由Abcam公司提供;cleaved-Caspase1(货号:HY-P80622)一抗由MedChemExpress公司提供;IX81倒置显微镜(日本Olympus公司);微型垂直电泳槽、电泳仪(美国 Bio-Rad 公司);Tanon5200 化学发光凝胶成像系统(上海天能科技有限公司)。雄性C57BL/6小鼠[(20±2)g,4 w]购买自常州卡文斯实验动物有限公司。
以β-胡萝卜素为关键词,在中药系统药理学数据库和分析平台(Traditional Chinese Medicine Systems Pharmacology Database,TCMSP)进行检索,以生物利用度(oral bioavailability,OB)≥30%和药物相似性≥0.18为筛选标准,借助UniProt数据库(https://www.uniprot.org/)进行靶点蛋白的转化以及非人源靶点的剔除。
以“Hyperuricemia”为关键词检索GeneCards(www.genecards.org/)、Digsee(http://digsee.com/)和DisGeNET(www.disgenet.org/)数据库,删除重复值,获得HUA相关基因。用R编程语言(版本4.0.3)分析这两个基因集,以确定β-胡萝卜素-HUA的共同靶标。
取β-胡萝卜素靶点与HUA靶点的交集,输入STRING数据库(https://www.stringdb.org/),选择相互作用评分大于0.7的靶点基因构建相互作用网络。使用 Cytoscape 软件(版本3.8.0版)可视化PPI网络。使用CytoNCA(Cytoscape软件编程)筛选出核心基因。
使用OmicShare(https://www.OmicShare.com/tools/home/soft/getsoft)提供的基于基因本体(gene ontology,GO)(http://geneontology.org/)和京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)(https://www.KEGG.jp/KEGG/pathway.html)的工具对1.4筛选的核心基因进行功能和途径富集分析,并选取排序前20位的生物学过程、细胞组成、分子功能及通路信息进行制图展示。
C57BL/6小鼠在恒温(24±1)°C和12/12 h光暗循环条件下适应性喂养7 d。小鼠随机分为五组(每组10只): 正常组、HUA(模型组)、阳性药别嘌醇(62.5 mg/kg)组[11]、20 mg/kg β-胡萝卜素组和40 mg/kg β-胡萝卜素组。除正常组外,所有小鼠均腹腔注射100 mg/kg氧嗪酸钾、灌胃500 mg/kg次黄嘌呤,氧嗪酸钾及次黄嘌呤剂量选择参考文献[12-14],正常组灌胃并腹腔注射相应体积0.3% CMC-Na溶液。氧嗪酸钾与黄嘌呤均溶于0.3% CMC-Na溶液中,连续14 d造模。在给药前,从正常组和模型组中随机选择3只小鼠,测定并比较其血清
血清尿酸水平,以确保HUA小鼠模型建立成功(模型组血清尿酸水平高于正常组2倍)。随后,阳性药组每天灌胃给予62.5 mg/kg别嘌醇,β-胡萝卜素组小鼠分别每天灌胃给与20、40 mg/kg β-胡萝卜素,小鼠连续给药14 d。别嘌醇和β-胡萝卜素混悬于溶剂(配方:10 ml/L DMSO + 40 ml/L PEG400 +5 ml/L Tween-80 + 45 ml/L生理盐水)[15]。模型组和正常组灌胃相应体积溶剂,β-胡萝卜素的剂量根据预试验实验结果结合文献确定[16]。本实验研究获得了青岛市第八人民医院动物实验伦理委员会的批准(审批号:IACUC-2022-11-08)。
小鼠禁食过夜后,用玻璃毛细采血管行小鼠眼眶取血,4°C、1 000 ×g离心10 min,获得血清。采集肾脏,4%多聚甲醛固定部分肾脏用于病理检测,其余肾脏取材后立即-80℃保存用于ELISA检测。试剂盒测定血清中的血清尿酸、尿素氮和肌酐水平。ELISA试剂盒用于检测肾组织中IL-1β 和IL-18水平。
肾脏用石蜡包埋并切成4 μm的切片。切片放入二甲苯中浸泡两次,每次10 min。切片依次在无水乙醇、95%、85%、70%乙醇中浸泡5 min,使组织水化。之后,切片滴加苏木素染色液染色10 min,蒸馏水洗去多余染液,用1%盐酸乙醇分化,再用双蒸水洗净。加入弱碱性促蓝液使细胞核染蓝色,清洗后切片冲洗干净。切片浸泡在伊红染色液中2 min后依次在95%和100%酒精中浸泡5 min。用封片胶将切片与封片粘合,显微镜下观察染色结果。
使用RIPA裂解液对肾脏组织进行裂解处理并提取总蛋白,用BCA蛋白浓度测定试剂盒对提取的蛋白进行浓度测定。将变性后的蛋白样本上样到SDS-PAGE凝胶上,进行电泳。电泳结束后,用湿转法进行转膜。转膜结束后,将PVDF膜与NLRP3、ASC、cleaved-Caspase1或GAPDH一抗抗体在4℃下孵育过夜。一抗孵育结束后,将膜用TBST缓冲液清洗3次加入对应的HRP标记的二抗工作液,在室温下孵育1 h。将膜用TBST缓冲液清洗3次。将化学发光底物均匀滴加到膜上,并在暗室中用X胶片进行曝光和显影。
石蜡包埋的肾脏切片用二甲苯脱石蜡,再用不同浓度的酒精脱水。切片封闭处理后,将NLRP3一抗与切片进行孵育。将二抗滴加在切片上进行孵育,孵育结束后,PBS缓冲液清洗切片。使用DAB显色剂对切片进行显色处理,使用苏木素染料对切片进行复染。复染后,使用封片剂对切片进行封片。显微镜下观察切片染色情况,分析NLRP3蛋白在肾组织中的表达水平,根据阳性细胞数量行半定量分析。
数据统计分析软件使用SPSS 22.0,并以()表示,多组间比较采用单因素方差分析(ANOVA),组间两两比较采用Tukey检验。检验水准α=0.05。
在TCMSP、CTDbase和Swiss Target Prediction数据库中,以β-胡萝卜素为关键词,检索出254个作用靶点。在GeneCards、Digsee和DisGeNET数据库中,检索出170个HUA相关基因。两种检索结果取交集,获得15个共有基因。见图1。
将15个共有基因信息输入STRING数据库,构建各靶点间的PPI网络,见图2。结果表明,这15个基因间共涉及15个节点和86条边,各靶点之间存在较强的相关性,置信度评分≥0.4。经最大集团中心度(maximal clique centrality,MCC)算法筛选1次,白蛋白(albumin)、IL-1β、氧化物酶体增殖因子活化受体A(peroxisome proliferator-activated receptor A,PPARA)、环氧酶2(cyclooxygenase 2)等节点度值较高,其可能为β-胡萝卜素治疗HUA的关键靶点。
对15个共有基因进行KEGG通路及GO基因富集分析。生物过程(biological process,BP)在尿酸代谢、炎症反应调节、循环系统中的血管过程和小分子代谢过程的调控等方面显著富集,见图3A。细胞组分(cell components)在脂蛋白颗粒、蛋白-脂质复合体、细胞顶端、顶端质膜等方面显著富集,见图3B。分子功能(molecular function)在脂蛋白颗粒受体结合、跨膜转运蛋白活性、单糖结合、蛋白结合等方面显著富集,见图3C。此外,KEGG富集分析表明,15个基因在多个通路中富集,包括核因子-κB(nuclear factor-κB,NF-κB)、肿瘤坏死因子(tumor necrosis factor,TNF)、单磷酸腺苷活化的蛋白激酶(adenosine monophosphate- activated protein kinase,AMPK)、叉头转录因子(forkhead transcription factor,FOXO)、Toll样受体(toll-like receptors,TLR)、丝裂原激活的蛋白激酶(mitogen-activated protein kinase,MAPK)、低氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)、磷脂酰肌醇-3-激酶/蛋白激酶B(phosphatidylinositol -3-kinase/protein kinase B,PI3K/AKT)和NLRP3炎性小体等。其中,NLRP3炎性小体信号通路富集最为明显,见图3D。
如图4A所示,模型组小鼠血清尿酸、肌酐和尿素氮水平明显高于正常组,见图3A~C。与模型组相比,阳性药和不同剂量β-胡萝卜素均能显著降低模型组小鼠血清尿酸、肌酐和尿素氮水平。与模型组相比,β-胡萝卜素显著降低肾脏炎性因子IL-1β和IL-18水平,见图4D、E。
正常组小鼠肾脏外观光滑,颜色红润,质地柔软,形态饱满。模型组小鼠肾脏颜色由红润变为棕黄色,肾脏表面出现颗粒状或结节状突起。与模型组相比,40 mg/kg β-胡萝卜素组和阳性药组小鼠肾脏质地和颜色趋于恢复正常,见图5A。模型小鼠的肾脏则呈现出明显的病理特征:肾小球发生萎缩,肾小管扩张,见图5B。在20 mg/kg β-胡萝卜素组中,肾小球和肾小管病变有所改善,但效果尚不全面。40 mg/kg β-胡萝卜素和阳性药组小鼠肾小球结构较完整,肾小管扩张程度减轻。
免疫组化染色实验结果表明,与模型相比,β-胡萝卜素能显著降低HUA小鼠肾组织中NLRP3表达水平,见图6A、B。Western blot实验证实β-胡萝卜素显著降低肾组织NLRP3,ASC和cleaved-caspase1表达水平,见图6C、D。
本研究通过整合网络药理学预测与动物实验验证,阐明了β-胡萝卜素改善HUA肾损伤的作用机制。网络药理学分析揭示,β-胡萝卜素与HUA的15个共同作用靶点中,NLRP3炎症小体通路富集最为显著,提示其可能是β-胡萝卜素干预HUA的核心环节。这一预测在体内实验中得到充分验证:β-胡萝卜素不仅能有效降低HUA小鼠血清尿酸、肌酐和尿素氮水平,减轻肾脏病理损伤,还可显著抑制肾组织NLRP3、ASC及cleaved-Caspase-1的蛋白表达,同时抑制IL-1β和IL-18的释放。这些结果共同表明,β-胡萝卜素通过靶向抑制NLRP3炎症小体活化,阻断炎性级联反应,从而改善HUA肾损伤。
已有文献报道β-胡萝卜素水平升高与HUA发病率减少,β-胡萝卜素还能减轻急性肾损伤模型小鼠肾脏组织中氧化应激[17-18];上述研究提示通过饮食或补充剂的形式摄入β-胡萝卜素,可能是一种有效且安全的HUA治疗策略,但β-胡萝卜素对于HUA的作用尚不明确。网络药理学基于其系统性与整体性的特点,为探究化合物作用于疾病的分子机制提供了新思路,这一方法可提高药物靶点发现的效率。本文采用网络药理学对β-胡萝卜素治疗HUA的作用机制进行了初步探究。为阐明其分子机制,利用β-胡萝卜素和HUA的共同潜在靶点构建PPI网络。KEGG信号通路富集分析提示,β-胡萝卜素治疗HUA的机制主要涉及多条炎症信号通路,包括NF-κB、TNF、AMPK、FoxO、TLR、MAPK、HIF-1、PI3K/AKT和NLRP3炎性小体等。其中NLRP3炎性小体富集最显著,提示β-胡萝卜素可能通过调控NLRP3炎性小体来发挥治疗HUA作用。
NLRP3炎性小体作为固有免疫系统的一个核心组成部分,在机体的免疫反应调控及疾病发生与发展过程中扮演重要角色。其主要包括三个结构域,NLRP3、ASC和cleaved-Caspase1。NLRP3炎症小体在HUA相关肾损伤中的关键作用已被广泛证实,高尿酸诱导其激活与血清尿酸、尿素氮、肌酐升高及肾组织病理损伤高度相关[19-21]。本研究结果显示,β-胡萝卜素能够显著降低HUA小鼠血清中的尿酸、尿素氮和肌酐水平,病理学分析也显示β-胡萝卜素对HUA小鼠肾组织中肾小球体积缩小、结构不规则以及肾小管水肿等病理学变化有一定的减轻功效,提示其改善肾功能的[22]。尤为重要的是,β-胡萝卜素能够显著降低HUA小鼠肾脏组织中NLRP3、ASC和cleaved-Caspase-1的蛋白表达水平,从而有效抑制NLRP3炎症小体的活化,减轻肾脏炎症反应,这与葛鑫等[23]报道的β-胡萝卜素通过抑制NLRP3减轻金黄色葡萄球菌性乳腺炎,以及异丙肾上腺素诱导心肌纤维化模型中β-胡萝卜素下调NLRP3表达的研究逻辑一致[24],提示β-胡萝卜素的抗炎作用机制可能与其对NLRP3炎症小体的调控密切相关。此外,二氢小檗碱阻断NLRP3炎性小体缓解HUA肾损伤[25],以及黄芩苷通过干预NLRP3/Caspase-1通路减轻造影剂急性肾损伤的最新证据[26],也为β-胡萝卜素以NLRP3为核心靶点的改善HUA肾损伤提供了间接佐证。作为天然抗氧化剂,β-胡萝卜素可能通过清除活性氧(reactive oxygen,ROS)阻断NLRP3的氧化应激激活,或直接调控NF-κB等上游靶点(如PPI网络中的核心靶点TNF)间接抑制NLRP3炎症小体组装[27]。值得注意的是,除NLRP3通路外,KEGG富集分析还提示AMPK、TLR等通路可能参与调控,暗示β-胡萝卜素的作用具有多靶点协同特性。
尽管本研究揭示了β-胡萝卜素对HUA的治疗作用及其潜在机制,但仍有一些问题需要进一步探讨。一方面,β-胡萝卜素对NLRP3炎症小体的具体调控机制尚不完全清楚,未来研究可以深入探讨其分子机制,包括其是否通过直接作用于NLRP3蛋白或其上游信号通路来抑制炎症小体的活化。另一方面,β-胡萝卜素在不同剂量下的治疗效果和安全性需要进一步评估,以确定其最佳治疗[28]。此外,β-胡萝卜素在人类临床试验中的疗效和安全性也需要进一步验证。
综上所述,本研究通过网络药理学和体内实验验证,揭示了β-胡萝卜素对HUA小鼠肾脏损伤的保护作用及其潜在机制。这些发现不仅为β-胡萝卜素作为一种新型HUA治疗药物提供了实验依据,也为未来的研究提供了新的方向。
  • 山东省重大科技创新工程项目(2019JZZY011121)
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doi: 10.20043/j.cnki.MPM.202506411
  • 接收时间:2025-06-24
  • 首发时间:2026-10-29
  • 出版时间:2025-11-10
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  • 收稿日期:2025-06-24
基金
山东省重大科技创新工程项目(2019JZZY011121)
作者信息
    1.青岛市第八人民医院药学部,山东 青岛 266000
    2.青岛市公共卫生临床中心药剂科,山东 青岛 266000

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周佳莹,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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