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Article(id=1190669171034832906, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1190669163988398295, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.1207.2024.1227, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1722873600000, receivedDateStr=2024-08-06, revisedDate=null, revisedDateStr=null, acceptedDate=1729612800000, acceptedDateStr=2024-10-23, onlineDate=1761807251938, onlineDateStr=2025-10-30, pubDate=1745769600000, pubDateStr=2025-04-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1761807251938, onlineIssueDateStr=2025-10-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1761807251938, creator=13701087609, updateTime=1761807251938, updator=13701087609, issue=Issue{id=1190669163988398295, tenantId=1146029695717560320, journalId=1189873630562394117, year='2025', volume='50', issue='4', pageStart='367', pageEnd='503', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1761807250258, creator=13701087609, updateTime=1761807667423, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1190670913772339410, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1190669163988398295, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1190670913772339411, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1190669163988398295, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=475, endPage=482, ext={EN=ArticleExt(id=1190669171273908235, articleId=1190669171034832906, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Effect of mangiferin on hSOD1G93A-induced pyroptosis in mice via activating Nrf2/HO-1 signaling pathway, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To explore the effect of mangiferin (MF) on pyroptosis in an amyotrophic lateral sclerosis (ALS) cell model by regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway. Methods (1)Mouse NSC-34 cell lines transfected with hSOD1WT and hSOD1G93A plasmids were randomly divided into blank group, model group, MF (100 μmol/L) group, MF (200 μmol/L) group. MF was added into the culture plate for 24 hours. Cell viability was assessed using CCK-8 kit. Lactate dehydrogenase (LDH) release was measured using LDH cytotoxicity detection kit. Levels of inflammatory factors interleukin (IL)-1β and IL-18 in cell supernatant were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Nrf2, HO-1, NADPH quinone oxidoreductase-1 (NQO-1), NOD-like receptor protein 3 (NLRP3), gasdermin D (GSDMD)-N and caspase-1 was detected by Western blotting. (2)Mouse hSOD1G93A NSC-34 cells were randomly divided into model group, MF(200 μmol/L) group, Nrf2-siRNA group and Nrf2-siRNA+MF(200 μmol/L) group. The cells were transiently transfected with Nrf2-siRNA using LipofectamineTM 3000. Western blotting was used to detect the protein expression levels of Nrf2, HO-1, NQO-1, NLRP3, caspase-1 and GSDMD-N. Results (1) The results of the CCK-8 assay showed that after the hSOD1G93A NSC-34 cells were treated with MF at concentrations of 300 μmol/L and below for 24 hours, the changes in cell viability were not significant (P>0.05). Compared with blank group, the release of LDH, the contents of IL-1β and IL-18 in the cell culture supernatant of model group were increased (P<0.001); the protein expression levels of Nrf2, HO-1, and NQO-1 were decreased (P<0.05 or P<0.01); the protein expression levels of NLRP3, caspase-1, and GSDMD-N were increased (P<0.05 or P<0.01 or P<0.001). Compared with model group, the release of LDH, the contents of IL-18 and IL-1β in the culture supernatant in MF(100 μmol/L) and MF(200 μmol/L) groups were decreased (P<0.001); the protein expression levels of NLRP3, caspase-1 and GSDMD-N were decreased (P<0.05 or P<0.001), and the expression levels of Nrf2, HO-1 and NQO-1 were increased (P<0.05 or P<0.01). (2) Compared with model group, the protein expession levels of Nrf2, NO-1 and NQO-1 were increased (P<0.05 or P<0.001) in MF(200 μmol/L) group, while the protein expression levels of NLRP3, caspase-1 and GSDMD-N were decreased (P<0.001); the protein expression levels of Nrf2 and HO-1 were decreased in Nrf2-siRNA group (P<0.01 or P<0.001), while the protein expression levels of NLRP3, caspase-1 and GSDMD-N were increased (P<0.001). Compared with Nrf2-siRNA group, the protein expression levels of Nrf2, HO-1 and NQO-1 in Nrf2-siRNA+MF(200 μmol/L) group were increased (P<0.01 or P<0.001), and the protein expression levels of NLRP3, caspase-1 and GSDMD-N were decreased (P<0.001). Conclusion MF can inhibit pyroptosis in the ALS cell model through Nrf2/HO-1 signaling pathway, playing a protective role.

, correspAuthors=Xu-Sheng Huang, authorNote=null, correspAuthorsNote=
E-mail:
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目的 探究芒果苷(MF)调控核因子E2相关因子2/血红素氧合酶-1(Nrf2/HO-1)信号通路对肌萎缩性侧索硬化(ALS)细胞模型焦亡的影响。方法 (1)转染hSOD1WT质粒和hSOD1G93A质粒的NSC-34细胞系，随机分为空白组、模型组、MF(100 μmol/L)组、MF(200 μmol/L)组；采用MF处理细胞24 h。使用CCK-8法检测细胞活力；乳酸脱氢酶(LDH)细胞毒性检测试剂盒检测LDH释放量；ELISA法检测培养上清液中白细胞介素(IL)-1β和IL-18的含量；Western blotting检测Nrf2、HO-1、NADPH醌氧化还原酶(NQO-1)、NOD样受体蛋白3(NLRP3)、gasdermin D(GSDMD)-N、胱天蛋白酶-1(caspase-1)的表达水平。(2)小鼠hSOD1G93A NSC-34细胞随机分为模型组、MF(200 μmol/L)组、Nrf2-siRNA组、Nrf2-siRNA+MF(200 μmol/L)组，采用LipofectamineTM 3000瞬时转染Nrf2-siRNA，Western blotting检测Nrf2、HO-1、NQO-1、NLRP3、caspase-1和GSDMD-N蛋白的表达水平。结果 (1)CCK-8法检测结果显示，300 μmol/L及以下浓度MF处理24 h后，hSOD1G93A NSC-34细胞活力无明显变化(P>0.05)。与空白组比较，模型组细胞培养上清液中LDH释放量及IL-1β和IL-18含量增加(P<0.001)，Nrf2、HO-1和NQO-1蛋白表达水平下降(P<0.05或P<0.01)，NLRP3、caspase-1和GSDMD-N蛋白表达水平升高(P<0.05或P<0.01或P<0.001)。与模型组比较，MF(100 μmol/L)组和MF(200 μmol/L)组细胞培养上清液中LDH释放量、IL-18和IL-1β含量减少(P<0.001)，NLRP3、caspase-1、GSDMD-N蛋白表达水平降低(P<0.05或P<0.001)，Nrf2、HO-1和NQO-1蛋白表达水平升高(P<0.05或P<0.01)。(2)与模型组比较，MF(200 μmol/L)组小鼠hSOD1G93A NSC-34细胞中Nrf2、HO-1和NQO-1蛋白表达水平明显升高(P<0.05或P<0.001)，NLRP3、caspase-1和GSDMD-N蛋白表达水平明显降低(P<0.001)；Nrf2-siRNA组细胞中Nrf2、HO-1蛋白表达水平降低(P<0.01或P<0.001)，而NLRP3、caspase-1和GSDMD-N蛋白表达水平升高(P<0.001)。与Nrf2-siRNA组比较，Nrf2-siRNA+MF(200 μmol/L)组细胞中Nrf2、HO-1和NQO-1蛋白表达水平升高(P<0.01或P<0.001)，NLRP3、caspase-1和GSDMD-N蛋白表达水平降低(P<0.001)。结论 MF可通过Nrf2/HO-1信号通路抑制ALS细胞模型焦亡，发挥细胞保护作用。

, correspAuthors=黄旭升, authorNote=null, correspAuthorsNote=
黄旭升， E-mail：
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苏博洋，医学硕士，主要从事肌萎缩侧索硬化方面的研究

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苏博洋，医学硕士，主要从事肌萎缩侧索硬化方面的研究

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苏博洋，医学硕士，主要从事肌萎缩侧索硬化方面的研究

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Nat Commun, 2016, 7: 11624., articleTitle=Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription, refAbstract=null), Reference(id=1190669424177857430, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, doi=null, pmid=null, pmcid=null, year=2021, volume=2021, issue=null, pageStart=9925561, pageEnd=null, url=null, language=null, rfNumber=[29], rfOrder=28, authorNames=Xiao L, Dai Z, Tang W, journalName=Oxid Med Cell Longev, refType=null, unstructuredReference=Xiao L, Dai Z, Tang W, et al. Astragaloside Ⅳ alleviates cerebral ischemia-reperfusion injury through NLRP3 inflammasome-mediated pyroptosis inhibition via activating Nrf2[J]. 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Neurochem Res, 2023, 48(1): 172-187., articleTitle=Role of transcription factor Nrf2 in pyroptosis in spinal cord injury by regulating GSDMD, refAbstract=null), Reference(id=1190669424320463768, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, doi=null, pmid=null, pmcid=null, year=2024, volume=397, issue=5, pageStart=3065, pageEnd=3075, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=Shi YS, Zhang Y, Luo X, journalName=Naunyn Schmiedebergs Arch Pharmacol, refType=null, unstructuredReference=Shi YS, Zhang Y, Luo X, et al. 1,7-diphenyl-4-hepten-3-one mitigates Alzheimer's-like pathology by inhibiting pyroptosis via activating the Nrf2 pathway[J]. Naunyn Schmiedebergs Arch Pharmacol, 2024, 397(5): 3065-3075., articleTitle=1,7-diphenyl-4-hepten-3-one mitigates Alzheimer's-like pathology by inhibiting pyroptosis via activating the Nrf2 pathway, refAbstract=null), Reference(id=1190669424391766937, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, doi=null, pmid=null, pmcid=null, year=2016, volume=42, issue=5, pageStart=459, pageEnd=474, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=Saha S, Sadhukhan P, Sil PC, journalName=Biofactors, refType=null, unstructuredReference=Saha S, Sadhukhan P, Sil PC. Mangiferin: a xanthonoid with multipotent anti-inflammatory potential[J]. 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****P<0.0001

, figureFileSmall=FieR1b02FLcHiPTaa4RDjA==, figureFileBig=4S5iLrPynr8of2WMw0pMIA==, tableContent=null), ArticleFig(id=1190669420251988844, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=EN, label=Fig.3, caption=Effect of mangiferin (MF) on LDH release amount from hSOD1G93A NSC-34 cells, figureFileSmall=C/P/J7uuxSvx4oX9iCqZTg==, figureFileBig=+6t0ey+Wd1luMgmLmAqWfw==, tableContent=null), ArticleFig(id=1190669420306514797, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=CN, label=图3, caption=芒果苷(MF)对hSOD1G93A NSC-34细胞培养上清液中LDH释放量的影响

LDH. 乳酸脱氢酶；***P<0.001

, figureFileSmall=C/P/J7uuxSvx4oX9iCqZTg==, figureFileBig=+6t0ey+Wd1luMgmLmAqWfw==, tableContent=null), ArticleFig(id=1190669420365235054, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=EN, label=Fig.4, caption=Effects of mangiferin (MF) on IL-1β and IL-18 release from hSOD1G93A NSC-34 cells, figureFileSmall=BwOiwsiJ+ghMux4EK/bFFg==, figureFileBig=xDiiUIzwIFX5mLVUaRV4GA==, tableContent=null), ArticleFig(id=1190669420419761007, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=CN, label=图4, caption=芒果苷(MF)对hSOD1G93A NSC-34细胞培养上清液中IL-1β和IL-18含量的影响

IL-1β. 白细胞介素-1β；IL-18. 白细胞介素-18；***P<0.001

, figureFileSmall=BwOiwsiJ+ghMux4EK/bFFg==, figureFileBig=xDiiUIzwIFX5mLVUaRV4GA==, tableContent=null), ArticleFig(id=1190669420491064176, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=EN, label=Fig.5, caption=Effects of mangiferin (MF) on the expression of Nrf2, HO-1, and NQO-1 proteins in hSOD1G93A NSC-34 cells (Western blotting), figureFileSmall=03TkN2DbXz5srCkW3jKP4w==, figureFileBig=FRNraj141oSrtbUf14Z+Yg==, tableContent=null), ArticleFig(id=1190669420549784433, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=CN, label=图5, caption=芒果苷(MF)对hSOD1G93A NSC-34细胞中Nrf2、HO-1、NQO-1蛋白的影响(Western blotting)

Nrf2. 核因子E2相关因子2；PCNA. 增殖细胞核抗原；HO-1. 血红素氧合酶-1；NQO-1. NADPH醌氧化还原酶-1；*P<0.05，**P<0.01

, figureFileSmall=03TkN2DbXz5srCkW3jKP4w==, figureFileBig=FRNraj141oSrtbUf14Z+Yg==, tableContent=null), ArticleFig(id=1190669420608504690, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=EN, label=Fig.6, caption=Effect of mangiferin (MF) on the NLRP3/caspase-1/GSDMD pathway in hSOD1G93A NSC-34 cells (Western blotting), figureFileSmall=BNCwA6tvZ93cj0NQw61s4w==, figureFileBig=Ku39QHVxjQNsNFyx9iOy9A==, tableContent=null), ArticleFig(id=1190669420717556595, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=CN, label=图6, caption=芒果苷(MF)对hSOD1G93A NSC-34细胞中NLRP3/caspase-1/GSDMD通路的影响(Western blotting)

NLRP3. NOD样受体蛋白3； GSDMD-N. Gasdermin D蛋白N端片段；caspase-1. 胱天蛋白酶-1；*P<0.05，**P<0.01，***P<0.001

, figureFileSmall=BNCwA6tvZ93cj0NQw61s4w==, figureFileBig=Ku39QHVxjQNsNFyx9iOy9A==, tableContent=null), ArticleFig(id=1190669420784665460, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=EN, label=Fig.7, caption=Expression of Nrf2 mRNA after transfection of Nrf2-siRNA into hSOD1G93A NSC-34 cells, figureFileSmall=kKcgiaDOQgQtFuKx+r/jGQ==, figureFileBig=9NHOD4kO3B+n0saH20hTEg==, tableContent=null), ArticleFig(id=1190669420855968629, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=CN, label=图7, caption=Nrf2-siRNA瞬时转染hSOD1G93A NSC-34细胞后Nrf2 mRNA的表达水平

Nrf2. 核因子E2相关因子2；***P<0.001

, figureFileSmall=kKcgiaDOQgQtFuKx+r/jGQ==, figureFileBig=9NHOD4kO3B+n0saH20hTEg==, tableContent=null), ArticleFig(id=1190669420910494582, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=EN, label=Fig.8, caption=Effects of mangiferin (MF) on Nrf2/HO-1 signaling pathway and the pyroptosis of hSOD1G93A NSC-34 cells (Western blotting), figureFileSmall=6lELDZzXELItbz024saWHA==, figureFileBig=IrXfeB2dXI6vAEbXhSdC6A==, tableContent=null), ArticleFig(id=1190669420969214839, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=CN, label=图8, caption=芒果苷(MF)对Nrf2/HO-1信号通路和hSOD1G93A NSC-34细胞焦亡的影响 (Western blotting)

Nrf2. 核因子E2相关因子2；HO-1. 血红素氧合酶-1；NQO-1. NADPH醌氧化还原酶-1；NLRP3. NOD样受体蛋白3；GSDMD-N. Gasdermin D蛋白N端片段；caspase-1. 胱天蛋白酶-1；*P<0.05，**P<0.01，***P<0.001

, figureFileSmall=6lELDZzXELItbz024saWHA==, figureFileBig=IrXfeB2dXI6vAEbXhSdC6A==, tableContent=null), ArticleFig(id=1190669421023740792, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=EN, label=Tab.1, caption=

Primer sequences for PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
基因上游(5'-3')下游(5'-3')
Nrf2-siRNA1GACCUCCUUAGACUCAAAUAUUUGAGUCUAAGGAGGUC
Nrf2-siRNA2CCGAAUUACAGUGUCUUAAUUAAGACACUGUAAUUCGG
Nrf2-siRNA3CUCGCAUUGAUCCGAGAUAUAUCUCGGAUCAAUGCGAG
GAPDHAGGTCGGTGTGAACGGATTTGTGTAGACCATGTAGTTGAGGTCA
), ArticleFig(id=1190669421082461049, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1190669171034832906, language=CN, label=表1, caption=

PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因上游(5'-3')下游(5'-3')
Nrf2-siRNA1GACCUCCUUAGACUCAAAUAUUUGAGUCUAAGGAGGUC
Nrf2-siRNA2CCGAAUUACAGUGUCUUAAUUAAGACACUGUAAUUCGG
Nrf2-siRNA3CUCGCAUUGAUCCGAGAUAUAUCUCGGAUCAAUGCGAG
GAPDHAGGTCGGTGTGAACGGATTTGTGTAGACCATGTAGTTGAGGTCA
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芒果苷激活Nrf2/HO-1信号通路在hSOD1G93A诱导的小鼠NSC-34细胞焦亡中的作用
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苏博洋 1, 2 , 何正卿 3 , 刘静 4 , 李懋 1, 2 , 黄旭升 1, 2, *
解放军医学杂志 | 基础研究 2025,50(4): 475-482
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解放军医学杂志 | 基础研究 2025, 50(4): 475-482
芒果苷激活Nrf2/HO-1信号通路在hSOD1G93A诱导的小鼠NSC-34细胞焦亡中的作用
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苏博洋1, 2, 何正卿3, 刘静4, 李懋1, 2, 黄旭升1, 2, *
作者信息
  • 1解放军医学院，北京 100853
  • 2解放军总医院第一医学中心神经内科，北京 100853
  • 3首都医科大学附属北京友谊医院神经内科，北京 100050
  • 4解放军总医院第二医学中心老年医学研究所/国家老年疾病临床医学研究中心，北京 100853

    • 苏博洋，医学硕士，主要从事肌萎缩侧索硬化方面的研究

通讯作者:

黄旭升， E-mail：
Effect of mangiferin on hSOD1G93A-induced pyroptosis in mice via activating Nrf2/HO-1 signaling pathway
Bo-Yang Su1, 2, Zheng-Qing He3, Jing Liu4, Mao Li1, 2, Xu-Sheng Huang1, 2, *
Affiliations
  • 1Medical School of Chinese PLA, Beijing 100853, China
  • 2Department of Neurology, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
  • 3Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
  • 4Institute of Geriatrics/National Clinical Research Center of Geriatrics Disease, the Second Medical Center of Chinese PLA General Hospital, Beijing 100853, China
出版时间: 2025-04-28 doi: 10.11855/j.issn.0577-7402.1207.2024.1227
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摘要
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目的 探究芒果苷(MF)调控核因子E2相关因子2/血红素氧合酶-1(Nrf2/HO-1)信号通路对肌萎缩性侧索硬化(ALS)细胞模型焦亡的影响。方法 (1)转染hSOD1WT质粒和hSOD1G93A质粒的NSC-34细胞系，随机分为空白组、模型组、MF(100 μmol/L)组、MF(200 μmol/L)组；采用MF处理细胞24 h。使用CCK-8法检测细胞活力；乳酸脱氢酶(LDH)细胞毒性检测试剂盒检测LDH释放量；ELISA法检测培养上清液中白细胞介素(IL)-1β和IL-18的含量；Western blotting检测Nrf2、HO-1、NADPH醌氧化还原酶(NQO-1)、NOD样受体蛋白3(NLRP3)、gasdermin D(GSDMD)-N、胱天蛋白酶-1(caspase-1)的表达水平。(2)小鼠hSOD1G93A NSC-34细胞随机分为模型组、MF(200 μmol/L)组、Nrf2-siRNA组、Nrf2-siRNA+MF(200 μmol/L)组，采用LipofectamineTM 3000瞬时转染Nrf2-siRNA，Western blotting检测Nrf2、HO-1、NQO-1、NLRP3、caspase-1和GSDMD-N蛋白的表达水平。结果 (1)CCK-8法检测结果显示，300 μmol/L及以下浓度MF处理24 h后，hSOD1G93A NSC-34细胞活力无明显变化(P>0.05)。与空白组比较，模型组细胞培养上清液中LDH释放量及IL-1β和IL-18含量增加(P<0.001)，Nrf2、HO-1和NQO-1蛋白表达水平下降(P<0.05或P<0.01)，NLRP3、caspase-1和GSDMD-N蛋白表达水平升高(P<0.05或P<0.01或P<0.001)。与模型组比较，MF(100 μmol/L)组和MF(200 μmol/L)组细胞培养上清液中LDH释放量、IL-18和IL-1β含量减少(P<0.001)，NLRP3、caspase-1、GSDMD-N蛋白表达水平降低(P<0.05或P<0.001)，Nrf2、HO-1和NQO-1蛋白表达水平升高(P<0.05或P<0.01)。(2)与模型组比较，MF(200 μmol/L)组小鼠hSOD1G93A NSC-34细胞中Nrf2、HO-1和NQO-1蛋白表达水平明显升高(P<0.05或P<0.001)，NLRP3、caspase-1和GSDMD-N蛋白表达水平明显降低(P<0.001)；Nrf2-siRNA组细胞中Nrf2、HO-1蛋白表达水平降低(P<0.01或P<0.001)，而NLRP3、caspase-1和GSDMD-N蛋白表达水平升高(P<0.001)。与Nrf2-siRNA组比较，Nrf2-siRNA+MF(200 μmol/L)组细胞中Nrf2、HO-1和NQO-1蛋白表达水平升高(P<0.01或P<0.001)，NLRP3、caspase-1和GSDMD-N蛋白表达水平降低(P<0.001)。结论 MF可通过Nrf2/HO-1信号通路抑制ALS细胞模型焦亡，发挥细胞保护作用。

肌萎缩侧索硬化  /  芒果苷  /  核因子E2相关因子2  /  细胞焦亡  /  信号通路

Objective To explore the effect of mangiferin (MF) on pyroptosis in an amyotrophic lateral sclerosis (ALS) cell model by regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway. Methods (1)Mouse NSC-34 cell lines transfected with hSOD1WT and hSOD1G93A plasmids were randomly divided into blank group, model group, MF (100 μmol/L) group, MF (200 μmol/L) group. MF was added into the culture plate for 24 hours. Cell viability was assessed using CCK-8 kit. Lactate dehydrogenase (LDH) release was measured using LDH cytotoxicity detection kit. Levels of inflammatory factors interleukin (IL)-1β and IL-18 in cell supernatant were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Nrf2, HO-1, NADPH quinone oxidoreductase-1 (NQO-1), NOD-like receptor protein 3 (NLRP3), gasdermin D (GSDMD)-N and caspase-1 was detected by Western blotting. (2)Mouse hSOD1G93A NSC-34 cells were randomly divided into model group, MF(200 μmol/L) group, Nrf2-siRNA group and Nrf2-siRNA+MF(200 μmol/L) group. The cells were transiently transfected with Nrf2-siRNA using LipofectamineTM 3000. Western blotting was used to detect the protein expression levels of Nrf2, HO-1, NQO-1, NLRP3, caspase-1 and GSDMD-N. Results (1) The results of the CCK-8 assay showed that after the hSOD1G93A NSC-34 cells were treated with MF at concentrations of 300 μmol/L and below for 24 hours, the changes in cell viability were not significant (P>0.05). Compared with blank group, the release of LDH, the contents of IL-1β and IL-18 in the cell culture supernatant of model group were increased (P<0.001); the protein expression levels of Nrf2, HO-1, and NQO-1 were decreased (P<0.05 or P<0.01); the protein expression levels of NLRP3, caspase-1, and GSDMD-N were increased (P<0.05 or P<0.01 or P<0.001). Compared with model group, the release of LDH, the contents of IL-18 and IL-1β in the culture supernatant in MF(100 μmol/L) and MF(200 μmol/L) groups were decreased (P<0.001); the protein expression levels of NLRP3, caspase-1 and GSDMD-N were decreased (P<0.05 or P<0.001), and the expression levels of Nrf2, HO-1 and NQO-1 were increased (P<0.05 or P<0.01). (2) Compared with model group, the protein expession levels of Nrf2, NO-1 and NQO-1 were increased (P<0.05 or P<0.001) in MF(200 μmol/L) group, while the protein expression levels of NLRP3, caspase-1 and GSDMD-N were decreased (P<0.001); the protein expression levels of Nrf2 and HO-1 were decreased in Nrf2-siRNA group (P<0.01 or P<0.001), while the protein expression levels of NLRP3, caspase-1 and GSDMD-N were increased (P<0.001). Compared with Nrf2-siRNA group, the protein expression levels of Nrf2, HO-1 and NQO-1 in Nrf2-siRNA+MF(200 μmol/L) group were increased (P<0.01 or P<0.001), and the protein expression levels of NLRP3, caspase-1 and GSDMD-N were decreased (P<0.001). Conclusion MF can inhibit pyroptosis in the ALS cell model through Nrf2/HO-1 signaling pathway, playing a protective role.

amyotrophic lateral sclerosis  /  mangiferin  /  nuclear factor E2 related factor  /  pyroptosis  /  signaling pathway
苏博洋, 何正卿, 刘静, 李懋, 黄旭升. 芒果苷激活Nrf2/HO-1信号通路在hSOD1G93A诱导的小鼠NSC-34细胞焦亡中的作用. 解放军医学杂志, 2025 , 50 (4) : 475 -482 . DOI: 10.11855/j.issn.0577-7402.1207.2024.1227
Bo-Yang Su, Zheng-Qing He, Jing Liu, Mao Li, Xu-Sheng Huang. Effect of mangiferin on hSOD1G93A-induced pyroptosis in mice via activating Nrf2/HO-1 signaling pathway[J]. Medical Journal of Chinese People’s Liberation Army, 2025 , 50 (4) : 475 -482 . DOI: 10.11855/j.issn.0577-7402.1207.2024.1227
正文
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肌萎缩性侧索硬化(amyotrophic lateral sclerosis，ALS)是一种同时累及上下运动神经元的神经退行性疾病，主要临床表现为肌无力、肌萎缩、肌束颤等[1]。ALS预后不良，患者多于发病后3~5年死于呼吸衰竭或肺部感染，其发病机制尚不明确[2]。14%~20%的家族性ALS和1%~7%的散发性ALS是由Cu2+/Zn2+超氧化物歧化酶(SOD1)基因突变所致[3]。人SOD1基因突变已被广泛用于构建ALS细胞模型和动物模型[4-5]。细胞焦亡是一种近年发现的程序性细胞死亡途径[6]。在神经退行性疾病发病过程中，错误折叠的蛋白质可诱导NOD样受体蛋白3(NOD-like receptor protein 3，NLRP3)炎症小体激活并使其蛋白构象发生改变，进而活化胱天蛋白酶-1(caspase-1)[7]；活化的caspase-1切割gasdermin D(GSDMD)蛋白，释放出其N端活性域肽段，诱导细胞膜穿孔破裂、细胞死亡[7-8]。此外，活化的caspase-1可介导白细胞介素(interleukin，IL)-1β和IL-18的释放，参与炎症反应。这种导致质膜破裂以及IL-1β和IL-18释放到细胞外诱导细胞死亡的过程称为细胞焦亡[6]。已发现在SOD1G93A转基因小鼠和ALS患者的中枢神经系统中IL-1β水平升高和caspase-1激活[7]。在散发性和C9orf72基因突变的ALS患者死后的脊髓和大脑皮质组织中观察到NLRP3炎症小体以及caspase-1、GSDMD激活[9]，提示焦亡可能是导致皮质和脊髓神经元死亡的原因之一，在ALS发病机制中起一定作用。
芒果苷(mangiferin，MF)是一种广泛存在于植物中的多酚类化合物，具有抗炎、抗氧化、抗肿瘤等作用[10]。研究显示，MF可激活核因子E2相关因子2(nuclear factor E2 related factor 2，Nrf2)[11-12]，在氧化应激和炎症的调节中发挥重要作用，可抑制NLRP3激活，从而发挥抗焦亡作用[13]。在SOD1G93A转基因ALS小鼠模型中，Nrf2表达下降，NLRP3表达升高[14]。激活Nrf2信号通路可缓解ALS模型小鼠的运动障碍，减少运动神经元丢失，延长小鼠生存期[15]。MF在ALS中的作用目前尚不清楚。本研究探讨了MF调控Nrf2/血红素氧合酶-1(heme oxygenase-1，HO-1)信号通路对ALS模型细胞焦亡的影响，旨在为ALS的治疗研究提供参考。
1 材料与方法
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1.1 细胞系
小鼠NSC-34细胞系以及采用慢病毒转染hSOD1野生型(hSOD1WT)质粒和hSOD1突变型(hSOD1G93A)质粒的NSC-34细胞，均由哈尔滨医科大学附属第一医院丰宏林教授团队提供。
1.2 实验材料
MF(HY-N0290，美国MCE公司)；DMEM培养基、胎牛血清、青霉素-链霉素溶液、胰蛋白酶、Trizol试剂和LipofectamineTM 3000转染试剂(11965092、A5669701、15070063、25200056、15596018CN、L3000008，美国赛默飞世尔科技有限公司)；RIPA裂解液(R0010，北京索莱宝科技有限公司)；5× 蛋白变性上样液(LT101，上海雅酶生物科技有限公司)；IL-1β和IL-18 ELISA试剂盒(JL8442、JL20253，上海江莱生物科技有限公司)；CCK-8试剂、ECL显影液、BCA试剂盒、HiScript Ⅲ RT SuperMix、Taq Pro Universal SYBR qPCR Master Mix(A311-01、E423、E112、R323、Q712，南京诺唯赞生物科技有限公司)；乳酸脱氢酶(lactate dehydrogenase，LDH)检测试剂盒(C0016，上海碧云天生物技术股份有限公司)；抗Nrf2、HO-1、NADPH醌氧化还原酶-1(NADPH quinone oxidoreductase-1，NQO-1)、NLRP3、胱天蛋白酶-1(caspase-1)、增殖细胞核抗原(PCNA)抗体和HRP标记的山羊抗兔IgG、HRP标记的山羊抗鼠IgG(16396-1-AP、10701-1-AP、67240-1-Ig、19771-1-AP、31020-1-AP、60097-1-Ig、SA00001-2、SA00001-1，武汉三鹰生物技术有限公司)；抗GSDMD-N、GAPDH抗体(ab219800、ab8245，英国Abcam公司)；Nrf2-siRNA和基因引物序列(北京擎科生物科技有限公司)。
1.3 方法
1.3.1 细胞分组
为探究MF是否通过Nrf2信号通路抑制细胞焦亡，(1)将小鼠NSC-34细胞随机分为4组：空白组、模型组、MF(100 μmol/L)组、MF(200 μmol/L)组。空白组采用hSOD1WT NSC-34细胞，其他各组均采用hSOD1G93A NSC-34细胞。观察MF对小鼠NSC-34细胞活力、LDH释放量，炎性因子IL-1β、IL-18、Nrf2、HO-1、NQO-1、NLRP3、caspase-1、GSDMD-N蛋白表达水平的影响。(2)将小鼠hSOD1G93A NSC-34细胞随机分为4组：模型组、MF(100 μmol/L)组、Nrf2-siRNA组、Nrf2-siRNA+MF(200 μmol/L)组采用LipofectamineTM 3000瞬时转染Nrf2-siRNA。观察MF对敲低Nrf2表达的小鼠NSC-34细胞Nrf2、HO-1、NQO-1、NLRP3、GSDMD-N、caspase-1蛋白表达的影响。
1.3.2 细胞培养
使用完全培养基(90%DMEM，10%胎牛血清，1%青霉素-链霉素溶液)培养细胞，置于5% CO2、37 ℃恒温培养箱中，每隔2 d更换一次新鲜培养基。
1.3.3 CCK-8法检测细胞活力
将hSOD1G93A NSC-34细胞以1×104个/孔接种到96孔板，置于5% CO2、37 ℃的细胞培养箱中培养，待细胞贴壁后加入不同浓度的MF进行预处理，浓度梯度为0、50、100、200、300、400 μmol/L。24 h后弃去培养基，每孔加入100 μl CCK-8检测液，置于细胞培养箱中孵育2 h后使用酶联免疫检测仪(美国赛默飞世尔科技有限公司)在450 nm处检测吸光度。
1.3.4 LDH释放量测定
取各组细胞培养上清液，按照LDH细胞毒性检测试剂盒说明书进行操作，使用酶联免疫检测仪在490 nm波长处检测吸光度，并计算各组LDH释放量。
1.3.5 ELISA法检测炎性因子IL-1β和IL-18的含量
取各组细胞培养上清液，1000 r/min离心5 min后取上清，按照ELISA试剂盒说明书进行操作，使用酶联免疫检测仪在450 nm处检测吸光度，并根据标准曲线计算炎性因子含量。
1.3.6 实时荧光定量PCR(quantitative real-time PCR，qPCR)检测mRNA水平
在细胞转染小干扰RNA(small interfering RNA，siRNA)24 h后检测靶mRNA的水平。使用Trizol试剂从细胞中提取总RNA。通过紫外生物光度计(德国Eppendorf公司)检测总RNA浓度。根据制造商说明书，使用HiScript Ⅲ RT SuperMix进行反转录得到cDNA，使用Taq Pro Universal SYBR qPCR Master Mix进行PCR扩增，引物序列见表1。
1.3.7 Western blotting检测Nrf2、HO-1、NQO-1、NLRP3、GSDMD-N、caspase-1蛋白表达水平
各组细胞培养至密度为80%~90%时加入含蛋白抑制剂的RAPI裂解液(6孔板，120 μl/孔)，置于冰上裂解5 min。将样品在4 ℃下12 000 r/min离心15 min，取上清，用BCA试剂盒进行蛋白浓度测定，剩余上清液加入5× 蛋白变性上样液，在沸水中煮15 min。取蛋白样品行SDS-PAGE凝胶电泳(100 V 20 min；160 V 30 min)，随后转到PVDF膜上(220 mA，80 min)，使用TBST溶液配制的5%脱脂奶粉封闭100 min，分别加入抗Nrf2(1:3000)、HO-1(1:3000)、NQO-1(1:3000)、GAPDH(1:5000)、NLRP3(1:3000)、GSDMD-N(1:1000)、caspase-1(1:3000)、PCNA(1:5000)抗体在4 ℃下孵育过夜，TBST洗涤3次×10 min，然后在室温下分别加入HRP标记的山羊抗兔IgG(1:2000)和HRP标记的山羊抗鼠IgG(1:1000)二抗孵育1 h，TBST洗涤3次。按照1:1的比例配制ECL显影液，并置于显影仪中曝光拍照。
1.3.8 细胞转染
将hSOD1G93A NSC-34细胞均匀铺于6孔板中(8×105个细胞/孔)，待细胞密度达70%~80%后，每孔加入2 ml不含抗生素的细胞培养液，根据LipofectamineTM 3000转染试剂说明书配制转染溶液，随后将溶液逐滴加入到每孔中，按十字方向轻摇混匀，5% CO2、37 ℃培养箱中孵育6 h，更新细胞培养液。Nrf2-siRNA引物序列见表1。
1.4 统计学处理
采用 GraphPad Prism 8.0.2软件进行统计分析。所有数据均为计量资料，且均符合正态分布，以x±s表示，多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。实验独立重复3次。P<0.05为差异有统计学意义。
2 结果
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2.1 MF对hSOD1G93A NSC-34细胞活力的影响
MF的化学结构如图1所示。用300 μmol/L及以下浓度MF处理24 h后，hSOD1G93A NSC-34细胞存活率未发生明显变化(P>0.05，图2)。因此，选取100 μmol/L和200 μmol/L MF用于后续干预实验。
2.2 MF对hSOD1G93A NSC-34细胞培养上清液中LDH释放量的影响
与空白组比较，模型组细胞培养上清液中LDH释放量明显增加(P<0.001)；与模型组比较，MF(100 μmol/L)组和MF(200 μmol/L)组细胞培养上清液中LDH释放量均明显减少(P<0.001，图3)。
2.3 MF对hSOD1G93A NSC-34细胞培养上清液中炎性因子IL-1β和IL-18含量的影响
与空白组比较，模型组细胞培养上清液中IL-1β和IL-18含量明显增加(P<0.001)；与模型组比较，MF(100 μmol/L)组和MF(200 μmol/L)组细胞培养上清液中IL-18和IL-1β含量均明显减少(P<0.001，图4)。
2.4 MF对hSOD1G93A NSC-34细胞中Nrf2/HO-1信号通路的影响
与空白组比较，模型组细胞Nrf2、HO-1和NQO-1蛋白表达水平均明显降低(P<0.05或P<0.01)；与模型组比较，MF(100 μmol/L)组和MF(200 μmol/L)组细胞Nrf2、HO-1、NQO-1蛋白表达水平均明显升高(P<0.05或P<0.01，图5)。
2.5 MF对hSOD1G93A NSC-34细胞NLRP3/caspase-1/GSDMD通路的影响
与空白组比较，模型组细胞NLRP3、caspase-1和GSDMD-N蛋白表达水平明显升高(P<0.01或P<0.001)；与模型组比较，MF(100 μmol/L)组和MF(200 μmol/L)组细胞NLRP3、caspase-1和GSDMD-N蛋白表达水平明显降低(P<0.05或P<0.001，图6)。
2.6 MF对hSOD1G93A NSC-34细胞Nrf2/HO-1信号通路和细胞焦亡的影响
使用3种不同Nrf2-siRNA瞬时转染入小鼠hSOD1G93A NSC-34细胞中，qPCR检测结果显示，Nrf2-siRNA2抑制效果最佳，用于后续实验(图7)。与模型组比较，MF(200 μmol/L)组小鼠hSOD1G93A NSC-34细胞Nrf2、HO-1、NQO-1蛋白表达水平明显升高(P<0.05或P<0.001)，NLRP3、GSDMD-N和caspase-1蛋白表达水平明显降低(P<0.001)；Nrf2-siRNA组细胞Nrf2、HO-1蛋白表达水平明显降低(P<0.01或P<0.001)，而NLRP3、GSDMD-N和caspase-1蛋白表达水平明显升高(P<0.001)。与Nrf2-siRNA组比较，Nrf2-siRNA+MF(200 μmol/L)组细胞Nrf2、HO-1和NQO-1蛋白表达水平明显升高(P<0.01或P<0.001)，NLRP3、GSDMD-N和caspase-1蛋白表达水平明显下降(P<0.001，图8)。
3 讨论
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经典的细胞焦亡途径主要依靠NLRP3炎症小体激活caspase-1蛋白，使其切割GSDMD而释放N端，在细胞膜形成孔洞，导致细胞膜破裂[7,16]。Zhang等[17]发现，在症状前阶段SOD1G93A转基因小鼠的脊髓运动神经元中可检测到NLRP3，疾病晚期脊髓中星形胶质细胞和小胶质细胞中NLRP3表达增加。在SOD1G93A转基因小鼠腰髓中可检测到NLRP3炎症小体活化及切割的GSDMD表达增加[18]。近期研究发现，Vps54点突变的ALS小鼠模型颈髓组织神经元中NLRP3、caspase-1和GSDMD蛋白表达水平上调，提示NLRP3炎症小体激活和细胞焦亡参与了ALS小鼠模型的运动神经元变性和神经炎症[19]。本研究中，与空白组比较，SOD1G93A诱导的NSC-34细胞中NLRP3、GSDMD-N、caspase-1蛋白表达水平均明显升高。
细胞焦亡包括非经典焦亡和不完全焦亡途径[20]。非经典焦亡途径依赖caspase-4/5/11，这些炎性caspases可直接裂解GSDMD并启动细胞焦亡[20-21]。此外，在缺少caspase-1/11的巨噬细胞中，NLRP3炎症小体能够活化caspase-3/8，进而切割GSDME释放N端，引起不完全焦亡[7,22]。在ALS中以上两种焦亡途径的相关研究较少。仅一项研究报道在SOD1G93A小鼠腰髓组织及TDP-43转染的原代小鼠皮质神经元中发现GSDME-N水平增高，敲除GSDME后小鼠运动功能有明显改善，寿命延长，提示ALS中存在不完全焦亡[23]。
MF可通过抑制NF-κB通路而抑制细胞焦亡级联反应，减少脂多糖诱导的小鼠骨髓源性巨噬细胞中GSDMD释放N端，对细胞焦亡发挥调节作用[24-25]。此外，MF可通过TLR4/PI3K/Akt信号通路抑制NLRP3炎症小体的激活，从而降低下游caspase-1的表达，抑制GSDMD介导的细胞焦亡，发挥缓解关节炎症和骨侵蚀的作用[26]。本研究结果显示，100 μmol/L和200 μmol/L MF能够有效抑制ALS细胞模型的焦亡，而超过300 μmol/L的MF对ALS细胞模型的细胞活力产生了明显的抑制作用。LDH是一种稳定的胞质酶，广泛存在于人体细胞中，当细胞膜损伤时其会快速释放到细胞培养液中。本研究检测到ALS细胞模型释放的LDH增多，而加入MF处理后，LDH释放量减少。此外，MF可明显降低NLRP3、caspase-1和GSDMD-N蛋白的表达水平，以及细胞上清液中炎性因子IL-18和IL-1β的含量，提示MF可减轻炎症反应并抑制细胞焦亡，从而起到细胞保护作用。
Nrf2信号通路在调节细胞应激和氧化还原平衡等方面发挥关键作用[27]。近年研究显示，Nrf2与细胞焦亡信号通路密切相关，Nrf2表达量增加可抑制NLRP3及人黑素瘤缺乏因子2(absent in melanoma 2，AIM2)炎性小体，减弱炎症反应，进而抑制焦亡[28-29]。在神经系统中，Nrf2可抑制GSDMD介导的小胶质细胞焦亡并促进脊髓损伤修复[30]。在AD小鼠模型(APP/PS1小鼠)和细胞模型(HT22细胞系)中，1,7-二苯基-4-庚烷-3-酮可通过激活Nrf2途径抑制焦亡，减轻小鼠脑中β-淀粉样蛋白的沉积[31]。已有研究显示，MF可激活Nrf2信号通路[32]。本研究结果显示，MF可促进Nrf2易位入细胞核并激活Nrf2，从而增加其下游抗氧化酶HO-1和NQO-1的表达；此外，使用Nrf2-siRNA敲低Nrf2的表达后，观察到细胞焦亡增加；在此基础上给予MF处理可增加Nrf2蛋白的表达并抑制NLRP3、caspase-1和GSDMD-N蛋白的表达。
本研究仍存在一定的不足之处。首先，虽然报告了ALS中存在细胞焦亡这种细胞程序性死亡方式，与既往研究结果[14-16]一致，但未探究细胞焦亡参与ALS的具体病理生理机制及其在发病机制中所占的比重；其次，本研究未设置阳性对照组，无法确定MF对ALS的疗效。目前经美国FDA批准治疗ALS的上市药品包括利鲁唑、依达拉奉和Tofersen，尚无研究表明这3种药物可通过调控细胞焦亡而发挥作用，可在后续动物实验中设置阳性对照组探究MF对ALS动物模型运动功能、寿命等的影响。
综上所述，本研究结果显示，MF可在ALS细胞模型中通过激活Nrf2/HO-1信号通路抑制经典的细胞焦亡途径，但其用于ALS的治疗效果有待进一步验证。
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doi: 10.11855/j.issn.0577-7402.1207.2024.1227
  • 接收时间：2024-08-06
  • 首发时间：2025-10-30
  • 出版时间：2025-04-28
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  • 收稿日期：2024-08-06
  • 录用日期：2024-10-23
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    1解放军医学院，北京 100853
    2解放军总医院第一医学中心神经内科，北京 100853
    3首都医科大学附属北京友谊医院神经内科，北京 100050
    4解放军总医院第二医学中心老年医学研究所/国家老年疾病临床医学研究中心，北京 100853

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黄旭升， 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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