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Article(id=1308841942197301861, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-1552, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1766419200000, receivedDateStr=2025-12-23, revisedDate=1772553600000, revisedDateStr=2026-03-04, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981836126, onlineDateStr=2026-09-21, pubDate=1783785600000, pubDateStr=2026-07-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981836126, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981836126, creator=13701087609, updateTime=1789981836126, updator=13701087609, issue=Issue{id=1308841897058198067, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='7', pageStart='2377', pageEnd='2820', issueExtLink='null', onlineDate='null', pubDate='1783785600000', pubDateStr='2026-07-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981825365, creator='13701087609', updateTime=1789984154811, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851667525792021, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851667525792022, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841897058198067, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2514, endPage=2522, ext={EN=ArticleExt(id=1308841942407017062, articleId=1308841942197301861, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Halorotetin B exhibits anti-inflammatory effects by targeting MDM2 to inhibit the MAPK signaling pathway, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Halorotetin B is a natural terpenoid compound isolated from the tunic of Halocynthia roretzi. Studies have shown that this compound exhibits significant anti-tumor activity. However, its anti-inflammatory potential remains unexplored, likely owing to the multi-target nature of natural compounds. In this study, we investigated the anti-inflammatory activity of Ha. B. The results showed that Ha. B significantly inhibited the production of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 cells. Mechanistically, network pharmacology analysis and Western blot assays verified that Ha. B exerts its anti-inflammatory function by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Finally, natural product target prediction revealed that Ha. B may directly target mouse double minute 2 (MDM2). Cellular thermal shift assay (CETSA) results confirmed that Ha. B could interact with MDM2 in cells, and molecular docking was performed to simulate their physical binding mode. Meanwhile, RNA interference experiments further verified that Ha. B exerts its anti-inflammatory activity through binding to the E3 ubiquitin ligase MDM2.

, authors=Yi-ming MA1, Jun-zhi ZHU1, Jian-hui LI1, Bo DONG1, 2, Shan-hao HAN1, *, authorsList=Yi-ming MA, Jun-zhi ZHU, Jian-hui LI, Bo DONG, Shan-hao HAN, authorCompany=null, correspAuthors=Shan-hao HAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308841946995585647, articleId=1308841942197301861, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=Halorotetin B通过靶向MDM2调控MAPK信号通路抑制细胞炎症因子分泌, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

Halorotetin B是从真海鞘(Halocynthia roretzi) 被囊中分离的一种天然萜类化合物。研究表明, 该化合物具有显著的抗肿瘤活性。然而, 由于其多靶点特性, 该化合物是否具有抗炎活性尚不清楚。本研究探究了Ha. B的抗炎活性。结果表明, 在细菌脂多糖(lipopolysaccharide, LPS) 诱导的RAW264.7细胞中, Ha. B能显著抑制促炎因子肿瘤坏死因子α (tumor necrosis factor-alpha, TNF-α) 和白细胞介素6 (interleukin-6, IL-6) 的产生。机制上, 网络药理学分析及蛋白质免疫印迹实验阐明了Ha. B通过调控MAPK (mitogen-activated protein kinase) 信号通路发挥抗炎功能。最后, 天然产物靶点预测揭示了Ha. B可能的直接作用靶蛋白, 细胞热转移分析(cellular thermal shift assay, CETSA) 实验结果表明Ha. B可在细胞内与鼠双微体蛋白2 (mouse double minute 2, MDM2) 发生相互作用, 分子对接实验模拟了其物理结合模式。RNA干扰实验进一步证实, Ha. B通过结合E3泛素连接酶MDM2, 发挥抗炎活性。

, authors=马一鸣1, 朱俊至1, 李建辉1, 董波1, 2, 韩善浩1, *, authorsList=马一鸣, 朱俊至, 李建辉, 董波, 韩善浩, authorCompany=null, correspAuthors=韩善浩, authorNote=

作者贡献:

马一鸣负责实验设计、实验操作、数据分析和文章撰写; 李建辉参与部分实验操作; 朱俊至、董波参与部分数据分析; 韩善浩负责课题设计、实验指导、文章写作与修改。

, correspAuthorsNote=
韩善浩, Tel: 17806296833, E-mail:
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B) inhibits the production of inflammatory factors in lipopolysaccharide (LPS)-induced RAW264.7 cells. A: Cytotoxicity of Ha. B on RAW264.7 cells; B: Ha. B inhibited NO production in a dose-dependent manner in LPS-induced RAW264.7 cells; C-E: The production of tumor necrosis factor-alpha (TNF-α, C), interleukin (IL)-6 (D), reactive oxygen species (ROS, E) after treated with Ha. B in LPS-induced RAW264.7 cells. n = 3, x ± s. ****P < 0.000 1 vs control group; #P < 0.05, ##P < 0.01, ###P < 0.001, ####P < 0.000 1 vs LPS group. ns: Not significant, figureFileSmall=cgEqahdmhLPy8djOz+43Cg==, figureFileBig=GvBiUbyLtnlMNtIUcJh4xw==, tableContent=null), ArticleFig(id=1308841951294747292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841942197301861, language=EN, label=null, caption=null, figureFileSmall=/IUve6bzDqcKrXrwloR3Yw==, figureFileBig=PlnLHDhYsQpyY4SJY33hLw==, tableContent=null), ArticleFig(id=1308841951391216285, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841942197301861, language=CN, label=Fig.2, caption=Ha. B exerts its anti-inflammatory effects by inhibiting the MAPK signaling pathway. A: Venn diagrams of Ha. B targets and disease targets; B: Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis of 110 potential targets; C: The MAPK signaling pathway expression proteins were detected using Western blot; D-F: Statistical analysis of p-p38 (D), p-ERK1/2 (E) and p-JNK1/2 (F). n = 3, x ± s. ****P < 0.000 1 vs control group; ##P < 0.01, ###P < 0.001, ####P < 0.000 1 vs LPS group, figureFileSmall=/IUve6bzDqcKrXrwloR3Yw==, figureFileBig=PlnLHDhYsQpyY4SJY33hLw==, tableContent=null), ArticleFig(id=1308841951466713758, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841942197301861, language=EN, label=null, caption=null, figureFileSmall=/dJs43Lbc3Kv3S6AY+DB8w==, figureFileBig=aPr9qc8moSuNvn5is7B/Uw==, tableContent=null), ArticleFig(id=1308841951525434015, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841942197301861, language=CN, label=Fig.3, caption=Ha. B exerts its anti-inflammatory effects by binding to mouse double minute 2 (MDM2). A: Venn diagrams of Phammapper targets, SwissTargetPredication targets and disease targets; B, C: Comparison with methanol treatment: Degradation level of MDM2 protein in cells treated with Ha. B (50 μmol·L-1) at different temperatures (37, 47, 57, 67 and 77 ℃) (B), and statistical analysis (C); D: Binding mode diagram of the interaction between Ha. B and amino acid residues of MDM2; E: Surface representation of the binding pocket and interaction interface between Ha. B and MDM2 protein. n = 3, x ± s. **P < 0.01, figureFileSmall=/dJs43Lbc3Kv3S6AY+DB8w==, figureFileBig=aPr9qc8moSuNvn5is7B/Uw==, tableContent=null), ArticleFig(id=1308841951592542880, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841942197301861, language=EN, label=null, caption=null, figureFileSmall=1RF08q/iSOxvgB/LvpfTXw==, figureFileBig=x4Ld2pd67eAwyHukzHBywA==, tableContent=null), ArticleFig(id=1308841951672234657, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841942197301861, language=CN, label=Fig.4, caption=Ha. B exerts its anti-inflammatory effects dependent on the MDM2 protein. A, B: Detection of MDM2 protein expression after knockdown by Western blot (A), and statistical analysis (B); C: Inhibitory effect of Ha. B on NO production before and after MDM2 protein knockdown; D: Western blot analysis of MDM2 knockdown effect on Ha. B-inhibited TNF-α expression; E: Western blot was used to detect the effect of MDM2 knockdown on Ha. B-mediated regulation of the p38 MAPK pathway; F: Molecular mechanism of Ha. B exerting anti-inflammatory activity. n = 3, x ± s. **P < 0.01, figureFileSmall=1RF08q/iSOxvgB/LvpfTXw==, figureFileBig=x4Ld2pd67eAwyHukzHBywA==, tableContent=null)], attaches=null, journal=Journal(id=1189982048455397383, delFlag=0, nameCn=药学学报, nameEn=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, issn=0513-4870, eissn=null, cn=11-2163/R, coden=null, periodic=0, language=CN, oaType=null, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=null, officePhone=null, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=BTxjudbJDVO4PqdBR6On6Q==, journalPrice=null, startedYear=null, abbrevIsoEn=null, journalRemark=null, publicationField=null, createdTime=1761643429151, updatedTime=1788948913902, createdBy=18614031015, updatedBy=13041195026, firstLetterCn=Y, 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Halorotetin B通过靶向MDM2调控MAPK信号通路抑制细胞炎症因子分泌
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马一鸣 1 , 朱俊至 1 , 李建辉 1 , 董波 1, 2 , 韩善浩 1, *
药学学报 | 研究论文 2026,61(7): 2514-2522
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药学学报 |研究论文 2026 , 61 (7) : 2514 -2522
Halorotetin B通过靶向MDM2调控MAPK信号通路抑制细胞炎症因子分泌
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马一鸣1, 朱俊至1, 李建辉1, 董波1, 2, 韩善浩1, *
作者信息
  • 1中国海洋大学方宗熙海洋生物进化与发育中心, 山东 青岛 266003
  • 2青岛海洋科学与技术国家实验室海洋生物与生物技术实验室, 山东 青岛 266237
通讯作者:
韩善浩, Tel: 17806296833, E-mail:
作者简介:

作者贡献:

马一鸣负责实验设计、实验操作、数据分析和文章撰写; 李建辉参与部分实验操作; 朱俊至、董波参与部分数据分析; 韩善浩负责课题设计、实验指导、文章写作与修改。

Halorotetin B exhibits anti-inflammatory effects by targeting MDM2 to inhibit the MAPK signaling pathway
Yi-ming MA1, Jun-zhi ZHU1, Jian-hui LI1, Bo DONG1, 2, Shan-hao HAN1, *
Affiliations
  • 1Fang Zongxi Center for Marine Evo-Devo, Ocean University of China, Qingdao 266003, China
  • 2Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
出版时间: 2026-07-12 doi: 10.16438/j.0513-4870.2025-1552
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摘要
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Halorotetin B是从真海鞘(Halocynthia roretzi) 被囊中分离的一种天然萜类化合物。研究表明, 该化合物具有显著的抗肿瘤活性。然而, 由于其多靶点特性, 该化合物是否具有抗炎活性尚不清楚。本研究探究了Ha. B的抗炎活性。结果表明, 在细菌脂多糖(lipopolysaccharide, LPS) 诱导的RAW264.7细胞中, Ha. B能显著抑制促炎因子肿瘤坏死因子α (tumor necrosis factor-alpha, TNF-α) 和白细胞介素6 (interleukin-6, IL-6) 的产生。机制上, 网络药理学分析及蛋白质免疫印迹实验阐明了Ha. B通过调控MAPK (mitogen-activated protein kinase) 信号通路发挥抗炎功能。最后, 天然产物靶点预测揭示了Ha. B可能的直接作用靶蛋白, 细胞热转移分析(cellular thermal shift assay, CETSA) 实验结果表明Ha. B可在细胞内与鼠双微体蛋白2 (mouse double minute 2, MDM2) 发生相互作用, 分子对接实验模拟了其物理结合模式。RNA干扰实验进一步证实, Ha. B通过结合E3泛素连接酶MDM2, 发挥抗炎活性。

真海鞘  /  活性产物  /  MAPK信号通路  /  鼠双微体蛋白2  /  抗炎

Halorotetin B is a natural terpenoid compound isolated from the tunic of Halocynthia roretzi. Studies have shown that this compound exhibits significant anti-tumor activity. However, its anti-inflammatory potential remains unexplored, likely owing to the multi-target nature of natural compounds. In this study, we investigated the anti-inflammatory activity of Ha. B. The results showed that Ha. B significantly inhibited the production of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 cells. Mechanistically, network pharmacology analysis and Western blot assays verified that Ha. B exerts its anti-inflammatory function by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Finally, natural product target prediction revealed that Ha. B may directly target mouse double minute 2 (MDM2). Cellular thermal shift assay (CETSA) results confirmed that Ha. B could interact with MDM2 in cells, and molecular docking was performed to simulate their physical binding mode. Meanwhile, RNA interference experiments further verified that Ha. B exerts its anti-inflammatory activity through binding to the E3 ubiquitin ligase MDM2.

Halocynthia roretzi  /  bioactive product  /  MAPK signaling pathway  /  MDM2  /  anti-inflammatory
马一鸣, 朱俊至, 李建辉, 董波, 韩善浩. Halorotetin B通过靶向MDM2调控MAPK信号通路抑制细胞炎症因子分泌. 药学学报, 2026 , 61 (7) : 2514 -2522 . DOI: 10.16438/j.0513-4870.2025-1552
Yi-ming MA, Jun-zhi ZHU, Jian-hui LI, Bo DONG, Shan-hao HAN. Halorotetin B exhibits anti-inflammatory effects by targeting MDM2 to inhibit the MAPK signaling pathway[J]. Acta Pharmaceutica Sinica, 2026 , 61 (7) : 2514 -2522 . DOI: 10.16438/j.0513-4870.2025-1552
正文
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炎症是许多疾病发病机制中的主要反应, 如神经退行性疾病、阿尔茨海默病、肺炎和自身免疫性疾病[1]。在此过程中, 巨噬细胞是对抗外源性病原体的炎症反应的主要介质[2]。巨噬细胞是血液单核细胞来源的吞噬细胞, 在先天性免疫和适应性免疫中发挥重要作用。这些细胞具有病原体相关分子模式(pathogen-associated molecular patterns, PAMP) 受体, 如Toll样受体(Toll-like receptors, TLRs) 和晚期糖基化终末产物受体(receptor for advanced glycation end products, RAGE), 能够识别细胞外抗原, 如脂多糖(lipopolysaccharide, LPS)[3]。LPS的作用包括激活细胞外调节蛋白激酶1/2 (extracellular regulated protein kinases 1/2, ERK1/2)、c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK) 和p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinases, p38 MAPKs), 最终调控诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)、环氧化酶-2 (cyclooxygenase-2, COX-2)、肿瘤坏死因子α (tumor necrosis factor-alpha, TNF-α)、白细胞介素6 (interleukin 6, IL-6) 和白细胞介素1β (interleukin 1β, IL-1β) 等炎症调节因子表达的转录因子的活性[4-8]。但过度产生的促炎细胞因子, 如TNF-α、IL-1β和IL-6, 可触发组织损伤[9]。因此, 抑制促炎细胞因子是治疗炎症相关疾病的有效策略[10]。
天然产物是药物发现工作中重要的先导化合物来源[11]。在过去的几十年里, 科学家从大陆和海洋生物体中分离出了成千上万个生物活性代谢物[12, 13]。许多海洋来源的代谢物通过在体外、体内(小鼠) 模型和临床试验中有效地抑制促炎细胞因子而发挥抗炎作用[14]。海鞘是脊索动物门(Chordates), 尾索动物亚门(Urochordata) 中的被囊类动物[15]。海鞘生活环境的复杂性和多样性, 使其能够产生丰富的次级代谢产物。迄今为止, 已从海鞘[16, 17]中鉴定了约1 200个结构明确的天然化合物, 为抗炎药物的开发提供了丰富的先导化合物来源。
真海鞘(Halocynthia roretzi) 原产于日本太平洋沿海地区和南鹿半岛海区, 此外在韩国东南海岸也都有分布[18]。真海鞘产生的生物活性天然产物已有一些先前的报道, 如壬酰胺[19]和一些生物活性肽[20]。此外, 真海鞘内囊干粉提取物在小鼠体内可以有效降低地塞米松引起的高血糖反应[21]。
Ha. B是在真海鞘被囊中分离出来的一种萜类化合物, 研究表明, 该化合物能够通过靶向泛素结合酶E2C (ubiquitin-conjugating enzyme E2C, UBE2C) 诱导肿瘤细胞周期阻滞[22]。值得注意的是, 慢性炎症与肿瘤的发生发展存在着密不可分的联系, 且研究表明天然化合物往往具有多靶点的特性[23], 这提示Ha. B可能同时具备抗肿瘤与抗炎的双重潜力。基于上述特征, 本课题组推测Ha. B可能是一种潜在的抗炎化合物。
本研究以LPS诱导的RAW264.7巨噬细胞为研究对象, 初步探究了Ha. B的抗炎活性。Ha. B可降低LPS诱导的RAW264.7细胞中促炎因子的水平, 抑制炎症相关MAPK信号通路的激活, 具有进一步开发为天然抗炎药物的潜能。
材料与方法
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药物与试剂  DMEM细胞培养基(货号: L100KJ) 购自上海源培生物科技有限公司; 磷酸缓冲盐溶液(货号: P1020) 购自北京索莱宝科技有限公司; 胎牛血清(货号: 10091148) 购自美国Gibco公司; 青霉素-链霉素-两性霉素B溶液(货号: PB80121) 购自武汉普诺赛生命科技有限公司; 细菌脂多糖(货号: L2603) 购自美国Sigma公司; 地塞米松(货号: D137736) 购自上海阿拉丁生物有限公司; 小鼠TNF-α检测试剂盒(货号: PT513)、小鼠IL-6检测试剂盒(货号: PI301)、活性氧(ROS) 检测试剂盒(货号: S0033S)、一氧化氮检测试剂盒(货号: S0021S) 均购自上海碧云天生物科技有限公司; LipofectamineTM 3000转染试剂(L3000015) 购自Invitrogen公司; GAPDH抗体(货号: HC301-02)、tubulin抗体(货号: HC101-01)、山羊抗兔IgG (货号: HS101-01)、山羊抗鼠IgG (HS-201-01) 购自北京全式金生物科技有限公司; phospho-p38 MAPK (Thr180/Tyr182) 抗体(货号: 10745-1-AP)、phospho-ERK1/2 (Thr202/Tyr204) 抗体(货号: 28733-1-AP)、phospho-JNK1/2 (Thr183/Tyr185) 抗体(货号: 60666-1-ig)、ERK1/2抗体(货号: 11257-1-AP)、JNK抗体(货号: 24164-1-AP)、p38 MAPK抗体(货号: 80379-2-RR) 均购自武汉三鹰生物技术有限公司; MDM2抗体(货号: Q00987)、TNF-α抗体(货号: 346654) 购自正能生物有限公司。
细胞株及细胞培养  小鼠单核巨噬细胞RAW264.7购自中国科学院细胞库。细胞培养采用具有1%双抗和10%胎牛血清DMEM完全培养基。RAW264.7细胞的传代指将细胞培养至融合率达到80%后, 将瓶壁上的细胞均匀吹散吸取适量转移至新的培养基中培养, 于37 ℃、5% CO2恒温培养箱(美国Thermo Fisher公司) 中孵育。
CCK8法测定细胞毒性  将RAW264.7细胞以1×104个/孔接种在96孔板, 弃去上清, 设置空白组与实验组; 实验组分别在完全培养基中加入50、25、12.5 μmol·L-1 Ha. B培养24 h。弃上清, 加入CCK8试剂37 ℃孵育30 min, 使用酶标仪(美国Tecan公司) 在490 nm吸光度下检测对照组和实验组的吸光度值, 并计算增殖抑制率。
Griess法测定NO的含量  RAW264.7细胞以1×104个/孔接种在96孔板, 弃去上清, 设置空白组、LPS (模型) 组和实验组, 其中LPS (模型) 组给予最终浓度为100 ng·mL-1 LPS; 实验组分别在完全培养基中加入50、25、12.5 μmol·L-1 Ha. B, 1 h后给予LPS (终浓度为100 ng·mL-1) 培养24 h后收集上清液, 根据Griess试剂盒说明书, 检测细胞上清液中NO含量。
ELISA法测定炎症因子的含量  细胞处理方法同上, 收集细胞上清液。分别将样品按照每孔100 μL加入预包被板孔中, 用封板膜(透明) 封住反应孔, 室温孵育120 min。洗板5次, 最后一次置于厚吸水纸上拍干。每孔加入生物素化抗体100 μL。用封板膜(透明) 封住反应孔, 室温孵育60 min。洗板5次, 且最后一次置于厚吸水纸上拍干。每孔加入辣根过氧化物酶标记Streptavidin 100 μL。用封板膜(白色) 封住反应孔, 室温避光孵育20 min。洗板5次, 且最后一次置于厚吸水纸上拍干。每孔加入显色剂TMB溶液100 μL, 用封板膜(白色) 封住反应孔, 室温避光孵育20 min。加入终止液50 μL, 混匀后立即测量A450值。根据标准曲线计算细胞上清液中炎症因子IL-6和TNF-α的浓度。
蛋白质免疫印迹法检测MAPK信号通路中相关蛋白的表达  RAW264.7细胞以6×105个/孔接种在6孔板, 弃去上清, 设置空白组、LPS组和实验组, 其中LPS组给予终浓度为100 ng·mL-1 LPS; 实验组分别在完全培养基中加入50、25、12.5 μmol·L-1 Ha. B, 1 h后加入LPS培养24 h, 收集细胞, 加入细胞裂解液裂解细胞30 min后收集样品。加入5×loading buffer煮沸10 min, 样品放于-20 ℃保存。配制10% SDS-PAGE凝胶, 加入样品进行蛋白电泳。待电泳结束后, 进行转膜, 将条带转至PVDF膜上。TBST洗涤两次, 加入5%脱脂牛奶封闭2 h, TBST洗涤3次, 加入一抗4 ℃孵育12 h。TBST洗涤3次, 室温孵育二抗2 h, TBST洗涤3次, 在PVDF膜上滴加显影液, 在化学发光成像仪(瑞士梅特勒公司) 中显影。
RNA干扰  RAW264.7细胞以2×105个/孔接种在12孔板, 待细胞密度达到50%时, 加入终浓度为100 nmol·L-1 si-RNA [鼠双微体蛋白2 (mouse double minute 2, MDM2): 正向序列-CAGCCAAGAAAGCGUGAAATT, 反向序列-UUUCACGCUUUCUUGGCUGTT; si-NC: 正向序列-UUCUCCGAACGUGUCACGUTT, 反向序列-ACG UGACACGUUCGGAGAATT] 孵育24 h, 收集细胞及上清进行后续实验。
ROS测定  RAW264.7细胞以6×105个/孔接种在6孔板, 弃去上清, 设置空白组、LPS组和实验组, 其中LPS组给予终浓度为100 ng·mL-1 LPS; 实验组分别在完全培养基中加入50、25、12.5 μmol·L-1 Ha. B, 1 h后加入LPS培养24 h, 吸弃培养液, 分别用DCFH-DA (10 μmol·L-1) 作为ROS检测探针孵育15 min。弃去上清孵育液。用1 mL PBS洗涤两次后, 加入100 μL PBS, 于倒置荧光显微镜(日本NIKON公司) 下拍摄。
网络药理学分析  网络药理学用于初步预测生物活性成分抗炎活性的潜在靶点、通路和机制[24]。首先在Pharmmapper与Swisstarget数据库预测Ha. B的结合靶点。同时, 本研究使用在线人类孟德尔遗传数据库(OMIM)、Drugbank数据库、治疗靶标数据库(TTD)、GeneCards数据库, 通过“炎症”关键词筛选炎症相关基因。随后根据Venn网站制作的Venn图筛选Ha. B抗炎症的共同靶点。最后, 将所得的靶点进行KEGG通路分析。
分子对接  MDM2的蛋白结构由Protein Data Bank (PDB ID: 0hbm) 提供。利用Pymol软件对蛋白质结构中的水分子和配体分子进行删除、氢化和电荷操作。使用Autodock软件对目标蛋白和配体进行分子对接, 得到所有可能的构象。随后根据自由能的估计值评估结果[25]。
细胞热转移分析(cellular thermal shift assay, CETSA)  RAW264.7细胞以6×105个/孔接种在6孔板, 弃去上清, 设置空白组与实验组, 实验组中加入终浓度为25 μmol·L-1 Ha. B, 培养24 h。弃上清, 收集并裂解细胞。设置加热温度梯度为37、47、57、67、77 ℃。随后将空白组与实验组的细胞裂解液置于PCR仪(美国BioRad公司) 中按温度梯度分别加热处理7 min, 室温静置3 min。待其冷却后加入5×loading buffer煮沸10 min, 样品放于-20 ℃保存[26]。
统计学分析  通过GraphPad Prism 9.0版进行统计分析。对于柱形图: 数据以平均值±标准差表示。Welch校正后, 通过单因素方差分析、t检验确定显著性。所有数据在显著性检验前均通过Shapiro-Wilk正态性检验判断数据的正态性。以P < 0.05为差异有统计学意义。
结果
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1　Ha. B的抗炎活性
本研究首先采用CCK8法检测Ha. B对RAW264.7细胞的潜在细胞毒性。结果表明, 在加入LPS (100 ng·mL-1) 诱导的情况下, Ha. B在12.5、25和50 μmol·L-1时细胞存活率均大于80%, 表明上述浓度的Ha. B对RAW264.7细胞无明显细胞毒性(图1A), 可以用于后续抗炎效果检测。NO的产生可用于评价细胞内的炎症状态, NO检测结果显示, 100 ng·mL-1 LPS使NO含量显著增加, 表明细胞炎症被成功诱导。与LPS组相比, 加入不同浓度Ha. B后, NO的产生量显著降低。同时, 加入阳性对照药物地塞米松(50 μmol·L-1) 后[27], NO的生成量也显著降低。上述结果表明, Ha. B以浓度依赖的方式抑制巨噬细胞释放NO (图1B)。为了进一步探究化合物Ha. B抗炎效果, 本研究检测了TNF-α与IL-6两种细胞炎症因子, 结果表明, Ha. B在25和50 μmol·L-1两个浓度时能够显著抑制IL-6与TNF-α的产生(图1C、D)。此外, 为探究化合物Ha. B对LPS诱导的氧化应激的影响, 本研究检测了Raw264.7细胞中ROS的水平。如图1E所示, 与对照组相比, LPS刺激显著提高了细胞内ROS的生成。经Ha. B处理后, LPS诱导的ROS水平呈现显著的浓度依赖性下降。上述结果均说明, Ha. B有显著的抗炎活性。
2　Ha. B抑制MAPK信号通路
为了探究Ha. B发挥抗炎活性的分子机制, 基于网络药理学分析方法中的数据库, 本研究得到263个Ha. B的潜在靶点和2 698个与炎症相关的基因, Venn图整合结果显示共有164个共同靶点(图2A)。随后, 将164个共同靶点进行KEGG富集分析, 得到与Ha. B抗炎活性相关的信号通路(图2B)。前期研究表明, LPS刺激能够增加Raw264.7细胞中ERK、p38 MAPK和JNK的磷酸化水平, 这些因子均与MAPK信号通路密切相关。此外, MAPKs信号通路还能够上调包括TNF-α、IL-1β和IL-6在内的促炎基因的表达。基于上述结果, 本课题组推测Ha. B的抗炎活性可能与MAPK通路有关。因此, 本研究检测了化合物Ha. B处理后ERK、p38 MAPK和JNK的磷酸化水平(图2C)。定量结果统计显示(图2D~F), Ha. B显著降低了LPS诱导的Raw264.7细胞中磷酸化ERK1/2、p38 MAPK及JNK1/2的表达水平, 表明其对LPS诱导的促炎细胞因子产生的抑制作用与MAPKs信号通路密切相关。
3　Ha. B通过结合MDM2发挥抗炎作用
为了进一步探究Ha. B通过何种途径抑制MAPK信号通路发挥抗炎作用, 本研究预测并验证了Ha. B的直接作用靶点。Pharmmapper数据库和SwissTargetPredication数据库预测表明, Ha. B具有多个潜在作用靶点。随后, 将预测得到的可能作用靶点取交集, 得到25个候选靶蛋白(图3A)。根据以往研究, MDM2可以通过激活MAPK和NF-κB信号通路促进类风湿性关节炎[28]。因此, 推测Ha. B可能通过结合MDM2, 影响下游MAPK信号通路, 进而发挥抗炎功能。CETSA实验表明, Ha. B处理24 h后, MDM2蛋白的热稳定性显著增加, 表明Ha. B可以在细胞内与MDM2蛋白结合(图3B、C)。为进一步探究其分子结合模式, 本研究利用分子对接软件(AutoDockTools, Version 1.5.7), 并选择了结合能水平最低的嵌合体模型, 利用Pymol软件进行了可视化处理(PyMOL Molecular Graphics System, Version 2.5.4)。结果表明, Ha. B能够与MDM2蛋白结合, 结合自由能为-2.1 mol·kcal-1, 其相互作用可能依赖于MDM2蛋白的第94位Lys (图3D、E)。以上结果说明, Ha. B可能通过与MDM2蛋白结合, 影响MAPK信号通路, 发挥抗炎功能。
4　Ha. B的抗炎作用依赖于MDM2蛋白
为了进一步验证MDM2是Ha. B发挥抗炎作用的关键靶蛋白, 本研究进行了RNA干扰实验。通过转染siRNA, 对细胞内MDM2蛋白进行敲降, Western blot实验结果表明, 转染siRNA后, MDM2蛋白水平显著降低(图4A、B)。在此基础上, 进一步探究了Ha. B在MDM2敲降前后, 对LPS诱导的NO生成、TNF-α表达及p38 MAPK通路活化的调控作用。结果表明, 在对照组细胞中, Ha. B可显著抑制NO的释放, 然而在MDM2敲降组细胞中, Ha. B对NO与TNF-α生成的抑制效果显著低于对照组(图4C、D), 对p-p38抑制效应削弱(图4E)。以上结果表明, MDM2是Ha. B发挥抗炎作用的重要靶蛋白。
讨论
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本研究通过探究天然抗肿瘤化合物Ha. B的抗炎活性, 揭示了Ha. B可显著抑制TNF-α、IL-6等炎症因子的产生。同时, 网络药理学分析及验证表明Ha. B通过调控MAPK信号通路发挥抗炎功能, 天然产物靶点预测及验证表明E3泛素连接酶MDM2可能为Ha. B发挥抗炎功能的结合靶点(图4F)。
在机体几乎所有组织中, 巨噬细胞作为免疫细胞, 是外来物质的直接作用者和主要应答者[29]。在炎症的各个阶段如起始、发展和消退[30]都有巨噬细胞的参与。RAW264.7细胞是研究各种化合物免疫调节活性的常用细胞模型。RAW264.7细胞可分泌多种炎症介质和促炎细胞因子, 包括NO、TNF-α、IL-6等。NO的生成量与细胞炎症活化程度呈正相关, 可直接反映药物的抗炎效果[31]。本研究证明了Ha. B以浓度依赖的方式抑制了NO的产生。ROS是细胞氧化应激反应的主要介质, 细胞内过多的ROS可能通过降低线粒体膜电位[32], 损伤线粒体, 激发炎症反应。本研究发现Ha. B以浓度依赖的方式抑制了ROS的产生。TNF-α是一种经典的炎症标志物, 它是炎症级联反应的中心, 可诱导多种炎症因子的产生, 介导免疫反应, 最终导致细胞凋亡和组织损伤。IL-6是一种具有促炎和抗炎双重作用的多功能细胞因子, 高浓度的IL-6会引起一系列的炎症损伤, 也是各种急慢性炎症反应的重要介质[33]。本研究证实了Ha. B能显著抑制TNF-α和IL-6的过度释放。这些结果表明, Ha. B可以抑制这些促炎细胞因子的生成。
MAPK信号通路是一类重要的丝氨酸/苏氨酸蛋白激酶, 在细胞炎症反应中执行关键功能, 通过调节促炎细胞因子和介质的产生来调控炎症进程[34]。在哺乳动物细胞中, 经典的MAPK通路主要包括3个主要亚族: ERK、JNK和p38。在正常生理状态下, 这些激酶以非活化状态存在于细胞质中。当细胞受到如LPS等外界刺激时, 会触发MAPK信号通路级联磷酸化反应。具体而言, 上游激酶(如MAPKKK) 激活MAPKK, 进而磷酸化并激活MAPK (ERK、JNK、p38)[35]。随后, 活化的MAPKs转运入核, 磷酸化特定的转录因子(如c-Fos, c-Jun, ATF-2), 从而调控IL-6、TNF-α和IL-1β等多种炎症细胞因子的表达[36]。因此, MAPK通路的转导是炎症发生发展中的一个关键过程。临床抗炎药物地塞米松同样通过抑制MAPK信号通路的激活发挥抗炎功能[37], 但可能引起高血压、高血脂等不良反应。Ha. B来源于可食用真海鞘, 近期研究表明该化合物在发挥抗肿瘤功能时不会产生明显毒副作用, 暗示了Ha. B可能在发挥抗炎功能时具有良好的安全性。在本研究中, Ha. B预处理能够显著抑制LPS诱导的ERK、JNK和p38蛋白的磷酸化水平。这表明Ha. B可以通过MAPK信号通路发挥其抗炎活性。
MDM2作为一种E3泛素连接酶, 是p53肿瘤抑制蛋白的关键负调控因子[38]。有研究表明, MDM2可促进组织炎症反应, 而其抑制剂则表现出显著抗炎效应[39]。此外, 过表达MDM2能激活MAPK信号通路, 从而导致关节炎的发生[28]。CETSA实验与分子对接的结果均表明MDM2与Ha. B具有较强的结合能力, MDM2蛋白为Ha. B发挥抗炎功能的关键靶蛋白。在之前开发的靶向MDM2的众多药物中, 多数用于肿瘤的治疗。前期研究[40]及本研究结果说明MDM2同样可以作为炎症治疗和抗炎药物开发的靶点。
尽管分子对接和基于细胞的功能实验表明, Ha. B的抗炎活性可能源于其与MDM2蛋白的相互作用, 但并未通过直接的生物物理实验验证两者在体外的特异性结合。另外, Ha. B在复杂的生物体内环境中是否具有相同的抗炎功效、药代动力学特性等仍待探究。综上所述, 本研究探究了Ha. B在RAW264.7中的抗炎作用及其分子机制, 为将其开发为海鞘来源的天然抗炎药物提供了理论依据, 也为开发以MDM2为靶点的新型抗炎药物奠定了前期基础。

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2026年第61卷第7期
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doi: 10.16438/j.0513-4870.2025-1552
  • 接收时间：2025-12-23
  • 首发时间：2026-09-21
  • 出版时间：2026-07-12
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  • 收稿日期：2025-12-23
  • 修回日期：2026-03-04
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    1中国海洋大学方宗熙海洋生物进化与发育中心, 山东 青岛 266003
    2青岛海洋科学与技术国家实验室海洋生物与生物技术实验室, 山东 青岛 266237

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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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