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Article(id=1320436303976579115, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1320436284418544199, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202512047, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1765296000000, receivedDateStr=2025-12-10, revisedDate=1768492800000, revisedDateStr=2026-01-16, acceptedDate=null, acceptedDateStr=null, onlineDate=1792746147388, onlineDateStr=2026-10-23, pubDate=1772208000000, pubDateStr=2026-02-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1792746147388, onlineIssueDateStr=2026-10-23, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1792746147388, creator=13701087609, updateTime=1792746147388, updator=13701087609, issue=Issue{id=1320436284418544199, tenantId=1146029695717560320, journalId=1319373162502258839, year='2026', volume='48', issue='4', pageStart='387', pageEnd='522', issueExtLink='null', onlineDate='null', pubDate='1772208000000', pubDateStr='2026-02-28', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1792746142725, creator='13701087609', updateTime=1792750115637, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1320452948077953743, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1320436284418544199, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1320452948077953744, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1320436284418544199, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=420, endPage=432, ext={EN=ArticleExt(id=1320436304215654444, articleId=1320436303976579115, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=Targeting host mitochondrial respiration: artemisinin derivative potentiates macrophage bacterial clearance by up-regulating antibacterial autophagy via immunometabolic mechanism, columnId=1320434418116837551, journalTitle=Journal of Army Medical University, columnName=Basic Medicine, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the effect and mechanism of a novel artemisinin derivative, disuccinate artemisinin (DA), in enhancing bacterial clearance by upregulating antibacterial autophagy in macrophages through targeting host mitochondrial respiration.

Methods

The experiment utilized E. colistrains ATCC 35218 and FITC-labeled K12 to infect the mouse macrophage cell line RAW264.7. Phagocytosis of bacteria by macrophages under different time points and doses was assessed via fluorescence imaging to determine the optimal drug dosage and time point. The impact of the drug on antibacterial autophagy in macrophages was evaluated using colony counting, Western blotting and immunofluorescence co-localization assay. Autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin A1 were employed to examine the effect of autophagy suppression on drug efficacy through colony counting and immunofluorescence co-localization. Glucose deprivation was induced using low-glucose medium, and its influence on drug action was observed via fluorescent bacterial counting and immunofluorescence co-localization. Glycolytic intervention was investigated using the glycolytic activator oligomycin A and inhibitor 2-deoxy-D-glucose (2-DG), with effects monitored through fluorescent bacterial counting and immunofluorescence co-localization. Mitochondrial respiration was modulated with the activator carbonyl cyanide 4-trifluoromethoxy phenylhydrazone (FCCP) and inhibitor rotenone, and its impact on drug action was assessed via fluorescent bacterial counting and immunofluorescence co-localization. The effect of the drug on mitochondrial respiration in macrophages was determined by measuring the oxygen consumption rate (OCR) using cellular energy metabolism assays.

Results

DA concentration-dependently enhanced macrophage phagocytosis and clearance of both drug-resistant ATCC35218 and sensitive K12 E. coli (P<0.05). Immunofluorescence and immunoblotting demonstrated DA upregulated antibacterial autophagy (P<0.01), remaining effective when autophagy initiation was blocked (P<0.01) but losing efficacy upon autophagic flux inhibition (P<0.01). Under glucose deprivation, DA retained its autophagy-enhancing effect (P<0.01). Both activation and inhibition of glycolysis limited DA’s efficacy (P<0.01). Maximizing mitochondrial respiration with FCCP abolished DA’s pro-phagocytic and autophagy-enhancing effects (P<0.01), whereas respiratory blockade with rotenone preserved them (P<0.01). Metabolic analysis showed DA restored infection-impaired maximal mitochondrial respiration, spare respiratory capacity, and ATP production (P<0.01).

Conclusion

DA enhances bacterial clearance by upregulating antibacterial autophagy through restoration of mitochondrial respiration in infected macrophages, representing a host-directed anti-infective candidate targeting mitochondrial metabolism.

, authors=Pan WANG, Chenzhen BAO, Ting ZHU, Yanyan CEN, Xichun PAN, authorsList=Pan WANG, Chenzhen BAO, Ting ZHU, Yanyan CEN, Xichun PAN, authorCompany=null, correspAuthors=Yanyan CEN, Xichun PAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2026 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, 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=1320436307252330553, articleId=1320436303976579115, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=靶向宿主线粒体呼吸：青蒿素衍生物通过上调抗菌性自噬增强巨噬细胞清除细菌的免疫代谢机制, columnId=1320434418343329969, journalTitle=陆军军医大学学报, columnName=论著·基础医学, runingTitle=null, highlight=null, articleAbstract=
目的

基于宿主线粒体呼吸，探究一种新的青蒿素衍生物（disuccinate artemisinin， DA）通过上调巨噬细胞抗菌性自噬从而促进细菌清除的作用和机制。

方法

实验采用大肠杆菌菌株ATCC 35218和FITC-K12荧光细菌感染小鼠巨噬细胞株RAW264.7，采用荧光成像检测不同时间与不同剂量下巨噬细胞吞噬细菌数量，确定药物适宜剂量与最佳时间点；采用平板菌落计数法、Western blot、免疫荧光共定位等方法，确定药物对巨噬细胞抗菌性自噬的影响；采用自噬抑制剂3-甲基腺嘌呤（3-methyladenine，3-MA）和巴夫洛霉素A1（bafilomycin A1），通过平板菌落计数法、免疫荧光共定位等方法，检测自噬抑制对DA作用的影响；采用低糖培养基对细胞进行葡萄糖剥夺，通过荧光细菌计数和免疫荧光共定位观察葡萄糖剥夺对药物作用的影响；采用糖酵解激活剂寡霉素A（oligomycin A）与糖酵解抑制剂2-脱氧葡萄糖（2-deoxy-d-glucose，2-DG），通过荧光细菌计数和免疫荧光共定位观察糖酵解干预对药物作用的影响；采用线粒体呼吸激活剂碳酰氰-4-三氟甲氧基苯腙（carbonyl cyanide 4-trifluoromethoxy phenylhydrazone，FCCP）和线粒体呼吸抑制剂鱼藤酮（rotenone），通过荧光细菌计数、Western blot共定位观察线粒体呼吸干预对药物作用的影响；通过细胞能量代谢检测巨噬细胞耗氧率（oxygen consumption rate， OCR）确定药物对巨噬细胞线粒体呼吸的影响。

结果

细菌吞噬实验显示，DA可以浓度依赖地促进巨噬细胞吞噬和清除大肠杆菌（P<0.05），对耐药菌ATCC 35218和敏感菌K12均有效，最佳工作浓度为10 μg/mL，观察吞噬和清除的时间点分别为1 h和4 h（P<0.01）。免疫荧光和免疫印迹结果表明，DA通过上调抗菌性自噬发挥作用（P<0.01），在自噬激活抑制时仍有效（P<0.01），但自噬流抑制导致其失去作用（P<0.01）。在葡萄糖剥夺条件下，DA仍能上调巨噬细胞抗菌性自噬（P<0.01）；不论是激活还是抑制糖酵解，均导致DA上调巨噬细胞抗菌性自噬作用受限（P<0.01）。激活线粒体最大呼吸后，DA抑制巨噬细胞吞噬细菌并且不能上调抗菌性自噬（P<0.01）；阻断线粒体呼吸后，DA仍能上调巨噬细胞吞噬细菌能力和抗菌性自噬（P<0.01）。细胞能量代谢分析结果表明，DA可恢复细菌感染导致的巨噬细胞线粒体最大呼吸、线粒体保留呼吸和线粒体呼吸相关ATP生成受损，具有上调线粒体呼吸的作用（P<0.01）。

结论

DA通过改善细菌感染时的巨噬细胞线粒体呼吸，从而上调抗菌性自噬以促进清除细菌，是一种靶向线粒体呼吸的宿主导向抗感染候选药物。

, authors=王攀, 鲍晨震, 朱婷, 岑彦艳, 潘夕春, authorsList=王攀, 鲍晨震, 朱婷, 岑彦艳, 潘夕春, authorCompany=null, correspAuthors=岑彦艳, 潘夕春, authorNote=null, correspAuthorsNote=
潘夕春，E-mail：
岑彦艳，E-mail：
PAN Xichun，E-mail：
CEN Yanyan，E-mail：
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A：The structure of DA；B and C：The effects of different concentrations of DA on the phagocytosis of E. coli by RAW264.7 cells （1 h）；D and E：The effecs of 10 μg/mL DA on the uptake （1 h） and clearance （4 h） of E.coli by RAW264.7 cells

, figureFileSmall=OksFPR7QucM8u8p/VXL/bg==, figureFileBig=6nNBBIKJ36Ycitcwq1DgkQ==, tableContent=null), ArticleFig(id=1320436313480872033, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=EN, label=Figure 2, caption=Influence of DA on antibacterial autophagy of macrophages, figureFileSmall=51BYpseYakB0sFK3L8jXMQ==, figureFileBig=ikYFkpo2qskgP83YjATxxg==, tableContent=null), ArticleFig(id=1320436313787056226, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=CN, label=图2, caption=DA对巨噬细胞抗菌性自噬的影响

A and B：The effects of MDC on the DA-enhanced phagocytosis of E. coli by RAW264.7 cells；C：The effects of DA on the colocalization of internalized E.coli with LC3B in RAW264.7 cells at 1 h and 4 h post-exposure；D and E：The effects of DA on LC3B expression in RAW264.7 cells at 1 h post-exposure to E.coli

, figureFileSmall=51BYpseYakB0sFK3L8jXMQ==, figureFileBig=ikYFkpo2qskgP83YjATxxg==, tableContent=null), ArticleFig(id=1320436313849970787, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=EN, label=Figure 3, caption=Effect of autophagy inhibition on DA-upregulated antibacterial autophagy in macrophages, figureFileSmall=NbtSHDBbT7wfphlxjW1RLA==, figureFileBig=8ZJf10zSeja7B1C/KVnT7g==, tableContent=null), ArticleFig(id=1320436313933856868, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=CN, label=图3, caption=自噬抑制对DA上调巨噬细胞抗菌性自噬的影响

A：The effects of 3-MA or bafilomycin A1 on the DA-enhanced phagocytosis of E.coli by RAW264.7 cells；B：The effects of 3-MA or bafilomycin A1 on the DA-enhanced colocalization of internalized E.coli with LC3B in RAW264.7 cells at 1 h post-exposure to E.coli

, figureFileSmall=NbtSHDBbT7wfphlxjW1RLA==, figureFileBig=8ZJf10zSeja7B1C/KVnT7g==, tableContent=null), ArticleFig(id=1320436314177126501, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=EN, label=Figure 4, caption=Effect of glucose deprivation on DA-enhanced antibacterial autophagy in macrophages, figureFileSmall=J2haUSfihIcYPINDU5sB1g==, figureFileBig=YKTEV9Y6YDMhG5wKPiI0FA==, tableContent=null), ArticleFig(id=1320436315846459494, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=CN, label=图4, caption=葡萄糖剥夺对DA促进巨噬细胞抗菌性自噬的影响

A and B：The effects of glucose deprivation on the DA-enhanced phagocytosis of E. coli by RAW264.7 cells；C：The effects of glucose deficiency on the DA-enhanced colocalization of internalized E. coli with LC3B in RAW264.7 cells at 1 h post-exposure to E.coli

, figureFileSmall=J2haUSfihIcYPINDU5sB1g==, figureFileBig=YKTEV9Y6YDMhG5wKPiI0FA==, tableContent=null), ArticleFig(id=1320436315947122791, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=EN, label=Figure 5, caption=Effect of glycolytic intervention on DA-enhanced antibacterial autophagy in macrophages, figureFileSmall=Gu1XEIAQxQ1ejbhHpMI6TQ==, figureFileBig=6bfnMrHC17RG4WtAnQqIUQ==, tableContent=null), ArticleFig(id=1320436316031008872, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=CN, label=图5, caption=糖酵解干预对DA促进巨噬细胞抗菌性自噬的影响

A and B：The effects of oligomycin A and 2-DG on the DA-enhanced phagocytosis of E. coli by RAW264.7 cells；C：The effects of oligomycin A and 2-DG on the DA-enhanced colocalization of internalized E. coli with LC3B in RAW264.7 cells at 1 h post-exposure to E.coli

, figureFileSmall=Gu1XEIAQxQ1ejbhHpMI6TQ==, figureFileBig=6bfnMrHC17RG4WtAnQqIUQ==, tableContent=null), ArticleFig(id=1320436316123283561, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=EN, label=Figure 6, caption=Effect of mitochondrial respiration intervention on DA-enhanced antibacterial autophagy in macrophages, figureFileSmall=N+HKSGtHUbCaj/ki+K1cKw==, figureFileBig=1sa7YR8qQt0BwzgUnQhqWw==, tableContent=null), ArticleFig(id=1320436316249112682, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1320436303976579115, language=CN, label=图6, caption=线粒体呼吸干预对青蒿素衍生物DA促进巨噬细胞抗菌性自噬的影响

A and B：The effects of FCCP and rotenone on the DA-enhanced phagocytosis of E. coli by RAW264.7 cells；C：The effects of FCCP and rotenone on the DA-enhanced colocalization of internalized E. coli with LC3B in RAW264.7 cells at 1 hour post-exposure to E.coli； D and E：Observation of the effects of DA on mitochondrial respiration in RAW264.7 cells at 1 h post-exposure to E.coli by Seahorse assay

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靶向宿主线粒体呼吸：青蒿素衍生物通过上调抗菌性自噬增强巨噬细胞清除细菌的免疫代谢机制
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王攀 , 鲍晨震 , 朱婷 , 岑彦艳 , 潘夕春
陆军军医大学学报 | 论著·基础医学 2026,48(4): 420-432
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陆军军医大学学报 |论著·基础医学 2026 , 48 (4) : 420 -432
靶向宿主线粒体呼吸：青蒿素衍生物通过上调抗菌性自噬增强巨噬细胞清除细菌的免疫代谢机制
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王攀, 鲍晨震, 朱婷, 岑彦艳 , 潘夕春
作者信息
  • 1陆军军医大学（第三军医大学）药学与检验医学系药理学教研室，重庆
通讯作者:
潘夕春，E-mail：
岑彦艳，E-mail：
PAN Xichun，E-mail：
CEN Yanyan，E-mail：
Targeting host mitochondrial respiration: artemisinin derivative potentiates macrophage bacterial clearance by up-regulating antibacterial autophagy via immunometabolic mechanism
Pan WANG, Chenzhen BAO, Ting ZHU, Yanyan CEN , Xichun PAN
Affiliations
  • 1Department of Pharmacology， Faculty of Pharmacy and Laboratory Medicine， Army Medical University（Third Milirary Medical University）， Chongqing， China
出版时间: 2026-02-28 doi: 10.16016/j.2097-0927.202512047
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摘要
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目的

基于宿主线粒体呼吸，探究一种新的青蒿素衍生物（disuccinate artemisinin， DA）通过上调巨噬细胞抗菌性自噬从而促进细菌清除的作用和机制。

方法

实验采用大肠杆菌菌株ATCC 35218和FITC-K12荧光细菌感染小鼠巨噬细胞株RAW264.7，采用荧光成像检测不同时间与不同剂量下巨噬细胞吞噬细菌数量，确定药物适宜剂量与最佳时间点；采用平板菌落计数法、Western blot、免疫荧光共定位等方法，确定药物对巨噬细胞抗菌性自噬的影响；采用自噬抑制剂3-甲基腺嘌呤（3-methyladenine，3-MA）和巴夫洛霉素A1（bafilomycin A1），通过平板菌落计数法、免疫荧光共定位等方法，检测自噬抑制对DA作用的影响；采用低糖培养基对细胞进行葡萄糖剥夺，通过荧光细菌计数和免疫荧光共定位观察葡萄糖剥夺对药物作用的影响；采用糖酵解激活剂寡霉素A（oligomycin A）与糖酵解抑制剂2-脱氧葡萄糖（2-deoxy-d-glucose，2-DG），通过荧光细菌计数和免疫荧光共定位观察糖酵解干预对药物作用的影响；采用线粒体呼吸激活剂碳酰氰-4-三氟甲氧基苯腙（carbonyl cyanide 4-trifluoromethoxy phenylhydrazone，FCCP）和线粒体呼吸抑制剂鱼藤酮（rotenone），通过荧光细菌计数、Western blot共定位观察线粒体呼吸干预对药物作用的影响；通过细胞能量代谢检测巨噬细胞耗氧率（oxygen consumption rate， OCR）确定药物对巨噬细胞线粒体呼吸的影响。

结果

细菌吞噬实验显示，DA可以浓度依赖地促进巨噬细胞吞噬和清除大肠杆菌（P<0.05），对耐药菌ATCC 35218和敏感菌K12均有效，最佳工作浓度为10 μg/mL，观察吞噬和清除的时间点分别为1 h和4 h（P<0.01）。免疫荧光和免疫印迹结果表明，DA通过上调抗菌性自噬发挥作用（P<0.01），在自噬激活抑制时仍有效（P<0.01），但自噬流抑制导致其失去作用（P<0.01）。在葡萄糖剥夺条件下，DA仍能上调巨噬细胞抗菌性自噬（P<0.01）；不论是激活还是抑制糖酵解，均导致DA上调巨噬细胞抗菌性自噬作用受限（P<0.01）。激活线粒体最大呼吸后，DA抑制巨噬细胞吞噬细菌并且不能上调抗菌性自噬（P<0.01）；阻断线粒体呼吸后，DA仍能上调巨噬细胞吞噬细菌能力和抗菌性自噬（P<0.01）。细胞能量代谢分析结果表明，DA可恢复细菌感染导致的巨噬细胞线粒体最大呼吸、线粒体保留呼吸和线粒体呼吸相关ATP生成受损，具有上调线粒体呼吸的作用（P<0.01）。

结论

DA通过改善细菌感染时的巨噬细胞线粒体呼吸，从而上调抗菌性自噬以促进清除细菌，是一种靶向线粒体呼吸的宿主导向抗感染候选药物。

青蒿素衍生物  /  巨噬细胞  /  抗菌性自噬  /  线粒体呼吸
Objective

To investigate the effect and mechanism of a novel artemisinin derivative, disuccinate artemisinin (DA), in enhancing bacterial clearance by upregulating antibacterial autophagy in macrophages through targeting host mitochondrial respiration.

Methods

The experiment utilized E. colistrains ATCC 35218 and FITC-labeled K12 to infect the mouse macrophage cell line RAW264.7. Phagocytosis of bacteria by macrophages under different time points and doses was assessed via fluorescence imaging to determine the optimal drug dosage and time point. The impact of the drug on antibacterial autophagy in macrophages was evaluated using colony counting, Western blotting and immunofluorescence co-localization assay. Autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin A1 were employed to examine the effect of autophagy suppression on drug efficacy through colony counting and immunofluorescence co-localization. Glucose deprivation was induced using low-glucose medium, and its influence on drug action was observed via fluorescent bacterial counting and immunofluorescence co-localization. Glycolytic intervention was investigated using the glycolytic activator oligomycin A and inhibitor 2-deoxy-D-glucose (2-DG), with effects monitored through fluorescent bacterial counting and immunofluorescence co-localization. Mitochondrial respiration was modulated with the activator carbonyl cyanide 4-trifluoromethoxy phenylhydrazone (FCCP) and inhibitor rotenone, and its impact on drug action was assessed via fluorescent bacterial counting and immunofluorescence co-localization. The effect of the drug on mitochondrial respiration in macrophages was determined by measuring the oxygen consumption rate (OCR) using cellular energy metabolism assays.

Results

DA concentration-dependently enhanced macrophage phagocytosis and clearance of both drug-resistant ATCC35218 and sensitive K12 E. coli (P<0.05). Immunofluorescence and immunoblotting demonstrated DA upregulated antibacterial autophagy (P<0.01), remaining effective when autophagy initiation was blocked (P<0.01) but losing efficacy upon autophagic flux inhibition (P<0.01). Under glucose deprivation, DA retained its autophagy-enhancing effect (P<0.01). Both activation and inhibition of glycolysis limited DA’s efficacy (P<0.01). Maximizing mitochondrial respiration with FCCP abolished DA’s pro-phagocytic and autophagy-enhancing effects (P<0.01), whereas respiratory blockade with rotenone preserved them (P<0.01). Metabolic analysis showed DA restored infection-impaired maximal mitochondrial respiration, spare respiratory capacity, and ATP production (P<0.01).

Conclusion

DA enhances bacterial clearance by upregulating antibacterial autophagy through restoration of mitochondrial respiration in infected macrophages, representing a host-directed anti-infective candidate targeting mitochondrial metabolism.

artemisinin derivative  /  macrophage  /  antibacterial autophagy  /  mitochondrial respiration
王攀, 鲍晨震, 朱婷, 岑彦艳, 潘夕春. 靶向宿主线粒体呼吸：青蒿素衍生物通过上调抗菌性自噬增强巨噬细胞清除细菌的免疫代谢机制. 陆军军医大学学报, 2026 , 48 (4) : 420 -432 . DOI: 10.16016/j.2097-0927.202512047
Pan WANG, Chenzhen BAO, Ting ZHU, Yanyan CEN, Xichun PAN. Targeting host mitochondrial respiration: artemisinin derivative potentiates macrophage bacterial clearance by up-regulating antibacterial autophagy via immunometabolic mechanism[J]. Journal of Army Medical University, 2026 , 48 (4) : 420 -432 . DOI: 10.16016/j.2097-0927.202512047
正文
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鉴于目前细菌耐药快速进展与新型抗菌药物研发相对滞后的突出矛盾，从宿主的角度出发，开发能增强机体抗细菌感染能力的治疗措施，已成为一种值得探索的可行策略［1］。宿主导向治疗（host-directed therapy， HDT）策略通过激活机体自身的免疫防御，如增强免疫细胞活性、平衡炎症反应等机制清除病原体，具有降低细菌耐药风险、治疗难治性感染（如超级细菌感染和混合感染等）的潜在价值，已成为抗菌药物研发的新焦点［2-3］。因此，开发基于HDT策略的新型抗细菌感染药物，并探究其作用机制和靶点，具有重要的临床意义。
巨噬细胞是天然免疫系统中负责感知和清除病原体、参与炎症反应、提呈抗原的重要细胞群［4］。在细菌入侵机体时，巨噬细胞吞噬入侵细菌，然后经溶酶体途径降解［4］。由吞噬作用形成的含细菌囊泡（bacteria-containing vesicles， BCVs）也可进一步招募自噬关键蛋白，如剪切成熟的微管相关蛋白轻链3（microtubule- associated protein light chain 3，LC3）形成自噬体，后者与溶酶体融合形成自噬溶酶体（autolysosome），最后经溶酶体途径降解细菌，该过程称抗菌性自噬或异自噬［5］。研究表明，采用小分子药物上调巨噬细胞的抗菌性自噬，可显著促进机体吞噬和清除胞内生存菌，如伤寒沙门菌、结核分枝杆菌、多重耐药金黄色葡萄球菌，并减轻病原菌感染导致的急性炎症损伤，从而提高感染小鼠的生存率［6］。与之相反，抑制机体抗菌性自噬，或者病原菌通过分泌效应蛋白劫持自噬途径，将导致结核分枝杆菌、铜绿假单胞菌和多重耐药金黄色葡萄球菌等胞内生存菌的免疫逃逸甚至增殖［7-8］。总之，上调巨噬细胞的抗菌性自噬有利于清除细菌，而抑制抗菌性自噬损害清除功能，甚至导致胞内生存菌的免疫逃逸甚至增殖［4-5］。因此，巨噬细胞的抗菌性自噬是HDT类抗细菌感染药物的理想靶点。然而，现有的自噬激活药物（如雷帕霉素、伊马替尼、维生素D3等）缺乏靶向性与特异性，可能导致代谢紊乱、免疫失衡，还有诱导耐药进展的潜在风险［6］。目前，临床实践中尚缺乏能特异性、安全地诱导巨噬细胞抗菌性自噬的HDT类药物。
为解决上述问题，本研究聚焦一种新的青蒿素衍生物（disuccinate artemisinin， DA），基于线粒体呼吸机制探究其上调巨噬细胞抗菌性自噬的作用，旨在揭示线粒体呼吸在DA上调巨噬细胞抗菌性自噬中的关键作用，为开发基于线粒体代谢稳态调控的HDT类抗感染药物提供候选药物。
1　材料与方法
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1.1　主要试剂与实验仪器
小鼠单核/巨噬细胞系RAW264.7、产超广谱β-内酰胺酶（extended spectrum β-lactamase， ESBL）大肠杆菌（Escherichia coli， E. coli）菌株ATCC 35218购自美国典型培养物保藏中心；胎牛血清、低热原DMEM高糖培养基和低糖培养基、FITC标记大肠杆菌K12、Alexa FluorTM Plus 555偶联羊抗小鼠IgG二抗、辣根过氧化物酶标记羊抗小鼠IgG二抗购自美国Invitrogen公司；DAPI、Western blot检测试剂盒、IP细胞裂解液购自中国碧云天公司；LC3B、热休克蛋白90抗体（heat shock protein 90，HSP90；1∶1 000）抗体购自美国Cell Signaling公司；3-甲基腺嘌呤（3-methyladenine， 3-MA）、巴夫洛霉素A1（bafilomycin A1）、单丹磺酰戊二胺（monodansyl cadaverine， MDC）、寡霉素A（oligomycin A）、2-脱氧葡萄糖（2-deoxy-d-glucose， 2-DG）、碳酰氰-4-三氟甲氧基苯腙（carbonyl cyanide 4-trifluoromethoxy phenylhydrazone，FCCP）、鱼藤酮（rotenone）、抗霉素A购自中国MedChemExpress公司；DA由本课题组前期合成，分子式为C19H28O8，化学名为二氢青蒿素-1，2-α-琥珀酸-乙二醇-琥珀酸双酯；Seahorse XF细胞线粒体压力测定试剂盒、Seahorse XFe96细胞代谢分析系统购自日本Agilent公司；化学发光成像仪购自美国Bio-rad公司；激光共聚焦显微镜购自德国Zeiss公司。
1.2　细胞与细菌培养
RAW264.7采用含10%胎牛血清的DMEM高糖培养基在37 ℃、5%CO2恒温培养箱中培养。当细胞融合度达80%，用移液管吹下细胞，并按1∶3比例进行传代，选用处于对数生长期的细胞进行细胞实验。
在LB平板上挑取ATCC 35218单菌落接种到LB培养基中，在37 ℃振荡培养箱中活化至对数生长期，以4 ℃、8 000 r/min离心5 min，收集细菌并用DMEM漂洗3次，调整浓度到1×109 CFU/mL备用。
1.3　吞噬细菌实验
将生长良好的RAW264.7接种到预置盖玻片的24孔板（1×105 个/孔）。细胞贴壁伸展后，加入FITC-K12荧光细菌和DA（10 μg/mL）对细胞进行处理，其中DA和其他干预药物提前1 h加入，然后加入FITC-K12荧光细菌（感染复数为10，即1×106 CFU/孔）。处理完毕后用PBS（0.01 mol/L， pH值为7.2~7.4）洗去胞外细菌，依次用4%多聚甲醛固定10 min、DAPI（5 μg/mL）染细胞核5 min，封片后在激光共聚焦显微镜下观察细菌内化情况，并采集图像，定量分析每100个细胞的细菌吞噬数量。基于荧光标记细菌开展以下实验：①量效关系实验，分为Medium组、E.coli组，E.coli+DA组（5、10、20 μg/mL），细菌加入1 h后终止实验，并统计结果（n=10）；②时效关系实验，分为1 h-E.coli组、1 h-E.coli+DA组、4h-E. coli组、4h-E. coli+DA组（n=15），细菌加入1 h或4 h后终止实验并统计结果；③葡萄糖剥夺实验，分为High glucose-Medium组、High glucose-E.coli组、High glucose-E.coli+DA组、Low glucose-Medium组、Low glucose-E.coli组、Low glucose-E.coli+DA组（n=8），分别采用正常DMEM和低糖DMEM培养基培养，细菌加入1 h后终止实验，并统计结果；④糖酵解干预实验，分为Oligomycin A-E.coli组、Oligomycin A-E.coli+DA组、2-DG-E.coli、2-DG-E.coli+DA组（n=8），分别添加寡霉素A（15 μmol/L）或2-DG（5 mmol/L）干预糖酵解，细菌加入1 h后终止实验，并统计结果；⑤线粒体呼吸干预实验，分为FCCP-E.coli组、FCCP-E.coli+DA组、Rotenone-E.coli组、Rotenone-E.coli+DA组（n=8），分别加入FCCP（10 μmol/L）或鱼藤酮（0.5 μmol/L）干预线粒体呼吸，细菌加入1 h后终止实验，并统计结果。基于大肠杆菌ATCC 35218开展以下实验：⑥MDC干预实验，分为MDC-E.coli组、MDC-E.coli+DA组、Control-E.coli组、Control-E.coli+DA组（n=5），加入大肠杆菌（1×106 CFU/孔），MDC（50 μmol/L）与DA（10 μg/mL）同时加入，细菌加入1 h后终止实验，PBS洗去胞外细菌并刮下细胞，超声裂解细胞（功率100 W，超声5 min，工作10 s/间隔10 s）后，将裂解物涂布到LB平板上培养过夜，菌落计数后，根据平板菌落计数结果统计每100个细胞所吞噬细菌数量；⑦自噬干预实验，分为Control-E.coli组、Control-E.coli+DA组、3-MA-E.coli组、3-MA-E.coli+DA组、Bafilomycin A1-E.coli组和Bafilomycin A1-E.coli+DA组（n=6），加入大肠杆菌1×106 CFU/孔，3-MA（4 mmol/L）或巴夫洛霉素A1（1 μmol/L）与DA（10 μg/mL）同时加入，细菌加入1 h后终止实验，并进行菌落计数和统计，操作同MDC干预实验。
1.4　免疫荧光实验
抗菌性自噬采用免疫荧光法，观察RAW264.7细胞内LC3B与大肠杆菌的共定位进行观察。将RAW264.7接种到预置盖玻片的24孔板（1×105 个/孔），待细胞伸展，加入FITC-K12荧光细菌（1×106 CFU/孔）、DA（10 μg/mL）及干预药物进行处理。处理完毕后，用PBS洗去胞外细菌，依次用4%多聚甲醛固定10 min、细胞封闭（PBS+1%BSA）20 min，并通透（PBS+0.1%Triton X-100）20 min，然后用小鼠LC3B抗体（1∶200）在4 ℃孵育过夜和Alexa FluorTM Plus 555偶联羊抗小鼠IgG二抗（1∶200）在室温孵育2 h，最后用DAPI（5 μg/mL）染细胞核5 min，封片后在激光共聚焦显微镜下观察，并采集图像，采用剖面模式分析胞内绿色荧光（细菌）与红色荧光（LC3B）共定位情况。抗菌性自噬干预实验包括：①时效关系实验，分为1 h-Medium组、1 h-E.coli组、1h-E.coli+DA组、4 h-Medium组、4 h-E.coli组、4 h-E.coli+DA组；②葡萄糖剥夺实验；③自噬干预实验；④糖酵解干预实验；⑤线粒体呼吸干预实验。除时效关系实验外，其余实验分组同“1.3”部分的吞噬细菌实验。
1.5　Western blot检测
将RAW264.7接种到6孔板中（2×106个/孔）。细胞贴壁后，加入ATCC 35218和DA处理，其中DA提前1 h加入，然后加入细菌（2×107 CFU/孔）处理1 h。处理完毕后，用PBS洗去胞外细菌，用IP细胞裂解液提取总蛋白并定量。各组取20 μg蛋白用于Western blot实验，按照试剂盒说明书进行操作，主要流程如下：在15%分离胶中进行SDS-PAGE电泳直至蛋白条带完全分开；用0.2 μm PVDF膜进行湿法转膜，转膜条件为冰浴内恒流（250 mA）电转2 h；转印好的膜在室温封闭（PBS+0.5%tween-20+5%BSA）2 h；在4 ℃用小鼠LC3B抗体（1∶1 000）孵育条带过夜，内参采用HSP90抗体（1∶1 000）；洗膜去除非特异结合的抗体，加入辣根过氧化物酶标记羊抗小鼠IgG二抗（1∶10 000）室温孵育2 h；洗膜去除非特异结合的二抗后，在化学发光成像仪下对条带进行显影和分析（n=3）。
1.6　细胞能量代谢检测
细胞代谢分析采用Seahorse XF细胞线粒体压力测定试剂盒进行。实验参考试剂盒说明书中氧气消耗速率（oxygen consumption rate， OCR）实验方案进行，主要流程如下：将生长良好的RAW264.7接种到XF96细胞培养板中（1.5×104 个/孔），总体积为80 μL，自然沉降1 h待细胞均匀贴壁后，移至培养箱中培养过夜，至细胞完全伸展、融合度约90%；实验分组为Medium组、E.coli（1.5×105 CFU/孔）组和E.coli+DA（10 μg/mL）组，DA提前1 h加入，然后加入细菌处理1 h；探针板每孔加入200 μL无菌水，37 ℃，过夜水化；检测当天配制检测液，药物处理结束后，用检测液清洗细胞2次，保留培养孔内检测液终体积为180 μL，继续培养1 h；用检测液将寡霉素A（15 μmol/L）、FCCP（10 μmol/L）、鱼藤酮/抗霉素A（均为0.5 μmol/L）混合液配制为相应浓度，按要求加入到探针板加药孔内；将探针板和水化板组合，放入细胞代谢分析系统托盘中进行校准；将水化板取下并将细胞培养板放到托盘上，测量细胞能量代谢；测量结束后对细胞进行计数，对测量数据进行归一化处理和统计（n=3）。
1.7　统计学分析
实验结果采用x¯±s记录，数据分析采用独立样本t检验或单因素方差分析进行分析，在GraphPad Prism 9.0中统计。所有检验均双侧，P<0.05为差异具有统计学意义。
2　结果
收起
2.1　青蒿素衍生物DA提高巨噬细胞清除大肠杆菌能力
DA由本课题组前期合成，分子式为C14H28O8（图1A）。为确定DA的最佳剂量与检测时间点，采用FITC-K12荧光细菌，通过荧光成像观察不同浓度和处理时间条件下DA对RAW264.7吞噬和降解细菌的影响。成像结果显示，作为对照的Medium组无内吞细菌；细菌组（E.coli组）在吞噬细菌1 h后，胞内仅有少量细菌（绿色亮点），且仅少数巨噬细胞吞噬细菌；而DA显著促进巨噬细胞吞噬细菌，并随DA浓度升高，其吞噬作用增强。结果表明，DA在短时间内（1 h）浓度依赖地增强巨噬细胞对于大肠杆菌的吞噬作用（P<0.05，图1B、C）。
在确认DA具有增加巨噬细胞吞噬细菌的作用后，本研究继续观察DA促进巨噬细胞吞噬细菌的动态过程。基于预实验结果，选择1 h和4 h作为观察时间点，选择中等剂量DA（10 μg/mL）作为干预剂量。结果显示：在巨噬细胞吞噬细菌1 h后，与1 h-E.coli组比较，1 h-E.coli+DA组巨噬细胞吞噬细菌数量显著增加，再次表明DA在短时间内显著促进巨噬细胞吞噬细菌（P<0.01）；在巨噬细胞吞噬细菌4 h后，4 h-E.coli+DA组较4 h-E.coli组细胞内平均细菌数量显著下降（P<0.01，图1D、E），证实DA处理在较长时间后显著促进巨噬细胞杀灭细菌。提示DA对巨噬细胞吞噬和清除细菌的促进作用，该作用呈现显著的浓度与时间依赖性，是一种潜在的HDT类抗细菌感染候选药物。
2.2　DA上调巨噬细胞抗菌性自噬
为探究DA作用是否与经典内吞途径有关，采用网格蛋白抑制剂MDC抑制巨噬细胞内吞，通过平板菌落计数观察内吞抑制对DA促进吞噬大肠杆菌作用的影响。结果表明：未经MDC处理时，DA处理1 h后巨噬细胞吞噬ATCC 35218能力显著提高（P<0.01），与前述结果一致；而MDC处理后，MDC-E.coli组和MDC-E.coli+DA组的细胞内平均细菌数量（每100个细胞吞噬细菌数量）均显著下降（P<0.01），并且DA仍能显著上调巨噬细胞吞噬ATCC 35218的数量（P<0.01，图2A、B）。结果证实，DA促进巨噬细胞吞噬大肠杆菌的作用与经典内吞途径无关。
为进一步探讨DA是否通过抗菌性自噬发挥作用，采用免疫荧光观察巨噬细胞内FITC标记大肠杆菌（绿色荧光）与自噬标记分子LC3B（红色荧光）的共定位情况。在吞噬大肠杆菌1 h后，1 h-E.coli组巨噬细胞内大肠杆菌和LC3B均呈散点状分布，且部分发生共定位，即部分含大肠杆菌囊泡（Escherichia-containing vesicle，ECV）为含大肠杆菌自噬体（Escherichia-containing autophagosome，ECA）；DA处理组胞内菌量显著增多，且全部与LC3B斑点共定位即全部为ECA，提示DA的作用确实与促进抗菌性自噬有关（图2C）。在吞噬大肠杆菌4 h后，4 h-E.coli组的细胞细内菌量较1 h-E.coli组未减少，且多数大肠杆菌不与LC3B共定位；而4 h-E.coli+DA组的细胞内细菌量显著减少，并且所有大肠杆菌不与LC3B共定位（图2C）。结果提示，DA在早期（1 h）上调巨噬细胞抗菌性自噬的激活促进吞噬大肠杆菌，随后（4 h）促进巨噬细胞ECA的降解以清除细菌；由于此时多数LC3B随ECA被降解，胞内残留的细菌与LC3B无明显共定位。
为确认DA上调抗菌性自噬，采用Western blot观察DA对巨噬细胞吞噬细菌时LC3B表达的影响（1 h）。结果显示，细菌组LC3B-Ⅱ未显著上调，但DA处理后LC3B-Ⅱ显著上调（P<0.05，图2D、E），再次证实DA具有上调巨噬细胞抗菌性自噬的作用。
2.3　自噬流抑制损害DA上调巨噬细胞抗菌性自噬的作用
为探讨DA的作用是否与巨噬细胞抗菌性自噬有关，采用自噬激活抑制剂3-MA（抑制PI3K-Ⅲ）和自噬降解抑制剂巴夫洛霉素A1（抑制自噬溶酶体）干预自噬。平板菌落计数实验（1 h）表明：Control-E.coli组与Control-E.coli+DA组比较，DA显著提高巨噬细胞吞噬大肠杆菌（ATCC 35218）能力（P<0.01），与前述结果一致；在3-MA干预下，巨噬细胞吞噬细菌数量显著减少（P<0.01），DA仍能促进巨噬细胞吞噬细菌、但作用被削弱（P<0.01），表明DA的作用依赖于正常的自噬激活；在巴夫洛霉素A1干预下，虽然Bafilomycin A1-E.coli组的胞内细菌数量较Control-E.coli组显著增加（P<0.01），但DA促进巨噬细胞吞噬细菌的作用也消失，表明DA的作用依赖于正常的自噬通量（图3A）。结果提示，巨噬细胞吞噬大肠杆菌及DA的作用均依赖于自噬，抑制自噬激活导致DA的作用削弱、抑制自噬降解导致DA的作用丧失。
实验进一步采用免疫荧光技术探究自噬抑制对DA上调抗菌性自噬（E.coli-LC3B共定位）的影响，确认DA通过激活抗菌性自噬发挥作用。结果显示：在Control-E.coli组中细菌内吞较少、且以ECV为主即多数细菌未与LC3B共定位，而DA显著增加胞内细菌数量且全部为ECA，再次证实DA上调抗菌性自噬；在3-MA干预下，细菌内吞显著减少、部分为ECA，DA增加胞内细菌数量且全部为ECA，表明DA仍能上调抗菌性自噬；在巴夫洛霉素A1干预下，细菌内吞显著增多且以ECA为主，DA处理不再进一步增加胞内细菌数量（图3B）。该结果提示，DA通过上调抗菌性自噬促进巨噬细胞吞噬大肠杆菌，该作用依赖于正常的自噬通量，但DA可能通过PI3K-Ⅲ非依赖途径上调抗菌性自噬。
2.4　葡萄糖剥夺损害DA上调巨噬细胞抗菌性自噬的作用
为探究DA的作用是否与能量供应有关，采用低糖培养基观察葡萄糖剥夺对巨噬细胞抗菌性自噬的影响。细菌吞噬实验（1 h）表明，在高糖培养基中DA显著促进巨噬细胞吞噬大肠杆菌（P<0.01）；在低糖培养基中，巨噬细胞吞噬活性显著降低（P<0.01），虽然DA仍能显著促进吞噬细菌（P<0.01），但远低于在高糖培养基中的活性（P<0.01，图4A、B）。免疫荧光实验（1 h）表明：在高糖培养基中，DA上调抗菌性自噬；在低糖培养基中，虽然DA仍能上调抗菌性自噬，但作用减弱（图4C）。结果提示，葡萄糖剥夺损害DA上调巨噬细胞抗菌性自噬的作用。
2.5　糖酵解干预限制DA上调巨噬细胞抗菌性自噬的作用
为探讨糖酵解干预对DA作用的影响，采用寡霉素A激活糖酵解及采用2-DG抑制糖酵解，观察巨噬细胞吞噬细菌能力及抗菌性自噬情况（1 h）。荧光细菌吞噬实验表明，Control-E.coli+DA组与Control-E.coli组相比，DA显著促进巨噬细胞吞噬大肠杆菌（P<0.01）；在寡霉素A的干预下，巨噬细胞吞噬能力显著降低（P<0.01），DA仅略增加胞内菌量（P<0.05）；在2-DG的干预下，巨噬细胞吞噬细菌量也显著降低（P<0.01），DA也仅轻度增加胞内菌量（P<0.05，图5A、B）。结果提示，不论激活还是抑制糖酵解均损害巨噬细胞吞噬细菌能力并损害DA的上调作用。免疫荧光实验结果显示：在Control-E.coli+DA组中，DA能显著上调抗菌性自噬，与前述结果一致；在寡霉素A的干预下，DA上调抗菌性自噬的作用减弱；在2-DG的干预下，DA也仅能轻度上调抗菌性自噬，作用减弱（图5C）。结果表明，不论激活还是抑制糖酵解均能限制DA上调巨噬细胞抗菌性自噬的作用，提示糖酵解与DA的作用有关但不是关键作用机制。
2.6　DA通过改善巨噬细胞线粒体呼吸上调抗菌性自噬
为探讨DA的作用是否与改善线粒体呼吸有关，采用FCCP激活线粒体呼吸及采用鱼藤酮抑制线粒体呼吸，观察巨噬细胞吞噬能力及抗菌性自噬的改变。荧光细菌吞噬实验（1 h）显示：在Control-E.coli+DA组中，DA显著促进巨噬细胞吞噬大肠杆菌（P<0.01）；在FCCP-E.coli组中，与Control-E.coli组相比，巨噬细胞吞噬能力显著上升（P<0.01），DA处理后反而显著下降（P<0.01），提示DA与FCCP发生拮抗；在鱼藤酮的干预下，与Control-E.coli组相比，巨噬细胞吞噬细菌能力显著降低（P<0.01），DA仍能促进吞噬细菌（P<0.01，图6A、B）。结果提示DA与FCCP单用时均能促进吞噬细菌，但联用时发生拮抗导致细胞吞噬能力下降，提示DA可能也通过增强线粒体呼吸发挥作用；而线粒体呼吸抑制状态下，DA仍能上调巨噬细胞吞噬细菌能力。免疫荧光实验结果表明：在Control-E.coli+DA组中，DA显著上调抗菌性自噬，与前述结果一致；在FCCP的干预下，DA不能上调抗菌性自噬，无论FCCP单用还是联合DA均导致胞内不与细菌共定位的LC3斑点增多，提示FCCP激活其它自噬类型并拮抗DA的作用；在鱼藤酮的干预下，DA仍能上调抗菌性自噬（图6C）。结果提示，DA通过改善巨噬细胞线粒体呼吸上调抗菌性自噬，该作用在呼吸链阻断时依然存在。
为探讨DA对巨噬细胞线粒体呼吸的影响，采用细胞能量代谢分析实验测定大肠杆菌和DA处理后巨噬细胞的OCR动态变化。结果显示：E.coli组线粒体最大呼吸（FCCP诱导）、线粒体保留呼吸（寡霉素A诱导）及线粒体呼吸相关ATP产量均显著下降（P<0.01），而DA处理后上述线粒体呼吸功能异常均恢复正常（图6D、E）。结果证实，DA能逆转细菌感染所致的巨噬细胞线粒体呼吸抑制，从而上调抗菌性自噬以清除细菌。
3　讨论
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3.1　G-细菌耐药的严峻现状与临床挑战
全世界细菌耐药相关死亡人数约495万人/年，排名前3的病原菌依次为大肠杆菌、金黄色葡萄球菌和肺炎克雷伯菌［9］。我国临床分离病原菌中检出率排名前3的依次为大肠杆菌、肺炎克雷伯菌和金黄色葡萄球菌，与全球数据相似。在所有临床分离株中，G-菌检出率达71.7%，其中耐三代头孢菌素大肠杆菌检出率已达52.9%，表明以耐药大肠杆菌为代表的G-耐药菌已成为国内细菌耐药的优势菌株，亟需探究新的治疗策略。碳青霉烯类和氨基糖苷类是临床治疗G-耐药菌感染的主要抗生素，但存在毒性大、副作用多及价格昂贵等问题，亟需研发新的药物和疗法［10］。本研究选用的ATCC 35218菌株为产ESBL大肠杆菌，对三代头孢菌素、广谱青霉素类乃至β-内酰胺酶抑制剂复方制剂等药物均具有耐药性［11］。
3.2　DA作为新型HDT候选药物的潜在优势
青蒿素及其衍生物如双氢青蒿素、青蒿琥酯等是治疗疟疾的一线药物［12］。此外，近来的报道也显示青蒿素及其衍生物具有抗肿瘤、抗炎、抗感染等活性［13］。基于这些发现，本研究前期在青蒿琥酯结构基础上，设计了一个新的双琥珀酯衍生物，即在青蒿琥酯的琥珀酯侧链上再连接一个琥珀酸，命名为DA。在本研究中，DA对巨噬细胞吞噬和清除大肠杆菌耐药株（ATCC 35218）和敏感株（K12）均具有良好的促进作用，有望成为一种新的HDT类抗感染候选药物。DA的潜在优势包括：①DA对耐药菌和敏感菌均有作用，表现出通用型的抗菌活性，这正是HDT类抗感染药物的特征；②DA通过调节宿主免疫功能间接杀灭细菌，从根本上规避了诱导细菌耐药的风险，而传统抗生素类药物则无法避免耐药［14］。
3.3　DA恢复线粒体呼吸从而上调巨噬细胞抗菌性自噬的独特作用机制
自噬是机体清除细菌的一种重要途径，可清除多种G+细菌和G-细菌［15］。本研究采用经典吞噬作用抑制剂和自噬抑制剂，确认DA通过上调巨噬细胞抗菌性自噬发挥作用。因此，本研究证实抗菌性自噬是一个有效的HDT类靶点［16］。
研究表明，巨噬细胞的抗菌性自噬等功能均受到能量代谢的严格调控［17］。细菌感染诱导巨噬细胞发生代谢重编程，从依赖于线粒体呼吸转变到有氧糖酵解，这种感染状态下的糖酵解偏好有利于迅速产能以应对细菌感染［17］。但是，糖酵解产物如乳酸能抑制三羧酸循环和氧化磷酸化，此外感染诱导的一氧化氮也能直接抑制电子传递复合物，导致线粒体呼吸受损［17-18］。三羧酸循环和线粒体呼吸受损后，巨噬细胞的产能效率降低，同时线粒体代谢产物如琥珀酸和活性氧（reactive oxygen species， ROS）蓄积，最终导致巨噬细胞炎症小体活化甚至焦亡［18］。一旦巨噬细胞的线粒体呼吸失衡，其抗菌性自噬功能受损，导致机体天然免疫防线被攻破［19］。因此，维持线粒体呼吸稳态有利于促进巨噬细胞抗菌性自噬，但目前相关靶向药物仍有待开发。本研究发现，DA通过改善巨噬细胞线粒体呼吸，上调抗菌性自噬，为确认线粒体呼吸是HDT类靶点提供了转化医学证据。与传统的激活自噬药物（如雷帕霉素、伊马替尼、维生素D3等）相比［20］，DA的独特机制具有更高的靶向性和安全性，是一种有潜力的HDT类抗感染候选药物。
本研究仍存在一些研究局限：①DA的体内药效评价有待开展；②DA改善线粒体呼吸的分子靶点有待确认。根据现有结论，可以推测DA可能作用于三羧酸循环的某一关键节点改善线粒体呼吸，从而增强巨噬细胞的抗菌性免疫反应。未来的研究拟在体内模型中评价DA的药效活性、确证作用靶点和阐明药-靶互作细节，为DA的临床转化提供更坚实的临床前研究基础。
综上所述，本研究发现了青蒿素衍生物——DA，能够以浓度和时间依赖性的方式，促进巨噬细胞吞噬和清除细菌。其作用机制为，DA通过改善感染状态下受损的线粒体呼吸功能，进而特异性地上调巨噬细胞抗菌性自噬。从代谢免疫的角度，揭示了线粒体呼吸是连接宿主代谢稳态与抗菌免疫的关键枢纽，为开发新一代靶向宿主代谢的抗菌策略提供了新的理论依据和方向。

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doi: 10.16016/j.2097-0927.202512047
  • 接收时间：2025-12-10
  • 首发时间：2026-10-23
  • 出版时间：2026-02-28
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  • 收稿日期：2025-12-10
  • 修回日期：2026-01-16
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    1陆军军医大学（第三军医大学）药学与检验医学系药理学教研室，重庆

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潘夕春，E-mail：
岑彦艳，E-mail：
PAN Xichun，E-mail：
CEN Yanyan，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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