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Article(id=1195362268297867768, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195362264082592240, articleNumber=1001-2494(2025)08-0828-11, orderNo=null, doi=10.11669/cpj.2025.08.007, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1723737600000, receivedDateStr=2024-08-16, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1762926173518, onlineDateStr=2025-11-12, pubDate=1744646400000, pubDateStr=2025-04-15, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762926173518, onlineIssueDateStr=2025-11-12, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762926173518, creator=13701087609, updateTime=1762926173518, updator=13701087609, issue=Issue{id=1195362264082592240, tenantId=1146029695717560320, journalId=1190317699101192196, year='2025', volume='60', issue='8', pageStart='777', pageEnd='890', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1762926172514, creator=13701087609, updateTime=1762928092119, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1195370315556635165, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195362264082592240, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1195370315560829470, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195362264082592240, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=828, endPage=838, ext={EN=ArticleExt(id=1195362268478222842, articleId=1195362268297867768, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Guicao Baidu Decoction Inhibits Mitochondrial Apoptosis to Interfere with Bortezomib-Related Peripheral Neuropathy, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To investigate the distribution of prevalent traditional Chinese medical syndromes associated with bortezomib-related peripheral neuropathy(BiPN), the efficacy of Guicao Baidu(GCBD) decoction combined with a PD(bortezomib combined with dexamethasone)-based regimen in the treatment of BiPN patients, and the likely mechanism. METHODS A retrospective analysis of the clinical data of 17 myeloma patients with peripheral neuropathy associated with bortezomib was conducted. Peripheral neuropathy of varying degrees was observed in these individuals following a bortezomib-based regimen administered from January 2019 to December 2023. Symptom score scale was formulated for the objective BiPN syndrome differentiation. Peripheral neuropathy was evaluated using the National Cancer Institute's Common Toxicity Criteria for Adverse Events(NCI-CTCAE). GCBD decoction was administered orally. The effectiveness was assessed by looking at the visual analogue scale(VAS) score, neuroelectrophysiology, tumor treatment function evaluation/gynecological tumor group neurotoxicity subscale(FACT/GOG-Ntx) score, and NCI-CTCAE grade. The possible ingredients and targets of GCBD decoction in intervening BiPN were then predictd using mass spectrometry analysis and network pharmacology approaches. Molecular docking technology was utilized to confirm the binding activity between GCBD decoction's components and targets, while gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) enrichment analysis were employed to investigate its mode of action. Furthermore, nerve growth factor(NGF)-induced PC12 cells were employed to generate a BiPN cell model. By assessing cell viability, reactive oxygen species(ROS) levels, neurite length, apoptosis levels, mitochondrial number, mitochondrial membrane potential, apoptotic protein expression, and mitochondrial translocation of BAX, the therapeutic mechanism of GCBD decoction was identified. RESULTS The syndrome differentiation types of BiPN patients were characterized mostly by qi and blood shortage, yang deficiency, cold coagulation, and blood stasis. GCBD decoction substantially reduced BiPN, peripheral neuropathy(PN) grade, FACT score, and VAS score(P<0.01 or P<0.05). Network pharmacology analysis obtained 3541 potential targets for GCBD decoction to interfere with BiPN, among which apoptotic proteins such as BCL2-Associated X (BAX), P53, B-cell lymphoma-2 (BCL-2), and Caspase-3 (CASP3) were the core targets. The GO and KEGG pathway enrichment indicated that one of the key pathways through which GCBD decoction intervened in BiPN was mitochondrial apoptosis. It was shown by molecular docking that several GCBD decoction monomers exhibited strong docking activity with the mitochondrial apoptotic proteins BAX, BCL-2, and CASP3. CONCLUSION This study preliminarily explors the TCM syndrome differentiation of BiPN patients, reveals the mechanism of GCBD decoction in inhibiting mitochondrial apoptosis and improving BiPN, and provids new ideas for reducing the toxic and side effects of chemotherapy in clinical practice.

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目的 观察硼替佐米相关周围神经病变(bortezomib-induced peripheral neuropathy,BiPN)常见中医证型分布规律及科室协定方归草败毒饮联合硼替佐米+地塞米松(PD)治疗BiPN患者的疗效,并初步研究其可能机制。方法 回顾性分析17名BiPN骨髓瘤患者临床资料,这些患者在2019年1月至2023年12月接受硼替佐米为基础的方案治疗后出现不同程度的周围神经病变。拟定症状积分量表以客观化BiPN辨证分型。采用美国国家癌症研究所共同毒性标准不良事件(National Cancer Institute Common Terminology Criteria for Adverse Events,NCI-CTCAE)对周围神经病变进行分级,口服归草败毒饮治疗。所有入组患者均治疗1个疗程,通过观察NCI-CTCAE分级、肿瘤治疗功能评估/妇科肿瘤组神经毒性亚量表(functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity,FACT/GOG-Ntx)评分、视觉模拟量表(visual analogue scale,VAS)评分,检测患者神经电生理来评估疗效。随后,结合质谱分析与网络药理学方法预测归草败毒饮干预BiPN的潜在作用成分与靶点,应用基因本体论(gene ontology,GO)、京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析探索其作用机制,并通过分子对接技术验证了归草败毒饮成分与靶点之间的结合活性。最后,应用神经生长因子(nerve growth factor,NGF)诱导的PC12细胞建立BiPN细胞模型,通过检测细胞活力、活性氧(reactive oxygen species,ROS)水平、神经突长度、细胞凋亡水平、线粒体数量、线粒体膜电位、凋亡蛋白表达及B淋巴细胞瘤-2(B-cell lymphoma-2,BCL-2)相关X蛋白(BCL2 associated X protein,BAX)的线粒体转位明确归草败毒饮的治疗机制。结果 BiPN患者辨证分型以气血两虚、阳虚寒凝、瘀血内阻为主。归草败毒饮可以有效缓解BiPN,降低周围神经病变(peripheral neuropathy,PN)分级、提高FACT评分、降低VAS评分(P<0.01或P<0.05)。网络药理学分析获得归草败毒饮干预BiPN的3 541个潜在靶点,其中BAX、肿瘤蛋白P53(tumor protein P53,P53)、BCL-2、胱天蛋白酶3(caspase-3,CASP3)等凋亡蛋白为核心靶点。GO和KEGG通路富集提示线粒体凋亡是归草败毒饮干预BiPN的重要作用途径。分子对接验证了归草败毒饮多种单体与线粒体凋亡蛋白BAX、BCL-2、CASP3等具有良好的对接活性。细胞实验表明,归草败毒饮可以改善硼替佐米诱导的PC12细胞模型的活力下降,降低ROS,抑制细胞凋亡,促进PC12细胞神经突生长,并增加线粒体的数量、改善线粒体膜电位及凋亡相关蛋白水平,减少BAX线粒体易位。结论 本研究初步探究了BiPN患者中医辨证分型,揭示了归草败毒饮抑制线粒体凋亡改善BiPN的作用机制,为临床减轻化疗毒副作用提供了新的思路。

, correspAuthors=崔兴, authorNote=null, correspAuthorsNote=
*崔兴,男,博士,主任医师,博士生导师 研究方向:中医治疗血液和肿瘤疾病临床及基础研究 Tel:(0531)58251302
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付佳琪,女,硕士研究生 研究方向:中西医结合治疗肿瘤及血液疾病

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付佳琪,女,硕士研究生 研究方向:中西医结合治疗肿瘤及血液疾病

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付佳琪,女,硕士研究生 研究方向:中西医结合治疗肿瘤及血液疾病

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J Ethnopharmacol, 2016, 185:361-369., articleTitle=Paeoniflorin protects Schwann cells against high glucose induced oxidative injury by activating Nrf2/ARE pathway and inhibiting apoptosis, refAbstract=null), Reference(id=1195390958259974872, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, doi=null, pmid=null, pmcid=null, year=2009, volume=1283, issue=null, pageStart=139, pageEnd=147, url=null, language=null, rfNumber=[36], rfOrder=35, authorNames=WANG H, XU Y, YAN J, journalName=Brain Res, refType=null, unstructuredReference=WANG H, XU Y, YAN J, et al. Acteoside protects human neuroblastoma SH-SY5Y cells against beta-amyloid-induced cell injury[J]. Brain Res, 2009, 1283:139-147., articleTitle=Acteoside protects human neuroblastoma SH-SY5Y cells against beta-amyloid-induced cell injury, refAbstract=null), Reference(id=1195390958339666649, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, doi=null, pmid=null, pmcid=null, year=2004, volume=26, issue=3, pageStart=397, pageEnd=406, url=null, language=null, rfNumber=[37], rfOrder=36, authorNames=DAS K P, FREUDENRICH T M, MUNDY W R, journalName=Neurotoxicol Teratol, refType=null, unstructuredReference=DAS K P, FREUDENRICH T M, MUNDY W R. Assessment of PC12 cell differentiation and neurite growth: a comparison of morphological and neurochemical measures[J]. Neurotoxicol Teratol, 2004, 26(3): 397-406., articleTitle=Assessment of PC12 cell differentiation and neurite growth: a comparison of morphological and neurochemical measures, refAbstract=null)], funds=[Fund(id=1195390955550454448, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, awardId=82274491, language=CN, fundingSource=国家自然科学基金面上项目资助(82274491), fundOrder=null, country=null), Fund(id=1195390955638534833, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, awardId=82074348, language=CN, fundingSource=国家自然科学基金面上项目资助(82074348), fundOrder=null, country=null), Fund(id=1195390955697255090, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, awardId=ZR2023LZL009, language=CN, fundingSource=山东省自然科学基金创新发展联合基金项目资助(ZR2023LZL009), fundOrder=null, country=null), Fund(id=1195390955764363955, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, awardId=202225014, language=CN, fundingSource=济南市临床医学科技创新计划项目资助(202225014), fundOrder=null, country=null), Fund(id=1195390955827278516, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, awardId=202328072, language=CN, fundingSource=济南市临床医学科技创新计划项目资助(202328072), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1195390952153068155, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, xref=1, ext=[AuthorCompanyExt(id=1195390952161456764, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, companyId=1195390952153068155, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1 The First Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan 250013, China), AuthorCompanyExt(id=1195390952169845373, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, companyId=1195390952153068155, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1 山东中医药大学第一临床医学院, 济南 250013)]), AuthorCompany(id=1195390952257925758, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, xref=2, ext=[AuthorCompanyExt(id=1195390952262120063, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, companyId=1195390952257925758, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2 Oncology Center of the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250001, China), AuthorCompanyExt(id=1195390952270508672, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, companyId=1195390952257925758, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2 山东中医药大学第二附属医院肿瘤中心, 济南 250001)])], figs=[ArticleFig(id=1195390954044699294, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Fig.1, caption=Relationship between TCM syndrome differentiation and PN classification in patients

A-TCM syndrome differentiation of BiPN patients; B-the relationship between PN classification and TCM classification of BiPN.

, figureFileSmall=RXyfJzNA6OzpIH4+eiP58w==, figureFileBig=J4nu5YDgYf0PnDfxJwHUhQ==, tableContent=null), ArticleFig(id=1195390954116002463, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=图1, caption=BiPN患者中医辨证分型及其与周围神经病变(PN)分级的关系

A-硼替佐米诱导的周围神经病变(BiPN)患者中医辨证分型;B-PN分级与BiPN中医分型的关系。

, figureFileSmall=RXyfJzNA6OzpIH4+eiP58w==, figureFileBig=J4nu5YDgYf0PnDfxJwHUhQ==, tableContent=null), ArticleFig(id=1195390954204082848, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Fig.2, caption=Guicao Baidu(GCBD) decoction improves the symptoms of peripheral neuropathy in patients. n=17,$\stackrel{-}{x}$±s

A-PN grade before and after application of GCBD decoction; B-the effect of GCBD decoction on neuropathic pain in patients with BiPN; C-the effect of GCBD decoction on neuroelectrophysiology in patients with BiPN; 1) P<0.01, vs before the treatment; FACT-functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity subscale; VAS-the visual analogue scale; MCV-motor nerve; SCV-sensory nerve conduction velocity; MN-sciatic nerve; CPN-common peroneal nerve.

, figureFileSmall=slGZfqkC3bqnZl8yCTiDbQ==, figureFileBig=DR0KtCtAnM5Q3oLkZ49r1w==, tableContent=null), ArticleFig(id=1195390954266997409, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=图2, caption=归草败毒饮改善患者周围神经病变症状。n=17,$\stackrel{-}{x}$±s

A-应用归草败毒饮前后PN分级;B-归草败毒饮对BiPN患者神经性疼痛的影响;C-归草败毒饮对BiPN患者神经电生理的影响;与治疗前相比,1) P<0.01;FACT-肿瘤治疗功能评估/妇科肿瘤组神经毒性亚量表;VAS-视觉模拟量表;MCV-运动神经传导速度;SCV-感觉神经传导速度;MN-坐骨神经;CPN-腓总神经。

, figureFileSmall=slGZfqkC3bqnZl8yCTiDbQ==, figureFileBig=DR0KtCtAnM5Q3oLkZ49r1w==, tableContent=null), ArticleFig(id=1195390954342494882, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Fig.3, caption=Network pharmacology analysis of GCBD decoction on bortezomib-related peripheral neuropathy

A-total ion current chromatogram of serum containing GCBD decoction for identification; B-Venn diagram of intersection target of GCBD decoction and BiPN; C-intersection target PPI network diagram, the darker the color and the larger the shape, the higher the degree value of the node; D-GO biological function enrichment map of intersection targets; E-enrichment map of intersection target KEGG pathway; F-molecular docking pattern diagram of monomer components and core targets of GCBD decoction.

, figureFileSmall=7jeLlpQRozVfN/j9ZQ3Svw==, figureFileBig=1ICW4ko/slLBc8F2//KqHg==, tableContent=null), ArticleFig(id=1195390954409603747, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=图3, caption=归草败毒饮干预硼替佐米相关周围神经病变网络药理学分析

A-归草败毒饮含药血清鉴定总离子流图谱;B-归草败毒饮与BiPN交集靶点韦恩图;C-交集靶点蛋白-蛋白交互网络图,颜色越深、形状越大代表该节点度值越高;D-交集靶点GO生物学功能富集图;E-交集靶点KEGG通路富集图;F-归草败毒饮单体成分与核心靶点分子对接模式图。

, figureFileSmall=7jeLlpQRozVfN/j9ZQ3Svw==, figureFileBig=1ICW4ko/slLBc8F2//KqHg==, tableContent=null), ArticleFig(id=1195390954472518308, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Fig.4, caption=GCBD decoction containing serum improved bortezomib-induced PC12 cell injury. n=5,$\overline{x}$±s

A-effects of different concentrations of GCBD decoction containing serum on the viability of PC12 cells; B,C-effects of different concentrations of GCBD decoction-containing serum on ROS levels in PC12 cells; 1) P<0.05, 2) P<0.01, vs control group; 3) P<0.01, vs model group.

, figureFileSmall=1trGr5XLbxrxRMfrT+AgBA==, figureFileBig=X8vNg56EzcjTy1a28TOcSw==, tableContent=null), ArticleFig(id=1195390954548015781, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=图4, caption=归草败毒饮含药血清改善硼替佐米诱导的PC12神经细胞损伤。 n=5,$\overline{x}$±s

A-不同浓度归草败毒饮含药血清对PC12细胞活力的影响;B、C-不同浓度归草败毒饮含药血清对PC12细胞ROS水平的影响;与对照组比较,1) P<0.05, 2) P<0.01;与模型组比较,3) P<0.01。

, figureFileSmall=1trGr5XLbxrxRMfrT+AgBA==, figureFileBig=X8vNg56EzcjTy1a28TOcSw==, tableContent=null), ArticleFig(id=1195390954606736038, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Fig.5, caption=GCBD decoction containing serum promotes neurite growth of PC12 cells. n=5,$\stackrel{-}{x}$±s

1) P<0.05, 2) P<0.01,vs control group; 3) P<0.01,vs model group

, figureFileSmall=N6wROCeJDpvkIvj/8+4McA==, figureFileBig=z61IWa8vDuVSWVdJjBxpmQ==, tableContent=null), ArticleFig(id=1195390954678039207, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=图5, caption=归草败毒饮含药血清促进PC12细胞神经突生长。n=5,$\stackrel{-}{x}$±s

与对照组比较,1) P<0.05, 2) P<0.01;与模型组比较,3) P<0.01。

, figureFileSmall=N6wROCeJDpvkIvj/8+4McA==, figureFileBig=z61IWa8vDuVSWVdJjBxpmQ==, tableContent=null), ArticleFig(id=1195390954753536680, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Fig.6, caption=GCBD decoction containing serum inhibits mitochondrial apoptosis of PC12 nerve cells. n=5,$\overline{x}$±s

A, B-the effect of GCBD decoction containing serum on the apoptosis of PC12 cells; C,D-the effect of GCBD decoction containing serum on mitochondrial membrane potential of PC12 cells; E-the effect of GCBD decoction containing serum on mitochondrial DNA copy number of PC12 cells; F-the effect of serum containing GCBD decoction on the level of apoptotic protein in PC12 cells; 1) P<0.01, vs control group; 2) P<0.01, vs model group.

, figureFileSmall=78U5XWiqrHkXfVOWNAGYkw==, figureFileBig=7T8NG28rb4EKY666m4l6aQ==, tableContent=null), ArticleFig(id=1195390954820645545, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=图6, caption=归草败毒饮含药血清抑制PC12神经细胞线粒体凋亡。 n=5,$\overline{x}$±s

A、B-归草败毒饮含药血清对PC12细胞凋亡的影响;C、D-归草败毒饮含药血清对PC12细胞线粒体膜电位的影响;E-归草败毒饮含药血清对PC12细胞线粒体DNA拷贝数的影响;F、G-归草败毒饮含药血清对PC12细胞凋亡蛋白水平的影响;与对照组比较,1) P<0.01;与模型组比较,2) P<0.01。

, figureFileSmall=78U5XWiqrHkXfVOWNAGYkw==, figureFileBig=7T8NG28rb4EKY666m4l6aQ==, tableContent=null), ArticleFig(id=1195390954887754410, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Fig.7, caption=Effects of GCBD decoction on mitochondrial translocation of BAX in PC12 cells. n=5,$\overline{x}$±s

1) P<0.01, vs control group; 2) P<0.01, vs model group.

, figureFileSmall=KsFFiKARXa02E/sRGSsMlw==, figureFileBig=+V2UXkZmTOW+WAWLIcZ+0w==, tableContent=null), ArticleFig(id=1195390955021972139, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=图7, caption=归草败毒饮对PC12细胞B淋巴细胞瘤-2相关X蛋白(BAX)线粒体易位的影响。 n=5,$\overline{x}$±s

与对照组比较,1) P<0.01;与模型组比较,2) P<0.01。

, figureFileSmall=KsFFiKARXa02E/sRGSsMlw==, figureFileBig=+V2UXkZmTOW+WAWLIcZ+0w==, tableContent=null), ArticleFig(id=1195390955126829740, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Tab.1, caption=

Primer sequences of RT-qPCR

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene Primer sequences(5'-3')
16S rRNA F:GGTGCAGCCGCTATTAAAGG
R:ATCATTTACGGGGGAAGGCG
ACTB F:TGACGTGGACATCCGCAAAG
R:CTGGAAGGTGGACAGCGAGG
), ArticleFig(id=1195390955231687341, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=表1, caption=

反转录实时定量聚合酶链式反应(RT-qPCR)引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
Gene Primer sequences(5'-3')
16S rRNA F:GGTGCAGCCGCTATTAAAGG
R:ATCATTTACGGGGGAAGGCG
ACTB F:TGACGTGGACATCCGCAAAG
R:CTGGAAGGTGGACAGCGAGG
), ArticleFig(id=1195390955332350638, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=EN, label=Tab.2, caption=

Docking activity between monomers of GCBD decoction and apoptosis-related proteins

, figureFileSmall=null, figureFileBig=null, tableContent=
Monomer
in GCBD		 Apoptosis-
related proteins		 Binding energy
/J·mol-1		 LibDock
score
Isoliquiritigenin BAX -183 983.032 97.384
BCL2 -184 953.720 81.902
CASP3 -179 978.944 75.794
Naringenin BAX -147 979.712 115.741
BCL2 -158 301.640 91.590
CASP3 -164 874.704 82.901
), ArticleFig(id=1195390955403653807, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195362268297867768, language=CN, label=表2, caption=

归草败毒饮单体成分与凋亡蛋白对接活性

, figureFileSmall=null, figureFileBig=null, tableContent=
Monomer
in GCBD		 Apoptosis-
related proteins		 Binding energy
/J·mol-1		 LibDock
score
Isoliquiritigenin BAX -183 983.032 97.384
BCL2 -184 953.720 81.902
CASP3 -179 978.944 75.794
Naringenin BAX -147 979.712 115.741
BCL2 -158 301.640 91.590
CASP3 -164 874.704 82.901
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归草败毒饮抑制线粒体凋亡干预硼替佐米相关周围神经病变的临床及试验研究
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付佳琪 1 , 孙润洁 2 , 崔兴 2, *
中国药学杂志 | 论著 2025,60(8): 828-838
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中国药学杂志 | 论著 2025, 60(8): 828-838
归草败毒饮抑制线粒体凋亡干预硼替佐米相关周围神经病变的临床及试验研究
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付佳琪1, 孙润洁2, 崔兴2, *
作者信息
  • 1 山东中医药大学第一临床医学院, 济南 250013
  • 2 山东中医药大学第二附属医院肿瘤中心, 济南 250001

    • 付佳琪,女,硕士研究生 研究方向:中西医结合治疗肿瘤及血液疾病

通讯作者:

*崔兴,男,博士,主任医师,博士生导师 研究方向:中医治疗血液和肿瘤疾病临床及基础研究 Tel:(0531)58251302
Guicao Baidu Decoction Inhibits Mitochondrial Apoptosis to Interfere with Bortezomib-Related Peripheral Neuropathy
Jiaqi FU1, Runjie SUN2, Xing CUI2, *
Affiliations
  • 1 The First Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan 250013, China
  • 2 Oncology Center of the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250001, China
出版时间: 2025-04-15 doi: 10.11669/cpj.2025.08.007
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目的 观察硼替佐米相关周围神经病变(bortezomib-induced peripheral neuropathy,BiPN)常见中医证型分布规律及科室协定方归草败毒饮联合硼替佐米+地塞米松(PD)治疗BiPN患者的疗效,并初步研究其可能机制。方法 回顾性分析17名BiPN骨髓瘤患者临床资料,这些患者在2019年1月至2023年12月接受硼替佐米为基础的方案治疗后出现不同程度的周围神经病变。拟定症状积分量表以客观化BiPN辨证分型。采用美国国家癌症研究所共同毒性标准不良事件(National Cancer Institute Common Terminology Criteria for Adverse Events,NCI-CTCAE)对周围神经病变进行分级,口服归草败毒饮治疗。所有入组患者均治疗1个疗程,通过观察NCI-CTCAE分级、肿瘤治疗功能评估/妇科肿瘤组神经毒性亚量表(functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity,FACT/GOG-Ntx)评分、视觉模拟量表(visual analogue scale,VAS)评分,检测患者神经电生理来评估疗效。随后,结合质谱分析与网络药理学方法预测归草败毒饮干预BiPN的潜在作用成分与靶点,应用基因本体论(gene ontology,GO)、京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析探索其作用机制,并通过分子对接技术验证了归草败毒饮成分与靶点之间的结合活性。最后,应用神经生长因子(nerve growth factor,NGF)诱导的PC12细胞建立BiPN细胞模型,通过检测细胞活力、活性氧(reactive oxygen species,ROS)水平、神经突长度、细胞凋亡水平、线粒体数量、线粒体膜电位、凋亡蛋白表达及B淋巴细胞瘤-2(B-cell lymphoma-2,BCL-2)相关X蛋白(BCL2 associated X protein,BAX)的线粒体转位明确归草败毒饮的治疗机制。结果 BiPN患者辨证分型以气血两虚、阳虚寒凝、瘀血内阻为主。归草败毒饮可以有效缓解BiPN,降低周围神经病变(peripheral neuropathy,PN)分级、提高FACT评分、降低VAS评分(P<0.01或P<0.05)。网络药理学分析获得归草败毒饮干预BiPN的3 541个潜在靶点,其中BAX、肿瘤蛋白P53(tumor protein P53,P53)、BCL-2、胱天蛋白酶3(caspase-3,CASP3)等凋亡蛋白为核心靶点。GO和KEGG通路富集提示线粒体凋亡是归草败毒饮干预BiPN的重要作用途径。分子对接验证了归草败毒饮多种单体与线粒体凋亡蛋白BAX、BCL-2、CASP3等具有良好的对接活性。细胞实验表明,归草败毒饮可以改善硼替佐米诱导的PC12细胞模型的活力下降,降低ROS,抑制细胞凋亡,促进PC12细胞神经突生长,并增加线粒体的数量、改善线粒体膜电位及凋亡相关蛋白水平,减少BAX线粒体易位。结论 本研究初步探究了BiPN患者中医辨证分型,揭示了归草败毒饮抑制线粒体凋亡改善BiPN的作用机制,为临床减轻化疗毒副作用提供了新的思路。

硼替佐米  /  周围神经病变  /  归草败毒饮  /  辨证分型  /  美国国家癌症研究所共同毒性标准不良事件分级  /  线粒体凋亡

OBJECTIVE To investigate the distribution of prevalent traditional Chinese medical syndromes associated with bortezomib-related peripheral neuropathy(BiPN), the efficacy of Guicao Baidu(GCBD) decoction combined with a PD(bortezomib combined with dexamethasone)-based regimen in the treatment of BiPN patients, and the likely mechanism. METHODS A retrospective analysis of the clinical data of 17 myeloma patients with peripheral neuropathy associated with bortezomib was conducted. Peripheral neuropathy of varying degrees was observed in these individuals following a bortezomib-based regimen administered from January 2019 to December 2023. Symptom score scale was formulated for the objective BiPN syndrome differentiation. Peripheral neuropathy was evaluated using the National Cancer Institute's Common Toxicity Criteria for Adverse Events(NCI-CTCAE). GCBD decoction was administered orally. The effectiveness was assessed by looking at the visual analogue scale(VAS) score, neuroelectrophysiology, tumor treatment function evaluation/gynecological tumor group neurotoxicity subscale(FACT/GOG-Ntx) score, and NCI-CTCAE grade. The possible ingredients and targets of GCBD decoction in intervening BiPN were then predictd using mass spectrometry analysis and network pharmacology approaches. Molecular docking technology was utilized to confirm the binding activity between GCBD decoction's components and targets, while gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) enrichment analysis were employed to investigate its mode of action. Furthermore, nerve growth factor(NGF)-induced PC12 cells were employed to generate a BiPN cell model. By assessing cell viability, reactive oxygen species(ROS) levels, neurite length, apoptosis levels, mitochondrial number, mitochondrial membrane potential, apoptotic protein expression, and mitochondrial translocation of BAX, the therapeutic mechanism of GCBD decoction was identified. RESULTS The syndrome differentiation types of BiPN patients were characterized mostly by qi and blood shortage, yang deficiency, cold coagulation, and blood stasis. GCBD decoction substantially reduced BiPN, peripheral neuropathy(PN) grade, FACT score, and VAS score(P<0.01 or P<0.05). Network pharmacology analysis obtained 3541 potential targets for GCBD decoction to interfere with BiPN, among which apoptotic proteins such as BCL2-Associated X (BAX), P53, B-cell lymphoma-2 (BCL-2), and Caspase-3 (CASP3) were the core targets. The GO and KEGG pathway enrichment indicated that one of the key pathways through which GCBD decoction intervened in BiPN was mitochondrial apoptosis. It was shown by molecular docking that several GCBD decoction monomers exhibited strong docking activity with the mitochondrial apoptotic proteins BAX, BCL-2, and CASP3. CONCLUSION This study preliminarily explors the TCM syndrome differentiation of BiPN patients, reveals the mechanism of GCBD decoction in inhibiting mitochondrial apoptosis and improving BiPN, and provids new ideas for reducing the toxic and side effects of chemotherapy in clinical practice.

bortezomib  /  peripheral neuropathy  /  Guicao Baidu decoction  /  syndrome differentiation  /  NCI-CTCAE grading  /  mitochondrial apoptosis
付佳琪, 孙润洁, 崔兴. 归草败毒饮抑制线粒体凋亡干预硼替佐米相关周围神经病变的临床及试验研究. 中国药学杂志, 2025 , 60 (8) : 828 -838 . DOI: 10.11669/cpj.2025.08.007
Jiaqi FU, Runjie SUN, Xing CUI. Guicao Baidu Decoction Inhibits Mitochondrial Apoptosis to Interfere with Bortezomib-Related Peripheral Neuropathy[J]. Chinese Pharmaceutical Journal, 2025 , 60 (8) : 828 -838 . DOI: 10.11669/cpj.2025.08.007
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硼替佐米作为第一个临床使用的蛋白酶体抑制剂,其疗效可靠、价格便宜,目前仍然是多发性骨髓瘤的一线首选药物[1]。然而,硼替佐米具有显著的神经毒性,并有可能通过各种机制损害神经纤维,导致患者发生硼替佐米诱导的周围神经病变(bortezomib-induced peripheral neuropathy,BiPN),BiPN的发生率为20%~40%[2-3]。BiPN的发生严重限制了硼替佐米的临床应用。目前,BiPN的治疗主要依赖于神经保护剂和减轻神经疼痛的药物,这些药物的临床疗效有限[4-5]。因此,迫切需要更有效的方法来减轻BiPN。
目前中医药治疗BiPN的方法包括:中药内服[6-13]、中药外用[14]、针灸疗法[15]、中药单体[16-19]等,但应用于临床上且机制明确的中药复方较少。本研究旨在挖掘中医药宝库,为中医药治疗肿瘤及其相关并发症提供依据。
1 方法
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1.1 临床数据
硼替佐米相关周围神经病变骨髓瘤患者17例(女7例,男10例;年龄45~85岁,中位65岁)。所有患者均接受硼替佐米+地塞米松治疗(硼替佐米剂量为1~1.3 mg·m-2,第1、4、8、11天或第1、8、15、22天;地塞米松20 mg·d-1,1~2、4~5、8~9、11~12 d或1~2、8~9、15~16、22~23 d),每4周为1个疗程。除硼替佐米+地塞米松治疗方案外,部分患者还接受了来那度胺或环磷酰胺治疗。使用归草败毒饮治疗1个疗程后,对所有患者进行评估。所有患者均来自山东中医药大学第二附属医院肿瘤血液科和山东中医药大学附属医院血液科,所有参与者根据赫尔辛基宣言签署知情同意书。伦理号:(2020)伦审第(010)号-KY。
采用美国癌症研究所共同毒性标准不良事件(National Cancer Institute Common Terminology Criteria for Adverse Events,NCI-CTCAE)4.0进行BiPN分级。采用肿瘤治疗/妇科肿瘤组功能评估神经毒性亚量表(functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity,FACT/GOG-Ntx)评分和视觉模拟量表(visual analogue scale,VAS)评分评估神经毒性症状和神经性疼痛。应用肌电图诱发电位仪进行神经传导速度检测,检测过程中保证患者皮温维持在30~32 ℃。检测并计算患者正中神经与腓总神经的运动神经传导速度(motor nerve conduction velocity,MCV)和感觉神经传导速度(sensory nerve conduction velocity,SCV)(公式1~2)。
MCV=两记录电极之间的距离(m)/动作电位潜伏期之差(s)
SCV=刺激电极与记录电极之间的距离(m)/动作电位起始潜伏期(s)
参考标准为正中神经传导速度>50 m·s-1,腓总神经传导速度>45 m·s-1,当低于正常值范围的20%,提示神经传导速度减慢[20]。
1.2 实验材料
SD大鼠雌雄各半,SPF级,6~8周龄,体质量180~220 g[北京维通利华实验动物技术有限公司,许可证号:SCXK(京)2016-0006]。饲养于山东中医药大学附属医院动物房,经山东中医药大学附属医院动物实验伦理委员会审核(AWE-2019-038);PC12细胞系(SCSP-517,中国科学院细胞库);硼替佐米(大连美仑生物技术有限公司,批号:MB1040)。
CCK-8试剂盒(批号:E-BC-K138-F)、线粒体膜电位检测试剂盒(批号:C2006)(北京碧云天生物技术有限公司);活性氧(reactive oxygen species,ROS)检测试剂盒(批号:BTK024,武汉贝茵莱生物);抗B淋巴细胞瘤-2(B-cell lymphoma-2,BCL-2)、BCL2相关X蛋白(BCL2 associated X protein,BAX)、胱天蛋白酶3(caspase-3,CASP3)抗体(批号:sc-7382、sc-65532、sc-56046,美国Santa Cruz Biotechnology);大鼠β神经生长因子(β-NGF,美国R&D system公司)。
1.3 含药血清的制备
归草败毒饮全方组成为:炙甘草10 g、甘草10 g、桂枝15 g、当归12 g、白芍9 g、细辛3 g、通草6 g、生姜10 g、党参15 g、生地黄40 g、熟地黄20 g、阿胶15 g、麦冬10 g、火麻仁9 g、酸枣仁6 g、大枣25 g、全蝎6 g、雷公藤6 g。饮片购自山东中医药大学第二附属医院,按照《中国药典》2020年版规定的工艺配制中药水煎液。按照大鼠和人类的等效剂量换算后,将SD大鼠胃饲10 mL·kg-1的归草败毒饮,含有10.5 g·kg-1的生药,每天2次,连续3 d,末次给药后1 h,在麻醉下从腹主动脉采集血液样本,离心(3 000 r·min-1,10 min),分离含有药物的血清,4 ℃冰箱中保存备用。
1.4 归草败毒饮干预硼替佐米相关周围神经病变的网络药理学分析
应用超高效液相色谱-高分辨率质谱鉴定归草败毒饮含药血清有效成分,利用TCMSP(https://old.tcmsp-e.com/tcmsp.php)、TCMID(http://www.megabionet.org/tcmid/)、CTD(http://ctdbase.com/)数据库筛选化合物潜在作用靶点。通过OMIM(https://www.omim.org/)、GeneCards(https://www.genecards.org/),以“bortezomib-induced peripheral neuropathy”“peripheral nerve injuries”“inherited peripheral neuropathy”为关键词获取BiPN靶点。运用R语言将药物与疾病靶点取交集,导入STRING网站获得蛋白互作(PPI)网络,应用Cytoscape 3.10.2软件Network Analyer模块进行分析。借助R clusterProfiler包对靶点蛋白进行基因本体论(gene ontology,GO)、京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集及可视化分析,并应用Cytoscape构建“靶点-通路”网络。最后,应用Discovery Studio验证归草败毒饮核心成分与靶点结合活性。
1.5 PC12细胞分组及处理
应用含有50 ng·mL-1大鼠β-NGF的1640完全培养基培养PC12细胞5 d后,使PC12细胞分化为神经元样细胞。将分化后的PC12神经元样细胞接种至6孔板,37 ℃、5% CO2培养箱培养细胞。
待细胞汇合率约为70%~80%时,更换培养基,分为对照组(Control)、模型组(Model,50 nmol·L-1硼替佐米[21])归草败毒饮低剂量组(GCBD-L,终浓度含体积分数为5%的血清原液+50 nmol·L-1硼替佐米)、归草败毒饮中剂量组(GCBD-M,终浓度含体积分数为10%的血清原液+50 nmol·L-1硼替佐米)和归草败毒饮高剂量组(GCBD-H,终浓度含体积分数为20%的血清原液+50 nmol·L-1硼替佐米)。不同浓度的归草败毒饮含药血清处理12 h。
1.6 细胞活性检测
PC12细胞调整细胞密度为每毫升2×105个,以每孔100 μL接种于96孔板,分别在24和48 h加入CCK 8溶液10 μL,在37 ℃、CO2培养箱中孵育2 h后,应用酶标仪于450 nm处进行检测,计算各组细胞活性。
1.7 2',7'-二氯荧光素二乙酸酯(2',7'-dichlorodihydrofluorescein diacetate,DCFH-DA)荧光探针检测PC12细胞ROS水平
各组细胞应用PBS冲洗后,按照说明书,加入终浓度为10 μmol·L-1的DCFH-DA,37 ℃孵育30 min。PBS冲洗后用4',6-二脒基-2-苯基吲哚(DAPI)复染,再冲洗3次。使用激光共聚焦显微镜对细胞进行成像,测定绿色荧光(表示ROS)的分布和表达(激发波长488 nm,发射波长525 nm),Image J软件评估免疫荧光强度。
1.8 PC12神经元长度测定
各组干预后的PC12细胞应用质量分数为4%的多聚甲醛室温固定,质量分数为5%的牛血清白蛋白室温封闭30 min。加入Acti-stain 488 phalloidin,使其与F-actin结合,4 ℃过夜,PBS洗涤后,体积分数为80%的甘油包埋。然后使用DAPI进行细胞核染色。使用ImageXpress Micro XL分析神经突长度。
1.9 流式细胞术检测PC12细胞凋亡水平
每组收集1×105个细胞,加入100 μL 1×结合缓冲液(Binding Buffer)重悬细胞,然后加入5 μL Annexin V-FITC和10 μL PI染色液轻轻混匀,避光、室温反应10~15 min;加入400 μL 1×Binding Buffer,混匀置于冰上,于1 h内用流式细胞仪检测PC12细胞凋亡率。
1.10 线粒体膜电位检测
采用线粒体膜电位检测试剂盒测定线粒体膜电位(mitochondrial membrane potential,MMP)。将处理后的细胞与线粒体膜电位荧光探针(JC-1)染色液孵育20 min,然后用PBS洗涤2次。用流式细胞仪测定荧光。
1.11 反转录实时定量聚合酶链式反应(RT-qPCR)检测线粒体DNA相对拷贝数
提取各组细胞总RNA,进行RNA浓度和纯度检测后逆转录为cDNA,使用SYBR Green qPCR试剂盒进行扩增。以线粒体基因组中16S rRNA为待检测基因,ACTB为内参。采用2-ΔΔCt法对16S rRNA的mRNA相对表达量进行分析。引物具体序列见表1。
1.12 Western blot检测线粒体凋亡蛋白水平
各组细胞培养48 h后,收集5×105个细胞,提取总蛋白,BCA蛋白检测试剂盒进行定量分析。制备分离胶,通过电泳、转膜、洗膜,加入一抗4 ℃孵育过夜,稀释比例:BCL-2(1∶1 000)、BAX(1∶1 000)、CASP3(1∶2 000)。洗膜后与HRP标记的二抗(1∶5 000)作用。ECL显色后曝光,采用ImageJ 8.0软件进行分析,以GAPDH为内参,计算目的蛋白相对表达量。
1.13 线粒体BAX共定位检测
取各组细胞,加入500 nmol·L-1的Mito-Tracker Red CMXRos工作液标记线粒体,加入BAX抗体(1∶100)在4 ℃孵育过夜。通过激光共聚焦显微镜在550 nm处分析波长,观察线粒体BAX共定位情况。
1.14 统计学方法
实验结果采用SPSS 26进行统计分析。计量资料以均数±标准差($\overline{x}$±s)表示。两组间差异采用Student's t检验,多组间差异采用单因素方差分析。以P<0.05为差异有统计学意义。
2 结果
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2.1 BiPN患者辨证分型结果
应用桑基图展示了17例病人辨证分型结果及周围神经病变(PN)分级与证型之间的关系。BiPN患者以阳虚寒凝、气血两虚、瘀血内阻为主,分别为8、6、3例(图1A)。其中,阳虚寒凝的PN患者最多,气血两虚证次之。进一步评估BiPN患者中医辨证分型与PN严重程度的关系,结果显示,1级PN患者多辨证为气血两虚证,而2、3级PN患者多辨证为阳虚寒凝、瘀血内阻(图1B)。提示BiPN是一种本虚标实的疾病,本虚体现在气血亏虚、阳气虚弱,标实体现在寒凝瘀血内阻,本虚则不荣,标实则不通,气血运行受阻而痛。这为临床应用中医干预BiPN提供了具体思路,也为扶正祛瘀的归草败毒饮有效应用提供了临床证据。
2.2 归草败毒饮改善BiPN患者临床症状
对应用归草败毒饮治疗前后的BiPN患者进行PN分级评估、疼痛评分、神经电生理运动神经检测。结果发现归草败毒饮不仅能够缓解患者病情进展,并能够显著降低部分患者PN分级(图2A),显著降低患者疼痛评分(图2B,P<0.01),并显著改善患者运动神经、感觉神经传导速度(图2C,P<0.01)。
2.3 归草败毒饮干预硼替佐米相关周围神经病变的网络药理学分析
质谱鉴定获得归草败毒饮含药血清成分253个(图3A),根据数据库获得归草败毒饮作用靶点3 741个,BiPN相关靶点19 836个,取交集后得到3 541个中药潜在作用靶点(图3B)。PPI网络拓扑分析显示BAX、肿瘤蛋白P53(tumor protein P53,P53)、BCL-2、CASP3等凋亡蛋白是归草败毒饮干预BiPN的重要靶点(图3C)。GO和KEGG通路富集发现交集靶点主要参与“regulation of apoptotic process”“response to oxidative stress”“occurs in mitochondrion”等生物学过程及磷脂酰肌醇3激酶-蛋白激酶B (phosphatidylinositol-3-kinase-protein kinase B,PI3K-AKT)、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK),提示线粒体凋亡是归草败毒饮干预BiPN的重要作用途径(图3D、E)。进一步分析归草败毒饮成分及其作用机制,发现有多种单体成分能够作用于BAX、BCL-2、CASP3等线粒体凋亡核心靶点,以异甘草素、柚皮素为例,应用分子对接技术展现了归草败毒饮单体与BAX、BCL-2、CASP3等具有良好的对接活性(图3F,表2)。
2.4 归草败毒饮含药血清改善硼替佐米诱导的PC12神经细胞损伤
应用NGF诱导PC12细胞分化为神经细胞,构建BiPN细胞模型,并给予不同浓度的归草败毒饮含药血清进行干预。结果发现,20%归草败毒饮含药血清能够显著改善硼替佐米诱导的PC12神经细胞活力下降(P<0.01,图4A),并降低ROS水平(P<0.01,图4B、C)。基于以上结果,选择体积分数20%归草败毒饮含药血清作为最适浓度进行后续指标检测。
2.5 归草败毒饮含药血清促进PC12细胞神经突生长
进一步检测归草败毒饮对硼替佐米干预后PC12细胞神经突生长的影响,结果表明,硼替佐米显著抑制了PC12细胞神经突生长,而归草败毒饮能够显著逆转硼替佐米对PC12细胞神经突生长的抑制作用(P<0.01,图5)。
2.6 归草败毒饮含药血清抑制PC12细胞线粒体凋亡
与对照组相比,模型组PC12细胞凋亡水平显著升高,而归草败毒饮含药血清显著降低了硼替佐米诱导的神经细胞凋亡(P<0.01,图6A、B)。随后对线粒体膜电位、线粒体DNA拷贝数、线粒体凋亡蛋白水平进行检测,发现硼替佐米处理后的PC12细胞线粒体膜电位水平(P<0.01,图6C、D)、mtDNA(P<0.01,图6E)及BCL-2/BAX蛋白水平(P<0.01,图6F、G)显著下降,提示线粒体凋亡的发生,而归草败毒饮能够显著提高线粒体膜电位、线粒体DNA拷贝数及BCL-2/BAX比例,逆转了硼替佐米诱导的PC12细胞凋亡。
2.7 归草败毒饮含药血清对PC12细胞线粒体BAX共定位的影响
与对照组相比,模型组细胞线粒体结构表现为点棒状,提示线粒体分裂的发生,BAX染色与线粒体共定位均显著增加(P<0.01,图7),提示线粒体凋亡途径的激活。归草败毒饮含药血清干预后,BAX线粒体易位显著逆转。
3 讨论
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根据BiPN的临床表现,应归属于中医“痿证”“血痹”等范畴[22]。对于此病的中医学病机目前没有确切的共识,但研究发现其多与阳虚、气虚、血瘀等因素有关[23]。本研究首先通过对17例BiPN患者进行回顾性分型,应用桑基图展示中医辨证分型结果及其与PN分级的关系(图1),发现BiPN患者主要辨证为阳虚寒凝证、气血两虚证及瘀血内阻证,其中阳虚寒凝证患者占比最高,且PN分级更高,这与既往的研究一致,提示了BiPN虚实夹杂的病机本质。依据《黄帝内经》“血气者,喜温而恶寒,寒则泣不能流,温则消而去之”“寒者热之…结者散之…虚者补之”治则,BiPN治疗过程中合理运用扶正、温阳、化瘀、止痛等中药,可能会取得一定疗效。
基于以上临床证据与中医理论,本研究合炙甘草汤、当归四逆汤二方并加雷公藤、全蝎,创立科室协定方归草败毒饮。炙甘草汤与当归四逆汤均出自《伤寒论》,炙甘草汤具有气血双补、阴阳并调之功,当归四逆汤则是养血活血、散瘀止痛的经典方剂。全蝎可通络止痛,雷公藤是活血通络佳品。全方以扶正温阳祛瘀为主,兼以通络止痛,临床应用于包括硼替佐米在内多种化疗药物相关周围神经病变的治疗,卓有成效。本研究应用NCI-CTCAE分级、FACT/GOG-Ntx量表、VAS量表,评估BiPN患者应用归草败毒饮前后PN分级及疼痛评分,并检测患者神经电生理,结果表明归草败毒饮能够延缓患者PN进展并降低患者PN分级,显著减轻患者疼痛,显著提高运动及感觉神经传导速度(图2)。
线粒体为神经元的各种活动提供能量,几乎是能量的唯一提供者,在神经细胞中尤为重要,被认为是神经病变的关键调节因子[24]。研究表明,线粒体凋亡与其伴随的氧化应激是化疗相关周围神经病变的重要发病机制,参与弥漫性脱髓鞘、轴突变性、神经再生修复障碍等病理过程[25]。硼替佐米能够通过介导线粒体Ca2+稳态失调、线粒体氧化呼吸链活性降低、线粒体Na+-K+泵失衡等多种方式,诱导神经细胞线粒体损伤,促进线粒体凋亡,导致轴突变性、BiPN发生[26-28]。调控线粒体凋亡可作为改善BiPN的重要切入点。BCL-2家族是最经典的线粒体凋亡调控因子,抑凋亡因子BCL-2与促凋亡因子BAX相互作用调控线粒体膜通透性及相关凋亡因子的释放,最终通过CASP3途径诱导细胞凋亡。其中,促进BAX激活及其向线粒体的易位是硼替佐米诱导细胞线粒体凋亡、导致神经毒性的重要机制[29]。
药理学研究发现,归草败毒饮中的多种成分在调控线粒体功能、改善周围神经病变等方面具有广泛作用。炙甘草汤及当归四逆汤均能够减轻外周神经炎症和氧化应激,增强神经传导速度,减轻神经性疼痛[30-31]。异甘草素是甘草的重要有效成分,能够通过清除氧自由基减少线粒体损伤,抑制神经细胞凋亡,对于防治神经损伤性疾病具有良好潜力[32]。柚皮素是甘草中的主要黄酮成分之一,能够参与氧化应激、炎症反应、钙超载等多种病理过程抑制细胞凋亡,发挥神经保护作用[33]。芍药苷作为芍药的主要有效成分,具有抗氧化、减轻神经炎症和疼痛的功效[34],能够降低ROS水平并抑制BAX、CASP3的表达抑制神经细胞凋亡,发挥神经保护作用[35],本研究前期也证明了其能够通过促进Parkin介导的线粒体自噬改善BiPN[17]。地黄中的苷类化合物毛蕊花糖苷能够通过下调BAX/BCL-2,抑制线粒体凋亡,保护神经细胞[36]。本研究借助网络药理学分析获得归草败毒饮干预BiPN作用靶点3 541个,其中BAX、BCL-2、CASP3等线粒体凋亡蛋白是其核心靶点(图3)。GO和KEGG通路富集提示了线粒体凋亡是归草败毒饮干预BiPN的重要作用途径,分子对接验证了归草败毒饮单体成分与线粒体凋亡蛋白BAX、BCL-2、CASP3具有良好的对接活性。
PC12细胞能够在NGF刺激下向神经细胞分化,是周围神经病变研究中常用的细胞模型[37]。本研究应用NGF诱导分化的PC12细胞构建BiPN细胞模型,给予不同浓度的归草败毒饮含药血清进行干预,发现20%归草败毒饮含药血清组能够显著提高PC12神经细胞活力、降低ROS水平(图4)。选用该浓度进行后续干预,结果表明,归草败毒饮含药血清能够显著促进PC12细胞神经突生长(图5)。进一步对PC12神经细胞凋亡水平、线粒体膜电位、线粒体DNA拷贝数、线粒体凋亡蛋白表达、BAX线粒体易位等方面进行评估(图6~7)。线粒体膜电位的降低是启动线粒体依赖性细胞凋亡的关键事件。本研究发现硼替佐米能够诱导PC12细胞线粒体膜电位下降,而归草败毒饮通过提高线粒体膜电位抑制PC12细胞凋亡,并增加线粒体DNA拷贝数恢复线粒体数量。为明确归草败毒饮是否通过BCL-2/BAX调控线粒体凋亡发挥其神经保护作用,本研究通过Western blot及线粒体免疫荧光共定位评估线粒体凋亡相关蛋白BCL-2、BAX、CASP 3的表达及BAX线粒体易位情况。与既往研究一致,本研究证实了硼替佐米诱导线粒体凋亡是其导致神经细胞毒性的重要机制,而归草败毒饮可显著上调BCL-2表达,下调BAX、CASP3水平,并减少BAX线粒体易位,抑制线粒体凋亡以减轻硼替佐米诱导的神经细胞损伤。
综上,本研究阐述了BiPN患者中医辨证分型及其与PN分级的关系,并证实了归草败毒饮通过抑制线粒体凋亡途径改善BiPN,为归草败毒饮防治肿瘤并发症提供了基础依据。
基金
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  • 国家自然科学基金面上项目资助(82274491)
  • 国家自然科学基金面上项目资助(82074348)
  • 山东省自然科学基金创新发展联合基金项目资助(ZR2023LZL009)
  • 济南市临床医学科技创新计划项目资助(202225014)
  • 济南市临床医学科技创新计划项目资助(202328072)
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doi: 10.11669/cpj.2025.08.007
  • 接收时间：2024-08-16
  • 首发时间：2025-11-12
  • 出版时间：2025-04-15
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  • 收稿日期：2024-08-16
基金
国家自然科学基金面上项目资助(82274491)
国家自然科学基金面上项目资助(82074348)
山东省自然科学基金创新发展联合基金项目资助(ZR2023LZL009)
济南市临床医学科技创新计划项目资助(202225014)
济南市临床医学科技创新计划项目资助(202328072)
作者信息
    1 山东中医药大学第一临床医学院, 济南 250013
    2 山东中医药大学第二附属医院肿瘤中心, 济南 250001

通讯作者:

*崔兴,男,博士,主任医师,博士生导师 研究方向:中医治疗血液和肿瘤疾病临床及基础研究 Tel:(0531)58251302
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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