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类叶牡丹关节注射液治疗类风湿性关节炎的作用机制
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          吕邵娃 ，邬芸煜，刘泉莉，任雨涵，郭玉岩，匡海学（黑龙江中医药大学教育部北药基础与应用研究重点实验室/
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          黑龙江省中药及天然药物药效物质基础研究重点实验室，哈尔滨 150040）

          中图分类号  R965      文献标志码  A      文章编号  1001-0408（2025）08-0926-06
          DOI  10.6039/j.issn.1001-0408.2025.08.06

          摘   要  目的  探究类叶牡丹关节注射液治疗类风湿性关节炎（RA）的作用机制。方法  类叶牡丹中的主要皂苷类成分通过Swiss
          Target Prediction网站获取作用靶点，与从GeneCards、OMIM数据库中收集的RA治疗靶点并取交集，基于网络药理学建立交互网
          络，进行基因本体功能、京都基因与基因组百科全书（KEGG）通路富集分析。采用大耳兔背部注射弗氏完全佐剂建立RA模型进
          行验证，比较各组大耳兔关节炎指数评分、膝关节直径和痛阈值变化，观察滑膜组织形态变化，检测血清和关节滑液中肿瘤坏死因
          子α（TNF-α）、白细胞介素1β（IL-1β）、IL-6水平以及滑膝关节膜组织中Janus激酶2（JAK2）、信号转导与转录激活因子3（STAT3）
          蛋白的磷酸化水平。结果  网络药理学筛选出类叶牡丹关节注射液与RA的交集靶点有143个，构建“药物-成分-靶点”网络后获取
          核心成分为刺囊酸、齐墩果酸、常春藤皂苷元、葳岩仙皂苷A、葳岩仙皂苷C等；蛋白质-蛋白质相互作用网络构建排前10名的核心
          靶点分别为 SRC、STAT3、MAPK1、EGFR、PIK3CA、MAPK3、GRB2、JUN、PTPN11、JAK2；KEGG 通路富集分析结果显示，类叶牡丹
          关节注射液治疗RA主要涉及JAK/STAT信号通路等。实验验证结果显示，与模型组比较，类叶牡丹关节注射液可减轻大耳兔膝
          关节肿胀和滑膜层增生，使下层结缔组织增生减少、炎症细胞和毛细血管数量减少；显著降低关节炎指数评分（类叶牡丹低剂量组
          除外），膝关节直径，血清和关节滑液中TNF-α、IL-1β、IL-6水平以及JAK2、STAT3蛋白的磷酸化水平（P＜0.05或P＜0.01）；显著升
          高痛阈值水平（P＜0.01）。结论  类叶牡丹关节注射液中刺囊酸、齐墩果酸、常春藤皂苷元、葳岩仙皂苷A、葳岩仙皂苷C可能是缓
          解RA炎症反应的核心成分，其作用机制可能与抑制JAK/STAT信号通路、减轻炎症反应有关。
          关键词  类叶牡丹；类叶牡丹关节注射液；类风湿性关节炎；JAK/STAT信号通路；网络药理学

          Mechanism of joint injection of Caulophyllum robustum Maxim in the treatment of rheumatoid arthritis
          LYU Shaowa，WU Yunyu，LIU Quanli，REN Yuhan，GUO Yuyan，KUANG Haixue（Key Laboratory of Basic and
          Applied  Research  of  Northern  Medicine，  Ministry  of  Education，  Heilongjiang  University  of  Chinese  Medicine/
          Heilongjiang  Provincial  Key  Laboratory  of  Pharmacodynamic  Substances  of  Traditional  Chinese  Medicine  and
          Natural Medicine， Harbin 150040， China）

          ABSTRACT    OBJECTIVE  To  explore  the  mechanism  of  joint  injection  of  Caulophyllum  robustum  Maxim  in  the  treatment  of
          rheumatoid  arthritis （RA）.  METHODS  The  targets  of  main  saponins  in  C.  robustum  Maxim  were  obtained  from  Swiss  Target
          Prediction，  and  the  RA  treatment  targets  collected  from  the  GeneCards  and  OMIM  database  were  intercrossed  to  establish  an
          interaction  network  based  on  network  pharmacology.  Gene  ontology  analysis  and  Kyoto  Encyclopedia  of  Genes  and  Genomes
         （KEGG）  pathway  analysis  were  performed.  RA  model  was  established  by  injecting  complete  Freund’s  adjuvant  into  the  back  of
          rabbits  for  verification.  The  arthritis  index  score，  knee  diameter  and  pain  threshold  of  rabbits  were  compared.  Pathological
          examination of rabbit synovial tissue was carried out. The levels of tumor necrosis factor α （TNF-α）， interleukin-1β （IL-1β） and
          IL-6  in  rabbit  serum  and  synovial  fluid  were  detected.  The  phosphorylation  levels  of  tyrosine  protein  Janus  kinase  2 （JAK2）  and
          signal  transducer  and  activator  of  transcription  3 （STAT3）  proteins  in  rabbit  synovium  were  detected.  RESULTS  Network
          pharmacology  identified  143  intersection  targets  between  the  drug  and  RA. After  the  construction  of  the “drug-component-target”
          network，  the  core  components  of  the  network  were  echinocystic  acid，  oleanolic  acid，  hederagenin，  cauloside A  and  cauloside  C，
          etc. Additionally，  the  top  10  core  targets  of  PPI  network  were  SRC，  STAT3，  MAPK1，  EGFR，  PIK3CA，  MAPK3，  GRB2，  JUN，
          PTPN11  and  JAK2.  The  results  of  KEGG  pathway  analysis  showed  that  the  JAK/STAT  signaling  pathway  was  mainly  involved  in
          the  treatment  of  RA  by  joint  injection  of  C.  robustum  Maxim.  Results  of  validation  test  showed  that  compared  with  model  group，
          joint  injection  of  C.  robustum  Maxim  could  reduce  the  swelling  of  rabbit  knee  joint，  relieve  the  hyperplasia  of  synovial  layer，
          reduce  the  hyperplasia  of  lower  connective  tissue，  and  reduce  the  number  of  inflammatory  cells  and  capillaries. The  arthritis  index
          score （excluding  low-dose  group  of  C.  robustum  Maxim），  knee  diameter，  the  levels  of  TNF-α，  IL-1β  and  IL-6  in  serum  and
                                                              synovial fluid， and the protein phosphorylation levels of JAK2
              Δ 基金项目 国家自然科学基金项目（No.82474098）
                                                              and  STAT3  were  decreased  significantly （P＜0.05  of  P＜
             ＊第一作者 教授，硕士生导师。研究方向：中药新药与新剂型。
          E-mail：lswa5599@hotmail.com                         0.01），  while  the  pain  threshold  were  reduced  significantly
              # 通信作者 教授，博士生导师。研究方向：中药性味理论及中药                 （P＜0.01）.  CONCLUSIONS  The  core  components  that  may
          药效物质基础。电话：0451-87267047。E-mail：HXKUANG56@163.       alleviate  the  inflammatory  response  of  RA  in  joint  injection  of
          com                                                 C.  robustum  Maxim  could  include  echinocystic  acid，  oleanolic


          · 926 ·    China Pharmacy  2025 Vol. 36  No. 8                               中国药房  2025年第36卷第8期
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