| 2,646 | 53 | 102 |
| 下载次数 | 被引频次 | 阅读次数 |
目的:桃红四物汤调控核因子E2相关因子(Nrf2)/Kelch样ECH关联蛋白1(Keap1)/血红素氧合酶-1(HO-1)信号通路介导的铁死亡在膝骨关节炎(KOA)中的作用机制。方法:40只SD大鼠随机分为假手术对照组、模型对照组、桃红四物汤9 g/kg组、双醋瑞因胶囊0.0045 g/kg组，每组各10只；各组均采用内侧半月板失稳手术造模，造模成功1 w后各组灌胃给予相应的药物或无菌水，1次/d,连续8 w。干预完成后，检测各组大鼠血清白介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、IL-18含量及关节软骨组织丙二醛(MDA)含量、超氧化物歧化酶(SOD)活力、活性氧(ROS)含量；透射电镜观察大鼠软骨线粒体数量、形态、结构及分布情况；Western Blot法检测大鼠关节软骨组织Keap1、Nrf2、HO-1、谷胱甘肽过氧化物酶4(GPX4)、肿瘤抑制蛋白53(P53)、溶质载体家族7成员11重组蛋白(SLC7A11)的表达。结果:与假手术对照组比较，模型对照组Mankin和OARSI病理评分增加，IL-1β、TNF-α、IL-18、MDA、ROS含量显著升高，Keap1、P53蛋白表达显著上调，SOD活力显著降低，Nrf2、HO-1、GPX4、SLC7A11蛋白表达显著下调(P<0.01);与模型对照组比较，桃红四物汤组Mankin和OARSI病理评分降低，IL-1β、TNF-α、IL-18、MDA、ROS含量降低，Keap1、P53蛋白表达显著下调，SOD活力显著升高，Nrf2、HO-1、GPX4、SLC7A11蛋白表达显著上调(P<0.01)。结论:桃红四物汤可能通过激活Nrf2/Keap1/HO-1信号通路抑制大鼠关节软骨铁死亡。
Abstract：Objective:To investigate the mechanism of Taohong Siwu Decoction(桃红四物汤) in regulating the Nrf2/Keap1/HO-1 signaling pathway-mediated ferroptosis in knee osteoarthritis(KOA). Methods:40 SD rats were randomly divided into a sham surgery group, a model control group, Taohong Siwu Decoction(9 g/kg) group, and a diacerein capsule(0.0045 g/kg) group, with 10 rats in each group. Rat models were established by using medial meniscus instability surgery. After successful modeling for one week, rats were given corresponding medication or the same dose of sterile water by gavage, once a day for eight weeks. After the intervention was completed, the levels of serum interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),interleukin-18(IL-18),as well as the levels of malondialdehyde(MDA),superoxide dismutase(SOD),and reactive oxygen species(ROS) in articular cartilage tissue were detected. The number, morphology, structure, and distribution of cartilage mitochondria in each group were observed by transmission electron microscopy. Western blot was used to detect the expression of Keap1,Nrf2,HO-1,glutathione peroxidase 4(GPX4),tumor suppressor protein 53(P53),and solute carrier family 7 member 11 recombinant protein(SLC7A11) in rat articular cartilage. Results:Compared with the sham surgery group, the pathological scores of Mankin and OARSI in the model control group were increased, the levels of IL-1β,TNF-α,IL-18,MDA,and ROS were significantly increased, and the protein expressions of Keap1 and P53 were significantly up-regulated. The SOD activity was significantly decreased, and the protein expressions of Nrf2,HO-1,GPX4,and SLC7A11 were significantly down-regulated(P<0.01). Compared with the model control group, the pathological scores of Mankin and OARSI in the Taohong Siwu Decoction group were decreased, and the levels of IL-1β,TNF-α,IL-18,MDA,and ROS were decreased. The protein expressions of Keap1 and P53 were significantly down-regulated. The SOD activity was increased, and the protein expressions of Nrf2,HO-1,GPX4,and SLC7A11 were significantly up-regulated(P<0.01). Conclusion:Taohong Siwu Decoction may inhibit ferroptosis in rat articular cartilage by activating the Nrf2/Keap1/HO-1 signaling pathway.
[1]Pereira T V,Jüni P,Saadat P,et al.Viscosupplementation for knee osteoarthritis:systematic review and meta-analysis[J].BMJ,2022,378(7):e069722-e069734.
[2]Hunter D J,Schofield D,Callander E.The individual and socioeconomic impact of osteoarthritis[J].Nat Rev Rheumatol,2014,10(7):437-441.
[3]LI Z,HUANG Z,BAI L.The P2X7 Receptor in Osteoarthritis[J].Front Cell Dev Biol,2021,9(2):628330-628342.
[4]FAN M,LI Y,YAO C,et al.DC32,a Dihydroartemisinin Derivative,Ameliorates Collagen-Induced Arthritis Through an Nrf2-p62-Keap1 Feedback Loop[J].Front Immunol,2018,27(9):2762-2776.
[5]SUN X,OU Z,CHEN R,et al.Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J].Hepatology,2016,63(1):173-184.
[6]Ansari M Y,Ahmad N,Haqqi T M.Oxidative stress and inflammation in osteoarthritis pathogenesis:Role of polyphenols[J].Biomed Pharmacother,2020,129(9):110452-110476.
[7]GUO Y,XU Y,HE M,et al.Acupotomy Improves Synovial Hypoxia,Synovitis and Angiogenesis in KOA Rabbits[J].J Pain Res,2023,16(3):749-760.
[8]Lu K,Alcivar A L,Ma J,et al.NRF2 Induction Supporting Breast Cancer Cell Survival Is Enabled by Oxidative Stress-Induced DPP3-KEAP1 Interaction[J].Cancer Res,2017,77(11):2881-2892.
[9]邝高艳，严可，陈国茜，等.活血化瘀法对兔创伤性膝骨关节炎模型关节液中IL-6及TNF-α的影响[J].时珍国医国药，2017,28(1):25-28.
[10]李益亮，姚金龙，梁爽，等.桃红四物汤对兔软骨损伤模型noggin蛋白表达的影响——骨伤名师孙达武学术思想与临床经验研究(四)[J].湖南中医药大学学报，2022,42(5):715-719.
[11]段航，曾凡，王林华，等.基于网络药理学与实验验证探讨桃红四物汤对兔退变软骨细胞凋亡的影响[J/OL].中药药理与临床：1-21[2023-11-14].https://doi.org/ 10.13412/j.cnki.zyyl.20230719.001.
[12](清)吴谦等编.御纂医宗金鉴下[M].北京：人民卫生出版社，2006:868-867.
[13]姚金龙，冯海波，李益亮，等.桃红四物汤对ANFH模型大鼠Notch1受体蛋白表达的影响——骨伤名师孙达武学术思想与临床经验研究(三)[J].湖南中医药大学学报，2022,42(5):709-714.
[14]WANG B W,JIANG Y,YAO Z L,et al.Aucubin Protects Chondrocytes Against IL-1β-Induced Apoptosis In Vitro And Inhibits Osteoarthritis In Mice Model[J].Drug Des Devel Ther,2019,13(10):3529-3538.
[15]Gerwin N,Bendele A M,Glasson S,et al.The OARSI histopathology initiative- recommendations for histological assessments of osteoarthritis in the rat[J].Osteoarthritis Cartilage,2010,3(10):S24-S34.
[16]Maríalexandre J,Sánchezizquierdo D,Gilabertestellés J,et al.miRNAs Regulation and Its Role as Biomarkers in Endometriosis.[J].International Journal of Molecular Sciences,2016,17(1):93-105.
[17]TONG L,YU H,HUANG X,et al.Current understanding of osteoarthritis pathogenesis and relevant new approaches[J].Bone Res,2022,10(1):60-72.
[18]Sims N A.Influences of the IL-6 cytokine family on bone structure and function[J].Cytokine,2021,146(10):155655-155667.
[19]ZHAO Y,SONG W,WANG Z,et al.Resveratrol attenuates testicular apoptosis in type 1 diabetic mice:Role of Akt-mediated Nrf2 activation and p62-dependent Keap1 degradation[J].Redox Biol,2018,14(4):609-617.
[20]CAI D,YIN S,YANG J,et al.Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis[J].Arthritis Res The,2015,17(11):269-280.
[21]MIAO Y,CHEN Y,XUE F,et al.Contribution of ferroptosis and GPX4's dual functions to osteoarthritis progression[J].EBioMedicine,2022,76(2):103847-103859.
[22]Seibt T M,Proneth B,Conrad M.Role of GPX4 in ferroptosis and its pharmacological implication[J].Free Radic Biol Med,2019,133(7):144-152.
[23]Alim I,Caulfield J T,Chen Y,et al.Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke[J].Cell,2019,177(5):1262-1279.
[24]CAI D,YAN H,LIU J,et al.Ergosterol limits osteoarthritis development and progre- ssion through activation of Nrf2 signaling[J].Exp Ther Med,2021,21(3):194-210.
基本信息:
DOI：10.13412/j.cnki.zyyl.20240221.002
中图分类号:R285.5
引用信息:
[1]段航,曾凡,王林华,等.桃红四物汤调控Nrf2/Keap1/HO-1信号通路介导的铁死亡在膝骨关节炎中的作用机制[J].中药药理与临床,2024,40(07):10-15.DOI:10.13412/j.cnki.zyyl.20240221.002.
基金信息:
国家自然科学基金项目(编号：81874476、82274543); 第六批名老中医药专家学术经验继承指导老师项目(编号：rsk-011-14); 湖南省自然科学基金项目(编号：S2023JJMSXM2877); 湖南省研究生创新课题(编号：CX20220804,CX20220814); 湖南省中医药管理局“十四五”第一批中医药领军人才培养项目(编号：rsk-023-01); 湖南中医药大学中医学科建设“揭榜挂帅”项目(编号：22JBZ026)
2024-02-22
2024-02-22
2024-02-22