小豆蔻明通过调节Notch/NF-κB信号通路介导的细胞焦亡减轻蒽环类药物所致大鼠的心脏毒性  

Cardamomine attenuates cardiotoxicity induced by anthracyclines in rats by regulating Notch/NF-κB signal pathway mediated pyroptosis

作　　者：于晓磊[1] 李文鑫 陈盼盼 梁云飞[1] 崔艳荣 焦海静 徐繁[1] YU Xiao-lei;LI Wen-xin;CHEN Pan-pan;LIANG Yun-fei;CUI Yan-rong;JIAO Hai-jing;XU Fan(Departmentot of Oncology,Affliated Hospital of Chengde Medical University,Chengde 067000,Hebei Province,China)

机构地区：[1]承德医学院附属医院肿瘤科,河北承德067000

出　　处：《中国临床药理学杂志》2024年第9期1277-1281,共5页The Chinese Journal of Clinical Pharmacology

基　　金：河北省自然科学基金资助项目(H2021406036)。

摘　　要：目的研究小豆蔻明(CAR)通过调节Notch/核转录因子κB(NF-κB)信号通路介导的细胞焦亡对蒽环类药物所致大鼠心脏毒性的保护作用。方法腹腔注射阿霉素(DOX)建立大鼠心脏毒性模型,将模型大鼠随机分为DOX组、CAR低剂量组、CAR高剂量组、Jagged1组。另取10只大鼠作为对照组。对照组和DOX组给予等量0.9%NaCl,CAR低、高剂量组分别给予大鼠40、80 mg·kg^(-1)CAR灌胃,Jagged1组灌胃80 mg·kg^(-1)CAR+和25 ng·kg^(-1)Jagged1,每天1次,连续4周。用试剂盒检测心肌损伤标志物肌酸激酶同工酶(CK-MB)、肌钙蛋白Ⅰ(cTnⅠ);用免疫组化法观察焦亡蛋白Nod样受体蛋白3(NLRP3)、消皮素D(GSDM-D)表达;用蛋白质印迹法检测检测心肌组织Notch1、磷酸化NF-κB p65(p-NF-κB p65)蛋白表达。结果对照组、DOX组、CAR低剂量组、CAR高剂量组和Jagged1组的CK-MB水平分别为(48.51±5.39)、(175.93±13.27)、(106.83±9.73)、(83.71±8.39)和(126.08±9.74)U·L^(-1),cTnⅠ水平分别为(1.95±0.18)、(12.46±1.83)、(7.15±0.64)、(4.13±0.38)和(8.01±0.78)ng·mL^(-1),NLRP3蛋白的平均光密度值分别为0.19±0.07、0.36±0.05、0.25±0.05、0.21±0.03和0.31±0.06,GSDM-D的平均光密度值分别为0.18±0.04、0.43±0.06、0.24±0.03、0.19±0.04和0.32±0.05。DOX组上述指标与对照组比较,在统计学上差异均有统计学意义(均P<0.05);CAR低、高剂量组上述指标与DOX组比较,在统计学上差异均有统计学意义(均P<0.05),且CAR低、高剂量组上述指标比较,在统计学上差异均有统计学意义(均P<0.05);Jagged1组上述指标与CAR高剂量比较,在统计学上差异均有统计学意义(均P<0.05)。结论CAR能改善DOX心脏毒性大鼠心肌损伤,降低氧化应激、炎症反应和细胞焦亡,其作用机制可能与抑制Notch/NF-κB通路有关。Objective To investigate the protective effect of cardamomine(CAR)on anthracycline-induced cardiotoxicity in rats by regulating the pyroptosis mediated by Notch/nuclear factor-κB(NF-κB)signal pathway.Methods The rat model of cardiotoxicity was established by intraperitoneal injection of doxorubicin(DOX).The model rats were randomly divided into DOX group,CAR-L group CAR-H group and Jagged1 group.Another 10 rats were taken as the control group.The control group and the DOX group were given the same amount of 0.9%NaCl.The CAR-L group and CAR-H group were given 40 and80 mg·kg^(-1)CAR by gavage,respectively.The Jagged1 group was given 80 mg·kg^(-1)CAR+and 25 ng·kg^(-1)Jagged1 by gavage once a day for 4 weeks.Myocardial injury markers creatine kinase isoenzyme(CK-MB)and troponinⅠ(cTnⅠ)were detected by kit.The expression of pyroptosis protein Nod-like receptor protein 3(NLRP3)and desquamate D(GSDM-D)were observed by immunohistochemistry.The expression of Notch1 and phosphorylated NF-κB p65(p-NF-κB p65)protein in myocardial tissue was detected by Western blotting.Results The levels of CK-MB in control group,DOX group,CAR-L group,CAR-H group and Jagged1 group were(48.51±5.39),(175.93±13.27),(106.83±9.73),(83.71±8.39)and(126.08±9.74)U·L^(-1);the levels of cTnⅠwere(1.95±0.18),(12.46±1.83),(7.15±0.64),(4.13±0.38)and(8.01±0.78)ng·mL^(-1);the average optical density of NLRP3 protein were 0.19±0.07,0.36±0.05,0.25±0.05,0.21±0.03 and 0.31±0.06;the average optical density of GSDM-D were 0.18±0.04,0.43±0.06,0.24±0.03,0.19±0.04 and 0.32±0.05.There were significant differences in the above indexes between DOX group and control group(allP<0.05).There were significant differences in the above indexes between CAR-L group,CAR-H group and DOX group(all P<0.05),and there were significant differences between CAR-L group and CAR-H group(allP<0.05).The above indexes in Jagged1 group were significantly different from those in CAR-H group(allP<0.05).Conclusion CAR can improve myocardial injury in DOX cardioto

关 键 词：小豆蔻明 心脏毒性 蒽环类药物 细胞焦亡 Notch/核转录因子κB信号通路 

分 类 号：R28[医药卫生—中药学]