延胡索总生物碱对糖尿病心肌病大鼠铜死亡的调控作用及机制  

Effects and mechanism of total alkaloids of Corydalis Rhizoma on the regulation of cuproptosis in rats with diabetic cardiomyopathy

作　　者：李君 齐雅芝 唐娅 曹睿 徐强[1] 韩玉生 LI Jun;QI Yazhi;TANG Ya;CAO Rui;XU Qiang;HAN Yusheng(School of Basic Medicine,Heilongjiang University of Chinese Medicine,Harbin 150040,China)

机构地区：[1]黑龙江中医药大学基础医学院,哈尔滨150040

出　　处：《中国药房》2025年第7期801-806,共6页China Pharmacy

基　　金：国家自然科学基金面上项目(No.82074530);黑龙江中医药大学科研基金项目(No.X200902)。

摘　　要：目的基于沉默信息调节因子1(Sirt1)/肿瘤抑制因子53(P53)信号通路,探讨延胡索总生物碱(TAC)对糖尿病心肌病(DCM)大鼠铜死亡的调控作用及机制。方法采用高脂高糖饲料喂养+腹腔注射链脲佐菌素建立DCM大鼠模型。取32只造模成功的大鼠随机分为模型组和TAC低、中、高剂量组(7、10.5、14 mg/kg),每组8只。另取8只大鼠以正常饲料喂养作为正常对照组。各组大鼠灌胃相应药物或生理盐水,每天1次,连续4周。末次给药后,检测大鼠空腹血糖(FBG)水平;检测大鼠血清和心肌组织中肌酸激酶(CK)、CK同工酶MB(CK-MB)、乳酸脱氢酶(LDH)水平;观察大鼠心肌组织病理学形态、纤维化程度及Cu^(2+)沉积情况;检测大鼠心肌组织中Cu^(2+)、谷胱甘肽(GSH)水平以及Sirt1/P53信号通路相关蛋白[Sirt1、P53、溶质家族载体7成员11(SLC7A11)]、铁硫簇相关蛋白[铁氧还蛋白1(FDX1)、硫辛酸合成酶(LIAS)、线粒体乌头酸酶2(ACO_(2))、泛醌氧化还原酶核心亚基S8(NDUFS8)、二氢硫辛酸乙酰基转移酶(DLAT)、二氢硫辛酸二酰基转移酶(DLST)]、热休克蛋白70(HSP70)表达水平。结果与正常对照组相比,模型组大鼠FBG水平,血清和心肌组织中CK、CK-MB、LDH水平,心肌组织中Cu^(2+)水平以及P53、HSP70蛋白表达水平均显著升高(P<0.05);心肌组织中GSH水平和Sirt1、SLC7A11、FDX1、LIAS、ACO_(2)、NDUFS8、DLAT、DLST蛋白表达水平均显著降低(P<0.05);心肌组织病理损伤严重,出现较多炎症细胞浸润,且纤维化明显,Cu^(2+)沉积增多。与模型组比较,TAC各剂量组大鼠上述大部分定量指标均显著逆转(P<0.05);心肌组织病理损伤减轻,纤维化和Cu^(2+)沉积减少。结论TAC可改善大鼠DCM,其作用机制可能与激活Sirt1/P53信号通路活性,促进GSH与Cu^(2+)的螯合作用,抑制心肌细胞铜死亡有关。OBJECTIVE To investigate the effects and mechanism of total alkaloids of Corydalis Rhizoma(TAC)on the regulation of cuproptosis in rats with diabetic cardiomyopathy(DCM)based on silence information regulator 1(Sirt1)/tumor protein 53(P53)signaling pathway.METHODS DCM rat model was induced by high-fat and high-sugar diet and intraperitoneal injection of streptozotocin.Thirty-two model rats were randomly divided into model group,TAC low-dose,medium-dose and high-dose groups(7,10.5,14 mg/kg),with 8 rats in each group.An additional 8 rats were assigned to normal control group.Related drugs or normal saline were administered intragastrically in each group,once a day,for 4 weeks.After the last medication,the fasting blood glucose(FBG)levels of the rats were measured.The levels of myocardial creatine kinase(CK),creatine kinase isoenzyme(CK-MB),and lactate dehydrogenase(LDH)in serum and myocardial tissue of rats were all detected.The pathological morphology,fibrosis degree,and Cu^(2+)deposition of myocardial tissue in rats were observed.The levels of Cu^(2+)and glutathione(GSH)in myocardial tissue,the expressions of Sirt1/P53 signaling pathway-related proteins[Sirt1,P53,solute carrier family 7 membrane 11(SLC7A11)],and iron-sulfur cluster-related proteins[ferredoxin 1(FDX1),lipoic acid synthetase(LIAS),aconitase 2(ACO_(2)),NADH-ubiquinone oxidoreductase core subunit S8(NDUFS8),dihydrolipoamide acetyltransferase(DLAT),dihydrolipoamide succinyltransferase(DLST)],and heat shock protein 70(HSP70)were all determined.RESULTS Compared with normal control group,the model group exhibited significantly elevated levels of FBG,CK,CK-MB and LDH in both serum and myocardial tissue,as well as increased levels of Cu^(2+)in myocardial tissue and the expression of P53 and HSP70 proteins(P<0.05);the level of GSH and the expression levels of Sirt1,SLC7A11,FDX1,LIAS,ACO_(2),NDUFS8,DLAT,and DLST proteins in myocardial tissue were all significantly decreased(P<0.05);the myocardial tissue exhibited severe pathological damage,with numerous infla

关 键 词：延胡索总生物碱 糖尿病心肌病 铜死亡 Sirt/P53信号通路 铁硫簇 

分 类 号：R965[医药卫生—药理学]