柚皮素通过抑制NF-κB-iNOS/COX-2通路减轻小鼠糖尿病肝损伤  

Naringin attenuates diabetic hepatopathy in mice by inhibition of NF-κB-iNOS/COX-2 pathway

作　　者：刘思佳 吴堃 任凯强 邱红梅[1] 蒋青松[1] LIU Sijia;WU Kun;REN Kaiqiang;QIU Hongmei;JIANG Qingsong(Department of Pharmacology,Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology,Chongqing Key Laboratory of Drug Metabolism,College of Pharmacy,Chongqing Medical University,Chongqing 400016,China;De-partment of Hepatobiliary Surgery,Chongqing General Hospital,Chongqing 400013,China;Department of Pharmacy,the People's Hospital of Yongchuan,Chongqing 402160,China)

机构地区：[1]重庆医科大学药理教研室,重庆市生物化学与分子药理学重点实验室,重庆400016 [2]重庆市人民医院肝胆外科,重庆400013 [3]重庆市永川区人民医院药剂科,重庆402160

出　　处：《中国病理生理杂志》2023年第3期445-450,共6页Chinese Journal of Pathophysiology

基　　金：重庆市自然科学基金资助项目(No.cstc2017jcjAX0211);重庆市渝中区科技计划项目(No.20160127)。

摘　　要：目的探讨核因子(NF-κB)-诱导型一氧化氮合酶(iNOS)/环加氧酶2(COX-2)信号通路在柚皮素治疗减轻小鼠糖尿病肝损伤中的作用。方法将昆明小鼠分为正常对照组、糖尿病肝损伤模型组、低剂量(25 mg·kg^(-1)·d^(-1),灌胃)柚皮素治疗组及高剂量(75 mg·kg^(-1)·d^(-1),灌胃)柚皮素治疗组,每组10只。长期高能量饮食联合多次小剂量链脲菌素(STZ;40 mg·kg^(-1)·d^(-1)×5 d,腹腔注射)建立小鼠糖尿病肝损伤模型。HE染色观察肝脏形态学变化;生化试剂盒检测小鼠血脂及肝功能改变;每周监测空腹血糖(FBG)水平;qRT-PCR检测肝脏NF-κB、iNOS和COX-2的mRNA表达;Western blot法检测肝脏NF-κB、iNOS和COX-2蛋白表达。结果给予STZ 7 d,小鼠FBG水平持续高于11.1 mmol/L,4周后肝脏病理变化及肝功能检测提示出现肝损伤。再过4周(即实验结束时),模型组小鼠肝细胞内可见脂肪变性,还伴有炎症细胞浸润,血脂和肝功能水平均显著升高(P<0.01),同时肝脏NF-κB、iNOS和COX-2的表达显著上调(P<0.01)。柚皮素治疗呈剂量依赖性地减轻肝组织损伤,保护肝功能,显著降低血脂水平(P<0.01);同时,NAR使NF-κB、iNOS和COX-2的表达下调(P<0.01)。另外,柚皮素也显著降低模型组FBG水平(P<0.05),但较正常对照组仍显著升高(P<0.01)。结论柚皮素对小鼠糖尿病肝损伤的治疗作用可能与其抑制NF-κB-iNOS/COX-2信号通路有关。AIM To investigate the effect of naringenin on diabetic hepatopathy in mice and its possible molecular mechanism.METHODS Male Kunming mice were divided into diabetic hepatopathy model group,naringenin treatment(intragastric administration at 25 and 75 mg·kg^(-1)·d^(-1))groups and normal group(n=10).A long-term high-energy diet and intraperitoneal injection of multiple low-dose streptozotocin(STZ;40 mg·kg^(-1)·d^(-1)×5 d)were used to establish the diabetic hepatopathy model in mice,and naringenin was given for 4 weeks.The pathological changes of the liver tissues were observed by HE staining.Blood alanine aminotransferase(ALT)and aspartate aminotransferase(AST)were measured.Blood total cholesterol(TC)and triglyceride(TG)levels were determined by commercial kits.Fasting blood glucose(FBG)was monitored weekly.The mRNA and protein expression levels of nuclear factor-κB(NF-κB),inducible nitric oxide synthase(iNOS)and cyclooxygenase-2(COX-2)in liver were determined by qRT-PCR and Western blot,respectively.RESULTS After 7 d of STZ treatment,FBG in mice was higher than 11.1 mmol/L.Four weeks later,liver damage was observed.After another 4 weeks,steatosis and inflammatory cell infiltration were observed in hepatocytes,and serum TC,TG,ALT and AST levels were significantly increased in diabetic mice(P<0.01).Furthermore,the mRNA and protein levels of NF-κB,iNOS and COX-2 in the liver were up-regulated(P<0.01).Naringenin attenuated the structural and functional liver damage in diabetic mice,and reduced serum TC and TG levels in a dose-dependent manner(P<0.01).Naringenin also significantly down-regulated the expression of NF-κB,iNOS and COX-2(P<0.01).In addition,naringenin reduced FBG in diabetic hepatopathy mice although it remained higher than that in normal group(P<0.01).CONCLUSION Naringenin alleviates hepatic injury in diabetic hepatopathy mice probably via inhibition of the NF-κB-iNOS/COX-2 signaling pathway.

关 键 词：柚皮素 糖尿病肝病 NF-κB-iNOS/COX-2信号通路 

分 类 号：R587.1[医药卫生—内分泌] R575[医药卫生—内科学]