柴胡皂苷调节HIF-1α/BNIP3信号通路抑制线粒体自噬治疗肝胃不和型功能性消化不良大鼠  

Saikosaponin regulates HIF-1α/BNIP3 signaling pathway to inhibit mitochondrial autophagy for the treatment of functional dyspepsia in rats with liver-gastric disharmony

作　　者：祁正亮 刘晓[2] 田曼 QI Zheng-liang;LIU Xiao;TIAN Man(Dept of Geriatry,Hubei Provincial Hospital of Traditional Chinese Medicine(Affiliated Hospital of Hubei University of Chinese Medicine,Hubei Provincial Institute of Traditional Chinese Medicine),Wuhan 430061,China;College of Traditional Chinese Medicine,Hubei University of Chinese Medicine,Wuhan 430065,China)

机构地区：[1]湖北省中医院(湖北中医药大学附属医院,湖北省中医药研究院)老年病科,湖北武汉430061 [2]湖北中医药大学中医学院,湖北武汉430065

出　　处：《中国药理学通报》2024年第12期2256-2261,共6页Chinese Pharmacological Bulletin

基　　金：湖北省自然科学基金资助项目(No 2023 AFD175)。

摘　　要：目的探究柴胡皂苷调节缺氧诱导因子-1α(HIF-1α/腺病毒E1B相互作用蛋白3(BNIP3)信号通路对肝胃不和型功能性消化不良(functional dyspepsia,FD)大鼠胃窦组织线粒体自噬的影响。方法采用复合因素法构建肝胃不和型FD大鼠模型,随机分为空白组、模型组、吗丁啉组、柴胡皂苷低、中、高剂量组,其中吗丁啉组以2.7 mg·kg^(-1)吗丁啉灌胃,柴胡皂苷低、中、高剂量组分别腹腔注射2、4、8 mg·kg^(-1)柴胡皂苷,模型组和空白组给予相同剂量生理盐水灌胃和腹腔注射,连续干预7 d。观察各组大鼠胃肠功能:胃排空率、小肠推进率,ELISA法检测血清胃动素(MTL)、胃泌素(GAS)含量,HE染色观察胃窦组织病理变化,透射电镜观察胃窦组织线粒体结构,试剂盒检测ROS、MDA、SOD水平,Western blot检测胃窦组织线粒体LC3、Beclin1、p62、HIF-1α、BNIP3蛋白表达。结果与空白组相比,模型组大鼠胃窦组织少量炎性细胞浸润,线粒体肿胀、变形,出现大量自噬体,胃排空率、小肠推进率、MTL、GAS、SOD、P62降低,ROS、MDA水平、LC3Ⅱ/LC3Ⅰ、Beclin1、HIF-1α、BNIP3蛋白表达升高(P<0.05);与模型组相比,吗丁啉组和柴胡皂苷低、中、高剂量组胃窦组织症状明显改善,线粒体嵴清晰,自噬体减少,胃排空率、小肠推进率、MTL、GAS、SOD、p62升高,ROS、MDA水平、LC3Ⅱ/LC3Ⅰ、Beclin1、HIF-1α、BNIP3蛋白表达降低(P<0.05)。结论柴胡皂苷能够改善肝胃不和型FD大鼠肠胃功能,抑制线粒体自噬,其作用机制可能与抑制HIF-1α/BNIP3信号通路有关。Aim To investigate the effect of saikosaponin on mitochondrial autophagy in rats with functional dyspepsia(FD)of liver stomach disharmony type by regulating the hypoxia inducible factor-1α(HIF-1α)/BCL2/adenovirus E1B interacting protein 3(BNIP3)signaling pathway.Methods A compound factor method was used to construct a liver stomach disharmony type FD rat model.The rats were randomly separated into a blank group,a model group,a dompendone group,and low,medium,and high dose saikosaponin groups,with 10 rats in each group.The gastrointestinal function of rats in each group was observed,including gastric emptying rate and small intestine propulsion rate,ELISA method was applied to detect serum levels of motilin(MTL)and gastrin(GAS),histopathologic changes of the gastric sinus were observed by HE staining,transmission electron microscopy was applied to observe the mitochondrial structure of gastric antrum tissue,reagent kit was applied to detect levels of ROS,MDA,and SOD,Western blot was applied to detect the expression of mitochondrial LC3,Beclin1,p62,HIF-1α,and BNIP3 proteins in gastric antrum tissue.Results Compared with the blank group,the gastric antrum tissue of rats in the model group showed a small amount of inflammatory cell infiltration,mitochondrial swelling and deformation,and a large number of autophagosomes,the gastric emptying rate,small intestine propulsion rate,MTL,GAS,SOD,and p62 were greatly reduced,the levels of ROS,MDA,the protein expression of LC3Ⅱ/LC3Ⅰ,Beclin1,HIF-1α,and BNIP3 were greatly increased(P<0.05);compared with the model group,the symptoms of gastric antrum tissue were greatly improved in the dompendone group,low,medium,and high-dose saikosaponin groups,with clear mitochondrial cristae and reduced autophagosomes,the gastric emptying rate,small intestine propulsion rate,MTL,GAS,SOD,and p62 were greatly increased,the levels of ROS,MDA,the protein expression of LC3Ⅱ/LC3Ⅰ,Beclin1,HIF-1α,and BNIP3 were greatly reduced(P<0.05).Conclusion Saikosaponin can improve gastrointestinal

关 键 词：肝胃不和型功能性消化不良 线粒体自噬 柴胡皂苷 HIF-1α/BNIP3信号通路 大鼠 胃窦组织 

分 类 号：R-332[医药卫生] R256R284.1R322.44R329.24R392R573