摘要
目的基于hedgehog(Hh)信号通路探讨木犀草素(Lut)对妊娠糖尿病(GDM)大鼠胎盘功能障碍的改善作用及潜在机制。方法随机选择雌鼠20只作为对照组,以正常饲料喂养。剩余雌鼠以高脂高糖饲料喂养8周后与雄性大鼠合笼,取妊娠大鼠,腹腔注射35 mg/kg的链脲佐菌素以构建GDM雌鼠模型;将造模成功的雌鼠随机分为模型组、SAG组(Hh信号通路激活剂SAG 50 mg/kg)、Lut低剂量组(Lut 40 mg/kg)、Lut高剂量组(Lut 80 mg/kg)、Lut高+ITR组(Lut 80 mg/kg+Hh信号通路拮抗剂伊曲唑康50 mg/kg),每组20只。各药物组雌鼠灌胃相应药液,每天1次,持续19 d。末次给药后,检测各组雌鼠的糖脂代谢参数(空腹血糖、空腹胰岛素水平和胰岛素抵抗指数)、胎盘质量和通透性[以伊文思蓝(EB)含量表示],观察其胎盘组织病理变化,检测其胎盘组织中超氧化物歧化酶(SOD)活性及丙二醛(MDA)、还原型谷胱甘肽(GSH)含量以及Sonic Hh(Shh)、Patched-1(Ptch1)、Smoothened(Smo)、Gil家族锌指蛋白1(Gli1)的表达水平。结果与对照组相比,模型组大鼠胎盘组织中毛细血管管腔狭窄,血管周围可见纤维化区域;其糖脂代谢参数、胎盘质量、EB及MDA含量均显著升高,SOD活性、GSH含量及Shh、Ptch1、Smo、Gli1蛋白的表达水平均显著降低(P<0.05)。与模型组相比,SAG组和Lut低、高剂量组大鼠胎盘组织中毛细血管管腔变宽,血管周围纤维化明显减少;糖脂代谢参数、胎盘质量、EB及MDA含量均显著降低,SOD活性、GSH含量及Shh、Ptch1、Smo、Gli1蛋白的表达水平均显著升高(P<0.05);且Lut高剂量组上述参数与SAG组相比差异均无统计学意义(P>0.05)。Hh信号通路拮抗剂伊曲唑康可显著逆转Lut对上述指标的改善作用(P<0.05)。结论Lut可改善GDM大鼠的糖代谢参数,降低胎盘通透性,减轻其胎盘组织病理损伤和氧化应激,上述作用可能与激活Hh信号通路有关。
OBJECTIVE To explore the improving effect of luteolin(Lut)on placental dysfunction in rats with gestational diabetes mellitus(GDM)and its potential mechanism based on hedgehog(Hh)signaling pathway.METHODS Twenty female rats were randomly selected as a control group and fed a normal diet.The remaining female rats were fed a high-fat and high-sugar diet for 8 weeks and then caged with male rats.Pregnant rats were administered 35 mg/kg streptozotocin intraperitoneally to establish GDM models.Successfully modeled female rats were randomly allocated to model group,SAG group(Hh signaling pathway activator SAG 50 mg/kg),Lut low-dose group(Lut 40 mg/kg),Lut high-dose group(Lut 80 mg/kg),and Lut high+ITR group(Lut 80 mg/kg+Hh signaling pathway antagonist itraconazole 50 mg/kg),with 20 rats in each group.Female rats in each drug group were intubated with the corresponding drug solution once a day for 19 days.After the final administration,the serum glucosefat metabolic parameters(levels of fasting blood glucose and fasting insulin,insulin resistance index),placental quality,placental permeability[Evan’s blue(EB)content],and pathological changes in placental tissue were observed.The activities of superoxide dismutase(SOD),the contents of malondialdehyde(MDA)and reduced glutathione(GSH),and the protein expressions of Sonic Hh(Shh),Patched-1(Ptch1),Smoothened(Smo)and Gli family zinc finger-1(Gli1)in placental tissue were detected.RESULTS Compared with the control group,rats in the model group showed narrow capillary lumens,perivascular fibrosis in placental tissue,and a significant increase in serum glucose-fat metabolic parameters,placental quality,contents of EB and MDA,while there was a significant decrease in SOD activity,GSH content,and protein expressions of Shh,Ptch1,Smo and Gli1(P<0.05).Compared with the model group,rats in the SAG group,Lut low-dose and high-dose groups had widened capillary lumens,a significant decrease in perivascular fibrosis in placental tissue,serum glucose-fat metabolic parameters,placental qualities,EB and MDA contents,while there was a significant increase in SOD activities,GSH contents,and protein expressions of Shh,Ptch1,Smo and Gli1(P<0.05),with the high-dose group showing no significant difference compared to the SAG group(P>0.05).The Hh signaling pathway antagonist itraconazole could significantly reverse the improving effects of Lut on the above indicators(P<0.05).CONCLUSIONS Lut can improve glucose metabolism parameters of GDM rats,reduce placental permeability,alleviate pathological damage to placental tissue,and reduce oxidative stress.These effects may be related to the activation of the Hh signaling pathway.
作者
胡殿鹏
张举
侯奕忻
程琳
卢佳璐
HU Dianpeng;ZHANG Ju;HOU Yixin;CHENG Lin;LU Jialu(Dept.of Basic Medicine,Nanyang Medical College,Nanyang Henan 473000,China;Dept.of Obstetrics,the First Affiliated Hospital of Nanyang Medical College,Nanyang Henan 473000,China)
出处
《中国药房》
CAS
北大核心
2024年第22期2763-2768,共6页
China Pharmacy
基金
南阳市科技计划项目(No.KJGG196)
河南省社会科学界联合会调研课题(No.SKL-2019-589)。
