Detoxification mechanism of psoralea corylifolia reverse compatibility based on the AMPK/GSK-3β/Nrf2 signaling pathway

WANG Jing; WEI Wenxin; LI Xingyu; CHEN Sikai; ZHANG Mengmeng; LI Yao; DONG Taiwei; GAO Feng; LI Min; XI Miaomiao; XIE Yundong; WEI Peifeng

doi:10.3969/j.issn.1006-2157.2023.05.012

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Detoxification mechanism of psoralea corylifolia reverse compatibility based on the AMPK/GSK-3β/Nrf2 signaling pathway

Experimental Studies | 更新时间：2023-06-05

- Detoxification mechanism of psoralea corylifolia reverse compatibility based on the AMPK/GSK-3β/Nrf2 signaling pathway
- Journal of Beijing University of Traditional Chinese Medicine Vol. 46, Issue 5, Pages: 665-675(2023)
- 作者机构：
  
  1.陕西中医药大学　咸阳　712046
  2.南昌大学玛丽女王学院
  3.陕西中医药大学第二附属医院
- 作者简介：
  
  Prof. WEI Peifeng, Ph. D., Master’s Supervisor. Second Affiliated Hospital of Shaanxi University of Chinese Medicine, No. 831, Longtaiguan Road, Fengxi New Town, Xixian New District, Xianyang 712021. E-mail: weipeifeng@163.com
- 基金信息：
  
  National Natural Science Foundation of China(82204790);"Special Support Plan" Talent Project Subject of Shaanxi Province;Traditional Chinese Medicine "Double Chain Integration" Young and Middle-aged Scientific Research Innovation Team Construction Project(2022-SLRH-YQ-008);Innovation Team Construction Project of Second Affiliated Hospital of Shaanxi University of Chinese Medicine(2020XKTD-A04)
- DOI：10.3969/j.issn.1006-2157.2023.05.012
  CLC： R285.5
- Received：13 October 2022，
  
  Published Online：03 March 2023，
  
  Published：30 May 2023
- 稿件说明：
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WANG Jing, WEI Wenxin, LI Xingyu, et al. Detoxification mechanism of psoralea corylifolia reverse compatibility based on the AMPK/GSK-3β/Nrf2 signaling pathway[J]. Journal of beijing university of traditional chinese medicine, 2023, 46(5): 665-675.
DOI：

WANG Jing, WEI Wenxin, LI Xingyu, et al. Detoxification mechanism of psoralea corylifolia reverse compatibility based on the AMPK/GSK-3β/Nrf2 signaling pathway[J]. Journal of beijing university of traditional chinese medicine, 2023, 46(5): 665-675. DOI： 10.3969/j.issn.1006-2157.2023.05.012.

摘要

目的

探讨补骨脂的反成配伍对大鼠肝脏的减毒作用及作用机制。

方法

80只SD大鼠采用随机数字表法分为空白组、模型组、补骨脂组、补骨脂＋制何首乌1∶1组、补骨脂＋制何首乌1∶2组、补骨脂＋制何首乌2∶1组、补骨脂＋熟地黄1∶1组、补骨脂＋五味子1∶1组，每组10只大鼠。除空白组外，其他组皮下注射氢化可的松(25 mg/kg)制备肾阳虚大鼠模型，每日1次，连续注射14 d。大鼠建立肾阳虚模型后，给予相应药物干预，各组给药剂量均为12.6 g/kg，连续灌胃4周。HE染色观察大鼠肝脏组织病理变化。酶联免疫吸附测定检测大鼠血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP)、直接胆红素(DBIL)和总胆红素(TBIL)水平，以及肝组织中超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-Px)表达水平。实时荧光PCR检测核因子E2相关因子2(Nrf2)、Kelch样环氧氯丙烷相关蛋白1(Keap1)、血红素加氧酶－1(HO-1)、醌氧化还原酶1(NQO1)mRNA的表达。蛋白质印迹法检测AMP活化蛋白激酶(AMPK)/糖原合成酶激酶－3β(GSK-3β)/Nrf2信号通路中磷酸化AMPK(p-AMPK)、磷酸化GSK-3β(p-GSK-3β)、Nrf2、HO-1的蛋白表达。

结果

与补骨脂组比较，补骨脂与补阴药制何首乌、熟地黄及五味子配伍后大鼠肝小叶结构改善，炎性浸润细胞减少。与补骨脂组比较，补骨脂＋制何首乌1∶2组、补骨脂＋熟地黄1∶1组、补骨脂＋五味子1∶1组大鼠血清中AST、ALT、ALP、DBIL、TBIL水平均降低(

0.01)；补骨脂＋制何首乌1∶2组大鼠肝组织SOD、GSH-Px、MDA的表达改善(

0.01)；补骨脂＋制何首乌1∶2组Nrf2、HO-1、NQO1 mRNA水平上调(

0.01)，Keap1 mRNA水平下调(

0.01)；补骨脂＋制何首乌1∶2组、补骨脂＋制何首乌2∶1组、补骨脂＋熟地黄1∶1组、补骨脂＋五味子1∶1组p-AMPK、p-GSK-3β、Nrf2、HO-1蛋白表达均升高(

0.05，

0.01)。

结论

补骨脂配伍补阴药制何首乌、熟地黄及五味子可改善补骨脂所致的肝损伤，其作用机制可能是通过激活AMPK/GSK-3β/Nrf2信号通路，抑制氧化应激状态来发挥对肝脏的保护作用，补骨脂与何首乌配伍比例1∶2减毒效果最佳。

Abstract

Objective

To investigate the attenuating effect of reverse compatibility of psoralea corylifolia on rat liver and the underlying mechanism.

Methods

According to the random number table method

80 SD rats were divided into the blank group

the model group

the psoralea corylifolia group

the psoralea corylifolia + polygonum multiflorum 1∶1 group

the psoralea corylifolia + polygonum multiflorum 1∶2 group

the psoralea corylifolia + polygonum multiflorum 2∶1 group

the psoralea corylifolia + rehmannia glutinosa 1∶1 group

the psoralea corylifolia + schisandra chinensis 1∶1 group

with 10 rats in each group. Rats in all groups except for the blank group were subcutaneously injected with hydrocortisone (25 mg/kg) once a day for 14 days to establish a rat model of kidney yang deficiency. After the model of kidney yang deficiency was established

the rats were given corresponding drugs for 4 weeks; the drug dose was 12.6 g/kg in each group. HE staining was used to observe the pathological changes of rat liver tissue. The serum levels of alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

direct bilirubin (DBIL) and total bilirubin (TBIL) and the expression levels of superoxide dismutase (SOD)

malondialdehyde (MDA)

and glutathione peroxidase (GSH-Px) in liver tissue were detected by ELISA. The mRNA expression levels of NF-E2-related factor 2 (Nrf2)

Kelch-like epichlorohydrin-related protein 1 (Keap1)

heme oxygenase-1 (HO-1)

and quinone oxidoreductase NADH1 (NQO1) were detected by real-time PCR. The protein expression levels of phosphorylated AMPK (p-AMPK)

phosphorylated GSK-3β (p-GSK-3β)

Nrf2

and HO-1

which were involved in the AMPK/GSK-3β/Nrf2 signaling pathway

were determined by Western blotting.

Results

Compared with the psoralea corylifolia group

the structure of hepatic lobules in rats was improved and the inflammatory infiltration cells were reduced after the compatibility of psoralea corylifolia and medicinals for replenishing yin such as polygonum multiflorum

rehmannia glutinosa and schisandra chinensis. Compared with the psoralea corylifolia group

the serum levels of AST

ALT

ALP

DBIL

and TBIL of rats in the psoralea corylifolia+ polygonum multiflorum 1∶2 group

the psoralea corylifolia+ rehmannia glutinosa 1∶1 group

the psoralea corylifolia+ schisandra chinensis 1∶1 group were reduced (

0.01); the expression levels of SOD

GSH-Px and MDA in liver tissue of rats were improved in psoralea corylifolia+ polygonum multiflorum 1∶2 group (

0.01); the mRNA levels of Nrf2

HO-1

and NQO1 were up-regulated (

0.01) and the mRNA level of Keap1 was down-regulated (

0.01) in the psoralea corylifolia+ polygonum multiflorum 1∶2 group; the protein expression levels of p-AMPK

p-GSK-3β

Nrf2

and HO-1 were increased in the psoralea corylifolia+ polygonum multiflorum 1∶2 group

the psoralea corylifolia+ polygonum multiflorum 2∶1 group

the soralea corylifolia+ rehmannia glutinosa 1∶1 group

and the soralea corylifolia+ schisandra chinensis 1∶1 group (

0.05

0.01).

Conclusion

The compatibility of psoralea corylifolia and medicinals for replenishing yin polygonum multiflorum

rehmannia glutinosa and schisandra chinensis can improve the liver injury caused by psoralea corylifolia. The mechanism may be to activate the AMPK/GSK-3β/Nrf2 signaling pathway and inhibit the oxidative stress state to play a protective role in the liver. The compatibility ratio of psoralea corylifolia and polygonum multiflorum 1∶2 has the best attenuation effect.

关键词

Keywords

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