Integrated untargeted and targeted metabolomics to reveal therapeutic effect and mechanism of Alpiniae oxyphyllae fructus on Alzheimer's disease in APP/PS1 mice

Shengnan Zhou; Liwei Liu; Yuanyuan Zhang; Zhibo Zhang; Hanbing Li; Feng Fan; Jiuming He; Jian Kang; Lihua Zuo

doi:10.3389/fphar.2022.1104954

Integrated untargeted and targeted metabolomics to reveal therapeutic effect and mechanism of Alpiniae oxyphyllae fructus on Alzheimer's disease in APP/PS1 mice

Front Pharmacol. 2023 Jan 11:13:1104954. doi: 10.3389/fphar.2022.1104954. eCollection 2022.

Authors

Shengnan Zhou^{1

2

3}, Liwei Liu^{1

2

3}, Yuanyuan Zhang^{1

2

3}, Zhibo Zhang^{1

2

3}, Hanbing Li⁴, Feng Fan⁵, Jiuming He⁶, Jian Kang^{1

2

3}, Lihua Zuo^{1

2

3}

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
² Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, Henan, China.
³ Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, Zhengzhou, Henan, China.
⁴ College of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China.
⁵ Department of Neurointerventional radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
⁶ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Introduction: Alpiniae oxyphyllae Fructus (AOF) has been abundantly utilized for the treatment of diarrhea, dyspepsia, kidney asthenia, and abdominal pain in China. AOF is effective for treating AD in clinical trials, but its exact mode of action is yet unknown. Methods: In this study, metabolomics was combined to ascertain the alterations in plasma metabolism in APP/PS1 transgenic mice, the therapy of AOF on model mice, and the dynamic variations in 15 bile acids (BAs) concentration. Results: 31 differential biomarkers were finally identified in APP/PS1 group vs. the WT group. The levels of 16 metabolites like sphinganine (Sa), lyso PE (20:2), lysoPC (17:0), glycocholic acid (GCA), deoxycholicacid (DCA) were increased in APP/PS1 group, and those of 15 metabolites like phytosphingosine, cer (d18:0/14:0), and fumaric acid were reduced in APP/PS1 group. After AOF treatment, 29 of the 31 differential metabolites showed a tendency to be back-regulated, and 15 metabolites were significantly back-regulated, including sphinganine (Sa), lyso PE (20:2), glycocholic acid (GCA), deoxycholic acid (DCA). The relationship between BAs level and AD had been received increasing attention in recent years, and we also found notable differences between DCA and GCA in different groups. Therefore, a BAs-targeted metabonomic way was established to determine the level of 15 bile acids in different groups. The consequence demonstrated that primary BAs (CA, CDCA) declined in APP/PS1 model mice. After 3 months of AOF administration, CA and CDCA levels showed an upward trend. Conjugated primary bile acids (TCA, GCA, TCDCA, GCDCA), and secondary bile acids (DCA, LCA, GDCA, TDCA, TLCA GLCA) ascended in APP/PS1 group. After 3 months of AOF treatment, the levels of most BAs decreased to varying degrees. Notably, the metabolic performance of DCA and GCA in different groups was consistent with the predictions of untargeted metabolomics, validating the correctness of untargeted metabolomics. Discussion: According to metabolic pathways of regulated metabolites, it was prompted that AOF ameliorated the symptom of AD mice probably by regulating bile acids metabolism. This study offers a solid foundation for further research into the AOF mechanism for the therapy of AD.

Keywords: Alpiniae oxyphyllae fructus; alzheimer’s disease; bile acids; targeted metabolomics; untargeted metabolomics.

Grants and funding

This study was supported by the National Natural Science Foundation of China (No.82003921), the National Key R&D Program of China (2021YFC2401105), the National Natural Science Foundation of Henan Province (222,300,420,303), the key research and promotion project of Henan province (222102310082), the Joint project of medical science and technology of Henan Province (LHGJ20190280 and LHGJ20220418), the Open Foundation of Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province (SZZD202216), the key scientific research project of Henan institution of higher education (No. 21A320057), the Joint Construction Project of Henan Medical Science Project (No.SBGJ22002078), and Health Science and Technology Innovation Excellent Talents Training Project for Young and Middle-aged in Henan Province (No.YXKC2020058) and the Foundation of Basic Research for young Teachers of Zhengzhou University (No.JC22862049).