A novel microbial and hepatic biotransformation-integrated network pharmacology strategy explores the therapeutic mechanisms of bioactive herbal products in neurological diseases: the effects of Astragaloside IV on intracerebral hemorrhage as an example

En Hu; Zhilin Li; Teng Li; Xueping Yang; Ruoqi Ding; Haoying Jiang; Hong Su; Menghan Cheng; Zhe Yu; Haigang Li; Tao Tang; Yang Wang

doi:10.1186/s13020-023-00745-5

A novel microbial and hepatic biotransformation-integrated network pharmacology strategy explores the therapeutic mechanisms of bioactive herbal products in neurological diseases: the effects of Astragaloside IV on intracerebral hemorrhage as an example

Chin Med. 2023 Apr 17;18(1):40. doi: 10.1186/s13020-023-00745-5.

Authors

En Hu^{1

2}, Zhilin Li^{1

2}, Teng Li^{1

2}, Xueping Yang^{1

2}, Ruoqi Ding^{1

2}, Haoying Jiang^{1

2}, Hong Su^{1

2}, Menghan Cheng^{1

2}, Zhe Yu^{1

2}, Haigang Li³, Tao Tang^{4

5}, Yang Wang^{6

7}

Affiliations

¹ Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
³ Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, People's Republic of China, 410219.
⁴ Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008. tangtaotay@csu.edu.cn.
⁵ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008. tangtaotay@csu.edu.cn.
⁶ Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008. wangyang_xy87@csu.edu.cn.
⁷ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008. wangyang_xy87@csu.edu.cn.

Abstract

Background: The oral bioavailability and blood-brain barrier permeability of many herbal products are too low to explain the significant efficacy fully. Gut microbiota and liver can metabolize herbal ingredients to more absorbable forms. The current study aims to evaluate the ability of a novel biotransformation-integrated network pharmacology strategy to discover the therapeutic mechanisms of low-bioavailability herbal products in neurological diseases.

Methods: A study on the mechanisms of Astragaloside IV (ASIV) in treating intracerebral hemorrhage (ICH) was selected as an example. Firstly, the absorbed ASIV metabolites were collected by a literature search. Next, the ADMET properties and the ICH-associated targets of ASIV and its metabolites were compared. Finally, the biotransformation-increased targets and biological processes were screened out and verified by molecular docking, molecular dynamics simulation, and cell and animal experiments.

Results: The metabolites (3-epi-cycloastragenol and cycloastragenol) showed higher bioavailability and blood-brain barrier permeability than ASIV. Biotransformation added the targets ASIV in ICH, including PTK2, CDC42, CSF1R, and TNF. The increased targets were primarily enriched in microglia and involved in cell migration, proliferation, and inflammation. The computer simulations revealed that 3-epi-cycloastragenol bound CSF1R and cycloastragenol bound PTK2 and CDC42 stably. The In vivo and in vitro studies confirmed that the ASIV-derived metabolites suppressed CDC42 and CSF1R expression and inhibited microglia migration, proliferation, and TNF-α secretion.

Conclusion: ASIV inhibits post-ICH microglia/macrophage proliferation and migration, probably through its transformed products to bind CDC42, PTK2, and CSF1R. The integrated strategy can be used to discover novel mechanisms of herbal products or traditional Chinses medicine in treating diseases.

Keywords: 3-epi-cycloastragenol; Astragaloside IV; Biotransformation; Cycloastragenol; Gut microbiota; Herbal products; Intracerebral hemorrhage; Liver; Microglia; Network pharmacology.

Abstract

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