Abstract
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.
Graphical Abstract
Funder
National Natural Science Foundation of China
Key Research and Development Program of Hunan Province of China
Hunan TCM Scientific Research Program
Fundamental Research Funds for Central Universities of the Central South University
The Excellent Clinical Talent Training Project of SATCM
The Leadership Training Project of HNATCM
Shennong Young Scholar Foundation of Hunan Province
Publisher
Springer Science and Business Media LLC
Subject
Complementary and alternative medicine,Pharmacology
Cited by
1 articles.
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