“…Further functional enrichment analyses of the additional targets after ASIV biotransformation showed that most of the top enriched pathways were also relevant to cell migration (GO: positive regulation of cell migration; KEGG: Rap1 signaling pathway; KEGG: Focal adhesion), proliferation (GO: regulation of cell proliferation), and inflammation (GO: chemokine signaling pathway) (Fig. 5 ; Additional file 1 : Table S1), which differed from the results of ASIV [ 17 ] (Additional file 1 : Table S2). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…In addition, a previous study applies a classic network pharmacology scheme to investigate the therapeutic mechanism of ASIV on ICH. It reports that orally administrated ASIV downregulates the levels of the master pro-inflammatory transcript factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), in the post-ICH brain [ 17 ]. In comparison, our new strategy additionally suggests that ASIV can inhibit microglia/macrophage proliferation and migration after microbial and hepatic biotransformation.…”
Section: Resultsmentioning
confidence: 99%
“…Worse still, few therapeutic methods are currently proven effective in ICH patients [ 15 ]. Fortunately, several herbal products and traditional Chinese medicine (TCM) have shown considerable efficacy in preclinic studies, such as Astragaloside IV (ASIV) [ 17 , 18 ]. However, the BBB hampers drugs from accessing brain parenchyma.…”
Section: Introductionmentioning
confidence: 99%
“…The discrepancy between the significant efficacy and the low BBB permeability makes it necessary to consider other ways like microbial and hepatic biotransformation when exploring the therapeutic mechanisms of herbal medicines in ICH. ASIV is one of the main bioactive ingredients in the widely prescribed TCM, Astragali Radix , in ICH patients [ 17 ]. Previous studies have revealed the neuroprotective effect of ASIV in ICH and other neurological diseases [ 17 , 19 , 20 ].…”
Section: Introductionmentioning
confidence: 99%
“…ASIV is one of the main bioactive ingredients in the widely prescribed TCM, Astragali Radix , in ICH patients [ 17 ]. Previous studies have revealed the neuroprotective effect of ASIV in ICH and other neurological diseases [ 17 , 19 , 20 ]. However, the reported OB of ASIV is low, 2.2–3.7% in rats and 7.4% in dogs, and the gastrointestinal permeability is also weak [ 21 , 22 ].…”
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
“…Further functional enrichment analyses of the additional targets after ASIV biotransformation showed that most of the top enriched pathways were also relevant to cell migration (GO: positive regulation of cell migration; KEGG: Rap1 signaling pathway; KEGG: Focal adhesion), proliferation (GO: regulation of cell proliferation), and inflammation (GO: chemokine signaling pathway) (Fig. 5 ; Additional file 1 : Table S1), which differed from the results of ASIV [ 17 ] (Additional file 1 : Table S2). Fig.…”
Section: Resultsmentioning
confidence: 99%
“…In addition, a previous study applies a classic network pharmacology scheme to investigate the therapeutic mechanism of ASIV on ICH. It reports that orally administrated ASIV downregulates the levels of the master pro-inflammatory transcript factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), in the post-ICH brain [ 17 ]. In comparison, our new strategy additionally suggests that ASIV can inhibit microglia/macrophage proliferation and migration after microbial and hepatic biotransformation.…”
Section: Resultsmentioning
confidence: 99%
“…Worse still, few therapeutic methods are currently proven effective in ICH patients [ 15 ]. Fortunately, several herbal products and traditional Chinese medicine (TCM) have shown considerable efficacy in preclinic studies, such as Astragaloside IV (ASIV) [ 17 , 18 ]. However, the BBB hampers drugs from accessing brain parenchyma.…”
Section: Introductionmentioning
confidence: 99%
“…The discrepancy between the significant efficacy and the low BBB permeability makes it necessary to consider other ways like microbial and hepatic biotransformation when exploring the therapeutic mechanisms of herbal medicines in ICH. ASIV is one of the main bioactive ingredients in the widely prescribed TCM, Astragali Radix , in ICH patients [ 17 ]. Previous studies have revealed the neuroprotective effect of ASIV in ICH and other neurological diseases [ 17 , 19 , 20 ].…”
Section: Introductionmentioning
confidence: 99%
“…ASIV is one of the main bioactive ingredients in the widely prescribed TCM, Astragali Radix , in ICH patients [ 17 ]. Previous studies have revealed the neuroprotective effect of ASIV in ICH and other neurological diseases [ 17 , 19 , 20 ]. However, the reported OB of ASIV is low, 2.2–3.7% in rats and 7.4% in dogs, and the gastrointestinal permeability is also weak [ 21 , 22 ].…”
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
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