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Network pharmacology and experimental investigation of Rhizoma polygonati extract targeted kinase with herbzyme activity for potent drug delivery.

ABSTRACT: Rhizoma polygonati (Huangjing, RP) has been used for a long history with many chemical components in inducing anti-cancer, anti-aging, anti-diabetes, anti-fatigue, and more prevention of diseases or acts as nutrition sources in food. Here we investigated RP extract combination with kinase inhibitors in anti-cell growth and blockade in pathways targeting kinases. Experimental investigation and network pharmacology analysis were applied to test the potent kinase-mediated signaling. Herbzyme activity was determined by substrate with optical density measurement. Extract of processed RP inhibits cell growth in a much greater manner than alone when applied in combination with inhibitors of mTOR or EGFR. Moreover, processing methods of RP from Mount Tai (RP-Mount Tai) play essential roles in herbzyme activity of phosphatase suggesting the interface is also essential, in addition to the chemical component. The network pharmacology analysis showed the chemical component and target networks involving AKT and mTOR, which is consistent with experimental validation. Finally, EGFR inhibitor could be associated with nano-extract of RP-Mount Tai but not significantly affects the phosphatase herbzyme activity in vitro. Thus the processed extract of RP-Mount Tai may play a dual role in the inhibition of cell proliferation signaling by both chemical component and nanoscale herbzyme of phosphatase activity to inhibit kinases including mTOR/AKT in potent drug delivery of kinase inhibitors.

SUBMITTER: Xie Y

PROVIDER: S-EPMC8526013 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease (AD) has become a worldwide disease affecting human health and resulting in a heavy economic burden on the healthcare system. Polygonati rhizoma (PR), a kind of traditional Chinese medicine (TCM), is known to improve learning and memory abilities. However, its AD-treating material basis and therapeutic potential for the treatment of AD have remained unclear. Therefore, the present study aimed to uncover the key active ingredients of PR and its therapeutic potential for the treatment of AD. First, we used comparative metabolomics to identify the potential key active ingredients in the edible and medicinal PR. Second, network pharmacology was used to decipher the effects and potential targets of key active ingredients in the PR for the treatment of AD, and molecular docking was further used to identify the binding ability of those active ingredients with AD-related target of AChE. The rate of acetylcholinesterase (AChE) inhibition, oxidative stress, neuroprotective effects, and anti-inflammatory activity were assessed in vitro to screen the potential active ingredients in the PR with therapeutic potential against AD. Finally, APPswe/PS1dE9 AD mice were used to screen the therapeutic components in the PR. Seven overlapping upregulated differential metabolites were identified as the key active ingredients, among which cafestol, isorhamnetin, and rutin have AChE inhibitory activity, anti-inflammatory activity, and neuroprotective effects in vitro validation assays. Furthermore, in vivo results showed that cafestol, isorhamnetin, and rutin displayed several beneficial effects in AD transgenic mice by reducing the number of Aβ-positive spots and the levels of inflammatory cytokines, inhibiting the AChE activity, and increasing the antioxidant levels. Each compound is involved in a different function in the early stages of AD. In conclusion, our results corroborate the current understanding of the therapeutic effects of PR on AD. In addition, our work demonstrated that the proposed network pharmacology-integrated comparative metabolomics strategy is a powerful way of identifying key active ingredients and mechanisms contributing to the pharmacological effects of TCM.

Project description:Rhizoma Drynariae has been widely used for the treatment of osteoarthritis (OA), but its potential targets and molecular mechanisms remain to be further explored. Targets of Rhizoma Drynariae and OA were predicted by relevant databases, and a protein-protein interaction (PPI) network was constructed to identify key targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to obtain related pathways and then select significant pathways associated with OA. The OA chondrocyte model was established by inflammatory factor-induced SW1353 chondrocytes, and molecular docking was conducted to verify the above theoretical prediction. The results showed that a total of 86 Rhizoma Drynariae-OA interaction targets were identified, among which IL-6 and AKT1 were the key targets in the PPI network. Luteolin was the most critical component of Rhizoma Drynariae. KEGG results indicated that the effects of Rhizoma Drynariae on OA are associated with the PI3K/AKT, TNF, IL-17, apoptosis, and HIF-1 signaling pathway. The PI3K/AKT pathway can activate the downstream NF-κB pathway and further regulate the transcription and expression of downstream IL-6, IL-17, HIF-1α, Bax, and TNF, suggesting that the PI3K/AKT/NF-κB pathway is the critical pathway in the treatment of OA with Rhizoma Drynariae. Active components of Rhizoma Drynariae and key proteins of the PI3K/AKT/NF-κB signaling pathway were subjected to molecular docking, whose results showed that luteolin and IKK-α played a critical role. In vitro experiments indicated that both aqueous extracts of Rhizoma Drynariae (AERD) and luteolin inhibited the expression of IL-6 and HIF-1α and suppressed the activation of PI3K/AKT/NF-κB, IL-17, and TNF pathways. The measurement of mitochondrial membrane potential (Δψm) indicated that AERD and luteolin can decrease the LPS-induced early apoptotic cells. Luteolin had a more prominent inhibitory effect than AERD in the abovementioned in vitro experiments. In conclusion, the therapeutic mechanism of Rhizoma Drynariae against OA may be closely related to the inhibition of the PI3K/AKT/NF-κB pathway and downstream pathways, and luteolin plays a vital role in the treatment.

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Network pharmacology and experimental investigation of Rhizoma polygonati extract targeted kinase with herbzyme activity for potent drug delivery.

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