Abstract
Diarrhea continues to be a major public health problem and is thought to be the cause of 525,000 child fatalities annually. Studies have shown that Macleaya cordata (Willd.) R.Br., Papaveraceae, has a good therapeutic effect on diarrhea due to its action on ion channels. However, its antidiarrheal mechanisms and key targets are not supported by scientific research. This study aimed to identify the mechanisms of action and targets of the primary active antidiarrheal compounds of M. cordata. We used network pharmacology and molecular docking to identify the antidiarrheal mechanisms and the key targets of M. cordata and its main chemical constituents. Subsequently, the experiments performed with dihydrosanguinarine (25, 50, and 100 mg/kg), which included the evaluation of the inhibitory potential of the epidermal growth factor receptor in osimertinib-induced diarrhea, real-time quantitative PCR, and western blotting, were performed for further verification of its mechanism of action. The findings revealed that of all the genes, tyrosine-protein kinase Lck, receptor tyrosine-protein kinase Erbb2, and epidermal growth factor receptor had the highest capacity of action, and the NF-kappa B and the calcium signaling pathways may play essential roles in M. cordata against diarrhea. Dihydrosanguinarine is the most active ingredient, and it significantly inhibits the increase in incidence and decreased the fecal water content of osimertinib-induced diarrhea. Western blot and qRT-PCR showed that dihydrosanguinarine works as an antidiarrheal agent by upregulating the expression of the core target epidermal growth factor receptor, affecting the NF-kappa B and the calcium ion signaling pathways, downregulating the expression of calcium-activated chloride channel and NK-kappa B P-65.
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The data that support the finding of this study are available from the corresponding author upon reasonable request and some data that support the finding of this study are available in the supplementary material of this article.
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Funding
Dr. Zunlai Sheng is supported by the National Natural Science Foundation of China (Grant No. 32373057). Dr. Chunli Chen is supported by the 2022 ESI International High Impact Research Article Cooperation Program (No. 212–54900112), the National Natural Science Foundation of Heilongjiang Province (No. YQ2022C017), and the International Postdoctoral Exchange Fellowship Program from the Office of China Postdoctoral Council (No. 2020106 and PC2020013).
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LG, CC, and ZS conceived and designed the study. LG and XX performed the experiments. CC and YZ acquired the data. LG, XX, and YZ analyzed the data. LG drafted and critically revised the article. LG, XX, YZ, CC, and ZS proofread the final manuscript.
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The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).
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Guo, L., Xue, X., Zhou, Y. et al. Deciphering the Antidiarrheal Mechanisms of Macleaya cordata by Combining Network Pharmacology, Molecular Docking, and Experimental Evaluations. Rev. Bras. Farmacogn. 34, 637–646 (2024). https://doi.org/10.1007/s43450-024-00514-x
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DOI: https://doi.org/10.1007/s43450-024-00514-x