Background: To anticipate the potential molecular mechanism of Astragalus membranaceus (AM) and its monomer, Calycosin, against peritoneal fibrosis (PF) and related muscle atrophy using mRNA-seq, network pharmacology, and serum pharmacochemistry. Methods: Animal tissues were examined to evaluate a CKD-PF mice model construction. mRNA sequencing was performed to find differential targets. The core target genes of AM against PF were screened through network pharmacology analysis, and CKD-PF mice models were given high- and low-dose AM to verify common genes. Serum pharmacochemistry was conducted to clarify which components of AM can enter the blood circulation, and the selected monomer was further validated through cell experiments for the effect on PF and mesothelial mesenchymal transition (MMT) of peritoneal mesothelial cells (PMCs). Results: The CKD-PF mice models were successfully constructed. A total of 31,184 genes were detected in the blank and CKD-PF groups, and 228 transcription factors had significant differences between the groups. Combined with network pharmacology analysis, a total of 228 AM-PF-related targets were identified. Androgen receptor (AR) was the remarkable transcription factor involved in regulating transforming growth factor-β1 (TGF-β1). AM may be involved in regulating the AR/TGF-β1 signaling pathway and may alleviate peritoneal dialysis-related fibrosis and muscle atrophy in CKD-PF mice. In 3% peritoneal dialysis solution-stimulated HMrSV5 cells, AR expression levels were dramatically reduced, whereas TGF-β1/p-smads expression levels were considerably increased. Conclusion: AM could ameliorate PF and related muscle atrophy via the co-target AR and modulated AR/TGF-β1 pathway. Calycosin, a monomer of AM, could partially reverse PMC MMT via the AR/TGF-β1/smads pathway. This study explored the traditional Chinese medicine theory of “same treatment for different diseases,” and supplied the pharmacological evidence of “AM can treat flaccidity syndrome.”
Background Peritoneal fibrosis (PF) causes peritoneal dialysis (PD) withdrawal due to ultrafiltration failure. Qixue Huazheng formula (QXHZF), comprising Astragalus membranaceus , Centella asiatica , and Ligusticum sinense , is applied to treat PD-related peritoneum injury related; however, the active components, core genes, and underlying mechanism involved remain unclear. Methods The anti-PF effects of QXHZF were verified in vivo and in vitro . Targets underlying QXHZF-mediated improvement of PD-induced PF were predicted using network pharmacology analysis. Metabolites associated with QXHZF treatment of PD-related PF were analyzed by serum metabolomics. Integration of network pharmacology and serum metabolomics findings identified potentially important pathways, metabolites, and targets, and molecular docking studies confirmed the interactions of key components and targets. Western blotting (WB), quantitative real-time PCR (qRT-PCR), TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and flow cytometry were conducted. Results QXHZF had potent therapeutic efficacy against PF according to WB, qRT-PCR, and pathological section examination. Network pharmacological analysis indicated that multiple QXHZF compounds contributed to improving PF by modulating various targets and pathways. Differential metabolites were identified by serum metabolomics analysis. Integrated data analysis indicated that steroid hormone biosynthesis, the Ras signaling pathway, apoptosis, and estrogen signaling contributed to the effects of QXHZF. Metabolite-target network and molecular docking analyses revealed that QXHZF can bind to estrogen receptor 1 (ESR1) and rapidly accelerated fibrosarcoma 1 (RAF1) through its components. WB demonstrated that QXHZF treatment reversed activation of the above-mentioned signaling pathways, thereby inhibiting PD fluid-induced PF. Conclusion QXHZF can significantly ameliorate PD-induced PF and may regulate estrogen signaling, the Ras pathway, and apoptosis in this context.
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